HPN 2022 April

HOSPITAL PROFESSIONAL NEWS IRELAND

HPN April 2022 Issue 95 HOSPITALPROFESSIONALNEWS.IE

Ireland’s Dedicated Hospital Professional Publication

IN THIS ISSUE:

INTRODUCING

NEWS: Startling New Figures on Stroke Page 8 REPORT: Emergency General Surgery Report Page 12 PERSPECTIVES: Fatigue in the 21st Century Health Workforce Page 16 FEATURE: Treatment Potential of Innate lymphocytes for HIV Page 28

FOR THE TREATMENT OF MODERATE TO SEVERE

atopic dermatitis

in adults and adolescents 12 years and older who are candidates for systemic therapy1

MARKETING AUTHORISATION HOLDER: AbbVie Deutschland GmbH & Co. KG, Knollstrasse, 67061 Ludwigshafen, Germany.

Further information is available from AbbVie Limited, 14 Riverwalk, Citywest Business Campus, Dublin 24, Ireland.

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance; website: www.hpra.ie.

LEGAL CLASSIFICATION: POM (S1A).

Full Summary of Product Characteristics is available at www.medicines.ie Reference 1. RINVOQ Summary of Product Characteristics, available on www.medicines.ie ©2022 AbbVie Inc.

All rights reserved.

IE-RNQ_AD-220036 | March 2022

This Publication is for Healthcare Professionals Only

CPD: Management of Multiple Myeloma Page 31 CARDIOLOGY FOCUS: Anticoagulation in Atrial Fibrillation Page 36 CARDIOLOGY FOCUS: Professor Ian Graham on Cardiovascular Collaboration Page 60

Joining Excellence and Innovation Hospital Professional Awards 2022

+ m 0

Date: Saturday 8th October, 2022

D E T A IDE1

Venue: The O’Reilly Hall, University College Dublin

To mark what has been an incredibly tumultuous year, IPN Communications are thrilled to announce that the Hospital Professional Awards will once again take to the stage in 2022.

2022 Award Categories:

Hospitals have faced an especially challenging year. They have risen to the occasion with aplomb. That’s why we want this year’s Awards to be the biggest yet – not only in recognition of excellence, but as applause to the teams around Ireland who helped keep the country going during the pandemic pressures.

 Grunenthal Advancing the Standard of Care in Pain Management Award

The Awards will represent a celebration of all hospital healthcare teams who were working tirelessly on the frontline, for their incredible efforts during the Covid-19 pandemic.

 Medisource Hospital Pharmacy Technician of the Year

DW

mmended for therapeutic and prophylactic dosage ranges. Low body weight creased risk of bleeding at prophylactic and treatment dose ranges. Obese gher risk for thromboembolism however there is no consensus for dose patients should be observed carefully. Heparins can suppress adrenal terone leading to hyperkalaemia, particularly in patients such as those with chronic renal failure, pre-existing metabolic acidosis, taking medicinal o increase potassium; plasma potassium should be monitored regularly nts at risk. Fertility, Pregnancy and Lactation: Enoxaparin sodium should gnancy only if the physician has established a clear need. Enoxaparin sodium ng breastfeeding. Interactions: Not Recommended: Systemic salicylates, d at anti-inflammatory doses, and NSAIDs including ketorolac. Other g. alteplase, reteplase, streptokinase, tenecteplase, urokinase) and aution: Platelet aggregation inhibitors including acetylsalicylic acid used at ose (cardioprotection), clopidogrel, ticlopidine, and glycoprotein IIb/IIIa ted in acute coronary syndrome due to the risk of bleeding. Dextran 40. ticoids. Medicinal products increasing potassium levels. Adverse Reactions: epatic enzyme increases (mainly transaminases > 3 times the upper limit of rhage, thrombocytosis (platelet increase >400 G/L). Common: Haemorrhagic cytopenia, allergic reaction, headache, urticaria, pruritus, erythema, injection / pain / other reaction (such as oedema, haemorrhage, hypersensitivity, ss, pain, or reaction). Uncommon: Hepatocellular liver injury, bullous irritation, skin necrosis at injection site, intracranial haemorrhage, emorrhage. Rare: Eosinophilia, cases of immuno-allergic thrombocytopenia in some cases thrombosis was complicated by organ infarction or limb ylactic/anaphylactoid reactions including shock, spinal/neuraxial haematoma g degrees of neurologic injuries including long-term or permanent paralysis, njury, alopecia, cutaneous vasculitis, skin necrosis, injection site nodules, wing therapy > 3 months, hyperkalaemia. Please refer to the SPCs for full eutical Precautions: Do not mix with other products. Do not store above eze. Legal Category: POM. Marketing Authorisation (MA) Numbers: PA540/97/4; Clexane 4,000IU: PA540/97/5; Clexane 6,000 IU: PA540/97/6; : PA540/97/7; Clexane 10,000 IU: PA540/97/1; Clexane Forte 12,000 IU: ane Forte 15,000 IU: PA540/97/2 MA Holder and further information is uest from: Sanofi Ireland Ltd., 18 Riverwalk, Citywest Business Campus, act IEmedinfo@sanofi.com Tel: 01 403 5600. Date of Preparation: June

 GSK Excellence in Respiratory Initiative of the Year Award

 Accord Innovation in Aseptic Compounding Award  GSK ViiV Infectious Diseases Project of the Year

 Novartis Neurology- Neurological Innovation Award

The HPAs are the most influential and respected networking event, lauding excellence, innovation and service development; judged by key influencers including renowned respected experts.

 Sanofi Hospital Specialist Award

The foundation for these Awards lies in our collaboration with leading pharmaceutical companies; without their investment and support, the event would not be possible.

 MSD Excellence in Oncology Award

Entry forms will be available shortly. We look forward to welcoming you all to The O’Reilly Hall at University College Dublin on Saturday 8th September 2022 for what promises to be an unmissable night.

 Hospital Pharmacy Team of the Year

Further details to be confirmed in the next issue

 Excellence in Haematology Award

 Galapagos Multidisciplinary Team Award

 Pharmasource Hospital Pharmacist of the Year Award

 Consultant-Led Team of the Year  Young Hospital Pharmacist of the Year

If it’s out there...

For further informationwe contact Aoife Jackson can source it for you at:

aoife@ipn.ie or Kelly Jo Eastwood at: kelly-jo@ipn.ie

ts should be reported. Reporting forms and information can be found at: www.hpra.ie; E-mail: medsafety@hpra.ie. events can also be reported to Sanofi Ireland Ltd. Tel: 01 403 5600. ernatively, send via Email to IEPharmacovigilance@sanofi.com

nofi Data on File for Clexane use.

153c 2018 (10,000 IU (100mg)/1ml) and June 2018 (15,000 IU (150mg)/1ml) n: August 2018 MEDISOURCE LOGO

For more information please contact: Free Phone 1800 440 440 I PharmaSource@uniphar.ie I www.uniphar.ie Navy Blue Colour (Text in logo) Pantone - 5265c CMYK - C77% M70% Y0% K40% Aqua Marine Colour (Symbol) Pantone - 3115c CMYK - C63% M0% Y18% K0%

10/08/2018 10:39

A combined force against LUTS and BPH

49% of men with LUTS report bladder and prostate symptoms1 VESOMNI treats the symptoms of both the bladder and prostate2 Abbreviated Prescribing Information - Vesomni 6 mg/0.4 mg modified release tablets. Please read the Summary of Product Characteristics (SPC) before prescribing. Presentation: Each tablet contains a layer of 6 mg solifenacin succinate, corresponding to 4.5 mg solifenacin free base and a layer of 0.4 mg tamsulosin hydrochloride, corresponding to 0.37 mg of tamsulosin free base. Indication: Treatment of moderate to severe storage symptoms (urgency, increased micturition frequency) and voiding symptoms associated with benign prostatic hyperplasia (BPH) in men who are not adequately responding to treatment with monotherapy. Posology and method of administration: Adult males, including older people: One Vesomni tablet (6 mg/0.4 mg) once daily taken orally with or without food. The maximum daily dose is one Vesomni tablet. The tablet must be swallowed whole, intact without biting or chewing. Do not crush the tablet. Special populations (see also contraindications below): Renal impairment: Severe renal impairment (creatinine clearance ≤ 30 mL/min): Treat with caution, maximum daily dose in these patients is one Vesomni tablet.

Hepatic impairment: Moderate hepatic impairment (Child-Pugh score of 7-9): Treat with caution, maximum daily dose in these patients is one Vesomni tablet. In patients with severe hepatic impairment (Child-Pugh score > 9), the use of Vesomni is contraindicated. Concomitant treatment with moderate and strong inhibitors of CYP450 3A4: e.g. verapamil, ketoconazole, ritonavir, nelfinavir, itraconazole: Treat with caution, maximum daily dose should be limited to one Vesomni tablet.

Paediatric population: There is no relevant indication for use of Vesomni in children and adolescents.

Contraindications: Patients with hypersensitivy to the active substance(s) or to any of the excipients (see SPC). Patients undergoing haemodialysis. Patients with severe hepatic impairment. Patients with severe renal impairment who are also treated with a strong cytochrome P450 (CYP)3A4 inhibitor e.g. ketoconazole. Patients with moderate hepatic impairment who are also treated with a strong CYP3A4 inhibitor e.g. ketoconazole. Patients with severe gastrointestinal conditions (including toxic megacolon), myasthenia gravis or narrow-angle glaucoma and patients at risk for these conditions.

Patients with a history of orthostatic hypotension. Special Warnings and Precautions for Use: Vesomni should be used with caution in patients with: severe renal impairment; risk of urinary retention; gastrointestinal obstructive disorders; risk of decreased gastrointestinal motility; hiatus hernia/ gastroesophageal reflux and/or who are concurrently taking medicinal products (such as bisphosphonates) that can cause or exacerbate oesophagitis; autonomic neuropathy. The patient should be examined in order to exclude the presence of other conditions, which can cause similar symptoms to benign prostatic hyperplasia. Other causes of frequent urination (heart failure or renal disease) should be assessed before treatment with Vesomni is initiated. If a urinary tract infection is present, appropriate antibacterial therapy should be started. QT prolongation and Torsade de Pointes have been observed in patients with risk factors, such as pre-existing long QT syndrome and hypokalaemia, who are treated with solifenacin succinate. Angioedema with airway obstruction has been reported in some patients on solifenacin succinate and tamsulosin. If angioedema occurs, Vesomni should be discontinued and not restarted. Appropriate therapy and/or measures should be taken. Anaphylactic reaction has been reported in some patients treated with solifenacin succinate. In patients who develop anaphylactic reactions, Vesomni should be discontinued and appropriate therapy and/or measures should be taken. As with other alpha1-adrenoceptor antagonists, a reduction in blood pressure can occur in individual cases during treatment with tamsulosin, as a result of which, rarely, syncope can occur. Patients starting treatment with Vesomni should be cautioned to sit or lie down at the first signs of orthostatic hypotension (dizziness, weakness) until the symptoms have disappeared. The ‘Intraoperative Floppy Iris Syndrome’ (IFIS, a variant of small pupil syndrome) has been observed during cataract and glaucoma surgery in some patients on or previously treated with tamsulosin hydrochloride. IFIS may increase the risk of eye complications during and after the operation. Therefore, the initiation of therapy with Vesomni in patients for whom cataract or glaucoma surgery is scheduled is not recommended. Discontinuing treatment with Vesomni 1-2 weeks prior to cataract or glaucoma surgery is anecdotally considered helpful, but the benefit of treatment discontinuation has not been established. During pre-operative assessment, surgeons and ophthalmic teams should consider whether patients scheduled for cataract or glaucoma surgery are being or have been treated with Vesomni in order to ensure that appropriate measures will be in place to manage IFIS during surgery. Vesomni should be used with caution in combination with moderate and strong inhibitors of CYP3A4 and it should not be used in combination with strong inhibitors of CYP3A4, e.g., ketoconazole, in patients who are of the CYP2D6 poor metaboliser phenotype or who are using strong inhibitors of CYP2D6, e.g., paroxetine.

Interactions: Pharmacological interactions: Concomitant medication with other anticholinergic medicinal products may result in more pronounced therapeutic and undesirable effects. Allow approximately one week after stopping treatment with Vesomni before commencing any anticholinergic therapy. The therapeutic effect of solifenacin may be reduced by concomitant administration of cholinergic receptor agonists. Pharmacokinetic interactions: Pharmacokinetic interactions involving the potential for other medicinal products to affect Vesomni exposures: Interactions with CYP3A4 and CYP2D6 inhibitors: See Contraindications, Posology and administration and Special warnings and precautions above. Concomitant administration may lead to increased exposure to both solifenacin (ketoconazole 400 mg/day resulted in a 1.5-fold increase in Cmax and a 2.8-fold increase in AUC). and tamsulosin (ketoconazole 400 mg/day resulted in a 2.2-fold increase in Cmax and a 2.8-fold increase in AUC). Vesomni should be used with caution in combination with strong CYP3A4 inhibitors. Vesomni should not be given together with strong CYP3A4 inhibitors in patients who are also CYP2D6 poor metabolizer phenotype or who are using strong CYP2D6 inhibitors. See SPC for details of the effects of other CYP3A4 and CYP2D6 inhibitors. Inducers: Inducers of CYP3A4 (e.g. rifampicin) may decrease the plasma concentrations of solifenacin and tamsulosin. Information available for the individual active substances: Solifenacin can reduce the effect of medicinal products that stimulate the motility of the gastrointestinal tract, such as metoclopramide and cisapride. Solifenacin did not affect the pharmacokinetics of digoxin, or the pharmacokinetics or effect on prothrombin time of R- or S-warfarin. Co-administration of tamsulosin and other alpha1-adrenoreceptor antagonists could lead to hypotensive effects. Diclofenac and warfarin may increase the elimination rate of tamsulosin. No interactions have been seen when tamsulosin was given concurrently with atenolol, enalapril or theophylline. Fertility, pregnancy and lactation: The effect of Vesomni on fertility has not been established. Ejaculation disorders have been observed in short and long term clinical studies with tamsulosin. Events of ejaculation disorder, retrograde ejaculation and ejaculation failure have been reported in the post authorization phase.

Vesomni is not indicated for use in women. Driving and use of machines: No studies have been performed, however patients should be informed about the possible occurrence of dizziness, blurred vision, fatigue and uncommonly somnolence, which may negatively affect the ability to drive or use machines. Undesirable Effects: Summary of the safety profile: Vesomni may cause anticholinergic undesirable effects of, in general, mild to moderate severity. The most frequently reported adverse reactions during the clinical studies performed for the development of Vesomni were dry mouth (9.5%), followed by constipation (3.2%) and dyspepsia (including abdominal pain; 2.4%). Other common undesirable effects are dizziness (including vertigo; 1.4%), vision blurred (1.2%), fatigue (1.2%), and ejaculation disorder (including retrograde ejaculation; 1.5%). Acute urinary retention (0.3%, uncommon) is the most serious adverse drug reaction that has been observed during treatment with Vesomni in clinical studies. List of adverse reactions: the ‘Vesomni frequency’ below reflects adverse drug reactions that have been observed during the double-blind clinical studies performed for the development of Vesomni (based on reports of treatment-related adverse events, which have been reported by at least two patients and occurred with a frequency higher than for placebo in the double-blind studies). The ‘solifenacin frequency’ and ‘tamsulosin frequency’ below reflect adverse drug reactions (ADRs) previously reported with one of the individual components (as presented in the Summary of Product Characteristics (SmPCs) of solifenacin 5 and 10 mg and tamsulosin 0.4 mg respectively that may also occur when receiving Vesomni (some of these have not been observed during the clinical development program of Vesomni). The frequency of adverse reactions is defined as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data). The adverse events are grouped by MedDRA system organ class preferred term (PT). Vesomni frequency: Nervous system disorders: Common: dizziness Eye disorders: Common: vision blurred Gastrointestinal disorders: Common: dry mouth, dyspepsia, constipation Skin and subcutaneous tissue disorders: Uncommon: pruritus Renal and urinary disorders: Uncommon: Urinary retention*** Reproductive system and breast disorders: Common: ejaculation disorders including retrograde ejaculation and ejaculation failure General disorders and administration site conditions: Common: fatigue Solifenacin 5mg & 10mg frequency#: Infections and infestations: Uncommon: urinary tract infection, cystitis Immune system disorders: Not known: anaphylactic reaction* Metabolism and nutrition disorders: Not known: decreased appetite*, hyperkalemia* Psychiatric disorders: Very rare: hallucination*, confusional state* Not known:

References: 1. Sexton CC, et al. BJU Int 2009; 103(Suppl 3): 12-23. 2. VESOMNI Summary of Product Characteristics.

Date of preparation: July 2019 Job code: VESOM_2019_0003_IE

delirium* Nervous system disorders: Uncommon: somnolence, dysgeusia Rare: dizziness*, headache* Eye disorders: Common: vision blurred Uncommon: dry eyes Not known: glaucoma* Cardiac disorders: Not known: palpitations*, Torsade de Pointes*, electrocardiogram QT prolongation*, atrial fibrillation*, tachycardia* Respiratory, thoracic and mediastinal disorders: Uncommon: nasal dryness Not known: dysphonia* Gastrointestinal disorders: Very common: dry mouth Common: dyspepsia, constipation, nausea, abdominal pain Uncommon: gastro-oesophageal reflux disease, dry throat Rare: vomiting*, colonic obstruction, faecal impaction, Not known: ileus*, abdominal discomfort* Hepatobiliary disorders: Not known: liver disorder*, liver function test abnormal* Skin and subcutaneous tissue disorders: Uncommon: dry skin Rare: pruritus*, rash* Very rare: urticaria*, angioedema*, erythema multiforme* Not known: exfoliative dermatitis* Musculoskeletal and connective tissue disorders: Not known: muscular weakness* Renal and urinary disorders: Uncommon: difficulty in micturition Rare: urinary retention***Not known: renal impairment* General disorders and administration site conditions: Uncommon: fatigue, perhiperal oedema Tamsulosin 0.4mg frequency#: Nervous system disorders: Common: dizziness Uncommon: headache Rare: syncope Eye disorders: Not known: vision blurred*, Intraoperative Floppy Iris Syndrome (IFIS)**, visual impairment* Cardiac disorders: Uncommon: palpitations Not known: atrial fibrillation*, arrhythmia*, tachycardia* Vascular disorders: Uncommon: orthostatic hypotension Respiratory, thoracic and mediastinal disorders: Uncommon: rhinitis Not known: dyspnoea*, epistaxis* Gastrointestinal disorders: Uncommon: constipation, nausea, diarrhea, vomiting Skin and subcutaneous tissue disorders: Uncommon: pruritus, rash, urticaria Rare: angioedema Very Rare: Stevens-Johnson syndrome Not known: erythema multiforme*, exfoliative dermatitis* Reproductive system and breast disorders: Common: ejaculation disorders including retrograde ejaculation and ejaculation failure Very rare: priapism General disorders and administration site conditions: Uncommon: asthenia. #: The ADRs from solifenacin and tamsulosin included are the ADRs listed in the summary of product characteristics of both products. *: from post-marketing reporting. Because these spontaneously reported events are from the worldwide post-marketing experience, the frequency of events and the role of solifenacin or tamsulosin and their causation cannot be reliably determined. **: from post-marketing reporting, observed during cataract and glaucoma surgery. ***: see Special warnings and precautions for use. Long-term safety of Vesomni: The profile of undesirable effects seen with treatment up to 1 year was similar to that observed in the 12-week studies. The product is well-tolerated and no specific adverse reactions have been associated with long-term use.

Description of selected adverse reactions: For urinary retention see Special warnings and precautions for use. Older people: The therapeutic indication of Vesomni, moderate to severe storage symptoms (urgency, increased micturition frequency) and voiding symptoms associated with BPH, is a disease affecting elderly men. The clinical development of Vesomni has been performed in patients 45 to 91 years of age, with an average age of 65 years. Adverse reactions in the elderly population were similar to the younger population. Reporting of suspected adverse reactions: see below. Overdose: Overdosage with the combination of solifenacin and tamsulosin can potentially result in severe anticholinergic effects plus acute hypotension. Refer to SPC for details of treatment of overdose. Legal Category: Prescription Only Medicine (SIB). Nature and contents of container: Aluminium blister packs containing 30 tablets. Product Authorisation Number: PA1241/016/001. Marketing Authorisation holder: Astellas Pharma Co. Ltd. Further information is available from: Astellas Pharma Co. Ltd, 5 Waterside, Citywest Business Campus, Naas Road, Dublin 24. Phone: +3531 467 1555. Summary of Product Characteristics with full prescribing information available upon request. Job number: VESOM_2019_0001_IE Date of preparation of API: 24 May 2019 Reporting suspected adverse reactions after authorisation of the medicinal product is important.

It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via: HPRA Pharmacovigilance Astellas Pharma Co. Ltd Earlsfort Terrace, IRL - Dublin 2 Tel: + 353 1 467 1555 Tel: +353 1 6764971 E-mail: Irishdrugsafety@astellas.com Fax: +353 1 6762517 Website: www.hpra.ie E-mail: medsafety@hpra.ie.

April Issue Issue 95

5

Contents

Foreword

European Medicines Agency appointment for Dr Nolan P6

Editor In one of our leading news stories this month, we reveal how the Government’s Waiting List Action Plan launched just some weeks ago has fallen at the first hurdle. The latest figures from the National Treatment Purchase Fund (NTPF) show increases rather than reductions in the number of people waiting for care.

Hospital staffing crisis continues to worsen P10 Sector stability and patient access to medicines P15 Fatigue amongst the healthcare workforce P16

The ¤350 million plan set out a target to reduce waiting lists for outpatient appointments, inpatient and day case treatment, and GI (gastrointestinal) endoscopies by more than 132,000 (18%) by the end of the year compared with the number waiting at the start of 2022.

6

Advances in effectiveness and tolerability for spinal cord stimulation P18 New opportunities in accessing international cancer trials P22

16

A closer look at asthma and allergic rhinitis P26

As talks on Consultant contracts continue to stall in the absence of a new Independent Chair, the IHCA has renewed its call on Government to effectively address the record hospital waiting lists by ending the pay discrimination introduced in 2012 against Consultants contracted after that date. Turn to page 7 to read the full story.

REGULARS CPD: Multiple Myeloma P31 Feature: HER2-Positive Breast Cancer P36 Cardiology Focus: Cardiac and Non-Cardiac Outcomes P38

As Hospital Professional News was going to press, the European Association of Hospital Pharmacists annual congress was taking place in Vienna. The 26th Congress served as the backdrop for the launch of the results from the Association’s first Special Interest Group (SIG) focusing on Hazardous Medicinal Products.

18

Cardiology Focus: Proximal Aortic Aneurysms P43 Cardiology Focus: Management of Cardioembolic Stroke P47 Clinical R&D: P80 Hospital Professional News is a publication for Hospital Professionals and Professional educational bodies only. Subscription rate for Hospital Professional News ¤60 plus vat per year.

All rights reserved by Hospital Professional News. All material published in Hospital Professional News is copyright and no part of this magazine may be reproduced, stored in a retrieval system of transmitted in any form without written permission.

IPN Communications Ltd have taken every care in compiling the magazine to ensure that it is correct at the time of going to press, however the publishers assume no responsibility for any effects from omissions or errors.

PUBLISHER IPN Communications Ireland Ltd Clifton House, Lower Fitzwilliam Street, Dublin 2 (01) 669 0562 GROUP DIRECTOR Natalie Maginnis n-maginnis@btconnect.com EDITOR Kelly Jo Eastwood DIGITAL MARKETING & EDITORIAL EXECUTIVE Danielle Norton danielle@hospitalprofessionalnews.ie

However, two months into 2022 and instead of an expected reduction of around 22,000 people, the latest NTPF figures released today confirm that 12,800 additional people have in fact been added to these three main waiting lists since the start of the year - a 34,800 shortfall.

22

EDITORIAL editorial@hospitalprofessionalnews.ie ACCOUNTS Rachel Wilson cs.ipn@btconnect.com BUSINESS ACCOUNT MANAGER/CPD LEAD Sibongile Mude - swan@ipn.ie MARKETING & ADVERTISING EXECUTIVE Ashling Goodall ashling@hospitalprofessionalnews.ie CONTRIBUTORS

Professor Connail McCrory | Dr Deborah Galvin Dr Dale Whelehan | Dr Nicola Maher Ruth Morrow | Professor Derek G. Doherty Dr Graeme Sullivan | Professor Siobhan Glavey Dr Triona Ni Chonghaile | Christine McAuliffe Joseph McCambridge | Katherine McDonald Líbhan Collins | Barry Dyer | Carmel Halley Matthew Barrett | Mark Ledwidge | Dr Katie Ridge Kenneth McDonald | Kate O’Callaghan Saleem Jahangeer | Theresa Lowry Lehenan Gill Douglas | Shameer Rafee | Dr Niall Conlon Jonathan Gallagher | Dr Elizabeth O’Brien Dr Sinead Mulhern | Dr Jonathan Lyne Professor Ian Graham | Dr Virginia Silvari Frances O’Brien | Mr Paul Lennon

HOSPITALPROFESSIONALNEWS.IE

@HospitalProNews HospitalProfessionalNews

Hospital pharmacists that attended the launch, learned that there is no European definition for hazardous medicinal products and no clear European-wide guidance on their management. They exchanged with Joan Peppard and Falko Schüllner, who presented the SIG results, on the high awareness across EAHP’s member countries about hazardous medicinal products and the significant efforts that were made at an institutional level into the management of hazardous medicinal products thanks to the work of pharmacists over the years. However, despite these efforts, both speakers stressed at the launch that there remains an exposure risk to healthcare workers and caregivers that needs to be addressed.

The May issue of HPN will carry an in-depth report from this Congress.

Our Special Focus this month is on the wide-ranging topic of Cardiology and we carry a number of excellent clinically-contributed articles ranging from Christine McAuliffe, Lead Clinical Pharmacist in Tallaght University Hospital’s Interdisciplinary Atrial Fibrillation clinic discussing the role of pharmacists in AF to Dr Jonathan Lyne, Consultant Cardiologist and Electrophysiologist with Beacon Hospital and Blackrock Clinic updating readers on Pacing Developments.

I hope you enjoy the issue.

HOSPITAL PROFESSIONAL NEWS IRELAND Ireland’s Dedicated Hospital Professional Publication

HOSPITALPROFESSIONALNEWS.IE | HPN • APRIL 2022

6

News

Future of EPI for Hospital Pharmacists Inspired by a project carried out in Belgium and Luxembourg evaluating the effectiveness of the electronic patient information leaflet and the key principles created by the European Medicines Agency (EMA) and the Heads of Medicines Agencies (HMA), the European Association of Hospital Pharmacists (EAHP) conducted a survey on the use of electronic product information (ePI) in European hospitals.

The survey was carried out in cooperation with the InterAssociation Task Force for electronic product information composed out of Medicines for Europe, EFPIA (European Federation of Pharmaceutical Industries and Associations) and AESGP (Association of the European Self-Care Industry) from March to April 2021 and targeted hospital pharmacists in

36 European countries, ultimately receiving 534 answers.

Reflecting on the process and the results of the survey, former EAHP Board member Steffen Amann, who was involved in the project from the start, highlighted that “Digitalisation is revolutionising healthcare provision in hospitals across Europe. For EAHP it was consequently very important to learn more about the use of electronic patient leaflets and the future potential of electronic product information. It will take a lot of activity to overcome the lack of means to work with digital information, which not surprisingly is one of the main barriers for the use of ePI in hospitals.”

Almost 60% of respondents reported that healthcare professionals use the digital version when they wish to obtain

information on a medicine.

Hospital pharmacists (93%) are those using most frequently the digital format of the product information followed by physicians (71%) and nurses (43%). Given that the survey only targeted hospital pharmacists, it should be noted that the presumed behaviour of both healthcare professionals and patients are always the opinion of the hospital pharmacists' answering the survey.

The survey reveals that patients are usually not provided with paper package leaflets and only 21% of respondents reported that medicines information is provided orally to patients. In this regard, the majority of respondents see the potential of further informing patients by giving them access to ePI. It would also ensure that the information accessed is up to date.

The report nevertheless acknowledged that some challenges should be addressed concurrently, especially equipping hospitals with the appropriate IT infrastructure while at the same time taking into account the structural preconditions of hospitals in Europe regarding the technical equipment to use ePI in daily practice.

EAHP's President András Süle pointed out that “The survey report provides very relevant information on the overall use of printed package leaflets and the prevalence of the application of product information in a digital format within EAHP's membership.

Hopefully, this snapshot analysis of the situation in Europe will help improve access to the up-to-date product information on medicines when and where it is needed in the hospital.”

EMA Appointment for Dr Nolan Dr Lorraine Nolan

The European Medicines Agency’s Management Bord has elected Dr Lorraine Nolan as chair of the Board for a three-year period.

Dr Nolan is the Chief Executive of the Irish Health Products Regulatory Authority (HPRA), a post she has held since January 2016. She has served as vicechair of EMA’s Management board since October 2019 and as member of the EMA Management Board since early

2016. Dr Nolan has more than twenty years’ experience in the area of medicines and wider health products’ regulation and has held a number of different roles at senior level within HPRA since joining the Irish regulator in 2001. She is a chemist by training having completed her PhD at Trinity College Dublin in drug development.

Dr Nolan takes over from Christa Wirthumer-Hoche, Head of the Austrian Medicines and Medical Devices Agency, who has completed two three-year mandates as chair of EMA’s Management Board since March 2016.

“It is a great honour to be appointed to lead EMA’s Management Board. What has been evident throughout the past

two years of the pandemic, and is clear also in the context of the devastating conflict in Ukraine, is that EMA must remain agile, responsive and ready to show leadership and solidarity in light of significant developments in the environment in which it operates.”, said Dr Nolan.

“As chair, my focus will be to continue and further enhance the strong partnership between EMA, national agencies and the European Commission.

Collectively, we must ensure that EMA continues to deliver the highest standards of public and animal health protection while maintaining its global reputation as a modern, progressive and transparent regulator”.

The vice-chair of the Board will be elected at its next meeting which will take place on 15-16 June 2022.

Handbook for Action Plans on Antimicrobial Resistance The World Health Organization (WHO) recently released an Implementation handbook for national action plans on AMR that provides guidance for the human health sector. This publication aims on the one hand at providing a practical, stepwise approach to national action plan implementation within the human health sector. On the other hand, it offers a process and a collation of WHO tools to prioritise, implement, monitor and evaluate national action plan activities.

This publication links to the endorsement of the Global action plan on antimicrobial resistance (AMR) at the World Health Assembly in 2015 that calls on countries to develop and implement national action plans on AMR. The development itself does not pose the biggest challenge, but countries seem to struggle with the implementation of the plan based on evidence-based prioritization of activities, systematic monitoring of progress, and ensuring the sustainability of efforts. The implementation handbook seeks to address this.

The target audience of the publication includes national/subnational stakeholders working on AMR within the human health sector. This includes national health authorities, national multi-sectoral coordination groups, senior technical experts and policymakers involved in implementing AMR activities at all levels of the health system, and implementation partners to accelerate sustainable implementation and monitoring and evaluation of national action plans on AMR.

APRIL 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

News

7

Team of the Year Award for Pharmacy The Aseptic Compounding Unit (ACU) team, St. Vincent’s Private Hospital

The Aseptic Compounding Unit (ACU) team at St. Vincent’s Private Hospital have won first place in the ‘Pharmacy Team of year’ category at European level for 2022 at the Love your Pharmacist Awards.

Their winning submission highlighted all of the work that was undertaken to implement the CATO project, an integrated software solution for chemotherapy that provides support throughout all stages of therapy planning, within our pharmacy unit.

This project transformed all processes within the Pharmacy Department and within the clinical areas of cancer. It has improved the quality and safety of the cancer treatment pathway for patients and also improved the efficiency and traceability of many of the processes carried out during the patient journey.

The pharmacy team also had to procure, replace, install and validate 2 new isolators while providing the same level of service to our patients, and all against the backdrop of a pandemic. During

these challenging times, the team managed all SVUH oncology patients for a period of 3 months which resulted in increased levels of activity, however, the

multidisciplinary aspect of the CATO project and the hard work of all involved allowed the team to bring the project to fruition on time, as planned.

This award is to be announced and presented at the European Hospital Pharmacist Association congress in Vienna, Austria from 23-25 March.

Waiting List Plan ‘Falls at First Hurdle’ The Irish Hospital Consultants Association (IHCA) has warned that the Government’s Waiting List Action Plan launched just three weeks ago has fallen at the first hurdle, with the latest figures from the National Treatment Purchase Fund (NTPF) showing increases rather than reductions in the number of people waiting for care.

The €350 million plan set out a target to reduce waiting lists for outpatient appointments, inpatient and day case treatment, and GI (gastrointestinal) endoscopies by more than 132,000 (18%) by the end of the year compared with the number waiting at the start of 2022.* However, two months into 2022 and instead of an expected reduction of around 22,000 people, the latest NTPF figures released today confirm that

12,800 additional people have in fact been added to these three main waiting lists since the start of the year - a 34,800 shortfall.** The IHCA says that outpatient appointments have seen the biggest increases in the number of people waiting – a further 9,200 people added to the list, instead of the pro rata target reduction of 21,600 people by the end of February.

comes as NTPF figures confirm there are 896,631 people on some form of hospital waiting list, including 99,190 children. This is an increase of 19,600 (2%) in the past year, or around 54 people added to public hospital waiting lists every single day since the end of February 2021.

Consultants have raised concerns that outpatient waiting lists will need to decrease by an average of 13,900 per month between now and the end of 2022 if the overall Waiting List Action Plan target of reducing the number awaiting an outpatient appointment to 487,000 is to be achieved.

More than 118,600 people have been added to NTPF waiting lists since the start of the pandemic two years ago - an increase of 15%. Outpatient waiting lists alone have increased by 68,000 (12%) since 2020, with the number of those waiting to be assessed by a Consultant almost doubling to 626,658 in the past eight years – a 94% (+303,000) increase.

The warning from Consultants over the Government and HSE’s unrealistic waiting list targets

As talks on Consultant contracts continue to stall in the absence of a new Independent Chair,

the IHCA has renewed its call on Government to effectively address the record hospital waiting lists by ending the pay discrimination introduced in 2012 against Consultants contracted after that date. Consultants say this is a critical step towards re-establishing trust and making Ireland a more competitive market for highly skilled medical and surgical specialists.

IHCA President Professor Alan Irvine, said, “Solutions cannot emerge from a vacuum or by skirting around the clear and sustainable actions. This approach over the last decade has severely undermined trust and is driving our highly trained medical and surgical specialists abroad, leaving our patients without access to the care they need and deserve.”

HOSPITALPROFESSIONALNEWS.IE | HPN • APRIL 2022

8

News

White Coat Ceremonies for Medical Students Daragh Browne and Jade Sleator pictured after the White Coat Ceremonies

to the pandemic we have had to reschedule the White Coat Ceremony on more than one occasion; it is a great pleasure to convene in person to mark this significant milestone. You have commenced your studies at a time of great challenge and change, and also one of great opportunity. We know that you, as our newest healthcare students, are committed to becoming the healthcare professionals and leaders of the future.”

During the ceremony, Jyoti Dhawan, President of the RCSI Students’ Union, and Emmanuel Eguare, Students’ Union Education Officer, delivered presentations describing their student life experiences.

More than 770 students took part in White Coat Ceremonies at RCSI University of Medicine and Health Sciences recently.

The White Coat Ceremony is undertaken as a commencement ceremony for all physician associate, medicine, physiotherapy and pharmacy

students – marking their new role as student health professionals.

Students were invited by Professor P. Ronan. O’Connell, RCSI President, to make a commitment to professionalism that mirrors the graduates’ declaration recited at their conferring day.

The declaration signals the

responsibilities they must begin to undertake as future health professionals from the start of their academic training.

Professor Cathal Kelly, RCSI ViceChancellor, welcomed the new students, “Today is a momentous and joyous occasion for all of you, your family and friends. Due

Dhawan commented, “Over the next few years, sail from this shore and do something that scares you, whether that be in sports, the arts, academics, or even a new hobby. Give it a shot. You will surprise yourself with what you can achieve. Even if you fail, you will do better the next time, and learn many lessons along the way.

Both your successes and your failures will equally define you, and contribute to the confidence you will develop over the years as a healthcare student.”

New Ipsos Survey for IPHA Over nine in 10 people believe vaccines are effective - an increase of 12 points since shortly before the pandemic, according to new research carried out by Ipsos for the Irish Pharmaceutical Healthcare Association (IPHA).

The research shows that 91% of people believe vaccines, in general, are effective. When the same question was asked in late 2019, 79% of people said they believed vaccines were effective.

Doctors and nurses, with 91%, are trusted for accurate information about vaccines. They are followed by scientists and vaccine specialists with 85%, pharmacists with 81% and official health websites with 77%. One-third of people, or 33%, trust traditional media sources for accurate information about vaccines.

Politicians were trusted by 13% of people. The least trusted information source, with 9%, was user-generated online content.

Over four in five people, or 84%, trust the medical evidence on vaccines. ‘Vaccine believers’ people who think vaccines are effective and trust the medical evidence - have increased by 11 points since a similar poll was taken in late 2019.

Four in five people, or 80%, believe there is misinformation about vaccines - up 15 points since shortly before the pandemic.

Almost one-third of people, or 31%, believe there isn’t enough information available about vaccines. Women and younger people are more likely than men and older age cohorts to seek information about vaccines, according to the survey.

APRIL 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

The survey finds that 57% have received adult vaccination for diseases other than Covid-19.

These diseases could include flu, mumps, rubella, Hepatitis B, whooping cough and pneumococcal disease.

Bernard Mallee, Director Communications and Advocacy at IPHA, said, “There is clear public confidence in vaccines to stop diseases and people trust experts with the facts about vaccines. It is probable that Covid-19 has heightened public awareness of the role of vaccines in improving health. Even though we have a world-class vaccination rate for Covid-19, a significant number of adults remain unvaccinated for other vaccinepreventable diseases. We hope that can change.

“Before the introduction of

vaccines for smallpox, rubella, measles, pneumonia, tuberculosis and polio, outbreaks of these diseases caused serious harm to communities in Ireland. Covid-19 is the latest chapter in a story of breakthrough science for better public health. It is encouraging that public trust in science is strong. It means more of us can stay safe throughout life.”

With the exception of clean, safe drinking water, vaccination is among the most successful and cost-effective public health interventions ever. The World Health Organisation estimates that vaccines save up to three million lives every year. IPHA’s life-course immunisation campaign, ‘Progress. Developed

by Vaccines’, is live on Twitter, Facebook and Instagram, and on ipha.ie.

10 News

of 412 permanent Consultant posts are vacant, with an additional 5 posts of unknown status and likely vacant. This is an increase of an additional 81 vacant Consultant posts, or 24%, over the past 9 months.** A further 354 permanent Consultant posts are currently filled by temporary or locum Consultants - an increase of 20% (+59 posts) on the number in May 2021. In addition, 66 posts are currently filled on an agency basis.

Worsening Hospital Staffing Crisis The increase in the number of Consultant posts vacant or filled on a temporary or agency over the past year is as follows:

New data from the HSE has revealed that the number of approved Consultant posts that are vacant or filled on a temporary, locum or agency basis has reached an all-time high of 837 posts.

Approved Consultant Posts

May 2021

Feb 2022

Difference (%)

Permanent Filled

2,886

3,019

+133 (5%)

This means that more than a fifth (22%) of all permanent Consultant posts are now not filled as needed, which is an increase of 110 posts, or 15%, since May 2021.

Temporary/Locum

295

354

+59 (20%)

Agency Filled

77

66

-11 (14%)

Vacant Post

331

412

+81 (24%)

Unknown Status (likely vacant)

24

5

-19 (79%)

TOTALS

3,613

3,856

+243 (7%)

The Irish Hospital Consultants Association (IHCA) has today (21 March 2022) said that this latest vacancy data is a cause for serious concern, amid worries of the impact of Consultant staffing shortages on the delivery of health services and the quality of patient care.

The Association has reiterated the urgent need for the Minister for Health, Stephen Donnelly, to re-establish the contract talks, which have stalled since last December, under an Independent Chair agreed with the representative organisations to oversee negotiations.

The new HSE figures,* analysed by the IHCA, confirm that as of 7 February 2022 a total of 412 permanent Consultant posts are vacant, with an additional 5 posts of unknown status and likely vacant. This is an increase of an

The specialties with the largest number of approved Consultant posts filled on a comes as almost 900,000 people

The specialties with the largest additional 81 vacant Consultant temporary/locum agency number basis are: of approved Consultant posts, or 24%, over the or past posts filled on a temporary/locum 9 months.** • Medicine - 99 posts; or agency basis are: A further 354 permanent • Psychiatry - 63 posts; • Medicine - 99 posts; Consultant posts are currently filled by temporary or locum • Psychiatry - 63 posts; Consultants - an increase of 20% • Surgery - 61 posts; (+59 posts) on the number in May • Anaesthesiology - 37 posts.

2021. In addition, 66 posts are currently filled on an agency basis.

The increase in the number of Consultant posts vacant or filled on a temporary or agency over the past year is seen in the table.

Of the 66 approved Consultant posts filled by agency staff, half (33 posts) are in Psychiatry.

The worsening consultant recruitment and retention crisis

— equivalent to 18% of the population of Ireland — are on some form of hospital waiting list published by the National Treatment Purchase Fund (NTPF).** More than 240,000 are waiting longer than a year for an outpatient appointment, inpatient/day case procedure or a GI (Gastrointestinal) scope. Of these, over 150,000 have been waiting longer than 18 months to be assessed by a hospital consultant.

Pharma Summit 2022 After a two-year hiatus due to covid restrictions, the Pharmaceutical Managers’ Institute (PMI) are absolutely delighted to confirm that the PMI Annual Pharma Summit returns on May 19th in Fitzpatrick Castle Hotel. The team are really looking forward to meeting with all their members in person again after such a long absence.

This agenda is being finalised now, keep an eye out in future issues of HPN for further details or visit www.thepmi.ie

Early detection of cancer related lymphoedema The Irish Cancer Society has announced the launch of a threeyear pilot project taking place in University Hospital Limerick focusing on the early detection of cancer related lymphoedema.

Lymphoedema is a swelling that can occur in the arm, hand or trunk after cancer treatments including surgery, radiotherapy, chemotherapy and endocrine therapies. These treatments can compromise the lymphatic system and lead to a build-up of lymph

fluid which causes pain, skin changes and reduced function.

This can be very distressing and adversely affect quality of life.

Early detection of lymphoedema can reduce the risk of developing lifelong lymphoedema by 95%.

Initially all breast and gynaecological cancer patients receiving treatment in University Hospital Limerick that are deemed high risk for lymphoedema will be referred to the service.

Each patient will then have

APRIL 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

their Lymphoedema Index score measured by a certified lymphoedema therapist in the physiotherapy department of the hospital pre and post treatment.

If required, patients will then be treated with compression garments, skin care and tailored exercise programmes and monitored for up to two years.

The programme also offers education & information sessions, online resources and support to patients throughout their involvement with the project.

Dr Denis O’Keeffe, Consultant Haematologist and Director of Cancer Services for UL Hospitals Group, said, “We are delighted to see this project being opened in University hospital Limerick. The early detection of lymphoedema in high risk patients will provide the opportunity to treat and prevent more serious long term issues. It will also provide great support for patients who develop this very difficult and often challenging complication.”

50mgs once daily

50mgs once daily

Her 10th shopping trip since the day she started BETMIGA1

Prescribing Information: Please read the Summary of Product Characteristics (SPC) before prescribing. Presentation: Prolonged-release tablet, containing mirabegron 25mg/50mg. Indication: Symptomatic treatment of urgency, increased micturition frequency and/or urgency incontinence as may occur in adult patients with overactive bladder (OAB) syndrome. Posology and method of administration: The recommended dose is 50 mg once daily. A lower dose of 25mg is recommended for specific patient populations (renal and hepatic impairment) as well as in specific patient populations in combination with strong CYP3A inhibitors such as itraconazole, ketoconazole, ritonavir and clarithromycin.

Renal impairment: End stage renal disease (GFR < 15 mL/min/1.73 m2 or patients requiring haemodialysis): Not recommended. Severe renal impairment (GFR 15 to 29 mL/min/1.73 m2): Reduce dose to 25 mg. Severe renal impairment and concomitant strong CYP3A inhibitors: Not recommended. Moderate renal impairment (GFR 30 to 59 mL/min/1.73 m2): 50 mg. Moderate renal impairment and concomitant strong CYP3A inhibitors: Reduce dose to 25 mg. Mild renal impairment (GFR 60 to 89 mL/min/1.73 m2): 50 mg. Mild renal impairment and concomitant strong CYP3A inhibitors: Reduce dose to 25 mg. Hepatic impairment: Severe hepatic impairment (Child-Pugh Class C): Not recommended. Moderate hepatic impairment (Child-Pugh B): Reduce dose to 25 mg. Moderate hepatic impairment and concomitant strong CYP3A inhibitors: Not recommended. Mild hepatic impairment (Child-Pugh A): 50 mg. Mild hepatic impairment and concomitant strong CYP3A inhibitors: Reduce dose to 25 mg. The tablet is to be taken once daily, with liquids, swallowed whole and is not to be chewed, divided, or crushed. It may be taken with or without food Contraindications: Hypersensitivity to the active substance or to any of the excipients (see the SPC for a list of excipients). Severe uncontrolled hypertension defined as systolic blood pressure ≥180 mm Hg and/or diastolic blood pressure ≥110 mm Hg. Special warnings and precautions for use: Renal impairment: Betmiga has not been studied in patients with end stage renal disease (GFR < 15 mL/min/1.73 m2 or patients requiring haemodialysis) and, therefore, it is not recommended for use in this patient population. Data are limited in patients with severe renal impairment (GFR 15 to 29 mL/min/1.73 m2); based on a pharmacokinetic study a dose reduction to 25 mg is recommended in this population.

This medicinal product is not recommended for use in patients with severe renal impairment (GFR 15 to 29 mL/min/1.73 m2) concomitantly receiving strong CYP3A inhibitors. Hepatic impairment: Betmiga has not been studied in patients with severe hepatic impairment (Child-Pugh Class C) and, therefore, it is not recommended for use in this patient population. This medicinal product is not recommended for use in patients with moderate hepatic impairment (Child-Pugh B) concomitantly receiving

Date of preparation: June 2019

strong CYP3A inhibitors. Hypertension: Mirabegron can increase blood pressure. Blood pressure should be measured at baseline and periodically during treatment with mirabegron, especially in hypertensive patients. Data are limited in patients with stage 2 hypertension (systolic blood pressure ≥ 160 mm Hg or diastolic blood pressure ≥ 100 mm Hg). Patients with congenital or acquired QT prolongation: Betmiga, at therapeutic doses, has not demonstrated clinically relevant QT prolongation in clinical studies. However, since patients with a known history of QT prolongation or patients who are taking medicinal products known to prolong the QT interval were not included in these studies, the effects of mirabegron in these patients is unknown. Caution should be exercised when administering mirabegron in these patients. Patients with bladder outlet obstruction and patients taking antimuscarinic medicinal products for OAB: Urinary retention in patients with bladder outlet obstruction (BOO) and in patients taking antimuscarinic medicinal products for the treatment of OAB has been reported in postmarketing experience in patients taking mirabegron. A controlled clinical safety study in patients with BOO did not demonstrate increased urinary retention in patients treated with Betmiga; however, Betmiga should be administered with caution to patients with clinically significant BOO. Betmiga should also be administered with caution to patients taking antimuscarinic medicinal products for the treatment of OAB. Interactions: Pharmacokinetic interactions: Mirabegron is a substrate for CYP3A4, CYP2D6, butyrylcholinesterase, uridine diphosphoglucuronosyltransferases (UGT), the efflux transporter P-glycoprotein (P-gp) and the influx organic cation transporters (OCT) OCT1, OCT2, and OCT3. Pharmacokinetic interactions involving the potential for other medicinal products to affect mirabegron exposures: Increases in mirabegron exposure due to drug-drug interactions may be associated with increases in pulse rate. Strong CYP3A inhibitors See Posology and administration above for dose adjustments recommended during concomitant use of strong CYP3A inhibitors in patients with renal or hepatic impairment. Mirabegron exposure (AUC) was increased 1.8-fold in the presence of the strong inhibitor of CYP3A/P-gp ketoconazole. CYP2D6 inhibitors: No dose adjustment is needed for mirabegron when administered with CYP2D6 inhibitors (or in patients who are CYP2D6 poor metabolisers). Inducers: Inducers of CYP3A (such as rifampicin) or P-gp may decrease the plasma concentrations of mirabegron. No dose adjustment of mirabegron is required as this effect is not expected to be clinically relevant.

Pharmacokinetic interactions involving the potential for mirabegron to affect exposures to other medicinal products: Inhibition of CYP2D6: Moderate and time dependent inhibition of CYP2D6 by mirabegron may result in clinically relevant drug interactions. CYP2D6 activity recovers within 15 days after discontinuation of mirabegron. Caution is advised if mirabegron is co-administered with medicinal

products metabolized by CYP2D6 with a narrow therapeutic index such as thioridazine, Type 1C antiarrhythmics (e.g.flecainide, propafenone) and tricyclic antidepressants (e.g., imipramine, desipramine). Caution is also advised if mirabegron is co-administered with CYP2D6 substrates that are individually dose titrated. Inhibition of P-gp: Mirabegron is a weak inhibitor of P-gp. For patients who are initiating a combination of Betmiga and digoxin, the lowest dose for digoxin should be prescribed initially. Serum digoxin concentrations should be monitored and used for titration of the digoxin dose to obtain the desired clinical effect. The potential for inhibition of P-gp by mirabegron should be considered when Betmiga is combined with sensitive P-gp substrates e.g. dabigatran. Fertility, pregnancy and lactation: The effect of mirabegron on human fertility has not been established.

Betmiga is not recommended during pregnancy and in women of child-bearing potential not using contraception. Mirabegron should not be administered during breast feeding. Refer to SPC for full guidance. Driving and use of machines: Betmiga has no or negligible influence on the ability to drive and use machines.

Undesirable effects: Summary of the Safety Profile: the safety of Betmiga was evaluated in 8433 patients with OAB, of which 5648 received at least one dose of mirabegron in the phase 2/3 clinical program, and 622 patients received Betmiga for at least 1 year (365 days). In the three 12-week phase 3 double blind, placebo controlled studies, 88% of the patients completed treatment with this medicinal product, and 4% of the patients discontinued due to adverse events. Most adverse reactions were mild to moderate in severity. The most common adverse reactions reported for patients treated with Betmiga 50 mg during the three 12-week phase 3 double blind, placebo controlled studies are tachycardia and urinary tract infections.

The frequency of tachycardia was 1.2% in patients receiving Betmiga 50 mg.

Tachycardia led to discontinuation in 0.1% patients receiving Betmiga 50 mg. The frequency of urinary tract infections was 2.9% in patients receiving Betmiga 50 mg.

Urinary tract infections led to discontinuation in none of the patients receiving Betmiga 50 mg. Serious adverse reactions included atrial fibrillation (0.2%). Adverse reactions observed during the 1-year (long term) active controlled (muscarinic antagonist) study were similar in type and severity to those observed in the three 12-week phase 3 double blind, placebo controlled studies. The following adverse reactions were observed with mirabegron in the three 12-week phase 3 double blind, placebo controlled studies. The frequency of adverse reactions is defined as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be established from the available data) Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. The adverse events

References: 1. Freeman R, et al. Current Medical Research and Opinion 2017. https://doi.org/10.1080/03007995.2017.1419170.

are grouped by MedDRA system organ class. Infections and infestations: Common: urinary tract infection Uncommon: vaginal infection, cystitis Psychiatric disorders: Not known: Insomnia*, confusional state* Nervous system disorders: Common: headache* dizziness* Eye disorders: Rare: eyelid oedema Cardiac disorders: Common: tachycardia Uncommon: palpitation, atrial fibrillation Vascular disorders: Very rare: Hypertensive crisis* Gastrointestinal disorders: Common: nausea*, constipation*, diarrhoea* Uncommon: dyspepsia, gastritis Rare: lip oedema Skin and subcutaneous tissue disorders: Uncommon: urticaria, rash, rash macular, rash papular, pruritus Rare: leukocytoclastic vasculitis, purpura, angioedema* Musculoskeletal and connective tissue disorders: Uncommon: joint swelling Renal and urinary disorders: Rare: urinary retention* Reproductive system and breast disorders: Uncommon: vulvovaginal pruritus Investigations Uncommon: blood pressure increased, GGT increased, AST increased, ALT increased (*observed during post-marketing experience). Reporting of suspected adverse reactions: see below. Legal category: POM (S1B) Marketing Authorisation number: EU/1/12/809/003 - 25mg EU/1/12/809/010 - 50mg. Marketing Authorisation holder: Astellas Pharma Europe B.V. Sylviusweg 62, 2333 BE Leiden, The Netherlands. Further information is available from: Astellas Pharma Co., Ltd, 5 Waterside, Citywest Business Campus, Dublin 24. Phone: +3531 467 1555. Summary of Product Characteristics with full prescribing information available upon request. Job number: BET_2019_0002_IE Date of preparation of API: 27 May 2019.

Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via: HPRA Pharmacovigilance Astellas Pharma Co. Ltd Earlsfort Terrace, IRL - Dublin 2 Tel: + 353 1 467 1555 Tel: +353 1 6764971 E-mail: Irishdrugsafety@astellas.com Fax: +353 1 6762517 Website: www.hpra.ie E-mail: medsafety@hpra.ie.

Approval code: BET_2019_0004_IE

12

Report

New Concept for Emergency Surgery Patients Cross-border Centre for Personalised Medicine Emergency General Surgery Cluster Creates a new concept in the treatment of Emergency Surgery Patients

Mr Michael Sugrue, Surgeon at Letterkenny University Hospital

A new report was launched last month entitled ‘Emergency General Surgery Report Improving Outcomes and Saving Lives.’ It was launched by the Emergency General Surgery consortium.

The Centre for Personalised Medicine’s, Emergency Surgery Research cluster was formed following almost 10 years of planning between Letterkenny University Hospital, Ulster University, Western Health and Social Care Trust, working with partners in the Letterkenny Institute of Technology, University of the Highlands and Islands, NHS Scotland, Randox Laboratories and Randox Teoranta, United Health Group / Optum, Clinishare Ltd., Health Analytics Ltd., Northern Ireland Clinical Research Services, National University of Ireland Galway, Donegal Clinical Research Academy, Clinical Translational Research and Innovation Centre

The Centre for Personalised Medicine, Clinical Decision Making, and Patient Safety (CPM) focuses on five disease areas, which are: emergency surgery, acute kidney injury, cardiovascular disease, diabetes, and dementia.

The Emergency Surgery Outcomes Advancement Project (eSOAP) commenced during late 2018 and is situated within the CPM. It has been reported previously that EGS, and its associated burden, accounts for more than half of the surgical workload across the UK National Health Service (NHS) and half of all surgical mortality within the United States. This is compounded by an inefficient triage of patients presenting with abdominal pain, wide variability in diagnostic pathology testing

The Emergency Surgery Outcome Advancement Project (eSOAP) was funded by the EU’s INTERREG VA Programme, which is managed by the Special EU Programmes Body (SEUPB).

APRIL 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

rates between clinical teams, and wide variability in outcome rates following emergency surgery.

This marked variation in outcomes and the provision of care is exacerbated by the high risk nature of the specialty. The challenges confronting EGS services in the Republic of Ireland, Northern Ireland, and Scotland are coherent with those highlighted previously in England.

Essentially these are relative to concerns around training, workforce, and operational issues.

These are central to variations in the outcomes that have been identified across EGS and have been amplified by both the Health Service Executive/Royal College of Surgeons in Ireland and the Nuffield Trust/Royal College of Surgeons of England.

This situation has been further aggravated by the Covid-19 crisis during 2020/2021. Within the context of EGS care in Ireland, in 2014 50% of all general surgical activity nationally (Table 1) occurred in Model 3 Hospitals.

This is an index of 17 hospitals, including Letterkenny University Hospital, that admit similar groupings of acute medical and surgical patients. Facilities at Model 3 Hospitals include an Acute Medical Assessment Unit (AMAU), a 24-h ED, and Intensive Care Unit. The analysis of consultant manpower within these hospitals indicates a system under pressure.

A number of contemporary and pivotal strategic reports relating to EGS care in Ireland, the United Kingdom, Great Britain and

13

for 10% of emergency hospital admission world-wide with over 150,000 hospital admission annually in the island of Ireland and two million in the EU.

Ireland, and the United States provide a contextual backdrop to the ongoing challenges and limitations across the scope of EGS. These reports have emphasised the need for improvements in the delivery of the quality and safety of EGS care whilst outlining possible mechanisms through which this transformation can be achieved.

They also refer to the overriding need to enhance the patient experience of EGS care.

The 350 page document reports some unique achievements, which if implemented in the EU could reduce mortality in critically ill emergency surgery patients resulting in over 20,000 lives being potentially saving and reducing complications.

Innovative Approaches

Mr Michael Sugrue, Surgeon at Letterkenny University Hospital and project lead, said the team created a unique data registry, combined with new contemporary clinical pathways and analysis of delivery of care to over 6000 patients. Mr Sugrue said the team worked to develop new key outcome indicators in surgery, the first such performance indicators assessed in this patient population in Europe.

The collaborative interregional research team’s research is an innovative approach to Emergency General Surgery Care (EGS). EGS patients account

Professor Boermeester, Professor of Surgery University of Amsterdam praised the work saying it was ‘one of the first real attempts in Emergency Surgery to incorporate

performance and key outcome analysis in patients care and was a remarkable achievement.’

Professor Bill Schwab, from the University of Pennsylvania (USA), considered an expert in emergency medical, surgical and trauma systems said “…the recommendations of this report, when implemented, would have far reaching effects by improving the quality and efficiency of care and outcomes of patients across Ireland, Northern Ireland and Scotland.”

Professor Ravi Vorha, a world expert in Emergency Surgery systems delivered a keynote address at Derry City Hotel at the closing conference of the Centre of Personalised Medicine Conference on March 23rd and said he felt that “the work done by the EGS Research Cluster and their achievements have created a platform to vastly improve care of emergency patients. The implications of this research could positively affect the health of over 2 million annual admissions in the EU.”

HOSPITALPROFESSIONALNEWS.IE | HPN • APRIL 2022

14

Report

Table 1. Elective and acute inpatient and day case discharges for Model 2, 3 and 4 hospitals

Table 1. Elective and acute inpatient and day case discharges for Model 2, 3 and 4 hospitals

Hospital model (M)

M2

M3

M4

Inpatients

2,545

12,149

14,274

Day cases

10,666

17,347

11,098

Sub-total (%)

13,211 (19.4%)

29,506 (43.3%)

25,371 (37.3%)

Inpatients

1,684

24,506

14,874

Day cases

19,228

42,777

22,885

Sub-total (%)

20,922 (16.6%)

67,283 (53.4%)

37,759 (30%)

Grand total (%)

34,133 (12.6%)

96,789 (49.9%)

63,130 (32.5%)

Had surgical procedure

No surgical procedure

(Mealy et al. 2017)

A number of contemporary and pivotal strategic reports relating to EGS care in Ireland16, 17, the United Kingdom3, 15, 19, Great Britain and Ireland20, and the United States21 provide a contextual collaboration with industry from These his home in the US they shouldto bethe an ongoing integral part of backdrop challenges and limitations acrossand the scopesaid of EGS. reports have health providers. that the achievements of this Emergency Surgery Care in the emphasised the need for improvements in the delivery of the quality and safety of EGS care whilst Ireland and UK.” small research group were truly Professor William outlining possible mechanisms through which thisCampbell transformation can be achieved.

They also refer remarkable. He said “the research Nobel Laureate in Medicine and The EASC Course has been output of the emergency general to overriding to enhancePhysiology the patient experience of EGS care. was delighted with runthe in 12 countries need teaching Professor Martin Curley, Director, Digital Transformation and Open Innovation, HSE

Professor Martin Curley whose team in HSE’s Digital Transformation Division created the eSOAP registry and digital support for the project felt “this was only the beginning of a new era in Irish and European Health Care and the introduction of agile responsive, scalable Digital systems will ensure better patient safety and outcomes.”

Research partners, Mr Brendan Skelly in Altnagelvin and Professor Angus Watson in Scotland, feel that the education programme, which they have lectured on, called the Emergency Abdominal Surgery Course (www.easccourse.com) has now 12 become a world leading education programme in emergency general surgery. Mr Skelly said the courses are so “comprehensive

surgery report points to innovative the research outcome. Professor Consultants, Trainees, Nurses and concepts in delivery of care in Campbell had supported Medical students in four unique appendicitis, as well to as host definitions Letterkenny University Hospital Donegal Clinical Research Academy were pleased one research scholarships for 3 courses. Professor Watson said and in new approaches to cholecystitis, medical students during the it “is one of the best educational of the world’s first summits on performance in Emergency General Surgery in June of 2016. The and bowel obstruction.” project. Professor Campbell surgical events that have been Donegal laidsurgery a foundation stone in the development of key performance indicators in created in Summit emergency in 12 decade.” the last EGS .

Mr Michael Sugrue said focusing on clinical care is crucial for patients with emergency general surgery conditions such as appendicitis, acute inflammation of the gallbladder or bowel problems. He said “key outcome and performance indicators provide a template to set new benchmarks in surgical care”. Mr. Sugrue has made a call for the government to act on the implementation of the recommendations in this report.

The team would like to thanks the Special EU Programmes Body (SEUPB) is a North/ South Implementation Body sponsored by the Department of Finance in Northern Ireland and the Department of Public Expenditure and Reform in Ireland. It is responsible for managing two EU Structural Funds Programmes, PEACE IV and INTERREG VA which are designed to enhance cross-border cooperation, promote reconciliation and create a more peaceful and prosperous society. The Programmes operate within a clearly defined area including Northern Ireland, the Border Region of Ireland and in the case of INTERREG VA, Western Scotland.

The team have recommended the creation of a national policy in emergency general surgery care, with collaboration to include The report can be downloaded www.dcra.ie defined outcomes, integrated use General Emergency Surgery Report Improving Outcomes and Saving Lives of digital technology in all aspect https://dcra.ie/pdfs/EMERGE-Emergency-Generalincluding radiology, nursing and surgery. The data generated by Surgery-Patient-Management-System-2022.pdf the registry will allow greater

APRIL 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

News 15 Examining Sector Stability and Patient Access to Medicines The Guaranteed Irish Annual Pharmaceutical Forum, sponsored

by MSD Ireland, featured an industry leading line-up within the pharmaceutical sector. Hosted

by Mairead McCaul Managing Director of MSD Ireland Human Health, the panel discussion featured industry thought leaders Dr. Thorsten Giesecke General Manager Commercial Business at Janssen Sciences Ireland, and Matt Moran Director of BioPharmaChem Ireland, Ibec.

The panel outlined Ireland’s position as the third largest exporter of pharmaceuticals globally, employing over 45,000 people in Ireland directly with an added growth value of ¤15 billion to the local economy. “This year, 35 new medicines for a range of medical conditions will be proposed. These conditions include arthritis, multiple sclerosis, psoriasis and many forms of cancer…these medicines could treat almost 17,500 patients here in Ireland” said Mairead McCaul Managing Director of MSD Ireland Human Health.

The panel discussed sector opportunities including sector

stability, continuous growth & development, the sector’s commitment to nurturing talent, and harnessing a holistic pharma-healthcare ecosystem.

Examining these trends, Mairead McCaul affirmed “…we have a well and proven track record as a successful location for highgrowth multinationals. One-third of multinationals in Ireland have been here for over 20 years, showing the longevity, resilience and commitment these companies have to Ireland.”

Mairead McCaul, Managing Director of MSD Ireland Human Health

Sector stability remains an attraction for Ireland as a hub for pharmaceuticals globally. Matt Moran Director of BioPharmaChem Ireland, Ibec added “…as well as being an industry dominated by foreign direct investment, it’s an extremely stable sector.

Multinationals pay around ¤15 billion in corporation tax, and it’s the security which this brings that is very important.”

While Ireland is a global leader in the pharmaceutical industry, patient access to medicines is somewhat limited. According to Thorsten Giesecke General Manager Commercial Business at Janssen Sciences Ireland, “Studies have shown 35% of medicines licensed in Europe, most of which are made in Ireland, are available to patients in Ireland. This is an opportunity where if Government looks at the industry holistically to include manufacturing, clinical research and the domestic health service, they can drive this eco-system.”

The panel also highlighted industry challenges such as the disconnect between Government policy and the pharmaceutical sector, as well as the delayed reimbursement of Gene and Cell Therapy (GCT).

Closing the event, Mairead McCaul Managing Director, MSD Ireland Human Health said, “I’m delighted to have been part of this thought -provoking and insightful discussion this morning.

Events such as this facilitate crucial discussions with fellow industry experts to explore how we can build on our past and current success as an industry and continue to thrive and hold our place as a global leader in the pharmaceutical industry.

MSD Ireland is a long-standing member of Guaranteed Irish and acknowledges the role it plays in promoting Ireland and facilitating networking opportunities such as this.”

Pharmacists Must Stand with Ukraine Pharmacy organisations across Europe and indeed the world, are calling on pharmacists to provide aid to Ukraine.

The International Pharmaceutical Federation (FIP), made the request on behalf of its member organisation the All-Ukrainian Pharmaceutical Chamber.

“FIP will always endeavour to support our colleagues across the world, responding to their requests and not acting alone. We will always assess need against request, but our offer of support is universal and equitable. We are witnessing heroic efforts by the Ukrainian people and our pharmacy colleagues. It is truly moving, inspiring and terrifying in equal measure,” said FIP CEO Catherine Duggan.

The organisation said in a statement, “A world where everyone benefits from access to safe, effective, quality and affordable medicines and health technologies, as well as from pharmaceutical care services provided by pharmacists, in collaboration with other healthcare professionals is the vision that FIP is working towards. FIP condemns all acts of violence or war causing suffering, and has long supported the pharmacy profession in humanitarian work.

“As healthcare professionals, pharmacists have an ethical duty and responsibility of providing aid to others in disaster situations. We remind all our members and others of our Statement of Policy on the role of the pharmacist in the management of disasters, be they natural or man-made, war, civil disorder or pandemics.

Ground-breaking Trial for Beacon Hospital Beacon Hospital together with Dr Jonathan Lyne, Director of Electrophysiology, are delighted to announce that they have been selected as one of only 12 cardiac centres of excellence in the world to take part in a ground-breaking clinical trial.

Beacon Hospital is the only centre in Ireland to be selected. The other 11 selected centres are located in the USA and the UK. The trial is working on a new type of Cardiac Resynchronisation

Dr Jonathan Lyne

Therapy (CRT) for heart failure patients. This technique utilises the hearts own electrical wiring system known as conduction system pacing.

Congratulations to Professor Lyne and all in Beacon Hospital’s Cath Lab, Clinical Trials and Research Institute teams.

HOSPITALPROFESSIONALNEWS.IE | HPN • APRIL 2022

16 Fatigue

Fatigue in the 21st century healthcare workforce – New understandings and solutions for personnel “It’s precisely those who are busiest who most need to give themselves a break.” — Pico Iyer, The Art of Stillness.

Acceptance

Resistance

Strain

Disengaged

 minor decrement

 no decrement

 minor decrement

 significant decrement

Written by Dr Dale Whelehan, Behaviour Scientist The quote above is one that resonates a lot with me - and should to most healthcare workers. The past two years (and many years before that) have been challenging, and the above and beyond has been expected on a daily basis. It can often seem like the system is broken and beyond repair - leaving many feeling helpless. I hope my insights can share a small bit of light into helping you with your health and wellbeing over the coming months.

Introduction I’m delighted to be joining as a regular contributor to discuss all things related to fatigue, burnout, sleep and rest. My background is in physiotherapy and I recently completed my PhD in the behavioural sciences exploring how issues related to fatigue can manifest themselves in healthcare workers. I also explored how we can begin to resolve some of those modifiable aspects of our day-today lives, as well as the systems we work in to make ourselves feel better and perform better.

In this introductory article I am going to briefly discuss the science behind how we experience fatigue and why we experience

it. I hope by the end of it you will leave with a fresh understanding.

Academic theories can often seem impenetrable and difficult to apply in the real-world. In this piece, I will outline some of the main theories around fatigue management in the workplace and offer a practical set of strategies for you to use.

In subsequent articles I'll be talking more in-depth about the complexity of these issues and hope to get your input, and input from other experts in the field, in designing solutions to make healthcare the people-centred sector it should be.

Historical views of fatigue management When we talk about fatigue, cognitive load theory1 is often referenced. This theory suggests that as individuals we have a finite amount of information we can store in what is termed our ‘working memory’ at any given time. Working memory is the conscious experience of knowledge as experienced in real time. When individuals are overburdened with too much information, they experience what

APRIL 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

is known as a ‘cognitive overload’ and they experience a subjective experience of fatigue.

Emerging thoughts on fatigue management While cognitive load is useful as a concept for thinking about fatigue, more recent research looks at issues around self-determination, motivation, and how the individual has a more influential role in the prevention and management of the fatigued state. Popularised in the 2010’s by a book called ‘The Psychology of Fatigue’2, motivation can be said to play a pivotal role in determining how an individual reacts to a work task. Let us take a work task like charting a patient’s medications as an example. This new theory suggests we can optimise our work in a more nuanced way.

Using Figure 1, let us imagine we are ten minutes into designing the task and suddenly we begin to feel a small ‘urge’ of discomfort. This is the first emotional signal of the fatigue state. It tells you that your current task is not aligning with your desired goals, whether they be personal goals (e.g., you would

Figure 1: Relationship between subjective experience of ‘fatigue’ and associated impact on performance3

rather be working on practicing an inservice you’re presenting at in the evening) or somatic goals (e.g., a need to sleep or eat). We typically push through the urge, employing a series of strategies to ‘concentrate’ on the task. In doing so, we continue to increase the level of fatigue we experience until eventually we enter a phase known as the ‘strain’ phase. In this instance, fatigue is high. Should we decide to pursue further, we will enter the ‘disengaged’ phase whereby there will be significant fatigue and after-effects, and associated decrement in performance.

What does this mean for our performance in work?

So, what does that relationship tell us? First, it tells us how ‘goals’ can shape our experience of fatigue – so if we can make the tasks we are completing somewhat more goal-oriented,

17 Figure 2: The importance of ‘self-determination’ in modelling workload

Supportive networks Workload

Autonomy

Organisational Needs

then we may not experience that downward trajectory of higher fatigue levels. Secondly, it tells us the importance of addressing any other goals which are in conflict with our current task, even if it means taking a small amount of time away from the task at hand to address these goals. Third, it offers us a ‘signal’ that we can begin to use to raise levels of self-awareness and therefore avoid states of experiencing high fatigue on a regular basis. Finally, the theory provides us with an insight into the relationship between work and non-work activities. Should

individuals enter the ‘strain’ or ‘disengaged’ phases of fatigue, they risk impacting their non-work time and activities, thus creating a cycle of insufficient opportunity to engage in desired activities and non-recovery.

When considering how we can better manage fatigue in our lives, the framework of basic psychological needs can be a good cognitive reminder for us to use. These have been defined as competency (I.e., a perception that you feel you are achieving something), autonomy (I.e., a

feeling of volition over your own actions and your behaviours), and relatedness (I.e., a sense of closeness to those around you)4. Fulfilling these needs in the workplace, through appropriate workload modelling (Figure 2) is important to maintain motivation in the workplace. Similarly, engaging in fulfilling and nourishing these needs in non-work settings is important in the prevention of longer-term fatigue related issues (e.g., burnout). Individuals can identify activities which promote a perceived sense of competency (I.e., learning a new skill), a sense

of autonomy (I.e., having an hour every evening, void of family or friend influences to engage in a desired behaviour), and relatedness (I.e., keeping in regular touch with those who you connect with most).

Key lessons and insights Fatigue is not necessarily a ‘good’ or ‘bad’ feeling. It simply is an emotional signal that tells us that current tasks are in contravention to desired goals. With that in mind, we should focus our efforts on making work-related tasks more goal-oriented and enjoyable; while also taking the time to pause when we experience fatigue and see if alternative activities need to be employed for longer term performance sustainability and optimal wellbeing. With that in mind, why not try and lean into recognising the onset of fatigue signals in your day-to-day life for the next few days. Identify the triggers that seem to exacerbate those signals and see if you can modify your workday to prevent the fatigue from increasing.

References 1 Chandler and Sweller (1991), Cognitive Load Theory 2 Hockey (2013), The Psychology of Fatigue 3 Whelehan (2021), To survive or to thrive: An investigation into fatigue and associated factors on surgical performance 4 Deci and Ryan (2004), Self-determination theory

HOSPITALPROFESSIONALNEWS.IE | HPN • APRIL 2022

18 Chronic Pain

Spinal Cord Stimulation – Advances in Effectiveness and Tolerability Written by Professor Connail McCrory and Dr Deborah Galvin, Trinity Translational Medicine Institute, Trinity College Dublin

cerebrospinal fluid including VEG-F, IL-10, in addition to the cellular constituents including CD4/ CD8 ratios and glial cell activation favouring constituent relationships that promote recovery from chronic neuropathic pain.

Other factors that promote spinal cord stimulation include the removal of the necessity of the “trial of stimulation,” in addition to the technical improvements.

Professor Connail McCrory

Dr Deborah Galvin

Chronic neuropathic pain (CNP) is a specific form of chronic pain. It is caused by a dysfunction of the somatosensory nervous system.

It affects approximately 8% of the population. In addition to trauma and stroke, a number of medical conditions contribute to activation of CNP including diabetes, multiple sclerosis, complications of common surgeries such as hernia repair, breast surgery, vasectomy and neurodegenerative disorders. It is associated with cancer chemotherapy also. This is a common and difficult problem to treat.

usage and this required a further visit to the operating theatre.

IPG replacement was usually performed in the daycare unit.

Therefore, spinal cord stimulation was seen as extremely expensive and access to it was limited primarily by funding concerns.

A significant expenditure both financially and in terms of the pain service time was required to employ the therapy for one patient. Other concerns expressed by funders related to lack of knowledge regarding how this system actually worked.

It has been recognized that spinal cord stimulation in appropriately selected patients is more effective than pharmacological therapy and avoided the daily use of medication with associated compliance issues and development of tolerance and side-effects. However, spinal cord stimulation was initially very expensive with a significant workup preplacement, a requirement of two visits to the operating theatre with associated inpatient stay and significant complication rates. In addition to this, the most expensive component of the spinal cord stimulator, the implantable pulse generator (IPG) needed to be replaced every 3 to 5 years depending upon

However, clinical researchers in this field over the last 15 years in particular have made significant improvements in our knowledge regarding the initiating, maintenance and recovery factors involved in the development of chronic neuropathic pain and also developed a greater understanding of the functioning of spinal cord stimulation in vivo. This has been married with successful technological developments over a similar time period.

There are now many more options in terms of programming the IPG which means the system is much more versatile. Traditionally lowfrequency stimulation was used which was paraesthesia-based.

This has significant limitations and effectiveness in addition to

APRIL 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

the fact that some patients found paraesthesia was uncomfortable.

The development of higherfrequency stimulation and removal of paraesthesia-based stimulation has made this treatment more acceptable to the majority of patients. Furthermore, the development of burst stimulation, which more closely mimics physiological neural function is improving efficacy.

There is growing evidence that CNP is initiated, maintained and recovered by changes in the neural proteome and cellular immune function. There is a growing body of clinical work that demonstrates spinal cord stimulation in vivo alters the proteome within the cerebrospinal fluid and t-cell phenotype. There is therefore growing information regarding how spinal cord stimulation works and this tends to support higher frequencies of stimulation. The mode of action of spinal cord stimulation has developed beyond the idea that the resultant electrical field caused the interneurons to modulate pain signaling in the dorsal columns – the gate theory of pain control. There is a growing body of clinical evidence which identifies that spinal cord stimulation can modulate peptides implicated in CNP pathophysiology in the

After a patient had been deemed suitable for spinal cord stimulation the traditional approach was that the patient underwent a trial whereby the electrode lead was inserted under sedation and connected to an externalized power source. The patient went home for a period of time which could range from 2 to 3 days to one month in some European countries. The rationale for trial was an attempt to prove the system would help the patient prior to implantation of the IPG which was the most expensive part of the system.

However, it also opened up the possibility of infection due to the externalized lead and did not mimic accurately the situation of having an implanted stimulator.

Numerous restrictions were required including being unable to shower or drive as well as appropriate attention being paid to this bulky system which meant that it did not accurately reflect an implanted system. There was no comprehensive evidence supporting this and recently the International Neuromodulatory Society has very much challenged this mandated approach. As always in medical practice, patient selection is absolutely crucial and this is more relevant than carrying out a trial. Today it is acceptable to proceed straight to implantation of the spinal-cord stimulator if the clinician deems this is the best treatment for a given patient.

This change in practice has significant implications in terms of the cost of providing the service and potential complications by reducing the number of operating theatre visits from two to one. The

BRING

PROTECTION TO LIFE

BY REDUCING THE RISK OF THE COMPOSITE OF DECLINING KIDNEY FUNCTION, ESKD, AND RENAL OR CV DEATH*1 FORXIGA is now approved for adult patients with CKD.2

treatment

GFR

FORXIGA 10 mg Once daily.

No titration required

*In DAPA-CKD, the primary endpoint showed that FORXIGA in conjunction with other CKD therapies reduced the relative risk of the composite endpoint of ≥50% sustained decline in eGFR, reaching ESKD, and renal or CV death by 39% (5.3% ARR) vs placebo with other CKD therapies in 4304 adult patients with CKD with an eGFR of 75 to 25 mL/ min/1.73m2 (median follow-up of 2.4 years; p<0.001).1 DAPA-CKD was stopped early due to efficacy benefit, because of the unplanned early stop, this secondary endpoint is considered nominally significant; Secondary endpoints showed that FORXIGA in conjunction with other CKD therapies reduced the relative risk of the composite of CV death or hHF by 29% (1.8% ARR: nominal p=0.009) and also reduced the relative risk of all-cause mortality by 31% (2.1% ARR; nominal p=0.004) vs placebo with other CKD therapies.

There were comparable rates of the individual component of CV death, FORXIGA vs placebo (3.0% vs 3.7%; HR 0.81; 95% CI, 0.58, 1.12)1 ©AstraZeneca 2022. All Rights Reserved.

ABRIDGED PRESCRIBING INFORMATION

FORXIGA (dapagliflozin) 5MG & 10MG FILM-COATED TABLETS. ®

Consult Summary of Product Characteristics (SmPC) before prescribing.

Indications: Adults and children aged 10 years and above: Type 2 diabetes mellitus: For the treatment of insufficiently controlled type 2 diabetes mellitus as an adjunct to diet and exercise, as monotherapy when metformin is considered inappropriate due to intolerance, or in addition to other medicinal products for the treatment of type 2 diabetes.

Adults: Heart Failure: Indicated in adults for the treatment of symptomatic chronic heart failure with reduced ejection fraction. Chronic kidney disease: Indicated in adults for the treatment of chronic kidney disease.

Presentation: Film-coated tablets. 5mg or 10mg of dapagliflozin (as propanediol monohydrate). Each 5mg tablet contains 25mg of lactose. Each 10mg tablet contains 50mg of lactose.

Dosage and Administration: Adults: Type 2 diabetes mellitus: The recommended dose is 10mg once daily. Consider a lower dose of insulin or insulin secretagogue such as a sulphonylurea when used in combination with dapagliflozin to reduce the risk of hypoglycaemia. Children and adolescents: No dose adjustment in children aged 10 years and above. No safety and efficacy data available for children below 10 years of age. Heart Failure: The recommended dose is 10mg once daily. Chronic kidney disease: The recommended dose is 10 mg once daily. Children and adolescents: <18 years: Safety and efficacy not yet established. Elderly: ≥65 years: No dose adjustment is recommended based on age. Renal impairment: No dose adjustment is required based on renal function. Due to limited experience, it is not recommended to initiate treatment with dapagliflozin in patients with GFR < 25 mL/min. If GFR falls below 45 mL/min, additional glucose lowering treatment should be considered in patients with diabetes mellitus if further glycaemic control is needed. Mild or moderate hepatic impairment: No dose adjustment. Severe hepatic impairment: Starting dose of 5mg is recommended, if well tolerated, dose may be increased to 10mg. Method of administration: Forxiga can be taken orally at any time of day with or without food.

Tablets should be swallowed whole.

Contraindications: Hypersensitivity to dapagliflozin, or excipients.

Warnings and Precautions: Renal impairment: Due to limited experience, it is not recommended to initiate treatment with dapagliflozin in patients with GFR < 25 mL/min. The glucose lowering efficacy of dapagliflozin is dependent on renal function, and is reduced in patients with GFR < 45 mL/min and is likely absent in patients with severe renal impairment.

Hepatic impairment: Exposure is increased in patients with severe hepatic impairment. Use in patients at risk of volume depletion and/or hypotension: Dapagliflozin increases diuresis which may lead to a modest decrease in blood pressure, it may be more pronounced in patients with very high blood glucose concentrations. Exercise caution in patients for whom a dapagliflozin induced drop in blood pressure could pose a risk, such as patients on anti hypertensive therapy with a history of hypotension or elderly patients. Careful monitoring of volume status and electrolytes is recommended in conditions leading to volume depletion, such as acute gastrointestinal illness. In volume depleted patients temporary interruption Veeva ID: IE-3514 Date of Prep: February 2022

of dapagliflozin is recommended until volume depletion is corrected. Diabetic ketoacidosis (DKA): Rare cases of DKA, including life-threatening and fatal cases, have been reported in patients treated with SGLT2 inhibitors, including dapagliflozin. In a number of cases, the presentation of the condition was atypical with only moderately increased blood glucose values, below 14mmol/L (250mg/dL). The risk of DKA must be considered in the event of non-specific symptoms such as nausea, vomiting, anorexia, abdominal pain, excessive thirst, difficulty breathing, confusion, unusual fatigue or sleepiness.

Patients should be assessed for ketoacidosis immediately if these symptoms occur, regardless of blood glucose level. In patients where DKA is suspected or diagnosed, dapagliflozin treatment should be stopped immediately. Treatment should be interrupted in patients who are hospitalised for major surgical procedures or acute serious medical illnesses.

Monitoring of ketones is recommended in these patients.

Measurement of blood ketone levels is preferred to urine.

Treatment with dapagliflozin may be restarted when the ketone values are normal and the patient’s condition has stabilised.

Before initiating dapagliflozin, factors in patient history that may predispose to ketoacidosis should be considered. Patients who may be at higher risk of DKA include patients with a low beta cell function reserve (e.g. patients with low C peptide or latent autoimmune diabetes in adults (LADA) or patients with a history of pancreatitis), patients with conditions that lead to restricted food intake or severe dehydration, patients for whom insulin doses are reduced and patients with increased insulin requirements due to acute medical illness, surgery or alcohol abuse. SGLT2 inhibitors should be used with caution in these patients. Restarting SGLT2 inhibitor treatment in patients experiencing a DKA while on SGLT2 inhibitor treatment is not recommended, unless another clear precipitating factor is identified and resolved. Dapagliflozin should not be used for treatment of patients with type 1 diabetes. Necrotising fasciitis of the perineum (Fournier’s gangrene): Postmarketing cases have been reported in female and male patients taking SGLT2 inhibitors. Urgent surgical intervention and antibiotic treatment is required. Advise patients to seek medical attention if they experience a combination of pain, tenderness, erythema, or swelling in the genital or perineal area, with fever or malaise.

Either uro-genital infection or perineal abscess may precede necrotising fasciitis. If suspected, discontinue Forxiga and institute prompt treatment (including antibiotics and surgical debridement). Urinary tract infections: Temporary interruption of dapagliflozin should be considered when treating pyelonephritis or urosepsis. Elderly (≥65 years): Elderly patients are more likely to have impaired renal function, be treated with medicines such as anti-hypertensives or diuretics, and be at a greater risk of volume depletion. Cardiac failure: Experience with dapagliflozin in NYHA class IV is limited. Chronic kidney disease: There is no experience with dapagliflozin for the treatment of chronic kidney disease in patients without diabetes who do not have albuminuria. Patients with albuminuria may benefit more from treatment with dapagliflozin. Lower limb amputations: Counsel patients with diabetes on routine preventative foot care as an increase in cases of lower limb amputation (primarily of the toe) has been observed in long term, clinical studies in type 2 diabetes mellitus with SGLT2 inhibitors. Urine laboratory assessments: Patients will test positive for glucose in the urine due to mechanism of action.

Lactose: Patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take Forxiga.

Drug Interactions: Diuretics: Dapagliflozin may add to the diuretic effect of thiazide and loop diuretics and may increase the risk of dehydration and hypotension. Insulin and insulin secretagogues: Consider a lower dose of insulin or insulin secretagogue when used in combination with dapagliflozin to reduce the risk of hypoglycaemia. Interference with 1,5 AG assay: Monitoring glycaemic control with 1,5-AG assay is not recommended as measurements of 1,5 AG are unreliable in assessing glycaemic control in patients taking SGLT2 inhibitors.

Alternative methods should be used.

Pregnancy and Lactation: Not recommended during the second and third trimesters of pregnancy. Treatment should be discontinued when pregnancy is detected. Do not use whilst breast-feeding.

Ability to Drive and Use Machines: Alert patients on the risk of hypoglycaemia when dapagliflozin is used in combination with a sulphonylurea or insulin.

Undesirable Events: Consult SmPC for full list of side effects.

Very common (≥1/10): Hypoglycaemia (when used with SU or insulin). Common (≥1/100 to <1/10): Vulvovaginitis, balanitis and related genital infections, urinary tract infection, dizziness, rash, back pain, dysuria, polyuria, haematocrit increased, creatinine renal clearance decreased during initial treatment, dyslipidaemia. Uncommon (≥1/1,000 to < 1/100): Fungal infection, volume depletion, thirst, constipation, dry mouth, nocturia, vulvovaginal pruritus, pruritus genital, blood creatinine increased during initial treatment, blood urea increased, weight decreased. Rare (≥ 1/10,000 to < 1/1,000): Diabetic ketoacidosis (when used in type 2 diabetes mellitus).

Very Rare (< 1/10,000): Angioedema, necrotising fasciitis of the perineum (Fournier’s gangrene).

Legal Category: Product subject to prescription which may be renewed (B).

Marketing Authorisation Number: EU/1/12/795/002; EU/1/12/795/007.

Marketing Authorisation Holder: AstraZeneca AB, SE-151 85 Södertälje, Sweden.

Further product information available on request from: AstraZeneca Pharmaceuticals (Ireland) DAC, Block B, Liffey Valley Office Campus, Dublin 22. Tel: +353 1 609 71 00.

FORXIGA is a trademark of the AstraZeneca group of companies.

Date of API preparation: 11/2021 Veeva ID: IE-3322

Adverse events should be reported directly to: HPRA Pharmacovigilance, Website: www.hpra.ie Adverse events should also be reported to AstraZeneca Patient Safety on Freephone 1800 800 899 References: 1. Heerspink HJL et al. N Engl J Med. 2020;383(15):1436–1446.

2. FORXIGA 10 mg film-coated tablets. Summary of product characteristics. November 2021.

CKD = chronic kidney disease; CV = cardiovascular; DAPACKD = Dapagliflozin And Prevention of Adverse outcomes in Chronic Kidney Disease; ESKD = end-stage kidney disease; hHF = hospitalisation for heart failure; HR = hazard ratio.

20 Chronic Pain use of combination prophylactic antibiotic therapy at implantation has also reduced infection rates. Other technological improvements apart from the programming include superior anchors for stabilizing the leads, reducing the chances of lead migration, which was a significant problem in the past, and much smaller rechargeable IPG’s. The historical larger IPG’s could cause significant problems in terms of pouch pain whereby the patient found the IPG implantation site to be problematically painful. The situation could arise whereby the chronic neuropathic pain complaint had improved however the patient was now experiencing a surgical issue which was pouch pain. This was very unsatisfactory for both the clinician and patient.

The smaller modern IPG’s have significantly reduced this complication. Furthermore, the modern IPG’s can last from 8 to 10 years depending upon usage.

This has significantly prolonged the lifespan of the IPG. This again is a significant cost saving in terms of reducing the number of visits to theatre in the patient’s lifetime and the number of IPG’s required in a patient’s lifetime.

Spinal cord stimulation has developed into a much more effective, affordable and userfriendly therapy. Traditionally funding bodies expressed serious concerns about the cost of this therapy for one patient who had a disease that was not seen as life-threatening. The new developments in terms of removal of the mandate to trial, the smaller IPG with a much longer lifespan requiring fewer replacements and reduction in complication rates make spinal-cord stimulation more affordable. The advent of new programming paradigms has made the system more effective.

Therefore, the future for spinal cord stimulation is bright.

News IMO issues ‘Overcrowding’ Warning

The Irish Medical Organisation (IMO) has warned the Oireachtas Committee on Health that the scale of hospital overcrowding in Ireland represents a persistent and grave danger to patients which cannot be ignored.

Representing the IMO, Dr Mick Molloy, Emergency Department (ED) Consultant and member of the IMO Consultant Committee told the Committee that our record hospital waiting lists are the direct results of the failure by successive governments to invest in bed capacity, infrastructure and the medical workforce to meet the needs of a growing and ageing population.

The IMO believes that without concerted and sustained investment across our health

Dr Mick Molloy, Emergency Department (ED) Consultant

Doctors (NCHDs) to fill service requirements while working unsafe and illegal hours.

system the overcrowding problem will never be adequately addressed and patients will continue to be in “grave danger.”

“Patients’ lives are at risk, and we can no longer accept the status quo. Emergency Department overcrowding is associated with increased mortality (within 30 days) and poorer outcomes for patients, while it also impacts on staff with doctors across the health service experiencing high levels of stress and burnout.”

Dr Molloy said, “When the present Taoiseach was Minister for Health over 20 years ago the bed capacity need was identified at 5,000 more beds. Since that time there has been little positive growth in capacity yet our population has grown by more than a million people and we are now at a point of frightening waiting lists, inability to deliver timely care and too few doctors in the system. This represents a real and grave threat to patients.”

The IMO warned that not only does Ireland compare extremely poorly to our international counterparts with regard to beds per population and bed occupancy rates, but this is exacerbated by the crisis in our medical workforce. 20% of consultant posts across the country are unfilled, and we continue to rely on Non-Consultant Hospital

APRIL 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

Dr Molloy also told the Committee that Covid-19 is not an excuse for the overcrowding crisis and says that urgent and simultaneous investment is needed in the following areas: 1. Urgent investment in acute bed capacity and infrastructure including: • Immediate investment in temporary modular builds • Develop finance and implement a multi-annual capital investment programme in acute bed capacity to include: • 5,000 additional public acute beds; • investment in stand-alone public hospitals for elective care and • increase critical care capacity to 550 critical care beds;

2. Immediate action taken to recruit and retain doctors to work in the health service, including targeted measures to address our unprecedented number of Consultant vacancies including ; • Immediate reversal of the unequal two-tier pay system for consultants and the negotiation of a new fit for purpose contract to attract consultants to a career in the HSE • Increase the number of specialist training posts to meet future medical workforce requirements – a 38% increase in training posts is required to meet future medical workforce requirements but there is no plan to implement this.

3. Ongoing investment in the health and social care needs of older people.

4. Continued investment in the development of General Practice including: • Supports for new and established to employ additional GPs, practice nurses and other support staff; • Investment in a programme of GP care for nursing home patients that reflects the complexity of care required.

News 21

A First for Blackrock Clinic New technology offers significant potential benefits to patients undergoing catheter ablation for atrial fibrillation The Blackrock Clinic has become the first hospital in Ireland to use a novel ultra-cold curvilinear catheter ablation system to treat patients with atrial fibrillation.

element. The configuration and orientation of the curvilinear element in the heart is controlled by an exchangeable stylet and a deflectable sheath.

Atrial fibrillation, or AF, is an irregular and often rapid heart rhythm, and it is the most common sustained cardiac arrhythmia with a growing prevalence.

Professor David Keane, director of the cardiac electrophysiology service at the Blackrock Clinic, said that the advantages of the novel system include the efficiency of the ultra-cold ablation system, the flexibility and subsequent conformability of the curvilinear ablation element to adopt to the patient’s atrial anatomy, as well as the incorporation of a warming balloon to protect the oesophagus.

When undetected and untreated, AF in some patients can lead to potential complications including stroke or heart failure.

Furthermore, AF is associated with a small reduction in longevity and an associated increased incidence of dementia.

A key component of catheter ablation of AF is electrical isolation of the pulmonary veins from the left atrium.

Conventional catheter ablation of AF is achieved by thermal (radiofrequency) or cryothermal energy. Cryo-balloons have been used for many years, and can achieve low temperatures in the heart muscle and isolate the pulmonary veins.

Recently, a novel technology has been developed to achieve much lower temperatures (well below minus 120°C) in the targeted heart muscle to achieve pulmonary vein isolation.

This novel technology (iCLAS Adagio, CA, USA) uses nitrogen near its liquid-vapour critical point as a freezing source delivered through a curvilinear ablation

Catheter ablation of atrial fibrillation works best in patients with early disease and is more effective in patients with paroxysmal AF and is considerably less effective in patients with long-standing persistent AF. A sub-analysis of the largest randomised trial of AF ablation indicated no prognostic benefit of AF ablation in patients over 75 years of age and in this older cohort the only indication for ablation would be for the relief of symptoms not relieved by medication.

In contrast, for selected patients under 75 years of age AF ablation can be associated with a significant improvement in outcome over a five year followup period.

Prior to consideration of ablation, patients with AF need to be

assessed for anticoagulation and control of risk factors contributing to AF including smoking cessation, weight management, exercise, alcohol consumption and blood pressure management.

Professor Keane and the team at Blackrock Clinic carried out the first procedure using iCLAS in February, and the hospital’s CEO James O’Donoghue said that this demonstrated Blackrock’s ongoing commitment to making industry-leading technology available to Irish patients at the earliest opportunity.

“With all the indicators suggesting that the number of people who develop AF will increase significantly in coming years, Irish patients need to know that the best possible care is available to them.

“Once again, Blackrock Clinic is proud to be the first Irish hospital to make this available and our talented and dedicated staff will continue to provide world-class cardiology care and treatment long into the future,” O’Donoghue said.

“This novel technology comes at an exciting time for cardiac electrophysiology (EP), with the further development of new technology such as pulse field ablation (PFA) which is also due to start in Blackrock Clinic this year. To support these new technologies, the hospital is currently building a third dedicated EP cath lab which will be in operation by November of this year.”

Illegal Medicines at ‘All Time High’ The Health Products Regulatory Authority (HPRA) has stated that the volume of detained illegal medicines in 2021 remained at a near record high, with its enforcement section detaining 1,604,589 million dosage units of falsified and other illegal products in 2021.

most significant categories of illegal products detained included sedatives (46%), anabolic steroids (13%), analgesics (10%) and erectile dysfunction medicines (6%). The breakdown is:

• 56,385 units of Covid-19 medicines were detained, including 28,302 units of Ivermectin

• Sedative medicines – 741,492 units detained (583,805 units detained in 2020)

• 461 websites, e-commerce listings and/or social media pages amended or shutdown

The HPRA states that the online supply of prescription products into and within Ireland is illegal and stresses that consumers can have no guarantee of the safety or quality of medicines they are seeking to buy outside of the regulated pharmacy supply chain.

• Anabolic steroids – 204,843 units detained (101,683 units detained in 2020)

• 5 prosecution cases initiated, and seven voluntary formal cautions issued

• Analgesic medicines – 161,670 units detained (145,921 units detained in 2020)

According to Grainne Power, Director of Compliance with the HPRA, the high number of illicit medicines detected in 2021 is very concerning and when combined with the 2020 figures means

In the 12 months of 2021, the

• Erectile dysfunction – 103,816 units were detained (484,846 in 2020 which

included one detention of over 370,000 tablets)

that over 3.2 million units were detained over a two-year period.

“The HPRA has over many years identified that a significant proportion of detained products are falsely labelled, do not contain accurate information on the strength of active ingredient they contain, or have been found to contain a different ingredient altogether. When you consider also that these products are often delivered without a leaflet, instructions for use or information on the correct dose, the illegal supply of unregulated and potentially fake medicines clearly presents a significant risk to public health,” says Ms Power.

HOSPITALPROFESSIONALNEWS.IE | HPN • APRIL 2022

22 News

Raising Kidney Disease Awareness To mark World Kidney Day on Thursday 10 March clinical staff from the Portiuncula Kidney Clinic will hold an information awareness stand for patients in the outpatient department from 9am, from left: Grace Gannon, Advanced Nurse Practitioner Cardiology; Dr Paul O’Hara, Consultant General Physician and Nephrologist and Hilda Clarke, Clinical Nurse Specialist Diabetes

World Kidney Day took place recently, Thursday 10 March marks a global campaign aimed at raising awareness of the importance of our kidneys and encourages everyone worldwide to be aware of the disease and actively know what their own kidney health measures are.

Chronic Kidney Disease (CKD) is a common disease with an estimated one in 10 adults worldwide having the disease. In addition, kidney disease related mortality continues to increase yearly and is projected

to be the 5th leading cause of death by 2040.

Dr Paul O’Hara, Consultant General Physician and Nephrologist in Portiuncula University Hospital (PUH) explains, “The main job of your kidneys is to remove toxins and excess water and salts from your blood. Kidneys also help to control your blood pressure, produce red blood cells and keep your bones healthy. Diabetes, obesity and high blood pressure are key risk factors for Chronic Kidney Disease.

“Education is a key part of managing any chronic illness and kidney disease is no different.

World Kidney Day allows us to highlight the importance of screening for CKD in high risk groups, including all patients with diabetes, obesity (Body Mass Index >30) and hypertension. I encourage everyone to protect their kidneys by stopping smoking, eating a healthy diet low in salt, exercising daily, having regular health checks for diabetes and high blood pressure and avoiding

prolonged use of anti-inflammatory pain killers. In those with advanced kidney failure and who are suitable, transplantation remains the best treatment option. The act of organ donation is a life-saving event and everyone is encouraged to carry an organ donor card and discuss their wishes with their loved ones.

“I started the Portiuncula Kidney Clinic in December 2021 to serve the needs of patients with kidney problems within the hospital catchment area, mainly East Galway and Roscommon and we deal with the entire spectrum of kidney conditions with referrals from both the hospital and GPs. Patients with kidney transplants and those who are on haemodialysis are cared for in the main centre in Galway University Hospitals.”

Clinical staff from the Portiuncula Kidney Clinic recently held an information awareness stand for patients in the outpatient department. Advanced nurse practitioners from the Cardiology and Diabetes clinics were also available to raise awareness of high blood pressure, obesity and diabetes as the leading causes of kidney disease in Ireland.

New Opportunity to Access International Cancer Trials Roche Products (Ireland) Ltd. and Cancer Trials Ireland have announced a new partnership to deliver the first nationally accessible educational Molecular Tumour Board (MTB) in Ireland, following a successful pilot programme.

The MTB is aimed at improving patients’ lives by identifying the most appropriate treatment options for oncology patients, including innovative new cancer trials both here in Ireland and internationally.

This educational MTB aims to support treatment teams by providing insights through multidisciplinary discussions on the genomic findings, their clinical implications, and potential treatment options.

The new partnership between Roche Ireland and Cancer Trials Ireland follows a successful pilot programme, which was rolled out between November 2020 and December 2021. During that time, sixteen institutions participated in discussing more than 30 patient cases, all with complex genomics or novel biomarkers identified via multigene sequencing reports.

Of the cases discussed, 80%

Verena Murphy, CTI and Deirdre Poretti, Roche Ireland

of presenters confirmed that the MTB discussions helped to confirm, modify or change the treatment plan for at least one of their patients.

Speaking about the plans for the next phase of the MTB, Dr. Verena Murphy, Head of Research & Business Development with Cancer Trials Ireland, said, “We are excited to take over the management of the Molecular Tumour Board, and we will make this valuable, innovative resource available to the entire Cancer Trials Ireland network. We are planning to collect gained insights to build a national knowledge platform for personalised treatment, which will be of enormous benefit for cancer patients.”

Precision oncology holds the promise of improved efficiency,

APRIL 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

better care and the reduction of ineffective treatments and costs.

Speaking about the first nationally accessible Molecular Tumour Board in Ireland, Dr. Brian Bird, Consultant Medical Oncologist at the Bon Secours Hospital Cork, commented, “The MTB helps me confidently choose the best targeted therapies for my lung cancer patients based on modern Next Generation Sequencing

of blood and tissue and deal with unexpected findings like hereditary cancer syndromes in pancreatic cancer. I’ve also learnt the value of testing for the same target using different methods to get a full understanding of how to help the patient.”

For more information about Cancer Trials Ireland, visit: https://www.cancertrials.ie/

24 Epilepsy

Caring for Women with Epilepsy in Pharmacy Written by Dr Nicola Maher, Consultant Obstetrician and Gynaecologist, Rotunda Hospital, Dublin

led to many women choosing to stop medications without advice from their doctor or pharmacist.

Dr Nicola Maher has a special interest in medical conditions in pregnancy and in particular epilepsy. Together with Sinead Murphy Advanced Nurse Practitioner in Epilepsy they run a dedicated antenatal service for women with epilepsy. Patients are seen throughout their pregnancy and preconceptual counselling is also provided. Dr Maher also is a member of the Irish Medicines in Pregnancy Service (IMPS), a multidisciplinary service based at the Rotunda Hospital which provides information and expertise to support safe and effective use of medicines before, during and after pregnancy.

In Ireland approximately 25% (10000) of all people diagnosed with epilepsy are women of childbearing potential. Pharmacists are among the most trusted professions by society and are ideally placed to support and advise women who maybe planning a pregnancy or indeed are pregnant. Whether at the point of collecting prescribed regular anti-seizure medication or indeed at initiation or ceasing of contraception, opportunities exist for pharmacists to discuss pregnancy in women with epilepsy.

Fortunately most women with epilepsy remain well during their pregnancy. However, up to 30% of women with epilepsy will notice a worsening of seizure control in pregnancy which can place mothers and their unborn babies at risk during the pregnancy. Some of the most commonly prescribed anti-seizure medications enjoy excellent safety profiles. None the less pregnant women often have significant anxiety around taking medication. The legacy of Valproate and the general cautions and warnings that surround medication use in pregnancy have

Poorly controlled epilepsy is not without serious risk to pregnant women. While these are rare, many are often preventable. Maternal mortality reports across the UK and Ireland frequently refer to maternal deaths where patients had stopped their medication due to pregnancy. Ensuring patients are fully informed of the often reassuring safety profile of their medication and providing them with accurate, up to date information are key to caring for women with epilepsy. Patients with epilepsy should be advised not to stop taking their anti-seizure medication without first speaking to their doctor.

Pre Pregnancy All women planning a pregnancy should be offered preconceptual counselling with their neurology service and an obstetrician. This affords the opportunity to review medications and assess seizure history as well as perform serum drug levels if needed. Women with epilepsy of childbearing potential should be prescribed Folic Acid 5mg daily to reduce the incidence of neural tube defects which can be higher with some anti-seizure medications.

Contraception choice in women with epilepsy depends on their antiseizure medication. Carbamazepine for example a cytochrome enzyme inducer can lead to reduced efficacy of the combined oral contraception. Lamotrigine levels can be affected by the combined oral contraceptive pill and can lead to toxicity side effects on the pill free interval. The FSRH have excellent guidance on contraceptive use for women taking anti-seizure medication.

Nausea and Vomiting in Pregnant Women with Epilepsy Many women experience infrequent nausea and vomiting in pregnancy and this can place women at epilepsy at risk of seizures due to lost medication

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doses. As a general rule, if a woman vomits within one hour of taking her anti-seizure medications a second dose can be taken. If persistent vomiting is a problem, women should see their GP or visit their obstetric caregiver.

Effective antiemetics are essential in managing hyperemesis in pregnancy which can affect up to 3% of all pregnant women.

woman prescribed Valproate does not stop taking it without consulting their doctor. Should a woman who is taking valproate become pregnant an urgent review with a neurologist should be arranged.

Anti-Seizure Medications Safety Profiles

There is not enough data to confirm or rule out any additional risks in pregnancy in women taking the above medication.

These are second line agents often used where other treatments have been unsuccessful in controlling seizures. Studies are ongoing to evaluate their safety profile in pregnancy. The absence of this data does not equate to known harm for the fetus and again women should be advised not to stop their medication without consulting with their doctor.

LAMOTRIGINE AND LEVETIRACETAM are amongst the most commonly prescribed antiseizure medications in use today and pose no additional risks to the fetus in pregnancy. The background rate of all congenital anomalies (babies born with structural birth defects) in pregnancy is approximately 2% and neither of these drugs affect this rate. Patients taking these medications should be reassured that they are safe to take in pregnancy and that they should be encouraged to continue to take their medications to reduce seizure risks. Studies in relation to risk of developmental delay are also reassuring.

CARBAMAZEPINE, TOPIRAMATE and PHENYTOIN Carbamazepine is a very effective anti-seizure medication. Many women who take carbamazepine have very well controlled epilepsy for years. Carbamazepine confers a small additional risk to the fetus in pregnancy. The congenital anomaly rate associated with Carbamazepine use in pregnancy is 4-5%. Similarly Topiramate which is less commonly prescribed for epilepsy confers a risk of approximately 6% of congenital abnormality. Women being prescribed these medications would especially benefit from preconceptual consultations with their neurologist and obstetrician. Individualised risk benefit discussions can be made to discuss medication best suited to the woman to optimise seizure control, while minimising risks of congenital anomaly. Phenytoin, less commonly prescribed is associated with a 6% risk of congenital anomaly. Studies in relation to developmental delay with these medication are contradictory and a risk cannot be excluded.

SODIUM VALPROATE. A pregnancy prevention programme is in existence in Ireland since 2018 for Valproate containing medications. Children exposed in utero have up to 40% risk of serious developmental disorders in addition to 10% risk of congenital abnormality. It is important that any

Lacosamide, Brivaracetam, eslicarbamazepine, clozapam, zonisamide, gabapentin and pregabalin.

Serum Drug Levels what role do they play?

Physiologic and pharmacokinetics changes in pregnancy (e.g. increased volume of distribution, changes to renal elimination, altered hepatic enzymes) may alter serum plasma levels of antiseizure medication in pregnancy.

Lamotrigine and Levetiracetam are particularly susceptible to variation in serum plasma level, especially in the third trimester and regularly require increased dosages in latter stages of pregnancy.

Ideally a pre-pregnancy serum level at a time of good seizure control or an early pregnancy level is taken in order to have a target pregnancy level. Levels are then repeated each trimester to maintain target levels. Often patients will remain on a higher dose for the initial two weeks postpartum due to the increased fatigue related seizure risk at this time. Any postpartum dose changes should be made following consultation with their neurology team. It should be noted that the use of drug levels varies in clinical practice and some studies do not support routine use. Should a pregnant woman experience a seizure a drug level is always taken and doses often increased prior to the result being available.

Thankfully pregnancy for most women with epilepsy remains uncomplicated and they are not at increased risk of any obstetric complications of pregnancy.

Maintaining seizure control while providing up to date information on medication safety profiles are key to the care of women with epilepsy in pregnancy.

Launching Noradrenaline 1mg/ml concentrate for solution for infusion.

Your patients, your profession, our passion.

ABBREVIATED PRESCRIBING INFORMATION: Consult the Summary of Product Characteristics for further information. Additional information is available upon request. Noradrenaline (Norepinephrine) Kabi 1mg/ml concentrate for solution for infusion. Active ingredient: 1ml concentrate for solution for infusion contains 1mg noradrenaline (norepinephrine) base equivalent to 2mg noradrenaline (norepinephrine) tartrate. Contains 3.4mg sodium per ml. Indications: In adults for use as an emergency measure in the restoration of blood pressure in cases of acute hypotension. Posology and method of administration: When diluted as recommended, each litre contains 40mg noradrenaline base equivalent to 80mg noradrenaline tartrate. If dilutions other than 40mg per litre are used, check infusion rate calculation carefully before starting treatment. Initial rate of infusion – 10-20ml/hour (0.16-0.32ml/min); equivalent to 0.4-0.8mg/hour noradrenaline base. Lower initial infusion rate of 5ml/hour (0.08ml/min); equivalent to 0.2mg/hour noradrenaline base may be preferred. Titration of dose – Once infusion has been established, titrate dose in steps of 0.05-0.1mcg/kg/min of noradrenaline base according to pressor effect observed (see SmPC for details). Continue infusion until adequate blood pressure and tissue perfusion maintained without therapy. Carefully monitor patient. Should only be administered by healthcare professionals familiar with use of noradrenaline and with appropriate monitoring facilities.

Avoid abrupt infusion withdrawal; reduce infusion gradually. No experience in treatment of hepatic or renal impairment. Dose selection for an elderly patient should be cautious, starting at the low end of the dosing range. Safety and efficacy in patients less than 18 years old has not been established. Method of administration – Intravenous use only after dilution. Infuse at a controlled rate using either syringe pump, infusion pump or drip counter. Administer via a central venous catheter. If not using a central venous catheter administer into a large vein whenever possible, particularly an antecubital vein to minimize risk of ischemic necrosis.

Avoid catheter tie-in technique if possible. Contraindications: Hypersensitivity to the active substance or to any of the excipients, hypotension due to blood volume deficit. Do not use with cyclopropane and halothane anaesthetics as this may cause serious cardiac arrhythmias including ventricular fibrillation. Special warnings and precautions for use: Do not use undiluted. Contraindicated in patients who are hypotensive from blood volume deficits except as an emergency measure to maintain coronary and cerebral artery perfusion until blood volume replacement therapy can be completed. Should only be used in conjunction with appropriate blood volume replacement. If whole blood or blood plasma is indicated to increase blood volume, administer separately (e.g. use Y-tubing, individual containers). Prolonged administration may result in plasma volume depletion which should be continuously corrected by appropriate fluid and electrolyte replacement therapy.

Frequently check blood pressure and rate of flow to avoid hypertension. Particular caution in patients with coronary, mesenteric or peripheral vascular thrombosis, hypotension following myocardial infarction, angina (particularly Prinzmetal’s variant angina), diabetes, hypertension or hyperthyroidism, major left ventricular dysfunction associated with acute hypotension (supportive therapy should be initiated simultaneously with diagnostic evaluation; reserve noradrenaline for patients with cardiogenic shock and refractory hypotension, in particular those without elevated systemic vascular resistance), liver failure, severe renal dysfunction,

Fresenius Kabi Limited Fresenius Kabi Ireland Unit 3B Fingal Bay Balbriggan, Co. Dublin Ireland

ischemic heart diseases and elevated intracranial pressure. Reduce dose if heart rhythm disorders occur during treatment. Cardiac arrhythmias may arise when used in conjunction with cardiac sensitizing agents and may be more likely in patients with hypoxia or hypercarbia. Elderly patients may be especially sensitive to the effects of noradrenaline. Not recommended in children. Where indicated, appropriate replacement therapy of blood or fluid together with adoption of the supine position with elevation of the legs, must be instituted and maintained prior to and/or during therapy with noradrenaline. During infusion, record blood pressure every two minutes from the time the administration started until the desired blood pressure is obtained and then every five minutes thereafter if infusion continued. Constantly watch flow rate and never leave patient unattended.

Hypertension may eventually lead to acute pulmonary oedema, arrhythmia or cardiac arrest. Caution in patients receiving pressor amines with chloroform, enflurane or other halogenated anaesthetics (may cause serious cardiac arrhythmias) or any other cardiac sensitising agent or in patients who exhibit profound hypoxia or hypercarbia. Extreme caution in patients receiving monoamine oxidase inhibitors or within 14 days of cessation of such therapy and in patients receiving tricyclic antidepressants, adrenergic- serotoninergic drugs or linezolid. Overdoses or conventional doses in hypersensitive persons may cause severe hypertension with violent headache, photophobia, stabbing retrosternal pain, pallor, intense sweating and vomiting. The infusion site should be checked frequently for free flow. Care should be taken to avoid extravasation of noradrenaline tartrate into the tissues, as local necrosis might ensue due to the vasoconstrictive action of the drug (see SmPC for antidote for extravasation ischaemia). Blanching along the course of the infused vein warrants consideration of changing infusion site at intervals. Avoid administration via the veins of the leg in elderly patients or in those suffering from occlusive vascular diseases. Noradrenaline interacts with other medicinal products; some combinations are inadvisable or require additional precautions and close medical supervision – see SmPC. Undesirable effects: Anxiety, insomnia, confusion, weakness, psychotic state, transient headache, tremor, acute glaucoma, bradycardia, arrhythmia, electrocardiogram change, tachycardia, cardiogenic shock, stress cardiomyopathy, palpitations, increase in the contractility of the cardiac muscle resulting from the beta- adrenergic effect on the heart (inotrope and chronotrope), acute cardiac insufficiency, hypertension, peripheral ischaemia including gangrene of the extremities, plasma volume depletion with prolonged use, dyspnoea, respiratory insufficiency or difficulty, nausea, vomiting, paleness, scarification of the skin, bluish skin colour, hot flushes or skin redness, skin rash, hives or itching, retention of urine, extravasation, necrosis at injection site. Legal Category: POM Marketing Authorisation Number: PA2059/073/001 Marketing Authorisation Holder: Fresenius Kabi Deutschland GmbH; Else-Kröner Straße 1, 61352 Bad Homburg v.d.Höhe, Germany Further Information: See the SmPC for further details. Adverse events should be reported. Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2, Tel: +353 1 6764971, Fax: +353 1 6762517. Website: www.hpra.ie, E-mail: medsafety@hpra.ie. Adverse events should also be reported to Fresenius Kabi Limited via email Pharmacovigilance.GB@Fresenius-Kabi.com. Date of Preparation: January 2022 FPI-0041

Website: www.fresenius-kabi.com/ie/ Email: FK-enquiries.ireland@fresenius-kabi.com Phone: +353 (0)1 841 3030

Date of Prep: March 2022 Job Code: IE-IVF-2200006

26 Allergies/Asthma

Asthma and Allergic Rhinitis Written by Ruth Morrow, Respiratory Nurse Specialist, Asthma Society of Ireland the “asthmatic response”. With the increase in secretions, plugging of the smaller airways result. Asthma is a condition where not only bronchospasm occurs but muscle constriction, mucosal swelling, and an increase in secretions in the lumen in the airways (Figure 1).

Allergic Rhinitis Asthma is characterized by variable respiratory symptoms such as wheeze, shortness of breath, chest tightness and cough, and variable expiratory airflow limitation. It is usually associated with airway inflammation (GINA, 2021).

The exact cause of asthma remains unknown. Numerous triggers can cause symptoms, and these differ from person to person. As spring and summer emerges, this can be a challenging time as various pollen levels start to increase.

The clinical features of asthma (wheeze, cough, shortness of breath and chest tightness) result from changes in the airways as a result of abnormal sensitivity called bronchial hyper-reactivity.

The muscle of the bronchial walls becomes hypertrophied causing occlusion of the airway resulting in constriction of the muscle causing bronchospasm. Secondly, in the mucosal, submucosa and smooth muscle layers of the bronchi and bronchioles, inflammatory cells infiltrate. Eosinophils, neutrophils, macrophages, mast cells and plasma cells are found in varying numbers. All these cells contain chemical mediators that produce

Persistance Symptoms

 < 4 days per week

 > 4 days per week

 or < 4 weeks at a time

 ≥ 4 weeks at a time

Mild

It is estimated that over 80% of people with asthma have allergic rhinitis (AR). AR is also a risk factor for asthma. 10-40% of people who have AR also have asthma. AR is more likely to develop initially with asthma developing later.

Therefore, people with AR should be assessed for asthma due to the increased risk of developing asthma. Similarly, patients with persistent asthma should be assessed for AR.

 Normal sleep  Normal daily activities  Normal work and school  No troublesome symptoms

Moderate to severe (One or more items)  Abnormal sleep  Impairment of daily activities, sport and leisure  Difficulties caused at school or work  Troublesome symptoms Figure 2: Classification of allergic rhinitis (ARIA, 2019)

Symptoms of Allergic Rhinitis Typical symptoms of seasonal (Hayfever) and perennial allergic rhinitis are  Sneezing  Itchy, blocked, or runny nose  Red, itchy, or watery eyes  Itchy throat, inner ear, or mouth  Postnasal drip (a drip of mucus from the back of the nose into the throat)  Headaches  Loss of concentration and generally feeling unwell  Reduced sensation of taste and smell

Figure 1: Pathology of asthma

Air trapped in alveoli Relaxed smooth muscles

Normal airway

Intermittent Symptoms

Wall inflamed and thicken Asthmatic airway Asthmatic airway during attack

APRIL 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

Tightened smooth muscles

Patients may experience all or some of the above. Symptoms may be confused with symptoms of COVID19.

at a low pressure whereas saline spray is a low volume delivered at high pressure. The advantages of saline douching include:

The term “united airway disease” or “one airway disease” is opportune, as both rhinitis and asthma are chronic inflammatory diseases affecting both the upper and lower airways. Both conditions can be triggered by allergic or non-allergic triggers and present several phenotypes. Assessment and management of allergic rhinitis and asthma should be jointly carried out, leading to better control of both conditions.

 Direct cleansing

Classification In 2019, the classification of “seasonal” and “perennial” rhinitis was changed to “intermittent” and “perennial” rhinitis (ARIA, 2019).

Intermittent rhinitis occurs less than 4 days per week or for less than 4 weeks. Persistent rhinitis lasts more than 4 days and longer than 4 weeks. Both intermittent and persistent AR can be mild or moderate/severe (see Figure 2).

Pharmacological interventions ARIA 2019 There are several treatment options available to the patient and a combination of these options may be required for optimal relief of symptoms. These are outlined in Table 1. Saline douching/ nasal irrigation should also be encouraged and is available either as a saline rinse or saline spray.

Saline rinsing involves high volume

 Removal of mucous and inflammatory mediators  Reduces bacterial burden  Reduces mucus thickness  Improves mucocillary function by increasing ciliary beat frequency Smoking cessation should be encouraged at every opportunity.

Smoking increases the likelihood of chronic nasal symptoms and may be associated with the development of nasal polyposis.

Passive smoking, environmental exposure, e-cigarettes and vaping also increase the likelihood of chronic nasal symptoms and nasal polyposis.

Mild intermittent AR treatment options include oral and nasal decongestants which can be used as a rescue medication. These medications will reduce nasal congestion and should be used for no longer than 7 days and should be avoided in pregnancy and breastfeeding. Oral H1 antagonists block the physiological effects from mast cell-derived histamine.

2nd generation antihistamines are preferred due to their less sedating effect and are available over the counter. Antihistamines are also available intranasally or intraocular.

● ●

Reduces mucus thickness Improves mucocillary function by increasing ciliary beat frequency

Smoking cessation should be encouraged at every opportunity. Smoking increases the likelihood of chronic nasal symptoms and may be associated with the development of nasal polyposis. Passive smoking, environmental exposure, e-cigarettes and vaping also increase the likelihood of chronic nasal symptoms and nasal polyposis.

Drug therapy options Symptoms Oral H1 antagonists Sneezing, rhinorrhoea, nasal itch, eye symptoms Intranasal HI antagonist Sneezing, rhinorrhoea, nasal itch Intraocular HI antagonist Eye symptoms Intraocular cromones Eye symptoms Intranasal Decongestants Nasal blockage Oral Decongestants Nasal blockage Leukotriene Receptor Antagonists (LTRA) Rhinorrhoea, nasal blockage, eye symptoms Intranasal Corticosteroids (INCS) All symptoms Oral Corticosteroids All symptoms Immunotherapy All symptoms Table 1: Pharmacological options of allergic rhinitis Intranasal corticosteroid (INCS) eosinophils. The procedure directs asthma should be offered a Mild intermittent AR treatment options include oral and nasal decongestants which can be used as a is the 1st line treatment for plan. It should be reviewed a combination of UV-B. UV-A rescue medication.

These medications will reduce nasal congestion and should be used forand no longer than frequently, any time moderate/severe intermittent and and visible light into the nasal persistent AR. These medications are used once or twice daily to each nostril and good technique is essential and should be checked at every opportunity. If the nasal cavity is very obstructed, a nasal spray may not be effective. Nasal drops may be more effective in this scenario. Nasal spray and nasal drop technique can be viewed on https://www.asthma.ie/ about-asthma/resources/inhalertechnique-videos.

The efficacy of INCS is not improved when used with oral corticosteroids (OCS). Figure 4 provides a stepwise approach to the management of AR. Sublingual Immunotherapy (SLIT)/ Allergen Immunotherapy (AIT) is now recommended by GINA (2021) as a treatment option for patients with asthma who are sensitised and have allergic rhinitis. Immunotherapy is also recommended by ARIA (2019) for patients with AR who do not achieve an optimal response from oral H1 or INCS therapies. These medications are not available on the GMS and can be prescribed

by GPs. Immunotherapy Sublingual immunotherapy (SLIT)/ Allergen Immunotherapy (AIT) is recommended by GINA (2021) as a treatment option for patients who are sensitised and have allergic rhinitis. Immunotherapy is also recommended by ARIA (2019) for patients who have AR and who do not get an optimal response from oral H1 or INCS therapies.

There are three SLIT/AIT products available in Ireland to treat allergy grass pollen, tree pollen and house dust mite allergy. These are taken sublingually daily for three years.

cavity. Endonasal phototherapy is generally well tolerated and effective and is a treatment option when pharmacological treatment is insufficient or contraindicated.

medication is changed. These can be downloaded for free from asthma.ie and should be filled out with the patient’s healthcare professional.

Surgical Intervention

Exam time…

It is considered that allergic rhinitis is a medical condition that requires medical intervention. However, if symptoms are unilateral or if there is a septal deviation, nasal polyps or tumour present, surgery should be considered. Patients will still need to have an AR plan in place post-surgical intervention.

Walker et al (2007) showed that allergic rhinitis can have a significant impact on exam performance and results with students dropping a grade in the state exams compared with their mock exams. Students should be advised to have their allergic rhinitis assessed and treatment started well in advance of sitting exams, usually around Easter time.

Some other useful tips during exam time include:

Lifestyle Intervention  Keep windows closed at night-time or when the pollen count is high.  Monitor the pollen tracker on www.asthma.ie (from April to September) and minimize time spent outdoors when the pollen count is high.  Apply Vaseline around nostrils when outdoors to trap pollen.  Wear wraparound sunglasses to minimize levels of pollen irritating the eyes. Splash the eyes with cold water to help flush out pollen and soothe and cool the eyes.  Shower, wash your hair and change clothes if you have been outdoors for an extended time.  Exercise in the morning rather than the evening when there are higher rates of pollen falling.  Avoid drying clothes outdoors and shake clothes outside before bringing them inside –, particularly bedclothes.

Endonasal Phototherapy

 Minimise contact with pets that have been outdoors and are likely to carry pollen.

Endonasal phototherapy has an immunosuppressive effect by inhibiting allergen-induced histamine released from mast cells. It also induces apoptosis in the T-lymphocytes and

 Put an Asthma Action Plan in place. An Asthma Action Plan contains all the information a person with asthma needs to keep their condition in control. Every person with

• Use non-sedating antihistamines • Students should tell the adjudicator if their seasonal allergic rhinitis is bothering them.

• Splash the eyes with cold water before going into the exam room.

• Try not to sit near an open window.

• Keep a supply of tissues and effective, quick-acting treatments close at hand just in case.

Special Considerations in Allergic Rhinitis Children under 4 years Outdoor allergens are unusual in children under 2 years of age. Type 2 sub-endotype IL4/ IL-13 are associated with AR in children. IL-5 is associated with asthma. Treatment of children under 4 should focus on allergen avoidance and saline spray.

Cetirizine is the oral H1 antagonist of choice. Cetirizine is licensed from 2 years, but good safety is reported from 6 months of age.

For moderate/severe persistent AR, intranasal corticosteroids such as Fluticasone or Mometasone should be considered 1st line

27 Table 1: Pharmacological options of allergic rhinitis

treatment. Long term followup studies suggest no growth retardation if used as a once-daily dose. Caution should be taken in children who are also using inhaled or topical corticosteroids for asthma or dermatitis. In children, with resistant symptoms and those with co-existing asthma, leukotriene receptor antagonists should be considered. Parents should be educated about possible side effects of sleep disturbance and mood disorders.

Pregnancy AR affects 20% of pregnancies and women with pre-existing AR can experience an increase in symptoms. Medications should be avoided where possible and should be used if benefits to the mother are greater than the risk to the foetus. Medication should be avoided in the first trimester if possible. Topical administration of medication should be the first line where possible.

Conclusion This article has explored the relationship between asthma and allergic rhinitis. Pharmacological and non-pharmacological interventions for the management of AR have been discussed.

Special considerations in children and pregnancy have also been addressed. The impact of allergic rhinitis on health and well-being is significant, with many people experiencing impairment of daily activities, learning and cognitive function, as well as reduced productivity at work and school.

Optimal control of symptoms through pharmacological and non-pharmacological treatment regimes in combination with education, self-management and empowerment is paramount to managing this distressing condition.

References Bousquet, J.J., Schünemann, H.J., Togias, A. et al, 2019, Next-generation ARIA care pathways for rhinitis and asthma: a model for multimorbid chronic diseases. Clin Transl Allergy 9, 44.

Global Initiative for Asthma, 2021, Global Strategy Management and Prevention. Available at www. ginasthma.org Samantha Walker, Saba Khan-Wasti, Monica Fletcher, Paul Cullinan, Jessica Harris, Aziz Sheik, 2007, Seasonal allergic rhinitis is associated with a detrimental effect on examination performance in United Kingdom teenagers: a case-control study. Allergy Clin Immunol 2007 Aug;120(2):381-7.

HOSPITALPROFESSIONALNEWS.IE | HPN • APRIL 2022

28 HIV

The Treatment Potential of Innate lymphocytes for HIV infection Written by Professor Derek G. Doherty, Discipline of Immunology, School of Medicine, Trinity College Dublin

The current COVID-19 pandemic has shifted attention away from the human immunodeficiency virus (HIV) pandemic which has been ongoing for 40 years and has claimed over 36 million lives.

And it is not over – currently there are more than 37 million people living with HIV. Until the mid-1990s, a positive HIV test meant almost certain progression to death within 10-15 years, but now with antiretroviral therapy (ART), HIV-positive people can live relatively normal healthy lives.

Over 60% of people with HIV live in sub-Saharan Africa, and equitable access to ART in these regions took many years. But now over 27 million people worldwide are on ART for HIV - about 73% of the people who need it. With 1.5 million new infections every year and the majority being treated, the number of people living with HIV is increasing year on year.

The immunodeficiency caused

by HIV is the result of the virus infecting and killing CD4 T cells.

CD4 T cells are the commanders of adaptive immune responses.

They learn the nature of the threat to the body, be it a virus, a bacterium, a parasitic worm or a tumour, and they release cytokines, chemical messengers that recruit and activate the appropriate weapons of the immune response. But CD4 T cell numbers decline during HIV infection and when they drop below 200 per microlitre of blood, the body is defenseless against a myriad of pathogens and tumours, the condition termed the acquired immunodeficiency syndrome (AIDS). People with AIDS are susceptible to infections by many pathogens, with tuberculosis being the most common cause of death.

Despite the major advances in vaccine development, a vaccine

against HIV has yet to be produced. To date, the best result has been the RV144 clinical trial, which was tested on more than 16,000 subjects and resulted in 31% protection against persistent HIV infection after 3 years. There are several reasons for the failure to develop an efficacious vaccine against HIV. In addition to the depletion of CD4 T cells, which are required for responses to vaccines, HIV has evolved many tricks to evade or subvert the immune system. Being an RNA virus, HIV is particularly susceptible to mutations occurring during replication, leading to the generation of new variants that escape recognition

by T cells and antibodies. HIV can exist in latent form with its genome integrated into the host cell genome and no virus particles present, making it invisible to the immune system, but capable of later re-emerging as replicating virus. HIV also produces a protein, called Nef, which can specifically inhibit components of the immune system.

As mentioned above, CD4 T cells are the commanders of the immune system. CD4 T cells give the orders to CD8 T cells and other cells to kill virus-infected cells. CD4 and CD8 T cells have cell-surface antigen receptors that specifically recognize peptide fragments of proteins derived from viruses and other pathogens, allowing exquisite specificity in adaptive immune responses.

Less studied are ‘innate T cells’ - unconventional T cells that do not recognise peptides - instead they recognize lipids, phosphates or other metabolites produced by pathogens or by host cells in response to infection by pathogens. Many of the antigens recognized by innate T cells are common to many different microorganisms, meaning that innate T cells do not display the high degree of antigen-specificity seen for conventional T cells.

However, innate T cells exhibit many properties that make them essential contributors to antiviral immunity. Firstly, they recognize antigens that are not encoded by DNA and therefore are not subject

APRIL 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

to mutational changes. Secondly, while conventional T cells take several days to differentiate into effector cells after antigen recognition, innate T cells exist as effector cells and can elicit their effector functions within minutes.

Once activated, they can kill virusinfected cells and release early bursts of cytokines that recruit and activate other cells of the immune system, thereby shaping and polarizing adaptive immune responses. Innate T cells can activate and regulate dendritic cells, macrophages, neutrophils, natural killer cells, myeloidderived suppressor cells and conventional T cells via contactdependent and cytokine-mediated interactions. Importantly, innate T cells can promote antigen presentation by dendritic cells and antibody production by B cells – essential for immunity against viruses. Furthermore, they can selectively promote or suppress the responses of other immune cells. Research by us and others is attempting to figure out how to selectively turn on or off individual functional activities of innate T cells in order to therapeutically activate the appropriate immune responses to combat particular pathogens.

Three subsets of innate T cells are depleted from the circulation of people with HIV and especially people who progress to AIDS. These are natural killer T (NKT) cells, mucosa-associated invariant T (MAIT) cells and a subset of gamma/delta (γδ) T cells, termed Vδ2 T cells. These depletions could be due to activationinduced cell death, killing by the virus, or migration to particular tissues such as the gut, but several lines of evidence suggest that they are contributing to immunity against HIV. In particular, Vδ2 T cells which recognize phosphate antigens, can kill HIV-

Conserved nonpeptide antigen

Semi-invariant antigen receptor

infected cells, including latentlyinfected cells, and inhibit HIV replication within cells. Therefore, it is likely that restoration and activation of Vδ2 T cell numbers will promote immunity against HIV and may be used as an adjunct to ART. Immunotherapies utilising Vδ2 T cells are showing promise in clinical trials for cancer. Strategies employed include in vivo activation of Vδ2 T cells using phosphate antigens – this can be achieved using aminobisphosphonate drugs, such as zoledronate and pamidronate, which are licenced for the treatment of bone resorption diseases but also activate Vδ2 T cells by inducing the production of endogenous phosphates. Alternatively, Vδ2 T cells can be isolated from patients’ blood and expanded ex vivo using aminobisphosphonates or phosphate antigens, before being adoptively transferred back to the patient. Similar clinical trials for cancer are ongoing using glycolipids to activate NKT cells either in vivo or ex vivo in adoptive transfer regimens. Future work is required to determine if innate T cells can similarly be used to treat infectious diseases.

Innate T cells show promise as targets for therapy for HIV infection. Since they are activated by conserved non-peptide ligands, they can be easily expanded to high numbers in tissue culture. Their functions can be ‘tweaked’ to optimise their antiviral activities by stimulating with various synthetic ligands in the presence of particular cytokines. Clinical trials involving NKT cells and γδ T cells are ongoing in cancer patients with promising results. The next step is to take these treatments into patients with infectious disease, and HIV remains the holy grail for such therapies.

Kill infected cells Kill tumour cells Kill bacteria and fungi Maturation of antigenpresenting cells

AntigenPresenting cell

Innate T cell

Activation of T cells, B cells, natural killer cells, macrophages, neutrophils, antibody responses Immune regulation/suppression Tissue repair

News 29 Women’s Health Action Plan On International Women’s Day and as part of Women’s Health Week 2022, the Minister for Health Stephen Donnelly has launched the Women’s Health Action Plan 2022-2023, the first Women’s Health Action Plan published in Ireland.

The Action Plan was developed by the Department of Health in partnership with the HSE, the National Women and Infants Health Programme, the European Institute for Women’s Health, the Irish College of General Practitioners, and the National Women’s Council of Ireland through the work of the Women’s Health Taskforce.

The Action Plan sets out women’s priorities for women’s health. It is underpinned by the voices and perspectives of women, their advocates and women’s health professionals who have provided their insights and experiences through a range of listening projects and engagements undertaken by the Women’s Health Taskforce 2020-2021.

Orla O’Connor, Director of the National Women’s Council Women’s health is a top priority for this government and is strongly supported in Budget 2022 with ¤31 million additional funding for new developments in women’s health. This funding will enable: • ¤8.66 million additional funding for continued implementation of the National Maternity Strategy • ¤9 million to fund access to contraception for women aged 17-25 • ¤5.3 million to grow access to “see and treat” gynaecology clinics (20 nationally); specialist menopause clinics (4 nationally); and specialist endometriosis services (2 nationally) • ¤5 million to bring the Women’s Health Fund to an investment of ¤10 million to support innovative new approaches to women’s health nationwide (illustrated in this Plan)

Orla O’Connor, Director of the National Women’s Council and member of the Women’s Health Taskforce welcomed the launch of the Action Plan, “The Women’s Health Taskforce made the conscious decision to put women’s voices at the heart of health policy and implementation, and this Plan seeks to deliver on what many women shared through

the ‘Radical Listening’ exercise an ask for a person-centred and accessible health system, which works to meet women’s needs as they arise. This Plan provides strong steps towards building that future for women in Ireland and our task is now to drive forward these actions that will be the critical levers for delivering meaningful change.”

Managing Obesity Irish and German scientists have just identified how specific immune cells can work together in fat to cause inflammation that leads to weight gain and obesity. Their work pinpoints new avenues to exploit the regulation of that inflammation in fat tissue, thereby suggesting new ways to manage obesity.

There is a global epidemic in obesity in adults and children, with obese people predisposed to develop diabetes, cardiovascular disease, and cancer. New therapies are needed to help tackle this issue. In their research, the scientists identified how “checkpoint proteins” and immune cells alter inflammatory cells within the fat tissue to cause obesity. In people with obesity (Body Mass Index BMI> 30 kg/m2) these changes in checkpoint expression in the visceral fat was predictive of the person’s weight. The scientists then showed that modifications in the so-called immune checkpoint proteins of mice on a Western “high fat” diet were linked to dramatic reductions in the development of obesity and diabetes.

The study, just published in the leading international biomedical journal Science Translational Medicine, was led by Professor Padraic Fallon from Trinity College Dublin’s School of Medicine, and Dr Christian Schwartz, a former EMBO Fellow in Trinity and now a Principal Investigator at the University Hospital Erlangen. Professor Fallon, who is based in the Trinity Biomedical Sciences Institute, commented, “This new process of checkpoint regulation of cells in visceral fat of obese individuals advances our understanding of how the immune system controls diet-induced weight gain that can lead to conditions such as obesity and type 2 diabetes. “Our discovery has broader impacts on addressing how obesity influences co-morbidity with other diseases, as shown in the COVID-19 pandemic, where obese individuals that are infected with SARS-CoV-2 are more likely to develop severe disease that requires intensive care and also have an increased risk of mortality.”

Link between High Cholesterol and Heart Disease ‘Inconsistent’ New research from RCSI University of Medicine and Health Sciences has revealed that the link between ‘bad’ cholesterol (LDL-C) and poor health outcomes, such as heart attack and stroke, may not be as strong as previously thought.

in the various iterations of expert guidelines for the prevention of CVD. Statins are now commonly prescribed by doctors, with one third of Irish adults over the age of 50 taking statins, according to previous research.

Published in JAMA Internal Medicine, the research questions the efficacy of statins when prescribed with the aim of lowering LDL-C and therefore reducing the risk of cardiovascular disease (CVD).

The new findings contradict this theory, finding that this relationship was not as strong as previously thought. Instead, the research demonstrates that lowering LDL-C using statins had an inconsistent and inconclusive impact on CVD outcomes such as myocardial infarction (MI), stoke, and all-cause mortality.

Previous research has suggested that using statins to lower LDL-C positively affects health outcomes, and this is reflected

In addition, it indicates that the

overall benefit of taking statins may be small and will vary depending on an individual’s personal risk factors.

The lead author on the paper is Dr Paula Byrne from the HRB Centre for Primary Care Research based in RCSI’s Department of General Practice. Commenting on the findings, Dr Byrne said: “The message has long been that lowering your cholesterol will reduce your risk of heart disease, and that statins help to achieve this. However, our research indicates that, in reality, the benefits of taking statins are varied and can be quite modest.”

The researchers go on to suggest that this updated information should be communicated to patients through informed clinical decision-making and updated clinical guidelines and policy.

This important discovery was a collaboration with Professor Susan M Smith, also of RCSI and with researchers from the University of New Mexico, USA, (Dr Robert DuBroff), the Institute for Scientific Freedom in Denmark (Dr Maryanne Demasi), Bond University in Australia (Dr Mark Jones) and independent researcher Dr Kirsty O’Brien.

HOSPITALPROFESSIONALNEWS.IE | HPN • APRIL 2022

CPD 86: MULTIPLE MYELOMA Figure 3. Research Team:

Continuing Professional Development

CPD 60 Second Summary Multiple myeloma (MM) is a haematological malignancy of terminally differ¬entiated plasma cells, and is the second most common haematological malignancy in the Western World (after non-Hodgkin lym¬phoma).

It represents approximately 2% of total cancer cases. Around 361 people are diagnosed with MM each year in Ireland. Men are slightly more at risk (1.2:1.0 sex ratio). The median age at onset is 69 years old, and approximately 63% of patients diagnosed with MM are older than 65 years.

High-dose chemotherapy plus autologous stem-cell transplant (ASCT) remains the standardof-care. Transplant-ineligible patients receive induction regimens according to their frailty status. In both groups, the use of scientifically-informed, evidence-based combinations of novel therapeutic agents including immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), dexamethasone and more recently monoclonal antibodies (mAbs), has transformed the treatment paradigm. However, genomic and clonal evolution in the tumour-promoting bone marrow milieu underlies relapse in most patients, and new therapies are urgently required.

Novel agents that specifically target and exploit (a) MM tumour cell pathway vulnerabilities and/ or (b) the tumour:bone marrow microenvironment interface are under intense investigation.

Combinatorial approaches targeting MM cells, disrupting MM cell/BM interactions and augmentation of anti-MM immune responses dramatically improve treatment responses and are the focus of ongoing, extensive research efforts.

Figure 3. Research Team:

Figure 3. Research Team:

31

AUTHORS: Graeme P. Sullivan1, Siobhán Glavey2, Tríona Ní Chonghaile1,3# 1 Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephen’s Green, Dublin 2, Ireland.

Pathology Department, Smurfit Building, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin 9, Ireland.

2

Graeme Sullivan Dr. Tríona Dr. Ní Graeme Chonghaile Sullivan Dr.Prof.

Graeme Dr. Siobhán Tríona Sullivan Glavey Ní Chonghaile Dr. TríonaProf.

Ní Chonghaile Siobhán Glavey Pro Centre for Systems Medicine, Dr. Department of Postdoctoral Research Fellow, Group Postdoctoral Targeted Research Fellow,Postdoctoral Consultant Research Haematologist/Clinician Group Leader, Fellow, Targeted Group Consultant Leader, Targeted Haematologist/Clinician Consulta Dr. Leader, Graeme Sullivan, Prof.

Siobhán Dr. Tríona Ní Physiology and Medical Physics, Royal College of Targeted Therapeutics in Cancer Therapeutics Targeted Therapeutics in Cancer in Cancer Targeted Scientist, Therapeutics Beaumont Therapeutics inHospital Cancer in Cancer and Therapeutics Scientist,inBeaumont Cancer Hospital and Scientist Postdoctoral Glavey,RCSI Consultant Chonghaile, Group Surgeons in Ireland, 123 St Stephen's Green, Laboratory, RCSI Dublin 2, Laboratory, Laboratory, RCSI RCSI Laboratory, Laboratory, RCSI RCSI Laboratory, RCSI RCSI Research Fellow, Haematologist/ Leader, Targeted Ireland.

Targeted Therapeutics Clinician, Scientist, Therapeutics in #To whom correspondence should be addressed: in Cancer Laboratory, Beaumont Hospital Cancer Laboratory, Tel:+353014028579 Email: tnichonghaile@rcsi.com RCSI and RCSI RCSI

3

1. REFLECT - Before reading this module, consider the following: Will this clinical area be relevant to my practice?

knowledge gap - will this article satisfy those needs - or will more reading be required?

2. IDENTIFY - If the answer is no, I may still be interested in the area but the article may not contribute towards my continuing professional development (CPD). If the answer is yes, I should identify any knowledge gaps in the clinical area.

4. EVALUATE - Did this article meet my learning needs - and how has my practise changed as a result?Have I identified further learning needs?

3. PLAN - If I have identified a

5. WHAT NEXT - At this time you may like to record your learning for future use or assessment. Follow the

4 previous steps, log and record your findings.

Published by HPN. Copies can be downloaded from www.irishpharmacytraining.ie Disclaimer: All material published is copyright, no part of this can be used in any other publication without permission of the publishers and author.

Multiple Myeloma: Marrow, Milieus, Microenvironments and Mortality Introduction Multiple myeloma (MM) is a haematological malignancy of terminally differ¬entiated plasma cells, and is the second most common haematological malignancy in the Western World (after non-Hodgkin lym¬phoma).

It represents approximately 2% of total cancer cases. Around 361 people are diagnosed with MM each year in Ireland. Men are slightly more at risk (1.2:1.0 sex ratio). The median age at onset is 69 years old, and approximately 63% of patients diagnosed with MM are older than 65 years. The lifetime risk of getting MM is approximately 1 in 125 (0.8%).

Despite being a rare disease, incidence is increasing – primarily owing to an aging population.

There has been a >120% increase in MM cases from the 1990s to now. MM remains an incurable, mortal disease.

Disease development The clonal plasma cells that causes MM are derived from postgerminal center B cells. In health, following antigen exposure (e.g. viral or bacterial infections), naïve B cells normally proliferate and subsequently undergo somatic hypermutation of the IgH and IgL

VDJ sequences. This process produces long-lived plasma cells that provide durable, sustained antibody production. These cells reside in the bone marrow (BM) and are an important part of humoral immunity. Abnormal clonal plasma cell development mimics these normal biological processes but results in excessive amounts of intact immunoglobulin. These malignant plasma cells chiefly reside in the BM, but can also be found in the peripheral blood and other extramedullary sites, including soft tissue and organs.

This is particularly true of the latter stages of the disease. MM is character¬ised by the secretion of a monoclonal immunoglobulin protein (known as M protein or monoclonal protein). This aberrant protein is made by the aforementioned abnormal plasma cells. In 15–20% of patients, the MM cells secrete only monoclonal free light chains, and, in <3% of patients, these cells secrete no monoclonal protein. The clinical features of multiple myeloma are typically driven by monoclonal protein, the malignant cells or cytokines secreted by the malignant cells. Signs of end-organ damage, such as hypercalcaemia (C), renal insufficiency (R), anaemia (A), and/or bone disease (B)

with pathologic lytic lesions or fractures, are commonly referred to as CRAB features and form part of the diagnosis of multiple myeloma.

Multiple myeloma progression Importantly, MM exists in a spectrum of disorders referred to as monoclonal gammopathies.

Within this grouping, monoclonal gammopathy of undetermined significance (MGUS) is characterised by infiltration of clonal plasma cells into the BM and secretion of monoclonal protein, and is the most common form. MGUS is asymptomatic and consistently precedes the development of MM. Typically, MGUS demonstrates low levels of abnormal protein (<3.0 g/dL), abnormal plasma cells (<10%) and patients do not exhibit CRAB features. A proportion of patients experience an intermediate stage, referred to as smouldering multiple myeloma (SMM), with elevated abnormal protein (>3.0 g/dL) and plasma cells (>10 and <60%), but again without CRAB features. Around 15% of MGUS patients subsequently progress to active MM, and approximately 20% progress to myeloma or a related condition (AL amyloidosis, Waldenstrom macroglobulinaemia or a lymphoproliferative disorder).

32

CPD 86: MULTIPLE MYELOMA

Specifically, diagnosis of MM requires 10% or more abnormal plasma cells in the BM plus one or more signs of end-organ damage (CRAB). Even without CRAB features, patients who exhibit myeloma-defining events (clonal BM plasma cells of >60%, serum : ratio >100 fold, and/or >1 bone focal lesion on magnetic resonance imaging (MRI) or positron emission tomography (PET)/computed tomography (CT) scan are also treated, as the risk of progression to symptomatic disease is approximately 80% at 2 years. Most recently, nextgeneration sequencing (NGS) analysis of MGUS-SMM-MM patients has proven to be a useful tool to decipher the chronology of disease initiation events. In the near future, the combination of genomic signatures and biomarkers of disease burden might enable identification of those SMM patients who could benefit from early intervention to avoid progression to MM. Prognostic Factors The primary genomic events involved in MM are the acquisition of hyperdiploidy or translocations affecting the IGH genes; these events are mutually exclusive.

Secondary genomic events include chromosomal translocations, copy-number variations and single-nucleotide variants Genomic events underlying MM affect multiple signalling pathways including MYC, NF κB, and MAPK pathways, plasma-cell differentiation, cell-cycle regulation and DNA-damage sensing and

A

repair. Clinical and laboratory factors including disease stage, cytogenetic abnormalities, and depth of response to therapy can impact survival of MM patients. Cytogenetic analysis and fluorescence in situ hybridisation (FISH)-based genetic profiling should be routinely performed to evaluate disease biological behavior and prognosis. Among the poor prognostic markers, del(17p) and t(4;14) are the most informative; concomitant secondary cytogenetic abnormalities may impact prognosis. The International Staging System (ISS), based on albumin and β2-microglobulin levels, is most widely used and has been revised (R-ISS) to incorporate lactate dehydrogenase (LDH) and high-risk-FISH abnormalities.

Given the genomic complexity of MM, more sophisticated techniques including gene expression profiling, mutational status, and copy number abnormalities have been used, alone or in combination with FISHbased approaches, to more deeply characterise disease biology and prognosis. For example, newly diagnosed MM (NDMM) patients carrying del(17p) may be further stratified using subclonal analysis.

Targeted sequencing has been used as an alternative to whole exon sequencing to specifically analyse fractions of the genome and provide more accurate risk stratification. Although not yet widely incorporated into practice, these approaches will help to define future personalised treatment strategies in MM.

B

Outcomes Historically, MM was associated with a poor prognosis, with a 5 year age-standardised overall survival rate of 27.5% (according to Irish data from 1994-1998). The subsequent introduction of novel drugs: proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and potent monoclonal antibodies (mAbs) significantly improved the clinical outcomes of patients with MM and drove up the 5-year overall survival to 52.1% in Ireland, which is comparable to other jurisdictions (52.6 % for the U.K., 54.0% for the USA). However, progress has plateaued at this level. There is an urgent need to redouble our research efforts to unstick and build upon the advancements made to date.

Management High-dose chemotherapy plus autologous stem-cell transplant (ASCT) remains the standardof-care for newly diagnosed patients under 70 years of age with satisfactory cardiac, pulmonary, hepatic and renal function. Transplant-ineligible patients receive induction regimens according to their frailty status. In both groups, the use of scientifically-informed, evidencebased combinations of novel therapeutic agents including IMiDs, PIs, dexamethasone and more recently mAbs, has transformed the treatment paradigm. However, genomic and clonal evolution in the tumour-promoting BM milieu underlies relapse in most patients, and new therapies are required.

C

Figure 1. Multiple myeloma tumour cell lines exhibit exquisite sensitivity to proteasome inhibition with bortezomib (Velcade®) (A-C) A panel of multiple myeloma (MM) cell lines (A) JJN3, (B) MM1S and (C) KMS18 cells were grown overnight and treated with titrations of bortezomib, as indicated, for 24 hrs. After 24 hrs, cells were harvested and analysed by flow cytometry for determination of apoptosis by Annexin V/Propidium Iodide assay.

LATEST TREATMENTS AND RESEARCH Exploitation of MM pathway vulnerabilities Tumour cells rely on survival mechanisms that are imprinted during cellular lineage development: lineagedependency. Bortezomib, a first-in-class proteasome inhibitor (PI), has clearly demonstrated the dependency of MM cells on the protein quality control pathway as a therapeutic target.

The ubiquitin-proteasome system (UPS) is the main mechanism for maintaining protein homeostasis. In MM, increased aberrant protein turnover and immunoglobulin production exerts robust pressure on this system, making it exquisitely sensitive to proteasome inhibition.

Exploiting this vulnerability with a PI, such as bortezomib, is a logical first-line and (typically) successful treatment approach.

However, bortezomib has broad, pleiotropic effects. It triggers intrinsic and extrinsic myeloma cell apoptosis and cell cycle arrest. It also modifies bone turnover and osteoclast activity in the bone marrow. Furthermore, bortezomib inhibits the NF-κB pathway (via degradation of its inhibitor, IκB). NF-κB is a major oncogenic pathway in MM: it mediates MM cell survival and DNA repair, promotes interactions of MM cells with BM stromal cells via the transcription of adhesion molecules, as well as modulating the transcription and release of cytokines in the BM microenvironment (such as IL-6, VEGF, IGF-1), which in turn mediate MM growth and drug resistance, and confer immunosuppression in the BM milieu. Subsequent generations of orally available PI (including carfilizomib and ixazomib) were developed to help overcome bortezomib resistance and offer additional PIs to the armamentarium.

Targeting upstream components of the UPS has also recently emerged as a promising strategy to overcome PI resistance.

Therapeutic targeting of deubiquitylating enzymes (DUBs) and the 19S proteasomeassociated ubiquitin receptor Rpn13 overcame PI resistance in preclinical studies. However, the first human trial of USP14/ UCHL5 DUB inhibitor for relapsed/ refractory MM (RRMM) was stopped owing to dose-limiting

33 toxicity. Another novel and attractive approach to overcome PI resistance is the concomitant blockade of the aggresome/ autophagy pathway using an inhibitor of histone deacetylase 6 (HDAC6), which is recruited to maintain proteostasis balance as an adaptive response mechanism.

Several groups, including our own, are actively pursuing the development of novel targeted, selective HDAC6 inhibitors with therapeutic potential.

A

Lineage vulnerabilities in MM also include aberrant transcription factor (TF) regulatory networks controlling the lineage factor IRF4. However, direct targeting of TFs is a challenging strategy and there are no inhibitors for clinical use available at present.

Notably, repression of IRF4 transcription is observed posttreatment with lenalidomide, which triggers cereblon (CRBN)mediated degradation of the IRF4 transcriptional activator IKZF3.

Building on this knowledge, a new platform technology has been developed to trigger selective protein degradation. Proteolysistargeting chimeras (PROTACS) are designed by conjugating the small-molecule binder of the target protein to an E3 ubiquitin ligase binding scaffold such as the analogs of thalidomide which bind CRBN. This exciting approach will allow for therapeutic degradation of protein substrates that are otherwise difficult to target.

noting that the role of mutations in MM has not been fully elucidated, only TP53 mutation (affecting 6-8% of newly diagnosed patients) demonstrably confers worse outcome. Related to this, tumour-targeted treatments in MM are often compromised by intra-clonal heterogeneity.

Deep sequencing has identified a complex subclonal structure in MM with different patterns of clonal evolution impacted by BM, immune response, and therapy thus making successful targeting of the above highly difficult. p

Exploitation of MM cell clone vulnerabilities

Targeting MM epigenetic modifications

MM is characterised by genetic and biological heterogeneity.

Despite this, a number of targetable oncogenic dependencies have become apparent, particularly driver mutations and translocations.

Alteration of the transcriptional program of MYC, and of its functional collaborators promotes pro-tumour signaling and plasma cell survival. Frequent gene mutations in MM include RAS (KRAS or NRAS) with downstream activation of the MAPK pathway, BRAF, DIS3, and FAM46C. Other signalling pathways affected include the NF-κB pathway (affected by copy number loss, mutation, and translocations) and the PI3K pathway (dysregulated in the absence of genetic change).

Apoptotic pathway dysregulation occurs, with BCL2 dependency in patients with t(11;14) and MCL1 dependency in other patients observed. However, it is worth

Epigenetic alterations affect regulation of gene activity and expression, without altering gene sequence. Such alterations are associated with MM onset and progression, and modulate several important biological processes.

Global hypomethylation of the genome characterises the MGUS>MM transition. In contrast, pervasive genome re-methylation occurs in the transition from MM to a more aggressive plasma cell leukaemic stage. Specific epigenetic targets include the type II arginine methyltransferase PRMT5 in MM. Inhibition of PRMT5 results in MM cell killing via NF-κB blockade, thus providing the rationale for clinical trials targeting PRMT5 in MM.

B

Figure 2. Ex vivo primary multiple myeloma patient samples respond differentially to a panel of BH3 mimetics (A) Ex vivo primary patient MM cells were isolated, CD138+ cells sorted, purified and stained by H&E followed by microscopic evaluation.

(B) Primary MM cell cultures, as above, were treated with a panel of BH3 mimetics, as indicated, and analysed by flow cytometry for determination of apoptosis by Annexin V/Propidium Iodide assay.

Histone deacetylases (HDAC) are generally hyperactive in MM. HDAC inhibitors are the most studied epigenetic drugs that have led to clinical trials and

approval of the non-selective HDAC inhibitor panobinostat in combination with bortezomib in relapsed/refractory disease.

Increased toxicity observed with panobinostat prompted the development of HDAC6selective inhibitors (ricolinostat and citarinostat/ACY-241), which show promising results and lower toxicity in combination with bortezomib and dexamethasone.

Increasing interest surrounds the use of microRNA-targeting strategies in MM. Preclinical data have defined their oncogenic (miR-221/222,-21,-17-92 cluster) or tumour suppressive (miR29b,-34a,-125b,-15,-16) roles in MM associated with repression or overexpression, respectively, of genes involved in essential pro-survival pathways. Several candidates are being tested in other diseases and will soon be evaluated in MM, using miRNA replacement or inhibition strategies. Theoretically, as they are endogenous antisense of mRNAs, their replacement is hypothesised to induce a “natural” effect on the targets, with less off-target effects compared to siRNA-mediated targeting strategies. In addition, the recent availability of suitable in vivo delivery systems now permits their use in clinical trials.

Targeting the tumour-bone marrow microenvironment interface Disrupting the interactions of MM cells with the BM represents an ideal therapeutic strategy in MM, as demonstrated by

the IMiDs (which remain active against MM even in the protective milieu of the BM. Cellular and non-cellular components of this niche support MM cell proliferation, migration, survival and drug resistance, while also conferring immunosuppression, and therefore represent targets for novel therapeutics under investigation by our group and others. Disease progression is mediated by intrinsic factors of the clonal cells along with factors that mediate a permissive tumour microenvironment. The MM tumour niche comprises the components of the BM microenvironment– cellular (stromal cells, osteoblasts, osteoclasts, endothelial cells and immune cells) and noncellular extracellular matrix (ECM).

Immunomodulatory drugs (IMiDs) Comprehensive clinical trials have led to the approval of the IMiD thalidomide and its more potent analogs lenalidomide and pomalidomide for treatment of MM and RRMM. These agents exert direct effects on MM cells including growth arrest and caspase-8-mediated apoptosis, associated with CRBN-dependent degradation of IKZF1/3 followed

by IRF4 downregulation, as mentioned earlier. In the BM microenvironment, IMiDs abrogate MM cell adhesion to the BM, modulate cytokine and growth factor secretion, inhibit angiogenesis and upregulate T-, NK-, and NK-T-cell-based immunity while downregulating T-reg cells. Mechanistically, binding

34

CPD 86: MULTIPLE MYELOMA dexamethasone to treat RRMM; whether it is effective in daratumumab-refractory disease remains to be determined.

Monoclonal antibody technologies have also provided the framework for the development of Ab-drug conjugates (ADC) and bispecific T-cell engagers (BiTE). B-cell maturation antigen (BCMA)directed ADCs are currently under investigation in both preclinical and clinical settings, and represent a promising approach due to the highly specific expression of BCMA on MM cells and role of the BCMA/ APRIL pathway in supporting MM cell survival in the BM.

to CRBN has been implicated in mediating the immune effects of IMiDs, as IKZF1/3 degradation in T cells increases their secretion of cytokines, notably IL-2. This mechanism is also associated with increased NK and NK-T-cell cytotoxicity and antibody-dependent cellular cytotoxicity (ADCC) (i.e., antiCD38, daratumumab and -CD20, rituximab) observed after IMiD treatment. Preclinical and clinical studies confirm the strong synergism of IMiDs with PI and with mAb treatment.

Immune-based therapies Loss of immune surveillance supports MM tumour growth and resistance, and is associated with alterations in nonlymphoid and immune cells in the bone marrow.

There is also increasing evidence that evolving immune dysfunction is an important determinant of progression from MGUS/SMM to symptomatic MM. Immune escape is also mediated, at least in part, by increased expression of immune checkpoints, i.e., PD-1/PD-L1, in T cells and MM cells. Alas, results with immune-checkpoint blockade via PD-1/PD-L1 in MM have been disappointing thus far. No single agent activity of the humanised anti-PD-1mAb pembrolizumab has been shown, and importantly, two randomised clinical trials

evaluating pembrolizumab in combination with IMiDs to treat RRMM were terminated owing to excessive mortality.

Thankfully, multiple mAbs that target MM surface antigens and trigger ADCC, antibody-dependent cellular phagocytosis, complement activation, and direct effects on MM cells have proven efficacious.

Elotuzumab and daratumumab target SLAMF7 and CD38, respectively. Elotuzumab also activates NK cells and is approved in combination with lenalidomide or pomalidomide in RRMM. Daratumumab, in particular, has shown remarkable efficacy and frequency of response. This has led to its approval as a single agent or in combination with IMiD and PI in both newly diagnosed and RRMM. Notably, a recent (GRIFFIN) trial compared standard lenalidomide-bortezomibdexamethasone with or without daratumumab in transplant eligible patients, and showed deeper responses and minimal residual disease negativity rates in the daratumumab-treated patient cohort. The recent approval of subcutaneous daratumumab will significantly reduce patient treatment times and accessibility.

More recently, in March 2021, a new CD38-directed mAb, isatuximab, has been approved in combination with carfilizomib-

Cellular therapies, in particular chimeric antigen receptor (CAR) T-cell approaches are under active investigation and receiving a lot of attention owing to their success in other haematologic conditions (particularly diffuse large B cell lymphoma and mantle lymphoma). Their success is predicated on the identification of unique and highly expressed MM antigenic targets. Among a variety of targets, B-cell maturation antigen (BCMA/TNFRSF17) is the most frequently used due to its selectivity for normal plasma and MM cells. Several CAR-T products have been clinically tested in heavily pre-treated (PI-IMiD-CD38 mAb) RRMM, and have demonstrated remarkable, deep MRD responses. Increased clinical use of and experience with such therapies has also helped to ameliorate the more commonly observed toxicities of CAR-T cells (cytokine release syndrome and neurotoxicity). To date, however, most patients have relapsed, and ongoing research is assessing mechanisms of resistance to CAR-T, utilising combination immune approaches with CAR-T, and using CAR-T earlier in the disease course in order to achieve more durable responses.

Looking to the future There have been incredible advances in the range of therapies available to clinicians treating MM. Despite this, management of MM patients remains challenging: acquisition of resistance underlies relapse in most patients. The development of second-generation potent drugs of the same class has helped to overcome both PI and IMiD resistance, as have combination therapies

with agents targeting pathways mediating resistance. Identification of biomarkers of patient MM resistance/sensitivity may further inform sequential and combination therapies in the future. The first example of biomarker-driven anti-MM treatment in MM is the Bcl-2 inhibitor venetoclax/ABT199, whose safety and efficacy are predicated upon occurrence of t(11;14) or presence of high levels of BCL2. Several trials in RRMM demonstrate the efficacy of venetoclax, as monotherapy and in combination, restricted to this patient subset.

Agents targeting novel MM vulnerabilities are urgently needed.

Resistance is now beginning to appear for immune-based approaches. Loss of targeted antigens (such as BCMA, CD38) is a common event, either due to loss with tumour evolution or to suppression in the face of immune pressure. Multi-antigen targeting may potentially overcome this obstacle, and several trials are evaluating this strategy. Additional resistance may be intrinsic to the technology or modality, for example ongoing efforts are directed at increasing CAR-T cell expansion and persistence in vivo to promote CAR-T cell persistence.

Lastly, T-cell exhaustion and the immunosuppressive BM may contribute to both targeted- and immune-therapy resistance.

Restoration of host anti-MM immunity represents an important unmet need in MM. With >100 active clinical trials in stage 3 or later development at present, these needs are receiving great attention.

Combinatorial approaches targeting MM cells, disrupting MM cell/BM interactions and augmentation of anti-MM immune responses have dramatically improved treatment responses and duration. Key obstacles to overcome MM mortality include (i) constitutive and evolving genomic heterogeneity in MM cells, as well as (ii) the immunosuppressive BM milieu. Going forward, integration of multi-omics sequencing technologies profiling both the MM cell and BM accessory/immune cells will help identify therapeutic targets and translate to novel rationally designed, selective, targeted and immune therapies.

Past successes have shown us the future is bright for MM research!

References on request

News 35 New Initiative to Reduce Waiting Lists The Irish Society of Physiotherapists (ISCP) has launched a Competency Framework for Advanced Practice Physiotherapists and calls on Government to amend the legislation to allow physiotherapists to refer for X-ray and create the Advanced Practice Physiotherapy (APP) grade, both of which will achieve significant cost savings to the health service.

Speaking at the launch, Dr Marie Ó Mír, ISCP Advanced Practice Officer said, “For over two decades physiotherapists with extensive post graduate experience and qualifications have been working in roles with advanced scope, but lack of a standardised approach has led to much variation in roles. This framework was developed to support the delivery of safe and effective expert services to the public and to demonstrate the ISCP’s commitment to working with the Department of Health and HSE in developing policy for the implementation of the advanced practice grade.”

The ISCP presented a comprehensive report to the Minister for Health, Stephen Donnelly, the Department of Health (DoH) and the Health Service Executive (HSE) in March 2021,

Rachel Maguire ISCP Head of Professional Development, Dr. Marie Ó Mír, ISCP Advanced Practice Officer

which demonstrates the massive savings physiotherapists are consistently delivering for the Health Service Executive.

As a direct result of activity of physiotherapists with advanced scope nationally: • More than 160,000 new patients have been removed from orthopaedic and rheumatology waiting lists nationally by physiotherapists since 2012 • Waiting lists for Rheumatology appointments are 130% shorter • ¤104,040 was saved at one hospital site over a 9-month period in respiratory medicine, with an average reduction in length of hospital stay of 2 nights compared to previous medical care • 70% reduction in wait time in an Emergency Department

Outpatient Department waiting lists continue to grow exponentially and are worse than ever after the COVID-19 Pandemic. The answer to managing waiting lists lies not just in manpower resourcing but also in fully utilising the skills of current staff and delivering a multiprofessional workforce. This in turn will REDUCE:

2. the need for multiple patient contacts along the pathway, thereby increasing timeliness and consistency in the management of certain conditions

1. the need for medical professionals to make referrals for investigations, thereby improving patient flow

4. costs across the pathway whereby patients are seen by the right clinician at the right time

3. inappropriate demands on medical professionals and therefore improving access to medical care for those who need it,

Mater Hospital to Virtually Host New European Course on Precision Medicine: A Focus on Clinical Utility Between April 25th-27th 2022 the Mater will host (virtually) the first European Society Human Genetics (ESHG) Course/Workshop on Precision Medicine: A Focus on Clinical Utility.

The course, developed by a team led by Dr James O’Byrne, Consultant Physician at the National Centre for Inherited Metabolic Disorders, Mater Misericordiae University Hospital (MMUH) through a collaboration between the ESHG and a MMUHTrinity College Dublin- University College Dublin.

Dr O’Byrne said the course is timely given the new therapies that will be increasingly available to patients in the years ahead.

“We estimate that about 300 new targeted therapies will be available to patients by 2030, so the era of Precision Health and Medicine is firmly here.”

“The recent advances in the field of genomic/ multi-omic medicine has led to an explosion of new information about what underlies health and what constitutes disease”. “This has armed clinicians in 2022 with the capacity to significantly improve upon what they have always practiced, taking a personalised and tailored approach to medicine by establishing the most accurate diagnosis possible and then selecting the most appropriate treatments or preventative measures according to welldefined, biologically-informed disease subtypes, accounting for individual differences in genetic make-up, behaviours, cultures, lifestyles and the environment” “However the appropriate education to allow for the implementation of these medical advances in an effective, efficient and safe way remains inadequate”

“This new ESHG course has been developed to help bridge this educational gap with the primary aim of this course to help train the next generation of clinicians and scientists to be able to translate precision medicine into effective clinical benefit”.

“It will give participants an up-todate knowledge of the principles of precision medicine and a practical knowledge of the field, applicable to almost every area of medical practice/ interest.”

This is the first CME accredited ESHG event held in/ delivered

by Ireland and “is truly a collaborative effort with over 20 clinical and academic institutions chipping in to make this a world class event” Dr O’Byrne said. “We hope to deliver this course in person in the coming years but for 2022

to date, over 300 people from 43 countries/ 5 continents have registered (with some registrants from low-middle income countries receiving scholarships to attend) and it promises to be a memorable event.”

For more information or to register for this virtual course go to : https:// reg.eshgprecisionmedicine.com Note: The 1st European Society of Human Genetics Course on: Precision Medicine: A Focus on Clinical Utility, Dublin, Ireland, 25/04/2022-27/04/2022 has been accredited by the European Accreditation Council for Continuing Medical Education (EACCME®) with 18 European CME credits (ECMEC®s).

Course content will be available online for 3 months for all registrants.

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Anticoagulation in Atrial Fibrillation: The Role of the Pharmacist Introduction Atrial Fibrillation (AF) is the most common sustained cardiac arrhythmia affecting at least 3% of the Irish population currently. AF is an age-related condition with worldwide prevalence predicted to more than double in the coming decades. This presents a significant health burden as almost one in every three strokes are associated with AF and AFrelated strokes tend to be more severe, posing the greatest risk for neurological disability.

Written by Christine McAuliffe, MPSI. Christine is the lead clinical pharmacist in Tallaght University Hospital’s interdisciplinary Atrial Fibrillation clinic. Christine’s primary role is in the area of anticoagulation with direct oral anticoagulants for patients with Atrial Fibrillation. In this article she outlines some of the main practice points for pharmacists to be aware of when looking after these patients and highlights some useful reference sources.

Table 1

Management of AF generally includes the implementation of either a rate or rhythm control strategy and for most patients, initiation of oral anticoagulation (OAC) to prevent stroke.

The risk of stroke is calculated using the CHA2DS2-VASc Score as outlined in Table 1. For most patients with AF we err on the side of anticoagulation. The European Society of Cardiology (ESC) recommends that all patients scoring 1 or greater should be considered for OAC (except females scoring only 1 on the basis of gender alone who are considered low risk).

Direct Oral Anticoagulants (DOACs) have widely replaced warfarin as the agents of choice due to their efficacy, convenience and reduced, but by no means eliminated, potential for interactions. As increasing age is a prominent AF

risk factor, all patients with AF will eventually qualify for lifelong anticoagulation therapy and so it is really important for pharmacists to have an in-depth understanding of these medications.

There are however a number of checks that can be performed in the community pharmacy setting to ensure safe DOAC prescribing and dispensing without the need to access laboratory results.

DOAC Dosing and Method of Administration

Pharmacists and their teams should ensure an appropriate dosing schedule has been prescribed for the specific indication. Apixaban and dabigatran should always be prescribed twice daily in the setting of AF and any alternative dosing schedule should be queried.

There are four DOACs currently available – dabigatran, apixaban, rivaroxaban and edoxaban. All are licensed for a number of different indications and have different dose reduction criteria.

The HSE medicines management programme have produced a succinct table1 which amalgamates the information from the four individual summary of product characteristics (SPCs) and is very useful as a quick reference guide.

All four DOACs are renally cleared to some degree. Therefore creatinine clearance must be calculated using the Cockroft and Gault equation at initiation of therapy and recalculated periodically to ensure accurate dose selection. In hospital, with access to laboratory results, one of the primary roles of the pharmacist in relation to anticoagulant therapy is confirmation that the patient is prescribed the appropriate dose for their renal function. Both overand under- dosing in the area of anticoagulation puts the patient at risk of the severe consequences of either a serious bleeding event or stroke.

Where patients have their medications blister packed in a Monitored Dosage System (MDS) by the pharmacy team it is important to ensure the DOAC times of administration are spaced appropriately. In the case of twice daily DOACs the administration times should ideally be at 12 hourly intervals.

Dabigatran is not suitable for MDS dispensing and should always be supplied to the patient in its original packaging. Where patient adherence would be compromised by supplying dabigatran separately this should be discussed with the prescriber. There is likely an alternative DOAC the patient could be switched to which is suitable for MDS dispensing, thereby increasing adherence and safety.

It is possible to confirm that an appropriate dose of DOAC has been prescribed in some situations.

For example a reduced dose of dabigatran is recommend for all patients 80 years and over and the presence of certain P-glycoprotein (P-gp) inhibitors necessitates a licensed dose reduction for both edoxaban and dabigatran. Where such cases are encountered in the pharmacy it should be flagged to the prescriber and a dose reduction recommended.

There are other prescribing decisions which are less clear-cut e.g. where patients prescribed dabigatran are between 75 and 80 years old or have gastritis. In these cases prescribers are advised to consider a dose reduction. These decisions are made on a risk-benefit basis and it can be difficult for pharmacists to make meaningful clinical interventions around dosing for these patients in the absence of a full clinical history.

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Patient Education and Adherence Patient and carer education is one of the most important interventions by healthcare professionals (HCPs) for patients on DOACs. In-depth education should be provided at initiation of DOAC therapy and reinforced periodically thereafter.

Patients should be counselled on the following points - indication for DOAC therapy, importance of strict adherence (no DOAC = no protection from stroke), modality of intake (once or twice daily, intake with food for rivaroxaban etc.), management of missed doses, increased risk of bleeding, over the counter medications to avoid and advice given to inform HCPs of DOAC therapy in advance planned procedures (dentist etc.).

Written information should be provided. An alert card is included in the packaging of each of the four DOACs and patients should be advised to carry this on their person at all times. The Irish Medication Safety Network (IMSN) have produced a patient information booklet on anticoagulation in AF. It contains information on the condition of AF and includes general and specific information on all four DOACs. It can be accessed, along with the link to a patient safety video, on the IMSN website (https://imsn.ie/direct-oralanticoagulants-doacs/) or hard copies can be ordered from Bayer. (dominic.redmond@bayer.com).

Adherence should be assessed on an ongoing basis. Asking patients in a non-judgemental way whether they have missed any doses of medication recently can open this conversation.

Twice daily dosing regimens have

been associated with reduced adherence. Patients who report missing doses of a twice daily DOAC despite adequate education should be advised that there are once daily DOAC options available and should be referred to the prescriber for consideration of a switch in therapy.

Interactions Interactions affecting DOACs can be pharmacokinetic or pharmacodynamic in nature.

For the most part information on important interactions can be found in the SPC and/or the BNF - reference sources familiar to all pharmacists. The European Heart Rhythm Association (EHRA) have produced a Practical Guide2 on many different aspects of DOAC therapy in AF. The guide was first produced in 2013 and is currently in its third iteration. It contains a wealth of information in relation to DOAC prescribing and ongoing monitoring and is one of the key references I consult regularly. The EHRA guide includes an extensive section on DOAC interactions which is a really useful resource for pharmacists in practice.

DOAC pharmacokinetics are affected by concomitant administration of medications which either inhibit or induce the P-gp transporter and/or CYP3A4 isoenzyme. Some combinations such as dabigatran and the P-gp inhibitor dronedarone are contraindicated by the manufacturer due to an unacceptable increase in plasma concentrations of DOAC. The EHRA guide contains information on additional potential interactions not included in the SPCs and also provides some guidance around instances where a

patient may have more than one risk factor affecting DOAC plasma levels present.

Clinically relevant pharmacodynamic drug-drug interactions generally involve the co-prescription of medications which increase the risk of bleeding.

Patients taking DOACs should be advised to avoid the use of nonsteroidal anti-inflammatory drugs.

The concomitant administration of a low dose antiplatelet such as aspirin or clopidogrel with a DOAC is indicated in some instances. However, pharmacists should query the ongoing need for antiplatelet therapy in patients who are newly prescribed a DOAC. Where the indication for the antiplatelet was primary prevention it should be discontinued to minimise the bleeding risk.

A complex scenario arises when AF patients undergo coronary stenting. Such patients will require a period of treatment with “triple therapy” following their stenting procedure i.e. dual antiplatelet therapy (with clopidogrel and aspirin) and a DOAC. Where such a situation arises clear instruction from the cardiology team in secondary care should be communicated to the patient, the GP and the pharmacist outlining the short, intermediate and longterm plan for antiplatelet and DOAC therapy.

In most instances DOACs should not be prescribed alongside other anticoagulants and any such prescription should be clarified with the prescriber. An exception however is the scenario where a patient is switching from DOAC to warfarin therapy where continuation of DOAC may be required for a

number of days due to the slow onset of action of warfarin. Full details on switching between anticoagulants is discussed in detail in the EHRA guide.

Selective serotonin reuptake inhibitors (SSRIs), and other antidepressants with affinity for serotonin receptors, are associated with an increased risk of bleeding.

This risk increases further in the presence of DOACs. Where a combination of medications which increase a patients bleeding risk are co-prescribed, it’s worth highlighting that gastroprotection with a proton pump inhibitor or H2-receptor antagonists should be considered.

Conclusion DOACs are an essential treatment for the prevention of stroke in patients with AF. They are also highrisk medications. Pharmacists and their teams in community are central to ensuring the safe and effective use of DOACs through patient education, adherence checks and regular medication review.

References 1. Medicines Management Programme HSE: Anticoagulation Prescribing Tips. https://www. hse.ie/eng/about/who/cspd/ ncps/medicines-management/ oral-anticoagulants/ (2020).

Accessed 27/02/2022.

2. Steffel J, Collins R, Antz M, Cornu P, Desteghe L, Haeusler KG, et al. 2021 European Heart Rhythm Association Practical Guide on the Use of Non-Vitamin K Antagonist Oral Anticoagulants in Patients with Atrial Fibrillation.

EP Europace. 2021;23(10):161276. doi: 10.1093/europace/ euab065.

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Cardiac and Non-Cardiac Outcomes Reassuring cardiac and non-cardiac outcomes for heart failure patients managed in a disease management programme during the COVID-19 pandemic Written by Joseph McCambridge1 Katherine McDonald1 Líbhan Collins1 Barry Dyer1 Carmel Halley1 Matthew Barrett1 - St Vincent’s Healthcare Group, Elm Park, Dublin 4, Ireland Mark Ledwidge1 Kenneth McDonald1 - St Vincent’s Healthcare Group, University College Dublin, Dublin 4, Ireland The impact of COVID-19 on outcomes for patients with established heart failure (HF) has been limited to the risk of acute heart failure admission (AHF)1, 2, 3, 4, 5 and risk of in-hospital mortality.3 Little if any commentary has been provided on the threat of the pandemic on noncardiovascular outcomes among HF patients and also whether the threat to HF outcomes is different dependent on HF phenotype.

Furthermore, observations to date have not been stated to have come from within a disease management programme (DMP), the structure of which could mitigate some of the impact of COVID-19 through remote monitoring.

We analysed the impact of the COVID-19 pandemic on all elective and emergency hospitalisations and mortality in a HF population managed in a DMP. We also assessed any difference in outcomes between those with HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF).

We undertook a retrospective analysis of hospitalisations and deaths among two sequential HF cohorts attending our HF unit (HFU). Emergency hospitalisation was recorded as AHF, acute cardiovascular but not HF-related (ACV) and non-cardiovascular (ANCV). Elective hospitalisation was noted as cardiovascular (ECV) and non-cardiovascular (ENCV).

The first cohort (C1) included all patients who attended the HFU for the first time with a new diagnosis of HF in 2018. Hospitalisation and death rates of this cohort were evaluated in the period January to August 2019. The second cohort (C2) included patients who first attended the HFU in 2019, and the hospitalisation and death rates of this cohort were assessed from January to August 2020. This comparison allowed C1 to act as a form of ‘historical’ control for C2 with patients managed in the same unit. The patient cohorts included new community diagnoses of

HF and hospital discharges following AHF admission. The months January to August in 2020 were chosen as they corresponded with the first surge of COVID-19 cases internationally and in Ireland, and the period of maximal disruption to chronic HF management in our HFU. During this period, much of our standard HF outpatient management was delivered remotely through our DMP, including nurse-provided weekly calls to post-discharge patients and doctor telephonic consultation to any patient reporting concerning issues. These contacts were complemented by virtual consultation services to the family doctor. In-person consultations with patients were restricted to those with likely HF problems not resolving with telephonic advice and those patients requiring face-to-face review following AHF admission.

Further detail on service disruption

in our unit has been discussed in a recent publication showing good clinician and patient satisfaction with remote telephonic monitoring of HF patients during the COVID-19 pandemic.6 Patient demographics for this study were taken from the HF database in the HFU. Hospitalisation data were extracted from the Hospital In-Patient Enquiry (HIPE) database from the three hospitals within our region. Mortality data were taken from both the HFU database and www.rip.ie. Statistical analysis was performed using SPSS Statistics 27. A p value < 0.05 was taken as significant.

Hospitalisation and mortality rates were analysed in 479 patients in C1 and 493 patients in C2.

Baseline demographics are shown in Table 1. Patients were of similar mean age, gender and had similar baseline comorbidities.

Weekly national case numbers of

COVID-19 infection in Ireland for this period are shown in Fig. 1.

Table 1. SD, standard deviation; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; EF, ejection fraction; Table 1. SD, standard deviation; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; EF, ejection fraction; NYHA, New York Heart Association *Cohort 1 implies the cohort of patients who first attended the heart failure unit (HFU) in 2018 and whose admissions between January-August 2019 were analysed in this study; Cohort 2 implies the cohort of patients who first attended the HFU in 2019 and whose admissions between January-August 2020 were analysed in this study †EF unknown for 30 patients in Cohort 1 and 37 patients in Cohort 2.

Baseline Demographics Cohort 1* (n = 479) Cohort 2* (n = 493) p-value Age at first attendance, mean (SD)

74 (13.2)

74 (12.3)

Male

254 (53%)

278 (56.4%)

0.32

Diabetes

102 (21.3%)

84 (17%)

0.11

Hypertension

164 (34.2%)

183 (37.1%)

0.38

Ischaemic heart disease

79 (16.5%)

76 (15.4%)

0.71

Haemoglobin at baseline in g/dL, mean (SD)

12.9 (1.8)

13.2 (6.3)

0.76

Creatinine at baseline in μmol/L, mean (SD)

106 (51)

100 (47)

0.31

• HFpEF (EF ≥ 50%)

229 (51%)

237 (52%)

0.77

• HFrEF (EF < 50%)

220 (49%)

219 (48%)

0.77

•I

24 (5%)

22 (4.5%)

0.73

• II

163 (34%)

173 (35.1%)

• III

268 (56%)

275 (55.8%)

• IV

24 (5)

23 (4.6%)

Heart failure phenotype†

NYHA class, n (%)

Table 1. SD, standard deviation; HFpEF, heart failure with preserved ejection

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fraction; HFrEF, heart failure with reduced ejection fraction; EF, ejection

39

Fig. 1. The first confirmed COVID-19 infection in Ireland was detected on February 28th 2020. The above figures were sourced from the Central Statistics Office of Ireland.

NYHA, New York Heart Association *Cohort 1 implies the cohort of patients who first attended the heart failure unit (HFU) in 2018 and whose admissions between January-August 2019 were analysed in this study; Cohort 2 implies the cohort of patients who first attended the HFU in 2019 and whose admissions between January-August 2020 were analysed in this study †EF unknown for 30 patients in Cohort 1 and 37 patients in Cohort 2.

In the 2020 period (C2) during the first wave of the COVID-19 pandemic, there was a trend to fewer patients admitted for AHF, ANCV, ECV and ENCV in comparison to C1 in 2019, though these findings were not statistically significant. ACV admissions were marginally but not significantly greater in C2 (Fig. 2). In addition, there was a trend to a shorter length of stay for C2 for AHF management (8.6 vs 10 days; p = 0.3).

Overall mortality was low in each cohort during the time periods analysed with no significant difference found (1.7% in C1 vs.

0.6% in C2, p = 0.137).

We report on the morbidity and mortality risk for HF patients managed within a DMP during the first phase of the COVID-19 pandemic. No increased emergency admission risk was identified across all admission types. In addition, outcomes were similar for the two major HF phenotypes.

These data are encouraging considering the multiple threats

that COVID-19 can present to HF patients. A possible explanation is that these threats are counterbalanced by access to a DMP, linking dominantly by virtual means. Telephonic remote assessments of patients were complemented by virtual consultations with general practitioners (GPs) to support community management of patients. A previous study from our unit showed that the majority of patients with established HF experiencing an acute decompensation sought a medical assessment in the community prior

to presenting to hospital- most commonly in a HF clinic or GP practice.7 This, and the anecdotal evidence of patients’ reluctance to present directly to hospital during the pandemic, suggests a high likelihood that a significant proportion patients experiencing HF symptoms sought or would seek care within the infrastructure provided by the DMP. However, in the recently published GUIDE-HF trial a similar reduction in HF event rates was demonstrated during the COVID-19 era, along with a reduction in pulmonary pressures

Analysis according to HF phenotype demonstrated similar trends in both HFpEF and HFrEF patients. However, HFrEF patients had a trend towards a larger decrease in the relevant admission categories in C2, during the COVID-19 era (Fig. 3).

Fig. 2. AHF, acute heart failure; CV, cardiovascular; non-CV, non-cardiovascular.

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CARDIOLOGY FOCUS: CARDIAC OUTCOMES

particularly in the control group.8 This suggests that there are also other factors that likely interplay to explain changes in disease progression and event rates in HF patients during the pandemic.

have contributed to protecting against ANCV admissions. A trend towards higher ACV admissions in the COVID-19 era was observed, possibly linked to a reduction in ECV admissions allowing issues to graduate to need for emergency care.

The restrictions on movement during the pandemic may also

While the results are reassuring, it is important to note that the impact

of the pandemic was assessed over a short period. Longer term impact requires analysis and in particular the impact on titration of disease modifying therapy that might have resulted from lack of face-to-face appointments.

Additional limitations include our retrospective design and the small number of events. However, our analysis provides a direct

comparison of patients at the same stage of their HF syndrome managed in the same setting.

In conclusion, we found no deleterious short-term impact of the COVID-19 pandemic on emergency admissions or mortality in a HF cohort. These encouraging data might reflect the beneficial impact of continuing access to care through the DMP structure of care.

References available on request

Fig. 3. AHF, acute heart failure; CV, cardiovascular; non-CV, noncardiovascular; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction.

Heart News Major Heart Disease Study Twenty minutes of daily moderate to vigorous exercise in early old age (70-75) may best stave off major heart disease, including heart failure, in late old age (80+), a new study has suggested.

The findings of the research published online in the journal Heart, reinforce the maxim of ‘better late than never,’ when it comes to exercise, but earlier on in older age is better still, concluded a linked editorial in the same journal.

Relatively few studies have looked exclusively at whether exercise in later life can help ward off heart disease and stroke in old age.

To plug this knowledge gap, researchers from Italy drew on data from a study of 3,099 older Italians (65 and above).

Initial assessments, including a detailed medical history, physical examination, scans, and a battery of blood tests were carried out between 1995 and 1997, with two further assessments 4 and 7 years later.

At the start of the study, women were more likely than men to have 4+ coexisting conditions, with a higher prevalence of osteoarthritis, osteoporosis, and chronic kidney disease; chronic obstructive pulmonary disease (COPD) and diabetes were more common among the men.

Participants filled in questionnaires on their physical activity levels at each of the time points. Moderate physical activity included walking, bowls, and fishing, while vigorous

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physical activity included gardening, gym workouts, cycling, dancing, and swimming.

Those whose physical activity added up to 20 or more minutes a day were defined as active; those who clocked up less than this were defined as inactive. Men were more likely to be physically active than women.

The health of all the participants was then tracked through linkage to hospital discharge records and death certification up to the end of December 2018. The final analysis included 2,754 participants with complete data, of whom 1,398 were women.

During the monitoring period, 1,037 new diagnoses of heart disease, heart failure, and stroke were made.

The largest reduction in risk was observed for new cases of coronary heart disease and heart failure in late old age. No significant association between physical activity and stroke was observed.

Most of the participants had stable active physical activity patterns over time. Patterns of stable-high physical activity were associated with a significantly (52%) lower risk of cardiovascular disease among men compared with those with stable-low patterns.

The greatest benefits seemed to occur at the age of 70. Risk was only marginally lower at the age of 75, and no lower at the age of 80-85, suggesting that improving physical activity earlier in old age might have the most impact, say the researchers.

For patients living with heart failure,

Time is essential.

So is starting with ENTRESTO®1-4 Change the heart. Change heart failure 5-9 Reverse adverse cardiac remodelling, improve cardiac structure and pumping function, and target HF via a unique dual MOA that inhibits neprilysin and RAAS

Safety and tolerability profile similar to ACEi 5,10-12 In all stages of the HFrEF patient journey whether initiated in the hospital or outpatient setting

Make a lasting difference patients can feel 5,10,11,13-15 Help your patients stay out of the hospital, live longer, and feel better, so they have more time for what matters most

Start ENTRESTO® as early as possible in your HFrEF patients to help keep them at home and better protected†1-4 ENTRESTO® is indicated in adult patients for treatment of symptomatic chronic heart failure with reduced ejection fraction.

MOA=mechanism of action; RAAS=Renin-Angiotensin-Aldosterone System; HFrEF=heart failure with reduced ejection fraction. *In place of an ACEi or ARB. †For PCRS reimbursement of ENTRESTO®, HF patients must meet the following criteria: HFrEF ≤ 35%, currently prescribed ACEi/ARB therapy, symptomatic (NYHA Class II-IV), Systolic Blood Pressure ≥ 100 mmHG, Potassium ≥ 5.4mmol/L. Abbreviated Prescribing Information Please refer to Summary of Product Characteristics (SmPC) before prescribing.

Entresto® (sacubitril valsartan) 24 mg/26 mg film-coated tablets, 49 mg/51mg film-coated tablets and 97mg/103mg film-coated tablets Presentation: Film-coated tablets of 24 mg/26 mg, 49 mg/51mg and 97 mg/103 mg of sacubitril and valsartan respectively (as sacubitril valsartan sodium salt complex). Indications: In adult patients for treatment of symptomatic chronic heart failure with reduced ejection fraction. Dosage and administration: The recommended starting dose of Entresto is one tablet of 49 mg/51 mg twice daily, doubled at 2-4 weeks to the target dose of one tablet of 97 mg/103 mg twice daily, as tolerated by the patient. In patients not currently taking an ACE inhibitor or an ARB, or taking low doses of these medicinal products, a starting dose of 24 mg/26 mg twice daily and slow dose titration (doubling every 3 - 4 weeks) are recommended. A starting dose of 24 mg/26 mg twice daily should be considered for patients with SBP ≥100 to 110 mmHg, moderate or severe renal impairment (use with caution in severe renal impairment) and moderate hepatic impairment. Do not co-administer with an ACE inhibitor or an ARB. Do not start treatment for at least 36 hours after discontinuing ACE inhibitor therapy. Entresto may be administered with or without food. The tablets must be swallowed with a glass of water. Splitting or crushing the tablets is not recommended. Contraindications: Hypersensitivity to the active substances or to any of the excipients. Concomitant use with ACE inhibitors. Do not administer until 36 hours after discontinuing ACE inhibitor therapy. Known history of angioedema related to previous ACE inhibitor or ARB therapy. Hereditary or idiopathic angioedema. Concomitant use with aliskiren-containing medicinal products in patients with diabetes mellitus or in patients with renal impairment (eGFR <60 ml/min/1.73 m2). Severe hepatic impairment, biliary cirrhosis and cholestasis. Second and third trimesters of pregnancy.

Warnings/Precautions: Dual blockade of the renin angiotensin-aldosterone system (RAAS): Combination with an ACE inhibitor is contraindicated due to the increased risk of angioedema. Sacubitril/valsartan must not be initiated until 36 hours after taking the last dose of ACE inhibitor therapy. If treatment with sacubitril/valsartan is stopped, ACE inhibitor therapy must not be initiated until 36 hours after the last dose of sacubitril/valsartan. Combination of sacubitril/valsartan with direct renin inhibitors such as aliskiren is not recommended. Sacubitril/valsartan should not be co-administered with another ARB containing product. Hypotension: Treatment should not be initiated unless SBP is ≥100 mmHg. Patients with SBP <100 mmHg were not studied. Cases of symptomatic hypotension have been reported in patients treated with sacubitril/valsartan during clinical studies, especially in patients ≥65 years old, patients with renal disease and patients with low SBP (<112 mmHg). Blood pressure should be monitored routinely when initiating or during dose titration with sacubitril/valsartan. If hypotension occurs, temporary down-titration or discontinuation of sacubitril/valsartan is recommended. Impaired or worsening renal function: Limited clinical experience in patients with severe renal impairment (estimated GFR <30 ml/min/1.73m2). There is no experience in patients with end-stage renal disease and use of sacubitril/valsartan is not recommended. Use of sacubitril/valsartan may be associated with decreased renal function, and down-titration should be considered in these patients. Hyperkalaemia: Treatment should not be initiated if the serum potassium level is >5.4 mmol/l. Monitoring of serum potassium is recommended, especially in patients who have risk factors such as renal impairment, diabetes mellitus or hypoaldosteronism or who are on a high potassium diet or on mineralocorticoid antagonists. If clinically significant hyperkalaemia occurs, consider adjustment of concomitant medicinal products or temporary down-titration or discontinuation of sacubitril/valsartan. If serum potassium level is >5.4 mmol/l discontinuation should be considered. Angioedema: Angioedema has been reported with sacubitril/valsartan. If angioedema occurs, discontinue sacubitril/valsartan immediately and provide appropriate therapy and monitoring until complete and sustained resolution of signs and symptoms has occurred. Sacubitril/valsartan must not be re-administered. Patients with a prior history of angioedema were not studied. As they may be at higher risk for angioedema, caution is recommended if sacubitril/valsartan is used in these patients. Black patients have an increased susceptibility to develop angioedema. Patients with renal artery stenosis: Caution is required and monitoring of renal function is recommended. Patients with NYHA functional classification IV: Caution should be exercised due to limited clinical experience in this population. Patients with hepatic impairment: There is limited clinical

experience in patients with moderate hepatic impairment (Child Pugh B classification) or with AST/ALT values more than twice the upper limit of the normal range. Caution is therefore recommended in these patients. B-type natriuretic peptide (BNP): BNP is not a suitable biomarker of heart failure in patients treated with sacubitril/valsartan because it is a neprilysin substrate. Psychiatric disorders: hallucinations, paranoia and sleep disorders, in context of psychotic events, have been associated with sacubitril/valsartan use. Consider discontinuation if patient experiences such events. Interactions: Contraindicated with ACE inhibitors, 36 hours washout is required. Use with aliskiren contraindicated in patients with diabetes mellitus or in patients with renal impairment (eGFR <60 ml/min/1.73 m2). Should not be co-administered with another ARB. Use with caution when co-administering sacubitril/ valsartan with statins or PDE5 inhibitors. No clinically relevant drug-drug interaction was observed when simvastatin and sacubitril/valsartan were coadministered. Monitoring serum potassium is recommended if sacubitril/valsartan is co-administered with potassium-sparing diuretics or substances containing potassium (such as heparin). Monitoring renal function is recommended when initiating or modifying treatment in patients on sacubitril/ valsartan who are taking NSAIDs concomitantly. The combination of sacubitril/valsartan and lithium is not recommended. If the combination proves necessary, careful monitoring of serum lithium levels is recommended. Co-administration of sacubitril/valsartan and furosemide reduced Cmax and AUC of furosemide by 50% and 28%, respectively, with reduced urinary excretion of sodium. Co-administration of nitroglycerin and sacubitril/valsartan was associated with a treatment difference of 5 bpm in heart rate compared to the administration of nitroglycerine alone, no dose adjustment is required. Coadministration of sacubitril/valsartan with inhibitors of OATP1B1, OATP1B3, OAT3 (e.g. rifampicin, ciclosporin), OAT1 (e.g. tenofovir, cidofovir) or MRP2 (e.g. ritonavir) may increase the systemic exposure of sacubitril or valsartan. Appropriate care should be exercised. Co-administration of sacubitril/valsartan with metformin reduced both Cmax and AUC of metformin by 23%. When initiating therapy with sacubitril/valsartan in patients receiving metformin, the clinical status of the patient should be evaluated. Fertility, pregnancy and lactation: The use of sacubitril/valsartan is not recommended during the first trimester of pregnancy and is contraindicated during the second and third trimesters of pregnancy. It is not known whether sacubitril/valsartan is excreted in human milk, but components were excreted in the milk of rats. Sacubitril/valsartan is not recommended during breast-feeding. A decision should be made whether to abstain from breast-feeding or to discontinue sacubitril/valsartan while breast-feeding, taking into account the importance of sacubitril/ valsartan to the mother. No available data on the effect of sacubitril/valsartan on human fertility. Undesirable effects: Very common: Hyperkalaemia, hypotension, renal impairment. Common: Anaemia, hypokalaemia, hypoglycaemia, dizziness, headache, syncope, vertigo, orthostatic hypotension, cough, diarrhoea, nausea, gastritis, renal failure, acute renal failure, fatigue, asthenia. Uncommon: Hypersensitivity, postural dizziness, pruritus, rash, angioedema.

Rare: Hallucinations, sleep disorders. Very rare: Paranoia. Please refer to SmPC for a full list of adverse events for Entresto. Pack sizes: Entresto 24 mg/ 26 mg - 28 tablet pack; Entresto 49 mg/51 mg - 28 and 56 tablet pack; Entresto 97 mg/103 - 56 tablet pack. Legal Category: POM. Marketing Authorisation Holder: Novartis Europharm Limited, Vista Building, Elm Park, Merrion Road Dublin 4, Ireland. Marketing Authorisation Numbers: Entresto 24 mg/26 mg film coated tablets EU/1/15/1058/001; Entresto 49 mg/51 mg film coated tablets EU/1/15/1058/002-003; Entresto 97 mg/103 mg film coated tablets EU/1/15/1058/006. Full prescribing information is available on request from Novartis Ireland Ltd, Vista Building, Elm Park Business Park, Merrion Road, Dublin 4. Tel: 01 2601255 or at www.medicines.ie. Detailed information on this product is also available on the website of the European Medicines Agency http://www.ema.europa.eu. Prescribing Information last revised: May 2021 Reporting suspected adverse reactions of the medicinal product is important to Novartis and the HPRA. It allows continued monitoring of the benefit/risk profile of the medicinal product. All suspected adverse reactions should be reported via HPRA Pharmacovigilance, website www.hpra.ie. Adverse events could also be reported to Novartis preferably via www.report.novartis.com or by email: drugsafety.dublin@novartis.com or by calling 01 2080 612.

REFERENCES: 1. Seferovic PM, Ponikowski P, Anker SD, et al. Clinical practice update on heart failure 2019: pharmacotherapy, procedures, devices and patient management. An expert consensus meeting report of The Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail. 2019;21(10):1169-1186. 2. Hollenberg SM, Stevenson LW, Ahmad T, et al. 2019 ACC expert consensus decision pathway on risk assessment, management, and clinical trajectory of patient hospitalized with heart failure: a report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. 2019;74(15):1966-2011. 3. Maddox TM, Januzzi JL, Allen, LA, et al; 2021 Update to the 2017 ACC Expert Consensus Decision Pathway for Optimization of Heart Failure Treatment: Answers to 10 Pivotal Issues About Heart Failure With Reduced Ejection Fraction. J Am Coll Cardiol. 2021 Feb, 77 (6) 772–810. 4. CaReMe Heart Failure in Adults: Diagnosis & Management Algorithm. Available at: cardionewsuk.org. (Accessed: November 2021). 5. ENTRESTO Summary of product characteristics. Available at www.medicines.ie 6. Januzzi JL Jr, Prescott MF, Butler J, et al; for the PROVE-HF Investigators. Association of change in N-terminal pro–b-type natriuretic peptide following initiation of sacubitril-valsartan treatment with cardiac structure and function in patients with heart failure with reduced ejection fraction [published online ahead of print September 2, 2019].

JAMA. doi:10.1001/jama.2019.12821. 7. Desai AS, Solomon SD, Shah AM, et al; for the EVALUATE-HF Investigators. Effect of sacubitril-valsartan vs enalapril on aortic stiffness in patients with heart failure and reduced ejection fraction; a randomized clinical trial. JAMA. 2019;322(11):1077-1084.

8. Ramani GV, Uber PA, Mehra MR. Chronic heart failure: contemporary diagnosis and management. Mayo Clin Proc. 2010;85(2):180-195. 9. McDonagh T, Metra M et al ESC Scientific Document Group, 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: Developed by the Task Force for the diagnosis and treatment of acute and chronic heart failure of the ESC With the special contribution of the HFA of the ESC, European Heart Journal, 2021;ehab368, https://doi.org/10.1093/eurheartj/ehab368 10. McMurray JJV, Packer M, Desai AS, et al; for the PARADIGM-HF Investigators and Committees; Angiotensin–neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371(11):993-1004. 11. Velazquez EJ, Morrow DA, DeVore AD, et al; for the PIONEER-HF Investigators. Angiotensin–neprilysin inhibition in acute decompensated heart failure. N Engl J Med. 2019;380(6):539-548. 12. Wachter R, Senni M, Belohlavek J, et al; on behalf of the TRANSITION Investigators. Initiation of sacubitril/valsartan in haemodynamically stabilised heart failure patients in-hospital or early after discharge: primary results of the randomised TRANSITION per approved citation: study [published online ahead of print May 27, 2019]. Eur J Heart Fail. 2019. doi:10.1002/ehjf.1498. 13. Claggett B, Packer M, McMurray JJV, et al; for the PARADIGM-HF Investigators. Estimating the long-term treatment benefits of sacubitril–valsartan. N Engl J Med. 2015;373(23):22892290. 14. Lewis EF, Claggett BL, McMurray JJV, et al. Health-related quality of life outcomes in PARADIGM-HF. Circ Heart Fail. 2017;10(8):e003430. 15. Chandra A, Lewis EF, Claggett BL, et al. Effects of sacubitril/valsartan on physical and social activity limitations in patients with heart failure. A secondary analysis of the PARADIGM-HF trial. JAMA Cardiol. 2018;3(6):498-505.

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CARDIOLOGY FOCUS: VTE Venous Thromboembolism (VTE) is one of the mos

Developing a VTE Risk Assessment manifests clinically Video in Deep Veinfor Thrombosis (DVT), w Clinicians: Including the end userEmbolism (PE), which can form insitu or t Pulmonary

(1, 2). Venous Thromboembolism is a major global bu

Written by: Kate O’Callaghan Venous Thromboembolism (VTE) is one of the most common cardiovascular diseases. This manifests clinically in Deep Vein Thrombosis (DVT), whereby a blood clot forms in the leg and Pulmonary Embolism (PE), which can form insitu or the clot in the leg travels to the lungs (PE).1, 2 Venous Thromboembolism is a major global burden and with the population aging the incidence of this disease is likely to increase.3 Reports note that approximately 10 million cases of VTE occur every year, incurring an economic burden, increasing hospital length of stay, the clinician burden, and increase in medication usage.3 Despite being a potentially preventable disease4 and with national guidelines in place stating the need to assess for VTE risk assessment for all patients admitted to hospital5, pharmacological thromboprophylaxis (PT) is still underutilized. A recent Irish report noted that 70% of hospital acquired VTE (VTE during an admission or 90 days post admission) were preventable.6 Balancing the need for the thromboprophylaxis with the risk of bleeding and without the use of risk prediction tools, the risk of over or under utilisation of thromboprophylaxis can occur.7 The inclusion of the end user in the diffusion of healthcare technology has proven to be an important tool that can have a positive influence on the use of VTE risk assessments.7 With the utilisation of digital health interventions becoming more prominent, the aim of this research was to examine the evidence in relation to the use of digital health as a means to assess risk of VTE and guide evidence-based treatment.

This research is based in part on Haemostasis Research Foundation sessions and their participation a final year dissertation for the and support from line Managers, in obtaining feedback on the incidence of this disease is will likely to increase (3). Repo taught MSc Digital Health course there has been the opportunity video be garnered through the for this project to continue and offered by UCC. The title of the completion of a survey tool. This develop. The initial prototype of research was: Exploring clinicians’ feedback be used to make cases of VTE occur every year,willincurring an economic the video has been created and perspectives on the current Venous further improvements for future the next step is to obtain feedback Thromboembolism risk assessment iterations and sharing of the video. from clinicians on the further practices in Cork University stay, the clinician burden, and increase inOnce medication (3).isDespit the 3rd versionusage of the video development and implementation Hospital and their acceptability made clinicians will again be asked of this video in practice. towards an e-learning platform to complete the survey the with the disease place stating need to as for VTE risk assessments in the(4) and with national guidelines in aim of revisiting the utility and also From the literature review, there is future. The second stage of this assessing any potential behavioural certain positivity seen in utilising project now works in collaboration patients admitted hospital pharmacological thromboprophylaxi changes or intentions to change human to factor elements, (5), whereby between the Haematology Dept. behaviours from the clinical the end user is involved in the (Dr Maeve Crowley) in CUH and the standpoint.

The overarching implementation technology, acquired report noted that 70% ofofhospital VTE (VTE duringaim anofadmiss Cork University Business School, this project is to include a VTE risk such as the development of a VTE UCC (Dr Wendy Rowan). The assessment video into clinicians risk assessment and prescription original research was qualitative in preventable (6).

Balancing need thromboprophylaxis teaching, so that it can be played with t process as a whole.the Nwulu et al. for the nature and aimed at understanding (2014) explored education in the at each rotation in order to assist the clinician’s experience of VTE utility of the VTE risk assessments clinicians with: risk and completingof therisk risk prediction tools, the risk of over or under utilisation of thrombo and the importance of prophylaxis assessment in CUH (Image shows • VTE Risk reminders to assess was seen to improve outcomes some feedback from clinicians).

9 healthcare todaytechnology and tomorrow. has proven to of the end user the diffusion of in ain longitudinal cohort study There was a desire to understand and the need for increased • Reducing VTE morbidity and if clinicians felt there was more time in orientation is cited as an mortality.

(7). With the util training needed andpositive if so, what influence on the use of VTE risk assessments improvement that needs to be • Complete the VTE Risk would this training look like. After 8 made. Similarly, in a recent 2019 Every Admission. analysing the qualitative data using Brazilian study education seen becoming more prominent, thewas aim of thisAssessment researchat was to examine th thematic analysis, the development to be a positive aspect for on-going If you are reading this and of a VTE risk assessment video was in this area.10 to get involved and identified as a needdigital and different health research as a means to assess risk ofwould VTElikeand guide evidence-base offer some support and feedback to elements within the video design The next step for this research is this research project, then were categorised in relation to to obtain continued support and please contact Kate at: clinical motivators to prompt and advice from clinicians. The second (kate.ocallaghan@hse.ie). remind clinicians to complete phase of the study is based on the VTE risk assessment. With the support from the HIHI Spark Ignite Process, and mentorship from Ali Rose Sisk, a successful funding application to the Irish

APRIL 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

video development cycles with quantitative feedback from research participants. The 2nd and 3rd iterations of the video prototype will be shown to SHOs at their teaching

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CARDIOLOGY FOCUS: ANEURYSM

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Overview of Proximal Aortic Aneurysms Anatomy of the proximal aorta An understanding of the anatomy of the proximal aorta is essential when considering aortic aneurysms.

The proximal aorta is divided into several segments (Figure 1):  Root: extends from Left ventricular outflow tract up to the sinotubular junction(STJ).

Contains the coronary ostia, aortic valve and sinuses of Valsalva.  Ascending Aorta: above the STJ up to the level of the innominate artery  Arch: contains the epi-aortic vessels – The innominate artery, left common carotid artery and left subclavian artery.

Aortic arch Ascending thoracic aorta

Sinotubular junction Aortic root (Sinuses of Valsalva)

Mr Saleem Jahangeer, Consultant Cardiac and Aortic Surgeon, St James’s Hospital Dublin aorta@stjames.ie

 Descending Aorta: Extending from the left subclavian artery to the level of the diaphragm.

Annulus Descending thoracic aorta

Proximal aortic aneurysms An aneurysm is defined as a dilatation of more than 1.5 times the size of the normal aorta.

In cases of aortic aneurysm, approximately 60% occurs in the Root/Ascending aorta, 10% in the arch, 40% in the descending aorta, and 10% in the thoracoabdominal aorta; however, an aneurysm may involve multiple aortic segments.

Very rarely, the aneurysmal process can involve the whole aorta; from aortic root to the iliac bifurcation.

Thoracic aortic aneurysms are asymptomatic in more than 95% of cases until diagnosed. The annual incidence of TAAs has been assessed at 6 to 10 cases/100,000 patient-years. Interestingly, the incidence of TAAs appears to be increasing, most probably due to an aging population and more frequent imaging.

Risk Factors for Aortic aneurysms: A. Age/Atherosclerosis B. High Blood Pressure/Bicuspid aortic valve C. Connective tissue disorders – e.g. Marfan’s Syndrome D. Dissections / Cystic media degeneration E. Trauma, aortitis, infection, syphilis F. Family history

Figure 1

Natural history of aortic aneurysms The normal aorta expands by 0.9mm/10 years in male and 0.7mm/10 years in female.

In the presence of an aneurysmal wall, expansion tends to occur faster in larger aneurysms (Law of Laplace). In dimensions > 5cm, the rate of expansion can be around 0.8cm per year.

Patients with familial aortopathy have faster growth rates of 0.21 cm/year compared with patients with sporadic TAAs (0.16 cm/year) and thus present earlier.

The main complications of an enlarging aortic aneurysm are: Aortic dissection and Aortic rupture, both of which can be fatal.

Other complications would include mass effect on adjacent structures (e.g. tracheal compression) and aortic valve regurgitation due to stretching of the valve commissural posts.

The annual risk of rupture or dissection is ∼2% for aneurysms between 4.0 and 4.9 cm, and reaches nearly 7% for sizes >6.0 cm. There is a drastic increase in

the risk of rupture or dissection beyond a diameter of 6.0cm (Figure 2). Other independent risk factors for rupture include pain, age, smoking history and COPD. Bicuspid Aortopathy It is important to consider bicuspid aortic valve when discussing aortic aneurysm.

The incidence of aortic dilation and acute complications (rupture and dissection) is higher in patients with BAV.

Marfan’s aortas grow at 0.1 cm/ year, Loeys-Dietz syndrome can grow faster than 1.0 cm/year, resulting in mean age of death at 26 years.

Figure 2: Coady MA, Rizzo JA, Hammond GL, Mandapati D, Darr U, Kopf GS, Elefteriades JA. What is the appropriate size criterion for resection of thoracic aortic aneurysms? J Thorac Cardiovasc Surg. 1997 Mar;113(3):476-91; discussion 489-91. doi: 10.1016/ S0022-5223(97)70360-X. PMID: 9081092.

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CARDIOLOGY FOCUS: ANEURYSM shows a 4-D flow MRI indicating the wall stress with bicuspid R/L fusion compared to a trileaflet aortic valve.

Figure 3: Adapted from Sievers HH, Schmidtke C. J Thorac Cardiovasc Surg 2007; 133:1226-1233

The combination of aortic coarctation and BAV is assumed to be associated with a higher risk of ascending aortic dilatation and dissection, and current European Society of Cardiology (ESC) guidelines advise therefore to operate at a lower threshold in the presence of a coarctation in BAV patients.

Diagnosis of aortic aneurysms Bicuspid aortic valve (BAV) is the most common congenital heart defect, affection around 1.4% of the population. BAV is a highly heritable trait, but the genetic causes remain largely elusive.

NOTCH1 is the only proven candidate gene to be associated with BAV. BAV has only 2 leaflets (functional or anatomical) as compared to the three leaflets of a normal aortic valve (Figure 3).

BAV are classified according to Siever’s Classification (Figure 4):

Figure 4

Type 0: No raphe Type 1: 1 raphe Type 2: 2 raphes The most common types of leaflet fusions are Right/Left fusion (70%), Right/Non-Coronary fusion (10-20%) and Left/Non-Coronary fusion (5-10%).

A Right/Left fusion tend to generate a right-handed helical flow in the aorta, resulting in dilatation of the Ascending +/Root of the aorta. A Right/NonCoronary fusion generates a lefthanded helical flow which almost always only result in the dilation of the ascending aorta. Figure 5

As mentioned, the vast majority of aortic aneurysms are clinically silent. Most aneurysms are incidentally diagnosed clinically, whether it is on a chest X-ray or CT scan done for another indication. Aortic aneurysms can also be incidentally picked up on echocardiogram. However, the smaller field of view with echocardiogram usually limits the diagnosis to the aortic root and ascending aorta only.

The gold standard diagnostic tool for aortic aneurysms remains a CT aortogram with contrast.

A gated CT scan is preferred to avoid motion artefact at the aortic root for accurate measurements.

Magnetic Resonance Angiography (MRA) also provides excellent diagnostic images and avoids exposure to ionising radiation.

MANAGEMENT OF AORTIC ANEURYSMS Medical Therapy The aim of medical therapy is to decrease the shear stress on the aortic wall by decreasing blood pressure and cardiac contractility.

B-Blockers are the first line anti-hypertensive agent with a target systolic BP of no more than 120mmHg. In patients with Marfan’s syndrome, prophylactic use of beta-blockers, angiotensinconverting enzyme (ACE) inhibitor, and angiotensin II receptor blocker have been shown to reduce either the progression of the aortic dilation or the occurrence of complications.

Figure 5: Adapted from Shan Y, Li J, Wang Y, et al. Aortic shear stress in patients with bicuspid aortic valve with stenosis and insufficiency. J Thorac Cardiovasc Surg. 2017;153(6):1263-1272.e1. doi:10.1016/j.jtcvs.2016.12.059

Most patients with aortic diseases have comorbidities such as coronary artery disease, chronic kidney disease, diabetes mellitus, dyslipidaemia and hypertension.

It is important that treatment and

Ascending aorta replacement

Aortic Root replacement

APRIL 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

Aortic Arch replacement

Aortic Arch replacement with Frozen Elephant trunk

Figure 6

45 of surgery is to prevent aortic dissection or risk of rupture by replacing the aneurysmal aorta and restoring the aortic dimensions back to normal.

The type and extent of surgery will depend on which segments of the aorta are involved. Surgery for thoracic aortic aneurysm can range from a simple interposition graft to more complex procedures such as aortic root replacements, arch replacements and Frozen elephant trunk procedures (Figure 6) Indications for surgical intervention Indications for surgery are based mainly on the aortic dimensions and derived from findings on natural history regarding the risk of complications weighed against the risk of elective surgery.

Other than absolute size, other factors such as connective tissue disease, rate of expansion, family history, concomitant aortic valve surgery and symptoms are important to consider when deciding the timing of surgery.

Figure 7 prevention strategies must be similar to those indicated for the above diseases. To prevent blood pressure spikes, competitive sports should be avoided in patients with an enlarged aorta.

Generally speaking, in patients with no elastopathy, surgery should be considered for ascending aorta/root/arch aneurysms measuring 55mm or more. In patients with connective tissue disorders such as Marfan’s, a lower threshold of 50mm is generally indicated. If high risk factors are present along with Marfan’s, surgery is indicated at a size threshold of >45mm.

Isometric exercise with a high static load (e.g. weightlifting) should be discouraged.

Surgical Intervention Surgical intervention provides definitive repair of the aneurysmal aortic segment. The main principle

In bicuspid valve patients, surgery should be performed when the maximal aortic diameter is ≥55 mm; these face a lower risk of complications than in Marfan’s patients. A lower threshold of 50 mm can be considered in bicuspid patients with additional

risk factors, such as family history, systemic hypertension, coarctation of the aorta, or rapid increase in rate of expansion.

In patients undergoing aortic valve surgery who also have a dilated aorta, the aorta is replaced as well if the diameter is >45mm.

The latest guidelines from the ESC are summarised below (Figure 7): Surveillance Patients with aortic disease usually require life-long surveillance, regardless of the initial treatment strategy (medical or surgical).

This surveillance consists of clinical evaluation, reassessment of a patient’s medical therapies and treatment goals, as well as imaging of the aorta. These patients should be followed up in a dedicated surveillance aortic clinic.

Given the silent nature of aortic aneurysms, dedicated surveillance is vital to tackle this silent killer.

In patients with aneurysm that have yet to reach threshold for surgical intervention, surveillance is particularly important to monitor rate of expansion of the aneurysm and plan surgical intervention to avoid any potential dissection or rupture. In patients who had surgery, it is important to monitor the remaining segments of aorta over time, as it is not uncommon for these patients to develop aneurysmal segments of the remaining native aortic segments over time. We have recently set up a surveillance clinic dedicated for proximal aortic aneurysms here at St James’s Hospital.

Any referrals of suspected proximal aortic aneurysms can be sent by email: aorta@stjames.ie

Heart News Link between High Cholesterol and Heart Disease ‘Inconsistent’ New research from RCSI University of Medicine and Health Sciences has revealed that the link between ‘bad’ cholesterol (LDL-C) and poor health outcomes, such as heart attack and stroke, may not be as strong as previously thought.

Published in JAMA Internal Medicine, the research questions the efficacy of statins when prescribed with the aim of lowering LDL-C and therefore reducing the risk of cardiovascular disease (CVD).

Previous research has suggested that using statins to lower LDL-C positively affects health outcomes,

and this is reflected in the various iterations of expert guidelines for the prevention of CVD. Statins are now commonly prescribed by doctors, with one third of Irish adults over the age of 50 taking statins, according to previous research.

The new findings contradict this theory, finding that this relationship was not as strong as previously thought. Instead, the research demonstrates that lowering LDL-C using statins had an inconsistent and inconclusive impact on CVD outcomes such as myocardial infarction (MI), stoke, and all-cause mortality.

In addition, it indicates that the overall benefit of taking statins may be small and will vary depending on an individual’s personal risk factors.

The lead author on the paper is Dr Paula Byrne from the HRB Centre for Primary Care Research based in RCSI’s Department of General Practice. Commenting on the findings, Dr Byrne said: “The message has long been that lowering your cholesterol will reduce your risk of heart disease, and that statins help to achieve this. However, our research indicates that, in reality, the benefits of taking statins are varied and can be quite modest.”

The researchers go on to suggest that this updated information should be communicated to patients through informed clinical decision-making and updated clinical guidelines and policy.

This important discovery was a collaboration with Professor Susan M Smith, also of RCSI and with researchers from the University of New Mexico, USA, (Dr Robert DuBroff), the Institute for Scientific Freedom in Denmark (Dr Maryanne Demasi), Bond University in Australia (Dr Mark Jones) and independent researcher Dr Kirsty O’Brien.

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CARDIOLOGY FOCUS: CLINICAL TRIALS

Heart Failure- What do the Guidelines Tell Us? Written by Dr Virginia Silvari, Senior Hospital Pharmacist (Cardiology), Cork University Hospital

The initiation of sacubitril/valsartan during hospital admission following acute HF decompensation not only caused a reduction in NT-proBNP, a biomarker of neurohormonal activation, hemodynamic stress, and subsequent cardiovascular events in HF patient, but also reduced the risk of hospitalisation.6, 7 III. The Sodium-Glucose CoTransporter 2 (SGLT2) inhibitors dapagliflozin and empagliflozin, are now recommended for patients with HFrEF to reduce the risk of hospitalisation and death. The RCTs that informed this recommendation were:

Heart failure (HF) is a complex clinical syndrome where the efficiency of the heart is impaired and it is unable to meet the demands of the body. HF is a major healthcare concern as it is associated with high mortality, morbidity, and substantial economic burden on health care systems.1 In patients with HF, the treatment goals are to reduce mortality, improve clinical status, improve quality of life (QoL) and prevent hospital admissions.2 In 2021, the European Society of Cardiology (ESC) released the latest guidelines for the diagnosis and treatment of acute and chronic HF.3 New concepts and recommendations make the 2021 guidelines a significant step forward from the previous ESC guidelines released in 2016.4 From a Pharmacist’s perspective, the following points are of particular interest:

patients with HF with reduced ejection fraction (HFrEF), where EF is <40%, to reduce the risk of hospitalisation and death. Two RCTs informed this recommendation: • PIONEER-HF: Comparison of Sacubitril–Valsartan versus Enalapril on Effect on N-terminal pro b-type natriuretic peptide (NT-proBNP) in Patients Stabilized from an Acute Heart Failure Episode.6 • TRANSITION: Comparison of Pre- and Post-discharge Initiation of Sacubitril/ Valsartan Therapy in HF With Reduced Ejection Fraction Patients After an Acute Decompensation Event.7

I. The introduction of new terminology for HF classification. HF with midrange ventricular Ejection Fraction (EF) has been renamed in the 2021 HF guidelines as ‘HF with mildly reduced EF’ (HFmrEF) when EF is between 41-49%. This change in terminology was supported by the evidence gained in HF Randomised Control Trials (RCTs) that showed how patients with EF 41-49% benefited from similar treatment to patients with EF<40.5 II. The 2021 HF guidelines recommend sacubritil/valsartan, an Angiotensin Receptor Neprilysin Inhibitor (ARNI), as a replacement for the Angiotensin-Converting Enzyme inhibitors (ACEi) or Angiotensin receptor blockers (ARBs) for APRIL 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

• DAPA-HF: Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure8 • EMPEROR-Reduced: Empagliflozin Outcome Trial in Patients with Chronic Heart Failure and a Reduced Ejection Fraction.9 The DAPA-HF trial which prospectively evaluated the efficacy and safety of dapagliflozin in patients with HFrEF, regardless of the presence or absence of diabetes, showed a 26% reduction of the primary outcome. The primary outcome was a composite of worsening HF or death from cardiovascular causes in patient treated with dapagliflozin in addition to standard treatment, compared to placebo and standard treatment.8 The EMPEROR-

Reduced trial which prospectively evaluated the efficacy and safety of empagliflozin in patients with HFrEF, regardless of the presence or absence of diabetes showed a 24% reduction of the primary outcome, which was a composite of death from cardiovascular causes or hospitalization for worsening HF in patients treated with empagliflozin in addition to standard treatment, compared to standard treatment and placebo.9 The new evidence- based treatment options: the ARNI (in place of ACEi or ARBs) and SGLT2 inhibitors are now available for the optimal management of patients with HF. These agents have proven to help reduce hospitalization and mortality in patients with HF. In addition to β- blockers and mineralocorticoid receptor antagonists, ARNI and SGLT2 inhibitors have become a fundamental part of the Guideline-Directed Medical Therapy (GDMT) for HF. Now that these new evidencebased HF treatments have become a fundamental part of the GDMT, it is important/ imperative that healthcare professionals adopt the use of these medications in their practice to improve outcomes for HF patients.

References available on request

CARDIOLOGY FOCUS: STROKE

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Management of Cardioembolic stroke Written by Gill Douglas, Shameer Rafee, Department of Neurology, St Vincent’s University Hospital Stroke remains a leading cause of death and disability globally. While 10-15% of strokes are haemorrhagic in nature, ischaemic stroke, due to thrombosis, embolism or systemic hypoperfusion, accounts for over 80% of cases. Acute ischaemic strokes are time sensitive due to the reperfusion treatments like thrombolysis and thrombectomy.

Accurately identifying stroke mechanism is important as it allows for evidence based recommendations for therapy and developing future preventative strategies. The TOAST classification is commonly used in stroke research and subdivides ischaemic stroke into 5 categories - a) large artery atherosclerosis, b) cardioembolism, c) small vessel occlusion, d) stroke of other determined aetiology and, e) stroke of undetermined aetiology (cryptogenic).

Approximately 20% of ischaemic strokes are cardioembolic.

Cardioembolic strokes are associated with a worse prognosis and are often more disabling.

Emboli originating from cardiac chambers are capable of occluding larger, more proximal cerebral arteries. Cardioembolic strokes have been associated with both short and long term recurrence, with incidence expected to rise worldwide due to aging populations and increasing life expectancy. They classically present with stroke of worse severity (higher NIHSS scores). Ischaemic strokes in different vascular territories are suggestive of a cardiac source, as well as stroke following valsalva manoeuvre, the presence of decreased levels of consciousness and cortical signs such as Wernicke’s aphasia, global aphasia without hemiparesis and visual field defects.

Many cardiac disorders are recognised as potential sources of embolism- atrial fibrillation (AF) remains the most significant.

It’s the most common sustained arrythmia, with its prevalence increasing in the older person. It is recognised as precipitating 50% of cases of cardioembolic strokethis may be preventable with early identification and treatment. The CHADS2VASC score can be used to predict the risk of ischaemic stroke in patients with AF. Treatment with anticoagulation can significantly reduce morbidity and

mortality and can prevent around 70% of strokes in those with AF. While atrial fibrillation is the leading cause of cardioembolic stroke, it is important to recognise other potential cardiac sources of embolism such as chamber dysfunction, valvular disease or a mechanical prosthetic valve, and infectious aetiologies like endocarditis. Myocardial infarction (MI) can lead to left ventricular dysfunction and focal areas of dyskinesia. This can result in stasis and formation of mural thrombi, leaving these patients at high risk of embolic stroke. Acute MI is considered aetiological if stroke occurs within one month of the MI. Valvular disease, including mechanical valves, also carry a high risk of embolic events and while the incidence of rheumatic mitral valve disease has decreased in recent times, it still carries a significant burden of disease in endemic and developing regions. Embolism should also be a consideration in infective endocarditis. While infective endocarditis is itself a relatively uncommon, it’s important to note that 20% of cases of endocarditis with intracardiac vegetations are complicated by embolic stroke, with the mitral valve the most frequent source of emboli. Prompt antibiotic therapy typically reduces this potential.

While there is no defined clinical criteria for the diagnosis of cardioembolic stroke, the clinical approach should include a detailed history, clinical exam, neuroimaging, ECG and, importantly, echocardiography.

Inpatient telemetry can be used to diagnose paroxysmal atrial fibrillation. Prolonged monitoring with outpatient holter monitors are recommended if suspicion remains for a cardioembolic source. Longer automated cardiac monitoring has been shown to be useful in detecting paroxysmal AF- even a 30-day recording can improve AF detection rates 5-fold (EMBRACE trial).

In 2014, the term “embolic stroke of undetermined source” (ESUS) was introduced as a subset of cryptogenic strokes for patients with non-lacunar strokes and no identifiable mechanism.

The most prevalent source of emboli is thought to remain cardiac. Although initially AF was

“Anticoagulation is a safe and effective method or reducing stroke recurrence.

Targeting cardioembolic strokes through improved detection and early treatment can reduce the global burden of stroke” considered a major factor, it is now thought to be less important for a number of reasons: studies have shown that embolic events are not temporally close to AF captured on monitoring, ESUS patients are phenotypically different from AF related strokes and, incidence of AF detection in ESUS patients is similar to nonESUS strokes. This is an area that warrants targeted research.

Transthoracic echocardiography (TTE) is often performed as a matter of routine. Transoesophageal echocardiography (TOE) is most reliable in detecting ventricular dysfunction and dysmotility, as well as interatrial shunts, atrial septal defects, and thrombosis at the atrial appendage. TOE is also useful in detecting patent foramen ovale (PFO). The association between PFO as a cause of cardioembolic stroke can be tenuous. PFO is present in about 25% of the population, and may serve as a channel for the shunting of a thrombus from the venous to the arterial circulation, a phenomenon known as paradoxical embolism.

It is believed that only a small minority of strokes can be linked causally with PFO e.g. stroke after valsalva in the presence of

Gill Douglas

a PFO or presence of deep vein/ pulmonary thromboses. A history of obstructive sleep apnoea can also be suggestive as it increases right to left shunting. The extent of shunting can be assessed intra-procedurally during TTE or TOE with agitated saline. The presence and size of the shunt can help with deciding which patients should undergo closure. The Gore-REDUCE trial showed that, with careful patient selection, PFO closure was associated with lower risk of recurrence.

Cardiac embolism should be recognised as an important source of ischaemic stroke.

It carries a high mortality and risk of complications as well as a high incidence of stroke recurrence. Inpatient assessment may be insufficient to diagnosis of AF; longer term monitoring is often warranted, particularly in cases of cryptogenic strokes.

Anticoagulation is a safe and effective method or reducing stroke recurrence. Targeting cardioembolic strokes through improved detection and early treatment can reduce the global burden of stroke.

References available on request

HOSPITALPROFESSIONALNEWS.IE | HPN • APRIL 2022

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CARDIOLOGY FOCUS: CARDIAC PSYCHOLOGY

Meeting of Hearts & Minds – The Practice of Cardiac Psychology Written by Jonathan Gallagher, Senior Psycholgist, Beaumont Hospital, Dublin - Dr Elizabeth O'Brien, Senior Clinical Psychologist, St Vincent's University Hospital and Dr Sinead Mulhern, Principal Clinical Levine et al Psychologist, Mater Hospital PSYCHOLOGICAL FACTORS & CARDIOVASCULAR DISEASE (CVD) A cardiac event such as a heart attack can be a psychologically devastating experience, with profound and enduring consequences. Frequently its onset is sudden, distressing and potentially life-threatening.

Even if this is not the case, mere knowledge of this new disease status can trigger strong and frequently long-term emotional reactions as well as prompting significant lifestyle changes.

Jonathan Gallagher

Downloaded from http://ahajournals.org by on March 16, 2022

Dr Elizabeth O'Brien

Perhaps unsurprisingly, psychological distress is highly prevalent in patients with cardiovascular disease (CVD).

Anxiety, depression and insomnia disorder affect approximately one-third of people with CVD, and up to one in four cardiac patients experience clinically significant levels of posttraumatic stress (PTSD)1-4. Furthermore, psychological distress is linked to increased future cardiac events and mortality, poorer quality of life, increased suicide risk, greater healthcare costs and poorer long-term psychological adjustment5. Unfortunately, there is also evidence that during the COVID-19 pandemic psychological distress has increased in cardiac patients and this has been exacerbated by social isolation, treatment nonadherence, physical inactivity, and an increase in unhealthy lifestyle behaviours6,7.

COMMON PSYCHOLOGICAL RESPONSES TO CVD

Dr Sinead Mulhern

In the initial aftermath of a cardiac event, the focus is understandably on the patient’s physical recovery, and many people feel relief or even gratitude for having survived.

However, once a person begins to feel better physically, the emotional distress they have been holding at bay can surface. It may feel safer for this to emerge after things appear to have stabilised medically.

Although this can be a normal part of the recovery process it can be quite frightening if the person hasn’t experienced this kind of emotional vulnerability previously.

APRIL 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

Table 1. Effect Estimates for Associations of Negative Psychological Factors With Cardiovascular Events and Conditions Negative psychological factors

Parameter/ end point

Effect estimates (95% CI)

Depression

Incident MI

RR, 1.30 (1.22–1.40)42

Incident CHD

RR, 1.30 (1.18–1.44)42

Stroke

RR, 1.45 (1.31–1.61)45

Obesity

RR, 1.37 (1.17–1.48)49

Hypertension

RR, 1.42 (1.09–1.86)51

Diabetes

RR, 1.32 (1.18–1.47)52

CVD mortality

RR, 1.41 (1.13–1.76)39

Incident CHD

RR, 1.41 (1.23–1.61)39

Coronary artery spasm

RR, 5.20 (4.72–5.40)40

Incident stroke

RR, 1.71 (1.18–2.50)39

Heart failure

RR, 1.35 (1.11–1.64)39

Work-related stress

Incident CVD events

RR, 1.4 (1.2–1.8)18

Any-cause stress

Incident CHD/CHD mortality

RR, 1.27 (1.12–1.45)19

PTSD

Incident CHD

RR, 1.61 (1.46–1.77)22

Social isolation and loneliness

Incident CVD events

RR, 1.5 (1.2–1.9)18

Pessimism

CHD mortality

OR, 2.17 (1.21–3.89)50 (highest vs lowest quartile)

Anger and hostility

Incident CHD

HR, 1.19 (1.05–1.35)33

Recurrent CHD

HR, 1.24 (1.08–1.42)33

Anxiety

CHD indicates coronary heart disease; CVD, cardiovascular disease; HR, hazard ratio; MI, myocardial infarction; OR, odds ratio; PTSD, posttraumatic stress disorder; and RR, risk ratio.

Summary of Findings: Negative Psychological Health and CVD

attacks after a cardiac event After the initial sense of shock and need help understanding subsides, emotional vulnerability why this happens and figuring can manifest in different ways for to respond differently cardiac patients: Calculated RRs for associationsout ofhow negative psychologito the triggers for panic (e.g.  and fear having calAnxiety factors andofcardiovascular risk are given in Table 1, abdominal breathing). another heart attack is very and a summary of key relevant studies on negative  Low mood, depression or common, and this typically hopelessness affects many eases for people as they begin psychological health and CVD patients is provided in the Online with heart disease. to re-engage with their lives.

Data Supplement (Supplemental Table 1A–1E).

Taken This is often accompanied by However, for many their fear can a feeling of grief about what’s be so great that they restrict together, these studies highlight the potential adverse been lost (e.g. a sense of their activities (e.g. avoiding immortality, physical limitations), impact of poor psychological functioning, psychological exercise) to the point where and can lead to a sense of this interrupts their lives and stress, trauma, anger and hostility, andwith mental health disconnect life and its compromises their health. sense Given of purpose meaning. of disorders on cardiovascular health. theor nature  Many people experience panic Depression is common, and

this work, most human studies in this area are observational, with many involving large administrative databases or self-reporting of exposures. The potential thus exists for bias from misclassification and confounding,

P A

Th ch st pr pi fa ne sim ca th a ou el th to th sa ps of ca m th ap fo ca ex in ar efi

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49 patients are afraid to close their eyes at night for fear they may not wake up. Improving one’s ability to unwind and slow down can be important here, and brief psychological treatments for insomnia (CBT-I) are particularly effective.

ER LACIGOLOHCYSP NOMMOC can be compounded by fatigue

see who can support them with

AND GUIDELINES

natsrednwhich u si sulimits cof ethe ht individual’s ,tneve caidrac a fothis htachallenge. mretfa laSocial itini ehsupport t nI fully revewoHability .devito vru s gengage nivah rin oflife. edutitarg neisvehugely ro feimportant iler leef einlphelping oep tI .ecafrSocial us nacisolation yab ta and/or gnidlolack h neofeb evah cardiac yeht sspatients ertsid latonoadjust itometo perceived support can deepen the impact of depressed mood.

If an individual doesn’t have an emotional connection with Levine et al person to process the another grief they’re experiencing, they may need to look externally to

sometimes multiple lifestyle changes (e.g. exercise, dietary patterns, smoking, alcohol reduction).

 Sleep problems are especially common in newly diagnosed cardiac patients, and many

 Some people may even feel traumatised by their cardiac event. For example, if they nearly died or were shocked on the way to hospital; or if their implantable device (ICD) went off. Or maybe they were very distressed in ICU and were convinced they were going to die. Sometimes in the aftermath of such an experience people develop symptoms of posttraumatic stress disorder (PTSD) which can include reliving the trauma or having flashbacks or nightmares, feeling very alert to future risk and feeling very anxious. These symptoms often resolve but at times can remain very frightening.

Reported Associated Behavioral and Biological Detrimental Processes

Smoking ini a on Physical inac vity Poor ea ng and overea ng Weight gain Medica on noncompliance ------ Ac va on of the hypothalamicpituitary-adrenal axis Dysregula on of the autonomic nervous system Inflamma on Hypercoagulability Increased arterial s ffness Endothelial dysfunc on Inducible myocardial ischemia

 Where stress has been ongoing, people may be placing high demands on themselves which result in an overly demanding lifestyle.

Now, this can lead to feeling overwhelmed by pressures that feel unchangeable, and this may need to be addressed.

 Mental and behavioural habits that perpetuate the stress cycles people are caught in can add additional suffering and impede physical recovery. For example, people often need help getting unstuck from thinking traps that drive automatic or unhelpful behaviour. This may include guilt about previous lifestyle choices made, regrets, self-blame or  People may feel anger if they self-criticism. These common believe their cardiac issue thinking styles can hold was not identified in time, people back and lower mood, or even towards others (e.g.

Psychological Health and the Mind-Heart-Body Connection particularly in those patients employer, family members) who had a lot of negative selfwhom they perceive to have talk before their cardiac event. contributed to their high stress

Nega ve Psychological Health Stress Nega ve outlook Anxiety Anger and hos lity Depression

levels. Personality traits such as hostility place patients at additional cardiovascular risk, and outburst of anger have been shown to serve as triggers of acute cardiovascular events8.

Posi ve Psychological Health

Changes in Behavioral, Psychosocial, and Biological Processes

Smoking cessa on Increased medica on adherence Increased physical ac vity ---- Effec ve emo on regula on Flexible stress management Posi ve social rela onships ---- Decreased inflamma on Lower LDL, VLDL Lower BP

Improved Cardiovascular Health

Reduced cardiovascular risk factors Decreased incident CVD Secondary preven on

Happiness Posi ve affect Emo onal vitality Op mism Sense of purpose Gra tude Psychological well-being Mindfulness

Reported Associated Behavioral and Biological Beneficial Processes

Smoking cessa on Increased physical ac vity Heart-healthy ea ng Weight loss Increased medica on adherence Preven ve screening ---- Blood pressure reduc on Be er glucose control

Figure. Negative and positive associations of psychological health and cardiovascular risk and health and potential biologically plausible mechanisms of how improved psychological health can lead to decreased cardiovascular risk.

Figure concept inspired by Levine,2 Kubzansky et al,54 Rozanski,166 and many other sources. BP indicates blood pressure; CVD, cardiovascular disease; LDL, lowdensity lipoprotein; and VLDL, very-low-density lipoprotein.

in inflammatory markers182 associated with improved cardiovascular prognosis. Although there are conflicting

| HPN • APRIL associated with lower rates of hospitalization at 1 year HOSPITALPROFESSIONALNEWS.IE 2022 compared with usual care (incidence rate ratio, 0.47

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CARDIOLOGY FOCUS: CARDIAC PSYCHOLOGY

 Relationships and sexual health are also significantly impacted in the aftermath of a cardiac diagnosis and individuals need to feel confident in having a safe space to speak openly about these important concerns should they need to.

MECHANISMS: HOW PSYCHOLOGICAL FACTORS AFFECT CARDIOVASCULAR HEALTH The mind and body are inextricably linked, and psychological well-being has direct effects that mediate improvements in cardiovascular health. Better psychological well-being is associated with lower blood pressure, a lower prevalence of metabolic syndrome, a more favourable lipid profile, a lower likelihood of smoking, increased exercise levels and greater adherence to a hearthealthy diet9-11. Conversely, anxiety and chronic stress have been shown to increase inflammation, increase blood pressure and stress hormones such as cortisol which can impact coronary arteries and increase the risk of cardiac events.

Similarly, depression has also been shown to be linked with increased inflammation, reduced physical activity, continued smoking, weight gain and poorer adherence to secondary preventive medications (SPMs). While psychological components are clearly linked with both health behaviours and factors that are directly related to cardiovascular health, improving the psychological wellbeing of cardiac patients is key to optimising their health outcomes.

PSYCHOLOGICAL CARE FOR CARDIAC PATIENTS DURING CARDIAC REHABILITATION (CR) In many respects, cardiac rehabilitation (CR) is the ideal setting in which to address the psychological needs of cardiac patients. CR is a comprehensive, multi-disciplinary chronic disease management programme that incorporates core components such as patient assessment, supervised exercise training with continuous ECG monitoring (telemetry), nutritional counselling, management of cardiac risk factors (lipids, diabetes, blood pressure, weight) and psychological management. To ensure comprehensive cardiac care, some CR programmes have a psychologist on staff as a fully integrated member of the MDT. Systematic reviews demonstrate that the psychological component drives the benefits achieved

by CR, and that psychological interventions not only improve

CR programmes also provide psychological distress and quality In the case of individual therapy of life, but also reduce cardiac (e.g. anxiety, depression, psychological interventions CARDIAC PSYCHOLOGY IN IRELAND: SERVICE EXAMPLES events and hospitalizations12,13. adjusting to adverse life events) delivered by appropriately trained the intention in exploring mental health professionals, and From a psychological Beaumont Hospital: standpoint, psychological distress is to allow that patients with psychological cardiac patients experiencing its expression, to acknowledge it, difficulties are followed in a stepped psychological difficulties present 16-18 to offer the treatment . is fullyand mannerPsychology through toservice remission Beaumont Hospital has a dedicated Cardiac which integrated withpatient its Cardiology to CR in broadly two different strategies to address stress and ways: their distress ‘new’ Department.

Patients iscan access psychological care as working required in during phase (Coronary Care) and Psychologists CR the inpatient factors currently contributing to following psychology their recentreferrals cardiacare also received provide a range of CR psychological individual from both the programme and the Failure Service theoutpatient distress. Heart A concurrent aim event; or they’ve had ongoing treatments to meet the needs can be to focus on aspects of life (Supportive Unit). stress priorHeart to their health issues of cardiac patients. Where that are meaningful that can be which is now adding to their possible, a matched or stepped expanded upon, particularly in current distress (e.g. health carethe model is employed During CR, all patients routinely meet with cardiac psychologistallowing at the beginning of the and this the case of programme, existential difficulties anxiety). Many of these patients treatment complexity to be difficulties. enables timely identification of patients at increased risk of psychological As well as affording each patient experienced following a near also have other psychological and matched to patient need. This death experience. the time and space to telland their individual story, patients identify the role of the psychologist as an integral component behavioural problems have allows for simpler low-intensity never a mental health of psychological of CR. encountered This normalises the inclusion psychological issues in cardiac care and ensures high levelsprovided of patientby Additional expertise interventions professional At before. cardiacmotivational psychologists includes initially but also provides for engagement. this juncture, brief individual interventions (e.g. supportive counselling, interviewing) psychological preparation specialist mental health care to Participating in CR is a process are also delivered as appropriate. for cardiac surgery, weight be available to those patients of recovery where patients grow management, psychosexual requiring it. This model has been together in their confidence to counselling, insomniainto treatment, All patients are to attend group psychoeducational which are incorporated the CR shown to be both accessiblesessions to re-engage withinvited their lives afterweekly small medication adherence, family and associated with adjustment programme.

TheseBecause sessions are a CBT-framework and address to heart disease, health-related a cardiac event. theybased onpatients support (e.g. caregiver burden in increased satisfaction with are monitored exercise,coping. Additional lifestyle changes,during and adaptive group sessions address sleep,heart weight management, managing failure), neuropsychological cardiac care19. they feel safe to push themselves depressed mood, stress and heart disease, overwork & exhaustion, treatment adherence, the psychology of lifestyle eating assessment, maintaining physically and this helps them Inevent. parallel with exercise training changes, training of cardiology and resuming sexualof activity to restore a sense trust after in a cardiac (ET), many patients during CR team members, research, clinical their bodies and the expectation benefit psychologically from brief audit and quality improvement, that they will recover well This interventions such as supportive and advocacy. process is reinforced by targeted counselling, motivational education on behavioural risk CARDIAC PSYCHOLOGY IN interventions to assist with factors (e.g. diet, medications, IRELAND: SERVICE EXAMPLES changing health behaviours and/ smoking) which enhances the or targeted psychoeducational Beaumont Hospital: patient’s understanding of their group sessions (e.g. adjusting heart condition and their sense to adverse life events, managing Beaumont Hospital has a of control over their health. The depressed mood, resuming sexual dedicated Cardiac Psychology group context has a normalising activity after a cardiac event, service which is fully integrated effect as it enables people to managing fatigue). with its Cardiology Department. share their experiences with Patients can access psychological others. This allows patients to Stress management training care as required during the both benefit from the support (SMT) - when fully integrated with inpatient phase (Coronary Care) of their peers and to learn that CR - not only helps patients to and individual psychology they are not the “only ones” to reduce stress but is proven to referrals are also received from feel this way. CR can also be a deliver an incremental benefit on both the CR programme and the good time for people to pause cardiac outcomes (e.g. recurrent outpatient Heart Failure Service and re-evaluate what’s important events, hospital readmissions) (Supportive Heart Unit). to them in life and where they when compared to CR alone. wish to spend their time and Similarly, many psychologists During CR, all patients attention going forward. Cardiac are also trained in the delivery of routinely meet with the cardiac patients are often acutely aware mindfulness-based interventions psychologist at the beginning of of the opportunity to review and (MBI) which can help CR patients the programme, and this enables improve their quality of life that to learn an effective coping timely identification of patients at is not afforded to those who die strategy for managing stress increased risk of psychological suddenly. This can sometimes and a way of approaching difficulties. As well as affording come to be seen as a ‘silver psychological distress differently. each patient the time and space to lining’ that accompanies a recent For patients with insomnia, tell their individual story, patients realisation of life’s fragility.

Cognitive Behavioural Therapy identify the role of the psychologist for Insomnia (CBT-I) is the as an integral component of CR. THE ROLE OF THE recommended first-line treatment, This normalises the inclusion of PSYCHOLOGIST IN CR is highly effective, and its benefits psychological issues in cardiac care The psychological benefits of are proven to persist at 10-year and ensures high levels of patient exercise training (ET) are wellfollow up20-22. engagement. At this juncture, 14 established and ET is proven to be brief individual interventions Frequently, certain cardiac patients a highly cost-effective intervention (e.g. supportive counselling, (e.g. survivors of sudden cardiac for improving depressed mood motivational interviewing) are also 15 arrest, SCAD) present with unique in cardiac patients . This can be delivered as appropriate. and complex psychological needs particularly effective when allied to (e.g. device-related shock anxiety, All patients are invited to the social support received by staff PTSD) that are best delivered by attend weekly small group and/or peers during CR. However, an experienced clinician familiar international guidelines continue to psychoeducational sessions recommend that comprehensive with cardiology. which are incorporated into the

APRIL 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

wtATTR-CM: A DISEASE THAT OFTEN GOES UNDETECTED1 Introducing the wtATTR-CM estimATTR—an online tool that was developed based on an artificial intelligence/machine learning (AI/ML) algorithm to learn how combinations of clinical conditions are associated with this underrecognised disease.2-4 Wild-type transthyretin amyloid cardiomyopathy (wtATTR-CM) is an underrecognised, progressive, infiltrative disease that can often be overlooked as a cause of heart failure.1,3,4 Once diagnosed, untreated patients with wtATTR-CM have a median survival of ~3.5 years.5-7 The wtATTR-CM estimATTR is an easy-to-use educational tool that was built leveraging AI/ML and can estimate the probability of wtATTR-CM in hypothetical heart failure scenarios. The tool allows you to test various combinations of clinical conditions in a hypothetical patient, see what combinations are associated with wtATTR-CM, and help distinguish from heart failure due to other causes.2 This tool is for educational purposes only, and it is not to be used in a clinical setting for the suspicion or diagnosis of wtATTR-CM in individual patients.

www.estimattr.ie

References: 1. Witteles RM, Bokhari S, Damy T, et al. Screening for transthyretin amyloid cardiomyopathy in everyday practice. JACC Heart Fail. 2019;7(8):709-716. 2. Huda A, Heitner S, Calambur V, et al. A machine learning framework for predicting risk of wild-type transthyretin amyloid cardiomyopathy. Poster presented at: XVII International Society of Amyloidosis Symposium; September 14-18, 2020; virtual. 3. Mohammed SF, Mirzoyev SA, Edwards WD, et al. Left ventricular amyloid deposition in patients with heart failure and preserved ejection fraction. JACC Heart Fail. 2014;2(2):113-122.

4. González-López E, Gallego-Delgado M, Guzzo-Merello G, et al. Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fraction. Eur Heart J. 2015;36(38):2585- 2594.

5. Connors LH, Sam F, Skinner M, et al. Heart failure resulting from age-related cardiac amyloid disease associated with wildtype transthyretin: a prospective, observational cohort study. Circulation.

2016;133(3):282-290. 6. Pinney JH, Whelan CJ, Petrie A, et al. Senile systemic amyloidosis: clinical features at presentation and outcome. J Am Heart Assoc. 2013;2(2):e000098. 7. Grogan M, Scott CG, Kyle RA, et al. Natural history of wild-type transthyretin cardiac amyloidosis and risk stratification using a novel staging system. J Am Coll Cardiol. 2016;68:1014-1020.

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CR programme. These sessions are based on a CBT-framework and address adjustment to heart disease, health-related lifestyle changes, and adaptive coping.

Additional group sessions address sleep, weight management, managing depressed mood, stress and heart disease, overwork & exhaustion, treatment adherence, the psychology of eating and resuming sexual activity after a cardiac event.

As part of Beaumont’s steppedcare pathway, patients can also access a comprehensive Stress Management Training (SMT) Programme specifically designed for cardiac patients.

This multicomponent intervention combines psychoeducation, group support and cognitive behaviour therapy for groups of 10-12 patients. Here patients acquire an extensive repertoire of relaxation techniques and psychological skills targeting stress, anxiety, sleep and anger/hostility.

Beaumont Hospital have also developed a comprehensive Heart Failure Self-Management Programme to support patients living with HF, including those unable to participate in exercisebased CR. The ‘UPBEAT’ programme targets the health of both patients and their caregivers (e.g. caregiver burden) and has been shown to be effective in improving HF self-management, psychological distress and medication adherence in patients living with HF. All patients completing the CR programme are also followed up by the cardiac psychologist.

For patients requiring additional support at this point, treatment options are discussed with the patient and onward referrals are made as appropriate (e.g. referral for stress management, individual therapy, GP, community mental health team and/or Irish Heart Foundation patient support group).

For sensitive treatment-related issues (e.g. erectile dysfunction), a referral to the cardiology clinic is facilitated on the patient’s behalf.

Psychological support is also provided to partners of patients where appropriate.

St Vincent’s University Hospital (SVUH): The Cardiac Psychology service at SVUH has evolved over time and currently employs both a senior clinical psychologist (1.0 WTE) and a psychotherapist (0.3 WTE). SVUH also provide a stepped care model delivering a service for patients across the spectrum of cardiac disease.

Lower intensity and group-based interventions are offered for mild to moderate distress, and higher intensity interventions (e.g. individual psychological therapy) are offered where there is greater complexity to the presenting difficulties and more severe distress. All psychological interventions are evidencedbased in accordance with best clinical guidance, and encompass cognitive behavioural therapy (CBT), interpersonal therapy, mindfulness-based interventions (MBI), compassion-focused therapy, short term Kleinian psychotherapy and integrative approaches (depending on the clinical presentation).

SVUH’s Cardiac Psychology service provides input to the CR programme, and consultation is provided as required, on both an inpatient and outpatient basis. Patient assessment and individual input (e.g. formulation and intervention) can be initiated at any point of a patient’s care journey. All patients attending the CR programme can benefit from two psycho-educational group sessions where participants learn about stress, depression, how these difficulties can impact heart health, coping strategies and signposting to further help, and planning for post-CR behaviour maintenance. Mindfulness based interventions (MBI) such as mindfulness-based stress reduction (MBSR) and mindfulness based cognitive therapy (MBCT) are 8-week group interventions run by the SVUH Psychology Department and are also available to these patients. MBI have been shown to reduce stress, depression, improve quality of life and help individuals manage ongoing chronic conditions23.

Patients living with heart failure (HF) are at increased risk of psychological problems such as depression and anxiety, which can in turn negatively impact cardiac outcomes. Patients with HF can access SVUH’s Cardiac Psychology service at different stages of their illness from diagnosis to episodes of acute decompensated HF, disease progression through to end of life.

CR is proven to be effective with this patient population, and the Cardiac Psychology Service also contribute to the 8-week multidisciplinary CR programme for patients with HF. A clinic also runs from the Heart Failure Unit offering individual therapy for those with more moderate to severe distress.

MBI is a helpful follow-on for those appropriate who are discharged from CR or individual therapy, and patients with HF are accepted to this programme.

APRIL 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

Patients with arrhythmias or an implantable cardiac device attending SVUH can also avail of the Cardiac Psychology service.

Although most patients receiving an implantable cardioverter defibrillator (ICD) or pacemaker adjust without psychological difficulties, a significant proportion of patients can experience specific psychological challenges.

Some patients with an ICD can develop problems with body image due to the implant, or anxiety in response to either cardiac symptoms or due to the device delivering therapy (i.e. an electric shock). Some will develop post-traumatic stress problems such as hypervigilance or feeling on edge, avoiding things that cause distress or re-living distressing experiences (e.g. nightmares). Notably, the prevalence of PTSD in patients with an ICD has been shown to be greater than that for Gulf War veterans24. The Cardiac Psychology service contribute to a multidisciplinary group education session for those who have been recently fitted with a device to help support patients’ awareness and independent selfcare. In addition, psychological therapy, in particular CBT and trauma-informed cognitive therapy are available to patients requiring individual support.

As well as direct clinical work with patients, SVUH’s Cardiac Psychology service collaborate with colleagues in other settings (e.g. the Irish Heart Foundation) to highlight the psychological needs of cardiac patients and to advocate for optimum service provision. Research and the provision of training to colleagues which is cognisant of the psychological needs of patients is also core business of the service.

Mater Misericordiae University Hospital (MMUH): In the Mater Hospital Cardiac Rehabilitation programme (CR) there is a principal clinical psychologist (WTE 0.4) appointed to the 8-week programme. All patients are invited to the 2-hour stress management talk given by the psychologist. During this talk, all patients are invited to take part in a mindfulness exercise and are then invited to participate in an 8-week mindfulness group.

Mindfulness-based interventions (MBI) have been associated with improvements across a range of physical and mental health outcomes, including improved depressive symptoms, anxiety, stress, quality of life, smoking cessation, healthy eating and physical activity25-27. In line with these findings, evaluations of MMUH groups have demonstrated

this to be an effective coping strategy for CR patients in terms of reducing anxiety and depression.

A pre-pandemic snapshot of the Cardiac Psychology service over 6 months showed that approximately 65 patients attended the stress management talk at the beginning of CR, and just over half of these patients (33) went onto to attend one of the 2 mindfulness groups run during this time. Feedback from the evaluation of the mindfulness programme has shown that patients viewed this an effective method to both manage stress and approach psychological distress differently. Additionally, patients indicated some improvements in mindfulness skills and self-compassion.

During the same 6-month period, 24 patients were seen for individual therapy sessions, and the average number of sessions received by patients was 4 (range 1 – 8 sessions). Areas of distress that were explored frequently included anxiety and depression and difficulties with adjustment to the cardiac event. In addition stress management, social and relationship difficulties were also addressed.

ACCESS TO PSYCHOLOGICAL CARE FOR CARDIAC PATIENTS IN IRELAND As we have seen, psychological factors are strongly linked with cardiac prognosis, and there is firm evidence underpinning psychological support for patients with heart disease. Furthermore, the need for psychological support has intensified during the recent pandemic. However, psychological services for cardiac patients in Ireland are poorly resourced nationally and characterised by inequitable access.

The recent National Survey of CR services28 conducted by Irish Heart Foundation (IHF) and the Irish Association of Cardiac Rehabilitation (IACR) showed that 80% (28/35) of CR centres had no access to psychological support for their patients. Yet, access to psychology was the highest rated service required (50% of CR Centres) to improve the quality of CR. Similarly, the IHF have deemed psychology a priority area and added: “the lack of psychological services and supports is emerging as one of the issues of greatest concern to the people in our patient advocacy network”.

CR programmes in Ireland are anxious to provide their patients with access to this essential service. The multidisciplinary team (MDT) for each CR centre should include dedicated and adequate psychology staffing. Our patients deserve nothing less.

References available on request

CARDIOLOGY FOCUS: PACING

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Pacing Developments The earliest recorded description of pacing was in 1882 and its now over 60 years since the first patients received an implantable cardiac pacemaker. Many lives have been saved and quality of life improved by these early devices and the many subsequent developments implemented over the following decades.

Important developments include the implantable cardioverter defibrillator (ICD) in 1980 and then more recently a treatment for heart failure with cardiac resynchronisation therapy (CRT), first described in 1984 followed by the development in recent years of conduction system pacing (CSP).

Indications for pacing Pacemakers are indicated for symptomatic bradycardia and also in cases of atrio-ventricular (AV) block for improving prognosis. In the main cardiac resynchronisation pacemakers are indicated in patients who develop significant intraventricular conduction delay (bundle branch block) or those with left ventricular (LV) impairment who are expected to receive a high degree or percentage of heart beats activated from conventional right ventricular (RV) pacing. Right ventricular pacing is associated with the development of LV impairment (pacing induced cardiomyopathy) and has been shown to increase mortality. Particularly at risk are those with pre-existing LV impairment. Approximately 10-20% of patients with normal LV function will develop LV

impairment following significant RV pacing (>40% ventricularly paced beats). ICDs were originally inserted for survivors of cardiac arrest (secondary prevention implantation) but it has become apparent that high risk patients could be identified prior to sudden cardiac death (primary prevention implantation). Current practice is therefore to insert the majority of ICDs for those judged to be at high risk of ventricular arrhythmia as a primary prevention measure.

However the prediction of sudden death risk remains challenging although this has been assisted greatly by developments in a number of clinical areas including for example, imaging with cardiac MRI to image myocardial fibrosis and in some specific cardiomyopathies, genetic testing.

Developments in implantation techniques Many developments within surgical specialties have crossed over from operating theatres to the cardiac catheterisation suite. From dissolvable sutures to diathermy and haemostasis techniques, submuscular implantation, regional anaesthesia and nerve blocks. Technological advances in imaging quality and interventional ultrasound techniques have also improved safety in guiding central venous access where standard vein dissection (cut down technique) for pacing lead insertion is not adequate.

Standardised surgical preparation including hair clipping, single

dose pre-implantation intravenous antibiotics, normothermia and normoglycaemia have helped minimise infection risk. Further developments have allowed many device procedures to be performed without interrupting anticoagulation reducing the risk of stroke related to withholding anticoagulants. Without the use of diathermy or other haemostasis technique the development of a post procedure haematoma carries a significant increased risk of infection.

Remote follow up Current pacemakers and defibrillators are capable of largely functioning autonomously.

Automatic threshold testing reducing battery depletion, detection of arrythmia such as atrial fibrillation and longevity monitoring are just three of the advantages of remote monitoring.

Particularly during the COVID era the ability to monitor patients safely remotely has been invaluable. Over the coming years this will likely continue to expand and lead to less frequent attendance for patients in person within traditional pacing clinics. Early devices required a specific ‘transmitter’ to be present near the patient, usually left at home to send data to the device company. Newer devices connect to a patients mobile phone through an app from the device company allowing almost continuous connection to the remote monitoring data server.

Integration of other biometric data

Dr Jonathan Lyne, Consultant Cardiologist and Electrophysiologist, Beacon Hospital and Blackrock Clinic

from the mobile phone and the patient alongside the device data will likely provide a more detailed assessment of patients status especially in heart failure and other chronic cardiac conditions.

Magnetic resonance imaging in patients with devices MRI conditional devices have become an industry standard across almost all devices from basic pacemakers to defibrillators.

Large studies have shown there is no issue in patients who have defibrillators deactivated during scanning. Patients however still require attendance for a pacing check usually immediately preceding and following their MRI to ensure the device is functioning appropriately and safely.

Figure 1. Leadless pacemaker insertion and device (Medtronic Micra)

Figure 1. Leadless pacemaker insertion and device (Medtronic Micra) HOSPITALPROFESSIONALNEWS.IE | HPN • APRIL 2022

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CARDIOLOGY FOCUS: PACING

Developments in bradycardia pacing The demand for bradycardia pacing in an ageing population is growing rapidly. An important development has been the recognition of the deleterious effects of a high burden of ventricular pacing. Focus on reducing the risks of these patients developing heart failure from a pacing induced cardiomyopathy has been on software algorithms and more recently techniques to utilise pacing of the patients own conduction tissue. This technique is known as conduction system pacing (CSP) and includes His bundle pacing to target the atrioventricular node and more recently left bundle branch pacing from a lead inserted across the interventricular septum.

Further developments have included leadless pacemakers implanted into the right ventricle.

Initially these have been single chamber, ventricular pacing and sensing only devices but more recently an atrial sensing device utilising motion detection of the device corresponding with atrial contraction has become available. Undergoing further clinical evaluation are leadless pacemakers specially for atrial

pacing only and devices that are integrated to provide both atrial and ventricular pacing using Bluetooth communication between the devices.

Developments in Internal Defibrillators Over a number of years battery developments have resulted in both smaller device sizes and also in longer device longevity. This will reduce the frequency of generator changes and the potential complications of such procedures such as infection.

The majority of patients receiving an internal defibrillator have a diagnosis of ischaemic cardiomyopathy or dilated (non ischaemic) cardiomyopathy. Most patients have a primary prevention indication, mainly determined by left ventricular ejection fraction in most conditions. Secondary prevention patients may have had a sustained arrythmia or resuscitated from a cardiac arrest and are also indicated to receive a device in most cases.

Modern imaging techniques such as cardiac MRI (CMR) to assess ventricular function and fibrosis within the mid ventricular wall is also a risk factor for sudden cardiac death in some conditions.

Figure 2: Conventional dual chamber pacing (left) and Cardiac resynchronisation therapy utilising a conduction system pacing technique (left bundle branch pacing) combined with conventional left ventricular lead implantation.

1. High right atrial lead 2. Right ventricular lead 3. Right ventricular defibrillator lead 4. Left bundle branch pacing lead 5. Coronary sinus pacing lead

In specific patients the inducibility of sustained ventricular arrhythmia by electrophysiology testing (ventricular pacing) may be used to help guide a decision of defibrillator insertion for a specific patient.

There is a choice of subcutaneous or conventional transvenous internal defibrillators. Most patients receive transvenous systems which can provide ATP (anti tachycardia pacing) to overdrive and terminate a ventricular arrythmia thereby not requiring a device shock or defibrillation.

Subcutaneous defibrillators using a lead underneath the skin and not within the vascular system have been shown to be effective and safe, they are able to discriminate between normal rhythms and ventricular tachycardia. Without a transvenous lead within the heart they utilise a surface electrocardiogram (ECG) created between the lead and the defibrillator device instead to detect abnormal rhythms requiring treatment.

Cardiac resynchronisation therapy (CRT) Biventricular pacing to provide cardiac resynchronisation therapy was first described over 25 years ago. CRT has been extensively proven to be one of the most clinically and cost effective cardiovascular therapies in terms of reductions in mortality and heart failure (HF) hospitalisation. Critical to decision making for a patients suitability for this therapy is the presence of electrical conduction delay (bundle branch block) across the heart assessed by the surface ECG QRS duration and pattern, alongside significant LV systolic impairment, ejection fraction <35% in patients receiving optimal heart failure therapy.

However CRT should also be considered for an additional group of patients who are predicted to receive a high degree of right ventricular pacing and who have left ventricular impairment, which is likely to worsen with RV apical pacing. Therefore for a patient requiring a pacemaker in the setting of complete or high grade AV block with reduced LV function should be considered for a CRT device to prevent a deterioration in ventricular function from pacing alone.

Advances is lead implantation techniques and hardware advances including delivery systems and modern quadripolar (vs. bipolar) pacing leads has permitted very high implant rates and avoiding complications such as diaphragm pacing from inadvertent phrenic nerve capture. Improved venous access techniques using intraprocedural ultrasound, venoplasty and balloon dilatation of peripheral and central veins including the superior vena cava have increased procedural success rates and reduced indications for epicardial pacing leads usually applied via an invasive thoracotomy.

Ensuring >92% of heart beats are from CRT is vital, patients with frequent ventricular ectopics or atrial fibrillation require medication alteration, ectopic focus ablation or AV nodal ablation in some to increase the percentage of CRT ventricular pacing therapy, is proven to improve outcomes including reducing mortality.

Software innovations to optimise the fusion of intrinsic cardiac conduction, through the AV node and native cardiac conduction tissue and pacing, largely from the left ventricular lead appears to be beneficial. Investigations are ongoing into whether mutlitipoint

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1.

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4.

2.

Dual chamber pacing

Dual chamber pacing

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LOT-CRT pacing

LOT-CRT pacing

FigureAPRIL 2: Conventional dual chamber pacing (left) and Cardiac resynchronisation therapy utilising a conduction 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE system pacing technique (left bundle branch pacing) combined with conventional left ventricular lead

S U S P E C T AT T R - C M ( T R A N S T H Y R E T I N A M Y L O I D C A R D I O M YO PAT H Y )

A L I F E - T H R E AT E N I N G D I S E A S E T H AT C A N G O U N D E T E C T E D Life-threatening, underrecognized, and underdiagnosed, ATTR-CM is a rare condition found in mostly older patients in which misfolded transthyretin proteins deposit in the heart.1-7 It is vital to recognize the diagnostic clues so you can identify this disease.

C O N S I D E R T H E F O L L O W I N G C L I N I C A L C L U E S , E S P E C I A L LY I N C O M B I N AT I O N , T O R A I S E S U S P I C I O N F O R AT T R - C M A N D T H E N E E D F O R F U R T H E R T E S T I N G

HFpEF INTOLERANCE DISCORDANCE DIAGNOSIS ECHO NERVOUS SYSTEM heart failure with preserved ejection fraction in patients typically over 60 years old5-7

to standard heart failure therapies (ACEi, ARBs, and beta blockers)8-10 between QRS voltage and left ventricular (LV) wall thickness11-13

of carpal tunnel syndrome or lumbar spinal stenosis3,8,14-20

showing increased LV wall thickness6,13,16,21,22

—autonomic nervous system dysfunction-including gastrointestinal complaints or unexplained weight loss6,16,23,24

L E A R N H O W T O R E C O G N I Z E T H E C L U E S O F AT T R - C M AT :

SUSPECTANDDETECT.IE

References 1. Sipe JD, Benson MD, Buxbaum JN, et al. Amyloid fibril proteins and amyloidosis: chemical identification and clinical classification International Society of Amyloidosis 2016 Nomenclature Guidelines. Amyloid. 2016;23(4):209-213.

2. Maurer MS, Elliott P, Comenzo R, Semigran M, Rapezzi C. Addressing common questions encountered in the diagnosis and management of cardiac amyloidosis. Circulation. 2017;135(14):1357-1377. 3. Connors LH, Sam F, Skinner M, et al. Heart failure due to age-related cardiac amyloid disease associated with wild-type transthyretin: a prospective, observational cohort study. Circulation. 2016;133(3):282-290. 4. Pinney JH, Whelan CJ, Petrie A, et al. Senile systemic amyloidosis: clinical features at presentation and outcome. J Am Heart Assoc. 2013;2(2):e000098. 5. Mohammed SF, Mirzoyev SA, Edwards WD, et al. Left ventricular amyloid deposition in patients with heart failure and preserved ejection fraction. JACC Heart Fail. 2014;2(2):113-122. 6. Maurer MS, Hanna M, Grogan M, et al. Genotype and phenotype of transthyretin cardiac amyloidosis: THAOS (Transthyretin Amyloid Outcome Survey). J Am Coll Cardiol. 2016;68(2):161-172.

7. González-López E, Gallego-Delgado M, Guzzo-Merello G, et al. Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fraction. Eur Heart J. 2015;36(38):2585-2594. 8. Narotsky DL, Castano A, Weinsaft JW, Bokhari S, Maurer MS. Wild-type transthyretin cardiac amyloidosis: novel insights from advanced imaging. Can J Cardiol. 2016;32(9):1166.e1-1166.e10. 9. Brunjes DL, Castano A, Clemons A, Rubin J, Maurer MS. Transthyretin cardiac amyloidosis in older Americans. J Card Fail. 2016;22(12):996-1003. 10. Castaño A, Drach BM, Judge D, Maurer MS. Natural history and therapy of TTR-cardiac amyloidosis: emerging disease-modifying therapies from organ transplantation to stabilizer and silencer drugs. Heart Fail Rev. 2015;20(2):163-178. 11. Carroll JD, Gaasch WH, McAdam KP. Amyloid cardiomyopathy: characterization by a distinctive voltage/mass relation. Am J Cardiol. 1982;49:9-13. 12. Cyrille NB, Goldsmith J, Alvarez J, Maurer MS. Prevalence and prognostic significance of low QRS voltage among the three main types of cardiac amyloidosis. Am J Cardiol. 2014;114(7):1089-1093. 13. Quarta CC, Solomon D, Uraizee I, et al. Left ventricular structure and function in transthyretin-related versus light-chain cardiac amyloidosis. Circulation. 2014;129(18):1840-1849. 14. Connors LH, Prokaeva T, Lim A, et al. Cardiac amyloidosis in African Americans: Comparison of clinical and laboratory features of transthyretin V122I amyloidosis and immunoglobulin light chain amyloidosis. Am Heart J. 2009;158(4):607-614. 15. Nakagawa M, Sekijima Y, Yazaki M, et al. Carpal tunnel syndrome: a common initial symptom of systemic wild-type ATTR (ATTRwt) amyloidosis. Amyloid. 2016;23(1):58-63. 16. Rapezzi C, Merlini G, Quarta CC, et al. Systemic cardiac amyloidoses: disease profiles and clinical courses of the 3 main types. Circulation.

2009;120(13):1203-1212. 17. Sperry BW, Reyes BA, Ikram A, et al. Tenosynovial and cardiac amyloidosis in patients undergoing carpal tunnel release. J Am Coll Cardiol. 2018;72(17): 2040-2050. 18. Westermark P, Westermark GT, Suhr OB, Berg S. Transthyretin-derived amyloidosis: probably a common cause of lumbar spinal stenosis. Ups J Med Sci. 2014;119(3):223-228. 19. Yanagisawa A, Ueda M, Sueyoshi T, et al. Amyloid deposits derived from transthyretin in the ligamentum flavum as related to lumbar spinal canal stenosis. Mod Pathol. 2015;28(2):201-207. 20. Sueyoshi T, Ueda M, Jono H, et al. Wild-type transthyretin-derived amyloidosis in various ligaments and tendons. Hum Pathol.

2011;42(9):1259-1264. 21. Phelan D, Collier P, Thavendiranathan P, et al. Relative apical sparing of longitudinal strain using two-dimensional speckle-tracking echocardiography is both sensitive and specific for the diagnosis of cardiac amyloidosis. Heart. 2012;98(19):1442-1448. 22. Ternacle J, Bodez D, Guellich A, et al. Causes and consequences of longitudinal LV dysfunction assessed by 2D strain echocardiography in cardiac amyloidosis. JACC Cardiovasc Imaging.

2016;9(2):126-138. 23. Coelho T, Maurer MS, Suhr OB. THAOS - The Transthyretin Amyloidosis Outcomes Survey: initial report on clinical manifestations in patients with hereditary and wild-type transthyretin amyloidosis. Curr Med Res Opin. 2013;29(1):63-76. 24. Swiecicki PL, Zhen DB, Mauermann ML, et al. Hereditary ATTR amyloidosis: a single-institution experience with 266 patients. Amyloid. 2015;22(2):123-131.

The health information contained in this ad is provided for educational purposes only.

Date of Preparation: February 2021 GCMA code: PP-RDP-IRL-0105

3:

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pacing from a quadripolar left ventricular pacing lead provides benefits that overcome the inevitable battery drain of pacing from more than one site.

Conduction System Pacing (CSP) – His bundle pacing (HBP) and Left bundle branch pacing (LBBp) Pacing the conduction tissue of the heart directly is an exciting development within cardiology.

CSP has the potential to supersede conventional right ventricular pacing. The benefits are in replicating the natural electrical conduction of the heart with a physiological narrow QRS morphology similar to intrinsic conduction. One major benefit of CSP has been its ability to reverse left bundle branch block, potentially replacing conventional CRT in the future once further data is available from upcoming trials. Thus far small trials have shown significant benefits in terms of reduction of heart failure, atrial fibrillation and mortality in those receiving >40% RV pacing. The exact physiological mechanism whereby pacing near the conduction system can reverse left bundle branch block is controversial and much debated There has been concern that pacing leads inserted into the fibrous His bundle region at the AV node have higher thresholds

and therefore reduced battery longevity. A new development of pacing the left bundle branch of the His Purkinjie system, transeptally appears to overcome these issues. So far the technique has been shown to be reproducible, teachable and lower thresholds on these very stable leads in the medium term. Studies in patients undergoing LBBp lead insertion in the setting of heart failure also suggests a response in ejection fraction superior to conventional CRT. This technique of implantation of a pacing lead within the ventricular septum may be combined with conventional left ventricular lead pacing via the coronary sinus (LOT-CRT).

Potentially overcoming some of the limitations in resynchronisation of patients with intraventricular conduction delay (within the ventricular conducntion tissue) with conventional techniques. Our own research is assessing this technique against conventional CRT devices, in particular its safety and the learning curve for lead implantation against conventional biventricular pacing.

For some patients often due to the presence of previous leads and potentially occlusion of the superior vena cava access for leads to achieve intracardiac pacing is not possible. Although procedures to cross and recanalize previously occluded central veins is possible for

some patients the risks may be significant. Therefore procedures to implant pacing devices either epicardially (thoracoscopically) or endocardially from arterial access retrogradely across the aortic have are possible. One such system uses ‘induction pacing’ with a transmitter inserted initially very similar to a standard pacemaker generator subcutaneously.

Followed by the insertion of a pacing ‘seed’ within the left ventricular cavity to pace the myocardium. Thereby avoiding the necessity of venous access to pace the left ventricle and achieve cardiac resynchronisation by biventricular pacing if this pacing ‘seed’ is implanted in the left ventricular free wall.

Lead Extraction and Access Management Many patients require a number of pacing procedures throughout their lifetime. Both through the failure of the leads inserted at their initial implant procedure but also over time if upgrading to more complex systems such as resynchronisation is required. In some cases venous access may also be blocked or narrowed necessitating the use of techniques such as venoplasty to dilate narrowed veins to permit venous access. This may also necessitate the removal of a non functional or previously abandoned lead(s) by extraction of the lead but using this ‘channel’ to pass a wire simultaneously to maintain access for a new lead to be inserted.

However if additional leads are added without removing an old lead (extraction) the procedural risks of extraction are avoided but the old leads can increase the risk of future complications: • Higher risk of future device infection • More complex future lead extraction (removal) • Higher risk of occlusion (thrombus or venous stricture of the vein or damage to heart structures) • May complicate or prevent the ability to perform an MRI scan Extraction of failed leads that may have fractured or require removal due to infection is also an increasing requirement for any device service. Techniques and equipment have evolved significantly to improve both the success of extraction of leads in their entirety as well as the safety of the procedure. Although this complex procedure still requires specific training and competency there is also a requirement for a cardiac surgical back up team in case of emergency. Leads that have been in situ for many years (> 10 years), and in particular specific leads such as dual coil defibrillator leads with a high voltage coil within the superior vena cava or specific lead models known to fragment resulting in significant scar tissue in growth require careful pre procedural planning and consideration of ‘hybrid’ techniques. Hybrid extraction includes not only removing the lead(s) required from the site of venous entry of the lead(s) but the assistance of snaring the lead as well to provide counter traction either from a superior jugular vein of inferiorly from the inferior vena cava.

Despite these developments lead extraction remains challenging and with significant risks and is therefore performed in specific centres like ours with appropriate expertise. However in published studies high volume operators show clinical success rates of around 98% for successful lead removal. The risk of internal bleeding, cardiac tamponade or haemothorax among other risks is 0.5%. With an ageing population, improvements in heart failure managment and increasing implantation indications it is inevitable that we will see a rapid increase in all device related procedures over coming years.

Figure 3: Snare extraction technique from inferior (femoral vein) access (left). Rotational extraction sheath (Cook Evolution) from superior access, over the lead in situ (right).

APRIL 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

CARDIOLOGY FOCUS: EXERCISE

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Exercise: The Most Cost-Effective in Treatment of Depression in Patients with Coronary Heart Disease New research from the Healthcare Outcomes Research Centre and Department of Health Psychology at RCSI indicates that exercise is more costeffective than psychotherapy or medication in the treatment of depression in individuals with coronary heart disease.

Coronary heart disease is a narrowing or blockage of the blood vessels in the heart.

The disease cannot be cured but can be treated with lifestyle changes, medicine and/or surgery.

Many individuals with coronary heart disease experience moderate or severe acute depression that may also require treatment.

Published in the Journal of Psychosomatic Research, the study entitled "Depression interventions for individuals with coronary artery disease – costeffectiveness calculations from an Irish perspective" examined the cost and the effectiveness of four types of treatments for depression in individuals with coronary heart disease. The four treatments studied were antidepressants, psychotherapy, collaborative care (multi-disciplinary team care) and supervised group exercise.

The study authors state that while a range of ‘evidence-based depression interventions are

Written with Dr Frank Doyle, Senior Lecturer in Psychology, Department of Health Psychology, Royal College of Surgeons Ireland

available, these may not always be suitable for cardiac patients due to patient preference, concerns about patient safety, such as drug interactions, or a lack of CAD specialisation among intervention providers.’

The study built on previous research that found exercise to be the most effective treatment for depression in coronary heart disease. In the present study, the cost of administering each of the four treatment types was analysed against the rate of reoccurrence of depression eight weeks later. The costs studied included the cost of antidepressants, the frequency of contact between patient and staff members, and the cost of staff time.

At eight weeks, the study found that group exercise treatment resulted in a cost of ¤526 per patient who achieved remission from depression (i.e. was successfully treated). This cost was followed closely by treatment with antidepressants which amounted to ¤589 per remission.

Individual psychotherapy costed

¤3,117 per remission and collaborative care amounted to ¤4,964 per remission.

Additionally, the authors suggest that future trials should explore the cost-effectiveness of other group treatments.

Main Findings The study authors state that their main findings ‘suggest that very cost-effective depression treatment can already be delivered within 8 weeks, whereas for longer treatment duration only pharmacotherapy is cost-effective.

While aimed at prevention of CAD

and depression, as opposed to treatment, results from the EuroFIT trial confirm the low cost of group exercise interventions and point to their potential as a cost-effective long-term health strategy.’

Dr Samira Jabakhanji, Healthcare Outcomes Research Centre, RCSI states, "The findings of this research indicate that, within a very short time, group exercise most effectively treats depression in individuals with coronary heart disease, and notably it is the most cost-effective treatment.

This is followed closely by antidepressants. The study gives us important insight into planning future depression treatment in this patient group in terms of delivering the best outcomes and value for both health service and patients."

Dr Frank Doyle, Department of Health Psychology and study principal investigator at RCSI, says, "Studies such as this are valuable to policy-makers as they combine the relative costs and effectiveness of treatments, allowing resources to be better targeted for patients. This work clearly shows that exercise is a sound investment for mood management in people with coronary heart disease."

Established in 2016, the Healthcare Outcomes Research Centre (HORC) is dedicated to the development and dissemination of evidence-based research on healthcare outcomes that informs healthcare policy and improves patient outcomes.

References are available on request

HOSPITALPROFESSIONALNEWS.IE | HPN • APRIL 2022

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CARDIOLOGY FOCUS: NEWS

Shortness of Breath Heralds Worse Survival than Chest Pain for Heart Attack Patients Just 76% of heart attack patients with dyspnoea or fatigue as their main symptom are alive at one year compared to 94% of those with chest pain as the predominant feature. That’s the finding of research presented today at ESC Acute CardioVascular Care 2022, a scientific congress of the European Society of Cardiology (ESC).1 “Dyspnoea and extreme tiredness were more common heart attack symptoms in women, older people and patients with other conditions such as high blood pressure, diabetes, kidney disease and lung disease,” said study author Dr Paulo Medeiros of Braga Hospital, Portugal. “While our study did not show that these symptoms cause poorer outcome, they were warning signs of greater risk.”

Chest pain is the hallmark presentation of myocardial infarction2 but other complaints such as shortness of breath, upper abdominal or neck pain, or transient loss of consciousness (blackouts) may be the reason to attend the emergency department.3 This study investigated which patients tend to present with atypical complaints and whether these symptoms result in the same consequences as chest pain.

The study focused on non-STelevation myocardial infarction (NSTEMI), a type of heart attack in which an artery supplying blood to the heart becomes partially blocked. The researchers used data from the Portuguese Registry of Acute Coronary Syndromes. The study included 4,726 patients aged

18 years and older admitted with NSTEMI between October 2010 and September 2019.

The average age of study participants was 68 years and 71% were men. Patients were divided into three groups according to their main symptom at presentation. Chest pain was the most common presenting symptom (4,313 patients; 91%), followed by dyspnoea/fatigue (332 patients; 7%) and syncope (81 patients; 2%).4 Patients with dyspnoea/fatigue were significantly older than those in the other two groups, with an average age of 75 years compared with 68 years in the chest pain group and 74 years in the syncope group. Those with dyspnoea/ fatigue were also more commonly women (42%) compared to patients with chest pain as the main symptom (29% women) or syncope (37% women). Compared to the other two groups, patients with dyspnoea/fatigue as their main symptom were more likely to have high blood pressure, diabetes, chronic kidney disease and chronic obstructive pulmonary disease (COPD).

The researchers compared rates of survival between the three groups at one year. At one year after the heart attack, 76% of patients in the dyspnoea/fatigue group were alive compared with 94% of the chest pain group and 92% of the syncope group. During the year after their heart attack, 76% of patients in the dyspnoea/ fatigue group avoided being hospitalised for a cardiovascular

reason compared with 85% of the chest pain group and 83% of the syncope group.

Dr Medeiros said, “Patients presenting with shortness of breath or fatigue had a worse prognosis than those with chest pain. They were less likely to be alive one year after their heart attack and also less likely to stay out of hospital for heart problems during that 12-month period.”

The researchers then conducted a multivariate analysis to assess whether chest pain, dyspnoea/fatigue or syncope were independent predictors of one-year survival. The analysis was adjusted for age, COPD, atrial fibrillation, left ventricular ejection fraction, major bleeding, and ventricular tachycardia. None of the symptoms emerged as independent predictors.

Dr Medeiros explained, “Shortness of breath was more common among patients that died during

the year after their heart attack.

However, when considering all of the studied variables, the type of presenting symptom was not an independent predictor of mortality, meaning that we cannot specifically state that shortness of breath was the reason for the worse outcome. Poorer survival may be due to other factors in those patients, such as reduced heart pump function.”

He concluded, “This study highlights the need to consider a diagnosis of myocardial infarction even when the primary complaint is not chest pain. This may be particularly important for women and older patients where diagnosis could be delayed and result in worse outcomes. In addition to the classic heart attack symptom of chest pain, pressure, or heaviness radiating to one or both arms, the neck or jaw, people should seek urgent medical help if they experience prolonged shortness of breath.”

World Obesity Day The Government needs to tackle the “intense marketing” of junk food to kids to protect children from childhood obesity, the Irish Heart Foundation has said.

Speaking on World Obesity Day, Mr Chris Macey, Director of Advocacy at the Irish Heart Foundation, said that no significant progress on protecting children from childhood obesity can be made until the Government tackles the key drivers of the obesity epidemic.

According to Mr Macey, these key

drivers include the high volume and availability of energy dense, nutrient poor food and beverages – including the emergence of a global snack food industry now worth $374 billion a year; the intense marketing of these products; their relative cheapness compared to healthy alternatives.

“The first step must be to follow the UK’s plan to protect children in particular from relentless pestering by junk food companies by introducing an online marketing ban and a 9pm TV advertising

APRIL 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

watershed for all unhealthy food and beverages,” Mr Macey said.

“The State’s own research estimates that 85,000 of this generation of children on the island of Ireland will die prematurely due to overweight and obesity. But this number is likely to be even higher after a pandemic which has seen children’s intake of unhealthy foods increase and their access to physical activity fall,” he added.

Obesity is a chronic, complicated disease as well as a driver of other

diseases such as heart disease and stroke, with serious implications for individuals, families, societies and economies. The need to act has been made more urgent by the impact of the Covid19 pandemic on weight related behaviours in children, young people and adults.

Obesity is one of the biggest public health challenges in Ireland today, affecting many thousands of people, yet those living with obesity lack support and face stigma at work, home and in the health system.

FOR YOURSELF, WOULD YOU CONSIDER

BOTH EFFICACY AND SAFETY?

Choose both efficacy and safety with ELIQUIS®

ELIQUIS is a factor Xa inhibitor that offers superior risk reduction in stroke and systemic embolism, with significantly less major bleeding vs. warfarin in non-valvular AF patients.1,* • Superiority demonstrated on stroke / systemic embolism vs. warfarin 1 • Superiority demonstrated on major bleeding vs. warfarin 1 ELIQUIS® (apixaban) PRESCRIBING INFORMATION Ireland Consult Summary of Product Characteristics (SmPC) before prescribing PRESENTATION: Film-coated tablets; 5 mg and 2.5 mg apixaban. INDICATION (SPC section 4.1): Prevention of stroke and systemic embolism in adults with non-valvular atrial fibrillation (NVAF) with one or more risk factors, such as prior stroke or transient ischaemic attack (TIA), age ≥ 75 years, hypertension, diabetes mellitus or symptomatic heart failure (NYHA Class ≥ II). Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE in adults (see Special warnings and precautions for information on haemodynamically unstable PE patients). Prevention of venous thromboembolic events (VTE) in adults who have undergone elective hip or knee replacement surgery (2.5 mg only). DOSAGE AND ADMINISTRATION (SPC section 4.2): Oral. Taken with water, with or without food. Prevention of stroke and systemic embolism in patients with NVAF: The recommended dose is 5 mg twice a day. In patients who meet at least two of the following criteria: serum creatinine ≥ 1.5 mg/dL (133 micromole/L), age ≥ 80 years, or body weight ≤ 60 kg the recommended dose is Eliquis, 2.5 mg twice daily. Patients with severe renal impairment (creatinine clearance 15-29 ml/min) should receive Eliquis 2.5 mg twice daily. Therapy should be continued long term. Treatment of DVT, treatment of PE and prevention of recurrent DVT and PE (VTEt): The recommended dose for the treatment of acute DVT and treatment of PE is 10 mg twice daily for the first 7 days followed by 5 mg twice daily. As per available medical guidelines, short duration of treatment (at least 3 months) should be based on transient risk factors (e.g. recent surgery, trauma, immobilisation). The recommended dose for the prevention of recurrent DVT and PE is 2.5 mg twice daily. When prevention of recurrent DVT and PE is indicated, the 2.5 mg twice daily dose should be initiated following completion of 6 months of treatment with Eliquis 5 mg twice daily or with another anticoagulant. The duration of overall therapy should be individualised after careful assessment of the treatment benefit against the risk for bleeding. Prevention of VTE (VTEp): elective hip or knee replacement surgery: The recommended dose is 2.5 mg twice a day. The initial dose should be taken 12 to 24 hours after surgery. Hip replacement surgery, the recommended duration of treatment is 32 to 38 days. Knee replacement surgery, the recommended duration of treatment is 10 to 14 days. Missed Dose for All Indications: If a dose is missed, Eliquis should be taken immediately and then continue with twice daily dose as before. Switching: Switching treatment from parenteral anticoagulants to Eliquis (and vice versa) can be done at the next scheduled dose. These medicinal products should not be administered simultaneously. Switching treatment from VKA therapy to Eliquis: Warfarin or other VKA therapy should be discontinued and Eliquis started when the international normalized ratio (INR) is < 2. Switching treatment from Eliquis to VKA therapy: Administration of Eliquis should be continued for at least 2 days after beginning VKA therapy. After 2 days of co- administration of Eliquis with VKA therapy, an INR should be obtained prior to next scheduled dose of Eliquis. Co-administration of Eliquis and VKA therapy should be continued until the INR is ≥2. Renal Impairment - mild or moderate renal impairment: For the prevention of VTE in elective hip or knee replacement surgery (VTEp), for the treatment of DVT, treatment of PE and prevention of recurrent DVT and PE (VTEt), no dose adjustment is necessary. For the prevention of stroke and systemic embolism in patients with NVAF and serum creatinine ≥ 1.5 mg/dL (133 micromole/L) associated with age ≥ 80 years or body weight ≤ 60 kg, a dose reduction is necessary. In the absence of other criteria for dose reduction (age, body weight), no dose adjustment is necessary. Severe renal impairment (creatinine clearance 15-29 mL/min): For the prevention of VTE in elective hip or knee replacement surgery (VTEp), for the treatment of DVT, treatment of PE and prevention of recurrent DVT and PE (VTEt), Eliquis is to be used with caution. For the prevention of stroke and systemic embolism in patients with NVAF, patients should receive the lower dose of Eliquis 2.5mg twice daily. In patients with creatinine clearance < 15 mL/min, or in patients undergoing dialysis, there is no clinical experience therefore Eliquis is not recommended. See SmPC for further details. Hepatic impairment: Contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk. Not recommended in patients with severe hepatic impairment. Use with caution in patients with mild or moderate hepatic impairment (Child Pugh A or B). No dose adjustment is required in patients with mild or moderate hepatic impairment. Use with caution in patients with elevated liver enzymes (ALT/AST >2 x ULN) or total bilirubin ≥ 1.5 x ULN. Prior to initiating Eliquis, liver function testing should be performed. Catheter ablation (NVAF): Patients can continue Eliquis use while undergoing catheter ablation. Cardioversion (NVAF): Eliquis can be initiated or continued in NVAF patients who may require cardioversion. See SmPC for further details. Patients with NVAF and acute coronary syndrome (ACS) and/or percutaneous coronary intervention (PCI): There is limited experience of treatment with apixaban at the recommended dose for NVAF patients when used in combination with antiplatelet agents in patients with ACS and/or undergoing PCI after haemostasis is achieved. See SmPC for further details. Paediatric population: Eliquis is not recommended in children and adolescents below the age of 18. CONTRAINDICATIONS (SPC section 4.3): Hypersensitivity to active substance or to excipients, active clinically significant bleeding, hepatic disease associated with coagulopathy and clinically relevant bleeding risk, lesion or condition if considered a significant risk factor for major bleeding, see SmPC for further details. Concomitant treatment with any other anticoagulant agent except under specific circumstances of switching anticoagulant therapy or when unfractionated heparin (UFH) is given at doses necessary to maintain an open central venous or arterial catheter or when UFH is given during catheter ablation for atrial fibrillation, see SmPC for further details. WARNINGS AND PRECAUTIONS (SPC section 4.4): Haemorrhage risk: Carefully observe for signs of bleeding. Use with caution in conditions with increased risk of haemorrhage. Discontinue administration if severe haemorrhage occurs. An agent to reverse the anti-factor Xa activity of apixaban is available. For information on reversal and managing bleeding, see SmPC for further details.

Interaction with other medicinal products affecting haemostasis: Concomitant treatment with any other anticoagulant is contraindicated (see contraindications). Concomitant use of Eliquis with antiplatelet agents increases the risk of bleeding. Care with concomitant SSRIs, SNRIs or NSAIDs, including acetylsalicylic acid. Following surgery, other platelet aggregation inhibitors are not recommended concomitantly with Eliquis. In patients with atrial fibrillation and conditions that warrant mono or dual antiplatelet therapy, a careful assessment of the potential benefits against the potential risks should be made before combining this therapy with Eliquis. A clinical trial enrolled patients with atrial fibrillation with ACS and/or undergoing PCI and a planned treatment period with a P2Y12 inhibitor, with or without ASA, and oral anticoagulant (either apixaban or VKA) for 6 months. Concomitant use of ASA increased the risk of ISTH (International Society on Thrombosis and Hemostasis) major or CRNM (Clinically Relevant Non-Major) bleeding in apixaban-treated subjects. See SmPC for further details. Use of thrombolytic agents for the treatment of acute ischemic stroke: Limited experience. Patients with prosthetic heart valves: safety and efficacy of Eliquis have not been studied in patients with prosthetic heart valves, with or without atrial fibrillation. Therefore, the use of Eliquis is not recommended in this setting. Patients with antiphospholipid syndrome: Direct acting Oral Anticoagulants (DOACs), including Eliquis, are not recommended for patients with a history of thrombosis who are diagnosed with antiphospholipid syndrome (see SmPC for further details). Surgery and invasive procedures: Discontinue at least 48 hours prior to elective surgery or invasive procedures with a moderate or high risk of bleeding.

Discontinue at least 24 hours prior to elective surgery or invasive procedures with a low risk of bleeding. If surgery or invasive procedures cannot be delayed, appropriate caution should be exercised, taking into consideration an increased risk of bleeding. Eliquis should be restarted after the invasive procedure or surgical intervention as soon as possible provided the clinical situation allows and adequate haemostasis has been established. For patients undergoing catheter ablation for atrial fibrillation, Eliquis treatment does not need to be interrupted. Temporary discontinuation: Discontinuing anticoagulants, including Eliquis, for active bleeding, elective surgery, or invasive procedures places patients at an increased risk of thrombosis. Lapses in therapy should be avoided and if anticoagulation with Eliquis must be temporarily discontinued for any reason, therapy should be restarted as soon as possible. Spinal/ epidural anaesthesia or puncture: Patients treated with antithrombotic agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal haematoma which can result in long- term or permanent paralysis. The risk of these events may be increased by the post- operative use of indwelling epidural catheters or the concomitant use of medicinal products affecting haemostasis. Indwelling epidural or intrathecal catheters must be removed at least 5 hours prior to the first dose of Eliquis. The risk may also be increased by traumatic or repeated epidural or spinal puncture.

Patients are to be frequently monitored for signs and symptoms of neurological impairment (e.g., numbness or weakness of the legs, bowel or bladder dysfunction). If neurological compromise is noted, urgent diagnosis and treatment is necessary. Prior to neuraxial intervention the physician should consider the potential benefit versus the risk in anticoagulated patients or in patients to be anticoagulated for thromboprophylaxis. There is no clinical experience with the use of Eliquis with indwelling intrathecal or epidural catheters. See SmPC for further details. Haemodynamically unstable PE patients or patients who require thrombolysis or pulmonary embolectomy: Eliquis is not recommended as an alternative to unfractionated heparin in patients with pulmonary embolism who are haemodynamically unstable or may receive thrombolysis or pulmonary embolectomy since the safety and efficacy of Eliquis have not been established. Patients with active cancer: Patients with active cancer can be at high risk of both venous thromboembolism and bleeding events. When apixaban is considered for DVT or PE treatment in cancer patients, a careful assessment of the benefits against the risks should be made. Renal impairment: see dosage and administration section. Elderly patients: Increasing age may increase haemorrhagic risk. Also, the co-administration of Eliquis with ASA in elderly patients should be used cautiously because of a potentially higher bleeding risk. Body weight: Low body weight (< 60 kg) may increase haemorrhagic risk. Hepatic impairment: see dosage and administration section. Interaction with Inhibitors of CYP3A4 and P-gp: Not recommended with strong inhibitors of both CYP3A4 and P-gp. These medicinal products may increase Eliquis exposure by 2-fold or greater in the presence of additional factors that increase Eliquis exposure (e.g. severe renal impairment) see SmPC for further details. Interaction with Inducers of CYP3A4 and P-gp: Eliquis should not be used for the treatment of DVT and PE in patients receiving concomitant systemic treatment with strong inducers of both CYP3A4 and P-gp since efficacy may be compromised. Concomitant systemic treatment with strong inducers of both CYP3A4 and P-gp, Eliquis should be used with caution for the prevention of VTE in elective hip or knee replacement surgery, for the prevention of stroke and systemic embolism in patients with NVAF and for the prevention of recurrent DVT and PE, though no dose adjustment for Eliquis is required during concomitant therapy with such medicinal products. Hip fracture surgery: Eliquis has not been studied in clinical trials in patients undergoing hip fracture surgery.

Therefore, it is not recommended in these patients. Laboratory parameters: Clotting tests (PT, INR, and aPTT) are affected by the mechanism of action of apixaban. Changes observed at the expected therapeutic dose are small and subject to a high degree of variability, see SmPC for further details. Information about excipients: Eliquis contains lactose. Patients with galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take Eliquis. DRUG INTERACTIONS (SPC Section 4.5): Eliquis should be used with caution when co-administered with SSRIs/SNRIs, NSAIDs, ASA and/or P2Y12 inhibitors because these medicinal products typically increase the bleeding risk. There is limited experience of co-administration with other platelet aggregation inhibitors (such as GPIIb/IIIa receptor antagonists, dipyridamole, dextran or sulfinpyrazone) or thrombolytic agents. As such agents increase the bleeding risk, co-administration of these products with Eliquis is not recommended. See SmPC for further details.Due to an increased bleeding risk, concomitant treatment with any other anticoagulants is contraindicated, except under specific circumstances of switching anticoagulant therapy, when UFH is given at doses necessary to maintain an open central venous or arterial catheter or when UFH is given during catheter ablation for atrial fibrillation. Administration of activated charcoal reduces Eliquis exposure. Also see contraindications and special warnings and precautions section; Consult SmPC (contraindications, special warnings and precautions and drug interactions) for full details on interactions. PREGNANCY AND LACTATION (SPC section 4.6): Pregnancy: As a precautionary measure, it is preferable to avoid the use of apixaban during pregnancy. Breastfeeding: A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from apixaban therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. UNDESIRABLE EFFECTS (SPC section 4.8): Increased risk of occult or overt bleeding from any tissue or organ, which may result in post haemorrhagic anaemia. The signs, symptoms, and severity will vary according to the location and degree or extent of the bleeding. Frequencies: common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available data). Prevention of VTE in adult patients who have undergone elective hip or knee replacement surgery (VTEp): Common: anaemia; haemorrhage*; haematoma*; nausea; contusion. Uncommon: thrombocytopenia*; epistaxis*; haematochezia*; liver function test abnormal (including blood bilirubin increased*); haematuria*; specific haemorrhage such as gastrointestinal*, abnormal vaginal*, urogenital*, post procedural*, wound secretion*, incision site*, operative*. Rare: hypersensitivity*; anaphylaxis*; haemoptysis*; gingival bleeding*; specific haemorrhage such as eye (including conjunctival)*, rectal*, muscle*. Not known: angioedema*; specific haemorrhage such as brain (encompassing intracranial, intraspinal)*, intra-abdominal*, respiratory tract*, haemorrhoidal*, mouth*, retroperitoneal*, traumatic*, erythema multiforme*. Prevention of stroke and systemic embolism in adult patients with NVAF, with one or more risk factors (NVAF): Common: anaemia; haemorrhage*; haematoma*; hypotension (including procedural hypotension); epistaxis*; nausea; gingival bleeding*; gamma-glutamyltransferase increased; haematuria*; contusion; specific haemorrhage such as eye (including conjunctival)*, gastrointestinal*, rectal*. Uncommon: thrombocytopenia*; hypersensitivity*; anaphylaxis*; haemoptysis*; haematochezia*; liver function test abnormal (including blood bilirubin increased*); specific haemorrhage such as brain (encompassing intracranial, intraspinal)*, intra-abdominal*, haemorrhoidal*, mouth*, abnormal vaginal*, urogenital*, post procedural*, wound secretion*, incision site*, operative*, traumatic*. Rare: specific haemorrhage such as respiratory tract*, retroperitoneal*, muscle*. Very Rare: erythema multiforme*. Not known: angioedema*.

Treatment of DVT and PE, and prevention of recurrent DVT and PE (VTEt): Common: anaemia; thrombocytopenia*; haemorrhage*; haematoma*; epistaxis*; nausea; gingival bleeding*; gamma-glutamyltransferase increased; alanine aminotransferase increased; skin rash; haematuria*; contusion; specific haemorrhage such as gastrointestinal*, mouth*, rectal*, abnormal vaginal*, urogenital*. Uncommon: hypersensitivity*; anaphylaxis*; haemoptysis*; haematochezia*; liver function test abnormal (including blood bilirubin increased*); specific haemorrhage such as eye (including conjunctival)*, haemorrhoidal*, muscle*, post procedural*, wound secretion*, incision site*, operative*, traumatic*. Rare: specific haemorrhage such as brain (encompassing intracranial, intraspinal)*, respiratory tract*. Not Known: angioedema*; specific haemorrhage such as intra-abdominal* and retroperitoneal*, erythema multiforme*. *Denotes serious adverse reaction Refer to SmPC for all other adverse events LEGAL CATEGORY: POM. MARKETING AUTHORISATION NUMBER (SPC section 8): EU/1/11/691/002-3, EU/1/11/691/008, EU/1/11/691/014 PACKAGE QUANTITIES: Carton of 20 film-coated tablets 2.5 mg, 60 film-coated tablets 2.5 mg, 56 film-coated tablets 5 mg, 28 film- coated tablets 5 mg. MARKETING AUTHORISATION HOLDER (SPC section 7): Bristol-Myers Squibb/Pfizer EEIG, Plaza 254, Blanchardstown Corporate Park 2, Dublin 15, D15 T867, Ireland FOR FURTHER INFORMATION CONTACT: medical.information@bms.com or 1 800 749 749 (Ireland) DATE OF PREPARATION: April 2021 ADDITIONAL INFORMATION AVAILABLE ON REQUEST Approval Code: 432-IE-2100041

Adverse events should be reported. Reporting forms and information can be found at: Ireland - via HPRA Pharmacovigilance at www.hpra.ie Adverse events should also be reported to Bristol-Myers Squibb via medical.information@bms.com or 1 800 749 749 (Ireland)

*with one or more risk factors, such as prior stroke or transient ischaemic attack (TIA); age≥ 75 years; hypertension; diabetes mellitus; symptomatic heart failure (NYHA Class ≥ II) AF = Atrial Fibrillation. Reference: 1. Granger CB et al. N Engl J Med 2011; 365: 981–992.

Date of approval: May 2021 Job code: PP-ELI-IRL-0497 www.eliquis.ie

60

CARDIOLOGY FOCUS: COLLABORATION

The European Society of Cardiology's Cardiovascular Risk Collaboration- Is it Relevant to Irish Healthcare Professionals?

Written by Ian M Graham, Professor of Cardiovascular Medicine, Trinity College Dublin

The CRC's overall structure may be summarised from a review published in the Journal of the American College of Cardiology5.

Co-Chair, ESC Cardiovascular Risk Collaboration

7. The CRC believes that the future of risk estimation may lie in applying artificial intelligence to both genetic and environmental factors to allow more personalised risk estimation from early life on, using an exposure time model rather than age per se.

Introduction

Take home messages 1. In 2020 the Board of the European Society of Cardiology (ESC) established a multidisciplinary Cardiovascular Risk Collaboration (CRC) in the European Heart health Institute in Brussels.

2. In apparently healthy persons, the risk of a heart attack or stroke relates strongly to the combined effects of smoking, cholesterol level and blood pressure, often combined with overweight, inactivity and consequent diabetes.

3. Clinical estimation of these effects is imperfect, therefore all guidelines on cardiovascular disease (CVD) prevention recommend some form of risk chart or calculator.

4. The previously used European Society of Cardiology's (ESC) risk estimation system, SCORE, estimated 10 year risk of fatal CVD and there was a strong demand to estimate risk of total (fatal and non-fatal) CVD events.

5. The CRC responded to this by developing total event charts for both middle aged (SCORE2) and older persons (SCORE2-OP).

These have been included in the 2021 ESC Guidelines on CVD Prevention in Clinical Practice1.

This paper outlines the rationale for the ESC's Cardiovascular Risk Collaboration and its various work packages. We then present its first two completed deliverables, the SCORE22 and SCORE2-OP3 (older persons) risk charts, and finish with some thoughts for the future.

The CRC The Cardiovascular Risk Collaboration (CRC) was stablished by the Board of the ESC in 2020 to contribute to the ESC's mission to reduce the burden on cardiovascular disease by researching new aspects of risk estimation and developing their practical application.

The CRC's work is arranged SCORE22: through a number of work The ESC's original SCORE2 system packages that include, among other was a powerful brand but based on activities, the development of new old data with a limited number of The work is arranged through riskCRC's estimation systems, exploration This paper outlines the rationale for the ESC's Cardiovascular Risk Collaboration andaitsnumber of work packages that include, among other variables.

It was criticised because 2 the development ofthe new riskas estimation systems, exploration of new data science Because CVD generally arises of data science tools such various work packages.

We then present its firstactivities, twonew completed deliverables, SCORE2 3 (older persons) it estimated only the risk of CVDof assome artificial intelligence applying them to new data sources, integration fromSCORE2-OP a combination of risk factors, artificial intelligence and and risk charts., andtools finishsuch with thoughts forapplying theand future. imaging into risk estimation, developing new decision supportwas systems, providing mortality, and there a strong and clinical estimation of these them tomodalities new data sources, resources for of other European Heart Health Institute activities, and providing knowledge demand for total event (fatal +non-to effects is poor, all CVD prevention integration imaging modalities assist developing countries. fatal CVD) charts. This proved more guidelines recommend some sort of The CRC into risk estimation, developing risk estimation system such as the challenging than one might have new decision support systems, will now focus on the first two major delivered by theto CRC, and 4 Collaboration (CRC) wasWe The Cardiovascular Risk stablished by the Board of the ESC in 2020projects European SCORE or the American expected, due theSCORE2 heterogeneity providing resources for other (older persons).

Whileby the risk charts are presented here, a new interactive risk to contribute to the ESC's mission to reduce the SCORE2-OP burden on cardiovascular disease Pooled Cohort Equation.

However, and very variable quality of nonEuropean Heart Health Institute calculationtheir App is in final application. test phase researching new aspects of risk estimation practical these systems are relatively crude, and developing activities, and providing knowledge fatal event data throughout Europe. attempt to apply population data to to assist developing countries.

It was based on 680,000 individuals Because CVD generally arises from of risk factors, and clinical estimation of individuals, and generally starta combinat1on at from 45 cohorts in 13 countries. A these effects is poor, all CVD guidelines riskfirst estimation Werecommend will now some focussort onofthe two age 40after 40 years ofprevention possible multiplicative approach was used 4 or the American Pooled Cohort Equation. However, system such as the European SCORE major projects delivered by the exposure to risk factors. to convert mortality to total events. these systems are relatively crude, attempt to apply population data to individuals, and CRC, SCORE2 and SCORE2-OP The process may be summarised generally start at age 40after 40 years of possible exposure to risk factors.

It was therefore decided to develop (older persons). While the risk from the graphical abstract from the a multidisciplinary partnership charts are presented here, a new main SCORE2 paper4: It therefore decided to develop partnership to explore these towas explore these issues under aamultidisciplinary interactive risk calculation Appissues is in under a steering Committee: steering Committee:

6. All current risk estimation systems are imperfect- they start too late, around age 40, are dominated by age effects, and are much better at estimating risk in populations than in individuals.

APRIL 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

final test phase

Ireland is classified as a moderate risk country and the appropriate chart is as follows. It will be noted that non-HDL cholesterol is used rather than the total cholesterol in SCORE because the former relates somewhat more closely to risk: SCORE2-OP3: SCORE2-OP was developed in response to demands for a risk estimation system for use in older persons, in view of the ageing

events. The process may be summarised from the graphical abstract from the main SCORE2 paper4:

61

Ireland is classified as a moderate risk country and the appropriate chart is as follows. It will be noted that non-HDL cholesterol is used rather than the total cholesterol in SCORE because the former relates somewhat more closely to risk: The chart appropriate to Ireland is as follows. It will be noted that gender differences are modest, perhaps because the highest risk men have already died.

Risk estimation: can we see the future?

populations of Europe. It uses • The results apply to populations similar methods to SCORE2 but was 3: and their application to SCORE2-OP more challenging because of more individuals is less certain. limited andwas less reliableinend pointto demands for a risk estimation system for use in SCORE2-OP developed response • The effects are dominated data in olderinpeople with older persons, view of combined the ageing populations of Europe. It uses similar methods to age and which is of course competing causes of death.

The SCORE2 but was more challenging because of moreby limited less reliable end point data a measure of graphical abstract illustrating its causes ofessentially in older people combined with competing death. The graphical abstract 5 5 exposure time rather than a risk development also illustrates the also illustrates the four risk regions of Europe used in both illustrating its development factor as such.

SCORErisk publications: four regions of Europe used in both SCORE publications: Based on the work and thoughts of Brian Ference, the CRC is The chart appropriate to Ireland attempting to address some of is as follows. It will be noted that these issues. This approach regards gender differences are modest, risk as exposure time, such as units perhaps because the highest risk men have already died. of cholesterol, BP or total risk over time. This reduces the problem of Risk estimation: can we see the domination of present systems the future? by age. Future risk is determined by the rate of rise of these variables.

All current risk estimation systems Mendelian randomisation studies share substantial limitationssuggest that the rise in cholesterol • They are based on cohorts that and blood pressure from early life usually start at around age 40, on is substantially determined by thus missing the effect of many polymorhisms that may have a years of potential exposure small impact on five year risk but to risk. a very large impact on lifetime, 50-70 year risk. To this must be • The techniques used, such added the progressively more as Cox, essentially derive important impact of lifestyle and multipliers and cannot allow environmental factors. It is planned for complex biological to apply artificial intelligence interactions within different risk techniques to these issues in an factor combinations.

attempt to achieve more precise 2. SCORE2 working group and ESC All current risk estimation systems share substantialCardiovascular limitationsrisk collaboration. and personalised risk estimates • They are based on cohorts that usually startSCORE2 at around risk age prediction 40, thus missing the applicable at a much earlier stage, effect of many years of potential exposure toalgorithms:new risk. models to estimate perhaps in the 20s. Further, the • The techniques used, such as Cox, essentially10-year derive multipliers and cannot allow for risk of cardiovascular gradient (expected rate of rise within different risk factor combinations. complex biological interactions disease in Europe. of risk) may helpapply to determine • The results to populations and their application individuals is less certain.

EuropeantoHeart Journal (2021) 00, subjects could benefit from • Thewho effects are dominated by age which is of1–16. course essentially a measure of doi:10.1093/eurheartj/ehab309. earlierexposure lifestyletime advice and perhaps rather than a risk factor as such.

3. SCORE2-OP working group and easrly imaging such as CT ESC Cardiovascular risk calcium scoring, and othersofinBrian Ference, the Based on the work and thoughts CRC is attempting to address some of collaboration. SCORE2-OP risk these issues.

This approach regards risk as exposure time, such as units of cholesterol, BP or whom this would be expected to prediction algorithms: estimating total risk over time.

This reduces domination of present systems by age. have a very low yield.

Somethe ofproblem of theincident cardiovascular event risk in Future risk is determined by the rate of rise of theseolder variables.

Mendelian these issues are addressed in an persons in four randomisation geographical studies suggest the rise in cholesterol and blood pressure from early life on is editorial that that accompanied the risk regions. substantially determined by polymorhisms that may have a small impact on five year risk 6 SCORE2 papers.

European Heart Journal (2021) 00,

but a very large impact on lifetime, 50-70 year risk. To this must be added the progressively 1–13 doi:10.1093/eurheartj/ehab312

more important impact of lifestyle and environmental factors. It is planned to apply artificial In conclusion, we have presented 4. Conroy RM,more Pyorala K, Fitzgerald intelligence to theseand issues in an attempt to achieve precise and an outline techniques of the rationale work AP et al. Estimation risk personalised estimates applicable at a much earlier stage, perhaps in of theten-year 20s. Further, plan of the risk ESC Cardiovascular cardiovascular disease the gradient (expected rate rise of risk) may helpof tofatal determine subjects who couldin Risk Collaboration.

Theofnew Europe: thesuch SCORE benefit from earlier lifestyle advice and perhaps easrly imaging as CTproject. calcium European scoring, SCORE2 and SCORE2-OP risk Heart Journal 2003; 24:987-1003. estimation systems have been 5. Graham IM, Di Angelantonio E, presented and we summarise what Visseren F et al. Systematic Coronary may be a radical new approach to Risk Evaluation (SCORE). JACC risk estimation.

Focus seminar: the best of population

References 1. Visseren FLJ (Chairperson), Francois Mach* (Chairperson). 2021 ESC Guidelines on cardiovascular disease prevention in clinical practice European Heart Journal (2021) 00, 1 111, doi:10.1093/eurheartj/ ehab484.

research studies 4/8. Journal of the American College of Cardiology 2021;77: 3046-57.

6. Tokozoglu L, Torp-Pedersen C. (Editorial). Redefining cardiovascular risk prediction: Is the crystal ball clearer now? European Heart Journal (2021) 00, 1–4, doi:10.1093/ eurheartj/ehab310

HOSPITALPROFESSIONALNEWS.IE | HPN • APRIL 2022

62

CARDIOLOGY FOCUS: ATRIAL FIBRILLATION

Current Developments in Atrial Fibrillation Interview with Theresa Lowry Lehnen, a Clinical Nurse Specialist and Associate Lecturer Institute of Technology Carlow

Aetiology of AF

minute). Patients may also present with signs and symptoms of acute CVA or other organ damage due to systemic emboli.

Atrial fibrillation is multi factorial in nature. Abnormalities or damage to the heart's structure are the most pericarditis, heart valve and congenital heart disease. A family history of and AF may also increase Diagnosis Screening common causes.

the risk. AF is also associated“Atrial withfibrillation other is medical conditions, suchexplains, as, pneumonia, Theresa “Diagnostic lung more common investigation of AF typically with increased age and affects sleep apnoea, cancer, pulmonary embolism, sarcoidosis, obstructive hyperthyroidism and includes a complete medical history certain groups of people more than physical examination, ECG, full others,” adds Theresa. obesity. A number of triggers are associated with the conditionand including smoking, excessive blood count, Urea and Electrolytes “WhileWhen it can sometimes alcohol and or coffee consumption. no other affect medical conditions associated and serumare thyroid stimulatingwith it, people who are physically very hormone level.

All patients who it is called lone atrial fibrillation.” fit, AF is more common in people

Characterised by the rapid and irregular beating of the atrial chambers of the heart, episodes of which may become longer or continuous over time, Atrial fibrillation (AF) is the most common cardiac arrhythmia diagnosed in clinical practice. The condition affects more than 33 million people around the world.

In Ireland, 11% of people over the age of 80 have atrial fibrillation and it affects more than 40,000 people in Ireland aged over 50 years.

AF is associated with a significant risk of transient ischemic attack, ischemic stroke, systemic embolism, and death. While not immediately life-threatening, it does carry a five-fold higher risk of stroke caused by the formation of blood clots in the heart and blocked blood vessels in the brain.

present with symptoms of AF with other heart conditions such should have at minimum their pulse as hypertension,especially atherosclerosis, Atrial fibrillation is often asymptomatic, in the checked elderly,for but manyaspatients irregularities well as cardiomyopathy, pericarditis, a 12-lead ECG. experience palpitations, rapid and irregular heartbeat, vague chest discomfort or symptoms heart valve and congenital heart “ECG findings for AF indicate the disease. A family history of AF of heart failure such as weakness, light-headedness and dyspnoea, particularly when the absence of P waves, irregularly may also increase the risk. AF is irregular R-R andwith the signs also associated with other medical ventricular rate is very rapid (140 to 160 beats/minute). Patients may alsointervals present presence of f (fibrillatory) waves conditions, such as, pneumonia, and symptoms of acute CVA or lung other organ damage due to systemic between emboli. the QRS complexes. cancer, pulmonary embolism, Fibrillatory waves are irregular in sarcoidosis, obstructive sleep timing and morphology with baseline apnoea, hyperthyroidism and undulations at rates up to or > 300/ obesity. A number of triggers 4.2 by paroxysmal atrial fibrillation. minute, best seen in lead V1 and not are associated with the condition Diagnosis and Screening A further 280,000–340,000 new always apparent in all leads. including smoking, excessive ischemic strokes, 3.5–4 million alcohol and or coffee consumption. hospitalizations for AF and 100–120 “Other diagnostic medical tests for AF Theresa explains, “Diagnostic investigation AF typically includes a complete history When no otherof medical conditions million outpatient visits can also be include CXR and echocardiogram. are associated with it, it is called addedphysical to these figures.” and examination, ECG, full blood count, Urea and Electrolytes and isserum Echocardiography carriedthyroid lone atrial fibrillation.” out to assess for structural AF constitutes a public health stimulating hormone level. All patients who present with symptoms of AF should have at Atrial fibrillation is often heart defects such as left atrial challenge with high comorbidity asymptomatic, especially in as a 12-lead enlargement, minimum their pulse for irregularities as well ECG. left ventricular wall and increased mortality riskchecked and is the elderly, but many patients motion abnormalities suggesting a significant cause of increasing experience palpitations, rapid past or present ischemia, valvular health care costs globally. An “ECG findings AF indicate the of P waves, irregular R-R intervalsand and andabsence irregular heartbeat, vagueirregularly disorders and cardiomyopathy estimated 1.4% offor all adults over chest discomfort or symptoms of to identify additional risk factors 65 years living with undiagnosed AF the presence of f (fibrillatory) heart waves between the QRS complexes.

Fibrillatory waves are failure such as weakness, for stroke such as atrial blood means more cases of unmanaged light-headedness and dyspnoea, stasis, thrombus or complex atrial fibrillation will create even irregular in timing and morphology with baseline undulations at rates up aortic to or particularly when the ventricular plaque. Atrial thrombi are more further economic strain on our >healthcare 300/minute, best seen in leadrate V1isand apparent all leads. very not rapidalways (140 to 160 beats/ inlikely systems. in the atrial appendages,

According to Theresa Lowry Lehnen, the percentage of people with AF increases with age with 0.1% under 50 years, 4% between 60-70 years and 14% over 80 years of age being affected.

Theresa, who is a Clinical Nurse Specialist and Associate Lecturer Institute of Technology Carlow adds, “Due to increased lifespan, atrial fibrillation is on the rise and predicted to affect 14-17 million people in Europe by 2030, with 120,000-215,000 new cases per year (estimated incidence 0.23–0.41 per 1,000 person/years).

“In particular, 7–8.5 million people will be affected by permanent AF, 3.5–4.2 by persistent AF, and 3.5–

APRIL 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

63 where they are best detected by transoesophageal rather than transthoracic echocardiography.”

Atrial fibrillation is a progressive disorder. The exact electropathological mechanisms underlying persistence of AF are at present unknown and none of the available recording techniques can determine the degree and extensiveness of atrial electropathology or determine the stage of the condition at any time in the process.

Treatment Treatment of atrial fibrillation varies from person to person and depends on the type of AF, symptoms, treatment of any underlying cause, age, and overall health.

to restore normal heart rhythm.

The aim is to reduce the resting heart rate to < 90 beats per minute, however, in some people the target is < 110 bpm.

The first step, she notes, is “First line drugs include beta to try to find the cause of the blockers such as propranolol or atrial fibrillation. “For example, atenolol and nonhydropyridine hyperthyroidism can sometimes calcium channel blockers such as be the underlying cause of AF and diltiazem or verapamil, which slows medication to control the condition Classification of Atrial Fibrillation the conduction of impulses to the can correct the symptoms of ventricles. Digoxin may be added The European Society of Cardiology atrial fibrillation. If no underlying to control the heart rate further.

(ESC) distinguishes five types of AF cause is found, treatment of Digoxin is usually only effective based on presentation and duration AF is usually aimed at either for controlling the ventricular rate of arrhythmia seen in the table at rhythm or rate control. Since AF at rest and should therefore only the foot of the page. induces electrical, structural, and be used as a monotherapy in contractile remodelling, therapy Complications predominantly sedentary patients. aimed at prevention or restoration “Other diagnostic tests for AF include CXR and Echocardiography is carried of remodelling andechocardiogram. consequently The absence of atrial contractions “Anti-arrhythmic drugs can be restoration of sinus rhythm should in atrial fibrillation predisposes the classified clinically into those wall out to assess for structural heart defects such as left atrial enlargement, left ventricular be the first choice strategy. The patient to thrombus formation. that act on supraventricular Theresa “Risk of stroke suggesting different AF treatment modalities motionsays, abnormalities past or present ischemia, valvular disorders and arrhythmias (example verapamil), is higher in older patients and include pharmacological therapy, both supraventricular and stasis, cardiomyopathy and to identify additional risk factors for stroke such as atrial blood in those with mechanical heart electrical cardioversion, pacemaker ventricular arrhythmias (example valves, rheumatic valvular disease, implantation amiodarone) and those that thrombus or complex aortic plaque.

Atrialcombined thrombiwith areHis more likely in the atrial appendages, hyperthyroidism, hypertension, bundle ablation or surgical isolation act on ventricular arrhythmias where left they are systolic best detected by transoesophageal rather than transthoracic diabetes, ventricular of the pulmonary veins with or (example lidocaine).

They can also dysfunction, or previous without additional linear lesions/ be classified according to their echocardiography.” thromboembolic events. Systemic substrate modification. effect on the electrical behaviour emboli can also cause malfunction of myocardial cells during activity “Anti-arrhythmic medication can or necrosis of other organs. Atrial (Vaughan Williams Classification).

Atrial fibrillation is a progressive disorder.

The exact electro-pathological mechanisms control atrial fibrillation by restoring fibrillation may impair cardiac Class I antiarrhythmic medications normal heart rhythm and controlling output.

Loss ofpersistence atrial contraction underlying of AF are at present unknown and none of the available recording are membrane stabilising drugs the rate at which the heart beats. can lower cardiac output at normal example lidocaine and flecanide. techniques can determine the degree and extensiveness of atrial electro-pathology or The choice of anti-arrhythmic heart rate by about 10%. Such a Class II are beta blockers. Class depends on the type of AF, decrease is usually well tolerated determine the stage of the condition at any time in the process. III include amiodarone and sotalol comorbidities, side effects of the except when the ventricular rate and Class IV are calcium channel medicine chosen and response to becomes too fast (> 140 beats/ blockers, including verapamil, but therapy. Some patients may need minute), or when patients already Classification of Atrial Fibrillation not dihydropyridines. more than one anti-arrhythmic have borderline or low cardiac to control atrial fibrillation and a output. In such cases, cardiac “The negative inotropic effects failure may develop.” variety of medications are available tend to The European Society of Cardiology (ESC) distinguishes five typesofofantiarrhythmic AF based ondrugs presentation

and duration of arrhythmia.

First diagnosed AF

Every patient who presents with AF for the first time irrespective of the duration or the presence and severity of AF related symptoms.

Paroxysmal AF

AF that terminates spontaneously, usually within 48 hours although AF paroxysms may continue for up to 7 days. After 48 hours spontaneous conversion is low and anticoagulation must be considered.

Persistent AF

Continuous AF sustained for more than 7 days or requires termination by cardioversion, either with drugs or by direct current cardioversion.

Longstanding persistent AF

Continuous AF of greater than 12 month’s duration. It is usually decided to adopt a rhythm control strategy at this stage.

Permanent AF

Permanent AF is said to exist when the presence of the arrhythmia is accepted by the patient and physician. Rhythm control interventions, by definition, are not pursued in patients with permanent AF.

Reference: Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology

Reference: Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology

be additive. Special care should be taken if two or more are used, especially if myocardial function is impaired. Many medications that are effective in countering arrhythmias can also provoke them in some instances. Patients must be monitored closely as common side effects of anti-arrhythmic medications include, hypotension, fatigue, nausea, vomiting, possible issues with liver, kidneys, thyroid or lungs and heart rhythm disorders.

Amiodarone causes sensitivity to sunlight and skin changes are common, therefore, sun protection is important when taking this medication.”

Aspirin is not recommended to prevent strokes caused by atrial fibrillation. Theresa explains, “Patients with a high or moderate level of risk of stroke or thrombus formation due to atrial fibrillation, are usually prescribed an anticoagulant such as warfarin or a newer type of anticoagulant-novel oral anticoagulants (NOACs) also called direct oral anticoagulants (DOACs), such as dabigatran, rivaroxaban, apixaben or edoxaben.

There are fewer dietary and medication interactions with the newer agents, and less need for monitoring. NOACs are at least as effective or superior to warfarin for stroke prevention in patients with non-valvular atrial fibrillation, and are at least as safe or safer in terms of bleeding risk, according to three large clinical trials.

“NOACs have major pharmacologic advantages over warfarin, which is a vitamin K antagonist, including rapid onset/offset of action, few drug interactions and predictable pharmacokinetics.

Practical advantages of novel oral anticoagulants over warfarin include fixed once or twice-daily oral dosing without the need for coagulation monitoring. Potential drawbacks include a risk of bleeding that might be increased in patients over 75 years of age, the lack of a routine laboratory test to reliably measure anticoagulant effect and previously, the lack of an antidote for reversal.

“Choice of NOAC is influenced by the patients individual characteristics, including risk of stroke or VTE, risk of bleeding and comorbidity, in particular renal dysfunction. It is also recommended that one of the bleeding risk scores, such as the HAS-BLED score, be used to help risk-assess patients. The choice of agent should take into consideration the patient’s age,

Complications | HPN • APRIL 2022 HOSPITALPROFESSIONALNEWS.IE The absence of atrial contractions in atrial fibrillation predisposes the patient to thrombus

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CARDIOLOGY FOCUS: ATRIAL FIBRILLATION

weight and creatinine clearance, as dose adjustment may be required.”

Pharmacologic cardioversion, also referred to as chemical cardioversion, uses anti-arrhythmic medication instead of an electrical shock. Pharmacological cardioversion is often used for the treatment of atrial fibrillation of recent onset. Flecainide, ibutilide, propafenone and vernakalant can be used in patients with no structural heart disease. Where structural heart disease is present, intravenous amiodarone is the drug of choice. Flecainide administered intravenously in patients with AF For patients who have been in AF for longer than 12-24 hours, or in whom the duration of the of recent onset has been shown to pharmacologic AV nodal blockade, About a third of people with atrial restore sinus rhythm 72-95 a %minimum flutter also have atrial fibrillation. with adenosine, but such arrhythmia is notinclear, period of anticoagulation of example three weeks is recommended of patients, with greatest success therapy does not terminate atrial “Both conditions carry increased before cardioversion.

“Even if echocardiography has demonstrated no thrombus before rates in those who receive treatment flutter. Treatment of atrial flutter risk of stroke. In atrial fibrillation, within 24 hours of atrial fibrillation focuses on ventricular rate control, cardioversion, patients should be anticoagulated for at least one month post cardioversion, the atria beat irregularly. In atrial onset. When AF has persisted rhythm control, and prevention of the atria beat regularly, but for >48mechanical hours, pharmacological thromboembolism.

Patients since atrial function flutter, may than return slowly after cardioversion,” Theresa adds.with faster usual and more often cardioversion is much less likely to chronic or recurrent atrial flutter than the ventricles, and there may be effective. Amiodarone appears require an oral anticoagulant. The Differentiation between andbeats Atrial Fibrillation be four atrial to every one to be the most effective agent forAtrial Flutter choice among the therapies is ventricular beat.

During atrial flutter, restoring sinus rhythm in patients based on the same considerations unlike atrial fibrillation, electrical with persistent atrial “Atrial flutter is fibrillation. much less common than atrial fibrillation but itsfor causes and hemodynamic as atrial fibrillation.

Patients activity in the atria is coordinated. often require cardioversion or atrial atria do contract, but at a very For patients who have in AF she The consequences arebeen similar,” says. flutter substrate ablation.” rapid rate of 250 to 350 times per for longer than 12-24 hours, or in minute.

This rate is too fast to allow whom the duration of the arrhythmia Atrial Fibrillation is the most About a third of people with atrial flutter also have atrial fibrillation. every impulse to be conducted is not clear, a minimum period of common cardiac arrhythmia through the atrioventricular node anticoagulation of three weeks is affecting at least 3% of Irish adults the ventricles.

Because the fibrillation, “Both conditions increasedtorisk of stroke.

In atrial the atria beat irregularly. recommended before carry cardioversion. over 60 and is associated with AV node cannot usually conduct “Even if echocardiography has almost one in three strokes in In atrial flutter, the atria beat regularly, but faster than usual and more often than the at this rate, typically half of the demonstrated no thrombus before Ireland. Globally the prevalence of impulses get through (2:1 block), cardioversion, patients should be AF is rising and approximately 600 ventricles, and there may be four atrial beats to every one ventricular beat. During atrial resulting in a regular ventricular anticoagulated for at least one men and 375 women per 100,000 rate of 150 beats/minute. flutter, unlike atrial fibrillation, electrical activity inThethe atria population is coordinated.

The atria do month post cardioversion, since are affected.

In the 2017 diagnosis of atrial flutter is by mechanical atrial function may report “Burden of Stroke in Europe” contract, but at a very rapid rate of 250 to 350 times per minute.

This rate is too fast to electrocardiography. In typical return slowly after cardioversion,” the Stroke Alliance for Europe flutter, ECG shows continuous Theresaevery adds. impulse to be conducted through the atrioventricular signalled a possible 58%ventricles. increase allow node to the and regular atrial activation with a in the absolute number of strokes in Differentiation Atrial saw tooth pattern, most obvious Because the between AV node cannot usually conduct at this rate,intypically of the get Irelandhalf over the next impulses decade.

Flutter and Atrial Fibrillation leads II, III, and aVF. through (2:1 block), resulting in a regular ventricular rateScreening of 150forbeats/minute.

Atrial FibrillationThe in “Atrial flutter is much less common “Carotid sinus massage can General Practice diagnosis of atrial is by electrocardiography.

In typical flutter, ECG shows continuous than atrial fibrillation butflutter its causes increase AV block and better Projections show that the number and hemodynamic consequences expose the typical flutter waves. and regular atrial activation with a saw tooth pattern, inliving leads II,stroke III, and A similar response may followmost obvious of people with as aaVF. are similar,” she says.

chronic condition will rise from 3,718,785 in 2015 to 4,631,050 in 2035, representing an increase of 25% or almost one million people across Europe. There are approximately 8,000 strokes in Ireland annually, a third of which are associated with atrial fibrillation.

In 2015, HIQA published a ‘Health technology assessment (HTA) of a national screening programme for atrial fibrillation in primary care’.

The HTA announced that a national screening programme for atrial fibrillation for over 65s in primary care would be cost-effective.

HIQA’s Director of Health Technology Assessment Dr Máirín Ryan, said; “Based on the best available evidence, annual opportunistic pulse palpation for those aged 65 and older is expected to lead to reductions in the incidence and severity of atrial fibrillation-related strokes assuming that those detected by screening have a comparable risk of stroke as those detected through routine care.”

Almost 11% of Irish adults aged 65 years and over attending general practice have atrial fibrillation. The HSE (2015) study ‘Atrial Fibrillation Screening in General Practice’ concluded that “opportunistic screening for an irregular pulse in General Practice to assist in the detection of AF is both feasible and beneficial”.

Theresa concludes, “General practices are well placed to opportunistically screen older patients and are ideal in terms of the pathway for treatment for those identified. Opportunistic screening for an irregular pulse carried out by GPs and GPNs “has the potential to be an extremely important stroke prevention strategy, capable of saving society and the health service significant social and economic costs”.

References available on request

“Carotid sinus massage can increase AV block and better expose the typical flutter waves.

2022response • HPN | HOSPITALPROFESSIONALNEWS.IE AAPRIL similar may follow pharmacologic AV nodal blockade, example with adenosine,

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CARDIOLOGY FOCUS: EP DEVELOPMENTS

Cardiac Electrophysiology (EP) Developments Cardiac Electrophysiology (EP) describes the study of the heart’s electrical system to identify the mechanisms of cardiac arrhythmia.

Despite only being developed during the mid-1960s to 1970s, technological advancements have, and continue to, occur rapidly within this field.

Catheters were first used for intra-cardiac recording in the mid1960s, with dedicated protocols for ‘programmed’ stimulation or testing, developed in the mid1970s. The first microprocessorbased stimulator was developed in 1980, with the ability to deliver a pulse of current through a catheter in the heart to study a patient’s conduction system. A year later, the first ablation procedures were performed, using direct current (DC) shocks through an external defibrillator to ablate a patient’s AV node. All of these involved the sole use of X-ray to place catheters

Focal AT Macro AT (Including atrial flutter)

AVNRT

Overt Pre-Excitation or AVRT Asymptomatic PreExcitation

SVT in Congenital heart disease (adults)

and identify the location of cardiac structures. Unfortunately, DC energy creates a large area of injury lacking the precision required to treat many arrhythmia circuits.

The development of radiofrequency (RF) ablation as a method of creating a permanent thermal myocardial injury occurred some years later in the late 1980s. It has standardised the treatment of a multitude of cardiac arrhythmias without the reliance on subsequent pacemaker implantation from AV node ablation. Cryoablation techniques – ‘freezing’ as a form of permanent thermal myocardial injury - were also developed around this time.

Despite advantages of reduced collateral damage, RF ablation currently remains the most commonly used strategy for treating most arrhythmias.

The first 3D mapping system,

developed in 1995, has optimised the integration of an intracardiac anatomy with the electrophysiological features of an arrhythmia. The ability to create a real time cardiac chamber geometry comes from magnetic location technology (Carto, Biosense Webster). It identifies the location of sensors within special catheters and calculates the location of the catheter according to current frequencies thereby creating a reconstruction of a heart as the catheter is moved around a chamber. The subsequent geometry can then display the volume of scar within a chamber (by measuring the peak-to-peak amplitude of signals in contact with myocardium from the sensorbased catheter), and/or the timing of arrhythmias to identify its origin or perpetuating circuit.

Advances in mapping systems has enabled real-time catheter

Dr Jonathan Lyne, Consultant Cardiologist and Electrophysiologist, Beacon Hospital and Blackrock Clinic

ESC (2019) Recommendation Catheter ablation for recurrent focal AT, especially if incessant or causing tachycardiomyopathy Catheter ablation should be considered after the first episode of symptomatic typical atrial flutter Catheter ablation is recommended for symptomatic, recurrent episodes of CTI-dependent flutter Catheter ablation in experienced centres is recommended for symptomatic, recurrent episodes of non-CTI-dependent flutter Catheter ablation is recommended in patients with persistent atrial flutter or in the presence of depressed LV systolic function due to tachycardiomyopathy Catheter ablation is recommended for symptomatic, recurrent AVNRT

Class 1

Level B

11a

B

1

A

1

B

1

B

1

B

Absence from therapy should be considered for minimally symptomatic patients with very infrequent, short-lived episodes of tachycardia Catheter ablation of accessory pathway is recommended in patients with symptomatic, recurrent AVRT Performance of an EP study, with isoprenaline, is recommended to risk stratify individuals with high-risk occupations/hobbies, and those who participate in competitive athletics Catheter ablation is recommended in asymptomatic patients in whom EP testing with isoprenaline identifies high-risk properties Catheter ablation is recommended in asymptomatic patients in whom EP testing identifies high-risk properties after discussing the risks, especially of heart block associated with ablation of anteroseptal or mid-septal pathways, and benefits of the procedure Performance of an EP study to risk stratify individuals with asymptomatic pre-excitation should be considered Invasive stratification with an EP study is recommended in patients without ‘low-risk’ characteristics at non-invasive risk stratification Catheter ablation may be considered in a patient with asymptomatic pre-excitation, and a low-risk AP at invasive or non-invasive risk stratification Catheter ablation should be considered in patients with asymptomatic pre-excitation and LV dysfunction due to electrical dyssynchrony Catheter ablation may be considered in patients with low-risk asymptomatic pre-excitation in appropriately experienced centres according to patient preferences Catheter ablation in experienced centres should be considered

11a

C

1

B

1

B

1

B

1

C

11a

B

1

C

11b

C

11a

C

11b

C

11a

C

11a

C

In patients with SVT planned for surgical repair of a congenital heart disease anomaly, preoperative catheter ablation or intraoperative surgical ablation should be considered

Historically, SVT ablation procedures were performed without 3D mapping systems; catheters HOSPITALPROFESSIONALNEWS.IE | HPN • APRIL 2022 were placed under fluoroscopy guidance and testing manoeuvres using pacing were used to

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CARDIOLOGY FOCUS: EP DEVELOPMENTS

Reconstruction of right atrial anatomy and ablation with zero fluoroscopy using 3D mapping for SVT ablation (septal accessory pathway)

may not be visible, ‘concealed’.

Electrophysiological testing can be performed to identify the presence of an accessory pathway and to test its function.

Atrial tachycardias are commonly focal in origin but occur from one or more sites within atrial tissue.

This includes both atria and their connections to other structures such as pulmonary veins within the left atrium and great vessels such as the aorta.

Reconstruction of right atrial anatomy and ablatio Atrial flutter commonly results from with zero fluoroscopy using 3D mapping for SVT a circuit within the right atrium that circulates around the tricuspid ablation (septal accessory pathway).

valve annulus (cavotricuspid isthmus dependent flutter). Other atrial flutter circuits are atypical but may conduct around other structures such as surgical Reconstruction of right atrial anatomy and ablation atriotomy scars (incisional flutter) with zero fluoroscopy using 3D mapping for SVT or anatomical boundaries such as the fossa ovalis. ablation (septal accessory pathway).

visualisation with up to 1mm precision but is typically only compatible with RF therapy.

This increases the accuracy and safety of targeted RF ablation alongside significant reductions in fluoroscopy and subsequent radiation exposure both for patients and operators. The use of cryotherapy still typically requires high volumes of X-ray in comparison due to the inability of those catheters to recreate a cardiac chamber geometry.

imaging, and/or intra-cardiac echocardiography during an ablation procedure may be used by some Electrophysiologists. A relatively recent ability to integrate ultrasound images with 3D mapping systems may improve the efficacy and safety of all ablation procedures, especially for patients with difficult/complex anatomy.

Developments in AF ablation Developments in AF ablation

AV nodal reentry tachycardia (AVNRT) is the most common type of SVT. It results from a circuit circulating within the AV node that includes conduction occurring across two pathways in opposite directions within the AV node. Typically this includes two physiologically distinct channels within the AV node known as the fast and slow pathways.

Increasing knowledge and experience of EP studies and ablation procedures led to updated guidelines released by the European Society of Cardiology in 2019. Whilst some changes were made to the recommended medications in some arrhythmias, the promotion for catheter ablation as a form of chronic therapy has increased significantly.

Historically, SVT ablation procedures were performed without 3D mapping systems; catheters were placed under fluoroscopy guidance and testing manoeuvres using pacing were used to identify the type of SVT. Despite being considered ‘low risk ablation procedures’, patients with SVTs that require ablation near the conduction system of the heart are at risk of permanent pacemaker implantation as a complication.

The demand for Developments treatment of AF rapidly is increasing rapidly due to an agein Ablation The demand for treatment of AF inisSVTincreasing due to an ageing population and is AV rentry tachycardia occurs SVT is a term that encompasses known to increase the risk ofmortality, all-cause heart failure, and when a mortality, circuit involvesand conduction known to increase the risk of all-cause heart failure, thromboembolism.

Whilstthrom atrial arrhythmias other than atrial across the AV node but also across fibrillation (AF); tachycardia, an accessory (extra) Separately, developments in treatment withwith anticoagulants andsinus rate control medication ispathway. well medication recognised, there still a recog treatment anticoagulants rate control isiswell atrial tachycardias (including andThese accessory pathways may cardiac imaging have also atrial flutter), AV node re-entry withbe visible1-2% on an ECG appear been utilised additional large gapforin access to ablation for patients, only of anpatients with AF estimated to tachycardia (AVNRT), and AV reas ‘prexcitation’ suchwith as in Wolffonly 1-2% of patients w safety precautions within large gap in access to ablation for patients, undergo ablation, the inclusion guidelines.

Parkinson White syndrome or entry tachycardia (AVRT).in numerous EP. Pre-procedural cardiac despite undergo ablation, despite the inclusion in numerous guidelines.

AF

AF

ESC (2020) Recommendation Class For the decision on catheter ablation, it is recommended to take into consideration the procedural risks and the major 1 risk factors for AF recurrence following the procedure and discuss them with the patient ESC (2020) Recommendation Repeated PVI procedures should be considered in patients with AF recurrence provided the patient’s symptoms were IIa For the on catheter ablation, it is recommended to take into consideration the procedura improved afterdecision the initial PVI AF catheter ablationfor afterAF antiarrhythmic drug failure therapy risk factors recurrence following the procedure and discuss them with the patient AF catheter ablation for PVI should be considered for rhythm control after one failed or intolerant to beta-blocker IIa Repeated PVIsymptoms procedures should be considered in patients with AF treatment to improve of AF recurrences in patients with paroxysmal and persistent AFrecurrence provided the patien Firstimproved line therapy after the initial PVI AF catheter ablation ablation for PVI should/may be considered as first-line control therapy to improve symptoms in AF catheter after antiarrhythmic drugrhythm failure therapy selected patients with symptomatic: AF ablation fororPVI should be considered for rhythm control after one failed orIIaintolerant - catheter Paroxysmal AF episodes, Persistent AF without risk factorsof forAF AF recurrence as an alternative to anti-arrhythmic drugs class I persistent AF treatment to improvemajor symptoms recurrences in patients with paroxysmal and or III considering patient choice, benefit, and risk IIb First line therapy Techniques and technologies Use AF of additional ablation lesionsfor beyond (low voltage areas, lines, fragmented ectopic foci, rotors, and therapy IIb to imp catheter ablation PVIPVI should/may be considered asactivity, first-line rhythm control others) may be considered but is not well established selected patients with symptomatic: Recommendations pertaining to sex-related differences in AF - symptomatic Paroxysmal AForepisodes, Women with paroxysmal persistent AFor should be offered timely access to rhythm control therapies, IIa including AF-catheter ablation, when medical reasons Persistent AFappropriate without for major risk factors for AF recurrence as an alternative to anti-arrh

or III considering patient choice, benefit, and risk Techniques andvary technologies AF techniques between paroxysmal and persistent AF patients, but all aim to | HOSPITALPROFESSIONALNEWS.IE APRILablation 2022 • HPN Use of additional ablation lesions beyond PVI (low areas, lines,veins fragmented activity, treat the ‘triggers’ of AF. These triggers are mainly fromvoltage the pulmonary from the left ectopi

As such, the use of ‘advanced’ 3D mapping systems has meant that mapping of these arrhythmias has increased in popularity due to improved safety and efficacy. Of late, technological advancements in these systems has resulted in the reduction, or obliteration, of the need for X-ray to perform diagnostic EP and ablation procedures. The ability to recreate a patient’s cardiac anatomy in 3D using these mapping systems, without X-ray, has become the focus of many EP labs - pertinent in the current era of a dramatic rise in the knowledge of the effect of radiation on electrophysiologists, staff, and patients alike, with long-term health effects. Even in patients with complex congenital anomalies, the use of 3D mapping for ablation of these SVT arrhythmias is further enhanced by the ability to integrate preprocedural imaging modalities such as CT, MRI, or intra-cardiac echocardiography with the chamber geometry for improved understanding of the mechanism of arrhythmias.

Developments in AF ablation The demand for treatment of AF is increasing rapidly due to an ageing population and is known to increase the risk of all-cause mortality, heart failure, and thromboembolism. Whilst treatment with anticoagulants and rate control medication is well recognised, there is still a large gap in access to ablation for patients, with only 1-2% of patients with AF estimated to undergo ablation, despite the inclusion in numerous guidelines.

AF ablation techniques vary between paroxysmal and persistent AF patients, but all aim to treat the ‘triggers’ of AF. These triggers are mainly from the pulmonary veins from the left atrium. Electrical isolation of these veins (PVI) is the cornerstone of AF ablation for all patients as first line therapy.

Radiofrequency ablation has been demonstrated as the most costeffective method of treating AF, for both paroxysmal and persistent AF patients. Several approaches have been developed for RF ablation of AF, but the end point for persistent AF ablation patients is still under debate, with long-term success rates for persistent patients being around 70% after one ablation procedure. Recent advances and developments around ablation strategies has vastly improved the success rates of maintaining a normal rhythm in many AF patients although inter-operator variation in ablation strategy varies widely.

As redo procedures have, until recently, demonstrated a disappointing level of chronic pulmonary vein isolation,

can still be utilised to complete all targets of abl the tip of the ablation catheter has been suggest 67 and has the ability to automatically adjust saline ir tip does not overheat or have any char formation High Power Short Duration ablation technique for pulmonary vein isolation (90Watt 4seconds)

historically been considered more 3D reconstruction of a patient’s Current RF therapy require technical time consuming than balloon techniques anatomy doesn’t occur during counterparts. As such, some the procedure. have historically been Electrophysiologists are known to considered more time con Due to the popularity and speed use Cryoballoon treatments for AF. of balloon therapy techniques some Electrophysiologists are known to use Cryob Cryotherapy is often utilised when for AF, RF balloon therapy only pulmonary vein is utilised technology, with associated Cryotherapy isisolation often when only pulmon required for a patient, normally integration into 3D mapping those with a ‘normal’ heart and systems, is currently normally those with a ‘normal’ heart onand paroxys paroxysmal AF. Whilst there is a early market release in some fast-learning curve associated with European centres. It is hoped associated with this therapy, it cannot be used to t this therapy, it cannot be used to that it will provide the learning treat any other arrhythmias that curve of balloon therapy but alongside AF, such as atrial tachycardia or atria often occur alongside AF, such as with advantages of having the Of late, there has been vast interest atrial tachycardia or atrial flutter. concurrent ability to recreate 3D available result suboptimal in high power, short duration Similarly, theballoons restrictive sizingmay of geometry in rapidly and the capacity ablat ablation. Historically, pulmonary available balloons may result in to safely re-ablate specific target or abnormally sized. vein isolation for AF was performedangulated suboptimal ablation in patients areas within the pulmonary veins technological advancements have focused on improving RF lesion durability. The last decade has seen an introduction of contact force-sensing catheters. These ablation catheters provide an indication of the amount of contact that the ablation catheter has with the myocardium. This improved knowledge of tissue contact results in fewer RF ablations and improved lesion formation thereby improving both acute, and chronic success for AF ablation patients.

with relatively low powers (3040 Watts) and moderate time durations for each RF lesion, giving lesions that were more affected by conductive heating effects rather than resistive heating. The latest technology and research suggests that high power (90 Watts), short duration RF applications cause a larger zone of resistive heating. This provides shallower but broader lesions, which may increase the lesion durability, lower procedural times, reduce the opportunity for collateral damage to structures such as the oesophagus, and minimise the dwell time of catheters within the arterial system. Where ablation for persistent AF patients requires additional ablation lesions in areas of thicker myocardial tissue, or for other concurrent arrhythmias, the same RF ablation catheters can still be utilised to complete all targets of ablations. Precise temperature feedback from the tip of the ablation catheter has been suggested to improve the safety profile of ablation and has the ability to automatically adjust saline irrigation rates and power to ensure that the tip does not overheat or have any char formation.

Current RF therapy techniques require technical expertise on the part of the physician and have

whose pulmonary veins are angulated or abnormally sized.

in cases of difficult or abnormal vein anatomy.

A new ultra-low cryoablation system has just been released which has the capacity to be circular, linear, or curved in shape.

It is hoped therefore that this can be used outside of isolation of the pulmonary veins for successful treatment of more AF patients than current Cryoballoon technology.

Ultra-low cryoablation cools the tissue to -190°C compared to -70-80°C with traditional cryotherapy and thus should create more transmural lesions. Research into this new technology is ongoing.

An alternative form of irreversible myocardial injury, by a technique called electroporation, is receiving a large amount of interest worldwide as the first non-thermal ablation technique for treatment of cardiac arrhythmias. PFA therapy causes cell death via a series of rapid, high voltage electrical pulses which damages targeted cell membranes of tissue in close proximity to the catheter. Having been used for the treatment of tumours in oncology, many companies are currently investigating the optimal waveform ‘recipe’ for safety and long-term success for use within AF ablation.

Due to its tissue specificity, it is proposed that it will provide a form of ablation therapy that will limit damage to other noncardiac structures that are at risk from RF or Cryo therapies as well as enabling extremely rapid AF ablation procedural times.

Laser balloon therapy is another available form of ablative therapy, but is used infrequently within EP centres, possibly due to the more established Cryo and RF therapy techniques currently in existence. Like other Cryoballoon technologies, it is typically used only in patients with paroxysmal AF. It too has a relatively short learning curve and recent developments in the balloon have improved procedural and fluoroscopy times.

Additional use of the integration of imaging techniques such as intra-cardiac echocardiography can be especially important when performing Cryoballoon or laser balloon ablation where

Patients with persistent AF are thought to have other substrates outside of the pulmonary veins, explaining the reduced success rates for these patients if ablation is limited to PVI only. As such, additional triggers within the left and right atrium are sought

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area covered with these catheters, alongsid enables extremely fast mapping of chamber ischemia, 3D mapping is often

CARDIOLOGY FOCUS: EP DEVELOPMENTS

of chamber geometry, even in hemodynamically unstable VT.

abnormal electrograms. Howev to target all areas of late condu or maintains the VT circuit(s).

Octaray catheter; 48 electrodes, ablationandand rapiddoesn’t coverage necessari of electroana the EP study and ablation. This can help assist with ensuring catheter contact with the tissue during ablation, as well as early detection of complications. The ICE catheter can be used to trace surface contours of the imported ultrasound images, onto prior CT or MRI scans within the 3D mapping system. As well as improving safety, this can reduce procedure and fluoroscopy times as well as improving success rates.

Octaray catheter; 48 electrodes, 8 splines, for improved and rapid coverage of electroanatomical information during complex cardiac mapping procedures

For patients with stable VT, mapping in the arrhythmia does provide the best success rates for ablation procedures. For those with hemodynamically unstable VT, such as patients with ischemia, 3D mapping is often performed in sinus rhythm, with labelling and targeting of abnormal electrograms. However, in patients with high scar volumes, it may be unachievable to target all areas of late conduction when it is unknown which zone of late activation causes or maintains the VT circuit(s). Targeting all areas results in an unnecessarily high volume of ablation and doesn’t necessarily improve success rates.

during complex cardiac mapping

for these patients. RF ablation is typically the first form of ablation therapy offered for these patients. In patients where at least one RF ablation has failed to maintain sinus rhythm, a hybrid approach has been developed in the last few years. Here, minimally invasive surgery via a pericardioscopic approach from the upper abdomen, enables a cardiac surgeon to use RF energy epicardially to create block ablation lesions in both atria. This is pertinent in areas such as the posterior wall, which is renowned for having epicardial connections, where surgical ablation can assist in overall lesion integrity with concomitant, or subsequent endocardial ablation to validate the surgical ablation lines and, if necessary, add additional lines.

Use of the scar map to demo techniques such as ‘DeEP’ and conduction’ regions of disease For patients with stable VT, mapping in th These strategies use various pa for ablation procedures. For those with hem within a ventricle within areas vastly improved the strategy a often substantial. and functional information prior to the EP study. They can be used with delayed enhancement to identify and localise areas of scar as potential targets during the ablation procedure. Importing these scans into the mapping software provides real-time assessment of areas of scar, slow conduction, and border zones with healthy tissue that may cause re-entry VT circuits and be the target of ablation.

In some patients with papillary muscle VT, or VTs in areas of difficult anatomy for catheter manipulation, 3D mapping alongside intracardiac echocardiography enables realtime imaging of the heart during

In patients where a surgical option is not feasible, ongoing technological advancements with RF ablation strategies for persistent AF are ongoing. An example of this is Vein of Marshall ethanol infusion as an advocate for endocardial RF ablation of this bundle, thought to initiate or perpetuate AF in persistent patients. The highly challenging and limited success for RF endocardial ablation of the mitral isthmus has limited AF ablation techniques in this region to date and ethanol ablation thus far has identified limited complications but great success rates of both acute and chronic success for persistent AF patients.

Developments in VT ablation Historically, ablation of VT was only considered after failure of antiarrhythmic drugs and/or an increased frequency in ICD shock therapy. Research into the mechanisms of non-ischemic and ischemic cardiomyopathies have improved strategies for ablating VT over the last two decades and can often prevent some disease advancement.

Pre-procedural imaging is common via MRI or CT to provide anatomical

Recent technological advancements in 3D mapping systems allow simultaneous mapping of the volume of scar alongside the ability to localise multiple VTs at the same time, with safety. This is important for patients with multiple ectopics, multiple VTs or substrates, and for whom extremely long procedural times are not well tolerated.

Voltage (scar) map of a ventricle performed to identify areas of scar, slow conduction, and zones with healthy tissue. This can be used to compare with subsequent DeEP maps for targeted ablation of ischemic VT

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In terms of improvements in catheter technology, use of multipolar catheters with small electrode spacings identifies abnormal electrograms in small areas of myocardium that are missed when creating 3D maps using catheters with widely spaced electrodes. The surface area covered with these catheters, alongside increased electrode count and elongated splines enables extremely fast mapping

Use of the scar map to demonstrate areas of diseased tissue, alongside newly described techniques such as ‘DeEP’ and/ or ‘ILAM’ mapping, can help identify more specific ‘delayed conduction’ regions of diseased myocardium that are likely to be critical to the VT circuit. These strategies use various pacing protocols to improve specificity of target ablation areas within a ventricle within areas or channels of noticeable conduction delay.

To date this has vastly improved the strategy and success rates for ischemic VTs where the volume of scar is often substantial.

CARDIOLOGY FOCUS: HYPERTENSION

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Hypertension in Older Adults The prevalence, awareness, treatment and control of hypertension in older adults with an Intellectual Disability in Ireland: a cross sectional study Written by: Frances O’Brien1,2, Philip McCallion2, 4, Rachael Carroll2, Máire O’Dwyer2, 3, Eilish Burke1,2, Mary McCarron1,2 1

School of Nursing and Midwifery, Trinity College Dublin, 24 D’Olier Street, Dublin 2, Ireland.

2

IDS-TILDA, Trinity Centre for Ageing and Intellectual Disability, School of Nursing and Midwifery, Trinity College Dublin, Dublin 2, Ireland

3

School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Dublin, Ireland

4

School of Social Work, Temple University, Philadelphia, Pennsylvania, USA

Introduction Cardiovascular diseases (CVD) accounts for almost one third of mortality worldwide1 and is the second most common cause of death in Ireland, at 30.5%.2 In addition to family history, hypertension, hypercholesterolemia, diabetes, smoking status and obesity are known risk factors for CVD development.3 From these, hypertension has been identified as the risk factor of greatest prevalence and impact,3-4 accounting for almost 50% of ischemic heart disease mortality.5 Consequently, reducing or controlling hypertension should logically decrease CVD and related deaths.

in people with an intellectual disability (ID), along with the levels of control. This is despite international concerns regarding high levels of overweight and obesity,8-11 low levels of physical activity and unhealthy nutrition practices12 and high abdominal obesity10, 13-16 in the ID population.

Further, some people with ID have increased CVD risk due to syndrome specific risk factors such as in Prader–Willi syndrome and cerebral palsy.17,18,19 Other syndromes such as Down syndrome, despite early childhood congenital heart disease, are associated with reduced risk for CVD as adults.10, 20

Much of the research surrounding hypertension prevalence, awareness, treatment and control has focused on the general population. The prevalence of hypertension in those aged ≥18 years is 30–45%, and this increases steeply with the progression of age.3,6 In Ireland, cross sectional data from the Irish Longitudinal Study on Ageing (TILDA), which involves a nationally representative sample of older community adults aged >50 years, reported a weighted hypertension prevalence of 63.7%.7 Of those classified as hypertensive, 54.4% were aware they had hypertension, 58.9% were on antihypertensive treatment, with blood pressure controlled in just over half (51.6%).7 Murphy and colleagues7 concluded their study by drawing attention to the high prevalence of hypertension identified in Irish people over 50 and the low levels of awareness, treatment and control. They recommend population and primary care level interventions to reduce prevalence and improve awareness, detection and management.

Past prevalence and risk studies on CVD and hypertension in persons with ID are largely limited by small, under-representative samples, lack of objective measures, and inconsistency in definitions. This has led to conflicting reports of lower,21 comparable10, 22-24 or higher levels of risk for persons with ID,25 when compared to the general population. In New York, Janicki et al.11 reported under-recognition of CVD in adults with ID compared to the general population, despite both groups having similar CVD mortality. Also in the US, Erickson and Kornexl26 identified a trend for lower proportions of people with ID as having a diagnosis of hypertension despite no significant differences between their diastolic blood pressure (DBP) recordings and those of the general population. Similarly, a national Swedish study21 reported that older adults with ID were less likely than the general population to have a diagnosis of hypertension and to be prescribed medication for it. Further, for those prescribed treatment, medications tended to be of the older variety compared to that prescribed for the general population.

There has not been the same attention given in Ireland, to the prevalence of CVD, the role of hypertension and its treatment or indeed its under-treatment

Recent studies on mortality in people with ID have highlighted that the steady increase in their longevity has stalled over the last decade.27-29 In particular,

Frances O’Brien

it has been reported that treatable conditions, risk factors and associated behaviours are not being addressed to the same extent as for the general population.27, 30, 31 Under recognition, under diagnosis and less evidence of active management of conditions and modifiable risk factors in people with ID as compared to the general population, have been raised as concerns.27 In order to address such concerns and in particular to advance the management of modifiable health risks and their consequences, this study aims to: 1. Identify the prevalence, awareness, treatment and control of hypertension in older adults with an Intellectual Disability.

2. Identify the predictors of awareness, treatment and control of hypertension in the same population.

Methods This study utilises data collected in Wave 2 (2013-2016) of the Intellectual Disability Supplement to the Irish Longitudinal Study on Ageing (IDS-TILDA).

Study Sample: The IDS-TILDA sample was drawn from The National Intellectual Disability Database (NIDD), which collates information on all people with an ID in the Republic of Ireland who are eligible for or receiving services.32,33 A random sample

of 1,600 people aged >40 years was identified from the NIDD and invited to participate in Wave 1 of the IDS-TILDA study. An age of >40 years was selected because of the lower life expectancy for some individuals with ID and earlier onset of age-related morbidities in this population e.g. dementia.34,35 In total, 753 persons participated in Wave 1, meaning an overall response rate of 46% and 8.9% of the total population of persons >40 years registered on the 2008 NIDD database. A comparison with the published demographics of the 2008 NIDD cohort confirmed that the IDSTILDA sample was representative of the larger NIDD sample.36 For Wave 2 of IDS-TILDA, all living Wave 1 respondents (n=719) were invited to participate, from which 708 (98%) agreed to participate. Wave 2 participants were eligible for inclusion in this study, if they completed the IDS-TILDA self or informant report measures AND completed the objective measurement of their blood pressure.

Consent and Data collection: Accessible material and full explanation supported informed consent. Based upon the ethical approval received, able participants provided written consent independently yet could request the support of a person they knew well in completing the pre-interview questionnaire (PIQ) and computer assisted personal

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CARDIOLOGY FOCUS: HYPERTENSION was calculated. Prevalence of hypertension was defined as SBP ≥140mmHg or DBP ≥ 90mmHg,37 and/ or currently taking antihypertensive medications.

Wave 1

automated oscillometric BP monitor. Measurements were have worked with the individual completed as per protocol, in for at least 6 months. The PIQ clinics familiar to participants, by interview (CAPI). Equally, as per and CAPI and data collection Awareness: A specific the same research clinician, using ethical approval, for those unable dichotomous (yes/no) procedures were validated in the accessible explanatory materials.

20question to provide consent independently, asked if participants (or their pilot study and subsequently in Following a period of rest, two a family member, keyworker or proxies) were aware of having Wave 1. measurements were recorded support person who knew the received a doctor’s diagnosis while seated, with one-minute participant well (Proxy), consented Outcome Measures of 2. hypertension.

Figure 1: Flow Chart for IDS-TILDA study participation at Wave 1 and Wave This study rest between recordings.

From on their behalf and supported these two measures, the mean Prevalence: Blood pressure (BP) them throughout the process. Paid Treatment: In the pre-interview used Wave 2 data.was measured using a digital systolic and diastolic measure staff members were required to questionnaire, participants/proxies were asked “Can you tell me what medications (including prescribed and over the counter, herbal Inclusion criteria for participation in the IDSmedicines) you take on a regular basis – like every day or every TILDA study: week?” Interviewers subsequently confirmed this information with Registered on the National Intellectual medication prescription data Disability Database (NIDD) in 2008 and obtained from accompanying health care personnel. Medications aged 40 years and over. were coded by two pharmacists using the World Health Organization (WHO) Anatomical Therapeutic Chemical (ATC) classification system,38 a method described in detail elsewhere.39 Antihypertensive treatment was defined as exposure to one or more of: anti-adrenergic agents, diuretics, beta-blockers, calcium 1,600 Patient Identifier Numbers channel blockers, ACE inhibitors randomly selected from the NIDD and and ARBs. Combination therapy included taking two or more individuals invited to participate antihypertensives concurrently.

Medicines were recorded by brand or generic name, including

N= 753 persons aged 41-90 recruited.

Response Rate= 46% Representing 8.9% of NIDD database

Figure 1: Flow Chart for IDS-TILDA study participation at Wave 1 and Wave 2. This study used Wave 2 data

Lost to follow-up n=25 RIP

Wave 2

All Wave 1 living participants (n=719) were re-invited to participate Response rate: 98% N=708 examined for eligibility n=7 RIP

Confirmed Eligible Participants N= 551

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Lost to follow-up

Excluded n=92 did not participate in health fair n=58 participants who did not complete objective measures AND self or informant report measures.

71

Table 2: Hypertension prevalence in adults with ID ≥ 40 years (N=551), by age a and significant predictors of prevalence.

Table 2: Hypertension prevalence in adults with ID ≥ 40 years (N=551), by age and gender and significant predictors of prevalence

prescription and non-prescription and over the counter, and length of time the participants were taking medicines and all data was anonymised.

Control: Measured blood pressure data were used to determine how well hypertension was being managed, with BP control defined as SBP <140 mmHg and DBP <90 mmHg. Covariates: Demographic covariates included age by group (for comparison across studies), sex, level of ID (mild, moderate and severe/profound, based upon self-report or review of records or knowledge of the Proxy) and type of residence (independent/ family, community group home and residential care). Behavioural factors included current smoking status, problem drinking, body mass index (BMI), waist circumference and level of physical activity. Smoking levels were selfreported. Self-reported problem drinking was defined as 3 or more/ day or >7 per week for women and 4 drinks or more/day or >14 per week for men.40 Physical activity was self-assessed using the International Physical Activity Questionnaire (IPAQ) short form which categorises physical activity as low, moderate or high, based on the intensity, duration and frequency of activities undertaken in the preceding week.41 The research clinician measured height and weight. BMI (weight in kg/height in m2) was classified as: underweight < 18.5; normal weight 18.5 to < 25; overweight 25 to < 30; obese ≥30.42,43 Surrogate measurements in the form of the Mid Upper Arm Circumference

n

%

95% CI

Prevalence

194/ 551

35.2

31.2-39.2

Age* 44-49 50-64 65+

27/151 105/281 56/112

17.9 37.7 50.0

14.7-21.1 33.6-41.8 45.8-54.2

Gender Female Male Diabetes * History of CVD* Down Syndrome*

105/312 89/239 33/42 20/34 13/100

33.7 37.2 78.6 58.8 13

29.8-37.6 33.2-41.2 66.2 – 91.0 42.3 – 75.4 6.41 – 21.12

p value

<0.001

0.38 <0.001 0.003 <0.001

*Indicates significance for prevalence of hypertension.

CVD: Cardiovascular Disease

(MUAC) or Ulna length to measure height were used to estimate BMI,44,45 for those for whom traditional measurement was not possible. As MUAC measurement of BMI yields three levels of classification (underweight, normal and overweight), these three levels of BMI are used throughout this analysis, with overweight and obese combined into a single category.

Waist circumference (associated with increased risk of diabetes and cardiovascular disease such as high cholesterol and hypertension) was also measured by the research clinician and classified using WHO cut-offs.46 Morbidity covariates, which included the presence of diabetes and CVD (angina, heart attack, open heart surgery, angioplasty/ stent insertion, congestive heart failure, stroke or transient

ischaemic attack) was based on reporting ever having a doctor’s diagnosis of these conditions or self-reporting having undergone a related procedure. Access to primary healthcare was assessed using three mutually exclusive categories of medical insurance (i) a medical card that provides free access to general practitioner (GP) care and heavily subsidised prescribed medicines (ii) GP card only and (iii) neither of these.

Participants were also divided into those who had Down syndrome and those who did not.

Ethical Considerations: The study conformed to the principles outlined in the Declaration of Helsinki.47 Ethical approval was obtained from the Faculty of Health Sciences Ethics Committee at Trinity College Dublin and from all participating service providers (N=138).

Statistical analysis Descriptive statistics measured prevalence and awareness of hypertension as well as medication management approaches.

Descriptives also measured the same variables for those ≥ 50 years, to facilitate discussion of findings here with previous reports of hypertension in the general population in Ireland. For the total sample, bivariate tests of association were conducted using Pearson's chi-squared test or where appropriate linear by linear p-value or fisher's exact p-value. Binary logistic regression determined risk factors for awareness, treatment and control

17

Table 4: Hypertension prevalence, Table 4: Hypertension prevalence, awareness, treatment and control in adults with ID ≥50 awareness, treatment and control in adults with ID ≥50 years (N=393) years (N=393)

Adults with ID ≥50years

Prevalence (n=393) % 95% CI n 41.2

36.3-46.1

162

Aware (n=159) * % 95% CI n 47.8

40.055.6

76

Treated (n=160$) % 95% CI n 68.

8

61.676.0

110

Controlled (n=110) % 95% CI n 70.0

61.478.6

77

* Missing = 3 missing doctor’s diagnosis variable $ missing = 2 missing medication variable Missing level of ID for 13 participants with hypertension HOSPITALPROFESSIONALNEWS.IE | HPN • APRIL 2022

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CARDIOLOGY FOCUS: HYPERTENSION

of hypertension. Purposeful selection of variables for inclusion in the regression models was of independent variables significant in a bi-variate analysis and/ or deemed important after two independent reviews of the literature. Crude odds ratios were used to measure the magnitude and strength of the predictors.

Both crude odds ratios (cORs) and 95% confidence intervals (CIs) are reported for significant associations. Underweight participants were removed from the bivariate analysis due to small numbers and IPAQ scores were reclassified as low and moderate/ high. Statistical significance was set at p = 0.05. The statistical software SPSS V 22 was used to conduct the analyses.

history of CVD (6.2%) and were smokers (6.9%). The mean systolic and diastolic BP measurements was 118.59mmHg (SD 17.93) and 75.72mmHg (SD 12.19) respectively. Table 1 presents the full sample characteristics.

Prevalence, Awareness, Treatment and Control The prevalence of hypertension was 35.2% (95% CI 31.2-39.2%) (Table 2). Prevalence was higher in men (37.2%) than in women (33.7%), although the difference was not statistically significant (p=0.38). Prevalence was significantly higher in the oldest versus the youngest age group (p =0.000), in those with diabetes (p <0.001) and in those with a history of CVD (p=0.003). Conversely, having Down syndrome was associated with lower prevalence of hypertension (p<0.001) (Table 2).

70.8% of the total sample, with greater control noted in females (78.3%) than in males (60.8%) (Table 3).

For participants ≥50 years (n=393), the more commonly reported age cut-off in general population studies, prevalence was 41.2% (95% CI 36.3-46.1%) awareness, 47.8% (95% CI 40.0-55.6%), treatment, 68.8% (95% CI 61.676.0) and control, 70% (95% CI 61.4-78.6%) (Table 4).

diagnosis of diabetes, followed by age. Those with diabetes were 5.2 times more likely to be treated for hypertension compared to those who did not have a doctor’s diagnosis of diabetes (cOR=5.167, 95% CI 1.729-15.44). Those aged over 65 years were 5 times more likely to be treated for hypertension than those aged 44-49 (cOR=5.046, 95% CI 1.844-13.809). The cOR for those with severe ID indicated that they are 3.1 times less likely to be treated for hypertension than those with mild ID (cOR=.323, 95% CI .125-.838).

Among those being treated in Of those who were treated for the full sample with medicines hypertension, gender and diabetes data (n=153) (≥40 years), the were significantly associated with most commonly reported BP control. Females were 2.3 medicine classes were ACE times more likely than males to inhibitors (36.8%), diuretics have their BP controlled (cOR=2.3, (34.9%) and calcium channel 95% CI 1.04-5.18), while control blockers (26.3%). Just over four was 4.6 times more likely in those in ten (42.8%) were prescribed with diabetes than those without combination therapy (Table 5). (cOR=4.57, 95% CI 1.28-16.39).

For participants ≥50 years in the In this study, obesity and level of full sample with medicines data physical activity were not significant and antihypertensive treatment RESULTS predictors of awareness (obesity, (n=133), the more commonly Of those participants objectively Study Sample p=0.953; physical activity, p=0.519), reported medication classes classified as hypertensive, only treatment (obesity, p= 0.968; were ACE inhibitors (39.1%), 44.3% reported awareness of In total, 551 individuals from physical activity, p=0.712) and diuretics (35.3%) and betablockers receiving such a diagnosis from the 708 Wave 2 participants, * $ control (obesity, p =0.599; physical with Treated 45.9% prescribed Prevalence (n=393) Controlled (n=110) their doctor, with marginally Awaregreater (n=159)(26.3%), (n=160 ) completed the IDS-TILDA self or activity p=0.787) of hypertension. combination therapy (Table 5). awareness in females (44.7%) than informant report measures AND % of blood 95% CImales (43.9%). n 95% CI Factors n % 95% CI n Discussion % 95% CI n As % age increased, objective measurement associated with awareness also increased from pressure and thus comprised awareness, treatment and Adults Prevalence of hypertension in 23.1% in the youngest age 40.0- control of hypertension the study sample (See Figure 1 61.661.4population group to 50.9% in the oldest age with ID 41.2 36.3-46.1 162 47.8 68.

110this representative 70.0 76 77 for flowchart). Proxy 55.6 78.623% and of adults with ID was Age and level of ID 76.0 were group. Level of ID was inversely respondents completed 37% of ≥50years 29% lower for those aged ≥40 significantly8associated with associated with awareness; those the report measures. and ≥ 50 years respectively, than awareness of hypertension (Table most aware (62.5%) had mild ID, Demographics and Clinical participants in the representative 6). The cOR for awareness and while those less aware had severe/ Characteristics general Irish population TILDA older age was 3.46 (95% CI 1.2profound ID (31.0%) (Table 3). study.7 There were however, 9.9) for those aged over 65, and Participants ranged in age from Of those with hypertension, some similar trends with higher 2.86 (95% CI 1.06-7.69) for those 44 to 92 years (mean 56.6 SD 64.2% were being treated with rates for men as compared to aged 50-64, relative to those in the 9.3), 56.6% were female, while antihypertensive medication. As women, and in older age cohorts. youngest age group. Those with 50% had a moderate level of ID. age increased, level of treatment severe/profound ID were 3.7 times The vast majority of participants also increased from 38.5% in the more likely to be unaware they had (83.2%) had waist circumferences youngest age group to 75.9% in hypertension, than those with mild that placed them at increased/ the oldest age group. Those with ID (cOR=0.269, 95%CI: 0.11-0.67). substantially increased risk of mild ID had the highest level of CVD, 68.4% were overweight/ Age, level of ID and diabetes treatment at 78.0% decreasing obese, while 72.1% reported were significantly associated with to 53.5% for those with severe/ Table 5: Antihypertensive medication low levels of physical activity. A treatment (Table 6). The strongest profound ID. Among those on use in the total IDS-TILDA predictors were having a doctor’s minority had diabetes (7.8%), a treatment, BP was controlled in population with medicines data, in

17

Table 4: Hypertension prevalence, awareness, treatment and control in adults with ID ≥50 years (N=393)

* Missing = 3 missing doctor’s diagnosis variable $ missing = 2 missing medication variable Missing level of ID for 13 participants with hypertension

Table 5: Antihypertensive medication use in the total IDS-TILDA population with adults with ID ≥40 years (n=677) medicines data, in adults with ID ≥40 years (n=677) and ≥50 years (n=489). and ≥50 years (n=489)

Adults with ID ≥44years (n=153) Adults with ID ≥50years (n=133)

ACE Inhibitors

Diuretics

Beta Blockers

% (n) 34.9 (53)

Calciumchannel blockers % (n) 26.3 (40)

% (n) 36.8 (56)

39.1 (52)

35.3 (47)

28.6 (38)

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Antiadrenergic agents % (n) 2.0(3)

Combination Therapy

% (n) 24.3 (37)

Angiotensin Receptor Blockers % (n) 19.1 (29)

26.3 (35)

21.8 (29)

2.3(3)

45.9 (61)

% (n) 42.8 (65)

73 Overall, prevalence was lower than that reported in other studies of people with ID in the Netherlands,10 Sweden21 and the US.11 The differences in findings may reflect that our sample: 1) was drawn from a nationally representative study population of people with ID, 2) was carried out in tandem with the general Irish population study (TILDA) using the same measurement and diagnostic criteria, 3) included objective measurement of blood pressure in persons with all levels of ID, and across various living circumstances including those living in community and independently, and 4) obtained detailed information about treatment with antihypertensive medicines. While further confirmatory studies are needed, a more robust understanding of hypertension prevalence and its management in adults with ID has emerged.

Differences with the general Irish population, confirmed by specifically looking at those with ID ≥ 50 years, are evident. Lower rates of hypertension, higher detection and greater efficacy of medication were found in those with ID, as was a lessor impact of risk factors such as obesity and low levels of physical activity.

Among the diagnosed groups in both studies, participants with ID were more likely to be receiving antihypertensive treatment and when receiving treatment, participants with ID were more likely to have their blood pressure controlled and were taking less combination therapy, compared to TILDA participants.7 Of interest, when hypertension was

diagnosed, antihypertensive therapy was both more likely to be used and to be effective in managing blood pressure, a finding that should encourage greater effort at treatment.

Antihypertensive compliance is reported to be higher among individuals with ID who are living in supervised residences and have frequent contact with a care provider.48 Care providers may administer prescribed medications daily, which may provide some explanation for this finding regarding medication adherence and subsequent effectiveness.

The most frequently reported antihypertensive medication classes in this study were ACE inhibitors (36.8%), diuretics (34.9%), calcium-channel blockers (26.3%) and Beta-Blockers (24.3%). These findings are similar to those of Vacek and colleagues49 who used Kansas Medicaid data to characterise antihypertensive medication use for adults with ID aged 18-64 years who had prescription claims over one year. For TILDA participants, ACE inhibitors were also the most commonly reported medication used, with diuretics being the fourth most common (23.1%). Although diuretics remain the cornerstone of antihypertension treatment, their dysmetabolic effects may increase the risk of new onset diabetes, particularly when combined with betablockers.37 Given the evidence that diabetes occurs more frequently in people with ID than the general population,21 diuretic use in the treatment of

hypertension in one-third of the ID population may require further exploration.

The findings regarding low levels of awareness of a diagnosis of hypertension in this ID population further supports the prior concern

by Janicki and colleagues11 that there may not be sufficient active case finding. Despite the European Society of Cardiology guidelines4 recommending that a total risk assessment, (which includes BP monitoring), be routinely carried out on all adults > 40 years of age, these guidelines have not been implemented in the ID population in Ireland and no such data has been published. Research is therefore required to establish a CVD risk profile for this vulnerable population. Nonetheless, lack of case finding alone does not provide a full explanation for the low rates of objectively established hypertension in adults with ID, despite the high levels of risk factors, as compared to the general population. Given this measured disconnect between risk and prevalence, additional research is needed to understand what protective factors may be present in this population and to further consider the presumed link between obesity, low levels of physical activity (more prevalent in people with ID) and measured/ diagnosed hypertension.

The examination of factors associated with awareness, treatment and control of hypertension, highlights that for persons with ID, their level of ID is an additional important and unique consideration, in that the greater their level of intellectual disability, the lower their level of awareness and treatment. Further, a concurrent diagnosis of diabetes is associated with greater levels of treatment, which raises concerns that those without a diabetes diagnosis, but with hypertension, are less likely to be treated.

The study has strengths and limitations. Proxy respondents completed just over one third of the interviews, which could have introduced respondent bias. In order to reduce the chances of this from occurring, proxy respondents were required to be family members or key staff members who knew the participant well.

In addition, using self-report questionnaires, as was the case in this study, runs the risk of recall bias along with the risk of over and under reporting, particularly if results are reliant on only one measurement. To counteract this and in line with the previously reported TILDA general population study and recommendations

of epidemiological studies, independent measures of blood pressure were completed 50 and medication prescription data were double checked. This added to the study’s validity with respect to data on blood pressure prevalence, treatment and control.

Further, providing some analyses on those ≥ 50 years facilitated direct comparison with the TILDA general population sample and added value to the study.

Conversely, data on medications were not completely transparent and it was difficult to differentiate if beta-blockers were used for dual or other indications, for example migraine and anxiety.

Conclusion This study provides the most comprehensive information to date on the prevalence, level of awareness, treatment and control of hypertension in older adults with ID in Ireland. In addition, it has facilitated some comparisons between the ID and the general population. Increased population and primary care level interventions to reduce hypertension prevalence and improve awareness, detection and management has been recommended for all adults over 50 years in Ireland.7 This study provides evidence that greater attention to screening in those with severe and profound levels of ID and in those without diabetes is required. Moreover, the findings that when hypertension is diagnosed, people with ID appear to respond particularly well to hypertension treatments should encourage addressing the undertreatment found here.

Implications for practice • The under-treatment and lower awareness levels among those with more severe ID requires addressing.

• Increase screening for hypertension in individuals with severe/profound levels of ID and in those without diabetes.

• When hypertension is diagnosed, people with ID respond well to hypertension treatments.

• Research is required to establish a CVD risk profile for this vulnerable population.

References available on request

HOSPITALPROFESSIONALNEWS.IE | HPN • APRIL 2022

74 Urticaria

Latest Advances in Chronic Spontaneous Urticaria Written by Dr Katie Ridge & Dr Niall Conlon, Department of Immunology, St James’s Hospital, Dublin/Trinity College Dublin

surveys have established that home administration is largely favoured by patients over hospital attendance.10 Importantly, omalizumab has changed the landscape for this cohort of patients, the majority of whom will experience a significant improvement in symptoms and quality of life following anti IgE treatment.

5.

Church MK, Kolkhir P, Metz M, Maurer M. The role and relevance of mast cells in urticaria. Immunol Rev. 2018 Mar;282(1):232–47.

6.

Lacour J-P, Khemis A, GiordanoLabadie F, Martin L, StaumontSalle D, Hacard F, et al. The burden of chronic spontaneous urticaria: unsatisfactory treatment and healthcare resource utilization in France (the ASSURE-CSU study). Eur J Dermatol EJD. 2018 Dec 1;28(6):795–802.

7.

Zuberbier T, Abdul Latiff AH, Abuzakouk M, Aquilina S, Asero R, Baker D, et al. The international EAACI/GA2LEN/EuroGuiDerm/ APAAACI guideline for the definition, classification, diagnosis, and management of urticaria.

Allergy. 2022 Mar;77(3):734–66.

8.

Ridge K, Redenbaugh V, Conlon N. Omalizumab Reduces Unplanned Healthcare Interactions in Irish Patients With Chronic Spontaneous Urticaria. Front Allergy. 2021 Dec 23;2:810418.

Denman S, El-Shanaway T, Carne E, Devlin L, Savic S. Multicentre experience of home omalizumab treatment for chronic spontaneous urticaria. Eur J Hosp Pharm Sci Pract. 2020 Nov;27(6):367–8.

References Dr Katie Ridge

Dr Niall Conlon

Chronic spontaneous urticaria (CSU) is a common but poorly recognised skin condition affecting children and adults with an estimated prevalence of 1%.1 It is characterised by unpredictable eruptions of itchy hives. Swelling of the skin or mucous membranes, known as angioedema is seen in approximately half of all cases.

CSU is distressing for patients and is associated with markedly impaired quality of life and psychological comorbidity.2,3 This often neglected disorder has higher point prevalence in females.4

The first-line treatment for CSU is second generation antihistamines.

However, a high proportion of patients will not respond to antihistamine treatment even when prescribed at high doses.

Omalizumab is a safe and effective monoclonal antibody directed against IgE. It is recommended in CSU that is refractory to high dose antihistamines.7 It is however a high cost medicine that typically requires specific funding approval with in-hospital administration and monitoring, thus demanding administrative and clinical support.

In Ireland, patient access to omalizumab in refractory CSU is allocated on a case by case basis in a handful of specialist centres.

The primary effector cell in CSU is the mast cell. Mast cell degranulation in CSU is multifactorial. Novel mechanisms at play include ‘autoallergy’ whereby IgE is directed against an element of self or by autoimmunity whereby IgG is directed against IgE or its receptor.5 Our improved understanding of underlying pathology has helped us to differentiate this condition from other allergic diseases.

Despite this, misconceptions are common. Both patients and health care providers can interpret the symptoms of CSU as representing evidence of food allergy. This leads to inappropriate testing for food sensitisation and can result in unnecessarily restricted diets and increased patient anxiety. Time to diagnosis can be prolonged and patients typically report multiple healthcare attendances before a diagnosis is established. In Europe, the mean time to diagnosis is 2-4 years.6

A recent study conducted at St. James’s Hospital revealed the high number of unplanned healthcare attendances seen in patients with CSU when their disease is active.8 Importantly, the study demonstrated a dramatic reduction in unplanned healthcare interactions after commencing omalizumab, with a 98% reduction in ED attendances and a 97.7% reduction in GP attendances. These data suggest that omalizumab, delivered in a specialist centre, may benefit patients with CSU by reducing disease activity and reducing the need for unscheduled care. The transition towards self-administration of omalizumab provides an opportunity for understanding how the delivery of this treatment can be optimised in an Irish setting.9,10 Patient satisfaction

APRIL 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

1.

Fricke J, Ávila G, Keller T, Weller K, Lau S, Maurer M, et al.

Prevalence of chronic urticaria in children and adults across the globe: Systematic review with meta-analysis. Allergy. 2020 Feb;75(2):423–32.

2.

Maurer M, Abuzakouk M, Bérard F, Canonica W, Oude Elberink H, Giménez-Arnau A, et al. The burden of chronic spontaneous urticaria is substantial: Real-world evidence from ASSURE-CSU. Allergy. 2017 Dec;72(12):2005–16.

3.

Tzur Bitan D, Berzin D, Cohen A. The association of chronic spontaneous urticaria (CSU) with anxiety and depression: a nationwide cohort study.

Arch Dermatol Res. 2021 Jan;313(1):33–9.

9.

4.

Savic S, Leeman L, El-Shanawany T, Ellis R, Gach JE, Marinho S, et al. Chronic urticaria in the real-life clinical practice setting in the UK: results from the noninterventional multicentre AWARE study. Clin Exp Dermatol.

2020 Dec;45(8):1003–10.

10. King C, Cox F, Sloan A, McCrea P, Edgar JD, Conlon N. Rapid transition to home omalizumab treatment for chronic spontaneous urticaria during the COVID-19 pandemic: A patient perspective.

World Allergy Organ J. 2021 Oct;14(10):100587.

RESPIRATORY OBESITY

ELDERLY

CARDIAC

WHEN CONTROL OF NMB REVERSAL IS WHAT MATTERS

BRIDION INDICATIONS • Reversal of rocuronium (ROC) or vecuronium (VEC) induced neuromuscular block (NMB) in adults.

• For routine reversal of ROC-induced block in children and adolescents aged 2 to 17 years.1 investigated in patients receiving ROC or VEC in the ICU setting. Do not use sugammadex to reverse block induced by nonsteroidal blockers such as succinylcholine or benzylisoquinolinium compounds, or steroidal blockers other than ROC or VEC. Conditions associated with prolonged circulation time such as cardiovascular disease, old age, or oedematous state may cause longer recovery times. Be prepared for possible drug hypersensitivity reactions. This medicinal product contains up to 9.7 mg sodium per ml, equivalent to 0.5 % of the WHO recommended maximum daily intake of 2 g sodium for an adult. OVERDOSE No dose related adverse events nor serious adverse events were reported. Sugammadex can be removed using haemodialysis with a high flux filter. INTERACTIONS Toremifene and fusidic acid may displace rocuronium or vecuronium from sugammadex and delay recovery (no clinically relevant capturing interactions are expected). Interaction of sugammadex with hormonal contraceptives may lead to a decrease in progesterone exposure equivalent to one missed daily dose of oral contraceptive (no displacement interactions are expected). In general sugammadex does not interfere with laboratory tests, with the possible exception of the serum progesterone assay where interference is observed at sugammadex plasma concentrations of 100 μg/ml plasma. In a study doses of 4 mg/kg and 16 mg/kg sugammadex resulted in maximum mean prolongations of the activated partial thromboplastin time by 17 and 22% respectively and prothrombin time by 11% and 22% respectively. These were of short duration (≤ 30 minutes). In in vitro experiments pharmacodynamic interaction was noted with vitamin K antagonists, unfractionated heparin, low molecular weight heparinoids, rivaroxaban and dabigatran. PREGNANCY AND LACTATION Pregnancy and Lactation: Caution in pregnant women. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from sugammadex therapy, taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman. The effects on human fertility have not been investigated. SIDE EFFECTS Refer to SmPC for complete information on side effects. Common (≥ 1/100 to < 1/10): Anaesthetic complications including movement of limbs or body or coughing during anaesthesia, grimacing, or suckling on the endotracheal tube, airway complication of anaesthesia, procedural hypertension and procedural complication. Uncommon (≥ 1/1,000 to < 1/100): Hypersensitivity reactions, including anaphylaxis, have occurred in some patients and volunteers. Other less common and rarely reported side effects are listed in the SmPC. In clinical studies with subjects treated with rocuronium or vecuronium, where sugammadex was administered using a dose labelled for the depth of neuromuscular blockade, an incidence of 0.2% was observed for recurrence of neuromuscular blockade as based on neuromuscular monitoring or clinical evidence. The use of lower than recommended doses may lead to an increased risk of recurrence of neuromuscular blockade after initial reversal and is not recommended. HANDLING See SmPC for details of compatability with infusion solutions. Physical incompatibility has been reported with verapamil, ondansetron and ranitidine. PACKAGE QUANTITIES 10 vials of 2 ml, 10 vials of 5 ml.

LEGAL CATEGORY POM. Marketing Authorisation Numbers EU/1/08/466/001-002. Marketing Authorisation Holder Merck Sharp & Dohme B.V., Waarderweg 39, 2031 BN Haarlem, The Netherlands. Date of review of prescribing information: April 2020. © Merck Sharp and Dohme B.V., 2020. All rights reserved. Further information is available on request from: MSD, Red Oak North, South County Business Park, Leopardstown, Dublin 18 or from www.medicines.ie. Date of preparation: July 2020. EMEA/H/C/000885/II/0036.

Reference: 1. Bridion SPC April 2020

PREDICTABLE. COMPLETE. RAPID.

Adverse events should be reported. Reporting forms and information can be found at www.hpra.ie.

Adverse events should also be reported to MSD (Tel: 01-299 8700)

Red Oak North, South County Business Park, Leopardstown, Dublin D18 X5K7 Ireland

IE-XBR-00032

BRIDION® 100 MG/ML SOLUTION FOR INJECTION (Sugammadex) ABRIDGED PRODUCT INFORMATION Refer to Summary of Product Characteristics (SmPC) before prescribing. PRESENTATION Vials of 200mg (2 ml) or 500mg (5 ml). INDICATIONS Reversal of rocuronium (ROC) or vecuronium (VEC) induced neuromuscular (NM) block in adults. For routine reversal of ROC-induced block in children and adolescents aged 2 to 17 years. DOSAGE AND ADMINISTRATION I.V. as a single bolus injection administered rapidly (within 10 seconds), into an existing I.V. line, by/under the supervision of an anaesthetist. Use appropriate technique to monitor recovery of NM block. Dose depends on the level of block to be reversed, not the anaesthetic regimen. Adults: Routine reversal following ROC- or VEC-induced block: • 4 mg/kg if recovery has reached at least 1-2 post-tetanic counts (PTC). Median recovery time (T4/T1 = 0.9) ≅ 3 minutes. • 2 mg/kg if recovery has occurred up to at least T2 following ROC- or VEC-induced block. Median recovery time (T4/T1 = 0.9) ≅ 2 minutes. Median recovery time (T4/T1= 0.9) is slightly faster with ROC- than VEC-induced block. Immediate reversal of ROC-induced block: 16 mg/kg. Median recovery time (T4/T1 = 0.9) ≅ 1.5 minutes when 16 mg/kg is given 3 minutes after a bolus dose of 1.2 mg/kg ROC. Not recommended for immediate reversal of VEC-induced block.

Re-administration of sugammadex: For post-operative recurrence of block after an initial dose of 2 mg/kg or 4 mg/kg, repeat dose of 4 mg/kg is recommended. Following a second dose of sugammadex, monitor the patient closely to ascertain sustained return of neuromuscular function. Re-administration of ROC or VEC after sugammadex: Up to 4 mg/kg Sugammadex a waiting time of 5 minutes for re-use of 1.2 mg/kg ROC; 4 hours waiting time for re-use of 0.6 mg/kg ROC or 0.1 mg/kg VEC. With ROC onset of NM block may be prolonged and duration of NM block may shortened. After immediate reversal, 16 mg/kg sugammadex, a waiting time of 24 hours is recommended. See SPC for patients with mild or moderate renal impairment. Special populations: Renal impairment: For mild and moderate renal impairment use adult dose. Not recommended in severe renal impairment (including patients requiring dialysis). Elderly: Use adult dose although recovery times are slower. Obese: In obese patients, including morbidly obese patients (body mass index ≥ 40 kg/m2), adult dose based on actual body weight. Hepatic impairment: Caution in patients with severe hepatic impairment, or impairment with coagulopathy. Children and adolescents (2-17 years): 2 mg/kg for routine reversal of ROC-induced block at T2. Not recommended in other routine reversal situations. Not recommended for Immediate reversal. May be diluted for accuracy of dose. Term newborn infants and infants: Not recommended. CONTRA-INDICATIONS Hypersensitivity to sugammadex or to any excipients. PRECAUTIONS AND WARNINGS Ventilatory support is mandatory for patients until adequate spontaneous respiration is restored following reversal of block. Should block reoccur following extubation, adequate ventilation should be provided. The use of lower than recommended doses may lead to an increased risk of neuromuscular blockade after an initial reversal and is not recommended. Caution should be exercised when considering the use of sugammadex in patients receiving anticoagulation for a pre-existing or co-morbid condition. An increased risk of bleeding cannot be excluded in patients with hereditary vitamin K dependent clotting factor deficiencies; with pre-existing coagulopathies; on coumarin derivatives and at an INR above 3.5; using coagulants who receive a dose of 16mg/ kg sugammadex. If re-administration of ROC or VEC is required in patients with mild or moderate renal impairment after routine sugammadex reversal a waiting time for re-use of 0.6 mg/kg ROC or 0.1 mg/kg VEC should be 24 hours. If a shorter waiting time is required, the ROC dose for a new NM blockade should be 1.2 mg/kg within 30 minutes after Sugammadex administration. For re-administration of ROC or VEC after immediate reversal a waiting time of 24 hours is recommended. If neuromuscular block is required before the recommended waiting time has passed, a nonsteroidal neuromuscular blocking agent should be used. The use in patients with severe renal impairment is not recommended including those requiring dialysis. If neuromuscular block is reversed, while anaesthesia is continued, additional doses of anaesthetic and/or opioid should be given as clinically indicated. Marked bradycardia with cardiac arrest have been observed within minutes after administration, closely monitor patients for hemodynamic changes during and after reversal. Treat with anti-cholinergic agents such as atropine if clinically significant bradycardia observed. Sugammadex has not been

76 Oncology

An Overview of Head & Neck Cancer Written by Mr Paul Lennon, Consultant Otolaryngologist, Head and Neck Surgeon, St. James's Hospital, Royal Victoria Eye and Ear, and Blackrock Clinic

• Hypopharynx; • Larynx; • Major Salivary glands; • Nasal cavity and Paranasal sinuses • Unknown Primary tumours of the Head and Neck • Cutaneous Carcinoma of the Head and Neck*

from GPs, Dermatologists, General surgeons and the Head and Neck Surgeons listed above. In the main the smaller tumours are managed by simple excision. Larger malignancies that require, for example, neck dissection, parotidectomy, lateral temporal bone resection, rhinectomy, or complex reconstruction, and or adjuvant radiotherapy would often be discussed and managed by Head and Neck surgeons.

Incidence • Thyroid cancer –Thyroid cancers in Ireland are often managed by It is difficult to precisely estimate the number of Head and Neck CancerIncidence diagnosed per year Head and Neck surgeons, and their respective MDTs, whilst is a a challenge for a number of reasons. The complexity and diversity of tumours from estimate a data It is difficult to precisely large number of patients are also the number of Head and Neck managed by General surgeons. management It is also very patients Cancer diagnosed with per year Head and Neck cancerpoint (HNC) of view.

The terms mouth cancer and difficult to put a number on the for a number of reasons. The is an umbrella term to describe throat cancer are often used • Others- Sarcomas of the Head malignanciescolloquially managed

by Head and Neck MDTs. Bymanaged examining dataand collected complexity diversity of by acutaneous group of malignancies and Neck are usually to describe such tumours is a challenge from a managed by physicians from a in conjunction with the Sarcoma cancers. From an AJCC staging the National bewhilst estimated that approximately 940 data management point of view. number of specialitiesCancer who have Registry Ireland (NCRI), it can MDT, a large number point of view Head and Neck It is also very difficult to put a subspecialised in the area. From of lymphomas are diagnosed with Cancers of the (C32) cancer includes the following sites:Mouth and Pharynx (C00-14), numberLarynx on the patients withand apatients surgical pointwere of view,diagnosed these

by Head and Neck Surgeons, cutaneous malignancies managed would usually be Otolaryngologists andin subsequently managed • Oral cavity; Thyroid (C73) Nasal 2017. As yet unpublished suggests

by Head and data Neck MDTs. By (ENT) and Maxillofacial (MaxFax) Cavity (C31) and Sinuses (C32)

by Haematologist or Medical examining data collected by the surgeons, but also a number of • Nasopharynx; Oncologist. that surgeons. this number will be over 1100 patients in 2019. This data suggestedNational the Cancer number ofIreland Registry Plastic Internationally, * Cutaneous Carcinoma of the (NCRI), it can be estimated that some Head and Neck surgeons • HPV mediated oropharyngeal Head and Neck Malignancies has increased 300%Head since 2001. Figure 1 approximately 940 patients were and Neck are extremely initially train as general surgeons cancer; diagnosed with Cancers of the numerous and may be managed before subspecialising in Head and Fig 1. Incidence of Head• and Neck Cancer in Ireland 2000-2017, Data from NCRI Mouth and Pharynx (C00-14), by a large number of physicians, Neck cancer.

HPV negative oropharynx;

Head and Neeck Cancer, Ireland 2000-2017, NCRI 1200

1000

800

600

400

200

0

2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 C00-14 lip oral cavity and pharynx

APRIL 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

C32 larynx

C73 thyroid gland

Total

77

Larynx (C32) and Thyroid (C73) Nasal Cavity (C31) and Sinuses (C32) in 2017. As yet unpublished data suggests that this number will be over 1100 patients in 2019.

This data suggested the number of Head and Neck Malignancies has increased 300% since 2001 This may be a slight overestimation patients managed by Head and Neck MDTs due to the inclusion of all Thyroid cancers, but it also does not include Sarcoma of the Head and Neck and other miscellaneous malignancies.

However in reality it is likely an underestimation as from audit data from the St. James’s Head and Neck MDT suggests that 10% of the workload can be attributed to Cutaneous Malignancy. Therefore a number close to 1200 patients a year may be more accurate.

The increase in incidence is being driven in the main by an increased incidence of Thyroid cancer and HPV positive oropharyngeal cancer, with specific explanations for each which I will discuss later.

Unfortunately we are also seeing a slight rise in number of tobacco driven Laryngeal cancer.

Upper Aerodigestive Tract cancers The majority of the patients we treat are diagnosed with squamous cell carcinoma (SCC) of the upper aerodigestive tract. These patients are frequently men (~75%), and on

average approximately 65 years of age. The major risk factors for SCC of the Head and Neck remain smoking and alcohol intake.

Smoking increases a patients risk 5 fold, whilst excessive alcohol 3 fold. There is however a multiplier effect, with 15 times the risk seen in smokers who also drink heavily.

Betel nut chewing is a major risk factor for oral cancers in India, where it is amongst the most common cancers diagnosed.

• An unexplained persistent sore throat especially in those with risk factors

Signs and Symptoms

• Large or rapidly progressive skin lesion of the Head and Neck

There are a number of “red flag” signs and symptoms that are recognised and warrant a referral to a Head and Neck cancer clinic.

In general such a referral should be considered when the symptoms persists for more than 3 weeks, these include • Persistent unexplained hoarseness • An unexplained lump in the neck, of recent onset or a one changed over a period of 3 – 6 weeks.

• Unexplained ulceration of the oral cavity or mass • Unexplained progressive dysphagia to solids, with/ without weight loss • An unexplained persistent swelling in the parotid or submandibular gland

• Referred otalgia with normal examination/tympanogram, with any of the above symptoms • Unexplained persistent unilateral serous otitis media/ effusion in an adult • Unexplained new or rapidly enlarging Thyroid lump

A rapid access clinic has been established in the Royal Victoria Eye and Ear for such patients, with the view that the patients would be seen within two weeks.

Patients are usually seen in clinic, are examined, which usually includes a flexible nasopharyngeal laryngoscopy, and if appropriate a biopsy or FNA under local anaesthetic may be performed. Patients often require an EUA, or panendoscopy to establish a biopsy proven diagnosis of malignancy.

Investigations often include CT, MRI and PET-CT in those with advanced malignancies. Patients are then discussed at MDT, where a management strategy is formulated. Radiotherapy and surgery are the mainstay of treatments for SCC of the Head and Neck. Chemotherapy

is often used concurrently with radiotherapy, and in the non-curative setting. Up to 10% of our patients will have distant metastases of extremely advanced locally disease at their presentation.

Treatment The choice of radiotherapy or surgery depends on multiple factors, but some generalisations can be made. Tumours in the oral cavity are primarily treated with surgical excision, often with a neck dissection. Early vocal cord tumour can be excised by Laser, whilst patients presenting with T4 or recurrent disease in the larynx will require a laryngectomy.

Curative radiotherapy, frequently combined with chemotherapy, can be employed with organ preservation as a goal or to decrease the morbidity associated with surgical excision, when survival outcomes are similar or superior to surgery. This included many laryngeal tumours, nasopharyngeal, hypopharyngeal and oropharyngeal tumours.

Radiotherapy is also often given in the adjuvant setting, post-surgical resection. Radiotherapy is usually given over a period of 6-7 weeks, and in general is well tolerated.

Adverse effects such a dry mouth are common, but more severe side effects necessitating NG or PEG feeding is sometimes required.

When radiotherapy is utilized in

HOSPITALPROFESSIONALNEWS.IE | HPN • APRIL 2022

78 Oncology the curative setting, a PET-CT is undertaken 3-4 months after the end of treatment, to ensure a complete response. Salvage surgery may be required if there is residual disease.

The patients that undergo major surgical resections, and thus account for the majority of patients in hospital, fall into two broad categories- those undergoing an oral cavity or oropharyngeal resection often with a free flap reconstruction, or those undergoing a laryngectomy or pharyngolaryngectomy. Patients undergoing either of these procedures will require extensive preoperative management and post-operative rehabilitation.

A large number of allied health professionals are therefore crucial to the patients care. These include Speech and Language therapist, Dieticians, Physiotherapists, and social workers. Patients are also seen by restorative dentists, before both surgery and radiotherapy, and often in the post-operative setting. Clinical nurse specialist are also essential in the management of such patients, guiding them through what can be a daunting journey, and co-ordinating their complex care. A tracheostomy may be required temporarily, and therefore specialist nurses are invaluable in managing such patients. Patients can be admitted for a number of weeks, often including an ICU stay postoperatively. The rehabilitation of swallow and speech can be challenging depending on the extent of surgical excision, but even those post laryngectomy can re-establish intelligible speech.

It includes the tonsils, the soft palate, the posterior pharyngeal wall and the back or base of tongue ( this is part of the tongue that can't be easily seen, and is much more like the tonsils than the muscular front or anterior two thirds of the tongue).

Traditionally, like most Head and Neck Cancers, the major risk factor for oropharyngeal cancer were cigarette smoking, excess alcohol consumption, advanced age and male gender.

Although a link between Head and Neck Cancer and Human Papilloma Virus (HPV) has been known since the 1980s, it was only when rapidly increasing incidences in OPSCC were noted in patients without traditional risk factors in the 2000s, that HPV as a causative agent for OPSCC was more widely researched. A landmark paper by Ang et al. in 2010 demonstrated that HPV positive OPSCC who were nonsmokers had a vastly superior (93.5%) 3 year survival, compared to HPV negative OPSCC smokers (41.6% 3 year survival). Further studies corroborated these finding and a distinct carcinogenic pathway was identified.

This has cumulated in HPV mediated OPSCC being recognised as a separate entity in the 8th AJCC staging manual published in 2018. An audit of Irish cancer centres from 2014-2018 demonstrated that 46% of OPSCC were HPV+ve. This is inline with many developed countries, although some studies have shown a much higher percentage.

Audit data from St. James’s Hospital in 2020 revealed that 41 of 55 OPSCC patients (74.5%) were HPV positive.

Recent advances in the field include preoperative digital planning of resections requiring Patients with oropharyngeal bony reconstruction. This allows cancer typically present with the ablative and reconstructive unilateral symptoms, of persistent surgeon to plan the surgery in sore throat, for more than three advance, and exact guides to weeks, with referred otalgia. A be made that allow both teams unilateral enlarged or ulcerated to operate concurrently. This tonsil can often be seen. Patients shortens operative time, and has with HPV+ve OPSCC often present been shown to improve outcomes 24:41 1202/40/72 with large cystic neck nodes, and for the patients. Robotic surgery, relatively small primary tumours. specifically trans oral robotic In older staging systems, a surgery (TORS), allowed larger patient with this clinical picture, tumours in the oropharynx to for example T2N2bM0, would be be excised per-orum eliminating classified as Stage IVa, and HPVthe need for lip split and ve OPSCC would still be staged mandibulotomy associated with this way. However with the new traditional surgery. Studies show AJCC staging, a patient with the some promise, but again, it same clinical picture, and HPV+ve, appears that the proven treatment would be T2N1M0, and classified modality of Radiotherapy is safer, as Stage I. and remains the standard of care.

TORS is sure to find a place in our Unfortunately, this has not armamentarium, but it is unclear meant that there has been a yet as to what that will be. change in our standard of care in the management of HPV+ve HPV mediated Oropharyngeal OPSCC, which is generally either Cancer radiotherapy alone, or most often concomitant chemotherapy and The oropharynx is part of the radiotherapy. Although a number throat at the back of the mouth.

APRIL 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

Lm/gm 52 dexertemeP of studies have been carried out to examine the safety in deescalating these treatments, either through decreasing the dose of radiotherapy or substituting chemotherapy for a less toxic immunotherapy, these studies have thus far failed to demonstrate improved outcomes. Therefore, although HPV+ve patients may have a lower overall stage than their HPV-ve counterparts, they will, at present, receive the same treatment paradigms.

proved papillary thyroid cancers up to 1.5cms.

In Ireland, no screening program was established, but we have still seen a large increase in incidence, for similar reasons.

Thyroid nodules are often seen incidentally on imaging for other indications, such as MRI spines and CT chests. These are then investigated and for the same reasons as above, malignancies may be diagnosed. It can be challenging to establish whether a thyroid nodule is benign or malignant. Nodules are classified as 1-5 ( U or TiRads classification) on ultrasound to give an indication as to their likelihood of malignancy.

An FNA will also give a 1-5 result (Thy system), with a Thy5 denoting malignancy. These investigations therefore need to be carefully considered, as it can be difficult to allay the fears of a patient with a thyroid nodule.

elbats erutarepmet moor A etartnecnoc etulid-ot-ydaer

Thyroid Cancer The incidence of thyroid cancer has increase 5 fold over the past 25 years in Ireland. This spectacular increase however is not an isolated finding, and pales in comparison to South Korea, where a 15 fold increase in incidence was seen and Thyroid cancer is now the most common cancer in women in the country, almost double the incidence of Breast cancer. These phenomena can be explained in the main by over-diagnosis. In South Korea a screening program was established, where a thyroid ultrasound was offered to patients.

This led to a large number of nodule being discovered, investigated and thyroidectomies being performed. This led to the massive increase in number of Thyroid cancers.

This can be explained by a number of autopsy studies which demonstrated that up to a third of patients, with no prior history of thyroid disease, had a malignancy at post mortem. The authors of one study suggested that this may be as high as 100%, had the thyroids been dissected to extremely sizes. This implies that we may all have tiny thyroid cancers, that are subclinical and in the vast majority of times will likely remain so. This is supported by a number of studies that have successfully observed small biopsy proven thyroid cancers, with Ito in Japan accumulating over 1000 patients with up to 1cm tumours. Memorial Sloan Kettering in New York offer an active surveillance program for biopsy

The vast majority of Thyroid cancers are well-differentiated malignancies, with the vast majority of these being papillary thyroid cancers, but also include follicular and hurtle cell cancers.

In patients under 55 years of age, and with tumours less than 4cm in size, a thyroid lobectomy will be both diagnostic and curative in the main. Larger tumours, in older patients, or with adverse histological features may require total or completion thyroidectomy and adjuvant radioactive iodine. Medullary thyroid cancer is a challenging and thankfully uncommon malignancy, that can be familial in origin and is associated with MEN2a and MEN2b. Children with these syndromes require a thyroidectomy at a very young age, to prevent the development of medullary thyroid cancer. Finally Anaplastic thyroid cancer is one of the most aggressive solid organ malignancies in humans, with a median survival measured in just a number of months. Patients usually present with inoperable 1 ddni.A_noitpO_4v_eruhcorB_pp4_4A_dexertem tumours, but fortunately as few as 10 patients a years are diagnosed with these tumours in Ireland.

Date for your Diary *** The inaugural conference of the multi-disciplinary Irish Head and Neck Society (IHNS) is due to take place on Friday and Saturday, 6-7 May, 2022, at the Kilkenny Convention Centre, Lyrath Estate, Kilkenny, Ireland

Pemetrexed 25 mg/mL

Launching A room temperature stable

ready-to-dilute concentrate Launching Noradrenaline Pemetrexed 25 mg/mL 1mg/ml concentrate for A multi-targeted anti-cancer antifolate agent In three presentations solution for infusion.

100mg/4ml

500mg/20ml

1,000mg/40ml

Your patients, your profession, our passion.

P_KF_36791

PRESCRIBING INFORMATION: Consult the Summary of Product Characteristics for further information. Additional information is available upon request. Pemetrexed Fresenius Kabi 25mg/ml concentrate for solution for infusion.

Active ingredients: Pemetrexed diacid. One vial of 4ml concentrate contains 100mg pemetrexed. One vial of 20ml concentrate contains 500mg pemetrexed. One vial of 40ml concentrate contains 1,000mg pemetrexed. Excipients with known effect – 4ml vial - 964mg hydroxypropylbetadex, 20ml vial – 4820mg hydroxypropylbetadex, 40ml vial – 9640mg hydroxypropylbetadex. Indications: In combination with cisplatin - treatment of chemotherapy naïve patients with unresectable malignant pleural mesothelioma, first line treatment of locally advanced or metastatic non-small cell lung cancer other than predominantly squamous cell histology. Monotherapy – Maintenance treatment of locally advanced or ABBREVIATED PRESCRIBING INFORMATION: Consult the Summary of Product further metastatic non-small cell lung cancer other than predominantly squamous cell histologyCharacteristics in patients whosefordisease has information is available upon request. Noradrenaline (Norepinephrine) 1mg/mlor notinformation. progressed Additional immediately following platinum-based chemotherapy, second line treatment of locallyKabi advanced metastatic non-small cell lung other thaningredient: predominantly squamous cell histology.forPosology method concentrate for solution for cancer infusion.

Active 1ml concentrate for solution infusionand contains 1mgof administration: administer under supervision of a noradrenaline physician qualified in the use of anti-cancer chemotherapy. noradrenalineOnly (norepinephrine) basethe equivalent to 2mg (norepinephrine) tartrate. Contains 3.4mg Administer as ml. an intravenous 10 minutes on the first day of in each cycle. of Seeblood SmPC for further sodium per Indications: infusion In adultsover for use as an emergency measure the21-day restoration pressure in 2 information on handling, administering and dilution.

In combination with cisplatin – Recommended dose is 500mg/m cases of acute hypotension. Posology and method of administration: When diluted as recommended, each litreof body surface40mg area noradrenaline (BSA) administered an intravenous infusion over 10 minutes on the first day ofother eachthan 21-day40mg cycle. contains baseasequivalent to 80mg noradrenaline tartrate.

If dilutions 2 BSA infused over two hours approximately 30 minutes after completion of the Recommended dose of cisplatin is 75mg/m per litre are used, check infusion rate calculation carefully before starting treatment. Initial rate of infusion pemetrexed infusion on the first day of each 21-day cycle. Patients must receive adequate anti-emetic treatment and – 10-20ml/hour (0.16-0.32ml/min); equivalent to 0.4-0.8mg/hour noradrenaline base. Lower initial infusion appropriate hydration prior to and/or after receiving cisplatin (see also cisplatin SmPC). As single agent – In the treatment of 5ml/hour (0.08ml/min); to 0.2mg/hour noradrenaline may be2 preferred.

Titrationasofan BSA administered of rate non-small cell lung cancer afterequivalent prior chemotherapy, recommended dose base is 500mg/m dose – Once infusion has10been established, titrate in steps 0.05-0.1mcg/kg/min noradrenaline base intravenous infusion over minutes on the first daydose of each 21-dayofcycle.

Pre-medicationofregimen: To reduce the according to pressor effect observed (see SmPC for details).

Continue infusion until adequate blood incidence and severity of skin reactions, a corticosteroid should be given the day prior to, on the day of, and thepressure day after and tissueadministration. perfusion maintained without therapy.

Carefullyto monitor patient. Shouldorally only twice be administered pemetrexed Corticosteroid should be equivalent 4mg of dexamethasone daily. Patients by healthcare familiar with oral use folic of noradrenaline and with appropriate monitoring facilities. must also receiveprofessionals vitamin supplementation; acid or a multivitamin containing folic acid (350 to 1000 Avoid abrupt withdrawal; reduce gradually. experience treatment of hepatic renal micrograms) on ainfusion daily basis.

At least five dosesinfusion of folic acid must beNo taken during theinseven days preceding theorfirst dose of impairment. pemetrexed Dose and dosing mustforcontinue during the should full course of therapystarting and forat21the days lastdosing dose of selection an elderly patient be cautious, lowafter end the of the 19763_FK_Pemetrexed_A4_4pp_Brochure_v4_Option_A.indd 1 (1000 micrograms) in of theadministration week preceding pemetrexed.

Patients must alsoinreceive anless intramuscular injection of vitamin B12 established. range. Safety and efficacy patients than 18 years old has not been Method may be given the– first dose of pemetrexed and once every threeat cycles thereafter.rate Subsequent vitamin B12 injections Intravenous use only after dilution.

Infuse a controlled using either syringe pump, infusion pumpon theorsame as pemetrexed.

Before each dose complete including differential white cell count drip day counter.

AdministerMonitoring: via a central venous catheter.

If notblood usingcount a central venous catheter administer (WCC) platelet Prior possible, to each chemotherapy blood be collected into and a large veincount. whenever particularly anadministration antecubital vein to chemistry minimize tests risk ofshould ischemic necrosis.to evaluate renal and tie-in hepatictechnique function. Before the start of any cycle of chemotherapy, patients areactive required to have absolute Avoid catheter if possible.

Contraindications: Hypersensitivity to the substance or to neutrophil count (ANC) ≥ 1500 cells/mm3 and platelets ≥ 100,000 cells/mm3. Creatinine clearance should be ≥ 45 ml/min. any of the excipients, hypotension due to blood volume deficit. Do not use with cyclopropane and halothane Total bilirubin should be ≤ 1.5 times upper limit of normal. Alkaline phosphatase (AP), aspartate aminotransferase (AST or anaesthetics as this may cause serious cardiac arrhythmias including ventricular fibrillation.

Special warnings SGOT) and alanine aminotransferase (ALT or SGPT) should be ≤ 3 times upper limit of normal. AP, AST and ALT ≤ 5 times and limit precautions use: Do not use has undiluted. patients whoAtare from blood upper of normalfor is acceptable if liver tumourContraindicated involvement. Doseinadjustments: the hypotensive start of a subsequent cycle volume an emergency measure to maintain coronary and cerebral perfusioncycle untilof should be deficits based onexcept nadir as haematologic counts or maximum non-haematologic toxicity fromartery the preceding blood Treatment volume replacement therapy can be completed. only be used in conjunction with appropriate therapy. may be delayed to allow sufficient time Should for recovery.

Upon recovery patients should be retreated bloodthevolume replacement.

If whole or blood plasma is indicated to increase bloodasvolume, using guidelines as follows, which blood are applicable for pemetrexed Fresenius Kabi used single administer agent or in separatelywith (e.g.cisplatin. use Y-tubing, individual containers).

Prolonged result– Nadir in plasma combination Haematologic toxicities (dose modify both administration pemetrexed and may cisplatin) ANC < volume 500/mm3 3 3 , or nadir platelets < 50,000/mm regardless nadir ANC: 75%replacement of previous dose.

Nadir and nadir platelets 50,000/mm depletion which ≥should be continuously corrected by appropriate fluid ofand electrolyte therapy.

3 with bleeding regardless of nadir ANC: 50% of previous dose.

Non-haematologic toxicities Grade platelets < 50,000/mm Frequently check blood pressure and rate of flow to avoid hypertension. Particular caution in patients≥with 3 (excluding Freseniusthrombosis, Kabi shouldhypotension be withheld until resolution to less infarction, than or equal to the coronary, neurotoxicity) mesenteric or- pemetrexed peripheral vascular following myocardial angina patient’s pre-therapy value. Treatment should bediabetes, resumedhypertension accordingly – Any grade 3 or 4 toxicities except mucositis, or (particularly Prinzmetal’s variant angina), or hyperthyroidism, major left ventricular 2 ) of pemetrexed and any diarrhoea requiring hospitalisation or grade 3 or(supportive 4 diarrhoea:therapy 75% ofshould previous (mg/msimultaneously dysfunction associated with acute hypotension bedose initiated with 2 ) and 100% of previous cisplatin dose (mg/m2). cisplatin.

Grade 3 or 4 mucositis: 50% of previous pemetrexed dose (mg/m diagnostic evaluation; reserve noradrenaline for patients with cardiogenic shock and refractory hypotension, Neurotoxicity – Patients should discontinue therapy if Grade 3 or 4 neurotoxicity is observed. CTC Grade 0-1: 100% of in particular those without elevated systemic vascular resistance), liver failure, severe renal dysfunction, previous pemetrexed and cisplatin dose (mg/m2). CTC Grade 2: 100% of previous pemetrexed dose (mg/m2) and 50% of previous cisplatin dose (mg/m2). Discontinue treatment with pemetrexed Fresenius Kabi if a patient experiences any haematologic or non-haematologic Grade 3 or 4 toxicity after 2 dose reductions or immediately if Grade 3 or 4 neurotoxicity is observed. Elderly – No dose reductions other than those recommended for all patients are necessary.

Fresenius Kabi Limited Fresenius Kabi Ireland Unit 3B Fingal Bay Balbriggan, Co. Dublin Ireland

Paediatric population – No relevant use in malignant pleural mesothelioma and non-small cell lung cancer. Renal impairment – (Standard Cockcroft and Gault formula or GFR measured Tc99m-DPTA serum clearance method). In clinical studies patients with creatinine clearance of ≥ 45ml/min required no dose adjustments other than those recommended for all patients. Not recommended in patients with creatinine clearance below 45ml/min. Hepatic impairment – Patients with hepatic impairment have not been specifically studied. Contraindications: Hypersensitivity to the active substance or to any of the excipients, breast-feeding, concomitant yellow fever vaccine. Special warnings and precautions for use: Monitor patients for myelosuppression. Pemetrexed should not be given until ANC returns to ≥ 1500 cells/mm3 and platelet count to ≥ 100,000 cells/mm3. Dose reductions for subsequent cycles based on nadir ANC, platelet count and ischemic non-haematologic heart diseases andtoxicity elevated intracranial pressure. dose ifmust heartberhythm disorders maximum seen from previous cycle.Reduce All patients instructed to takeoccur folicduring acid and treatment. arrhythmias may arise whentreatment-related used in conjunction with Pre-treatment cardiac sensitizing agents and may(or a prophylactic measure to reduce toxicity. with dexamethasone vitamin B12 asCardiac equivalent) can reduce the incidence and severity of skin reactions.

Not recommended in patients with creatinine be more likely in patients with hypoxia or hypercarbia.

Elderly patients may be especially sensitive to the clearance < 45ml/min. Patients with mild to moderate renal insufficiency clearance 45-79ml/min) effects ofofnoradrenaline.

Not recommended in children.

Where indicated,(creatinine appropriate replacement therapyshould of avoid NSAIDs, or acetylsalicylic acidof(>the 1.3gsupine daily) for 2 dayswith before, on the day of, and pemetrexed bloodtaking or fluid together with adoption position elevation of the legs,2 days mustfollowing be instituted and administration.

In patients with mild to moderate renal insufficiency NSAIDs with long elimination half-lives should maintained prior to and/or during therapy with noradrenaline. During infusion, record blood pressure every two be interrupted for at prior to, on thestarted day of, and least 2 daysblood following pemetrexed administration.

Patients minutes from theleast time5 days the administration untilatthe desired pressure is obtained and then every should be regularly monitored for acute tubular necrosis,watch decreased renaland function and signs andunattended. symptoms of five minutes thereafter if infusion continued.

Constantly flow rate never leave patient nephrogenic diabetes insipidus. Drainage of third space fluid collection prior to pemetrexed treatment should be Hypertension may eventually lead to acute pulmonary oedema, arrhythmia or cardiac arrest. Caution in patients considered but may not be necessary. Patients should receive adequate antiemetic treatment and appropriate hydration receiving pressor with chloroform, enflurane or otherand halogenated anaesthetics (maybeen cause serious prior to and/or afteramines receiving treatment.

Serious cardiovascular cerebrovascular events have uncommonly cardiac arrhythmias) any other sensitising in patients who exhibit profoundcytotoxic hypoxiaagent. or reported during clinicalorstudies with cardiac pemetrexed, usually agent when or given in combination with another hypercarbia.

Extreme caution in patients receiving monoamine oxidase inhibitors or within 14 days of cessation Concomitant use of live attenuated vaccines is not recommended. Sexually mature males are advised not to father a child of such therapyandand in 6patients receiving Contraceptive tricyclic antidepressants, adrenergicdrugs or of during treatment up to months thereafter. measures or abstinence areserotoninergic recommended. Possibility linezolid. Overdoses in hypersensitive persons maybefore causestarting severe treatment. hypertension with of irreversible infertility; or menconventional advised to doses seek counselling on sperm storage Women violent headache, photophobia, pain, pallor,treatment intense sweating and vomiting.

Theofinfusion childbearing potential must use stabbing effective retrosternal contraception during with pemetrexed.

Cases radiation pneumonitis reported in frequently patients treated with radiation either be prior, during or subsequent to pemetrexed therapy; site should be checked for free flow.

Care should taken to avoid extravasation of noradrenaline 27/04/2021 14:42 24:41 1202/40/7 particular attention should be these patients caution other radiosensitising agents. of radiation tartrate into the tissues, as paid localtonecrosis might and ensue due with to the vasoconstrictive action ofCases the drug (see recall in patients who received ischaemia). radiotherapyBlanching weeks or years of cyclodextrins may SmPCreported for antidote for extravasation along previously. the courseAccumulation of the infused vein warrants occur in patientsofwith moderate to severe dysfunction. cause fatigue,via patients should be cautioned against consideration changing infusion site renal at intervals.

AvoidMay administration the veins of the leg in elderly driving or or operating if thisocclusive occurs. Undesirable effects:Noradrenaline (Associated with pemetrexed monotherapy or in patients in thosemachinery suffering from vascular diseases. interacts with other medicinal combination with cisplatin) Infection, pharyngitis, sepsis, dermo-hypodermitis, neutropenia, leukopenia, decreased products; some combinations are inadvisable or require additional precautions and close medical supervision haemoglobin, febrile neutropenia, decreased platelet count, pancytopenia, autoimmune haemolytic anaemia, – see SmPC. Undesirable effects: Anxiety, insomnia, confusion, weakness, psychotic state, transient headache, hypersensitivity, anaphylactic shock, dehydration, taste disorder, peripheral motor neuropathy, peripheral sensory tremor, acute glaucoma, bradycardia, accident, arrhythmia, electrocardiogram change, tachycardia,conjunctivitis, cardiogenic shock, neuropathy, dizziness, cerebrovascular ischemic stroke, intracranial haemorrhage, dry eye, stress cardiomyopathy, palpitations, increase the oedema, contractility of surface the cardiac muscle resulting the increased lacrimation, keratoconjunctivitis sicca, in eyelid ocular disease, cardiac failure, from arrhythmia, beta- adrenergic on the heart artery (inotrope and supraventricular chronotrope), acute cardiacperipheral insufficiency, hypertension, angina, myocardial effect infarction, coronary disease, arrhythmia, ischaemia, pulmonary peripheralinterstitial ischaemia including gangrene the extremities, plasma volume prolonged use, embolism, pneumonitis, stomatitis, of anorexia, vomiting, diarrhoea, nausea,depletion dyspepsia,with constipation, abdominal dyspnoea, respiratory insufficiency or difficulty, nausea, vomiting, paleness, scarification of the skin, bluish pain, rectal haemorrhage, gastrointestinal haemorrhage, intestinal perforation, oesophagitis, colitis, increased alanine skin colour, hot flushes or skin redness, skin rash, hiveshepatitis, or itching,rash, retention of urine, extravasation, necrosis at aminotransferase, increased aspartate aminotransferase, skin exfoliation, hyperpigmentation, pruritis, erythema alopecia, urticaria, erythema, Stevens-Johnson syndrome, toxic epidermal necrolysis, pemphigoid, injectionmultiforme, site. Legal Category: POM Marketing Authorisation Number: PA2059/073/001 Marketing Authorisation dermatitis bullous, acquired epidermolysis bullosa, erythematous oedema, pseudocellulitis, dermatitis, eczema, prurigo, Holder: Fresenius Kabi Deutschland GmbH; Else-Kröner Straße 1, 61352 Bad Homburg v.d.Höhe, Germany Further decreased creatinine blood creatinine, renal failure, GFR,Healthcare nephrogenic diabetes insipidus, Information: See theclearance, SmPC forincreased further details.

Adverse events shoulddecreased be reported. professionals are renal necrosis, fatigue, pyrexia, oedema, mucosal inflammation, GGT,- Dublin radiation askedtubular to report any suspected adversepain, reactions via chest HPRA pain, Pharmacovigilance, Earlsfortincreased Terrace, IRL oesophagitis, radiation pneumonitis, recall phenomenon.

Legal Category: POM Marketing Authorisation Numbers: 2, Tel: +353 1 6764971, Fax: +353 1 6762517. Website: www.hpra.ie, E-mail: medsafety@hpra.ie. Adverse events EU/1/16/1115/003, EU/1/16/1115/005.

Marketing Authorisation Holder: Fresenius Kabi DeutschlandDate GmbH, should also beEU/1/16/1115/004, reported to Fresenius Kabi Limited via email Pharmacovigilance.GB@Fresenius-Kabi.com.

Else-Kroner-Straße 1, 61352 Bad Homburg v.d.Höhe, Germany. Further Information: See the SmPC for further details. of Preparation: January 2022 FPI-0041 Adverse events should be reported. Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2, Tel: +353 1 6764971, Fax: +353 1 6762517. Website: www.hpra.ie, E-mail: medsafety@hpra.ie. Adverse events should also be reported to Fresenius Kabi Limited via email Pharmacovigilance.

GB@Fresenius-Kabi.com. Date of Preparation: May 2021 Job code: API/Pemetrexed/02

Website: www.fresenius-kabi.com/ie/ Email: FK-enquiries.ireland@fresenius-kabi.com Phone: +353 (0)1 841 3030

Fresenius Kabi Limited Fresenius Kabi Ireland Unit 3B Fingal Bay, Balbriggan, Co. Dublin, Ireland

Website: www.fresenius-kabi.com/ie/ Email: FK-enquiries.ireland@fresenius-kabi.com Phone: +353 (0)1 841 3030

Date of Prep: March 2022 Job Code: IE-IVF-2200006

Date of Prep: May 2021 Ref: IV/ONCO/PEME/01/2021

80 Clinical R&D IRISH REIMBURSEMENT GRANTED FOR RINVOQ® (UPADACITINIB), AN ORAL JAK INHIBITOR APPROVED FOR THE TREATMENT OF BOTH ADULTS AND ADOLESCENTS ≥12 YEARS* WITH MODERATE TO SEVERE ATOPIC DERMATITIS1 AbbVie has announced the availability in Ireland of upadacitinib, an oral, selective and reversible Janus Kinase (JAK) inhibitor, for the treatment of moderate to severe atopic dermatitis in adults and adolescents 12 years and older who are candidates for systemic therapy. This is now available to prescribe via the HSE-Medicines Management Programme under a HSE-Managed Access Protocol.

On August 24 last, the European Commission (EC) approved a recommended dose of upadacitinib for atopic dermatitis in adults of 15 mg or 30 mg once daily based on individual patient presentation, and 15 mg once daily for adolescents (12-17 years of age) and adults 65 years and older. Upadacitinib can be used with or without topical corticosteroids (TCS).

The EC approval was supported by data from one of the largest registrational Phase 3 programs in atopic dermatitis with more than 2,500 adults and adolescents with moderate to severe disease These studies evaluated the efficacy and safety of upadacitinib monotherapy (Measure Up 1 [MU1] and Measure Up 2 [MU2]) and with topical corticosteroids (AD Up [AU]) compared to placebo. In all three studies, the co-primary endpoints were at least a 75 percent improvement in the Eczema Area and Severity Index (EASI 75) and validated Investigator's Global Assessment for Atopic Dermatitis (vIGA-AD) score of 0/1 (clear or almost clear) at week 16.

atopic dermatitis patients in Ireland.

The degree and early onset of skin clearance and itch relief in the upadacitinib Phase 3 clinical studies are very encouraging.

AbbVie’s Irish General Manager Andres Rodrigo said: “I very much welcome the HSE’s timely approval of upadacitinib for patients with atopic dermatitis, which is a highly debilitating condition with limited therapeutic options currently.

Ireland will be among the first European countries to provide access to upadacitinib for atopic dermatitis, which was approved by the EMA in August 2021.

“It will provide significant improvement to patient’s quality of life, impacting positively on both their physical and psychological well-being.1 Our company’s Irish employees support the manufacture of upadacitinib for global supply, and it is very encouraging that locally made innovation is being made available to Irish citizens.” * The recommended dose of upadicitinib is 15mg once daily for adolescents weighing at least 30kg. The safety and efficacy of RINVOQ in children with atopic dermatitis below the age of 12 years have not been established.

No data are available. No clinical exposure data are available in adolescents <40kg. The posology in adolescent patients 30kg to <40kg was determined using population pharmacokinetic modelling and simulation. **Reimbursement of RINVOQ on the High-Tech Arrangement under a managed access protocol is confined to the treatment of moderate-to-severe refractory AD in adults and adolescents 12 years and older for whom immunosuppressant treatment has failed or is not tolerated or is contraindicated. The prescribing of RINVOQ under the High-Tech

Alan Irvine, Professor of Dermatology, Trinity College Dublin, Ireland, who was a upadacitinib clinical study investigator, welcomed the availability of a new treatment option for Irish patients with atopic dermatitis.

Arrangement is confined to consultant dermatologists who have agreed to the terms of the HSE-Managed Access Protocol and have been approved by the HSE-Medicines Management Programme.

He stated: “Eczema is a chronic relapsing inflammatory skin disease, characterised by intense itch, dry skin and typically distributed skin lesions. The burden experienced by patients and their care-givers is significant, with chronic itch and sleep disturbance, negatively affecting overall quality of life.

References are available on request

“Clinicians need more tools to help them treat and manage this complex disease. It is very welcome to now have an additional treatment option in upadacitinib available for moderate to severe

NEW COUNTRY MANAGER FOR NEURAXPHARM Neuraxpharm Group (Neuraxpharm), a leading European specialty pharmaceutical company focused on the central nervous system (CNS), has announced that Tom Coogan has been appointed Country Manager for Ireland.

The appointment reinforces Neuraxpharm’s management team in Ireland with an experienced executive who will focus on

APRIL 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

establishing Neuraxpharm as CNS specialist in the north-western European country.

With Tom Coogan, Neuraxpharm can rely on a dedicated entrepreneur with highly relevant market expertise. He has a proven track record in successfully building the Ireland business of Grünenthal Pharma Ltd (Grünenthal) to become a leading player in Ireland in the field of pain management and related diseases.

At Neuraxpharm, he will focus on advancing the company’s position in Ireland by applying his profound expertise of the Irish market to strategically grow the business further and ensure the successful development of the product portfolio in line with the Group’s.

Tom Coogan combines a strong start-up mind-set with nearly thirty years of experience in the pharmaceutical industry. He joins Neuraxpharm from Grünenthal, where he most recently served as Managing Director. Since 2004, he has successfully built Grünenthal’s Ireland business to become a top 20 ranked Pharma Company in Ireland. Tom Coogan was National Sales Manager at Lundbeck Ireland from 2001 to 2004, having previously held positions as a CNS Hospital Specialist at Organon from 1999 to 2001 and as a Hospital Representative at Upjohn from 1993 to 1998.

Dr. Jörg-Thomas Dierks, CEO of Neuraxpharm, commented: "We are very pleased to announce the appointment of Tom Coogan as our new Country Manager for Ireland. We are certain that with his experience and hands-on mentality, Tom will help us elevate our business in Ireland to the next level. I am looking forward to working with him and to jointly expanding our position as the leading CNS company with a broad and diverse portfolio."

Tom Coogan, newly appointed Country Manager for Ireland added: "I am excited to join Neuraxpharm as Country Manager. With its acquisition of Medinutrix in 2020, Neuraxpharm has become a serious player in Ireland. I look forward to working with my new team and to making available all of my expertise to further expand our business."

Neuraxpharm has established its operations in Ireland in December 2020 through the acquisition of the specialty pharmaceutical company Medinutrix (trading as Aribamed) and will leverage its CNS expertise to provide access to suitable products out of its extensive portfolio, including the recently acquired Buccolam® for emergency treatment of epileptic children and adolescents. Tom

Coogan will be taking over from Craig Bowen, who will concentrate on his position as Neuraxpharm UK’s General Manager going forward.

RCSI TO MAKE PHYSICIAN ASSOCIATE STUDIES COURSE AVAILABLE IN HYBRID FORMAT RCSI University of Medicine and Health Sciences has announced a pilot hybrid version of its Physician Associate Studies course, to commence in January 2023. The aim of the pilot is to encourage a wider distribution of physician associates nationally.

Previously, enrolment in Physician Associate Studies at RCSI required students to be based in the Dublin area. With the new hybrid programme, students have the option of training in local communities anywhere in Ireland and attending lectures online.

On-campus attendance would only be required for certain activities such as the induction programme and 2 days per month for skills training sessions.

The MSc in Physician Associate Studies was launched by RCSI in 2016 and is the only programme of its kind in Ireland. Highly-skilled healthcare professionals, physician associates provide a broad range of medical services in a wide variety of workplaces (including all types of hospital and surgical care, GP practices and community health services).

Working collaboratively with the entire medical team, physician associates are trained to perform history and physical exams, order and interpret appropriate investigations, establish diagnoses and propose treatment plans. There are now 46 physician associates working in Irish healthcare.

While all physician associate students hold a foundation degree in health science or a sciencerelated area, they come from a diverse range of backgrounds from healthcare to academia.

Professor Lisa Alexander, Director of Physician Associate Studies at RCSI, welcomed the new learning model, saying: “In designing the new remote/hybrid model for Physician Associate Studies, our priority is to ensure the equivalent educational experience as our Dublin based course, while also providing flexibility for prospective students.

“This new format will allow eligible students to remain in their home communities to complete the programme, thus making it more accessible, while also promoting a new philosophy of partnering with local communities to grow their health workforce locally.”

81 Joining the hybrid programme is subject to successful completion of the admissions process and commitment and confirmation from clinical partners of local placements in hospitals and GP settings.

To learn more about Physician Associate Studies and the new remote learning option, visit the RCSI website.

EARLY SCREENING FOR KIDNEY DISEASE World Kidney Day which was celebrated on 10th March 2022 aims to bridge the knowledge gap to better kidney care. To mark World Kidney Day, the Irish Kidney Association (IKA), in association with the HSE’s National Renal Office (NRO), ran an awareness campaign to highlight the importance of early screening for Chronic Kidney Disease (CKD).

Diabetes Ireland is supporting the campaign to ensure that the core messaging about looking after your kidneys reaches one of the most common at-risk groups, i.e., people living with diabetes.

Chronic Kidney Disease (CKD) significantly increases the risk of negative outcomes in people living with diabetes, cardiovascular disease and high blood pressure

amongst other health conditions.

The IKA’s campaign aims to highlight that it is possible to prevent or slow down the progression of kidney disease through lifestyle changes and medication and that it all starts with simple blood and urine tests done through your GP to measure and monitor your kidney health.

The tagline message for the Irish Kidney Association’s campaign is ‘We’re Counting on You’. This represents the importance for the public to be proactive in managing their kidney health and that they are being ‘counted on’ to get a simple blood test and urine test which will reveal their kidney function ‘numbers’. These ‘numbers’ will represent how well the kidneys are functioning in filtering blood and removing waste from the body. If Chronic Kidney Disease (CKD) is detected early enough, its progression, through the five stages of CKD, can be slowed down supporting better patient outcomes.

Risk factors towards developing Chronic Kidney Disease (CKD) include o Diabetes o Hypertension (High blood pressure)

o Cardiovascular Disease o Cancer o Liver conditions o Autoimmune diseases o Pre-eclampsia o Obesity o Family health history of kidney disease o Aged over 50 o Long term use of over-thecounter medications In backing the Irish Kidney Association’s campaign for kidney health screening Prof. George Mellotte, the National Clinical Lead for Renal Services stated, “People with Chronic Kidney Disease are medically vulnerable to the effects of high blood pressure, diabetes and cardiovascular disease. It is important that people with Chronic Kidney Disease are identified so that they can seek the appropriate treatment in a timely manner".

Speaking in advance of World Kidney Day 2022, Ms. Carol Moore, Chief Executive, Irish Kidney Association said, “as there is no public health screening programme for kidney disease in Ireland, we hope that the ‘Counting On You’ awareness campaign to mark World Kidney

Day will encourage the public to take action to look after their kidney health. We are pleased that the National Renal Office is endorsing the campaign and are delighted to be working closely with Diabetes Ireland to highlight the importance of kidney health screening as diabetes is one of the main risk factors for chronic kidney disease”.

The success of the campaign is also reliant on the valued support of healthcare professionals including GPs and Pharmacists.

The Irish Pharmacy Union is supporting the campaign through sharing its message on its digital and print platforms. Some independent pharmacy chains are also promoting the campaign to their customers. The collaboration between all these interest groups in supporting the campaign is an indicator of the importance of monitoring kidney health.

For more information www.ike.ie/kidneyhealth, www.worldkidneyday.org and www.diabetes.ie Patients attending the event included Rachel O'Hora who lives in Seapoint Dublin (a native of Mayo) who is awaiting a combined kidney and pancreas transplant and Raymond O'Brien, from Salthill in Galway, who like Rachel is also living with Type 1 diabetes but has undergone a kidney transplant. He attended the photocall with his wife Ethna and three children including 9 year old twins Jack and Amy and 11 year old Isabel.

HOSPITALPROFESSIONALNEWS.IE | HPN • APRIL 2022

82 Clinical R&D HEALTH AND SAFETY EXECUTIVE (HSE) APPROVES ADTRALZA®

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LEO Pharma welcomes the news that the Health Service Executive (HSE) has approved tralokinumab for reimbursement in Ireland via the High-Tech Scheme.3 This approval makes tralokinumab the first reimbursed biologic that specifically targets the IL-13 cytokine alone, a driver of atopic dermatitis signs and symptoms, for use within Ireland.1,2,3 Tralokinumab is the first high affinity, human monoclonal antibody developed to specifically bind to and inhibit the IL-13 cytokine in adult patients with uncontrolled moderate-tosevere atopic dermatitis who are candidates for systemic therapy.1,2 Tralokinumab is available in a 150 mg/mL prefilled syringe for subcutaneous injection with an initial dose of 600 mg followed by 300 mg every other week.7 Tralokinumab can be used with or without topical corticosteroids (TCS).7 “I am delighted that patients with moderate-to-severe Atopic Dermatitis in Ireland will now have access to tralokinumab, an important new treatment option for these patients.

Atopic Dermatitis is much more than a skin condition, it can have a profound effect on the emotional and psychological wellbeing of patients, as well as on their physical health,” said Professor Alan Irvine, Consultant Dermatologist, School of Medicine Trinity College Dublin.

The evidence supporting the efficacy and safety of tralokinumab comes from four randomised, multicentre, doubleblind, placebo-controlled, phase III studies: ECZTRA 1, ECZTRA 2, ECZTRA 3 in patients with moderate-to-severe atopic dermatitis and ECZTRA 7 in patients with severe disease.4,5,6

Tralokinumab was approved by the European Commission (EC) for adults with moderate-tosevere atopic dermatitis who are candidates for systemic therapy in Europe and by the Medicines & Healthcare products Regulatory Agency (MHRA) in Great Britain, in June 2021. The MHRA and EC decisions are valid in the UK and all European Union Member States, Iceland, Norway, and Liechtenstein. Tralokinumab is also approved for use in Canada, the United Arab Emirates and was approved by the U.S. Food and Drug Administration (FDA) on the 27th December 2021.

References on request

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SPRAVATO® (ESKETAMINE) NASAL SPRAY APPROVED The Janssen Pharmaceutical Companies of Johnson & Johnson has announced that SPRAVATO® (esketamine) nasal spray has been granted reimbursement in Ireland for the treatment of adults living with treatment-resistant major depressive disorder (TRD), in combination with a selective serotonin reuptake inhibitor (SSRI) or serotonin and norepinephrine reuptake inhibitor (SNRI). People are considered to have TRD if they have not responded to at least two different treatments with antidepressants in the current moderate-to-severe depressive episode.1

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Ireland has one of the highest rates of mental illness in Europe and it is estimated that approximately 150,000 people per year are living with severe depression (also known as Major Depressive Disorder or MDD) here.2,3 Major Depressive Disorder (MDD), the underlying disorder associated with Treatment Resistant Depression (TRD), is a severely debilitating psychiatric disorder. For these patients, the main goal of treatment is to relieve the symptoms of depression, and ultimately achieve remission,

ACCORD HEALTHCARE LAUNCH ICATIBANT ACCORD 30 MG SOLUTION FOR INJECTION IN 3 ML PRE-FILLED SYRINGE Accord Healthcare is delighted to announce the launch of another High-Tech medicine to their already extensive portfolio of High-Tech medicines: Icatibant Accord 30 mg which comes in a pack of one 3 ml pre-filled syringe.

This medicine is indicated for symptomatic treatment of acute attacks of hereditary angioedema (HAE) in adults, adolescents and children aged 2 years and older, with C1-esterase-inhibitor deficiency.

Please refer to the Summary of Product Characteristics (SPC) for further information. The SPC will be available from the launch date at www. hpra.ie and for Healthcare Professionals at www.accord-healthcare.ie.

Icatibant Accord will be available from both full-line wholesalers from launch. For further information please contact Accord in Cork on 021461 9040 or visit www.accord-healthcare.ie Think High-Techs, Think Accord

APRIL 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

with few, if any, symptoms of depression remaining.4 However, about one third of people with MDD do not respond to currently available treatments.5

Further prescribing information can be found at https://www. medicines.ie/medicines/ spravato-28-mg-nasal-spraysolution-35070/spc

The approval of esketamine is based on data from a clinical trial programme in patients with TRD, including over 1,600 patients treated with esketamine.

The five Phase 3 trials included three short-term studies, one randomised withdrawal and maintenance of effect study, and one long-term safety study.6,7,8,9,10* These data demonstrated that treatment with esketamine nasal spray plus a newly initiated oral antidepressant was associated with a greater reduction in depressive symptoms compared to a newly initiated oral antidepressant plus placebo nasal spray, in adult patients (18-64 years), with the onset of efficacy as early as Day 2.6 Approximately 70 percent of esketaminetreated patients responded to treatment, with a ≥50 percent symptom reduction. Furthermore, approximately half of all treated patients achieved remission at the end of the 4 week studies.1 Continued treatment with esketamine nasal spray plus oral antidepressant reduced the risk of relapse by 70 percent among patients with stable response and by 51 percent in patients in stable remission, compared to continuing treatment with oral antidepressant alone.9

References on request

The decision to prescribe esketamine should be determined by a psychiatrist.1 Esketamine is intended to be self-administered by the patient under the direct supervision of a healthcare professional.1 A treatment session consists of nasal administration of esketamine and a postadministration observation period.

Both administration and post -administration observation of esketamine should be carried out in the appropriate clinical setting.1

BAYER’S NEW TREATMENT KERENDIA® (FINERENONE) APPROVED IN EU The European Commission has granted marketing authorization in the European Union (EU) for finerenone under the brand name Kerendia®. Kerendia® (10 mg or 20 mg), a non-steroidal, selective mineralocorticoid receptor antagonist, is indicated for the treatment of chronic kidney disease (stage 3 and 4 with albuminuria) associated with type 2 diabetes in adults.

Finerenone is different to existing CKD in T2D treatments. It acts by blocking mineralocorticoid receptor (MR) overactivation, which is thought to contribute to CKD progression and cardiovascular damage.

“The worrying reality is that chronic kidney disease in type 2 diabetes is the leading cause of end-stage kidney disease, which ultimately means that the kidneys no longer support the body’s needs and patients need dialysis or a kidney transplant to stay alive.

Early intervention is associated with a better prognosis, and it is key to prevent further end-organ damage by reducing the risk of kidney function loss,” said Dr. Michael Devoy, Chief Medical Officer and Head of Medical Affairs and Pharmacovigilance at Bayer’s Pharmaceuticals Division.“The approval of Kerendia offers physicians a new path to protect these vulnerable patients by reducing their risk of cardiovascular events and delaying kidney disease progression.”

The approval of Kerendia in the EU is based on the results of the pivotal Phase III FIDELIO-

83 DKD study, presented at the American Society of Nephrology’s (ASN) Kidney Week 2020 and simultaneously published in the New England Journal of Medicine (NEJM) in October 2020.

In July 2021, Kerendia was approved by the U.S. Food and Drug Administration (FDA) based on the positive results of the FIDELIO-DKD Phase III study. In December 2021, Kerendia received a Grade A recommendation in the new treatment guidelines of the American Diabetes Association (ADA), “Standards of Medical Care in Diabetes 2022” for the treatment of patients with CKD and T2D who are at increased risk for cardiovascular events or CKD progression or are unable to use a sodium-glucose cotransporter 2 inhibitor.

Finerenone has also been submitted for marketing authorization in multiple other countries worldwide and these are currently under review.

LENALIDOMIDE CLONMEL Clonmel Healthcare is delighted to announce the launch of Lenalidomide Clonmel 5mg, 10mg, 15mg, 20mg, 25mg hard capsules.

Lenalidomide Clonmel is indicated for the treatment of multiple myeloma, myelodysplastic syndromes, mantle cell lymphoma and follicular lymphoma.

Lenalidomide is structurally related to thalidomide, which is a known human teratogen that causes severe life-threatening

birth defects. An unborn child is likely to be harmed if exposed to lenalidomide during pregnancy, therefore a pregnancy prevention programme (PPP) is in place for all lenalidomide products and applies to all patients prescribed lenalidomide.

In order to support HCPs in fulfilling the requirements of the lenalidomide PPP, Clonmel Healthcare in collaboration with a number of other Marketing Authorisations Holders, has created an online platform called the Patient Safety Hub (PSH) which may be used by prescribers and pharmacies.

It is available at www.patientsafetyhub.ie. A user guide and training videos on use of the PSH are also available to access via the hub.

Full prescribing information is available on request or alternatively please go to www.clonmel-health. ie. Medicinal product subject to medical prescription.

Please contact Clonmel Healthcare on 01-6204000 if you require any additional information.

PA 126/320/002, 004-007. PA Holder: Clonmel Healthcare Ltd., Clonmel, Co. Tipperary. Date prepared: February 2022. 2022/ ADV/LEN/030H. EC MSRKETING AUTHORISATION FOR JARDIANCE® Empagliflozin (Jardiance®) has been granted a marketing authorisation by the European Commission (EC) for the treatment

of adults with symptomatic chronic heart failure.[i] With this latest approval, empagliflozin becomes the first and only clinically proven treatment that can significantly improve outcomes for adults across the full spectrum of symptomatic chronic heart failure, which includes heart failure with preserved ejection fraction (HFpEF).

What does this new approval mean for the heart failure clinical landscape?

• Until now, there were no approved and clinically effective treatments that address all forms of heart failure, including HFpEF, which has previously been described as the single largest unmet need in cardiovascular medicine.[i],[ii] • Heart failure is one of the leading causes of avoidable hospitalisations, and readmissions to hospital among people with heart failure leads to poor survival.[iii],[iv],[v] • Marketing authorisation was granted based on data from the landmark EMPEROR-Preserved Phase III clinical trial, the first of its kind to significantly show a relative reduction in the composite primary endpoint of cardiovascular death or hospitalisation for heart failure with empagliflozin, compared to placebo, on top of standard of care in patients with HFpEF.[vi] • This marketing authorisation is valid in all EU member states, including the Republic of Ireland.

Neil Johnson, CEO of Croí, Irish patient organisation fighting against heart disease and stroke, and Executive Director of the Global Heart Hub says, “It’s estimated that over 60 million people worldwide are living with heart failure. This complex medical condition very often has a devastating impact on quality of life: physically, emotionally and even financially for those who can no longer work. New treatments for a heretofore underserved population of patients which can improve outcomes and reduce hospital admissions is just great news for patients. The impact of new and emerging treatments on quality of life, from a patient and carer perspective, cannot be overstated because they provide hope and comfort in the knowledge that heart failure can be treated. This in turn has an enormously positive impact on overall mental health and wellbeing by decreasing anxiety, stress and worry.”

The UK authorisation by the Medicines and Healthcare Products Regulatory Agency (MHRA) is anticipated to follow in the coming months. Do let us know if the MHRA announcement will be of interest to cover, as we will have a suite of interview slots available including: people living with heart failure, patient group representatives, healthcare professionals working in the field and a spokesperson from Boehringer Ingelheim.

References on request

NEW – GLUCORX AIDEX - CONTINUOUS GLUCOSE MONITOR Windzor Pharma are delighted to announce the launch of GlucoRX Aidex to the Irish Market. Aidex is a continuous Glucose Monitor available for all patient types.

The sensors are small and secure and can be used on the arm or the abdomen. Each transmitter has a lifespan of 3 years and each sensor lasts up to 14 days. All data is submitted from the sensor to the GlucoRx Aidex app making it easy to track your glucose levels during the day.

For more information, training or to order please contact orders@windzorpharma.com Transmitters and sensors are available through UDW and Uniphar and PCO. Sensor GMS code 85241

HOSPITALPROFESSIONALNEWS.IE | HPN • APRIL 2022

HELP YOUR PATIENTS

THE ITCH & RASH OF MODERATE TO SEVERE ATOPIC DERMATITIS 1 RINVOQ demonstrated in an integrated analysis of the MEASURE UP 1 & 2 monotherapy studies at Week 16: • EASI 75 skin clearance rates of 76% and 65% for patients treated with RINVOQ 30 mg QD and 15 mg QD, respectively, vs 15% with placebo (p<0.001 for both comparisons)2 • Itch reduction (mean percent change from baseline in Worst Pruritus NRS) of –70% and –58% for RINVOQ 30 mg QD and 15 mg QD, respectively, vs –24% with placebo (p<0.001 for both comparisons)2

RINVOQ, the first and only oral JAK inhibitor indicated for the treatment of both

adults and adolescents ≥12 years* with moderate to severe Atopic Dermatitis in the EU2-4 PRESCRIBING INFORMATION (PI) RINVOQ® (upadacitinib) 15 mg and 30mg prolonged-release tablets.

Refer to Summary of Product Characteristics (SmPC) for full prescribing information. PRESENTATION: Each 15 mg prolonged-release tablet contains upadacitinib hemihydrate, equivalent to 15mg of upadacitinib. Each 30mg prolonged-release tablet contains upadacitinib hemihydrate, equivalent to 30 mg of upadacitinib. INDICATION: Treatment of moderate to severe active rheumatoid arthritis (RA) and active psoriatic arthritis (PsA) in adult patients who have responded inadequately to, or who are intolerant to one or more disease-modifying anti-rheumatic drugs (DMARDs). RINVOQ may be used as monotherapy or in combination with methotrexate. Treatment of active ankylosing spondylitis (AS) in adult patients who have responded inadequately to conventional therapy. Treatment of moderate to severe atopic dermatitis (AD) in adults and adolescents 12 years and older who are candidates for systemic therapy. DOSAGE AND ADMINISTRATION: Intended for use under guidance and supervision of a physician experienced in diagnosis and treatment of conditions for which upadacitinib is indicated. Dosage: RA, PsA and AS: The recommended oral dose is 15mg once daily. Consideration should be given to discontinuing treatment in patients with AS who have shown no clinical response after 16 weeks of treatment. Some patients with initial partial response may subsequently improve with continued treatment beyond 16 weeks. AD (adults): The recommended oral dose is 15 mg or 30 mg once daily based on individual patient presentation. 30 mg once daily dose may be appropriate for patients with high disease burden and for patients with an inadequate response to 15 mg once daily. The lowest effective dose for maintenance should be considered. For patients ≥ 65 years of age, the recommended dose is 15mg once daily. AD (adolescents from 12 to 17 years): The recommended oral dose is 15mg once daily for adolescents weighing at least 30 kg. Adults and adolescents 12 years and older: Upadacitinib can be used with or without topical corticosteroids. Topical calcineurin inhibitors may be used for sensitive areas such as the face, neck, and intertriginous and genital areas. Consideration should be given to discontinuing upadacitinib treatment in any patient who shows no evidence of therapeutic benefit after 12 weeks of treatment. Special Populations: Elderly: For AD, doses higher than 15mg once daily not recommended in patients aged 65 years and older. Limited data for patients aged 75 and older. Renal: No dose adjustment required in mild-moderate renal impairment. Upadacitinib 15mg once daily should be used with caution in patients with severe renal impairment.

Upadacitinib 30 mg once daily is not recommended for patients with severe renal impairment. Upadacitinib has not been studied in subjects with end stage renal disease. Hepatic impairment: No dose adjustment is required in patients with mild (Child Pugh A) or moderate (Child Pugh B) hepatic impairment. Should not be used in patients with severe (Child Pugh C) hepatic impairment. Paediatric Population: No data available in the following paediatric patient populations: children with AD below the age of 12 years; children and adolescents with RA, PsA and AS aged 0 to less than 18 years. CONTRAINDICATIONS: Hypersensitivity to active substance or excipients. Active tuberculosis (TB) or active serious infections. Severe hepatic impairment. Pregnancy. SPECIAL WARNINGS AND PRECAUTIONS: See SmPC for full details. Immunosuppression: Combination use, with immunosuppressants e.g. azathioprine, ciclosporin, tacrolimus, and biologic DMARDs or other JAK inhibitors has not been evaluated in clinical studies and is not recommended as the risk of additive immunosuppression cannot be excluded. Serious infections: Serious and fatal infections have been reported. Caution when treating patients ≥65 years. Frequently reported – pneumonia and cellulitis. Bacterial meningitis has been reported. Opportunistic infections reported – TB, multidermatomal herpes zoster, oral/oesophageal candidiasis, and cryptococcosis. Do not initiate treatment in patients with active, serious infection, including localised infections. Consider the risk/benefit of treatment in patients with: chronic or recurrent infection, history of serious or opportunistic infection, those exposed to TB, those who have resided or travelled in areas of endemic TB or endemic mycoses, those with underlying conditions that may pre-dispose patients to infection. Closely monitor patients and interrupt treatment if there are signs and symptoms of infection pre and post treatment. Tuberculosis: Pre-screen patients for active or latent TB. RINVOQ should not be given to patients with active TB. Consider anti-TB therapy in patients with previously untreated latent TB or in patients with risk factors for TB infection. Consult with a physician with experience in TB therapy to assess whether initiating anti-TB therapy is appropriate for an individual patient. Monitor patients for the development of signs and symptoms of TB, including patients who tested negative for latent TB infection prior to initiating therapy.

Viral reactivation: Cases of herpes virus reactivation have been reported e.g. herpes zoster. If herpes zoster is reactivated, consider interruption of upadacitinib therapy until the episode resolves. Screen for viral hepatitis and monitor regularly for reactivation before starting and during therapy with upadacitinib. Patients, positive for hepatitis C antibody/hepatitis C virus RNA and hepatitis B surface antigen/hepatitis B virus DNA were excluded from clinical studies. If hepatitis B virus DNA is detected while receiving RINVOQ, a liver specialist should be consulted. Vaccination: Use of live, attenuated vaccines during or immediately prior to therapy is not recommended. It is recommended that patients be brought up to date with all immunisations, including

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prophylactic zoster vaccinations prior to starting therapy, in agreement with current immunisation guidelines.

Malignancy: Immunomodulatory therapies may increase the risk of malignancies including lymphoma and nonmelanoma skin cancer in RA patients. Malignancies were observed in clinical studies. Periodic skin examination recommended for patients who are at increased risk for skin cancer. See SmPC for full details. Haematological abnormalities: Do not start therapy if Absolute Neutrophil Count <1 x 109 cells/L, Absolute Lymphocyte Count <0.5 x 109 cells/L and Hb <8 g/dL. Monitor patients and temporarily stop therapy if abnormal haematological parameters as specified are detected during routine patient management. Diverticulitis: Events of diverticulitis have been reported in clinical trials and post-marketing. Upadacitinib should be used with caution in patients with diverticular disease and especially in patients chronically treated with concomitant medications associated with an increased risk of diverticulitis. Patients presenting with new onset abdominal signs and symptoms should be evaluated promptly for early identification of diverticulitis to prevent gastrointestinal perforation. Cardiovascular Risk: RA patients have an increased risk for cardiovascular disorders. Manage patient’s risk factors for e.g. hypertension, hyperlipidaemia as per usual standard of care. Lipids: Monitor total cholesterol, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) at 12 weeks and thereafter according to international guidelines. Elevated LDL in clinical trials decreased to pre-treatment levels in response to statin therapy, although evidence is limited. The effect of these lipid parameter elevations on cardiovascular morbidity and mortality has not been determined.

Hepatic transaminase elevations: Monitor liver enzymes at baseline and thereafter according to routine patient management. Prompt investigation of the cause of liver enzyme elevation is recommended to identify potential cases of drug-induced liver injury. In such cases therapy should be interrupted until this diagnosis is excluded.

Venous thromboembolism: Deep vein thrombosis (DVT) and pulmonary embolism (PE) have been reported in patients receiving JAKi, including upadacitinib. Use therapy with caution in patients at high risk for DVT/PE. Risk factors should be determined by patients age, obesity and medical history of DVT/PE, patients undergoing major surgery and prolonged immobilisation. If clinical features of DVT/PE occur discontinue therapy, evaluate and treat promptly. INTERACTIONS: Upadacitinib is metabolised mainly by CYP3A4 and plasma exposures may be affected

by CYP3A4 inhibitors or inducers. Upadacitinib 15 mg once daily should be used with caution in patients receiving chronic treatment with strong CYP3A4 inhibitors. Upadacitinib 30 mg once daily dose is not recommended for patients receiving chronic treatment with strong CYP3A4 inhibitors. See SmPC for full details. FERTILITY, PREGNANCY AND LACTATION: Upadacitinib is contraindicated during pregnancy. Women of childbearing potential should be advised to use effective contraception during treatment and for 4 weeks following the final dose of upadacitinib. Female paediatric patients and/or their parents/caregivers should be informed about the need to contact the treating physician once the patient experiences menarche while taking upadacitinib.

Upadacitinib should not be used during breast-feeding. The effect of upadacitinib on human fertility has not been evaluated. ADVERSE REACTIONS: Refer to SmPC for full details on adverse reactions. Very common adverse reactions (≥1/10): upper respiratory tract infections, acne. Common adverse reactions (≥1/100 to <1/10): bronchitis, herpes zoster, herpes simplex, folliculitis, influenza, anaemia, neutropaenia, hypercholesterolaemia, cough, abdominal pain, nausea, urticaria, fatigue, pyrexia, increased blood CPK/ALT/AST, increased weight and headache.

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance; website: www.hpra.ie.

LEGAL CLASSIFICATION: POM (S1A). MARKETING AUTHORISATION NUMBER/ PRESENTATION: EU/1/19/1404/001 and EU/1/19/1404/006 – Calendar blister packs containing 28 prolonged-release tablets. MARKETING AUTHORISATION HOLDER: AbbVie Deutschland GmbH & Co. KG, Knollstrasse, 67061 Ludwigshafen, Germany.

Further information is available from AbbVie Limited, 14 Riverwalk, Citywest Business Campus, Dublin 24, Ireland.

DATE OF REVISION: December 2021. PI-1404-005 Abbreviations: EASI – eczema activity and severity index; NRS – numerical rating scale; QD – once daily; EU – European Union. * The recommended dose of RINVOQ is 15mg once daily for adolescents weighing at least 30kg. The safety and efficacy of RINVOQ in children with atopic dermatitis below the age of 12 years have not been established. No data are available. No clinical exposure data are available in adolescents <40kg. The posology in adolescent patients 30kg to <40kg was determined using population pharmacokinetic modelling and simulation.2 Reference: 1. Langan S. et al. Atopic dermatitis. The Lancet. 2020;396(10247):345-360. DOI: https://doi.org/10.1016/ S0140-6736(20)31286-1. 2. RINVOQ Summary of Product Characteristics, available on www.medicines.ie 3. Baricitinib Summary of Product Characteristics, available on www.medicines.ie 4. Abrocitinib Summary of Product Characteristics, available on www.medicines.ie

IE-RNQ_AD-220017 | February 2022