HPN 2022 July

HOSPITAL PROFESSIONAL NEWS IRELAND

HPN July 2022 Issue 98 HOSPITALPROFESSIONALNEWS.IE

Ireland’s Dedicated Hospital Professional Publication

IN THIS ISSUE: NEWS: Recognising the contribution of women doctors Page 5

50mgs once daily

50mgs once daily

REPORT: EAHP Annual Congress in Vienna Page 8

Her 10th shopping trip since the day she started BETMIGA1

FEATURE: Updates in the Diagnosis of COPD Page 18 CONFERENCE: Irish College of Opthalmologists Page 22

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.

10988_Betmiga_SHOPPING_A4_MAY19_01.indd 1

This Publication is for Healthcare Professionals Only

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

10/07/2019 16:41

CPD: Management of Melanoma Page 31 ENDOCRINOLOGY FOCUS: Polycystic Ovary Syndrome Page 35 FEATURE: Proximal Aortic Aneurysm Page 72

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.

July Issue Issue 98

3

Contents

Foreword

Medical Council recognises role of women doctors P5

Editor Minister for Health Stephen Donnelly published the Sláintecare Action Plan for 2022 last month, but was met with criticism in doing so.

New President for RCSI P6 Hospital pharmacists gather at EAHP 2022 Congress P8

The Irish Hospital Consultants Association who have voiced their concerns that the Plan for 2022 was issued almost six months into the year – an increasing trend that the Minister and Department of Health must reverse, they said.

5

Ireland’s spending on medicines ‘stable’ P12

“Last week marked 5 years since the Government launched Sláintecare, yet at the halfway point of the 10-year plan, we are faced with a health service, staff and patients who are suffering more than ever,” said a spokesperson. Turn to page 5 to read the full story.

An overview of Benign Prostatic Hyperplasia P16 Latest developments in eye care discussed at ICO Conference P22

8

New Microbiota Research Could Lift the Fog on Chemobrain P26 REGULARS CPD: Melanoma P31 Endocrinology Focus: Nutrition, Obesity and Cancer P38

22

Her statement comes timely on the heels of the news that the Royal College of Surgeons in Ireland has announced the election of Professor Laura Viani as the new President of the College, with Professor Deborah McNamara as Vice President – a first in the College’s history as two females take up office together.

Endocrinology Focus: Obesity and available Treatments P50 Endocrinology Focus: Hypothyroidism P53 Feature: Proximal Aportic Aneurysm P72

You can read more about these appointments on page 6.

22

Clinical R&D: P80 Hospital Professional News is a publication for Hospital Professionals and Professional educational bodies only.

EDITORIAL editorial@hospitalprofessionalnews.ie

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.

ACCOUNTS Rachel Wilson cs.ipn@btconnect.com

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

In other news, the Irish Medical Council marked International Womens Day by recognising the continued and increasing contribution of women doctors to the medical landscape in Ireland.

“While the number of female doctors on the register is increasing, particularly among younger doctors, there is still work to be done in forging gender parity in the profession. Gender balance is not solely a women's issue, but also an economic issue, and improving the situation for female medics will positively affect patients,” says President Dr Suzanne Crowley.

CONTRIBUTORS

Dr Sinead Walsh | Dr Padraic Ridge Dr Emma Porter | Saleem Jahangeer Michael W. O’Reilly | Helen M. Roche Dr Sarah Cooney | Dr Kate Gajewska Clair Naughton | Dr Karl Neff Dr Shane Cullinan | David Fitzgerald Mary Higgins | Ciara Coveney Catherine Chambers | Recie Davern Ayyad Alruwaily | Heshma Alruwaili John Garvey | Dr Paul Cornes Theresa Lowry-Lehnen Kathleen A.J. Mitchelson Professor Carel Le Roux Lauren Madden Doyle

DESIGN DIRECTOR Ian Stoddart Design

HOSPITALPROFESSIONALNEWS.IE

@HospitalProNews HospitalProfessionalNews

Meanwhile, hospital pharmacists recently gathered European Association of Hospital Pharmacists Congress in Vienna. This was the first in-person event for the Association since the Covid-19 pandemic started. Joan Peppard, previous President of EAHP discusses the emerging themes and topics covered alongside y Gonzalo Marzal López EAHP Project Portfolio Manager.

One in ten people around the world are living with diabetes, a lifelong condition listed by the World Health Organisation in 2019 as one of the top ten leading causes of deaths globally.

The condition is just one of a number of those covered in our Endocrinology Special Focus for this issue, including Dr Kate Gajewska who writes about accessing diabetes technology in Ireland, Dr Karl Neff writing about the current available treatments for obesity and Dr Shane Cullinan who gives readers an overview of hypothyroidism: a reminder of the often forgotten intricacies.

I hope you enjoy the issue.

HOSPITAL PROFESSIONAL NEWS IRELAND Ireland’s Dedicated Hospital Professional Publication

HOSPITALPROFESSIONALNEWS.IE | HPN • JULY 2022

4

News

New Appointment at HPRA The Health Products Regulatory Authority (HPRA) has announced the appointment of Dr Finnuala Lonsdale as Director of Human Product Authorisation and Registration. Dr Lonsdale will provide strategic and operational leadership to the Human Product Authorisation and Registration Department and will work closely with the management team to oversee the assessment of human clinical trials and registrations or variations of human medicinal products activities of the HPRA. Dr Lonsdale trained as a medical doctor in South Africa undergoing further specialist medical training in South Africa, Canada and the United Kingdom.

She also holds a master’s degree in Business Administration as well as postgraduate qualifications in Clinical Pharmacology, Alliance Management and Regulatory Practice.

Dr Lonsdale has clinical experience both in the tropics and in the circumpolar regions and administrative experience as the Chief of Medical Staff for a Canadian Regional Healthcare Authority.

Since 2002 Dr Lonsdale has primarily been involved in pharmaceutical medicine, firstly as a clinical investigator and then during a 10-year period at AstraZeneca in the governance of clinical trials and in particular strategic alliances conducting clinical trials. She holds the Diploma in Pharmaceutical Medicine and is a Fellow of the Faculty of Pharmaceutical Medicine in the United Kingdom.

Her most recent position prior to joining the HPRA was with the Home Office in the United Kingdom where she was the strategy lead for a programme of regulatory reform for the Animals in Science Regulatory Unit.

Dr Finnuala Lonsdale

Sláintecare Action Plan for 2022 The Minister for Health Stephen Donnelly has published the Sláintecare Action Plan 2022.

The 2022 Sláintecare Action Plan sets out the ongoing priorities to improve our health and social care services.

The main areas of focus this year include: • addressing waiting lists • further developments in shifting care to the community • further investment in innovation, enhanced capacity and access to care • implementing digital and eHealth solutions in line with Government’s recently published national digital framework “Harnessing Digital”

• introducing the Sláintecare Consultant Contract • progressing the National Elective Ambulatory Strategy through the provision of new elective capacity in Cork, Dublin and Galway • the realignment of acute and community services via Regional Health Areas However the Minister was met with criticism from the Irish Hospital Consultants Association who have stated, “It is concerning that the Sláintecare Action Plan for 2022 has been issued almost six months into the year – an increasing trend that the Minister and Department of Health must reverse.

“Last week marked 5 years since the Government launched Sláintecare, yet at the halfway

JULY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

point of the 10-year plan, we are faced with a health service, staff and patients who are suffering more than ever.

“There has been a 54% increase in people waiting on some form of hospital list since the plan was launched in 2017 – with almost 900,000 adults and children across the country in need of care.

“Today’s publication, however, does little to adequately address the key deficits causing these excessive waiting lists in our public hospitals, with the glaring omission of any clear Consultant staffing plan to deliver on the proposed reforms and actions.

“Without addressing the shortage of Consultants, hospital beds, theatres, diagnostics and other facilities the Government will not

address the core problems facing our public hospitals.

“This is the third plan brought forward in the last four months, following the publication of the Government’s Waiting List Action Plan, and the HSE’s Service Plan for 2022. While the Government and health service management sit drawing up their targets, and “plans to implement plans”, the opportunities to tackle our waiting lists, address our staffing crises and save our ageing facilities are passing them by.

“We are disappointed that none of these plans commit to a specific target for the number of additional hospital Consultants to be appointed and in-post during 2022 or beyond, nor agreed actions to make this target a reality.”

News

5

Scholarship Award for Aoife Congratulations to Aoife Delaney, Chief II Medication Safety Pharmacist, Pharmacy Department, Cork University Hospital on being awarded an Employment-based PhD Scholarship for Health Science Professionals by the College of Medicine and Health UCC. Aoife's research is a collaboration between the Pharmacy Department Cork University Hospital and the School of Pharmacy, UCC. She will investigate medication safety communication strategies, and the development of a quality improvement intervention in an Irish hospital setting.

This research will make an important contribution to new knowledge, and advance research in the area of medication safety, to improve patient outcomes.

Aoife will be supervised by Dr Aoife Fleming Lecturer in Clinical Pharmacy Practice, UCC, Dr Kirstyn James Consultant in Geriatric Medicine, Cork University Hospital, Dr Suzanne McCarthy Senior Lecturer in Clinical Pharmacy Practice, UCC and Ms Deirdre Lynch, Chief Pharmacist, Cork University Hospital.

Dr Suzanne McCarthy, Dr Aoife Fleming, Ms Aoife Delaney, Ms Deirdre Lynch and Dr Kirstyn James

Break the Bias – Doctors Urged The Medical Council marked International Women’s Day by recognising the continued and increasing contribution of women doctors to the medical landscape in Ireland.

Medical Council President, Dr Suzanne Crowe, said that while the number of doctors on the Irish medical register has been increasing year on year, the number of young female doctors has also risen steadily over the past decade. “Given this year’s International Women’s Day theme of Breaking the Bias, this is an opportune time to highlight the dedication and contribution of women doctors to Irish healthcare.

“While the number of female doctors on the register is increasing, particularly among younger doctors, there is still work to be done in forging gender parity in the profession. Gender balance is not solely a women's issue, but also an economic issue, and improving the situation for female medics will positively affect patients.

“Medicine, like many professions, has traditionally been male dominated, and I know of many women doctors who face gendered assumptions daily, when a patient might be expecting a male surgeon or specialist.

“At the end of 2021, there were 25,959 doctors on the Medical Register, 45% of whom were

Dr Suzanne Crowe, President, Irish Medical Council

“While the number of female doctors on the register is increasing, particularly among younger doctors, there is still work to be done in forging gender parity in the profession” female. There were 11,055 doctors on the Specialist Register, with 4,946 females. That’s 45% of the specialist register, when compared to just 38% ten years ago.

“This trend is particularly evident among younger doctors in the 20 – 35-year-old category, where in 2021, 53% were females and 47% were males, the same as the previous year. While challenging gendered stereotypes, female doctors should expect equal treatment with their male

counterparts, but employers and training bodies must also take into account the necessity to allow a work-life balance for all.

“The Medical Workforce Intelligence Reports that the Medical Council publishes annually, highlights that family remains to be a reason why many doctors voluntarily leave the Medical Council register each year. Many of those that leave the register are women who feel that being a mother and caring for a family can make it difficult for them to maintain a good work life balance. In particular, maternity leave, and the demands of balancing both home and medical professional practice and the long working hours have been cited as reasons.

“The past two years have also added an increased burden for all doctors, as a result of the COVID-19 pandemic.

The challenges faced by the workforce, especially around childcare issues during lockdowns, and the fear of bringing an unknown illness home to family, brought great stress and worry to an already fraught situation. While we hope to have left the worst behind, lessons should be learned around managing some of these issues going forward.

“As a doctor working in a children’s hospital, I work with a lot of great women, and will spend the day celebrating all they, and all women in medicine, do for their patients.”

HOSPITALPROFESSIONALNEWS.IE | HPN • JULY 2022

6

News

New President for RCSI Female President and female Vice President elected together for the first time in College’s history Pictured (right) is Professor Laura Viani, newly elected President of RCSI with Professor Deborah McNamara, RCSI’s new Vice President

my great honour to be elected today as President of the Royal College of Surgeons in Ireland.

The RCSI (Royal College of Surgeons in Ireland) has announced the election of Professor Laura Viani as the new President of the College and Professor Deborah McNamara as Vice President. Professor Viani takes up office following the College’s biennial Council Elections which have seen a female President and female Vice President taking up office together for the first time in RCSI’s history.

Professor Laura Viani is a consultant otolaryngologist and neurotologist at Beaumont Hospital and the Children’s University Hospital Temple Street.

She is Director and Professor of

the National Cochlear Implant Programme and Hearing Research Centre and is founder of this national specialty. She replaces outgoing President, Professor P. Ronan O’Connell.

Professor Deborah McNamara, a consultant general and colorectal surgeon at Beaumont Hospital, has been elected as the new Vice President. She has built a deep experience of the healthcare system as co-lead of the National Clinical Programme in Surgery and as a national healthcare quality improvement leader.

Speaking on her appointment, Professor Laura Viani said: “It is

“My presidency of RCSI follows the global pandemic and HSE cyber-attack which have presented our surgical community with challenges that will shape the future of surgery for years to come.

“With unprecedented numbers of patients having operations cancelled and on surgical waiting lists, it is critical that we secure the future of surgical services for our patients. Providing the highest standards of surgical training and fostering of surgical professional excellence is central to maintaining these vital services.

“The rise of online learning has opened up new opportunities to bring together surgeons from

around the world, united in the task of re-establishing safe, timely and equitable access to elective surgery. I look forward to working with our community of 10,000 Fellows and Members across 87 countries and sharing our expertise as we build a virtual network for continuing surgical education.

“I am particularly conscious of supporting our surgical trainees whose training has been disrupted over the past few years. RCSI will continue to use the excellent facilities of the National Clinical and Surgical Skills Centre at 26 York Street to provide innovative ways of training to complement hospital experience. I will advocate on behalf of our trainees to ensure our future surgeons will gain a world-class training experience.”

Professor Laura Viani has more than 30 years’ experience as a consultant otolaryngologist and neurotologist and is internationally renowned as a leader in hearing sciences and surgery.

Over 30 years ago, she conceived of the idea of a National Cochlear Implant Program and persuaded the Department of Health of its necessity and established the programme at Beaumont Hospital.

In 2016, she set up a multiinstitutional hearing research centre involving RCSI, Trinity College Dublin (TCD) and universities in USA and Latin America.

Critical Pressures on Health Service Dr Clive Kilgallen, the new President of the Irish Medical Organisation (IMO) has warned that the health services are facing a series of crises including unacceptable waiting lists, an exhausted workforce, poor morale and major problems with recruitment and retention of doctors.

Dr Kilgallen said the coming year would be critical for patients as there is a pent-up post Covid demand for treatments and care.

Dr Kilgallen was making his inaugural address to the AGM of the Irish Medical Organisation (IMO) which took place today in Aviva Stadium in Dublin. This was the first in-person AGM held by the IMO since 2019 as Covid forced the cancellation of AGMS in 2020 and 2021.

He also also confirmed that the NCHD Ballot for Industrial Action will continue with the result expected on the 9th June next. Dr. Kilgallen noted that the Minister for Health (who addressed the AGM) had accepted the arguments of the IMO that the situation facing NCHDs was – in the words of the Minister – “completely unacceptable”. Dr. Kilgallen said it was now for the HSE and Department of Health to commence negotiations with the IMO to resolve these serious issues.

Dr Kilgallen said that the Covid Pandemic exposed the fragility of the health system and while everyone had made heroic efforts to manage the crisis over the past two years, the reality after Covid was the same as the reality before Covid. All sections of the

JULY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

health services are under-pressure following years of under-resourcing.

He added that the country needs an additional 1,600 general practitioners in the next six years.

In the acute hospital sector, there are almostr 850 unfilled consultant positions and the National Doctors Training and Planning group in the HSE estimates that we will need an extra 2,000 consultants by 2029. In terms of bed capacity, we need 5,000 acute beds.

Mental health has always been underfunded and suffers greatly and Public health and Community Health doctor numbers are half of what are needed.

On NCHDs, Dr Kilgallen said, “These doctors are the future of our medical services. Without NCHDs, there will be no future general

practitioners, consultants or public health doctors. When I listen to their stories, they feel forgotten.

They feel they are being treated with contempt. They feel that they do not matter.

“As we have heard in their own powerful words today and in recent weeks, many of our NCHDs are working between 70 and 80 hours a week; with many of them working shifts of more than 24 hours. They are not even being paid fully for the hours they work. The current contract simply does not meet the needs of the NCHDs or the reality of the new demographics of the medical workforce. We don’t want industrial action – nobody does, but something has to give. And let me be very clear, the NCHD dispute has the absolute support of doctors across the country.”

ENJOY SUMMER FUN WITH FORTINI SMOOTHIE

THE ONLY * PAEDIATRIC SMOOTHIE ST YLE ONS** WITH

15% REAL FRUIT 300 6.8

7.2

2.8

FREEZE

FOR ICE LOLLIES!

PRODUCTS AVAILABLE FOR PROFESSIONAL EVALUATION^: SCAN THE QR CODE CONTACT NUTRICIA FOR A LOLLY MOULD AND RECIPE CARD FOR YOUR PATIENTS FREEPHONE 1800 923 404 This information is intended for healthcare professionals only.

The Fortini range are Foods for Special Medical Purposes for the dietary management of disease related malnutrition and growth failure in children from one year onwards and must be used under medical supervision. *Datacards reviewed form competitor websites June 2021 ** ONS: Oral Nutritional Supplement ^ Product can be provided to patients upon the request of a Healthcare Professional. They are intended for the purpose of professional evaluation only.

Nutricia Ireland, Block 1, Deansgrange Business Park, Deansgrange, Co. Dublin.

Date of publication, June 2021

NUTRITIONALLY COMPLETE FOR CHILDREN AGED

1+ YEARS

GMS

APPROVED

8

EAHP Congress

Hospital Pharmacists gather for 26th EAHP Congress in Vienna Written by Gonzalo Marzal López EAHP Project Portfolio Manager and Joan Peppard, Past President, EAHP Dr. András Süle, EAHP President

The EAHP Congress is a great opportunity to meet one’s friends and colleagues from across Europe and in 2022 this was a special occasion. This was the first EAHP in person Congress since the COVID-19 pandemic started in 2020 (EAHP held a virtual Congress in March 2021). The 26th EAHP Congress was held in Vienna from 23rd to 25th of March 2022. Around 2000 participants from 50 different countries participated at this Congress.

All COVID-19 protocols were followed, and the organisation made sure that all participants enjoyed this in person event while staying safe.

the presentation by a well-known lecturer from the ‘real’ Irish capital, Stephen – take a bow!

As the EAHP President Andras Süle and EAHP Scientific Chairman Thomas Derijt explained during the opening ceremony, the era in which hospital pharmacists were just box movers triggered by a medical prescription is part of the past. Thomas described the

“Hospital pharmacists – changing roles in a changing world” was the theme of this Congress.

The presentations aimed to explore and further expand on the changing roles of hospital pharmacists in this evolving scene. The theme of the congress was an inspiration to prepare for this changing world and provide tools to hospitals pharmacists to embrace the opportunities to guarantee optimal patient care within the available resources, and it admirably succeeded in these goals. Lecture theatres were full and many smaller meeting rooms had full signs including

JULY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

evolution of the hospital pharmacy professions as following a steep curve and still to reach the summit.

The quick changing scene creates the opportunity to embrace new challenges and responsibilities for our profession.

The three keynotes presentations were focussed on the future of hospital pharmacy. The first Keynote presentation “Value

based healthcare – hospital pharmacists should claim their sea” was dedicated to valuebased healthcare as a possible financing model to keep healthcare affordable in the future. Keynote 2 – “What people want from their medicines – Making shared decisions” focused on what really matters to the patients and the importance of putting the patient

9 international congresses, shared expertise on hospitals’ integrated health information systems and represented the EAHP Greek delegation for almost 20 years.

at the centre of medication management. The keynote 3 “The era of cell and gene therapies in oncology – Fiction, poetry, or science?” provided intriguing insights on the science and the processes of these new therapies and gave an outlook on what to expect in the near future. Besides the keynotes, the Congress held more than 30 sessions and workshops linked with the changing roles theme as well as lessons learned from the pandemic.

This EAHP Congress also marked the 50th anniversary of EAHP and some surprises linked with the anniversary were prepared.

A history walk with 30 posters was set up in the exhibition area that led participants through the history of EAHP since its foundation in 1972. In addition, the anniversary marked the creation of a new EAHP award: the “EAHP Board of Directors Professional Excellence Award”. This award is for individuals that have

made a significant contribution in making EAHP’s vision and mission a reality. The first award was given to Dr. Leonidas Tzimis from Greece, an experienced hospital pharmacist who has collaborated with EAHP for many years. Leonidas has worked for 40 years as a hospital pharmacist in Greece and has supported the transition of an old-fashioned hospital to a digital one, authored more than 130 publications and presentations for national and

The 26th EAHP Congress was also an opportunity to showcase and launch the outcomes of the EAHP Special Interest Group (SIG) on Hazardous Medicinal Products. The EAHP SIGs are a new initiative launched in 2021 that build on the knowledge and experience of European hospital pharmacists to focus on specific topics. The speakers for this session described the different classification systems for hazardous medicinal products in Europe, best practices identified, outcomes of the survey initiatives and the recommendations for improving the current landscape.

Finally, more than 400 posters and 70 Good Practice initiatives were accepted by the EAHP Scientific Committee and included in the poster area for participants to see and to consider for application to their own practice areas. Once again, this in-person Congress was indeed a perfect opportunity to network and meet face to face, an opportunity we really missed in 2020 and 2021. Well done to all involved.

News HIQA Publishes Annual Report The Health Information and Quality Authority (HIQA) has published its annual report for 2021, outlining its role in working to improve the quality and safety of Ireland’s health and social care services.

The report details the organisation’s work to regulate and monitor services, develop national standards and guidance, provide evidence synthesis and health technology assessments to support key policy decisionmaking, and to further develop health information in Ireland. The report also includes the Report of the Chief Inspector of Social Services, and details a summary of over 1,800 inspections of services during the year.

HIQA’s Chief Executive, Angela Fitzgerald, said: “In 2021, HIQA continued to place a focus on safeguarding and human rights, including in the national standards and guidance we develop, and in how services are regulated. As the regulator, we continued to

monitor the safety and quality of health and social care services, responding to risk as appropriate.

We commenced work in the area of homecare, calling for the reform and regulation of such services to better safeguard the people receiving care and support in their own homes. We also launched an online learning course to support front-line staff to implement a human rights-based approach to their work in services.

“Collaboration with other bodies also remains a key area of focus for HIQA. For example, we worked with the Department of Health and HSE on the National Care Experience Programme, including the rollout of the 2021 National Inpatient Experience Survey which asked patients about the impact of COVID-19 on their care.

HIQA published 113 evidence synthesis reviews or advice on COVID-19 for the Minister for Health, Department of Health and National Public Health Emergency Team. This work shows the value

HIQA Chief Executive, Angela Fitzgerald

and importance of using scientific evidence to shape the public health decision-making process.”

During the year, HIQA highlighted how reform is urgently needed in the regulation of social care services, and in Ireland’s health information system to better serve the needs of people using health and social care services.

Angela Fitzgerald continued: “2021 was a busy year for HIQA,

as highlighted in this report. As we prepare to take on new roles and responsibilities in a number of new areas — including through the commencement of the Patient Safety Bill and the inspection of International Protection Accommodation Services — we remain committed to protecting and upholding the human rights of all people using health and social care services in Ireland.”

HOSPITALPROFESSIONALNEWS.IE | HPN • JULY 2022

10 News

The Value of Value Added Medicines A new report, which focuses on the benefits of using Value Added Medicines in an EU context, has been published by Medicines for Ireland. ‘Value Added Medicines: Advancing Medicine Repurposing in the EU’ builds on the 2021 published report ‘Discussion Document on the Contribution of Value Added Medicines (VAMs) in Ireland’. It has been produced in conjunction with sister organisation, Medicines for Europe.

Value Added Medicines (VAMs) are medicines based on known molecules that address healthcare needs and deliver relevant improvements for patients and healthcare professionals. VAMs are key drivers for access to medicines and are increasing patient quality of life for chronic diseases, while offering significant benefits to the healthcare community.

VAMs offer a wide range of benefits from ensuring better adherence

and compliance, to keeping healthcare costs down by reducing the need for patients to be moved to expensive next line therapies.

The importance of using VAMs to address unmet medical needs in a timely and cost-effective manner has been highlighted during the Covid 19 pandemic.

The 2022 report stresses that in order to make medicine repurposing a success on an EU level we need to employ all resources at hand to connect different actors. One such connection which can uniquely be addressed by the EU is to assist academia and non-commercial stakeholders in conducting research, as well as facilitating their partnering with the industry in making repurposed medicines available to patients.

The early involvement of industry in repurposing projects opens a range of opportunities like new

indications, different/adjusted delivery forms, changing dosage and combining different therapies to meet the needs of the patient community and to bring to market new treatment options in an accessible and affordable way.

that rewards innovation with appropriate incentives, whilst recognising the potential longterm value and savings that VAMs can bring to the State.”

Furthermore, for more repurposing projects to come to fruition, we need to adapt the EU pharmaceutical ecosystem, starting with recognising the need for a tailored development approach for VAMs, including repurposed medicines. VAMs should be acknowledged as a separate group of medicines in EU legislation.

“At MFI, we are committed to improving patient care and delivering value to the HSE and are proud to drive stakeholder engagement on this important topic,” said Clodagh Kevans, Chair of the MFI VAM Committee.

“We believe that we need a new and simplified regulatory pathway for VAMs in Ireland, which would bring us into line with other major European countries to ensure that our patients and healthcare system is not left behind.

“Ireland can learn a lot from our EU peers. The industry needs to continually innovate, meanwhile, the state and regulators still have an important role to play,” said Padraic O’Brien, Chairperson of MFI. “We need a system

“We also need a shift in mindset from one that focuses purely on cost to an outlook that is centred around better outcomes for patients taking a holistic look at the whole patient journey,” she continued.

Code of Practice Published Medicines for Ireland have announced the publication of the MFI, Code of Practice V2.0.

Medicines for Ireland are committed to ensure that all members advertising medicinal products aimed at both healthcare professionals and the public is conducted in a responsible, ethical, compliant and professional manner.

The Codes set out specific standards for pharmaceutical companies with regard to ethical and regulatory advertising and promotional interactions with the Healthcare Community. The Codes are not intended to address or regulate commercial terms and conditions relating to the price, sale and distribution of medicines, which must always be in compliance with applicable rules and requirements. The principles set forth in the Codes are mandatory and shall be implemented by all Members.

The organisation stated, “Medicines for Ireland and our parent association Medicines for Europe are committed to ensure that all members advertising medicinal products aimed at both healthcare professionals and the public is conducted in a responsible, ethical, compliant and professional manner.

“As a member of Medicines for Europe, all Medicines for Ireland members are committed to the ethical standards set out in Medicines for Europe Code of Conduct (www.medicinesforeurope.com). Medicines for Ireland has developed this supplementary Code of Marketing Practice to outline Irish specific requirements additional to the parent Medicines for Europe Code of Conduct. Both Codes should be read in conjunction and are intended to be a self-regulatory standard and are without prejudice to any existing or future legislation. Where there is any gap or inconsistency between standards, the stricter requirement shall always apply.”

The full document can be viewed at: https://www.medicinesforireland.ie/wp-content/uploads/2022/05/Medicines-for-Ireland-Code-ofPractice-V2.0.pdf

FMD Use and Learn Ends The Falsified Medicines Directive (2011/62/EU) ‘(FMD’) introduced new requirements from February 2019 for safety features on prescription medicines packaging, enabling the packs to be authenticated as genuine prior to supply to patients.

FMD has been in a ‘use and learn’ phase in Ireland since February 2019 due, in part, to the impact of Covid-19 and Brexit. The use and learn phase ended for wholesalers on 9th May 2022 and for pharmacies and hospitals for 30th May 2022. After these dates, pharmacies, hospitals and wholesalers may not supply packs that generate alerts when scanned unless the alert has been fully investigated and a root cause has been found and falsification ruled out.

Detailed guidance has been developed for pharmacies, hospitals, wholesalers on what to do next if there is an alert and is available on the IMVO website (www.imvo.ie).

JULY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

I haVe the will to work out eVery day.

But I still need help to lose weight and keep it off.

Your patients with obesity have the will.

You can offer them the way.

Patient portrayal.

ROBERTO, civil servant; Age: 48 BMI: 39

Abbreviated Prescribing Information Saxenda® Liraglutide injection 3 mg. Please refer to the full Summary of Product Characteristics (SmPC) before prescribing. Saxenda® 6 mg/ml solution for injection in a prefilled pen. One pre-filled pen contains 18 mg liraglutide in 3 ml. Indication: Adults: Saxenda® is indicated as an adjunct to a reduced-calorie diet and increased physical activity for weight management in adult patients with an initial Body Mass Index (BMI) of ≥ 30 kg/m² (obesity) or ≥ 27 kg/m² to < 30 kg/ m² (overweight) in the presence of at least one weight-related comorbidity. Treatment with Saxenda® should be discontinued after 12 weeks on the 3.0 mg/day dose if patients have not lost at least 5% of their initial body weight. Adolescents (≥12 years): Saxenda® can be used as an adjunct to a healthy nutrition and increased physical activity for weight management in adolescent patients from the age of 12 years and above with obesity (BMI corresponding to ≥30 kg/m2 for adults by international cut-off points)* and body weight above 60 kg. Treatment with Saxenda should be discontinued and re-evaluated if patients have not lost at least 4% of their BMI or BMI z score after 12 weeks on the 3.0 mg/day or maximum tolerated dose. *See table 1 in SmPC. Posology and administration: Adults: The starting dose is 0.6 mg once daily. Dose should be increased to 3.0 mg once daily in increments of 0.6 mg with at least one-week intervals to improve gastro-intestinal (GI) tolerability. If escalation to the next dose step is not tolerated for two consecutive weeks, consider discontinuing treatment. Adolescents (≥12 years): A similar dose escalation schedule as for adults should be applied.

The dose should be increased until 3.0 mg (maintenance dose) or maximum tolerated dose has been reached (see SmPC).

Adults and Adolescents: Daily doses higher than 3.0 mg are not recommended. Saxenda® is administered once daily at any time, independent of meals, subcutaneously injected in the abdomen, thigh or upper arm, preferably around the same time of the day. Saxenda® must not be administered intravenously or intramuscularly. Saxenda® should not be used in combination with another GLP-1 receptor agonist. When initiating treatment in patients with type 2 diabetes mellitus, consider reducing the dose

of concomitantly administered insulin or insulin secretagogues (such as sulfonylureas) to reduce risk of hypoglycaemia. Blood glucose self-monitoring is necessary to adjust the dose of insulin or insulin-secretagogues. The safety and efficacy of Saxenda in children below 12 years of age has not been established.

Contraindications: Hypersensitivity to the active substance or to any of the excipients. Special warnings and precautions for use: Saxenda® must not be used as a substitute for insulin in patients with diabetes mellitus. Diabetic ketoacidosis has been reported after rapid discontinuation or dose reduction of insulin.

There is no clinical experience in patients with congestive heart failure New York Heart Association (NYHA) class IV and therefore Saxenda® is not recommended for use in these patients.

Saxenda® is not recommended in patients: aged 75 years or more, treated with other products for weight management, with obesity secondary to endocrinological or eating disorders or to treatment with medicinal products that may cause weight gain, with severe renal impairment including end-stage renal disease, with severe hepatic impairment. Saxenda® must be used with caution in patients with mild or moderate hepatic impairment.

Saxenda® is not recommended in patients with inflammatory bowel disease and diabetic gastroparesis. Acute pancreatitis has been observed with the use of GLP-1 receptor agonists, patients should be informed of the characteristic symptoms. If pancreatitis is suspected, Saxenda® should be discontinued; if acute pancreatitis is confirmed, Saxenda® should not be restarted. In clinical trials for weight management, a higher rate of cholelithiasis and cholecystitis was observed in patients on Saxenda® than those on placebo, therefore inform patients of characteristic symptoms. Use with caution in patients with thyroid disease. An increase in heart rate was observed with liraglutide in clinical trials. Heart rate should be monitored at regular intervals and patients informed of the symptoms of increased heart rate. For patients who experience a clinically relevant sustained increase in resting heart rate, treatment with Saxenda® should be discontinued. Patients treated with Saxenda® should be advised of the potential risk of dehydration in relation

Novo Nordisk Limited, First Floor, Block A, The Crescent Building, Northwood Business Park, Santry, Dublin 9, D09 X8W3, Ireland.

Tel: 01 8629 700, Fax: 01 8629 725, Lo call: 1 850 665665. infoireland@novonordisk.com www.novonordisk.ie Saxenda® and the Apis bull logo are registered trademarks owned by Novo Nordisk A/S. Date of preparation: January 2022. IE22SX00004.

to GI side effects and take precautions to avoid fluid depletion.

Signs and symptoms of dehydration, including renal impairment and acute renal failure have been reported. Patients with type 2 diabetes mellitus receiving Saxenda® in combination with insulin and/or sulfonylurea may have an increased risk of hypoglycaemia.

Dizziness can be experienced mainly during the first 3 months of treatment, therefore use caution when driving or using machines if dizziness occurs. Episodes of clinically significant hypoglycaemia have been reported in adolescents (≥12 years) treated with liraglutide; patients should be informed about characteristic symptoms of hypoglycaemia and appropriate actions. Fertility, pregnancy and lactation: Saxenda® should not be used during pregnancy or breastfeeding. If a patient wishes to become pregnant, or pregnancy occurs, treatment with Saxenda® should be discontinued. Undesirable effects: Very common (≥1/10): headache, nausea, vomiting, diarrhoea, constipation. Common (≥1/100 to <1/10): hypoglycaemia, insomnia, dizziness, dysgeusia, dry mouth, dyspepsia, gastritis, gastro-oesophageal reflux disease, abdominal pain upper, flatulence, eructation, abdominal distension, cholelithiasis, injection site reactions, asthenia, fatigue, increased lipase, increased amylase. Uncommon (≥1/1,000 to <1/100): dehydration, tachycardia, pancreatitis, delayed gastric emptying, cholecystitis, urticaria, malaise. Rare (≥1/10,000 to <1/1,000): anaphylactic reaction, acute renal failure, renal impairment. The SmPC should be consulted for a full list of side effects. Legal category: POM MA number: 5 x 3 ml pre-filled pens EU/1/15/992/003 For complete prescribing information, please refer to the SmPC which is available on www.medicines.ie or by email from infoireland@novonordisk.com or from the Clinical, Medical and Regulatory Department, Novo Nordisk Limited, 1st Floor, Block A, The Crescent Building, Northwood Business Park, Santry, Dublin 9, Ireland. Date last revised: November 2021.

Adverse events should be reported to the Health Products Regulatory Authority. Information about adverse event reporting is available at www hpra.ie. Adverse events should also be reported to Novo Nordisk on Tel: 1850 665 665 or complaintireland@novonordisk.com

liraglutide

12 News

Ireland’s Spending on Medicines ‘Stable’ In 2016, the State spent ¤1.9 billion on medicines while the overall health budget was ¤13.5 billion.

That means, based on current Government health expenditure estimates for 2021, we are spending almost 1% less on medicines today than we did five years ago as a proportion of the overall health budget.

Ireland’s spend on medicines as a proportion of overall health expenditure is below the average of 15 other European countries, according an industry analysis of official Irish figures, alongside an international study.

However, some countries that spend roughly the same proportion of their health budgets on medicines are much faster in making the latest treatments available to patients.

Last year, the State spent ¤2.54 billion on medicines, pharmacy and wholesaling costs – 13.4% of the overall health budget of almost ¤19 billion – according to estimated figures from Irish Government Economic Evaluation Service in the Department of Public Expenditure and Reform.

A new study by health analysts IQVIA for EFPIA, the biopharmaceutical industry’s representative organisation in Europe, called ‘Understanding Net Pharmaceutical Expenditure Dynamic in Europe’, shows that spending on medicines in 15 European countries is around 15% of total healthcare expenditure.

The surveyed countries were Norway, UK, Sweden, Demark, Slovenia, Belgium, Ireland, Croatia, France, Italy, Germany, Spain, Hungary, Bulgaria and Czechia.

The IQVIA analysis shows that Belgium, France, Italy, Germany and Spain spend between 14% and 18% of their overall health expenditure on medicines. But all of these countries are, on average, faster than Ireland in making new medicines available to their patients.

Belgium is seven days faster, France is 44 days faster, Italy is 112 days faster, Germany is 408 days faster and Spain is 24 days faster. The figures are from the latest EFPIA Patient WAIT Indicator Survey which measured time to reimbursement of medicines newly authorised by the European Medicines Agency.

In the survey, Ireland places 24th out of 35 countries reporting data for time to availability for 160 innovative new medicines, with an average of 541 days to reimbursement.

EFPIA’s study finds that spending on medicines has been ‘stable’ as a share of total healthcare expenditure in surveyed countries for the past 20 years.

“In that period, the innovation pipeline has been strong,” said a spokesperson for the Irish Pharmaceutical Healthcare Association, the organisation representing the research-based biopharmaceutical industry.

“But even when spending on medicines as a proportion of overall health expenditure is roughly in line with other western European countries, Ireland is much slower to make the latest treatments available to patients. Through sustained Government investment and the new supply Agreement, Ireland should aspire to be among the fastest countries in Europe to adopt innovative new medicines.

“New lines of cancer medicines like targeted therapies and immunotherapies are improving patient outcomes. Hepatitis C medicines are curing patients and, sometimes, replacing liver transplants. Many rare diseases, which previously had no treatments, can now be managed.

Despite these breakthroughs, spending on medicines in many European countries, including Ireland, has been stable.”

The EFPIA study finds that overall healthcare expenditure has been growing faster than medicines expenditure. It argues that health systems have a long-term sustainability problem driven by ageing populations and the burden of chronic disease and multi-morbidity.

“For many chronic diseases like diabetes and cardiovascular disease, the cost of medicines is a very small part of the overall cost of the disease, especially if you count the broader societal costs.

Medicines reduce unnecessary emergency visits, hospitalisations and complications.

“The recent visit to Dublin

by Emily Whitehead, the first paediatric patient in the world to receive a CAR-T, shows the impact of innovation. Emily, who had a rare cancer, is now 17.

Some advanced therapies, like CAR-T, come with high upfront costs. But they could off-set a lifetime of chronic treatment.

“That means they have long-term value – both for the patient and for the health system that pays for them. We need new payment models that are suitable for this new paradigm. These challenges can only be cracked through multi-stakeholder dialogue, especially between industry, State patients and doctors,” said the IPHA spokesperson.

International Accreditation for Smarmore Castle Clinic Dr Hugh Gallagher and Keith Cassidy Smarmore Castle Clinic, a 32-bed detox and addiction rehab clinic near Ardee, Co. Louth, has been awarded a major international accreditation recognising Excellence in International Best Practice, Legislation and Regulatory Standards.

The prestigious award was received from the Comparative Health Knowledge System (CHKS), a UK health organisation which provides independent recognition of commitment to quality improvement for boards, external regulators and patients. The CHKS

JULY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

award follows a comprehensive assessment by a team of external senior healthcare professionals which examined a range of activities undertaken at Smarmore Castle Clinic.

Located in a 13th century castle, and surrounded by 15 acres of gardens, Smarmore Castle Clinic offers an unrivalled environment in which patients can take the first steps on the road to recovery from addiction.

News of the recognition comes as the Health Service Executive (HSE) has entered into an agreement with Smarmore Castle Clinic to provide public funding for patients in need of inpatient detox and rehab from alcohol and drugs.

Keith Cassidy, Clinic Manager at Smarmore Castle Clinic, said, “We are delighted to receive this esteemed award which recognises the tireless work undertaken in this clinic towards the rehabilitation of patients. Our healing and selfreflective approach seek to show both patients and their families that there is life after addiction. Lives can be rebuilt.

“Smarmore Castle Clinic has quickly become one of the leading addiction treatment centres in Ireland and we are committed to offering people freedom from addiction. We will continue to improve our services in the months and years ahead, with recovery front and centre of everything that we do.”

News 13 Addressing Gaps in Doctor Training An RCSI working group, established to review the training and career development supports that are available to NCHD in the Irish Healthcare System, has made a series of recommendations that if implemented will help support surgical NCHD’s in their career development and lead to the improvement of their skills and knowledge all of which should lead to better outcomes for patients.

More than 1,000 non-consultant hospital doctors (NCHDs) work in Irish surgical departments.

NCHDs provide the backbone of 24/7 emergency surgical services. It is essential that they possess the requisite skills and competencies needed to deliver high quality and safe care. The majority (64%) of surgical NCHDs do not occupy a specialist training post approved by the National Doctors Training and Planning and funded by the HSE. These doctors

are referred to as non-training scheme doctors (NTSDs).

In November 2020, the President of RCSI established a Short Life Working Group (SLWG) tasked with investigating the recruitment and career expectations of surgical NTSDs, to report on the educational opportunities and support structures available and to provide recommendations on how RCSI could support NTSD development and professional needs. The Working Group, chaired by Council Member, Mr James Geraghty, included significant NTSD representation.

Mr James Geraghty said: ‘The majority of the non-training scheme doctors are from outside the EU and are not graduates of an Irish Medical School. These doctors make an invaluable contribution to the delivery of healthcare in Ireland. The majority

of surgical units across the country depend on NTSDs to maintain emergency surgical services.

The aim of the RCSI Short Life Working Group was to address the gap in education and training and support these doctors to enhance their clinical skills and knowledge, career development and professional needs. The recommendations, if implemented, will enrich our health service and ultimately benefit patients.’

As part of its remit the SLWG undertook an in-depth survey among NTSDs to gain greater understanding of NTSD recruitment, career expectations and training supports.

The survey revealed that although the NTSDs generally reported a positive experience working and living in Ireland, their expectations were very different to the reality they experienced. Many had

come to Ireland expecting to be able to access specialist training programmes. They felt they had not received adequate information regarding available career pathways and found themselves on short term (6 -12 month) contracts with the recurrent stresses of visa and work permit renewal.

The SLWG has made a series of recommendations across a range of areas including: recruitment and retention of non-EU doctors; pre-employment information on living and working in Ireland; and continued professional development.

The recommendations are pragmatic and designed to have a positive impact on quality and patient safety in the Irish healthcare system, to support a culture of NTSD supervision and training and to improve the quality of life for NTSDs and their families.

Summer Conferring Ceremonies RCSI University of Medicine and Health Sciences’ summer conferring ceremonies continued yesterday with 80 candidates graduating from the 2021 and 2022 classes.

RCSI Honorary Doctorate was awarded to Professor Patrick McGorry, an Irish-born, Australian psychiatrist known worldwide for his development and scaling up of early intervention and youth mental health services, and for mental health innovation, advocacy and reform

From the School of Postgraduate Studies, 11 Master of Science (MSc) by research candidates, 12 Doctor of Medicine (MD) graduates and 44 Doctor of Philosophy (PhD) graduates were conferred in the ceremony at the RCSI campus on St Stephen’s Green.

The candidates have carried out cutting-edge studies in research areas including COVID-19, tuberculosis and Down’s syndrome.

The degree of Master of Science (MSc) Physician Associate was awarded to 13 candidates. 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).

The RCSI Honorary Doctorate was awarded to Professor Patrick McGorry, an Irish-born, Australian psychiatrist known worldwide for his development and scaling up of early intervention and

youth mental health services, and for mental health innovation, advocacy and reform.

Commenting on the success of RCSI’s newest cohort of graduates, Professor Cathal Kelly, Vice Chancellor and CEO/Registrar of RCSI, said: “We are delighted to be able to gather in person once again to celebrate with the graduates on this momentous day. Today’s conferring marks the culmination of many years of hard work and is a testament to the graduates’

dedicated focus to a career in health sciences. They are now part of the RCSI graduate community who faced adversity and challenge to continue and complete their studies during a global pandemic.

Their hard work and resilience will be long-remembered.”

The graduates were addressed

by Professor Laura Viani, Vice President of RCSI, who told them: “Health science professionals of the future will need to be adaptive to the constant expansion of medical, pharmacy and systems

knowledge, changes in technology, medicines, increased patient, and societal expectations in addition to regulatory change; all of which require a commitment to life-long learning and an ability to adapt to the changing world that we live in.

The awards presented here today will give you a solid foundation to continue on this exciting journey.

“RCSI is proud of our commitment to developing healthcare leaders who make a difference worldwide; this is our ambition for you.”

HOSPITALPROFESSIONALNEWS.IE | HPN • JULY 2022

14 News

Multi Million Euro State-of-the-Art Breast Opens Professor Arnold Hill, Breast Cancer Ireland Chairman and Professor of Surgery, Beaumont Hospital with Dr Deirdre Duke, Consultant Radiologist, Beaumont Hospital

A separate board room will allow the entire multidisciplinary team to discuss personalised patient treatment plans.

Last month saw the Beaumont Breast Centre, of which Breast Cancer Ireland is a major donor, officially open its doors with Mrs Sabina Higgins present as Guest of Honour – making the First Lady of Ireland one of the very first to step inside the doors of this world class facility, that will benefit over 10,000 Irish women per year, for decades to come.

This brand-new Breast Centre, which cost circa ¤6m, is spread across three floors in a purposebuilt facility in Beaumont Hospital,

Dublin. The building incorporates eight consulting suites, five imaging rooms with the very latest tomosynthesis 3D mammography and breast ultrasound equipment, a prosthesis and post mastectomy underwear fitting suite, and a dedicated counselling suite.

The Cancer Clinical Trials Unit which coordinates and facilitates national and international clinical trials / translational research is on the top floor with offices for clerical staff, clinical nurse specialists and data managers.

Professor Arnold Hill, Breast Cancer Ireland Chairman and Professor of Surgery, Beaumont Hospital and a driving force behind the development of the new Breast Centre said, “What’s most important is that there are a number of aspects of the building that will fundamentally change breast cancer care for the better. With everything in the one location, including imaging and examination facilities, along with a fully integrated Cancer Clinical Trials Unit under the one roof, this is the key to advancing breast cancer care. Through clinical trials we can learn what is going to prolong survival and this will allow us to defeat this disease in the long term”. He continued “One

such trial that we’re particularly excited by is in the area of HER2 positive breast cancer, funded

by Breast Cancer Ireland via the 100k in 30 Days initiative. This trial involves a particular drug that is relatively non-toxic and allows us to reduce, potentially, the amount of chemotherapy that women might need, while achieving a 100% response rate. This would, in effect, mean a transformation in the outcome for this particular subtype of breast cancer. This new concept of “chemotherapy deescalation” whereby you reduce the amount of chemotherapy by only giving it to those who will benefit from it for the shortest possible time represents a major breakthrough in treatment.

Through constant research we can be immensely optimistic for the 450 patients that will be diagnosed with breast cancer each year in this building.”

1.7 million women worldwide face a diagnosis of breast cancer each year, of whom 460,000 are in the EU and 3,800 are in Ireland. However, data shows that survival rates are improving year on year, currently standing at 85% with mortality rates reducing by 2% each year, and importantly, local control of breast cancer is improving year on year.

Ireland Professionals Regulator Launches New Strategy CORU, Ireland’s health and social care professional’s regulator, is predicting significant growth in the number of professionals it regulates. By 2026, CORU estimates it will oversee the work of 35,000 registrants, an increase of almost 50% on today’s number of over 23,000. However, the body has cautioned that such growth will require a change in how it regulates to deliver a more sustainable regulatory model.

CORU was established in 2005 as a multi-profession health and social care regulator. The body currently regulates the work of over 23,000 professionals across 12 distinct professions, while a further six have been designated for regulation.

Launching the new strategy Chairperson Mo Flynn said, “CORU plays a vital role in protecting the public, by ensuring that the country’s health and social professionals consistently deliver care to the highest standards.

An absolute priority for CORU over the coming years will be opening statutory registers for all designated professions.

“Significant progress has been made over the past two years and Ireland’s Social Care Workers Register will now open in November 2023. This will be the largest of the 17 professions that CORU will regulate. Considering they often work with some of the most vulnerable members of our society this will be a milestone in our mission to protect the public.”

“We are focussed on making similar progress with the other professions designated for regulation. Much work has already been done on advancing the regulation of Counsellors, Psychotherapists and Psychologists and this will be a strong focus in the years ahead.”

CORU has identified five strategic priorities for the coming years:

JULY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

• Progress regulation of the six remaining designated professions • Ensure regulation protects the public and supports health and social care professionals • Build the organisational capabilities while evolving a sustainable regulatory model • Increase awareness of CORU’s role to the public and professionals • Anchor regulatory interventions in evidence informed research and insights With a significant increase in the remit of CORU Ms. Flynn cautioned that a more sustainable model of regulation needs to be implemented. “The current model of regulation CORU must operate is too complex, too reliant on a large number of volunteers and requires over 120 statutory meetings a year.

As we add more boards these pressures will increase.”

“A new governance structure is required to ensure the efficient delivery of appropriate regulation.

We are committed to working with the Department of Health to achieve this and deliver ‘right touch’ regulation while maintaining a relentless focus on public protection.”

Concluding Mo Flynn, Chairperson of the Health and Social Care Professionals Council, paid tribute to health and social care workers for their efforts throughout the pandemic. “Our registrants continued to provide care and treatment to the public despite risk of infection, fear of transmission to family members and friends and unprecedented restrictions. Throughout the pandemic, they have been an embodiment of professionalism and demonstrated tremendous dedication to their patients and service users. The country is better off for their efforts.”

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.

16 BPH

An overview on BPH (Benign Prostatic Hyperplasia) Written by Jasim Siddiqui, MBBS, Urology Registrar at Our Lady of Lourdes Hospital & Mr Ronan Long, MB, BCh, BAO, MCh, MMed SCI, FRCS(Urol), Consultant Urologist at Our Lady of Lourdes Hospital, Louth County Hospital and Mater Private Outreach Clinic Drogheda.

A transrectal or abdominal ultrasound & cystoscopy is considered in assessing Prostate size, shape & morphology, which play an important role in decision-making for the treatment and differential diagnosis of male LUTS/BPH. Role of PSA in BPH

Definition: BPH (benign prostatic hyperplasia) refers to the non-malignant growth or hyperplasia of prostate tissue.

A benign prostatic enlargement (BPE) can cause bladder Outflow Obstruction (BOO) and is a common cause of lower urinary tract symptoms (LUTS)in men.

Epidemiology: The prevalence of histological BPH increases with age, affecting approximately 42% of men between the ages of 51 and 60 years and 82% of men between the ages of 71 and 80 years.1 The global lifetime prevalence of BPH is around 25%.2 Aetiology & Pathophysiology: Hyperplasia in the prostate is stimulated by androgens.

The main androgen is dihydrotestosterone, which is converted from testosterone by the enzyme 5-alpha reductase.

Lower urinary tract symptoms resulting from hyperplasia are mainly due to 2 components: a static component related to an increase in benign prostatic tissue mainly at the transitional zone, narrowing the urethral lumen and a dynamic component related to an increase in prostatic smooth muscle tone mediated by alpha-adrenergic receptors.3 The aetiology is multifactorial with advancing age, endogenous androgens and prostate volume increasing the risk of developing symptoms. Black men appear to have a higher risk and Asian men have a lower risk.4 Potential

causal risk factors include Obesity, smoking, male pattern baldness, family history of BPH & metabolic syndrome.

Progression from pathologic BPH to clinical BPH (i.e., the presence of symptoms) may require additional factors such as prostatitis, vascular effects, and changes in the glandular capsule.5 Making the Diagnosis: The diagnosis of benign prostatic hyperplasia (BPH) can often be suggested based on the history alone. In men above the age of 50, history and symptoms suggestive of BPH include possible voiding and storage symptoms. Voiding symptoms include hesitancy, intermittency, weak stream, straining, incomplete emptying & post void dribbling.

Storage symptoms include urinary frequency, nocturia, and urgency.

A small proportion of men present with the inability to pass urine and is associated with suprapubic pain and a palpable bladder, which is a complication of untreated BPH. This is a urological emergency and the bladder requires immediate drainage. Men presenting under the age of 50 with voiding LUTS are unlikely to have BPH. Examination: Examination for BPH begins with abdominal, digital rectal examination(DRE) and a focused neurological examination. The DRE should assess perianal sensation, anal tone, prostate size and for any prostatic irregularity.

A prostate nodule on DRE should

JULY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

prompt PSA levels. Decreased anal sphincter tone or the lack of a bulbocavernosus muscle reflex may indicate an underlying neurological disorder.

Investigations: All patients should have a urine dipstick and/or culture and sensitivity to rule out a UTI or haematuria. NICE guidelines recommend that all patients with LUTS suggestive of renal impairment should have a serum creatinine and eGFR. If renal impairment is present, an ultrasound scan should be requested to assess for hydronephrosis and post-void residual.

Patients should be advised to record a frequency/volume chart voiding diary for a few days, which is a useful tool to objectify symptoms and detect polyuria.6 Assessment of the severity of the patient’s symptoms and the impact on their quality of life is done using the IPSS (International Prostate Symptom Score), a selfadministered questionnaire with 8 questions.7 (Image 1 on page 17) Investigations may include a urinary flow rate and post-void residual estimation. Post-void residuals greater than 200ml may indicate a less favourable response to treatment.

Urodynamic or Pressure flow studies provide the most complete means of determining the presence of outlet obstruction, but its use is optional.7

PSA has a useful role in the assessment of LUTS by acting as a surrogate marker in benign disease for an enlarged prostate.

The weight of evidence suggests that men with a PSA >1.4ng/ml should be considered at increased risk of disease progression of BPH.8,9 A note of caution should remain that a PSA test cannot replace a DRE and should not be done in its absence.

The presence of BPH symptoms does not predispose to prostate carcinoma and therefore it is not essential in men with BPH unless an abnormal prostate is felt on DRE or the patient is specifically concerned about or has a family history of prostate carcinoma [10]. The NICE guidelines also recommend that a PSA test is offered only after full counselling.

One must also exclude a UTI prior to a PSA test and not perform the test within a month of a proven UTI. Approach To Treatment: The aim of treating BPH with LUTS is to relieve symptoms and improve quality of life, as well as to attempt to prevent progression of disease and the development of complications.

These aims need to be balanced against the potential side-effects of treatment. Therefore, watchful waiting is an option recommended for many men.

Watchful waiting is the recommended strategy for patients with BPH who have mild symptoms (International Prostate Symptom Score ≤7) and for those with moderate-to-severe symptoms (IPSS score ≥8) who are not bothered by their symptoms and are not experiencing complications of BPH. In patients

17 with mild symtoms, medical therapy is not likely to improve their quality of life.11 These Patients may also benefit from behavioural and lifestyle modifications including reducing fluids at night, limiting caffeinated and alcoholic beverages, avoiding, or modifying the timing of diuretics or medications that increase urinary retention, and use of techniques to help control bladder symptoms.

Patients managed expectantly with watchful waiting are re-evaluated annually.

Conservative & Interventional Treatment: In general, medical therapy is offered as first-line management for patients with moderate to severe symptoms of BPH who do not require surgery.7

An alpha-blocker is considered as initial therapy for most patients and a 5-alpha reductase inhibitor can be added for those patients at risk of progression.7 Patients are evaluated 4 to 12 weeks after starting medical therapy. Patients need to be assessed using the IPSS; further evaluation may include a post-void residual (PVR) and uroflowmetry.

Modification in treatment is required where patients do not show improvement in symptoms and/or experience intolerable side effects.

Interventional therapy (e.g., Transurethral resection of prostate [TURP]) – For patients with moderate-to-severe LUTS and those who have developed acute urinary retention, or other complications of BPH.

TURP is accepted as the criterion standard for relieving bladder outlet obstruction (BOO) secondary to BPH.11

Select surgical intervention (e.g., transurethral resection) alleviate symptoms of urinary obstruction by reduction of prostatic bulk.12

In current clinical practice, most patients with BPH do not present with obvious surgical indications; instead, they often have milder lower urinary tract symptoms (LUTS) and, therefore, are initially treated with medical therapy. Several minimally invasive treatments for BOO are also available.

References:

Counselling & patient education play important role in determining intervention, which can include behavioural/lifestyle modifications, medical therapy, and/or surgical options.

3. D'Ancona C, Haylen B, Oelke M, et al.

The International Continence Society (ICS) report on the terminology for adult male lower urinary tract and pelvic floor symptoms and dysfunction. Neurourol Urodyn. 2019 Feb;38(2):433-77.

Summary:

4. Masumori N, Tsukamoto T, Kumamoto Y, et al. Japanese men have smaller prostate volumes but comparable urinary flow rates relative to American men: results of community-based studies in 2 countries. J Urol. 1996 Apr;155(4):1324-7.

BPH is hyperplasia of both epithelial and stromal prostatic components. A key characteristic of BPH is increased stromal: epithelial ratio. Prostatic hyperplasia can eventually result in bladder outlet obstruction.

Obstruction has both a static component due to increased volume of tissue, particularly in a transition zone, and a dynamic component due to increases in stromal smooth muscle tone. A large number of alpha-adrenergic receptors are present in the prostate capsule, stroma, and the bladder neck.

The predominant alpha-1 receptor in prostatic stromal tissue is the alpha-1A receptor. Treatment of symptomatic BPH is mainly accomplished through relaxation of smooth muscle tone with alphablockers and the reduction of the size of the glandular component following inhibition of the formation of dihydrotestosterone by 5-alpha-reductase inhibitors.

Image 1: IPSS Score Mild score: 0 to 7; Moderate score: 8 to 19; Severe score: 20 to 35

1. Berry SJ, Coffey DS, Walsh PC, et al.

The development of human benign prostatic hyperplasia with age. J Urol.

1984 Sep;132(3):474-9.

2. Lee SW, Chan EM, Lai YK. The global burden of lower urinary tract symptoms suggestive of benign prostatic hyperplasia: a systematic review and meta-analysis. Sci Rep. 2017 Aug 11;7(1):7984.

5. Isaacs JT, Coffey DS. Etiology and disease process of benign prostatic hyperplasia. Prostate. 1989;15(S2):3350.

6. Nickel JC, Aaron L, Barkin J, et al.

Canadian Urological Association guideline on male lower urinary tract symptoms/benign prostatic hyperplasia (MLUTS/BPH): 2018 update. Can Urol Assoc J. 2018 Oct;12(10):303-12.

7. Lerner LB, McVary KT, Barry MJ et al. Management of lower urinary tract symptoms attributed to benign prostatic hyperplasia: AUA guideline.

2021 [internet publication].

8. Bartsch G, Fitzpatrick JM, Schalken JA et al. BJU Int 2004; 93 Suppl 1: 279. Roehrborn CG, McConnell J, Bonilla J et al. J Urol 2000; 163: 13-20.

10. Hewitson P, Austoker J. BJU Int 2005; 95 Suppl 3: 16-32 11. [Guideline] Parsons JK, Dahm P, Köhler TS, Lerner LB, Wilt TJ. Surgical Management of Lower Urinary Tract Symptoms Attributed to Benign Prostatic Hyperplasia: AUA Guideline Amendment 2020. J Urol.

2020 Oct. 204 (4):799-804.

12. Patel AK, Chapple CR. Benign prostatic hyperplasia: treatment in primary care. BMJ. 2006 Sep 9;333(7567):535-9.

NEWS - EMA adopts first list of critical medicines On 7 June 2022, EMA’s Medicines Shortages Steering Group (MSSG) adopted the list of critical medicines for the COVID-19 public health emergency.

The medicines included in the list are authorised for COVID-19 and their supply and demand will be closely monitored to identify and manage potential or actual shortages.

Given the current stage of the pandemic, the published list contains all the approved vaccines and therapeutics in the European Union (EU) to prevent or treat COVID-19. It will be updated to reflect changes in the pandemic situation which may give rise to an increased risk of shortages of particular medicines, or following the authorisation of new medicines. The list does not replace national guidance on vaccination and the clinical management of COVID-19.

Marketing authorisation holders (MAHs) of medicines included in the list are required to regularly update EMA with relevant information, including data on potential or actual shortages and available stocks, forecasts of supply and demand. In addition, Member States will provide regular reports on estimated demand for critical medicines at national level. This will enable the MSSG to recommend and coordinate appropriate EU-level actions to the European Commission and EU Member States in order to prevent or mitigate potential or actual shortages of critical medicines to safeguard public health.

The MSSG was recently established under Regulation (EU) 2022/123, which assigns a reinforced role to the Agency in crisis preparedness and management for medicines and medical devices to monitor shortages and ensure a robust response to major events or public health emergencies, and to coordinate urgent actions on the supply of medicines within the EU.

HOSPITALPROFESSIONALNEWS.IE | HPN • JULY 2022

18 COPD

An Update on the Diagnosis and Management of COPD Written by P.C. Ridge; S.M. Walsh Department of Respiratory Medicine, University Hospital Galway, Ireland | National University of Ireland, Galway Correspondence: Dr Padraic Ridge, Department of Respiratory Medicine, Galway University Hospitals, Galway, Ireland E mail: p.macaniomaire1@gmail.com Assessment of a patient with suspected COPD The three main symptoms of COPD are dyspnoea, chronic cough, and sputum production. The first and most common symptom reported by patients is dyspnoea on exertion. Less commonly, patients describe symptoms of wheeze, fatigue and anorexia.

Dr Padraic Ridge

Introduction Chronic obstructive pulmonary disease (COPD) is a common condition characterised by persistent respiratory symptoms with non-variable airways disease (obstruction) and/or alveolar damage (emphysema). It is caused by significant exposure to noxious gases or particles.1 In this article, we review the disease pathogenesis, epidemiology, approach to assessment, diagnosis and chronic disease management for a patient.

Pathogenesis Cigarette smoke is the most common risk factor for COPD worldwide, accounting for approximately 80% of cases. Pipe tobacco and marijuana are other risk factors.1 Passive exposure to cigarette smoke can also lead to COPD by increasing the total burden of inhaled particles and gases that the lungs are exposed to. Other causes include burning of biomass fuels, air pollution and occupational exposures, including those experienced by sculptors and gardeners.2 Interestingly, not all individuals who smoke will develop COPD. Even in those who are heavy smokers, less than 50% will develop COPD during their lifetime.3 This variability is believed to be due to a complex interplay between the type and intensity of noxious exposures and individual factors such as genetics, age, gender, airway

The key findings on clinical examination of a patient with COPD are usually absent until significant impairment of lung function has occurred.8 Tachypnoea occurs Dr Sinead Walsh with activity, with increasing respiratory rate in proportion to disease severity. Use of hyper-responsiveness, infections available on accessory requestrespiratory muscles andReferences overall lung development and paradoxical indrawing of the 1, 4, 5 in childhood. lower intercostal spaces (Hoover sign) indicates airway hyperinflation Epidemiology and a flattened diaphragm.

Other findings on thoracic The prevalence of COPD is examination include a barrel chest, increasing worldwide and is hyperresonance on percussion, expected to continue to rise due diffusely decreased breath sounds, to ongoing exposure to COPD and prolonged expiration. risk factors, particularly smoking, in developing countries and an Diagnosis and staging aging population in developed 3, 6 countries. The global burden Diagnosis of COPD is based on of disease study reported COPD a triad of causative exposure, FIGURE 1: cause of as the third leading symptoms and spirometry. death worldwide.7 The estimated Spirometry is the most worldwide COPD mean prevalence reproducible and objective is 13.1%, however data in many measurement of airflow limitation.1 It measures the volume of air that a geographic areas is scarce.4, 6

Figure 1

FIGURE 2:

JULY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

patient can forcibly exhale from the point of maximal inspiration (forced vital capacity, FVC) and the volume of air that is exhaled during the first second of this manoeuvre (forced expiratory volume in one second, FEV1). The ratio of the FEV1/FVC is calculated. Airflow obstruction is a post-bronchodilator FEV1/FVC ratio less than 70%. At diagnosis patients should have the severity of their airflow limitation classified according to the GOLD (Global Initiative for Chronic Obstructive Lung Disease) guidelines. This classifies patients with a FEV1/ FVC ratio less than 70% into four categories (GOLD 1 – 4), based on their FEV1 value (FIGURE 1).

Symptom burden should be assessed using the mMRC (Modified British Medical Research Council questionnaire) or the CAT (COPD Assessment test).

An assessment of exacerbation risk should also occur. A COPD exacerbation is an acute worsening of respiratory symptoms that results in additional therapy.9 Exacerbations can be classified as mild, moderate or severe. The best predictor of having frequent exacerbations (defined as two or more exacerbations in one year) is a history of previous exacerbations.10 Using these variable individuals may be classified as GOLD A – D1

19 Figure 2

(FIGURE 1). This classification system divides individuals into phenotypes of those who are relatively asymptomatic (A), symptomatic on a daily basis (B), have regular exacerbations but are asymptomatic in between episodes (C) and those who are symptomatic on a daily basis and suffer relatively frequent acute exacerbation of their symptoms requiring oral steroids (D).

This phenotypic subdivision of individuals into those who are breathless or who exacerbate frequently allows more targeted therapy. Typically those who are breathless benefit from bronchodilator therapy and those who suffer frequent exacerbations benefit from anti-inflammatory treatment1 (FIGURE 2).

In our practice we obtain a chest radiograph in all new suspected COPD patients. While it does not diagnose COPD, it can be useful at excluding alternative diagnoses and establishing the presence of comorbidities including pulmonary fibrosis, pleural disease, kyphoscoliosis and cardiomegaly.

We obtain routine laboratory investigations, including FBC to check for eosinophilia. We screen for alpha one antitrypsin deficiency in concordance with WHO recommendations.11 For those with recurring exacerbations we check an immunoglobulin level to screen for hypogammaglobinaemia.

MANAGEMENT 1. Smoking Cessation The cornerstone of treatment for COPD is smoking cessation and must be stressed with those who continue to smoke at every encounter.1 Individuals should be offered both non-pharmacological and pharmacological (nicotine replacement therapy, bupropion, varenicline etc.) assistance to quit.1 Unfortunately, COPD is invariably a progressive disease as damaged lung is unrecoverable and lung function will continue to decline with age regardless of smoking status. However if individuals continue to smoke lung function will decline much more rapidly and ultimately result in a much higher symptom burden at a much earlier stage.12 Electronic cigarettes (e cigarettes/ vaping) have increased in popularity as an alternative to cigarettes. In addition to nicotine, they can contain other chemicals, the long-term health effects of which are largely unknown.1 However, they have been associated with vaping-associated lung injury, alveolar haemorrhage

and death.1 E-cigarette use is increasing among Irish teenagers.13 FIGURE There is a3: perception that e-cigarettes may be healthier than cigarettes in this age group. There is a lack of information about e-cigarettes from school education programmes on smoking.13 2. Bronchodilator therapy Dyspnoea is multi-factorial in COPD. Contributing factors include: • Airway obstruction • Parenchymal destruction • Dynamic hyper-inflation leading to air trapping, small airways collapse and negative effect on compliance resulting in increased work of breathing and subjective shortness of breath (SOB)14 • Systemic effects of COPD including sarcopenia15 Bronchodilators address the airways obstruction, altering airway smooth muscle tone, leading to widening of the airways and improving dynamic hyperinflation.

Available inhalers include short acting and long acting beta agonists (SABA/LABA) and muscarinic antagonists (SAMA/ LAMA). These therapies have been shown to improve dyspnoea, improve exercise performance and reduce the frequency of exacerbations. In asthma, LABA monotherapy (without an inhaled corticosteroid) is associated with an increased mortality. This is not the case with COPD where monotherapy is safe1 (FIGURE 2).

Combination bronchodilator therapy of a LABA and a LAMA in a single inhaler demonstrate improved patient reported outcomes, compared to monotherapies alone, with improved quality of life demonstrated.1

3. Anti-inflammatory Exacerbations in COPD are predominantly due to viral infections and airway inflammation.

Therefore anti-inflammatory therapies form a cornerstone in COPD therapy for those who are frequent exacerbators.

to therapy. As it can cause QT prolongation, an ECG should be performed prior to initiating therapy and one month post initiating therapy. Patients should be counselled to monitor for signs of ototoxicity, palpitations and diarrhoea.18 Data is limited in those who are active smokers.19

Inhaled Corticosteroids

Roflumilast

Inhaled corticosteroids (ICS) in combination with LABA therapy are useful for dampening airway inflammation, thereby reducing exacerbation frequency. They also have a positive effect on lung function and dyspnoea.1 There is an ever growing body of evidence that eosinophilia is a useful biomarker for predicting a positive response to ICS therapy.16 While ICS therapy has been shown to reduce exacerbations and improve symptoms, they have been associated with a slight increase in pneumonia, especially in those with eosinophils <0.3u/L and more severe disease. We therefore consider ICS therapy in those with two or more exacerbations per year, eosinophils ≥0.3u/L or a history of asthma/atopy.1, 11, 17

Roflumilast is a phosphodiesterase inhibitor and works by reducing intracellular cyclic adenosine monophosphate (cAMP). It reduces inflammation in the airway but has no immediate bronchodilator effect. It may be a reasonable add-on therapy in selected patients with a chronic bronchitic phenotype of COPD with severe airflow obstruction and a history of exacerbations.

In some individuals, roflumilast may be intolerable as it can be associated with severe, nausea, headaches, diarrhoea and weight loss.20 We avoid starting this treatment in those with a low body mass index. Roflumilast is not approved for reimbursement under the community drug schemes in Ireland.

Azithromycin

4. Pulmonary Rehabilitation

Azithromycin is a macrolide antibiotic. It has antimicrobial effects but also has an anti inflammatory effect in the airway and interferes with biofilm formation. It can be added on to therapy in former smokers who continue to exacerbate despite maximal inhaled therapy. It is recommended to be continued for one year but in practice individuals remain on it for much longer due to its’ exacerbation lowering effects.1 Prior to initiating therapy, sputum samples should be checked, and non-tuberculous mycobacterial colonisation should be excluded as this is a contra-indication

Pulmonary rehabilitation has been shown to be of tremendous benefit in patients with COPD. It improves dyspnoea and quality of life. In those discharged from hospital, pulmonary rehabilitation reduces the re-admission rate by approximately 50%.21 - 23 It is recommended for GOLD B-D patients and for those discharged from hospital with an exacerbation of COPD (ideally within 4 weeks of discharge)1 Pulmonary rehabilitation consists of an 8-12 week course consisting of a supervised incremental physiotherapy program where patients build up their muscle

HOSPITALPROFESSIONALNEWS.IE | HPN • JULY 2022

20 COPD strength. Patients also receive education regarding their condition, lifestyle advise, dietetic input (if required) and are taught breathing exercises and the benefit of pacing.24 Interestingly while pulmonary rehabilitation improves dyspnoea it has no direct effect on lung function. COPD is a systemic disease resulting in inefficient sarcopenic muscles. Pulmonary rehab works by increasing aerobic fitness, reducing lactic acidosis production and thus breathlessness.15 5. Long Term Oxygen Therapy (LTOT), Ambulatory Oxygen Therapy (AOT) and Non-invasive Ventilation (NIV)

body for people affected by COPD. By providing patients with knowledge of their condition, how to take their inhalers, how to control the sensation of breathlessness, it enables patients to live well with COPD. There are local COPD support groups throughout Ireland, providing regular exercise classes. Every patient should have a selfmanagement plan for their COPD (FIGURE 3).

7. Surgery and bronchoscopic interventions

bullous disease there are surgical options to help with dyspnoea.

This can be done surgically through bullectomy or lung volume reduction surgery. Here the dead space or area of wasted ventilation is removed. This allows the healthier, compressed lung to re-expand and contribute more to ventilation.29 The same effect can achieved bronchoscopically by blocking off the ineffectual lung endoscopically, leading to its’ collapse allowing the more effective lung to re-expand.1

In those with predominantly upper lobe emphysematous disease or

Those with very severe COPD who are deemed fit should

LTOT is indicated in the following scenarios:25 1. PaO2 ≤7.3kPa (3 weeks apart) 2. PaO2 ≥7.3kPa to ≤8kPa with pulmonary hypertension, pedal oedema or raised haematocrit 3. Palliative reasons Ambulatory oxygen is indicated in those who:26 1. Are on LTOT and are active outside the house (to help them get the required 15 hours per day) 2. Significantly desaturate on exertion and can walk further with the use of AOT Non-invasive ventilation (NIV) is indicated in those who:25, 27 1. Demonstrate symptomatic hypercapnia (headache, confusion, lethargy) 2. Are post hospitalisation if PaCO2 is persistently raised28 3. Require LTOT but develop hypercapnia from same 6. Other interventions Vaccination against Influenza virus, Pneumococcus and SARS-Cov-2 (COVID-19) are recommended

by GOLD.1 Vaccination reduces serious illness, exacerbations and mortality in COPD patients.

COPD is associated with a number of comorbidities, including cardiovascular disease, metabolic syndrome, skeletal muscle dysfunction, osteoporosis, gastro-oesophageal reflux, sinus disease, anxiety, depression and lung cancer.1 These comorbidities influence mortality and hospitalisations in a patient with COPD. Therefore, they should be sought for and treated appropriately.1 In very severe COPD, palliative care input should be sought to aid with refractory dyspnoea.1 COPD Support Ireland is Ireland’s national support and advocacy

JULY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

be referred for lung transplantation assessment.1 Conclusion COPD is a prevalent disease with a high disease burden.

Management focuses predominantly on early diagnosis, improving symptoms of shortness of breath and reducing exacerbations for which we have a growing armament of treatment options.

References available on request

Figure 3

News 21 Informing Genetic Disease Research A new study by RCSI University of Medicine and Health Sciences examining population genetics across Europe has analysed the diverse ancestries of people living in the UK. This knowledge has the potential to inform future health research on genetic factors leading to disease.

The study, led by researchers at the RCSI School of Pharmacy and Biomolecular Sciences and the SFI FutureNeuro Research Centre, has been published in Proceedings of the National Academy of Sciences.

The RCSI and FutureNeuro researchers used the UK Biobank, a database of genetic and health information of over 500,000 participants from the UK, to examine population genetics and ancestry across Europe.

The study analysed the genetic ancestry data of individuals in the UK Biobank who reported having a European birthplace outside of the UK – about 1% of the dataset.

Researchers catalogued where individuals shared segments of their genome with other individuals, meaning they had a common ancestor within the past 3,000 years.

With this information, the researchers could group individuals with more segments in common than on average into three branches, corresponding to southern, central-eastern, and northwestern Europe.

By studying the patterns of the genome sharing, the researchers were able to infer historical patterns such as population size and how genetically isolated specific European regions are,

relative to each other. In general, people from southern Europe were found to have less in common genetically with each other than in other areas, due to the larger population sizes and therefore usually greater number of ancestors in the region.

An exception to this was Malta which, being an island, was found to have a smaller pool of ancestors. This is the first large sample analysis of Maltese population genetics. Identifying European regions such as Malta with specific histories of genetic isolation could potentially aid the discovery of genetic factors contributing to disease.

In addition to building and expanding upon previous knowledge in Europe, the results present the UK Biobank as a source of diverse ancestries

beyond the UK. This has the potential to complement and inform researchers interested in specific communities or regions across Europe and the world.

Professor Gianpiero Cavalleri, Professor of Human Genetics at RCSI, Deputy Director of FutureNeuro and senior author on the paper, commented: “This research has shown the diversity of European ancestries sampled by the UK Biobank and has enabled us show the “big picture” of the genetic landscape of Europe, including new insights into communities such as within Malta. This work suggests similar gains of knowledge could be found within non-European ancestry groups using the UK Biobank, groups that are typically excluded from genetic analyses.”

New Replacement Orthopaedic Theatres at Merlin Park Two new replacement orthopaedic operating theatres on the Merlin Park site, which cost ¤10.57m to design, build and equip, were used for the first time last month.

Mary Keane, Clinical Nurse Manager 2 and Mr John Galbraith, Consultant Orthopaedic Surgeon

Prior to the opening of the new theatres, there was only one orthopaedic theatre on the Merlin Park site. This was the only facility available in Galway University Hospitals (GUH) to provide elective orthopaedic procedures. The two new replacement theatres are required to restore full elective orthopaedic procedures in Merlin Park University Hospital and address orthopaedic waiting lists.

Construction of the 620m2 theatre building began in March 2021 following a public procurement tendering for a main contractor. The build consists of two operating theatres, two anaesthesia rooms, a recovery area and other ancillary accommodation to support the theatre suites. The theatre building is connected to the main hospital block by a link corridor which is the access point for patients and staff.

The hospital has been providing 10 theatre sessions per week; this will increase to 20 sessions per week when two fully functional theatres are in place which will enable

approximately 4,000 procedures per annum to be carried out.

Demand for orthopaedic services is increasing year on year as is the complexity and sub specialisation within orthopaedic surgery. GUH is currently recruiting staff to increase the number of theatre sessions to 20 per week and will also be seeking funding to staff the old theatre in 2023 to assist in providing further capacity.

Mr Aiden Devitt, Consultant Orthopaedic Surgeon said, “The new operating theatres are a major

enhancement for the hospital and for orthopaedic services in the west and I am extremely proud of everyone involved in bringing this long-awaited project to completion. We now have a state of the art theatre suite which will double our capacity for surgical procedures and will reduce waiting times for patients.

Our orthopaedic patients will be treated in a modern, spacious and technologically advanced facility and I am delighted to be commencing procedures in the new theatres this week.”

Ms Chris Kane, Hospital Manager said, “This is a significant investment in healthcare infrastructure for the people living along the western seaboard who come to Galway for their surgery. The theatres have been built and equipped to a very high specification to enable us to deliver the best possible care to our patients.

“We look forward to resuming a full elective orthopaedic surgery service in Merlin Park University Hospital.

HOSPITALPROFESSIONALNEWS.IE | HPN • JULY 2022

22 ICO Conference

ICO Annual Conference – Latest Developments in Eye Care The Irish College of Ophthalmologists Annual Conference 2022 took place from Monday 16th to Wednesday 18th May 2022 at the Kilkenny Convention Centre, Lyrath Estate. Over 200 ophthalmologists in practice and training gathered for the three-day meeting to hear the latest clinical and scientific updates and developments in the specialty from national and international eye experts.

Symposia topics included a clinical session on Ocular Surface Disease; a service delivery session on 'Planning for the Future' examining Medical Retina and Telemedicine/Virtual Review, IOP Clinics and Glaucoma Diagnostic Hubs; whilst a separate symposium focused on the Integrated Eye Care Team highlighted the model of eye care implementation at national, regional and community level.

A separate clinical session on Recent Clinical Trials in Glaucoma, Myopia and Retina also featured on the programme.

It was a great honour and privilege for the ICO to welcome Professor Stanley Chang, K.K. Tse and Ku Teh Ying Professor of Ophthalmology, Columbia University, New York to present this year's Annual Mooney Lecture. A specialist in vitreoretinal disorders and surgery, Prof Chang has pioneered many of the surgical techniques currently used in this field.

Parallel workshop sessions on Ocular Movement and OCTA, in addition to the paper and poster sessions (ICO Honorary Medals and prize presentations) and the SOE Young Ophthalmologist Lecture 2022 were among the other highlights of this year's reunion conference, following a two year break for the conference due to Covid restrictions.

Addressing delegates, ICO President, Mr Tim Fulcher said it was wonderful to return to an in person meeting for members in 2022 following a difficult two years throughout Covid.

Professor Stanley Chang, K.K. Tse and Ku Teh Ying Professor of Ophthalmology, Columbia University Department of Ophthalmology, Annual Mooney Lecturer 2022 with Professor David Keegan, Clinical Professor of Ophthalmology and Retina (University College Dublin) and Consultant Ophthalmic Surgeon, Mater Misericordiae University Hospital, Dublin.

Mr Tim Fulcher, President, Irish College of Ophthalmologists with keynote speakers from the 'Delivering Integrated Care in Ireland' symposium which took place on the opening day of the OCO Annual Conference 2022 L-R Dr Margarat Morgan, Consultant Medical Ophthalmologist, Royal Victoria Eye and Ear Hospital, Professor William Power, Clinical Lead for Ophthalmology and Consultant Ophthalmic Surgeon, Royal Victoria Eye and Ear Hospital, Dublin; Ms Chriosa O’Connor, Optometrist, Mater Misericordiae University Hospital, Dublin and Professor David Keegan, UCD Clinical Professor of Ophthalmology and Retina, UCD School of Medicine, University College Dublin. National Clinical Lead for Diabetic Retinopathy Screening.

"Our Annual Conference has always been an extremely valuable educational meeting for the specialty and important collegiate occasion for our members. It is crucial to return to in person engagement forums to discuss the latest developments and learnings amongst colleagues, difficult and unusual cases and of course all we have learnt about our specialty and service delivery management as a result of the pandemic.

“Despite the challenges of the past two years, much progress has taken place in the specialty of ophthalmology with investment into the new Integrated Eye Care Teams at community and hospital level, and the establishment of dedicated cataract theatres. There is much more to be done to address the waiting lists in ophthalmology and our focus, alongside the work of the National Clinical Programme led

by Prof William Power, remains on delivering a service equipped to manage the areas of greatest patient demand.

“We are very fortunate to once again be welcoming leading experts from home and overseas to the ICO Annual Conference, who will impart their exceptional knowledge to the benefit of all in attendance and our health service over the three-day meeting."

JULY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

Annual Mooney Lecture 2022 ‘Improving the Outcomes of Surgery for Retinal Detachment’ Professor David Keegan formally introduced Professor Chang, noting the incredible contribution Professor Chang has made to the speciality throughout his career, retina in particular and his status as a pioneer of several revolutionary surgical approaches to treat complicated forms of retinal detachment which have led to improved outcomes for patients worldwide.

Professor Chang’s subject for the 2022 Mooney Lecture discussed the four different methods of treating retinal detachment – pneumatic retinopexy (injection of a gas bubble, with positioning, and laser), scleral buckling alone, vitrectomy, and vitrectomy and scleral buckling.

The characteristics of the retinal detachment, such as size and number of tears or extent, cannot be determined by the surgeon, but the selection of the procedure and the adjuncts used in the surgical management are critical to achieving a successful outcome.

Evidence -based data on the outcomes of the different methods of the treatment for retinal detachment were discussed and surgical techniques that enhance the outcomes.

23 Professor Chang highlighted the exciting future developments for improving the anatomic and visual outcomes in retinal detachment surgery.

TALK OVERVIEWS Professor David Keegan

Planning for the Future

Clinical Professor of Ophthalmology and Retina (University College Dublin)

Ms Dawn Sim, Medical Director in Product Development Ophthalmology, Genentech Roche, Honorary Consultant Ophthalmologist,, Moorfields Eye Hospital, UK, Associate Professor, Institute of Ophthalmology, University College London gave her talk 'The Idiosyncrasies of Telemedicine in Ophthalmology' virtually at the Planning for the Future Symposium.

Ms Dawn Sim opened the ‘Planning for the Future’ symposium (Wednesday, 18th May) with her (virtual) talk on the topic ‘The idiosyncrasies of Telemedicine in Ophthalmology’. Ms Sims obtained her PhD from the UCL Institute of Ophthalmology for her work on endothelial progenitor stem cells and has published extensively on diabetic retinopathy, age-related macular degeneration, and retinal vein occlusions.

Her presentation at the ICO Conference discussed new technologies in retinal imaging, digital health, and the field of teleophthalmology. Dawn is working with device-agnostic platforms to facilitate the acceleration of new technology and artificial intelligence software into clinical practice.

Ms Aoife Doyle, Consultant Ophthalmic Surgeon, Royal Victoria Eye and Ear Hospital and St James's Hospital, Dublin highlighted the work of the Lean Team at Ireland East Hospital Group and of the ophthalmology team at RVEEH with CHO6 and CHO7 in her talk ‘Transitioning Stable Glaucoma Care to the Community’.

Having closely followed developments in glaucoma care in the UK in recent years, Ms Aoife Doyle set up a virtual glaucoma clinic

Consultant Ophthalmic Surgeon (Mater University and Mater Private Hospitals) Talk: Establishment of a Novel Governance Structure to Transform, Integrate and Deploy Regional Eye Care - the virtual Accountable Care Organisation (vACO)

Ms Dawn Sim, Medical Director in Product Development Ophthalmology, Genentech Roche

at RVEEH in 2018. A key component of this was the early adoption of an electronic record (Medisight) for patient management.

During the Covid-19 pandemic Ms Doyle worked together with the Lean Team at Ireland East Hospital Group and Professor Colm O’Brien to set up a Drive-Through IOP clinic at the City West Facility that saw over 650 patients from RVEEH and MMUH between August 2020 – July 2021.

She participated in a Lean Healthcare initiative on glaucoma in 2020-2021 and after further training was awarded a Bronze qualification for work on delivery of virtual care, improving visual field capacity and establishing and managing the RVEEH side of the City West Initiative.

With her team, Ms Doyle has recently extended that model to the CHO7 area together with

Professor David Keegan said, "We have established, over the last year, a novel governance structure to manage integrated eye care in the North East thus opening a path to tackling one of the longest wait lists, by specialty, in the region. Ophthalmology also has one of the highest waitlists in the country with nearly 50000 patients waiting for an outpatient appointment and > 8000 waiting for surgery. In the North East alone we estimate 14000 patients are awaiting an outpatient appointment with over 3000 patients waiting for surgery, most of whom for cataract surgery. Eye care is delivered by 6 distinct healthcare organisations who have all committed to working together to achieve our goals. Our clear focus is on reducing avoidable vision impairment and blindness by reorganising our service delivery via a transformation plan and unique voluntary governance structure.

“As a means to tackle this, we have instituted the collaborative governance structure called the Virtual Accountable Care Organisation (vACO) to integrate, transform and deploy eye care services in the North East. We are near completion of the first year of the development of this pathway and already we are seeing impact on our wait lists.”

Dr Margaret Morgan Consultant Medical Ophthalmologist, Royal Victoria Eye and Ear Hospital, Dublin and CHO7 Talk: Eye Care in the non-Acute Setting Dr Margaret Morgan provided an update on the CHO7 Adult Ophthalmology Service one year on from the establishment of the team and unit. Dr Margaret Morgan discussed how the service came about, the set-up process, progress made to date and the future direction.

Mr Jonathan Clarke, Consultant Ophthalmologist, Moorfields Eye Hospital, London, Ms Evelyn O'Neill, Consultant Ophthalmologist, Mater Misericordiae University Hospital, Dublin, Mr Tim Fulcher, (Chair), ICO President and Consultant Ophthalmic Surgeon, Mater Misericordiae University Hospital, Dublin, and Ms Aoife Doyle, Consultant Ophthalmic Surgeon, Royal Victoria Eye and Ear Hospital and St James's Hospital, Dublin

Dr. Margaret Morgan, Consultant Medical Ophthalmologist (Royal Victoria Eye and Ear Hospital and CHO7) with staff training commenced to introduce a similar clinic in CHO6. This is helping to more efficiently deliver care to people with glaucoma in the community and closer to home. Ms Doyle said it will also help to improve capacity for the hospital eye services to see the more complex and surgical patients and reduce waiting times, improving outcomes in glaucoma care through the collaboration of the hospital and community eye care services.

In his talk, panelist guest speaker Mr Jonathan Clarke, Moorfields Eye Hospital, London, discussed the set up and safe assessment of diagnostic (virtual) clinic pathways

HOSPITALPROFESSIONALNEWS.IE | HPN • JULY 2022

24 ICO Conference Professor Conor Murphy of the Royal Victoria Eye and Ear Hospital and RCSI presented on complex inflammatory disorders of the anterior segment that lead to progressive and often sight threatening and painful conjunctival fibrosis. The principles of the diagnosis and management in both the acute and chronic phases of mucous membrane pemphigoid and Stevens Johnson syndrome were described. The key message was that early recognition and appropriate immunosuppressive and supportive therapies lead to a far better prognosis and quality of life in the long term for affected patients.

The final lecture was given (virtually) by former Associate Professor at Harvard Medical School and Chairman of TFOS Mr David Sullivan PhD. Mr Sullivan discussed the influence of an individuals sex (male or female) and steroid hormones on dry eye disease.

Professor Conor Murphy, Professor of Ophthalmology, Royal College of Surgeons in Ireland, Consultant Ophthalmic Surgeon, Royal Victoria Eye and Ear Hospital, Mr Samer Hamada, Clinical Lead and Consultant Ophthalmic Surgeon, Queen Victoria Hospital NHS Foundation Trust, UK, Ms Nikolina Budimlija, Ocular Surface Specialist, Institute of Eye Surgery, Waterford and Mr Tom Flynn, Consultant Ophthalmic Surgeon, Bon Secours Hospital, Cork.

A consultant in the glaucoma service at Moorfields Eye Hospital since 2009, Mr Clarke is Clinical Trials Lead for the glaucoma service with a responsibility for delivering clinical trials for new pharmaceutical treatments. He is also Joint Director of the Moorfields North Division, involved in testing and setting up new models of care including virtual clinics for glaucoma and medical retina patients.

Ms Evelyn O'Neill, Consultant Ophthalmologist, Mater Misericordiae University Hospital, Dublin provided an overview of the changes that were made at the Mater Eye Emergency Department during the pandemic in her talk highlighting the transitioning of care and lessons learned during COVID. Ocular Surface Disease Symposium Keynote speakers at the ICO Annual Conference 2022 (16th-18th May Kilkenny Convention Centre, Lyrath Estate Hotel) Ocular Surface Disease Symposium were;

Mr David Sullivan, Chairman, Board of Directors, Tear Film & Ocular Surface Society (TFOS), Boston, US

Professor Conor Murphy, Professor of Ophthalmology, Royal College of Surgeons in Ireland, Consultant Ophthalmic Surgeon, Royal Victoria Eye and Ear Hospital, Mr Samer Hamada, Clinical Lead and Consultant Ophthalmic Surgeon, Queen Victoria Hospital NHS Foundation Trust, UK, Ms Nikolina Budimlija, Ocular Surface Specialist, Institute of Eye Surgery, Waterford and Mr Tom Flynn, Consultant Ophthalmic Surgeon, Bon Secours Hospital, Cork Mr David Sullivan, Chairman, Board of Directors, Tear Film & Ocular Surface Society (TFOS), Boston, US and former Associate Professor, Department of Ophthalmology, Harvard Medical School gave a virtual presentation 'Ménage à Trois: Sex, Sex Steroids and Dry Eye Disease' at the Ocular Surface Disease Symposium, Mr Tom Flynn, Bon Secours Hospital Cork opened the Ocular Surface Disease symposium on day 2 (Tuesday, 17th May) of the ICO Annual Conference with his talk ‘Allergic eye disease: myths, mysteries and modern medicine’ . Mr Flynn discussed how allergic eye disease is a broad umbrella term for a variety of ocular surface conditions each with specific and different presentation and prognosis. He outlined the presentation and treatment of seasonal allergic conjunctivitis and atopic keratoconjunctivitis, with emphasis on management of steroid-dependent disease.

New biologic treatments for atopic dermatitis were also discussed.

Guest panelist, Mr Samer Hamada from Queen Victoria Hospital London continued the same topic in children in his talk entitled ‘Paediatric Ocular Surface Disease: JOMO (joy of missing out!) to FOMO and also talked about specific ocular surface problems in peadiatric population.

JULY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

Mr Sullivan said, "One of the most compelling epidemiologic features of dry eye disease (DED) is that it occurs predominantly in females. That such a sex-related difference exists in the prevalence of an eye disease is not a surprise, as the influence of sex on the eye has been known since the time of Hippocrates.

In the late 1800s there was widespread belief among European physicians that ocular health was dramatically influenced by sex, and that males were by no means as prone to diseases of the eye from sexual causes as females.

Since that time, many sex-related differences in the eye have been attributed to the effects of sex steroids (e.g. androgens and estrogens)."

Mr David Sullivan discussed how researchers at the Tear Film & Ocular Surface Society (TFOS) believe that recognition of these sexrelated differences and the determination of their underlying basis (e.g. sex steroid action) are extremely important. He explained such understanding may be translated into new insights into the physiological control of ocular tissues, as well as the generation of novel therapeutic strategies to treat DED. Miss Yvonne Delaney, Dean of Postgraduate Education, Irish College of Ophthalmologists is pictured during her talk to delegates at the ICO Annual Conference on the significant milestones and recent developments of the ICO National Training Programmes, and in particular the dedicated Medical Ophthalmology specialty training programme which was launched in 2017 in response to demand for specialists in the area.

Miss Yvonne Delaney, Dean of Postgraduate Education, Irish College of Ophthalmologists is pictured during her talk to delegates

25 TALK OVERVIEWS: Professor Billy Power Clinical Lead for Ophthalmology and Consultant Ophthalmic Surgeon, Royal Victoria Eye and Ear Hospital, Dublin Talk: The National Clinical Programme for Ophthalmology: Supporting the Delivery of Integrated Care Professor Power provided an overview and historical context of the Clinical Programme for Ophthalmology and Model of Care, focusing on the implementation of the integrated eye care team and dedicated cataract clinics. He also discussed the new clinical pathways for cataract, medical retina and paediatrics, the benefits and the potential challenges going forward.

Ms Chriosa O Connor Optometrist, Mater Misericordiae University Hospital, Dublin Talk: The Role of an Optometrist in a Multidisciplinary team Optometry is a new profession to join the HSE Ophthalmology Multidisciplinary (Integrated Eye Care) team in Ireland.

Chriosa O’Connor gave an overview of what roles optometrists are currently involved in since joining, including paediatrics and adult roles and transformation teams. Also what roles they could do in the future, with training and support.

Pictured (l-r) at the 'Recent Clinical Trials' session at the Irish College of Ophthalmologists Annual Conference were chair Ms Janice Brady, Consultant Ophthalmologist, University Hospital Waterford, Prof Ian Flitcroft, Consultant Ophthalmologist, Children’s Health Ireland (CHI) Temple Street and Mater Misericordiae University Hospital, Dublin (myopia focus) and Prof Tunde Peto Professor of Clinical Ophthalmology, Queen’s University, Belfast (medical retina)

ICO Dean of Postgraduate Education, Miss Yvonne Delaney, hosted a session at the ICO Conference to update members on the significant progress and development of the ICO National Training Programmes over recent years. In particular, Miss Delaney discussed the advancement of the dedicated Medical Ophthalmology specialty training programme, launched in 2017.

The standalone programme was developed in response to the demand for ophthalmic specialists to treat patients in the areas of greatest eyecare demand, namely medical retina, glaucoma amd paediatric ophthalmology, coupled with an increasing ageing demographic and the huge expansion of new medical treatments for sight threatening conditions.

This has led to a big shift in how we practice and deliver medical ophthalmology and the reconfigured national training programme has been designed to address workforce and service demands, with the curriculum mapped to the National Clinical Programme for Ophthalmology Model of Care.

Professor Anthony King, Consultant Ophthalmologist, Nottingham University Hospital, NHS and Honorary Professor of Clinical Ophthalmology at the University of Nottingham, UK gave a virtual presentation at the session on 'The Treatment of Advanced Glaucoma Study - Outcomes at 24 months'.

Ms McElnea delivered the European Society of Ophthalmology (SOE) Lecture 2022 on the topic “Oculoplastics and Orbit Today” at the ICO Annual Conference which took place from 16-18th May in the Kilkenny Convention Centre, Lyrath Estate Hotel.

Ms McElnea presented and reviewed a number of emergent ophthalmic plastics and orbit related cases of interest to trainees, general ophthalmologists and sub-specialists alike, and the safe and appropriate management of these conditions all of which have important systemic associations.

Ms Elizabeth McElnea (centre), Consultant Ophthalmologist, University Hospital Galway with Miss Yvonne Delaney, Dean of Postgraduate Education, ICO and Prof Colm O'Brien, Consultant Ophthalmic Surgeon, Mater Misericordiae and Chair of the ICO Scientific Committee.

Ms McElnea completed fellowship training in oculoplastic, orbit and lacrimal disease at the Royal Victorian Eye and Ear Hospital in Melbourne, Victoria and in cornea and anterior segment disease at Royal Perth Hospital in Perth, Western Australia before returning to Ireland and her current post at University Hospital Galway.

HOSPITALPROFESSIONALNEWS.IE | HPN • JULY 2022

New Microbiota Research Could Lift the Fog on Chemobrain Written by Dr Sarah-Jane Leigh, Government of Ireland Postdoctoral Fellow at APC Microbiome Ireland, an SFI Research Centre headquartered at University College Cork

“The mechanisms underpinning these chemobrain symptoms are poorly understood, posing a serious impediment to their clinical management” Cancer is the second-leading cause of death in Europe and imposes significant human and economic costs. Research in recent decades has primarily focused on reducing mortality and relapse rates, leading to considerable improvements to established treatment regimens as well as the advent of new therapies, specifically the development of immunotherapies and more targeted anti-cancer agents. These advancements in treatment options have dramatically improved patient care and survival for several cancers and have also exposed a number of issues around the long-term side effects of cancer therapies that impact quality of life.

What is chemobrain?

A large subset of cancer patients and survivors frequently report neuropsychiatric symptoms and impairments during and following cancer treatment, including impaired cognition, increased incidence of mood and anxiety disorders, and increased pain and fatigue which collectively resembles “brain fog” and has been termed “chemobrain”. These impairments are most frequent during and immediately following therapy, although some cancer survivors

experience these symptoms for decades after the resolution of their cancer, interfering with their well-being and return to normal life. These neuropsychiatric impairments are often difficult to quantify: while patients’ subjective reports indicate sluggish thinking and poorer cognitive performance following therapy, these are often not well captured by standard neuropsychological testing utilised in the majority of studies to date. This is most likely because standard neuropsychological tests were originally designed for diagnosis of focal lesions of the central and peripheral nervous systems, rather than diffuse damage throughout the brain.

Approaches using methods from cognitive psychology, which are designed to assess cognitive performance within healthy populations, have identified that cancer patients and survivors suffer from difficulties with concentration and attention, short-term memory and executive function.

What the Research Tells us While most research so far has shown that these neuropsychiatric symptoms and impairments are associated with traditional cytotoxic chemotherapy regimens in cancer

JULY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

patients and survivors, there is emerging evidence that newer immunotherapies1 and targeted cancer therapies2 may have similar impacts on brain health and function. The mechanisms underpinning these chemobrain symptoms are poorly understood, posing a serious impediment to their clinical management. Similarly to cancer patients and survivors, in vivo experiments with chemotherapeutic agents induce impairments in cognition and increased anxiety-like and pain behaviours. These experiments have shown that chemotherapeutic agents increase neuroinflammation, reduce neurogenesis and neurotransmitter availability, and alter neuronal morphology throughout the central and peripheral nervous systems when administered in both healthy animals and those with cancerous tumours.

The gut microbiota, cancer and chemobrain The human gastrointestinal tract is populated by an ecosystem of bacteria and other micro-organisms, collectively known as the gut microbiota, that have co-evolved alongside humans to produce a complex symbiotic relationship. The gut microbiota supports host physiology through improved energy harvest, strengthened gut integrity and barrier function, protection from infection, immune modulation3, and brain health and function.4 A healthy gut microbiota is thought to reduce the risk of cancer development, while altered gut microbiota community as well as specific gut microbes can increase the likelihood of developing gastrointestinal cancers5 (for example, Helicobacter pylori causes stomach ulcers and increases the prevalence of stomach and small intestine cancers while Fusobacterium nucleatum promotes colorectal cancer development). Furthermore, the gut microbiota can modulate cancer therapy effectiveness through direct and indirect interactions with cancer drugs: chemotherapies can transiently shift gut microbiota composition and microbial metabolite production, and baseline

The lived experience of cancer treatment means people often take longer than they anticipated to get back on their feet and fully engaged in life, and this is often due in part to chemobrain. Understanding the mechanisms at play can help find some much-needed solutions to this problem and deliver potential interventions for these behavioural impairments. The study of how microbiota-drug interactions alter drug benefits and side effects is a relatively new avenue of research with substantial scope to yield impactful new discoveries.

The development of microbiota-targeted therapies holds promise for the management of these troublesome side effects that cloud quality of life for cancer patient and survivor.

“Understanding the mechanisms at play can help find some muchneeded solutions to this problem and deliver potential interventions for these behavioural impairments” microbiota composition and exposure to antibiotics influences patient responses to immunotherapy.6

Twitter @SarahJane_Leigh Linkedin Sarah-Jane Leigh Twitter @Pharmabiotic Linkedin APC Microbiome Ireland Facebook Pharmabiotic Instagram microbiomeireland

The gut microbiota also appears to be involved in cancer therapy side effects involving the gut (diarrhoea and nausea), infection risk as well as changes in the central and peripheral nervous systems. A recent systematic review assessing the role of the microbiota in side effects reported by cancer patients concluded that microbiota composition was associated with fatigue, anxiety, depression, sleep quality, cognitive impairment and peripheral neuropathy in patients undergoing chemotherapy.7 These results are in line with emerging evidence from experiments in vivo where chemotherapy-related fatigue8 and peripheral neuropathy9 are related to microbiota composition and can be modified through interventions targeting the microbiota. So far, only a few drugs and neuropsychological symptoms have been examined and several experts in the field have identified the microbiota as a potential site for intervention in chemobrain.

References: 1. Joly F, Castel H, Tron L, Lange M, Vardy J. Potential Effect of Immunotherapy Agents on Cognitive Function in Cancer Patients.

J Natl Cancer Inst. 2020;112(2):123-127. doi:10.1093/jnci/djz168 2. Abdel-Aziz AK, Mantawy EM, Said RS, Helwa R. The tyrosine kinase inhibitor, sunitinib malate, induces cognitive impairment in vivo via dysregulating VEGFR signaling, apoptotic and autophagic machineries. Exp Neurol.

2016 Sep;283(Pt A):129-41. doi: 10.1016/j. expneurol.2016.06.004.

3. Sekirov I, Russell SL, Antunes LCM et al.

Gut Microbiota in Health and Disease.

Physiological Reviews. 2010;90(3):859-904. doi: 10.1152/physrev.00045.2009.

What is the role of drug-microbiota and brain-microbiota interactions in chemobrain?

Professors Gerard Clarke, John Cryan, and I at APC Microbiome Ireland, a Science Foundation Ireland funded research centre dedicated to the study of host-microbe interactions, are combining behavioural neuroscience and neuropharmacology approaches to address how traditional and novel cancer drugs may induce chemobrain through modulation of the gut microbiota, in collaboration with a multidisciplinary team spanning pharmacy, pharmacomicrobiomics (the study of drugmicrobiota interactions), microbiology and oncology. Our current project is grounded in the hypothesis that host-microbiota and drug-microbiota interactions underlie cancer-therapy associated behavioural impairment. Specifically, we propose that different cancer therapies will present unique drug-microbiota interactions that will modify host-microbiota interactions and subsequently behaviour.

4. Cryan, J., Dinan, T. Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nat Rev Neurosci. 2012 13, 701–712. https://doi. org/10.1038/nrn3346 5. Helmink, B.A., Khan, M.A.W., Hermann, A. et al. The microbiome, cancer, and cancer therapy. Nat Med 25, 377–388 (2019). https:// doi.org/10.1038/s41591-019-0377-7 6. Leigh SJ, Lynch CMK, Bird BRH, et al. Gut microbiota-drug interactions in cancer pharmacotherapies: implications for efficacy and adverse effects. Expert Opin Drug Metab Toxicol. 2022 Jan;18(1):5-26. doi: 10.1080/17425255.2022.2043849.

7. Song BC, Bai J. Microbiome-gut-brain axis in cancer treatment-related psychoneurological toxicities and symptoms: a systematic review. Support Care Cancer. 2021 Feb;29(2):605-617. doi: 10.1007/s00520-02005739-9.

8. Grant CV, Loman BR, Bailey MT, Pyter LM. Manipulations of the gut microbiome alter chemotherapy-induced inflammation and behavioral side effects in female mice. Brain Behav Immun. 2021 Jul;95:401-412. doi: 10.1016/j.bbi.2021.04.014.

9. Ramakrishna, C., Corleto, J., Ruegger, P.M. et al. Dominant Role of the Gut Microbiota in Chemotherapy Induced Neuropathic Pain. Sci Rep 9, 20324 (2019). https://doi. org/10.1038/s41598-019-56832-x

HOSPITALPROFESSIONALNEWS.IE | HPN • JULY 2022

Strength of Balance

Indicated for the treatment of moderate to severe active rheumatoid arthritis in adults who have responded inadequately to, or are intolerant to one or more disease modifying anti-rheumatic drugs.1 May be used as monotherapy or in combination with methotrexate.1 Refer to Summary of Product Characteristics (SmPC) before prescribing, and for full prescribing information.

JYSELECA® filgotinib 100 mg or 200 mg film-coated tablets. Indication: Jyseleca is indicated for the treatment of moderate to severe active rheumatoid arthritis in adult patients who have responded inadequately to, or who are intolerant to one or more disease modifying anti rheumatic drugs (DMARDs). Jyseleca may be used as monotherapy or in combination with methotrexate (MTX). Dosage: Adults: 200 mg once daily. Taken orally with/without food. It is recommended that tablets are swallowed whole. Laboratory Monitoring: Refer to the SmPC for information regarding laboratory monitoring and dose initiation or interruption.

Elderly: A starting dose of 100 mg once daily is recommended for patients aged 75 years and older as clinical experience is limited. Renal impairment: No dose adjustment required in patients with estimated creatinine clearance (CrCl) ≥ 60 mL/min. A dose of 100 mg of filgotinib once daily is recommended for patients with moderate or severe renal impairment (CrCl 15 to < 60 mL/min).

Not recommended in patients with CrCl < 15 mL/min. Hepatic impairment: Mild/moderate hepatic impairment: no dose adjustment required. Severe hepatic impairment: not recommended. Children (< 18years): Safety and efficacy not yet established. Contraindications: Hypersensitivity to the active substance or to any of the excipients. Active tuberculosis (TB) or active serious infections. Pregnancy. Warnings/Precautions: See SmPC for full information. Immunosuppression: Combination use, with immunosuppressants e.g. azathioprine, ciclosporin, tacrolimus, or biologic DMARDs (bDMARDs) or other Janus kinase (JAK) inhibitors is not recommended as a risk of additive

immunosuppression cannot be excluded. Infections: Infections, including serious infections such as pneumonia and opportunistic infections e.g. tuberculosis (TB), oesophageal candidiasis, and cryptococcosis have been reported. Risk benefit should be assessed prior to initiating in patients with risk factors for infections (see SmPC). Patients should be closely monitored for the development of signs and symptoms of infections during and after filgotinib treatment. Treatment should be interrupted if the patient is not responding to antimicrobial therapy, until infection is controlled. There is a higher incidence of serious infections in the elderly aged 75 years and older, caution should be used when treating this population. Tuberculosis: Patients should be screened for TB before initiating filgotinib, and filgotinib should not be administered to patients with active TB. Viral reactivation: Cases of herpes virus reactivation (e.g., herpes zoster), were reported in clinical studies (see SmPC). If a patient develops herpes zoster, filgotinib treatment should be temporarily interrupted until the episode resolves. Screening for viral hepatitis and monitoring for reactivation should be performed. Malignancy: Immunomodulatory medicinal products may increase the risk of malignancies. Malignancies were observed in clinical studies (see SmPC). Fertility: In animal studies, decreased fertility, impaired spermatogenesis, and histopathological effects on male reproductive organs were observed (see SmPC). The potential effect of filgotinib on sperm production and male fertility in humans is currently unknown. Haematological abnormalities: Do not start therapy, or temporarily stop, if Absolute Neutrophil Count (ANC) <1 × 109 cells/L, ALC <0.5 × 109 cells/L or haemoglobin <8 g/dL. Temporarily stop therapy if these values are observed during routine patient

JYSELECA, GALAPAGOS and the JYSELECA and GALAPAGOS logos are registered trademarks of Galapagos NV. © 2022 Galapagos NV. All rights reserved.

JYSELECA – a preferential JAK1 inhibitor for moderate to severe RA1 JYSELECA shows more than 5x greater potency for JAK1 over JAK2/3 and TYK21* Balancing sustained efficacy2-6 with acceptable tolerability1,7

*This is based on biochemical assays, the clinical consequence of this is unknown.

Common adverse events (≥1/100 to <1/10) include: nausea, upper respiratory tract infection, urinary tract infection, dizziness.1

Visit strengthofbalance.co.uk to learn more management. Vaccinations: Use of live vaccines during, or immediately prior to, filgotinib treatment is not recommended. Lipids: Treatment with filgotinib was associated with dose dependent increases in lipid parameters, including total cholesterol, and high-density lipoprotein (HDL) levels, while low density lipoprotein (LDL) levels were slightly increased (see SmPC). Cardiovascular risk: Rheumatoid arthritis patients have an increased risk for cardiovascular disorders. Patients should have risk factors (e.g., hypertension, hyperlipidaemia) managed as part of usual standard of care. Venous thromboembolism: Events of deep venous thrombosis (DVT) and pulmonary embolism (PE) have been reported in patients receiving JAK inhibitors including filgotinib. Caution should be used in patients with risk factors for DVT/PE, such as older age, obesity, a medical history of DVT/PE, or patients undergoing surgery, and prolonged immobilisation. Lactose content: Contains lactose; patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take filgotinib. Pregnancy/ Lactation: Filgotinib is contraindicated in pregnancy. Filgotinib should not be used during breast-feeding. Women of childbearing potential must use effective contraception during and for at least 1 week after cessation of treatment.

Driving/Using machinery: No or negligible influence, however dizziness has been reported. Side effects: See SmPC for full information. Common (≥1/100 to <1/10): nausea, upper respiratory tract infection, urinary tract infection and dizziness. Uncommon (≥1/1000 to <1/100): herpes zoster, pneumonia, neutropenia, hypercholesterolaemia and blood creatine phosphokinase increase.

Serious side effects: See SmPC for full information Legal category: POM Pack:

30 film-coated tablets/bottle Price: UK Basic NHS cost: £863.10; Ireland: POA Marketing authorisation number(s): Jyseleca 100mg film-coated tablets EU/1/20/1480/001 EU/1/20/1480/002 Jyseleca 200mg film-coated tablets EU/1/20/1480/003 EU/1/20/1480/004 Further information: Galapagos UK, Belmont House, 148 Belmont Road, Uxbridge UB8 1QS, United Kingdom 00800 7878 1345 medicalinfo@glpg.com Jyseleca® is a trademark. Date of Preparation: January 2022 IE-RA-FIL-202112-00003 Additional monitoring required Adverse events should be reported.

For Northern Ireland, reporting forms and information can be found at yellowcard.mhra.gov.uk or via the Yellow Card app (download from the Apple App Store or Google Play Store).

Adverse events should also be reported to Galapagos via email to Drug.safety.UK.Ireland@glpg.com or 00800 7878 1345 Adverse events should be reported.

For Ireland, reporting forms and information can be found at www.hpra.ie and can be reported to HPRA on +353 1 6764971.

Adverse events should also be reported to Galapagos via email to Drug.safety.UK.Ireland@glpg.com or 00800 7878 1345

References: 1. JYSELECA SPC. Available at: www.medicines.org.uk / www.medicines.ie. Last accessed: January 2022. 2. Combe B, et al. Ann Rheum Dis 2021;doi:10.1136/annrheumdis-2020-219214.

3. Genovese MC, et al. JAMA 2019;322 (4):315–325. 4. Westhovens R, et al. Ann Rheum Dis 2021;doi:10.1136/annrheumdis-2020-219213. 5. Combe B, et al. Poster presented virtually at ACR, November 3–10, 2021. 6. Buch MH, et al. Poster presented virtually at ACR, November 3–10, 2021. 7. Genovese MC, et al. Poster presented virtually at the European League Against Rheumatism (EULAR) 2020 E-Congress, June 3–6, 2020.

January 2022 IE-RA-JY-202201-00001

(pembrolizumab) Infusion 25mg/ml

KEYTRUDA as monotherapy is indicated for the treatment of advanced (unresectable or metastatic) melanoma in adults.1 Survival results from KEYNOTE-006 An open-label, multicentre, randomised, controlled, phase 3 study of KEYTRUDA monotherapy vs Ipilimumab for patients with advanced Melanoma.1-3 7-Year Overall Survival in the intention-to-treat population*

In participants who completed 2 years of KEYTRUDA and achieved Stable Disease or better*

KEYTRUDA 37.8% vs Ipilimumab 25.3% HR 0.70 (95 % CI 0.58 to 0.83)

5-year Overall Survival was 92.9% 5-year Progression Free Survival was 70.1% 103/556 (18.5%) of patients obtained stable disease or better

In the as-treated population, any grade adverse events of any cause occurred in 442 (80%) of 555 participants in the pembrolizumab group and 190 (74%) of 256 participants in the Ipilimumab group. Grade 3 or worse adverse events of any cause occurred in 96 (17%) in the pembrolizumab group and 50 (20%) in the Ipilimumab group.

system can occur simultaneously. Immune-related adverse reactions are immune-related pneumonitis, immune-related colitis, immune-related hepatitis, immune-related nephritis, immune-related endocrinopathies (including adrenal insufficiency, hypophysitis, type 1 diabetes mellitus, diabetic ketoacidosis, hypothyroidism, and hyperthyroidism), Immune-related skin adverse reactions (also including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)), Refer to SmPC for more information and management of immune-related adverse reactions. Complications of allogeneic Haematopoietic Stem Cell Transplant (HSCT): Cases of graft-versus-host-disease (GVHD) and hepatic veno-occlusive disease (VOD) have been observed in patients with classical Hodgkin lymphoma undergoing allogeneic HSCT after previous exposure to pembrolizumab. Infusion-related reactions: Grades 1, 2, 3 or 4 infusion reactions including hypersensitivity and anaphylaxis, could be seen with pembrolizumab treatment. Refer to SmPC for more information and management of infusion-related reactions. Overdose: There is no information on overdose with pembrolizumab. In case of overdose, monitor closely for signs or symptoms of adverse reactions and treat appropriately. INTERACTIONS No formal pharmacokinetic drug interaction studies have been conducted with pembrolizumab. No metabolic drug drug interactions are expected. The use of systemic corticosteroids or immunosuppressants before starting pembrolizumab should be avoided because of their potential interference with the pharmacodynamic activity and efficacy of pembrolizumab. Corticosteroids can be used as premedication, when pembrolizumab is used in combination with chemotherapy, as antiemetic prophylaxis and/or to alleviate chemotherapy-related adverse reactions. FERTILITY, PREGNANCY AND LACTATION Women of childbearing potential Women of childbearing potential should use effective contraception during treatment with pembrolizumab and for at least 4 months after the last dose of pembrolizumab. Pregnancy No data on use in pregnant women. Do not use during pregnancy unless the clinical condition of the woman requires treatment with pembrolizumab. Breast-feeding It is unknown whether pembrolizumab is secreted in human milk. A risk to newborns/ infants cannot be excluded. Fertility No clinical data available. SIDE EFFECTS Refer to SmPC for complete information on side effects. Pembrolizumab is most commonly associated with immune-related adverse reactions. Most of these reactions resolved with appropriate medical treatment or withdrawal of pembrolizumab. The most serious adverse reactions were immune-and infusion-related adverse reactions. When pembrolizumab is administered in combination with axitinib or lenvatinib, refer to the SmPC for axitinib or lenvatinib prior to initiation of treatment. For additional lenvatinib safety information related to advanced RCC see the SmPC for Kisplyx and for advanced EC see the SmPC for Lenvima. Monotherapy: Very Common: anaemia, hypothyroidism, decreased appetite, headache, dyspnea, cough, abdominal pain, nausea, vomiting, constipation, musculoskeletal pain, arthralgia, asthenia, oedema, pyrexia, diarrhoea, pruritus, rash, fatigue. Common: pneumonia, thrombocytopenia, neutropenia, lymphopenia, hyponatraemia, hypokalaemia, hypocalcaemia, insomnia, neuropathy peripheral, lethargy, dry eye, cardiac arrhythmia (including atrial fibrillation), hypertension, hyperthyroidism, insomnia, dizziness, dysgeusia, pneumonitis, colitis, dry mouth, severe skin reactions, vitiligo, dry skin, alopecia, eczema, dermatitis acneiform, erythema, dermatitis, myositis, pain in extremity, arthritis, influenza like illness, chills, AST and ALT increases, increase in blood alkaline phosphatase, hypercalcaemia, blood bilirubin increased, blood creatinine increased, infusion related reaction. In combination with chemotherapy: Very Common: neutropenia, anaemia, thrombocytopenia, leukopenia, hypothyroidism, hypokalaemia, decreased appetite, insomnia, neuropathy peripheral, headache, dizziness, dysgeusia, dyspnoea, cough, nausea, diarrhoea, vomiting, abdominal pain, constipation, alopecia, rash, pruritus, arthralgia, musculoskeletal pain, myositis, pyrexia, fatigue, asthenia, oedema, ALT increase, AST increased. Common: pneumonia, febrile neutropenia, lymphopenia, infusion related reaction, adrenal insufficiency, thyroiditis, hyperthyroidism, hyponatraemia, hypocalcaemia, lethargy, dry eye, cardiac arrhythmia (including atrial fibrillation), hypertension, pneumonitis, colitis, gastritis, dry mouth, hepatitis, severe skin reactions, erythema, dermatitis acneiform, dermatitis, dry skin, eczema, pain in extremity, arthritis, acute kidney injury, influenza-like illness, chills, blood creatinine increased, blood alkaline phosphatase increased, hypercalcaemia, blood bilirubin increased. In combination with axitinib or lenvatinib: Very Common: urinary tract infection, anaemia, hypothyroidism, decreased appetite, headache, dysgeusia, hypertension, dyspnoea, cough, diarrhoea, abdominal pain, nausea, vomiting, constipation, rash, pruritus, arthralgia, musculoskeletal pain, myositis, pain in extremity, fatigue, asthenia, oedema, pyrexia, lipase increased, alanine aminotransferase increased, aspartate aminotransferase increased, blood creatinine increased. Common: pneumonia, neutropenia, thrombocytopenia, lymphopenia, leukopenia, infusion-related reaction, adrenal insufficiency, hyperthyroidism, thyroiditis, hyponatraemia, hypokalaemia, hypocalcaemia, insomnia, dizziness, neuropathy peripheral, lethargy, dry eye, cardiac arrhythmia (including atrial fibrillation), pneumonitis, colitis, pancreatitis, gastritis, dry mouth, hepatitis, severe skin reactions, dermatitis, dry skin, erythema, dermatitis acneiform, alopecia, arthritis, nephritis, influenza like illness, chills, amylase increased, blood bilirubin increased, blood alkaline phosphatase increased, hypercalcaemia. PACKAGE QUANTITIES KEYTRUDA 25 mg/mL: 4 mL of concentrate in a 10 mL Type I clear glass vial. Legal Category: POM. Marketing Authorisation numbers EU/1/15/1024/002 Marketing Authorisation holder Merck Sharp & Dohme B.V., Waarderweg 39, 2031 BN Haarlem, The Netherlands. Date of revision: May 2022. © 2022 Merck & Co., Inc., Rahway, NJ, USA and its affiliates.. All rights reserved. Further information is available on request from: MSD, Red Oak North, South County Business Park, Leopardstown, Dublin, D18 X5K7 or from www.medicines.ie. II109_II117_II110 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: 01-2998700) References 1. KEYTRUDA (pembrolizumab) SmPC. Available at: www.medicines.ie. Accessed June 2022 2. Robert C, Carlino MS, McNeil C, et al. 7-Year Follow-Up of KEYNOTE-006: Pembrolizumab Versus Ipilimumab in Advanced Melanoma. Poster 104. Presented at the 18th International Congress of the Society for Melanoma Research; October 28-31, 2021; Virtual.

3. C. Robert, A. Ribas, J. Schachter et al. Pembrolizumab versus ipilimumab in advanced melanoma (KEYNOTE-006): post-hoc 5-year results from an open-label, multicentre, randomised, controlled, phase 3 study. Lancet Oncol. 2019; 20: 1239-1251

Red Oak North, South County Business Park, Leopardstown, Dublin D18 X5K7, Ireland.

IE-KEY-00588

KEYTRUDA® (pembrolizumab) ABRIDGED PRODUCT INFORMATION Refer to Summary of Product Characteristics before prescribing. PRESENTATION KEYTRUDA 25 mg/mL: One vial of 4 mL of concentrate contains 100 mg of pembrolizumab. INDICATIONS KEYTRUDA as monotherapy is indicated for the treatment of advanced (unresectable or metastatic) melanoma in adults. KEYTRUDA as monotherapy is indicated for the adjuvant treatment of adults with Stage III melanoma and lymph node involvement who have undergone complete resection. KEYTRUDA as monotherapy is indicated for the first-line treatment of metastatic non-small cell lung carcinoma (NSCLC) in adults whose tumours express PD-L1 with a ≥50% tumour proportion score (TPS) with no EGFR or ALK positive tumour mutations. KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of metastatic non-squamous NSCLC in adults whose tumours have no EGFR or ALK positive mutations. KEYTRUDA, in combination with carboplatin and either paclitaxel or nab-paclitaxel, is indicated for the first-line treatment of metastatic squamous NSCLC in adults.

KEYTRUDA as monotherapy is indicated for the treatment of locally advanced or metastatic NSCLC in adults whose tumours express PD-L1 with a ≥1% TPS and who have received at least one prior chemotherapy regimen. Patients with EGFR or ALK positive tumour mutations should also have received targeted therapy before receiving KEYTRUDA. KEYTRUDA as monotherapy is indicated for the treatment of adult and paediatric patients aged 3 years and older with relapsed or refractory classical Hodgkin lymphoma (cHL) who have failed autologous stem cell transplant (ASCT) or following at least two prior therapies when ASCT is not a treatment option. KEYTRUDA as monotherapy is indicated for the treatment of locally advanced or metastatic urothelial carcinoma in adults who have received prior platinum-containing chemotherapy. KEYTRUDA as monotherapy is indicated for the treatment of locally advanced or metastatic urothelial carcinoma in adults who are not eligible for cisplatin-containing chemotherapy and whose tumours express PD L1 with a combined positive score (CPS) ≥ 10. KEYTRUDA as monotherapy or in combination with platinum and 5-fluorouracil (5-FU) chemotherapy, is indicated for the first-line treatment of metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC) in adults whose tumours express PD-L1 with a CPS ≥ 1. KEYTRUDA as monotherapy is indicated for the treatment of recurrent or metastatic HNSCC in adults whose tumours express PD-L1 with a ≥ 50% TPS and progressing on or after platinum-containing chemotherapy.

KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of advanced renal cell carcinoma (RCC) in adults. KEYTRUDA, in combination with lenvatinib, is indicated for the first line treatment of advanced renal cell carcinoma in adults. KEYTRUDA as monotherapy is indicated for the adjuvant treatment of adults with renal cell carcinoma at increased risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions. KEYTRUDA as monotherapy is indicated for the first line treatment of metastatic microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer in adults. KEYTRUDA as monotherapy is indicated for the treatment of the following MSI H or dMMR tumours in adults with (a) unresectable or metastatic colorectal cancer after previous fluoropyrimidine based combination therapy, (b) advanced or recurrent endometrial carcinoma, who have disease progression on or following prior treatment with a platinum containing therapy in any setting and who are not candidates for curative surgery or radiation, (c) unresectable or metastatic gastric, small intestine, or biliary cancer, who have disease progression on or following at least one prior therapy. KEYTRUDA, in combination with platinum and fluoropyrimidine based chemotherapy, is indicated for the first-line treatment of locally advanced unresectable or metastatic carcinoma of the oesophagus or HER-2 negative gastroesophageal junction adenocarcinoma in adults whose tumours express PD-L1 with a CPS ≥ 10. KEYTRUDA, in combination with chemotherapy as neoadjuvant treatment, and then continued as monotherapy as adjuvant treatment after surgery, is indicated for the treatment of adults with locally advanced, or early stage triple negative breast cancer at high risk of recurrence. KEYTRUDA, in combination with chemotherapy, is indicated for the treatment of locally recurrent unresectable or metastatic triple negative breast cancer in adults whose tumours express PD L1 with a CPS ≥ 10 and who have not received prior chemotherapy for metastatic disease. KEYTRUDA, in combination with lenvatinib, is indicated for the treatment of advanced or recurrent endometrial carcinoma in adults who have disease progression on or following prior treatment with a platinum containing therapy in any setting and who are not candidates for curative surgery or radiation. KEYTRUDA, in combination with chemotherapy with or without bevacizumab, is indicated for the treatment of persistent, recurrent, or metastatic cervical cancer in adults whose tumours express PD L1 with a CPS ≥ 1. DOSAGE AND ADMINISTRATION See SmPC for full details. Therapy must be initiated and supervised by specialist physicians experienced in the treatment of cancer. The recommended dose of KEYTRUDA in adults is either 200 mg every 3 weeks or 400 mg every 6 weeks administered as an intravenous infusion over 30 minutes. The recommended dose of KEYTRUDA as monotherapy in paediatric patients aged 3 years and older with cHL is 2 mg/kg bodyweight (up to a maximum of 200 mg), every 3 weeks administered as an intravenous infusion over 30 minutes. For use in combination, see the Summary of Product Characteristics (SmPC) for the concomitant therapies. KEYTRUDA must not be administered as an intravenous push or bolus injection. When administering KEYTRUDA as part of a combination with intravenous chemotherapy, KEYTRUDA should be administered first. Treat patients until disease progression or unacceptable toxicity (and up to maximum duration of therapy if specified for an indication). For the adjuvant treatment of melanoma or RCC, KEYTRUDA should be administered until disease recurrence, unacceptable toxicity, or for a duration of up to one year. Refer to the SmPC for dosing in neoadjuvant and adjuvant treatment of locally advanced, or early stage triple-negative breast cancer at high risk of recurrence. KEYTRUDA, as monotherapy or as combination therapy, should be permanently discontinued (a) For Grade 4 toxicity except for: endocrinopathies that are controlled with replacement hormones; or haematological toxicity, only in patients with cHL in which KEYTRUDA should be withheld until adverse reactions recover to Grade 0-1; (b) If corticosteroid dosing cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks; (c) If a treatment-related toxicity does not resolve to Grade 0 1 within 12 weeks after last dose of KEYTRUDA; (d) If any event occurs a second time at Grade ≥ 3 severity. Patients must be given the Patient Alert Card and be informed about the risks of KEYTRUDA. Special populations Elderly: No dose adjustment necessary. Renal impairment: No dose adjustment needed for mild or moderate renal impairment. No studies in severe renal impairment. Hepatic impairment: No dose adjustment needed for mild hepatic impairment. No studies in moderate or severe hepatic impairment. Paediatric population: Safety and efficacy in children below 18 years of age not established except in paediatric patients with cHL. CONTRAINDICATIONS Hypersensitivity to the active substance or to any excipients. PRECAUTIONS AND WARNINGS Assessment of PD-L1 status When assessing the PD-L1 status of the tumour, it is important that a well-validated and robust methodology is chosen to minimise false negative or false positive determinations. Immune-related adverse reactions Immune-related adverse reactions, including severe and fatal cases, have occurred in patients receiving pembrolizumab. Most immune related adverse reactions occurring during treatment with pembrolizumab were reversible and managed with interruptions of pembrolizumab, administration of corticosteroids and/or supportive care. Immune related adverse reactions have also occurred after the last dose of pembrolizumab. Immune-related adverse reactions affecting more than one body

Date of Preparation: June 2022

*This is a 7-year follow-up post-hoc analysis and no statistical conclusions can be drawn from these results

CPD 89: MELANOMA Continuing Professional Development

CPD 60 Second Summary Malignant melanoma is the fifth most common invasive cancer nationally, with rising incidence. The main risk factor for its development is ultraviolet radiation exposure, especially intense and intermittent exposures and sun burn in fair-skinned individuals. Most cases of melanoma affect middle-aged individuals, though a significant proportion affect young adults. Males over 50 tend to present with thicker tumours, often on the trunk, and have a worse prognosis than females. Most melanomas occur de novo, with approximately 30% arising within a pre-existing mole.

Early detection and prompt excision of melanoma remains the most important element of management, with rapidaccess pigmented lesions set up nationally for this purpose.

Early stages of melanoma have excellent prognosis.

Historically, the prognosis for advanced and metastatic melanoma was very poor, though dramatic improvements in the landscape of melanoma treatment have been made in the last decade with the advent of a variety of systemic therapies for advanced and metastatic disease. These include targeted therapies such as BRAF and MEK inhibitors for BRAF-mutated melanoma, and immunotherapy agents in the form of immune checkpoint inhibitors and programmed cell-death protein 1 (PD-1) inhibitors.

Primary prevention strategies and public health messaging emphasise the importance of adequately protecting skin from the sun and selfsurveillance for early detection of suspicious lesions.

31

AUTHOR: Dr Emma Porter. Dermatology Registrar, University Hospital Limerick

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.

Malignant Melanoma of the Skin Introduction Malignant melanoma is the fifth most common invasive cancer in Ireland, with approximately 20 cases per 100,000 per year - one of the highest incidence rates globally - and rising incidence.1 Ultraviolet (UV) radiation exposure is the main risk factor for development of melanoma, particularly intense and intermittent exposures in fair-skinned individuals.2,3 Sun bed exposure is widely recognised to increased risk of melanoma, particularly when used in younger age groups.4 Further risk factors include multiple melanocytic naevi, dysplastic naevus syndrome, a family history of melanoma, and immunosuppression. Familial genetic mutations with high penetrance are rare, with CDKN2A most frequently reported in these cases. In genome-wide association studies, single nucleotide polymorphisms in multiple genes related to nevogenesis and pigmentation have been associated with melanoma, including melanocortin 1 receptor, the gene which underlies red hair and freckles.5 Median age at diagnosis was 64 years for melanoma between 2011 and 2015 in Ireland. Melanoma patients, particularly females,

tend to have a younger age profile than those with non-melanoma skin cancers, with almost 31% of all female patients and 20% of males diagnosed before age 50. Paediatric melanoma is rare.6 Males over 50 tend to present with thicker tumours, often on the trunk, and have worse prognosis.

Epidemiological studies suggest that women with melanoma have a better prognosis, regardless of whether pre or postmenopausal and when adjustments for tumour characteristics are taken into account.7,8 The majority of melanomas occur de novo, with 30% arising within a pre-existing naevus. There is emerging evidence suggesting differing characteristics of these melanomas, with naevusassociated melanoma associated with lower depth of invasion and similarities in body sites.9 Histopathological subtypes of melanoma include superficial spreading, the most common, representing a radial growth phase, and nodular (vertical growth phase). Other types include acral (hands and feet), spitzoid and desmoplastic (spindle cells).

In-situ melanoma is considered pre-cancerous, non-invasive and is limited to the epidermis, without evidence of dermal invasion on histology. Lentigo maligna is

a subset of melanoma in situ with histological evidence of photodamage, typically seen on sun-exposed areas such as the face in elderly individuals.

Diagnosis When diagnosed and treated early, melanoma has an excellent prognosis. Stage 1A carries a 5-year survival rate of 99%.

Diagnostic and therapeutic advances contribute to further improvement in survival in all stages, though advanced melanoma still carries a poor prognosis and one fifth of patients are at stage III or IV at the time of diagnosis.1 The National Cancer Control Programme (NCCP) has developed the National Melanoma GP Referral Guidelines (Figure 1) for assessment and referral of suspicious lesions via a standardised pathway to a dermatologist or plastic surgeon, the National Pigmented Lesion GP Referral form.10,11 There are 14 rapid access centres nationally to where referrals can be sent.

Standardised referral forms support inclusion of relevant clinical data for pigmented lesions including the ‘ABCDE’ system of lesion abnormalities (see Figure 1) and environmental and genetic risk factors.

Guidelines (Figure 1) for assessment and referral of suspicious lesions via a standardised pathway to a dermatologist or plastic surgeon, the National Pigmented Lesion GP Referral form. 10,11 There are 14 rapid access centres nationally to where referrals can be sent. Standardised referral forms support inclusion of relevant data for pigmented lesions including the ‘ABCDE’ system of lesion CPD 89:clinical MELANOMA abnormalities (see Figure 1) and environmental and genetic risk factors.

32

Figure 1. National Melanoma GP Referral Guidelines

identification of occult nodal metastasis with SLNB can allow consideration of systemic adjuvant therapy with an aim to reduce the risk of relapse and improve survival.

Radiological imaging NICE Guidelines 2015 and European consensus guidelines from 2019 for the management of melanoma outline recommendations for baseline staging imaging for melanoma patients – including stage IIC melanoma and above.12 A summary of these recommendations is illustrated in Table 1 (on page 34). These are general guidelines, and an individualised plan is made for each patient following multidisciplinary review.

Systemic therapy in advanced/ metastatic disease

Figure 1. National Melanoma GP Referral Guidelines

Melanoma is usually clinically Clinical margins as recommended allow. After histopathological

by NICE Guidelines are 0.5cm for suspected before histopathological confirmation, cases are discussed Melanoma is usually clinically suspected before histopathological confirmation. The use of Stage 0 or in situ melanoma, 1cm confirmation. The use of at dedicated multidisciplinary dermoscopy by dermatologists is used as standard in analysis of pigmented lesions and can for Stage I melanoma andfacilitate 2cm for dermoscopy by dermatologists meetings. The diagnosis of 17 Stage II. In some cases, topical is used as standard in analysis melanoma is explained in detail differentiation from benign lesions, and prompt excision where atypical features are present. 12 In imiquimod can be considered for of pigmented lesions and can to patients in a clinic setting, and melanoma in situ, for example if facilitate differentiation from benign information provided, usually with complete surgical excision would lesions, and prompt excision where support from a dedicated skin cause unacceptable morbidity or atypical features are present.12 In cancer clinical nurse specialist. disfigurement. special cases and where available, Following primary excision, confocal reflectance microscopy Sentinel lymph node biopsy histopathological findings are used is a further diagnostic tool in to determine staging – based on Sentinel lymph node biopsy improving clinical diagnosis. the 8th edition of the American (SLNB) involves sampling of the The COVID-19 pandemic Joint Committee on Cancer first node(s) in the draining nodal introduced unprecedented (AJCC) staging system, shown basin of the melanoma, e.g. the 15 challenges to healthcare systems in Figure 2. Breslow thickness, axillary nodes for a melanoma on worldwide, and limited access to or the depth in millimetres of the upper limb. This is a prognostic non-emergency services resulted tumour invasion into the dermis, or staging procedure rather than in lower levels of referral, and later is the most important pathological therapeutic, is typically carried out diagnosis of melanoma and skin feature, followed by the presence by plastic surgeons at the time of 13,14 Many centres cancer in general. of ulceration. Tumours with a wide local excision, and requires report more advanced tumours at Breslow thickness of <0.8mm general anaesthetic. This is offered diagnosis, though national figures and without ulceration are pT1a, to patients with tumours ≥0.8mm are not currently available. carrying an excellent prognosis Breslow thickness, estimated to (99% 5-year survival). In contrast, carry a 5% risk of sentinel lymph Management for example, a 50-year-old male node positivity. Preceding 2017, with a melanoma with Breslow the standard of care was complete Primary excision lymph node dissection for those thickness >4mm with ulceration Early detection of melanoma with a positive SLNB, however on an extremity, and no metastatic and prompt, complete excision the landmark studies MSLT-I and spread at diagnosis, has a 5-year influences prognosis and survival MSLT-II showed that there is no survival rate of 70%.16 and is the first line of management. melanoma-specific survival benefit A 2mm surgical margin around the for those that have SLNB, nor for Wide local excision lesions and a cuff of subcutaneous those with a positive SLNB who Wide local excision is performed fat is taken on primary excision. undergo immediate lymph node for all melanomas, with the aim to Some centres offer samedissection versus ultrasound surveillance.18,19 However, reduce the risk of local recurrence. day excision where resources

Metastatic disease has historically been associated with poor survival.20 Ten years ago, median overall survival of those with advanced-stage melanoma was 6-9 months.21 With the advent of targeted therapy and immunotherapy for the treatment of metastatic melanoma in the last decade, outcomes are dramatically improving.22 In 2010, targeted treatment for BRAFmutated melanoma was groundbreaking.23 This has evolved to treatment with a combination of BRAF and MEK inhibition, to reduce resistance seen in BRAF inhibitor monotherapy.24 However, less than 25% of melanomas in Ireland are BRAF-mutated, lower than other countries where this figure is closer to 40%.25 Melanoma is an immunogenic tumour, and a BRAF mutation is not required for immunotherapy.

Agents include immune checkpoint inhibitors including anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), such as ipilimumab, and programmed cell-death protein 1 (PD-1) inhibitors such as pembrolizumab and nivolumab.26 Toxicity with treatment, however, is a significant factor considered by oncologists when exploring options with patients with advanced melanoma, and not all patients will be suitable or have a preference for treatment. Several

33

Figure 2: AJCC 8th edition melanoma staging system. Source:

Figure 2: AJCC 8th edition melanoma staging system. Source: Keung Balch C,J,Gershenwald J,the etAJCC al. Key Keung E, Balch C,E, Gershenwald et al. Key changes in eighth edition melanoma staging system. Melanoma Lett. 2018;36(1): changes in the AJCC eighth edition melanoma staging system. Melanoma Lett. 2018;36(1):1–9.

1–9

Wide local excision Wide local excision is performed for all melanomas, with the aim to reduce the risk of local recurrence.

Clinical margins as recommended by NICE Guidelines are 0.5cm for Stage 0 or in situ melanoma, 1cm for Stage I melanoma and 2cm for Stage II. 17 In some cases, topical imiquimod can be considered for melanoma in situ, for example if complete surgical excision would cause unacceptable morbidity or disfigurement.

NICE Guidelines 2015 and European consensus guidelines from 2019 for the management of melanoma outline recommendations for baseline staging imaging for melanoma patients – including stage IIC melanoma and above.15 A summary of these recommendations is illustrated in Table 1. These are general guidelines, an individualised plan is made for each patient following multidisciplinary CPD 89:and MELANOMA review.

34

Guideline

Stage

Staging at baseline

Surveillance

Schedule of surveillance

NICE Guidelines 2015

Stage IIC no SLNB and

CT TAP +/- Brain

CT TAP

Stage III

CT or MRI brain if age <24 years

+/- Brain

Every 6 months for the first 3 years

Stage IIC

US

LN US

European consensus guidelines 2019

Every 3 – 6 months for the first 1-3 years

b. Chronic low intensity UV exposure c. Intense intermittent UV exposure

MRI brain CT TAP / PET-CT MRI Brain US

1. Which of the following is the strongest exogenous risk factor for melanoma development? a. Smoking

CT TAP / PET-CT

Stage III & higher

CPD Questions

LN US

CT TAP / PET-CT

Every 6 months for the first 1-3 years 3 – 6 months for the first 1-3 years

MRI brain CT TAP / PET-CT MRI Brain

3 – 6 months for the first 1-3 years

Table 1. Summary of recommendations for baseline and surveillance imaging from most recent melanoma of the immunotherapy agents are may a small number management guidelines.

Abbreviations: CTonly TAPrequire – Computed tomography of thorax, abdomen and1.pelvis.

MRI of – Table Summary approved resonance for reimbursement clinic reviews over the space of Magnetic imaging.byPET-CT –ofPositron emitted tomography-computed tomography.

US – Ultrasound. recommendations for baseline and

the HSE, including pembrolizumab, the first year before discharge, as surveillance imaging from most ipilimumab, nivolumab, along risk of recurrence is much lower.13 recent melanoma management Systemic advanced/metastatic with multipletherapy agents forin BRAF Regular clinical disease review facilitates guidelines. Abbreviations: CT mutation-positive unresectable or identification of recurrent disease, Metastatic disease has historically been associated with poor survival. 20 Ten ago, median overall TAPyears – Computed tomography of 27 metastatic melanoma. and monitors for development of a 21 thorax, abdomen and pelvis. MRI survival of those with advanced-stage melanoma was 6-9 months.

With the advent of targeted second primary melanoma (which – Magnetic resonance imaging. therapy immunotherapy treatment oftometastatic melanoma in thePET-CT last decade, outcomes can occur in up 10% of patients) Adjuvantand treatment of stage III for the – Positron emitted 22 melanoma or a non-melanoma skin cancer.

It tomography-computed tomography. are dramatically improving. In 2010, targeted treatment for BRAF-mutated melanoma was groundalso provides the opportunity for US – Ultrasound 23 Adjuvant therapy in melanoma breaking.

This has evolved to treatment with aeducation combination of BRAF and MEK inhibition, to reduce further patient regarding aims to reduce the risk of relapse 24 photoprotection However, and self- less than 25% of melanomas in Ireland are resistance seen in BRAF inhibitor monotherapy. and improve overall survival in surveillance, and psychological 25 BRAF-mutated, lowertothan to 40%.

Melanoma is an patients with moderate high other countries where this figure is closer Primary Prevention support. Patients with later stage risk resected melanoma. immunogenic tumour, Funding and a BRAF mutation is not required for immunotherapy.

Agents include melanoma may require surveillance Public health campaigns for was made available for nivolumab imaging (see Table 1). prevention of melanoma, and skin in February 2021 as monotherapy cancer in general, focus on safe for the adjuvant treatment of Vitamin D sun practices of avoiding sun adults with stage III melanoma burn, seeking shade, covering up, and lymph node involvement Following a diagnosis of using sunscreens and avoiding the who have undergone complete melanoma, the change in use of sun beds. The SunSmart resection, and pembrolizumab in behaviour in reducing sun campaign, with the ‘5 S’s’ of Slip, May 2021. It is anticipated that exposure is likely to result in Slap, Slop, Slide and Seek shade, licensing and funding for further lower levels of vitamin D has been most widely adopted, agents will continue to expand in synthesis over time, with introduced first in Australia over the near future. suboptimal levels common in the 30 years ago where it has been 28 general population at a baseline. shown to have a positive impact Clinical follow up There is some evidence that on sun-related behaviours.30 This vitamin D plays a role in melanoma Patients with melanoma are is the primary messaging used survival; higher serum vitamin D followed up in a dermatology in Ireland, promoted by Healthy is associated with thinner primary clinic with full skin examination Ireland, and emphasised each melanoma and better outcome, and assessment of draining lymph year typically beginning in May although a causal mechanism node basins on a regular basis, with media campaigns. These 29 has not been established. frequency and duration depending sun protection practices are Serum 25-hydroxyvitamin D3 on clinical stage. The first five recommended especially between levels are typically measured years are most important, as this 11am and 3pm from April to for melanoma patients to allow is the period in which 90% of September even on a cloudy advice on supplementation, with metastases occur.12 Early stage day in Ireland, and when the UV an ideal range considered to be melanoma, such as melanoma Index is 3 or greater. Children and outdoor workers should have in situ and Stage IA melanoma, 60-85 nmol/L.

d. Multiple melanocytic naevi 2. True or False: Survival rates for melanoma are better in males than females.

3. For melanoma with a positive sentinel lymph node biopsy, which of the following is the first management step? a. Complete lymph node dissection b. Ultrasound surveillance c. Commencement of adjuvant immunotherapy d. Discussion at multidisciplinary meeting 4. True or false: Systemic treatment options for a patient with metastatic nonBRAF-mutated melanoma include immunotherapy such as pembrolizumab and nivolumab, and targeted therapies such as BRAF and MEK inhibitors 5. What is the lowest stage of melanoma for which baseline imaging is recommended by NICE Guidelines 2015? a. Stage IB b. Stage IIA c. Stage IIC d. Stage IIIA

particular care taken in these measures. Furthermore, healthcare professionals can play an important role in further promoting these primary prevention practices for all patients we encounter.

References available on request

ENDOCRINOLOGY FOCUS

35

PCS

Tip of the iceberg: the hidden health consequences of polycystic ovary syndrome Written by Lauren Madden Doyle1,2, Michael W. O’Reilly1,2 1. Department of Endocrinology, Beaumont Hospital 2. Endocrinology Research Group, Department of Medicine, Royal College of Surgeons in Ireland (RCSI) Polycystic ovary syndrome (PCOS) is the most common endocrine disorder affecting women of reproductive age, with an estimated prevalence of 6-13% depending on diagnostic criteria applied.1,2 The Rotterdam diagnostic criteria were introduced in 2003 and largely replaced the 1990 National Institutes of Health (NIH) criteria. As per Rotterdam, PCOS can be diagnosed on identification of two of the following three criteria: (i) oligo- or amenorrhoea, (ii) clinical and/or biochemical evidence of androgen excess or (iii) sonographic evidence of polycystic ovaries.

This was an expansion on the previous NIH criteria, which did not include ultrasound as a diagnostic factor for PCOS. Typically, patients report a constellation of symptoms which include features of androgen excess such as hirsutism, acne or alopecia, as well as irregular or absent periods, subfertility and in many cases difficulty losing weight. Traditionally, the health impact of PCOS has focused on reproductive dysfunction, with much emphasis on anovulatory infertility and oligomenorrhoea.

In recent years, focus has shifted to the overarching associated

Lauren Madden Doyle

Michael W. O’Reilly

HOSPITALPROFESSIONALNEWS.IE | HPN • JULY 2022

36

ENDOCRINOLOGY FOCUS PCS

metabolic derangements and other long term health complications.2,6 This transition in our understanding of PCOS as a chronic metabolic condition with lifelong health implications is important, and increasing awareness amongst healthcare professionals and the general public remains a challenge. Up to 50% of women with underlying PCOS remain undiagnosed, and the first international clinical practice consensus guideline was only published in 2018.27 The role of androgen excess and insulin resistance Before considering the excess metabolic morbidity and health complications of PCOS, a brief discussion of the underlying pathogenesis is warranted.

Androgen excess is a cardinal pathological feature of PCOS, with both ovarian and adrenal phenotypes of androgen excess reported. The pathogenesis of androgen excess in PCOS reflects a complex interplay between insulin resistance and androgen metabolism, with hyperinsulinaemia driving androgen generation at the level of the ovary, adrenal and even adipose tissue.22 Weak adrenal androgenic precursors including androstenedione (A4) and dehydroepiandrosterone (DHEA) may be activated in peripheral tissues into more potent androgens such as testosterone (T) and dihydrotestoterone (DHT), while T may also be produced and secreted directly by ovarian luteal cells.

Clinically, patients will present with classic symptoms of androgen excess, namely hirsutism, acne & frontotemporal alopecia.

Generally these develop over a more protracted timeframe, and features of overt virilisation such as clitoromegaly or deepening of the voice, as observed in virilising ovarian or adrenal neoplasms, are notably absent. Cosmetic implications of androgen excess have traditionally been the focus of management in PCOS, however recent studies have linked biochemical hyperandrogenism with a direct impact on cardiovascular & metabolic health. Elevated serum T alongside low sex hormone binding globulin (SHBG) levels are closely linked with metabolic perturbations in PCOS9,10,.

These include insulin resistance, impaired glucose tolerance (IGT), type 2 diabetes mellitus (T2DM), dyslipidaemia and non-alcoholic

fatty liver disease (NAFLD). Rather than purely associative, we see emerging evidence that androgen excess is directly complicit in mediating some of the metabolic health complications in women with PCOS. Insulin resistance, a strong risk factor for development of overt hyperglycaemia, has been linked with PCOS since early models of pathogenesis. Whilst not included in diagnostic criteria, up to 75% of women with PCOS demonstrate features of insulin resistance.3,4 This observation is independent of BMI, and in vivo data suggest an intrinsic defect of insulin signalling in skeletal muscle in PCOS. The direction of causality linking androgen excess and insulin resistance in PCOS is unclear, and the associations between these metabolic perturbations remains a key focus of research in this condition.

The concept of PCOS as a disorder of insulin resistance is not a new one, with metformin employed as a therapeutic agent for menstrual cycle regulation and to enhance rates of spontaneous pregnancy in those with PCOS for decades. Initially insulin resistance results in reduced peripheral glucose uptake at key sites such as muscle, with compensatory hyperinsulinaemia maintaining euglycaemia for many years. Ultimately, however, beta cell failure can lead to overt hyperglycaemia, a process that appears to be expedited by the presence of obesity and androgen excess.2,4,5 PCOS & metabolic disease: type 2 diabetes and beyond Two large meta-analyses have demonstrated the association between PCOS and both IGT and T2DM7.8 These showed a three-fold increase in risk of IGT in women with a diagnosis of PCOS, with the highest risk demonstrated in patients of Asian ethnicity.

Similarly, the risk of T2DM was also shown to be four-fold increased compared to the general population.

The implications of insulin resistance in PCOS extend far beyond an impact on glycaemic control. Similar to IGT and T2DM, a large UK-based population study derived from primary care records has demonstrated an increased risk of NAFLD in women with PCOS. This study of 63,000 women compared with 121,000 controls found that a diagnosis of PCOS conferred a 2.0-2.4 fold increase in the risk of NAFLD.

JULY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

Significantly, this also linked circulating T levels with an increased risk of NAFLD, which highlights a potential independent role for hyperandrogenism as a potential pathogenic factor in the aetiology of PCOS-related fatty liver disease.2,9,10 Traditionally, women during their reproductive years have been perceived as having low overall cardiovascular risk, particularly in comparison to their male counterparts. A diagnosis of PCOS however, appears to change this risk profile. Overall, while the absolute risk of major adverse cardiovascular events (MACEs) remains low, data has shown there is an increased risk of cardiovascular morbidity in the PCOS cohort.

A recent retrospective cohort study of 176,000 women with PCOS in the UK CPRD dataset demonstrated a 26% increase in nonfatal myocardial infarction (MI), revascularisation & angina, when compared to age & weight adjusted controls.1, 11,12 Further analysis highlighted risk of progression was highest in those with increased BMI, T2DM & from regions of socioeconomic deprivation. While morbidity is increased, overall cardiovascular mortality and risk of cerebrovascular events is unchanged, likely due to the young age profile. Mechanistically, there are a number of potential drivers of this increased risk of cardiovascular events. At a biochemical level, insulin resistance appears to cause vasoconstriction due to reduced nitric oxide production, and leads to increased lipid trafficking and lipolysis, with patients at a subsequent increased risk of hypertension, dyslipidaemia and likely atherosclerosis. Patients with PCOS demonstrate significant derangements in lipid profiles, with reduced HDL cholesterol levels & increased triglycerides, while LDL-C levels remain unchanged.12 Anovulatory infertility and reproductive morbidity in PCOS It is long established that women with PCOS experience anovulatory cycles which manifest as oligo- or amenorrhoea. The pathological basis of anovulation appears also to be multifactorial; increased follicle recruitment may be driven by an interplay between luteninising hormone (LH) secretion and insulin, while androgen excess may lead to subsequent arrest of follicular development and consequent failure of ovulation.

Strategies to help with ovulation in PCOS primarily include weight loss through a combination of

dietary and lifestyle modifications, and metformin. Both are employed in an effort to reduce peripheral insulin resistance and address hyperinsulinaemia, with a secondary knock-on effect on ovulation. Several studies have demonstrated the efficacy of metformin in restoring ovulation through its mechanism as an insulin sensitising agent.23,24 Additional ovulation induction agents utilised to overcome anovulatory infertility include clomiphene and letrozole. Clomiphene is a selective oestrogen receptor modulator (SERM), which enhances follicular development via hypothalamic stimulation and FSH/LH production. Letrozole, an aromatase inhibitor, also enhances endogenous FSH levels and is used to induce ovulation in those desiring fertility.

Reproductive outcomes may be better for letrozole compared to clomiphene,25 and the former is recommended as first line therapy for ovulation induction in the 2018 clinical practice guideline; however larger scale randomised controlled trials are required to confirm this.27 Antenatally, patients with PCOS have an increased risk of pregnancy related complications, largely due to its associations with metabolic risk factors. One retrospective study in Japan of 1,000,000 patients on a national database highlighted an increased risk of first trimester miscarriage in the context of a prior diagnosis of PCOS. This appeared to be reduced when metformin was used as an agent for ovulation induction.17 Another metaanalysis also identified PCOS as an independent risk factor for multiple antenatal and neonatal complications including gestational diabetes mellitus (GDM), pregnancy induced hypertension (PIH) & pre-eclampsia (PET), preterm delivery, caesarean delivery, neonatal hypoglycaemia and neonatal death.18 Mental Health & Quality of Life Indices in PCOS Multiple studies have demonstrated an increased risk of depression and anxiety in patients with a diagnosis of PCOS.2,16,19,20 This is likely multifactorial, with cosmetic manifestations such as hirsutism, increased BMI & poor body image playing a role, in addition to concerns regarding subfertility. However, even when controlling for these factors, PCOS has emerged as an independent risk factor for depression & anxiety.

The role of hyperandrogenism & insulin resistance on cortical pathways may be a potential driver of this phenomenon.19,20 It is not surprising given its multiple

ENDOCRINOLOGY FOCUS

37

13. Lim SS, Davies MJ, Norman RJ, Moran LJ. Overweight, obesity and central obesity in women with polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod Update. 2012 Nov-Dec;18(6):618-37. doi: 10.1093/humupd/dms030. Epub 2012 Jul 4. PMID: 22767467 14. Barry JA, Azizia MM, Hardiman PJ. Risk of endometrial, ovarian and breast cancer in women with polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod Update. 2014 Sep-Oct;20(5):748-58.

15. Kumarendran B, Sumilo D, O'Reilly MW, et al. Increased risk of obstructive sleep apnoea in women with polycystic ovary syndrome: a population-based cohort study. Eur J Endocrinol. 2019;180(4):265-272

implications, that PCOS is also associated with reduced health related quality of life scores.

Emerging health issues in PCOS The long-term health impacts of PCOS extend beyond the increased cardiometabolic risk profile. Women with PCOS have a significantly increased risk of endometrial cancer compared to the background female population.

This is due to the unopposed proliferative effect of oestrogen on the endometrial lining caused by anovulatory cycles, with ectopic oestrogen production by increased adipose tissue also contributing in those with increased BMI.2,6,14 Theoretically, this increased oestrogen exposure may also predispose to breast cancer, however meta-analyses have thus far failed to demonstrate a concrete link between PCOS & breast cancer.14 PCOS also increases risk of obstructive sleep apnoea (OSA), independent of BMI. A recent observational cohort study of over 76,000 women with PCOS in the U.K. showed an increased risk of OSA across all ranges of BMI, with the highest risk observed in those with elevated BMI and documented anovulation or hirsutism. Insulin resistance, androgen excess and low luteal phase progesterone levels have all been postulated as potential mechanistic factors in the pathogenesis of OSA in PCOS.15 There is increasing evidence of neurological sequelae of androgen exposure in PCOS. Idiopathic intracranial hypertension (IIH) shares similar demographic features to PCOS, largely affecting women of reproductive age with co-existent obesity.

A recent study highlighted the presence of a convincing androgen excess phenotype in women with IIH, potentially implicating hyperandrogenism in its pathogenesis.26 Whether

this represents a severe variant of PCOS or a distinct clinical androgen excess phenotype remains unclear at this point.

However its importance is clear not only a potential therapeutic target for IIH, but also in the identification of androgen excess as a driver of other co-morbidities in the PCOS population.

Conclusion PCOS is a complex heterogeneous condition, with a spectrum of severity and multiple different phenotypes, and our understanding of the condition is continuing to expand. Our current perspective has evolved dramatically since the turn of the century, and it is now clearly defined as a complex chronic condition with far-reaching metabolic, reproductive and other multi-system complications.

Current research in PCOS is targeted at identifying those at highest risk of metabolic manifestations, and further elucidating the relationship between insulin resistance & hyperandrogenism.

The diversity of clinical phenotypes of women with PCOS remains a diagnostic & therapeutic challenge.

It has become increasingly clear it is a condition with expansive long term health consequences largely attributed to its metabolic risk.

As a condition which affects an estimated 5% of the population, given its metabolic burden, it undoubtedly has far-reaching public health consequences.

PCOS has often been dismissed as a purely reproductive health problem, but the bulk of emerging evidence reframes it as a chronic systemic metabolic disorder. This shift in understanding is crucial.

Future horizons for PCOS are centred on establishing which patient cohort shoulders the burden of this metabolic risk, and identifying a targeted treatment for its pathogenesis.

References 1. Fauser BC, Tarlatzis BC, Rebar RW, et al. Consensus on women's health aspects of polycystic ovary syndrome (PCOS): The Amsterdam ESHRE/ASRM-sponsored 3rd PCOS Consensus Workshop Group. Fertil Steril. 2012;97:28–38.e25 2. Allen LA, Shrikrishnapalasuriyar N, Rees DA. Long-term health outcomes in young women with polycystic ovary syndrome: A narrative review. Clin Endocrinol (Oxf). 2021 Oct 7.

3. Rosenfield RL, Ehrmann DA.The Pathogenesis of Polycystic Ovary Syndrome (PCOS): The Hypothesis of PCOS as Functional Ovarian Hyperandrogenism Revisited. Endocr Rev. 2016 Oct;37(5):467520.

4. Moghetti, P., Tosi, F. Insulin resistance and PCOS: chicken or egg?. J Endocrinol Invest 44, 233–244 (2021) 5. Andrea Dunaif, Insulin Resistance and the Polycystic Ovary Syndrome: Mechanism and Implications for Pathogenesis, Endocrine Reviews, Volume 18, Issue 6, 1 December 1997, Pages 774–800, 6. Cooney, L., Dokras, A. Beyond fertility: polycystic ovary syndrome and long-term health, Fertility and Sterility Vol. 110, No. 5, October 2018 0015-0282 7. Kakoly NS, Khomami MB, Joham AE, Cooray SD, Misso ML, Norman RJ, et al.

Ethnicity, obesity and the prevalence of impaired glucose tolerance and type 2 diabetes in PCOS: a systematic review and meta-regression. Hum Reprod Update 2018;4:455–67.

8. Moran LJ, Misso ML, Wild RA, Norman RJ. Impaired glucose tolerance, type 2 diabetes and metabolic syndrome in polycystic ovary syndrome: a systematic review and metaanalysis. Hum Reprod Update 2010;16:347–63.

9. Kumarendran, B., O'Reilly, M. W., Manolopoulos, K. N., Toulis, K. A., Gokhale, K. M., Sitch, A. J., Wijeyaratne, C. N., Coomarasamy, A., Arlt, W., & Nirantharakumar, K. (2018). Polycystic ovary syndrome, androgen excess, and the risk of nonalcoholic fatty liver disease in women: A longitudinal study based on a United Kingdom primary care database. PLoS medicine, 15(3), e1002542. https://doi.org/10.1371/journal.pmed.1002542 10. Sanchez-Garrido MA, Tena-Sempere M. Metabolic dysfunction in polycystic ovary syndrome: Pathogenic role of androgen excess and potential therapeutic strategies.

Mol Metab. 2020;35:100937. doi:10.1016/j. molmet.2020.01.001 11. Berni TR, Morgan CL, Rees DA. Women with polycystic ovary syndrome have an increased risk of major cardiovascular events: a population study. J Clin Endocrinol Metab.

2021;106:3369 12. Wekker V, van Dammen L, Koning A, et al. Long-term cardiometabolic disease risk in women with PCOS: a systematic review and meta-analysis. Hum Reprod Update.

2020;26(6):942-960. doi:10.1093/humupd/ dmaa029

16. Hart R, Doherty DA. The potential implications of a PCOS diagnosis on a woman's longterm health using data linkage. J Clin Endocrinol Metab. 2015 Mar;100(3):911-9. doi: 10.1210/jc.2014-3886. Epub 2014 Dec 22. Erratum in: J Clin Endocrinol Metab. 2015 Jun;100(6):2502 17. Pan ML, Chen LR, Chen KH. The Risk of Subsequent Miscarriage in Pregnant Women with Prior Polycystic Ovarian Syndrome: A Nationwide Population-Based Study.

Int J Environ Res Public Health. 2021 Aug 4;18(16):8253.

18. Yu HF, Chen HS, Rao DP, Gong J. Association between polycystic ovary syndrome and the risk of pregnancy complications: A PRISMA-compliant systematic review and metaanalysis. Medicine (Baltimore). 2016 De ;95(51):e4863 19. Cooney LG, Lee I, Sammel MD, Dokras A. High prevalence of moderate and severe depressive and anxiety symptoms in polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod. 2017 May 1;32(5):1075-1091 20. Dokras A, Stener-Victorin E, Yildiz BO, Li R, Ottey S, Shah D, Epperson N, Teede H. Androgen Excess- Polycystic Ovary Syndrome Society: position statement on depression, anxiety, quality of life, and eating disorders in polycystic ovary syndrome. Fertil Steril. 2018 May;109(5):888-899 21. Cena H, Chiovato L, Nappi RE. Obesity, Polycystic Ovary Syndrome, and Infertility: A New Avenue for GLP-1 Receptor Agonists. J Clin Endocrinol Metab. 2020 Aug 1;105(8):e2695–709.

22. O'Reilly MW, Kempegowda P, Walsh M, Taylor AE, Manolopoulos KN, Allwood JW, Semple RK, Hebenstreit D, Dunn WB, Tomlinson JW, Arlt W. AKR1C3-Mediated Adipose Androgen Generation Drives Lipotoxicity in Women With Polycystic Ovary Syndrome. J Clin Endocrinol Metab. 2017 Sep 1;102(9):3327-3339 23. Fleming R, Hopkinson ZE, Wallace AM, Greer IA, Sattar N. Ovarian function and metabolic factors in women with oligomenorrhea treated with metformin in a randomized double blind placebocontrolled trial. J Clin Endocrinol Metab. 2002 Feb;87(2):569-74 24. Sharpe A, Morley LC, Tang T, Norman RJ, Balen AH. Metformin for ovulation induction (excluding gonadotrophins) in women with polycystic ovary syndrome. Cochrane Database of Systematic Reviews 2019, Issue 12 25. Franik S, Eltrop SM, Kremer JAM, Kiesel L, Farquhar C. Aromatase inhibitors (letrozole) for subfertile women with polycystic ovary syndrome. Cochrane Database of Systematic Reviews 2018, Issue 5 26. O'Reilly MW, Westgate CS, Hornby C, et al. A unique androgen excess signature in idiopathic intracranial hypertension is linked to cerebrospinal fluid dynamics. JCI Insight.

2019;4(6):e125348. Published 2019 Mar 21.

27. Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome. Teede HJ, Misso ML, Costello MF, Dokras A, Laven J, Moran L, Piltonen T, Norman RJ; International PCOS Network.Fertil Steril. 2018.

HOSPITALPROFESSIONALNEWS.IE | HPN • JULY 2022

38

ENDOCRINOLOGY FOCUS OBESITY

Nutrition, Obesity and Cancer Risk Written by Kathleen A.J. Mitchelson1 and Helen M. Roche1,2 UCD Conway Institute, Nutrigenomics Research Group and Institute of Food and Health, University College Dublin, Dublin, Ireland and 2Institute for Global Food Security, Queen’s University Belfast, Belfast, Northern Ireland 1

Global obesity rates are continuously increasing, having tripled in the last fifty years. Obesity is linked with the occurrence of several co-morbidities including cardiovascular disease, insulin resistance and type 2 diabetes.

More recently, obesity has emerged as a major determinate of some cancers. There are at least 13 types of cancer which have a higher incidence rate in those who are overweight or obese, including breast, oesophageal and colorectal cancer. Additionally, individuals Figure 1: High-fat diet induced obesity with increased visceral adipose tissue. Diets predominantly composed of saturated fats (SFA) versus monounsaturated fats (MUFA) differ in adipose tissue profiles following a high-fat diet.

who are heavier, with a higher body mass index (BMI) at cancer diagnosis have a higher risk of developing a second, unrelated cancer.

Classic features of obesity include metabolic disease, characterised by high blood glucose levels, insulin resistance and persistent low grade inflammation, collectively termed ‘metabolic inflammation’. Poor diet is a well-known driver of metabolic inflammation. Dietary elements and their digested components either increase or decrease inflammation. However, we are only just beginning to understand how the foods we eat might influence cancer risk. We need to better understand if/how

High-fat diet with Saturated Fat High Metabolic Disease Risk High Cancer Risk

different dietary ingredients can regulate metabolic inflammation when a person develops obesity and consumes a high-fat diet (HFD) within the context of cancer. This will allow for a more complete understanding of the role that obesity has on metabolic inflammation in cancer pathogenesis.

OBESITY, INFLAMMATION AND GASTROINTESTINAL CANCER How does obesity and adipose effect inflammation?

The classical hallmark of obesity is the increase in adipose tissue mass. Adipose tissue is where we store excess energy as fat cells.

Although adipose tissue was initially thought to just store excess

energy, it is now appreciated to have important endocrine functions, secreting cytokines and adipokines which communicate with other cells effecting their behaviour. Adipose tissue is primarily comprised of fat-storing cells called adipocytes, which are surrounded by other cell types that play important roles in human health called the stromal vascular fraction (SVF). SVF is composed of a heterogenous collection of cells including fibroblasts, pre-adipocytes, endothelial cells and immune cells among others. These cells help adipose tissue to communicate with other organs by influencing the signals released. In obesity, the fat cells increase in number and expand in size to store excess energy.

High-fat diet with Monounsaturated Fat Lower Metabolic Disease Risk Lower Cancer Risk?

↑ adipocyte size (hypertrophy) ↓ ↓ adipocyte number (hyperplasia) ↑ ↑ pro-inflammatory macrophages ↓ ↑ pro-inflammatory cytokines ↓ ↑ insulin levels ↓ ↑ hormones↓ ↑ growth factors ↓ ↑ inflammation ↓ ↑ cancer cell production ↓?

↑/↓ Effect of HFD - SFA ↑/↓ Effect of HFD - MUFA

Figure 1 High-fat diet induced obesity with increased visceral adipose tissue Diets composed of saturated fats (SFA) versus monounsaturated JULY 2022 • predominantly HPN | HOSPITALPROFESSIONALNEWS.IE

(pembrolizumab) Infusion 25mg/ml

KEYTRUDA as monotherapy is indicated for the adjuvant treatment of adults with stage III (stage III A-C) melanoma and who have undergone complete resection.1

Results from KEYNOTE-054 A double-blind, randomised, controlled, phase 3 trial of KEYTRUDA monotherapy vs Placebo in adjuvant treatment of stage III Melanoma.1-3 3.5 Year Recurrence-Free Survival in the intention-to-treat population

3.5 Year distant Metastasis-Free Survival in the intention-to-treat population

KEYTRUDA 59.8% vs Placebo 41.4% HR 0.59 (95 % CI 0.49 to 0.70; p < 0.0001)

KEYTRUDA 65.3% vs Placebo 49.4% HR 0.60 (95% CI 0.49 to 073; p < 0.0001)

system can occur simultaneously. Immune-related adverse reactions are immune-related pneumonitis, immune-related colitis, immune-related hepatitis, immune-related nephritis, immune-related endocrinopathies (including adrenal insufficiency, hypophysitis, type 1 diabetes mellitus, diabetic ketoacidosis, hypothyroidism, and hyperthyroidism), Immune-related skin adverse reactions (also including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)), Refer to SmPC for more information and management of immune-related adverse reactions. Complications of allogeneic Haematopoietic Stem Cell Transplant (HSCT): Cases of graft-versus-host-disease (GVHD) and hepatic veno-occlusive disease (VOD) have been observed in patients with classical Hodgkin lymphoma undergoing allogeneic HSCT after previous exposure to pembrolizumab. Infusion-related reactions: Grades 1, 2, 3 or 4 infusion reactions including hypersensitivity and anaphylaxis, could be seen with pembrolizumab treatment. Refer to SmPC for more information and management of infusion-related reactions. Overdose: There is no information on overdose with pembrolizumab. In case of overdose, monitor closely for signs or symptoms of adverse reactions and treat appropriately. INTERACTIONS No formal pharmacokinetic drug interaction studies have been conducted with pembrolizumab. No metabolic drug drug interactions are expected. The use of systemic corticosteroids or immunosuppressants before starting pembrolizumab should be avoided because of their potential interference with the pharmacodynamic activity and efficacy of pembrolizumab. Corticosteroids can be used as premedication, when pembrolizumab is used in combination with chemotherapy, as antiemetic prophylaxis and/or to alleviate chemotherapy-related adverse reactions. FERTILITY, PREGNANCY AND LACTATION Women of childbearing potential Women of childbearing potential should use effective contraception during treatment with pembrolizumab and for at least 4 months after the last dose of pembrolizumab. Pregnancy No data on use in pregnant women. Do not use during pregnancy unless the clinical condition of the woman requires treatment with pembrolizumab. Breast-feeding It is unknown whether pembrolizumab is secreted in human milk. A risk to newborns/ infants cannot be excluded. Fertility No clinical data available. SIDE EFFECTS Refer to SmPC for complete information on side effects. Pembrolizumab is most commonly associated with immune-related adverse reactions. Most of these reactions resolved with appropriate medical treatment or withdrawal of pembrolizumab. The most serious adverse reactions were immune-and infusion-related adverse reactions. When pembrolizumab is administered in combination with axitinib or lenvatinib, refer to the SmPC for axitinib or lenvatinib prior to initiation of treatment. For additional lenvatinib safety information related to advanced RCC see the SmPC for Kisplyx and for advanced EC see the SmPC for Lenvima. Monotherapy: Very Common: anaemia, hypothyroidism, decreased appetite, headache, dyspnea, cough, abdominal pain, nausea, vomiting, constipation, musculoskeletal pain, arthralgia, asthenia, oedema, pyrexia, diarrhoea, pruritus, rash, fatigue. Common: pneumonia, thrombocytopenia, neutropenia, lymphopenia, hyponatraemia, hypokalaemia, hypocalcaemia, insomnia, neuropathy peripheral, lethargy, dry eye, cardiac arrhythmia (including atrial fibrillation), hypertension, hyperthyroidism, insomnia, dizziness, dysgeusia, pneumonitis, colitis, dry mouth, severe skin reactions, vitiligo, dry skin, alopecia, eczema, dermatitis acneiform, erythema, dermatitis, myositis, pain in extremity, arthritis, influenza like illness, chills, AST and ALT increases, increase in blood alkaline phosphatase, hypercalcaemia, blood bilirubin increased, blood creatinine increased, infusion related reaction. In combination with chemotherapy: Very Common: neutropenia, anaemia, thrombocytopenia, leukopenia, hypothyroidism, hypokalaemia, decreased appetite, insomnia, neuropathy peripheral, headache, dizziness, dysgeusia, dyspnoea, cough, nausea, diarrhoea, vomiting, abdominal pain, constipation, alopecia, rash, pruritus, arthralgia, musculoskeletal pain, myositis, pyrexia, fatigue, asthenia, oedema, ALT increase, AST increased. Common: pneumonia, febrile neutropenia, lymphopenia, infusion related reaction, adrenal insufficiency, thyroiditis, hyperthyroidism, hyponatraemia, hypocalcaemia, lethargy, dry eye, cardiac arrhythmia (including atrial fibrillation), hypertension, pneumonitis, colitis, gastritis, dry mouth, hepatitis, severe skin reactions, erythema, dermatitis acneiform, dermatitis, dry skin, eczema, pain in extremity, arthritis, acute kidney injury, influenza-like illness, chills, blood creatinine increased, blood alkaline phosphatase increased, hypercalcaemia, blood bilirubin increased. In combination with axitinib or lenvatinib: Very Common: urinary tract infection, anaemia, hypothyroidism, decreased appetite, headache, dysgeusia, hypertension, dyspnoea, cough, diarrhoea, abdominal pain, nausea, vomiting, constipation, rash, pruritus, arthralgia, musculoskeletal pain, myositis, pain in extremity, fatigue, asthenia, oedema, pyrexia, lipase increased, alanine aminotransferase increased, aspartate aminotransferase increased, blood creatinine increased. Common: pneumonia, neutropenia, thrombocytopenia, lymphopenia, leukopenia, infusion-related reaction, adrenal insufficiency, hyperthyroidism, thyroiditis, hyponatraemia, hypokalaemia, hypocalcaemia, insomnia, dizziness, neuropathy peripheral, lethargy, dry eye, cardiac arrhythmia (including atrial fibrillation), pneumonitis, colitis, pancreatitis, gastritis, dry mouth, hepatitis, severe skin reactions, dermatitis, dry skin, erythema, dermatitis acneiform, alopecia, arthritis, nephritis, influenza like illness, chills, amylase increased, blood bilirubin increased, blood alkaline phosphatase increased, hypercalcaemia. PACKAGE QUANTITIES KEYTRUDA 25 mg/mL: 4 mL of concentrate in a 10 mL Type I clear glass vial. Legal Category: POM. Marketing Authorisation numbers EU/1/15/1024/002 Marketing Authorisation holder Merck Sharp & Dohme B.V., Waarderweg 39, 2031 BN Haarlem, The Netherlands. Date of revision: May 2022. © 2022 Merck & Co., Inc., Rahway, NJ, USA and its affiliates.. All rights reserved. Further information is available on request from: MSD, Red Oak North, South County Business Park, Leopardstown, Dublin, D18 X5K7 or from www.medicines.ie. II109_II117_II110 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: 01-2998700) References 1. KEYTRUDA (pembrolizumab) SmPC. Available at: www.medicines.ie. Accessed June 2022 2. Eggermont AM, Blank CU, Mandalà M, Long GV, Atkinson VG, Dalle S, et al; for the EORTC Melanoma Group. Adjuvant pembrolizumab versus placebo in resected stage III melanoma (EORTC 1325-MG/KEYNOTE-054): distant metastasis-free survival results from a double-blind, randomised, controlled, phase 3 trial. Lancet Oncol 2021;22:643–654.

3. Eggermont AMM, Blank CU, Mandala M, et al. Protocol for: adjuvant pembrolizumab versus placebo in resected stage III melanoma. (N Engl J Med. 2018;378(19):1789–1801.) doi:10.1056/NEJMoa1802357.

Red Oak North, South County Business Park, Leopardstown, Dublin D18 X5K7, Ireland.

IE-KEY-00594

KEYTRUDA® (pembrolizumab) ABRIDGED PRODUCT INFORMATION Refer to Summary of Product Characteristics before prescribing. PRESENTATION KEYTRUDA 25 mg/mL: One vial of 4 mL of concentrate contains 100 mg of pembrolizumab. INDICATIONS KEYTRUDA as monotherapy is indicated for the treatment of advanced (unresectable or metastatic) melanoma in adults. KEYTRUDA as monotherapy is indicated for the adjuvant treatment of adults with Stage III melanoma and lymph node involvement who have undergone complete resection. KEYTRUDA as monotherapy is indicated for the first-line treatment of metastatic non-small cell lung carcinoma (NSCLC) in adults whose tumours express PD-L1 with a ≥50% tumour proportion score (TPS) with no EGFR or ALK positive tumour mutations. KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of metastatic non-squamous NSCLC in adults whose tumours have no EGFR or ALK positive mutations. KEYTRUDA, in combination with carboplatin and either paclitaxel or nab-paclitaxel, is indicated for the first-line treatment of metastatic squamous NSCLC in adults.

KEYTRUDA as monotherapy is indicated for the treatment of locally advanced or metastatic NSCLC in adults whose tumours express PD-L1 with a ≥1% TPS and who have received at least one prior chemotherapy regimen. Patients with EGFR or ALK positive tumour mutations should also have received targeted therapy before receiving KEYTRUDA. KEYTRUDA as monotherapy is indicated for the treatment of adult and paediatric patients aged 3 years and older with relapsed or refractory classical Hodgkin lymphoma (cHL) who have failed autologous stem cell transplant (ASCT) or following at least two prior therapies when ASCT is not a treatment option. KEYTRUDA as monotherapy is indicated for the treatment of locally advanced or metastatic urothelial carcinoma in adults who have received prior platinum-containing chemotherapy. KEYTRUDA as monotherapy is indicated for the treatment of locally advanced or metastatic urothelial carcinoma in adults who are not eligible for cisplatin-containing chemotherapy and whose tumours express PD L1 with a combined positive score (CPS) ≥ 10. KEYTRUDA as monotherapy or in combination with platinum and 5-fluorouracil (5-FU) chemotherapy, is indicated for the first-line treatment of metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC) in adults whose tumours express PD-L1 with a CPS ≥ 1. KEYTRUDA as monotherapy is indicated for the treatment of recurrent or metastatic HNSCC in adults whose tumours express PD-L1 with a ≥ 50% TPS and progressing on or after platinum-containing chemotherapy.

KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of advanced renal cell carcinoma (RCC) in adults. KEYTRUDA, in combination with lenvatinib, is indicated for the first line treatment of advanced renal cell carcinoma in adults. KEYTRUDA as monotherapy is indicated for the adjuvant treatment of adults with renal cell carcinoma at increased risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions. KEYTRUDA as monotherapy is indicated for the first line treatment of metastatic microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer in adults. KEYTRUDA as monotherapy is indicated for the treatment of the following MSI H or dMMR tumours in adults with (a) unresectable or metastatic colorectal cancer after previous fluoropyrimidine based combination therapy, (b) advanced or recurrent endometrial carcinoma, who have disease progression on or following prior treatment with a platinum containing therapy in any setting and who are not candidates for curative surgery or radiation, (c) unresectable or metastatic gastric, small intestine, or biliary cancer, who have disease progression on or following at least one prior therapy. KEYTRUDA, in combination with platinum and fluoropyrimidine based chemotherapy, is indicated for the first-line treatment of locally advanced unresectable or metastatic carcinoma of the oesophagus or HER-2 negative gastroesophageal junction adenocarcinoma in adults whose tumours express PD-L1 with a CPS ≥ 10. KEYTRUDA, in combination with chemotherapy as neoadjuvant treatment, and then continued as monotherapy as adjuvant treatment after surgery, is indicated for the treatment of adults with locally advanced, or early stage triple negative breast cancer at high risk of recurrence. KEYTRUDA, in combination with chemotherapy, is indicated for the treatment of locally recurrent unresectable or metastatic triple negative breast cancer in adults whose tumours express PD L1 with a CPS ≥ 10 and who have not received prior chemotherapy for metastatic disease. KEYTRUDA, in combination with lenvatinib, is indicated for the treatment of advanced or recurrent endometrial carcinoma in adults who have disease progression on or following prior treatment with a platinum containing therapy in any setting and who are not candidates for curative surgery or radiation. KEYTRUDA, in combination with chemotherapy with or without bevacizumab, is indicated for the treatment of persistent, recurrent, or metastatic cervical cancer in adults whose tumours express PD L1 with a CPS ≥ 1. DOSAGE AND ADMINISTRATION See SmPC for full details. Therapy must be initiated and supervised by specialist physicians experienced in the treatment of cancer. The recommended dose of KEYTRUDA in adults is either 200 mg every 3 weeks or 400 mg every 6 weeks administered as an intravenous infusion over 30 minutes. The recommended dose of KEYTRUDA as monotherapy in paediatric patients aged 3 years and older with cHL is 2 mg/kg bodyweight (up to a maximum of 200 mg), every 3 weeks administered as an intravenous infusion over 30 minutes. For use in combination, see the Summary of Product Characteristics (SmPC) for the concomitant therapies. KEYTRUDA must not be administered as an intravenous push or bolus injection. When administering KEYTRUDA as part of a combination with intravenous chemotherapy, KEYTRUDA should be administered first. Treat patients until disease progression or unacceptable toxicity (and up to maximum duration of therapy if specified for an indication). For the adjuvant treatment of melanoma or RCC, KEYTRUDA should be administered until disease recurrence, unacceptable toxicity, or for a duration of up to one year. Refer to the SmPC for dosing in neoadjuvant and adjuvant treatment of locally advanced, or early stage triple-negative breast cancer at high risk of recurrence. KEYTRUDA, as monotherapy or as combination therapy, should be permanently discontinued (a) For Grade 4 toxicity except for: endocrinopathies that are controlled with replacement hormones; or haematological toxicity, only in patients with cHL in which KEYTRUDA should be withheld until adverse reactions recover to Grade 0-1; (b) If corticosteroid dosing cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks; (c) If a treatment-related toxicity does not resolve to Grade 0 1 within 12 weeks after last dose of KEYTRUDA; (d) If any event occurs a second time at Grade ≥ 3 severity. Patients must be given the Patient Alert Card and be informed about the risks of KEYTRUDA. Special populations Elderly: No dose adjustment necessary. Renal impairment: No dose adjustment needed for mild or moderate renal impairment. No studies in severe renal impairment. Hepatic impairment: No dose adjustment needed for mild hepatic impairment. No studies in moderate or severe hepatic impairment. Paediatric population: Safety and efficacy in children below 18 years of age not established except in paediatric patients with cHL. CONTRAINDICATIONS Hypersensitivity to the active substance or to any excipients. PRECAUTIONS AND WARNINGS Assessment of PD-L1 status When assessing the PD-L1 status of the tumour, it is important that a well-validated and robust methodology is chosen to minimise false negative or false positive determinations. Immune-related adverse reactions Immune-related adverse reactions, including severe and fatal cases, have occurred in patients receiving pembrolizumab. Most immune related adverse reactions occurring during treatment with pembrolizumab were reversible and managed with interruptions of pembrolizumab, administration of corticosteroids and/or supportive care. Immune related adverse reactions have also occurred after the last dose of pembrolizumab. Immune-related adverse reactions affecting more than one body

Date of Preparation: June 2022

In the as-treated population, any grade adverse events of any cause occurred in 475 (93.3%) of 509 participants in the pembrolizumab group and 453 (90.2%) of 502 participants in the placebo group. Grade 3 or worse adverse events of any cause occurred in 161 (31.6%) in the pembrolizumab group and 93 (18.5%) in the placebo group.

40

ENDOCRINOLOGY FOCUS OBESITY

Also, the number of immune cells, T-cells and macrophages in the SVF increase. This increased cell presence disrupts the signalling system and thought to be integral to the development of chronic low-grade inflammation. This haywire signalling from adipose tissue could play an important role in obesity related cancer risk.

Generally, inflammation is viewed as a beneficial response of the immune system following injury or infection. However, persistent, non-resolving inflammation is thought to play an important role in obesity related cancer risk.

Is all adipose considered equal?

There are two main adipose (or fat) depots within the body, subcutaneous adipose tissue (SAT) which lies just underneath the skin and visceral adipose tissue (VAT) which lines the internal organs.

When adipose storage capacity is exceeded during HFD, fatty acids ‘spill out’ from adipose, increasing circulating free fatty acid concentrations within the blood resulting in accumulation in other peripheral tissues. Fat accumulation in other tissues paired with the increase in the number and activation state of immune cells leads to coordinated modulation and induction of metabolic inflammation. Even though this occurs in both the SAT and VAT depots, the VAT is thought to be the more important source of pathogenic signals.

Does obesity and visceral adipose tissue impact cancer risk?

Whilst it is accepted that obesity is linked to multiple cancer types, potentially contributing to up to

20% of cancer related deaths, exactly how this happens is less evident. Central adiposity, or VAT, seems to be particularly problematic. There are several potential mechanisms wherein the presence of excess visceral adipose mass surrounding the gastrointestinal organs, may promote cancer. Firstly, the increased basal levels of inflammation and this chronic steady state of inflammation may damage or change normal cell behaviour potentially increasing risk of tumour formation. Secondly, obesity may impair the immunosurveillance potential of immune cells to detect aberrant cells for removal. Also, obesity increases the secretion of several hormones, including insulin and insulin-like growth factor 1 (IGF-1) which may trigger cancer development.

In addition to promoting carcinogenesis, obesity may also affect the tumour microenvironment through reduced anti-tumour immunity preventing disease resolution.

Importance of obesity and specific adipose tissue depots are evident in the risk and progression of gastrointestinal cancers, specifically oesophageal and colorectal cancer. VAT of non-cancer, non-obese cancer and obese cancer patients have been studied. Interestingly, noncancer and non-obese cancer patients VAT characteristics were similar in the ability to decrease cell growth rate and invasiveness in oesophageal adenocarcinoma cancer (OAC).

Alternatively, VAT from obese cancer patients displayed an enhanced pathogenic response in OAC cells. Additionally, an increase specifically in VAT

mass is positively associated with colorectal cancer (CRC) prevalence in both men and women. VAT signals may advance tumour progression through possible pro-inflammatory/lipid pathway alterations. If that is in fact the case, the question would be could adipose biology be re-programmed to reduce cancer risk? The relationship between cancer and obesity has reinforced the importance of nutrition in gastrointestinal cancers. Current research is actively investigating the different mechanisms that explain if / how diet related obesity either triggers the initiation or promotes the progression of different cancers.

Dietary Modulators of Metabolic Inflammatory Disease Obesity is attributed to excess energy intake but not all energy is considered equal with some nutrients being more deleterious than others. Recent work from our team, and others, demonstrate that dietary elements, including dietary fatty acids, can have differential impacts on adipose tissue profile, metabolism and inflammation. Dietary fatty acids differ in their health effects.

Saturated fats (SFA) have no double bonds in their carbon backbone while monounsaturated fats (MUFA) have one double bond. Diets high in SFA (e.g. those rich in processed foods enriched in palm oil, coconut oil) induced a very adverse hypertrophic adipose profile consisting of larger adipocyte cell size and insulin resistant state. In contrast, MUFA (e.g. typically found in olive oil as part of the Mediterranean diet) do not, despite equal obesity.

Diets high in MUFA instead result in a healthier more functional, hyperplasia adipose profile

which is an increase in adipocyte cell number. Usually feeding a HFD rich in SFA increases the secretion of pro-inflammatory cytokines such as interleukin - 1β (IL-1β). IL-1β is a predominant proinflammatory cytokine in obesity, metabolic disease and cancer.

However our work suggests that IL-1β inflammation maybe impacted by the type of dietary fats in the diet. Macrophages secrete less IL-1β following stimulation when fed a diet high in MUFA, compared to a SFA rich diet. Distinct fatty acids elicit individual effects on metabolic inflammation. Replacement of SFA with MUFA may represent a dietary intervention strategy to dampen HFD mediated metabolic inflammation. Furthermore, adipose hypertrophy within the visceral adipose tissue produces a greater risk of both metabolic risk, OAC and CRC (Figure 1). We are interested in investigating if feeding different fats can alter the risk of diet induced obesity and OAC/CRC risk.

Conclusions It is probable that diet directly impacts the health and progression towards obesity, metabolic disease and cancer.

A greater understanding of the mechanisms behind the different dietary elements driving disease progression are necessary. Novel dietary interventions may be useful as a supplementary treatment approach to manage and/or prevent cancer progression.

Funding K.A.J.M. and H.M.R. are funded

by Precision Oncology Ireland (18/SPP/3522), a Science Foundation Ireland Strategic Partnership Programme.

News

Haemochromatosis Week There are at least 20,000 undiagnosed cases of Haemochromatosis also known as “iron overload” in Ireland, the Irish Haemochromatosis Association (IHA) has said.

This year, to mark World Haemochromatosis Awareness Week, 1st – 7th June 2022, the IHA aims to raise awareness of the condition and is urging people to ‘Get Checked for Haemochromatosis,’ to highlight the symptoms in order to save lives – symptoms that range from chronic tiredness and joint

pain to abdominal pain and sexual dysfunction.

Haemochromatosis is a genetic condition which causes the body to absorb too much iron. Over time this leads to a build-up of iron in the blood, bones, and organs like the liver and the heart. People with Haemochromatosis have a faulty gene which causes the normal system of iron absorption in the body to break down.

Early diagnosis is vital and if left untreated, can lead to organ damage or even premature death.

JULY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

While heart damage caused by haemochromatosis is thankfully not seen very often, when too much iron deposits in the liver it can cause cirrhosis and, in the heart, it can cause cardiomyopathy or problems with the heart muscle. It can also lead to heart failure.

Haemochromatosis is more common in Ireland than anywhere else in the world, as one in five people carry one copy of the gene and one in every 83 Irish people carry two copies of the gene,

predisposing them to develop iron overload.

Professor Suzanne Norris, Consultant in Hepatology and Gastroenterology at St James’s Hospital in Dublin said, “Ireland has the highest rates of Haemochromatosis in the world.

Ill-health from Haemochromatosis and the development of serious complications such as cirrhosis can be prevented by simple treatment and life expectancy in treated noncirrhotic patients is normal. Early diagnosis is therefore critical.”

Legal Category: POM S1A. Marketing Authorisation Holder: Pfizer Europe MA EEIG, Boulevard de la Plaine 17, 1050 Bruxelles, Belgium. For further information please contact: Pfizer Healthcare Ireland, 9 Riverwalk, National Digital Park, Citywest Business Campus, Dublin 24 or Medical Information on 1800 633 363 or at medical.information@pfizer.com T 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.

Refer to section 4.8 of the SPC for how to report adverse reactions.

Please see summary of product characteristics for more information.

PP-BIO-IRL-0149

All rights reserved.

September 2021

ENDOCRINOLOGY FOCUS

42

TYPE 2 DIABETES

Type 2 Diabetes: A Cluster of Diseases Personalised medicine in diabetes will improve care with reduced resources if we become better at diagnosing the various forms of type 2 diabetes Written by Professor Carel Le Roux, MBChB, FRCP, FRCPath, PhD, Diabetes Complications Research Centre, UCD and Dr Sarah Cooney, MBChB, Academic Intern, Beaumont Hospital

Professor Carel Le Roux

Dr Sarah Cooney

Type 2 diabetes is a heterogeneous syndrome caused by abnormalities in carbohydrate and fat metabolism. The causes of type 2 diabetes are multifactorial and include both genetic and environmental elements that affect beta cell function and tissue sensitivity.1 However, despite this

expansive description, in clinical practice currently type 2 diabetes tends to be oversimplified with a one size fits all approach. Recent developments have changed our understanding of the diversity within type 2 diabetes, which may hold the key to better treatment.

796

As it stands currently, the all-purpose approach can be seen in every aspect of type 2 diabetes. There are no hallmark clinical features, and both clinical presentation and complications vary widely between patients.2 The diagnosis is one of exclusion, based on hyperglycaemia once type 1 diabetes, monogenic or secondary causes have been ruled out as the source. The lack of a uniting diagnostic step is one of many indicators that there are likely multiple processes ongoing, that cannot all be detected through a single means.3 This may be where personalised medicine can make a difference. New technologies and analytic methods allow us to discover more refined disease subtypes that help to optimise disease management to match individual pathology.

Personalised medicine had its beginnings, and shows most benefit when it comes to monogenic, and typically rare

diseases. In type 2 diabetes this breakthrough first came in the discovery of mature onset diabetes of the young or MODY. This paved the way for the role of genetics in type 2 diabetes and theories began to emerge of type 2 diabetes as an end result of multiple pathologies- in a similar way to anaemia having a wide range of distinct causes and pathophysiological pathways.

However, as research progressed, rather than the discovery of further monogenic or high impact genes to be targeted in treatment, genome wide association studies (GWAS) identified that the majority of genetic variance is caused by a large number (>400) of common variants. Type 2 Diabetes is instead a polygenic disease with limited contribution from low frequency variants. Put into practice this means that for the majority of people it is not a single genetic variant that will be the cause for development of type 2 diabetes

Diabetologia (2017) 60:793–799 Figure 1

Diabetes component pathways

Individual

a

Diabetes

HbA1c =8.0%

b

HbA1c =8.0%

c

HbA1c =8.0%

d

HbA1c =5.0%

Not diabetes Low

High

Type 2 diabetes risk

Fig. 1 The ‘palette’ model of type 2 diabetes. The concepts are illustrated using a model of six diabetes component pathways (‘base colours’) and four individuals, of whom have diabetes. The grids display the range JULY 2022 • HPN | three HOSPITALPROFESSIONALNEWS.IE of trait variation for each of these component pathways and the position of

two dimensions here for illustrative purposes) with respect to the status of each of the component pathways (with hue denoting the mixture of type 2 diabetes-associated contributions and saturation broadly reflecting diabetic status). Some individuals, such as individual ‘a’, lie at the extremes and

COMBINING POWER AND CONFIDENCE AGAINST LDL-C* IN THE TREATMENT OF

HYPERCHOLESTEROLAEMIA

Rosuvastatin + Ezetimibe

Rosuvastatin + Ezetimibe

20 mg/10 mg

10 mg/10 mg

Rosuvastatin + Ezetimibe

40 mg/10 mg

Suvezen is indicated for substitution therapy in adult patients who are adequately controlled with rosuvastatin and ezetimibe given concurrently at the same dose level as in the fixed combination, but as separate products, as adjunct to diet for treatment of primary hypercholesterolaemia (heterozygous familial and nonfamilial) or homozygous familial hypercholesterolaemia1 Prescribing Information: Suvezen (rosuvastatin/ ezetimibe) film-coated tablets Please refer to the Summary of Product Characteristics (SmPC) for full prescribing details.

Presentations: Suvezen 10mg/10mg, 20mg/10mg and 40mg/10mg: Each film-coated tablet contains 10mg; 20mg or 40mg of rosuvastatin (as rosuvastatin calcium) respectively, and 10mg ezetimibe. Indication: Suvezen is indicated for substitution therapy in adult patients who are adequately controlled with rosuvastatin and ezetimibe given concurrently at the same dose level as in the fixed combination, but as separate products, as adjunct to diet for treatment of primary hypercholesterolaemia (heterozygous familial and non-familial) or homozygous familial hypercholesterolaemia. Dosage and Administration: The patient should be on and continue, an appropriate lipid-lowering diet, during treatment with Suvezen. Suvezen is not suitable for initial therapy. Treatment initiation or dose adjustment, if necessary, should only be done with the monocomponents and after setting the appropriate doses the switch to the fixed dose combination of the appropriate strength is possible. Patient should use the strength corresponding to their previous treatment. The recommended dose is one Suvezen tablet daily. To be administered at any time of the day, with or without food. The tablet should be swallowed whole with a drink of water. If co-administered with bile acid sequestrant (BAS), administration of Suvezen should occur either ≥2 hours before or ≥4 hours after administration of a BAS. Special populations: Paediatric (<18 years): Safety and efficacy has not been established. Elderly (>70 years): Starting dose of 5 mg rosuvastatin is recommended. The combination is not suitable for initial therapy. Hepatic impairment: Mild: No dosage adjustment is required. Moderate/Severe: Treatment with Suvezen is not recommended. Renal impairment: Mild: No dose adjustment is necessary. Moderate (creatinine clearance <60 ml/min): The recommended start dose is rosuvastatin 5mg. Race: The recommended start dose is rosuvastatin 5 mg for patients of Asian ancestry due to increased systemic exposure. The fixed dose combination is not suitable for initial therapy. Monocomponent preparations should be used to start the treatment or to modify the dose. Suvezen 40 mg/10 mg tablets are contraindicated in these patients. Genetic polymorphisms: In patients who are known to have specific types of genetic polymorphisms that can lead to increased rosuvastatin exposure, a lower daily dose of Suvezen is recommended.

Dosage in patients with pre-disposing factors to myopathy: The recommended start dose is rosuvastatin 5mg in patients with pre-disposing factors to myopathy. Suvezen 40 mg/10 mg tablets are contraindicated in some of these patients.

Concomitant therapy: The risk of myopathy (including rhabdomyolysis) is increased when Suvezen is administered concomitantly with certain medicinal products that may increase the plasma concentration of rosuvastatin (e.g. ciclosporin and certain protease inhibitors including combinations of ritonavir with atazanavir, lopinavir, and/or tipranavir). Whenever possible, alternative medications should be considered, and, if necessary, consider temporarily discontinuing Suvezen therapy. In situations where co-administration of these medicinal products with Suvezen is unavoidable, the benefit and the risk of concurrent treatment and rosuvastatin dosing adjustments should be carefully considered. Contraindications: Hypersensitivity to the active substances or excipients. Pregnancy, breast-feeding and in women of childbearing potential not using appropriate contraceptive measures. Active liver disease or any serum transaminase elevations which are unexplained, persistent or exceeding 3x the upper limit of normal (ULN). Severe renal impairment (creatinine clearance <30ml/min); myopathy or receiving concomitant ciclosporin. 40mg/10mg dose contraindicated in patients with predisposing factors for myopathy/rhabdomyolysis; such factors include: Moderate renal impairment (creatinine clearance <60ml/min), hypothyroidism, personal or family history of hereditary muscular disorders, previous history of muscular toxicity with another HMG-CoA reductase inhibitor or fibrate, alcohol abuse, situations where an increase in plasma levels of rosuvastatin may occur, Asian patients, concomitant use of fibrates.

Precautions and Warnings: Skeletal muscle effects: have been reported in rosuvastatin-treated patients with all doses and in particular with doses >20mg. As with other HMG-CoA reductase inhibitors, reporting rate for rhabdomyolysis is associated with use at doses >40mg. Post-marketing experience with ezetimibe, cases of myopathy and rhabdomyolysis have been reported. If myopathy is suspected based on muscle symptoms or is confirmed by a creatine phosphokinase (CPK) level, Suvezen and any of these other agents that the patient is taking concomitantly should be immediately discontinued. All patients starting therapy with Suvezen should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness, particularly if associated with malaise or fever. Creatine kinase (CK) measurement: CK should not be measured following strenuous exercise or in the presence of a plausible alternative cause of CK increase. If CK levels are significantly elevated at baseline (>5x ULN) a confirmatory test should be carried out within 5 – 7 days. If the repeat test confirms a baseline CK >5x ULN, treatment should not be started. Patients with pre-disposing factors for myopathy/rhabdomyolysis: Caution should be exercised in these patients.

Risk: benefit of treatment should be considered and clinical monitoring is recommended. CK levels should be measured in these patients. Therapy should be discontinued if CK levels are markedly elevated (>5x ULN) or if muscular symptoms are severe and cause daily discomfort. If symptoms resolve and CK levels return to normal, then consideration should be given to re-introducing treatment at the lowest dose. Immune-mediated necrotising myopathy (IMNM): Clinically characterised by proximal muscle weakness and elevated serum CK, has been reported very rarely during or after treatment with statins, including rosuvastatin, despite discontinuation of statin treatment. In clinical trials an increase in the incidence of myositis and myopathy has been seen in patients receiving other HMG-CoA reductase inhibitors together with fibric acid derivatives. Suvezen should not be used in any patient with an acute, serious condition suggestive of myopathy or predisposing to the development of renal failure secondary to rhabdomyolysis (e.g. sepsis, hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte disorders; or uncontrolled seizures). Liver effects: In controlled coadministration trials in patients receiving ezetimibe with statin, consecutive transaminase elevations ≥3x ULN have been observed. It is recommended that liver function tests be carried out prior to, and 3 months following, the initiation of treatment. Rosuvastatin should be discontinued or the dose reduced if the level of serum transaminases is >3x ULN. The reporting rate for serious events is higher at the 40mg dose. In patients with secondary hypercholesterolaemia caused by hypothyroidism or nephrotic syndrome, the underlying disease should be treated prior to initiating therapy with rosuvastatin. Liver disease and alcohol: As with other HMG-CoA reductase inhibitors, rosuvastatin should be used with caution in patients who consume excessive quantities of alcohol and/or have a history of liver disease. Renal effects: Proteinuria has been observed in patients treated with higher doses of rosuvastatin and was transient or intermittent in most cases. Proteinuria has not been shown to be predictive of acute

Single-pill combination of rosuvastatin and ezetimibe available in 3 doses**

or progressive renal disease. An assessment of renal function should be considered during routine follow-up of patients treated with a dose of 40mg. Diabetes mellitus: Some evidence suggests that statins raise blood glucose and in some patients, at high risk of future diabetes, may produce a level of hyperglycaemia where formal diabetes care is appropriate. This risk, however, is outweighed by the reduction in vascular risk with statins and therefore should not be a reason for stopping statin treatment. Patients at risk (fasting glucose 5.6 – 6.9mmol/l, BMI >30kg/m2, raised triglycerides, hypertension) should be monitored both clinically and biochemically according to national guidelines.

Interstitial lung disease: Exceptional cases have been reported with some statins, especially with long term therapy.

Presenting features can include dyspnoea, non-productive cough and deterioration in general health (fatigue, weight loss and fever). If it is suspected, statin therapy should be discontinued. Severe cutaneous adverse reactions: Stevens-Johnson syndrome (SJS) and drug reaction with eosinophilia and systemic symptoms (DRESS), which could be life-threatening or fatal, have been reported with rosuvastatin. If signs and symptoms suggestive of this reaction appears, Suvezen must be discontinued immediately and an alternative treatment should be considered. Treatment with Suvezen must not be restarted at any time. Protease inhibitors: Increased systemic exposure to rosuvastatin has been observed in subjects receiving rosuvastatin concomitantly with various protease inhibitors in combination with ritonavir. Consideration should be given both to the benefit of lipid lowering by use of Suvezen in HIV patients receiving protease inhibitors and the potential for increased rosuvastatin plasma concentrations when initiating and up titrating rosuvastatin doses in patients treated with protease inhibitors. The concomitant use with certain protease inhibitors is not recommended unless the dose of rosuvastatin is adjusted. Fibrates: The safety and efficacy of ezetimibe administered with fibrates have not been established. If cholelithiasis is suspected in a patient receiving Suvezen and fenofibrate, gallbladder investigations are indicated and therapy should be discontinued. Anticoagulants: If Suvezen is added to warfarin, another coumarin anticoagulant, or fluindione, the International Normalised Ratio (INR) should be appropriately monitored. Fusidic acid: Suvezen must not be co-administered with systemic formulations of fusidic acid or within 7 days of stopping fusidic acid treatment. In patients where the use of systemic fusidic acid is considered essential, statin treatment should be discontinued throughout the duration of fusidic acid treatment. There have been reports of rhabdomyolysis (including some fatalities) in patients receiving fusidic acid and statins in combination. The patient should be advised to seek medical advice immediately if they experience any symptoms of muscle weakness, pain or tenderness. Statin therapy may be reintroduced seven days after the last dose of fusidic acid. In exceptional circumstances, where prolonged systemic fusidic acid is needed, e.g., for the treatment of severe infections, the need for co-administration of Suvezen and fusidic acid should only be considered on a case by case basis and under close medical supervision. Suvezen contains lactose monohydrate and sodium: Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine. This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodiumfree’. Interactions: Contraindicated combinations: Ciclosporin. Not-recommended combinations: Fibrates and other lipid-lowering products, protease inhibitors, transporter protein inhibitors and fusidic acid. Other possible interactions: Cytochrome P450 enzymes, antacids, colestyramine, anticoagulants, Vitamin K antagonists, erythromycin, oral contraceptive/hormone replacement therapy. When coadministering rosuvastatin with other medicinal products known to increase exposure to rosuvastatin, doses should be adjusted (see SmPC for full details). The maximum daily dose should be adjusted so that the expected rosuvastatin exposure would not likely exceed that of a 40mg daily dose of rosuvastatin taken without interacting medicinal products. Fertility, Pregnancy and Breastfeeding: No clinical data are available on the use of ezetimibe during pregnancy. Potential risk from inhibition of HMG-CoA reductase outweighs the advantage of treatment during pregnancy. If a patient becomes pregnant during use of Suvezen, treatment should be discontinued immediately. Animal studies have shown excretion of medicinal product through breast milk. However, there are no data in humans. No clinical trial data on the effects of fertility in humans. Adverse Reactions: Adverse drug reactions previously reported with one of the individual components (ezetimibe or rosuvastatin) may be potential undesirable effects with Suvezen.

Common (≥1/100 to <1/10): diabetes mellitus, headache, dizziness, constipation, nausea, abdominal pain, diarrhoea, flatulence, myalgia, ALT and/or AST increased, asthenia and fatigue. Uncommon (≥1/1,000 to <1/100): decreased appetite, paraesthesia, hot flush, hypertension, cough, dyspepsia, gastroesophageal reflux disease, nausea, dry mouth, gastritis, pruritus, rash, urticaria, arthralgia, muscle spasms, neck pain, back pain, muscular weakness, pain in extremity, ALT and/or AST increased, blood CPK increased, gamma-glutamyltransferase increased, liver function test abnormal, chest pain, pain, asthenia, oedema peripheral. Rare (≥1/10,000 to <1/1,000): thrombocytopenia, hypersensitivity reactions including angioedema, pancreatitis, increased hepatic transaminases, myopathy (including myositis), rhabdomyolysis, lupus-like syndrome and muscle rupture. Very rare (<1/10,000): polyneuropathy, memory loss, jaundice, hepatitis, arthralgia, haematuria, gynaecomastia. Not known: thrombocytopenia, hypersensitivity (including rash, urticaria, anaphylaxis and angioedema), depression, peripheral neuropathy, sleep disturbances (including insomnia and nightmares), dizziness, paraesthesia, cough, dyspnoea, diarrhoea, pancreatitis, constipation, hepatitis, cholelithiasis, cholecystitis, Stevens Johnson syndrome, erythema multiforme, drug reaction with eosinophilia and systemic symptoms, immune-mediated necrotising myopathy, tendon disorders (sometimes complicated by rupture), myalgia, myopathy/ rhabdomyolysis, oedema, asthenia. Prescribers should consult the SmPC in relation to other adverse reactions.

Legal Category: POM. Marketing Authorisation Numbers: 10mg/10mg: PA0540/193/001; 20mg/10mg: PA0540/193/002; 40mg/10mg: PA0540/193/003. Marketing Authorisation Holder: Sanofi-Aventis Ireland Ltd. T/A SANOFI, Citywest Business Campus, Dublin 24, Ireland. Further information is available from: Sanofi, 18 Riverwalk, Citywest Business Campus, Dublin 24 or contact IEmedinfo@sanofi.com Date of Preparation: February 2022 (MAT-IE-2200101 v1.0)

Reference: 1. Suvezen Summary of Product Characteristics * LDL-C: Low-density lipoprotein Cholesterol ** Suvezen is available in 3 doses in Ireland. Suvezen 10mg/10mg, 20mg/10mg and 40mg/10mg: Each film-coated tablet contains 10mg; 20mg or 40mg of rosuvastatin (as rosuvastatin calcium) respectively, and 10mg ezetimibe.

Adverse events should be reported. Reporting forms and information can be found at www.hpra.ie; email: medsafety@hpra.ie Adverse events should also be reported to Sanofi Ireland Ltd. Tel: 01 403 5600.

Alternatively, send via email to IEPharmacovigilance@sanofi.com

MAT-IE-2101261 (v2.0) | April 2022

44

ENDOCRINOLOGY FOCUS Subclassification of diabetes based on clustering / R. B. Prasad & L. Groop

TYPE 2 DIABETES

estimation of resources could be focused more can be represented by different Fig. 1 subgroups. The data are fromwith theglucose ANDISforproject (All New Diabetics in Scania) (http://and Figure 2 The spectrum of diabetes insulin secretion, HOMA-B and on clusters 1-3 with clusters 4-5 1 shades reflecting the is.ludc.med.lu.se). The criteria relative used for diagnosis are as follows: T1D: age at onset < 35 years, C-peptide < 0.2 nmol insulin-sensitivity, HOMA-IS. The needing less frequent check upsL contribution of each 5 aim was to identify subgroups and more and GAD antibodies > 20; T1Dpathophysiological with relative insulin deficiency if C-peptide 0.2–0.6 nmol L 1. T2D: agepotential at onsetfor>primary 35 years, process.

7 of patients with similar aetiologyC-peptide care sole management. antibodies T2D with relative insulin deficiency 0.2–0.6 nmol L 1. LADA C-peptide > 0.6 nmol L 1, GADThose who have<10; a predominant but rather the accumulation of a of their diabetes. In 2018 they (latent autoimmune diabetes inpathway adults):will age onset > 35 years, GAD antibodies > 20; LADA light if GAD 10–20.

Similarly, to theantibodies palette model, be at seen in a purer large number of individually low identified five clusters based on clustering approach can also - for example the person who impact risk variants. singularthe hue The data clearlyEach illustrate difficulty classifying diabetic patients at diagnosis 19% this unclassifiable (adapted from these variables which had with different be used to help tailor treatment is reddish inGenetics, the diagram.

However, 6 variant only subtly increases theEpidemiology, risks of diabetic Prevention, complications.and Endocrinology: Diabetes.

Pathogenesis, Diagnosis, Treatment: Chapter 6. Genetics options themselves. Trials for those who have a diversity of risk of diabetes and it is only with of diabetes and Springer 2018). such as ADOPT and RECORD The first cluster, severe many contributors will publications end up a the amalgamation of diabetic many that complications. a that looked at these clusters autoimmune diabetes (SAID) is muddy brown or grey colour. As person is primed for developing found that SIRD responded characterised by the presence of discussed, this is the case for the disease.3 better to thiazolidinediones GADA, low insulin secretion and most patients. He acknowledged The discovery of complex trait and MARD responded better to poor metabolic control. The second this limitation and theorised etc.), and an appropriate genetic diagnosis degree of b-cell dysfunction (with the exception of 8 genetics through GWAS has sulphonylureas. cluster severe insulin deficient They may alsois a that we are better focusing our prompted theGCK development of prerequisite for optimal treatment [18].

MODY2, mutations).

Today, it is preferable to diabetes (SIDD) is characterised have implications forIndividuals response research efforts on individuals who statistical strategies focused by low insulin secretion, poor to bariatric surgery.

SIRD’s have a more dominant pathway with mutations in the KCJN11 gene have not only refer to the underlying causal gene than using on combining the myriad of metabolic control and risk of defining feature is marked insulin that can be targeted. severe The diabetes but also developmental defects, the MODY1,non2, 3significant etc. [15–17]. individually genetic A diagnosis of monogenic retinopathy. third cluster severe resistance and hyperinsulinaemia, Theas concept of a range of effects.

These are known sequencing as insulin resistant diabetes and[19, metabolic is known so-called DEND(SIRD) syndrome 20].surgery Notably, they diabetes requires many mutations in contributing pathways is polygenic scores and estimate an is characterised by severe insulin to target these pathways. A are extremely sensitive to sulfonylureas, and the same gene have been described to cause diaconsistent with the fact that individual's genetic susceptibility resistance, obesity, late onset retrospective study looked at the most patients respond to most to a disease.

However, these is markedly improved afterthatswitching betes.

With the advent of next-generation sequencandcondition markedly increased risk of different subgroups had treatments. The varying degrees scores make it evident that nephropathy.

The fourth cluster, undergone bariatric surgery from insulin to large doses of sulfonylureas ing technologies, this has become much more of response represent patients genetics is not the only element mild obesity related diabetes and compared outcomes in two [21, 22]. feasible today. whose pathophysiology most of the aetiology, as the 5% of (MOD) is characterised by obesity, centres. There was a marked aligns with that targeted by the individuals with the highest risk early onset of diabetes and good difference in rates of diabetes drug. The link between McCarthys scores have only an approximately metabolic control. The fifth cluster remission between clusters. The Heterozygous in the insulin Monogenic diabetes has become the poster child of model and personalised medicine threefold increased risk of T2DM mild age related diabetesmutations (MARD) SIRD subgroup showedgene 83% INS is that when it comes to those compared withmedicine the remainder are the second most cause of PND. precision inofdiabetes, as most mutations is characterised by late onset andcommon remission compared to 51%These of on the spectrum of the palette or the population.4 good metabolic control. non-SIRD. These are just of the mismutations result in the accumulation can and should be managed with specific therapurer hues- medication can be beginnings of the findings of the There a number of of routes Importantly, clusters were folded these proinsulin molecule the endoplasmic pies.are Carriers mutationstailored in thetoHNF1A target that(MODY3) pathway. cluster in model being applied to to disentangling the underlying equally valid in newly diagnosed 9 Forare example, if islet function is to treatment pathways. reticulum (ER) leading to ER stress and apoptoand HNF4A (MODY1) genes highly sensitive mechanism of type 2 diabetes, patients and patients with longer a major contributing pathway, and looking solely therapy, at genetics whereas sis [23].

Severe intrauterine growth retardation sulfonylurea heterozygous mutaterm diabetes (see figure 2 at the Looking to the future of precision sulfonylureas may be more does not tell the whole story. topoccurs of the page).

Thisin suggests medicine in type 2 diabetes, all beneficial for these patients. both carriers of INS as well as KCNJ11 tions in the GCK gene cause mild fasting hyperglyThe next theory focused more that the clusters are stable these models reflect steps towards mutations.

Of different note, most ofclassification these mutations caemia which does any“cluster” treatment The latest theory (15). on pathophysiological or not require rather than representing a refined method has elements common withfor molecular While this stages of the disease. that will provide powerfulhistory tool to occur desame novo, thereby knowledge of afamily Many oftaxonomy. the GCK carriers have been inon insulin McCarthys palette model in the is a different approach, still the They also linked back to genetic individualise treatment regimens not help with for identifying individuals to years before an appropriate genetic diagnosis was form of recognition of multiple principle of multiple parallel locidoes previously associated and identify patients most at risk contributing pathways, whileany pathologies prevailed. sequence. made and they could continue without diabetesa genetic risk score of complications. They show that having the distinct advantage that was significantly associated type 2 diabetes is more complex therapy.

In 2017 McCarthy introduced the they have managed to identify the with all clusters except for SIRD, than the measurement of a single concept of the palette model of dominant pathways that would be suggesting it may have a different metabolite-glucose, and that Secondary diabetes after pancreatitis diabetes (see figure 1 on page to target by identifying aetiology to the other clusters.6 combined information from a Neonatal (ND) or helpful diabetes with onset their at 42).

His theorydiabetes centred on the risk of complications. of variables or omics will Diabetes as a ofdisease ofnumber the endocrine pancreas birth first 6 months of life is also idea that or typeduring 2 diabetesthe is made Along with recognition provide a more useful stratification.

Diabetes in Scania(TND) is a studyand that up of a combination of multiple, Both pathophysiological contribution often develops after patients have suffered from an highly heterogeneous. transient The ultimate winners will be may change the future of how we simultaneous and common genetic and resultant phenotype, this patients living with This type 2 diabetes, exocrine inflammation, pancreatitis. is parpermanent forms (PND) have been reported thus classify type 2 diabetes.

This large and environmental risk factors. cluster study showed the effects but clinicians in primary and study have looked been at newlyshown diagnosed Itfar. assumed heterogeneity arising genes on ticularly development common of complicationsin South India, where Mutations in several to secondary care will also bepeople able to patients with type 2 diabetes and from a multiplicity of contributing which has the potential to change adopt to bettercalcific care develop fibrocalculous orour practice tropical cause neonatal diabetes (KCJN11, SUR1, GCK, INS, measured six simple variable at processes. In his palette model, clinical practice. Clusters 4 and for patients using fewer resources. diagnosis: age at diagnosis, BMI, 5 have low risk of complications each pathway is given a colour References available request 43 HbA1c, GADA, C-peptide together and thusªusing thisAssociation approach and individuals with diabetes 2018 The for the Publication of the Journal of Internalon Medicine

Journal of Internal Medicine, 2019, 285; 40–48 JULY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

ENDOCRINOLOGY FOCUS

45

TECHNOLOGY

Accessing Diabetes Technology in Ireland Technology used in diabetes care is changing lives of people living with diabetes. From insulin pumps and continuous glucose monitors (CGM) data to automated insulin delivery systems, ‘artificial pancreas’ that estimate and deliver insulin thanks to algorithms based on the CGM data. Technology improves management of diabetes, reduces the risk of diabetes complications – long term and severe, decreases the risk of hypoglycaemia, provides better data to inform insulin dosing, enables remote consultations, and most importantly – improves the quality of life, flexibility, and well-being. People with diabetes in Ireland are lucky to have some advanced technological tools (and all other medicines) reimbursed by the Long-Term Illness Scheme. The issue is that people with diabetes in Ireland – are frequently not using technology, many possible reasons.

Research on uptake and access to insulin pump therapy suggests that less than 7% of adults with type 1 diabetes were using pumps in Ireland in 2016, what seems to be low when compared to other Western-European countries (i.e.,

34% of adults in Germany, 15% in England and Wales). Training to commence insulin pump therapy is not available in more than half of adult diabetes clinics in Ireland, and among the main barriers to accessing it are limited resources, lack of expertise, awareness, and individual attitudes to technology of health-care professionals and people living with diabetes. The situation with insulin pump therapy looks better in paediatric care, so sooner than later, the need for improved access and follow up care for insulin pump users or those wiling to commence it will increase.

Glucose monitoring is changing diabetes care The interest and availability of continuous (CGM) or flash glucose monitoring (FGM) is much greater.

The tools that show the glucose patterns 24/7, inform whether blood glucose levels are falling down or raising, and provide the alarms (CGMs) when levels are off or are going to be off the target, are a lot more informative than standard blood glucose fingerpricking that allows for one-off

Written by Dr Kate Gajewska, Clinical Manager for Advocacy and Research, Diabetes Ireland

glucose measurement usually every couple of hours. People with diabetes are keen to use them to know more about diabetes and manage it better – the training to use it is also less intense than for the insulin pump therapy. CGM and FGM help everyone, both on pumps and injections. However, access to those is still an issue. A recent survey by Diabetes Ireland highlighted the frustration of many people with diabetes who are unable to start or had to stop using Flash Glucose Technology (FGM, Freestyle Libre) due to the lack of reimbursement and unaffordability.

Freestyle Libre is currently available only to people with Type 1 diabetes under 21 years of age, following a decision taken by the HSE in 2018. Since then, despite petitions, reports, letters and plenty of scientific evidence on the huge clinical benefits and improved quality of life, adults with diabetes still have to pay out-of-pocket to manage their diabetes with FGM. The survey conducted by Diabetes Ireland, which was completed by 754 participants at the end of 2021, has been done as part of the Patient Submission of Evidence requested by the National Centre for Pharmacoeconomics during the Health Technology Assessment (HTA) of Freestyle Libre. The HTA has been stopped and since then – Libre is still not reimbursed to adults with type 1 diabetes in Ireland. With these agerestrictions, Ireland is the only one country that does not reimburse FGM in the Western Europe.

Paying for health The survey included responses from people who used or are still using Libre, not using it, and from healthcare professionals (HCP). Of 292 of the Libre adult users who responded to the survey, 216 have or had to pay for Libre privately

It’s a game changer.

Finger prick provides a point in time reading but glucose monitoring provides an insightful trend, giving you more data and predictability, and better able to manage your diabetes as a result. (Adult, type 1 diabetes) (74%) at an approximate, minimum monthly cost of ¤120. 131 adults with diabetes are not using Libre anymore, mainly due to its cost.

Of those who have never tried Libre (152), the main reason why was that they could not afford it.

Among the respondents, 39% were FGM users, 22% were using CGM, and 37% standard blood glucose meters.

Overall, 98% of respondents living daily with diabetes and 92% of healthcare professional respondents believe that FGM should be reimbursed by the HSE for all people with diabetes based on clinical need. “The data clearly show how important the glucose monitoring technology is for people living with this burdensome condition, how it improves diabetes management, safety and most importantly quality of life” highlighted Dr Gajewska, Clinical Manager for Advocacy and Research, Diabetes Ireland.

Of the most important findings,

HOSPITALPROFESSIONALNEWS.IE | HPN • JULY 2022

46

ENDOCRINOLOGY FOCUS TECHNOLOGY

I have submitted several applications for Libre but all except one was rejected... & no reason given.

(Diabetes nurse, adult diabetes clinic)

It has changed my life, my HbA1c is the lowest it has been in 18 years because I can closely monitor changes in my sugars and identify patterns which allows me to adjust insulin dosage. Sadly, it comes with a huge cost burden and I have to sacrifice many things in order to keep my health intact. It should be available to everyone there should not be a price tag on people’s health’ (Adult, type 1 diabetes)

Dr Gajewska highlights that the majority of FGM users must pay privately to use it, which causes a significant financial burden. “One of the participants ‘had to give up their TV package’, and many had to choose and compromise on good diabetes management in order to pay their basic household expenses. Some use FGM only for a month and have a break to save money for the next month.

This is disheartening” continued Dr Gajewska adding that “Libre is reimbursed in almost all European countries and the national data from the registries show how it improves the diabetes outcomes in the population of people with diabetes. In many Western countries the newer Libre 2 (which alert on changing glucose values) is already reimbursed”.

The reimbursement of FGM under the Long-Term Illness Scheme (LTI) and removing the current age limit has been listed in Diabetes Ireland Pre-Budget Submission 2022 as a priority and will be again for 2023. “We can observe the increasing frustration among the diabetes community” says Mr Cormac Devlin, TD, Chairperson of the Diabetes Cross Parliamentary Group.

“Parliamentary Questions (PQs) questioning the unavailability of Freestyle Libre in Ireland are the

most ‘popular’ diabetes-related submissions to the Minister for Health. For example, a recent reply to a question about the rejection status of applications for FGM for people over 21 years based on clinical need stated that the proportion of rejected applications made by healthcare professionals is increasing annually from 35% in 2018 to 51% in 2020 – added Mr Devlin.

Health-care professional’s expertise not respected?

Another important survey insights showed that the majority of healthcare professional respondents had experienced the rejection of their FGM applications for their diabetes patients by the HSE with ‘no explanation provided’ which raises the question of whether it respects HCPs clinical judgment and expertise. Dr Kate Gajewska continued “Who should decide on the most appropriate treatment for a patient: an unnamed official or a diabetes specialist who knows the medical history, diabetes outcomes and the personal needs of their patient?

The HSE should trust the expertise of their well-trained diabetes specialists and allow them to make medical decisions according to their best knowledge, judgement, and clinical recommendations”.

JULY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

Professor Hilary Hoey, Consultant Paediatric Endocrinologist and Chairperson of Diabetes Ireland added “In diabetes management, data which can support patients’ and diabetes teams’ daily medical decision-making are key to minimizing the risk of costly complications development. What is difficult to understand is that some HCPs who have their FGM applications rejected, then request a more expensive CGM device for their patient, and these are much more likely to be approved”.

This is, however, good news, that people with diabetes can access continuous glucose monitoring in Ireland, and every year more and more people are using CGM. This is in line with newly proposed NICE guidelines, and EASD (European Association of Study on Diabetes) recommendations. For some, however, applications are also being rejected or not made at all.

Diabetes Ireland is continually calling for the removal of the age restriction currently in place for the Freestyle Libre so there is equal access to the technology for everyone based on clinical need. We believe that the Health Service Executive and National Centre for Pharmacoeconomics (NCPE) should trust and support those who live with diabetes (very often paying out of pocket to

access technology), and those who care for them. We believe that after 40 years of finger pricking, people with diabetes – in particular those on insulin, including those with type 2 diabetes - deserve equal access to technology that makes their lives easier, and their diabetes management better.

They deserve access to devices that protect them from hyper- and hypoglycaemia, allow for easy diabetes control and reactions, protects them from severe and long-term diabetes complications, and as a consequence improve their quality of life. People with diabetes should have access to either Flash or Continuous Glucose Monitoring, which improve their understanding of diabetes and supports the actions to be taken. We strongly believe that, nowadays, technology is the key to improving the health of those who live with diabetes.

References: https://www.diabetes.ie/ survey-highlights-frustrationamong-adults-living-withdiabetes-and-their-diabetesteams-regarding-lack-of-accessto-freestyle-libre-technology/ Gajewska KA, Biesma R, Bennett K, Sreenan S. Barriers and facilitators to accessing insulin pump therapy by adults with type 1 diabetes mellitus: a qualitative study. Acta Diabetol. 2021 Jan;58(1):93-105. doi: 10.1007/ s00592-020-01595-5. Epub 2020 Aug 30. PMID: 32862261.

Richard I.G. Holt, J. Hans DeVries, Amy Hess-Fischl, Irl B. Hirsch, et al.; The Management of Type 1 Diabetes in Adults. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).

Diabetes Care 1 November 2021; 44 (11): 2589–2625. https://doi. org/10.2337/dci21-0043

Toujeo® is available in two pre-filled insulin devices allowing you to choose the most suitable device for your patients

Toujeo® DoubleStar™ holds more units per pen than any other basal insulin pen on the market1-4 Shared features with Toujeo® SoloStar • Pen size • 5-second hold time5,6 • 42-day shelf life after first use1 • Same technical platform *Toujeo® DoubleStar™ is recommended for patients requiring at least 20 units of basal insulin per day1

References: 1. Toujeo® Summary of Product Characteristics.

2. Lantus® Summary of Product Characteristics.

3. Tresiba® Summary of Product Characteristics.

4. Levemir® Summary of Product Characteristics.

5. Toujeo® DoubleStarTM Package leaflet: information for the user.

6. Toujeo® SoloStar® Package leaflet: information for the user.

Prescribing Information: Toujeo® (insulin glargine 300 units/ml) Please refer to Summary of Product Characteristics (SmPC) before prescribing.

Presentation: Toujeo SoloStar and DoubleStar pre-filled pens. Each ml contains 300 units of insulin glargine. SoloStar pen contains 1.5ml (450 units) of solution for injection. DoubleStar pen contains 3ml (900 units) of solution for injection.

Indication: Treatment of diabetes mellitus in adults, adolescents and children from the age of 6 years. Dosage and Administration: Toujeo is administered subcutaneously, by injection into the abdominal wall, the deltoid or the thigh, once daily, at any time of the day, preferably at the same time every day. Injection sites must be rotated within a given injection area from one injection to the next in order to reduce the risk of lipodystrophy and cutaneous amyloidosis. The dose regimen (dose and timing) should be adjusted according to individual response. Do not administer intravenously. In type 1 diabetes mellitus, Toujeo must be combined with short-/ rapid-acting insulin to cover mealtime insulin requirements. In patients with type 2 diabetes mellitus, recommended daily starting dose is 0.2 units/kg followed by individual dose adjustments. Toujeo can also be given together with other anti-hyperglycaemic medicinal products. Switch between insulin glargine 100 units/ml and Toujeo: Insulin glargine 100 units/ml and Toujeo are not bioequivalent and are not directly interchangeable. When switching from insulin glargine 100 units/ml to Toujeo, this can be done on a unit to unit basis, but a higher Toujeo dose (approximately 10-18%) may be needed to achieve target ranges for plasma glucose levels. When switching from Toujeo to insulin glargine 100 units/ml, the dose should be reduced (approximately by 20%). Switching from other basal insulins to Toujeo: A change of dose and/or timing of the basal insulin and concomitant anti hyperglycaemic treatment may be required. Dose adjustments may also be required if the patient’s weight or lifestyle changes, the timing of insulin dose is changed or other circumstances arise that increase susceptibility to hypo- or hyperglycaemia. Toujeo must not be mixed or diluted with any other insulin or other medicinal products. Close metabolic monitoring is recommended during a switch and in the initial weeks thereafter. SoloStar 1-80 units per single injection in steps of 1 unit and DoubleStar 2-160 units in steps of 2 units.

When changing from Toujeo SoloStar to Toujeo DoubleStar, if the patient’s previous dose was an odd number then the dose must be increased or decreased by 1 unit. Toujeo DoubleStar prefilled pen is recommended for patients requiring at least 20 units per day. Special Populations: Insulin requirements may be diminished in the elderly or patients with renal or hepatic impairment.

Paediatric: When switching basal insulin to Toujeo, dose reduction of basal and bolus insulin needs to be considered on an individual basis, in order to minimise the risk of hypoglycaemia. The safety and efficacy of Toujeo in children and adolescents below 6 years of age have not been established. Contraindications: Hypersensitivity to insulin glargine or any excipients. Precautions and Warnings: Traceability: In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded. Toujeo is not the insulin of choice for treatment of diabetic ketoacidosis. Patients must be instructed to perform continuous rotation of the injection site to reduce the risk of developing lipodystrophy and cutaneous amyloidosis. There is a potential risk of delayed insulin absorption and worsened glycaemic control following insulin injections at sites

References: 1. Toujeo® Summary of Product Characteristics.

Date of preparation: August 2020 | MAT-IE-2000823 (v1.0)

with these reactions. A sudden change in the injection site to an unaffected area has been reported to result in hypoglycaemia. Blood glucose monitoring is recommended after the change in the injection site, and dose adjustment of antidiabetic medications may be considered. Hypoglycaemia: In case of insufficient glucose control or a tendency to hyper/hypoglycaemic episodes, the patient’s adherence to the prescribed treatment regimen, injection sites and proper injection technique and all other relevant factors must be reviewed before dose adjustment is considered. Particular caution should be exercised, and intensified blood glucose monitoring is advisable for patients in whom hypoglycaemic episodes might be of clinical relevance and in those where dose adjustments may be required. Warning signs of hypoglycaemia may be changed, less pronounced or absent in certain risk groups, potentially resulting in severe hypoglycaemia and loss of consciousness. Risk groups include patients in whom glycaemic control is markedly improved, hypoglycaemia develops gradually, an autonomic neuropathy is present, or who are elderly. The prolonged effect of subcutaneous insulin glargine may delay recovery from hypoglycaemia. Intercurrent illness: Requires intensified metabolic monitoring and often it is necessary to adjust the insulin dose. Insulin antibodies: administration may cause insulin antibodies to form. Use with pioglitazone: Cases of cardiac failure have been reported when pioglitazone was used in combination with insulin, especially in patients with risk factors for development of cardiac heart failure. If the combination is used, patients should be observed for signs and symptoms of heart failure, weight gain and oedema. Pioglitazone should be discontinued if any deterioration in cardiac symptoms occurs.

Medication errors: Insulin labels must always be checked before each injection to avoid errors between Toujeo and other insulins.

Patients must be instructed to never use a syringe to remove Toujeo from the SoloStar or DoubleStar pre-filled pen, A new sterile needle must be attached before each injection. Needles must not be re-used. Pregnancy and lactation: There is no data from exposed pregnancies in controlled clinical trials. However, there is a large amount of data on use of insulin glargine 100 units/ ml in pregnant women indicating no specific adverse effects on pregnancy and no specific malformative nor feto/neonatal toxicity.

The use of Toujeo may be considered during pregnancy, if clinically needed. Careful monitoring of glucose control is essential.

It is unknown if insulin glargine is excreted in breast milk. Interactions: Substances that affect glucose metabolism may require adjustment of insulin glargine. Adverse Reactions: Very common: Hypoglycaemia. Prolonged or severe hypoglycaemia may be life-threatening. Common: Lipohypertrophy, injection site reactions, including redness, pain, itching, hives, swelling, or inflammation.

Legal Category: POM. Marketing Authorisation Number: SoloStar 3 Pen pack: EU/1/00/133/034, DoubleStar EU/1/00/133/038.

Marketing Authorisation Holder: Sanofi Aventis Deutschland GmbH, D-65926 Frankfurt am Main, Germany. Further information is available from: Medical Information, Sanofi 18 Riverwalk, Citywest Business Campus, Dublin 24 or contact IEmedinfo@sanofi. com. Date of preparation: July 2020.

Adverse events should be reported. Reporting forms and information can be found at www.hpra.ie; email: medsafety@hpra.ie Adverse events should also be reported to Sanofi Ireland Ltd. Tel: 01 403 5600.

Alternatively, send via email to IEPharmacovigilance@sanofi.com

48

ENDOCRINOLOGY FOCUS EDUCATION

Structured Education for People living with Type 2 Diabetes Clair Naughton, Regional Development Officer, Diabetes Ireland

Type 2 diabetes (T2DM) is a condition that can be complex to manage, with most of the management decided on daily by the person living with diabetes.

Effective self-management of diabetes requires knowledge, skills and confidence as many decisions and healthy lifestyle choices need to be made by each individual day to day. Equipping a person with self-management skills and promoting empowerment in selfcare is challenging for healthcare professionals in a clinical setting, given the limited time for consultation and everything that needs to be discussed in a routine diabetes review. Self-management support interventions such as structured patient education (SPE) programmes are widely accepted to be an integral part of the management of T2DM. The HIQA Health Technology Assessment of Chronic Disease Self-Management Support

Interventions published in December 2015 showed there is very good evidence that SPE, can improve blood glucose control in patients with T2DM. This report also suggests that diabetes self-management education programmes are cost effective relative to usual care.

One of the recommendations from the HSE Model of Integrated care for the patients with Type 2 diabetes is that “within three months of being newly diagnosed with Type 2 diabetes people should receive a structured type 2 diabetes education package. This package will give the patient appropriate dietetic input and advice regarding their clinical care”.

Currently in Ireland there are three structured education programmes for people with T2DM: CODE – Community Orientated Diabetes Education, DESMOND – Diabetes Education and Self-Management

“I really enjoyed the CODE zoom meeting, and it was lovely to meet other people with type 2 diabetes. The zoom meeting really worked for me, I found it very informative, and it has helped me to understand diabetes better and the importance of keeping track and understanding the jargon of blood tests.”

Comments for CODE participant

for On-going and Newly Diagnosed diabetes and DISCOVER DIABETES - Diabetes Insights and self-care options via education and reflection. All three programmes are supported by the HSE and are free to attend.

CODE (Community Orientated Diabetes Education) is Diabetes Ireland’s structured education programme for people living with T2DM. Running since 2008, the programme shows positive results for people who attend in

biomedical markers, knowledge, empowerment, and quality of life.

CODE is philosophically based on empowerment, empathy, and self-efficacy. The structured curriculum is delivered by diabetes healthcare professionals with accredited facilitation training, using the theories of adult learning to ensure that learning is needs based, structured, developmental, and participatory.

The delivery of the programme is such that most of the learning takes places through group discussion and shared experiences. The format of the programme makes diabetes information more accessible and ensures that knowledge is imparted based on the unique needs of each group. CODE allows people to speak about their diabetes, in a supportive setting for the benefit of all in the group.

Time is allocated for feedback on self-management behaviours, healthy eating and physical activity planning, management targets and goal setting.

Currently being delivered online CODE supports and supplements care from the individual’s own diabetes team so that knowledge and skills are reinforced placing emphasis on the personal responsibility each individual has to manage their diabetes. CODE empowers individuals to take an active role in their diabetes care, to live healthily and to maintain and improve their quality of life through informed decision making.

Delivered over four 2-hour sessions (the first 3 sessions are held over 3 consecutive weeks, a 10 week phone call and a final session held at six months), CODE has the flexibility to meet the needs of each individual group.

Topics covered include: Week 1 • Personal story, what are the collective needs of the group • Explanation of types of diabetes, risk factors, signs and symptoms • What are normal glucose levels and understanding hypo and hyperglycaemia • Treatments for diabetes

JULY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

ENDOCRINOLOGY FOCUS

Type 2 & Prediabetes Online Programme

Improve your health & live a better life 4 sessions 2 hours duration 3 sessions over 3 weeks Final session 6 months later

Supported by the HSE

Diabetes explained Signs & symptoms/ Risk factors Blood glucose management Health eating with explanation on what foods raise glucose levels with advice on carbohydrates and portion sizes Physical activity and its benefits Planning behaviour change Complications relating to diabetes – Importance of a regular & annual review & what the tests mean

REGISTER AT WWW.DIABETES.IE TYPE 2 ONLINE EDUCATION

info@diabetes.ie

49

Week 2

Final sessions at 6 months

• Physical activity - benefits, barriers and recommendations

• Feedback on personal progress • Recap of topics healthy eating, physical activity and annual review checklist

• Understanding healthy eating guidelines for T2DM, • Understanding carbohydrates and how portions affect glucose levels • Individual goal setting Week 3 • Potential complications of diabetes and the importance of screening at annual review • Understanding routine blood results • Behaviour change and individual goal setting • Entitlements • Miscellaneous topics that are relevant to the group e.g driving, planning pregnancy Week 10 phone call with facilitator and each individual to give support, discuss personal goal setting and answer any queries the person may have.

01 842 8118

• Review of blood results and measurements • Entitlements, employment, travel insurance and any outstanding queries • Sign posting to additional resources HSE living well programme, Diabetes Ireland additional supports and membership Anyone wishing to do CODE can register their interest via the Diabetes Ireland website on www.diabetes.ie or telephone 01 842 8118 References Health Technology Assessment of Chronic Disease Self-Management support interventions. December 2015 Available at: https://www.hiqa.ie/reportsand-publications/health-technologyassessment/hta-chronic-disease-selfmanagement (assessed June 1st) Model of Integrated Care for Patients with Type 2 Diabetes 2018 available at: https://www.hse.ie/eng/about/who/ cspd/ncps/diabetes/moc/

Diabetes News

National Paediatric Diabetes Audit Study Report The National Office of Clinical Audit (NOCA) has announced the publication of the National Paediatric Diabetes Audit Feasibility Study Report.

The incidence of type 1 diabetes mellitus (T1DM) among children and young people in Ireland is one of the highest in Europe, with diabetes incidence rates in the top 25% worldwide. Over the last 25 years, the incidence rate has risen from 16.3 cases per 100,000 population <15yrs in 1997 to 27.3 per 100,000 in 2008 but more recent data shows a stabilisation of the rate to 27.1 cases per 100,000 population in 2018. Management of this chronic condition places huge demands on affected individuals, their families, and the health service. Paediatric T1DM care requires prioritisation because of its high incidence and the significant long-term consequences of suboptimal care.

No national paediatric diabetes audit (NPDA) exists in Ireland,

and available data originate from single-centre, stand-alone, or retrospective studies. The lack of reliable data precludes healthcare professionals from making informed decisions about how to improve services, and means that disparities in paediatric diabetes care may not be identified. A national audit of paediatric T1DM will highlight areas of good practice, identify areas for improvement and will support data-driven resource allocation.

Emer Gunne, Public and Patient Interest Representative remarked, “Our daughter has had a very positive experience on her patient journey, from an early diagnosis without diabetic ketoacidosis at the age of 11 years through to independently managing her diabetes with her diabetes pump at the age of 14 years, and we envisage a smooth transition to adult services on the horizon in a few years. All children, regardless of which centre they attend in Ireland,

deserve to have the highest level of care when diagnosed with type 1 diabetes mellitus (T1DM). Being involved in this feasibility study has meant that I have been able to use our daughter’s experience to be part of the process of improving care for the many children who will be diagnosed with T1DM in Ireland in the future”.

This study recommends the development of a National Audit of T1DM, with a phased approach. The first phase includes all paediatric T1DM patients aged under 16 years who attend the 19 paediatric centres nationally.

Phase 2 involves extending the audit to include affected young adults aged 16-25 years and Phase 3 will incorporate all patients with T1DM nationally. An Individual Health Identifier (IHI) for all with T1DM would support successful implementation of this audit and would allow linkage to existing datasets. Electronic data capture is essential to allow

complete, accurate and efficient data collection.

Professor Nuala Murphy, Chair of the National Paediatric Diabetes Audit Feasibility Steering Committee commented, "As a country, we invest a lot of money in diabetes care over each patients journey but at the moment, most of this spend is in treating preventable diabetes related complications. We know that tight blood glucose control has been shown definitively to prevent diabetes related complications, so investing early and empowering patients to achieve good control makes sense. Audit allows us to see what we are doing well and what we need to improve and we are outliers in international terms as we do not currently have a national paediatric diabetes audit.

This feasibility study supports the need for an audit and the next phase is audit development and implementation.”

HOSPITALPROFESSIONALNEWS.IE | HPN • JULY 2022

50

ENDOCRINOLOGY FOCUS OBESITY

Obesity: The Disease and the Available Treatments Written by Dr Karl J Neff St Vincent’s Health Group, Dublin Diabetes Complications Research Centre, Conway Institute, University College Dublin

the amount of body fat present, and so responds to reduced food intake as part of a planned calorie controlled diet in the same way as it would response to starvation: it activates two powerful physiological systems that prevent weight loss.6-8

Obesity the Disease Obesity is a disease that affects all facets of health and wellbeing, and is associated with a wide range of diseases, including type 2 diabetes, cardiovascular disease and cancer.1, 2 The morbidity associated with obesity is so significant that it limits life expectancy.3 As well as the effects on physical health, obesity has chronic and debilitating effects on psychosocial health and function. Obesity is associated with poor mental health outcomes, reduced social participation, reduced economic opportunity, and reduced quality of life.4-5 The negative effects of obesity on psychosocial function and health are partially attributable to obesity stigma. Obesity stigma is the term used to refer to discrimination based on weight.

In our society, many feel free to openly discriminate against people based on their weight. People with obesity are very likely to encounter stigma both in everyday life and in healthcare encounters.

Obesity stigma manifests in many ways. It most commonly manifests in public life in media commentary that describes people with obesity as ‘fat and lazy’ that could (but won’t) make better food choices

and do more exercise in order to lose weight. This narrative leaves people living with obesity feeling very alone in a world that judges them for their disease.

In healthcare, we are just as prone to obesity stigma as any other section of society. People with obesity often avoid presenting to healthcare providers with medical symptoms as they expect that every symptom will be attributed to their weight, and that they will not be listened to. Instead they will likely be told that things would get better if they would ‘just lose some weight’: something that they have probably heard and tried to do many times before (usually without success).

Obesity stigma is a result of a fundamental misunderstanding of obesity as a moral choice rather than a disease. For the majority of people with obesity, the physiological regulation of body fat is dysfunctional and metabolic maladaptation has developed that prevents sustainable weight loss.

This means that when people with obesity try to lose weight, physiological mechanisms are activated that defend against loss of body fat. In obesity, the hypothalamus (the energy homeostat of the body) has lost the ability to accurately gauge

JULY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

The first physiological defence mechanism is hunger. Reduction in food intake results in increased hunger. Hunger is an unconscious physiological reflex that can be consciously controlled to an extent.

People on a diet consciously resist their hunger in an effort to lose weight. For people who do not have obesity, this can be done with relative ease. If we do not have obesity, then the hypothallus recognises the adipose stores present and so moderates any increase in appetite.

However, people with obesity will be persistently hungry, and often have increased hunger, while on a diet.6-8 While they can consciously resist their hunger, with great effort, to achieve at least some weight loss, living in a constant state of perceived starvation is challenging to maintain.

For those that do sustain longterm resistance of hunger, and achieve weight loss, the second major physiological maladaptation comes into play. This is alteration of the basal metabolic rate. If hunger does not stimulate calorie ingestion, then the hypothalamus will downregulate the basal metabolic rate so that we burn fewer calories.8-10 This is why people usually find that despite sticking to a diet that initially resulted in weight loss (while feeling extremely hungry throughout), they ultimately hit a weight loss plateau. This occurs because the energy homeostat adjusts energy expenditure downwards to meet the reduced calorie intake. This means that people will continue to burn fewer calories for as long as there is a net calorie deficit.

The only way to overcome this mechanism is to consciously

reduce calorie intake to extremely low levels below the minimum basal metabolic rate needed for survival (i.e. a ‘starvation diet’ which for most equates to less than 600kcal per day). However, even if someone can achieve this, reintroduction of a diet with a calorie intake within recommended limits (e.g. 2000kcal per day) will produce weight regain, as their healthy 2000kcal a day diet will be in excess of the calories that they are expending by the end of their diet (which could be less than 1000kcal per day).8-10 Therefore, weight regain occurs as they are consuming more calories than they are burning.

Treating Obesity Given these powerful physiological mechanisms, obesity is a very difficult disease to treat. However, treatment should be actively offered to people with obesity as successful treatment results in improved physical health, with significant benefits in the prevention and treatment of obesity associated diabetes, cardiovascular disease and cancer. These benefits in physical health occur in tandem with myriad benefits in psychosocial health and functioning.

Diet and Exercise Based Approaches Given the two pathophysiological mechanisms inherent in the disease of obesity described above, it should be no surprise that for the majority of people with obesity, diet and exercise interventions alone will not achieve durable weight loss. Diet and exercise based treatment can be very effective in a small number of people. However, for most people with obesity diet and exercise based approaches are insufficient to treat the disease and result in significant weight loss.11-14 This is not due to lack of adherence with the programme.

Lack of weight loss in response to diet and exercise intervention is usually due to the physiological defences against weight loss described above.8-10, 12 At best, approximately 20% of people with obesity will achieve significant weight loss with diet and exercise programmes alone, meaning that 80% or more will not.13 However, diet and exercise programmes are very unlikely to cause harm and so, while ineffective in most people,

ENDOCRINOLOGY FOCUS

51

multiple health outcomes including a reduction in all-cause mortality.

In metabolic disease, surgery has particular benefits, and is a more effective treatment for type 2 diabetes than medical care alone.24, 25 Surgery improves glycaemic control but also reduces mortality and maintains control of diabetes in the long-term.21

remain the most reasonable first step in the treatment of obesity.

Ideally, a diet and exercise based intervention would be structured and led by a Dietician with support from an Exercise Physiologist and Psychologist. If such a programme is not available, then most commercially available programmes can at least offer clear structured advice on calorie reduction and peer support.

The dietary element of diet and exercise based interventions should be focused on calorie restriction. The mode of restriction, for example alternate day restriction versus daily continuous restriction, seems to be unimportant, with comparable results in the medium to long term.14 Similarly, the extent of restriction does not seem to be important in determining the ultimate weight loss. Very low calorie diets and more conventional calorie controlled diets have similar medium and long term outcomes.15 Exercise is an important component of these programmes.

This is because it enhances weight maintenance.16, 17 Exercise does not enhance the initial weight loss but does help to minimise weight regain after a dietary intervention.16, 17 If possible then individual prescription of exercise by a physiotherapist or an exercise physiologist who specialises in obesity should be included in a diet and exercise programme. A minimum of thirty minutes a day is needed for benefit, and this should involve both aerobic and resistance elements.

The resistance element is important to maintain muscle mass during weight loss, as this has been postulated to reduce hunger and aid long-term weight maintenance.17 Behavioural support is important to aid both weight loss and weight

loss maintenance.18 Peer support is part of this, but individual support offered by a specialist Psychologist can be of significant benefit. The focus should be on adapting food relationships and food environments. Most of us will use food as an emotional regulator, to help with stress management or to help alleviate sadness or anxiety. We build food environments to facilitate this, by keeping a source of ‘comfort food’ nearby for when we need it.

For people with obesity, this can compromise their diet and exercise therapy, and so behavioural interventions exploring emotional support and stress management can be an effective component of an obesity treatment programme.

Medical therapy When diet and exercise based programmes are unsuccessful, medication should be considered as next-line therapy. There are four medical options at present; orlistat, liraglutide (at a dose of 3mg daily rather than the 1.8mg dose used for diabetes), Semaglutide (at a dose of 2.4mg once weekly rather than the 1mg dose used to treat diabetes) and naltrexone/ bupropion. All of these can be prescribed safely in primary care but should be used in combination with, not instead of, a diet and exercise based programme to enhance effectiveness.

Orlistat is an agent that limits fat absorption in the gut, and if used with a sufficiently low fat diet, can result in weight loss of almost 10% with very few side effects.11 If a low-fat diet is not maintained during treatment then orlistat will cause intolerable steattorrhoea.

Therefore, an explanation of how the medication works, and a dietetic review, is advisable prior to starting orlistat to improve the likelihood that the medication will be effective and tolerable.

Both Liraglutide and Semaglutide change hypothalamic regulation of appetite and are more effective in the treatment of obesity than diet and exercise therapy alone.19, 20 These agents have a variance of effect. Some people will lose significant amounts of weight, comparable with some modalities of bariatric surgery, whereas some will not lose weight at all. When most effective they can produce weight loss in excess of 15%.19, 20 It remains impossible to predict who will respond to medication but within four months of use it will be clear if the individual will respond to therapy or not.

The combination treatment naltrexone-bupropion, when used with lifestyle interventions, can produce weight loss of up to 10%.19 The mechanism of action is not entirely understood, but is thought to act via modulation of central appetite and reward pathways. Both naltrexone and bupropion can interact with several other medications and are contraindicated in some medical conditions. Therefore, a comprehensive medical and drug history should be taken prior to prescription, and this combination should only be prescribed under close supervision.

Weight loss after surgery is a not a result of physical restriction or calorie malabsorption, as often believed. The major mechanism of weight loss after surgery is increased satiety and decreased hunger as a result of changes in gut hormones.26, 27 Surgery can also enhance energy expenditure, despite reduced food intake.28, 29 Therefore, surgery directly ameliorates the two major pathophysiological bases of the disease of obesity.

Surgery is the only treatment with evidence for long-term weight loss, and reduction in all cause mortality, and therefore should be considered in all people with obesity. While the peri-operative risks are low, these procedures are not ‘the easy option’ and are not suitable for everyone. Before proceeding a thorough multidisciplinary assessment is needed to ensure candidates are fully prepared to have an optimal response to surgery and that surgery is a suitable treatment for them.

Summary

Surgical treatment of obesity

Obesity is an increasingly prevalent disease that affects all aspects of human health. This results in associated disease, disability and a reduction in life expectancy. However, obesity can be successful treated. The treatment of obesity needs to be individualised, and can include diet, exercise and behavioural interventions, supplemented by medical or surgical interventions.

Given that there are treatment options available, people with obesity need to be recognised and offered referral for treatment.

If medical therapy is ineffective, then surgery should be considered. Obesity surgery (also called bariatric or metabolic surgery) is the most effective intervention in treating obesity and obesity-associated disease.

All procedures are performed laparoscopically with a very low rate of complications and result in a mean ten-year weight reduction of 25%.21-23 The weight loss associated with surgery is usually durable and occurs in tandem with significant improvements in

As a healthcare system, we need to do better for people with obesity, both in terms of our understanding of obesity and in the provision of treatment. In 2021, the HSE Model of Care for obesity was launched (https://www.hse. ie/eng/about/who/cspd/ncps/ obesity/model-of-care/) Hopefully, this will be the start of a new programme of expanded public sector provision of all treatment options for obesity so that we help people living with this insidious chronic disease.

HOSPITALPROFESSIONALNEWS.IE | HPN • JULY 2022

52

ENDOCRINOLOGY FOCUS NEWS

New WHO Report: Europe can Reverse its Obesity “Epidemic” The new WHO European Regional Obesity Report 2022, published on 3 May by the WHO Regional Office for Europe, reveals that overweight and obesity rates have reached epidemic proportions across the Region and are still escalating, with none of the 53 Member States of the Region currently on track to meet the WHO Global Noncommunicable Disease (NCD) target of halting the rise of obesity by 2025.

health in the years ahead, and will need significant effort to reverse.

New data on obesity and overweight

“Obesity knows no borders. In the Europe and Central Asia, no single country is going to meet the WHO Global NCD target of halting the rise of obesity,” said Dr Hans Henri P. Kluge, WHO Regional Director for Europe. “The countries in our Region are incredibly diverse, but every one is challenged to some degree. By creating environments that are more enabling, promoting investment and innovation in health, and developing strong and resilient health systems, we can change the trajectory of obesity in the Region.”

The report, launched at a press event on 3 May and presented at the European Congress on Obesity, reveals that in the European Region, 59% of adults and almost 1 in 3 children (29% of boys and 27% of girls) are overweight or living with obesity.

Obesity prevalence for adults in the European Region is higher than in any other WHO region except for the Americas.

Overweight and obesity are among the leading causes of death and disability in the European Region, with recent estimates suggesting they cause more than 1.2 million deaths annually, corresponding to more than 13% of total mortality in the Region.

Obesity increases the risk for many NCDs, including cancers, cardiovascular diseases, type 2 diabetes mellitus and chronic respiratory diseases. For example, obesity is considered a cause of at least 13 different types of cancer, and is likely to be directly responsible for at least 200 000 new cancer cases annually across the Region, with this figure set to rise further in the coming years.

Overweight and obesity are also the leading risk factor for disability, causing 7% of total years lived with disability in the Region.

Overweight people and those living with obesity have been disproportionately affected by the consequences of the COVID-19 pandemic. There have been unfavourable shifts in food consumption and physical activity patterns during the pandemic that will have effects on population

Obesity in Europe: an ongoing “epidemic” To address the growing epidemic, the report recommends a suite of interventions and policy options that Member States can consider to prevent and tackle obesity in the Region, with an emphasis on building back better after the COVID-19 pandemic.

Obesity is a disease – not only a risk factor Obesity is a complex disease that presents a risk to health. Its causes are much more complex than the mere combination of unhealthy diet and physical inactivity. This report presents the latest evidence, highlighting how vulnerability to unhealthy body weight in early life can affect a person’s tendency to develop obesity.

Environmental factors unique to living in modern Europe’s highly digitalized societies are also drivers of obesity. The report explores, for example, how the digital marketing of unhealthy food products to children, and the proliferation of sedentary online gaming, contribute to the rising tide of overweight and obesity in the European Region. However, it also looks at how digital platforms might also provide opportunities for the promotion and discussion of health and well-being.

Policy measures: what can countries do?

Addressing obesity is critical to achieving the Sustainable Development Goals and is a

JULY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

priority echoed in WHO’s European Programme of Work 2020–2025.

The new WHO report outlines how policy interventions that target environmental and commercial determinants of poor diet at the entire population level are likely to be most effective at reversing the obesity epidemic, addressing dietary inequalities and achieving environmentally sustainable food systems.

Obesity is complex, with multifaceted determinants and health consequences, which means that no single intervention can halt the rise of the growing epidemic.

Any national policies aiming to address the issues of overweight and obesity must have highlevel political commitment behind them. They should also be comprehensive, reaching individuals across the life course and targeting inequalities. Efforts to prevent obesity need to consider the wider determinants of the disease, and policy options should move away

from approaches that focus on individuals and address the structural drivers of obesity.

The WHO report highlights a few specific policies that show promise in reducing levels of obesity and overweight: • the implementation of fiscal interventions (such as taxation on sugar-sweetened beverages or subsidies for healthy foods); • restrictions on the marketing of unhealthy foods to children; • improvement of access to obesity and overweight management services in primary health care, as part of universal health coverage; • efforts to improve diet and physical activity across the life course, including preconception and pregnancy care, promotion of breastfeeding, school-based interventions, and interventions to create environments that improve the accessibility and affordability of healthy foods and opportunities for physical activity.

ENDOCRINOLOGY FOCUS

53

HYPOTHYROIDISM

Hypothyroidism: A Reminder of the Often Forgotten Intricacies Very little has changed with regard to the treatment of primary hypothyroidism since the introduction of levothyroxine sixty years ago. It is safe, effective and relatively cheap. For all these reasons, both condition and treatment often drop to the bottom of priority lists in terms of patient and medication review, which, much of the time, is reasonable and justified. However, when a drug acquires this ‘reputation’, there is a danger that important details become slowly diluted until in some instances they are forgotten about altogether. The fact is, there are some quite unique and critical points to levothyroxine treatment, which, if ignored, can result in suboptimal therapy and patient harm. Indeed research shows a third of patients are inadequately treated.1 Considering the burden of hypothyroidism with respect to associated comorbidities such as diabetes and cardiovascular disease, decreased quality of life and economic impact of same, a third of patients inadequately treated is significant. This article aims to highlight the salient points associated with hypothyroidism and levothyroxine therapy.

Background The thyroid produces two major hormones; Thyroxine (T4) and triiodothyronine (T3) in approximately a 4:1 ratio with most T4 subsequently being converted to T3 in the blood.

Release of these hormones is triggered by Thyroid Stimulating Hormone (TSH) from the pituitary gland, which itself is triggered by Thyrotropin Releasing Hormone (TRH) from the hypothalamus.

Initial diagnosis of hypothyroidism is usually on the basis of an elevated TSH level combined with a low free thyroxine level (FT4).

Accurate prevalence figures for hypothyroidism in Ireland are difficult to come by and largely unknown. Partly due to the fact that there is likely a large proportion of undiagnosed cases given the general and vague symptoms associated with the condition, which in some case can be mild, or even absent or silent and not trigger much concern (fatigue, weight gain, cold intolerance, dry skin hyperlipidaemia). Globally it

is generally accepted that up to 5% of the population are affected, with as many again undiagnosed. Worldwide, iodine deficiency is the most common cause of hypothyroidism (iodine being essential for thyroid hormone production in the thyroid gland). However, in areas of iodine sufficiency, 95% of cases are autoimmune in nature (Hashimoto’s thyroiditis).

Secondary and tertiary disease (insufficient production of thyroid stimulating hormone/thyroid releasing hormone from the pituitary/hypothalamus) are less common.

The mainstay of treatment for hypothyroidism is thyroid hormone replacement with levothyroxine (synthetic T4) and treatment tends to be lifelong. Levothyroxine is the second most commonly prescribed medication in the US and is considered an ‘essential medicine for basic healthcare’ by the WHO.1 Synthetic T3 also exists in the form of liothyronine which has a much shorter halflife. However it is unlicensed in Ireland and although it may potentially play a role in specialist situations such as myxoedema coma (severe hypothyroidism and medical emergency) or as a trial in combination with levothyroxine when symptoms have not ceased,2 NICE guidance does not recommend a routine role for liothyronine.3 Initiation of therapy For otherwise healthy patients under 50, levothyroxine is initiated at a dose of 50-100µg (taken on an empty stomach, half an hour before breakfast) and titrated until TSH falls to within desired range and symptomatic improvement is achieved. Most maintenance doses fall between 75-150µg/day with a maximum of 200µg.

Due to the long half-life of levothyroxine (6-7 days), TSH should not be measured until 4-6 weeks after initiation, as it can take this long for levels to return to normal. Similarly, dose titration should be done in 4 week intervals and 50 µg increments.

In patients over the age of 50 and/ or those with cardiac disease, an initial dose of 25-50µg/ day is recommended (or 50 µg on alternate days in the case

of cardiac disease) with 25 µg titration increments every 4 weeks.

Overtreatment with levothyroxine can induce or exacerbate cardiovascular disorders, including atrial and ventricular arrhythmias, atherosclerotic vascular disease, dyslipidaemia, and heart failure.

In fact, low circulating thyroid hormone levels may be providing a protective effect for the heart, hence caution is advised when aiming to increase levels.

Factors affecting dose requirements Levothyroxine is a narrow therapeutic index (NTI) drug, however dose control often doesn’t receive the same attention compared to other NTI-drugs such as digoxin and warfarin.

An understanding of the factors affecting plasma concentrations of the drug and/or endogenous thyroid hormone are required in order to find and maintain the optimal dose for a patient and avoid therapeutic failure or adverse drugs reactions.

Maintenance doses in excess of 150 µg are not commonly required, therefore other factors such as medication adherence, malabsorption, concomitant medications and comorbidities should be examined in patients not achieving adequate control in the 75-150 µg range.

Several commonly taken medications, including over the counter products can impair the absorption of levothyroxine including iron and calcium supplements, aluminium hydroxide (found in many antacids), and some proton pump inhibitors.

A gap of 4-5 hours should be observed between taking these medications and levothyroxine.

Inadequate treatment of existing hypothyroidism during pregnancy can be detrimental given the importance of these hormones to the baby’s development.

Levothyroxine is generally continued therefore, however thyroid hormone requirements increase during pregnancy due to increased oestrogen levels.

This means levothyroxine doses will often have to be increased during pregnancy. TSH levels should be monitored closely during each trimester and doses titrated accordingly.

Written by Dr Shane Cullinan, Lecturer in Pharmacy Practice Royal College of Surgeons Ireland

When symptoms of hypothyroidism are not subsiding despite an increasing dose of levothyroxine and TSH levels returning to normal, consideration should be given to other potential causes such as hypoadrenalism and anaemia which often accompany hypothyroidism and result in similar symptoms.

Amiodarone Amiodarone can be a particularly problematic drug when it comes to interpreting thyroid function and dosing of levothyroxine as it can induce both hypo- and hyperthyroidism. The molecular structure of the drug contains two atoms of iodine. A standard 200mg/day regime of amiodarone can result in 20-40 times the recommended daily dose of iodine.

Given that iodine is a principle substrate for the synthesis of thyroid hormones, this in turn can lead to elevated levels of thyroid hormone. This is rare however as the body normally initialises a protective mechanism against this called the Wolff-Chaikoff effect whereby excessive iodine levels inhibit thyroid hormone synthesis.

However, when the body fails to ‘escape’ from the WolffChaikoff effect, a phenomenon more commonly seen in patients with pre-existing autoimmune thyroiditis, this in turn leads to amiodarone induced thyroiditis

HOSPITALPROFESSIONALNEWS.IE | HPN • JULY 2022

54

ENDOCRINOLOGY FOCUS HYPOTHYROIDISM Conclusion Although a simple and effective treatment for hypothyroidism, levothyroxine therapy is not without its complications and warrants attention, particularly at the beginning of therapy.

1. Chiovato L, Magri F, Carlé A. Hypothyroidism in Context: Where We've Been and Where We're Going. Adv Ther.

2019 Sep;36(Suppl 2):47-58. doi: 10.1007/s12325-01901080-8. Epub 2019 Sep 4.

PMID: 31485975; PMCID: PMC6822815.

2. Leese, G.P. Nice guideline on thyroid disease: where does it take us with liothyronine?.

Thyroid Res 13, 7 (2020). https:// doi.org/10.1186/s13044-02000081-y

(AIH). Furthermore, amiodarone exhibits some intrinsic properties which compound this such as inhibition of conversion of T4 to T3 in peripheral tissues. Importantly, the half-life of amiodarone can be up to 100 days, meaning that it can have adverse effects on thyroid function even months after cessation which must be taken into account when monitoring a patient on levothyroxine and titrating doses.4

Subclinical debate Treatment of subclinical hypothyroidism, defined as elevated TSH, normal FT4 and very mild or no symptoms, has long been a matter of debate.

The benefits are not well proven, though thought to perhaps prevent progression to overt hypothyroidism, and these must be weighed against the potential risks including cardiovascular side effects. Indeed, some

evidence suggests subclinical hypothyroidism, in the absence of overt symptoms, is actually associated with longevity in older patients. NICE guidance recommends treating with a TSH of 10 mlU/litre or higher on 2 separate occasions 3 months apart (with symptoms in those aged over 65).3 Given the lack of data, several sources recommend basing the decision on whether to treat or not on individual circumstances.

3. NICE guideline (NG 145).

Thyroid disease: assessment and management. https://www. nice.org.uk/guidance/ng145/ evidence/e-management-ofhypothyroidism-pdf-6967421681 4. Narayana SK, Woods DR, Boos CJ. Management of amiodarone-related thyroid problems. Ther Adv Endocrinol Metab.

2011 Jun;2(3):115-26. doi: 10.1177/2042018811398516.

PMID: 23148177; PMCID: PMC3474631.

News

Inaugural European Hormone Day On 23 May 2022 it was European Hormone Day. On this occasion The European Society of Endocrinology (ESE) published “Milano Declaration 2022: Recognising the Key Role of Hormones in European Health” which summarises the key messages of the ESE White Paper published in May 2021, and calls on national and European policy makers to better address hormone health in current and future public health policies and research funding programmes.

With the support of nine dedicated Members of the European Parliament (MEPs) from different countries and political affiliations, and the overwhelming engagement of our own endocrine community

– with more than 60 endocrine societies and organisations also giving their endorsements - the Milano Declaration and European Hormone Day created a strong impact in its inaugural year. Many national endocrine societies also translated the materials and animations, and they are available in the Toolkit for use on www. europeanhormoneday.org to help the endocrine community to explain the role of hormones and why they matter.

With over 1200 tweets during the 12 hours of Monday 23 May achieving 4.33 million impressions, the activities around European Hormone Day at ECE and across Europe gained a lot of attention – the conversation continues still on Twitter! National

JULY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

media also picked up the story and ran it online and in print.

A large focus of the online engagement was around the activities on the European Hormone Day booth at the ECE Congress which actively promoted the Milano Declaration as well as European Hormone Day through lapel pins and photos in selfie frames that people could use to express their support for this new European Health Day. The engagement from the endocrine community at our annual congress was huge – and we hope that we saw you there taking your photo!

“We are still in the process of evaluating the overall impact of the campaign, but we are

confident that we managed to make our voice heard and helped to secure better policies and more research funding for our community. Please send us your comments and feedback on the 2022 European Hormone Day so we can collectively have an even stronger voice in future European Hormone Days,” said the organisation.

ENDOCRINOLOGY FOCUS

55

DIABETES IN PREGNANCY

The role of the multidisciplinary team in supporting women and babies Diabetes and Pregnancy team, National Maternity Hospital Written by David Fitzgerald, Mary Higgins, Ciara Coveney, Catherine Chambers and Recie Davern Introduction Diabetes is the most common significant medical condition to affect pregnant women, and it is important that women can avail of the best quality multidisciplinary team (MDT) care to support them prior to conception, during the pregnancy, labour and birth, and in the postnatal period as they adjust to new parenthood.

This article has been written by some members of the National Maternity Hospital Diabetes and Pregnancy multidisciplinary team.

Our ethos is simple: that women with diabetes are the experts by experience, and we are the experts by knowledge (and still learning) but that by working together we can share important decisions and provide respectful care.

While the article focuses mostly on care provided to women with preexisting diabetes (including, Type 1 diabetes (T1DM), type 2 diabetes (T2DM), mature onset diabetes of the young (MODY) or cystic fibrosis related diabetes (CFRD), amongst others) the principles can also be generally extrapolated to Gestational Diabetes (GDM), that is diabetes diagnosed in pregnancy, resolving after the birth but conferring an increased risk of diabetes in the future.

We have selected five specialities to write in this article, but it should be highlighted that other clinical staff may play important roles depending on the background and needs of the woman. The input of general practice, nephrology, medical social work, psychology, psychiatry, ophthalmology, lactation consultants, neurology, intensive care, anaesthesiology and numerous other clinical and non-clinical specialists have been invaluable. The woman herself, her partner and family remain in the centre of this care, with all input individualised to their circumstances and needs.

Midwifery Midwives recognise pregnancy, labour, birth and the post-natal period as a healthy and profound experience in women’s lives.

The ethos of midwifery care is to work in partnership with women.

Midwives who care for women with diabetes in pregnancy are specialist trained in both midwifery and diabetes care. Specialist diabetes midwives utilise their midwifery and diabetes expertise to act as an advocate for a pregnant woman from the preconception period right through to six weeks postnatal.

Specialist diabetes midwives undertake a comprehensive patient assessment including physical, psychological and social elements of care using evidencebased practice. They also coordinate assessment, planning, implementation, monitoring and re-evaluation of clinical assisted and specialised care pathways for women within multidisciplinary teams for thosewho are deemed to fall within a ‘high risk’ category.

Assessment of care takes in to account multiple factors including assessing pre-existing conditions, current glycaemic targets and recommending/starting pharmacolgical therapy for women with diabetes in pregnancy.

They support women to achieve optimum blood glucose levels for both maternal and fetal interest.

With the evolution of diabetes technology including continuous glucose monitoring and subcutaneous insulin pump therapy, specialist diabetes midwives have upskilled to be able to read complex glucose algorithms and recommend changes to therapeutic agents as a result.

Education and health promotion for women and their families are a cornerstone practice in midwifery to improve both short and longterm outcomes for mother and their infants. This includes the advent of initiatives such as antenatal expression of colostrum to educate and prepare women for their breastfeeding journey.

Specialist diabetes midwives provide most of the inpatient diabetes care for complex diabetes, supported by the wider MDT. All inpatients are seen by a member of the midwifery team to review glycaemic control and recommend changes to pharmacological treatments. Some specialist diabetes midwives also

have a prescribing qualification and prescribe diabetes agents/ consumables to both inpatients and outpatients. They discuss the management of blood glucose levels and pharmacological agents in the intrapartum period to ensure each woman feels in control of their diabetes for the birth of their baby.

Women are reviewed frequently in the postnatal period to assess for hypoglycaemia and the physiological changes that the postpartum period can bring.

Typically, we see a reduction in insulin requirements in the immediate postpartum period, often requiring a similar dose of insulin to the that of the prepregnancy period.

Mary Higgins, Obstetrician, Maternal Fetal Medicine Specialist

They link with each woman weekly in the six weeks postnatal period and see them with their MDT visit before referring them back to their general diabetes service.

Dietitian The role of the CORU registered dietitian on this dynamic team is to assess, diagnose and treat dietary and nutritional problems in a woman-centred and evidencebased approach. The dietitian who specialises in diabetes works collaboratively with the multidisciplinary team to provide an individualised dietary care plan for the duration of the woman’s pregnancy and for the first six weeks postnatally. Nutrition at the time of conception and during pregnancy has an impact on the immediate and long-term health of both mother and infant. Optimal maternal nutrition will give the infant the best start in life. Using behavioural change skills and empathy the dietitian focuses on supporting women to make positive lifestyle changes while being mindful of social factors and the limitations to change.

Women need clear and consistent guidance on the foods to avoid during pregnancy to reduce illness due to exposure to foodborne toxins and pathogens.

The dietitian meets the woman within the first week of booking with the hospital and will review the women regularly during her pregnancy. A comprehensive nutritional assessment will include

Ciara Coveney, Advanced Midwife Practitioner, Diabetes

Catherine Chambers, Senior Dietitian

Recie Davern, Endocrinology Fellow

HOSPITALPROFESSIONALNEWS.IE | HPN • JULY 2022

56

ENDOCRINOLOGY FOCUS DIABETES IN PREGNANCY Diabetes in pregnancy Midwifery Team - Left to Right - Ellie Ahern, Ciara Coveney, Eimear Rutter and Hannah Rooney

encounter. The blood glucose targets in pregnancy are also different to those outside of pregnancy and can take time to become familiar with. We review women every few weeks initially, but we also invite women to submit their blood glucose readings weekly, via email or telephone, for the endocrinology team to review. This helps us to support women during their pregnancy and allows us to work together to solve any issues that may arise.

a detailed history along with a review of relevant comorbidities such as Cystic Fibrosis, coeliac disease, renal disease, mental health issues, anaemia, irritable bowel syndrome etc.

The nutrients from foods eaten provide the body with protein, fat, carbohydrate, vitamins, and minerals. There are different requirements for different nutrients to support pregnancy and the growing infant. Carbohydrate is the nutrient that causes a rise in blood glucose levels. The cornerstone of the nutritional management of those managing diabetes during pregnancy is to educate women on how to spread their intake of carbohydrate throughout the day in a consistent way and to choose higher fibre/ lower carbohydrate foods that are slowly released within the body.

The dietitian provides update sessions on carbohydrate counting – accurate carbohydrate counting enables the endocrinology team to better determine insulin doses.

Education is now provided in oneto-one and joint sessions, phone consultations and video sessions.

Use of insulin pumps (CSII) and/ or continuous glucose monitors during pregnancy is growing; these technological supports are helpful in optimising glucose control.

The dietitian supports women to interpret the data particularly in understanding the effect food choices have on glucose levels.

The dietitian supports women who are admitted to hospital during

their pregnancy and at the time of the delivery. Use of the specific menu created by the catering department for those with diabetes is explained. Breastfeeding is encouraged and specific dietary advice is provided to ensure nutritional needs are met at that time. Other nutritional issues that arise during pregnancy may be nausea and vomiting, constipation, weight gain concerns, anaemia, patterns of hypoglycaemia, mental health issues or culturally relevant food choices.

Supporting women who are managing diabetes during pregnancy is very rewarding. The dietitian will coordinate and link with dietitians in the community and tertiary hospital diabetes centres both before and after pregnancy.

Endocrinologist The Endocrinologist is a medical doctor who specialises in the management of all forms of diabetes both during and outside of pregnancy. Our role begins in the preconception planning stage of a woman’s pregnancy journey.

Many women with pre-existing diabetes may be on agents that are not recommended in the first trimester of pregnancy.

We routinely counsel women of reproductive age in our general diabetes clinics to attend a pre pregnancy clinic prior to any plans for conception. In these clinics we start women on the higher 5mg dose of folic acid, transition off any teratogenic agents, ensure the management of any diabetic

JULY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

complications are optimised and aim to tighten glycaemic control to reach the optimum HbA1c levels.

During pregnancy, we will meet with women early in their antenatal course. At this visit we enquire about their history of diabetes.

We will ascertain the length of diagnosis; the presence of any diabetic complications and we assess women’s hypoglycaemic awareness. In Dublin we can arrange for referral to the Mater Miscericordiae University Hospital ophthalmology team who specialise in retinal screening in pregnancy as more regular screening is required during pregnancy. We also screen for other conditions that can be more common in women with pre-existing diabetes such as thyroid dysfunction.

Women receiving a wide range of anti-glycaemic therapies attend our clinic – continued subcutaneous insulin infusion (CSII), multi daily injections (MDIs) or oral agents. We have experience in using all these different therapies in pregnancy as well as continuous glucose monitors (CGM), though we do recommend the use of some finger prick blood glucose testing during pregnancy to help get the most accurate data.

A lot of women find that the placental hormones during pregnancy can make their diabetes difficult to manage and the Endocrinologist, along with the remainder of the multi- disciplinary team (MDT), are here to help women with any challenges they

At the time of birth, we can arrange a blood glucose management regime to suit whichever mode of delivery that the women and our obstetric colleague’s plan. We devise an insulin regime to manage blood glucose levels during the delivery to ensure stability to help reduce the chance of neonatal hypoglycaemia after birth. We will continue to support and work with women for the 6 weeks postpartum before arranging to transfer their diabetes care back to the practitioner who assisted with their diabetes prior to pregnancy.

Obstetrics The obstetrician, a medical doctor specialising in pregnancy and postnatal care, may be the lead named clinician within the multidisciplinary team, but remains very much one of a specialised group. Women with pre-existing diabetes are usually booked for early antenatal care, often attending at five- or six-weeks pregnancy. The first role of the obstetrician is often to confirm the viability of the pregnancy.

Early ultrasound can be affirming (a viable heartbeat), surprising (twins or triplets!) or devastating (miscarriage or ectopic pregnancy).

Since the 2018 referendum we also acknowledge that some women with diabetes may not wish to continue their pregnancy or may be diagnosed with a fetal abnormality and therefore termination of pregnancy may be requested. Whether the news is good or not, compassionate kind care is vital.

One of the most common complications of early pregnancy is nausea, vomiting or hyperemesis. Ultrasound to out rule an obstetric cause (multiple or molar pregnancy), linking with dietetics and offering the options

ENDOCRINOLOGY FOCUS

57

Pharmacy Team, Left to Right Linda Simpson, David Fitzgerald, Aine Toher, Louise Delany and Montse Corderroura

of medications are standard management, when available.

Women with diabetes often attend regularly throughout pregnancy, and regular reviews assuring them that the baby is growing and appears to be developing normally is reassuring.

The routine anatomy scan at 18-21 weeks’ gestation is often supplemented with a fetal heart scan (echocardiography) due to the increased risk of fetal cardiac abnormalities with maternal diabetes. Regular assessment of fetal growth is important; this is done by both measurement of the symphysiofundal height of the maternal abdomen, measuring the liquor volume around the baby and measuring fetal skeletal and abdominal growth by ultrasound.

The decision of mode and timing of birth is individualised to the women, her baby and her circumstances. Generally, the advice is that the baby should be born before the woman’s estimated due date, but how soon before will vary. Women with diabetes can, and do, deliver vaginally, but it is recognised that there is a higher rate of caesarean birth. This may be due to an increased rate of induction, bigger babies, maternal request or complications in labour. One of the most feared complications is that of shoulder dystocia – that the baby’s head will be born but that the shoulders are caught behind the maternal pelvic bones.

While every clinician working on the labour ward is trained for their role should there be a shoulder dystocia, prevention is better than treatment. However, this is complicated by the fact that over half of all shoulder dystocia emergencies occur in normally grown babies.

Postnatally women are monitored for complications of birth, including postpartum bleeding, infection and deep venous thrombosis. The psychological process of transition to parenthood should not be underestimated, and in some women further help may be required if they develop postnatal depression or psychosis.

Pharmacist Clinical pharmacists can play a vital role on the MDT, contributing to the management of obstetric

patients with pre-existing diabetes through utilising their knowledge of pharmacotherapy and experience in medication management. This role often begins at the stage of pre-conception planning, where pharmacists collaborate with the clinicians providing obstetric care to provide detailed counselling to patients. The importance of planning a pregnancy is emphasised with patients being advised to use contraception until they have achieved good blood glucose control. At this stage, pharmacists can contribute to a review of blood glucose targets, glucose monitoring, insulin regimens, and other medications for treating diabetes or its complications. Women with diabetes may be advised to use metformin as an adjunct to insulin in the preconception period and to stop all other oral blood glucoselowering agents. Patients who are taking statins, angiotensinconverting enzyme inhibitors or angiotensin-II receptor antagonists are advised to discontinue these medications due to the potential for embryo-toxicity or adverse pregnancy outcomes. Advise is given to take folic acid 5mg per day until 12 weeks’ gestation to reduce the risk of neural tube defects.

During pregnancy, good maternal glycaemic control is vital to reduce teratogenicity, but needs to be balanced against the risk of hypoglycaemic episodes which are associated with significant maternal and fetal risks and can occur more frequently due to impaired awareness of

hypoglycaemia in pregnancy.

Pharmacists can contribute medication expertise in making pharmacotherapeutic decisions on appropriate choice ofinsulins regimens and in providing education for patients so that they may self-manage their blood glucose levels. Pregnant women with insulin-treated diabetes will be advised to always have a fastacting form of glucose available such as glucose-containing drinks or dextrose tablets. Available evidence on the rapid-acting insulin analogues (aspart and lispro) and the long-acting isophane insulin, does not show adverse effects on pregnancy or the health of the baby, and as such they are the first line choices for insulin regimens during pregnancy.

Consideration can be given to continuing treatment with longacting insulin analogues such as detemir or glargine for patients who have established good blood glucose control with these agents before pregnancy.

During an inpatient admission, an essential role of the pharmacist as part of the MDT providing care for obstetric patients with pre-existing diabetes is to ensure that the patient fully understands their insulin regimen, or changes to it, has sufficient supply of insulin and most importantly that their regimen is prescribed on the drug chart and clinicians taking care of the patient are fully aware of their more complex needs. The process of medication history taking, and medicines reconciliation is of particular importance around

the time labour where blood glucose levels and insulin doses must be tightly managed. Of note is the need to give additional doses of insulin according to an agreed protocol for women with insulin-treated diabetes at risk of preterm labour and who are being administered corticosteroids for fetal lung maturation. Pharmacists play a role in the postnatal period, advising patients to reduce their insulin dose immediately after birth and providing advice on the use of oral blood glucose-lowering therapy while breastfeeding.

Conclusion We have described some aspects of our role in providing care to women with diabetes as part of a multidisciplinary team. Another core principle of our care is communication. It is incredibly satisfying when a problem in providing care is solved by a clinician’s expertise or knowledge, no matter what their speciality. It is for this reason that all of us would say that we have learned so much about the value of multidisciplinary care from our colleagues. In addition, the expertise and knowledge of women and their families have taught us a great deal about shared decision making and the importance of keeping women and babies in the centre of the care that we provide. This article is dedicated to the women and babies we care for, with the immense privilege that it is to do so.

HOSPITALPROFESSIONALNEWS.IE | HPN • JULY 2022

58

ENDOCRINOLOGY FOCUS OUTCOMES

Can Weight Loss Improve the Cardiovascular Outcomes of Patients with Obesity and Obstructive Sleep Apnea?

Written by by Ayyad Alruwaily1, Heshma Alruwaili1, John Garvey2 and Carel W. le Roux1,3,* Diabetes Complications Research Centre, Conway Institute, University College Dublin, D04 V1W8 Dublin, Ireland

1

Department of Respiratory Medicine, St Vincent’s University Hospital, D04 T6F Dublin, Ireland

2

Diabetes Research Group, School of Biomedical Sciences, Ulster University, BT52 1SA Coleraine, Ireland

3

Obstructive sleep apnea is characterized by repetitive upper airway collapse during sleep resulting in a temporary cessation of breathing (apnea), shallow breathing (hypopnea), or respiratory-related arousals.

The apnea–hypopnea index measures the number of apnea and hypopnea events per hour of sleep. The apnea–hypopnea index is used to further classify obstructive sleep apnea as mild (5 ≤ apnea–hypopnea index < 15), moderate (15 ≤ apnea–hypopnea index < 30), or severe (apnea– hypopnea index ≥ 30).1 The pathophysiology of obstructive sleep apnea is commonly believed to be primarily due to anatomical anomalies of the upper airway.

While a defect in the upper airway anatomy is common, it is not the only pathogenic process at work.

Anatomical and non-anatomical elements have been included in a novel model of obstructive sleep apnea pathogenesis. These non-anatomical aspects include (1) impairments in the upper airway dilator muscle function during sleep, (2) respiratory control instability, and (3) low respiratory arousal threshold.2 Obstructive sleep apnea has a global prevalence of 13-33% in middle-aged men and 6-19% in middle-aged women.3 The rising prevalence of obstructive sleep apnea in the recent decades has been linked to increasing rates of obesity.4 Obstructive sleep apnea has been linked with many different cardiovascular diseases including hypertension, stroke, heart failure, coronary artery disease, and atrial fibrillation.5,6 Adults with obstructive sleep apnea, in addition to increased risk of developing cardiovascular disease, also have worse cardiovascular outcomes.7 We reviewed the associations between obstructive sleep apnea and cardiovascular disease and whether weight loss may improve the cardiovascular outcomes of patients with obstructive sleep apnea and obesity.

Obstructive Sleep Apnea Increases the Risk Factors of Cardiovascular Disease Among the mechanisms which explain the association between obstructive sleep apnea and myocardial infarction (MI), common risk factors include male sex, age, hypertension, obesity, and smoking.8 However, other direct effects of obstructive sleep apnea merit consideration. The combination of repetitive apnea– hypopnea, hypoxia, and arousal from sleep increases sympathetic activity, which is maintained during wakefulness, thus increasing myocardial oxygen demand.9 The mechanistic understanding which connects obstructive sleep apnea and cardiovascular disease is poorly understood due to the diverse and complicated elements of obstructive sleep apnea and the multiple other comorbid conditions (especially obesity) impacting cardiovascular health. When obstructive apnea or hypopnea occurs, the upper airway collapses throughout sleep, affecting a complete or partial interruption of airflow even with sustained respiratory struggle. The sympathetic tone is stimulated, and respiratory work increases as opposed to the closed upper airway, increasing negative intrathoracic pressure.

Stimulation of the sympathetic tone across the parasympathetic system affects heart rate and blood pressure.10 Awakening from sleep terminates the asphyxia event, with re-establishing airflow and re-oxygenation but further increased sympathetic tone. Obstructive sleep apnea seems to be correlated with increased levels of inflammatory cytokines. Furthermore, metabolic dysregulation is observed in obstructive sleep apnea patients (with abnormalities in both fat and glucose metabolism. This contributes to atherosclerosis and endothelial damage with enhanced arterial stiffness.

However, it remains unclear whether metabolic abnormalities

JULY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

and inflammation are exacerbated by obstructive sleep apnea, whether these are epiphenomena are due to obesity.10 Hypertension Obstructive sleep apnea is common in middle-aged and older people, although hypertension is also prevalent among middle-aged and older people.

This increases the chance of significant complications between hypertension and obstructive sleep apnea. The level of the complications of hypertension and obstructive sleep apnea is significantly greater than expected.

Hypertension is prevalent in patients with obstructive sleep apnea and contributes to vascular injury and cardiovascular events.

Several pathophysiologic mechanisms contribute to the increased risk of hypertension in individuals with obstructive sleep apnea, including upregulation of neurohormonal pathways, endothelial dysfunction, and inflammation.6 Although patients with obstructive sleep apnea have a higher incidence of hypertension,11 the inverse is also true because patients with hypertension are more likely to experience sleep-disordered breathing, especially those who have failed to respond to traditional treatment. Up to 84% of this subset of patients may have undetected obstructive sleep apnea.12 Animal experiments have provided direct proof that obstructive sleep apnea causes hypertension. When obstructive sleep apnea is induced, it results in acute transient rises in nighttime blood pressure and ultimately culminates in persistent daytime hypertension.11 When blood pressure is strictly regulated in rats, it also decreases sleep apneas.13 In humans, a causal link between obstructive sleep apnea and hypertension has not been established because variables such as age and obesity confound

the association. However, epidemiological data suggest that hypertension was found in approximately 50% of patients with obstructive sleep apnea.7 Dyslipidemia Obstructive sleep apnea is commonly associated with elevated plasma triglycerides, low-density lipoprotein cholesterol (LDL-c), and total cholesterol.

Moreover, the reduction in highdensity lipoprotein (HDL) may, in part, be due to deleterious oxidative processes commonly found in patients with obstructive sleep apnea.14,15,16 The effect of treating obstructive sleep apnea in children with adenotonsillectomy is variable as regards the impact on lipid profiles17 because chronic intermittent hypoxia may affect both lipid biosynthesis and lipid peroxidation.18 Type 2 Diabetes Inflammation in patients with type 2 diabetes is characterized by elevated levels of proinflammatory cytokines or a rising number of white blood cells in the blood or tissue. Stimulation of the inflammatory process often indicates abnormalities such as tissue injury and organ dysfunction. Obesity might cause chronic low-grade inflammation and hat is involved in type 2 diabetes. In addition, adiposespecific cytokines (leptin adiponectin, leptin, and interleukin 6 (IL-6)) are secreted by visceral adipocytes and inflammatory cytokines (tumor necrosis factor α (TNF-α)). An elevated amount of fatty tissue draining into the chemokines, portal vein, and IL-6 production can induce liver and systemic insulin resistance.19,20 Although obesity is a serious risk factor for type 2 diabetes mellitus, coexistent severe obstructive sleep apnea may independently add to the risk. The relationship between intermittent hypoxia and insulin resistance21 has been assessed by evaluating the effect of hypoxia–reoxygenation cycles

W EThe Evolution of Precision N Science The Evolution of Precision Science

ud ied

1714

Sc t ien tifically S

ud ied

+

Sc t ien tifically S

Contains a unique combination of two Contains a unique combination of two clinically clinically researched synergetic researched synergetic strains.strains Calcium: Contributes to the normal function of digestive enzymes.

Pantothenic Acid, Vitamin B6: Contribute to the reduction of tiredness and fatigue.

✝Calcium: Contributes to the normal function of digestive enzymes.

Pantothenic Acid, Vitamin B6: Contribute to the reduction of tiredness and fatigue.

TM

Group

ENDOCRINOLOGY FOCUS

60

OUTCOMES

on insulin target tissues. Rodent models suggest that chronic exposure to intermittent hypoxia induces insulin resistance.22 Atrial Fibrillation Obstructive sleep apnea is a common risk factor for atrial fibrillation.23 Recurrent episodes of obstructive sleep apnea may lead to cardiac structural and electric remodeling. Repetitive episodes of obstructive sleep apnea in an animal model can cause atrial fibrosis and important changes in connexin-43 distribution and expression, thus leading to slow atrial conduction. This increases the vulnerability to arrhythmias, including atrial fibrillation.24 Furthermore, untreated obstructive sleep apnea doubles the risk of recurrence of atrial fibrillation in patients after electrical cardioversion. Treatment of obstructive sleep apnea with CPAP attenuates the risk of atrial fibrillation.25 Obstructive sleep apnea shares many common risk factors with atrial fibrillation.

The prevalence of both atrial fibrillation and obstructive sleep apnea is rising due to increases in obesity and cardiovascular disease. The close association between obstructive sleep apnea and cardiovascular disease, and atrial fibrillation and cardiovascular disease may obscure a directly causal relationship between atrial fibrillation and obstructive sleep apnea. The interplay of the pathophysiology of these chronic diseases is complex and likely bidirectional. Obstructive sleep apnea may contribute to atrial fibrillation, and, in turn, atrial fibrillation promotes the development of obstructive sleep apnea. Nonetheless, these entities are associated with one another, independently of other cardiovascular diseases.26

its associated risk factors in French patients with heart failure showed that 30% of syndromes were classified as central and 70% as obstructive.28 Coexisting sleep apnea in patients with heart failure has been associated with an increased risk of adverse outcomes, including mortality.29 Several pathophysiological processes resulting from apneic events may explain this association. These involve stimulation of the sympathetic nervous system30 and increased preload and afterload resulting from perturbation of intrathoracic pressure while struggling to inspire against blocked airways.31 Worsening hypertension, increased risk of arrhythmias including sudden cardiac death,32 and myocardial infarctions33 are other mechanisms by which sleep apnea may worsen outcomes in patients with heart failure.34 The relationship between obstructive sleep apnea and cardiovascular events remains unclear. A systematic review and meta-analysis conducted by Loke, Yoon K., et al. suggested that obstructive sleep apnea may be an independent risk factor for cardiovascular, stroke, and overall mortality. Due to imprecision and inconsistencies in the data, the strength of potential association between obstructive sleep apnea and ischemic heart disease remains unclear.35 A cohort study evaluating the relationship between

Heart Failure Sleep apnea is predictable in patients with heart failure, with a prevalence of between 50% and 70%.27 Mainly, central sleep apnea accounts for two-thirds of the sleep apnea cases in this population, while obstructive sleep apnea is less frequent.

Central sleep apnea is a frequent concomitant finding in patients with severely impaired cardiac function.27 Another study aimed to assess the prevalence of sleep-disordered breathing and

Figure 1

JULY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

obstructive sleep apnea-related variables and the risk of CV events revealed that several obstructive sleep apnea-related factors other than the apnea–hypopnea index were important predictors of a composite CV outcome.36 Hence, the need for a randomized controlled trial is crucial.

Continuous Positive Airway Pressure (CPAP) Reduces Risk Factors for Myocardial Infarction, Atrial Fibrillation, and Heart Failure Randomized controlled trials demonstrated that CPAP lowers blood pressure by 2–3 mm Hg.37 Among patients with obstructive sleep apnea and resistant hypertension, CPAP treatment for 12 weeks decreased the 24 h mean and diastolic blood pressure and increased the nocturnal blood pressure.38 CPAP also improved dyslipidemia (decrease in total cholesterol and LDL and increase in HDL). This may contribute to a potential reduction in cardiovascular and cerebrovascular events.39 In patients with moderate-to-severe obstructive sleep apnea, compliant CPAP usage may improve insulin secretion and insulin resistance.

The latter was associated with an improvement in leptin even after short-term CPAP therapy.40,41 Both epidemiological studies and cohort studies suggest that CPAP reduces atrial fibrillation recurrence risk after cardioversion and ablation.42,43 In 426 individuals undergoing pulmonary vein

isolation, 62 patients with verified obstructive sleep apnea who used CPAP had a higher rate of atrial fibrillation-free survival than those who did not use CPAP (72% vs. 37%). The atrial fibrillationfree survival rate among CPAP users was comparable to that of individuals without obstructive sleep apnea. However, randomized controlled trials are still awaited.44 Not surprisingly, given the association between obstructive sleep apnea and atrial fibrillation, there is also an association between obstructive sleep apnea and stroke.45,46 CPAP may attenuate this risk,46 but this has not been studied prospectively.

CPAP Does Not Reduce Myocardial Infarction The potential associations of CPAP to reduce composite cardiovascular events, all-cause, and cardiovascular death in patients with concomitant cardiovascular disease and obstructive sleep apnea rely on data from observational studies.47 There is currently no level 1 evidence to suggest that CPAP can prevent future cardiovascular events in patients, including obstructive sleep apnea and coronary artery disease.48 A randomized controlled trial that studied the impact of CPAP on cardiovascular outcomes showed no reduction in long-term adverse cardiovascular outcomes in the intention-to-treat population.49 A clinical trial comparing usual care with usual care plus CPAP therapy

ENDOCRINOLOGY FOCUS found that the addition of CPAP did not prevent cardiovascular events in patients with moderateto-severe obstructive sleep apnea and preexisting cardiovascular disease.50 However, no significant beneficial effects of CPAP were shown in patients with obstructive sleep apnea in the trials evaluating CPAP therapy on major adverse cardiovascular events.49,50,51 CPAP did not reduce the rate of complex cardiovascular events at a median follow-up of 3.7 years in the SAVE (Sleep Apnea Cardiovascular Endpoints) trial that randomized 2717 participants with cerebrovascular disease with moderate-to-severe obstructive sleep apnea or.50 Furthermore, no effect of CPAP therapy on major adverse cardiovascular events in obstructive sleep apnea with or without cardiovascular morbidities was shown in several metaanalyses of randomized trials.52,53,54 However, the study populations of the included studies are diverse, from the general population to patients with severe coronary artery disease (such as myocardial infarction), thus precluding definitive conclusions.

Obesity Obesity is a chronic multifactorial disease. Obesity is caused by inherited biological and ecological factors, diet, physical activity, and exercise choices. It is a medical problem that raises the threat of other diseases and health problems, such as high blood pressure, certain cancers, diabetes, and heart disease.55 Various risk factors, involving obesity, age, sex, heritable and race/ethnicity factors, are wellknown in the pathogenesis of sleep apnea. However, obesity has usually been known to be one of the most significant sleep apnea risk factors.56 Some crosssectional experiments have always found a connection between the obstructed sleep apnea risk and

body mass index. The registered prevalence of sleep apnea ranges from 40% to 90% in individuals with a body mass index > 40 kg/ m2 (severe obesity).57,58 Significant sleep apnea appears in over 70% of sleep apnea patients with obesity and 40% of people with obesity.59 Obesity is the only major obstructive sleep apnea risk factor that is variable. Weight decrease in the short term of one to two years steer to better metabolic control in patients with obstructive sleep apnea.60 A prospective study of Wisconsin citizens indicated that a 10% weight loss anticipated a 26% reduction in the sleep apnea severity apnea– hypopnea index [58]. Moreover, another cohort research observed decreased apnea occurrence after weight loss.61 Even though the mechanisms by which weight loss decrease obstructive sleep apnea symptoms are not entirely understood, factors such as decreased visceral fat deposition play an important role.62 Airway structures and altered neurophysiologic control of respiration during weight loss are likely also important.63 Moreover, obesity may control the chemoreflex function through neurohormonal mediators such as leptin, which reduces when sleep apnea patients lose weight.60 Therefore, these potential methods likely work in concert to act as a vicious cycle in the body weight gain pathogenesis and obstructive sleep apnea (Figure 1 on page 63).

Obesity complications such as hypertension, diabetes, insulin resistance, and obstructive sleep apnea increase the risk of cardiovascular diseases.64 Obesity may also independently contribute to atherosclerosis and coronary artery disease.47,65,66,67 To prevent or reverse obesity complications, more than 10% weight loss may be required,68 and the previously suggested 5% to 10% weight loss may not be sufficient.69,70

In the case of obesity, evaluation before the intervention should include a comprehensive weight history, a complete individual and family medical history, blood studies, a physical examination looking for signs of the complications of obesity, and a behavioral history.71 This approach may identify primary causes for weight gain, such as an endocrine disorder, medications linked with weight gain, an underlying eating disorder, or differences in the condition that have led to decreased activity and an energy imbalance. Body mass index and waist circumference should also be included in this initial evaluation. Blood tests should consist of a measurement of thyroid function, insulin sensitivity, liver function, and lipid profile.71 Once a diagnosis of obesity has been made, the management of obesity should be stratified.

Weight Loss as a Treatment to Reduce Cardiovascular Events Currently, no randomized control trials have shown that intentional weight loss reduces the cardiovascular death risk.73,74,75 Non-randomized long-term follow-up data from a prospective cohort Swedish Obese Subjects study showed that bariatric surgery resulted in reduced cardiovascular mortality and occurrence of first-time (fatal and nonfatal) cardiovascular events.76 The Look AHEAD clinical trial was designed to assess the long-term effects of nutritional therapy and exercise therapy delivered over ten years in patients with obesity and type 2 diabetes. The primary outcome was time to the incidence of a major cardiovascular disease event. The study revealed that weight loss produced improvements in HbA1c, systolic blood pressure, HDL triglycerides, and cholesterol at years 1 and 4 (all p ≤ 0.02),77 but no changes in cardiovascular events over ten years.77 However, the subgroup

61

of patients who lost more than 10% of their weight did have a reduction in mortality.78 Another two-year follow-up cohort study also demonstrated that 5–10% weight loss improves risk factors but not cardiovascular events.79 Weight Loss as a Treatment for Obstructive Sleep Apnea Although weight loss can facilitate obstructive sleep apnea treatment, it can rarely cure it and still requires a combination with continuous positive airway pressure.80 A systematic review and metaanalysis conducted to assess the effect of lifestyle therapy on the oxygen desaturation index, apnea– hypopnea index, and excessive daytime sleepiness among adults revealed significant reductions in all these components after weight loss. However, most patients still had diagnosable obstructive sleep apnea.81 The SCALE sleep apnea study compared the effects of 3.0 mg liraglutide to placebo on obstructive sleep apnea severity and body weight loss in patients with obstructive sleep apnea and obesity. This study showed that 3.0 mg liraglutide produced greater reductions in ischemic heart disease, body weight, systolic blood pressure, and HbA1c in patients with obesity with moderate/severe obstructive sleep apnea, but most patients still had diagnosable obstructive sleep apnea at the end of the study.82 A prospective multicenter study investigated the effects of a laparoscopic Roux–en–Y gastric bypass. One year after surgery, the prevalence of obstructive sleep apnea decreased, but more than half of those with obstructive sleep apnea at baseline still had it after surgery. Obstructive sleep apnea was cured in 45% and improved in another 33% of the patients, but moderate or severe obstructive sleep apnea persisted in 20% of

Table 1. Summary of weight loss as a treatment for cardiovascular events risk reduction, obstructive sleep apnea and to reduce cardiovascular events in patients with obstructive sleep apnea.loss as a treatment for cardiovascular events risk reduction, obstructive sleep apnea and to reduce cardiovascular events in Table 1. Summary of weight patients with obstructive sleep apnea.

Weight loss as a treatment to reduce cardiovascular events

Nonrandomized long-term follow-up data from the prospective cohort Swedish Obese Subjects study showed that bariatric surgery resulted in reduced cardiovascular mortality and occurrence of first-time (fatal and nonfatal) cardiovascular events.

The Look AHEAD clinical trial showed no changes in cardiovascular events over ten years.

Weight loss as a treatment for obstructive sleep apnea

Systematic review and meta-analysis revealed that lifestyle interventions cause significant reductions in the apnea–hypopnea index (AHI), oxygen desaturation index (ODI), and excessive daytime sleepiness (EDS) among adults, but all patients still had diagnosable obstructive sleep apnea.

The SCALE sleep apnea study showed that 3.0 mg liraglutide produced greater reductions in the apnea–hypopnea index.

Weight loss as a treatment to reduce cardiovascular events in patients with obstructive sleep apnea

Weight loss intervention is an effective strategy to improve cardiovascular risk in patients with obesity and obstructive sleep apnea [66], but whether this will reduce cardiovascular events remains to be determined.

HOSPITALPROFESSIONALNEWS.IE | HPN • JULY 2022

62

ENDOCRINOLOGY FOCUS OUTCOMES

the patients after the operation.83 A recent prospective cohort study showed that patients with moderate-to-severe obstructive sleep apnea may lose less weight with bariatric surgery than those with milder disease.84 A systematic review included 19 surgical (n = 525), and 20 nonsurgical (n = 825) studies assessing the body mass index and the apnea– hypopnea index before and after intervention.85 The results showed that bariatric surgery and nonsurgical weight loss both had beneficial effects on obstructive sleep apnea through body mass index and apnea–hypopnea index reduction. However, bariatric surgery may result in a significantly greater improvement in the body mass index and the apnea–hypopnea index than nonsurgical alternatives.85 The exact relationship between bariatric surgery and nonsurgical weight loss interventions in OSA resolution remains a challenge due to the need in randomized controlled trials.85 Weight Loss as a Treatment to Reduce Cardiovascular Events in Patients with Obstructive Sleep Apnea Cardiovascular events are the primary cause of mortality in

patients with obstructive sleep apnea and obesity [86]. CPAP combined with weight loss may improve obstructive sleep apnea pathophysiology and the apnea–hypopnea index and reduce cardiovascular risk.87,88 A randomized 24-week trial on 181 patients with moderate to severe obstructive sleep apnea and obesity comparing the effects of CPAP, weight loss, or combined CPAP and weight loss was conducted. Combining CPAP and weight loss did not reduce CRP levels more than either intervention alone. Weight loss provided an incremental reduction in serum triglycerides and the insulin resistance level when combined with CPAP. Weight loss and CPAP did incrementally reduce blood pressure compared with either intervention alone [89].

Another randomized control trial of 42 patients with obesity, severe obstructive sleep apnea (apnea– hypopnea index > 30 events/h) and treated with CPAP for a minimum of 6 months before the study allocated patients to an intensive weight loss program or standard lifestyle recommendations over 12 months. The effect of weight loss was assessed on obstructive sleep apnea severity and metabolic variables. The intensive weight loss program effectively reduces weight and obstructive

sleep apnea severity while also improving lipid profiles, glycemic control, and inflammatory markers [90]. The authors concluded that weight loss intervention is an effective strategy to improve cardiovascular risk in patients with obesity and obstructive sleep apnea,66 but whether this will reduce cardiovascular events remains determined.

Table 1 (bottom of page 64) summarizes the available data assessing the effect of weight loss as a treatment for cardiovascular events risk reduction, obstructive sleep apnea, and to reduce cardiovascular events in patients with obstructive sleep apnea.

This potential relationship is plausible because of prevailing pathophysiological mechanisms, but definitive evidence is still lacking. There is evidence that treatment with CPAP decreases blood pressure, but the impact of weight loss in patients with resistant hypertension is more profound than in those with acute obstructive sleep apnea. Current data supporting the impact of CPAP on cardiovascular events come from nonrandomized studies, and higher-quality evidence is needed to change clinical practice. We also require using the concept of individualized medicine for this matter and focusing on genetic variations

and why a few patients with OSA develop cardiovascular effects while others do not. Such research will assist in reporting on the clinical trials that are required to be performed. Weight loss in patients with obstructive sleep apnea produced improvements in HbA1c, systolic blood pressure, HDL cholesterol, and triglycerides, but thus far, no changes in cardiovascular events have been shown. This will require cooperation among specialists in cardiology and sleep apnea.

Conclusions Despite the association between cardiovascular disease and obstructive sleep apnea, randomized trials have failed to demonstrate that obstructive sleep apnea treatment improves the outcomes of cardiovascular events, even in patients with established cardiovascular disease.50 The combination of weight loss with continuous positive airway pressure (CPAP) appears to be more helpful than either treatment in isolation. Large well-controlled trials in patients with obstructive sleep apnea to evaluate the impact of different weight reduction programs on cardiovascular disease are still required.

References available on request

News

Improving Outcomes in Childhood Obesity Dr Grace O’Malley, Lecturer in the RCSI School of Physiotherapy Care Group and published in Frontiers in Nutrition, found that the W82GO Child and Adolescent Obesity Service at CHI Temple Street improves obesity-related outcomes for children and adolescents.

New research from RCSI University of Medicine and Health Sciences has analysed the impact of Ireland’s only obesity service for children and adolescents.

The W82GO Service is the only dedicated centre for paediatric and adolescent obesity management in the Republic of Ireland. It delivers tailored obesity interventions, including dietetic, psychological, medical, physiotherapy and medical social work support, as recommended by scientific guidelines.

This study, conducted by the RCSI Obesity Research and

As part of the W82GO Service, patients are referred by a

JULY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

paediatrician and then assessed by a physiotherapist, dietician and psychologist to develop personalised obesity treatment plans with the family, based on the child’s age and clinical need.

In this study, the researchers looked at outcomes for almost 700 children and adolescents from a range of socioeconomic backgrounds who had engaged with the service over 12 years. By comparing growth chart data from the baseline and final visit, they demonstrated an overall reduction in sex- and age-adjusted BMI across the cohort, indicating that engagement with the W82GO Service is linked to improvements in health. The findings showed that younger children especially benefited from the treatment.

Dr Grace O’Malley, Lecturer in the

RCSI School of Physiotherapy and senior author on the paper, commented on the findings, “Childhood obesity is a chronic disease that requires multidisciplinary and specialist intervention, however, access to treatment is limited globally.

We must evaluate the impact of evidence-based interventions in real-world settings in order to increase the translation of research into practice and enhance child health outcomes.

“Our research shows that the W82GO Service is an important intervention for managing severe obesity in children and young people. In particular, we found that the intervention was especially impactful for younger service users, and those who engaged in the service for more than 12 months.”

News 63 First National Survey on HIV-Related Stigma Researchers at NUI Galway are aiming to use a national survey into HIV-related stigma in healthcare settings to tackle the issue and improve health outcomes for people with the disease.

The first Joint National Survey on HIV-related stigma in healthcare settings will mean Ireland will be the first country in Europe that will have this kind of national-level data.

The study was launched by researchers at the Health Promotion Research Centre in NUI Galway. It can be accessed at www.nuigalway.ie/ hiv-stigma-survey.

It is the first of its kind in Europe as the researchers aim to learn both from people living with HIV and also those who provide healthcare for them.

The survey aims to measure stigma in healthcare settings, and is part of a wider study to develop guidelines to reduce HIV-related stigma and improve healthcare outcomes for people living with HIV. Dr Elena Vaughan, NUI Galway researcher and principal investigator on the Addressing HIV-stigma in Healthcare settings study, said, “This research will help us to get a sense of what the needs and priorities are - both of people working in healthcare and people living with HIV - so that a collaborative approach may be taken to address stigma in healthcare settings.

“Experiences of stigma in healthcare settings can put people off engaging with healthcare

Dr Elena Vaughan, Health Promotion Research Centre, NUI Galway, Credit - Aengus McMahon

“In addition to providing important information to help us reduce stigma in healthcare settings, the data generated from this project will be useful to programme and policy-makers in tracking progress in meeting commitments both to the SDGs and the Fast Track Cities Initiative”

services. This can have negative impacts on a person’s health.

There is also evidence to suggest that stigma inhibits people from accessing testing and treatment, and so is a driver of the epidemic more broadly.”

Approximately 7,000 people are living with HIV in Ireland.

Massive strides in the treatment of HIV mean that it is now easily managed with medication. People living with HIV are living long healthy lives and cannot pass on the virus when they are on effective treatment. However, stigma remains a serious problem for many people living with HIV, and this can affect their health and well-being Reducing HIV-related stigma is widely acknowledged as a key part of addressing the HIV epidemic.

In 2019, Dublin, Cork, Limerick and Galway were signed up to the Fast Track Cities Initiative – a global collaboration between UNAIDS, International Association of Providers of AIDS Care (IAPAC), and 300 cities and municipalities worldwide. The objective is to work towards reaching zero new HIV infections, zero AIDS-related deaths, and zero HIV-related stigma and discrimination by 2030. Stigma reduction is also

a stated aim of the Sustainable Development Goals, to which Ireland has also committed.

Dr Vaughan added, “Stigma in healthcare settings is among the key indicators recommended by UNAIDS to measure and evaluate the HIV response in individual countries. In addition to providing important information to help us reduce stigma in healthcare settings, the data generated from this project will be useful to programme and policy-makers in tracking progress in meeting commitments both to the SDGs and the Fast Track Cities Initiative.

Ireland will be the first country in Europe that will have this kind of national-level data.”

The survey is being launched just ahead of Irish AIDS Day on June 15, 2022 and will be live for the month of June.

The project is supported by HIV Ireland and funded by the Irish Research Council.

SIG Survey on the Use of Prefilled Syringes in Hospitals The European Association of Hospital Pharmacists (EAHP) has established a Special Interest Group (SIG) to gain more knowledge about the current and future use of prefilled medicines syringes (PFS) in hospitals. EAHP’s SIG focused on the Use of Prefilled Syringes in Intensive Care Units and Operating Theatres (financially supported by BD) has prepared two surveys targeting on the one hand professional associations and on the other hand health professionals and managers.

A PFS is a presentation of one or more active medicines, at the required concentration and volume, in the final syringe and ready for parenteral administration to the patient. PFS are intended to reduce error and minimise the time taken to prepare parenteral medicine by staff in clinical areas.

PFS are manufactured/prepared by the pharmaceutical industry or hospital pharmacies.

Several additional benefits and some disadvantages have been reported for PFS. The SIG is

preparing a comprehensive literature review on PFS. Usage of PFS in hospitals in North America has been considerably larger than in Europe for many years. Recently the use of PFS in some European countries has increased.

The surveys have been designed to collect the views and opinions of a range of health professionals, managers, and professional associations on the current and future use of PFS. Participation is completely voluntary. It should

take approximately 10 to 15 minutes to complete the survey.

Feedback can be shared until the 31st of August 2022. The survey for professional associations is available in English. The survey for individual health professionals and managers can be completed in eight different languages (English, French, German, Hungarian, Italian, Serbian, Spanish and Turkish).

EAHP’s SIG thanks the survey participants in advance for their participation.

HOSPITALPROFESSIONALNEWS.IE | HPN • JULY 2022

64

Cystic Fibrosis

Current Trends in Cystic Fibrosis Interview with Theresa LowryLehnen (PhD), CNS, GPN, RNP, South East Technological University

Cystic fibrosis (CF) is an inherited chronic disease, primarily affecting the lungs and digestive system of over 1,300 children and adults in Ireland and 70,000 people worldwide.1 Between 2008 and 2016, an average of 38 individuals in Ireland were diagnosed with CF each year, with 22 diagnosed in 2016.5 Ireland has the highest incidence per head of population of CF in the world, with three times the rate of the United States and the rest of the European Union.1 We spoke with Theresa Lowry Lehnen, Clinical Nurse Specialist and Associate Lecturer Institute of Technology Carlow to learn more about this lifelong condition.

the first time that the median age for PWCF reached 20 years (half of the population over 20 years and half under) while 8.9% of the PWCF population in Ireland was recorded as over 40 year’s old.

There were 1,266 individuals (565 children and 701 adults) with CF on the registry on the last day of 2016, representing 94.5% of people living with CF in Ireland in that year.

Theresa told us, “About 2,000 CFTR gene mutations have been identified to date. Genetic testing provides important information to assist the diagnosis and treatment

The symptoms and severity of cystic fibrosis vary from person to person. The majority of people have both respiratory and digestive problems. There is no cure for cystic fibrosis, however, life expectancy has increased steadily over the past 20 years, and today cystic fibrosis is no longer exclusive to childhood.

At the beginning of each year, the CF Registry of Ireland (the ‘registry’) conducts a survey of hospitals known to provide care to people with CF in the Republic of Ireland. The registry has gathered information on people with CF since 2002. The annual hospital census carried out by the registry in 2016 showed that 1,339 people were living with cystic fibrosis (PWCF) in Ireland. Most patients attended one hospital for CF care (n=1,107, 82.7%), whereas 17.3% (232) shared care at two or more hospitals. 2016 was also JULY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

of cystic fibrosis. F508del is the most commonly detected CFTR mutation in Irish people living with CF. “In 2016, 91.6% of the CF population had at least one copy, 15.2% at least one copy of G551D, and 5.8% at least one copy of R117H. All other CFTR mutations affect less than 5% of the CF population. Fifty-five percent of patients (55.6%) living with CF in Ireland in 2016 had two copies of the F508del mutation (F508del homozygous).

This compares with 46.1% in the United States and 50.3% in the United Kingdom in 2015. Thirtysix percent (36.0%) of people had just one copy of the F508del mutation (F508del heterozygous).

The F508del homozygous mutation is the most common CFTR gene mutation in people under 40 years. In those over 40, F508del heterozygous mutations are most common.”5 Cystic fibrosis affects multiple organ systems including the lungs, pancreas, upper airways, liver, intestine, and reproductive organs to varying degrees. Early diagnosis provides opportunities for earlier medical intervention.

Providing infants with the best possible care results in better nutritional and lung function outcomes later in life, says Theresa. “Optimised treatment prolongs the lives of people with cystic fibrosis, improving their quality of life,” she says.

“Improved diagnosis and symptomatic treatments have increased the survival rates of people with the condition, from a life span of only a few months in the 1950s to a global median age of 40 years today. The predicted median age of survival for a person in Ireland with CF is early to mid-30’s.”

Cystic fibrosis is caused by a gene mutation leading to dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, a chloride channel of exocrine glands. The defect leads to diminished chloride secretion which, in turn, leads to increased sodium absorption through epithelial sodium channels and removal of water from secretions, which become abnormally viscous. “The effects cause obstruction, inflammation, infection in the lungs and upper airways, tissue reorganisation and loss of function. The severity of the disease in the individual depends on variable organ sensitivity and on the genetically determined residual function of the CFTR protein. 99% of affected male patients are infertile because of obstructive azoospermia, and 87% of patients have exocrine pancreatic insufficiency. Disease severity particularly the degree of pulmonary involvement, also depends on other diseasemodifying genes and a number of factors including socioeconomic background,” says Theresa.2, 3

65 Diagnosis Most cases of cystic fibrosis are diagnosed through screening tests, which are carried out early in life. However, some babies, children and even young adults are diagnosed later following unexplained illness.

Symptoms Theresa explains, “People with cystic fibrosis present with a variety of symptoms, including, very salty-tasting skin, persistent coughing with phlegm, frequent lung infections, wheezing or shortness of breath, poor growth/ weight gain despite a good appetite and frequent greasy, bulky stools or difficulty in bowel movements.1 “Symptoms usually appear in the first year of life, although occasionally they can develop later. The thick, viscous mucus in the body affects a number of organs, particularly the lungs and digestive system. Typical respiratory symptoms include cough and wheeze. Recurring chest and lung infections are caused by the continual buildup of mucus in the lungs, which provides an ideal breeding ground for bacteria.7 Organisms detected in the airways of individuals with CF in Ireland in 2016 included Staphylococcus aureus (54.7%) and Haemophilus influenza (29.0%) found most frequently in children. Pseudomonas aeruginosa was detected in at least one respiratory sample of 60.3% of adults.5 Two strains of bacteria that commonly infect people with cystic fibrosis are Pseudomonas aeruginosa and Burkholderia cepacia complex.

They multiply in the thick mucus inside the lungs and may cause serious health problems and repeated chest infections. As more and more people with cystic fibrosis become infected with these bacteria, the bacteria become resistant to antibiotic treatment, which is why crossinfection is such a problem.

Lung infections caused by Pseudomonas aeruginosa and Staphylococcus aureus can become chronic, and cause an irreversible reduction in lung function.5, 7 “Chronic disease of the lungs and paranasal sinuses varies among patients with cystic fibrosis and can be difficult to distinguish from frequent recurrent bouts of bronchitis and/or pneumonia, especially in young children.

Children with cough, sputum production, or wheezing of more than three months’ duration, persistently abnormal radiological findings, persistently positive

bacterial cultures of respiratory secretions, or clubbing of the fingers should undergo diagnostic testing for cystic fibrosis even if their neonatal screening test was negative. The same applies for children with bilateral chronic rhinosinusitis with frequent exacerbations, with or without nasal polyps.2 “Cystic fibrosis causes mucus to block the ducts in the pancreas leading to malnutrition, steatorrhoea and diabetes. People with cystic fibrosis who develop diabetes may find it difficult to gain weight or may lose weight and see a decline in their lung function. Cystic fibrosis-related diabetes is usually controlled by regular injections of insulin.

Diabetes rarely occurs in children with cystic fibrosis.6 “Pancreatic insufficiency (PI) is manifested by voluminous, fatty, shiny, malodorous, pulp like stools, abdominal symptoms, dystrophy, and deficiencies of fat-soluble vitamins (e.g., hemolytic anemia due to vitamin E deficiency) and trace elements (e.g., zinc dermatosis). The diagnosis can be established by a low fecal elastase measurement. Patients with primary pancreatic insufficiency are at increased risk of chronic and/or recurrent pancreatitis.”4 In addition, Theresa reveals that people with cystic fibrosis are also prone to sinusitis and hay fever. She continues, “Older children with cystic fibrosis can develop a form of arthritis in joints such as the knee which improve with time and treatment. Older children and adults are prone to osteoporosis due to, repeated infection, poor growth or weight, lack of physical activity and lack of vitamins and minerals due to digestive problems. People with cystic fibrosis are more at risk of developing osteoporosis if they are taking steroids to help with lung infections. Osteoporosis as a result of cystic fibrosis may cause joint pain and cause bones to fracture more easily.

Bisphosphonates are taken to help maintain bone density.6 “One in ten babies with cystic fibrosis is born with meconium ileus and an operation to remove the blockage will probably be required.6 In nearly all men with cystic fibrosis, the spermatic tubes do not develop correctly, making them infertile. Women with cystic fibrosis may find their menstrual cycle becomes absent or irregular if they are underweight. There is also an increased thickness of cervical mucus, which may reduce fertility. However, most women with cystic fibrosis can conceive without any difficulty.6

If the bile ducts in the liver become blocked by mucus as the disease progresses, this can be serious and in some cases a liver transplant may be necessary.”6 Treatment There is no cure for cystic fibrosis.

The aim of treatment is to clear and control infections in the lungs and digestive system, and reduce long-term damage caused by infection and organ complications.

Talking about current treatments, Theresa says, “Inhaled bronchodilator drugs are treatments used to relax the muscles surrounding the airways and help the person breathe more easily. Antibiotics are prescribed to treat infections in the lungs.

All young children diagnosed with cystic fibrosis are started on a course of oral antibiotics to protect them from certain bacteria, which will be continued until they are three years of age. The number of days spent on IV antibiotics for pulmonary exacerbation for all people with CF in Ireland in 2016 came to a total of 14,084. The mean duration of pulmonary exacerbation treatment was 16.4 days and median duration was 14 days.5 Steroids are used to help reduce the swelling of the airways, which can help with breathing and DNase an enzyme, which is usually inhaled, is used to help thin and break down the viscous mucus in the lungs, so it is easier to expectorate.6 “Pancreatic enzyme replacement therapy (PERT) is required by almost all individuals with CF, due to pancreatic insufficiency.

When the exocrine pancreas no longer functions adequately, the production of pancreatic enzymes is reduced, leading to fat malabsorption. The consequences of this include steatorrhoea, malnutrition, and fat-soluble vitamin deficiencies. Ninety-one percent of patients with CF in Ireland received PERT in 2016.

Supplementary feeding can be required due to continued weight loss. Nearly 38% of individuals with CF required supplemental feeding in 2016. Approaches to supplemental feedings included oral supplementation, gastrostomy tube/button feeding, nasogastric tube feeding and total parenteral nutrition.5 “Pancreatic enzymes are taken before and during every meal and fat-containing snack or drink helping the digestive system break down food so that it can be digested and absorbed. The number of enzyme capsules taken needs to be adjusted depending on the amount of fat in the meal,

snack or drink. The enzymes should be taken with the meal and the timing may vary depending on the age of the person with cystic fibrosis. It is essential that people with cystic fibrosis receive advice about enzymes from a specialist cystic fibrosis dietitian.

Fat-soluble vitamin supplements (A, D, E and K) are taken to help replace lost vitamins and to prevent deficiencies. Because people with cystic fibrosis lose fat in their stools, they also lose the fat-soluble vitamins. Nutritional supplements can help compensate for poor digestion and provide additional energy and nutrients.”5, 6 People who have diabetes as a result of their cystic fibrosis, need to take insulin and manage their diet to control blood glucose levels.

Bisphosphonates are taken to treat osteoporosis, which can occur as a result of cystic fibrosis to help maintain bone density and reduce the risk of fractures. “It is important that people with cystic fibrosis are up to date with all the required vaccinations and should have the flu vaccine annually, as they are more susceptible to complications as a result of infection,” she adds.6 Daily physiotherapy is usually required and, if the person with cystic fibrosis has a chest infection the amount of airway clearance will need to be increased. Physiotherapy is tailored to the individual’s needs.

While physiotherapy for cystic fibrosis mainly focuses on airway clearance, the role of physiotherapy in cystic fibrosis has expanded to include daily exercise, inhalation therapy, posture awareness and in some cases for the management of incontinence.6 “A specialist CF physiotherapist will assess a person with cystic fibrosis and recommend the most appropriate techniques to use. Techniques may change as the person gets older or as their disease progresses. Some airway clearance techniques are done without the need for equipment and focus on specific breathing exercises, such as the active cycle of breathing techniques (ACBT) and autogenic drainage.

Other techniques use devices to help with the clearance of mucus. These devices use positive pressure to hold open the airways while some create vibrations. Techniques include positive expiratory pressure (PEP), oscillating positive expiratory pressure and high frequency chest wall oscillation (HFCWO).6 “In severe cases of cystic fibrosis, when the lungs stop working properly and all medical

HOSPITALPROFESSIONALNEWS.IE | HPN • JULY 2022

66

Cystic Fibrosis services and campaigning to improve lung transplantation rates in Ireland: Funding for medical and scientific research aimed at understanding, managing and treating cystic fibrosis: Funding for specialist cystic fibrosis multidisciplinary posts in hospitals throughout Ireland: Advice, information and advocacy services: Exercise, transplant and fertility grants: Support for public awareness about cystic fibrosis and information updates on new treatments and developments in CF, especially through their website and bimonthly newsletter ‘Spectrum’.”1

treatments have failed, a lung transplant may be required. Lung transplantation for cystic fibrosis has a good success rate: 70% of patients survive one or two years after transplantation and the longest surviving patients had their transplant operation over 15 years ago.6 “Hospitalisations recorded by ‘the registry’ reflect admission for a variety of reasons, both CF and non-CF related. In 2016, 954 hospitalisations were recorded in 497 individuals. Over seventy percent of hospitalisations (71.3%) were for the purpose of treating a pulmonary exacerbation. 363 individuals, 32.1% of individuals attending CF centres/clinics in that year were hospitalised for treatment of a pulmonary exacerbation; 20.8% of children (n=106) and 41.1% of adults (n=257). Of those hospitalised for treatment of a

pulmonary exacerbation in 2016, 44.4% (n=161) were admitted to hospital two or more times in the year. The cumulative total number of days spent in hospital by individuals with CF for treatment of a pulmonary exacerbation in 2016 was 9,278 days; 1,689 days for paediatric patients, 7,589 for adult patients. The CFRI recorded 6,792 outpatient visits to CF specialist centres and CF clinics across the country by 1,133 individuals with CF in 2016, however, CF day-unit and drop-in visit statistics are thought to be underestimated,” Theresa says.5 “The number of deaths from CF in Ireland varies from year to year. Since 2000, an average of 18 individuals died annually (range: 7 to 31). The deaths of 13 people with CF occurred in 2016 (9 female, 4 male). These individuals died between the ages of 11 and 59 years, with the

median age of death 32.5 years.

Deaths were due to respiratory/ cardio-pulmonary causes (n=9), transplant-related issues (n=2) and the cause of death in two individuals was not known to the registry at the time of reporting.5 “Cystic Fibrosis Ireland (CFI) is a voluntary organisation, initially set up by parents in 1963 to improve the treatment and facilities for people with CF in Ireland. CF Ireland supported by fundraising and voluntary contributions, co-operates with medical professionals to provide maximum assistance to both parents and children/ adults with cystic fibrosis. They provide: Funding towards new cystic fibrosis units around the country, including dedicated inpatient, day care and out-patient facilities: Advocacy to shape government policy, through the ‘Pollock Report’ on cystic fibrosis

Theresa concluded, “Better treatment strategies improve the duration and quality of life of people living with CF by controlling their symptoms.

Improved treatments can be developed using patient registries.

One of the CF registry’s founding principles is to promote and facilitate the use of clinical data in approved research projects.

The CFRI participates alongside other European countries in a long-term safety study of CF therapy ivacaftor. Cystic fibrosis registries gather information on all aspects of a patient’s condition acting as information databases for infection and treatment statistics. Detailed analysis of this information yields significant findings about the most effective treatments for CF. Through this analyses, better management and improved outcomes for individuals with CF can be achieved.”5 References available on request

Diabetes News

Cystic Fibrosis Ireland Express Concerns Cystic Fibrosis Ireland has expressed its deep concern that 35 children with cystic fibrosis (CF) aged between six and 11 years have been excluded from accessing the life-changing CF drug therapy, Kaftrio, due to a new pricing dispute between Boston-based pharmaceutical company, Vertex, and the Health Service Executive.

Cystic Fibrosis Ireland believes that this development is all the more unfair because 140 other children with CF in Ireland in that exact same age group, but with a different genotype, have already gained access to Kaftrio.

Philip Watt, CEO, Cystic Fibrosis Ireland, comments, “This dispute

has been crushing news to the parents of the 35 children concerned. Cystic Fibrosis Ireland understands that the reason these children have been excluded is because of their genotype, and that they are outside the 10-year Portfolio Agreement that was signed by the HSE and Vertex in 2017.

“Specifically, the 35 children excluded have a particular genotype combination that includes a minimal or unclassified gene which was not included in the original agreement. Cystic Fibrosis Ireland understands that Vertex is currently seeking an enhanced price for the 35 children concerned, which is different to

JULY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

the price charged for all other children and adults under the Portfolio Agreement. As a result, we understand that the HSE has been unwilling to accept this price and has instead referred the matter to the National Centre for Pharmacoeconomics (NCPE).

“The Portfolio Agreement fixed the price of a suite of drug therapies, including extensions based on age or genotype. It has prevented the ongoing disputes that once dominated access to previous CF drugs such as Orkambi. Until this matter is resolved, it means that the children affected will continue to experience significant delays in accessing Kaftrio and the enhanced quality of health and life that it brings.

“Once again children with CF in Ireland are the pawns caught up in a pricing dispute between pharma and the HSE. This is all the more heart-breaking because 140 other children with CF of the same age, but with a different genotype, recently secured access to Kaftrio. Going back to the old ways of doing business in negotiating access to life-changing medicines is simply unacceptable.

We implore the HSE and Vertex to resolve this issue quickly and to extend the Portfolio Agreement to all children with CF to ensure that the children concerned get immediate access and that this problem does not happen again.”

2022 NOMINATIONS NOW OPEN

PROFESSIONAL PROFESSIONAL 100 100 Our annual listing celebrating innovation and excellence in healthcare is coming soon.

To request an entry or nomination form please

To request an entry or nomination form please contact: contact: kelly-jo@ipn.ie sarah@hospitalprofessionalnews.ie

HOSPITAL PROFESSIONAL NEWS IRELAND Ireland’s Dedicated Hospital Professional Publication

68

Biosimilars

Biosimilars for Ireland 2022 – Past, Present & Future This article has been commissioned and supported by Pfizer Healthcare Ireland Written by Dr Paul Cornes, Comparative Outcomes Group, UK

The European Commission held its 7th annual Biosimilars Stakeholders’ Meeting on December 15, 2021, at the end of another troubled year for healthcare financing. This marks a timely opportunity to look again at Ireland’s progress with this class of medicines, and to predict the issues ahead for biosimilars.[1]

to just under ¤1bn in 2021.[2] The greatest budget pressures were from biologic treatments for cancer, and inflammatory diseases such as rheumatoid, inflammatory bowel diseases and psoriasis. Not only were more patients being treated, but each treatment cycle had become more expensive.

Biosimilars are follow-on versions of biologic medicines that have lost patent protection and are made by a second manufacturer.

This creates competition between brands that works to cut prices and free up budget to reinvest into healthcare.

It is this budget pressure that biosimilars were designed to relieve. Biosimilars were first

Biosimilars - the past Even before the Covid-19 Pandemic, Irish healthcare financing had been under pressure. The fastest growing section of the HSE budget was for speciality medicines for chronic disease. The Government had to find an additional ¤123 million each year for overall medicines spending from 2016-2021.

Within that, the High-Tech Drug arrangement had grown at an average of 11% a year with costs rising from ¤379m in 2012

Figure 1

approved in Europe in 2006 through the central regulatory process of the European Medicines Agency. However, local implementation is up to the Member States, and consequently each country was able to formulate its own biosimilar policies. Reports by Medicines for Ireland suggested that in implementation, Ireland had fallen behind its neighbours.

For example, 28 biosimilars had

been approved for use in the EU by June 2017 but at the same time only 11 biosimilars were reimbursable by the State.[3] Furthermore, research at the joint UK and Ireland Prescribing and Research in Medicines Management Conference identified the need for specific prescriber education to drive uptake.[4] [5] The shortfall in HSE budgets that were being lost by not changing patients to the best value brands of medicines were estimated to be upwards of ¤200m a year.[6] To address these issues a national education programme was initiated by the Health Products Regulatory Authority (HPRA) and after consultation, policies for change were developed by the HSA. They produced free written information for both healthcare professionals and patients as well as running face-to-face education meetings with the presentations available to download (figure 1).

To fund the professional time needed to counsel patients before changing to biosimilars, the HSE also agreed a ¤500 ‘gainshare’ incentive for each patient switched.[7] Biosimilars – the present Ireland has not been the only country playing catch up with biosimilars. After a slow start, the USA has been reporting significant changes. In the 201920 financial year, biosimilars had saved Europe (including the UK) ¤5.7Bn, or $6.5Bn USD at

Health Products Regulatory Authority and HSE– National Biosimilars Education programme and National Biosimilar Policy documents: Key documents Online Source – links checked Jan 30, 2022 HPRA Guide to Biosimilar Medicineshttps://www.hpra.ie/docs/default-source/publicationsfor-healthcare-professionals, version 3 forms/guidance-documents/guide-to-biosimilars-for-healthcareprofessionals-v3.pdf?sfvrsn=22 Biological and biosimilar medicines: https://www.hpra.ie/homepage/medicines/specialWhat patients should know topics/biosimilar-medicines/questions-and-answers-for-patients HPRA Information event for Biosimilars https://www.hpra.ie/docs/default-source/default-document– meeting slide decks available to library/biosimilar-medicines-information-evening---slides-fromdownload hpra-presentations.pdf?sfvrsn=4 Irish HSE Report: Biosimilar Medicines https://www.hse.ie/eng/services/publications/clinical-strategyin the Irish Healthcare setting (MMP and-programmes/biosimilar-medicines-in-the-irish-healthcare06/01/2016) setting.pdf Guidance for Biological Medicines in https://www.hse.ie/eng/about/who/acute-hospitalsAcute Hospitals by The National division/drugs-management-programme/protocols/guidanceSteering Committee for Biological for-biological-medicines-in-acute-hospitals.pdf?referrer=/wpMedicines in Acute Hospitals, V1 of content/uploads/2017/08/national-biosimilar-medicines-policyApril 2019. consultation-paper-2017.pdf/ Biosimilars – the present

JULY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

Ireland has not been the only country playing catch up with biosimilars. After a slow start, the USA has been

reporting significant changes. In the 2019-20 financial year, biosimilars had saved Europe (including the UK) €5.7Bn, or $6.5Bn USD at current exchange rates [ 8]. Despite starting a decade behind Europe before approving biosimilars, the USA matched the savings at $6.45Bn for the same period [ 9]. The US data showed that unlike past generations of prescribers in Ireland, where many prescribers opt to wait for real world data before switching patients, the uptake included such recently approved cancer therapeutics as biosimilar rituximab. [ 10.].

Figure 2: International impact - savings generated by Biosimilars in 2019-2020 financial year.

References in the text – xxx 7 & 8 for now Europe – includes UK USA €5.7Bn / $6.5Bn USD $6.45Bn at current exchange rates

69 Figure 2

In just 2 years between 2018 and 2020 – US physicians and Pharmacists increased biosimilar use by 800% [ 11].

[8] Education seemedrates. to have been a key in thisorchange, 2021 USOutcomes survey reported that over 80.0% of will require a more complex and forfactor employers insurersfor orathe current exchange Despite of Biosimilar Policy starting a decade behind national Initiativesto that of originators and labour intensive process (readers physicians perceived the Europe efficacy andfederal safety government of biosimilars to be highly comparable beforecomfortable approving biosimilars, should note that the “best value” plans such as US- [ 12] were using biosimilars inhealth all approved indications.

The impact of these policies for

the USA matched the savings at brand is not always the biosimilar, Medicare; they pay prescription “tiered” formulary design can be $6.45Bn for the same period.[9] for discounts offered by original drug claims and are responsible seen at clinic levels. of Forpolicy example, In keeping with the dual healthcare system aofdrug the United States, a variety positionsmedicines manufacturers may The US data showed thatpublic unlike and private for creating and updating Texas Oncology, a Community past generations of prescribers in formulary.

Thus, a PBM takes were adopted. More than 180 million Americans receive health care benefits through their employer, with sometimes prove the most Oncology Practice, planned to Ireland, where many prescribers cost-effective choice.[17] on several overlapping roles that large employers paying more than 80% of health care premiums through adopt sponsored healthasinsurance biosimilars the “best plans. opt to wait for real world data would have been divided between That healthcare delivered multiple different clinic and hospital value systems.

The largest Employers Although the details of the Irish products” in the US tiered before switching is patients, thethrough the HSE, insurers and individual system differ from those of the formulary for 2020. It created Benefits Organisation, ERIC, launchedclinics, a “Cost Savings & Competition uptake included such recently hospitals, and medicines Biosimilars Initiative” that employers USA and UK, the central polices an educational programme for 13 approved cancer therapeutics ] could implement immediately,aswhichwholesalers was based in onthe 4 key policies (figure 3). [ Irish system. are remarkably similar; and so are patients and clinical staff and biosimilar rituximab.[10] Crucial to the impact of the PBM the results. While the USA can identified all existing patients is the economies of scale that boast of an 800% overall increase In just 2 years between 2018 who would benefit from switching can be achieved in creating larger in biosimilar use over 2 years, Irish and 2020 – US physicians and with weekly reports. This enable and more competitive medicines policy can do even better! With Pharmacists increased biosimilar patients to be contacted during procurement tenders than could a programme focused on just use by 800%.[11] Education clinic or hospital visits and be achieved by each healthcare two anti-inflammatory biologics, seemed to have been a key factor educated and re-consented before provider working alone. One adalimumab and etanercept, it in this change, for a 2021 US switching. From a standing start large PBM, CVS, has explained has delivered an 850% increase survey reported that over 80.0% they achieved a 74-88% switch how they have contributed to in just one year. In June 2019, of physicians perceived the rate in 12 months and were saving the 800% biosimilar uptake prior to the prescribing changes, efficacy and safety of biosimilars $4 Million USD a month from just 3 improvement seen 2018 to just over 90 patients had been to be highly comparable to that biologics: bevacizumab, rituximab 2020.[14] In seeking to understand initiated on, or switched to a of originators and were and trastuzumab.[15] why physicians don’t prescribe best-value option. Over the next comfortable using biosimilars in Where one clinic can save biosimilars, they identified two 12 months this increased to all approved indications.[12] millions, a citywide approach can barriers. The first was education, over 8500 patients. That change In keeping with the dual save hundreds of millions. Greater with up to a quarter of US alone has delivered ¤22.7 million public and private healthcare Manchester, with a population 2.8 physicians claiming unfamiliarity in budget savings, while ¤3.6 system of the United States, a million, has reported that a similar with the medicines. The second million was distributed back to variety of policy positions were “best value” “tiered” approach was misaligned incentives, such the specialties as “gainsharing” adopted. More than 180 million to adalimumab, a biologic antias reimbursing a percentage of to reinvest in local services.[18] Americans receive health care inflammatory medicine had saved drugs costs to prescribers which The potential for Ireland is greater benefits through their employer, £312.6 million GBP (¤376m) in its promotes the use of the highest still with wider adoption by with large employers paying first year of operation.[16] cost brands and treatments. The physicians, as this was achieved more than 80% of health care result is described as a “Tiered” with only 50 % of prescriptions The emerging international premiums through sponsored formulary design which excludes for the “best value” product in consensus on using biosimilars health insurance plans. That June 2020. treatments of low clinical value means that physicians and healthcare is delivered through from routine reimbursement pharmacist in Ireland will multiple different clinic and Biosimilars – the future and directs prescribing to a recognise many of these US hospital systems. The largest US designated “best value product” For Ireland, the success of the and UK policies reflected in Employers Benefits Organisation, in each treatment category, “tiered formulary” model coupled the changes planned and ERIC, launched a “Cost Savings & coupled to a medicines education with a central prescribing hub implemented for their own Competition Biosimilars Initiative” programme. In a similar way to will have vindicated the HSE healthcare system. Saturday June that employers could implement the US ERIC-programme, the policy approach. Healthcare 1st, 2019 saw a great change in immediately, which was based on PBM takes on roles that in Ireland professionals can therefore specialist medicines; prescribing 4 key policies (figure 3).[13] would fall to the HSE, HPRA, the expect the system to have wider was changed to a online highHealth Information and Quality applications for future budget One feature of the US healthcare tech hub with “tiered” formulary Authority (HIQA), the National sustainability programmes. system is the Pharmacy Benefit brands directing automatic Centre for Pharmacoeconomics, However, an agreed multiManager (PBM). A PBM is a reimbursement to a preferred and the different medicines stakeholder approach will be company that administers, or “best value brand” choice while required to avoid unintentionally handles, the drug benefit program more expensive brand drugs procurement organisations.

Figure 3

Figure 3: The “ERIC” policy programme – USA Employer Strategies for the Use of Biosimilar Pharmaceuticals Step strategy 1 - Educate Increase understanding of biosimilars by health plan participants and health care providers through education and incentives.

2 - Clinical Promotion Adopt clinical management programs to promote best value prescribing 3 - Finance Design the payment features of prescription drug benefits to account for biosimilars.

4 - Prescribing Address biosimilar drugs when negotiating pharmacy benefit manager (PBM) contracts

One feature of the US healthcare system is the Pharmacy Benefit Manager (PBM). A PBM is a company that | HPN • JULY HOSPITALPROFESSIONALNEWS.IE 2022 administers, or handles, the drug benefit program for employers or insurers or the federal government

70

If such joint procurement agreements succeed in changing the drug pricing landscape for Europe, then the economic model for biosimilars may be broken – at least in Europe. This may underline the warnings discussed at the December 2021 European Commission meeting, that the original developers of biosimilars in Europe are already scaling back their involvement and drug pipelines. This threatens the sustainability of biosimilars as a European business, while increasing European dependence on imported medicines. [8]

Biosimilars Figure 4

Figure 4: International cooperative agreements to mitigate drug purchasing costs, including health technology assessment, policy exchanges and collaboration on horizon scanning, price negotiations and pooled procurement.

Group Year Countries Involved Baltic Partnership 2012 Estonia, Latvia, Lithuania Agreement Nordic Pharmaceuticals 2015 Denmark, Iceland, Norway, Sweden Forum Beneluxa Initiative 2015 Austria, Belgium, Ireland, Luxembourg, Netherlands Romanian and Bulgarian 2015 Bulgaria, Romania Initiative Sofia Declaration 2016 Bulgaria, Croatia, Estonia, North Macedonia, Hungary, Latvia, Romania, Serbia, Slovakia, Slovenia Valletta Declaration 2017 Croatia, Cyprus, Greece, Italy, Ireland, Malta, Portugal, Romania, Slovenia, Spain Conclusions

recreating the worst aspects of such US policy in Ireland. An american physician now requires two hours of administrative and clerical work for each hour of clinical time that physicians spend with patients.[19] Health systems need to plan well ahead, and the European Commission Biosimilars meeting of December 2021 was also an opportunity to look to the future.

Presentation predicted that biosimilars will remain central to cost-effective healthcare for the foreseeable future. Near 15% of all drug approvals by the European Medicines Agency were new biologics in 2020. To help pay for this between 10% - 40% of the current European biologics prescribing could be open to biosimilar alternatives, depending on each country. Even European nations with historically low access to biologic drugs are benefitting. For example, Central and Eastern European countries have seen a reduction of 1.5%– 2.5% on their total drug spend.

Key uptake data for the European meeting is provided through various industry organisations and are gathered in an IQVIA “Whitepaper” that accompanies each annual EC Biosimilar meeting.[8] This shows that Ireland’s biosimilar experience is not a one-off event, with many countries showing faster penetration year on year. For the most recent biosimilar launches, uptake now reaches 50% biosimilar use compared to that of the originator within less than 1-year. While previous molecules took over 2-years to reach an equivalent position.

Planning for the next wave of biosimilars in Ireland In the immediate future, the next “wave” of biosimilars is likely to involve colleagues in Ophthalmology for the first time as patents lapse for inhibitors of vascular endothelial growth

factors (VGEF-I) used to in biosimilar medicines fewer thanas five in 10,000 people brokenunderstanding – at least in Europe.

International confidence a class, coupled with a greater of the This manage macular degeneration AND it is predicted unlikely that may underline the warnings policiesto needed to implement been thewould hallmark of the alast year. discussed The result has been that both related age and diabetes. them have a treatment generate at the December 2021 European andand US policy Healthcare systems are delivering multi-billion savings to reinvest into more and better care Pharmacists makers sufficient return on investment European Commission meeting, need to plan for theIreland arrivalnow of seems to forhave developers without additional for more patients. discovered a way to benefit too; HSE changes that mirror that thepolicy original developers of biosimilars ranibizumab, incentives.

On the best current biosimilars in Europe are already many of theofsteps used in the USA have shown similar returns – with an 850% rise in anti-inflammatory aflibercept (and the off-label it takes 7 to 8 years scaling back their involvement biosimilar use as the standout statisticevidence, for the year.

VEGF-I treatment bevacizumab). to develop a biosimilar, at a and drug pipelines. This threatens The first ranibizumab biosimilar cost of between $100 million the sustainability of biosimilars The near futurebypoints to more opportunities to million save and widen patient access; just in the traditional was approved the European and $250 and requires as anot European business, while Medicines 2021 with both and pharmacologic anddiseases, clinical but now specialitiesAgency such as in oncology, haematology inflammatory for ophthalmology too. increasing European dependence [8] many more predicted to follow confirmatory randomised onplan imported medicines.

Leaning from past success, we can predict that this will require pharmacists to biosimilar education for to 2024.[24] This will be of global trials.[21] Orphan indications, by same time, the HSE will need to discover health professionals and patient organisations in eye diseases.

At the Conclusions importance as societies age and their very nature are rare diseases the most appropriate needed. rates of diabetes soar,incentives especiallyand gainshare making large scale clinical trials International confidence in in the middle-income nations impractical or perhaps even biosimilar medicines as a of world where theraises current Thethe longer-term view some uncertainties; while impossiblefor while thebiosimilars investmentof an addition 139 reference brands class, coupled with a greater brands are unaffordable many. risk may will be greater than for could appear by 2030, fortothis to succeed require changes to how orphan disease biosimilars understanding of the are policies a “blockbuster” alternative. regulatedahead and financed. needed to implement them have Looking to 2030 Yet orphan drugs are having been the hallmark of the last year. a disproportionate impact on The far future is even more The result has been that both healthcare budgets. For example, challenging; for 139 biologic European and US Healthcare in the USA orphan drugs have an drugs will lose patent protection systems are delivering multiaverage annual cost of $32,000, in Europe between 2021 and billion savings to reinvest into and more than a third at more 2030 and could face biosimilar more and better care for more than $100,000.[22] If orphan drug competition. This suggests that patients. Ireland now seems to biosimilars are to be developed, medicines regulators and health have discovered a way to benefit they may require both changes to service education programmes too; HSE policy changes that the current regulatory pathways might have to plan for 15 new mirror many of the steps used and novel financing agreements. launches each year. The challenge in the USA have shown similar will be to see if competitor brands The “wild card” in any future returns – with an 850% rise in are developed for all biologics, predictions may be the role that anti-inflammatory biosimilar use or whether biosimilars will only shared procurement may play in as the standout statistic for be developed to compete for the setting future medicines prices. the year. large “blockbuster” originators, While many in Ireland may be defined as selling more than $1Bn The near future points to more aware of the 2017 “Valletta a year. opportunities to save and widen Declaration” to cooperate on patient access; not just in the Health Technology Assessment, Of the 139 potential targets traditional specialities such as policy exchanges, price for biosimilars, only 13 have “blockbuster” status while another transparency pooled procurement, oncology, haematology and inflammatory diseases, but now few may have appreciated just 15 record current sales of $500Mn for ophthalmology too. Leaning how many such partnerships to 999Mn.[8] Most of those from past success, we can predict have been agreed since the EU agents are cancer therapeutics, that this will require pharmacists revised the public procurement confirming the central role of to plan biosimilar education for framework to enable cross-border oncology in both medicines’ health professionals and patient procurement (fig 4). The shared innovation and as the driver of our procurement of Covid-19 vaccines organisations in eye diseases. At drug-budget crisis. The remaining the same time, the HSE will need perhaps the most visible signs of biologics can be categorised to discover the most appropriate this process in action, delivering as typical “orphan indication” incentives and gainshare needed.

25% to 50% savings over the US medicines for rare diseases; agreed prices for the Pfizer and for which the development The longer-term view raises some Astra-Zeneca products.[23] investment may be uneconomic uncertainties; for while biosimilars without a change in biosimilar of an addition 139 reference brands If such joint procurement medicines regulation. could appear by 2030, for this to agreements succeed in changing succeed may require changes to the drug pricing landscape for Orphan drugs to a Medicine’s how orphan disease biosimilars are Europe, then the economic Regulator are defined by two regulated and financed. features; the disease affects model for biosimilars may be

JULY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

71

REFERENCES 1.

2.

3.

4.

5.

6.

Paul Cornes. Biosimilars – a 2020 perspective for Ireland. Hospital Professional News, Ireland. 2020; Nov:59-60. URL: https://issuu. com/ipncommunicationsltd/docs/ hpn_nov_2020_150dpi?fr=sMGIzZjM2NDEy. Accessed Jan 30, 2022 Prior S, Scott R, Hennessy M, Walker E. Spending Review 2021 - Review of High-Tech Drug Expenditure. Department of Public Expenditure and Reform & Research Services & Policy Unit, Department of Health. August, 2021. URL:https:// assets.gov.ie/193851/9490e8081774-440d-843a-28c3a9dc195c. pdf . Accessed Jan 29, 2022 O’Brien GL, Mulcahy M, Byrne S et al. Biosimilar Adoption and Acceptance in Ireland—Still More to Be Done. Value & Outcomes Spotlight July/August 2018, p29. URL: https://www.ispor.org/docs/default-source/publications/value-outcomes-spotlight/july-august-2018/ ispor-vos-august-2018-heor-article-biosimilar-adoption.pdf?sfvrsn=f787086a_2. Accessed Jan 29, 2022 Davio K. Research From the United Kingdom and Ireland Highlights Need for Provider Education on Biosimilars. Center for Biosimilars, August 7, 2018. URL:https:// www.centerforbiosimilars.com/ view/research-from-the-united-kingdom-and-ireland-highlights-need-for-provider-education-on-biosimilars. Accessed Jan 29, 2022 Sarnola K, Merikoski M, Jyrkkä J, et al. Physicians’ perceptions of the uptake of biosimilars: a systematic review. BMJ Open 2020;10:e034183. doi: 10.1136/ bmjopen-2019-034183 Coyle D. HSE could save ¤200m a year with off-patent drugs – report.

Irish Times, Tue, Sep 29, 2020, 07:05. URL:https://www.irishtimes. com/business/health-pharma/ hse-could-save-200m-a-year-withoff-patent-drugs-report-1.4366948.

Accessed Jan 29, 2022 7.

8.

9.

Paying hospitals to cut the drugs budget. Irish Times, Sat, Jun 1, 2019. URL:https://www.irishtimes. com/business/health-pharma/ paying-hospitals-to-cut-the-drugsbudget-1.3911275. Accessed Jan 29, 2022 Troein P, Newton M, Scott K, Mulligan C. The Impact of Biosimilar Competition in Europe 2021. IQVIA White Paper, Dec 16, 2021. URL: https://www.iqvia.com/library/ white-papers/the-impact-of-biosimilar-competition-in-europe-2021.

Accessed Jan 30, 2022 Adam J. Fein. The Booming Biosimilar Market of 2020. Drug Channels Institute. URL: https://www.drugchannels.net/2020/12/the-booming-biosimilar-market-of-2020. html#more. Accessed Jan 12, 2021

10. Shelbaya A, Kelton JM, Thompson J, Alvir JM, Maculaitis MC, Yang J. Real-world use and acceptance of biosimilar monoclonal antibodies of rituximab in oncology practice in the USA. Future Oncol. 2021 Oct;17(30):3941-3950. doi: 10.2217/ fon-2021-0618. Epub 2021 Jul 14.

PMID: 34259584 11. The Evidence Is Clear: Biosimilar Competition Will Achieve More Savings for Patients Than Build Back Better’s Negotiations. Biosimilars Council, Friday December 3, 2021. URL:https://biosimilarscouncil.org/resource/the-evidence-is-clear-biosimilar-competition-will-achieve-more-savings-for-patients-than-build-back-betters-negotiations/. Accessed Jan 9, 2022

12. Yang J, Blinzler K, Lankin J, Vijayakumar S, Maculaitis MC, Shelbaya A. Evolving Perceptions, Utilization, and Real-World Implementation Experiences of Oncology Monoclonal Antibody Biosimilars in the USA: Perspectives from Both Payers and Physicians. BioDrugs. 2021 Nov 25. doi: 10.1007/s40259-021-005093. Epub ahead of print. PMID: 34822141

29, 2022 18. Duggan, B., Smith, A. & Barry, M. Uptake of biosimilars for TNF-α inhibitors adalimumab and etanercept following the best-value biological medicine initiative in Ireland. Int J Clin Pharm 43, 1251–1256 (2021). https://doi.org/10.1007/s11096021-01243-0

13. Employer Strategies for Use of Biosimilar Pharmaceuticals. Paper was prepared in March 2020 for The ERISA Industry Committee (ERIC).

URL: https://www.eric.org/biosimilar-initiative/. Accessed August 23, 2021

19. Sinsky C, Colligan L, Li L, Prgomet M, Reynolds S, Goeders L, Westbrook J, Tutty M, Blike G. Allocation of Physician Time in Ambulatory Practice: A Time and Motion Study in 4 Specialties. Ann Intern Med. 2016 Dec 6;165(11):753-760. doi: 10.7326/M16-0961. Epub 2016 Sep 6. PMID: 27595430.

14. Biosimilars Help Support Members, Payors with Affordable Options.

CVS BRIEFING, July 22, 2021. URL: https://payorsolutions.cvshealth. com/insights/biosimilars-help-support-members-payors-with-affordable-options. Accessed July 23, 2021

20. Sharma A, Reddy P, Kuppermann BD, Bandello F, Lowenstein A. Biosimilars in ophthalmology: "Is there a big change on the horizon?". Clin Ophthalmol. 2018 Oct 24;12:2137-2143. doi: 10.2147/ OPTH.S180393. PMID: 30498330; PMCID: PMC6207386.

15. Lalan S. Wilfong, Neal Dave, Jody S. Garey, Sara Toth, Jim R. Schwartz, Lance Ortega, Chris Sellers, Barry Don Brooks. A successful model of biosimilar adoption in a community oncology practice. J Clin Oncol 39, 2021 (suppl 15; abstr 6514) DOI:10.1200/JCO.2021.39.15_suppl.6514

21. Blackstone EA, Joseph PF. The economics of biosimilars. Am Health Drug Benefits. 2013;6(8):469-478

16. Best Value Adalimumab Decision and Uptake Recommendation.

Greater Manchester High Cost Drugs Subgroup report, December 2018. URL: http://gmmmg.nhs. uk/docs/guidance/GM-best-value-adalimumab-recommendation-1-1.pdf. Accessed July 5, 2021 17. Paying hospitals to cut the drugs budget. Irish Times, Sat, Jun 1, 2019. URL:https://www.irishtimes. com/business/health-pharma/ paying-hospitals-to-cut-the-drugsbudget-1.3911275. Accessed Jan

22. Orphan Drugs in the United States.

Rare disease innovation and cost trends through 2019. IQVIA Dec 2020. URL:https://rarediseases. org/wp-content/uploads/2021/03/ orphan-drugs-in-the-united-statesNRD-2020.pdf. Accessed Jan 30, 2022 23. Hart C, What's behind the EU’s vaccine procurement woes? Supply Management, 5 February 2021.

URL: https://www.cips.org/supply-management/analysis/2021/ february/whats-behind-the-eus-vaccine-procurement-woes/. Accessed Jan 30, 2022 Job Code: PP-BIO-IRL-0152 Date of Preparation: February 2022

HOSPITALPROFESSIONALNEWS.IE | HPN • JULY 2022

72 Cardiology

Proximal Aortic Aneurysm surveillance clinic – St James’s Hospital “Aortic Clinic” Written by Saleem Jahangeer, Consultant Cardiothoracic and Aortic Surgeon, St James’s Hospital, Dublin

Introduction Proximal aortic aneurysms occur when the proximal aorta dilates to more than 1.5x the size of the normal aorta. 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.

Proximal or thoracic aortic aneurysms tend to be clinically silent and more than 95% of cases are asymptomatic at the time of diagnosis. Most of those aneurysms are diagnosed incidentally, when patients undergo investigations looking for another pathology. Symptomatic aneurysms present as emergencies usually as an impending rupture or an acute dissection, both being usually lethal.

The incidence of proximal aortic aneurysms has been increasing throughout the world. In the UK between 1999 and 2010 hospital admissions for thoracic aortic aneurysm from 4.4 to 9.0 per 100,000 population.1 These diseases have a high mortality; in the UK, mortality rates for thoracic aortic aneurysm is 7.5 per 100 000 inhabitants. While the increase in the incidence of proximal aneurysms has been largely attributed to a combination of an ageing population and more frequent imaging, there is evidence of a bona fide increase in the disease itself.2 The volume of aortic procedures performed has more than doubled in the last decade, reflecting the increasing burden of aortic disease.

Risk Factors for aortic aneurysms • Age, Atherosclerosis • Hypertension • Congenital/Connective tissue disorders – e.g. Marfan’s Syndrome, Bicuspid Aortic Valve • Hx of previous dissection • Drug use: Cocaine • Infection/inflammatory: Aortitis, Vasculitis, Syphilis • 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 aneurysms (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. 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 6.0 cm (Figure 1).

Size is not all what matters While the size of an aneurysms remains one of the most important predictors of rupture or dissection, there are other important factors that have to be considered: 1. Connective tissue disorders (CTD) CTD’s such as Marfan’s syndrome or Loeys-Dietz syndrome are very frequently associated

with aortopathy – Syndromic Aortopathy. In such conditions, aneurysmal-associated complications can occur at a smaller diameter. Prophylactic surgery is usually indicated at smaller diameter as compared to non-syndromic Aortopathies.

2. Bicuspid aortopathy Presence of a bicuspid aortic valve is often associated with an aortic aneurysm; the configuration of the bicuspid leaflets usually dictating which part of the proximal aorta will dilate.

Aortic intervention is usually recommended at a slightly lower threshold in patients undergoing bicuspid aortic valve replacement.

3. Family history Patients with a significant family history of acute aortic syndromes are at a higher risk themselves.

There is a large body of evidence implicating several genetic mutations such as ACTA2 or SMAD mutations. Patients with a family history (Non-Syndromic Familial Aortopathy) should be kept on a surveillance program.

4. Rate of expansion Rate of expansion of the aneurysmal segment is a very important predictor of complications. An aneurysm expanding at > 0.5cm per is an indication for surgery even if the aneurysm is less than 5.5cm.

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.

JULY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

73 Figure 2: Yale Aortic Index and the yearly risk of rupture

5. Aortic size index A drawback of using aortic diameter solely for risk estimation is the inability to factor in a significant determinant of aortic dimensions: the patient's body size. To this effect, an indexed aortic size, defined as aortic diameter divided by body surface area (BSA), has been introduced as a more patient-specific predictor of dissection, rupture, and death than absolute aortic diameter. The Yale Aortic Index (Figure 2) allows an estimated risk of annual rupture/complication based on the patient BSA. This allows for a more individualised approach in decision making rather than relying on size alone.

Aortic Surveillance Clinic The aortic surveillance clinic set up at St James’s Hospital is the first of its kind in Ireland.

Figure 2: Yale Aortic Index and the yearly risk of rupture

The clinic will enrol eligible patients in a surveillance programme to provide an integrated-care approach for management of patients with proximal aortic aneurysms.

Figure 3: Aortic Clinic Pathway

Referral Face to Face consultation Review of clinical data Post Aortic Dissection repair patients

Multi-disciplinary input Yes

Indications for surgery

Surveillance Programme

Surgical Intervention

Figure 3

No

• Interval imaging as per guidelines • RF modifications • Coordination of care between referring team/GP • Ongoing follow-up

Ongoing Surveillance

HOSPITALPROFESSIONALNEWS.IE | HPN • JULY 2022

74 Cardiology The main aim of this surveillance clinic is to monitor aneurysmal growth over time and select patients for prophylactic surgical repair once they meet guidelines criteria for intervention.

Offering prophylactic surgery at defined criteria prevents patients presenting acutely with life-threatening aneurysmal complications such as rupture or dissection.

All patients in Ireland will be suitable to be enrolled in the clinic.

Specialist level care and decision making will be provided to patients, with active participation of referring team and primary care to ensure the patient remains at the centre of the process. The frequency and imaging modality for surveillance patients will guideline-based and coordinated between the aortic team in SJH and the local centre for the patient.

The aortic clinic will also provide support and counselling to patients. Patients with a suspected familial aortopathy will be referred to a geneticist

for family investigations and molecular testing.

Surveillance will be life-long for the vast majority of patients. Even after surgical intervention, patients will still need to be monitored as the remaining segments of the native aorta can still expand over time.

The benefits of this surveillance programme can be summarised below: • Tertiary and centralised level of expertise and care.

• Individualised management – taking into considerations other important factors such as rate of progression, aortic index, family history and connective tissue disorders.

• Guidelines-directed management - defined frequency of investigations, defined criteria for intervention, evidence based management of modifiable risk factors.

• Integrated model of care Involvement of aortic surgeon,

referring physician and primary care teams, with the patient being at the centre of the process.

• Coordination of care between SJH and local centre regarding imaging, risk factors modification etc.

• Patient-focused decisionmaking process.

• Reduce loss of follow-ups.

• Aortic Database – Will allow provide a true picture of proximal aortic disease in Ireland.

• Ultimately reduce the incidence of acute aneurysmal-related complications (rupture and dissections).

There is currently a lack of ‘ownership’ of complex aortic patients in Ireland. With increasing incidence, complexity and awareness of proximal aortic aneurysms, there is a pressing need to offer these patients a dedicated and integrated-care

approach for management and surveillance of their aneurysms.

This is the aim of the Aortic Surveillance Clinic at St James’s Hospital.

Referral Process Referrals to the clinic can be made directly by GP’s or clinicians, by sending an email to aorta@ stjames.ie There will soon be an electronic referral form available on the St James’s Hospital website and Healthlink.

References 1. von Allmen RS, Anjum A, Powell JT. Incidence of descending aortic pathology and evaluation of the impact of thoracic endovascular aortic repair: a population-based study in England and Wales from 1999 to 2010. Eur J Vasc Endovasc Surg. 2013; 45:154–159 2. Epidemiology, prevalence, incidence, trends - J.A. Elefteriades (Ed.), Acute Aortic Disease, Informa Healthcare, New York, NY (2008), pp. 89-98

News

40 Fulbright Irish Awardees Bound For the USA Dr Jenny McSharry, Dr John P Gilmore and Dr Ruth Melia 2022-2023 Fulbright-HRB HealthImpact Irish Awardees

Colette Murray (Technological University Dublin) will visit the Center for Indian Education at Arizona State University to map how Irish Traveller and Indigenous children (Southwest USA) experience Early Childhood Education and Care systems through a Tribal Critical Race Theory lens.

Fulbright-EPA Scholar, Dr Nuala Flood (Queen’s University Belfast) will work with the Parsons School of Design to explore innovative design for place-based climate resilience. Raphael Onwunali, the inaugural recipient of the FulbrightFrederick and Anna Douglass Award and a graduate of Dublin City University, will travel to The University of Chicago to complete a Master of Public Policy.

The Secretary General of the Department of Foreign Affairs, Joe Hackett and the Deputy Chief of Mission at the U.S. Embassy in Dublin, Alexandra McKnight, on behalf of U.S. Ambassador to Ireland Clare Cronin, are pleased to announce 40 Fulbright Irish Awardees for 2022-2023.

Recipients were presented with Awards at a ceremony in Iveagh House recently.

The Fulbright Program has served to strengthen international relations for seventy-five years.

The Fulbright Commission in Ireland’s vision of inspiring minds to create a global culture of understanding is more important than ever in today’s increasingly polarised world. This year’s Irish awardees will undertake research, teaching and study in the USA spanning many disciplines. They will address pressing societal

JULY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

issues, engage with U.S. society, and share their knowledge when they return home.

As a Fulbright-TechImpact Scholar to The Berkeley Artificial Intelligence Research (BAIR) Lab at UC Berkeley, Dr Angela Butler (Intel Ireland) will investigate the fascinating connection that humans forge with artificial intelligence (AI). Fulbright-National University of Ireland Scholar Dr

These are just a few examples of the work that Fulbright Irish Scholars, Students, and Foreign Language Teaching Assistants (FLTAs) will undertake over the coming year.

The next round of applications for Fulbright Irish Awards will open on 31st August 2022, interested candidates should visit www.fulbright.ie for more information.

News 75 Trinity research fellow speaks at ASCO 2022 Louise Brennan speaks at ASCO 2022

The American Society of Clinical Oncology held its annual meeting in Chicago recently and Trinity Research Fellow Dr Louise Brennan from the Trinity Exercise Oncology Group was one of 5 presenters at the prestigious ASCO Voices session and looked at equality and innovation in cancer rehabilitation research.

ASCO Voices 2022 featured compelling narratives from 5 speakers, all who are striving to advance health equity through innovation. The session, themed ‘Advancing Equitable Cancer Care Through Innovation’, featured 7-minute presentations delivered to an in-person and online audience. Over 35,000 delegates attended the ASCO 2022 annual meeting (and an additional 9,000 globally joining online), with an aim to inspire hope and action in cancer care.

Dr Brennan’s talk centred on the ReStOre@Home study, a pilot telehealth rehabilitation programme for upper GI cancer which the Trinity Exercise Oncology Group operated in 2021 during the Covid-19 pandemic.

This telehealth programme enabled people to access highquality, multi-disciplinary cancer rehabilitation (despite Covid restrictions) and participate in research in a novel, innovative way.

While restrictions initially required all of the team’s clinical research to stop, they found that by embracing the crisis and finding new, innovative, ways of operating, they could improve the reach and the equality of their research. The team partnered with an Irish technology company, Salaso Health Solutions Ltd, and ran all components of the programme (group exercise,

group education, one-to-one physiotherapy and dietician sessions) through videocalls, using their Digital Therapies Platform.

Historically, it was a challenge for the researchers to recruit participants who lived far from their base in St James Hospital in Dublin and this group of patients were therefore being under-represented in their cancer rehabilitation studies.

The telehealth model of delivery allowed the team to reach patients living all over the country. It removed geographical constraints, and provided participants the freedom to join calls from whatever location they wish, and without needing to frequently travel to the hospital to take part in the rehabilitation programme.

Dr Louise Brennan, Trinity Research Fellow at the Trinity Exercise Oncology Group, said, “I was delighted to have the opportunity to speak at ASCO 2022 Annual Meeting in Chicago, in the ASCO Voices session.

The theme of this session was ‘Advancing Equitable Cancer Care Through Innovation.’ This was a unique and valuable opportunity to speak to such a large, diverse and influential group of global oncology professionals about

equality and innovation in cancer rehabilitation. It was a privilege to represent Trinity College and Trinity St James Cancer Institute at ASCO.” Trinity Exercise Oncology Group and the ReStOrE@Home rehabilitation programme The Trinity Exercise Oncology Group led by Professor Juliette Hussey has a particular interest in rehabilitation needs and interventions for patients following complex cancer surgery.

In early 2020 the group received ethical approval to launch the ReStOre II randomised controlled trial, investigating a 12-week multidisciplinary rehabilitation programme of supervised and self-managed exercise, dietary counselling and education compared to standard survivorship care for patients following surgery for oesophageal cancer. The research is funded by the Health Research Board.

Due to the Covid-19 pandemic, commencement of the trial was

not possible in 2020, but the team used that time to develop an innovative approach to delivery of rehabilitation and tested its feasibility. Throughout the pandemic many essential health services were delivered through telehealth. However, it was not known how a programme which incorporated multiple components including exercise prescription would translate into a telehealth mode of delivery. The team found the programme was feasible, safe and convenient for patients with at least a moderate level of digital skills.

Professor Hussey, said, “The ReStOre programme is important as has opened up another avenue for the potential to deliver rehabilitation to those living a distance from hospital and/or with other commitments that make travel difficult. The programme is a crucial part of the overall research in the Trinity St James’s Cancer Institute (TSJCI) where cancer survivorship is one of the four research themes.”

Dr Louise Brennan (far RHS) and fellow participant speakers at the ASCO Voices session

HOSPITALPROFESSIONALNEWS.IE | HPN • JULY 2022

76 ASCO 2022

Advancing Equitable Cancer Care through Innovation The theme of the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting was Advancing Equitable Cancer Care Through Innovation. From June 3 to 7 in Chicago, Illinois, and online, cancer researchers and clinicians from around the world gathered to discuss the latest research and how to ensure that all people receive the cancer care they need.

Some of the notable research presented at the Meeting is detailed below.

Novel Antibody-Drug Conjugate Doubles Progression-Free Survival in Metastatic Breast Cancer With Low HER2 Expression Levels The use of trastuzumab deruxtecan (Enhertu®), a new HER2-targeting antibody-drug conjugate, doubled progressionfree survival compared to standard-of-care treatment with conventional chemotherapy.

It also significantly improved overall survival for patients with metastatic breast cancers expressing low levels of the HER2 receptor, regardless of hormone receptor status. These practicechanging findings identify a new subset of breast cancer - called HER2-low - and redefine how a large proportion of metastatic patients will be treated. This new research was presented at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting.

“This trial’s findings show that trastuzumab deruxtecan doubles progression-free survival compared to chemotherapy alone in patients with HR+, HER2-low breast cancer. By effectively creating a new category of breast cancer, HER2-low, this trial will redefine how we classify breast cancer and will significantly expand the population of patients who can benefit from HER2targeted therapy,” said Jane Lowe Meisel, MD, ASCO Expert in breast cancers.

Key Findings In the DESTINY-Breast04 study, patients received either standard chemotherapy of the physicians’ choice (capecitabine, eribulin, gemcitabine, paclitaxel, or nab-paclitaxel), or trastuzumab deruxtecan, a new antibody-drug conjugate that links trastuzumab, a HER2 monoclonal antibody, to deruxtecan, a topoisomerase I inhibitor that interrupts DNA replication in cancer cells.

Trastuzumab (Herceptin®) has been proven to be effective in cancers with high HER2 expression (called HER2-positive breast cancer) but not in cancers with low HER2 expression levels, hence trastuzumab has only been available for a subset of breast cancer patients.

The primary endpoint, PFS, in patients with cancers that were HER2-low and hormone receptor

Dr Shanu Modi

JULY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

positive (HR+), was nearly double for trastuzumab deruxtecan vs. standard chemotherapy (10.1 vs. 5.4 months). The secondary endpoint of OS was also significantly better in the HER2low, HR+ subgroup of patients who received trastuzumab deruxtecan compared to standard therapy (23.9 vs. 17.5 months).

Treatment-related adverse events were fewer in the trastuzumab deruxtecan group than in patients who received standard chemotherapy (52.6% vs 67.4%). This is consistent with previous clinical trials of these drugs. No new safety concerns were identified.

“Our study shows that trastuzumab deruxtecan may be a new and highly effective targeted therapy option available for this newly defined patient population,” said lead author Shanu Modi, MD, who is a medical oncologist at Memorial Sloan Kettering Cancer Center in New York. “It is important for patients to know what level of HER2 their cancer expresses, not just whether it’s positive or negative, especially as HER2-low status can be determined using commonly available tests.”

HER2 expression is determined by a test that measures the amount of HER2 protein on a cancer cell and/ or a test that counts the copies of the HER2 gene in cancer cells.

An estimated 290,560 new cases of breast cancer will be diagnosed in the United States in 2022i.

Of those people who receive a diagnosis of the most aggressive form of the disease, metastatic breast cancer, approximately 15-20% of such cancers will be considered HER2 positive and would be eligible to be treated with HER2-targeted therapies.

The remaining 80% or so of metastatic breast cancers are currently categorized as HER2negative, and of these cancers, approximately 55-60% express low levels of HER2.

Next Steps Use of trastuzumab deruxtecan is currently being studied in patients with HER2-low metastatic breast cancer in several ongoing studies, several of which are exploring the minimum HER2-expression threshold required for trastuzumab deruxtecan activity.

Combination Regimen Improves Overall Survival in a Type of Newly Diagnosed Metastatic Colorectal Cancer, the First Advance With a Biologic Agent Over Standard of Care in a Decade The use of panitumumab (Vectibix®) plus mFOLFOX6 significantly improved overall survival in patients with RAS wild-type metastatic colorectal cancer that was classified as

77 Dr Takayuki Yoshino

left-sided compared to patients who received mFOLFOX6, a standard chemotherapy regimen, plus bevacizumab (Avastin®), a monoclonal antibody, according to a finding that was presented at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting.

Key Findings Patients with RAS wild-type (non-mutated) metastatic colorectal left-sided tumors who received panitumumab lived for 37.9 months from the start of treatment in the trial compared to 34.3 months for those who received bevacizumab; they had an 18% lower risk of death. PFS, where tumor size was stable or shrinking, was 13.7 vs. 13.2 months, respectively, which was statistically equivalent in both groups. The response rate, which is the percentage of patients with cancer that shrinks or disappears after treatment, and the curative resection rate, which indicates that no tumor remains in the body, were both higher with panitumumab compared to bevacizumab. For OS in right-sided tumors, there was no statistically significant difference between panitumumab and bevacizumab.

as patients had access to the drugs at some point, which has now been disproven,” said lead author Takayuki Yoshino, PhD, who is the Chief for the Department of Gastrointestinal Oncology and the Deputy Director of the National Cancer Center Hospital East in Kashiwa, Japan.

Panitumumab, approved for use in colorectal cancer by the U.S. Food and Drug Administration in 2006, is a human monoclonal antibody that targets the epidermal growth factor receptor (EGFR). Bevacizumab is a monoclonal antibody drug that targets the VEGF receptor.

Modified FOLFOX6 (mFOLFOX6), is a combination chemotherapy regimen that includes the drugs

leucovorin calcium (folinic acid), fluorouracil, and oxaliplatin.

No new drugs have demonstrated superior benefit over standardof-care treatments for a decade in newly diagnosed metastatic RAS wild-type colorectal cancer. Previous studies have retrospectively analyzed data comparing anti-EGFR antibody drugs and bevacizumab. Those studies did not provide consistent results. However, PARADIGM is the largest study conducted to date to prospectively assess the impact of panitumumab in a randomized study that also assesses the impact of primary tumor location per sidedness.

Results of the study suggest tumor

Julie Gralow

Adverse events were consistent with those previously reported.

“This trial demonstrates that if gene testing shows that a tumor is RAS wild-type, the choice of initial treatment with panitumumab plus mFOLFOX6 chemotherapy is superior to initial treatment with bevacizumab plus mFOLFOX6 chemotherapy for those people with left-sided tumors. It has long been believed that the sequence of metastatic colorectal cancer treatment does not matter as long

HOSPITALPROFESSIONALNEWS.IE | HPN • JULY 2022

78 ASCO 2022 location, along with gene testing, should be part of standard disease assessment as it can impact treatment decision-making.

Stem cell transplant improves progression-free survival for younger people with newly diagnosed multiple myeloma The use of autologous stem cell transplant (ASCT) early in the course of treatment showed a significant 21.4-month gain in median progression-free survival in younger, newly diagnosed multiple myeloma patients compared to patients who received chemotherapy without an initial transplant. No overall survival benefit has yet been seen using ASCT early compared to keeping it in reserve.

Patients were randomly assigned to an initial treatment with melphalan to aid in collecting stem cells, then ASCT, followed by two cycles of a tripletcombination therapy known as RVd - lenalidomide (Revlimid®), bortezomib (Velcade®) and dexamethasone - versus three cycles of RVd, followed by stem cell mobilization (stem cells collected for possible future use if the disease progresses), and then five more cycles of RVd. Both arms received lenalidomide

maintenance until progression or intolerable drug toxicity. This new research was presented at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting.

arm vs. 53% of patients in the ASCT arm. Of the patients in the non-transplant arm, 28% underwent a delayed transplant as part of this subsequent treatment.

“The prognosis for patients with multiple myeloma has improved substantially over the last 10 years.

These findings add to an overall positive trend for patients with multiple myeloma and provide information relevant to the optimal timing of stem cell transplant in this disease,” said ASCO Chief Medical Officer & Executive Vice President Julie R. Gralow, MD, FACP, FASCO.

There were 90 deaths in the nontransplant arm vs. 88 deaths in the ASCT arm, resulting in a four-year overall survival of 84% vs. 85%, respectively. These results were not statistically significant. Fiveyear overall survival estimates were not different, with median follow up now over six years.

Key Findings Patients were randomly assigned to two arms. In the first arm, patients received three cycles of RVd, stem cell mobilization, and an additional five cycles of RVd. Patients in the second arm received the chemotherapy drug melphalan, ASCT and then two cycles of RVd. Both arms received lenalidomide maintenance therapy until disease progression or intolerable drug toxicity.

Median progression-free survival was 46.2 months in the nontransplant arm vs. 67.6 months in the ASCT arm. Subsequent treatment was necessary for 63% of patients in the non-transplant

Adverse events were less common in the non-transplant arm vs. the ASCT arm, with overall adverse events occurring in 78% of the non-transplant patients vs. 94% of the ASCT patients. Blood-borne adverse events occurred in 61% of the non-transplant patients vs. 90% of ASCT patients. Ten percent of non-transplant patients developed secondary malignancies compared to 11% of ASCT patients, with a significantly higher rate of secondary acute myeloid leukemia or myelodysplastic syndromes in ASCT patients.

Initial quality-of-life scores associated with stem cell transplant in the ASCT arm were lower than in the non-transplant arm, however patients' quality of life subsequently recovered post-transplant.

“The findings from DETERMINATION will have importance for real-world practice and the treatment of younger patients with multiple myeloma by informing providers and patients alike of the important considerations to be made in selecting treatment options in

the newly diagnosed, transplanteligible setting, as well as important implications for future research," said lead author Paul G. Richardson, MD, Clinical Program Leader and Director of Clinical Research, Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute in Boston. Dr. Richardson also noted that this trial has the highest African American participation of any phase III study in this setting to date at 18%.

Multiple myeloma is a highly heterogeneous disease, and there have been a large number of newer drugs and regimens approved for use in the disease this past decade. As a result of the relatively long overall survival seen in this disease, many clinical trials have not yet shown an overall survival benefit with one regimen versus another.

Liquid Biopsy Can Help Identify the Need for Adjuvant Therapy in Stage II Colon Cancer In patients with stage II colon cancer, for which cancer DNA was not present in the blood (circulating tumor DNA, or ctDNA) post-surgical chemotherapy could be skipped without compromising recurrence-free survival.

Conversely, for patients where ctDNA was present after surgery, the rate of recurrence among those who received chemotherapy was low, suggesting a survival benefit from post-surgical chemotherapy, according to new research presented at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting.

“Liquid biopsies can be a useful tool for guiding treatment decisions. Thanks to the results of this study, we may now be able to use it to better identify which patient with stage II colon cancer would benefit from post-surgery treatment with chemotherapy and which ones can be spared the additional treatment, without compromising relapse-free survival,” said ASCO Expert Cathy Eng, MD, FACP, FASCO. Key Findings While the current standard of care for stage II colorectal cancer does not involve a ctDNA-directed approach to post-surgical chemotherapy, the randomized phase II DYNAMIC trial results demonstrated similar recurrence-free survival between a ctDNA-guided arm and a standard management arm, despite fewer patients receiving postsurgical chemotherapy.

Dr Paul Richardson

JULY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

In the ctDNA-guided arm, patients with a positive ctDNA test result were treated with adjuvant

79 Cathy Eng

chemotherapy while those with negative results were not, almost halving the total number of patients who needed to be treated with post-surgical chemotherapy compared to standard management (15.3% vs. 27.9%).

Of those who received postsurgical chemotherapy, oxaliplatin was given more frequently than fluoropyrimidine for ctDNA-guided patients compared to standard management patients (62.2% vs. 9.8%).

Patients with a negative ctDNA result, who did not receive postsurgical chemotherapy, had a very low risk of recurrence (7.5%); the risk was even lower in negative ctDNA patients without any clinical risk features (3.3%) or among those negative ctDNA patients with tumors that had grown into the outer lining of the bowel wall but had not grown through it (5.8%).

Patients with a positive ctDNA result, who received post-surgical chemotherapy, had a three-year recurrence-free survival rate of 86%. Guidance with ctDNA assessment was comparable to standard management for two-year recurrence-free survival (93.5% vs. 92.4%, respectively) and three-year recurrence-free survival (91.7% vs. 92.4%, respectively). Without post-surgical chemotherapy, the three-year recurrence-free survival for ctDNAnegative patients was 96.7% in the low-risk group and 85.1% in the high-risk group.

“The DYNAMIC study results are very encouraging because previous data suggest that patients with a positive ctDNA score after surgery have a very high recurrence risk if no further treatment is given. Our findings show that with adjuvant treatment, ctDNA-positive patients derive considerable benefit from chemotherapy such as an oxaliplatin-based regimen,” said lead author Jeanne Tie, MD, who is an Associate Professor at the Walter and Eliza Hall Institute of Medical Research and Peter MacCallum Cancer Center, Victoria, Australia.

Circulating tumor DNA can detect micro-metastatic disease (also referred to as minimal residual disease) after surgery, allowing for a more precise prediction of recurrence risk and patient selection for post-surgical therapy.

This is the first study to use ctDNA to direct post-surgical therapy in colon cancer.

Interactive Map of Oncology In an effort to highlight cancer care inequities during the COVID-19 pandemic, the American Society of Clinical Oncology (ASCO) has launched the Interactive Map of Oncology, a data visualization tool that allows users to explore geographic distribution of systemic and socioeconomic factors that influence cancer care delivery in the United States. Users can filter data on population demographics and risk factors by location overlaid

with COVID-specific data from the COVID-19 in Oncology Registry (also known as the ASCO Registry) and other authoritative sources.

“The new Interactive Map of Oncology mashes up cancer and COVID-19 data sources in a novel way, presenting ASCO Registry data alongside public data for U.S. population demographics, socioeconomic factors, disease and risk information, as well as details on the oncology workforce,” explained ASCO Chief Executive Officer Clifford A. Hudis, MD, FACP, FASCO. “We can now better identify inequities and steer resources to help us better serve all patients.”

In addition, physicians can use the tool to better understand the patient population they serve.

Because demographics related to age, gender, cancer type, and risk factors can be easily filtered, prior to patient visits physicians can use the Map data to discern key factors proximate to their location and close any knowledge gaps related to social, economic, and other area-based characteristics that may impact a patient’s health and well-being.

According to the 2022 State of Cancer Care in America data published by ASCO, only 10.5% of the 13,365 oncologists— defined as physicians active in patient care who report medical oncology or hematology/ oncology as their primary specialty—practiced in rural areas

of the United States.1 ASCO’s Interactive Map of Oncology uses two-panel visualization technique that allows users to see statistics in a way that better allows for a sense of scale, more fully highlighting care inequities.

When adding the COVID-related data, underserved regions with high COVID-19 and high cancer incidence and low vaccination rates become more apparent.

The ASCO Registry was launched in April 2020 to help the oncology community learn more about patterns, symptoms, and severity of COVID-19 among patients with cancer, as well as treatment delays and outcomes. The Registry collects longitudinal data on more than 6,000 patients from about 70 U.S. practices. The Map blends Registry data with timely national data. The number of new COVID-19 cases is updated daily, and the number of confirmed COVID-19 cases is updated hourly.

Information about vaccination rates by county and state is also available and updated periodically.

“The ASCO Registry is improving the understanding of the effects of COVID-19 on treatment plans and outcomes for patients with cancer,” said ASCO Chief Medical Officer Julie R. Gralow, MD, FACP, FASCO. “This meticulous collection of data from practices across the country has already begun to inform us about commonalities and best practices across cancer types.”

HOSPITALPROFESSIONALNEWS.IE | HPN • JULY 2022

80 Clinical R&D ‘THE ART OF MS – SYMPTOMS UNDER THE SPOTLIGHT’ EXHIBITION ‘The Art of MS – Symptoms Under the Spotlight’ is an art exhibition created by MS Ireland in partnership with Novartis Ireland and opened recently featuring 12 original works of art created by people living with MS in Ireland.

The exhibition has been organised to raise awareness of MS and the wide-ranging symptoms of the disease to mark World MS Day 2022.

The 12 works of art on display were shortlisted by a panel of judges and chosen for their ability to impactfully depict the many symptoms of MS, many of which are invisible and unknown to the general public such as fatigue, vision impairment, depression and difficulties with memory and thinking[i]. The exhibition will feature paintings, digital illustrations, freestanding sculptures and creative video content all of which aim to help the viewer better understand what it is like to live with MS day to day.

Pictured at the launch of The Art of MS – Symptoms Under the Spotlight are Ava Battles Chief Executive MS Ireland and Audrey Derveloy, General Manager, Novartis Ireland. Picture: Andres Poveda

Méabh Hennelly is a featured artist who lives with MS, aged 25. Her piece, entitled ‘Secret Central System’ is a 3D printed sculpture which is intact from the front and exposes the brain and spinal cord from the back, representing the hidden nature of MS. Ava Battles, Chief Executive of MS Ireland said “One of the big challenges for people living with MS is trying to articulate their symptoms to others when so much of their disease is invisible.

Without understanding, empathy is limited as people do not realise how debilitating the disease can be on all aspects of the person’s life. The beauty of our exhibition opening today is that people have been able to show through art what they find hard to articulate in words. I would encourage everyone to visit The Art of MS – Symptoms Under the Spotlight exhibition and show your support for the 9,000 people in Ireland living with this disease.”

Audrey Derveloy, General Manager and Country President, Novartis Ireland speaking about the opening of The Art of MS – Symptoms Under the Spotlight said, “At Novartis Ireland we are committed to supporting the community of people living with MS in Ireland as they navigate both the management of their disease as well as day to day life living with the broad ranging symptoms.

We hope that The Art of MS – Symptoms Under the Spotlight will help the wider community to better understand and proactively

JULY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

manage their disease and I would like to personally thank all the artists who have exhibited their work to mark World MS Day.” The Art of MS – Symptoms under the Spotlight is accessible to the public from Thursday 26 May to Wednesday 1 June 2022 from 9am-5pm and is located at the main foyer of Trinity Biomedical Sciences Institute, 152 - 160 Pearse St, Dublin 2.

Find more information about MS and to view the profiles of the artists who will feature at the exhibition at www.MS-Society.ie HSE LAUNCHES COMPETENCY FRAMEWORK The HSE Antimicrobial Resistance and Infection Control team (AMRIC) has launched the Competency Framework for Infection Prevention and Control Practitioners in Ireland.

This important framework was developed to support health care professionals pursuing specialist careers in infection prevention and control (IPC). It helps staff in identifying and gaining the specific competencies they will require as an IPC practitioner.

Framework is significant for the delivery of Ireland’s second One Health National Action on Antimicrobial Resistance 20212025, iNAP2, by helping to prevent and control the spread of infection and demonstrates Ireland’s commitment to best practice in this area. Importantly, it builds on the learning and experience from the COVID-19 pandemic response, a time when IPC was so important for safe environments for patients receiving care and the staff that delivered such care. I would like to congratulate the HSE National AMRIC Team for their leadership in developing and making available this valuable resource for healthcare professionals and service providers.”

The framework aims to support managers, in growing and developing a skilled infection prevention and control workforce by: • providing standardised core competencies required for IPC practitioners in Ireland • assist in curriculum design of post graduate training courses for IPC in Ireland

Dr Eimear Brannigan, HSE Clinical Lead, Antimicrobial Resistance Infection Control (AMRIC) commented, “Effective infection prevention and control (IPC) is central to providing clean, safe and high quality health and social care for people who use those services. It also protects those who deliver the services and the wider community. All healthcare services must have basic IPC capacity within their core staff complement, and must also have access to higher-level expertise to support decision-making when necessary. This new document has been developed by the AMRIC nursing team to support health care professionals pursuing specialist careers in IPC. It will help in identifying and gaining the specific knowledge and skills they will require as IPC practitioners.”

• support healthcare organisations in growing and developing skilled and educated IPC workforce

Rachel Kenna, Chief Nursing Officer, Department of Health says, “I am delighted to support the launch of this new Competency Framework for Infection Prevention and Control Practitioners in Ireland. This is the first such framework on IPC for Ireland and it is an important step forward in advancing IPC practice. It will also assist with maintaining and improving expertise in IPC among health staff and promoting a high-quality and consistent approach to IPC practices. This

Tiziana Life Sciences (Nasdaq: TLSA) ("Tiziana" or the "Company"), a biotechnology company enabling breakthrough immunotherapies via novel routes of drug administration, has reported positive clinical results from the second patient with Secondary Progressive Multiple Sclerosis (SPMS) in the ongoing study as part of an expanded access program at the Brigham and Women’s Hospital (BWH), Boston, MA. These results confirm the previously reported data, from the first SPMS patient after three

• support self-assessment of competence by the IPC practitioner • assist and complement staff appraisal and professional development plan processes.

This document will continue to support the growth and development of a skilled infection prevention and control workforce in Ireland.

TIZIANA LIFE SCIENCES ANNOUNCES POSITIVE CLINICAL RESULTS IN THE SECOND PATIENT WITH SECONDARY PROGRESSIVE MULTIPLE SCLEROSIS (SPMS)

81 months of treatment of the first SPMS patient. The treatment with foralumab, a fully human anti-CD3 monoclonal antibody, was welltolerated and improved clinical and PET imaging analyses.

The second patient, a young male in his 40s, was diagnosed with SPMS in 2014. Since then, the disease has been progressive, resulting in an accumulation of disability. Following completion of three months of treatment with intranasal foralumab (50 mcg; three times a week for two weeks, followed by one week off treatment), the patient showed improvement as measured by PET imaging, to assess inhibition of microglial activation, and by neurologic examination.

Approximately 10-30% reduction in PET signal was seen across brain regions (including cortex, thalamus, white matter, and cerebellum) in the second SPMS patient, which is comparable to the PET changes seen in the first SPMS patient following three months of treatment with intranasal foralumab. Clinically, the Timed 25-Foot Walk test and neurologic exam were also improved. Both the first and the second patient are continuing with the treatment and are in their 13th and 4th months of treatment, respectively.

Dr. Kunwar Shailubhai, Chief Executive Officer and Chief Scientific Officer of Tiziana Life Sciences, commented, "We are excited about the positive clinical responses seen in 2 out of 2 SPMS patients treated so far. Clinical data from both patients further validate our novel intranasal therapy with foralumab, which seems to overcome the bloodbrain barrier to allow therapeutic action of the drug."

The favorable safety, tolerability, and clinical responses from the first two SPMS patients were submitted to the U.S. Food and Drug Administration (FDA). The agency has now allowed Tiziana to treat an additional eight SPMS patients. Although the original dosing regimen with intranasal therapy with foralumab will remain the same (50 mcg; three times a week for two weeks, followed by one week off treatment), the revised dosing regimen has a provision for dose escalation up to 100 mcg (MWF) as an option to improve clinical benefit.

Dr. Howard Weiner, MD, Director of the Multiple Sclerosis Program at BWH and Chairman of Tiziana's Scientific Advisory Board, commented, "We are very pleased by both the biological and clinical improvement observed in the second patient after treatment with intranasal Foralumab for

three months, which provides confirmation that the intranasal dosing modulates the systemic immune response and in turn dampens brain inflammation. It is encouraging to see the consistency of response between the first and second patient and that the treatment was well tolerated."

Tanuja Chitnis, MD, Principal Investigator and Professor of Neurology at Harvard Medical School (HMS) and senior neurologist at BWH and Massachusetts General Hospital added, "Therapies to slow progression in multiple sclerosis are much needed as there are only a few options for non-active SPMS. I look forward to treating more patients under this same protocol."

Tarun Singhal, MD, Director of PET Imaging Program in Neurologic Diseases, associate neurologist and nuclear medicine physician at BWH commented, “Our current analyses suggest a consistency of response to intranasal foralumab, across the first two SPMS patients. We were also able to harmonize data across scanners and institutions, which has yielded very encouraging results. We look forward to our continued investigations of foralumab in SPMS patients, using additional PET analytical approaches.”

About Foralumab Foralumab (formerly NI-0401), the only entirely human anti-CD3 mAb, shows reduced release of cytokines after IV administration in healthy volunteers and in patients with Crohn's disease. In a humanized mouse model (NOD/ SCID IL2γc-/-), it was shown that while targeting the T-cell receptor, orally administered foralumab modulates immune responses of the T-cells and enhances regulatory T-cells (Tregs), thereby providing therapeutic benefit in treating inflammatory and autoimmune diseases without the occurrence of potential adverse events usually associated with parenteral mAb therapy. Once a day treatment for 10 consecutive days with intranasal foralumab was not only well tolerated but it also produced strong clinical responses in COVID-19 patients. Based on these studies, the intranasal and oral administration of foralumab offers the potential to become a well-tolerated immunotherapy for autoimmune and inflammatory diseases by the induction of Tregs.

the Falsified Medicines Directive (FMD) in Ireland. The Safety Features Oversight Group has been made aware of an issue regarding FMD alerts received when scanning four batches of French packs of Utrogestan products supplied as exempt medicinal products (EMPs) in Ireland.

• Utrogestan 200mg Capsules molle orale ou vaginale (Batch Numbers 200261 and 202225) • Utrogestan 100mg Capsules molle orale ou vaginale (Batch Numbers 214679 and 220486) If pharmacies scan and receive alerts for these four Utrogestan batches, they may supply the packs to patients under their existing procedures, unless they have overriding concerns that a falsified medicine is involved.

The alerts have been caused, in part, by decommissioning transactions that took place in another country, and there is no evidence that the products have been falsified.

If a pharmacist has reason to believe that the packaging has been interfered with, based on their examination of the antitamper device on the pack, they must report their concern to the HPRA (as a suspected quality defect via the usual reporting mechanisms) and not supply the pack.

INNOVATIVE NEW PROCEDURE AT GALWAY UNIVERSITY HOSPITAL Galway University Hospitals (GUH) is the first hospital in the country to introduce a new minimally invasive day case procedure to reduce blood pressure in patients. This means that patients arrive in the hospital in the morning, have the procedure and are able to return home the same day.

Professor Faisal Sharif, Consultant Cardiologist at GUH said, “We are probably the only hospital anywhere carrying out this procedure as a day case. Certainly we are the only hospital in the world carrying out the procedure, which is called renal artery denervation, using a product manufactured by Medtronic here in Galway.

“We are using renal artery denervation to help patients with high uncontrolled blood pressure or hypertension which is a major risk factor for stroke, heart attack, vascular disease and chronic kidney disease.

“Approximately 35% of the adult population in Ireland have hypertension and around one third of these patients are taking medication but their blood pressure is still uncontrolled. If we are able to control blood pressure we are able to reduce the risk of debilitating side effects. Even a small reduction in blood pressure can lead to a significant reduction of the risk of stroke or heart attack.

“We have participated in a number of clinical trials for renal artery denervation here in GUH that have shown reduction in blood pressure. Based on these results, renal artery denervation is now being carried out as a day case procedure. This has huge benefits for the patients in terms of reduced disruption to their lives, recovery at home and we are not dependent on the availability of beds for an overnight stay which can be a challenge with the current demands on inpatient care.

“At the moment we are carrying out one or two of these procedures every month to help patients control their blood pressure.

ADVICE ON FMD ASPECTS OF SUPPLYING UTROGESTAN 100MG AND 200MG CAPSULES AS EXEMPT MEDICINAL PRODUCTS IN IRELAND The Safety Features Oversight Group continues to oversee progress with implementation of

Consultant Cardiologist Professor Faisal Sharif who has introduced a day case procedure to address uncontrolled blood pressure at Galway University Hospitals, in the Cath Lab at the hospital

HOSPITALPROFESSIONALNEWS.IE | HPN • JULY 2022

82 Clinical R&D CANCER VACCINE BIOTECH CIMCURE RAISES ¤5 MILLION IN SEED ROUND INVESTMENT LED BY POSITRON VENTURES CimCure, a biotech spin-off of Amsterdam UMC, focusing on the development of a novel vaccinebased cancer immunotherapy through its Immune-Boost (iBoost) technology, has announced that it has raised little over ¤5 million in a financing Seed Round led

by Dutch VC Positron Ventures.

The round was supported by several investors with deep industry knowledge, including the investment vehicle of Tom Würdinger, professor at Amsterdam UMC. With the proceeds of this Seed Round CimCure will further advance the vaccine up until phase 1-2 clinical studies in humans. Dutch vaccine CDMO Intravacc will be CimCure’s partner for the development and production of the lead compound.

The vaccine-based immunotherapy developed by the team of Prof.

Dr Griffioen at the Amsterdam UMC and licensed to CimCure, has shown high effectiveness and safety, both in murine animal models and in an efficacy study in client-owned dogs with spontaneous bladder cancer.

Late May, some of the research results which underlie CimCure’s innovation were published in Nature Communications (Van Beijnum et al, 2022).

CimCure was founded in 2016 as a spin-off of Amsterdam UMC supported by Amsterdam UMC’s TTO Innovation Exchange Amsterdam and is led by Prof. dr. Arjan Griffioen, CSO, and Diederik Engbersen, CEO. Both have extensive experience in the biotech industry and started CimCure to commercialise a smart, effective and safe treatment strategy against all types of solid tumors at all stages, and can be combined with conventional and state-of-the-art anti-cancer strategies.

Joseph Peeraer, founding partner of Positron said, “We feel privileged to be able to invest in this promising iBoost technology and vaccine-based cancer immunotherapy, which might become a real game changer in the fight against cancer.

This investment in CimCure exemplifies our thesis to invest at an early stage in outstanding scientists who would like to bring a potentially groundbreaking and impactful innovation to market. Professor Griffioen’s invention may lead to a much less

demanding, cheaper and more effective cancer treatment.”

About CimCure’s vaccine-based immunotherapy CimCure develops cancer vaccines through its proprietary Immune-Boost (iBoost) technology of targeted conjugate vaccines. The company has identified specific targets in the tumor vasculature. Eradication of tumor blood vessels and inhibition of their growth will lead to inhibition of cancer growth.

This is an attractive approach for treatment of cancer. However, past and current angiostatic drugs are known for rapid induction of drug resistance and loss of effectiveness, due to intervention in tumor-produced growth factors or their receptors. CimCure’s approach directly targets the tumor blood vessels, which efficiently attenuates tumor growth directly and does not induce resistance. An additional advantage of targeting blood vessels is that the barrier function of the tumor vasculature for leukocytes can be overcome (Huinen et al, Nature Reviews Clinical Oncology, 2021).

INNOVATIVE NEW PROCEDURE AT GALWAY UNIVERSITY HOSPITAL Galway University Hospitals (GUH) is the first hospital in the country to introduce a new minimally invasive day case procedure to reduce blood pressure in patients. This means that patients arrive in the hospital in the morning, have the procedure and are able to return home the same day.

Professor Faisal Sharif, Consultant Cardiologist at GUH said, “We are probably the only hospital anywhere carrying out this procedure as a day case. Certainly we are the only hospital in the world carrying out the procedure, which is called renal artery denervation, using a product manufactured by Medtronic here in Galway.

“We are using renal artery denervation to help patients with high uncontrolled blood pressure or hypertension which is a major risk factor for stroke, heart attack, vascular disease and chronic kidney disease.

“Approximately 35% of the adult population in Ireland have hypertension and around one third of these patients are taking medication but their blood pressure is still uncontrolled. If we are able to control blood pressure

JULY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

we are able to reduce the risk of debilitating side effects. Even a small reduction in blood pressure can lead to a significant reduction of the risk of stroke or heart attack.

“We have participated in a number of clinical trials for renal artery denervation here in GUH that have shown reduction in blood pressure.

Based on these results, renal artery denervation is now being carried out as a day case procedure. This has huge benefits for the patients in terms of reduced disruption to their lives, recovery at home and we are not dependent on the availability of beds for an overnight stay which can be a challenge with the current demands on inpatient care.

“At the moment we are carrying out one or two of these procedures every month to help patients control their blood pressure.

Patients can contact our team directly to enquire about the procedure by calling Eileen Coen on 086 1455568. We then ask patients to wear a blood pressure monitor for 24 hours and we do other checks to make sure that they are suitable for the procedure.

“The feedback from our patients who have had renal artery denervation has been incredibly positive with all benefitting from the procedure with improved blood pressure and better future health prospects.”



DARZALEX® (DARATUMUMAB) APPROVED FOR REIMBURSEMENT IN IRELAND IN COMBINATION WITH BORTEZOMIB, THALIDOMIDE AND DEXAMETHASONE (VTD) FOR PATIENTS WITH NEWLY DIAGNOSED MULTIPLE MYELOMA WHO ARE TRANSPLANT ELIGIBLE Janssen, the Pharmaceutical Companies of Johnson & Johnson, has announced Darzalex® (daratumumab) in combination with bortezomib, thalidomide and dexamethasone (VTd) has been granted reimbursement in Ireland for the treatment of patients with newly diagnosed multiple myeloma who are eligible for autologous stem cell transplant (ASCT).

The announcement follows EC approval of daratumumab based on results from Part one of the Phase 3 CASSIOPEIA (MMY3006) study, published in The Lancet5 in June 2019 and presented at the 2019 American Society of Clinical Oncology (ASCO) Meeting.



Professor Philip Murphy, Consultant Haematologist, Beaumont Hospital said: “For Irish patients newly

diagnosed with multiple myeloma, the importance of early intervention with effective first-line treatments to maximise response cannot be emphasised enough. Improvements in the standard of care to provide patients with valuable extra time are vital. Data from the CASSIOPEIA study demonstrates that the addition of daratumumab in combination with VTd can lead to deep remissions and prolong PFS.” Dr Thorsten Giesecke, General Manager, Commercial Business, Janssen Sciences Ireland UC, said: “Janssen is committed to providing access for patients to daratumumab in earlier disease stages of multiple myeloma, a type of blood cancer that can have a devastating impact on the lives of those affected. Every year in Ireland about 350 people are diagnosed with this condition, and today’s reimbursement provides those who are newly diagnosed and transplant eligible, with a long-awaited additional frontline therapy.”

The Phase 3 CASSIOPEIA trial is a two-part study. Results from this first part of the trial showed that after consolidation, the stringent complete response (sCR) rate was significantly higher in the daratumumab-VTd arm (29 percent) compared to VTd alone (20 percent) (Odds Ratio [OR] = 1.60; 95 percent confidence interval [CI], 1.212.12; P<0.0010).2 At a median follow-up of 18.8 months, PFS was significantly improved in the daratumumab-VTd group compared to VTd alone (Hazard Ratio [HR] = 0.47; 95 percent CI, 0.33-0.67; P<0.0001), and the median PFS was not reached in either arm. The addition of daratumumab to VTd resulted in an 18-month PFS rate of 93 percent compared to 85 percent for VTd alone.

The most common (≥10%) Grade 3/4 treatment-emergent adverse events (TEAEs) for daratumumabVTd and VTd, respectively, were neutropenia (28 percent vs. 15 percent), lymphopenia (17 percent vs. 10 percent), stomatitis (13 percent vs. 16 percent) and thrombocytopenia (11 percent vs.

7 percent). In the daratumumabVTd combination arm, infusionrelated reactions occurred in 35 percent of patients.

SANOFI GRANTS REGENERON WORLDWIDE EXCLUSIVE LICENSE RIGHTS TO LIBTAYO® (CEMIPLIMAB) Sanofi restructures its immunooncology collaboration with Regeneron Pharmaceuticals, Inc. Under the amended and

83 restated license and collaboration agreement, Regeneron will obtain worldwide exclusive license rights to Libtayo. The Sanofi and Regeneron global immuno-oncology license and collaboration agreement was originally executed in 2015.

Prior to today, the companies had split Libtayo’s worldwide operating profits equally and co-commercialized Libtayo in the U.S., with Sanofi solely responsible for commercialization in the rest of the world.

Bill Sibold, Executive Vice President of Specialty Care & President of North America, Sanofi said, “Our diverse oncology portfolio doubled between 2019 and 2022 and now includes twelve compounds in clinical trials, each with a unique mechanism of action. Our early steps with Libtayo in immunooncology provided a strong foundation for our revitalized oncology efforts. Now, we are focused on leveraging our internal capabilities and advancing a new generation of oncology medicines.

We continue to maintain a strong partnership with Regeneron in immunology, and will work closely with them on the seamless transition of Libtayo to ensure there is no impact for patients.”

Under the terms of the amended and restated immuno-oncology license and collaboration agreement, Sanofi will transfer the rights to develop, commercialize, and manufacture Libtayo entirely to Regeneron, on a worldwide basis, over the course of a defined transition period (to start upon receipt of any required governmental clearances worldwide). In exchange, Sanofi will receive an upfront payment of $900 million, and an 11% royalty on worldwide net sales of Libtayo.

Sanofi will also be entitled to a $100 million regulatory milestone payment upon the first approval by either the FDA or European Commission of Libtayo in combination with chemotherapy for first-line treatment of certain patients with NSCLC, as well as sales-related milestone payments of up to $100 million in total over the next two years. The transaction is subject to clearance under competition law and is expected to close in the third quarter of 2022.

Regeneron will also accelerate reimbursement of the development balance associated with Regeneron and Sanofi’s separate Antibody Collaboration. Regeneron will increase from 10% to 20% the share of its profits that are paid to Sanofi to reimburse Sanofi-

funded development expenses, until Regeneron’s share of the total cumulative development costs incurred under the collaboration has been reached.

Sanofi continues to build its considerable expertise in oncology and has increased research and development capabilities, focusing on difficult to treat cancers including breast, blood, and lung. We are committed to translating scientific discoveries into potential new treatments and addressing critical gaps in cancer care.

UNAIDS RESPONDS TO VIIV’S ANNOUNCEMENT ON THE LICENSING OF LONG-ACTING CABOTEGRAVIR HIV medicine manufacturer Viiv has announced that it is “actively negotiating” a voluntary license with the Medicines Patent Pool on long-acting Cabotegravir.

The World Health Organization will soon issue updated global guidelines on the appropriate application of new long-acting HIV medicines.

Responding to the announcement made by Viiv, UNAIDS Deputy Executive Director a.i. Matt Kavanagh said, “Last year there were 1.5 million new HIV infections, which shows the urgency of global access to new tools to overcome this pandemic.

A successful global HIV response depends on the sharing of technologies. We are encouraged

by ViiV’s announcement of negotiations with the Med icines Patent Pool, which has followed engagement by UN partners, financing agencies, civil society, and others. The announcement is an important sign of progress toward affordable global access to this technology for the HIV response; it now needs to be followed by rapid action, in order to translate promises into medicines.

possible, to minimize the further wait for affordable products where they are most needed.

“Because generic manufacturing will take time to get running, even once a license is agreed, it is also key that ViiV name an interim price that is affordable for lowand middle-income countries.

“Those who need new HIV prevention tools most are too often those who get access last — but this need not happen.

“We can, as promised, end AIDS as a public health crisis by 2030 – if leaders act boldly to address the inequalities which have driven it. Hoarding life-saving science hurts everyone; it perpetuates pandemics. Sharing life-saving science benefits everyone."

MAYOR UNVEILS PROFESSOR GERRY O’SULLIVAN MEMORIAL STATUE On National Cancer Survivors Day, Sunday June 5, a life-sized statue was revealed by a West Cork community to honour the late Professor Gerry O’Sullivan, a pioneer in the field of cancer research, and founder of Cork Cancer Research Centre and the national charity Breakthrough Cancer Research.

The statue was officially unveiled in the Professor Gerry O’Sullivan Memorial Park, Caheragh, by the Mayor of the County of Cork, Cllr.

Gillian Coughlan and Professor of Sullivan’s widow Breda and family.

The keynote speaker at the event was one of the world’s most influential scientists, leading immunologist, author and broadcast personality, Professor Luke O’Neill. Professor O’Neill is a regular contributor to discussions on science and research on TV and radio in Ireland and around the world. Like many said of Professor O’Sullivan, he has an infectious enthusiasm and belief in the power of science to help us live better

lives, so those attending can expect to be inspired.

Professor O’Sullivan was a highly acclaimed surgeon, scientist and cancer researcher. His worldrenowned clinical expertise was matched by his belief in the power of research to mould a better future for people with cancer.

Chair of the committee Micheál Kirby, said, “Professor O’Sullivan died at the young age of 65 from cancer, a disease he had spent his whole career saving others from. We are so incredibly proud of his achievements and the man he became and want to encourage young people in our community to follow in his footsteps. Nothing is impossible when you have passion, determination and a kind heart. Gerry never forgot his roots in West Cork and we will always remember him.”

Professor O’Sullivan’s work continues with Breakthrough Cancer Research, an Irish medical cancer research charity that he founded on the unshakeable belief in Cork and in Ireland that we can make more survivors of cancer and we will do that through research. Breakthrough invest in world-class research in Ireland to impact the quality of life for cancer patients and to save lives. They are particularly focused on improving outcomes for cancers which are poorly served by current treatment options and have helped take 9 new treatments from the lab into clinical trial.

The statue unveiling is an event open to the public from 1.30pm4pm on Sunday 5th June. In addition to the commemoration ceremony, there will be dancing performances from the local national school, music with the St Fachtna’s Silver Band, facepainting and food trucks.

Professor Gerry O’Sullivan

“To have transformative impact as a tool for HIV prevention on the scale needed, it is vital that a license for this long-acting antiretroviral come quickly, with open non-exclusive terms for use and production across the world’s low- and middleincome countries. The licensing agreement should also be accompanied by an effective transfer of a technology package, to facilitate quality-assured manufacturers around the world to produce the medicines as soon as possible. There is an urgent need for large-scale production to get underway in Africa, Asia, Latin America and beyond, as soon as

HOSPITALPROFESSIONALNEWS.IE | HPN • JULY 2022

Legal Category: POM S1A. Marketing Authorisation Holder: Pfizer Europe MA EEIG, Boulevard de la Plaine 17, 1050 Bruxelles, Belgium. For further information please contact: Pfizer Healthcare Ireland, 9 Riverwalk, National Digital Park, Citywest Business Campus, Dublin 24 or Medical Information on 1800 633 363 or at medical.information@pfizer.com T 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.

Refer to section 4.8 of the SPC for how to report adverse reactions.

Please see summary of product characteristics for more information.

PP-BIO-IRL-0149

All rights reserved.

September 2021