Update cardiology issue 4 2018

Getting to grips with heart failure

UPDATE UPDATE

Latest evidence on lipid management Implantable cardiac defibrillators guidance American College of Cardiology 2018 meeting report

cardiology Volume 4 Issue 4 2018 | In association with The Medical Independent

UPDATE: Clinical Journal for all healthcare professionals specialising in, or with an interest in, cardiology

ATOZET®

Legal Category: POM. Marketing Authorisation Holder: Merck Sharp & Dohme Ltd., Hertford Road, Hoddesdon Hertfordshire EN11 9BU United Kingdom. Date of Review: October 2017. Further information is available on request from: MSD, Red Oak North, South County Business Park, Leopardstown, Dublin 18 or from www.medicines.ie. © Merck Sharp & Dohme Ireland (Human Health) Limited, 2018. All rights reserved.

Date of Preparation: January 2018.

Reference: 1. ATOZET SPC

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FOR PATIENTS WITH CORONARY HEART DISEASE AND A HISTORY OF ACUTE CORONARY SYNDROME AND/OR HYPERCHOLESTEROLAEMIA

cardiology

UPDATE

EDITORIAL

Evidence, guidelines, and advocacy

T

here can be few specialities that have such a wealth of evidence to inform practice as cardiology. During the course of my career I have seen the specialty evolve from one in which there was little evidencebase for practice as it then was: it didn’t need a double blind randomised crossover trial to show that defibrillation saved lives. Practice is now defined by the results of mega trials of tens of thousands of patients often conducted in multiple centres across the world. Over the past 30 years many of these trials have been “game changers”, landmark trials which changed practice on a global basis.

The GISSI trial was one of the first multi-centred mega trials conducted throughout Italy and in 1986 established the role of intravenous streptokinase in the management of myocardial infarction. ISIS 2 showed the added benefit of aspirin and although thrombolytic therapy was literally a lifesaver, it is now of course superseded by primary percutaneous coronary intervention (primary PCI), with consistent data from studies like PAMI showing the benefits of primary PCI and then data from DANAMI and PRAGUE, which showed the feasibility and advantages of transfer of patients to a primary PCI centre.

Thirty years ago Class IV heart failure had a 50 per cent one-year mortality, a prognosis similar to widespread cancer. Now many patients with poor left ventricular function can survive for years thanks to the benefits of ACE inhibitors shown by studies like SAVE, SOLVD and CONSENSUS. As a medical student I was taught that betablockers were contraindicated in heart failure; now patients worldwide survive because of them, based on the data from studies like COPERNICUS, CIBIS 2 and MERIT HF. The combination of sacubitril and valsartan showed a 20 per cent reduction in cardiovascular death in heart failure in the PARADIGMHF study.

In the world of devices we have evidence for the benefits of implantable defibrillators in patients with persisting impaired left ventricular function (ejection fraction less than 35 per cent) from studies like MADIT, and in lipid lowering we have gone from statin studies like 4S and WOSCOPS to the exciting new group of drugs, the PCSK9 inhibitors with studies like ODYSSEY and FOURIER. So we have a plethora of acronyms and a wealth of evidence. It would be impossible for any one individual to trawl through all the evidence and formulate an evidence-based management strategy for all their patients. Fortunately international bodies and professionals spend a great deal of effort and man hours in bringing together guidelines for each class of cardiological condition. We in the Irish Cardiac Society endorse the use of the European Society of Cardiology (ESC) guidelines, (escardio.org) and in Northern Ireland we follow NICE (National Institute of Health and Care Excellence). We are influenced by the Scottish Intercollegiate Guidelines Network (SIGN) and we often look across the Atlantic to the American College of Cardiology for their guidelines.

However, even when professional and international bodies distil the evidence into manageable practical guidance, we still have multiple sources of that guidance, sometimes with variation in the guidelines put out by different bod-

ies on the same topic. So who should we follow and what are the potential consequences of failure of adherence to guidelines?

Some years ago the interventional cardiology community was concerned that NICE guidelines on the use of drug-eluting stents denied their use to certain patients for whom there was evidence of benefit. I have frequent correspondence with dentists in my local community about the discrepancy between the NICE guidelines for the use of antibiotic prophylaxis for endocarditis and those published

by ESC. Specifically the issue is the ESC would indicate that antibiotic prophylaxis is indicated for patients who have had previous endocarditis, those with prosthetic valves and those with congenital cyanotic heart disease, whereas NICE has not advocated antibiotics for these groups, with the result that dentists are understandably wary of not abiding by NICE guidelines.

Must doctors comply with guidelines? That was the question asked in a guidance article provided by the UK’s Medical Defence Union. The consensus is that guidelines inform clinical practice but do not dictate it. Documentation from NICE itself has indicated that its guidance does not override individual responsibility of health professionals to take appropriate decisions according to the circumstances of the individual patient, in consultation with the patient. Whilst I personally adhere to NICE and ESC guidelines as far as possible, there are occasions when, for specific individual reasons, I will not fully adhere. In that situation I explain carefully to the patient the reasons for my management plan, ensure they understand and agree with it and carefully document the reasons for lack of adherence.

The UK General Medical Council specifically states “you must be familiar with guidelines and developments that affect your work” and also “you must listen to patients taking account of their views and respond honestly to their questions”. Regardless of what guidelines we follow for whatever condition, we have the responsibility to act as advocates for our patients. The Irish Medical Council has indicated the requirement for doctors to act as advocates for their patients, both in speaking on behalf of individuals to help make sure they receive appropriate healthcare and also by promoting the fair distribution of limited resources and fair access to care.

At the opening session of the American College of Cardiology, Dr Mary Norine Walsh, the outgoing President of the College, stressed the need for us all to act as advocates for patients. In a memorable address, she herself described how she had acted as an advocate for her octogenarian father who had presented with angina and yet who, even with the wealth of resources in the American healthcare system, experienced a delay in management of what was potentially a life-threatening disease. We in the North are fortunate that the Department of Health, Social Services and Public Safety (DHSSPS) adopt NICE guidelines, but even with that support, there can be a delay in implementation of therapies for which we have new and ever-evolving evidence. Not everywhere has a statutory requirement to follow guidelines and in those situations we must be fair advocates for patients, bringing into play the evidence-base, but ever being mindful to make efficient use of available resources.

Medical Editor, Dr Albert McNeill, Consultant Cardiologist Altnagelvin Hospital, Londonderry, Lead Clinician for Cardiology, Western Health and Social Care Trust, and President, Irish Cardiac Society

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cardiology

CONTENTS Editor: Paul Mulholland paul@mindo.ie

Latest evidence on lipid management

4-8

Medical Editor: Dr Albert McNeill

Current advice and the complexities of anticoagulants

9-10

Sales: Graham Cooke graham@greenx.ie

The management of atrial fibrillation

12-14

Designer: Emer Keogh emer@greenx.ie

Clinical approaches to palpitations

16-18

American College of Cardiology 2018 meeting

20-21

An update on TAVI

22-23

An overview of angina

25-26

Irish Heart Foundation heart failure campaign

27-28

Heart failure: Diagnosis and management

30-34

Taking the fight to heart failure

35-36

Irish Cardiac Society 2017 Annual Scientific Meeting

37-45

Patent foramen ovale closure

46-47

Publishers: Maura Henderson maura@greenx.ie Graham Cooke graham@greenx.ie

Update is published by GreenCross Publishing Ltd, Top Floor, 111 Rathmines Road Lower, Dublin 6 Tel: 01 441 0024 Fax: 01 547 2388 www.greencrosspublishing.ie

Update endeavours to ensure accuracy of information given and of claims made in articles and advertisements.

Nevertheless, no responsibility is accepted in respect of such information or claims. Any opinions expressed by contributors are entirely their own and do not purport to be the views of the Medical Independent.

Implantable cardiac defibrillators: The difficulty with guidelines 48-49

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Test your knowledge on cardiac arrhythmias

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Update is a clinical journal from GreenCross Publishing Ltd. Each issue of Update focuses on a single clinical area. As the name implies, the journal will address current thinking and new research in a given clinical area. Update has a multidisciplinary focus and will be circulated to consultants, GPs, pharmacists, ANPs, CNSs, and practice nurses.

UPDATE

GreenCross Publishing was established in 2007.

It is jointly owned by Graham Cooke and Maura Henderson.

Cardiology initiatives from the West

Power in Lowering Blood Pressure Coverdine film coated tablets (perindopril arginine/indapamide/amlodipine). Abbreviated Prescribing Information: Please refer to the Summary of Product Characteristics before prescribing. COMPOSITION* Coverdine 5mg/1.25mg/5mg film-coated tablets: 5 mg perindopril arginine (per) /1.25 mg indapamide (ind) /5 mg amlodipine (amlo); Coverdine 5mg/1.25mg/10mg film-coated tablets: 5 mg per/1.25 mg ind/10 mg amlo; Coverdine 10mg/2.5mg/5mg film-coated tablets: 10 mg per/2.5 mg ind/5mg amlo; Coverdine 10mg/2.5mg/10mg film-coated tablets: 10 mg per/2.5 mg ind/10 mg amlo. INDICATIONS* Substitution therapy for treatment of essential hypertension, in patients already controlled with perindopril/indapamide fixed dose combination and amlodipine, taken at the same dose level. DOSAGE AND ADMINISTRATION* One tablet per day, preferably in the morning and before a meal. The fixed dose combination is not suitable for initial therapy. If a change of the posology is required, titration should be done with the individual components. Paediatric population: should not be used.

CONTRAINDICATIONS* Dialysis patients. Patients with untreated decompensated heart failure. Severe renal impairment (Clcr < 30 mL/min). Moderate renal impairment (Clcr 30-60 mL/min) for Coverdine10mg/2.5mg/5mg and 10mg/2.5mg/10mg. Hypersensitivity to the active substances, to other sulphonamides, to dihydropyridine derivatives, any other ACE-inhibitor or to any of the excipients. History of angioedema (Quincke’s oedema) associated with previous ACE inhibitor therapy (see Warnings section). Hereditary/idiopathic angioedema. Second and third trimesters of pregnancy (see Warnings and Pregnancy and lactation sections). Lactation (see Pregnancy and lactation section). Hepatic encephalopathy. Severe hepatic impairment. Hypokalaemia. Severe hypotension. Shock, including cardiogenic shock. Obstruction of the outflow-tract of the left ventricle (e.g. high grade aortic stenosis).

Haemodynamically unstable heart failure after acute myocardial infarction. Concomitant use of Coverdine with aliskiren-containing products in patients with diabetes mellitus or renal impairment (GFR < 60mL/ min/1.73m2) (Interaction section). WARNINGS* Special warnings: Dual blockade of the renin-angiotensin-aldosterone system (RAAS): ACE- inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy. Neutropenia/agranulocytosis/ thrombocytopenia/anaemia: caution if collagen vascular disease, immunosuppressant therapy, treatment with allopurinol or procainamide, or combination of these complicating factors, especially if pre-existing impaired renal function. Monitoring of white blood cell counts. Hypersensitivity/angioedema, intestinal angioedema: stop treatment and monitor until complete resolution of symptoms. Angioedema associated with laryngeal oedema may be fatal. Concomitant use of mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus): patients may be at increased risk for angioedema (e.g. swelling of the airways or tongue, with or without respiratory impairment). Anaphylactoid reactions during desensitization: Caution in allergic patients treated with desensitization and avoid if venom immunotherapy. Temporarily withdrawal of ACE-inhibitor at least 24 hours before desensitization. Anaphylactoid reactions during LDL apheresis: Temporarily withholding ACE-inhibitor prior to each apheresis. Haemodialysis patients: consideration to use dialysis membranes other than high flux or antihypertensive agents other than ACE inhibitors. Pregnancy: no initiation during pregnancy, stop treatment and start alternative therapy if appropriate. Hepatic encephalopathy: stop treatment. Photosensitivity: stop treatment. Precautions for use: Renal function: In certain hypertensive patients without pre-existing apparent renal lesions and for whom renal blood tests show renal insufficiency, stop treatment and restart at a low dose or with one constituent only. Monitoring of potassium and creatinine, after two weeks of treatment and then every two months during therapeutic stability period. If bilateral renal artery stenosis or single functioning kidney: not recommended. Risk of arterial hypotension and/or renal insufficiency (in cases of cardiac insufficiency, water and electrolyte depletion, in patients with low blood pressure, renal artery stenosis, congestive heart failure or cirrhosis with oedema and ascites): start treatment at low doses and increase progressively. Hypotension and water and sodium depletion: Risk of sudden hypotension in presence of pre-existing sodium depletion (in particular if renal artery stenosis): Monitoring of plasma electrolytes, re-establish blood volume and pressure, restart treatment at a reduced dose or with only one of the constituents. Sodium levels: More frequent monitoring in elderly and cirrhotic patients. Potassium levels: Hyperkalaemia: Monitoring of serum potassium if renal insufficiency, worsening of renal function, age (> 70 years), diabetes mellitus, intercurrent events, in particular dehydration, acute cardiac decompensation, metabolic acidosis and concomitant use of potassium-sparing diuretics, potassium supplements or potassium salts, or other drugs associated with increases in serum potassium. Hypokalaemia: high risk for elderly and/or malnourished subjects, cirrhotic patients with oedema and ascites, coronary patients, patients with renal failure or heart failure, long QT interval: monitoring of serum potassium. May favor the onset of torsades de pointes, which may be fatal. Calcium levels: hypercalcemia: stop treatment before investigating the parathyroid function. Renovascular hypertension: if renal artery stenosis: start treatment at hospital at low dose; monitor renal function and potassium. Dry cough. Atherosclerosis: start treatment at low dose in patients with ischaemic heart disease or cerebral circulatory insufficiency. Hypertensive crisis. Cardiac failure/severe cardiac insufficiency: Caution if heart failure. Severe cardiac insufficiency (grade IV): start treatment under medical supervision with reduced initial dose. Aortic or mitral valve stenosis / hypertrophic cardiomyopathy: Caution if obstruction in the outflow tract of the left ventricle. Diabetic patients: If insulin dependent diabetes mellitus, start treatment under medical supervision with reduced initial dose; monitor blood glucose during the first month and/or in the case of hypokalaemia. Black people: higher incidence of angioedema and apparently less effective in lowering blood pressure than in non-blacks. Surgery / anaesthesia: stop treatment one day before surgery. Hepatic impairment: Mild to moderate: caution. Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes) death. Stop treatment if jaundice or marked elevations of hepatic enzymes. Uric acid: hyperuricemia: Increased tendency to gout attacks. Elderly: testing of renal function and potassium levels before treatment start. Dosage increase with care. INTERACTION(S)* Contraindicated: Aliskiren in diabetic or impaired renal patients. Not recommended: Lithium, Aliskiren in patients other than diabetic or impaired renal patients, Concomitant therapy with ACE inhibitor and angiotensin-receptor blocker, Estramustine, Potassium-sparing drugs (e.g. triamterene,amiloride,…), Potassium salts, Racecadotril, mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus), Dantrolene (infusion), Grapefruit or grapefruit juice. Special care: Baclofen, Non-steroidal anti-inflammatory medicinal products (included acetylsalicylic acid at high doses), Antidiabetic agents (insulin, hypoglycaemic agents), Non-potassium-sparing diuretics and Potassium-sparing diuretics (eplerenone, spironolactone), Torsades de pointes inducing drugs, Amphotericin B (IV route), glucocorticoids and mineralocorticoids (systemic route), tetracosactide, stimulant laxatives, Cardiac glycosides, Allopurinol, CYP3A4 inducers, CYP3A4 inhibitors. To be taken into consideration: Imipramine-like antidepressants (tricyclics), neuroleptics, other antihypertensive agents and vasodilators, tetracosactide, Allopurinol, cytostatic or immunosuppressive agents, systemic corticosteroids or procainamide, Anaesthetic drugs, Diuretics (thiazide or loop diuretics), Gliptines (linagliptine, saxagliptine, sitagliptine, vildagliptine), Sympathomimetics, Gold, Metformin, Iodinated contrast media, Calcium (salts), Ciclosporin, Atorvastatin, digoxin, warfarin, Tacrolimus, Simvastatin.

PREGNANCY AND BREASTFEEDING* Contraindicated during the second and third trimesters of pregnancy and lactation. Not recommended during the first trimester of pregnancy. FERTILITY* Reversible biochemical changes of spermatozoa in some patients treated by calcium channel blockers. DRIVE & USE MACHINES* May be impaired due to low blood pressure that may occur in some patients, especially at the start of treatment. UNDESIRABLE EFFECTS* Very common: oedema. Common: dizziness, headache, paraesthesia, vertigo, somnolence, dysgeusia, visual impairment, diplopia, tinnitus, palpitations, flushing, hypotension (and effects related to hypotension), cough, dyspnoea, abdominal pain, constipation, diarrhoea, dyspepsia, nausea, vomiting, change of bowel habit, pruritus, rash, rash maculo-papular, muscle spasms, ankle swelling, asthenia, fatigue. Uncommon: rhinitis, eosinophilia, hypersensitivity hypoglycaemia, hyperkalaemia reversible on discontinuation, hyponatraemia, insomnia, mood altered (including anxiety), depression, sleep disorder, hypoaesthesia, tremor, syncope, tachycardia, arrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation), vasculitis, bronchospasm, dry mouth, urticaria, angioedema, alopecia, purpura, skin discoloration, hyperhidrosis, exanthema, photosensitivity reaction, pemphigoid, arthralgia, myalgia, back pain, micturition disorder, nocturia, pollakiuria, renal failure, erectile dysfunction, gynaecomastia, pain, chest pain, malaise, oedema peripheral, pyrexia, weight increased, weight decreased, blood urea increased, blood creatinine increased, fall. Rare: confusional state, blood bilirubin increased, hepatic enzyme increased, psoriasis aggravation. Very rare: agranulocytosis, aplastic anaemia, pancytopenia, haemoglobin decreased and haematocrit decreased, leukopenia, neutropenia, haemolytic anaemia, thrombocytopenia, allergic reactions, hyperglycaemia, hypercalcaemia, hypertonia, neuropathy peripheral, stroke possibly secondary to excessive hypotension in high-risk patients, angina pectoris, myocardial infarction, possibly secondary to excessive hypotension in high risk patients, eosinophilic pneumonia, gingival hyperplasia, pancreatitis, gastritis, hepatitis, jaundice, hepatic function abnormal, erythema multiforme, Stevens-Johnson Syndrome, exfoliative dermatitis, toxic epidermic necrolysis, Quincke’s oedema, acute renal failure. Not known: Potassium depletion with hypokalaemia, particularly serious in certain high risk populations, extrapyramidal disorder (extrapyramidal syndrome), myopia, vision blurred, torsades de pointes (potentially fatal), possibility of onset of hepatic encephalopathy in case of hepatic insufficiency, possible worsening of pre-existing systemic lupus erythematosus, electrocardiogram QT prolonged, blood glucose increased, blood uric acid increased. OVERDOSE* PROPERTIES* Perindopril is an inhibitor of the angiotensin converting enzyme (ACE inhibitor) which converts angiotensin I to angiotensin II. Indapamide is a sulphonamide derivative with an indole ring, pharmacologically related to the thiazide group of diuretics. Amlodipine is a calcium ion influx inhibitor of the dihydropyridine group (slow channel blocker or calcium ion antagonist) and inhibits the transmembrane influx of calcium ions into cardiac and vascular smooth muscle. PRESENTATION* Box of 30 tablets of Coverdine, 5mg/1.25mg/5mg, 5mg/1.25mg/10mg, 10mg/2.5mg/5mg and 10mg/2.5mg/10mg. LES LABORATOIRES SERVIER, 50 rue Carnot, 92284 Suresnes cedex France. www.servier.com. Product Authorisation: PA0568/024/002-005. Supply Classification: POM. Further Information Available From: Servier Laboratories Ireland, 3 Block 2 West Pier Business Campus, Old Dunleary Road, Co. Dublin, Tel (01) 6638110, Fax (01) 6638120, www.servier.ie *For complete information, please refer to the Summary of Product Characteristics available on www.medicines.ie Date of last revision of text: April 2017 (date of last approved SmPC: April 2017)

Flexibility with 4 doses

Date of preparation: September 2017. 1718 C1 CDE PRESS AD References: 1. Tòth K, on behalf of the PIANIST Investigators. Am J Cardiovasc Drugs. 2014. DOI 10.1007/s40256-014-0067-2.

2. Pall D et al, Hypertonia és Nephrologia. 2012;16(3-4):119-123. 3. Coverdine SmPC April 2017.

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cardiology

Latest evidence on lipid management Dr Emmanuel Egom, Consultant Physician, St Marthaâ&#x20AC;&#x2122;s Regional Hospital, Antigonish, Nova Scotia, Canada; Mr Haaris Shiwani, Final Year Medical Student, Department of Clinical Medicine, Education Division, Trinity College Dublin; and Prof Vincent Maher, Consultant Cardiologist, Tallaght Hospital, Dublin

Introduction Atherosclerotic cardiovascular disease (ASCVD) continues to be the foremost cause of death worldwide, despite improvements in some countries over the last 20 years. On the basis of 2012 mortality rate data, more than 48,000 people die of ASCVD each day, an average of one death every one to two seconds. Figures for Ireland show that it is still above the European Union average for premature deaths from ASCVD. The cause of ASCVD are multifactorial, and may include factors related to lifestyles, age, male gender and other factors, such as arterial hypertension, type 2 diabetes and dyslipidaemia. Large epidemiological studies have found a strong and graded positive association between increasing plasma levels of low-density lipoprotein (LDL) cholesterol or decreasing plasma levels of high-density lipoprotein (HDL) cholesterol and increasing risk for ASCVD events. Despite the clinical long-term and near-term benefits of lowering cholesterol in, respectively, primary and secondary prevention of ASCVD, cholesterol levels remain undertreated, with many patients not achieving their recommended targets. This article will review the latest updates on lipid management with emphases on proprotein convertase subtilsin-kexin type 9 (PCSK9) inhibition and statins.

Management and classes of cholesterol- lowering agents Both lifestyle modifications and pharmacological treatment are essential to consider in the management of patients with dyslipidaemia. Dyslipidaemia may be primary or secondary. The possibility of secondary dyslipidaemia should, therefore be considered before initiating any pharmacological treatment. Treatment of the clinical entity causing secondary dyslipidaemia may obviate the need for lipid-lowering agents. There are currently available several lipid-lowering agents with different mechanism of action. The agents of choice for primary and secondary prevention of ASCVD remain the statins. Unfortunately, ASCVD events continue to occur in some patients on statins, despite receiving maximal tolerated therapy. Other patients develop side effects from statins that limit their use. As a result, intensive field- and laboratory-based investigations have been undertaken during the last decade to discover and develop newer modalities of treatment to lower LDL-cholesterol (C). Recently the Food and Drug Administration (FDA) approved two medications, which target a novel pathway to reduce LDL-C. They are monoclonal antibodies that inactivate PCSK9.

PCSK9 inhibitors Recent novel research activities have led to the identification of a relatively new target for treating dyslipidaemia, the Proprotein Convertase Subtilisin Kexin type 9 (PCSK9). In 2003, PCSK9 was

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first identified and in 2005, a PCSK9 loss-of-function mutation was reported to cause a decrease in LDL-C levels. Since then, inhibitors of PCSK9, particularly in the form of antibodies, have been intensively researched and are proving to be invaluable assets in the treatment of dyslipidaemia and ASCVD prevention.

Mode of action Proprotein convertase subtilisin kexin 9 (PCSK9) is a serine protease produced mainly in the liver and released into the plasma, where it interacts with an extracellular domain of the hepatocyte LDL receptors, as illustrated in Figure 1. This interaction prevents the recycling of LDL receptors leading to their degradation inside the hepatocytes, and ultimately to less clearance of LDL-cholesterol and thus increased plasma levels. In several epidemiological studies, carriers of the gain-of-function mutations in PCSK9 have higher levels of LDL-cholesterol as well as a higher risk of ASCVD compared to noncarriers. Other epidemiological studies found that carriers of loss-of-function mutations in PCSK9 have lower concentrations of LDL-cholesterol as well as a lower risk of ASCVD compared to noncarriers. Recent studies suggest that infusion of a monoclonal antibody to inhibit PCSK9 may provide clinical benefits across a wide range of clinical conditions as well as providing additional reductions in ASCVD risk even in subjects already on maximal statin therapy. Some of the clinical trials of PCSK9 inhibitors that were designed to investigate ASCVD endpoints are now complete and provide additional information on longer-term efficacy and safety.

Efficacy Alirocumab and evolocumab are the only two PCSK9 inhibitors currently licensed for clinical use. They comprise fully humanised monoclonal antibodies and bind circulating, free PCSK9. PCSK9 inhibitors form the basis of second- and thirdline treatment in secondary prevention of ASCVD events. Infusion of a monoclonal antibody to inhibit PCSK9 has shown to significantly reduce LDL-cholesterol levels in a dose-dependent manner, by as much as 70 per cent, and by as much as 60 per cent in individuals taking statins, while simultaneously increasing HDL-C 20. They may also have a role as second- and thirdline for the treatment of familial hypercholesterolaemia (FH) in combination with statins alone, or in addition to statins and ezetimibe. The greatest basis of this comes from the results of trials in patients without FH. There are, however, some trials conducted in patients with FH, in particular, ODYSSEY I and ODYSSEY II. These trials involved 735 patients with FH on maximal lipid-lowering therapy and elicited a 57.9 per cent and 51.4 per cent greater decline in LDL-cholesterol levels when compared to placebo, respectively.

cardiology

UPDATE

Adverse Limb Events (MALE), including acute limb ischemia, urgent peripheral revascularisation, and major amputation (0.27% versus 0.45%; HR, 0.58; 95% CI, 0.38–0.88; P=0.0093; ARR, 0.18%). This was evident across the different components of MALE, as well as being consistent irrespective of background statin intensity.

The ODYSSEY OUTCOMES trial constitutes one of the largest trials conducted assessing the cardiovascular outcomes of PCSK9 inhibitor use.

The study recruited 18,924 patients, with inadequate lipid control on highintensity statin therapy, who were randomised to reviving alirocumab or placebo. Drug therapy was aimed at Figure 1. Mechanism and role of PCK9 in low-density lipoprotein-cholesterol titrating LDL-C to 25-50mg/dl. Unlike metabolism FOURIER, ODYSSEY OUTCOMES enrolled a higher-risk patient population (A): LDL-Receptors (LDL-Rs) are found on the hepatocyte cell surface. PCSK9 particle interferes – those who were one to 12 months with the LDL-Receptor (LDL-R) recycling by preventing the separation of the LDL-R from LDL. PCSK9 particles binds to the LDL-R; upon LDL binding and internalisation, the PCSK9 particlepost-Acute Coronary Syndrome (ACS). bound LDL-R fails to separate from the LDL particle. As a result, the LDL-R is delivered to the The follow-up period was 48 months. lysosome and degraded, thus bypassing the process of recycling to the cell surface. (B): Upon The primary outcome measure, mabinding of an LDL particle to LDL-R, the LDL-R–LDL particle complex enters the hepatocyte in jor adverse cardiac events, was siga clathrin-coated vesicle. Intracellularly, the LDL and LDL-R dissociate. LDL is delivered to a nificantly lower in the alirocumab lysosome and degraded, while the LDL-R is recycled back to the cell surface. arm compared to placebo, 9.5 per cent Of the most highly anticipated trials regarding PCSK9 inhibiversus 11.1 per cent, Hazard ratio: 0.85 [95% CI, 0.78-0.93, P = tors and clinical outcomes was, however, the FOURIER trial.

0.0003]. Statistically significant major adverse cardiac events, The trial involved over 27,000 patients already on statin therapy in comparison to placebo, included myocardial infarction (6.6% with LDL-C levels of 70mg or greater and clinically-evident athvs. 7.6%, p = 0.006), ischaemic stroke (1.2% vs. 1.6%, p = 0.01), erosclerotic cardiovascular disease. The primary endpoint was unstable angina (0.4% vs. 0.6%, p = 0.02) and all-cause mortalrepresented by cardiovascular events such as myocardial infarcity (3.5% vs. 4.1%, p= 0.026). tion, stroke, hospital admission for unstable angina, coronary revascularisation and cardiovascular death. In comparison to Side effects placebo, evolocumab demonstrated a significant reduction in the risk of the primary endpoint, Hazard ratio: 0.85 [95% CI, Numerous trials conducted with PCSK9 inhibitors have elic0.79-0.92; P<0.001]. A recent meta-analysis by Karatasakis et al ited similar adverse effect rates of PCSK9 inhibitors as compared examined the FOURIER trial, along with 34 other randomised with placebo. Local injection site reactions represent probably controlled trials (all comparing treatment with and without most of the adverse effects seen with PCSK9 inhibitor use. AlPCSK9 inhibitors in patients with dyslipidaemia, including those though the FOURIER and ODYSSEY OUTCOMES trials did not with familial hypercholesterolaemia), to provide a comprehenfind any significant associations with neurocognitive toxicities, sive overview of the current status of the PCSK9 inhibitors, evothe earlier OSLER and ODYSSEY LONG TERM trials reported a locumab and alirocumab. The study encompassed cumulative minor increase in incidence of such symptoms. Consistently, the data from 45,539 patients, with a mean follow-up of 84.5 weeks.

EBBINGHAUS study, which uses data from 1,204 participants Although this study showed no statistical difference in all-cause of the FOURIER trial that were followed for a median time peand cardiovascular mortality when PCSK9 inhibitors were comriod of 19 months, demonstrated no statistically-significant difpared to no treatment, there was a statistically-significant reducference in the primary endpoint – the spatial working memory tion in myocardial infarction, OR: 0.72 [95% CI, 0.64–0.81], strategy index of executive function (a key component of CANand stroke, OR: 0.80 [95% CI, 0.67–0.96]. Of note, the data TAB). Furthermore, measurement of the secondary endpoints also suggested a potential benefit of lipid-lowering therapy in of: The five-choice reaction time test, spatial working memory peripheral arterial disease (PAD). FOURIER enrolled 3,642 patest and the paired associates learning test also showed no statients with PAD, of which 1,505 had no history of stroke or MI. tistically-significant difference between the evolocumab and plaEvolocoumab elicited a median reduction of LDL-cholesterol in cebo arms. Hypersensitivity reactions including, but not limited patients with symptomatic PAD of 94mg/dl. Furthermore, there to, rashes, pruritis, nummular eczema and vasculitis have also was a significant 21 per cent reduction in the primary endpoint been reported. Of note, increased Hepatitis C infectivity, colonic in these patients (2.5-year Kaplan-Meier rate, 13.3% versus neoplasms and insulin resistance have all been theorised to have 16.8%; HR, 0.79; 95% CI, 0.66– 0.94; P=0.0098). In addition, an association with PCSK9 inhibition, however, no clinical studa 42 per cent risk reduction was also observed regarding Major ies to date have shown such effects.

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Ongoing PCSK9-related research Novel methods of PCSK9 inhibition are currently being investigated. Inhibition of the LDL-R degradation via siRNA is under development. The recent phase 2, ORION-1 trial compared the use of inclisiran, a siRNA inhibitor of PCSK9, to placebo in patients on maximal statin dose. The study was successful in eliciting a 52.6 per cent reduction in LCL-C levels at six months with no serious adverse events reported. Interestingly, vaccinations against PCSK9 are being studied in early pre-clinical phases.

Given the positive results of ODYSSEY OUTCOMES, further studies investigating the cost-effectiveness of PCSK9 inhibitors are now warranted.

Statins Although the PCSK9 inhibition data are very promising, the agents of choice for primary and secondary prevention of ASCVD remain the statins. Since their introduction in the 1980s, statins have emerged as the one of the best-selling medication classes to date, with numerous trials demonstrating powerful efficacy in preventing cardiovascular outcomes. Currently available statins include atorvastatin, simvastatin, rosuvastatin, fluvastatin, lovastatin, pravastatin and in some countries, pitavastatin. The statins are commonly used in the treatment of hypercholesterolemia and mixed hyperlipidemia. As our understanding of LDL-cholesterol and ASCVD continues to grow, the concept of ‘lower is better’ has corresponded with a ‘more is better’ approach to statin-based treatment.

Mode of action of statins As β-hydroxy-β-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors, statins are competitive, reversible inhibitors of HMG CoA Reductase, the rate-limiting enzyme of cholesterol biosynthesis. In addition to reducing de novo cholesterol synthesis with the use of statins, liver cells sense the reduced levels of cholesterol production, inducing the activation of protease that slices the sterol-regulatory element-binding proteins (SREBPs) from the endoplasmic reticulum. In the nucleus, gene expression of LDL receptors is increased and translocation occurs into production of LDL receptors to be displayed on the cell surface for the uptake of LDL and its precursors (intermediate density – IDL and very low density – VLDL lipoproteins). Statins, therefore, result in a reduction in plasma cholesterol both by decreased cholesterol synthesis and by increased catabolism of LDL. By inhibiting the HMG CoA reductase, statins also inhibit production of specific prenylated protein metabolites downstream, such as geranylgeranyl pyrophosphate (GGPP) and farnesyl pyrophosphate (FPP). GGPP and FPP are lipid attachments that constitute key intermediates for post-translational events of several cell signalling proteins, including the Ras, Rac and Rho GTPase family members. Isoprenylation, or the attachment of these lipids, is fundamental for the activation and intracellular transport of these proteins that act as molecular switches controlling multiple pathways and cell functions such as maintenance of motility, cell shape, differentiation, factor secretion and proliferation. Considering that the key role prenylated proteins play, it is expected that statin effects may extend beyond their LDL -lowering actions (pleiotropic effects). These pleiotropic

6

effects of statins, which are cholesterol-independent, include reduction of the inflammatory process and accumulation of esterified cholesterol into macrophages, increased stability of the atherosclerotic plaques, increase of endothelial NO synthetase, restoration of platelets activity and of the coagulation process.

Statins efficacy The statins are currently the most powerful approved drugs for lowering LDL-C, with reductions in the range of 30 to 63 per cent. Simvastatin (40 to 80mg/day) may be more effective than atorvastatin (20 to 40mg/day) for increasing serum HDLcholesterol and apo A-I concentrations. However, rosuvastatin may be even more effective, raising HDL-C by up to 10 per cent.

Atorvastatin and rosuvastatin may be more effective at lowering triglycerides (14 to 33 per cent) than other statins in patients with hypercholesterolemia.

Side effects Several clinical trials have demonstrated the efficacy and safety of statin treatment. Nevertheless, a significant proportion of patients taking these drugs may experience some degree of intolerance, which in turn may result in statin discontinuation.

Muscle Injury: Although muscle toxicity remains a concern, severe myopathy is unusual, affecting perhaps 0.1 per cent of patients. The clinical features of statin-induced myopathy include symptoms such as muscle aches or myalgia, weakness, stiffness, and cramps. Muscle symptoms usually occur within the first six months of treatment, although they can begin months or even years after initiation of therapy. Statin-induced myopathy may resolve, or substantially abate, within two months of statin discontinuation, which may be helpful for determining the relationship of symptoms to statin use. Co enzyme Q10 (CoQ10) depletion may play a role in statin myopathy. Although there is little published evidence showing benefit of CoQ10 for the treatment of myopathy, our experience in Tallaght Hospital has been very good with a lot of patients reporting benefit (unpublished data).

Hepatic dysfunction: Clinical studies of statins have demonstrated a 0.5 to 3.0 per cent occurrence of persistent elevations in aminotransferases in patients receiving statins. This has primarily occurred during the first three months of therapy and is dose-dependent. While many drugs may cause liver disease, the evidence indicates that significant liver pathology attributable to statins is rare. The most commonly reported hepatic-adverse effect is the phenomenon known as “transaminitis” in which liver enzyme levels are elevated in the absence of histopathological changes.

Renal dysfunction: Reports of rosuvastatin-induced renal toxicity, largely proteinuria and hematuria, initially caused widespread concern. As a result, submission data for all statins were reviewed by the FDA, which eventually concluded that statins, including rosuvastatin, did not cause renal toxicity. There have been a number of reports about proteinuria with statins, particularly in patients receiving rosuvastatin or simvastatin. However, it is believed that proteinuria with statins is a benign finding. Statins may cause proteinuria through tubular inhibition of active transport of small molecular weight proteins.

Behavioral and cognitive: Early research suggested that lowering cholesterol concentrations may be associated with an in-

Konverge is indicated for the treatment of essential hypertension in adult patients whose blood pressure is not adequately controlled on olmesartan medoxomil or amlodipine monotherapy.

Konverge Plus is indicated for the treatment of essential hypertension as an add on therapy in adult patients whose blood pressure is not adequately controlled on the combination of olmesartan medoxomil and amlodipine taken as dual-component formulation.

Konverge Plus is indicated as substitution therapy in adult patients whose blood pressure is adequately controlled on the combination of olmesartan medoxomil, amlodipine and hydrochlorothiazide, taken as a dual-component (olmesartan medoxomil and amlodipine or olmesartan medoxomil and hydrochlorothiazide) and a single-component formulation (hydrochlorothiazide or amlodipine).

Legal Category: POM. Marketing Authorisation Numbers: PA 865/17/1-3 and PA 865/19/1-5. Marketed by: A. Menarini Pharmaceuticals Ireland. Further information: Available on request from A. Menarini Pharmaceuticals Ireland Ltd, Castlecourt, Monkstown Farm, Monkstown, Co. Dublin or may be found in the SmPC available at www.medicines.ie Co-promoter: DAIICHI SANKYO IRELAND LTD., Riverside One, Sir John Rogerson Quay, Dublin 2, Ireland. Date of Item: September 2017 Item Code: IR-KON-02-2017

A. MENARINI

PHARMACEUTICALS IRELAND LTD

Healthcare for Life

UPDATE

cardiology

crease in violent or suicidal deaths. Other studies showed that both chronically low and medically-lowered serum cholesterol may be associated with an increased incidence of depression.

Although concerns have been raised, statins do not appear to be associated with an increased risk of suicide or depression. There have been case reports of patients developing severe irritability and aggression associated with the use of statins. It is not known whether the statin use caused these symptoms, but very rare idiosyncratic reactions of this sort may be missed in controlled trials.

Concerns have also been raised in the media and popular press about cognitive dysfunction and memory loss associated with statin use. Evans and colleagues conducted a patient surveybased analysis, to characterise the adverse cognitive effects of statins in 171 patients (age range 34-86 years) who self-reported memory or other cognitive problems associated with statin therapy while participating in a previous statin effects study. The authors found that cognitive problems associated with statin therapy have variable onset and recovery courses, a clear relation to statin potency, and significant negative impact on quality-of-life.

Interestingly, a systematic review of randomised trials and observational studies found that published data do not suggest that statins harm cognition; however, the quality of the evidence was felt to be only low to moderate, particularly with regard to highintensity statin therapy.

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For patients who demonstrate actual intolerance to statin therapy, there are several therapeutic options that may be considered, including the use of different or lower-dose statins

Cancer: Preclinical studies found that very high-dose statin therapy increased the risk of liver tumours in rodents. Some, but not all, observational studies have also raised the possibility that use of statins may decrease overall risk of cancer and of specific cancers. In contrast, meta-analyses of randomised trials have consistently shown no effect of statins on cancer incidence or cancer mortality. Ten-year follow-up of the 4S trial and the West of Scotland Coronary Prevention Study (WOSCOPS) and 11-year follow-up of the Heart Protection Study (HPS) showed no increases in cancer deaths. In summary, there is no convincing evidence that statins increase or decrease the risk of cancer.

Diabetes Mellitus: Statins may have effects on glucose me-

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tabolism that might influence the development of diabetes mellitus in nondiabetics or affect glycemic control in patients with existing diabetes. Experimental evidence has been conflicting about whether statins as a group improve glucose metabolism or whether some statins show beneficial effects while others show harmful effects. It appears likely that statins may confer a small increased risk of developing diabetes, and that the risk is slightly greater with intensive statin therapy than moderate statin therapy.

Recently, Mansi and colleagues conducted a retrospective cohort study of tricare beneficiaries who were evaluated between October 1, 2003 and March 1, 2012, to examine the association between statin use and new-onset diabetes, diabetic complications, and overweight/obesity 85. 25,970 patients (3,982 statin users and 21,988 non-users) were identified as healthy adults at baseline. Of these, 3,351 statins users and 3,351 non-users were propensity score-matched. Statin users had higher odds of newonset diabetes (odds ratio [OR] 1.87; 95% confidence interval [95% CI] 1.67-2.01), diabetes with complications (OR 2.50; 95% CI 1.88-3.32), and overweight/obesity (OR 1.14; 95% CI 1.041.25). Diabetes, diabetic complications, and overweight/obesity were, therefore more commonly diagnosed among statin-users than similar non-users in a healthy cohort of adults. The authors concluded that short-term clinical trials might not fully describe the risk/benefit of long-term statin use for primary prevention.

Despite the above evidence, some experts still claim that the potential for an ASCVD risk-reduction benefit outweighs the excess risk of diabetes in all but the lowest-risk individuals.

Statin intolerance: Although data from clinical trials suggest low rates of statin side effects leading to discontinuation, it is not uncommon to find patients who are intolerant of one or more statins because of myalgias or other muscular symptoms. Less commonly, aminotransferase elevations require making changes in the statin, the statin dosage, or changes to another class of cholesterol-lowering therapy. As an increasing number of patients become eligible for lipid-lowering therapy, this is becoming a more prevalent issue. There are several measures that healthcare providers and their patients can take to reduce the risk of statin intolerance. These may include comprehensive pretreatment assessment, patient counseling, and ongoing monitoring. For patients who demonstrate actual intolerance to statin therapy, there are several therapeutic options that may be considered, including the use of different or lower-dose statins. In addition, non-statin alternatives or adjuncts for lowering LDL-C may be warranted.

Interventions to alleviate the symptoms of myalgia while continuing to take statins have also been considered.

Summary The main goal in the treatment of dyslipidaemia is to prevent future morbidity and mortality from ASCVD. In addition to lipid-lowering treatment, where statins are still the drugs of choice, diet, exercise and weight control should be an essential part of the management. Although the PCSK9 inhibition data is promising, major advancements in the search for other efficacious pharmacological agents to lower LDL-cholesterol or raise HDL-cholesterol with concomitant benefit on ASCVD are still ongoing.â&#x20AC;&#x192; References on request

cardiology

UPDATE

Current advice and the complexities of anticoagulants Dr David Burke, Consultant in Cardiology, Beacon Hospital and Clinical Director of Cardiology and Director of Medical Education, Beacon UCD Academy, Dublin The complex coagulation cascade has become better understood and we appreciate that inhibiting one element can essentially ‘turn off’ the entire process. The final steps of the pathway involve the conversion of prothrombin to thrombin via prothrombinase and factor Xa. Thrombin then goes on to convert fibrinogen to fibrin, producing a clot. Direct factor Xa inhibors (rivaroxaban, apixaban and edosxaban) reduce thrombin production by selectively inhibiting factor Xa and prothrombinase activity. Direct thrombin inhibitors (dabigatran), inhibit thrombin to prevent the formation of fibrin and the development of a clot.

The advent of novel oral anticoagulants (NOACs) has led to additional options when treating patients with or at risk of thromboembolic disease. In the cardiology realm, they have quickly become the standard of care in the treatment of nonvalvular atrial fibrillation in patients considered at higher risk of stroke. Every patient seems to have heard of and be aware of warfarin. When consultations push on to ‘blood thinners’, the question coming back is invariably – ‘you mean the rat poison?’ Patients are never keen; but nowadays the conversation seems easier given the fact that we are able to say there is an alternative. It is an alternative that is proven to be just as good if not better than warfarin in terms of stroke prevention, and with lower risk of overall bleeding.

The initial concerns relating to predictability and reversibility balanced out to some degree with the logistical simplicity when compared to the only previous choice in warfarin.

As we have built on our personal clinical experience with the medications, and as we watched four anticoagulants come on the market, the significant safety and efficacy evidence has bolstered our confidence. We have figured out and become accustomed to dosing variations in the setting of renal dysfunction, low weight and elderly patients, and learned the medication interaction listings.

Despite specific nuances between them, the novel anticoagulants have overall similar indications in reducing stroke risk and systemic embolism in non-valvular atrial fibrillation, and in treating and prevention of deep venous thrombosis and pulmonary embolism. Usual dosing and administration is less patient-specific than with warfarin, but does take into account at the outset a dosing adjustment dependent on renal indices and concomitant medications.

European Society of Cardiology guideline documents recommend the use of NOACs as the best anticoagulant option for stroke prevention in atrial fibrillation. American guidelines endorse NOACs in preference to warfarin for patients with difficulty in maintaining an INR within the target range.

The significant difference between warfarin and these newer agents relate to timing at onset of action, half-life, drug-drug interactions, the need for monitoring and then

the ability to monitor should it become necessary. These differences translate into similar efficacy with greater ease of administration and lower bleeding risk. All-cause mortality from novel oral anticoagulants has been proven lower than that from warfarin, driven largely by a decrease in fatal in-

“

Patients with excellent stable INR control on their warfarin and minimal bleeding side effect issues may have no significant benefit in switching to another agent

tracranial bleeding. In certain settings, warfarin may still be preferable or necessary, or novel anticoagulants may be contraindicated – prosthetic heart valves, pregnancy, severe renal impairment. One study found that dabigatran in the setting of mechanical heart valves was less effective and caused more bleeding than warfarin. Patients with excellent stable INR control on their warfarin and minimal bleeding side effect issues may have no significant benefit in switching to another agent.

Teasing out the differences between agents Understandably at this juncture there are no direct headto-head trials between the agents and this obviously makes it difficult to compare the efficacy and safety differences between them. Clinical trials used for the basis of drug approval were similar with most adopting a non-inferiority design comparing with warfarin. Primary endpoints invariably analysed composites of stroke or systemic thromboembolism.

Although the non-inferiority margins varied across studies, each new medication showed non-inferiority compared with warfarin. Each study also looked at safety, specifically ad-

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dressing bleeding risks.

Indirect comparisons between NOAC agents can be helpful despite the limitations of this approach. In looking at the efficacy and safety endpoints of four clinical trials (ENGAGE-AF, RE-LY, ROCKET-AF and ARISTOTLE) comparing NOACs with warfarin, we can extrapolate some differences. Compared with edoxaban (60mgs daily), apixaban was similar in efficacy, but was associated with reduced clinically-relevant or major bleeding (HR 0.79; 95% CI, 0.70-0.90). Dabigatran showed greater efficacy than edoxaban (stroke HR 0.73; 95% CI, 0.55-0.96), although it was associated with more ‘other location bleeding’. There was no apparent difference between edoxaban and rivaroxaban relating to efficacy or mortality, but rivaroxaban was associated with more major or clinically-relevant bleeding (HR 1.20; 95% CI, 1.08-1.32).

All four of the NOACs currently available on the market are substrates of the P-glycoprotein transporter, and rivaroxaban and apixaban are also substrates of the cytochrome P450 3A4. Any concomitantly administered medications that induce or inhibit CYP3A4 or P-glycoprotein will alter exposure of these drugs. Rivaroxaban and apixaban should not be administered with combined P-gp and CYP3A4 inihibitors such as ketoconazole, ritonavir or clarithromycin, or enzyme inducers such as carbamazepine, phenytoin, rifampicin or the previously more in vogue St Johns wort. Dabigatran and edoxaban should not be used with P-gp inducers such as rifampicin. A dose reduction for P-gp inhibitors and dabigatran is not necessary except in the setting of moderate renal impairment (creatinine clearance of 30-50ml/min).

Acute coronary syndrome and stenting Management of patients in certain clinical scenarios remains uncertain. In true non-valvular atrial fibrillation, the use of these agents is straightforward, but with the addition of other variables such as coronary stenting, the guidelines become less clear and there seem to be multiple opinions and strategies, most of these not grounded in sufficient solid data.

The treatment of patients with non-valvular atrial fibrillation and acute coronary syndrome reflects uncertain territory. In an attempt to achieve some sort of consensus and with a lack of sound evidence-based recommendations, the European Heart Rhythm Association (EHRA) conducted a multi-centre survey in 2014. At that time, there was a remarkable heterogeneity in approach to these patients in terms of combination and duration with anticoagulants and antiplatelet agents. In patients already on an anticoagulant, centres favoured ‘triple therapy’ with an anticoagulant and dual anti-platelet treatment in combination, but more went with warfarin as opposed to a novel anticoagulant in that setting due to bleeding concerns. Duration of triple therapy varied depending on the type of stent used and three to six months was most frequent with the use of drug-eluting stents.

The ACTIVE W trial showed that warfarin is superior treatment for atrial fibrillation patients compared with DAPT, while in patients undergoing stenting, DAPT was superior to the combination of warfarin and aspirin in the prevention of stent thrombosis. With this rationale, it is thought that in atrial fibrillation patients with an indication for NOAC, they should continue on the anticoagulant in combination with

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one or more antiplatelet agent when presenting with ACS. The randomised WOEST trial demonstrated that DAPT significantly reduced bleeding events and MACCE in patients with atrial fibrillation undergoing stenting, when compared with triple therapy. The study was, however, small and underpowered to show a difference in thrombotic events, such as stent thrombosis. The results are somewhat bolstered by large-registry data. The Danish registry of antithrombotic use in patients following MI and PCI showed that dual therapy (NOAC and Clopidogrel) reduced bleeding events (HR 0.78; CI 0.55-1.12) and thrombotic events (HR 0.69; CI 0.48-1.00) when compared to triple therapy. A subsequent analysis of the AFCAS registry showed that one-year safety and efficacy of all strategies (triple therapy, DAPT, and dual therapy) in patients with atrial fibrillation undergoing coronary stenting were comparable, suggesting that dual therapy is as safe as triple therapy with regard to thrombotic risk.

Several years later, the evidence is still lacking, but anecdotally there appears to be less ‘fear’ when combining the NOACs with antiplatelet therapy. The use of a NOAC with dual antiplatelet therapy for several months with a transition to a single antiplatelet agent at that point in combination with the anticoagulant, is no longer something that would make us nervous. Some would advocate the use of the anticoagulant alone, and then again, there is a more recent vogue in using the anticoagulant with a single antiplatelet agent.

The evidence will undoubtedly catch up with our real world practice. Evidence concerning the combination of NOACs and antiplatelet therapy is scarce, and an additional level of complexity in making decisions is added taking into account the newer generation of platelet inhibitors (ticagrelor or prasugrel). These have been shown to be more effective in reducing death, MI and stroke as compared with clopidogrel, but this is tempered with a higher bleeding risk. Data on the use of these new-generation P2Y12 inhibitors in the context of dual or triple therapy is limited.

Until we know more, the use of ticagrelor or prasugrel in the setting of double or triple therapy is not recommended as stated in the ESC consensus document. The PIONEERAF and RE-DUAL trials aim to evaluate the safety of two different rivaroxaban and dabigatran treatment strategies as compared to warfarin using differing combinations of antiplatelet therapy, such as clopidogrel or ticagrelor/prasugrel, in patients with non-valvular atrial fibrillation undergoing stent placement.

Conclusion Our familiarity, clinical experience and comfort with using direct thrombin inhibitors and factor Xa inhibitors make these anticoagulants no longer ‘novel’. They now form a cornerstone in stroke prevention in our patients with atrial fibrillation.

There are gaps in our confidence and expertise in certain clinical scenarios, but we continue to build our evidence-base in attempts to reduce the risk of stroke and minimise the trade-off of bleeding. New trials will clarify risk and benefits of different anticoagulant and antiplatelet combinations and the optimal duration of these therapies.

COSIMPREL

®

bisoprolol/perindopril

Dual Power to Protect 1-3

PROLOL

PER

IL

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PR

BISO

Cosimprel (bisoprolol fumarate/perindopril arginine). Abbreviated Prescribing Information: Please refer to the Summary of Product Characteristics before prescribing. COMPOSITION*: Cosimprel 5 mg/5 mg, 5 mg/10 mg, 10 mg/5 mg, 10 mg/10 mg film-coated tablets contain 5 mg bisoprolol fumarate (bis)/5 mg perindopril arginine (per), 5 mg bis/10 mg per, 10 mg bis/5 mg per, 10 mg bis/10 4 mg per. INDICATIONS*: Cosimprel is indicated as substitution therapy for treatment of hypertension and/or stable coronary artery disease (in patients with a history of myocardial infarction and/or revascularisation) and/or stable chronic heart failure with reduced systolic left ventricular function (Cosimprel 5 mg/5 mg and 10 mg/5 mg only) in adult patients adequately controlled with bisoprolol and perindopril given concurrently at the same dose level. DOSAGE AND ADMINISTRATION*: The usual posology is one tablet once daily. Patients should be stabilized with bisoprolol and perindopril at the same dose level for at least 4 weeks.

The fixed dose combination is not suitable for initial therapy. For patients stabilized with bisoprolol 2.5 mg and perindopril 2.5 mg or bisoprolol 2.5 mg and perindopril 5 mg: one half 5 mg/5 mg or 5 mg/10 mg tablet once daily. If a change of posology is required, titration should be done with the individual components. Renal impairment: In patients with renal impairment, the recommended dose should be based on creatinine clearance. 5 mg/5 mg: ClCR ≥ 60 (ml/min): 1 tablet; 30 < ClCR < 60: ½ tablet; ClCR< 30: not suitable, individual dose titration with monocomponents recommended. 5 mg/10 mg: ClCR ≥ 60: ½ tablet; ClCR < 60: not suitable. 10 mg/5 mg: ClCR ≥ 60: 1 tablet; ClCR < 60: not suitable. 10 mg/10 mg: not suitable. Hepatic impairment: no dosage adjustment. Elderly: administration according to the renal function. Paediatric population: safety and efficacy have not been established. Use is not recommended CONTRAINDICATIONS*: Hypersensitivity to the active substances, or to any of the excipients, or to any other ACE inhibitor; acute heart failure or during episodes of heart failure decompensation requiring i.v. inotropic therapy; cardiogenic shock; second or third degree AV block (without pacemaker); sick sinus syndrome; sinoatrial block; symptomatic bradycardia; symptomatic hypotension; severe bronchial asthma or severe chronic obstructive pulmonary disease; severe forms of peripheral arterial occlusive disease or severe forms of Raynaud’s syndrome; untreated phaeochromocytoma (see section WARNINGS*); metabolic acidosis; history of angioedema associated with previous ACE inhibitor therapy; hereditary or idiopathic angioedema; second and third trimesters of pregnancy (see sections WARNINGS*, PREGNANCY* and BREASTFEEDING*); concomitant use with aliskiren-containing products in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m²) (see sections WARNINGS*, INTERACTIONS* and Pharmacodynamic properties*). WARNINGS*: Hypotension: initiation should be closely monitored in patients who have been volume depleted, who have severe renin-dependent hypertension, with symptomatic heart failure, with or without associated renal insufficiency, with ischaemic heart or cerebrovascular disease. A transient hypotensive response is not a contraindication to further doses once the blood pressure has increased after volume expansion.

Hypersensitivity/Angioedema/Intestinal angioedema: stop treatment and monitor until complete resolution of symptoms.

Therapy with beta-blocker must be continued. Angioedema associated with laryngeal oedema may be fatal. Patients taking concomitant mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) therapy may be at increased risk for angioedema.

Hepatic failure: rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes) death: treatment should be discontinued if jaundice or marked elevations of hepatic enzymes. Black people: perindopril may be less effective and cause a higher rate of angioedema than in non-black.

Non-productive cough. Hyperkalaemia: frequent monitoring of serum potassium if renal insufficiency, worsening of renal function, age (>70 years), diabetes mellitus, dehydration, acute cardiac decompensation, metabolic acidosis, and concomitant use of potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, drugs associated with increases in serum potassium. Combination with lithium, potassium sparing drugs, potassium supplements, potassiumcontaining salt substitutes, calcium antagonists, Class I antiarrhythmic drugs, centrally acting antihypertensive drugs: not recommended. Dual blockade of the renin-angiotensin-aldosterone system (RAAS): concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of RAAS is therefore not recommended. ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy. Stopping treatment: abrupt cessation should be avoided. The posology should be decreased gradually, using the individual components, ideally over a period of two weeks.

Bradycardia: if resting heart rate drops below 50-55 beats/min and symptoms related to bradycardia, dose should be down titrated using the individual components with an appropriate dose of bisoprolol. Patients with first degree AV block, aortic and mitral valve stenosis, hypertrophic cardiomyopathy, diabetes, strict fasting: use with caution. Patients with Prinzmetal’s angina: Beta-blockers may increase the number and the duration of angina episodes. Renal impairment: daily dose should be adjusted on creatinine clearance. Monitor potassium and creatinine. In patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney, increases in blood urea and serum creatinine have been seen; with renovascular hypertension, increased

INDO

risk of severe hypotension and renal insufficiency. Patients with recent kidney transplantation, treated for heart failure with insulin dependent diabetes mellitus (type I), severely impaired renal function, severely impaired hepatic function, restrictive cardiomyopathy, congenital heart disease, haemodynamically significant organic valvular disease, or myocardial infarction within the last 3 months: no experience. Anaphylactoid reactions: reported in patients dialysed with high flux membranes; during LDL apheresis with dextran sulphate, rarely, patients have experienced life-threatening anaphylactoid reactions, temporarily withhold therapy prior to each apheresis; during desensitization treatment, when ACE inhibitor temporarily withheld, these reactions have been avoided, but reappeared upon inadvertent rechallenge. Neutropenia/agranulocytosis/thrombocytopenia/ anaemia: extreme caution in patients with collagen vascular disease, immunosuppressant therapy, treated with allopurinol or procainamide, periodic monitor of white blood cell counts advised. Bronchospasm (bronchial asthma, obstructive airways diseases): bronchodilating therapy should be given concomitantly. Anaesthesia: if it is necessary to withdraw beta-blocker before surgery, this should be done gradually and completed about 48 hours before anaesthesia. Treatment should be discontinued one day prior to surgery. Psoriasis: carefully balance the benefits/risks. Phaeochromocytoma: bisoprolol should be given with an alpha-receptor blocker. Thyreotoxicosis: symptoms may be masked. Pregnancy: stop treatment. If appropriate, start alternative therapy. INTERACTIONS*: Contra-indicated: Aliskiren in diabetic or impaired renal patients. Not recommended: Centrally acting antihypertensives such as clonidine and others (e.g. methyldopa, moxonidine, rilmenidine), Class I antiarrhythmic drugs (e.g. quinidine, disopyramide; lidocaine, phenytoin; flecainide, propafenone), Calcium antagonists of the verapamil type and to a lesser extent of the diltiazem type, Aliskiren, concomitant therapy with ACE inhibitor and angiotensin-receptor blocker, Estramustine, Potassium sparing diuretics (e.g. triamterene, amiloride...), Potassium (salts), Lithium. Requiring special care: Antidiabetic agents (insulins, oral hypoglycaemic agents), Non-steroidal anti-inflammatory medicinal products (NSAIDs) (including aspirin ≥ 3 g/day), antihypertensive agents and vasodilators, Tricyclic antidepressants/Antipsychotics/Anesthetics, Sympathomimetics, Calcium antagonists of the dihydropyridine type such as felodipine and amlodipine, Class-III antiarrhythmic drugs (e.g. amiodarone), parasympathomimetic drugs, Topical beta-blockers (e.g. eye drops for glaucoma treatment), Digitalis glycosides, Baclofen, Non-potassium-sparing diuretics, Potassium-sparing diuretics (eplerenone, spironolactone), Racecadotril, mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus). To be taken into consideration: Mefloquine, Monoamine oxidase inhibitors (except MAO-B inhibitors), Gliptins (linagliptin, saxagliptin, sitagliptin, vildagliptin), Gold. PREGNANCY AND BREASTFEEDING*: Not recommended during the first trimester of pregnancy and lactation. Contraindicated during the second and third trimesters of pregnancy. FERTILITY*. DRIVE AND USE MACHINES*: Reactions related to low blood pressure may occur in some patients. The ability to drive or operate machinery may be impaired. UNDESIRABLE EFFECTS*: Very Common: bradycardia. Common: headache, dizziness, vertigo, dysgeusia, paraesthesia, visual impairment, tinnitus, worsening of heart failure, hypotension and effects related to hypotension, feeling of coldness or numbness in the extremities, cough, dyspnoea, abdominal pain, constipation, diarrhoea, nausea, vomiting, dyspepsia, rash, pruritus, muscle cramps, asthenia, fatigue.

Uncommon: eosinophilia, hypoglycaemia, hyperkalaemia, hyponatraemia, mood altered, sleep disorder, depression, somnolence, syncope, palpitations, tachycardia, AV-conduction disturbances, orthostatic hypotension, vasculitis, bronchospasm, dry mouth, angioedema of face, extremities, lips, mucous membranes, tongue, glottis and/or larynx, urticaria, photosensitivity reactions, pemphigoid, hyperhidrosis, muscular weakness, arthralgia, myalgia, renal insufficiency, erectile dysfunction, chest pain, malaise, oedema peripheral, pyrexia, blood urea increased, blood creatinine increased, fall. Rare: rhinitis, nightmares, hallucinations, reduced tear flow, hearing disorders, hepatitis either cytolytic or cholestatic, hypersensitivity reactions (itching, flush, rash), psoriasis aggravation, potency disorders, hepatic enzyme increased, blood bilirubin increased, increased triglycerides. Very rare: agranulocytosis, pancytopenia, leukopenia, neutropenia, thrombocytopenia, haemolytic anaemia in patients with a congenital deficiency of G-6PDH, confusion, conjunctivitis, arrhythmia, angina pectoris, myocardial infarction and stroke possibly secondary to excessive hypotension in high-risk patients, eosinophilic pneumonia, pancreatitis, erythema multiform, alopecia, beta-blockers may provoke or worsen psoriasis or induce psoriasis-like rash, renal failure acute, haemoglobin decreased and haematocrit decreased. OVERDOSE*. PROPERTIES*: Bisoprolol is a highly beta1-selectiveadrenoceptor blocking agent, lacking intrinsic stimulating and relevant membrane stabilising activity. Perindopril is an inhibitor of the enzyme that converts angiotensin I into angiotensin II (ACE). PRESENTATION*: Tablet container of 30 film-coated tablets of Cosimprel 5 mg/5 mg, 5 mg/10 mg, 10 mg/5 mg, 10 mg/10 mg. LES LABORATOIRES SERVIER, 50 rue Carnot, 92284 Suresnes Cedex, France. www.servier.com. Product Authorisation: PA0568/029/001-004. Supply Classification: POM Further Information Available From: Servier Laboratories Ireland, Block 2 West Pier Business Campus, Old Dunleary Road, Co. Dublin, Tel (01) 6638110, Fax (01) 6638120, www.servier.ie * For complete information, please refer to the Summary of Product Characteristics available on www.medicines.ie Date of last revision of text: April 2017 (date of last approved SmPC: April 2017) REFERENCES: 1. Fox K M. Lancet. 2003;362(9386):782-8. 2. Dargie H J. Lancet. 1999;353(9146):9-13. 3. Bertrand M E. Am Heart J. 2015;170(6):1092-8.

4. Cosimprel SmPc April 2017.

Date of preparation: September 2017. 1718 C1 COS PRESS AD

UPDATE

cardiology

The management of atrial fibrillation Dr Deepti Ranganathan, Registrar, Cardiology, Beaumont Hospital, Dublin Atrial fibrillation (AF) is the most common clinically encountered arrhythmia, affecting approximately three per cent of the Irish population. This figure is expected to rise to 4.5 per cent by 2040. The direct cost of AF accounts for approximately one per cent of total healthcare spending in the UK (AF-related complications and treatment costs), and this will continue to increase dramatically unless AF is prevented and treated in a timely manner.

AF is a supraventricular arrhythmia, resulting in uncoordinated and ineffective atrial activity. The ventricles are activated in an irregular rate by conduction through the AV node, producing the characteristic ‘irrregularly irregular’ pulse.

AF can be fast or slow depending on the effectiveness of the AV node to block the impulses from the atria. In fast AF, an ineffective AV node block results in fast and irregular ventricular beats, which leads to ineffective filling of the ventricles and poor cardiac output, and stasis which predisposes to thrombus formation.

There is considerable morbidity and mortality associated with AF: 1. Patients with AF are at a five-fold increased risk of stroke. Cardioembolic strokes, secondary to AF, are likely to be more extensive with fatal outcomes or result in higher residual disability. In addition to stroke, systemic emboli can cause ischaemia of other organs such as the limbs, kidneys and GI tract.

2. Loss of atrial contribution, which accounts for approximately 10 per cent of cardiac output, can exacerbate congestive heart failure. Long-standing poorly rate-controlled AF can also result in tachycardia-induced cardiomyopathy.

3. AF is associated with a two-fold increase in dementia.

AF is often asymptomatic (silent AF), leading to its under-diagnosis. As a result, the 2016 ESC guidelines recommend opportun-

12

istic ECG screening in patients above the age of 65, which would display irregular RR interval with no discernible, distinct P waves.

Episodes lasting at least 30 seconds are currently accepted to be diagnostic.

Symptoms, if present, may include: • Palpitations.

• Dyspnea.

• Fatigue/weakness.

• Light-headedness/dizziness.

• Angina.

• Stroke.

The detection of asymptomatic AF by new technologies such as smartphone cases with ECG electrodes, has yet to be formally evaluated against established arrhythmia detection methods.

This article will review three cases of AF and discuss/highlight the approach taken in managing each case.

Discussion points from Case 1 Assessment of patients presenting with AF As with any patient assessment, haemodynamic stability needs to be established (ie, consciousness/vitals). Given that our patient was unstable, a clinical decision was made to perform urgent DCCV. Initial assessment should also include a complete medical history aimed at identifying any specific triggering factors. Patients should then undergo a clinical evaluation that includes thorough assessment of concomitant conditions, focusing on AF pattern, stroke risk-assessment and AF-related symptoms, as well as assessment of arrhythmia-related complications, such as thromboembolism or LV dysfunction.

Case 1

Cardiovascular causes

Non-cardiovascular causes

A 35-year-old gentleman presented to the emergency department with symptoms of acute onset palpitations and dizziness for the last three hours.

Vitals in triage: BP 110/89, HR 120bpm, 100% on RA, RR 12 He reports returning from Spain two days ago and had excess alcohol consumption during his holidays. While being assessed by the ED registrar, the patient starts to become drowsy.

Vitals repeated at this stage show: BP 80/50, HR 180bpm, 89% on RA Impression: Unstable AF, likely triggered by excess alcohol intake.

Management: Haemodynamically unstable AF - the patient underwent urgent electrical cardioversion under sedation and was given a stat dose of heparin. Post-cardioversion, the patient successfully returned to normal sinus rhythm with a heart rate of 70bpm and a BP of 120/90. The patient was monitored on a telemetry bed and was discharged later that day with direct oral anticoagulant (DOAC) therapy for the next four weeks. He was advised on lifestyle changes prior to discharge.

Coronary artery disease Valvular heart disease Hypertension Cardiomyopathy Congenital heart disease Heart failure Pericardial disease

Respiratory Pulmonary embolism Pneumonia COPD Lung carcinoma Sleep apnea

Metabolic Electrolyte imbalance Hyperthyroidism/ Thyrotoxicosis Hypothermia Diabetes Lifestyle Caffeine Alcohol Smoking Drugs - sympathomimetics

cardiology

Bloods

- FBC - U&E - Thyroid Function Test (TFT)

Establish diagnosis of AF Determine rate of AF Screen for conduction defects Rule out ischemia

TTE

Structural disease (eg, Valvular disease) LV and RV function Atrial size

- Holter monitor - TOE - Coronary angiogram - CT/MRI of brain

Clinical signs that require urgent involvement of specialised atrial fibrillation services • • • • •

- To rule out precipitating factors (refer to table) - To assess if patient suitable for DOAC (CrCl calculation)

ECG

Other investigations in selected patients

Haemodynamic instability.

Uncontrollable heart rate.

Symptomatic bradycardia not amenable to reduction of rate-control agents.

Severe angina/worsening LV function.

TIA/CVA.

Case 2 An 80-year-old lady, with a background history of hypertension and diabetes, presents to hospital with hemiplegia involving right side and a NIHSS score of 10. CT Brain showed middle cerebral artery occlusion. As part of her ischemic stroke workup (ECG, echocardiography and extended holter monitoring), it is found that she has atrial fibrillation with no notable symptoms (silent AF). TTE shows good LV systolic function with no significant valvular lesions and normal LA size.

Three-day holter monitoring demonstrated AF with ventricular response rate between 70-110bpm while the patient was on Bisoprolol 2.5mg/OD. Impression: Silent and adequately rate-controlled AF, likely resulting in cardioembolic CVA. Management: 1. Anticoagulation: CHA2DS2-VASc calculated at 7 (1 point each for hypertension, diabetes, female gender and 2 points each for age 80 and prior CVA) and HASBLED score of 2 (1 point each for prior stroke and age of 80). Following the 2016 ESC atrial fibrillation guidelines, an MRI scan was done on day six, which confirmed no haemorrhagic transformation. As such, an OAC was started six days after the acute event.

2. Rate vs rhythm control approach: Given the patient was asymptomatic we opted for rate-controlling her AF.

UPDATE

- Assess adequacy of rate control/recurrance of AF - Further assess valvular disease and LAA (to facilitate early cardioversion/catheter ablation) - Patients with symptoms of MI - Patients with signs of CVA

Following which, investigations aimed at identifying, triggering/ precipitating should be instigated.

Discussion points from Case 2 1. Anticoagulation in AF patients Antiplatelet monotherapy is NOT recommended for stroke prevention in AF patients, regardless of stroke risk.

An OAC should be considered in men with CHA2DS2-VASc score of one and women with a score of two, balancing the expected stroke reduction and bleeding risk as well as patient preference.

OACs are recommended in all male AF patients with a CHA2DS2VASc score of ≥2 and females AF patients with score of ≥3.

VKA (INR two to three or higher in the case of metallic valves) is recommended as the choice of anticoagulation in AF patients with moderate-to-severe mitral stenosis or mechanical heart valves, while DOACs (apixiban, dabigatran, edoxaban or rivaroxaban) are recommended in preference to VKA in AF patients who are eligible for a DOAC (mainly guided by CrCl).

2. Rate control in AF patients Rate control is an integral part of AF management and sometimes in AF patients. It is sufficient to improve AF-related symptoms. The choice of drug (ie, beta-blockers, calcium-channel blockers, cardiac glycosides) and the target heart rate depends on paDosing

Dabigatran

Aplxaban

Edoxaban

Rivaroxaban

Renal elimination

80%

27%

50%

66%

Normal 150mg BID 5mg BID 60mg daily A-fib dosing

20mg daily with evening meal

Renal CrCl 15-30 A-fib 75mg BID dosing

CrCl 15-50 15mg daily with evening meal

2.5mg BID CrCl 15-50 if ≥ 2 of the 30mg daily following: Age ≥ 80 Weight ≤ Avoid CrCl 60kg < 15 or > 95 SCr ≥ 1.5

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Case 3 A 75 year old gentleman, with paroxysmal AF, was reviewed in the cardiology outpatient department. He has a background history of IHD with prior multi-vessel PCI, diabetes (with good glycaemic control), hypertension (well controlled on two antihypertensive agents) and a hiatus hernia.

He had ongoing issues of palpitations associated with dizziness, with no notable falls/loss of consciousness. A holter performed prior to OPD, showed paroxysmal AF, which coincided with patientâ&#x20AC;&#x2122;s symptoms of palpitations.

Management: Given his ongoing symptoms, a decision was made to initiate anti-arrhythmic drugs (AAD) therapy to maintain sinus rhythm.

He was commenced on dronedarone, and was reassessed in clinic after two months with complete resolution of his symptoms.

The patient then decided to undergo catheter ablation after two years on AAD. He was reviewed one year after procedure and remains in sinus rhythm, without further symptoms. compared to no therapy, and should be in symptomatic AF patients. However, selection of AAD for long-term therapy should be guided by the presence of co-morbidities, cardiovascular risk and potential for serious arrhythmias, extra-cardiac toxic effects and patient preference. Safety, rather than efficacy in maintaining sinus rhythm, should primarily guide the choice of anti-arrhythmic drug for long-term rhythm control.

Catheter ablation for AF is an effective means of restoring and maintaining sinus rhythm in patients with symptomatic paroxysmal, persistent and probably long-standing AF. Currently, it is the second-line therapy after the failure of, or intolerance to anti-arrhythmic drug therapy. Pulmonary vein isolation (PVI) can be done either as a point-by-point radio frequency ablation or through cryoballoon ablation, with similar outcomes.

Conclusion tients characteristics, symptoms, LVEF and haemodynamics. Combination therapy may be warranted for adequate rate control. Lenient rate control is an acceptable initial approach (ie, HR <110bpm).

Discussion points from Case 3 Rhythm control in AF AAD therapy approximately doubles sinus rhythm maintenance

14

AF is the most common cardiac arrhythmia in developed countries. Timely diagnosis and appropriate management of AF helps to reduce morbidity and mortality as well as reduce healthcare costs associated with it. Every physician involved in day-to-day clinical practice should have a thorough understanding of the management of AF and identify a select group of patients who would benefit from a specialist assessment of their arrhythmia.

An app that I have found useful in my clinical practice for AF is AFManager

Drug

Adverse effect

Drug interaction

Flecainide

Dizziness, tremors, HF exacerbation

Digoxin

Propafenone

Asthma exacerbation, dizziness

Digoxin, warfarin

Amiodarone

Hyper/hypothyroidism, retinal deposits, pulmonary fibrosis, hepatopathy

Numerous, substrates of 3A4, 2D6, 2C9, 2C19, P-glycoprotein

Dronedarone

Abdominal pain, worsening HF, QT prolongation

3A4 inhibitors digoxin, statin, rivaroxaban

Sotalol

HF exacerbation, bradycardia, bronchospasm, TdP

N/A

Confidence Treating Patients at High Risk of Stroke or Bleeding1 More than 31 million patients treated across 7 indications worldwide2,3 ▼ This medicinal product is subject to additional monitoring. 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. See section 4.8 of the SPC for how to report adverse reactions.

Xarelto 10 mg / 15 mg / 20 mg film-coated tablets (rivaroxaban). Please refer to full SmPC before prescribing. Presentation: Film-coated tablet containing 10mg / 15 mg / 20 mg rivaroxaban. Contains lactose.

Indications: 10 mg: Prevention of venous thromboembolism (VTE) in adult patients undergoing elective hip or knee replacement surgery. Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) and prevention of recurrent DVT and PE in adults. 15 mg/20 mg: Prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation with one or more risk factors, such as congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, prior stroke or transient ischaemic attack. Treatment of DVT and PE, and prevention of recurrent DVT and PE in adults. Special populations: (for 15 mg / 20 mg only): specific dose recommendations apply for patients with moderate to severe renal impairment and in case of DVT/PE-patients only if the patient’s assessed risk for bleeding outweighs the risk for recurrent DVT/PE. Patients undergoing cardioversion: Xarelto can be initiated or continued in patients who may require cardioversion. Patients with non-valvular atrial fibrillation who undergo PCI (percutaneous coronary intervention) with stent placement: There is limited experience of a reduced dose of 15 mg Xarelto once daily (or 10 mg Xarelto once daily for patients with moderate renal impairment [creatinine clearance 30-49 ml/min]) in addition to P2Y12 inhibitor for a maximum of 12 months in patient with non-valvular atrial fibrillation who require oral anticoagulation and undergo PCI with stent placement. Dosage and Administration: Prevention of VTE in elective hip or knee replacement surgery: Recommended dose is 10 mg rivaroxaban taken orally once daily. The initial dose should be taken 6 to 10 hours after surgery, provided that haemostasis has been established. Duration of treatment depends on the individual risk of the patient for VTE which is determined by the type of orthopaedic surgery. For patients undergoing major hip surgery, treatment duration of 5 weeks is recommended. For major knee surgery, treatment duration of 2 weeks is recommended.

Prevention of stroke and systemic embolism: The recommended dose is 20 mg once daily, which is also the recommended maximum dose. Treatment of DVT, treatment of PE and prevention of recurrent DVT and PE: The recommended dose for the initial treatment of acute DVT or PE is 15 mg twice daily for the first three weeks followed by 20 mg once daily for the continued treatment and prevention of recurrent DVT and PE. When extended prevention of recurrent DVT and PE is indicated (following completion of at least 6 months therapy for DVT or PE), the recommended dose is 10 mg once daily. In patients in whom the risk of recurrent DVT or PE is considered high, such as those with complicated comorbidities, or who have developed recurrent DVT or PE on extended prevention with Xarelto 10 mg once daily, a dose of 20 mg once daily should be considered. Renal impairment: No dose adjustment is necessary in patients with mild renal impairment. Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation: In patients with moderate or severe renal impairment, the recommended dose is reduced to 15 mg once daily. Treatment of DVT, treatment of PE and prevention of recurrent DVT and PE: No dose adjustment is considered necessary in moderate to severe renal impairment; although a reduced dose of 15mg once daily should be considered if the patient’s assessed risk for bleeding outweighs the risk for recurrent DVT and PE. Xarelto is not recommended in patients with creatinine clearance < 15 mL/min. Hepatic impairment: Contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk, including cirrhotic patients with Child Pugh B and C. Contraindications: Hypersensitivity to the active substance or any of the excipients; active clinically significant bleeding; lesion or L.IE.MKT.02.2018.1772

condition if considered a significant risk for major bleeding; concomitant treatment with any other anticoagulants except under specific circumstances of switching anticoagulant therapy or when unfractionated heparin is given at doses necessary to maintain an open central venous or arterial catheter; hepatic disease associated with coagulopathy and clinically relevant bleeding risk including cirrhotic patients with Child Pugh B and C; pregnancy and breast feeding. Warnings and Precautions: Clinical surveillance in line with anticoagulation practice is recommended throughout treatment. Xarelto should be discontinued if severe haemorrhage occurs. Increasing age may increase haemorrhagic risk. Xarelto should be discontinued at the first appearance of a severe skin rash, or any other sign of hypersensitivity in conjuction with mucosal lesions. Not recommended: in patients with severe renal impairment (creatinine clearance <15 ml/min); in patients receiving concomitant systemic treatment with strong concurrent CYP3A4 and P-gp inhibitors, i.e. azole-antimycotics or HIV protease inhibitors; in patients with increased bleeding risk; in patients receiving concomitant treatment with strong CYP3A4 inducers unless the patient is closely observed for signs and symptoms of thrombosis; not recommended due to lack of data: in patients below 18 years of age, in patients concomitantly treated with dronedarone;in patients with prosthetic heart valves, in patients with PE who are haemodynamically unstable or may receive thrombolysis or pulmonary embolectomy. Use with caution: in conditions with increased risk of haemorrhage; in patients with severe renal impairment (creatinine clearance 15 - 29 ml/min) or with renal impairment concomitantly receiving other medicinal products which increase rivaroxaban plasma concentrations; in patients treated concomitantly with medicinal products affecting haemostasis; when neuraxial anaesthesia or spinal/epidural puncture is employed. In patients at risk of ulcerative gastrointestinal disease prophylactic treatment may be considered. Although treatment with rivaroxaban does not require routine monitoring of exposure, rivaroxaban levels measured with a calibrated quantitative anti-Factor Xa assay may be useful in exceptional situations. Contains lactose. Undesirable effects: Common: anaemia, dizziness, headache, eye haemorrhage, hypotension, haematoma, epistaxis, haemoptysis, gingival bleeding, gastrointestinal tract haemorrhage, gastrointestinal and abdominal pains, dyspepsia, nausea, constipation, diarrhoea, vomiting, pruritus, rash, ecchymosis, cutaneous and subcutaneous haemorrhage, pain in extremity, urogenital tract haemorrhage (menorrhagia very common in women < 55 years treated for DVT, PE or prevention of recurrence), renal impairment, fever, peripheral oedema, decreased general strength and energy, increase in transaminases, post-procedural haemorrhage, contusion, wound secretion. Uncommon: thrombocytosis, allergic reaction, dermatitis allergic, cerebral and intracranial haemorrhage, syncope, tachycardia, dry mouth, hepaticimpairment, urticaria, haemarthrosis, feeling unwell, increases in: bilirubin, blood alkaline phosphatase, LDH, lipase, amylase and GGT. Rare: jaundice, muscle haemorrhage, localised oedema, bilirubin conjugated increased, vascular pseudoaneurysm. Frequency not known: compartment syndrome or (acute) renal failure secondary to a bleeding. Post-marketing observations (frequency not assessable): angioedema and allergic oedema , cholestasis and hepatitis (incl. hepatocellular injury), thrombocytopenia, Stevens-Johnson syndrome/ Toxic Epidermal Necrolysis. Prescription only. Marketing Authorisation Holder: Bayer AG, 51368 Leverkusen, Germany. MA numbers: EU/1/08/472/001-024. Further information available from: Bayer Ltd., The Atrium, Blackthorn Road, Dublin 18. Tel: 01 2999313. Date of Preparation: 10/2017.

References: 1. The ROCKET AF trial studied patients with a mean CHADS2 score of 3.5 and two thirds of patients had a HASBLED of 3 or more. - Patel M.R., Mahaffey K.W., Garg J. et al. Rivaroxaban versus warfarin in non-valvular atrial fibrillation. N Engl J Med. 2011;365(10):883–91. 2. Calculation based on IMS Health MIDAS, Database: Monthly Sales September 2017. 3. Xarelto® (rivaroxaban). Summary of Product Characteristics as approved by the European Commission.

UPDATE

cardiology

Five tips on the clinical approach to palpitations Dr Emily Hodkinson, Consultant Cardiologist and Electrophysiologist, Beacon Hospital, Dublin Palpitations are a very common presenting complaint to front-line medical services (primary care and emergency departments (EDs)).

They are often a problematic symptom for several reasons: Palpitations often cause great anxiety and distress for the patient, which can put a lot of pressure on the consulted medic.

Most palpitations are benign, but a small minority can represent a life-threatening condition. Efforts to identify the latter can sometimes overshadow investigations and referrals.

The patient is commonly asymptomatic when they present to their GP, so evaluation for pathology must be undertaken in the absence of signs.

Investigations are often normal and can give false reassurance.

In this article, I will offer five tips on how to approach these patients — how to get the most out of the history, the electrocardiography (ECG) and other investigations and, perhaps most importantly, how to risk-stratify your patients.

Tip 1: What to ask in the history Inevitably, the patient with palpitations will be asymptomatic when they consult their GP/front-line medic. Therefore, the history is crucial in formulating a differential diagnosis.

First, find out what the patient means by ‘palpitations’ (if they use that word) — make sure they don’t actually mean chest pain.

Get a clear but detailed description of the patient’s palpitations.

Ventricular ectopic beats are often described as ‘missed beats’, ‘skipped beats’ or ‘jumps’.

Supraventricular tachycardias usually have a sudden onset, with an elevated heart rate and an abrupt offset. Atrioventricular nodal re-entrant tachycardia (AVNRT), atrioventricular re-entrant tachycardia (AVRT), atrial tachycardia and atrial flutters usually have a regular pulse whereas atrial fibrillation (AF) is irregular.

Ventricular tachycardia usually starts abruptly (sometimes the patient may describe some ‘missed beats’ beforehand), gives an elevated heart rate and often is poorly tolerated by the patient.

It is essential to ascertain (by direct questioning if necessary) whether there are any other symptoms associated with the palpitations.

This is very important in order to risk-stratify the patient.

Symptoms such as chest pain, syncope and pre-syncope are red flags and should prompt the medic to look for structural heart disease and to make an urgent onward referral.

Key questions to ask in the patient history • Triggers — activity, posture, emotion, eating.

• Onset, duration, frequency — abrupt or slow-rising?

Every day? How long do episodes last?

• Associated symptoms — syncope, pre-syncope, chest pain, breathlessness, dizziness.

• Background — past medical history, previous cardiac history, family history, particularly of SCD, prescribed medications, over-the-counter medications, drug use.

Tip 2: The value of clinical examination and basic investigations The purpose of the clinical examination in a patient who presents with palpitations is to assess for structural heart disease. A patient with palpitations in the presence of structural heart disease is automatically high-risk and almost always requires an onward referral to a cardiologist (see Tip 5).

When examining the patient, look out for murmurs (aortic stenosis), overload or respiratory crepitations suggesting left ventricular dysfunction and, of course, arterial hypertension (a cause of ventricular ectopy).

The value of basic, cheap and available investigations in formulating a differential diagnosis is perhaps under-appreciated.

A lot can be taken from a basic blood panel, for example.

Is the patient anaemic, causing a high output state and sinus tachycardia?

Does the patient have sinus tachycardia or even AF from thyrotoxicosis? What is the potassium? Is this actually renal failure?

Figure 1: Complete heart block

16

cardiology

Figure 2: Ventricular pre-excitation/WPW syndrome

UPDATE

indicating that the escape rhythm is coming from low in the conduction system. This is a high-risk situation.

Figure 2 shows ventricular pre-excitation, which, when it occurs in association with palpitations, gives the WPW syndrome.

The features of WPW evident on this ECG are: 1. Short PR interval (__).

This is caused by accelerated conduction between the atria and the ventricle as the action potential can bypass the AV node and get to the ventricle early via the accessory pathway.

2. Delta wave (↓).

A delta wave is the slurred upstroke of the QRS seen across the precordium and in the limb leads here.

It is formed by the fusion of myocardial activation via the AV node (gives a normal, rapid upstroke to the QRS) and myocardial activation via the accessory, or bypass tract (giving a very broad and abnormal QRS).

Figure 3 shows the long QT syndrome.

Here, the QT interval is extremely long (measures 640ms).

Normal intervals are <430ms for men and for <450ms women.

The correct way to measure the QT interval is using the Tangent Method, where one measures from the start of the QRS to the end of the T wave, as determined by a tangent line from the end of the T wave to the isoelectric baseline.

Tip 4: Getting the most out of ambulatory monitoring Figure 3: Long QT syndrome

Tip 3: Interpretation of the resting ECG Even in the absence of ‘active palpitations’, the resting ECG can be very useful in the hunt for pathology.

Again, you are looking for features that suggest underlying structural heart disease.

On the resting ECG, look out for: • Left bundle branch block.

• ST or T wave segment change suggestive of ischaemia.

• Q waves of an old myocardial infarction (MI).

• AF. • Left ventricular hypertrophy (LVH) by voltage with strain pattern.

• Delta wave of Wolff-Parkinson-White (WPW) syndrome.

• Heart block (first-, second- or third-degree).

• Abnormal QT interval.

On these pages, I have collated some ECGs of ‘lesser-spotted’ conditions associated with palpitations.

Figure 1 shows complete heart block.

On this ECG, we can see the following salient features of complete or third-degree heart block: 1. More P waves (↓) than QRS (*).

2. Regular P waves (not associated with a QRS complex).

3. Regular QRS complexes (usually at a slower rate than the P waves).

4. Dissociation between the atria and ventricles.

In this example, the QRS complexes are wide (>120ms),

The aim of any period of ambulatory monitoring is to get a symptomrhythm correlation, that is, to record the heart’s rhythm when the patient is having their symptoms of palpitations. This should give the

Figure 4: Medtronic Reveal LINQ implantable loop recorder

Figure 5: The AliveCor by Kardia

17

UPDATE

cardiology

rhythm diagnosis of the patient’s complaint, or indeed, demonstrate a normal sinus rhythm and rate, prompting a search for a non-cardiac cause.

In order to maximise the chance of obtaining a symptomrhythm correlate, the duration of the monitoring period must match the symptom frequency.

Daily symptoms should be captured on a 24-hour holter monitor, whereas if the patient reports infrequent monthly symptoms, an alternative form of monitoring should be sought.

In most cardiac departments, a variety of monitors are available. These usually include 24-hour, 48-hour, 72-hour, and seven-day monitors and patient-activated monitors, which can stay on for several weeks.

The newest generation of implantable loop recorders are extremely low-profile, with a battery life of up to three years (for example, the Reveal LINQ device by Medtronic, see Figure 4).

These devices are designed to be inserted in a procedure room within a few minutes and do not require any sutures.

They are most useful in patients with very infrequent symptoms. All have home-monitoring capability and both automatic and patient-activated recording.

A very useful recent development in the field of ambulatory monitoring has been that of hand-held smartphone monitors. The AliveCor by Kardia attaches to the back of a smartphone. The two metal thumb pads (see Figure 5) record and display a single-lead ECG. Recordings and events can then be saved for review later by a physician.

“

The aim of any period of ambulatory monitoring is to get a symptomrhythm correlation, that is, to record the heart’s rhythm when the patient is having their symptoms of palpitations

Tip 5: How to risk-stratify Perhaps the most important aspect in the approach to the patient with palpitations is risk stratification. Here, you identify the patient who is in danger or who needs urgent onward referral from the majority of patients who can be reassured.

Figure 6 shows a ‘traffic light’ approach to the risk

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●● Isolated palpitations. ●● Not provoked by exercise. ●● Not associated with syncope, dizziness, chest pain or breathlessness. ●● No history of structural heart disease, hypertension or heart failure. ●● No FHx of SCD. ●● Normal 12-lead ECG. ●● Palpitations associated with chest pain or dizziness. ●● Documented AF, flutter or sustained narrow complex tachycardia. ●● Good history suggestive of paroxysmal SVT. ●● Known or suggested structural heart disease, hypertension or heart failure. ●● Abnormal 12-lead ECG. ●● Palpitations during exercise. ●● Palpitations associated with syncope or pre-syncope. ●● Second- or third-degree AV block on 12-lead ECG. ●● Family history of sudden cardiac death or inheritable cardiac condition. ●● High-risk structural heart disease (severe AS, etc).

Figure 6: The ‘traffic light’ system for risk stratification of palpitations stratification.

Red-flag symptoms signalling urgent referral include syncope or pre-syncope in association with palpitations and symptoms during exercise.

The patient with known or suspected high-risk structural heart disease (severe aortic stenosis, previous MI, congenital abnormality) who presents with palpitations should always be referred onwards in an urgent manner, as they are at risk of ventricular tachycardia.

The same goes for patients who have a family history of inherited cardiac disease (hypertrophic or dilated cardiomyopathy, Long QT syndrome, etc) or of sudden cardiac death.

A 12-lead ECG showing a broad, complex tachycardia mandates emergency transfer to hospital, as does complete (third-degree) heart block.

Second-degree heart block on ECG should also be urgently referred to the ED, as the risk of progression to complete heart block is high here.

• Green — low risk.

Referral not usually required • Amber — medium risk.

Should be referred • Red — high risk.

Urgent/same-day referral to hospital References available on request

UPDATE

cardiology

American College of Cardiology 2018 Dr Albert McNeill, Consultant Cardiologist, Altnagelvin Hospital, Londonderry and President of the Irish Cardiac Society Snow lying at the side of the M1 as I drove from the North to Dublin airport late on a March night en route to the American College of Cardiology reminded me of the harsh winter that we have had, harsh not only weatherwise, but one in which we have seen increasing demands on stretched cardiological services throughout the island of Ireland. We have a population which is increasing in age and frailty, but for whom we have availability of evidencebased and guideline-driven therapies that we should strive to provide for our patients. There are manpower issues not only in medicine but also in nursing, clinical physiology and amongst other support staff. Resultant staff shortages result in mental, physical and emotional exhaustion and poor staff morale.

â&#x20AC;&#x153;

Those of us who treat patients with acute myocardial infarction, and in particular those of us whose experience dates back to the pre-thrombolytic and preprimary PCI era, worry about the potential for fatal arrhythmias in patients with significantly impaired left ventricular function but who do not fulfil guidelinebased criteria for implantation of a cardiovertible defibrillator

In her opening address Dr Mary Norine Walsh, the outgoing President of the American College of Cardiology, who had attended the Irish Cardiac Society Meeting in Londonderry, alluded to the pressures that cardiology staff are experiencing on the other side of the Atlantic: Stress and burnout among staff and issues with funding even within their healthcare system. However, despite the similar issues we face on both sides of the Atlantic, perhaps to a different degree in our different healthcare systems, she

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stressed the common and global need for patient-centred care, working in teams with multidisciplinary collaboration, and a need to strive for professionalism and clinical excellence, and our responsibility to act as advocates for patients.

The cardiological issues may be similar on both sides of the Atlantic, but at least there was no snow in Florida, unlike Washington last year. As always at the American College of Cardiology there were several late-breaking trials, at least some of which will be â&#x20AC;&#x153;game changersâ&#x20AC;? in cardiological practice.

Foremost among these was the presentation of the ODYSSEY trial which included 18,924 patients with a recent (less than 12 months) acute coronary syndrome enrolled at 1,315 sites in 57 countries (truly a global study). Patients were randomised to either subcutaneous alirocumab every two weeks or placebo with a primary endpoint of major cardiac event (MACE) of 9.5 per cent in the alirocumab versus 11.1 per cent in the placebo group. This is further evidence to strengthen the place of the PCSK9 inhibitor class of drugs and follows on from FOURIER, also presented at the American College of Cardiology last year. These are drugs, which will improve the outlook, for high-risk patients with hyperlipidaemia inadequately controlled by statins. As Dr Walsh said in her opening address we need to be advocates to ensure that patients get access to appropriate evidencebased therapies such as these.

Those of us who treat patients with acute myocardial infarction, and in particular those of us whose experience dates back to the pre-thrombolytic and pre-primary PCI era, worry about the potential for fatal arrhythmias in patients with significantly impaired left ventricular function but who do not fulfil guideline-based criteria for implantation of a cardiovertible defibrillator. The VEST study evaluated whether a wearable cardioverter-defibrillator (literally a defibrillator built into a vest) could reduce sudden cardiac death in immediate post-infarct period (less than 90 days) in patients with impaired left ventricular function. A total of 2,302 patients with acute infarction and an ejection fraction less than 35 per cent were randomised to wear a defibrillator versus guideline-directed medical therapy. The primary outcome was sudden cardiac death and death due to ventricular arrhythmias. Interestingly, there was no significant difference in primary endpoint between the two groups, but unexpectedly stroke deaths were significantly lower in the defibrillator group. Although the primary endpoint was not met, the investigators concluded that the use of a wearable cardiovertible defibrillator was reasonable to protect high-risk patients with a low ejection fraction post-myocardial infarction until evaluation for an implantable defibrillator.

In clinical cardiology we are continually challenged to find new ways of working in chronic disease management,

cardiology

such as the management of hypertension.Uncontrolled hypertension is a major problem among non-Hispanic black men in America and an innovative way of managing this issue was addressed in a Cluster-Randomised Trial of Blood-Pressure Reduction in Black Barbershops, presented at ACC and published simultaneously in the New England Journal of Medicine. A blood pressure less than 130/80mm Hg was achieved by 63.6 per cent of black men encouraged by their local barber to have follow-up in the barbershop by pharmacists who regularly checked BP, prescribed medications, monitored electrolytes and renal function and reported back to the patients’ general practitioners. Lead author, Dr Ronald G Victor, Director of the Hypertension Centre at Cedars-Sinai Medical Centre, Los Angeles, California, commented: “As black men tend to have many cardiovascular disease risk factors, marked BP reductions — if sustained using our approach and initiated widely — might reduce high hypertension-related disability and death among black men in the United States.” Similar data have been reported in the past from Texas; are we ready for such innovative approaches in Ireland?

It is always a pleasure for me to meet and work with my colleagues from the British Cardiovascular Society with whom we make up the British/Irish chapter of the ACC. In our joint meeting this year we linked up with the Lebanese Group; the emphasis was on electrophysiology and devices and Dr Conor McCann from the Belfast Trust represented our society in the discussion of guidelines for the use of devices. This meeting gave us an insight into the issues facing interventional electrophysiologists, how do we meet the challenge of providing an atrial fibrillation ablation service in developing countries, and how do we best apply guidelines for implantable devices to everyday practice.

Once again it was a pleasure for our Society to host what is now the annual Irish Cardiac Society reception for Irish and Irish American cardiologists at the American College of Cardiology. My thanks as always goes to Barbara Dalton for organising this event, which was once again a very successful meeting. This reception has grown out of a suggestion by Dr Kim Williams, former president of the ACC, that the Irish Cardiac Society should form closer links with the American College. The initial meeting in Chicago in 2016 was followed by a very successful meeting in Washington DC on St Patrick’s night last year. This year I had the pleasure of conferring honorary membership of our Society on Dr Williams and also Dr Michael Valentine, the incoming President of the ACC. Despite her hectic schedule Dr Mary Norine Walsh and her husband took time to attend our reception as did many of the other Irish American Cardiologists, including past President of the ACC Dr John Harold, who has become a firm friend of our Society and a regular attendee at our annual meeting, and it has been a pleasure and honour to form personal friendships with many of our American colleagues and their families, as well as forging professional relationships, which are to the mutual benefit of both Societies.

We were very pleased that Dr Noel Boyle, who is a Trinity graduate and currently cardiologist at UCLA Medical Centre, addressed us on his training and subsequent career in

UPDATE

America. This was an invaluable and informative evening for the registrars and fellows who were able to attend and we would urge any of you who plan to attend an American Cardiology meeting that you should make the American College a priority and if at all possible attend next year’s reception in New Orleans.

One of the many pleasures of my time as President of the Irish Cardiac Society has been the opportunity to meet and network with peers throughout the world. At ACC Convocation I met the President of the Nigerian Cardiol-

“

This meeting gave us an insight into the issues facing interventional electrophysiologists, how do we meet the challenge of providing an atrial fibrillation ablation service in developing countries, and how do we best apply guidelines for implantable devices to everyday practice

ogy Society and heard first-hand the challenges she and her colleagues face in the provision of cardiology care with few invasive facilities, similar to her colleagues in Kenya where the first cardiac catheterisation facility has only recently opened. It is particularly pleasing that our Society is held in high regard by colleagues globally and indeed Dr Walsh in her closing address made mention of the warm welcome that she had received at the Irish Cardiac Society in Derry/Londonderry.

Flying off from the warm Florida sunset to wintry Dublin I had several take-home messages: Once again ACC was the showcase for leading-edge cardiology, we have an evidence-base for new lipid-lowering therapy and innovations in healthcare delivery. Colleagues worldwide face challenges, some specific and some generic, in delivering cardiology care within their own societies. Despite those differences we all have a common responsibility as reminded by Dr Mary Norine Walsh to act as advocates for our patients and in so doing provide best evidence-based care in highly-motivated multidisciplinary professional teams.

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UPDATE

cardiology

Percutaneous transcatheter aortic valve implantation (TAVI) – An update in 2018 Dr Mark Hensey, Specialist Registrar in Cardiology; and Dr Martin Quinn, Consultant Cardiologist, St Vincent’s University Hospital, Dublin Aortic stenosis (AS) is the most common primary valve disease requiring intervention in Europe and North America. It carries significant morbidity and mortality and given the current aging population, it will become even more prevalent in the near future. Transcatheter aortic valve implantation (TAVI) involves the placement of an aortic valve prosthesis percutaneously, predominantly via the femoral artery. This negates the need for open heart surgery which, prior to the first TAVI performed in 2002, was the only option for the treatment of severe AS. The subsequent development of the TAVI procedure has arguably been the major advance in modern cardiology.

In the last 15 years, more than 350,000 procedures have been performed in more than 70 countries. A recent analysis showed that in Germany more TAVI procedures are being carried out per annum than surgical aortic valve replacements. The technology and procedure has become more streamlined with fewer complications and the indications for the procedure are expanding with growing evidence for lower-risk patient groups and patients with other aortic valve pathology. The success of the procedure has also led to the development of less invasive transcatheter approaches to the treatment of non-aortic valvular heart disease. In this article we aim to give an update on TAVI with specific emphasis on the application to new patient groups, procedural and technological advances.

Patient considerations The initial trials examining TAVI were centered on patients deemed unsuitable for surgical intervention. Subsequent trials demonstrated improved outcomes for TAVI versus surgery in high-risk patients (STS/EUROSCORE II >10% equivalent to a >10% recent of mortality during surgery) and similar outcomes have been shown for TAVI versus surgery in intermediate-risk patients (STS/EUROSCORE II ≥4% and ≤10%) with better outcomes for TAVI when the valve is delivered via the transfemoral route. This has led to international guidelines recommending TAVI in high-risk populations and ‘Heart Team’ discussion regarding patients at intermediate-risk, favouring TAVI in patients in whom the transfemoral approach is possible. There are other specific subgroups of patients in whom there is current interest in regarding TAVI. Low-risk patients The use of TAVI in low-risk patients is currently under investigation in several large randomised-controlled trials and it is likely that the indications for the procedure will grow. Doubts remain about the implementation of the procedure in younger populations (<75 years) due to the lack of data regarding longterm durability of the TAVI valves, although the available data demonstrates good performance and longevity comparable to bioprosthetic surgical valves. One further issue, however, is that

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it is known that bioprosthetic surgical valves degenerate quicker in younger patients, an issue which may become important if TAVI valves are implanted in this cohort.

Bicuspid aortic valves Approximately one to two per cent of the population is born with a bicuspid aortic valve and they are prone to the development of symptomatic aortic stenosis. There are specific anatomical considerations related to the use of TAVI in bicuspid valves such as a more oval annulus, uneven calcification and unequal leaflet size that add complexity to the procedure. These patients are also generally younger which, as discussed above, raises concerns regarding TAVI valve durability. Although there is no randomised-controlled data for the use of TAVI in bicuspid valves, registries have shown comparable outcomes with new generation devices to those in tricuspid anatomy, however, further research is required in the area.

Failing bioprosthetic valves The use of TAVI in failing bioprosthetic surgical valves (valvein-valve procedure) is an area of growing use and interest. It is an attractive approach to treat failing surgically-implanted bioprostheses as reoperation in these patients is associated with increased morbidity and mortality. The prosthetic valve provides a secure anchor for the TAVI valve to be placed within, although one concern is that the TAVI valve may not be fully expanded within the old prosthesis and that this may result in poor function and durability of the TAVI valve. This has led to the idea of fracturing the original valve ring with high pressure balloon inflation to allow full expansion of the TAVI valve, in fact device companies are developing surgical valves designed for this purpose. Registries again have shown favourable outcomes.

Aortic regurgitation To date, TAVI has generally been reserved for the treatment of AS; however, there is growing interest in the use of the procedure in pure aortic regurgitation (AR). This provides many challenges such as, the lack of calcification to provide anchoring for the prosthesis and aortic root dilatation, which is often associated with AR. Specific devices aimed at TAVI in pure AR have been developed and are currently under investigation.

Procedural developments The first TAVI procedure was performed via catherisation of the femoral vein, a transseptal puncture into the left atrium and passage through the mitral valve and left ventricle with subsequent anterograde placement of the prosthetic valve into the native aortic valve. This was a complex procedure with a steep learning curve and complications were common. The subsequent development of a transarterial retrograde technique via the femoral artery in 2005 was a major advance and allowed the widespread uptake of the procedure. Alternative routes for pa-

cardiology

tients with unsuitable ileofemoral arterial anatomy have also been developed, the most common being via the subclavian artery, the transapical route and the direct aortic route, of which the latter two both require a small surgical incision.

The predominant route remains the transfemoral approach.

Numerous advances have been made to simplify the process.

Prior to the procedure, CT scanning alone is being used to clarify coronary, aortic valvular and peripheral vascular anatomy rather than the more invasive combination of angiography and transoesophageal echocardiography.

The TAVI procedure has also developed from a prolonged one under general anaesthesia with transoesophageal echo guidance to a less invasive one utilising local anaesthesia with transthoracic echo guidance. It is now not unusual for a TAVI to be carried out in less than one hour. Recovery times have also been shortened, patients are mobilised on the same day as their TAVI and many centres are discharging patients day one post-procedure, with most patients being discharged within 72 hours.

Device developments There are several TAVI systems available in Europe for implantation. They are broadly split into two groups: Balloonexpandable, which are placed in the aortic annulus via inflation of an internal balloon; and self/mechanically-expandable valves, which are positioned in the aortic annulus and passively (self-expandable) or actively (mechanically-expandable) fixed into the aortic annulus. Each valve design has pros and cons and the choice of valve used is dependent on patient and anatomical features along with operator experience and preference.

Newer valve devices have focused on the reduction of the main complications associated with the TAVI procedure, namely vascular injury, paravalvular leak, cerebrovascular complications and conduction disturbances. Other developments in newer generation valves are the ability to reposition and even recapture valves to ensure accurate deployment.

A.

B.

C.

Fig.1. A. Edwards Sapien S3 balloon-expandable valve, B. Medtronic CoreValve Evolut R self-expandable valve, C. Boston Lotus mechanically-expandable valve Vascular injury The size of the vascular sheaths used to deliver the valves has decreased greatly and modern sheaths are almost half the size of first generation devices. This, along with the development of vascular-closure devices and techniques, has greatly reduced the rate of major bleeding and vascular complications associated with the TAVI procedure. Techniques and operator experience of managing these complications in the cath lab has also improved, greatly reducing the need for surgical intervention.

UPDATE

Fig 2. Complications of early versus new-generation transcatheter heart valves (THV) Barbanti et al. EuroIntervention 2017 Paravalvular leak The presence of paravalvular leak (aortic regurgitation in the space between the TAVI valve and the aortic annulus) was a frequent complication of early TAVI procedures and is known to predict poor outcomes. Newer devices have tackled this issue, largely by the development of outer skirts placed on the valves that have improved sealing between the valves and the annulus. Significant aortic regurgitation is now rare with modern TAVI valves.

Cerebrovascular and thrombotic complications There has been a significant reduction in cerebrovascular events from early experience. This is in the main explained by lower-profile delivery systems and increased operator experience. Several cerebral protection devices have also been developed. These devices are placed in aortic arch during the procedure and aim to prevent embolisation of clot or debris into the cerebral vasculature. They have been shown to reduce the number and size of subclinical embolisations but, as of yet, they have not been shown to reduce clinically-relevant strokes.

One recent concern is that of increased rates of subclinical valve leaflet thrombosis noted post-TAVI as compared to that of SAVR. This has been shown to increase the incidence of transient ischaemic attacks, but not strokes, and although multiple patient and device-specific factors have been proposed as potential contributors to the phenomenon, none have been proven. To date the optimal antiplatelet/antithrombotic regimen has not been clarified although most operators use either single or dual antiplatelet regimens post-TAVI, it is an area that requires more research.

Conduction distubances One of the most common complications of the TAVI procedure is conduction disturbance, which may ultimately require pacemaker insertion. This is due to the proximity of the aortic annulus to the conduction system in the left ventricular outflow tract. Balloon-expandable valves have the lowest rate of pacemaker insertion (12.4 per cent) with self-expandable (15.9 per cent) and mechanically-expandable devices (30.6 per cent) having respectively higher rates.

Conclusion In a relatively short period of time, TAVI has progressed from an experimental procedure to becoming the predominant method of treating severe aortic stenosis for high-risk patients. Its use in Ireland continues to grow and it serves as a roadmap in the development of less invasive ways of treating other severe valvular heart diseases, a process which is already well underway.

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with ®

ranolazine

Significantly improves exercise duration and reduces angina frequency1

WITH ®

ranolazine

RANEXA® included as a second line treatment for stable angina in ESC SCAD guidelines2 RANEXA® is indicated in adults as add-on therapy for the symptomatic treatment of patients with stable angina pectoris who are inadequately controlled or intolerant to first-line antianginal therapies (such as beta-blockers and/or calcium antagonists)3 Prescribing Information: Ranexa (ranolazine).

Please consult the Summary of Product Characteristics (SPC) for full prescribing information. Presentation: Prolonged-release tablets containing 375 mg, 500 mg or 750 mg of ranolazine. 750 mg tablet contains E102 and lactose. Use: Ranexa is indicated as add-on therapy for the symptomatic treatment of patients with stable angina pectoris who are inadequately controlled or intolerant to first-line antianginal therapies (such as betablockers and/or calcium antagonists). Dosage and administration: Oral administration. Patients should be instructed to present their Patient Alert Card (inside the box) and medication list to their health care professional at each visit. Adults: Initial dose is 375 mg twice daily. After 2-4 weeks, dose should be titrated to 500 mg twice daily and, according to patient’s response, further titrated to 750 mg twice daily. Concomitant treatment with moderate CYP3A4 and P-glycoprotein (P-gp) inhibitors: Careful dose titration is recommended. Renal impairment: Careful dose titration is recommended in mild to moderate renal impairment, and contraindicated in severe renal impairment. Hepatic impairment: Careful dose titration is recommended in mild hepatic impairment, and contraindicated in moderate to severe hepatic impairment. Elderly: Dose titration in the elderly should be exercised with caution. Low weight: Dose titration in patients with low weight should be exercised with caution. Congestive Heart Failure (CHF): Dose titration in moderate to severe CHF should be exercised with caution. Paediatric patients: No data in children below the age of 18 years. Ranexa tablets should be swallowed whole and not crushed, broken or chewed. They may be taken with or without food. Contra-indications: Hypersensitivity to the active substance or to any of the excipients. Severe renal impairment. Moderate or severe hepatic impairment. Concomitant administration of potent CYP3A4 inhibitors. Concomitant administration of Class Ia or Class III antiarrhythmics other than amiodarone. Warnings and Precautions: Caution should be exercised when prescribing or up titrating ranolazine to patients in whom an increased exposure is expected. QT prolongation: Caution should be observed when treating patients with a history of congenital or a family history of long QT syndrome, in patients with known acquired QT interval prolongation, and in patients treated with drugs affecting the QTc interval. Interactions: Co-administration with CYP3A4 inducers is expected to lead to lack of efficacy. Renal impairment: Check renal function at regular intervals during treatment. Interactions: CYP3A4 inhibitors: Increase plasma concentrations of ranolazine. Combining ranolazine with potent CYP3A4 inhibitors is contraindicated. CYP3A4 inducers: Avoid initiation with Ranexa during administration of CYP3A4 inducers.

CYP2D6 inhibitors: May increase plasma concentrations of ranolazine. Effect of ranolazine on other medicinal products: Dosage adjustment of sensitive CYP3A4 substrates and CYP3A4 substrates with a narrow therapeutic range may be required. Lower doses of CYP2D6 substrates may be required. Caution with CYP2B6 substrates.

Monitor digoxin levels following initiation and termination of Ranexa. Limit dose of simvastatin to 20mg once daily in patients taking Ranexa. Limit dose of atorvastatin and consider clinical monitoring in patients taking Ranexa. Monitor blood levels of tacrolimus when co-administering with Ranexa and adjust tacrolimus dose accordingly. Also recommended for other CYP3A4 substrates with a narrow therapeutic range. Drugs transported

by the Organic Cation Transporter-2 (OCT2): Plasma exposure of metformin increased in subjects with type 2 diabetes mellitus when co-administered with Ranexa. The exposure of other OCT2 substrates may also be affected. Theoretical risk that concomitant treatment with drugs known to prolong the QTc interval may increase the possible risk of ventricular arrhythmias. Pregnancy and lactation: Ranexa should not be used during pregnancy unless clearly necessary. Ranexa should not be used during breast-feeding. Effect on fertility unknown.

Side-effects: Generally mild to moderate in severity and often develop within the first 2 weeks of treatment.

Common (1-10%): dizziness, headache, constipation, vomiting, nausea, asthenia. Uncommon (0.1–1%): anorexia, decreased appetite, dehydration, anxiety, insomnia, confusional state, hallucination, lethargy, syncope, hypoaesthesia, somnolence, tremor, postural dizziness, paraesthesia, blurred vision, visual disturbance, diplopia, vertigo, tinnitus, hot flush, hypotension, dyspnoea, cough, epistaxis, abdominal pain, dry mouth, dyspepsia, flatulence, stomach discomfort, pruritus, hyperhydrosis, pain in extremity, muscle cramp, joint swelling, muscular weakness, dysuria, haematuria, chromaturia, fatigue, peripheral oedema, increased blood creatinine, increased blood urea, prolonged QT corrected interval, increased platelet or white blood cell count, decreased weight.

In a long term study, acute renal failure was also reported with an incidence less than 1% in placebo and ranolazine patients. Rare (0.1-0.01%): hyponatremia, disorientation, amnesia, depressed level of consciousness, loss of consciousness, coordination abnormal, gait disturbance, parosmia, impaired hearing, peripheral coldness, orthostatic hypotension, throat tightness, pancreatitis, erosive duodenitis, oral hypoaesthesia, angioedema, allergic dermatitis, urticaria, cold sweat, rash, acute renal failure, urinary retention, erectile dysfunction, elevated levels of hepatic enzyme. Increased incidence of congestive heart failure and transient ischaemic attacks seen in patients with history of chronic angina who had incomplete revascularisation after percutaneous coronary intervention and treated within 2 weeks with ranolazine (1000 mg twice daily [dose not approved in Europe]) in a placebo-controlled post-PCI trial. Elderly, renal impairment and low weight: In general, adverse events occurred more frequently among elderly patients and patients with renal impairment. Adverse events in patients with low body weight were similar to those of patients with higher weight. Please consult the SPC for further information. Pack size: 60 tablets. Legal category: POM. Marketing authorisation numbers: EU/1/08/462/001-006 Marketing Authorisation holder: Menarini International Operations Luxembourg S.A. Marketed by: A. Menarini Pharmaceuticals Ireland Ltd. Further information is available on request from A. Menarini Pharmaceuticals Ireland Ltd, 2nd Floor, Castlecourt, Monkstown Farm, Monkstown, Glenageary, Co. Dublin A96 T924 or may be found in the SPC. Last updated: January 2017.

References: 1. Chaitman, B.R., et al. JAMA, 2004; 291(3): p. 309-16.

2. Eur Heart J 2013;34:2949-3003. 3. Ranexa® Summary of Product Characteristics, December 2016.

Date of item: May 2017.

IR-RAN-05-2017

cardiology

UPDATE

Angina – getting ‘tighter’ control of the ‘tightness’ Dr David Burke, Consultant in Cardiology, Beacon Hospital, and Clinical Director of Cardiology and Director of Medical Education, Beacon UCD Academy, Dublin The days of our patients carrying around their little pink bottle in their pockets as a hopeful quick relief from chest tightness have largely become a thing of the past. As an interventional cardiologist, I feel that I have not done my job properly if one of my stable patients has to resort to a puff of GTN (glyceryl trinitrate). The advances in recent years in both interventional abilities, but almost more importantly, medical therapies, have allowed us to improve massively on patient quality-of-life.

For any patient presenting with chest discomfort, the focus from the outset becomes ensuring that it is not due to a cardiac cause.

Myocardial ischaemia results in angina pectoris, or classically a central chest ‘tightness’ that occurs with effort. We are all aware of a spectrum of variability in presenting symptoms outside of these typical descriptions, but the aim is timely diagnosis and treatment in order to reduce morbidity and mortality. Some of our patients will present with exertional shortness of breath, nausea, diaphoresis or even fatigue, as opposed to the classical chest discomfort. The initial presentation of myocardial ischaemia may be of a stable anginal pattern or an acute coronary syndrome.

For most patients, we are able to minimise frequency and severity of stable anginal symptoms through a combination of conventional medical therapies, which include beta-blockers, calcium channel blockers and nitrates. Newer agents such as ranolazine are effective when added to standard therapy in reducing symptoms and improving exercise tolerance.

All of our patients with coronary artery disease should receive optimal medical therapy. This sweeping statement not only refers to the use of appropriate medication, but also to the often less popular and poorly-sustained behavioural interventions that have been shown to have a significant impact in reducing the risk of cardiovascular events. We need to carefully and aggressively target risks associated with hypertension, smoking, diabetes and inactivity. Progression of coronary disease, even in our patients who have undergone revascularisation, is an important determinant of subsequent clinical outcome.

Conditions that may precipitate or aggravate myocardial ischaemia, such as hypertension, tachyarrhythmias like atrial fibrillation, thyroid irregularities, anaemia or valvular heart disease, should be tackled. Lifestyle modification forms a crucial cornerstone of standard treatment. The gradual build-up of regular exercise improves fitness and results in lower oxygen requirements for a given workload.

Initial investigation History and physical examination will often provide a convincing story that will make us immediately suspicious. Of course, some patients are less obvious. Stress testing is typically the first diagnostic test in assessing patients who are able to manage the treadmill. Beyond this, functional testing with dobutamine stress echo allows us to visualise left ventricular systolic function with increasing doses of dobutamine and faster heart rates. We look for cardiac wall motion abnormalities to ensure there is no apparent strain with tachycardia.

Cardiac MRI has fast become a very useful tool in assessing patients

for inducible ischaemia, particularly those following previous coronary interventions or with known moderate disease.

CT coronary angiography has helped in providing a single diagnostic tool in ruling out significant underlying coronary disease and will regularly form a part of our diagnostic algorithm. In patients with positive testing, the next step in firming-up our suspicion is a standard coronary angiogram — a test which itself has evolved over years. Most studies are now done via radial arterial access, which has proven easier on patients and is less likely to cause vascular issues.

Guidelines for therapy — tried and tested European and American guidelines are in agreement that betablockers form the first-line therapy in reducing anginal episodes and improving exercise tolerance. Beta-blockers relieve symptoms through a reduction in both heart rate and contractility. They are the only medications shown to prevent re-infarction and to improve survival in patients who have had previous heart attacks. In terms of choice, all beta-blockers appear to be equally effective in exertional angina.

Calcium channel blockers are used in combination with betablockers or as a substitute in situations in which beta-blockers are contraindicated or use is limited due to side-effects. Symptoms are improved through the effect of coronary and peripheral vasodilatation and reduction in myocardial contractility. Nowadays, the use of long-acting diltiazem or verapamil, or a second-generation dihydropyridine (amlodipine or felodipine), is preferred. Short-acting dihydropyridines, such as nifedipine should be avoided, as when used in conjunction with beta-blockers they can increase mortality after myocardial infarction (MI) and increase the frequency of acute MI in hypertensive patients.

Although differing physicians will have differing approaches, the use of beta-blockers as first-line would be preferential, as the survival benefit seen with beta-blockers in patients with previous MI or left ventricular systolic dysfunction has not been replicated with calcium channel blockers. Addition of a further agent, such as a calcium channel blocker or nitrate to the beta-blocker, is indicated if symptoms persist with monotherapy. If symptoms are persistent despite two agents, a third anti-anginal can be introduced, but the threshold for pushing on to coronary angiography at that point is low.

Nitrates were first used for the treatment of angina in the late 1800s and they are still widely used today. The mode of action is via venodilation, coronary vasodilatation and arteriolar dilatation, but the primary anti-ischaemic effect comes via decreased myocardial oxygen demand by producing systemic vasodilation — the main reason they are contraindicated when used in conjunction with vasodilators for erectile dysfunction. Nitrates are particularly useful in the setting of primarily vasospastic angina.

GTN spray still forms the frontline of treatment in the setting of acute anginal symptoms and when patients arrive emergently to hospital with an acute coronary syndrome, they will have invariably received multiple puffs of sublingual nitrate on the ambulance journey.

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cardiology

Long-acting nitrates are typically added to baseline beta-blocker therapy to control stable anginal symptoms. Chronic nitrate use in oral or topical patch form improves exercise tolerance and time-toonset of angina. The long-term utility of nitrates is somewhat limited by the gradual induction of nitrate tolerance. Interestingly, there has been no difference in efficacy among the various oral or dermal nitrate preparations and so use should depend on physician and, of course, patient, preference.

There is conflicting data available regarding the benefit of ACE inhibitors in the reduction of exercise-induced ischaemia. Overall, it would appear that there is no compelling evidence suggesting a benefit. Subsets of patients, such as those with hypertension, diabetes, poor left ventricular function or chronic kidney disease, appear to see benefit.

Ivabradine has also been recommended as an additional agent that may be used in the setting of refractory angina, although the addition of ivabradine to standard background therapy to reduce heart rate in patients with stable coronary artery disease without clinical heart failure did not improve patient outcome in the SIGNIFY trial.

Newer agents â&#x20AC;&#x201D; ranolazine Ranolazine has been approved for use in patients with refractory angina. Its method of action was originally thought to be by partial inhibition of fatty acid oxidation, but it was later realised that it had that effect only at serum levels not achieved with usual dosing.

The likely important mechanism for ranolazine is by prevention of calcium overload and subsequent increase in diastolic tension due to inhibition of late inward sodium channels. This sodium channel frequently fails to inactivate in several myocardial disease states, such as ischaemia and hypertrophy, with excess sodium ions entering the myocytes and leading to activation of the sodium/calcium exchanger, thereby giving rise to raised calcium concentrations.

Given the normal rapid inaction of the late inward sodium channel in normal myocytes, the drug does not exert any significant effect on the normal myocardium at usual doses, which likely increases its therapeutic window.

The usual initial dose is 500mg twice daily, but this can be uptitrated to 1,000mg twice daily if needed.

The beneficial effect in chronic stable angina has been shown in multiple randomised trials. The MARISA trial showed that treatment with ranolazine alone resulted in a dose-dependent increase in pain-free exercise duration and time to angina. Anginal episodes were significantly decreased with the use of ranolazine in combination with calcium channel blockers in the CARISA trial and when compared with placebo in the ERICA trial. The TERISA trial compared ranolazine versus placebo in patients with diabetes and stable angina. Anginal frequency and use of sublingual nitroglycerin were reduced by the drug.

Complex patients On balance, the most likely group who might require the introduction of escalating anti-anginal therapy are those patients who have incomplete revascularisation after percutaneous coronary intervention (PCI). Stenting techniques and abilities have evolved rapidly.

Left main or complex bifurcations stenting strategies have become commonplace, compared to a decade ago. We have become significantly less dependent on more invasive surgical treatments.

This patient group was evaluated in the RIVER-PCI trial, which

26

randomly assigned patients to ranolazine or placebo after incomplete revascularisation with PCI. Although there was symptomatic improvement, in fact there was no difference in the rate of primary efficacy endpoint, which was a complex composite of time to first occurrence of ischaemic-driven revascularisation or ischaemia-driven hospitalisation.

40 years of angioplasty Percutaneous therapies have become the gold standard in the treatment of coronary disease. The process has been fine-tuned and 2017 marks and celebrates the 40th anniversary of angioplasty.

Relatively primitive balloon angioplasty was followed by early bare metal stents, which subsequently led to drug-eluting stents. The drug-eluting stents in use today are the third- and fourth-generation counterparts of their predecessors that were approved for use in 2002. Drug-eluting stents consist of a metallic alloy frame (most commonly cobalt chromium) coated in a polymer that is covered with a drug, which slowly absorbs into the surrounding tissues over several months. Newer, fully-bioresorbable stents made of a polylactic acid frame are available and promise to dissolve away over several years, returning natural vasomotion to the formerly-diseased vessel.

There have been some concerns relating to in-stent re-stenosis that have stalled some of the initial enthusiasm, but work in this area continues.

Since its inception in the late 1970s, there has been no convincing evidence that PCI improves survival compared to medical therapy in patients with â&#x20AC;&#x2DC;stableâ&#x20AC;&#x2122; ischaemic heart disease. The COURAGE trial published in 2007 had a major impact on care and treatment. Patients with stable coronary artery disease were randomly assigned to aggressive medical therapy or aggressive medical therapy and PCI with bare metal stenting. All received optimal medical therapy. At median follow-up of 4.6 years, there was no significant difference between the two treatment strategies for the primary end-point of death from any cause and non-fatal myocardial infarction. Notably, patients in the PCI group underwent significantly fewer subsequent revascularisation procedures.

To add to the debate, a 2014 meta-analysis of all-cause mortality in 95 trials with almost 100,000 patients compared one type of coronary revascularisation (CABG or stenting) to another or placebo.

Newer generations of drug-eluting stents were associated with a reduced mortality, compared with medical treatment. Other metaanalyses comparing optimal medical therapy to PCI have differing conclusions relating to mortality benefit.

For patients with inadequate anginal symptom control with medical therapy, the addition of PCI has been shown to improve symptom severity and frequency.

Future targets Future treatment strategies will likely come at the heart from other angles. Stem cell therapy involving the transplantation of bone marrow stem cells has been evaluated as a therapeutic treatment option in patients following myocardial infarction or with ischaemic cardiomyopathies. Studies evaluating patients three months following intramyocardial injection of autologous bone marrow-derived mononuclear cells showed a statistically-significant, albeit modest, improvement in myocardial perfusion compared with placebo. Further extensive investigation is required to evaluate potential efficacy, but also safety.

cardiology

UPDATE

Failure is not an option Priscilla Lynch speaks to Dr Angie Brown about the Irish Heart Foundation’s new campaign to raise awareness of heart failure symptoms and highlights the resources available to GPs to treat the condition

O

ne-in-five people will develop heart failure (HF) in their lifetime. There are up to 90,000 people in Ireland living with HF and the estimated cost of the condition is €660 million per annum.

The Irish Heart Foundation (IHF) has launched a new campaign, ‘Pay Attention to the Signs’, to raise awareness of HF symptoms. The campaign, supported by Novartis, aims to encourage those aged 50 and over to be aware of the signs of HF, as early detection of the symptoms can significantly improve a patient’s prognosis.

Swollen ankles, fatigue and shortness of breath are warning signs that should never be ignored in patients, according to the campaign.

Due to Ireland’s ageing population, the condition is set to increase dramatically, leading to a rise in HF hospitali-

‘Ireland BEATS Heart Failure’ Croí, the Heartbeat Trust and Novartis recently announced the start of a new community health outcome study, ‘Ireland BEATS Heart Failure’. The study, officially launched in Galway by Minister of State at the Department of Rural and Community Development Seán Kyne, will run for two years, enrolling a total of 750 patients in the west and east of Ireland. It is the largest Ireland-only, community health outcome study of its kind.

Welcoming the study, Minister Kyne said: “We are delighted that this initiative has commenced in the west of Ireland and it gives general practitioners in the west a great opportunity to be involved in the largest community health outcome study of its kind in Ireland.”

This study is designed with the purpose of assessing whether timely access to diagnostics, access to specialist opinion and patient education can improve outcomes in HF patients.

The study also aims to describe the characteristics of HF patients in Ireland, the treatments they receive and the frequency of hospitalisations and emergency service visits.

Welcoming the study, Dr Yvonne Smyth, Consultant Cardiologist, Galway University Hospital and Clinical Lead of the HSE National Acute Medicine Programme, said: “Chronic diseases such as heart failure account for up 70 per cent of all illnesses in Ireland, and this figure is projected to increase as the population ages.”

Prof Ken McDonald, Consultant Cardiologist and Medical Director of the Heartbeat Trust, added: “Chronic illness threatens to overrun our healthcare systems. This ground-breaking study can be used as a test case to establish effective ways to better manage heart failure, one of the most complex of chronic diseases. It is a great achievement that the study has started in the west of Ireland and we look forward to the start of the pilot study in the east of Ireland soon.”

sations of more than 50 per cent over the next 25 years.

Dr Angie Brown, Consultant Cardiologist and Medical Director, Irish Heart Foundation, said that HF can often go unnoticed because its symptoms come on gradually. “It’s easy to attribute tiredness to a busy lifestyle, and breathlessness to being out of shape.

These are signs we need Dr Angie Brown to watch out for.”

One-in-five people over 65 years presenting to their GP with breathlessness will have unrecognised HF, Dr Brown told Update. Furthermore, the incidence is expected to increase substantially over the next 30 years, but despite this, Ireland’s public awareness of the signs, symptoms and causes of HF is very low, she noted.

“This is why our campaign is aimed at the general public.

In addition to the discussions on the radio, our campaign materials include posters, leaflets and a brochure; there is also information on our website or via the nurses helpline, 1800 25 25 50. Any GP can get in touch and receive the materials or download from our website [www.knowyourheart.ie].”

General practice Dr Brown said it is important that GPs remain aware of how common HF is. She said that while GPs are well aware of HF symptoms, it can often be difficult to diagnose.

“Some of the main symptoms are breathlessness and fatigue, which are quite non-specific and can be due to other things, such as a chest infection or underlying lung disease, or even in some people due to deconditioning. It is therefore important to have a high index of suspicion, particularly in patients with risk factors such as ischaemic heart disease, hypertension, valve disease or diabetes. If heart failure needs to be excluded, a blood test to measure the natriuretic peptides (BNP) is very useful, as it is elevated in heart failure. Patients can then be referred for an ECG, ECHO and specialist review.”

Once a diagnosis of HF has been made, the patient will be started on several types of medication (ACE inhibitors, beta-blockers, angiotensin receptor blockers (ARBs), hydralazine with nitrate, diuretics, aldosterone antagonists, sacubitril/valsartan, ivabradine and digoxin, etc) to improve the heart function, control blood pressure and heart

27

UPDATE

cardiology

rate, and remove any fluid from the lungs. These medications can improve symptoms as well as heart function and lower mortality. “Other treatment may be necessary, depending on the cause of heart failure — for instance, if it is due to a narrowed heart valve, this may need replacing, or if it is due to blocked heart arteries (ischaemic heart disease) then the patient may need a stent or a heart bypass.

Some people may need a special sort of pacemaker. All of the treatment available now means that people’s symptoms and prognosis if they have heart failure has improved compared to years ago, when these weren’t available,” Dr Brown said.

Gender Women often have different cardiac symptoms to men and can underplay their symptoms, Dr Brown noted.

“Women are protected in part by their hormones but after the menopause, the risk of developing heart disease increases and catches up with men, so it is equally important for women to be investigated for heart failure if they present with fatigue, dyspnoea, swelling of the ankle [and] some may complain of ‘gasping’ or inability to lie flat in bed or wake up at night breathless. Some may have palpitations or dizzy spells.”

In summary, Dr Brown said it is important for everyone to be aware of their HF risk factors, “so to get blood pressure, cholesterol and blood sugar checked, try and keep to a healthy weight, eat a healthy diet, cut down on alcohol, stop smoking and if a person has breathlessness, fatigue or swollen ankles, that they get a check-up with their GP”.

Patient information meetings The Irish Heart Foundation is holding two public information meetings on HF. The meetings are designed for people with HF and their families, healthcare staff and anyone with an interest in HF. Waterford The evening will feature talks by leading medical experts from University Hospital Waterford, including Consultant Cardiologist Dr Pat O’Callaghan, to increase awareness and understanding of the condition. The Foundation will launch a HF support group at this meeting.

Date: Thursday, 19 April.

Time: 6.30pm-9pm.

Location: Woodlands Hotel, Dunmore Road, Waterford.

Dublin The evening will feature talks by leading medical experts from the Mater Hospital, Dublin, including Consultant Cardiologist Prof Niall Mahon, to increase awareness and understanding of the condition.

Date: Thursday, 12 April Time: 6.30-9pm Location: Ashling Hotel, Parkgate Street

Resources The Irish Heart Foundation also runs a National Heart

28

and Stroke Helpline staffed by specialist nurses. Freephone 1800 25 25 50, Monday to Friday, 9am-5pm. A range of patient support and information booklets are available at https://irishheart.ie/publications/.

Heart Failure Virtual Clinics for GPs With the correct supports, HF can largely be managed in the community. The Heartbeat Trust has been at the forefront of development of structured care programmes for the prevention and management of HF, including a ‘virtual consultation’ service to enable specialists and GPs to discuss cases and reduce the need for outpatient department (OPD) referral by 80 per cent.

The Trust’s Heart Failure Virtual Clinics (HFVCs) are used to disseminate expert advice and education to GPs. Using a web conference platform, GPs can log in remotely and following presentation of a short CME topic, GPs can discuss their cases with Prof Ken McDonald, Consultant Cardiologist and Medical Director of the Heartbeat Trust, Dr Patricia Campbell, Consultant Cardiologist, and their specialist team. The HFVCs provide online, real-time conversations between the GP and specialist allowing speedy, focused interactions.

For GPs, the HFVC provides a dynamic learning environment, improved knowledge base, peer-to-peer support and most importantly, the necessary supports to maintain and treat HF patients in the primary care setting.

By managing HF in the community, the HFVC removes a step in the traditional care pathway, facilitating interaction between the specialist/GP. The HFVC care pathway is cost-efficient and creates a dynamic, collaborative communication environment compared to the traditional referral letter pathway. This in turn reduces costs and the need for patient travel and family inconvenience. Moreover, the HFVC reduces the need for OPD referrals, which frees-up hospital OPD slots for those in need of standard clinics, resulting in shorter waiting times and speedier reviews.

The HFVCs have been successfully running for the last few years. These virtual consultations are held bi-weekly from the Heartbeat Trust head office in Dublin and are currently on Wednesdays and Fridays, having recently expanded into the Carlow/Kilkenny region through support from the HSE. CME topics include (but are not limited to) diagnosis of HF, management of stable HF, troubleshooting medications in HF and other similar topics. Following the CME topic, up to six cases are discussed, which results in an intense hour of impartation of knowledge.

Patient referrals are accepted through email/fax and Healthlink via the HFVC referral tab.

Presently, there are over 150 GPs signed-up across the east coast, midlands and Carlow/Kilkenny region. According to the Trust, 100 per cent of participating GPs agreed that the HFVC advice was useful in treating their patients and that the patients benefited as a result of their participation in the HFVC. The patients were also happy to have their conditions discussed with experts and groups of GPs and relieved to not be referred to the OPD, the Trust said.

The Heartbeat Trust provides full training for first-time users or those requiring a refresher. For further information or to sign-up to the HFVC, please contact Ms Lisa McCudden on 0877474436 or email lisa@heartbeat-trust.org.

A res for your pource atients î&#x192;°

Helping your patients manage THEIR High Blood Pressure MyBP.ie is a website for people diagnosed with hypertension.

By visiting www.mybp.ie your patients can find videos and advice on the lifestyle changes that can help them manage their high blood pressure.

MyBP.ie is not intended to diagnose any medical condition or to replace consultation with a healthcare professional.

myEXERCISE -

Simple lifestyle changes can improve your overall heart health.

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Hypertension and stress can go hand in hand, find out how to counter those feelings.

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See how dietary changes can, over time, lower your blood pressure.

IR-MYBP-11-2018 Feb 2018

UPDATE

cardiology

An overview of heart failure Dr Dermot McCaffrey, Consultant Cardiologist and Heart Failure Specialist at Beacon Hospital, Dublin, and Clinical Lecturer/Assistant Professor of Medicine, University College Dublin Heart failure (HF) is becoming more prevalent in the setting of significant medical advances. In Ireland alone, 100,000 people are affected, resulting in 20,000 admissions a year. The increased prevalence is in part due to our success in altering the progression of cardiovascular disease. Patients are now surviving heart attacks, cardiomyopathies, hypertensive crisis, cancer, etc, resulting in a larger pool of survivors who then progress to HF. Among adults aged >40, it is estimated that one-in-five will be diagnosed with HF in their lifetime.

Primary care physicians are detecting at-risk patients in their 40s and 50s and altering disease progression. Checking for hypertension, diabetes, dyslipidaemia, advising regarding smoking, obesity, etc, and assessing family history allows GPs to target those at risk. Although enquiring

“

Unfortunately, access to echocardiograms remains limited in Ireland, which delays timely and accurate diagnosis, preventing early treatment that may avoid HF hospitalisations

With more HF patients, we will need more HF practitioners. This may be any practitioner with an interest in and knowledge of HF management, whether that be a GP, physician, cardiologist, nurse practitioner, etc. However, they need access to appropriate resources, eg, echocardiography, biomarker and cardiac MRI imaging. They need to identify when a patient is ‘not behaving or not responding’ as expected and have access to a HF service. The HF specialist may offer further management strategies, including device therapy, new drugs, inotropes or simply advise that the failing heart cannot be improved and have a frank discussion regarding palliative options and support.

An echocardiogram is essential to diagnose heart failure with reduced ejection fraction (HFrEF), which refers to patients with left ventricular ejection fraction (LVEF) <40 per cent, particularly as the European Society of Cardiology (ESC) now divides patients into those with mid-range LVEF, ie, 40-to-49 per cent, and those with preserved LVEF, ie, those with LVEF >50 per cent. Unfortunately, access to echocardiograms remains limited in Ireland, which delays timely and accurate diagnosis, preventing early treatment that may avoid HF hospitalisations.

Back to basics: Brief recap on the physiology of chronic HF The normal resting heart ejects 60 per cent of its volume, ie, an LVEF of 60 per cent. If a failing heart has an LVEF of 40 per cent, then there is 60 per cent volume left behind, causing higher pressures and high left ventricular enddiastolic pressure (LVEDP). Blood then backs up in the pulmonary veins and lungs, causing breathlessness. Over time, the LV volume and stretch result in cardiac dilatation and remodelling, further weakening the systolic function.

The sabre-toothed tiger about family history of premature atherosclerosis is the simplest ‘genetic test’ available, it has lost its sensitivity over the decades as people have smaller families, so there are more ‘false negative’ responses.

Despite earlier diagnosis and intervention, as people age, cardiovascular disease will catch up and ischaemic, valvular or hypertensive heart disease will eventually predispose them to HF. Earlier cancer diagnosis and treatments prolong survival, but some survivors will develop HF. Consider HF as an ‘elite club’ where you are already a provisional member, but the timing of your formal entry is yet to be determined. Our target in preventing HF is to ensure entry is as late as possible.

30

The heart in 2017 responds to low LVEF, as it did in Stone Age times. A tiger bites a caveman’s leg, he loses blood, ties a tourniquet, his blood pressure drops and this triggers his primeval responses. Adrenaline release causes increased heart rate and cardiac output. To reduce blood loss, there is vasoconstriction via the renin-angiotensin-aldosteronesympathetic (RAAS) system.

Fluid retention by renin and aldosterone prevents diuresis, so if the caveman’s family find him, he may survive to hunt another day. This same response is triggered in 2017 in HF when the LV fails with low LVEF, but no volume loss.

Initially, this may be helpful, but in the chronic setting, it is harmful and becomes part of the problem. The low LVEF activates the RAAS system, which starts a vicious circle

cardiology

where adrenaline increases the heart rate and cardiac demand and continued adrenaline activation become harmful. Persistent activation of B1 receptors becomes damaging and is analogous to ‘flogging a tired horse’, where more whipping does not improve the horse’s performance. So how does the heart protect itself?

Intrinsic response: the failing heart protects itself by altering the quantity and ratio of its β receptors. The normal heart has 80 per cent β1 and 20 per cent β2 receptors, but the failing heart has 60 per cent β1 and 40 per cent β2 receptors, which ameliorates the response to adrenaline. The failing heart also uncouples the β1 receptors from their energy source, eg, cGMP, resulting in reduced cardiomyocyte contraction.

Extrinsic support: Treatment with ‘trial-proven’ betablockers, eg, carvedilol, metoprolol succinate, nebivolol and bisoprolol, improves morbidity and mortality in chronic HF by 35 per cent. Only carvedilol in the COPERNICUS trial showed benefit in severe HF patients, New York Heart Association (NYHA) class IIIb/IV. Carvedilol is a non-selective beta blocker with β1-, β2- and α-blocking effects.

The α blockade causes vasodilation, allowing the failing heart to offload at the same time as its β receptors are being blocked. It is important to recall that the BEST trial in chronic HF with bucindolol showed no benefit, so not all beta-blockers are equal. Even HF beta-blockers can cause harm if not used appropriately, eg, in high doses to a fail-

From the European Society of Cardiology (ESC) 2016 Guidelines for the diagnosis and treatment of acute and chronic heart failure, the taskforce for the diagnosis and treatment of acute and chronic heart failure of the ESC. Developed with the special contribution of the Heart Failure Association (HFA) of the ESC Eur Heart J. 2016;37(27):2129-2200. doi:10.1093/eurheartj/ehw128

UPDATE

ing heart, they cause hypotension, acute renal failure and possibly death.

Debate on whether beta blockers exert their benefit by simply slowing the heart rate or by other mechanisms continues. Ivabradine slows the heart rate by inhibiting the I(f) channel of the sinoatrial node. Although it didn’t improve

“

Adrenaline also acts on α-receptors, causing vascular constriction. This initial adaptive response becomes harmful in the chronic situation, with increased afterload

the primary end-point in the SHIFT study, it did reduce HF hospitalisation. Ivabradine is useful for patients with persistent rates >70bpm, but especially for those who are beta blocker-intolerant, eg, asthmatics.

Exogenous stimulation of β receptors with inotropes such as dobutamine or by calcium sensitisers, such as levosimendan increases morbidity and mortality, but are useful in acute decompensated HF when used cautiously by experienced physicians and in the palliative situation.

Intrinsic response: When the LV is stretched by extra volume, the endocardium releases natriuretic peptides like BNP, which excretes both salt and water. A high BNP indicates the heart is defending itself in response to LV stretch.

Other peptides such as adrenomedullin and bradykinin have advantageous properties on vessels and renal perfusion in the HF setting. These are the body’s counter-regulatory response to persistent RAAS stimulation.

Extrinsic support: Treatment with an angiotensin receptor blocker and neprilysin inhibitor (ARNI) has been shown in the PARADIGM-HF study, published in August 2014, to reduce death from cardiovascular cause or HF hospitalisation by 20 per cent, reduce death from cardiovascular cause by 20 per cent, reduce HF hospitalisation by 21 per cent and all-cause mortality by 16 per cent. This was the first overwhelmingly positive HF drug study since the beta blockers trials of the 1990s.

The PARADIGM-HF trial compared LCZ696, a combination of valsartan (ARB) and sacubitril (neprilysin inhibitor) compared to enalapril (ACEi) in stable HF patients on optimal treatment with persistently low LVEF <40 per cent.

Sacubitril blocks the breakdown of BNP and other peptides

31

UPDATE

cardiology

and therefore ‘enhances’ the body’s own defence mechanism. LCZ696 is marketed as Entresto in Ireland.

Most patients in PARADIGM-HF were NYHA class II (72 per cent) or III (22 per cent). Although described as a ‘stable HF population’, they still carried significant risk, eg, mean LVEF 29 per cent, BNP 255pg/mL and 36 per cent had AF. The high primary end-point rate of 26.5 per cent on enalapril vs 21.8 per cent on LCZ696 suggests they were not low risk, even if stable. LCZ696 showed a significant benefit across all subgroups and improved quality-of-life, as demonstrated by KCCQ. LCZ696 is substituted for an ARB or ACEi but it is important that the ACEi is stopped >36 hours before initiation to avoid angio-oedema.

Patients in the LCZ696 arm were on less diuretic, as investigators were encouraged to reduce drugs to allow uptitration. Perhaps enhancing the endogenous natriuretic response rather than giving loop diuretics was beneficial.

There has been the concern that persistent loop diuretic use, may encourage ongoing RAAS stimulation and therefore be deleterious in the long-term.

The PARADIGM-HF findings were consistent with previous neutral endopeptidase (NEP) inhibitor trials such as OVERTURE, which compared an ACEi-NEP combination drug omapatrilat vs an ACEi alone, namely enalapril.

OVERTURE showed a non-significant six per cent reduction in the primary endpoint, but a significant nine per cent reduction in CV death or hospitalisation. Patients on omapatrilat had a 0.8 per cent risk of angio-oedema, so the

“

Patients should be on what is appropriate for them at whatever stage they are at during their HF course. Their treatment may be targeted to improve symptoms, to reduce hospitalisation or to prolong life, or perhaps all of the above

drug was not licenced. Omapatrilat caused more hypotension and dizziness without benefit, so there was a concern that we had reached a ‘vasodilatory ceiling’. PARADIGMHF has reassured us in this regard.

Extrinsic support: The ASCEND-HF trial assessed if boosting the patient’s own BNP response with exogenous BNP, namely an infusion of recombinant BNP called nesi-

32

ritide in ADHF, was helpful but it showed no benefit over standard care with diuretics. However, this trial looked at the acute decompensation (ADHF) setting.

Intrinsic response: Renin is released due to low renal perfusion and low sodium levels. Renin breaks down angiotensinogen to angiotensin I, which is cleaved in the lungs by angiotensin-converting enzyme (ACE) to angiotensin II; a most potent vasoconstrictor. Angiotensin II acts on the adrenals, causing aldosterone release, which causes salt and water retention at the expense of potassium loss. This results in fluid retention, high afterload and low potassium, all of which exacerbate heart failure. The only agents countering this process are the natriuretic peptides.

Extrinsic support: Treatment with the direct renin inhibitor (DRI) aliskiren showed no benefit when added to enalapril in HF patients and caused more hypotension, renal impairment and hyperkalaemia in the ATMOSPHERE study. Aliskiren is now only used for essential hypertension.

Intrinsic response: Symptoms of heart failure such as fatigue may be viewed as the body reducing its own workload to try to slow the heart rate and allow recovery. Historically, heart failure management was complete bed rest post-MI before there were beta-blockers.

Diuretics: Diuretics reduce the LVEDP, which improves coronary perfusion and dyspnoea. However, excess diuresis drops the LVEDP too quickly, with ‘loss of LV stretch’, which the failing heart requires. This causes hypotension and acute renal failure. The failing left ventricle utilises the Frank-Starling effect, ie, the strength of the heart’s systolic contraction is directly proportional to its diastolic expansion. So, diuretics need to be used judiciously.

Intrinsic response: Adrenaline also acts on α receptors, causing vascular constriction. This initial adaptive response becomes harmful in the chronic situation, with increased afterload. The body only has the natriuretic peptide (NP) system to counteract the RAAS system, so it is overwhelmed unless assisted externally.

Extrinsic support: Vasodilators such as ACEi have the strongest evidence of benefit (SOLVD, CONSENSUS, SAVE, etc) in chronic HF, which supports their first-line use. ARBs work downstream at the receptor site and are used for ACEi-intolerant patients (CHARM-Alternative).

Vasodilation by ACEi, ARB, ARNI, nitrates and hydralazine have all shown benefit in heart failure by either antagonising the RAAS system, enhancing the NP system or by directly dilating vessels.

Extrinsic support: To overcome the aldosterone component of RAAS, mineralocorticoid receptor antagonists (MRAs) such as spironolactone and eplerenone prevent salt and water retention. Aldosterone also increases myocardial collagen, interstitial fibrosis and endothelial dysfunction, resulting in increased stiffness, diastolic dysfunction and potential for arrhythmia.

The anti-fibrotic properties of MRAs most likely contributed to the results of the RALES and EMPHASIS-HF trials.

If patients have a HF hospitalisation or LVEF remains <35 per cent, they should have an MRA, especially if they have other ‘risk markers’ such as persistently-elevated BNP or QRS duration >130ms. Then, when they are stable, which may take some months, if LVEF remains <40 per cent and

IN MI PATIENTS,

THE SUPERIORITY OF

BRILIQUE VS CLOPIDOGREL

CAN MAKE THE DIFFERENCE*

*In the PLATO study, the secondary endpoint showed BRILIQUE 90mg twice daily (in combination with low dose aspirin 75150mg daily) reduced the relative risk of CV mortality by 21% (1.1% ARR) vs clopidogrel 75mg daily at 12 months (p=0.001)1 ABRIDGED PRESCRIBING INFORMATION BRILIQUE® 60MG & 90MG FILM-COATED TABLETS AND 90MG ORODISPERSIBLE TABLETS (ticagrelor). Consult Summary of Product Characteristics (SmPC) before prescribing. Use: Adults aged 18 years and older, co-administered with 75-150mg acetylsalicylic acid (ASA) daily unless specifically contraindicated, for the prevention of atherothrombotic events in patients with: acute coronary syndromes (ACS), or; a history of a myocardial infarction (MI) and a high risk of developing an atherothrombotic event. Presentation: Film-coated tablets containing 60mg or 90mg ticagrelor; Orodispersible tablets containing 90mg ticagrelor. Dosage and administration: ACS: Treatment should be initiated with a single 180mg loading dose (two tablets of 90mg available either as film-coated tablets or orodispersible tablets) and then continued at 90mg twice daily. Treatment with Brilique 90mg is recommended for 12 months in ACS patients unless discontinuation is clinically indicated. History of MI: 60mg twice daily for extended treatment in patients with a history of MI of at least one year and a high risk of an atherothrombotic event. Treatment may be started without interruption as continuation therapy after the initial one year treatment with Brilique 90mg or other adenosine diphosphate (ADP) receptor inhibitor therapy in ACS patients with high risk of an atherothrombotic event. Treatment can also be initiated up to 2 years from the MI, or within one year after stopping previous ADP receptor inhibitor treatment. Limited data on efficacy and safety of ticagrelor beyond 3 years of extended treatment. If a switch is needed, the first dose of Brilique should be administered 24 hours following the last dose of the other antiplatelet medication. Lapses in therapy should be avoided.

For oral use. 60mg and 90mg film-coated tablets: Tablet can also be crushed, mixed with water and either drunk or administered via a nasogastric tube (CH8 or greater). 90mg orodispersible tablet: Place tablet on tongue to disperse in saliva, then swallow with or without water.

Can also be dispersed in water and administered via a nasogastric tube.

Contraindications: Hypersensitivity to the active substance or to any of the excipients. Active pathological bleeding. History of intracranial haemorrhage. Severe hepatic impairment. Co-administration with strong

CYP3A4 inhibitors (e.g. ketoconazole, clarithromycin). Precautions: Use with caution in patients at an increased risk for bleeding (e.g. recent trauma or surgery, coagulation disorders or recent gastrointestinal bleeding) or those taking concomitant medication that may increase bleeding risk (e.g. NSAIDs, oral anticoagulants and/or fibrinolytics) within 24 hours of taking Brilique. Brilique should be stopped 7 days prior to elective surgery if the antiplatelet effect is not desired. In patients with a history of MI with prior ischaemic stroke, treatment beyond 1 year is not recommended. Not recommended in patients on renal dialysis.

Use with caution in patients with moderate hepatic impairment. Use with caution in patients with an increased risk of bradycardic events or when administered concomitantly with medicinal products known to induce bradycardia. Use with caution in patients with a history of asthma and/or COPD or a history of hyperuricaemia or gouty arthritis. Use in patients with uric acid nephropathy is discouraged. Creatinine levels may increase during treatment with Brilique, renal function should be checked according to routine medical practice and in ACS patients, one month after starting Brilique, paying special attention to patients ≥ 75 years, patients with moderate-to-severe renal impairment and those receiving concomitant treatment with an angiotensin receptor blocker (ARB). Premature discontinuation with any antiplatelet therapy including Brilique could result in an increased risk of cardiovascular death or MI due to the patient’s underlying disease and should therefore, be avoided. Co-administration of Brilique is not recommended with a high maintenance dose of ASA (> 300mg) or with doses of simvastatin > 40mg. Co-administration of ticagrelor with strong CYP3A inducers (e.g. rifampicin, phenytoin) is discouraged, as this may lead to a decrease in exposure and efficacy of ticagrelor. No data are available on concomitant use of Brilique with other drugs that also are potent P-glycoprotein (P-gp) inhibitors and moderate CYP3A4 inhibitors (e.g. verapamil, quinidine) that may increase ticagrelor exposure. If the association cannot be avoided, their concomitant use should be made with caution. Caution is advised in co-administration with medicinal products that alter haemostasis or with SSRIs. Brilique is not recommended during pregnancy and breastfeeding.

Patients who experience dizziness and confusion during treatment should

be cautious when driving or using machines. Undesirable events: Very Common: blood disorder bleedings, hyperuricaemia, dyspnoea Common: gout/gouty arthritis, dizziness, syncope, headache, vertigo, hypotension, respiratory system bleedings, gastrointestinal haemorrhage, diarrhoea, nausea, dyspepsia, constipation, subcutaneous or dermal bleeding, rash, pruritus, urinary tract bleeding, blood creatinine increased, post procedural haemorrhage and traumatic bleedings. Uncommon: tumour bleedings, hypersensitivity including angioedema, confusion, intracranial haemorrhage, eye haemorrhage, ear haemorrhage, retroperitoneal haemorrhage, muscular bleedings and reproductive system bleedings.

Consult SPC for a full list of adverse events. Legal category: POM. Marketing authorisation number: Brilique 60mg film-coated tablet EU/1/10/655/008; Brilique 90mg film-coated tablet EU/1/10/655/004; Brilique 90mg orodispersible tablet EU/1/10/655/013. Marketing Authorisation holder AstraZeneca AB, SE-151 85 Sodertalje, Sweden.

Further product information available on request from: Freephone 1800 800 899 or contact AstraZeneca UK Limited, Horizon Place, 600 Capability Green, Luton, Bedfordshire, LU1 3LU, United Kingdom.

BRILIQUE is a trademark of the AstraZeneca group of companies. Date of API preparation: 12/2017. API REF: IE-0601 Adverse events should be reported directly to: HPRA Pharmacovigilance, Earlsfort Terrace, Dublin 2.

Tel: +353 1 6764971 Fax: +353 1 6762517 Website: www. hpra.ie e-mail: medsafety@hpra.ie.

Adverse events should also be reported to AstraZeneca Medical Information on 1800 800 899.

1. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Eng J Med 2009; 361:104557.

MI = Myocardial Infarction ARR = Absolute Risk Reduction Approval ID: IE-0593

Improved outcomes matter

Date of preparation: December 2017

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symptomatic, NYHA class II/III, then they should be considered for LCZ696 instead of their ACEi/ARB. After any episode of ADHF, once stabilised and the cause clarified (eg, infection, anaemia, non-compliance, excess fluid or salt intake, etc), patients should be reassessed to prevent recurrences. This is especially pertinent now, as LCZ696 reduces HF hospitalisation by 20 per cent in patients who are at risk.

Device therapy: ‘Back of the envelope’ advice is that those with LVEF <35 per cent after three months of optimal pharmacotherapy (OPT) should be considered for an implantable cardiac defibrillator (ICD).

Cardiac resynchronisation therapy (CRT) is beneficial in those with left bundle-branch block with QRS >130ms and LVEF <35 per cent, despite three months of OPT. Decisions regarding device therapy should be made by HF specialists, with full and frank discussion with patients regarding the risks and benefits and the concept of ‘non-responders’.

However, not all patients who are prescribed ACEi or beta-blockers respond and yet we do not label them as ‘nonresponders’, so the concept is somewhat subjective.

“

Decisions regarding device therapy should be made by HF specialists, with full and frank discussion with patients regarding the risks and benefits and the concept of ‘non-responders’

‘Make the heart great again’ Reverse LV remodelling is the term used to describe when heart size and function, ie, LVEDD and LVEF, improves and this is usually assessed by echocardiogram or MRI. A dramatic example is Takotsubo cardiomyopathy, where a dilated LV with LVEF 25 per cent may be normal size, with an LVEF 60 per cent within weeks. Reverse LV remodelling when accompanied by normalisation of BNP is reassuring.

In chronic HF, after initiation with beta-blockers, the time course of reverse LV remodelling is that 60 per cent of the response at one year will be seen by three months (McCaffrey et al). This is an important observation, as it

34

suggests that you should wait three months after significant therapy changes before reviewing LVEF when deciding on management, eg, an ICD, as the LVEF may be >35 per cent.

Tick-box medicine ‘Medicine by numbers’ or ‘tick-box medicine’ is a concern, because doctors assume heart failure patients should be on all proven therapies, eg, ACEi/ARB/ARNI, betablockers, MRA, ICD, CRT, diuretic, +/-digoxin, +/- fluid restriction, +/-statins, +/-aspirin, etc, but they shouldn’t.

Patients should be on what is appropriate for them at whatever stage they are at during their HF course.

Their treatment may be targeted to improve symptoms, to reduce hospitalisation or to prolong life, or perhaps all of the above. Most ‘real-life’ HF patients would not meet the criteria for large phase 3 trials, either due to their young age (<55), comorbidities or the transient nature of their HF. Therefore, we often use Level of Evidence C (consensus of opinion or small studies or registries) and often Class of Recommendation II (conflicting evidence or divergence of opinion) decisions to guide us.

We also use our anecdotal experience, our familiarity with certain HF drugs, our patients’ ability to comply with instructions and our access to diagnostic services and consideration of costs both to the patient and the payer before we suggest various treatments, doses and combinations.

Going forward, the main goal remains HF prevention by reduction of modifiable cardiac risks. ESC HF prevention guidelines now include SGLT2 drugs, like empagliflozin for type 2 diabetics to delay the onset of HF (EMPA-REG OUTCOME trial). Future treatments may include anti-inflammatory therapies.

Recently in the CANTOS study, stable coronary artery disease patients with elevated CRP given canakinumab, a monoclonal interleukin-1 beta antibody, had less major adverse cardiac events (MACE).

Previous HF studies, eg, RECOVER, with anti-inflammatory agents like etanercept, a TNF inhibitor, were negative, although investigators believe this was a dosing issue.

So the inflammatory component of chronic HF remains a future target. In PARADIGM-HF, there was still a 21.8 per cent primary event rate in the ARNI arm where patients were on OPT in centres of excellence, so more needs to be achieved, as event rates would be still higher in ‘real-life’ practice.

We cannot reduce the ageing process and therefore ‘stiff hearts’ with impaired diastolic function and subsequent preserved systolic heart failure (HFpEF) is inevitable.

Therefore, if we live long enough, we will all join the HF club but our goal as physicians is to postpone entry.

Fortunately, with the HF therapies available to us, progress is being made and although the improvement is incremental, remember, with every positive adjustment, someone’s life is enhanced.

References on request

cardiology

UPDATE

Taking the fight to heart failure A major meeting recently heard about advances in the treatment of heart failure and how clinical data is being translated to better patient care, Pat Kelly reports

T

his meeting, which was held in Dublin recently and was facilitated by Novartis, featured an innovative format that linked related meetings simultaneously in Limerick, Cork, Galway and Waterford. Each event heard from a number of healthcare professionals from a range of disciplines, from cardiology consultants, to SpRs, to clinical nurse specialists, each with a special interest in heart failure (HF) and improving outcomes for this vulnerable patient population.

The Dublin forum was chaired by Prof Vincent Maher, Consultant Cardiologist at Tallaght Hospital, Dublin. Prof Maher began by explaining that when he began his career, a diagnosis of HF was “akin to a death sentence”. However, radical improvements in the understanding of the pathophysiology of HF and new therapeutic interventions have led to a sea change in the expectations of both clinicians and patients with this condition. This includes recent trials that have highlighted “dual attacks” on the pathophysiological mechanism of HF. Prof Maher introduced Prof Jim O’Neill from Connolly and Mater Hospital, Dublin, who spoke on ‘The Role of Natriuretic Peptides (NP) in HF’. Prof O’Neill outlined the difficulties in making a diagnosis of HF and presented a case study to illustrate this point. He provided a brief overview of the evolution in the understanding of NP, stating: “We are all very comfortable nowadays with the idea that while noradrenaline and adrenaline in the short-term provide a good adaptive response to certain situations, in the long-run this response is not good and has severe detrimental effects on the myocardium and the vasculature,” he said.

“We thought that we had reached the ‘glass ceiling’ of neurohormonal blockade… not only are NP good, they are one of a whole range of biomarkers,” said Prof O’Neill, who cautioned that the measurement of any biomarker in isolation within a clinical context “will never be acceptable”.

He also outlined that there is often some confusion around differentiating BNP and NT-pro-BNP, but there is good guidance from the European Society of Cardiology on how to differentiate HF from other causes of breathlesness. Drawing an analogy between HF and diabetes, he told the meeting: “If you think about it, BNP is like the ‘insulin’ of HF — it exists in a ‘pre’ state, in much the same way as insulin does… if you think of pro-BNP as being a pro-hormone, it’s cleaved effectively to NT-pro-BNP, which you can measure, and to BNP, which you can also measure.”

He explained that it is important to not just block neprilysin in isolation because doing this can cause an increase in angiotensin II. “HF is more like an endocrine disorder than a quick stent,” Prof O’Neill told the meeting. “Immortalising BNP will cause an increase in BNP levels. There is a theory that if we treat the patient well, eventually BNP levels will drop,” he concluded.

New advances The meeting also heard from Prof Niall Mahon, Consultant Cardiologist at the Mater Hospital, Dublin, who spoke on the topic of ‘New Advances in the Management of HF with Reduced Ejection Fraction (HFrEF)’. Prof Mahon described HF as “the great remaining challenge” in cardiology, but added that this is an “exciting time” to be working in the field.

He focused on advances in three areas — pharmaceutical therapies, embracing the “information age”, and the future of robotics. “We should stand back and appreciate just how far we have come in terms of how pharmacotherapy has changed the landscape of congestive HF,” he told the attendees. “The key to this has been the recognition that HFrEF is really a disease of raging hormones and it is the activation of these maladaptive hormones that drives the progression of the disease.”

He presented an overview of a number of trials to illustrate this progression up to the present day. “We now have a compound that combines an angiotensin receptor blocker with a neprilysin inhibitor, thereby antagonising the maladaptive responses and enhancing the beneficial responses,” he said.

“Effectively, this is the first drug in a new class of agents known as angiotensin receptor neprilysin inhibitors, or ARNIs.” He also outlined data from the pivotal PARADIGMHF trial, which is unique in that it saw clinicians “replacing a good therapy with what is an even better therapy” for HF patients with reduced ejection fraction.

He described how the results from the trial were “very exciting” among the cardiology community. These results included a significant reduction in the primary end-point, which was a combination of cardiovascular death or HF hospitalisation, as well as a reduction in deaths from cardiovascular causes alone, HF hospitalisations alone, and all-cause mortality (a key secondary endpoint). (McMurray J et al, European Journal of Heart Failure, 2013, DOI: 10.1093/ eurjhf/hft052) “This is not something you see very often in HF trials,” observed Prof Mahon. “We now have an agent that seems to be an enhancement and improvement on an agent that has been the cornerstone for the management of HFrEF.” Prof Mahon explained that having experience with the novel agent, the HF team have found it to be “well-tolerated and anecdotally, these patients appear to have benefitted”, he explained, adding that this therapeutic option has been commercially-available via the HSE since 1 December 2017.

Hospitalisations Prof Mahon also provided an overview on the future of ‘big data’ in medicine and the need to effectively harness this information. “There has been some interest in the telemedi-

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cine concept in HF and the key goal is to see if it can reduce HF hospitalisations,” said Prof Mahon.

“There are around 6,000 HF hospitalisations in Ireland annually and the average length of stay is 10 days, so this is a significant health economic burden, as well as the problem of morbidity for the patient. Not only that, every time a patient is admitted with acute decompensated HF, they end up on a lower part of the HF trajectory than if they had not been admitted.”

He also outlined the CardioMEMS device, which can allow a patient to be monitored remotely and in studies has been shown to significantly reduce the rates of HF hospitalisations and has guided clinicians to make more interventions in patients at risk of HF exacerbations. He outlined a case study of a patient in his clinic who had the device implanted, resulting in more focused HF management and improved outcome.

Prof Mahon concluded by describing the evolution of the HeartMate device, stating that the HeartMate III trial showed that using the device resulted in a reduction in pump thrombosis but for the future, he expressed hope that the device could also reduce rates of stroke and infection in these patients.

“

If a patient has moderate or severe renal impairment or moderate hepatic impairment, or their blood pressure is between 100-110mmHg, we are a little more cautious with those patients

Patient outcomes Attendees then heard from Dr Daniel O’Hare, Cardiology SpR in St Vincent’s University Hospital, Dublin, and the Heart Failure Unit at St Michael’s Hospital in Dun Laoghaire, who reported audit data on HF patients commenced on sacubitril/valsartan. Dr O’Hare reported findings on demographics and outcomes from St Michael’s experience to date.

The average age of these HFrEF patients is 70.5 years and the male:female ratio is 3:1, he explained, while noting that the average NT-pro-BNP in these patients was 2,200, compared to approximately 1,600 in the PARADIGM-HF trial.

36

He told the meeting that there is a 36-hour minimum washout period when switching from an ACE inhibitor, after which patients are commenced on sacubitril/valsartan. If the patient is responding well after four weeks, the therapy is increased to the next-higher dose, said Dr O’Hare.

“If a patient has moderate or severe renal impairment or moderate hepatic impairment, or their blood pressure is between 100-110mmHg, we are a little more cautious with those patients, said Dr O’Hare. We start with the lowest dose [24/26mg BID] but all going well, we up-titrate them, so it is a very hands-on approach.” One early benefit is that nearly 30 per cent of patients have reduced their daily dose of diuretic, he added. “The results we are seeing are almost identical to the PARADIGM-HF study,” he said.

He concluded: “The overall reduction in NT-pro-BNP is very promising; we can think of this as a surrogate marker of disease activity. We are seeing ventricular stretch reduced in the older patient population, who were sicker commencing therapy. This is very promising and I have no doubt that as this audit goes on, we will see benefits in clinical outcomes.”

Further opinions, audits and case studies were heard from around Ireland, including from Dr Pat O’Callaghan, Consultant Cardiologist at Waterford University Hospital, who reported vast improvement in many patients’ NYHA class and post-titration echo results. Heart failure nurse specialists also reported positive outcomes on patients quality-of-life.

Mortality During the Q&A session, it was also observed that the reduction in HF mortality observed in the PARADIGM-HF trial was not due to improved therapeutic options alone, but also to improvements in implementing such therapies and this is one area where HF nurse specialists play a crucial role.

Prof Maher told the attendees: “During some of these discussions, and during Prof Mahon’s presentation, we have heard that when you look at three different systems — the sympathetic nervous system, the natriuretic peptide system and the RAS system — when all three were dealt with, as we introduce an agent that brings into play the last element, it is almost akin to having a three-legged stool rather than a two-legged stool and this seems to be balancing things out from a clinical perspective.”

Speaking to Update at the event, Prof Maher addressed the concept of potential inertia among some physicians and patients when it comes to switching therapies, particularly when a patient is considered ‘stable’ on current therapy.

“The data is very strong to show that these agents will eventually replace the ACEis and the ARBs and therefore one would think that a simple substitution would be the answer.

“As we can see, you have to up-titrate the doses. The experience is growing with time so in the hospital setting, we will get more and more experience of how to do this titration safely and ultimately move it into primary care. I believe that after the first dose, the subsequent titrations should be done in primary care,” he told Update.

“This [HF] is a disorder that primary care is ideally suited for and of course that will help to keep patients close to their homes.”

cardiology

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Irish Cardiac Society 2017 Annual Scientific Meeting and AGM 5-7 October, Derry, Northern Ireland All reports by Pat Kelly

The Irish-American connection in providing cardiac care to patients The President of the American College of Cardiology delivered a revealing address to the Irish Cardiac Society 2017 Annual Scientific Sessions, addressing pharmacotherapy, innovative devices and the lack of data on HFpEF patients.

The opening address at the Irish Cardiac Society (ICS) Scientific Sessions 2017, held in Derry from 5 to 7 October 2017, was delivered by renowned cardiologist Dr Mary Norine Walsh, President of the American College of Cardiology (ACC), who was introduced by consultant cardiologist and founder of The Heartbeat Trust Prof Ken McDonald.

Dr Walsh delivered a talk titled ‘Heart Failure: Current Therapies and New Horizons’ and addressed the latest trends in mechanical circulatory support in cardiac transplantation.

She pointed out that in Europe and North America, between 1-to-2 per cent of the population have heart failure. “However, it’s not always the same type of heart failure encountered by GPs and cardiologists,” she told the attendees. “It’s also important to remember that the prevalence of heart failure goes up with age primarily because of HFpEF [heart failure with preserved ejection fraction] and this affects more women than men in general.

“What drives the prevalence of heart failure worldwide, overall, are diabetes and hypertension and in the elderly, we are seeing a lot of patients with HFpEF rather than HFrEF [heart failure with reduced ejection fraction].”

She pointed out that approximately 50 per cent of heart failure patients have preserved ejection fraction and these patients account for more than half of all heart failure hospitalisations.

“But importantly, we really don’t have a lot of clinical trial data on this patient population,” Dr Walsh pointed out. “As helpful as our newer heart failure therapies are, half of our heart failure patients [with HFpEF] are really not as healthy as the HFrEF population.”

Newer therapies Dr Walsh went on to discuss the latest heart failure therapies and outlined the more recent ACC/American Heart Association guidelines: “These were just recently released and is a really straightforward way to look at our heart failure patients,”

she explained. “Step one is simply diagnosing the patient with heart failure; step two is considering the various therapies; step three is individualising those therapies; and importantly, thereafter, we reassess and perhaps re-image the patient and reassess their LV [left ventricular] function and then look at further therapies. I call this to your attention because I think this is the most important piece of our new guidelines.”

She also referenced the PARADIGM-HF trial, as well as the newest heart failure therapy and its influence on survival rates.

“This is the angiotensin receptor blocker valsartan and neprilysin inhibitor sacubitril… the PARADIGM trial brought this therapy to us an option for patients,” said Dr Walsh, who also outlined the study design and end-points. “When we compare this combination therapy to an angiotensin receptor blocker and ACE inhibitor, we get a 20 per cent additional reduction in mortality for our patients with heart failure, so this really is a blockbuster drug.”

Mechanical support Dr Walsh pointed out the growing use of mechanical circulatory support for the indication of both bridge-to-transplantation and destination therapy. “This is a device that you can take ‘off the shelf’ and patients don’t have to wait for a donor heart, for example,” she said. “In people listed for transplant, they fare best in the current generation of therapies and even the people who are not eligible for transplant have improved survival compared to the previous era… more people are doing well on these devices.”

She explained that the newer versions of these devices are smaller and are fully magnetically-levitated, which decreases the amount of exposure to a patient’s blood, thereby reducing the risk of thrombo-embolic complications.

Speaking to Update, Dr Walsh explained that despite its modest size relative to other organisations, the ICS is held in high esteem internationally.

“The ACC has had a very close working relationship with the ICS for years and has also partnered with it for various chapter activities around the world; the ICS has been a very active partner of ours.”

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Diaspora Dr Walsh, who is Irish-American, referred to the large Irish diaspora of physicians in the US. “Our ancestors left Ireland and came to the US, and now we have the US — not just cardiologists, but other doctors — coming back to the homeland to find our relatives, which is wonderful.”

In terms of modern advances in heart failure treatment, Dr Walsh highlighted a number of areas. “Pharmacotherapy has seen two or three new agents in recent times, but we also now have ventricular assist devices, not to mention the growing use of resynchronisation therapy,” she said.

“But one of the concerns about the healthcare system here in Northern Ireland is the average waiting time of six months for an echocardiogram,” she told Update. “In the US, a patient can get an echocardiogram sometimes in the same day, or certainly within the same week for a patient who needs a diagnosis. So time to diagnose is pretty long here and we don’t

see that so much in the US.” However, one thing cardiac physicians across the island of Ireland have in common with their US counterparts is the increased emphasis on prevention and increasing public awareness in this area. “In the US, for the primary risk factors for developing heart failure and cardiovascular disease, there is a big push to ‘know your numbers’,” she explained. “This means knowing your blood pressure, knowing your blood sugar levels and knowing your cholesterol levels. When we see treatment of hypertension improving in any community, we see a decline in the prevalence of heart failure so having either community screening or people knowing their numbers and going to see their GP are all issues that we really push hard.

“What I notice about Ireland is that, while people can’t smoke indoors, there are many, many more people smoking outside compared to the US; the smoking rate is still higher overall here.”

Rise in US heart transplants is due to ‘opioid epidemic’ The President of the American College of Cardiology Dr Mary Norine Walsh revealed data that shows a significant rise in the rates of cardiac transplantation in the US and Canada, and a significant factor in this is an epidemic of opioid use.

Dr Walsh was addressing the ICS Scientific Sessions 2017, which was held recently in Derry. “The number of patients waiting for transplant who have cardiomyopathy that is not ischaemic is growing,” said Dr Walsh. “Our therapies for ischaemic heart disease are very effective and fewer patients are being transplanted for that disease. Cardiomyopathy continues to be the driving diagnosis in adult cardiac patients per transplantation.”

However, she added: “The increase in cardiac transplantation over the past five years has been seen in men more than women… the reason that there are more donors is because of anoxia and this is directly related to the opioid epidemic in the US. “So the sad outcome of this opioid epidemic is that there are more solid-organ transplants being done.”

Dr Walsh added that a decrease in US donor rates due to head trauma is due to improved public safety measures, such as motorcycle helmet and seat-belt laws. “Head trauma is still the number-one reason [for donations] but that is on the down-swing, but on the up-swing is the number of patients with anoxia as a diagnosis.”

Another interesting statistic, said Dr Walsh, is the rise in the number of US patients over the age of 65 years who are being transplanted. “This is not simply because there are more patients aged over 65 with cardiomyopathy — although that is true — but we have become much more comfortable with transplantation over the years and are transplanting patients with older donor hearts,” she told the attendees.

“When I started in this field, we would have never accepted a donor heart over the age of even 40. Now, if a 50- or 52-year-old donor heart is available, with a normal coronary angiogram, we would consider that a suitable donor for someone over the age of 65. Many centres are now transplanting patients in the age group between 65 and even 70 or 72 years.”

Inappropriate drugs being used in longterm care heart failure population During the ICS Scientific Sessions 2017, held recently in Derry, delegates heard data from pharmacist Ms Margaret

38

Birmingham of Cork University Hospital (CUH) showing that many heart failure patients are having inappropriate

t® Ferinjec v. only i. is the in the d e m iron na 2016 1 E SC H F lines Guide

Their world

awaits Iron deficiency (ID) in chronic heart failure (CHF): affects up to 1 in 2 patients2 can have a significant impact on a patient’s world3-5

Ferinject®: is a uniquely engineered complex6 improves physical performance, symptoms and quality of life in patients with heart failure1 Ferinject® is Ireland and Europe’s market leading IV iron7,8

Ferinject® (ferric carboxymaltose) Prescribing Information - Ireland For full prescribing information refer to the Summary of Product Characteristics (SmPC) Active ingredient: Ferric carboxymaltose (50mg/mL) Presentation: Solution for injection/infusion. Available as a 2mL vial (as 100mg of iron), 10mL vial (as 500mg of iron) and 20mL vial (as 1000mg of iron). Indication: Treatment of iron deficiency when oral iron preparations are ineffective or cannot be used. The diagnosis must be based on laboratory tests. Dosage and Administration: The posology of Ferinject follows a stepwise approach: Step 1: Determination of the iron need; The individual iron need for repletion using Ferinject is determined based on the patient’s body weight and haemoglobin (Hb) level. The table in the SmPC should be used to determine the iron need. Step 2: Calculation and administration of the maximum individual iron dose(s); Based on the iron need determined, the appropriate dose(s) of Ferinject should be administered: A single Ferinject administration should not exceed: • 15 mg iron/kg body weight (for administration by intravenous injection) or 20 mg iron/kg body weight (for administration by intravenous infusion) The maximum recommended cumulative dose of Ferinject is 1,000 mg of iron (20 mL Ferinject) per week. Administration rates for intravenous injection: For iron doses of 100mg to 200mg, there is no prescribed administration time. For doses >200mg to 500mg, Ferinject should be administered at a rate of 100mg iron/min. For doses >500mg to 1,000mg, the minimum administration time is 15 min. Administration of intravenous drip infusion: For iron doses of 100mg to 200mg, there is no prescribed administration time. For doses >200mg to 500mg, Ferinject should be administered in a minimum of 6 mins. For doses >500mg to 1,000mg, the minimum administration time is 15 mins. Ferinject must be diluted in 0.9% m/V NaCl, but not diluted to concentrations

less than 2 mg iron/mL. Step 3: Post-iron repletion assessments Contraindications: Hypersensitivity to Ferinject or any of its excipients. Known serious hypersensitivity to other parenteral iron products. Anaemia not attributed to iron deficiency. Iron overload or disturbances in utilisation of iron. Special warnings and precautions: Parenterally administered iron preparations can cause potentially fatal anaphylactic/ anaphylactoid reactions. The risk is enhanced for patients with known allergies, a history of severe asthma, eczema or other atopic allergy, and in patients with immune or inflammatory conditions. Ferinject should only be administered in the presence of staff trained to manage anaphylactic reactions where full resuscitation facilities are available (including 1:1000 adrenaline solution). Each patient should be observed for 30 minutes following administration. If hypersensitivity reactions or signs of intolerance occur during administration, the treatment must be stopped immediately. In patients with liver dysfunction, parenteral iron should only be administered after careful risk/ benefit assessment. Careful monitoring of iron status is recommended to avoid iron overload. There is no safety data on the use of single doses of more than 200mg iron in haemodialysis-dependent chronic kidney disease patients. Parenteral iron must be used with caution in case of acute or chronic infection, asthma, eczema or atopic allergies. It is recommended that treatment with Ferinject is stopped in patients with ongoing bacteraemia. In patients with chronic infection a benefit/risk evaluation has to be performed. Caution should be exercised to avoid paravenous leakage when administering Ferinject. Special populations: The use of Ferinject has not been studied in children. A careful risk/benefit evaluation is required before use during pregnancy. Ferinject should not be used during pregnancy unless clearly necessary

and should be confined to the second and third trimester. Undesirable effects: Common (≥1/100 to <1/10): Hypophosphatemia, headache, dizziness, flushing, hypertension, nausea, injection/infusion site reactions. Please consult the SmPC in relation to other undesirable effects. Legal category: POM Price: pack of 5 x 2ml = €142.50; pack of 5 x 10ml = €712.50; pack of 1 x 20ml = €270.75 MA Number: PA0949/004/001 Date of Authorisation: 11.04.2008 MA Holder: Vifor France, 100101 Terrasse Boieldieu, Tour Franklin La Défense 8, 92042 Paris La Défense Cedex, France Further details available from: Vifor Pharma UK Limited, The Old Stables, Bagshot Park, Bagshot, Surrey GU19 5PJ T: +44 1276 853 600 F: +44 1276 452 341 medicalInfo_UK@viforpharma.com Ferinject® is a registered trademark. Date of revision: 04/17 UK/FER/16/0188a(2)

Adverse events should be reported.

Reporting forms and information can be found at http://www.hpra.ie/homepage/about-us/report-an-issue Adverse events should also be reported to Vifor Pharma UK Ltd. Tel: +44 1276 853633

References: 1. Ponikowski P, et al. Eur Heart J 2016;18(8):891-975 2. Klip IT, et al. Iron deficiency in chronic heart failure: an international pooled analysis. Am Heart J. 2013;165(4):575-582 3. Cohen-Solal A, et al. Iron deficiency: an emerging therapeutic target in heart failure. Heart. 2014;100(18):1414-20 4. Okonko DO, et al.

Disordered iron homeostasis in chronic heart failure: prevalence, predictors, and relation to anemia, exercise capacity, and survival. J Am Coll Cardiol. 2011;58:124151 5. Comin-Colet J, et al. Iron deficiency is a key determinant of health-related quality of life in patients with chronic heart failure regardless of anaemia status. Eur J Heart Fail. 2013;15(10):1164-72 6. Geisser P, Port J Nephrol Hypert 2009; 23(1):11-6 7. Vifor Pharma UK, Data on File 85. 8. Vifor Pharma UK, Data on File 89.

Vifor Pharma UK. The Old Stables, Bagshot Park, Bagshot, Surrey, GU19 5PJ, UK T: +44 1276 853600 F: +44 1276 452341 W: www.viforpharma.co.uk

www.ferinject.ie Date of preparation: March 2018 Code: UK/FER/18/0069

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medicines prescribed for their condition.

Ms Birmingham presented data on behalf of Mr Seif El Hadidi of the School of Pharmacy at CUH relating to the prescribing of potentially inappropriate medicines to patients residing in long-term care facilities in Ireland. While there is some disparity in the data available on patients with heart failure in such facilities, using data from the US and Northern Europe, Ms Birmingham estimated the prevalence to be approximately 33 per cent among such residents, although “this prevalence may be underestimated,” she pointed out.

“There are a couple of reasons for this,” she explained, “including the atypical presentation of heart failure in very elderly patients and the role of comorbidities — our longterm care population tends to be highly comorbid and this presents problems in terms of diagnosis.”

Ms Birmingham told the attendees that recent studies in Northern Europe used natriuretic peptide screening to identify heart failure patients in long-term care facilities and found that the proportion of this population with low levels and who receive a clinical diagnosis of heart failure is very low, compared to the population with highly-elevated natriuretic peptide levels.

Ms Birmingham explained that the research looked at studies on inappropriate prescribing in general in long-term care facilities, one of which (O’Sullivan, 2011) revealed that the ‘STOPP-START’ tool, an Irish-developed tool to identify inappropriate prescribing, showed that up to 71 per cent of residents in long-term care facilities were being prescribed at least one inappropriate medication.

“We sought to use a heart failure-specific tool to identify the patient factors associated with the prescribing of inappropriate medicines in this patient population,” Ms Birmingham told the attendees.

In the retrospective, observational study, patients in the Cork area were looked at, including their comorbidities, medications and long-term care records, with prescription of a loop diuretic used as a surrogate marker of heart failure. The team also utilised the ‘Potentially Inappropriate Medicines in Heart Failure’ (PIMHF) tool, first published in the European Journal of Heart Failure in 2014, specifically designed to identify medicines that can in fact cause more harm than good to heart failure patients.

“There were 732 patients in 14 long-term care facilities from whom the data was collected,” said Ms Birmingham.

“Ninety-nine of those patients — or 13.5 per cent — had

heart failure reported in their nursing home records. However, in total from that 732, 232 patients were prescribed a loop diuretic, so that’s over 30 per cent.

“For the purposes of the study, we compared the heart failure patients and the loop diuretic patients and we found that there were no significant differences between the two groups in the long-term care facilities… comparing that 265 patients to the non-heart failure population, we see that they are older, have a greater number of medicines prescribed and have more cardiovascular comorbidities. Interestingly, they had a lower rate of dementia than other patients,” said Ms Birmingham.

She continued: “In terms of heart failure medicines prescribed, about 87 per cent of the population were prescribed a loop diuretic and over 50 per cent were prescribed a loop diuretic alone — they were not prescribed a typical, diseasemodifying heart failure therapy. Just 24 per cent were prescribed an ACE [inhibitor] and just 22 per cent were prescribed a beta-blocker.”

Ms Birmingham explained that six of the 11 items on the assessment tool were identified, meaning that 25 per cent of the patient population had at least one potentially inappropriate medicine prescribed to them, primarily NSAIDs. “Looking at the difference between those who were prescribed an inappropriate medicine and those who were not, key differences were that those prescribed an inappropriate medicine were more likely to be taking a greater number of medicines, were more likely to have diabetes and were less likely to be prescribed a loop diuretic,” she told the conference. “In terms of diabetes, this reflects the type of medicines that are listed on the PIMHF tool.”

Ms Birmingham concluded: “Heart failure patients in long-term care are at risk of being prescribed inappropriate medicines, in particular agents that may worsen heart failure symptoms. Pharmacists have a key role in providing medicines optimisation for long-term care patients, however, medicines optimisation is hampered by the fact that there are difficulties in confirming heart failure diagnosis in this patient population, as we see from the disparity in prescribing, in particular of loop diuretics.

“Quite interestingly, it seems that in those who are looking at medicines in this population, the loop diuretic is leading their decisions in the prescribing of medicines, rather than the diagnosis of heart failure, and which seems to be a marker of heart failure in this patient population.”

Virtual consultations on heart failure represent ‘a viable model’ of care for both GPs and patients Attendees at the recent ICS Scientific Sessions 2017 in Derry heard a report on the use of ‘virtual consultations’ between GPs and specialist cardiac physicians, and were told

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that this represents a viable model of care that could save travel and time for a vulnerable and potentially frail patient population.

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Dr Stephanie James informed the meeting about a new platform to help deal with heart failure in the community via ‘virtual consultations’, which was conducted from the Heart Failure Unit in St Vincent’s University Hospital, Dublin, and has been running since May 2014.

“As we know, the traditional referral pathway for any chronic disease can take six-to-nine months. These can often be vulnerable, elderly patients who will typically present to the GP in the meantime,” said Dr James. “This project involved using teleconferencing to mentor and educate primary care physicians in the community in the management of heart failure.”

Between May 2014 and November 2016, there were 152 consultations in total, she explained, divided into three types: New diagnostic cases; patients with known heart failure who are at risk of decompensating in the community; and therapeutic management queries. The main, typical comorbidities among these patients included heart disease, chronic kidney disease, diabetes, anaemia and COPD. Around 40 per cent of these cases required a follow-up review via virtual consultation.

“The challenges from our point of view were data protec-

UPDATE

tion and patient confidentiality, Internet connectivity and coverage and ease-of-use for the GP,” said Dr James. “We awarded CME points for the GPs who do these virtual consultations, as it involves 10 or 15 minutes of education update and knowledge exchange for the GP… our survey with primary care physicians indicates that they see the service as excellent and easy to use and patients are happy too because their cases are discussed with a specialist — almost all GPs said they would recommend the platform to their colleagues.”

GPs also said they felt the system took some pressure off them and helped them to feel more confident in dealing with heart failure patients, she said. The system began as one session per week and has now increased in frequency to two sessions each week.

“The heart failure virtual consult is a feasible model and is helpful to patients who may find it difficult to travel because of their age or comorbidities and they might sometimes be in long-term care,” concluded Dr James. “We also found that these consultations can lead to early diagnosis and also help GPs to initiate guideline-based therapy for patients.”

‘Common sense will prevail’ on crossborder care following Brexit Dr James Crowley, a consultant cardiologist based in Galway, has said that despite widespread anxiety over the future of cross-border care following Brexit, there will be little or no disruption to care pathways.

Speaking to Update at the ICS Scientific Sessions 2017 in Derry, Dr Crowley said: “For example, with regard to the Primary PCI [percutaneous coronary intervention] Programme — where angioplasty is performed for patients with acute ST elevation — the Donegal patient population are receiving their primary PCI in Altnagelvin.

“Doctors on both sides of the border are very keen to maintain that programme — in the interests of patient care, it’s the best thing to do. Derry is the nearest primary PCI hospital for people in Donegal, and people in Donegal are too far away from Galway to get their primary PCI there.”

In practical terms, this would present serious complications for a significant number of patients, said Dr Crowley.

“That [transporting patients to Galway] would be out of the time-frame, whatever way we would try to plan it; even with the use of helicopters, and so on, we would only get a very small number of the patients in Donegal who present with a STEMI to Galway on time,” he told Update.

“The way we work now is the solution to that. The Saolta Group wants us to continue this way. Also, the patients and cardiologists in the hospital in Altnagelvin are very happy with it and are very keen to continue the programme, so the only issue will be with regard to the border and how that will be managed, so we would hope that people will reach a

solution to this.

“There is no problem at the moment, but we would hope that if a problem did arise, we could resolve it and allow these services to be maintained… common sense will prevail, I believe. Everybody wants that, and I can’t see legal issues getting in the way.”

On a separate issue, Update asked Dr Crowley if, in terms of research, there is a dearth of knowledge on heart failure with preserved ejection fraction (HFpEF) patients, in comparison to those with reduced ejection fraction (HFrEF), and whether this patient population is in some way being left behind in terms of evidence-based research.

“I think there is a lot of research now going on into the HFpEF population — what we do know now is that a lot of the traditional strategies that have been developed for patients with HFrEF are probably not as effective in patients with HFpEF, so we still need a lot more information on that,” he said.

“It’s really only a few years ago that we began to recognise that there is a substantial proportion of patients with HFpEF and their mortality is actually as high as those with HFrEF,” he said. “People are focusing more now on HFpEF and recognising that this population may require different strategies and therapies. There is a lot going on in this area, it’s just that treatments have not yet been established. We have established therapies for HFrEF, but it seems that some of those are not as effective in HFpEF. “But it is good that there is a lot more recognition of the

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problem now and a lot more drug therapies that we are trying to use to treat the problem. We are definitely catching up.”

In terms of higher specialist training, in which Dr Crowley is National Specialty Director, as is Prof Brendan McAdam, he noted: “It’s always great to see the SpRs who are training abroad come back to Ireland to present at these meetings.

We are glad to say that virtually all of the SpRs in training here go abroad.

“I think it’s a sign of the quality of the programme and the quality of the trainees that virtually all of them become established in world-class centres across the globe. These people are working in the best centres in the world, but are still interested in coming back here to work.”

On the matter of continuing doctor emigration and its effects, Dr Crowley said: “In terms of delivering cardiology consultants to the population of Ireland, at least the trainees who decide to return home are exceptionally well-

trained, to the highest calibre worldwide. With regards to the HSE getting the highest-quality people returning, and in the private sector, they are trained to the highest standards worldwide, and that’s a credit to the HSE and the Government for allowing these programmes to be developed.

“If you look at the trainees and where they are training, you will see they are in the top-10 institutions in the world and they will be delivering the highest-quality care to the people of Ireland in the years to come.”

Dr Crowley will take up office as the ICS President at next year’s Scientific Sessions in Galway and he paid tribute to current President, Dr Albert McNeill. “This year has been a very successful meeting,” he told Update. “Attendances have been up and the number of submissions for presentation has also increased. The venue [the Millennium Forum] has been brilliant and we’ve had a great experience here in Derry, including the President’s dinner in the historic Guildhall, which was also a fantastic occasion.”

‘Male dominance’ in Irish cardiology Dr Noel Fitzpatrick delivered a presentation titled ‘The Who, Where and What of Irish Cardiology Higher Specialist Training Scheme: 1998-2017’ to the ICS Scientific Sessions 2017, held recently in Derry, and presented a real-world picture of where cardiology SpRs go following their training programme.

Among the aspects of Dr Fitzpatrick’s retrospective review, he and his co-authors looked at gender balance in Irish cardiology, “or perhaps that could be better described as ‘gender imbalance’,” Dr Fitzpatrick told the conference.

He delivered his presentation on behalf of his co-authors, who included ICS Executive Administrator, Ms Barbra Dalton, whom Dr Fitzpatrick described as “one of the hardestworking people in Irish cardiology”.

Analysing the number of cardiology trainees since 1998, Dr Fitzpatrick noted a “male dominance” in the field.

“Looking at those who have qualified, 72 per cent are male; however, we are swinging-back somewhat in terms of equality if you look at the people currently in training, with 57 per cent male and 43 per cent female. This is in remarkable contrast to HSE schemes across Ireland in general, where you have a 55 per cent female dominance and notably different to the trend across European Society of Cardiology (ESC) training, where at the moment 70 per cent of trainees

are female.”

Dr Fitzpatrick and his colleagues also looked at subspecialty training and locations and found that in previous years, there was a prominent preference among trainees to travel to North America, but recent years have seen parity with Europe as a preferred destination.

“Overall, some 53 per cent of trainees who qualified ended up with a post in Ireland,” said Dr Fitzpatrick. “Notably, there is a trend towards less appointments in Ireland over the past five years or so.”

With regards to private versus public appointments in Ireland, Dr Fitzpatrick said: “Most noticeably, in the past five years there has been a huge increase in private-only posts coming online in Ireland.

“My main conclusions from this is that there is huge disparity in the gender balance in Ireland in cardiology trainees and those who qualified versus other medical specialties throughout Ireland and Europe in general. There has also been a shift in the trend from doing subspecialty training exclusively in North America and in the rise in private-only posts,” he concluded.

“It would be good to include Northern Ireland trainees in this data and a comparison with the UK, so this is something we might update in the future.”

Lowering the bar on cholesterol levels The recent ICS Scientific Sessions 2017, held in Derry, heard a presentation from Prof Francois Mach, Head of Cardiology at University Hospital Geneva, Switzerland, on the topic ‘LDL-C in High-Risk Patients: From ‘High is Bad’

42

to ‘Lowest is Best’’.

Prof Mach told the conference: “We used to say ‘high is bad’, but I hope to convince you that the ‘lowest is the best’… there are some unmet needs in the cardiovascular

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cardiology

field — roughly 50,000 deaths per day mainly due to cardiovascular disease. This is a far higher death toll than from cancer or AIDS.” Most of the risk factors for cardiovascular disease are modifiable, Prof Mach pointed out, with the exceptions of age and genetics, but certainly diabetes, overweight and obesity and smoking, which he described as “a disaster”.

“When we talk about lipids, the fact is that it is almost impossible to develop atherothrombosis or atherosclerosis without cholesterol,” said Prof Mach. “There is always a correlation — the higher the cholesterol, the greater the risk of heart attack, stroke, or other atherothrombotic disease.”

In the past five or 10 years, trials with statins show that the lower the cholesterol level achieved, the lower the risk in patients, he said. He also raised the possibility of reducing or repairing genetic mutations that might contribute to risk in the years ahead.

“For very high-risk patients, the target value is 1.8mmol per litre, according to the guidelines. We should try to achieve this with statins…” he said, referencing clinical trials involving evolocumab, ezetimibe, atorvastatin and simvastatin. “Whatever time you start the statin after an acute myocardial infarction, the better the prospects for survival.

“If you lower LDL with a statin by 1mmol, you reduce the relative risk to 20-to-25 per cent,” he said. “Still, after 25 years, we do not know the answer to the question: ‘What is a normal LDL cholesterol level?’ We were all born with a cholesterol level of about 1.2mmol. Does this mean that this is the level we need to achieve throughout life? Probably not. But, for example, I am 56 years old — but we still can’t

exactly identify the target value for a ‘normal’ individual.

“But we do know that if everybody in this room takes a statin and measures LDL 24 hours afterwards, there is a broad response… and of course, we all absorb cholesterol differently.”

Presenting more data, Prof Mach explained that less-thanoptimal results achieved in lowering LDL levels among hospital patients is often linked to poor patient compliance and approximately 10 per cent of cardiovascular events in Europe could be associated with poor patient compliance with statins.

This could be improved with patient awareness, he added, pointing out that if statin therapy is not sufficient, guidelines suggest that physicians can consider the addition of a PCSK9 inhibitor, possibly in combination with monoclonal antibodies, which data show lowers the risk of future cardiovascular events.

“The future may lie in silencing the RNA,” Prof Mach concluded. “If you silence the RNA in the cell, you block the full production of the machinery needed to get PCSK9,” he said.

“The beauty here is that it could be injected only two or three times per year and will cost almost nothing, compared to a PCSK9 antibody.

“Phase 1 and 2 trials show that patients respond nicely and phase 3 is being launched now.

“In the early 1990s, high cholesterol was ‘bad’; then we had all the trials since then to show that ‘average is not good’; then ‘lower is better’; and now clearly, if this very low level in patients is confirmed, this will help us to change the guidelines and the target for very high-risk patients.”

‘No strategic plan’ in place for Irish cardiology appointments Dr James Crowley, Clinical Lead for Saolta University Health Care Group, told attendees at the recent ICS Scientific Sessions 2017 in Derry that the current system of cardiology appointments is far from ideal and is subject to an “amorphous” process.

Dr Crowley made his comments as he chaired a session at the conference on cardiology education and training.

Answering a question from the floor on the ease of access to information, or otherwise, for doctors practising abroad who may want to return to Ireland, Dr Crowley described the current system as “ad-hoc”.

Answering the point that there is “no easy way of making contact” for these doctors, Dr Crowley responded: “To my knowledge, there is no register at all of jobs that may be coming up. It seems to be very ad-hoc in the public and private sectors. Certainly, from my experience working in the Saolta Group, the way we arrive at the need for an appointment is… we tend to press management and have to demonstrate the need for an appointment and present a business case and eventually, through some amorphous, magical ap-

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proach, the post becomes approved and advertised. That’s how it seems to happen all the time.”

He continued: “There does not seem to be a strategic plan for the appointment of cardiologists, or [general] physicians for that matter, across the country; that’s my understanding of it. That’s why it’s impossible to match-up trainee-toneeds, and so on, across the country.”

He pointed out the number of cardiologists per head in Ireland falls far short of the European average and is a lower ratio than almost every other country in the EU. “Despite the fact that there have been a number of appointments over the past 10 years, there is still a significant need for an increase in the number of cardiologists in Ireland. It would be great if we had a strategic plan of the where, when and what type of cardiologists we are going to need over the next five or 10 years.”

He also drew attention to an impending need for dualaccredited cardiologists in the coming years outside tertiary referral hospitals. “This does highlight a problem that’s going to hit Ireland in the next few years,” said Dr Crowley.

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“How do you deliver cardiology services to, say, medical assessment units or hospitals other than tertiary referral hospitals — who will take care of these cardiology patients if they require dual-accredited physicians? Do we need to restructure these types of jobs?”

He added that the HSE needs guidance from the ICS in terms of the direction cardiology care should take in the years ahead. “We can’t lay the blame with Government all

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the time,” he said. “If we are not saying what we think needs to be done, it’s very hard for Government to come back and tell us what they are going to deliver on. This is probably something that we need to look at over the next couple of years, in terms of trying to define what is needed for the population of Ireland, particularly with the generalists and the subspecialties.”

ICS building ‘year-on-year’ ICS President Dr Albert McNeill described the continued growth in quality and attendance at each year’s conference as “remarkable”. Delivering his closing address at the ICS Scientific Sessions 2017 in Derry recently, Dr McNeill told attendees: “In terms of infrastructure and the type of infrastructure we have, year-on-year this Society builds; it builds in technology, it builds in scientific merit and it builds in the quality of speakers we have.

“I was really quite blown away — there must be few societies in the world that can attract this calibre of speakers.

Things will be different in Galway [at this year’s Sessions] and we have a 70th anniversary coming up in two years, when Dr [James] Crowley will be President, but year-onyear, things change and improve because of the work people have put in at all levels.”

Brian Maurer Young Investigator Award: Finalists and winner Finalist – Dr Matthew Barrett, Cardiology SpR, currently completing fellowship training in Chicago, US. ‘The Inferior Vena Cava — A Reproducible and Clinically-Useful Tool in the Monitoring and Treatment of Heart Failure Which Deserves Greater Clinical Prominence’ 1M Barrett, 2M Iacoviello, 2F Monitillo, 2D Grande, 2C Rizzo, 3A Patle, 3R Fox, 1Patricia Campbell, 3Rory O’Hanlon, 1Kenneth McDonald.

1. St Vincent’s University Hospital, Dublin.

2. Polyclinic Hospital of Bari, Italy.

3. St Michael’s Hospital, Dublin.

Finalist – Dr Ashraf Hamarneh, Cardiology Trainee from Northern Ireland.

‘The Effect of Remote Ischaemic Conditioning and Glyceryl Trinitrate on Perioperative Myocardial Injury in Cardiac Bypass Surgery Patients: The ERIC-GTN Study’ 1A Hamarneh, 2E Hardman, 2P Wicks, 2H Shanahan, 1H Bulluck, 1M Ramlall, 1R Chung, 1R Bell, 2R Cordery, 1D Yellon, 1,2,3,4D Hausenloy.

1. Hatter Cardiovascular Institute, University College London, UK. 2. Bart’s Heart Centre. Health NHS Trust, UK. 3. National Heart Research Institute, Singapore, National Heart Centre, Singapore.

4. Cardiovascular and Metabolic Disorders Programme, Duke-National University of Singapore, Singapore.

Finalist – Dr Barry Hennigan, Consultant Cardiologist based in Cork.

‘A Randomised, Controlled Trial in Stable Intermediate Coronary Lesions and Grey-Zone FFR Values with Evaluation of the Diagnostic Utility of Invasive Coronary Physiological Indices with Perfusion MRI: The GZFFR Study’ 1,3B Hennigan, 2,3C Berry, 2,3D Collison, 2,3D Corcoran, 3J McClure, 2H Eteiba, 3K Mangion, 2R Good, 2M McEntegart, 2KG Oldroyd.

1. The Mater Private Cork, Cork.

2. Golden Jubilee National Hospital, West of Scotland Heart and Lung Centre, Glasgow, UK. 3. University of Glasgow, UK. Finalist and Winner – Dr Grace O’Carroll, Cardiology SpR currently based in Wexford.

‘Subclinical Diastolic Dysfunction is Prevalent in Diabetes, Progresses Over Time and May Reflect a Handicap in Natriuretic Peptide Function.’

G O’Carroll, S Zhou, L McDonald, P Barrett, C Watson, M Ledwidge, V Harkins, J Gallagher, C Keane, K McDonald.

St Vincent’s University Hospital, Dublin.

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PFO closure for cryptogenic stroke: Selecting the right patient for closure Dr JJ Coughlan, Specialist Registrar, Cardiology; Dr Aidan Daly, SHO Cardiology; Dr Samer Arnous, Consultant Interventional Cardiologist; and Prof Thomas Kiernan, Consultant Interventional Cardiologist, Associate Professor of Medicine, University Hospital Limerick

Introduction A patent foramen ovale (PFO) is a channel allowing communication between the right and left atria in the heart. It is a remnant of the embryological changes that occur during the transition from foetal to adult circulation. Whilst often described as an anatomical anomaly, it is relatively common in the general population, with a prevalence of approximately 25 per cent in autopsy studies. Up to 40 per cent of strokes are defined as cryptogenic, meaning that no cause is identified despite investigation. The prevalence of PFO in patients with cryptogenic stroke (CS) has been found in some studies to be higher than that in the general population.This association has led to PFO being proposed as a potential pathophysiological mechanism for CS. Multiple pathophysiological mechanisms have been proposed to explain the apparent association between PFO and CS. The pre-eminent theory is that of paradoxical embolism, whereby a thrombus from the venous circulation travels from the venous system to the right atrium. The thrombus can then bypass the pulmonary circulation through the PFO, enter the left atrium and thus the systemic circulation, potentially resulting in an ischemic stroke.

Until recently, once a PFO was identified in a patient with cryptogenic stroke, it was not clear how to best manage this individual patient in order to further reduce their recurrent stroke risk.

Therapeutic options studied included antiplatelet therapy, anticoagulation, surgical closure and trans-catheter closure. While it had long been hypothesised that PFO closure might reduce the risk of recurrent ischemic neurological events, several trials had previously failed to demonstrate superiority of PFO closure over medical therapy.

In 2017, three randomised control trials (RESPECT6, CLOSE7 and GORE REDUCE8) demonstrated a superiority of device closure over medical therapy for prevention of future ischemic events in carefully selected patients with cryptogenic stroke. As such, percutaneous closure of PFOs now represents an evidence-based treatment modality for the management of cryptogenic stroke in these carefully selected patients.

It is inevitable that with the results of these recent trials and the associated increase in awareness, the number of patients referred for PFO closure will increase. However, physicians must try to ensure that the patients they consider for this procedure are appropriate and representative of the patients enrolled in the trials.

We have discussed the contemporary evidence base for PFO closure previously. In this article, we will focus on patient selection for PFO closure. To help identify patients who would benefit, we will attempt to answer three key questions a physician should consider when deciding whether or not to refer a patient with CS for PFO closure. These are:

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1. Is this a cryptogenic stroke?

2. Is this PFO pathogenic?

3. Should this PFO be closed?

1. Is this a cryptogenic stroke?

Cryptogenic stroke is defined by the TOAST criteria as a brain infarction that is not attributable to a source of definite cardio-embolism, large artery atherosclerosis, or small artery disease despite a standard vascular, cardiac and serologic evaluation. In practical terms, the ‘cryptogenic stroke’ we encounter in our clinical practice can be divided into three categories.

1. Stroke that is not fully investigated.

2. Stroke with multiple potential aetiologies.

3. Truly cryptogenic stroke.

Experts have sought to re-define true cryptogenic stroke as an ‘embolic stroke of undetermined source’ (ESUS). ESUS is defined as a radiologically confirmed non-lacunar brain infarct without: • Extra-cranial or intracranial atherosclerosis causing >50% luminal stenosis in arteries supplying the ischemic area.

• Major risk cardio-embolic source.

• Any other specific cause of stroke.

Before being classed as a CS, patients should have a thorough diagnostic workup, including: Brain imaging (CT and MRI), imaging of the intra- and extra-cranial arteries, electrocardiogram, echocardiogram and prolonged cardiac monitoring. Studies have shown that after this full workup, only ~10% of strokes are classified as ESUS. Therefore we consider it essential to complete a full diagnostic workup prior to referral for PFO closure.

2. Is this PFO pathogenic?

Given PFO is present in ~25 per cent of the population and ~40 per cent of those with cryptogenic stroke, it is important to remember that it may simply be an incidental finding. If a patient with cryptogenic stroke undergoes screening for PFO, there are three possibilities: 1.No PFO is identified. (~60%).

2. A PFO may be present and incidental (~20%).

3. A PFO may be present and pathogenic (~20%).

The Risk of Paradoxical Embolism (RoPE) score is an index created specifically to attempt to stratify CS patients with PFO by the likelihood that their stroke was related to their PFO. The RoPE study proposed a scoring system to determine which patients may benefit from higher-level intervention (PFO Closure) as a consequence of being higher risk for PFO-attributable cryptogenic stroke.

Using this score the PFO-attributable fraction of cryptogenic stroke

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varied from zer0 per cent (using 95% CI range 0-4%) with RoPE score zero to three to 88 per cent (at 95% CI range 83-91%) with RoPE score nine to 10. See Tables 1 and 2 for information on how to calculate a RoPE score and estimate PFO-attributable stroke fraction and two-year stroke/TIA recurrence.

While further study is needed to prospectively validate these scoring systems, the authors find them useful in daily practice as they encourage the treating physician to consider the patients cardiovascular risk profile. In addition, they serve as a reminder that not all PFOs identified in ‘cryptogenic stroke’ are pathogenic.

It should also be noted that those patients with the highest risk for PFO-attributable CS also have the lowest stroke recurrence rate.

Should this PFO be closed?

Once a patient has been identified as having a CS and a PFO, the question remains as to how they should be managed. Physicians must bear in mind that the patients enrolled in the PFO closure trials were highly selected. Previous trials with less stringent inclusion criteria failed to show a statistically significant benefit for PFO closure. As such, in order to ensure benefit from PFO closure, it is crucial that the patients put forward for consideration are representative of the patient populations studied.

For example, the age range in the three positive trials was 1860 years, 16-60 years and 18-59 years for RESPECT, CLOSE and GORE REDUCE respectively. As such, the authors would not recommend screening for patients with CS outside this age range at present. Similarly, patients with lacunar stroke were not included in the positive PFO closure trials (they were in some of the negative trials) and these patients should similarly not be considered for PFO closure. Conversely, some anatomical characteristics of PFOs, including associated atrial-septal aneurysm (ASA) and larger intra-atrial shunt have been associated with higher stroke risk.

Patients with these anatomical characteristics may derive greater benefit from PFO closure. The DEFENSE PFO trial randomised 120 patients with these high-risk features (PFO with atrial septal aneurysm, hyper-mobility or PFO size ≥2mm) to PFO closure and medical therapy versus medical therapy alone. They observed no primary endpoints in the closure group and six events in the medical therapy group (0% vs 13%, p=0.013). Enrolment in the trial was stopped early due to evidence from recent trials of the benefits of PFO closure.

RoPE Score PFO-attributable

Stroke fraction

0-3 0% 4 38% 5 34% 6 62% 7 72% 8 84% 9-10

88%

Estimated 2-year Stroke/TIA recurrence 20% 12% 7% 8% 6% 6% 2%

Table 2. This table shows likelihood that a CS is related to the PFO and the estimated 2-year Stroke/TIA recurrence based on a patients’ RoPE score

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RoPE Score Characteristic No history of hypertension No history of diabetes No history of stroke/TIA Non-smoker Cortical Infarct on Imaging

Age in Years 18-29 30-39 40-49 50-59 60-69 >70

Total

Points +1 +1 +1 +1 +1 +5 +4 +3 +2 +1 0

Table 1. RoPE Score Calculator

It is also important for physicians to remember that while a statistically-significant benefit was demonstrated from PFO closure in selected patients and the relative risk reduction appeared to be large, the absolute risk reduction was small and the stroke recurrence rate in both groups was low. The number needed to treat (NNT) for the RESPECT trial was 42 closures to prevent one stroke over five years. The CLOSE trial, which required patients to have an associated ASA/ large intra-atrial shunt had a NNT of 20 closures performed to prevent one stroke over five years. Overall, meta-analysis of the five major trials performed showed that PFO closure reduced recurrent stroke [OR 0.41, 95% CI 0.19-0.90; p = 0.03] and the combination of recurrent stroke + TIA (OR 0.53, CI 0.36-0.80; p = 0.002) compared to medical therapy. It is also important to remember that the procedure carries the risk of rare, but potentially serious complications, including an increased rate of new onset atrial fibrillation (OR 5.75, CI 3.09-10.70; p < 0.00001).

It is our duty as physicians to try to explain this complex riskbenefit ratio to patients so that they can make an informed decision together with regard to their treatment options. With all the relevant information to hand, some patients will opt to undergo PFO closure in order to further reduce their stroke risk. Others, reassured by their overall low recurrence rate will opt to continue with medical therapy. Fortunately, it appears that their recurrence rate is low with both treatment modalities.

Conclusion Based on the results of these three RCTs (RESPECT, CLOSE & GORE-REDUCE), in carefully selected patients, percutaneous closure of PFOs now represents an evidence-based treatment modality for reduction of stroke recurrence post-cryptogenic stroke Physicians should ensure that the patients they consider for PFO closure are representative of the patients enrolled in these trials.

Multidisciplinary discussion should be encouraged in order to ensure appropriate patient selection.

Patients should also be included in the decision-making process after being counseled with regard to the risk-benefit ratio of PFO closure versus medical therapy.

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ICDs: The difficulty with guidelines.

Dr Conor McCann, Consultant Cardiologist, Belfast Health and Social Care Trust, Belfast Implantable cardioverter defibrillators (ICDs) have been available for almost 40 years, during which time the technology has advanced considerably. The guidelines have also evolved, over the period, with widening criteria as the evidence base has grown. Initial devices were so large that only secondary prevention indications were considered appropriate. Now the majority of ICD implants are for primary prevention indications meaning that they are implanted prophylactically in individuals who have never suffered from a significant ventricular arrhythmia. Such individuals are considered to be at sufficient risk of a life-threatening arrhythmia that the risks associated with device implantation are acceptable. These risks are, however, not limited to the implant procedure itself but have the potential to adversely affect the lives of ICD recipients long-term. They include inappropriate shocks, psychological harm, device

â&#x20AC;&#x153;

The assumption is often made that countries or regions implanting higher numbers are going outside the guidelines, undertaking implantation where there is insufficient evidence of benefit. Audit has been viewed as a useful means to compare centres in the UK and a marker of a high quality service is strict adherence to NICE guidance

infection, and lead failure requiring extraction. It can be challenging to try and weigh up the risks and benefits for individual patients.

Guidelines have been developed to assist doctors facing these decisions, or rather to help patients take an informed decision themselves. Until recently the European Society of Cardiology guidelines were the most contemporaneous, but the American College of Cardiology/American Heart

48

Association/Heart Rhythm Society have recently released their updated document, available online ahead of publication. This document is extensive and detailed, incorporating important new evidence to help all of us deliver care to a high standard.

Variation Guidelines should standardise practice and reduce variation between physicians. However, comparison of implant practice demonstrates dramatic variation suggesting significant real-world barriers to implementation. Figure 1 shows the wide variation in new ICD implant rates across Europe.

ICDs are expensive devices and economic factors are likely to play an important role if different countries are compared.

However, the difference is still marked when only Western European countries of similar economic stature are compared. The UK attempts to factor cost-effectiveness into its own national guidance, published by the National Institute for Health and Care Excellence (NICE), and this may in part explain the relatively low implant rate for the UK when compared to the average for Western Europe (Figure 1). Yet implant rates vary significantly throughout the UK itself, with the ICD implant rate for Northern Ireland and England almost twice that of Scotland, based on the National Audit data for 2015. This suggests that the explanation for variation is not limited to economic factors.

The assumption is often made that countries or regions implanting higher numbers are going outside the guidelines, undertaking implantation where there is insufficient evidence of benefit. Audit has been viewed as a useful means to compare centres in the UK and a marker of a high-quality service is strict adherence to NICE guidance. Most insurance companies have introduced â&#x20AC;&#x153;payment rulesâ&#x20AC;? often with the requirement to obtain pre-authorisation in order to ensure compliance with guidelines, or at least their version of the guidelines.

The reality is more likely to be that countries or regions with low volumes are struggling to deliver what the guidelines lay out as good practice. For poorer countries it may simply be that ICDs are not seen as a high priority for healthcare spend. It may be difficult to justify their expense, particularly for primary prevention indications. Other barriers could be the availability of cath lab time for implantation, or of trained implanters, or even of diagnostic services to pickup heart failure patients who may benefit following the usual period of medical optimisation. In addition, there are often differences of opinion as to age-appropriateness, particularly for primary prevention indications. All these complex factors have reduced the ability of guidelines to standardise practice.

Primary and secondary prevention Recommending a secondary prevention ICD is gener-

cardiology

UPDATE

ous statement that a patient has no chance of benefiting from an ICD if they are never referred for consideration. Delivering education and regular updates to referring hospitals is extremely important to ensure appropriate referral.

Models to improve this type of variation have included appointment of implanting Cardiologists to District General Hospitals (DGH) with sessions at regional centres to attend MDT and perform device implantations.

Another approach has been to invite wide participation in the MDT meetings, often facilitated by teleconference link to include DGH cardiologists.

Guidelines not only address the issue of who should receive an ICD, they can also define minimum standards to improve the quality of ICD implantation and follow-up.

The British Heart Rhythm Society produce and regularly update a set of standards that they feel facilitate the safe delivery of high-quality, evidence-based, cardiac device therapy to all patients who may benefit. This includes identification of patients with device indications, implantation of the appropriate deFigure 1: Variation in new ICD implant rates throughout Europe in 2015 vice, patient and device follow-up, data collection, storage and subally straightforward, patients have already survived a mission for audit purposes. This life-threatening arrhythmia and have no reversible cause. document states that there should be a minimum of two Primary prevention devices on the other hand will divide active complex device implanting consultant cardiologists opinion to a greater degree. As mentioned above, there will per centre. often be a difference of opinion about appropriateness in A complex device is either an ICD or cardiac resynchroelderly patients. There is no age cut-off in the guidelines, nisation therapy (CRT) device. A complex device implanter which have generally adopted a prerequisite life expectancy should implant a minimum of 60 devices per year, of which of over one year before being eligible for ICD. It is difficult 30 must be complex. If the cardiologist implants CRT deto accurately predict life expectancy in a multi-morbid elvices at least 20 should be CRT implants. The document is derly patient, but it would be unusual to be able to categorispecific about what qualifies as an implant. cally state that someoneâ&#x20AC;&#x2122;s life expectancy is under one year.

The purpose of these standards is to encourage high volMulti-disciplinary team (MDT) meetings are now commonume centres of excellence, or rather to discourage small place within cardiology and help decision-making. A usevolume, occasional practice. ful meeting will include implanting doctors, heart failure To conclude, guidelines are extremely useful documents specialists, inherited heart disease specialists, and imaging laying out instruction on how to deliver high-quality, evspecialists. Recognising the additional decision-making idence-based, clinically effective, healthcare. However, in challenges in elderly patients some centres in the UK have the real world there are many barriers to implementation started inviting care of the elderly physicians to participate as demonstrated by wide variation in practice, evident bein cardiology MDTs. Such meetings will generally tend to tween and within individual countries. Each region should standardise the practice of the participants. look at ways to improve upon guideline compliance. Audit is a useful tool to help ensure implants were indicated.

A greater challenge, however, is to identify the unmet Referral pathways need of the region, the patients that havenâ&#x20AC;&#x2122;t even been diRegional referral pathways are also important when agnosed yet, or those not being referred for consideration considering variation in implant practice. It is an obviof an ICD.

49

UPDATE

cardiology

Cardiology initiatives from the West Mr Neil Johnson, Chief Executive, Croí, the West of Ireland Cardiac Foundation, outlines a number of new research and education initiatives in cardiology for healthcare professionals

T

he heart and stroke charity Croí, which is based in Galway, has recently expanded its multidisciplinary health team at the Heart and Stroke Centre in the city.

The charity, which was founded in 1985 and continues to support the development of cardiac and stroke services in the region, is leading the way in designing and testing lifestyle and behaviour change models of care focused on disease prevention and rehabilitation.

As an example of this, Croí is engaged in developing a model of community cardiac rehabilitation, which could supplement existing programmes that are hospital-based. This is a HSE Health and Wellbeing Division-funded initiative to address the identified need for increased and standardised provision of cardiac rehabilitation, which is a priority of the Health and Wellbeing Division, for implementation under the HSE’s National Framework for Self-Management Support for Chronic Conditions. This project aims to examine the feasibility of providing community-based cardiac rehabilitation and determining the effectiveness and scalability of such a programme in an Irish setting. The initiative, which is based on the Croí MyAction Programme, meets the British Association of Cardiac and Pulmonary Rehabilitation (BACPR) standards and core competencies.

A needs assessment of cardiac rehabilitation (phase 3) in Ireland, carried out in 2016, found that only 39 per cent of the need for cardiac rehabilitation is met by current capacity nationally, at the narrowest definition of need (ie, patients admitted to hospital with acute coronary syndrome; post-revascularisation; or heart failure). The gap in provision is variable around the country and similar in the Saolta Hospital Group to the national picture. When you broaden the criteria for referral to include patients with a wider range of conditions for which cardiac rehab is recommended, the deficit is even greater. Expansion of current capacity by a minimum of 61 per cent is required nationally.

Ideally, the development of a community-based cardiac rehabilitation programme should contribute to increased access and availability of cardiac rehab for the population and support current hospital provision, which is delivered by excellent cardiac rehab co-ordinators and staff who have been operating against a backdrop of significant cutbacks in recent years.

Leadership in prevention and recovery In 2014, Croí launched the National Institute for Preventive Cardiology (NIPC), affiliated to the College of Medicine, Nursing and Health Sciences at NUI Galway. The aims of the Institute are to provide leadership through discovery, training and applied programmes in the prevention and control of cardiovascular disease; promote healthier living; raise the standards of preventive cardiology practice; and prepare leaders to advance preventive healthcare in Ireland. Currently, over

50

1,200 healthcare professionals, educators and researchers have joined the NIPC Alliance, which provides regular updates on latest research, highlights hot topics, and profiles upcoming training and education opportunities.

Membership of the NIPC Alliance is free — see Mr Neil Johnson, CEO, Croí www.nipc.ie for further details and to sign-up for the monthly e-bulletin.

NIPC education and training opportunities include an MSc Degree and Postgraduate Diploma in Preventive Cardiology at NUI Galway, associated with the founding programme at Imperial College London. Applications are now open for the fifth year of this programme, which commences in September 2018. This level 9 course, which uses blended learning, is available as a one-year, full-time, in-service programme leading to an MSc, or a nine-month, full-time, in-service programme leading to a PG Diploma. Further details are available at www.nuigalway.ie/medicine.

Other upcoming NIPC education and training opportunities include a ‘Cholesterol Masterclass’, which takes place in the Herbert Park Hotel, Dublin, on Friday, 27 April. Key sessions include: Updates on ‘Lipid Guidelines for Optimal Management’ by Dr Patricia O’Connor, Consultant Physician and Clinical Pharmacologist, St James’s Hospital, Dublin; ‘Management of Lipids in Special Populations’ by Dr Dermot Neely, Consultant in Clinical Biochemistry and Metabolic Medicine, Newcastle upon Tyne NHS Trust; ‘Statin Intolerance — the Controversies’ by Dr Susan Connolly, Consultant Cardiologist, Western Health and Social Care Trust, Northern Ireland; ‘Familial Hypercholesterolaemia in Ireland’ by Dr Vivion Crowley, Consultant Chemical Pathologist, St James’s Hospital, Dublin; and ‘Challenges to Adherence’ with Dr Joe Gallagher, GP, Wexford. Register for free at www.nipc.ie/ conferences.html.

A recent NIPC course for GPs, hospital doctors, nurses and other healthcare professionals was a one-day workshop, ‘Demystifying the ECG’, which took place in the Croí Heart and Stroke Centre, Galway, on Saturday, 24 March. This excellent training course was delivered by Dr Paul Nolan, BSc ASCST, Chief Cardiac Physiologist at Galway University Hospital.

doctorcpd.ie Free independent CPD for Irish doctors by Irish doctors

C A

B

CPD Deadline — 1st May

• Anticoagulation and the management of venous thrombosis. 2 Credits Dr Denis O’Keeffe, Clinical Director of Diagnostics, Consultant Haematologist, University Hospital Limerick.

• Facial pain – diagnosis and management.

2 Credits Dr Aine O’Gara and Professor Connail McCrory Department of Pain Medicine, St. James’s Hospital.

• Cardiac arrhythmias. 2 Credits Dr Carthage Carroll, Clinical Director, DoctorCPD and Snr Reg, St Vincent’s Hospital

• Management of chronic kidney disease and iron deficiency. 1.5 Credits Dr Conall O Seaghdha MB MRCPI. Consultant Nephrologist and Renal Transplant Physician, Beaumont Hospital, Dublin. National Specialty Director, Nephrology, RCPI.

Just some of the modules available on doctorcpd.ie to help you achieve your target of 50 CPD hours by the CPD deadline on 1st May

UPDATE

cardiology

ASSESSMENT QUESTIONS

Cardiac arrhythmias Dr Carthage Carroll, Senior Registrar in Emergency Medicine, St Vincentâ&#x20AC;&#x2122;s University Hospital, Dublin Test your knowledge of atrial fibrillation with the following true/false questions and MCQs TRUE/FALSE QUESTIONS Q1:

AF can be diagnosed with a simple pulse check?

Q2: When the onset of AF is within 72 hours sinus rhythm can be safely restored using DCCV without the use of transoesophageal ECHO (TOE)?

Q3. An irregular atrial rate of 150bpm is associated with atrial flutter?

Q6: An agonal rhythm is characterised by rapid narrow QRS complexes but constitutes a benign pathophysiological condition?

Q7:

Osborn waves are seen as fibrillating waves on an ECG in someone with AF?

Q8: In atrial fibrillation the atria contract at a rate of 350 â&#x20AC;&#x201C; 600bpm?

Q4: Apixaban is a factor XI inhibitor?

Q9: The bundle of Kent is a recognised pathophysiological cause of AF?

Q5: The pulmonary veins are a common site of automatic foci in AF?

Q10: AV nodal re-entrant tachycardia is a form of ventricular tachycardia?

MCQS MCQ 1: Select all that apply (a) The three forms of remodelling associated with atrial fibrillation are electrical, structural and contractile. (b) Increased intra-atrial pressure is associated with AF. (c) The incidence of AF is higher in women than men. (d) The AFFIRM trial concluded that rhythm control was as efficacious as rate control in conferring a survival advantage in AF. (e) Calcium channel blockers are contraindicated in the treatment of AF.

MCQ 2: Select all that apply (a) Atrial tachycardia is definitively terminated with DCCV. (b) Atrioventricular dissociation has a poor prognosis. (c) AVNRT is the most common type of reentry SVT. (d) In AVNRT the tachycardia is initiated when a premature atrial complex is blocked in the fast pathway, but can conduct via the slow pathway.

(e) ST depression and left bundle branch block are characteristic ECG findings in a patient with Brugada syndrome.

MCQ 3: Select all that apply (a) Brugada syndrome is a genetically inherited disease. (b) In parts of Asia, Brugada syndrome appears to be the most common cause of natural death in men younger than 50. (c) Carotid sinus hypersensitivity should be considered in people presenting with unexplained falls. (d) ST segment alternans is the most common type of electrical alternans. (e) Digoxin has a broad therapeutic index.

MCQ 4: Select all that apply (a) Well-trained athletes are less likely to develop first degree heart block due to conditioning and remodelling of the SA node. (b) Junctional rhythms originate within ven-

tricular bundles. (c) Asymptomatic patients with a junctional rhythm due to increased vagal tone should be fitted with an ICD. (d) Romano-Ward syndrome and Jervell and Lang-Nielsen syndrome are associated with short QT syndrome. (e) Torsade de pointes is an example of a monomorphic ventricular tachycardia.

MCQ 5: Select all that apply (a) Long QT syndrome is associated with cardiac arrest while sleeping. (b) Lown-Ganong-Levine (LGL) syndrome is a pre-excitation syndrome characterised by a short PR interval on ECG. (c) LGL syndrome confers an increased mortality risk. (d) Patients with premature ventricular complexes (PVCs) on their ECGs should be started on an anti-arrhythmetic drug to prevent deterioration into ventricular fibrillation. (e) Increased mortality risk is associated with the use of digoxin in WPW.

The answers to the above questions and the complete CPD module are available on DoctorCPD. ie Successful completion of this module will earn you 2 CPD credits Please note: once you have registered with any of our CPD sites and/or The Medical Independent you have access to all our sites

52

ACT IVAT E T HE HEART ACT IVAT E LIFE

*

1,2

When you see HEART FAILURE,**

IT’S TIME FOR ENTRESTO

® 3,4

Patients on ENTRESTO® are more likely to: ✔ Live longer: 20% reduced risk of CV death vs enalapril3 ✔ Spend less time in hospital: 21% reduced risk of heart failure hospitalisation vs enalapril3 ✔ Live better: significant improvements in Quality of Life vs enalapril†3,5,6 ENTRESTO®: has a safety and tolerability profile comparable to enalapril2

ABBREVIATED ABBREV ABB REVIAT IATED ED PRE PRESCR PRESCRIBING SCRIBI IBING NG INF INFORM INFORMATION ORMATI ATION ON - Entrest EEntresto ntrestoo film film-coate lm-coated -coatedd tabl ttablets ablets ets ▼ This medicinal product is subject to additional monitorin monitori monitoring. n This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 44.88 of the SmPC for how to report adverse reactions prescribing Presentation: P reactions. Please refer to Summary of Product Characteristics (SmPC) before prescribing.

Film-coated tablets of 24 mg/26 mg, 49 mg/51mg and 97 mg/103 mg of sacubitril and valsartan respectively (as sacubitril valsartan sodium salt complex). Indications: In adult patients for treatment of symptomatic chronic heart failure with reduced ejection fraction. Dosage and administration: The recommended starting dose of Entresto is one tablet of 49 mg/51 mg twice daily, doubled at 2-4 weeks to the target dose of one tablet of 97 mg/103 mg twice daily, as tolerated by the patient. In patients not currently taking an ACE inhibitor or an ARB, or taking low doses of these medicinal products, a starting dose of 24 mg/26 mg twice daily and slow dose titration (doubling every 3 - 4 weeks) are recommended. A starting dose of 24 mg/26 mg twice daily should be considered for patients with SBP ≥100 to 110 mmHg, moderate or severe renal impairment (use with caution in severe renal impairment) and moderate hepatic impairment. Do not co-administer with an ACE inhibitor or an ARB. Do not start treatment for at least 36 hours after discontinuing ACE inhibitor therapy. Entresto may be administered with or without food. The tablets must be swallowed with a glass of water. Contraindications: Hypersensitivity to the active substances or to any of the excipients. Concomitant use with ACE inhibitors.

Do not administer until 36 hours after discontinuing ACE inhibitor therapy. Known history of angioedema related to previous ACE inhibitor or ARB therapy. Hereditary or idiopathic angioedema. Concomitant use with aliskiren-containing medicinal products in patients with diabetes mellitus or in patients with renal impairment (eGFR <60 ml/min/1.73 m2). Severe hepatic impairment, biliary cirrhosis and cholestasis. Second and third trimester of pregnancy. Warnings/Precautions: Dual blockade of the renin angiotensin-aldosterone system (RAAS): Combination with an ACE inhibitor is contraindicated due to the increased risk of angioedema. Entresto must not be initiated until 36 hours after taking the last dose of ACE inhibitor therapy. If treatment with Entresto is stopped, ACE inhibitor therapy must not be initiated until 36 hours after the last dose of Entresto. Combination of Entresto with direct renin inhibitors such as aliskiren is not recommended. Entresto should not be co administered with another ARB containing product. Hypotension: Treatment should not be initiated unless SBP is ≥100 mmHg. Patients with SBP <100 mmHg were not studied. Cases of symptomatic hypotension have been reported in patients treated with Entresto during clinical studies, especially in patients ≥65 years old, patients with renal disease and patients with low SBP (<112 mmHg). Blood pressure should be monitored routinely when initiating or during dose titration with Entresto. If hypotension occurs, temporary down-titration or discontinuation of Entresto is recommended. Impaired or worsening renal function: Limited clinical experience in patients with severe renal impairment (estimated GFR <30 ml/min/1.73m2). There is no experience in patients with end-stage renal disease and use of Entresto is not recommended. Use of Entresto may be associated with decreased renal function, and down-titration should be considered in these patients. Hyperkalaemia: Entresto should not be initiated if the serum potassium level is >5.4 mmol/l.

Monitoring of serum potassium is recommended, especially in patients who have risk factors such as renal impairment, diabetes mellitus or hypoaldosteronism or who are on a high potassium diet or on mineralocorticoid antagonists. If clinically significant hyperkalaemia occurs, consider adjustment of concomitant medicinal products or temporary down-titration or discontinuation of Entresto. If serum potassium level is >5.4 mmol/l discontinuation should be considered. Angioedema: Angioedema has been reported with Entresto. If angioedema occurs, discontinue Entresto immediately and provide appropriate therapy and monitoring until complete and sustained resolution of signs and symptoms has occurred. Entresto must not be re administered. Patients with a prior history of angioedema were not studied. As they may be at higher risk for angioedema, caution is recommended if Entresto is used in these patients. Black patients have an increased susceptibility to develop angioedema. Patients with renal artery stenosis: Caution is required and monitoring of renal function is recommended. Patients with NYHA functional classification IV: Caution should be exercised due to limited clinical experience in this population. Patients with hepatic impairment: There is limited clinical experience in patients with moderate hepatic impairment (Child Pugh B classification) or with AST/ALT values more than twice the upper limit of the normal range. Caution is therefore recommended in these patients. B-type natriuretic peptide (BNP): BNP is not a suitable biomarker of heart failure in patients treated with Entresto because it is a neprilysin substrate. Interactions: Contraindicated with ACE inhibitors, 36 hours washout is required. Use with aliskiren contraindicated in patients with diabetes mellitus or in patients with renal impairment (eGFR <60 ml/min/1.73 m2). Should not be co-administered with another ARB. Use with caution when co-administering Entresto with statins or PDE5 inhibitors. No clinically relevant drug-drug interaction was observed when simvastatin and Entresto were co-administered. Monitoring serum potassium is recommended if Entresto is co-administered with potassium-sparing diuretics or substances containing potassium (such as heparin). Monitoring renal function is recommended when initiating or modifying treatment in patients on Entresto who are taking NSAIDs concomitantly. Interactions between Entresto and lithium have not been investigated. Therefore, this combination is not recommended. If the combination proves necessary, careful monitoring of serum lithium levels is recommended. Co-administration of Entresto and furosemide reduced Cmax and AUC of furosemide by 50% and 28%, respectively, with reduced urinary excretion of sodium. Co-administration of nitroglycerin and Entresto was associated with a treatment difference of 5 bpm in heart rate compared to the administration of nitroglycerine alone, no dose adjustment is required. Co administration of Entresto with inhibitors of OATP1B1, OATP1B3, OAT3 (e.g. rifampicin, ciclosporin), OAT1 (e.g. tenofovir, cidofovir) or MRP2 (e.g. ritonavir) may increase the systemic exposure of LBQ657 or valsartan. Appropriate care should be exercised. Co-administration of Entresto with metformin reduced both Cmax and AUC of metformin by 23%. When initiating therapy with Entresto in patients receiving metformin, the clinical status of the patient should be evaluated. Fertility, pregnancy and lactation: The use of Entresto is not recommended during the first trimester of pregnancy and is contraindicated during the second and third trimesters of pregnancy. It is not known whether Entresto is excreted in human milk, but components were excreted in the milk of rats. Entresto is not recommended during breastfeeding. A decision should be made whether to abstain from breast feeding or to discontinue Entresto while breast feeding, taking into account the importance of Entresto to the mother. Adverse reactions: Very common: Hyperkalaemia, hypotension, renal impairment. Common: Anaemia, hypokalaemia, hypoglycaemia, dizziness, headache, syncope, vertigo, orthostatic hypotension, cough, diarrhoea, nausea, gastritis, renal failure, acute renal failure, fatigue, asthenia. Uncommon: Hypersensitivity, postural dizziness, pruritis, rash, angioedema.

Please refer to SmPC for a full list of adverse events for Entresto. Legal Category: POM. Pack sizes: Entresto 24 mg/26 mg - 28 tablet pack; Entresto 49 mg/51 mg - 28 and 56 tablet pack; Entresto 97 mg/103 - 56 tablet pack. Marketing Authorisation Holder: Novartis Europharm Limited, Frimley Business Park, Camberley GU16 7SR, United Kingdom. Marketing Authorisation Numbers: Entresto 24 mg/26 mg film coated tablets EU/1/15/1058/001; Entresto 49 mg/51 mg film coated tablets EU/1/15/1058/002-003; Entresto 97 mg/103 mg film coated tablets EU/1/15/1058/006.

Full prescribing information is available on request from Novartis Ireland Ltd, Vista Building, Elm Park Business Park, Merrion Road, Dublin 4. Tel: 01 2601255 or at www.medicines.ie Date of Creation of API Text: 26 Jul 2016.

References: 1. Fala L. Entresto (sacubitril/valsartan): first-in-class angiotensin receptor neprilysin inhibitor FDA approved for patients with heart failure. Am Health Drug Benefits. 2015;8(6):330-334. 2. Volpe M, Carnovali M, Mastromarino V. The natriuretic peptides system in the pathophysiology of heart failure: from molecular basis to treatment. Clin Sci. 2016;130(2):57-77. 3. McMurray JJV, Packer M, Desai AS, et al. Angiotensin–neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371(11):993-1004. 4. Entresto Summary of Product Characteristics http://www.medicines.ie/medicine/16531/SPC/Entresto+24mg+26mg%2c +49mg+51mg+and+97mg+103mg+film+coated+tablets/ Assessed January 2017 5. Packer M, McMurray JJV, Desai AS, et al. Angiotensin receptor neprilysin inhibition compared with enalapril on the risk of clinical progression surviving patients with heart failure. Circulation. 2015;131(1):54-61. 6. Okumura N, Jhund PS, Gong J, et al. Importance of clinical worsening of heart failure treated in the outpatient setting: evidence from the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF). Circulation. 2016;133(23):2254-2262. *The complementary cardiovascular benefits of ENTRESTO in patients with HFrEF are attributed to the enhancement of peptides that are degraded by neprilysin, such as natriuretic peptides (NP), by sacubitril and the simultaneous inhibition of the deleterious effects of angiotensin II by valsartan. **Heart failure with reduced ejection fraction † Secondary end point that measured the change from baseline to 8 months in the clinical summary score on the Kansas City Cardiomyopathy Questionnaire (KCCQ). CV=cardiovascular; HFrEF=heart failure with reduced ejection fraction © 2017 Novartis Pharma AG January 2017 IE02/ENT16-CNF107c