National Horizon Scanning Centre. Irbesartan (Aprovel) for prevention of cardiovascular complications in patients with persistent atrial fibrillation

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1 Irbesartan (Aprovel) for prevention of cardiovascular complications in patients with persistent atrial fibrillation August 2008 This technology summary is based on information available at the time of research and a limited literature search. It is not intended to be a definitive statement on the safety, efficacy or effectiveness of the health technology covered and should not be used for commercial purposes. The Research Programme is part of the National Institute for Health Research

2 Irbesartan (Aprovel) for prevention of cardiovascular complications in patients with persistent atrial fibrillation Target group Persistent atrial fibrillation (AF) adjunct therapy to anticoagulation treatment for the prevention of cardiovascular complications. Technology description Irbesartan (Aprovel) is an oral angiotensin II receptor blocker (ARB) mainly used for treatment of hypertension. Its mode of action is to block the activation of angiotensin II AT 1 receptors which directly causes vasodilation, a reduction in the secretion of vasopressin and a reduction in the production and secretion of aldosterone, the combined effect of which is a reduction in blood pressure. Irbesartan is postulated to reduce cardiovascular events in patients with AF by lowering blood pressure, reducing AF by promoting regression of left ventricular hypertrophy, preventing atrial remodelling, and preventing atherosclerotic vascular lesions by blocking the rennin-angiotensin system. Irbesartan 300mg is an oral formulation given once daily. Irbesartan is currently licensed for the treatment of hypertension and renal disease in hypertensive type 2 diabetes mellitus. Irbesartan is currently in phase III clinical trials for heart failure with preserved systolic function (HF-PSF). Innovation and/or advantages If results from ongoing trials are positive, irbesartan would be the first antihypertensive treatment to demonstrate a reduction in cardiovascular events in patients in AF irrespective of patients hypertensive status. Developer Bristol-Myers Squibb and sanofi-aventis. Availability, launch or marketing dates, and licensing plans: In phase III clinical trials. NHS or Government priority area: This topic is relevant to: The National Stroke Strategy (2007). The National Service Framework for Older People (2001). The National Service Framework for Coronary Heart Disease (2000). Relevant guidance NICE clinical guideline. Stroke: The diagnosis and acute management of stroke and transient ischaemic attacks NICE clinical guideline. The management of atrial fibrillation SIGN. Cardiac arrhythmias in coronary heart disease NLH guidance. Atrial fibrillation

3 American College of Cardiology (ACC), American Heart Association (AHA) and European Society of Cardiology (ESC). Guidelines for the management of patients with atrial fibrillation Clinical Knowledge Summaries. Atrial fibrillation - management Clinical Knowledge Summaries. Antiplatelet treatment Clinical Knowledge Summaries. Cardiovascular risk - assessment and management Clinical need and burden of disease AF is the most common sustained cardiac arrhythmia 2. In Scotland the prevalence of AF has been estimated at 8.4 cases per 1,000 population, and is higher amongst men (men 9.4 per 1,000 vs. women 7.9 per 1,000) 9. Applying this prevalence to England and Wales equates to 451,322 people with the condition. There were 109,646 finished consultant inpatient episodes for AF (ICD I48) in 2006/ AF is predominantly a disease of the elderly and its prevalence increases with age from 0.5% at age to almost 9% at age The population prevalence of AF has risen over time and is likely to increase in the future 11. AF remains a potent risk factor for thromboembolism, accounting for approximately 15% of all thromboembolic strokes 12. Comorbid factors such as hypertension, diabetes mellitus, congestive heart failure and prior stroke, all serve to increase the risk of stroke in AF, and the risks are cumulative 13. Existing comparators and treatments Rate control options include: beta-blockers or rate-limiting calcium-channel blockers (diltiazem or verapamil) are the preferred initial monotherapy digoxin (a cardiac glycoside) monotherapy especially if there is also heart failure electrophysiological or surgical interventions for rate and rhythm control If monotherapy is inadequate a beta-blocker or a rate-limiting calcium-channel blocker is given with digoxin. Rhythm control options include: amiodarone (class III antiarrhythmic agent) - requires specialist initiation and it has a high incidence of adverse effects. Antithrombotic therapy: Guidelines recommend the use of adjusted-dose warfarin for patients with AF at high risk and aspirin for those deemed at low risk or for those who cannot safely receive adjusted-dose warfarin 14. Efficacy and safety Trial code Sponsor Status Location Design Participants in trial NCT , ACTIVE-I: irbesartan vs placebo; phase III sanofi-aventis Ongoing America, Europe (inc. UK), China, Southeast Asia Randomised, double-blind, placebo controlled, factorial assignment. n=9,000; systolic bp 110mmHg; evidence of AF (eligible patients from ACTIVE-A or ACTIVE-W); not already receiving an ARB; no proven 3

4 Follow-up Primary outcome Secondary outcomes Expected reporting date indication for ARBs unless an ACE (angiotensin converting enzyme) inhibitor can be substituted. Randomised to irbesartan 300mg per day or placebo. 5 years. Composite outcome of stroke, MI or vascular death. Composite outcome of stroke, MI, vascular death or hospitalisation for heart failure. Total mortality, stroke, hospitalization for heart failure and other heart failure episodes. - Estimated cost and cost impact The annual cost of irbesartan 300mg once daily is 220 a. Potential or intended impact speculative Patients Reduced morbidity Quicker, earlier or more accurate diagnosis or identification of disease Reduced mortality or increased survival Improved quality of life for patients and/or carers None identified Services Increased use Service reorganisation required Staff or training required Decreased use. If vascular events and hospitalisation reduced. None identified Costs Increased unit cost compared to alternative New costs: additional therapy References Increased costs: more patients coming for treatment Savings: If vascular events and hospitalisation prevented Increased costs: capital investment needed 1 National Institute for Health and Clinical Excellence. Stroke: The diagnosis and acute management of stroke and transient ischaemic attacks. Clinical guideline. July National Institute for Health and Clinical Excellence. Atrial fibrillation - The management of atrial fibrillation. Clinical guideline CG036. June Scottish Intercollegiate Guidelines Network. Cardiac arrhythmias in coronary heart disease Clinical guideline 94. February National Library for Health. Atrial fibrillation. Guidance. January Available at: (9/11/07). 5 American College of Cardiology/American Heart Association/European Society of Cardiology. Guidelines for the management of patients with atrial fibrillation Clinical Knowledge Summaries. Atrial fibrillation - management. January Clinical Knowledge Summaries. Antiplatelet treatment. October Clinical Knowledge Summaries. Cardiovascular risk - assessment and management. July Murphy NF, Simpson CR, Jhund PS, et al. National survey of the prevalence, incidence, primary care burden and treatment of atrial fibrillation in Scotland. Heart. 2007: 93; The NHS Information Centre. Hospital Episode Statistics. Primary diagnosis: Available at: (Accessed a British National Formulary No. 55, March

5 30/06/2008). 11 Kannel WB, Wolf PA, Benjamin EJ et al. Prevalence, incidence, prognosis and predisposing conditions for atrial fibrillation: population-based estimates. Am J Cardiol. 1998; 82 (7) Suppl. 1: 2-9N. 12 Wolf PA, Mitchell JB, Baker CS, et al. Impact of atrial fibrillation on mortality, stroke, and medical costs. Arch Intern Med. 1998;158: Lip GYH, Boos C. Antithrombotic treatment in atrial fibrillation. Heart. 2006;92: Aguilar MI, Hart R, Pearce LA. Oral anticoagulants versus antiplatelet therapy for preventing stroke in patients with non-valvular atrial fibrillation and no history of stroke or transient ischemic attacks. Cochrane Database of Systematic Reviews 2007, Issue 3. Art. No.CD DOI: / CD Clinical Trials. NCT Atrial fibrillation clopidogrel trial with irbesartan for prevention of vascular events (ACTIVE I). Available at: (Accessed 14/07/2008). The National Institute for Health Research Research Programme is funded by the Department of Health. The views expressed in this publication are those of the author and not necessarily those of the NHS, the NIHR or the Department of Health The, Department of Public Health and Epidemiology University of Birmingham, Edgbaston, Birmingham, B15 2TT, England Tel: +44 (0) Fax +44 (0)