Apixaban for stroke prevention in atrial fibrillation August 2010 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 National Horizon Scanning Centre Research Programme is part of the National Institute for Health Research
Apixaban for stroke prevention in atrial fibrillation Target group Atrial fibrillation (AF) prevention of stroke in patients with additional risk factor/s for stroke. Technology description Apixaban (BMS 562247; BMS 562247-0) is an oral factor Xa inhibitor, which prevents the formation of thrombin thereby interrupting the coagulation cascade and preventing the conversion of fibrinogen to fibrin. It is intended to substitute current therapy for prevention of stroke in patients with AF at high risk of stroke. Apixaban is administered orally at 2.5 to 5mg twice daily (doses used in clinical trials) on an ongoing continuous basis. Apixaban is in phase III clinical trials for the prevention and treatment of venous thromboembolic events, including deep vein thrombosis and pulmonary embolism, and prevention of cardiovascular death, non-fatal myocardial infarction (MI), or ischaemic stroke in patients with acute coronary syndrome. Innovation and/or advantages If licensed, apixaban may offer a more convenient treatment option than currently available oral anticoagulants, and may offer an additional treatment option to those unable to take currently available anticoagulants. Developer Bristol-Myers Squibb. 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) and The National Service Framework for Coronary Heart Disease (2000). Relevant guidance NICE technology appraisal in development. Dronedarone within its licensed indication for the treatment of atrial fibrillation. Expected August 2010 1. NICE technology appraisal in development. Dabigatran etexilate for the prevention of stroke or systemic embolism in people with atrial fibrillation. Expected June 2 2011. NICE technology appraisal in development. Clopidogrel in combination with aspirin for the prevention of vascular events in people with atrial fibrillation. Expected date 3 of issue to be confirmed. NICE technology appraisal in development. Idraparinux sodium for the prevention of 4 stroke associated with atrial fibrillation. Suspended July 2007. NICE technology appraisal in development. Ximelagatran for the treatment and prevention of stroke and other thromboembolic complications associated with atrial 5 fibrillation. Suspended January 2005. NICE technology appraisal. Clopidogrel and modified-release dipyridamole in the prevention of occlusive vascular events. 2005 6. 2
NICE clinical guideline. Stroke: the diagnosis and initial management of acute stroke and transient ischaemic attacks (TIA). 2008 7. 8 NICE clinical guideline. The management of atrial fibrillation. 2006. SIGN. Management of patients with stroke: Rehabilitation, prevention and 9 management of complications, and discharge planning. 2010. 10 NHS Clinical Knowledge Summaries. Atrial fibrillation. 2009. 11 SIGN. Cardiac arrhythmias in coronary heart disease. 2007. American College of Cardiology, American Heart Association and European Society of Cardiology. Guidelines for the management of patients with atrial fibrillation. 2006 12. Clinical need and burden of disease AF is the most common sustained cardiac arrhythmia 13. Its prevalence increases with age from 0.5% at age 50-59 to almost 9% at age 80-89 9. The prevalence of AF is increasing due to an aging population and increasing survival from conditions predisposing to AF (e.g. hypertension, coronary heart disease and heart failure) 14. 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) 15. Applying this prevalence to England and Wales equates to around 450,000 people with the condition. There were 120,200 finished consultant in-patient episodes for AF (ICD I48) in NHS hospitals in England in 2008/09 16. AF increases the overall risk of stroke five-fold 17 and accounts for approximately 15% of all thromboembolic strokes 18. 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 19. Stroke affects approximately 110,000 people in England each year and accounts for 11% of all deaths in England and Wales 7. When strokes occur in association with AF, patients may experience a greater level of mortality, morbidity, disability and longer hospital stays than patients without AF 20. Existing comparators and treatments Guidelines recommend the use of adjusted-dose oral anticoagulation with vitamin K antagonists (VKA) such as warfarin for patients with AF at high risk, and antiplatelet agents such as aspirin for those deemed at low risk or for those who cannot safely receive oral anticoagulants 21. Efficacy and safety Trial AVERROES, NCT00496769; apixaban or acetylsalicylic acid (ASA); phase III. ARISTOTLE, NCT00412984; apixaban or warfarin; phase III. Sponsor Bristol-Myers Squibb. Bristol-Myers Squibb. Status Ongoing. Ongoing. Source of Publication 22, trial registry 23. Publication, trial registry 25. information Location EU (inc UK), USA, Canada and other countries. EU (inc UK), USA, Canada and other countries. Design Randomised, active-controlled. Randomised, active-controlled. 3
Participants and schedule Follow-up Primary outcomes Secondary outcomes Expected reporting date n=5,600 (planned); >50 years of age; AF; 1 additional risk factor for stroke a ; failed or unsuitable for VKA therapy. Randomised to apixaban at 5mg (2.5mg b in selected patients ) twice daily with ASA-placebo, or ASA at 81-324mg once daily with apixaban-placebo. Active treatment period until study completion (max 36 months); follow up at months 1, 3 and every 3 months thereafter until study completion. Stroke (ischemic or haemorrhagic) or systemic embolism; major bleeding (safety outcome). MI, vascular death, all cause death, composite of major vascular events, net clinical benefit. Study expected to complete August 2010. n=18,206; 18 years of age; AF; 1 additional risk factor for stroke b ; warfarin naive or experienced. Randomised to apixaban at 5mg (2.5mg in selected patients c ) twice daily with warfarin-placebo or warfarin (target INR 2-3) with apixaban-placebo. Active treatment and follow up until attainment of 448 primary study events (1-4 years). Non inferiority of apixaban in combined endpoints of stroke (ischemic or haemorrhagic) and systemic embolism; major bleeding (safety outcome). Superiority of apixaban in combined endpoints of stroke (ischemic or haemorrhagic) and systemic embolism; all cause death. Study expected to complete April 2011. Estimated cost and cost impact The cost of apixaban is not yet known. The annual cost of warfarin at 5mg per day and aspirin at 75mg per day is approximately 16 and 11 respectively 26. Claimed or potential impact speculative Patients Reduced mortality or increased length of survival Other: Reduction in associated morbidity or Improved quality of life for patients and/or carers Quicker, earlier or more accurate diagnosis or identification of disease None identified Services Increased use Service organisation Staff requirements Decreased use: potential for decreased requirement for oral anticoagulation therapy and monitoring of INR. Other: None identified Costs Increased unit cost compared to alternative Increased costs: more patients coming for treatment Increased costs: capital investment needed New costs: Savings: Other: uncertain unit cost compared to current alternatives. References 1 National Institute for Health and Clinical Excellence. Dronedarone within its licensed indication for the treatment of atrial fibrillation. Technology appraisal in development. Expected August 2010. a Additional risk factors included: prior stroke or transient ischaemic attack; age 75 years; arterial hypertension; diabetes mellitus; heart failure or left ventricular ejection fraction 35%-40%; peripheral arterial disease. b Patients who fulfilled any two of the following criteria received apixaban at 2.5mg twice daily: age 80 years; body weight 60 kg; serum creatinine 1.5mg/dL or 133µmol/L. 4
2 National Institute for Health and Clinical Excellence. Dabigatran etexilate for the prevention of stroke or systemic embolism in people with atrial fibrillation. Technology appraisal in development. Expected June 2011. 3 National Institute for Health and Clinical Excellence. Clopidogrel in combination with aspirin for the prevention of vascular events in people with atrial fibrillation. Technology appraisal in development. Expected date to be confirmed. 4 National Institute for Health and Clinical Excellence. Idraparinux sodium for the prevention of stroke associated with atrial fibrillation. Suspended technology appraisal. July 2007. 5 National Institute for Health and Clinical Excellence.Ximelagatran for the treatment and prevention of stroke and other thromboembolic complications associated with atrial fibrillation. Suspended technology appraisal. January 2005. 6 National Institute for Health and Clinical Excellence. Clopidogrel and modified release dipyridamole in the prevention of occlusive vascular events. Technology Appraisal TA90. London: NICE; May 2005. 7 National Institute for Health and Clinical Excellence. Stroke: the diagnosis and initial management of acute stroke and transient ischaemic attack (TIA). Clinical guideline CG68. London: NICE; July 2008. 8 National Institute for Health and Clinical Excellence. The management of atrial fibrillation. Clinical guideline CG36. London: NICE; June 2006. 9 Scottish Intercollegiate Guidelines Network. Management of patients with stroke: Rehabilitation, prevention and management of complications, and discharge planning. Clinical guideline 118. Edinburgh: SIGN; June 2010. 10 NHS Clinical Knowledge Summaries. Atrial fibrillation. Version1.0. August 2009. http://www.cks.nhs.uk/atrial_fibrillation#-385785 Accessed 9 August 2010. 11 Scottish Intercollegiate Guidelines Network. Cardiac arrhythmias in coronary heart disease. Clinical guideline 94. Edinburgh: SIGN; February 2007. 12 American College of Cardiology, American Heart Association and European Society of Cardiology. Guidelines for the management of patients with atrial fibrillation. Europace 2006;8:651 745. 13 Lip G and Khoo CW. Burden of atrial fibrillation. Current Medical Research and Opinion. 2009;25(5):1261-1263. 14 Stewart S, Murphy N, Walker A et al. Cost of an emerging epidemic: an economic analysis of atrial fibrillation in the UK. Heart 2004;90:286-292. 15 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;93:606-612. 16 HESonline. Hospital episode statistics, NHS England -Primary diagnosis: 3 character, 2008-09. www.hesonline.nhs.uk. 17 Turpie AGG. New oral anticoagulants in atrial fibrillation. European Heart Journal 2007;29:155-165 18 Wolf PA, Mitchell JB, Baker CS et al. Impact of atrial fibrillation on mortality, stroke, and medical costs. Archives of Internal Medicine 1998;158:229 234. 19 Lip G and Lim HS. Atrial fibrillation and stroke prevention. Lancet Neurology 2007; 6(11): 981-3. 20 Kannel WB, Wolf PA, Benjamin EJ et al. Prevalence, incidence, prognosis and predisposing conditions for atrial fibrillation: population-based estimates. American Journal of Cardiology. 1998;82(7)Suppl.1:2-9N. 21 Aguilar MI, Hart R and 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. 22 Eikelboom JW, O Donnel M, Yusuf S et al. Rationale and design of AVERROES: apixaban versus acetylsalicylic acid to prevent stroke in atrial fibrillation patients who have failed or are unsuitable for vitamin K antagonist treatment. American Heart Journal 2010;159:348-353. 23 ClinicalTrials.gov. A phase III study of apixaban in patients with atrial fibrillation (AVERROES). http://clinicaltrials.gov/ct2/show/nct00496769? Accessed 28 June 2010. 24 Lopes RD, Alexander JH, Al-Khatib SM et al. Apixaban for reduction in stroke and other thromboembolic events in atrial fibrillation (ARISTOTLE) trial: design and rationale. American Heart Journal 2010;159:331-339. 25 ClinicalTrials.gov. Apixaban for the prevention of stroke in subjects with atrial fibrillation (ARISTOTLE). http://clinicaltrials.gov/ct2/show/nct00412984? Accessed 28 June 2010. 26 British Medical Association and Royal Pharmaceutical Society of Great Britain. British National Formulary. BMJ Group and RPS Publishing. London; March 2010. 5
The National Institute for Health Research National Horizon Scanning Centre Research Programme is funded by the Department of Health. The views expressed in this publication are not necessarily those of the NHS, the NIHR or the Department of Health The National Horizon Scanning Centre, Department of Public Health and Epidemiology University of Birmingham, 90 Vincent Drive, Edgbaston, Birmingham, B15 2SP, England Tel: +44 (0)121 414 7831 Fax +44 (0)121 414 2269 www.haps.bham.ac.uk/publichealth/horizon 6