Issues in Emerging Health Technologies

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1 Issues in Emerging Health Technologies Issue 116 March 2010 New Anticoagulants for Stroke Prevention in Patients with Atrial Fibrillation Summary Dabigatran etexilate (Pradax) and rivaroxaban (Xarelto) are oral anticoagulants being tested as alternatives to vitamin K antagonists (VKAs) such as warfarin for stroke prevention in patients with atrial fibrillation (AF). They are currently approved in Canada only for prevention of venous thromboembolism (VTE) following elective total hip or knee replacement surgery. The drugs do not have the limitations of VKAs; i.e., narrow therapeutic window, variable dose-response relationship, slow onset and offset of action, food and drug interactions, and the need for regular laboratory monitoring and dose adjustment of international normalized ratio (INR). The current price of these drugs is higher than that of warfarin and laboratory monitoring, highlighting the need for full economic evaluations that consider offset costs due to potential clinical benefits. Patients with excellent INR control on warfarin may not benefit from a change in therapy, but VKA alternatives could have a role when warfarin is not an option or when the INR cannot be stabilized. The Technology In AF, an atrial thrombus can develop and embolize to block a cerebral artery and cause a stroke, the annual risk being 4% to 5% in patients with non-rheumatic AF. 1 For those at intermediate or high stroke risk, guidelines recommend prophylactic VKAs such as warfarin (Coumadin) that broadly inhibit coagulation by affecting four coagulation factors (II, VII, IX, and X). 1-4 The VKAs have been the only oral anticoagulants for over 60 years. 5,6 However, their many limitations include a narrow therapeutic window, variable dose-response relationship requiring frequent INR monitoring, numerous food and drug interactions, and slow onset and offset of action. 4,5,7,8 New anticoagulants have been developed, including dabigatran etexilate (Pradax, Boehringer Ingelheim) and rivaroxaban (Xarelto, Bayer). Both impact the coagulation cascade more specifically than do VKAs, with dabigatran being a direct inhibitor of thrombin and rivaroxaban a direct inhibitor of factor Xa. 6,9 Both have a rapid onset of action (peak concentrations in two to four hours, versus 72 hours for warfarin) and short half-lives (14 to 17 and five to 13 hours respectively, versus 40 hours for warfarin), making management before procedures easier. 5,6 Regulatory Status Dabigatran received a Health Canada Notice of Compliance (NOC) in June 2008, and rivaroxaban in September 2008; both are approved for prevention of VTE after elective total hip or knee replacement surgery. 10,11 They have been considered for public coverage for this indication by the Canadian Expert Drug Advisory Committee, which supported rivaroxaban 12 but not dabigatran. 13 Both drugs were approved in 2008 in the European Union for the postsurgical indication approved in Canada. 8,14,15 Neither drug is yet approved by the Food and Drug Administration in the United States. 16,17 Patient Group In Canada, AF is the most prevalent, sustained cardiac dysrhythmia, affecting 200,000 to 250,000 people. 18,19 The prevalence of AF rises sharply with age, being 0.2% at age 30 and > 12% at age 75; lifetime risk is about 25%. 1,20 AF is estimated to cause up to 15% of all strokes 20 and AF-related strokes are more severe, cause greater disability, and have a worse prognosis than strokes in patients without AF. 21 Patients considered to be at risk of stroke and advised to take long-term prophylactic VKAs include those with prior ischemic stroke, transient ischemic attack (TIA), or systemic embolism; or two or more risk factors including age >75 and history of hypertension, diabetes mellitus, moderately or severely impaired left ventricular systolic function, and/or heart failure (with one risk factor, patients may be advised to use a VKA or aspirin). 3

2 Current Practice Research has shown that VKAs reduce stroke in patients with AF by about 65% as compared with placebo. 7,22 The most commonly used VKA in North America is warfarin, but the related VKAs, acenocoumarol and phenprocoumon, see some uptake in Europe. 7 For primary prevention of stroke in AF, guidelines in Canada 1,2 and United States 3 recommend aspirin or warfarin, depending upon risk status (although most patients have significant risk factors where warfarin is the recommended treatment over aspirin). For secondary prevention of stroke in AF and mechanical cardiac valves, warfarin is recommended for those likely to be compliant with therapy and INR monitoring, and for those who are not at high risk of bleeding complications. 2 However, due to warfarin s limitations, the drug may not be prescribed and, when it is, rates of drug discontinuation and inadequate anticoagulation are high. 4,5,22,23 Of candidates appropriate for warfarin therapy, only 50% to 67% are treated. 7,22-24 Time within the therapeutic INR range (TTR) varies widely among centres and countries, with a median TTR of 65% (range 46% to 78%; Canada 69%). 25 The Evidence Dabigatran: Randomized Evaluation of Longterm anticoagulant therapy (RE-LY) was a phase III, industry-sponsored trial (n = 18,113) that randomized patients with AF and at least one risk factor for stroke to dabigatran 110 mg or 150 mg twice daily (b.i.d.), or adjusted-dose warfarin. 4,26 Patients were recruited from 951 clinical centres in 44 countries. Half had been on long-term VKA therapy and about 40% on aspirin; continued aspirin use was allowed. The primary efficacy outcome was annual stroke or systemic embolization rate, and median followup was two years. Blinding was applied to dabigatran dose but not to the warfarin group due to the latter s need for INR monitoring; detection bias is therefore possible. 22 The efficacy of dabigatran 110 mg b.i.d. versus warfarin was 1.53% versus 1.69% (relative risk [RR] 0.91, 95% confidence interval [CI] 0.74 to 1.11; P < 0.001); i.e., not significantly different. (Note: The primary analysis was designed to test non-inferiority of dabigatran versus warfarin.) 4 However, superior results were achieved for patients on dabigatran 150 mg b.i.d. versus warfarin (1.11% versus 1.69%; RR 0.66, 95% CI 0.53 to 0.82; P < 0.001). 4 Number-needed-to-treat (NNT) with dabigatran 150 mg b.i.d. to prevent one non-hemorrhagic stroke was 357 and NNT to prevent one hemorrhagic stroke was For the warfarin group, INR was within the therapeutic range 64% of the time. Subsequent calculations showed that the stroke risk for the dabigatran 150 mg b.i.d. versus warfarin groups would be similar at TTRs of at least 79%, although this may not be realistically achievable. 22,25 RELY- ABLE is a long-term extension of the RE-LY trial focusing on drug safety, primarily occurrence of major bleeding. 27 Estimated enrollment is 6,200 patients with expected completion of data collection in July Rivaroxaban: The ROCKET-AF study is a phase III, industry-sponsored, randomized, double-blind, double-dummy trial (n = 14,266) comparing the efficacy and safety of rivaroxaban 20 mg once daily to that of adjusted-dose warfarin in patients with nonvalvular AF and risk factors for stroke. 28,29 The study is powered to show non-inferiority of rivaroxaban versus warfarin for the primary efficacy end point, the composite of stroke and non-central Nervous System systemic embolism, followed by a superiority test if non-inferiority for rivaroxaban is demonstrated. 29 Patients were recruited up to mid-2009 and data collection is expected to end in May ,21 Treatment will span a mean of 18 months with a range of 12 to > 24 months. 30 Adverse Effects Dabigatran: RE-LY safety data reported major bleeding ( 20 g/l fall in hemoglobin, transfusion of two units of blood, or symptomatic bleeding in a critical area or organ) in ~ 3% and minor bleeding in ~ 14% of patients on dabigatran. 4 Major bleeding rates were not detectably different between the groups on dabigatran 150 mg b.i.d. versus warfarin, although the dabigatran group experienced significantly lower rates of intracranial bleeding (36/6,076 versus 87/6,022 patients; RR 0.40 [CI 0.27 to 0.60]; P < 0.001). The dabigatran 110 mg b.i.d. group experienced significantly lower rates of major, minor, and intracranial bleeding (the latter affecting

3 27/6,015 versus 87/6,022 patients, RR 0.31 [CI 0.20 to 0.47], P < 0.001) as compared with the warfarin group. Overall mortality rates of ~ 4% were not significantly different among groups (P = for dabigatran 150 mg b.i.d. versus warfarin), although there were significantly fewer deaths from vascular causes in patients taking dabigatran 150 mg b.i.d. (P = 0.04). Other AEs were not different among groups except for dyspepsia and myocardial infarction (MI). Dyspepsia was higher for dabigatran than warfarin (11.5% versus 5.8%; P < 0.001), possibly due to dabigatran s tartaric acid capsule core designed to improve absorption. Rates of myocardial infarction (MI) were higher for dabigatran (0.72% and 0.74% for dabigatran 110 mg b.i.d. and 150 mg b.i.d., versus 0.53% for warfarin; P = 0.07 for 110 mg b.i.d. and P = for 150 mg b.i.d.); calculations show that one MI would occur for every 500 patients on dabigatran. 22,31 Hepatotoxicity was not evident as it was for ximelagatran (Exanta), a direct thrombin inhibitor removed from the market in 2006, 5 although RE-LY follow-up was only two years so the hepatic risks of long-term dabigatran are unclear, as is guidance about frequency of liver function monitoring. Rates of study discontinuation were also higher for the dabigatran groups versus the warfarin group (15% versus 10% at one year, 21% versus 17% at two years; P < 0.001), with serious AEs (not defined) being a significant factor. Rivaroxaban: AE information is available from phase III studies carried out for post-orthopedic surgery indications in which patients were randomized to once-daily rivaroxaban 10 mg (n = 4,657) or enoxaparin 40 mg (n = 4692). 32 The safety profiles of both drugs were similar regarding AEs and serious AEs, including bleeding rates, which were 5.0% to 6.6% for any bleeding and 0.1% to 0.6% for major bleeding. 32 Administration and Cost For their current licensed indications, dabigatran comes as 75 mg and 110 mg oral capsules suggested b.i.d. at a price of $7.85 per day for the 110 mg dose 13,33 (although 150 mg b.i.d. was tested in the RE-LY trial and the price for this dose was not available). 4 Rivaroxaban is a 10 mg tablet recommended once daily at a price of $9.92 per day 12,32 (although 20 mg once daily is the dose employed in the ROCKET-AF trial). In contrast, warfarin costs $0.40 per day. 13 Future prices are subject to change if additional formulations become available. Concurrent Developments Aside from the standard VKA regimen for stroke prevention in patients with AF, alternatives include aspirin, low-dose warfarin plus aspirin, and clopidogrel plus aspirin. 23 Warfarin is superior to these alternatives in patients at high stroke risk, while aspirin is recommended for those at low risk. 23 A novel oral VKA, ATI-5923, is under development and is intended to be more stable than warfarin as it uses a different metabolic route. 7,23 Also being explored are a factor IX inhibitor and at least four additional factor Xa inhibitors. 7 Dabigatran and rivaroxaban are also being investigated as alternatives to parenteral agents for treatment of acute VTEs (deep vein thrombosis and pulmonary embolism), secondary prevention of recurrent symptomatic VTEs, 9 and acute coronary syndrome. 6,34 Rate of Technology Diffusion If uptake of dabigatran and rivaroxaban complies with the currently approved indication (i.e., VTE prevention in post-orthopedic surgery), these drugs would be used short term. As they largely overcome the limitations of VKAs, there is the potential for offlabel use for a number of other indications, some involving long-term use. However, despite the convenience, including elimination of INR monitoring, the price of these agents is significantly higher than that of VKAs. Implementation Issues As evidence accumulates, clinicians will need to decide whether patients already on warfarin with excellent INR control have anything to gain by switching; this will depend on compelling evidence of reduced risk of stroke outweighing harm from nonhemorrhagic AEs. 22 Additional issues include: optimal drug doses, response of warfarin-treated versus warfarin-naive patients, drug effect in the very elderly, lack of an antidote (although research is currently addressing this issue), 35 and drug performance in patients who were excluded from the clinical trials; e.g., those with liver or renal disease. 5,6,36,37

4 Dabigatran and rivaroxaban are intended to overcome many of the limitations of VKAs, particularly the need for regular laboratory monitoring and dosage adjustments, and slow onset and offset of action. However, the current price of these drugs is higher than that of warfarin combined with regular laboratory monitoring, highlighting the need for full economic evaluations that consider offset costs due to the potential clinical benefits of the new drugs. The drugs may prove to be useful for a subset of patients with AF; i.e., those for whom regular monitoring and dose adjustments are not possible and those who are unable to achieve therapeutic INR values. 6 References 1. Lam J. Clinical guide - stroke prevention in atrial fibrillation [Internet]. Mississauga (ON): Thrombosis Interest Group of Canada; p. [cited 2009 Feb 18] Lindsay P, et al. CMAJ [Internet] Dec 2 [cited 2009 Feb 19];179(12 Suppl):S1-S25. i?artid= &blobtype=pdf 3. Singer DE, et al. Chest Jun;133(6 Suppl):546S-92S. 4. Connolly SJ, et al. N Engl J Med Sep 17;361(12): Zikria J, et al. Discovery medicine [Internet] Dec;8(43): Zikria/2009/11/17/oral-anticoagulation-withfactor-xa-and-thrombin-inhibitors-is-there-analternative-to-warfarin/ 6. Garcia D, et al. Blood Jan 7;115(1): Umer Usman MH, et al. J Interv Card Electrophysiol Aug;22(2): Leung LLK. Anticoagulants other than heparin and warfarin Sep 24 [cited 2010 Jan 11]. In: UpToDate [database on the Internet]. Version Waltham (MA): UpToDate; c Subscription required. 9. Gross PL, et al. Arterioscler Thromb Vasc Biol Mar;28(3): Notice of compliance database [Internet]. Ottawa: Health Canada; Notice of Compliance Information: Pradax; 2008 Jun 10 [cited 2009 Nov 5] Notice of compliance database [Internet]. Ottawa: Health Canada; Notice of Compliance Information: Xarelto; 2008 Sep 15 [cited 2009 Nov 5] Common Drug Review. Rivaroxaban (Xarelto - Bayer, Inc.) [Internet]. Ottawa: Canadian Agency for Drugs and Technologies in Health; p. [cited 2009 Feb 17]. elto_complete-dec17-08.pdf 13. Common Drug Review. Dabigatran etexilate (Pradax - Boehringer Ingelheim Canada Ltd.) [Internet]. Ottawa: Canadian Agency for Drugs and Technologies in Health; p. [cited 2009 Feb 17]. mplete_pradax_january pdf 14. Commission of the European Communities. Commission decision of 18-III-2008 granting marketing authorisation under Regulation (EC) no 726/2004 of the European Parliament and of the Council for "Pradaxa - dabigatran etexilate mesilate", a medicinal product for human use [Internet]. Brussels: European Commission; 2008 Mar 18. [cited 2010 Jan 13]. Available from: icals/documents/communityregister/2008/ /dec_45828_en.pdf Decision no. C(2008) Commission of the European Communities. Commission decision of granting marketing authorisation under Regulation (EC) No 726/2004 of the European Parliament and of the Council for "Xarelto - rivaroxaban", a medicinal product for human use [Internet]. Brussels: European Commission; 2008 Sep 30. [cited 2010 Jan 13]. icals/documents/communityregister/2008/ /dec_49239_en.pdf Decision no. C(2008) Drugs@FDA [database on the Internet]. Silver Spring (MD): U.S. Food and Drug Administration, Center for Drug Evaluation and Research; [2004] - [cited 2010 Jan 14]. Available from: satfda/ 17. Boehringer Ingelheim. Dabigatran Etexilate: U.S. Fact Sheet [Internet]. Ridgefield (CT): Boehringer Ingelheim; [cited 2010 Jan 11]. les/dabigatran_factsheet.pdf

5 18. Heart and Stroke Foundation of Canada. Statistics [Internet]. In: News. Ottawa: Heart and Stroke Foundation of Canada; 2009 [cited 2009 Jan 21]. WJtE/b /k.34A8/Statistics.htm. 19. Heart and Stroke Foundation of Canada. The growing burden of heart disease and stroke in Canada 2003 [Internet]. Ottawa: The Foundation; 2003 May. [cited 2010 Jan 11]. pdf Prepared in Collaboration with the Centre for Chronic Disease Prevention and Control, Health Canada, the Canadian Cardiovascular Society, and the Heart and Stroke Foundation of Canada. 20. Humphries KH, et al. Population rates of hospitalization for atrial fibrillation/flutter in Canada [Internet]. In: Tu JV, Ghali WA, Pilote L, Brien S, editors. CCORT Canadian Cardiovascular Atlas. Oakville (ON): Pulsus Group; p Chapter 16 [cited 2010 Jan 11]. phries_20_9_04.pdf. 21. viva.vita international [Internet]. Leverkusen (DE): Bayer HealthCare AG. Bayer completes enrollment into major phase III study with rivaroxaban (ROCKET AF); 2009 [cited 2009 Nov 5]. php?id=36&no_cache=1&tx_ttnews%5btt_news %5D= Gage BF. N Engl J Med [Internet] Sep 17;361(12): df 23. Manning WJ, et al. Antithrombotic therapy to prevent embolization in nonvalvular atrial fibrillation Oct 16 [cited 2010 Jan 11]. In: UpToDate [database on the Internet]. Version Waltham (MA): UpToDate; c Subscription required. 24. National Horizon Scanning Centre. Dabigatran etexilate (Pradaxa) for stroke prevention in atrial fibrillation [Internet]. Birmingham: University of Birmingham; [cited 2009 Feb 17]. on/outputs/documents/2008/mayaugust/dabigatran_etexilate Pradaxa for_stro ke_prevention.pdf 25. Connolly SJ, et al. Circulation [Internet] Nov 11 [cited 2010 Feb 26];118(20): Ezekowitz MD, et al. Am Heart J May;157(5):805-10, e ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US); 2000 Feb -. Identifier NCT , RELY-ABLE Long Term Multi-center Extension of Dabigatran Treatment in Patients With Atrial Fibrillation Who Completed RE-LY Trial; 2008 Dec 12 [cited 2010 Jan 11; updated 2009 Dec 8] ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US); 2000 Feb -. Identifier NCT , Randomized, Double- Blind Study Comparing Once Daily Oral Rivaroxaban With Adjusted-Dose Oral Warfarin for the Prevention of Stroke in Subjects With Non-Valvular Atrial Fibrillation; 2006 Nov 23 [cited 2010 Jan 11; updated 2009 Nov 6] Patel M, et al. P4198: Rationale and design of the ROCKET AF study: comparison of rivaroxaban with warfarin for the prevention of stroke and systemic embolism in patients with atrial fibrillation [Internet]. Abstract presented at: ESC Congress 2009 (European Society of Cardiology) Aug 29 - Sept 2; Barcelona Bayer Health Care. About rivaroxaban clinical studies [Internet]. Leverkusen (Germany): Bayer Schering Pharma AG; [cited 2010 Jan 11]. varoxaban_clinical_studies.pdf 31. Tomoda H. N Engl J Med Dec 31;361(27): Comment on: N Engl J Med Sep 17;361(12): Xarelto [product monograph on the Internet]. Toronto: Bayer; 2008 Sep 10. [cited 2009 Nov 5]. 10SEP pdf 33. Pradax [product monograph on the Internet]. Burlington (ON): Boehringer Ingelheim Canada; 2009 Jul 31. [cited 2009 Nov 5]. ucts/product_monographs/pradax-pm.pdf

6 34. Oldgren J, et al. Randomised dabigatran etexilate dose finding study in patients with acute coronary syndromes post index event with additional risk factors for cardiovascular compications also receiving aspirin and clopidogrel: RE-DEEM [slides on the Internet]. Poster presented at: American Heart Association Scientific Sessions Nov 14-18; Orlando (FL). [cited 2010 Mar 16]. ns2009/slides/165_pslides.pdf 35. van Ryn J, et al. Dabigatran etexilate - a novel, reversible, oral direct thrombin inhibitor: Interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost. Forthcoming Hankey GJ. Curr Opin Neurol Feb;23(1): Camm AJ. Eur Heart J Nov;30(21): Cite as: Foerster V. New Anticoagulants for Stroke Prevention in Patients with Atrial Fibrillation [Issues in emerging health technologies issue 116]. Ottawa: Canadian Agency for Drugs and Technologies in Health; *********************** CADTH takes sole responsibility for the final form and content of this bulletin. The statements and conclusions in this bulletin are those of CADTH, and not those of its advisory committee members or reviewers. CADTH thanks the external reviewers who kindly provided comments on an earlier draft of this bulletin. Reviewers: Jo-Anne Wilson, BSc Pharm, ACPR, PharmD, Dalhousie University, James Brophy, MEng, MD, FRCP, PhD, McGill University. Production of this report is made possible by financial contributions from Health Canada, and the governments of Alberta, British Columbia, Manitoba, New Brunswick, Newfoundland and Labrador, Northwest Territories, Nova Scotia, Nunavut, Prince Edward Island, Saskatchewan, and Yukon. The Canadian Agency for Drugs and Technologies in Health takes sole responsibility for the final form and content of this report. The views expressed herein do not necessarily represent the views of Health Canada or any provincial or territorial government. ISSN (online) ISSN (print) PUBLICATIONS MAIL AGREEMENT NO RETURN UNDELIVERABLE CANADIAN ADDRESSES TO CANADIAN AGENCY FOR DRUGS AND TECHNOLOGIES IN HEALTH CARLING AVENUE OTTAWA ON K1S 5S8