Dabigatran, Rivaroxaban, or Apixaban versus Warfarin in Patients with Nonvalvular Atrial Fibrillation: A Systematic Review and Meta-Analysis of Subgroups

Antonio Gómez-Outes, Ana Isabel Terleira-Fernández, Gonzalo Calvo-Rojas, M Luisa Suárez-Gea, Emilio Vargas-Castrillón, Antonio Gómez-Outes, Ana Isabel Terleira-Fernández, Gonzalo Calvo-Rojas, M Luisa Suárez-Gea, Emilio Vargas-Castrillón

Abstract

Background. New oral anticoagulants (NOAC; rivaroxaban, dabigatran, apixaban) have become available as an alternative to warfarin anticoagulation in non-valvular atrial fibrillation (NVAF). Methods. MEDLINE and CENTRAL, regulatory agencies websites, clinical trials registers and conference proceedings were searched to identify randomised controlled trials of NOAC versus warfarin in NVAF. Two investigators reviewed all studies and extracted data on patient and study characteristics along with cardiovascular outcomes. Relative risks (RR) and 95% confidence intervals (CI) were estimated using a random effect meta-analysis. Results. Three clinical trials in 50,578 patients were included. The risk of non-hemorrhagic stroke and systemic embolic events (SEE) was similar with the NOAC and warfarin (RR = 0.93; 95% CI = 0.83-1.04), while the risk of intracranial bleeding (ICB) with the NOAC was lower than with warfarin (RR = 0.46; 95% CI = 0.33-0.65). We found differences in the effect size on all strokes and SEE depending on geographic region as well as on non-hemorrhagic stroke, SEE, bleeding and mortality depending on time in therapeutic range. Conclusion. The NOAC seem no more effective than warfarin for prevention of nonhemorrhagic stroke and SEE in the overall NVAF population, but are generally associated with a lower risk of ICB than warfarin.

Figures

Figure 1
Figure 1
Study identification, selection, and exclusions.
Figure 2
Figure 2
Nonhemorrhagic stroke and systemic embolic events.
Figure 3
Figure 3
Intracranial bleeding.
Figure 4
Figure 4
All strokes and systemic embolic events (intention-to-treat).
Figure 5
Figure 5
All strokes and systemic embolic events after study drug discontinuation.
Figure 6
Figure 6
Major bleeding.
Figure 7
Figure 7
Major gastrointestinal bleeding.
Figure 8
Figure 8
Mortality.

References

    1. Camm AJ, Kirchhof P, Lip GY, et al. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC) European Heart Journal. 2010;31(19):2369–2429.
    1. You JJ, Singer DE, Howard PA, et al. Antithrombotic therapy for atrial fibrillation: antithrombotic therapy and prevention of thrombosis, 9th ed: american college of chest physicians evidence-based clinical practice guidelines. Chest. 2012;141(2):e531S–e575S.
    1. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke. 1991;22(8):983–988.
    1. Gómez-Outes A, Suárez-Gea ML, Calvo-Rojas G, et al. Discovery of anticoagulant drugs: a historical perspective. Current Drug Discovery Technologies. 2012;9(2):83–104.
    1. Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Annals of Internal Medicine. 2007;146(12):857–867.
    1. Ansell J, Hirsh J, Hylek E, Jacobson A, Crowther M, Palareti G. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition) Chest. 2008;133(6):160S–198S.
    1. Friberg L, Hammar N, Ringh M, Pettersson H, Rosenqvist M. Stroke prophylaxis in atrial fibrillation: who gets it and who does not? Report from the Stockholm Cohort-study on Atrial Fibrillation (SCAF-study) European Heart Journal. 2006;27(16):1954–1964.
    1. European Medicines Agency. Pradaxa-summary of product characteristics. 2013, .
    1. European Medicines Agency. Xarelto-summary of product characteristics. 2013, .
    1. European Medicines Agency. Eliquis-summary of product characteristics. 2013, .
    1. Calvo-Rojas G, Gémez-Outes A. Clinical drug development in thromboembolic diseases: regulatory and methodological approach. Current Drug Discovery Technologies. 2012;9(2):105–118.
    1. Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Controlled Clinical Trials. 1996;17(1):1–12.
    1. Higgins JP, Altman DG, Gøtzsche PC, et al. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. British Medical Journal. 2011;343d5928
    1. Singer DE, Chang Y, Fang MC, et al. The net clinical benefit of warfarin anticoagulation in atrial fibrillation. Annals of Internal Medicine. 2009;151(5):297–305.
    1. Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. British Medical Journal. 2009;339b2700
    1. Cochran WG. The combination of estimates from different experiments. Biometrics. 1954;10(1):101–129.
    1. Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. British Medical Journal. 2003;327(7414):557–560.
    1. DerSimonian R, Laird N. Meta-analysis in clinical trials. Controlled Clinical Trials. 1986;7(3):177–188.
    1. Altman DG. Confidence intervals for the number needed to treat. British Medical Journal. 1998;317(7168):1309–1312.
    1. Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. Journal of the National Cancer Institute. 1959;22(4):719–748.
    1. The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan) [Computer program]. Version 5. 1, Copenhagen, 2011.
    1. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. The New England Journal of Medicine. 2009;361(12):1139–1151.
    1. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. The New England Journal of Medicine. 2011;365(10):883–891.
    1. Granger CB, Alexander JH, McMurray JJV, et al. Apixaban versus warfarin in patients with atrial fibrillation. The New England Journal of Medicine. 2011;365(11):981–992.
    1. Ezekowitz MD, Connolly S, Parekh A, et al. Rationale and design of RE-LY: randomized evaluation of long-term anticoagulant therapy, warfarin, compared with dabigatran. American Heart Journal. 2009;157(5):805.e2–810.e2.
    1. ROCKET AF Study Investigators. Rivaroxaban-once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation: rationale and design of the ROCKET AF Study. American Heart Journal. 2010;159(3):340–347.
    1. 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(3):331–339.
    1. Wallentin L, Yusuf S, Ezekowitz MD, et al. Efficacy and safety of dabigatran compared with warfarin at different levels of international normalised ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial. The Lancet. 2010;376(9745):975–983.
    1. Diener H-C, Connolly SJ, Ezekowitz MD, et al. Dabigatran compared with warfarin in patients with atrial fibrillation and previous transient ischaemic attack or stroke: a subgroup analysis of the RE-LY trial. The Lancet Neurology. 2010;9(12):1157–1163.
    1. Ezekowitz MD, Wallentin L, Connolly SJ, et al. Dabigatran and warfarin in vitamin K antagonist-naive and -experienced cohorts with atrial fibrillation. Circulation. 2010;122(22):2246–2253.
    1. Eikelboom JW, Wallentin L, Connolly SJ, et al. Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the randomized evaluation of long-term anticoagulant therapy (RE-LY) Trial. Circulation. 2011;123(21):2363–2372.
    1. Oldgren J, Alings M, Darius H, et al. Risks for stroke, bleeding, and death in patients with atrial fibrillation receiving dabigatran or warfarin in relation to the CHADS2 score: a subgroup analysis of the Re-Ly trial. Annals of Internal Medicine. 2011;155(10):660–667.
    1. Flaker G, Ezekowitz M, Yusuf S, et al. Efficacy and safety of dabigatran compared to warfarin in patients with paroxysmal, persistent, and permanent atrial fibrillation: results from the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) study. Journal of the American College of Cardiology. 2012;59(9):854–855.
    1. Hohnloser SH, Oldgren J, Yang S, et al. Myocardial ischemic events in patients with atrial fibrillation treated with dabigatran or warfarin in the RE-LY (Randomized evaluation of long-term anticoagulation therapy) trial. Circulation. 2012;125(5):669–676.
    1. Fox KAA, Piccini JP, Wojdyla D, et al. Prevention of stroke and systemic embolism with rivaroxaban compared with warfarin in patients with non-valvular atrial fibrillation and moderate renal impairment. European Heart Journal. 2011;32(19):2387–2394.
    1. Hankey GJ, Patel MR, Stevens SR, et al. Rivaroxaban compared with warfarin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a subgroup analysis of ROCKET AF. The Lancet Neurology. 2012;11(4):315–322.
    1. Easton JD, Lopes RD, Bahit MC, et al. Apixaban compared with warfarin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a subgroup analysis of the ARISTOTLE trial. The Lancet Neurology. 2012;11(6):503–5511.
    1. Lopes RD, Al-Khatib SM, Wallentin L, et al. Efficacy and safety of apixaban compared with warfarin according to patient risk of stroke and of bleeding in atrial fibrillation: a secondary analysis of a randomised controlled trial. The Lancet. 2012;380(9855):1749–1758.
    1. Connolly SJ, Ezekowitz MD, Yusuf S, Reilly PA, Wallentin L. Newly identified events in the RE-LY trial. The New England Journal of Medicine. 2010;363(19):1875–1876.
    1. Nagarakanti R, Ezekowitz MD, Oldgren J, et al. Dabigatran versus warfarin in patients with atrial fibrillation: an analysis of patients undergoing cardioversion. Circulation. 2011;123(2):131–136.
    1. Hori M, Connolly SJ, Ezekowitz MD, Reilly PA, Yusuf S, Wallentin L. Efficacy and safety of dabigatran vs. warfarin in patients with atrial fibrillation: sub-analysis in Japanese population in RE-LY trial. Circulation Journal. 2011;75(4):800–805.
    1. Diener H-C, Eikelboom J, Connolly SJ, et al. Apixaban versus aspirin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a predefined subgroup analysis from AVERROES, a randomised trial. The Lancet Neurology. 2012;11(3):225–231.
    1. Liesenfeld K-H, Lehr T, Dansirikul C, et al. Population pharmacokinetic analysis of the oral thrombin inhibitor dabigatran etexilate in patients with non-valvular atrial fibrillation from the RE-LY trial. Journal of Thrombosis and Haemostasis. 2011;9(11):2168–2175.
    1. Mueck W, Lensing AWA, Agnelli G, Decousus H, Prandoni P, Misselwitz F. Rivaroxaban: population pharmacokinetic analyses in patients treated for acute deep-vein thrombosis and exposure simulations in patients with atrial fibrillation treated for stroke prevention. Clinical Pharmacokinetics. 2011;50(10):675–686.
    1. Ezekowitz MD, Reilly PA, Nehmiz G, et al. Dabigatran with or without concomitant aspirin compared with warfarin alone in patients with nonvalvular atrial fibrillation (petro study) American Journal of Cardiology. 2007;100(9):1419–1426.
    1. Ogawa S, Shinohara Y, Kanmuri K. Safety and efficacy of the oral direct factor Xa inhibitor apixaban in Japanese patients with non-valvular atrial fibrillation. Circulation Journal. 2011;75(8):1852–1859.
    1. Connolly SJ, Eikelboom J, Joyner C, et al. Apixaban in patients with atrial fibrillation. The New England Journal of Medicine. 2011;364(9):806–817.
    1. Eikelboom JW, O’Donnell 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(3):348.e1–353.e1.
    1. FDA Briefing Information. Dabigatran Etexilate Mesylate Capsules, for the September 20, 2010 Meeting of the Cardiovascular and Renal Drugs Advisory Committee, 2013, .
    1. FDA Briefing Information for the September 8, 2011 Meeting of the Cardiovascular and Renal Drugs Advisory Committee. 2013, .
    1. FDA. Apixaban Clinical Review Addendum. December 17, 2012, .
    1. Boehringer Ingelheim Briefing Information. Dabigatran Etexilate Mesylate Capsules, for the September 20, 2010 Meeting of the Cardiovascular and Renal Drugs Advisory Committee. 2013, .
    1. Johnson & Johnson Briefing Information for the September 8, 2011 Meeting of the Cardiovascular and Renal Drugs Advisory Committee. .
    1. Patel MR, Hellkamp AS, Lokhnygina Y, et al. Outcomes of discontinuing rivaroxaban compared with warfarin in patients with nonvalvular atrial fibrillation: analysis from the ROCKET AF trial (Rivaroxaban Once-Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) Journal of the American College of Cardiology. 2013;61(6):651–658.
    1. Wallentin L, Lopes RD, Hanna M, et al. ARISTOTLE: efficacy and safety of apixaban compared with Warfarin at different levels of INR control for stroke prevention in 18, 202 patients with atrial fibrillation in the ARISTOTLE trial. Presentation at the European Society of Cardiology (ESC) Congress 2011. Paris, August 27–31, 2011, .
    1. Dentali F, Riva N, Crowther M, et al. Efficacy and safety of the novel oral anticoagulants in atrial fibrillation: a systematic review and meta-analysis of the literature. Circulation. 2012;126(20):2381–2391.
    1. Miller CS, Grandi SM, Shimony A, Filion KB, Eisenberg MJ. Meta-analysis of efficacy and safety of new oral anticoagulants (Dabigatran, Rivaroxaban, Apixaban) versus warfarin in patients with atrial fibrillation. American Journal of Cardiology. 2012;110(3):453–460.
    1. Eikelboom JW, Connolly SJ, Hart RG, et al. Balancing the benefits and risks of two doses of dabigatran compared with warfarin in atrial fibrillation. Journal of the American College of Cardiology. 2013;62(10):900–908.
    1. Meschia JF, Merrill P, Soliman EZ, et al. Racial disparities in awareness and treatment of atrial fibrillation: the REasons for geographic and racial differences in stroke (REGARDS) study. Stroke. 2010;41(4):581–587.
    1. Healey JS, Lip GY, Oldgren J, et al. Global variations in the 1-year rates of death and stroke in 15, 340 patients presenting to the emergency department with atrial fibrillation in 47 countries: the RE-LY AF Registry, " Presentation at the European Society of Cardiology (ESC) Congress 2012, Munich, August 25–29. 2012, .
    1. Connolly SJ, Pogue J, Eikelboom J, et al. Benefit of oral anticoagulant over antiplatelet therapy in atrial fibrillation depends on the quality of international normalized ratio control achieved by centers and countries as measured by time in therapeutic range. Circulation. 2008;118(20):2029–2037.
    1. Van Walraven C, Jennings A, Oake N, Fergusson D, Forster AJ. Effect of study setting on anticoagulation control: a systematic review and metaregression. Chest. 2006;129(5):1155–1166.
    1. Singer DE, Hellkamp AS, Piccini JP, et al. Impact of global geographic region on time in therapeutic range on warfarin anticoagulant therapy: data from the rocket AF clinical trial. Journal of the American Heart Association. 2013;2(1)e000067
    1. Flaherty ML. Anticoagulant-associated intracerebral hemorrhage. Seminars in Neurology. 2010;30(5):565–572.
    1. Fletcher J. Subgroup analyses: how to avoid being misled. British Medical Journal. 2007;335(7610):96–97.
    1. Sun X, Briel M, Walter SD, Guyatt GH. Is a subgroup effect believable? Updating criteria to evaluate the credibility of subgroup analyses. British Medical Journal. 2010;340c117
    1. Charland SL, Malone DC, Agatep BC, et al. Real-world risk of thromboembolism or bleeding with warfarin or dabigatran therapy in patients with atrial fibrillation, Presentation at the American Heart Association (AHA) Scientific Sessions 2012, Los Angeles, Calif, USA, November 3–7, 2012: abstract 16370.
    1. Gomes T, Mamdani MM, Holbrook AM, et al. Rates of hemorrhage during warfarin therapy for atrial fibrillation. Canadian Medical Association Journal. 2013;185(2):E121–E127.
    1. Simon TA, Huang HY, Kawabata H, et al. How well do the 56, 183 atrial fibrillation patients enrolled in the contemporary novel oral anticoagulant (NOAC) trials reflect the real world? American Public Health Association (APHA) 140th Annual Meeting & Expo, San Francisco, CA, October 23–31, 2012: paper 270987, .
    1. Committee for Medicinal Products for Human Use (CHMP) Pradaxa (dabigatran etexilate) European Public Assessment Report (EPAR). Procedure No.: EMEA/H/C/000829/II/0031, 23 August, 2012, .
    1. Han SY, Palmeri ST, Broderick SH, et al. Quality of anticoagulation with warfarin in patients with nonvalvular atrial fibrillation in the community setting. Journal of Electrocardiology. 2013;46(1):45–50.
    1. Van Spall HG, Wallentin L, Yusuf S, et al. Variation in warfarin dose adjustment practice is responsible for differences in the quality of anticoagulation control between centers and countries: an analysis of patients receiving warfarin in the RE-LY trial. Circulation. 2012;126(19):2309–2316.
    1. Heneghan C, Ward A, Perera R. Self-monitoring of oral anticoagulation: systematic review and meta-analysis of individual patient data. The Lancet. 2012;379(9813):322–334.

Source: PubMed

스폰서 및 공동 작업자

건강 상태

약물 개입

3
구독하다