Real-world comparison of major bleeding risk among non-valvular atrial fibrillation patients initiated on apixaban, dabigatran, rivaroxaban, or warfarin

Gregory Y. H. Lip; Allison Keshishian; Shital Kamble; Xianying Pan; Jack Mardekian; Ruslan Horblyuk; Melissa Hamilton

doi:10.1160/TH16-05-0403

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2016; 116(05): 975-986
DOI: 10.1160/TH16-05-0403

Stroke, Systemic or Venous Thromboembolism

Schattauer GmbH

Real-world comparison of major bleeding risk among non-valvular atrial fibrillation patients initiated on apixaban, dabigatran, rivaroxaban, or warfarin

A propensity score matched analysis

Gregory Y. H. Lip

¹University of Birmingham Institute of Cardiovascular Sciences, City Hospital, Birmingham, UK

²Aalborg Thrombosis Research Unit, Department of Clinical Medicine, Aalborg University, Aalborg, Denmark

,

Allison Keshishian

³STATinMED Research, Ann Arbor, Michigan, USA

,

Shital Kamble

⁴Bristol-Myers Squibb Company, Princeton, New Jersey, USA

,

Xianying Pan

⁴Bristol-Myers Squibb Company, Princeton, New Jersey, USA

,

Jack Mardekian

⁵Pfizer, Inc., New York, New York, USA

,

Ruslan Horblyuk

⁵Pfizer, Inc., New York, New York, USA

,

Melissa Hamilton

⁴Bristol-Myers Squibb Company, Princeton, New Jersey, USA

› Author Affiliations

Abstract

Summary

In addition to warfarin, there are four non-vitamin K antagonist oral anticoagulants (NOACs) available for stroke prevention in non valvular atrial fibrillation (NVAF). There are limited data on the comparative risks of major bleeding among newly anticoagulated NVAF patients who initiate warfarin, apixaban, dabigatran, or rivaroxaban, when used in ‘real world’ clinical practice. The study used the Truven MarketScan^® Commercial & Medicare supplemental US claims database. NVAF patients aged ≥18 years newly prescribed an oral anticoagulant 01JAN2013–31DEC2014, with a ≥1-year baseline period, were included (study period: 01JAN2012–31DEC2014). Major bleeding was defined as bleeding requiring hospitalisation. Propensity score matching (PSM) was used to balance age, sex, region, baseline comorbidities, and comedications. Cox proportional hazards models were used to estimate the PSM hazard ratio (HR) of major bleeding. Among 45,361 newly anticoagulated NVAF patients, 15,461 (34.1 %) initiated warfarin, 7,438 (16.4 %) initiated apixaban, 17,801 (39.2 %) initiated rivaroxaban, and 4,661 (10.3 %) initiated dabigatran. Compared to matched warfarin initiators, apixaban (HR: 0.53; 95 % CI: 0.39–0.71) and dabigatran (HR: 0.69; 95 % CI: 0.50–0.96) initiators had a significantly lower risk of major bleeding. Patients initiating rivaroxaban (HR: 0.98; 95 % CI: 0.83–1.17) had a non-significant difference in major bleeding risk compared to matched warfarin patients. When comparisons were made between NOACs, matched rivaroxaban patients had a significantly higher risk of major bleeding (HR: 1.82; 95 % CI: 1.36–2.43) compared to apixaban patients. The differences for apixaban-dabigatran and dabigatran-rivaroxaban matched cohorts were not statistically significant. Among newly anticoagulated NVAF patients in the real-world setting, apixaban and dabigatran initiation was associated with significantly lower risk of major bleeding compared to warfarin initiation. When compared to apixaban, rivaroxaban initiation was associated with significantly higher risk of major bleeding.

Note: The review process for this paper was fully handled by Christian Weber, Editor in Chief.

Supplementary Material to this article is available online at www.thrombosis-online.com.

Keywords

Non-valvular atrial fibrillation - major bleeding - warfarin - apixaban - dabigatran - rivaroxaban

Full Text

References

References
1 Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation: a major contributor to stroke in the elderly: the Framingham Study. Arch Intern Med 1987; 147: 1561-1564.
2 Savelieva I, Bajpai A, Camm AJ. Stroke in atrial fibrillation: update on patho-physiology, new antithrombotic therapies, and evolution of procedures and devices. Ann Med 2007; 39: 371-391.
3 January CT, Wann LS, Alpert JS. et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation. J Am Coll Cardiol 2014; 64: e1-76.
4 Hart RG, Pearce LA, Aguilar MM. Adjusted-dose warfarin versus aspirin for preventing stroke in patients with atrial fibrillation. Ann Intern Med 2007; 147: 590-592.
5 De Caterina R, Husted S, Wallentin L. et al. Vitamin K antagonists in heart disease: Current status and perspectives (Section III). Thromb Haemost 2013; 110: 1087-1107.
6 Ogilvie IM, Newton N, Welner SA, Cowell W, Lip GY. Underuse of oral anticoagulants in atrial fibrillation: a systematic review. Am J Med 2010; 123: 638-645.
7 Ruff CT, Giugliano RP, Braunwald E. et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet 2014; 383: 955-962.
8 Cunningham A, Stein CM, Chung CP. et al. An automated database case definition for serious bleeding related to oral anticoagulant use. Pharmacoepidemiol Drug Saf 2011; 20: 560-566.
9 Granger CB, Alexander JH, McMurray JJ. et al. Apixaban versus warfarin in patients with atrial fibrillation. New Engl J Med 2011; 365: 981-992.
10 Pattanayak CW, Rubin DB, Zell ER. Propensity score methods for creating co-variate balance in observational studies. Rev Esp Cardiol 2011; 6410: 897-903.
11 Baser O. Too Much Ado about Propensity Score Models? Comparing Methods of Propensity Score Matching. Value Health 2006; 09: 377-385.
12 Austin PC. An introduction to propensity score methods for reducing the effects of confounding in observational studies. Behavioral Res 2011; 46: 399-424.
13 Connolly SJ, Ezekowitz MD, Yusuf S. et al. Dabigatran versus warfarin in patients with atrial fibrillation. New Engl J Med 2010; 361: 1139-1151.
14 Patel MR, Mahaffey KW, Garg J. et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. New Engl J Med 2011; 365: 883-891.
15 Camm AJ, Amarenco P, Haas S. et al. XANTUS: a real-world, prospective, observational study of patients treated with rivaroxaban for stroke prevention in atrial fibrillation. Eur Heart J 2016; 37: 1145-1153.
16 Abraham NS, Singh S, Akexander GC. et al. Comparative Risk of gastrointestinal bleeding with dabigatran, rivaroxaban, and warfarin: population based cohort study. Br Med J 2015; 350: h1857.
17 Seeger JD, Bykov K, Bartels DB. et al. Safety and effectiveness of dabigatran and warfarin in routine care of patients with atrial fibrillation. Thromb Haemost 2015; 114: 1277-1289.
18 Southworth MR, Reichman ME, Unger EF. Dabigatran and postmarketing reports of bleeding. New Engl J Med 2013; 368: 1272-1274.
19 Graham DJ, Reichman ME, Wernecke M. et al. Cardiovascular, Bleeding, and Mortality Risks in Elderly Medicare Patients Treated With Dabigatran or Warfarin for Nonvalvular Atrial Fibrillation. Circulation 2015; 131: 157-163.
20 Lip GY, Larsen TB, Skjoth F. et al. Indirect comparisons of new oral anticoagulant drugs for efficacy and safety when used for stroke prevention in atrial fibrillation. J Am Coll Cardiol 2012; 60: 738-746.
21 Mantha S, Ansell J. An indirect comparison of dabigatran, rivaroxaban and apixaban for atrial fibrillation. Thromb Haemost 2012; 108: 476-484.
22 Larsen TB, Skjøth F, Nielsen PB. et al. Comparative effectiveness and safety of non-vitamin antagonist oral anticoagulants and warfarin in patients with atrial fibrillation: propensity weighted nationwide cohort study. Br Med J 2016; 350: 3189.
23 Ho CW, Ho MH, Chan PH. et al. Ischaemic stroke and intracranial haemorrhage with aspirin, dabigatran, and warfarin: impact of quality of anticoagulation control. Stroke 2015; 46: 23-30.
24 Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc 1999; 94: 496-509.
25 Austin PC, Lee DS, Fine JP. Introduction to the analysis of survival data in the presence of competing risks. Circulation 2016; 133: 601-609.

Supplementary Material

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