Gender Difference in Efficacy and Safety of Nonvitamin K Antagonist Oral Anticoagulants in Patients with Nonvalvular Atrial Fibrillation or Venous Thromboembolism: A Systematic Review and a Meta-Analysis of the Literature

Abstract

Introduction Limited information exists on gender-related differences in the safety and efficacy of non-vitamin K antagonist oral anticoagulants (NOACs).

Aim of the Study To assess the safety and efficacy of direct oral anticoagulants (DOACs)/NOACs in men and women pooling data from randomized controlled trials on the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (AF) and on the acute and extended treatment of venous thromboembolism (VTE).

Methods MEDLINE and EMBASE databases were searched up to June 2014. The efficacy outcome was defined as the prevention of stroke and systemic embolism (AF studies), or as the prevention of recurrent VTE or VTE-related death (VTE studies). The safety outcome was defined as the occurrence of major and/or clinically relevant nonmajor bleeding. Differences in the efficacy and safety outcomes were expressed as risk ratio (RR) with pertinent 95% confidence intervals (95% CI).

Results A total of 13 studies (> 100,000 patients) were included. DOACs appeared to have a similar efficacy and safety compared with vitamin K antagonists in female and male patients treated for nonvalvular AF and acute VTE. In the extended treatment of VTE NOACs had a RR of bleeding of 4.97 (95% CI 1.06, 23.41) in males and 1.33 (95% CI 0.63, 2.83) in females compared with placebo (subgroup difference chi-square test: 2.25, p = 0.13).

Conclusions No gender-related difference in the efficacy and safety of NOACs in patients with AF or acute VTE was found. A trend toward an increased risk of bleeding in male patients as compared with female patients was detected in the extended treatment of VTE.

Keywords

direct oral anticoagulants - atrial fibrillation - venous thromboembolism - gender

Note

The authors have no conflict of interest to declare.

• References

• 1 Reeves MJ, Bushnell CD, Howard G , et al. Sex differences in stroke: epidemiology, clinical presentation, medical care, and outcomes. Lancet Neurol 2008; 7 (10) 915-926
• 2 McRae S, Tran H, Schulman S, Ginsberg J, Kearon C. Effect of patient's sex on risk of recurrent venous thromboembolism: a meta-analysis. Lancet 2006; 368 (9533) 371-378
• 3 Berger JS, Roncaglioni MC, Avanzini F, Pangrazzi I, Tognoni G, Brown DL. Aspirin for the primary prevention of cardiovascular events in women and men: a sex-specific meta-analysis of randomized controlled trials. JAMA 2006; 295 (3) 306-313
• 4 Lapner S, Cohen N, Kearon C. Influence of sex on risk of bleeding in anticoagulated patients: a systematic review and meta-analysis. J Thromb Haemost 2014; 12 (5) 595-605
• 5 Seeland U, Regitz-Zagrosek V. Sex and gender differences in cardiovascular drug therapy. Handbook Exp Pharmacol 2012; (214) 211-236
• 6 Schulman S. Advantages and limitations of the new anticoagulants. J Intern Med 2014; 275 (1) 1-11
• 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 (9921) 955-962
• 8 van der Hulle T, Kooiman J, den Exter PL, Dekkers OM, Klok FA, Huisman MV. Effectiveness and safety of novel oral anticoagulants as compared with vitamin K antagonists in the treatment of acute symptomatic venous thromboembolism: a systematic review and meta-analysis. J Thromb Haemost 2014; 12 (3) 320-328
• 9 Moher D, Liberati A, Tetzlaff J, Altman DG ; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med 2009; 151 (4) 264-269 , W64
• 10 Schulman S, Kearon C ; Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost 2005; 3 (4) 692-694
• 11 Jadad AR, Moore RA, Carroll D , et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary?. Control Clin Trials 1996; 17 (1) 1-12
• 12 Connolly SJ, Ezekowitz MD, Yusuf S , et al; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361 (12) 1139-1151
• 13 Patel MR, Mahaffey KW, Garg J , et al; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365 (10) 883-891
• 14 Granger CB, Alexander JH, McMurray JJ , et al; ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365 (11) 981-992
• 15 Giugliano RP, Ruff CT, Braunwald E , et al; ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013; 369 (22) 2093-2104
• 16 Agnelli G, Buller HR, Cohen A , et al; AMPLIFY Investigators. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med 2013; 369 (9) 799-808
• 17 Bauersachs R, Berkowitz SD, Brenner B , et al; EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010; 363 (26) 2499-2510
• 18 Büller HR, Prins MH, Lensin AW , et al; EINSTEIN–PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012; 366 (14) 1287-1297
• 19 Schulman S, Kearon C, Kakkar AK , et al; RE-COVER Study Group. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009; 361 (24) 2342-2352
• 20 Schulman S, Kakkar AK, Goldhaber SZ , et al; RE-COVER II Trial Investigators. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation 2014; 129 (7) 764-772
• 21 Büller HR, Décousus H, Grosso MA , et al; Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med 2013; 369 (15) 1406-1415
• 22 Agnelli G, Buller HR, Cohen A , et al; PLIFY-EXT Investigators. Apixaban for extended treatment of venous thromboembolism. N Engl J Med 2013; 368 (8) 699-708
• 23 Schulman S, Kearon C, Kakkar AK , et al; RE-MEDY Trial Investigators; RE-SONATE Trial Investigators. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med 2013; 368 (8) 709-718
• 24 Hylek EM, Held C, Alexander JH , et al. Major bleeding in patients with atrial fibrillation receiving apixaban or warfarin: The ARISTOTLE Trial (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation): Predictors, Characteristics, and Clinical Outcomes. J Am Coll Cardiol 2014; 63 (20) 2141-2147
• 25 Pancholy SB, Sharma PS, Pancholy DS, Patel TM, Callans DJ, Marchlinski FE. Meta-analysis of gender differences in residual stroke risk and major bleeding in patients with nonvalvular atrial fibrillation treated with oral anticoagulants. Am J Cardiol 2014; 113 (3) 485-490
• 26 Harris DJ, Douglas PS. Enrollment of women in cardiovascular clinical trials funded by the National Heart, Lung, and Blood Institute. N Engl J Med 2000; 343 (7) 475-480
• 27 Murthy VH, Krumholz HM, Gross CP. Participation in cancer clinical trials: race-, sex-, and age-based disparities. JAMA 2004; 291 (22) 2720-2726
• 28 Bushnell C, McCullough LD, Awad IA , et al; American Heart Association Stroke Council; Council on Cardiovascular and Stroke Nursing; Council on Clinical Cardiology; Council on Epidemiology and Prevention; Council for High Blood Pressure Research. Guidelines for the prevention of stroke in women: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2014; 45 (5) 1545-1588
• 29 Feinberg WM, Blackshear JL, Laupacis A, Kronmal R, Hart RG. Prevalence, age distribution, and gender of patients with atrial fibrillation. Analysis and implications. Arch Intern Med 1995; 155 (5) 469-473