Meta-Analysis of Gender Differences in Residual Stroke Risk and Major Bleeding in Patients With Nonvalvular Atrial Fibrillation Treated With Oral Anticoagulants Samir B. Pancholy, MDa,*, Parikshit S. Sharma, MDa, Dipti S. Pancholy, MDa, Tejas M. Patel, MDb, David J. Callans, MDc, and Francis E. Marchlinski, MDc Studies comparing gender-specific outcomes in patients with atrial fibrillation (AF) have reported conflicting results. Gender differences in cerebrovascular accident/systemic embolism (CVA/SE) or major bleeding outcomes with novel oral anticoagulant (NOAC) use are not known. The goal of this analysis was to perform a systematic review and metaanalysis evaluating gender differences in residual risk of CVA/SE and major bleeding outcomes in patients with nonvalvular AF treated with either warfarin or NOAC. Sixty-four randomized studies were identified using keywords “gender,” “AF,” and “CVA.” Using the Preferred Reporting Items for Systemic Reviews and Meta-analysis method, 6 studies met criteria for inclusion in this meta-analysis. CVA/SE and major bleeding outcomes were separately analyzed in cohorts receiving warfarin and NOAC agents, comparing men with women. Women with AF taking warfarin were at a significantly greater residual risk of CVA/SE compared with men (odds ratio 1.279, 95% confidence interval 1.111 to 1.473, Z [ L3.428, p [ 0.001). No gender difference in residual risk of CVA/SE was noted in patients with AF receiving NOAC agents (odds ratio 1.146, 95% confidence interval 0.97 to 1.354, p [ 0.109). Major bleeding was less frequent in women with AF treated with NOAC. In conclusion, women with AF treated with warfarin have a greater residual risk of CVA/ SE and an equivalent major bleeding risk, whereas those treated with NOAC agents deemed superior to warfarin are at equivalent residual risk of CVA/SE and less major bleeding risk compared with men. These results suggest an increased net clinical benefit of NOAC agents compared with warfarin in treating women with AF. Ó 2014 Elsevier Inc. All rights reserved. (Am J Cardiol 2014;113:485e490) Atrial fibrillation (AF) is the most common sustained arrhythmia in developed nations.1e3 The incidence and prevalence of AF are increasing both in the United States and across the world.1,2 Despite greater prevalence of AF among men,3 studies have shown that the risk of cerebrovascular accident (CVA) and systemic embolization (SE) is greater among women compared with men. A 2.5-fold increase in the prevalence of AF is projected by the year 2050, likely to affect nearly 5.6 million Americans.4 In nonanticoagulated patients with AF, female gender is an independent risk factor for CVA/SE.5,6 This is reflected in the recently validated CHADS2-VASc scoring system.7,8 Data on gender differences in efficacy of warfarin for stroke prevention are conflicting.9e12 NOAC theoretically provide a more stable anticoagulant effect13; however it remains unclear if this pharmacokinetic advantage translates into an
a Department of Medicine and Cardiology, The Wright Center for Graduate Medical Center, Scranton, Pennsylvania; bDepartment of Cardiology, Seth N.H.L. Municipal Medical College, Ahmedabad, India; and c Department of Cardiology, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, Pennsylvania. Manuscript received September 16, 2013; revised manuscript received and accepted October 9, 2013. See page 489 for disclosure information. *Corresponding author: Tel: (570) 587-7817; fax: (570) 504-2780. E-mail address: [email protected] (S.B. Pancholy).
0002-9149/13/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2013.10.035
outcome benefit. Gender differences in CVA/SE outcomes with NOAC agents are largely unknown. We sought to analyze gender differences in the residual risk of CVA/SE and major bleeding in patients with AF treated with warfarin and NOAC and evaluate effect size of the point estimates, in a pooled sample from randomized trials reported in the published literature. Methods Using the keywords “atrial Fibrillation,” “gender,” “anticoagulation,” and “outcomes,” we searched indexed studies recorded in major databases including PubMed, EMBASE, Cochrane Library, and Google Scholar. The method outlined in the Preferred Reporting Items for Systemic Reviews and Meta-analysis document was used.14 A total of 452 relevant studies were identified on search using these databases and reviewed independently by 4 investigators to check if they met inclusion criteria. We included all randomized trials of AF with data on gender and anticoagulation with the composite end point of all stroke and systemic embolization at 1 year. All identified studies were screened initially by the title and abstract, and 37 prospective studies were identified. Two sets of analyses were performed: first set of analyses evaluating gender differences in patients treated with warfarin and second set analyzing gender differences in patients treated with NOAC. After a detailed review of trials, a total of 6 www.ajconline.org
486
The American Journal of Cardiology (www.ajconline.org)
A pooled analysis of differences in event rates of CVA/ SE between men and women treated with warfarin was performed. A primary analysis of differences in CVA/SE event rates between men and women treated with those agents that met superiority (in either intent-to-treat analysis or per-protocol analysis) compared with warfarin in the published literature was performed. A pooled analysis of gender differences in major bleeding, defined using International Society of Thrombosis and Hemostasis definition22 was performed for the cohorts treated with warfarin and NOAC agents deemed superior to warfarin. Results
Figure 1. Flow diagram describing the process of study selection (inclusion/ exclusion).
randomized controlled trials met inclusion criteria. Five randomized controlled trials reported gender-specific outcome differences in warfarin-treated patients.15e19 Gender-specific outcome data on patients treated with NOAC was pooled from the NOAC arm of 4 randomized controlled trials comparing warfarin and NOAC16e19 and 1 study reporting gender-specific data on patients treated with NOAC or aspirin.20 The gender-specific data for patients treated with apixabanin in that trial were included in this analysis and data from the aspirin arm was not used in the analysis. Figure 1 depicts the flow of study evaluation (inclusion and exclusion) process. Using a standardized data collection form, the data were independently abstracted. Any discrepancies in data were resolved through a review and consensus. Baseline characteristics for both study groups were extracted from the studies. The absolute number of the composite end point events was used for analysis. Comprehensive Meta-Analysis software (Biostat, Englewood, New Jersey)21 was used to perform the analysis. Heterogeneity was assessed using the I2 test, and an I2 of
a Department of Medicine and Cardiology, The Wright Center for Graduate Medical Center, Scranton, Pennsylvania; bDepartment of Cardiology, Seth N.H.L. Municipal Medical College, Ahmedabad, India; and c Department of Cardiology, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, Pennsylvania. Manuscript received September 16, 2013; revised manuscript received and accepted October 9, 2013. See page 489 for disclosure information. *Corresponding author: Tel: (570) 587-7817; fax: (570) 504-2780. E-mail address: [email protected] (S.B. Pancholy).
0002-9149/13/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2013.10.035
outcome benefit. Gender differences in CVA/SE outcomes with NOAC agents are largely unknown. We sought to analyze gender differences in the residual risk of CVA/SE and major bleeding in patients with AF treated with warfarin and NOAC and evaluate effect size of the point estimates, in a pooled sample from randomized trials reported in the published literature. Methods Using the keywords “atrial Fibrillation,” “gender,” “anticoagulation,” and “outcomes,” we searched indexed studies recorded in major databases including PubMed, EMBASE, Cochrane Library, and Google Scholar. The method outlined in the Preferred Reporting Items for Systemic Reviews and Meta-analysis document was used.14 A total of 452 relevant studies were identified on search using these databases and reviewed independently by 4 investigators to check if they met inclusion criteria. We included all randomized trials of AF with data on gender and anticoagulation with the composite end point of all stroke and systemic embolization at 1 year. All identified studies were screened initially by the title and abstract, and 37 prospective studies were identified. Two sets of analyses were performed: first set of analyses evaluating gender differences in patients treated with warfarin and second set analyzing gender differences in patients treated with NOAC. After a detailed review of trials, a total of 6 www.ajconline.org
486
The American Journal of Cardiology (www.ajconline.org)
A pooled analysis of differences in event rates of CVA/ SE between men and women treated with warfarin was performed. A primary analysis of differences in CVA/SE event rates between men and women treated with those agents that met superiority (in either intent-to-treat analysis or per-protocol analysis) compared with warfarin in the published literature was performed. A pooled analysis of gender differences in major bleeding, defined using International Society of Thrombosis and Hemostasis definition22 was performed for the cohorts treated with warfarin and NOAC agents deemed superior to warfarin. Results
Figure 1. Flow diagram describing the process of study selection (inclusion/ exclusion).
randomized controlled trials met inclusion criteria. Five randomized controlled trials reported gender-specific outcome differences in warfarin-treated patients.15e19 Gender-specific outcome data on patients treated with NOAC was pooled from the NOAC arm of 4 randomized controlled trials comparing warfarin and NOAC16e19 and 1 study reporting gender-specific data on patients treated with NOAC or aspirin.20 The gender-specific data for patients treated with apixabanin in that trial were included in this analysis and data from the aspirin arm was not used in the analysis. Figure 1 depicts the flow of study evaluation (inclusion and exclusion) process. Using a standardized data collection form, the data were independently abstracted. Any discrepancies in data were resolved through a review and consensus. Baseline characteristics for both study groups were extracted from the studies. The absolute number of the composite end point events was used for analysis. Comprehensive Meta-Analysis software (Biostat, Englewood, New Jersey)21 was used to perform the analysis. Heterogeneity was assessed using the I2 test, and an I2 of
