Effect of apixaban on all-cause mortality in atrial fibrillation : an imputed placebo analysis

OBJECTIVE: To indirectly compare the effect of apixaban and placebo/control (P/C) on mortality in patients with atrial fibrillation (AF) using a meta-analysis of previous trials comparing warfarin with P/C and aspirin with P/C. BACKGROUND: ARISTOTLE demonstrated the superiority of apixaban over warfarin in preventing stroke or systemic embolism (SSE) and AVERROES showed the superiority of apixaban over aspirin in preventing SSE. METHODS: We used the meta-analysis of Hart RG et al (Ann Intern Med 2007), which included 6 warfarin versus P/C trials (n=2900 patients) and 7 aspirin versus P/C trials (n=3895). The method of Bucher HC et al (J Clin Epidemiol 1997) was used to make an indirect comparison of odds ratios (OR). RESULTS: The meta-analysis reported 143 deaths in 1450 patients on P/C and 110 deaths in 1450 patients on warfarin, OR 0.74 (95% confidence interval, 0.57, 0.97). In ARISTOTLE, 669 deaths occurred in 9081 patients on warfarin and 603 deaths in 9120 patients on apixaban, OR 0.89 (0.79, 0.99). An indirect comparison of apixaban with P/C gives an estimated apixaban/placebo OR for death of 0.66 (0.50, 0.88), p=0.004. The meta-analysis reported 204 deaths in 1993 patients on P/C and 184 deaths in 1902 patients on aspirin, OR 0.86 (0.69, 1.07). In AVERROES, 140 deaths occurred in 2791 patients on aspirin and 111 deaths in 2807 patients on apixaban, OR 0.79 (0.62, 1.02). Indirect comparison of apixaban with P/C gives an estimated apixaban/placebo OR of 0.67 (0.48, 0.94), p=0.02. Both comparisons combined provide an estimated apixaban/placebo OR for death of 0.66 (0.53, 0.82), p=0.0002. CONCLUSIONS: This imputed placebo analysis suggests that apixaban significantly reduces all-cause mortality by about one-third in patients with AF. Study Supported by: Bristol-Myers Squibb Company and Pfizer Inc. Editorial assistance in formatting the abstract to ensure compliance with AAN guidelines was provided by Stephanie Finucane of Caudex Medical and was funded by Bristol-Myers Squibb Company and Pfizer Inc. Disclosure: Dr. McMurray has nothing to disclose. Dr. Hart has received personal compensation for activities with Sanofi-Aventis Pharmaceuticals Inc., and Bristol-Myers Squibb Co. Dr. Flaker has received personal compensation for activities with Pfizer Inc., Bristol-Myers Squibb Co., and Janssen Pharmaceuticals. Dr. Lopes has received personal compensation for activities with AstraZeneca, Bayer Pharmaceuticals Inc., Boehringer Ingleheim Pharmaceuticals Inc., Bristol-Myers Squibb Co., and Pfizer Inc. as a consultant. Dr. Lopes has received research support from Bristol-Myers Squibb Co., and GlaxoSmithKline Inc. Dr. Wang has received personal compensation for activities with Bristol-Myers Squibb Company as an employee. Dr. Hanna has received personal compensation for activities with Bristol-Myers Squibb Co. as an employee. Dr. Hanna holds stock and/or stock options in Bristol-Meyers Squibb Co. which sponsored research in which Dr Hanna was involved as an investigator. Dr. Alexander has received personal compensation for activities with Bristol-Myers Squibb Company, Pfizer Inc, Merck & Co., Inc., Schering-Plough Corporation, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Ortho-McNeil, Janssen Pharmaceutica, Polymedix, Regado Biosciences, and Bayer Pharmaceuticals Corporation. Dr. Alexander has received research support from from Bristol-Myers Squibb Company, Merck & Co., Inc., Schering-Plough Corporation, and Regado Briosciences. Dr. Granger has nothing to disclose. Dr. Wallentin has received personal compensation for activities with Abbott, Athera Biotechnologies, Merck & Co. Inc., and Regado Biosciences, AstraZeneca, Bristol-Myers Squibb Co./Pfizer Inc., GlaxoSmithKline Inc. Dr. Wallentin has received research support from AstraZeneca, Boehringer Ingelheim Pharmaceuticals Inc., Bristol-Myers Squibb Co./Pfizer Inc., GlaxoSmithKline Inc., and Merck & Co. Inc.