Real-World Comparative Effectiveness, Safety, and Health Care Costs of Oral Anticoagulants in Nonvalvular Atrial Fibrillation Patients in the U.S. Department of Defense Population

BACKGROUND: The ARISTOTLE trial demonstrated that apixaban had significantly lower rates of stroke/systemic embolism (SE) and major bleeding than warfarin; however, no direct clinical trials between apixaban and other direct oral anticoagulants (DOACs) are available. Few real-world studies comparing the effectiveness and safety between DOACs have been conducted. OBJECTIVE: To compare effectiveness, safety, and health care costs among oral anticoagulants (OACs) for nonvalvular atrial fibrillation (NVAF) patients in the U.S. Department of Defense (DoD) population. METHODS: Adult NVAF patients initiating warfarin or DOACs (apixaban, rivaroxaban, and dabigatran) were selected from U.S. DoD data from January 1, 2013, to September 30, 2015. The first OAC claim date was designated as the index date. Patients initiating another OAC were matched 1:1 to apixaban patients using propensity score matching to balance demographics and clinical characteristics. Cox proportional hazards models were used to estimate the risk of stroke/SE and major bleeding for each OAC versus apixaban. Generalized linear and two-part models with bootstrapping were used to compare all-cause health care costs and stroke/SE-related and major bleeding-related medical costs. RESULTS: Of the 41,001 eligible patients, 7,607 warfarin-apixaban, 4,129 dabigatran-apixaban, and 11,284 rivaroxaban-apixaban pairs were matched. Warfarin (HR = 1.84; 95% CI = 1.30-2.59; P < 0.001) and rivar-oxaban (HR = 1.46; 95% CI = 1.08-1.98; P = 0.015) were associated with a significantly higher risk of stroke/SE compared with apixaban. Dabigatran (HR = 1.17; 95% CI = 0.68-2.03; P = 0.573) was associated with a numerically higher risk of stroke/SE compared with apixaban. Warfarin (HR = 1.53; 95% CI = 1.24-1.89; P < 0.001), dabigatran (HR = 1.76; 95% CI = 1.27-2.43; P < 0.001), and rivaroxaban (HR = 1.59; 95% CI = 1.34-1.89; P < 0.001) were associated with higher risks of major bleeding compared with apixaban. Compared with apixaban, patients prescribed warfarin incurred numerically higher all-cause total health care costs per patient per month (PPPM) ($2,498 vs. $2,277; P = 0.148) and significantly higher stroke/SE-related ($118 vs. $46; P = 0.012) and major bleeding-related ($166 vs. $76; P = 0.003) medical costs. Dabigatran patients incurred numerically higher all-cause total health care PPPM costs ($2,372 vs. $2,143; P = 0.150) and stroke/SE-related medical costs ($61 vs. $32; P = 0.240) but significantly higher major bleeding-related costs ($114 vs. $58; P = 0.025). Rivaroxaban patients incurred significantly higher all-cause total health care costs ($2,546 vs. $2,200; P < 0.001) and major bleeding-related medical costs PPPM ($137 vs. $69; P < 0.001) but numerically higher stroke/SE-related medical costs PPPM ($58 vs. $38; P = 0.057). CONCLUSIONS: Among NVAF patients in the U.S. DoD population, warfarin and rivaroxaban were associated with a significantly higher risk of stroke/SE and major bleeding compared with apixaban. Dabigatran use was associated with a numerically higher risk of stroke/SE and a significantly higher risk of major bleeding compared with apixaban. Warfarin and dabigatran incurred numerically higher all-cause total health care costs compared with apixaban. Rivaroxaban was associated with significantly higher all-cause total health care costs compared with apixaban.