Comparative Stroke, Bleeding, and Mortality

ARTICLE IN PRESS Based on these results, dabigatran and apixaban were asso- ciated with a more favorable benefit − harm profile than rivaroxaban. Dabigatran and apixaban had similar thromboembolic stroke and all-cause mortality risk. Dabigatran was associ- ated with significantly increased major extracranial bleed- ing risk but significantly reduced intracranial hemorrhage risk, possibly supporting a more favorable benefit − harm profile for it compared with apixaban. Sensitivity analyses for dabigatran vs apixaban were largely consistent with the primary analysis, but indicated a small change in thrombo- embolic stroke and intracranial hemorrhage risk that might shift the benefit − harm profile in apixaban’s favor. Addi- tional studies are needed to clarify the comparative benefit − harm of these drugs. Seven observational studies compared our study NOACs against each other for thromboembolic stroke or bleeding risks . 5-11 These were generally small and underpowered. In 2, intracranial hemorrhage and extracranial bleeding were combined as a single outcome and separate estimates for each were not provided. 5,6 For thromboembolic stroke, one study found no difference in risk, consistent with our find- ings , 7 and one reported increased risk for rivaroxaban com- pared with apixaban . 8 Of the 4 studies examining intracranial hemorrhage, risk was increased for rivaroxaban compared with dabigatran in 2 , 7,9 and was reduced for dabi- gatran compared with apixaban in one , 9 in agreement with our study. None of these studies examined extracranial bleeding, but 4 did assess gastrointestinal bleeding risks across NOACs . 8-11 Rivaroxaban risk was increased in 0.73 1.04 0.38 0.80 Favors Dabigatran Favors Warfarin 0.81 1.38 0.65 0.72 Favors Rivaroxaban Favors Warfarin 0.66 0.51 0.54 0.71 Favors Apixaban Favors Warfarin Dabigatran vs. Warfarin (ref) Rivaroxaban vs. Warfarin (ref) Apixaban vs. Warfarin (ref) 0.3 0.5 0.7 1.0 1.5 2.0 0.3 0.5 0.7 1.0 1.5 2.0 0.3 0.5 0.7 1.0 1.5 2.0 Death Major Extracranial Bleeding Intracranial Hemorrhage Thromboembolic Stroke Hazard Ratio A 1.12 1.32 1.71 0.90 Favors Rivaroxaban Favors Dabigatran 1.23 2.70 1.21 1.02 Favors Rivaroxaban Favors Apixaban 1.10 2.04 0.70 1.14 Favors Dabigatran Favors Apixaban Rivaroxaban vs. Dabigatran (ref) Rivaroxaban vs. Apixaban (ref) Dabigatran vs. Apixaban (ref) 0.5 0.7 1.0 1.5 2.0 4.0 0.5 0.7 1.0 1.5 2.0 4.0 0.5 0.7 1.0 1.5 2.0 4.0 Death Major Extracranial Bleeding Intracranial Hemorrhage Thromboembolic Stroke Hazard Ratio B Figure 2 Adjusted hazard ratios with 95% confidence intervals from comparisons of each nonvitamin K antagonist oral anticoagu- lant (NOAC) vs warfarin (A) and each NOAC vs each other NOAC (B) for the outcomes of thromboembolic stroke, intracranial hem- orrhage, major extracranial bleeding, and all-cause mortality. Graham et al Comparative Safety and Effectiveness of Anticoagulants in Atrial Fibrillation 7