Comparative Stroke, Bleeding, and Mortality

ARTICLE IN PRESS 2 studies compared with dabigatran , 10,11 and was increased in 3 studies compared with apixaban . 8,10,11 Dabigatran risk was increased compared with apixaban in 2 studies . 9,11 These were consistent with our findings for gastrointestinal bleeding ( Supplementary Table 6 ) . Our study had several unique strengths. It was national in scope, and among studies comparing the 3 most widely marketed NOACs, was the largest by a factor of 2.7- to 60- fold, depending on the NOAC and comparator involved. Our study assessed a range of relevant clinical outcomes, including mortality, facilitating assessment of the overall balance of benefits and harms, and it applied a single pro- pensity score model to all 4 study cohorts simultaneously, resulting in a single adjusted population being used for all pairwise comparisons, thus providing HR estimates that can be directly compared with each other. Our study had several limitations. It was observational and may be subject to confounding by factors not adjusted for in the analysis (eg, quality of blood pressure control) or by residual channeling bias. Also, the mean duration of continuous anticoagulant use was < 5 months. Despite this, we had a larger number of patients still on therapy at 8 months than the number starting NOAC therapy in most other studies comparing these NOACs to each other . 5-11 Our study was restricted to patients aged 65 years or older, the age-group accounting for over 80% of atrial fibrillation patients . 28 The comparative effects of NOACs could be different in younger-aged populations. We studied only ini- tiators of standard-dose NOACs. Comparative effects may differ in patients treated with the lower dose. Because we excluded warfarin users less likely to be treated with an NOAC, our results may not be generalizable to them. How- ever, a post hoc analysis including all warfarin users yielded results largely consistent with the primary analysis. Finally, our study examined first-time users of an anticoag- ulant for stroke prevention in nonvalvular atrial fibrillation. Results could differ in patients switching from warfarin to an NOAC. 72,921 38,260 20,583 13,562 8,589 5,679 106,369 61,124 35,676 25,738 18,068 13,399 86,293 46,264 24,764 18,037 12,570 9,387 183,003 119,051 58,261 41,797 27,869 20,091 0.0 0.2 0.4 0.6 0.8 Apixaban Rivaroxaban Dabigatran Warfarin 0 60 120 180 240 300 Follow up Time (Days) Weighted Number at Risk Cumulative Adjusted Incidence Rate (%) Cohort Warfarin Dabigatran Rivaroxaban Apixaban Thromboembolic Stroke 72,921 38,260 20,583 13,562 8,589 5,679 106,369 61,124 35,676 25,738 18,068 13,399 86,293 46,264 24,764 18,037 12,570 9,387 183,003 119,051 58,261 41,797 27,869 20,091 0.0 0.2 0.4 0.6 0.8 Apixaban Rivaroxaban Dabigatran Warfarin 0 60 120 180 240 300 Follow up Time (Days) Weighted Number at Risk Cumulative Adjusted Incidence Rate (%) Cohort Warfarin Dabigatran Rivaroxaban Apixaban Intracranial Hemorrhage 72,921 38,260 20,583 13,562 8,589 5,679 106,369 61,124 35,676 25,738 18,068 13,399 86,293 46,264 24,764 18,037 12,570 9,387 183,003 119,051 58,261 41,797 27,869 20,091 0.0 0.5 1.0 1.5 2.0 2.5 3.0 Apixaban Rivaroxaban Dabigatran Warfarin 0 60 120 180 240 300 Follow up Time (Days) Weighted Number at Risk Cumulative Adjusted Incidence Rate (%) Cohort Warfarin Dabigatran Rivaroxaban Apixaban Major Extracranial Bleeding 72,921 38,260 20,583 13,562 8,589 5,679 106,369 61,124 35,676 25,738 18,068 13,399 86,293 46,264 24,764 18,037 12,570 9,387 183,003 119,051 58,261 41,797 27,869 20,091 0.0 0.5 1.0 1.5 2.0 Apixaban Rivaroxaban Dabigatran Warfarin 0 60 120 180 240 300 Follow up Time (Days) Weighted Number at Risk Cumulative Adjusted Incidence Rate (%) Cohort Warfarin Dabigatran Rivaroxaban Apixaban Major GI Bleeding Figure 3 Adjusted Kaplan-Meier plots for thromboembolic stroke, intracranial hemorrhage, major extracranial bleeding, and all- cause mortality, in cohorts of Medicare beneficiaries treated with warfarin, dabigatran, rivaroxaban, or apixaban for nonvalvular atrial fibrillation. Weighted cohort sizes are shown. 8 The American Journal of Medicine, Vol 000, No 000, && 2019