Comparative Stroke, Bleeding, and Mortality

ARTICLE IN PRESS hemorrhage changed as to whether differences were statisti- cally significant ( Supplementary Table 9 , available online). DISCUSSION NOAC vs Warfarin Among NOAC users with nonvalvular atrial fibrillation and warfarin users with similar baseline characteristics, each NOAC was associated with statistically significant reduc- tions in thromboembolic stroke, intracranial hemorrhage, and all-cause mortality compared with warfarin. Based on these findings, each NOAC was associated with a more favorable benefit − harm balance than warfarin. Our HR estimates for intracranial hemorrhage and major extracranial or gastrointestinal bleeding with each NOAC vs warfarin were similar to those reported in the pivotal pre- approval clinical trials . 1-3 For thromboembolic stroke, we found a reduced HR (protective effect) for dabigatran simi- lar to that reported in its pivotal trial , 1 but for rivaroxaban and apixaban, we found substantial reductions in risk that were not found in their respective trials . 2,3 For all-cause mortality, our HR estimates indicated greater risk reduction with each NOAC than was reported in the pivotal trials, where risk reductions of 11%-15% were observed, but was significant only for apixaban . 1-3 Despite close balance between cohorts for the large num- ber of covariates we adjusted for, residual confounding due to channeling of sicker patients to warfarin or unmeasured covariates is possible, and could have contributed to the dif- ferences between our study and the pivotal NOAC trials with respect to thromboembolic stroke and all-cause mortality risks. Another possibility is that warfarin control was better in the NOAC clinical trials than in the “real-world” commu- nity setting represented by our study. The time in therapeutic range among warfarin-treated patients in the NOAC trials was 62% for apixaban, 64% for dabigatran, and 55% for rivaroxaban , 1-3 while a national study of time in therapeutic range in the community setting reported an estimate of 48% among patients treated for < 6 months , 24 which could apply to much of our study population. A systematic review of published studies also found that warfarin control was signif- icantly better in randomized trials than in retrospective stud- ies . 25 Suboptimal warfarin control is associated with higher stroke, bleeding, and mortality risks . 26 Poorer quality warfa- rin control in our study population than in the pivotal trials might explain our findings of NOAC superiority for throm- boembolic stroke and all-cause mortality. NOAC vs NOAC Among NOACs, the risk of thromboembolic stroke was similar, but rivaroxaban was associated with significantly increased risk of intracranial hemorrhage compared with dabigatran and with significantly increased risks of major extracranial bleeding and death, compared with dabigatran or apixaban. Although the NOACs each have a half-life of about 12 hours, dabigatran and apixaban are dosed twice daily, while rivaroxaban is dosed once daily, which may account for our findings. Concern about once-daily dosing of rivaroxaban was raised during an FDA advisory commit- tee meeting convened prior to rivaroxaban’s approval . 27 8.1 9.0 11.2 8.8 5.6 3.3 8.6 4.8 35.5 26.9 25.9 14.6 23.8 21.5 29.6 21.0 Thromboembolic Stroke Intracranial Hemorrhage Major Extracran. Bleeding Death 0 10 20 30 40 Weighted Event Rates per 1000 person−years Cohort Warfarin (N=183,003) Dabigatran (N=86,293) Rivaroxaban (N=106,369) Apixaban (N=72,921) Figure 1 Adjusted incidence rates per 1000 person-years of thromboembolic stroke, intracranial hemorrhage, major extracranial bleeding, and all-cause mortality in Medicare beneficiaries with nonvalvular atrial fibrillation treated with warfarin, dabigatran, rivar- oxaban, or apixaban. Weighted cohort sizes are shown. 6 The American Journal of Medicine, Vol 000, No 000, && 2019