Comparative Stroke, Bleeding, and Mortality

ARTICLE IN PRESS INTRODUCTION In the pivotal randomized clinical trials of the nonvitamin K oral anticoagulants (NOACs) in patients with nonvalv- ular atrial fibrillation, dabigatran and apixaban were superior to, and rivaroxaban and edoxaban were noninfe- rior to, warfarin for stroke and systemic embolization prevention. 1-4 Each of the NOACs also reduced risk of intracranial hemorrhage. 1-4 There have been no head-to-head randomized trials to determine if any of the NOACs differ from the others with respect to their effects on stroke, bleeding, and mortality, and only a handful of observational studies have com- pared dabigatran, rivaroxaban, and apixaban, the 3 most widely mar- keted NOACs, to each other in the same study. 5-11 These were uniformly small, rarely examined thromboembolic stroke, and none assessed mortality. The question remains unanswered whether the NOACs are therapeutically similar or if clinically important differen- ces exist, which might lead pre- scribers and patients to prefer one over the others. To better assess the comparative safety and effectiveness of the com- monly marketed oral anticoagu- lants, we performed a large observational study in older US patients with atrial fibrilla- tion enrolled in fee-for-service Medicare, that compared each NOAC with warfarin and with each other NOAC for the outcomes of hospitalized thromboembolic stroke, intra- cranial hemorrhage, major extracranial bleeding, and all- cause mortality. METHODS Each of the NOACs is available in the United States at a standard dose intended for most nonvalvular atrial fibrillation patients and a lower dose for those with impaired renal func- tion (dabigatran, rivaroxaban, edoxaban), or a combination of at least 2 of impaired renal function, lower body weight, or advanced age (apixaban). We employed a new user desig n 12 to compare patients initiating treatment with warfa- rin or a standard dose of dabigatran (150 mg twice daily), rivaroxaban (20 mg once daily), or apixaban (5 mg twice daily). Edoxaban use was too low to study. From October 2010, when dabigatran was approved, through September 2015, patients enrolled in fee-for-service Medicare Part A (hospitalization), Part B (office-based care), and Part D (prescription drug coverage) were eligible for study inclusion if, on the date of a qualifying anticoagulant dispensing (index date), they had at least 6 months of continuous Medicare enrollment, were 65 years or older, and during the preceding 6 months, had an inpatient or outpatient diagnosis of atrial fibrillation or flutter based on International Classification of Diseases, Ninth Revision (ICD-9) coding, and had not filled a prescription for any of the study drugs or edoxaban. Patients were excluded if they were in a skilled nursing facility or nursing home or were receiving hospice care on the index date. Patients with a hospitalization extending beyond the index date were also excluded, as were kidney transplant recipients and dialysis patients. We also excluded patients with a potential alternative indication for anticoagu- lation in the 6 months preceding study entry (mitral valve disease, heart valve repair or replacement, deep vein thrombosis, pulmonary embolism, or joint replacement). During the 6 months preceding cohort entry, Medicare claims data on chronic medical conditions, risk factors for cardiovascular and bleeding events (including CHA 2 DS 2 -VASc [Congestive heart failure, Hypertension, Age ≥ 75 years, Diabetes mellitus, prior Stroke or TIA or thromboembo- lism, Vascular disease, Age 65- 74 years, Sex category] and HAS- BLED [Hypertension, Abnormal renal and liver function, Stroke, Bleeding, Labile international normalized ratio, Elderly, Drugs or alcohol] scores) , 13,14 and health care utilization were collected for each patient, as were data on dispensed medications. To improve the validity of the NOAC vs warfarin com- parisons, we performed 1:1 propensity score matching of warfarin to NOAC users with replacement , 15 thereby restricting the study population to all eligible NOAC users and warfarin users with characteristics very similar to the NOAC users ( Supplementary Table 1 , available online). To adjust for potential confounding, we used multinomial logistic regression to estimate stabilized inverse probability of treatment weights for the warfarin and individual NOAC cohorts, using the 3 NOAC cohorts pooled together as the reference for weighting . 16 Covariate balance was assessed using standardized mean differences, with a value ≤ 0.1 indicating a negligible difference between groups . 17 Follow-up began the day after cohort entry and continued until disenrollment from Medicare, a gap in anticoagulant days of supply exceeding 3 days, dispensing of another anti- coagulant, kidney transplantation or initiation of dialysis, admission to a skilled nursing facility or nursing home, trans- fer to hospice care, end of the study period, or study outcome occurrence, whichever came first. We chose a 3-day gap because of the short half-lives of the individual NOACs CLINICAL SIGNIFICANCE Nonvitamin K oral anticoagulants (NOACs) are used for stroke prevention in patients with atrial fibrillation, but no clinical trials have compared them against each other for effectiveness or safety. In an observational study of Medicare patients with nonvalvular atrial fibril- lation, risks of thromboembolic stroke, intracranial bleeding, and all-cause mortality were reduced in patients treated with apixaban, dabigatran, and rivaroxaban compared with warfarin patients having similar baseline char- acteristics. Among NOACs, apixaban and dabigatran had a more favorable benefit − harm bal- ance than rivaroxaban. 2 The American Journal of Medicine, Vol 000, No 000, && 2019