Annals of Internal Medicine • Vol. 167 No. 12 • 19 December 2017 Outcomes of Dabigatran and Warfarin for Atrial Fibrillation in Contemporary Practice Annals of Internal Medicine • Vol. 167 No. 12 • 19 December 2017 報告者：邱孟君 報告日期：2018/3/21

Introduction Dabigatran (150 mg twice daily) has been associated with lower rates of stroke than warfarin in trials of atrial fibrillation, but large-scale evaluations in clinical practice are limited. Objective: To compare incidence of stroke, bleeding, and myocardial infarction in patients receiving dabigatran versus warfarin in practice.

Methods Sentinel program The Sentinel program is a national surveillance system sponsored by the FDA for medical products. It includes a central coordinating center and 17 collaborating institutions and health care delivery systems contributing data from administrative, clinical, and pharmacy dispensing databases to the Sentinel Distributed Database. Most patients in the database are privately insured.

Methods The sample consisted of adults aged 21 years or older with atrial fibrillation initiating dabigatran or warfarin therapy between 1 November 2010 and 31 May 2014 Because of the data refresh schedule, the end date varied across sites, but most sites contributed data through 2013. Atrial fibrillation: at least 1 diagnosis of atrial fibrillation (427.31) or atrial flutter (427.32) from any setting in the 12 months before the date when dabigatran or warfarin was first dispensed (index date).

Anticoagulant Exposure Allowed all possible doses and dosing regimens in the analysis for both dabigatran and warfarin. Start time: dabigatran or warfarin was first dispensed (index date) . Person-time of continuous exposure was based on prescriptions dispensed for the index treatment. In primary analyses, we allowed a grace period of up to 7 days between the estimated end date of any prescription and the start date of the next prescription. We used a 7-day limit for early refills for both dabigatran and warfarin, such that for any refill that occurred within 7 days before the predicted end of a first prescription, the additional days were added to the end of the second prescription for consecutive prescriptions. 1st 2nd

Outcomes Patients were followed through the end of available data from each site or until they were censored because of treatment discontinuation, initiation of the comparator treatment (that is, warfarin or dabigatran), initiation of another anticoagulant treatment, nursing home or skilled-nursing facility admission, health system disenrollment, or death.

Covariates

Statistical Analysis To construct the matched cohort, we estimated a propensity score for initiating dabigatran therapy using logistic regression (PROC LOGISTIC in SAS) among all eligible patients starting treatment with dabigatran or warfarin within each participating data partner including all covariates described above. Standardized differences: Compared characteristics among those receiving dabigatran or warfarin using standardized differences, which were calculated as the difference in means or proportions of a variable divided by a pooled estimate of the SD of the variable. Cox proportional hazards: To compare the incidence of these outcomes in patients receiving dabigatran versus warfarin. Incidence rate differences: Estimated incidence rate differences, accounting for stratification by data partner by using inverse variance weights.

Sensitivity analyses 1. We assembled a separate variable-ratio–matched cohort, which allowed more than 1 patient receiving warfarin to be matched to each patient receiving dabigatran, and we did Cox regression stratified by data partner and matched set. Dabigatran, n = 25 289. Warfarin, n = 83 084. 2. We did conditional Cox regression only for the outcome of myocardial infarction. 3. 14-Day Grace Period for Classifying Continuous Drug Use. 4. Warfarin Use Based on Prescriptions and International Normalized Ratio Testing. 5. We rematched and evaluated whether differential associations existed between treatment groups and outcomes in prespecified subgroups by age (<65 years, 65 to 74 years, 75 to 84 years, and ≥85 years), sex, and reduced kidney function.

dabigatran warfarin Mean continuous follow-up 123 days (SD, 149) 102 days (SD, 119) Median Continuous follow-up 66 days (interquartile range, 36 to 151 days) (interquartile range, 36 to 123 days)

Conclusion Dabigatran vs warfarin intracranial hemorrhage ischemic stroke or extracranial hemorrhage myocardial infarction However, given the variability of findings for the outcome of myocardial infarction based on the analytic approach we used and results from other studies, the association between dabigatran and myocardial infarction remains uncertain.