Dabigatran, a competitive direct thrombin inhibitor used for prevention of stroke and systemic embolism in non-valvular atrial fibrillation (AF) patients, was approved by the FDA in 2010 based on the results of the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial. Post-marketing studies have raised concerns regarding risk of severe bleeding, particularly in the elderly population and in those with renal impairment. Additionally, as the majority of published studies regarding dabigatran use enrolled patients from the USA and Europe, limited data exists regarding the thromboembolic and bleeding risks in patients of Asian ethnicity. Chan et al. utilized the Taiwan National Health Insurance Research Database (NHIRD) to investigate the efficacy and safety of dabigatran compared to warfarin in AF patients through an observational cohort study.
The authors selected 9,940 dabigatran users and 9,913 warfarin users who were prescribed their respective treatments after June 1, 2012. Propensity score weighting was used to balance covariates across the two study groups, as the dabigatran group was older, had a higher proportion of hypertension, diabetes mellitus, stroke or TIA history, a lower proportion of prescribing anti-platelet agents, and higher CHA2DS2-VASC and HAS-BLED scores compared with the warfarin group. The median follow-up period was 0.67 years for dabigatran users and 0.73 years for warfarin users and was defined as the time from the index date until the first occurrence of any of the six study outcomes or the end of the study period (December 31, 2013).
The six outcomes studied were ischemic stroke, acute myocardial infarction, intracranial hemorrhage (identified using atraumatic hemorrhage discharge diagnosis codes), major gastrointestinal bleeding (requiring transfusion), all major bleeding events, and all-cause mortality. Although some patients accumulated multiple outcomes during the duration of the study, only the initial outcome was counted as patient management was changed due to the outcome in question.
Compared with the warfarin group, the dabigatran group was associated with a significantly reduced risk of ischemic stroke, intracranial hemorrhage, all hospitalized major bleeding events, and all-cause mortality (all p<0.0001) and a marginal decreased risk of acute myocardial infarction (HR 0.67, p=0.0803). There was no difference in major gastrointestinal bleeding between the two study groups (HR 0.99, p=0.9658).
This study highlights potential differences in the risk profile of patients of Asian ethnicity with respect to ischemic and hemorrhagic events while therapeutically anticoagulated. The results stand in contrast to the results of the RE-LY trial, which showed a significant reduction in the risk of both ischemic and hemorrhagic stroke and increased gastrointestinal bleeding risk at the 150 mg dose, which was the dose that was approved by the FDA for use in the USA. Interestingly, a majority (88%) of the patients in this cohort were prescribed the 110 mg dose, which showed comparable stroke and gastrointestinal bleeding risk to warfarin with a significant reduction in the risk of intracranial hemorrhage. The authors speculated this prescribing discrepancy may be due to a combination of a lower average BMI in Asian patients, higher risk of warfarin-related intracranial hemorrhage in Asian patients leading to physician discretion with dosing, and increased proportion of patients that are elderly with chronic kidney or liver disease due to restrictions on dabigatran prescribing under the Taiwanese national health system.
The study’s findings were compatible with subgroup analysis from RE-LY looking at the Asian participants that comprised 15.3% of that study’s population. Given that Asian patients tended to have more complications with warfarin and better efficacy and fewer complications with dabigatran, it may be reasonable to reconsider using dabigatran as a first-line therapy in this specific population. This decision making should also be made with the understanding of the limitations of observational cohort data as compared to prospective randomized data. Whether these findings would extend to a larger prospective randomized trial or with other novel oral anticoagulants with different mechanisms of action in the Asian population remains to be seen and represents an interesting potential avenue for future study.