Assessing Safety of Direct Thrombin Inhibitors, Direct Factor Xa Inhibitors and Vitamin K Antagonists in Patients with Atrial Fibrillation: A Nation-Wide Propensity Score Matched Cohort from Sweden

PURPOSE: To evaluate associations between first-time use of direct oral anticoagulants or vitamin K antagonists and bleeding risk or mortality in the elderly with atrial fibrillation in a real-world setting in Sweden. PATIENTS AND METHODS: The study population comprises first-time users, above age 60, of dabigatran, apixaban, rivaroxaban, or warfarin, with first atrial fibrillation occurrence within 6 months before dispensing (2012-2016). Outcomes were gastrointestinal, any, or intracranial bleeding, and mortality. Exposure started at first dispensing of a study drug. Follow-up continued until outcome, end of drug supply, dispensing of another study drug, death or end of study (December 2016). We conducted a propensity score matched, nationwide register-based cohort study including three treatment groups: direct thrombin inhibitors, direct factor Xa inhibitors and vitamin K antagonists, each compared to the other two, focusing on subgroups of age and sex. Cox proportional hazard models adjusted for CHA2DS2VASc and HAS-BLED scores provided hazard ratios with 95% confidence intervals. RESULTS: The matched study populations consisted of 7,264 patients for the direct thrombin inhibitors vs vitamin K antagonists comparison, 12,566 patients for the direct factor Xa inhibitors vs vitamin K antagonists comparison and 6,606 patients for the direct factor Xa inhibitors vs direct thrombin inhibitors comparison, in total 26,436 patients. Numerically high, but imprecise, hazard ratios for gastrointestinal bleeding were observed for women aged 75-80, 80-85, or above 85 years, eg 6.00 (1.02, 113.47) for direct thrombin inhibitors vs vitamin K antagonists. For both sexes, numerically high hazard ratios for any bleeding were observed in ages 80-85, or above 85 years, eg 2.90 (1.01, 10.41) for direct thrombin inhibitors vs vitamin K antagonists. Numerically high HRs for intracranial bleeding were observed for women aged 75-80 or 80-85 years, eg 2.70 (0.65, 18.19) for direct factor Xa inhibitors vs vitamin K antagonists. Excess mortality was observed in both sexes, across age groups, for naive and experienced anticoagulant users. CONCLUSION: The observed increased gastrointestinal bleeding risk in first-time users of direct thrombin inhibitors or direct factor Xa inhibitors is consistent with previous studies. The possible risk of excess mortality merits further studies.