Non-Vitamin K Antagonist Oral Anticoagulants and Angioedema: A Cohort and Case-Crossover Study

Abstract

Introduction: Patients taking non-vitamin K antagonist oral anticoagulants (NOACs) such as dabigatran, rivaroxaban, and apixaban have reported experiencing angioedema in randomized trials and routine care. Objective: The aim of this study was to quantify the association between NOACs and angioedema relative to warfarin among routinely treated patients with atrial fibrillation in a cohort study. We also compared warfarin users with non-users in a case-crossover study. Methods: We utilized a cohort design that drew eligible patients from the Truven Health MarketScan Commercial database, the Optum© Clinformatics® Data Mart, and Medicare. Within each database, we compared the 6-month relative rate of angioedema among new users of NOACs (dabigatran, rivaroxaban, apixaban) and new users of warfarin. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) after adjusting for confounders using propensity score stratification, and meta-analyzed the database-specific HRs using a random-effects model. We also estimated an odds ratio (OR) for the association between warfarin and angioedema using a case-crossover design, a self-controlled design that controls for time-invariant confounders. Results: In the cohort study, we observed 249 incident angioedema events among 267,681 NOAC initiators and 281,143 warfarin initiators across all databases. The meta-analyzed HR for angioedema comparing any NOAC versus warfarin was 0.98 (95% CI 0.76–1.27). In the case-crossover design, the OR for the association between warfarin and angioedema was 0.91 (95% CI 0.68–1.21) based on 431 cases. Conclusions: Our estimates were inconsistent with substantial short-term relative increases in the rate of angioedema associated with oral anticoagulant therapy.