Association between concurrent use of diltiazem and DOACs and risk of bleeding in atrial fibrillation patients

Background — Diltiazem is a commonly used medication in patients with atrial fibrillation (AF) with potential for a drug-drug interaction (DDI) with direct oral anticoagulants (DOACs). We aimed to assess the risk of major bleeding after co-prescription of diltiazem and DOACs among adults with AF.

Methods — We conducted a population-based, nested case–control study in Ontario, Canada. The study population included all patients with AF > 66 years on a DOAC between April 1, 2011, and March 31, 2018. Cases were patients admitted with major bleeding (index date). Each case was matched to two controls. We categorized exposure to diltiazem before the index date as: (a) current users (diltiazem use within 7 days); (b) recent users (diltiazem use within 8 to 90 days); and (c) unexposed (no diltiazem prescription or diltiazem prescription > 90 days before index date). Conditional logistic regression models were used to examine the association between bleeding and diltiazem co-prescription.

Results — Among 86,679 AF patients on a DOAC, the median age of AF patients was 80 years (interquartile range 75–85); 48.3% were women. We identified 2,766 cases (3.2%) who were hospitalized with major bleeding. After multivariable adjustment, there was a significant association between major bleeding and current use of diltiazem (adjusted odds ratio (aOR) 1.37; 95% confidence interval (CI) 1.08–1.73, p < 0.009) but no significant association between major bleeding and recent use of diltiazem (aOR 1.19, 95% CI 0.99–1.42, p = 0.06) as compared with the unexposed group.

Conclusions — Current use of diltiazem was associated with major bleeding among AF patients receiving a DOAC.