Major Bleeding Rates in Atrial Fibrillation Patients on Single, Dual, or Triple Antithrombotic Therapy

Patients with atrial fibrillation generally require anticoagulant therapy and, at times, therapy with additional platelet aggregation inhibitors. Data are scarce on bleeding rates in high-risk groups receiving combination therapy, such as the elderly or patients with a high CHA₂DS₂-VASc score.

We conducted a nationwide cohort study of Danish patients with atrial fibrillation ≥50 years of age. Treatments were ascertained from a prescription database. These included no anticoagulant treatment, and treatment with vitamin K antagonists, direct oral anticoagulants, platelet inhibitors, and combinations of antithrombotic drugs. Incidence rates (IRs) of major bleeding and hazard ratios were estimated overall, and also stratified by treatment modality, age, CHA₂DS₂-VASc score, and comorbidity. Major bleeding was defined as bleeding requiring hospitalization or causing death.

We identified 272 315 patients with atrial fibrillation. Median age was 75 years (interquartile range, 67-83) and 47% were women. Over a total follow-up period of 1 373 131 patient-years (PYs), 31 459 major bleeds occurred (IR 2.3/100 PYs; 95% CI, 2.3-2.3/100 PYs). In comparison with vitamin K antagonist monotherapy, adjusted hazard ratios of major bleeding were 1.13 (95% CI, 1.06-1.19) for dual antiplatelet therapy, 1.82 (95% CI, 1.76-1.89) for therapy with a vitamin K antagonist and an antiplatelet drug, 1.28 (95% CI, 1.13-1.44) for therapy of a direct oral anticoagulant with an antiplatelet drug, 3.73 (95% CI, 3.23-4.31) for vitamin K antagonist triple therapy, and 2.28 (95% CI, 1.67-3.12) for direct oral anticoagulant triple therapy. Subgroup analyses showed similar patterns. The IR for major bleeding was 10.2/100 PYs among patients receiving triple therapy. Very high major bleeding rates occurred among patients on triple therapy aged >90 years (IR 22.8/100 PYs) or with a CHA₂DS₂-VASc score >6 (IR 17.6/100 PYs) or with a history of major bleeding (IR 17.5/100 PYs).

Patients with atrial fibrillation on triple therapy experienced high rates of major bleeding in comparison with patients on dual therapy or monotherapy. The high bleeding rates observed in patients on triple therapy >90 years of age or with a CHA₂DS₂-VASc score >6 or with a history of a major bleeding warrants careful consideration of such therapy in these patients.