Major Bleeding Rates With Antithrombotic Therapy in Atrial Fibrillation  Results from a Nationwide Danish Cohort Study

The results of a study conducted by Rein et al. have shown that patients with atrial fibrillation on triple therapy experienced high rates of major bleeding compared with patients on dual therapy or monotherapy. The high bleeding rates observed in patients on triple therapy over the age of 90 years or with a CHA₂DS₂-VASc score over 6 or with a history of a major bleeding warranted careful consideration of such therapy in these patients. The results were published online ahead of print in Circulation.

Patients with atrial fibrillation generally require anticoagulant therapy, and at times therapy with additional platelet aggregation inhibitors. AF patients experiencing an MI or undergoing a PCI are concomitantly treated with an antiplatelet, such as aspirin, clopidogrel or both, because of an increased risk of coronary vascular events. Dual or triple antithrombotic therapy may be effective in reducing the risk of thromboembolic events, but the risk of bleeding inherent to treatment has been shown to increase with combinations of antiplatelet and oral anticoagulants. Therefore, the optimal treatment strategy when combining antiplatelets with oral anticoagulants in patients with atrial fibrillation (AF) and myocardial infarction (MI) or undergoing percutaneous coronary intervention (PCI) is unknown. Studies like the WOEST trial have already convinced many clinicians that triple therapy should be avoided. 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. Thus, the investigators set out to conduct a nationwide cohort study of Danish atrial fibrillation patients aged 50 years or older. Treatments were ascertained from a prescription database. These included no anticoagulant treatment, and treatment with vitamin K antagonists (VKAs), direct oral anticoagulants (DOACs), 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.

Rein and his colleagues 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 [incidence rate (IR) 2.3/100 PYs, 95% confidence interval (CI) 2.3-2.3/100 PYs]. Compared with VKA 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 VKA and an antiplatelet drug, 1.28 (95% CI 1.13-1.44) for therapy of a DOAC with an antiplatelet drug, 3.73 (95% CI 3.23-4.31) for VKA triple therapy and 2.28 (95% CI 1.67-3.12) for DOAC triple therapy. Subgroup analyses showed similar patterns. The IR for major bleeding was 10.2/100 PYs among triple-therapy patients. 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 over 6 (IR 17.6/100 PYs) or with a history of major bleeding (IR 17.5/100 PYs).

“The high rates of major bleeding found among patients receiving triple therapy raises the question whether concomitant use of three antithrombotic drugs is advisable,” primary investigator Nienke van Rein, Ph.D. from Leiden University Medical Center, Netherlands, remarked. She added, “However, risk factors for ischemic events and major bleeding overlap, making it hard to distinguish which patients are at high risk for major bleeding, but not at risk for ischemic events, and vice versa. In addition, due to confounding by indication, this nonrandomized study does not permit evaluation of the effectiveness of combinations of antithrombotic drugs (ie, medication could have been indicated due to high risk of thromboembolic outcomes). Still, these high bleeding rates emphasize that treatment with triple therapy should be as short as possible.”