Non-recommended dosing of direct oral anticoagulants in the treatment of acute pulmonary embolism is related to an increased rate of adverse events

Abstract

Dose adjustment of direct oral anticoagulants (DOACs) is not required in the setting of acute PE treatment according to the manufacturer's labelling, beyond the contraindication in severe renal insufficiency. We designed a prospective, multicenter cohort study to investigate the impact of prescription of non-recommended DOAC doses on 6-month adverse events. The primary endpoint was a composite of all-cause death, recurrent VTE, major bleeding, and chronic thromboembolic pulmonary hypertension (CTEPH). In total, among 656 patients discharged with DOACs between 09/2012 and 10/2016, 28 (4.3%) were not treated with a recommended DOAC dose. All the non-recommended DOAC dose prescriptions were under-dosed according to the drug labelling. After multivariate adjustment, age > 70 years, a history of coronary artery disease, creatinine clearance < 50 mL/min and concomitant aspirin therapy were independently associated with non-recommended DOAC dose prescription (C-statistic: 0.82; Hosmer Lemeshow test: 0.50). The primary composite endpoint occurred in 7/28 patients (25.0%) in the non-recommended dose group and in 38/628 patients (6.1%) in the recommended dose group, yielding a relative risk of 3.19 in the non-recommended dose group (95% CI 1.16-8.70; p < 0.001). The higher primary endpoint rate observed in the non-recommended dose group was driven by a significantly higher rate of major bleeding (7.1 vs. 1.4%; p = 0.008), with a non-significant trend toward a higher rate of death (7.1 vs. 2.2%; p = 0.23), recurrent VTE (3.6 vs. 1.4%; p = 0.31), and CTEPH (7.1 vs. 1.6%; p = 0.32). In conclusion, empiric dose reduction of DOACs was associated with 6-month adverse events in our real-life registry.

Keywords: Acute pulmonary embolism; Adverse events; Direct oral anticoagulants; Inappropriate dose prescription.