Non-recommended dosing of direct oral anticoagulants in the treatment of acute pulmonary embolism is related to an increased rate of adverse events at 6 months

Abstract

Dose adjustment of direct oral anticoagulants (DOACs) is not required in the setting of acute pulmonary embolism (PE) treatment according to the manufacturer's labelling, apart from a contraindication in patients with a creatinine clearance <30 mL/min. The present study aimed to investigate the impact of non-recommended DOAC dose prescription on 6-month adverse events. This is an observational, multicenter, multidisciplinary registry of acute PE from 09/2012 to 10/2016. The primary endpoint was a composite of all-cause death, recurrent venous thromboembolism (VTE), major bleeding, and chronic thromboembolic pulmonary hypertension (CTEPH). During the study period, 656 patients were discharged with DOACs (rivaroxaban: 614 patients (93.6%); apixaban 42 patients (6.4%)). Mean age was 63.6 ± 17.9 years, 46.9% were males. Overall, 628 (95.7%) were treated with the recommended dose of DOACs, and 28 (4.3%) were not. During the course of therapy, 16 patients died, 10 presented VTE, 11 had major bleeding, and 12 developed CTEPH. 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 ( P = 0.008), with a non-significant trend toward higher rates of death ( P = 0.23), recurrent VTE ( P = 0.31), and CTEPH ( P = 0.32) ( Fig. 1 ). Empiric dose reduction of DOACs was associated with an increased risk of 6-month adverse events in our real-life registry.