Direct oral anticoagulants in the treatment of venous thromboembolism, with a focus on patients with pulmonary embolism: an evidence-based review

Abstract

Antonio Gómez-Outes,1 Mª Luisa Suárez-Gea,1 Ramón Lecumberri,2 Ana Isabel Terleira-Fernández,3,4 Emilio Vargas-Castrillón3,41Division of Pharmacology and Clinical Evaluation, Medicines for Human Use, Spanish Agency for Medicines and Medical Devices (AEMPS), Madrid, Spain; 2Department of Hematology, University Clinic of Navarra, Pamplona, Spain; 3Department of Clinical Pharmacology, Hospital Clínico, Madrid, Spain; 4Department of Pharmacology, Universidad Complutense, Madrid, SpainAbstract: Pulmonary embolism (PE) is a relatively common cardiovascular emergency. PE and deep vein thrombosis (DVT) are considered expressions of the same disease, termed as venous thromboembolism (VTE). In the present review, we describe and meta-analyze the efficacy and safety data available with the direct oral anticoagulants (DOAC; dabigatran, rivaroxaban, apixaban, edoxaban) in clinical trials testing these new compounds in the acute/long-term and extended therapy of VTE, providing subgroup analyses in patients with index PE. We analyzed ten studies in 35,019 randomized patients. A total of 14,364 patients (41%) had index PE. In the acute/long-term treatment of VTE, the DOAC showed comparable efficacy in preventing recurrent VTE to standard treatment in patients with index PE (risk ratio [RR]: 0.88; 95% confidence interval [CI]: 0.70–1.11) and index DVT (RR: 0.93; 95% CI: 0.75–1.16) (P for subgroup differences =0.76). VTE recurrence depending on PE anatomical extension and presence/absence of right ventricular dysfunction was only reported in two trials, with results being consistent with those obtained in the overall study populations. In the single trial comparing extended therapy of VTE with DOAC versus warfarin, the point estimate for recurrent VTE tended to disfavor the DOAC in patients with index PE (RR: 2.05; 95% CI: 0.83–5.03) and in patients with index DVT (RR: 1.11; 95% CI: 0.49–2.50) (P for subgroup differences =0.32). In trials that compared DOAC versus placebo for extended therapy, the reduction in recurrent VTE was consistent in patients with PE (RR: 0.15; 95% CI: 0.01–1.82) and in patients with DVT (RR: 0.25; 95% CI: 0.10–0.61) (P for subgroup differences =0.71). The DOAC were associated with a consistently lower risk of clinically relevant bleeding (CRB) than standard treatment of acute VTE and higher risk of CRB than placebo for extended therapy of VTE regardless of index event. In summary, the DOAC were as effective as, and safer than, standard treatment of (hemodynamically stable) PE. Their efficacy in preventing recurrent VTE seemed consistent regardless of anatomical extension of PE (extensive, intermediate, or limit) or presence/absence of right ventricular dysfunction although the data are limited. For extended therapy, the DOAC were more effective than placebo in preventing recurrent VTE but were associated with an increase in CRB regardless of index event.Keywords: anticoagulant, pulmonary embolism, dabigatran, apixaban, rivaroxaban, edoxaban