Extended Treatment of Venous Thromboembolism with Reduced- Vs Full-Dose Direct Oral Anticoagulants in Patients at High Risk of Recurrence

BACKGROUND: Venous thromboembolism is a common, potentially fatal disease. Beyond the first 3 months of anticoagulation treatment, extending anticoagulation up to 12 or 24 months reduces the risk of recurrence by at least 80% in patients at high risk of recurrence, but this benefit is lost after stopping anticoagulation. Consequently, guidelines recommend indefinite anticoagulation in such patients. However, continued anticoagulation exposes patients to a linear increase in bleeding risk, which is expected to ultimately exceed the risk of recurrent venous thromboembolism after stopping anticoagulation.

To address this issue, lower-dose anticoagulation may reduce bleeding risk while maintaining similar efficacy in preventing recurrent venous thromboembolism. In the EINSTEIN-CHOICE and AMPLIFY-EXT studies, extended reduced-dose anticoagulation appeared as effective as and safer than full-dose. However, with the inclusion of a placebo or aspirin control group, both studies enrolled patients in whom physicians were uncertain about continuing anticoagulation. Consequently, robust evidence for recommending reduced- over full-dose anticoagulation in patients with a strong indication for extended treatment is lacking.

METHODS: The Reduced Dose Versus Full-Dose of Direct Oral Anticoagulant After Unprovoked Venous Thromboembolism (RENOVE) trial (ClinicalTrials.gov Identifier: NCT03285438) is an academic, multicenter, prospective, randomized, open, blinded end-point (PROBE) trial. In this study, we compared, using hierarchical sequential testing, extended anticoagulation with reduced-dose versus full-dose direct oral anticoagulants in patients with venous thromboembolism at high risk of recurrence initially treated for 6 to 24 months. Primary outcome was recurrent symptomatic venous thromboembolism (noninferiority hypothesis). Key secondary outcomes were clinically relevant bleeding and the composite of recurrent venous thromboembolism and clinically relevant bleeding (superiority hypotheses). Critical events were adjudicated by an independent committee blinded to treatment allocation.

RESULTS: During the 36-month median follow-up, recurrent venous thromboembolism occurred in 19 of 1383 patients in the reduced-dose group versus 15 of 1385 patients in the full-dose group (5-year cumulative incidence 2.2%; 95% confidence interval [CI], 1.1 to 3.3 versus 1.8%; 95% CI, 0.8 to 2.7; hazard ratio, 1.32; 95% CI, 0.67 to 2.60; P=0.23 for noninferiority). Clinically relevant bleeding occurred in 96 and 154 patients in the reduced- and full-dose groups, respectively (5-year cumulative incidence 9.9%; 95% CI, 7.7 to 12.1 versus 15.2%; 95% CI, 12.8 to 17.6). The composite outcome occurred in 113 and 166 patients in the reduced- and full dose groups, respectively (5-year cumulative incidence 11.8%; 95% CI, 9.4 to 14.3 versus 16.5%; 95% CI, 14.0 to 19.0). All-cause death occurred in 35 (4.3%) and 54 (6.1%) patients in the reduced- and full-dose groups, respectively.

CONCLUSIONS: In patients with venous thromboembolism who need extended anticoagulation, the noninferiority of a reduced-dose versus a full-dose of direct anticoagulants to prevent recurrent venous thromboembolism could not be proven. In the reduced-dose group, clinically relevant bleeding and the composite of recurrent venous thromboembolism or clinically relevant bleeding were lower than in the full-dose group and did not appear to be offset by an increased risk of death or arterial thromboembolic events.