Background: Apixaban and rivaroxaban are approved for the initial and extended treatment of venous thromboembolism (VTE). Both drugs have shown similar efficacy to prevent recurrent VTE, but cohort studies and a recent randomized controlled trial (RCT) suggest that, over the first 3 months of treatment, rivaroxaban use is associated with a significantly higher risk of clinically relevant bleeding (CRB) than apixaban. Whether the same phenomenon is observed during extended treatment, either at full or reduced dose, is unknown.

Methods: The RENOVE open-label multicenter RCT compared full-dose vs reduced-dose direct oral anticoagulants in patients with VTE who had completed at least 6 months of full-dose treatment and had an indication for extended anticoagulation (Lancet 2025, doi: 10.1016/S0140-6736(24)02842-3). Apixaban or rivaroxaban were permitted in the trial, and randomization was stratified according to the drug used. In this post hoc analysis, we aimed to compare the risk of bleeding between patients who received full-dose apixaban (5 mg bid) vs full-dose rivaroxaban (20 mg daily), and in patients who received reduced-dose apixaban (2.5 mg bid) vs reduced-dose rivaroxaban (10 mg daily). The primary endpoint for this analysis was CRB, and the primary outcome measure was the 5-year cumulative incidence of CRB. The incidence of recurrent VTE, major bleeding, the composite of CRB and recurrent VTE, arterial events and death from any cause were secondary outcome measures. Except for the effect of dose reduction, hazard ratios (HR) were adjusted on center, age, sex, BMI, and use of antiplatelet drugs.

Results: Of 2,768 patients in the intention-to-treat population, 1,385 patients assigned to full-dose received apixaban (n=630) or rivaroxaban (n=755), and 1383 patients assigned to reduced-dose received apixaban (n=625) or rivaroxaban (n=758). Baseline characteristics were broadly well-balanced between patients given apixaban or rivaroxaban, but median age (66.5 vs 62.6 years), the proportion of women (38.7 vs 32.1%) and proportion of patients with BMI ≥30 kg/m² (32.6 vs 28.8%) were slightly higher in patients given apixaban than in those given rivaroxaban. The maximum follow-up was 5 years, with a median of 37 months. In the full-dose subgroups, the 5-year cumulative incidence of CRB was 16.5% in patients given apixaban vs 14.4% in patients given rivaroxaban (adjusted HR [aHR] 1.02, 95% confidence interval [CI] 0.72-1.43). In the reduced-dose subgroups, the 5-year cumulative incidence of CRB was 11.0% in patients given apixaban vs 9.0% in patients given rivaroxaban (aHR 1.31, 95% CI 0.85-2.01). The 5-year cumulative incidence of major bleeding events was not significantly different between patients on apixaban or rivaroxaban, both in the full-dose subgroups (4.6% vs 3.5%, respectively, aHR 1.35, 95%CI 0.69-2.67) and reduced-dose subgroups (3.0% vs 1.6%, respectively, aHR 0.85, 95%CI 0.28-2.59). The 5-year cumulative incidence of recurrent VTE in the full-dose subgroups was 2.0% with apixaban vs 1.7 % with rivaroxaban (aHR 1.22, 95% CI 0.37-3.99), and 1.4% vs 2.7% in the apixaban and rivaroxaban reduced-dose subgroups, respectively (aHR 0.85, 95%CI 0.32-2.28). There was no significant difference between the two drugs at full or reduced dose in the incidence of the composite of CRB and recurrent VTE, arterial thromboembolic events, and death from any cause. Finally, the effect of dose reduction was consistent across the two drugs regarding the risk of CRB (aHR 0.68 [95%CI 0.47-0.98] for apixaban vs 0.57 [0.40-0.81] for rivaroxaban), the risk of VTE recurrence (aHR 1.33 [0.42-4.19] for apixaban vs 1.34 [0.55-3.27] for rivaroxaban), and the composite of CRB and VTE recurrence (aHR 0.74 [0.52-1.05] for apixaban vs 0.64 [0.46-0.89] for rivaroxaban).

Conclusion: In this post hoc analysis of the strata of a large RCT of patients with VTE who had completed at least 6 months of full-dose anticoagulation and had an indication for extended treatment, apixaban and rivaroxaban showed similar safety profiles at 5 years, both in the full- and reduced-dose subgroups comparisons, while dose reduction showed similar benefit on CRB risk with both drugs. In contrast with the first months of full-dose anticoagulation, rivaroxaban proved as safe as apixaban during extended treatment, whether at full or reduced dose. Ideally, these results would need to be confirmed in a specific randomized trial.

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2025
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