Reduced versus standard dose apixaban for secondary prevention of cancer-associated venous thromboembolism: A systematic review and meta-analysis

Abstract INTRODUCTION Cancer-associated venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), is a leading cause of morbidity and mortality in patients with malignancy. Current guidelines recommend extended anticoagulation in this population, but the optimal duration and dosing strategy remain debated. Apixaban is a direct oral anticoagulant (DOAC) with favorable efficacy and safety data in cancer-associated thrombosis, yet prolonged use at the standard dose (5 mg twice daily) raises concerns about bleeding. Dose de-escalation to 2.5 mg twice daily has been proposed to reduce bleeding risk during the extended phase of treatment. This study presents a systematic review and meta-analysis evaluating the efficacy and safety of reduced-dose versus standard-dose apixaban for secondary prevention of VTE in patients with cancer. METHODOLOGY A systematic search of PubMed and EMBASE was conducted through April 2025 to identify randomized controlled trials and observational studies comparing reduced-dose (2.5 mg BID) versus standard-dose (5 mg BID) apixaban in adult patients with cancer-associated VTE receiving extended-phase anticoagulation. Studies were included if they reported on at least one of the following outcomes: recurrent VTE, major bleeding, DVT, PE, clinically relevant non-major bleeding (CRNMB), or all-cause mortality. Risk ratios (RRs) and 95% confidence intervals (CIs) were pooled using a random-effects model. Leave-one-out sensitivity analyses and assessments of heterogeneity (I² statistic) were performed to ensure result robustness. RESULTS Three studies met eligibility criteria, including two randomized controlled trials and one prospective cohort study, enrolling 1,343 patients in the reduced-dose group and 1,277 in the standard-dose group. Pooled analysis found no significant difference in recurrent VTE (RR 0.77; 95% CI 0.50–1.18; p = 0.23), major bleeding (RR 0.51; 95% CI 0.24–1.11; p = 0.09), DVT (RR 0.87; 95% CI 0.42–1.79; p = 0.70), or PE (RR 0.75; 95% CI 0.40–1.41; p = 0.37). The incidence of CRNMB was significantly lower in the reduced-dose group (RR 0.68; 95% CI 0.48–0.96; p = 0.03). All-cause mortality did not differ significantly between groups (RR 1.08; 95% CI 0.66–1.77; p = 0.75). Heterogeneity was low across outcomes (I² < 25%), and sensitivity analysis confirmed the consistency of results across studies. CONCLUSION Reduced-dose apixaban (2.5 mg BID) appears non-inferior to standard-dose apixaban (5 mg BID) for the prevention of recurrent VTE in cancer patients requiring extended anticoagulation. Importantly, reduced dosing was associated with a significantly lower risk of clinically relevant non-major bleeding, without compromising efficacy or increasing mortality. These findings suggest that reduced-dose apixaban may offer a safer alternative for long-term anticoagulation in selected oncology patients. Further prospective, stratified studies are needed to validate these results and guide individualized anticoagulation strategies in cancer-associated thrombosis.