Background
International, phase 4, prospective, open-label, blinded endpoint (PROBE) randomized trial (COBRRA). 2,760 patients with acute symptomatic pulmonary embolism or proximal deep-vein thrombosis. Both apixaban and rivaroxaban are commonly used for acute VTE but no head-to-head RCT existed prior to this study. Patients randomized 1:1; treated for 3 months.
Interventions and follow up
Arm A: Apixaban 10 mg BID x 7 days then 5 mg BID (n=1,370)
Arm B: Rivaroxaban 15 mg BID x 21 days then 20 mg QD (n=1,390)
Primary endpoint: Clinically relevant bleeding (major + clinically relevant non-major, ISTH criteria) at 3 month
mFollow up: 3 month
Arm B: Rivaroxaban 15 mg BID x 21 days then 20 mg QD (n=1,390)
Primary endpoint: Clinically relevant bleeding (major + clinically relevant non-major, ISTH criteria) at 3 month
mFollow up: 3 month
Results
Clinically relevant bleeding: 3.3% (apixaban) vs 7.1% (rivaroxaban), RR 0.46, 95% CI 0.33–0.65, P<.001
Death (any cause): 0.1% vs 0.3%, RR 0.25, 95% CI 0.03–2.26 — not significant
Serious non-bleeding/non-VTE AEs: 2.7% vs 2.2%
Death (any cause): 0.1% vs 0.3%, RR 0.25, 95% CI 0.03–2.26 — not significant
Serious non-bleeding/non-VTE AEs: 2.7% vs 2.2%
Adverse events
Main adverse events: Primary outcome (clinically relevant bleeding) significantly lower with apixaban. Serious adverse events otherwise similar. Specific breakdown of major vs CRNM bleeding favors apixaban.
Conclusions
Apixaban was associated with significantly lower clinically relevant bleeding compared to rivaroxaban in acute VTE treatment over 3 months, without compromising efficacy. This is the first direct RCT comparing these two widely used DOACs for acute VTE.
Key Limitations
Key Limitations: Open-label design (PROBE) introduces potential assessment bias despite blinded endpoint adjudication. Three-month follow-up only — does not address longer-term outcomes. Recurrent VTE events not reported as a primary outcome; efficacy equivalence was assumed rather than demonstrated in this study. Dosing differences between drugs (twice-daily vs once-daily for rivaroxaban maintenance) may influence real-world adherence and outcomes.
Clinical Context
Both apixaban and rivaroxaban are guideline-recommended first-line options for VTE treatment. COBRRA provides the first head-to-head RCT evidence suggesting a bleeding advantage with apixaban, consistent with prior observational and indirect comparison data. This may influence DOAC choice in patients at higher bleeding risk. Thrombotic efficacy is considered equivalent based on indirect comparisons.
References
References: Castellucci LA et al, NEJM 2026 (COBRRA)