Background
Phase 3 double-blind RCT (MARINER). 12,024 acutely ill medical patients at high VTE risk (IMPROVE VTE score ≥4, or ≥2 with D-dimer >2× ULN) discharged after ≥3 days of hospitalization. Compared rivaroxaban 10 mg once daily for 45 days post-discharge versus placebo. Unlike MAGELLAN (which included in-hospital period), MARINER focused exclusively on the post-discharge period — recognizing that VTE risk extends after discharge but most prior trials included the hospitalization itself. Risk enrichment was required (higher IMPROVE VTE score threshold than MAGELLAN).
Interventions and follow up
Arm A: Rivaroxaban 10 mg once daily × 45 days post-hospital discharge (dose-reduced to 7.5 mg if CrCl 30–49 mL/min)
Arm B: Placebo × 45 days post-hospital discharge
Primary endpoint: Composite of symptomatic VTE (DVT or PE) or VTE-related death at 45 day
mFollow up: 45 days (primary endpoint); 75 day
Arm B: Placebo × 45 days post-hospital discharge
Primary endpoint: Composite of symptomatic VTE (DVT or PE) or VTE-related death at 45 day
mFollow up: 45 days (primary endpoint); 75 day
Results
Symptomatic VTE or VTE-related death at 45 days: 0.83% (rivaroxaban) vs 1.10% (placebo); HR 0.76, 95% CI 0.52–1.09 — P=.14 (not significant)
Fatal PE: 0.1% vs 0.3%; HR 0.44, 95% CI 0.22–0.89 — P=.023
Major bleeding: 0.28% vs 0.15%; HR 1.88, 95% CI 0.84–4.23 — P=.12
Clinically relevant non-major bleeding: 1.3% vs 0.6%; HR 2.18, P=.003
Fatal PE: 0.1% vs 0.3%; HR 0.44, 95% CI 0.22–0.89 — P=.023
Major bleeding: 0.28% vs 0.15%; HR 1.88, 95% CI 0.84–4.23 — P=.12
Clinically relevant non-major bleeding: 1.3% vs 0.6%; HR 2.18, P=.003
Adverse events
Main adverse events: Clinically relevant non-major bleeding significantly higher with rivaroxaban (1.3% vs 0.6%; P=.003). Major bleeding numerically higher (0.28% vs 0.15%) but not statistically significant. Fatal PE significantly lower with rivaroxaban (0.1% vs 0.3%; P=.023), but this was a secondary endpoint. No significant difference in intracranial bleeding. Net clinical benefit (primary VTE composite + major bleeding) was neutral.
Conclusions
Rivaroxaban post-discharge prophylaxis did not significantly reduce the primary composite of symptomatic VTE or VTE-related death in high-risk medical patients, and increased clinically relevant non-major bleeding — the trial was negative for its primary endpoint.
Key Limitations
Key Limitations: The primary endpoint event rate was lower than expected (1.1% vs projected ~3%), reducing power. Using symptomatic VTE only (excluding asymptomatic DVT) as the primary endpoint was clinically meaningful but reduced event rates vs APEX/MAGELLAN. The fatal PE reduction (P=.023) was a post-hoc or secondary finding. Risk enrichment (high IMPROVE VTE score) did not identify a group with clear net benefit. Even in the highest-risk subgroups, net benefit remained equivocal due to bleeding offset.
Clinical Context
MARINER was a negative trial for its primary endpoint. Despite fatal PE reduction, the overall risk-benefit for post-discharge extended DOAC prophylaxis in medical patients remains unfavorable for routine use. Current CHEST 2022 guidelines give a weak recommendation against extended pharmacological prophylaxis after acute medical illness unless bleeding risk is low and VTE risk is very high. MARINER reinforced the narrow window where extended prophylaxis may help, and the ongoing challenge of selecting the right patients.
References