Background
Phase 3 open-label, non-inferiority RCT (CARAVAGGIO). 1,170 patients with active cancer and acute proximal DVT or PE. Compared oral apixaban (no parenteral lead-in needed) to subcutaneous dalteparin for 6 months. Apixaban has a distinct metabolic profile compared to rivaroxaban/edoxaban — minimal renal excretion, CYP3A4-dependent. The trial was designed following signals from Hokusai-VTE Cancer and SELECT-D showing DOAC efficacy but GI bleeding concerns. Key hypothesis: apixaban provides VTE efficacy equivalent to dalteparin without the GI bleeding excess seen with edoxaban/rivaroxaban.
Interventions and follow up
Arm A: Apixaban 10 mg twice daily × 7 days, then 5 mg twice daily for 6 month
Arm B: Dalteparin 200 IU/kg once daily × 1 month, then 150 IU/kg once daily × 5 months (6 months total)
Primary endpoint: Recurrent VTE (symptomatic or incidental DVT or PE, or fatal PE) at 6 months — non-inferiority margin HR ≤1.75
mFollow up: 6 month
Arm B: Dalteparin 200 IU/kg once daily × 1 month, then 150 IU/kg once daily × 5 months (6 months total)
Primary endpoint: Recurrent VTE (symptomatic or incidental DVT or PE, or fatal PE) at 6 months — non-inferiority margin HR ≤1.75
mFollow up: 6 month
Results
Recurrent VTE: 7.2% (apixaban) vs 11.5% (dalteparin); HR 0.63, 95% CI 0.37–1.07 — non-inferior (P<.001 for non-inferiority)
Major bleeding: 3.8% vs 4.0%; HR 0.82, 95% CI 0.40–1.69 — P=.60 (not significantly different)
GI major bleeding: 1.9% vs 1.7% — no significant difference (unlike edoxaban/rivaroxaban)
Clinically relevant non-major bleeding: 9.0% vs 6.0%; HR 1.42, 95% CI 0.88–2.30 (non-significant)
Major bleeding: 3.8% vs 4.0%; HR 0.82, 95% CI 0.40–1.69 — P=.60 (not significantly different)
GI major bleeding: 1.9% vs 1.7% — no significant difference (unlike edoxaban/rivaroxaban)
Clinically relevant non-major bleeding: 9.0% vs 6.0%; HR 1.42, 95% CI 0.88–2.30 (non-significant)
Adverse events
Main adverse events: Major bleeding not significantly different between apixaban and dalteparin (3.8% vs 4.0%). GI major bleeding similar (1.9% vs 1.7%) — a key distinction from edoxaban and rivaroxaban. CRNMB numerically higher with apixaban (9.0% vs 6.0%) but not statistically significant. Fatal bleeding: 0.2% each arm. Net clinical benefit (VTE + major bleeding) favored apixaban.
Conclusions
Apixaban was non-inferior to dalteparin for VTE recurrence in cancer patients without a significant increase in major bleeding, including in GI cancer subgroups, establishing apixaban as the preferred DOAC for cancer-associated VTE.
Key Limitations
Key Limitations: Open-label design. Non-inferiority trial — efficacy point estimate (HR 0.63) numerically favors apixaban, but the trial was not powered for superiority. GI cancer subgroup analysis was exploratory — the trial included patients with GI malignancy but was not designed to definitively prove GI safety equivalence. 6-month primary duration is short for cancer patients; longer-term data limited. Patients with high thrombocytopenia or poor performance status underrepresented. Direct comparisons between DOACs for cancer-VTE are lacking.
Clinical Context
CARAVAGGIO (2020) is the definitive trial establishing apixaban as the preferred DOAC for cancer-associated VTE. The absence of a GI bleeding signal (unlike edoxaban/rivaroxaban) makes apixaban the guideline-preferred agent (ASCO 2021, NCCN, ISTH 2022). For patients with luminal GI cancer or GU cancer at high bleeding risk, dalteparin (LMWH) remains a reasonable alternative. Apixaban is preferred over LMWH for most cancer-VTE patients due to oral convenience, no injection burden, and equivalent or better efficacy.
References