CLOT

Background

Phase 3 open-label RCT (CLOT). 676 patients with active cancer and acute symptomatic proximal DVT, PE, or both. Randomized to low-molecular-weight heparin (dalteparin, Fragmin) monotherapy versus initial dalteparin followed by oral anticoagulant (VKA: warfarin or acenocoumarol) for 6 months. Cancer patients have high VTE recurrence rates and poor VKA control (fluctuating INR due to drug interactions, poor oral intake, procedures). This trial tested whether LMWH monotherapy was superior to warfarin in cancer-associated VTE.

Interventions and follow up

Arm A: Dalteparin 200 IU/kg once daily × 1 month, then 150 IU/kg once daily × 5 months (6 months total)
Arm B: Dalteparin 200 IU/kg once daily × 5–7 days, then VKA (warfarin or acenocoumarol) for 6 months (target INR 2.0–3.0)
Primary endpoint: Recurrent symptomatic VTE (objectively confirmed DVT or PE) at 6 month
mFollow up: 6 month

Results

Recurrent VTE at 6 months: 9% (dalteparin) vs 17% (VKA); HR 0.48, 95% CI 0.30–0.77 — P=.002
Major bleeding: 6% vs 4% (not statistically significant)
Overall survival at 6 months: 60% vs 58% — similar (P=NS; cancer prognosis dominated mortality)

Adverse events

Main adverse events: Major bleeding 6% (dalteparin) vs 4% (VKA) — numerically higher with LMWH but not statistically significant. Minor bleeding similar between arms. Injection-site reactions with LMWH. No difference in mortality at 6 months. VKA quality: ~46% time in therapeutic range in VKA arm, reflecting the well-documented INR lability in cancer patients.

Conclusions

Dalteparin monotherapy was superior to VKA for preventing recurrent VTE in cancer patients (9% vs 17%), without significantly increasing major bleeding, establishing LMWH as the standard of care for cancer-associated VTE for over a decade.

Key Limitations

Key Limitations: Open-label design. Only 6 months of follow-up; many cancer patients require longer anticoagulation. VKA TTR was poor (~46%), which likely exaggerated the benefit of LMWH over VKA. Does not compare LMWH to DOACs (DOACs not yet available at trial initiation, 2003). Dalteparin requires daily subcutaneous injection — patient burden is high. Low-TTR VKA arm may not reflect optimally managed VKA therapy.

Clinical Context

CLOT established LMWH as the preferred anticoagulant for cancer-associated VTE from 2003–2018. Subsequently, DOAC trials in cancer-VTE (Hokusai-VTE Cancer 2018, SELECT-D 2018, CARAVAGGIO 2020) demonstrated DOAC non-inferiority or superiority to LMWH, with the caveat of higher GI/GU bleeding risk with DOACs in GI/GU malignancies. Current ASCO, NCCN, and ASH guidelines recommend DOACs (apixaban, rivaroxaban, edoxaban) as preferred over LMWH for cancer-VTE unless luminal GI/GU malignancy or drug interactions — in which case LMWH remains preferred.

References

References: Lee AY et al, NEJM 2003 (CLOT); PMID 12853587