“Low-Molecular-Weight Heparin versus a Coumarin for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer”
by the Randomized Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer (CLOT) Investigators
N Engl J Med. 2003 Jul 10;349(2):146-53. [free full text]
Malignancy is a pro-thrombotic state, and patients with cancer are at significant and sustained risk of venous thromboembolism (VTE) even when treated with warfarin. Warfarin is a suboptimal drug that requires careful monitoring, and its effective administration is challenging in the setting of cancer-associated difficulties with oral intake, end-organ dysfunction, and drug interactions. The 2003 CLOT trial was designed to evaluate whether treatment with low-molecular-weight heparin (LMWH) was superior to a vitamin K antagonist (VKA) in the prevention of recurrent VTE.
Population: adults with active cancer and newly diagnosed symptomatic DVT or PE
The cancer must have been diagnosed or treated within past 6 months, or the patient must have recurrent or metastatic disease.
Intervention: dalteparin subQ daily (200 IU/kg daily x1 month, then 150 IU/kg daily x5 months)
Comparison: vitamin K antagonist x6 months (with 5-7 day LMWH bridge), target INR 2.5
primary = recurrence of symptomatic DVT or PE within 6 months follow-up
secondary = major bleeding, any bleeding, all-cause mortality
338 patients were randomized to the LMWH group, and 338 were randomized to the VKA group. Baseline characteristics were similar among the two groups. 90% of patients had solid malignancies, and 67% of patients had metastatic disease. Within the VKA group, INR was estimated to be therapeutic 46% of the time, subtherapeutic 30% of the time, and supratherapeutic 24% of the time.
Within the six-month follow-up period, symptomatic VTE occurred in 8.0% of the dalteparin group and 15.8% of the VKA group (HR 0.48, 95% CI 0.30-0.77, p=0.002; NNT = 12.9). The Kaplan-Meier estimate of recurrent VTE at 6 months was 9% in the dalteparin group and 17% in the VKA group.
6% of the dalteparin group developed major bleeding versus 6% of the VKA group (p = 0.27). 14% of the dalteparin group sustained any type of bleeding event versus 19% of the VKA group (p = 0.09). Mortality at 6 months was 39% in the dalteparin group versus 41% in the VKA group (p = 0.53).
Treatment of VTE in cancer patients with low-molecular-weight heparin reduced the incidence of recurrent VTE relative to the incidence following treatment with vitamin K antagonists.
Notably, this reduction in VTE recurrence was not associated with a change in bleeding risk. However, it also did not correlate with a mortality benefit either.
This trial initiated a paradigm shift in the treatment of VTE in cancer. LMWH became the standard of care, although access and adherence to this treatment was thought to be limited by cost and convenience.
Until last week, no trial had directly compared a DOAC to LMWH in the prevention of recurrent VTE in malignancy. In an open-label, noninferiority trial, the Hokusai VTE Cancer Investigators demonstrated that the oral Xa inhibitor edoxaban (Savaysa) was noninferior to dalteparin with respect to a composite outcome of recurrent VTE or major bleeding.
1. Wiki Journal Club
2. 2 Minute Medicine
3. UpToDate, “Treatment of venous thromboembolism in patients with malignancy”
4. “Edoxaban for the Treatment of Cancer-Associated Venous Thromboembolism,” NEJM 2017
Summary by Duncan F. Moore, MD