The CLOT trial: Dalteparin versus warfarin [Classics Series]

Classics Series, Landmark Trials in Medicine

1. Dalteparin, a low-molecular-weight heparin, is superior to warfarin in preventing recurrent venous thromboembolism in the setting of malignancy. 

2. There is no significant difference in risk of major bleeding with dalteparin as compared to warfarin.

Original Date of Publication: July 10, 2003

Study Rundown: Prior to the CLOT trial, patients with venous thromboembolism (VTE) in the setting of malignancy were treated similar to patients with other high-risk hypercoaguable states. That is, these patients were treated with long-term oral anticoagulation, like warfarin, with initial bridging with subcutaneous heparin or low-molecular-weight heparin (LMWH). There were questions as to whether the more predictable pharmacokinetics and drug interactions of LMWH could offer benefits compared to oral anticoagulants in the setting of cancer, given that these patients are often undergoing complex treatment regimes and are frequently further burdened with degrees of liver dysfunction and malnutrition.

The CLOT trial, from McMaster University, was published in NEJM in 2003. This landmark trial sought to address whether long-term anticoagulation with subcutaneous dalteparin offered benefit compared to oral anticoagulation in the cancer population in preventing recurrent VTE. The trial demonstrated that dalteparin is superior in preventing recurrent VTEs in the setting of malignancy when compared to oral anticoagulation with warfarin. There was no significant difference between the two therapies with regards to risk of bleeding. In the setting of acute VTE associated with malignancy without active bleeding, it is reasonable to initiate treatment with a LMWH, as opposed to oral vitamin K antagonists, for up to 6 months to prevent recurrent VTEs.

Click here to read the study in NEJM

Lead Study Investigator, Dr. Agnes Y. Y. Lee, MD, MSc, FRCPC, talks to 2 Minute Medicine: University of British Columbia, Medical Director, Thrombosis Program, Associate Professor of Medicine, Division of Hematology. 

alee-275x300“Ten years after the publication of the CLOT trial, it remains the largest randomized control trial evaluating the efficacy and safety of a low molecular weight heparin (LMWH) for treatment of cancer-associated thrombosis.  The CLOT trial established dalteparin as being a superior anticoagulant over vitamin K antagonist therapy and it was the pivotal study that led to the regulatory approval of dalteparin for the extended treatment of thrombosis in cancer patients. The clinically significant 52% risk reduction in symptomatic recurrent thrombosis changed practice worldwide.  The consistent results from other trials assessing other LMWHs also prompted international consensus guidelines to recommend the use of LMWH as the preferred therapy in patients with cancer and thrombosis.   Despite this, LMWH is often not used as the first line therapy because of its cost and need for once-daily subcutaneous injections. Future studies using novel oral anticoagulants to treat cancer patients with thrombosis are eagerly awaited.”

In-Depth [randomized, controlled study]: The study included 676 patients from 48 clinical centres in eight countries. Patients were eligible for the trial if they were adult patients with active cancer and newly diagnosed, symptomatic proximal deep-vein thrombosis, pulmonary embolism, or both. Patients were excluded from the trial if they weighed ≤40 kg, had an Eastern Cooperative Oncology Group (ECOG) performance status of 3 or 4, had been treated with therapeutic heparin for >48 hours before randomization, had active or serious bleeding in the 2 weeks prior, had platelet count <75,000/mm3, had contraindications to heparin treatment or contrast medium, had creatinine ≥3 times the upper limit of normal, were pregnant, or could not return for follow-up. Patients were randomized to two groups: 1) warfarin with initial bridging with dalteparin, and 2) dalteparin only. The study lasted a total of 6 months. The primary outcome was the first episode of objectively documented, symptomatic recurrent DVT and/or PE during the study period. Secondary outcomes studied included any bleeding event.

The incidence of recurrent thromboembolism in the dalteparin only group was significantly less than the oral anticoagulation group (HR 0.48; 95%CI 0.30-0.77). There was no significant difference in bleeding detected between the two groups, with 6% of patients in the dalteparin group and 4% in the oral anticoagulation group experiencing bleeding (p=0.27). The mortality rates were 39% and 41% in the dalteparin and oral anticoagulation groups (p=0.53), respectively, and it was noted that 90% of these deaths were attributed to progression of malignancy.

Image: PD

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