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Dalteparin is treatment of choice for cancer patients with VTE
Further studies are needed to confirm the agent's benefits for long-term management.
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The FDA has approved dalteparin for extended treatment of venous thromboembolism for patients with cancer.
The approval was based on data from the CLOT (Randomized Comparison of Low-Molecular-Weight Heparin vs. Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer) study. These data were published in The New England Journal of Medicine.
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Patients with cancer have a fourfold to sixfold higher risk for venous thromboembolism than those without cancer. Patients with cancer also have a higher risk for recurrent VTE and anticoagulant-related bleeding.
These observations may explain why cancer patients with VTE have a shorter survival than those without this complication. Furthermore, VTE has a negative impact on quality of life in patients with cancer, and VTE treatment can delay or interrupt the treatment of the cancer.
Current management of VTE consists of an initial five day to seven day course of unfractionated heparin or low-molecular-weight heparin followed by extended treatment with a vitamin K antagonist, such as warfarin, for three months to six months.
However, warfarin therapy in patients with cancer is complicated by comorbidities, such as hepatic metastasis, which can render warfarin dosing problematic; concurrent therapies, such as chemotherapy, which can cause thrombocytopenia or severe gastrointestinal disturbances; and the advanced age of many patients with cancer.
In addition, limited venous access renders monitoring of warfarin therapy difficult in patients with cancer. Also, because of its long half-life, warfarin is often held for extended periods prior to invasive procedures, or when there is persistent thrombocytopenia. Taken together, these factors help to explain why patients with cancer have higher rates of recurrent VTE and major bleeding with warfarin than those without cancer.
Dalteparin more efficacious
The CLOT study was an open-label, multicenter trial. It included 672 patients with cancer who had symptomatic VTE. All patients received initial treatment with dalteparin (Fragmin, Pfizer) for at least five days, after which they were randomly assigned to continued dalteparin or to a vitamin K antagonist for the next six months.
Compared with a vitamin K antagonist, extended treatment with dalteparin reduced the risk for recurrent VTE by 52% (from 17% to 9%, P=.002). The rate of major bleeding was not significantly higher with dalteparin (6%) than it was with a vitamin K antagonist (4%).
These results indicate that dalteparin is more efficacious than warfarin and that it is easier to administer in the cancer setting. Dalteparin is given in fixed, weight-adjusted doses without any coagulation monitoring. Although the CLOT investigators used multidose vials for initial treatment, prefilled syringes can be employed for most patients, which simplifies care.
After one month of treatment at a once-daily dose of 200 anti-Factor Xa units/kg, the dalteparin dose was reduced by about 25%, and this lower dose was then maintained for the remaining five months of therapy. In most cases, this translated into the next lower dose available in prefilled syringes.
Patients or their family members can usually be taught how to administer the subcutaneous injections. Therefore, home nursing care is rarely needed. The dalteparin dose is reduced if the platelet count falls below 100,000 mc/L, and held if the count falls below 50,000 mc/L.
In preparation for interventions, such as thoracentesis or central venous catheter insertion, the last dose of dalteparin can be given 24 hours prior to the procedure and treatment can be resumed after the procedure or the next day, depending on the invasiveness of the intervention.
Is extended treatment safe?
Post hoc analysis of the data from the CLOT trial suggests that survival is better with dalteparin compared with a vitamin K antagonist in patients with early stage cancer. This may occur because low-molecular-weight heparin has anticancer activity in cell culture systems and it reduces metastasis in animal models. Despite these promising results, however, further studies are needed to confirm that dalteparin improves survival in patients with cancer.
The recent FDA approval should open the door for reimbursement for dalteparin. After this barrier is overcome, extended dalteparin therapy should become the treatment of choice for cancer patients with VTE.
After six months of treatment, patients with metastatic cancer or those who continue to receive chemotherapy remain at risk for recurrent VTE if anticoagulation therapy is stopped. The CLOT trial supports the use of dalteparin for six months. Additional studies are needed to assess its benefits for longer term treatment.
For more information:
- Jeffrey Weitz, MD, is a professor in the department of medicine at McMaster University in Ontario, Canada and director of the Experimental Thrombosis and Atherosclerosis Program at the Hamilton Regional Cancer Center.
- Lee AY, Levine MN, Baker RI, et al. Low-molecular-weight heparin versus Coumadin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003;349:146-153.
- Lee AY, Rickles FR, Julian JA, et al. Randomized comparison of low molecular weight heparin and Coumadin derivatives on the survival of patients with cancer and venous thromboembolism. J Clin Oncol. 2005;23:2123-2129.