Approval of Dalteparin in cancer VTE
US FDA approves Dalteparin for the management of venous thromboembolism in cancer patients. In a landmark decision, the U.S. Food and Drug Administration (FDA) has approved a new indication for FRAGMIN® (dalteparin sodium injection), for the extended treatment of symptomatic venous thromboembolism (VTE) [proximal deep vein thrombosis (DVT) and/or pulmonary embolism (PE)] to reduce the recurrence of VTE in patients with cancer. This approval is yet another testimony of the crucial role of low molecular weight heparins (LMWHs) in the management of venous thromboembolism. Dalteparin represents the very first LMWH which is approved for this indication. This drug has been tested in several clinical settings where its efficacy in the management of thrmboembolism associated with malignancy has been validated.
This approval is mainly based on clinical results from the CLOT* study, which evaluated the safety and efficacy of Dalteaprin in reducing the recurrence of DVT/PE in patients with malignancy compared to an oral anticoagulant. Patients with acute DVT, PE or both were randomized into two groups of 338 patients each. The first group received Dalteparin for six months. The other group received Dalteparin for five to seven days, followed by oral anticoagulants for six months. Warfarin is an oral anticoagulant that has been used for many years as the standard drug in the long-term treatment of VTE. This study clearly demonstrated a much better clinical outcome in those patients treated with Dalteparin in comparison to those treated with warfarin. This suggests that LMWHs, such as Dalteparin exert additional therapeutic effects in cancer besides anticoagulation.
Venous thromboembolism (VTE) is a common cause of morbidity and mortality, affecting approximately 1 in 1,000 people in the general population annually in the United States.1,2 Since Armand Trousseau�??s recognition of the association between malignancy and venous thrombosis, 3 it has become widely accepted that cancer is an important and common cause of VTE. 4 Recent studies indicate that the presence of cancer is associated with a 4-fold increase in the risk of VTE, and 15% of patients with cancer will develop symptomatic VTE during the course of their illness. 5,6 As many as 30% to 50% of patients with cancer have evidence of VTE on autopsy.7 However, the prevalence and severity of VTE widely varies with different cancers.
Anticoagulants such as the LMWHS and oral anticoagulants, have an important role in treating the thromboembolic complications of cancer and in preventing their recurrence. Warfarin use is associated with substantial inter- and intra-individual variability in dosage requirements and the need for frequent dose monitoring, 8 a problem that is further amplifies in patients with cancer. Also, several studies have found that conventional management of VTE is associated with more recurrent thrombotic events and major bleeding in patients with cancer than among patients without malignancies. 9 The Clot study represents the pivotal clinical validation of the LMWH dalteparin as being more effective than warfarin in preventing recurrent VTE in patients with cancer, without increasing bleeding. 10 LMWH therapy may prolong survival among patients with cancer, 11-13 a finding that has prompted active investigation of LMWH specifically in this patient population.
The management of VTE in patients with cancer is changing at a rapid pace. The long-established association between malignancy and coagulation is being extended and refined, and an awareness of the molecular basis of coagulation along with knowledge of anticoagulation therapy is needed by those who treat patients with cancer. Accumulating evidence support the use of LMWHs for the prevention and treatment of VTE in patients with cancer. Data from clinical trials are impressive in their support of the safety, suitability and efficacy of LMWHs as therapy for VTE in patients with cancer, in both the inpatient and outpatient settings. The potential antineoplastic effects of LMWHs make these drugs an attractive therapeutic option for patients with cancer. It is expected that the currently ongoing and planned clinical trials with LMWHs in various cancer studies will provide additional supportive data on the therapeutic benefits of these drugs in the management of malignancy-associated thrombosis, contributing to an increased survival rate and improved quality of life.
The FDA approval for Dalteparin in the management of VTE in cancer patients now paves the way for other LMWHs such as Enoxaparin and Tinzaparin which have also demonstrated therapeutic efficacy in cancer patients. Moreover, improved mortality outcomes have been reported in several other studies. Thus, the LMWHs will play an important role in the overall management of cancer patients.
The CLOT study was conducted on specific LMWH, namely, Dalteparin which is distinguishable form other LMWHs. Therefore the clinical results obtained with this agent are product specific and may not be mimicked by other LMWHs at the designated dosage. Independent clinical trials with each of the individual LMWHs at their own optimized dosage and regimen may be required to validate the therapeutic safety and effects of other LMWHs. Therefore the improved outcome reported in the CLOT study, forming the basis of its approval, is product specific. Dalteparin and other LMWHs are polytherapeutic agents with multiple therapeutic effects including the control of cellular growth and angiogenesis. Warfarin and related anticoagulant drugs exhibit different mechanisms of action which are distinct from those of LMWHs. Similarly the newly developed oral anti-Xa and anti-IIa agents will have a narrow spectrum of action in cancer patients. Thus, the clinical effects of LMWHs in cancer represents an unique and enherent therapeutic effects of this class of anticoagulant drugs. Additional clinical trials are underway with several other LMWHs for the management of thrombosis associated with malignancy.
Debra A. Hoppensteadt, Ph.D.