Low-molecular-weight heparin in patients with advanced cancer: A phase 3 clinical trial

Abstract

Conclusion: Low-molecular-weight heparin does not provide survival benefit in patients with advanced cancer. Summary: It has been suggested that patients with cancer who develop venous thromboembolism (VTE) and are treated with low-molecular-weight heparin have a survival advantage over those treated with unfractionated heparin (Am J Med 1996;100:269-277 and Ann Intern Med 1999;130:800-809). The authors therefore sought to assess whether low-molecular-weight heparin might provide a survival advantage in patients with advanced cancer. This was a randomized clinical trial conducted between December 1998 and June 2001. Patients with advanced cancer were randomized to receive low-molecular-weight heparin or placebo. The study began as a double-blinded placebo-controlled trial with patients receiving injections daily of saline or 5000 U of low-molecular-weight heparin. Recruitment for the trial was low; therefore, the placebo arm was eliminated midway through the study. At this point, the study became open labeled, and patients received low-molecular-weight heparin injections and standard clinical care, or standard clinical care alone. The primary study end point was overall survival. There were 138 patients analyzed. Median survival for the combined standard-care and placebo groups was 10.5 months (95% confidence interval [CI], 7.6 to 12.2 months). Median survival for the low-molecular-weight heparin arms of the trial was 7.3 months (95% CI, 4.8 to 12.2). This was not significantly different from the placebo group (P = .46). Median survival times for unblinded and blinded low-molecular-weight heparin groups were 9.0 months and 6.2 months, respectively. Median survival time was 10.5 months in the standard-care group and 10.3 months in the placebo-blinded group. There was a 6% rate of significant VTE in the low-molecular-weight heparin arms and a 7% rate in the control arms. Major bleeding was 7% in the control arms and 3% in the low-molecular-weight heparin arms. Comment: It has been suggested for a number of years that low-molecular-weight heparin may confer a survival advantage over unfractionated heparin in patients with VTE and cancer. A pleiotropic effect of low-molecular-weight heparin was postulated. This study argues against such an effect. Weaknesses of the study include changing its design in mid-course and inclusion of four different groups of cancer patients, perhaps masking a treatment effect in one group vs another. The trial did demonstrate safety of low-molecular-weight heparin in patients with advanced cancer.