PRODIGE: A phase III randomized placebo-controlled trial of thromboprophylaxis using dalteparin low molecular weight heparin (LMWH) in patients with newly diagnosed malignant glioma

2011 Background: Venous thromboembolism (VTE) occurs in 20–30% of patients with malignant glioma per year of survival. We have conducted an RCT testing the efficacy and safety of long-term dalteparin for the prevention of VTE in newly diagnosed malignant glioma. Methods: Adults with newly diagnosed malignant glioma were randomized to receive dalteparin 5,000 anti-Xa units or placebo, both subcutaneously daily for 6 months starting within the first month after surgery. Patients were allowed to continue study medication for up to 12 months. Because of the poor prognosis of malignant glioma it was determined apriori that the primary outcome was 6-month VTE-free survival. In order to detect a 60% VTE hazard reduction with LMWH with 80% power, 512 patients were required. Results: Recruitment began October 2002 and was closed in May 2006 because of expiration of study medication and no further re-supply. Of the 563 patients screened at 15 centers, 174 were excluded. Of the 389 eligible patients approached for consent, 186 were randomized: 99 to LMWH, 87 to placebo. Twenty-one patients developed objectively confirmed VTE during the first 6 months: 9 on LMWH and 12 on placebo (11% and 17% respectively; HR=0.7, 95% CI: 0.37–1.5, p=0.3). Over the 12 months there were 5 (5.1%) major bleeds with LMWH and 1 (1.2%) with placebo (HR=4.0, 95%CI: 0.5–34, p=0.2). All major bleeds were intracranial. Twelve-month mortality was 48% for LMWH and 45% for placebo (HR=1.2, 95%CI: 0.7–1.9, p=0.5). Conclusions: Although there was a trend in favor of the LMWH reducing VTE this was not statistically significant, likely as a result of low power. There was also a trend for increased intracranial bleeding with LMWH. Our study confirms the high incidence of thromboembolism in these patients; however, the role of long-term anticoagulant thromboprophylaxis remains unclear. Supported in part by a grant in aid from Pfizer Inc. and the Ontario Cancer Research Network. The PRODIGE steering committee thanks Terri Finch for superb administrative support. Pfizer