Major bleeding rates after prophylaxis against venous thromboembolism: Systematic review, meta-analysis, and cost implications

Objectives: The frequency and consequences of major bleeding associated with anticoagulant prophylaxis for prevention of venous thromboembolism is examined. Methods: We conducted a systematic review and meta-analysis of controlled trials that reported rates of major bleeding after pharmaceutical thromboprophylaxis in patients undergoing major orthopedic surgery. Thromboprophylactic agents were divided into four groups:warfarin/other coumarin derivatives (WARF), unfractionated heparin (UFH), low molecular weight heparin (LMWH), and pentasaccharide (PS). Meta-analysis was conducted comparing LMWH with each of WARF, UFH, and PS. The frequency of re-operation due to major bleeding was reviewed and combined with published costs to estimate the mean cost of managing major bleeding events in these patients. Results: Twenty-one studies including 20,523 patients met inclusion criteria for the meta-analysis. No evidence of significant between-trial heterogeneity in risk ratios was found. Combined (fixed effects) relative risks (RR) of major bleeding compared with LMWH were WARF - RR 0.59 (95 percent confidence interval [CI], 0.44-0.80); UFH - RR 1.52 (95 percent CI, 1.04-2.23); PS - RR 1.52 (95 percent CI, 1.11-2.09). Seventy-one studies including 32,433 patients were included in the review of consequences of major bleeding. We estimated that the average cost of major bleeding is $113 per patient receiving thromboprophylaxis. Conclusions: LMWH results in fewer major bleeding episodes than UFH and PS but more than WARF. These events are costly and clinically important.