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

Int J Technol Assess Health Care. Fall 2004;20(4):405-14. doi: 10.1017/s026646230400128x.


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 dollars 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.

Publication types

  • Comparative Study
  • Meta-Analysis
  • Research Support, Non-U.S. Gov't
  • Review
  • Systematic Review

MeSH terms

  • Anticoagulants / adverse effects*
  • Anticoagulants / economics*
  • Costs and Cost Analysis
  • Hemorrhage / chemically induced*
  • Hemorrhage / economics*
  • Humans
  • Orthopedic Procedures / adverse effects
  • Orthopedic Procedures / economics
  • Reoperation / economics
  • Thromboembolism / prevention & control*
  • Venous Thrombosis / prevention & control*


  • Anticoagulants