Comparison of low-intensity warfarin therapy with conventional-intensity warfarin therapy for long-term prevention of recurrent venous thromboembolism

N Engl J Med. 2003 Aug 14;349(7):631-9. doi: 10.1056/NEJMoa035422.


Background: Warfarin is very effective in preventing recurrent venous thromboembolism but is also associated with a substantial risk of bleeding. After three months of conventional warfarin therapy, a lower dose of anticoagulant medication may result in less bleeding and still prevent recurrent venous thromboembolism.

Methods: We conducted a randomized, double-blind study, in which 738 patients who had completed three or more months of warfarin therapy for unprovoked venous thromboembolism were randomly assigned to continue warfarin therapy with a target international normalized ratio (INR) of 2.0 to 3.0 (conventional intensity) or a target INR of 1.5 to 1.9 (low intensity). Patients were followed for an average of 2.4 years.

Results: Of 369 patients assigned to low-intensity therapy, 16 had recurrent venous thromboembolism (1.9 per 100 person-years), as compared with 6 of 369 assigned to conventional-intensity therapy (0.7 per 100 person-years; hazard ratio, 2.8; 95 percent confidence interval, 1.1 to 7.0). A major bleeding episode occurred in nine patients assigned to low-intensity therapy (1.1 events per 100 person-years) and eight patients assigned to conventional-intensity therapy (0.9 event per 100 person-years; hazard ratio, 1.2; 95 percent confidence interval, 0.4 to 3.0). There was no significant difference in the frequency of overall bleeding between the two groups (hazard ratio, 1.3; 95 percent confidence interval, 0.8 to 2.1).

Conclusions: Conventional-intensity warfarin therapy is more effective than low-intensity warfarin therapy for the long-term prevention of recurrent venous thromboembolism. The low-intensity warfarin regimen does not reduce the risk of clinically important bleeding.

Publication types

  • Clinical Trial
  • Comparative Study
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Aged
  • Anticoagulants / administration & dosage*
  • Anticoagulants / adverse effects
  • Double-Blind Method
  • Drug Administration Schedule
  • Female
  • Follow-Up Studies
  • Hemorrhage / chemically induced
  • Humans
  • International Normalized Ratio
  • Male
  • Middle Aged
  • Pulmonary Embolism / mortality
  • Pulmonary Embolism / prevention & control*
  • Risk Factors
  • Secondary Prevention
  • Treatment Outcome
  • Venous Thrombosis / prevention & control*
  • Warfarin / administration & dosage*
  • Warfarin / adverse effects


  • Anticoagulants
  • Warfarin