Prognostic factors for recurrence of venous thromboembolism (VTE) or bleeding during long-term secondary prevention of VTE with ximelagatran

Summary

The oral direct thrombin inhibitor ximelagatran (24 mg twice daily) has been shown to significantly reduce the incidence of recurrent venous thromboembolism (VTE) vs. placebo over 18 months, with no significant influence on bleeding (THRIVE III). The influence of potential prognostic factors on the risk of recurrent VTE or major and/or minor bleeding and their impact on ximelagatran treatment was evaluated in theTHRIVE III study population. The effect of sex, age, body weight, renal function, malignancy, type of initialVTE event, and history of previousVTE events was investigated in the intention-to-treat population using Cox proportionate hazard modelling. Ximelagatran was administered to 612 patients and placebo to 611 patients. Within the placebo group, risk of recurrent VTE was higher among men than women (hazard ratio [HR]: 2.50,95% confidence interval [CI] 1.49, 4.17), and in patients with one or more than one previous VTE event (HR: 1.73, 95% CI 1.00, 2.99). There was a higher risk of bleeding among women than men in both the ximelagatran (HR: 1.49, 95% CI 1.06, 2.09) and placebo (HR: 1.48, 95% CI 1.01, 2.15) groups, and in placebo-treated patients with an initial pulmonary embolism (HR: 1.53, 95% CI 1.06, 2.23) compared to those with initial deep vein thrombosis. There were no significant interactions between treatment effect and any of the potential prognostic factors. In conclusion, the superior efficacy of ximelagatran vs. placebo was maintained in all subgroups. Long-term use of oral ximelagatran, without coagulation monitoring or dose adjustment, should be feasible and well tolerated in a wide cross-section of patients for the secondary prevention of VTE.

Keywords

Oral direct thrombin inhibitor - risk factors - THRIVE III - venous thromboembolism - ximelagatran

• References

• 1 Anderson FA Jr, Spencer FA. Risk factors for venous thromboembolism.. Circulation 2003; 107 (Suppl. 01) I9-116.
• 2 Heit JA, Silverstein MD, Mohr DN. et al. The epidemiology of venous thromboembolism in the community.. Thromb Haemost 2001; 86: 452-63.
• 3 Kearon C. Natural history of venous thromboembolism.. Circulation 2003; 107 (Suppl. 01) I22-I30.
• 4 Kyrle PA, Minar E, Bialonczyk C. et al. The risk of recurrent venous thromboembolism in men and women.. N Engl J Med 2004; 350: 2558-63.
• 5 Schulman S, Rhedin A-S, Lindmarker P. et al. A comparison of six weeks with six months of oral anticoagulant therapy after a first episode of venous thromboembolism.. N Engl J Med 1995; 332: 1661-5.
• 6 Murin S, Romano PS, White RW. Comparison of outcomes after hospitalisation for deep vein thrombosis or pulmonary embolism.. Thromb Haemost 2002; 88: 407-14.
• 7 Büller HR, Agnelli G, Hull RD. et al. Antithrombotic therapy for venous thromboembolic disease.. Chest 2004; 126 (Suppl. 03) 401S-28S.
• 8 Kearon C, Gent M, Hirsh J. et al. A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism.. N Engl J Med 1999; 340: 901-7.
• 9 Ridker PM, Goldhaber SZ, Danielson E. et al. Longterm, low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism.. N Engl J Med 2003; 348: 1425-34.
• 10 Kearon C, Ginsberg JS, Kovacs MJ. et al. Comparison of low-intensity warfarin therapy with conventional- intensity warfarin therapy for long-term prevention of recurrent venous thromboembolism.. N Engl J Med 2003; 349: 631-9.
• 11 Schulman S. Unresolved issues in anticoagulation therapy.. J Thromb Haemost 2003; 1: 1464-70.
• 12 Ansell J, Hirsh J, Poller L. et al. The pharmacology and management of the vitamin K antagonists.. Chest 2004; 126 (Suppl. 03) 204S-33S.
• 13 Francis CW, Berkowitz SD, Comp PC. et al. Comparison of the oral direct thrombin inhibitor ximelagatran with warfarin for the prevention of venous thromboembolism following total knee replacement: EXULT A.. N Engl J Med 2003; 349: 1703-12.
• 14 Eriksson BI, Agnelli G, Cohen AT. et al. Direct thrombin inhibitor melagatran followed by oral ximelagatran in comparison with enoxaparin for prevention of venous thromboembolism after total hip or knee replacement. The METHRO III study.. Thromb Haemost 2003; 89: 288-96.
• 15 Colwell CW, Berkowitz SD, Comp PC. et al. Oral direct thrombin inhibitor ximelagatran compared with warfarin for prevention of venous thromboembolism after total knee replacement.. J Bone Joint Surg Am.. In press.
• 16 Eriksson H, Wåhlander K, Gustafsson D. et al. A randomized, controlled, dose-guiding study of the oral direct thrombin inhibitor ximelagatran compared with standard therapy for the treatment of acute deep vein thrombosis: THRIVE I.. J Thromb Haemost 2003; 1: 41-7.
• 17 Fiessinger J-N, Huisman MV, Davidson BL. et al. Ximelagatran vs low-molecular-weight heparin and warfarin for the treatment of deep vein thrombosis: a randomized controlled trial.. JAMA 2005; 293: 681-9.
• 18 Executive Steering Committee on behalf of the SPORTIF III Investigators. Stroke prevention with the oral direct thrombin inhibitor ximelagatran compared with warfarin in patients with non-valvular atrial fibrillation (SPORTIF III): randomised controlled trial.. Lancet 2003; 362: 1691-8.
• 19 Wallentin L, Wilcox RG, Weaver WD. et al. Oral ximelagatran for secondary prophylaxis after myocardial infarction: the ESTEEM randomised controlled trial.. Lancet 2003; 362: 789-97.
• 20 Gustafsson D, Elg M. The pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor ximelagatran and its active metabolite melagatran: a mini-review.. Thromb Res 2003; 109: S9-S15.
• 21 Sarich TC, Johansson S, Schützer K-M. et al. The pharmacokinetics and pharmacodynamics of ximelagatran, an oral direct thrombin inhibitor, are unaffected by a single dose of alcohol.. J Clin Pharmacol 2004; 44: 388-93.
• 22 Bredberg E, Andersson TB, Frison L. et al. Ximelagatran, an oral direct thrombin inhibitor, has a low potential for cytochrome P450-mediated drug-drug interactions.. Clin Pharmacokinet 2003; 42: 765-77.
• 23 Lee WM, Larrey D, Olsson R. et al. Hepatic findings in long-term clinical trials of ximelagatran.. Drug Saf 2005; 28: 351-70.
• 24 Schulman S, Wåhlander K, Lundström T. et al. Secondary prevention of venous thromboembolism with the oral direct thrombin inhibitor ximelagatran.. N Engl J Med 2003; 349: 1713-21.
• 25 Levitan N, Dowlati A, Remick SC. et al. Rates of initial and recurrent thromboembolic disease among patients with malignancy versus those without malignancy. Risk analysis using Medicare claims data.. Medicine (Baltimore) 1999; 78: 285-91.
• 26 Prandoni P, Lensing AW, Prins MH. et al. Residual venous thrombosis as a predictive factor of recurrent venous thromboembolism.. Ann Intern Med 2002; 137: 955-60.