FREE NEJM E-TOC    HOME   |   SUBSCRIBE   |   CURRENT ISSUE   |   PAST ISSUES   |   COLLECTIONS   |   Search Term  Advanced Search

Sign in | Get NEJM's E-Mail Table of Contents — Free | Subscribe

Previous Volume 349:1713-1721 October 30, 2003 Number 18 Next

	Full Text PDF PDA Full Text PowerPoint Slide Set Editorial by Shapiro, S. S. Letters Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited E-mail When Letters Appear PubMed Citation

ABSTRACT

Background For many patients with venous thromboembolism, secondary prevention with vitamin K antagonists is not extended beyond six months, since the risk of recurrence may be outweighed by the risk of major bleeding.

Methods In a double-blind, multicenter trial, we randomly assigned 1233 patients with venous thromboembolism who had undergone six months of anticoagulant therapy to extended secondary prevention with the oral direct thrombin inhibitor ximelagatran (24 mg) or placebo, taken twice daily, for 18 months without monitoring of coagulation. At base line, bilateral ultrasonography of the legs and perfusion lung scanning were performed.

Results Data from 612 patients in the ximelagatran group and 611 in the placebo group were analyzed. The occurrence of the primary end point, symptomatic recurrent venous thromboembolism, was confirmed in 12 patients assigned to ximelagatran and 71 patients assigned to placebo (hazard ratio, 0.16; 95 percent confidence interval, 0.09 to 0.30; P<0.001). Death from any cause occurred in 6 patients in the ximelagatran group and 7 patients in the placebo group, and bleeding occurred in 134 patients and 111 patients, respectively (hazard ratio, 1.19; 95 percent confidence interval, 0.93 to 1.53; P=0.17). The incidence of major hemorrhage was low (six events in the ximelagatran group and five in the placebo group), and none of these hemorrhages were fatal. The cumulative risk of a transient elevation of the alanine aminotransferase level to more than three times the upper limit of normal was 6.4 percent in the ximelagatran group, as compared with 1.2 percent in the placebo group (P<0.001).

Conclusions Oral ximelagatran was superior to placebo for the extended prevention of venous thromboembolism. There was no significant increase in the frequency of bleeding complications, but there was an increase in the number of patients with a transient elevation in the alanine aminotransferase level.

Source Information

From the Coagulation Unit, Department of Medicine, Karolinska Hospital, Stockholm (S.S.); AstraZeneca Research and Development Mölndal, Mölndal (K.W., T.L., S.B.C.); the Department of Clinical Chemistry and Transfusion Medicine, Sahlgrenska University Hospital, Gothenburg (K.W.); and the Department of Medicine, Sahlgrenska University Hospital–Östra, Gothenburg (H.E.) — all in Sweden.

Address reprint requests to Dr. Schulman at the Coagulation Unit, Karolinska Hospital, S-171 76 Stockholm, Sweden, or at sam.schulman{at}ks.se.

Full Text of this Article

Related Letters:

Ximelagatran for Secondary Prevention of Venous Thromboembolism
Vaknansky A., Kupfer Y., Tessler S., Böger C., Schroll S., Holmer S., Schulman S., Eriksson H.
Extract | Full Text | PDF  
N Engl J Med 2004; 350:618-619, Feb 5, 2004. Correspondence

This article has been cited by other articles:

• Schulman, S., Beyth, R. J., Kearon, C., Levine, M. N. (2008). Hemorrhagic Complications of Anticoagulant and Thrombolytic Treatment: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 133: 257S-298S [Abstract] [Full Text]  
• Kearon, C., Kahn, S. R., Agnelli, G., Goldhaber, S., Raskob, G. E., Comerota, A. J. (2008). Antithrombotic Therapy for Venous Thromboembolic Disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 133: 454S-545S [Abstract] [Full Text]  
• Gross, P. L., Weitz, J. I. (2008). New Anticoagulants for Treatment of Venous Thromboembolism. Arterioscler. Thromb. Vasc. Bio. 28: 380-386 [Abstract] [Full Text]  
• The van Gogh Investigators, (2007). Extended Prophylaxis of Venous Thromboembolism with Idraparinux. NEJM 357: 1105-1112 [Abstract] [Full Text]  
• Thompson, J. L., Hamner, C. E., Potter, D. D., Lewin, M., Sundt, T. M., Schaff, H. V. (2007). Melagatran for thromboprophylaxis after mechanical valve implantation: Results in a heterotopic porcine model. J. Thorac. Cardiovasc. Surg. 134: 359-365 [Abstract] [Full Text]  
• Koscielny, J., Kiesewetter, H., Jorg, I., Harenberg, J. (2007). Ximelagatran for Treatment and Prophylaxis of Recurrent Events in Deep Vein Thrombosis. CLIN APPL THROMB HEMOST 13: 299-307 [Abstract]  
• Watson, H. G, Greaves, M. (2007). Review: New anticoagulants: a story of promise and disappointment. British Journal of Diabetes & Vascular Disease 7: 51-58 [Abstract]  
• Piazza, G., Goldhaber, S. Z. (2006). Acute Pulmonary Embolism: Part II: Treatment and Prophylaxis. Circulation 114: e42-e47 [Full Text]  
• Harenberg, J., Jorg, I., Weiss, C. (2006). Observations of Alanine Aminotransferase and Aspartate Aminotransferase in THRIVE Studies Treated Orally with Ximelagatran. International Journal of Toxicology 25: 165-169 [Abstract] [Full Text]  
• Eriksson, U. G., Dorani, H., Karlsson, J., Fritsch, H., Hoffmann, K.-J., Olsson, L., Sarich, T. C., Wall, U., Schutzer, K.-M. (2006). INFLUENCE OF ERYTHROMYCIN ON THE PHARMACOKINETICS OF XIMELAGATRAN MAY INVOLVE INHIBITION OF P-GLYCOPROTEIN-MEDIATED EXCRETION. Drug Metab. Dispos. 34: 775-782 [Abstract] [Full Text]  
• Bauer, K. A. (2006). New Anticoagulants. ASH Education Book 2006: 450-456 [Abstract] [Full Text]  
• Prandoni, P. (2005). How I treat venous thromboembolism in patients with cancer. Blood 106: 4027-4033 [Abstract] [Full Text]  
• Di Nisio, M., Middeldorp, S., Buller, H. R. (2005). Direct Thrombin Inhibitors. NEJM 353: 1028-1040 [Full Text]  
• McBride, B. F. (2005). A Preliminary Assessment of the Critical Differences Between Novel Oral Anticoagulants Currently in Development. J Clin Pharmacol 45: 1004-1017 [Abstract] [Full Text]  
• Ost, D., Tepper, J., Mihara, H., Lander, O., Heinzer, R., Fein, A. (2005). Duration of Anticoagulation Following Venous Thromboembolism: A Meta-analysis. JAMA 294: 706-715 [Abstract] [Full Text]  
• The PREPIC Study Group, (2005). Eight-Year Follow-Up of Patients With Permanent Vena Cava Filters in the Prevention of Pulmonary Embolism: The PREPIC (Prevention du Risque d'Embolie Pulmonaire par Interruption Cave) Randomized Study. Circulation 112: 416-422 [Abstract] [Full Text]  
• Gulseth, M. P. (2005). Ximelagatran: An orally active direct thrombin inhibitor. Am J Health Syst Pharm 62: 1451-1467 [Abstract] [Full Text]  
• Brinker, A., He, R., Desai, M., Gelperin, K., Robie-Suh, K. (2005). Safety of Ximelagatran. JAMA 293: 2859-2859 [Full Text]  
• Lip, G. Y.H. (2005). Stroke prevention in atrial fibrillation: the case for ximelagatran. Eur Heart J Suppl 7: E21-E25 [Full Text]  
• Katira, R, Chauhan, A, More, R S (2005). Direct thrombin inhibitors: novel antithrombotics on the horizon in the thromboprophylactic management of atrial fibrillation. Postgrad. Med. J. 81: 370-375 [Abstract] [Full Text]  
• Haines, S. T., Nutescu, E. A. (2005). Current and emerging treatment options for venous thrombosis: A case discussion. Am J Health Syst Pharm 62: 593-605 [Full Text]  
• Fiessinger, J.-N., Huisman, M. V., Davidson, B. L., Bounameaux, H., Francis, C. W., Eriksson, H., Lundstrom, T., Berkowitz, S. D., Nystrom, P., Thorsen, M., Ginsberg, J. S., for the THRIVE Treatment Study Investigators, (2005). Ximelagatran vs Low-Molecular-Weight Heparin and Warfarin for the Treatment of Deep Vein Thrombosis: A Randomized Trial. JAMA 293: 681-689 [Abstract] [Full Text]  
• SPORTIF Executive Steering Committee for the SPORT, (2005). Ximelagatran vs Warfarin for Stroke Prevention in Patients With Nonvalvular Atrial Fibrillation: A Randomized Trial. JAMA 293: 690-698 [Abstract] [Full Text]  
• Gurewich, V. (2005). Ximelagatran--Promises and Concerns. JAMA 293: 736-739 [Full Text]  
• Hirsh, J., O'Donnell, M., Weitz, J. I. (2005). New anticoagulants. Blood 105: 453-463 [Abstract] [Full Text]  
• Goldhaber, S. Z. (2004). Prevention of Recurrent Idiopathic Venous Thromboembolism. Circulation 110: IV-20-IV-24 [Abstract] [Full Text]  
• Dager, W. E, Vondracek, T. G, McIntosh, B. A, Nutescu, E. A (2004). Ximelagatran: An Oral Direct Thrombin Inhibitor. The Annals of Pharmacotherapy 38: 1881-1897 [Abstract] [Full Text]  
• McGuire, M., Dobesh, P. P. (2004). Therapeutic Update on the Prevention and Treatment of Venous Thromboembolism. Journal of Pharmacy Practice 17: 289-307 [Abstract]  
• Dobesh, P. P., Kim, K., Stacy, Z. (2004). The Future of Anticoagulation. Journal of Pharmacy Practice 17: 370-384 [Abstract]  
• Weitz, J. I., Hirsh, J., Samama, M. M. (2004). New Anticoagulant Drugs: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 126: 265S-286S [Abstract] [Full Text]  
• Levine, M. N., Raskob, G., Beyth, R. J., Kearon, C., Schulman, S. (2004). Hemorrhagic Complications of Anticoagulant Treatment: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 126: 287S-310S [Abstract] [Full Text]  
• Buller, H. R., Agnelli, G., Hull, R. D., Hyers, T. M., Prins, M. H., Raskob, G. E. (2004). Antithrombotic Therapy for Venous Thromboembolic Disease: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 126: 401S-428S [Abstract] [Full Text]  
• Kearon, C. (2004). Long-Term Management of Patients After Venous Thromboembolism. Circulation 110: I-10-I-18 [Abstract] [Full Text]  
• Weitz, J. I. (2004). New Anticoagulants for Treatment of Venous Thromboembolism. Circulation 110: I-19-I-26 [Abstract] [Full Text]  
• Sarich, T. C., Schutzer, K.-M., Dorani, H., Wall, U., Kalies, I., Ohlsson, L., Eriksson, U. G. (2004). No Pharmacokinetic or Pharmacodynamic Interaction Between Atorvastatin and the Oral Direct Thrombin Inhibitor Ximelagatran. J Clin Pharmacol 44: 928-934 [Abstract] [Full Text]  
• Sarich, T. C., Schutzer, K.-M., Wollbratt, M., Wall, U., Kessler, E., Eriksson, U. G. (2004). No Pharmacokinetic or Pharmacodynamic Interaction Between Digoxin and the Oral Direct Thrombin Inhibitor Ximelagatran in Healthy Volunteers. J Clin Pharmacol 44: 935-941 [Abstract] [Full Text]  
• Bates, S. M., Ginsberg, J. S. (2004). Treatment of Deep-Vein Thrombosis. NEJM 351: 268-277 [Full Text]  
• Prandoni, P. (2004). Ximelagatran prevented secondary venous thromboembolism. Evid. Based Med. 9: 107-107 [Full Text]  
• Nutescu, E. A., Bauman, J. L. (2004). Shifting Paradigms in Oral Anticoagulation Management. J CARDIOVASC PHARMACOL THER 9: 149-150  
• Ezekowitz, M. D., Falk, R. H. (2004). The Increasing Need for Anticoagulant Therapy to Prevent Stroke in Patients With Atrial Fibrillation. Mayo Clin Proc. 79: 904-913 [Abstract]  
• Elliott, C. G., Rubin, L. J. (2004). Mars or Venus -- Is Sex a Risk Factor for Recurrent Venous Thromboembolism?. NEJM 350: 2614-2616 [Full Text]  
• Dowd, M. B. (2004). Anticoagulation in the Elderly. Journal of Pharmacy Practice 17: 94-102 [Abstract]  
• Sarich, T. C., Johansson, S., Schutzer, K.-M., Wall, U., Kessler, E., Teng, R., Eriksson, U. G. (2004). The Pharmacokinetics and Pharmacodynamics of Ximelagatran, an Oral Direct Thrombin Inhibitor, Are Unaffected by a Single Dose of Alcohol. J Clin Pharmacol 44: 388-393 [Abstract] [Full Text]  
• Olsson, S.B. (2004). New advances in stroke prevention in atrial fibrillation: ximelagatran and direct thrombin inhibition. Eur Heart J Suppl 6: B20-B24 [Abstract] [Full Text]  
• (2004). Preventing VTE with Ximelagatran. Journal Watch Cardiology 2004: 4-4 [Full Text]  
• Vaknansky, A., Kupfer, Y., Tessler, S., Boger, C., Schroll, S., Holmer, S., Schulman, S., Eriksson, H. (2004). Ximelagatran for Secondary Prevention of Venous Thromboembolism. NEJM 350: 618-619 [Full Text]  
• Malik, I. (2004). JournalScan. Heart 90: 117-118 [Full Text]  
• Weitz, J. I., Middeldorp, S., Geerts, W., Heit, J. A. (2004). Thrombophilia and New Anticoagulant Drugs. ASH Education Book 2004: 424-438 [Abstract] [Full Text]  
• Lopez, J. A., Kearon, C., Lee, A. Y.Y. (2004). Deep Venous Thrombosis. ASH Education Book 2004: 439-456 [Abstract] [Full Text]  
• Goldhaber, S. Z., Elliott, C. G. (2003). Acute Pulmonary Embolism: Part II: Risk Stratification, Treatment, and Prevention. Circulation 108: 2834-2838 [Full Text]  
• (2003). Ximelagatran to Prevent Venous Thromboembolism. JWatch General 2003: 2-2 [Full Text]  
• Shapiro, S. S. (2003). Treating Thrombosis in the 21st Century. NEJM 349: 1762-1764 [Full Text]