 |
|
Ximelagatran vs Low-Molecular-Weight Heparin and Warfarin for the Treatment of Deep Vein Thrombosis
A Randomized Trial
Jean-Noel Fiessinger, MD;
Menno V. Huisman, MD;
Bruce L. Davidson, MD;
Henri Bounameaux, MD;
Charles W. Francis, MD;
Henry Eriksson, MD;
Torbjörn Lundström, MD;
Scott D. Berkowitz, MD;
Per Nyström, MSc;
Mona Thorsén, BSc;
Jeffrey S. Ginsberg, MD; for the THRIVE Treatment Study Investigators
JAMA. 2005;293:681-689.
Context Ximelagatran, an oral direct thrombin inhibitor with a rapid onset of action and predictable antithrombotic effect, has the potential to be a simple therapeutic alternative to current standard treatment of acute venous thromboembolism.
Objective To compare the efficacy and safety of ximelagatran with standard enoxaparin/warfarin treatment for the prevention of recurrent venous thromboembolism.
Design, Setting, and Patients Randomized, double-blind, noninferiority trial (Thrombin Inhibitor in Venous Thromboembolism [THRIVE] Treatment Study) of 2489 patients with acute deep vein thrombosis, of whom approximately one third had concomitant pulmonary embolism. The study was conducted at 279 centers in 28 countries from September 2000 through December 2002.
Interventions Patients were randomized to receive 6 months of treatment with either oral ximelagatran, 36 mg twice daily, or subcutaneous enoxaparin, 1 mg/kg twice daily, for 5 to 20 days followed by warfarin adjusted to maintain an international normalized ratio of 2.0 to 3.0.
Main Outcome Measures Recurrent venous thromboembolism, bleeding, and mortality.
Results Venous thromboembolism recurred in 26 of the 1240 patients assigned to receive ximelagatran (estimated cumulative risk, 2.1%) and in 24 of the 1249 patients assigned to receive enoxaparin/warfarin (2.0%). The absolute difference between ximelagatran and enoxaparin/warfarin was 0.2% (95% confidence interval [CI], –1.0% to 1.3%). This met the prespecified criterion for noninferiority. Corresponding values for major bleeding were 1.3% and 2.2% (difference, –1.0%; 95% CI, –2.1% to 0.1%), and for mortality were 2.3% and 3.4% (difference, –1.1%; 95% CI, –2.4% to 0.2%). Alanine aminotransferase levels increased to more than 3 times the upper limit of normal in 119 patients (9.6%) and 25 patients (2.0%) receiving ximelagatran and enoxaparin/warfarin, respectively. Increased enzyme levels were mainly asymptomatic. Retrospective analysis of locally reported adverse events showed a higher rate of serious coronary events with ximelagatran (10/1240 patients) compared with enoxaparin/warfarin (1/1249 patients).
Conclusions Oral ximelagatran administered in a fixed dose without coagulation monitoring, was as effective as enoxaparin/warfarin for treatment of deep vein thrombosis with or without pulmonary embolism and showed similar, low rates of bleeding. Increased levels of liver enzymes in 9.6% of ximelagatran-treated patients require regular monitoring; the mechanism requires further evaluation. Prospective assessment of coronary events in future studies is warranted.
Author Affiliations: Department of Vascular Medicine, Hôpital Européen Georges Pompidou, Paris, France (Dr Fiessinger); Department of General Internal Medicine, Leiden University Medical Center, Leiden, the Netherlands (Dr Huisman); Swedish Medical Center and University of Washington School of Medicine, Seattle (Dr Davidson); Department of Internal Medicine, University Hospital of Geneva, Geneva, Switzerland (Dr Bounameaux); Department of Medicine, University of Rochester, Rochester, NY (Dr Francis); Department of Medicine, Sahlgrenska University Hospital/Östra, Göteborg, Sweden (Dr Eriksson); AstraZeneca Research and Development Mölndal, Mölndal, Sweden (Dr Lundström, Mr Nyström, and Ms Thorsén); Department of Clinical Development, AstraZeneca LP, Wilmington, Del (Dr Berkowitz); and Department of Medicine, McMaster University, Hamilton, Ontario (Dr Ginsberg).
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati  Twitter
What's this?
RELATED ARTICLES
Ximelagatran vs Warfarin for Stroke Prevention in Patients With Nonvalvular Atrial Fibrillation: A Randomized Trial
SPORTIF Executive Steering Committee for the SPORTIF V Investigators
JAMA. 2005;293(6):690-698.
ABSTRACT
| FULL TEXT
Costs and Effectiveness of Ximelagatran for Stroke Prophylaxis in Chronic Atrial Fibrillation
Cara L. O’Brien and Brian F. Gage
JAMA. 2005;293(6):699-706.
ABSTRACT
| FULL TEXT
Ximelagatran—Promises and Concerns
Victor Gurewich
JAMA. 2005;293(6):736-739.
EXTRACT
| FULL TEXT
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES
|
Can We Rely on RE-LY?
Gage
NEJM 2009;361:1200-1202.
FULL TEXT
Pharmacology and Management of the Vitamin K Antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition)
Ansell et al.
Chest 2008;133:160S-198S.
ABSTRACT
| FULL TEXT
Antithrombotic Therapy for Venous Thromboembolic Disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition)
Kearon et al.
Chest 2008;133:454S-545S.
ABSTRACT
| FULL TEXT
New Anticoagulants for Treatment of Venous Thromboembolism
Gross and Weitz
Arterioscler. Thromb. Vasc. Bio. 2008;28:380-386.
ABSTRACT
| FULL TEXT
Patient Outcomes After Deep Vein Thrombosis and Pulmonary Embolism: The Worcester Venous Thromboembolism Study
Spencer et al.
Arch Intern Med 2008;168:425-430.
ABSTRACT
| FULL TEXT
New oral anticoagulants in atrial fibrillation
Turpie
Eur Heart J 2008;29:155-165.
ABSTRACT
| FULL TEXT
Melagatran for thromboprophylaxis after mechanical valve implantation: Results in a heterotopic porcine model
Thompson et al.
J. Thorac. Cardiovasc. Surg. 2007;134:359-365.
ABSTRACT
| FULL TEXT
Ximelagatran for Treatment and Prophylaxis of Recurrent Events in Deep Vein Thrombosis
Koscielny et al.
CLIN APPL THROMB HEMOST 2007;13:299-307.
ABSTRACT
Comparison of fixed-dose weight-adjusted unfractionated heparin and low-molecular-weight heparin for acute treatment of venous thromboembolism.
Kearon et al.
JAMA 2006;296:935-942.
ABSTRACT
| FULL TEXT
Observations of Alanine Aminotransferase and Aspartate Aminotransferase in THRIVE Studies Treated Orally with Ximelagatran
Harenberg et al.
International Journal of Toxicology 2006;25:165-169.
ABSTRACT
| FULL TEXT
New Anticoagulants
Bauer
ASH Education Book 2006;2006:450-456.
ABSTRACT
| FULL TEXT
How I treat venous thromboembolism in patients with cancer
Prandoni
Blood 2005;106:4027-4033.
ABSTRACT
| FULL TEXT
Enoxaparin in the Treatment of Deep Vein Thrombosis With or Without Pulmonary Embolism: An Individual Patient Data Meta-analysis
Mismetti et al.
Chest 2005;128:2203-2210.
ABSTRACT
| FULL TEXT
Direct Thrombin Inhibitors
Di Nisio et al.
NEJM 2005;353:1028-1040.
FULL TEXT
Ximelagatran: An orally active direct thrombin inhibitor
Gulseth
Am J Health Syst Pharm 2005;62:1451-1467.
ABSTRACT
| FULL TEXT
Safety of Ximelagatran
Brinker et al.
JAMA 2005;293:2859-2859.
FULL TEXT
New Oral Anticoagulant for DVT Is Effective -- But Is It Safe?
JWatch Emergency Med. 2005;2005:4-4.
FULL TEXT
Ximelagatran vs. Enoxaparin/Warfarin for VTE
Journal Watch Cardiology 2005;2005:1-1.
FULL TEXT
Ximelagatran: Effective but Hepatotoxic
JWatch General 2005;2005:4-4.
FULL TEXT
Ximelagatran--Promises and Concerns
Gurewich
JAMA 2005;293:736-739.
FULL TEXT
|
