Dabigatran versus warfarin in patients with atrial fibrillation.

BACKGROUND Warfarin reduces the risk of stroke in patients with atrial fibrillation but increases the risk of hemorrhage and is difficult to use. Dabigatran is a new oral direct thrombin inhibitor. METHODS In this noninferiority trial, we randomly assigned 18,113 patients who had atrial fibrillation and a risk of stroke to receive, in a blinded fashion, fixed doses of dabigatran--110 mg or 150 mg twice daily--or, in an unblinded fashion, adjusted-dose warfarin. The median duration of the follow-up period was 2.0 years. The primary outcome was stroke or systemic embolism. RESULTS Rates of the primary outcome were 1.69% per year in the warfarin group, as compared with 1.53% per year in the group that received 110 mg of dabigatran (relative risk with dabigatran, 0.91; 95% confidence interval [CI], 0.74 to 1.11; P<0.001 for noninferiority) and 1.11% per year in the group that received 150 mg of dabigatran (relative risk, 0.66; 95% CI, 0.53 to 0.82; P<0.001 for superiority). The rate of major bleeding was 3.36% per year in the warfarin group, as compared with 2.71% per year in the group receiving 110 mg of dabigatran (P=0.003) and 3.11% per year in the group receiving 150 mg of dabigatran (P=0.31). The rate of hemorrhagic stroke was 0.38% per year in the warfarin group, as compared with 0.12% per year with 110 mg of dabigatran (P<0.001) and 0.10% per year with 150 mg of dabigatran (P<0.001). The mortality rate was 4.13% per year in the warfarin group, as compared with 3.75% per year with 110 mg of dabigatran (P=0.13) and 3.64% per year with 150 mg of dabigatran (P=0.051). CONCLUSIONS In patients with atrial fibrillation, dabigatran given at a dose of 110 mg was associated with rates of stroke and systemic embolism that were similar to those associated with warfarin, as well as lower rates of major hemorrhage. Dabigatran administered at a dose of 150 mg, as compared with warfarin, was associated with lower rates of stroke and systemic embolism but similar rates of major hemorrhage. (ClinicalTrials.gov number, NCT00262600.)

[1]  Salim Yusuf,et al.  Effect of clopidogrel added to aspirin in patients with atrial fibrillation. , 2009, The New England journal of medicine.

[2]  S. Yusuf,et al.  Rationale and design of RE-LY: randomized evaluation of long-term anticoagulant therapy, warfarin, compared with dabigatran. , 2009, American heart journal.

[3]  S. Yusuf,et al.  Benefit of Oral Anticoagulant Over Antiplatelet Therapy in Atrial Fibrillation Depends on the Quality of International Normalized Ratio Control Achieved by Centers and Countries as Measured by Time in Therapeutic Range , 2008, Circulation.

[4]  S. Lévy,et al.  Comparison of idraparinux with vitamin K antagonists for prevention of thromboembolism in patients with atrial fibrillation: a randomised, open-label, non-inferiority trial , 2008, The Lancet.

[5]  J. Stangier.  Clinical Pharmacokinetics and Pharmacodynamics of the Oral Direct Thrombin Inhibitor Dabigatran Etexilate , 2008, Clinical pharmacokinetics.

[6]  M. Ezekowitz,et al.  Dabigatran with or without concomitant aspirin compared with warfarin alone in patients with nonvalvular atrial fibrillation (PETRO Study). , 2007, The American journal of cardiology.

[7]  S. Frostick,et al.  Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial , 2007, The Lancet.

[8]  K. Rathgen,et al.  The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects. , 2007, British journal of clinical pharmacology.

[9]  M. Aguilar,et al.  Meta-analysis: Antithrombotic Therapy to Prevent Stroke in Patients Who Have Nonvalvular Atrial Fibrillation , 2007, Annals of Internal Medicine.

[10]  Susan Regan,et al.  Major Hemorrhage and Tolerability of Warfarin in the First Year of Therapy Among Elderly Patients With Atrial Fibrillation , 2007, Circulation.

[11]  Silvia G Priori,et al.  ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation--executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Commit , 2006, Journal of the American College of Cardiology.

[12]  Samuel Wann,et al.  ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation-executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committ , 2006, European heart journal.

[13]  M. Pfeffer,et al.  Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial , 2006, The Lancet.

[14]  B. Gage,et al.  Use and Effectiveness of Warfarin in Medicare Beneficiaries With Atrial Fibrillation , 2006, Stroke.

[15]  H. Diener.  Stroke prevention using the oral direct thrombin inhibitor ximelagatran inpatients with nonvalvular atrial fibrillation. Pooled analysis from the SPORTIF III ad V studies. , 2006 .

[16]  B. Eriksson,et al.  Pharmacokinetic Profile of the Oral Direct Thrombin Inhibitor Dabigatran Etexilate in Healthy Volunteers and Patients Undergoing Total Hip Replacement , 2005, Journal of clinical pharmacology.

[17]  B. Gage,et al.  Selecting Patients With Atrial Fibrillation for Anticoagulation: Stroke Risk Stratification in Patients Taking Aspirin , 2004, Circulation.

[18]  H. Arnesen,et al.  Warfarin, aspirin, or both after myocardial infarction. , 2002, The New England journal of medicine.

[19]  J. Mayet,et al.  Anticoagulation for cardioversion of atrial fibrillation. , 2002, Minerva cardioangiologica.

[20]  M. Rich,et al.  Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. , 2001, JAMA.

[21]  Martha J. Radford,et al.  Validation of Clinical Classification Schemes for Predicting Stroke: Results From the National Registry of Atrial Fibrillation , 2001 .

[22]  O. Benavente,et al.  Antithrombotic Therapy To Prevent Stroke in Patients with Atrial Fibrillation , 1999, Annals of Internal Medicine.

[23]  W. Manning,et al.  Accuracy of Transesophageal Echocardiography for Identifying Left Atrial Thrombi: A Prospective, Intraoperative Study , 1995, Annals of Internal Medicine.

[24]  R. Cebul,et al.  Limitations of transesophageal echocardiography in the risk assessment of patients before nonanticoagulated cardioversion from atrial fibrillation and flutter: an analysis of pooled trials. , 1995, American heart journal.

[25]  F R Rosendaal,et al.  A Method to Determine the Optimal Intensity of Oral Anticoagulant Therapy , 1993, Thrombosis and Haemostasis.

[26]  F. Loop,et al.  Role of prophylactic anticoagulation for direct current cardioversion in patients with atrial fibrillation or atrial flutter. , 1992, Journal of the American College of Cardiology.

[27]  A. Labovitz,et al.  Superiority of transesophageal echocardiography in detecting cardiac source of embolism in patients with cerebral ischemia of uncertain etiology. , 1991, Journal of the American College of Cardiology.

[28]  Denis Roy,et al.  Usefulness of anticoagulant therapy in the prevention of embolic complications of atrial fibrillation. , 1986, American heart journal.

[29]  M. Ezekowitz,et al.  Left atrial mass: diagnostic value of transesophageal 2-dimensional echocardiography and indium-111 platelet scintigraphy. , 1983, The American journal of cardiology.

[30]  O. Orning,et al.  The efficacy of anticoagulant therapy in preventing embolism related to D.C. electrical conversion of atrial fibrillation. , 1969, The American journal of cardiology.

[31]  L. Mcdonald,et al.  Complications in 220 patients with cardiac dysrhythmias treated by phased direct current shock, and indications for electroconversion. , 1967, British heart journal.

[32]  J. Jude,et al.  Electroshock for atrial flutter and atrial fibrillation. Follow-up studies on 50 patients. , 1965, JAMA.

[33]  B. Lown,et al.  "Cardioversion" of atrial fibrillation. A report on the treatment of 65 episodes in 50 patients. , 1963, The New England journal of medicine.

[34]  B. Lown,et al.  New method for terminating cardiac arrhythmias. Use of synchronized capacitor discharge. , 1986, JAMA.

[35]  P. Zoll,et al.  Termination of Refractory Tachycardia by External Countershock , 1962 .

[36]  R. Miller,et al.  External Electrical Termination of Supraventricular Arrhythmias in Congenital Heart Disease , 1962, The Journal of pediatrics.

[37]  P. Zoll,et al.  The Effects of External Electric Currents on the Heart: Control of Cardiac Rhythm and Induction and Termination of Cardiac Arrhythmias , 1956, Circulation.