Status:
Trial complete. Results published in February 2005.
Purpose:
To compare the safety and efficacy of an oral direct thrombin inhibitor (ximelagatran) with those of warfarin (coumadin) in preventing stroke and systemic embolic events in patients with atrial fibrillation.
Interventions:
Warfarin
Anticoagulant (Vitamin K antagonist)
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Ximelagatran
Oral anticoagulant. Prodrug is transformed into melagatran, an active site-directed thrombin inhibitor, after gastrointestinal absorption.
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Location(s):
Europe, North America
Year Started:
2000
Design:
Randomized, open-label, parallel-group study, double blind, double-dummy treatment allocation and computerized algorithms to generate sham INR data.
Inclusion Criteria
Patients with chronic, non-valvular atrial fibrillation who have at least one of the following stroke risk factors: hypertension that requires treatment, but is below 180/100 mmHg, age > 75 years, history of previous stroke, transient ischemic attack (TIA), or systemic embolism, a left ventricular ejection fraction (LVEF) <40%, symptomatic congestive heart failure (CHF), or age > 65 years in combination with either coronary artery disease or diabetes mellitus, will be eligible for this trial.
Exclusion Criteria
Patients who have a history of stroke within the past 30 days or TIA within the past 3 days, who have of the any following conditions associated with an increased risk of bleeding: a history of intracranial, intraocular, spinal retroperitoneal or atraumatic intra-articular bleed, an overt gastrointestinal bleed within the past year, endoscopically-verified ulcer disease, surgical procedure, or trauma within the past 30 days, blood pressure consistently > 180/100 mmHg (with or without antihypertensive therapy), or a hemorrhagic disorder , who have lone atrial fibrillation without overt cardiovascular disease or a precipitating illness, transient atrial fibrillation caused by reversible disorders, rheumatic valve disease, a prosthetic heart valve or a history of valvular surgery, active endocarditis, current atrial myxoma or left ventricular thrombus, a history of hospitalization for acute coronary syndromes or percutaneous coronary artery interventions within the past 30 days, or have a planned electircal or chemical cardioversion, who have been treated with antiplatelets within the past 10 days or fibrinolytics within the past 20 days, who use other anticoagulants, aspirin > 100 mg/day, or continuously take NSAIDs, who require for chronic anticoagulant treatment for a reason other than atrial fibrillation (e.g. repeated deep vein thrombosis, hereditary thrombophilia), who have renal impairment (creatinine clearance < 30 mL/min), active liver disease, anemia, any history of a significant disabling stroke, or who have any planned major surgery, are excluded from this trial.
Patient Involvement:
Patients are randomized to receive either ximelagatran or warfarin. Warfarin is dosed to achieve an international normalized ratio (INR) of 2.0 - 3.0. Patients are treated for 12-28 months, during which time they have 15-18 follow-up visits. At each of these visits, blood tests, physical exams and electrocardiograms (EKG's) are performed. INRs will be monitored frequently.
Primary Outcome:
Incidence of stroke and systemic embolic events.
Secondary Outcome:
Stroke, death, TIA, myocardial infarction, major and minor bleeding.
Results:
A total of 88 primary events were recorded. The primary event rate with ximelagatran was 1.6% per year and with warfarin was 1.2% per year (P=.13). Composite end point of stroke, systemic embolism, myocardial infarction, or death occurred in 119 patients taking warfarin (4.3% per year) and 110 taking ximelagatran (4.2% per year; P = .84). There was no difference between groups in rates of major bleeding, but total bleeding (major and minor) was lower with ximelagatran (37% vs 47% per year; P<.001).
Source of Information:
Press reports 4/03. AstraZeneca. American Society of Hematology 2002 Meeting Abstract. JAMA. 2005 Feb 9;293(6):690-8.
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