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Stroke Prevention Using the Oral Direct Thrombin Inhibitor Ximelagatran in Patients With Nonvalvular Atrial Fibrillation - SPORTIF II
Description:
The goal of the SPORTIF II trial was to determine the tolerability and safety of a novel, oral direct thrombin inhibitor ximelagatran versus warfarin for prevention of stroke and systemic embolic events in patients with nonvalvular atrial fibrillation (NVAF) and at least one additional risk factor for stroke.
Hypothesis:
Treatment with the oral direct thrombin inhibitor ximelagatran is tolerable and safe with regard to thromboembolic events and bleedings compared with warfarin therapy.
Study Design
Study Design:
Patients Enrolled: 254
Mean Follow Up: 14 weeks
Mean Patient Age: Mean 69.5 years (range 39-95 years)
Female: 39
Patient Populations:
Age ≥18 years; history of chronic, intermittent (paroxysmal), or persistent NVAF verified by ≥2 ECGs during the prior year; and at least one risk factor for stroke, defined as: history of hypertension, age ≥65 years, previous stroke or TIA, previous systemic embolism, left ventricular (LV) dysfunction, diabetes, or coronary heart disease
Exclusions:
Stroke and/or systemic embolism within the previous two years; conditions associated with increased risk of bleeding; NVAF secondary to other reversible disorders (e.g., thyrotoxicosis); presence of mechanical heart valves; myocardial infarction, CABG, or PTCA within previous three months; diagnosis of LV aneurysm or atrial myxoma; treatment with either nonsteroidal anti-inflamatory drugs or fibrinolytics within previous week; renal impairment (calculated creatinine clearance <40 ml/min); systolic/diastolic blood pressure >180/100 mm Hg; history of rheumatic fever; liver insufficiency; hemoglobin <100 g/l or platelet count <100,000; and contraindications to warfarin treatment
Primary Endpoints:
Number of thromboembolic events and bleedings
Drug/Procedures Used:
Patients were randomized to one of three doses of fixed-dose ximelagatran (20, 40, or 60 mg twice daily, n=187), given in a double-blind manner or open-label dose-adjusted warfarin (international normalized ratio [INR] 2.0-3.0, n=67). Patients were treated with the study drug for 12 weeks.
Principal Findings:
No systemic embolic events were reported during the study. One nonfatal ischemic stroke occurred in the ximelagatran arm and none occurred in the warfarin arm. There was one transient ischemic attack (TIA) in the ximelagatran arms and two in the warfarin arm.
There were no fatal or critical-site bleeds in either arm. No major bleeding occurred in the ximelagatran arms, and one major bleed occurred in the warfarin arm. Minor bleeding occurred in the six patients in the warfarin arm, and four, five, and seven patients in the ximelagatran 20-mg, 40-mg, and 60-mg arms, respectively.
Adverse events (AEs) occurred during active treatment in 34 patients in the warfarin arm (50.7%) and 90 patients in the ximelagatran arms (48.1%), none of which were dose-related. Sixteen patients (8.6%) in the ximelagatran arms and six patients (9%) in the warfarin arm discontinued study treatment due to AEs.
Liver enzymes were elevated in eight patients (4.3%) in the ximelagatran arms, and none in the warfarin arm. The liver enzymes returned to normal levels in five patients who continued ximelagatran therapy and three patients who discontinued the drug.
Interpretation:
Among patients with NVAF and at least one additional risk factor for stroke, treatment with the novel, oral direct thrombin inhibitor ximelagatran was tolerable and safe with no difference in the primary endpoints of thromboembolic events and bleedings.
Unlike warfarin, ximelagatran does not require coagulation monitoring, and is delivered in a fixed oral dose. The 4.3% risk of elevations in liver enzymes, although transient, may require monitoring in patients treated with ximelagatran.
The larger, open-label SPORTIF III trial recently presented at the 2003 ACC Annual Scientific Session demonstrated noninferiority in stroke or systemic embolic events between warfarin and ximelagatran (36 mg bid fixed dose). The SPORTIF V trial is a double-blind trial of ximelagatran versus warfarin, and is currently underway. Ximelagatran is not yet commercially available.
References:
Petersen P, Grind M, Adler J. Ximelagatran versus warfarin for stroke prevention in patients with nonvalvular atrial fibrillation. SPORTIF II: a dose-guiding, tolerability, and safety study. J Am Coll Cardiol 2003;41:1445–51.
Keywords: Stroke, Ischemic Attack, Transient, Warfarin, Risk Factors, International Normalized Ratio, Azetidines, Benzylamines, Embolism, Diabetes Mellitus, Hypertension
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