Stroke Prevention Using the Oral Direct Thrombin Inhibitor Ximelagatran in Patients With Nonvalvular Atrial Fibrillation - SPORTIF III

Description:

The goal of the Stroke Prevention Using the Oral Direct Thrombin Inhibitor Ximelagatran in Patients With Nonvalvular Atrial Fibrillation (SPORTIF III) trial was to determine the safety and efficacy of a novel, oral direct thrombin inhibitor ximelagatran versus warfarin for prevention of stroke and systemic embolic events in patients with atrial fibrillation (AF) and at least one additional risk factor for stroke.

Hypothesis:

Treatment with the oral direct thrombin inhibitor ximelagatran is noninferior with regard to stroke and systemic embolic events compared with warfarin therapy.

Study Design

Study Design:

Patients Screened: 5,188
Patients Enrolled: 3,407
Mean Follow Up: Minimum 12 months (mean 17 months)
Mean Patient Age: Mean age 70 years

Patient Populations:

AF and ≥1 additional risk factor for stroke (previous stroke, hypertension, or CHF)

Primary Endpoints:

Prevention of all strokes (ischemic or hemorrhagic) and systemic embolic events, based on intention-to-treat

Secondary Endpoints:

Composite of death, stroke, systemic embolism, and MI; and safety variables, specifically bleeding and treatment discontinuation

Drug/Procedures Used:

Patients were randomized to fixed-dose ximelagatran (36 mg bid) (n=1704) or dose-adjusted warfarin (international normalized ratio [INR] 2.0-3.0, n=1703).

Principal Findings:

Mean INR in the warfarin arm was 2.5 across all measurements during the duration of the study. The primary end point of stroke or systemic embolism during follow-up occurred in 2.3% annually in the warfarin arm, and 1.6% annually in the ximelagatran arm (relative risk reduction [RRR] 29%, met noninferiority hypothesis).

In an on-treatment analysis, stroke or systemic embolism occurred in 2.2% annually in the warfarin arm and 1.3% annually in the ximelagatran arm (RRR 43%, p=0.018). There was no difference in intracranial hemorrhage (ICH; 0.2% with ximelagatran vs. 0.4% with warfarin, p=NS) or major bleed (1.3% with ximelagatran vs. 1.8% with warfarin, p=NS).

Congestive heart failure (CHF) occurred in 2.9% versus 3.9% (p=0.063), and myocardial infarction (MI) in 1.1% versus 0.6% (p=0.068) for ximelagatran versus warfarin, respectively. There was no difference in all-cause mortality (3.2% in each arm). Liver enzyme elevation >3x upper limit of normal occurred more frequently in the ximelagatran arm (6.5% vs. 0.7%, p<0.001).

Interpretation:

Among patients with nonvalvular AF and at least one additional risk factor for stroke, treatment with the novel, oral direct thrombin inhibitor ximelagatran was noninferior for the primary end point of stroke or systemic embolic events. Unlike warfarin, ximelagatran does not require coagulation monitoring, and is delivered in a fixed oral dose. The elevations in liver enzymes, although transient, may require monitoring in patients treated with ximelagatran.

Although this trial was open-label, the recently presented SPORTIF V trial was a double-blind trial of ximelagatran versus warfarin, which showed similar, noninferior primary endpoint results. Ximelagatran is not yet commercially available.

References:

Stroke prevention with the oral direct thrombin inhibitor ximelagatran compared with warfarin in patients with non-valvular atrial fibrillation (SPORTIF III): randomised controlled trial. Lancet 2003; 362: 1691–98.

Presented at Late-Breaking Clinical Trials, ACC 2003.

Presented at the European Society of Cardiology, Vienna, Austria, September 2003.

Clinical Topics: Anticoagulation Management, Heart Failure and Cardiomyopathies, Prevention, Nonstatins, Statins, Acute Heart Failure, Hypertension

Keywords: Myocardial Infarction, Stroke, Follow-Up Studies, Warfarin, Risk Factors, International Normalized Ratio, Intracranial Hemorrhages, Azetidines, Benzylamines, Heart Failure, Embolism, Hypertension


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