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Stroke Prevention Using the Oral Direct Thrombin Inhibitor Ximelagatran in Patients With Nonvalvular Atrial Fibrillation - SPORTIF V
Description:
The goal of the randomized, double-blind SPORTIF V 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: 4,763
Patients Enrolled: 3,922
Mean Follow Up: Mean 20 months
Mean Patient Age: Mean age 72 years
Female: 30
Patient Populations:
AF and ≥1 additional risk factor for stroke (age ≥75 years, previous stroke, or chronic heart failure)
Primary Endpoints:
All strokes (ischemic or hemorrhagic) and systemic embolic events, based on an intention-to-treat analysis for noninferiority
Secondary Endpoints:
On-treatment analysis of primary endpoint; composite of death, stroke, and systemic embolism; and safety variables, including bleeding and liver enzyme elevation
Drug/Procedures Used:
Patients were randomized in a double-blind manner to fixed-dose ximelagatran (36 mg bid) or dose-adjusted warfarin (international normalized ratio [INR] 2.0-3.0). Patients randomized to the ximelagatran arm underwent sham testing and dose modification of the dummy warfarin to mimic the INR management.
Principal Findings:
Mean INR in the warfarin arm was 2.4 during the duration of the study, and was within the target range of 2.0-3.0 in 68% of measurements. The primary endpoint of stroke or systemic embolism during follow-up occurred in 1.2% annually in the warfarin arm, and 1.6% annually in the ximelagatran arm, an absolute 0.45% annual increase in the ximelagatran arm (95% confidence interval [CI] -0.13 to 1.03, p=0.13), a difference which met the noninferiority hypothesis. For the composite of all-cause mortality and the primary endpoint, there was not a significant difference by treatment group (absolute 0.10% annual increase with ximelagatran (95% CI -0.97 to 1.2, p=0.86).
In an on-treatment analysis, there was an absolute 0.55% annual increase in the primary endpoint of stroke or systemic embolism in the ximelagatran arm (95% CI -0.06 to 1.16, p=0.09). There was no difference in intracranial hemorrhage (0.06% in both arms, p=NS) or major bleed (2.4% with ximelagatran vs. 3.1% with warfarin, p=0.16) but major or minor bleeding was lower with ximelagatran (37% vs 47% per year, p<0.001). Liver enzyme elevation >3x upper limit of normal occurred more frequently in the ximelagatran arm (6.0% vs. 0.8%, 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 compared with warfarin for the primary endpoint 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 may require monitoring in patients treated with ximelagatran.
The results of noninferiority in the double-blind SPORTIF V trial were similar to those seen in the open-label SPORTIF III trial of ximelagatran versus warfarin. Ximelagatran is not yet commercially available.
References:
SPORTIF Executive Steering Committee for the SPORTIF V Investigators. Ximelagatran vs Warfarin for Stroke Prevention in Patients With Nonvalvular Atrial Fibrillation. JAMA. 2005;293:690-698.
Presented by Dr. Jonathan L. Halperin at the November 2003 American Heart Association Annual Scientific Sessions, Orlando, FL.
Keywords: Stroke, Follow-Up Studies, Warfarin, Risk Factors, International Normalized Ratio, Intracranial Hemorrhages, Azetidines, Benzylamines, Heart Failure, Embolism, Confidence Intervals
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