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Lower Extremity Arterial Disease Event Reduction Trial - LEADER
Description:
The goal of the Lower Extremity Arterial Disease Event Reduction (LEADER) trial was to assess the effect of bezafibrate on the risk of coronary heart disease (CHD) and stroke in men with lower extremity arterial disease.
Hypothesis:
Treatment with bezafibrate will reduce the risk of CHD and stroke in men with lower extremity arterial disease.
Study Design
Study Design:
Patients Screened: 2,505
Patients Enrolled: 1,568
Mean Follow Up: median follow-up 4.6 years (range 3.1 to 7.8 years)
Mean Patient Age: mean age 68.2 years
Female: 0
Patient Populations:
Men with lower extremity arterial disease (confirmed with the Edinburgh claudication questionnaire)
Primary Endpoints:
Composite of all fatal and nonfatal CHD events and all strokes
Secondary Endpoints:
All coronary events and fatal and nonfatal events and stroke
Drug/Procedures Used:
Patients were randomized in a double-blind manner to bezafibrate 400 mg daily (n=783) or placebo (n=785).
Principal Findings:
There was no difference in the primary composite endpoint of CHD and stroke between the bezafibrate and placebo arms (150 vs. 160 events, relative risk [RR] 0.96, 95% confidence interval [CI] 0.76-1.21, p=0.72). There was also no difference in either component of the composite endpoint: major coronary events (90 and 111 events, RR 0.81, 95% CI 0.60-1.08, p=0.15) or stroke (60 and 49 events, RR 1.34, 95% CI 0.80-2.01, p=0.49).
Among the coronary events, 64 and 65 were fatal in the bezafibrate and placebo arms, respectively (RR 0.95, 95% CI 0.66-1.37, p=0.79) and 26 and 46 were nonfatal (RR 0.60, 95% CI 0.36-0.99, p=0.05). There was no difference in all-cause mortality (204 and 195 deaths, RR 1.03, 95% CI 0.83-1.26, p=0.81).
In the subgroup analysis, bezafibrate was associated with a reduction in nonfatal coronary events (RR 0.13, 95% CI 0.03-0.56) and all coronary events among men aged <65 years at entry (RR 0.38, 95% CI 0.20-0.72), but there was no significant difference in men 65-74 years (RR for all coronary events 0.87, 95% CI 0.55-1.37) or ≥75 years (RR for all coronary events 1.47, 95% CI 0.87-2.48). Intermittent claudication severity as assessed by the Edinburgh claudication questionnaire was reduced more in the bezafibrate arm than the placebo arm at year one (19.8% vs. 13.0%, p=0.001), year two (20.9% vs. 17.5%, p=0.01), and year three (19.2% vs. 18.9%, p=0.02), but not years 4-6 (15.4% vs. 18.2%, p=0.49).
Interpretation:
Among men with lower extremity arterial disease, bezafibrate was not associated with a reduction in the primary endpoint of CHD and stroke during a median 4.6 years of follow-up. Despite the lack of benefit in the primary composite endpoint, bezafibrate was associated with a reduction in the secondary endpoint of nonfatal CHD in all patients, driven primarily by the reduction in men aged <65 years.
Likewise, in the Bezafibrate Infarction Prevention (BIP) trial, which evaluated bezafibrate compared with placebo in patients with an established history of CHD, there was also no difference in the composite primary endpoint of fatal or nonfatal myocardial infarction or sudden death, despite an increase in high-density lipoprotein cholesterol and an almost 25% decrease in triglycerides in the bezafibrate group.
References:
Meade T, Zuhrie R, Cook C, Cooper J. Bezafibrate in men with lower extremity arterial disease: randomised controlled trial. BMJ 2002;325:1139-44.
Keywords: Intermittent Claudication, Risk, Myocardial Infarction, Stroke, Follow-Up Studies, Death, Sudden, Bezafibrate, Confidence Intervals, Surveys and Questionnaires, Triglycerides, Lipoproteins, HDL, Peripheral Vascular Diseases
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