Abstract
BackgroundRaised levels of both triglycerides and fibrinogen, each of which are reduced by bezafibrate, may contribute to lower extremity arterial disease (LEAD). This condition is characterized by a particularly high incidence of coronary heart disease (CHD) and stroke, but is little studied thus far in randomised controlled trials.MethodPatients were recruited through 85 practices in the British Medical Research Council General Practice Research Framework and through nine hospital vascular clinics. The treatment regimen, which is double-blind and placebo-controlled, is bezafibrate 400 mg/day. The 1568 patients recruited represent 86% of those eligible at screening.ResultsNone of the anticipated side effects (mainly gastrointestinal) differed between the two groups. Nearly 80% of the total person-years accrued at 3 years were spent on trial treatment. Bezafibrate significantly reduced total cholesterol by approximately 8.0% and low-density lipoprotein (LDL)-cholesterol by approximately 9.0%, and increased high-density lipoprotein (HDL)-cholesterol by approximately 11.0% initially, falling to about 6.0% at 3 years. Triglycerides were significantly reduced by about 23.0% and fibrinogen by about 14.0%. Plasma creatinine rose by approximately 11% in those on active treatment. All of these effects were highly significant (P < 0.0001). Bezafibrate had no effect on the level of C-reactive protein (CRP).ConclusionThe trial recruited an unusually high proportion of eligible patients, ensuring the general applicability of its results. The fibrinogen-lowering and lipid-modifying effects of bezafibrate were confirmed. Although bezafibrate lowers fibrinogen, it has no effect on CRP; this suggests that the reduction in fibrinogen is due to an effect on its metabolism rather than suppression of an inflammatory response.
Highlights
Accumulating epidemiological and clinical results [1,2,3] show strong associations of high plasma fibrinogen levels with both the onset and progression of arterial disease at all three main sites
Studies of polymorphisms associated with fibrinogen levels [7,8] have been equivocal regarding the relationship of the former with clinical events of coronary heart disease (CHD)
Recruitment Lower Extremity Arterial Disease Event Reduction (LEADER) is being carried out in men on the lists of 85 practices throughout the UK in the British Medical Research Council General Practice Research Frame-Apart from fibrinogen (Clauss method), total cholesterol, low-density lipoprotein (LDL)-cholesterol and high-density lipoprotein (HDL)-cholesterol levels, triglycerides, creatinine and alkaline phosphate were measured, alkaline phosphatase providing a measure of compliance with treatment
Summary
Accumulating epidemiological and clinical results [1,2,3] show strong associations of high plasma fibrinogen levels with both the onset and progression of arterial disease at all three main sites (ie heart, brain and lower extremities). Laboratory studies have indicated how fibrinogen affects several pathways that are known or suspected to be involved in thrombogenesis, principally the degree of blood viscosity, the amount of fibrin produced when the coagulation process is initiated, clot deformability, platelet aggregability and atherogenesis [6] This evidence suggests that high fibrinogen levels are of causal significance. Studies of polymorphisms associated with fibrinogen levels [7,8] have been equivocal regarding the relationship of the former with clinical events of CHD Raised levels of both triglycerides and fibrinogen, each of which are reduced by bezafibrate, may contribute to lower extremity arterial disease (LEAD). This condition is characterized by a high incidence of coronary heart disease (CHD) and stroke, but is little studied far in randomised controlled trials. The 1568 patients recruited represent 86% of those eligible at screening
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