Papers

Bezafibrate in men with lower extremity arterial disease: randomised controlled trial

Tom Meade, emeritus professor of epidemiology ^a, Riaz Zuhrie, clinical scientific officer ^b, Claire Cook, statistician ^b, Jackie Cooper, statistician ^b,  on behalf of MRC General Practice Research Framework

^a Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London WC1E 7HT, ^b MRC Epidemiology and Medical Care Unit, Wolfson Institute of Preventive Medicine, London EC1M 6BQ

Correspondence to: T Meade Tom.meade{at}lshtm.ac.uk

	Abstract

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Objective: To assess the effect of bezafibrate on the risk of coronary heart disease and stroke in men with lower extremity arterial disease.
Design: Double blind placebo controlled randomised trial.
Setting: 85 general practices and nine hospital vascular clinics.
Participants: 1568 men, mean age 68.2 years (range 35 to 92) at recruitment.
Interventions: Bezafibrate 400 mg daily (783 men) or placebo (785 men).
Main outcome measures: Combination of coronary heart disease and of stroke. All coronary events, fatal and non-fatal coronary events separately, and strokes alone (secondary end points).
Results: Bezafibrate did not reduce the incidence of coronary heart disease and stroke. There were 150 and 160 events in the active and placebo groups respectively (relative risk 0.96, 95% confidence interval 0.76 to 1.21). There were 90 and 111 major coronary events in the active and placebo groups respectively (0.81, 0.60 to 1.08), of which 64 and 65 were fatal (0.95, 0.66 to 1.37) and 26 and 46 non-fatal (0.60, 0.36 to 0.99). Beneficial effects on non-fatal events were greatest in men aged <65 years at entry, in whom benefit was also seen for all coronary events (0.38, 0.20 to 0.72). There were no significant effects in older men. There were 60 strokes in those on active treatment and 49 in those on placebo (1.34, 0.80 to 2.01). There were 204 and 195 deaths from all causes in the two groups respectively (1.03, 0.83 to 1.26). Bezafibrate reduced the severity of intermittent claudication for up to three years.
Conclusions: Bezafibrate has no effect on the incidence of coronary heart disease and of stroke combined but may reduce the incidence of non-fatal coronary events, particularly in those aged <65 years at entry, in whom all coronary events may also be reduced.

What is already known on this topic The beneficial effects of bezafibrate blood on lipids and fibrinogen concentrations should reduce the incidence of heart attacks and strokes So far, however, there is only limited evidence on clinical outcomes from randomised controlled trials What this study adds Treatment with bezafibrate was not associated with a reduction in the combined incidence of heart attacks and strokes, though there were substantially fewer non-fatal heart attacks in those taking bezafibrate Bezafibrate was associated with a reduction in the incidence of all heart attacks, especially non-fatal, in men aged <65 years Bezafibrate seems to reduce the severity of intermittent claudication for two or three years

	Introduction

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Evidence from epidemiological research has shown strong associations between high plasma fibrinogen concentrations and the onset and progression of arterial disease.^1-3 Fibrinogen affects several pathways involved in thrombogenesis.⁴ This evidence suggests that high fibrinogen concentrations are an important cause. On the other hand, the effects of lowering concentrations need to be established through randomised trials so that not only can the role of fibrinogen be clarified but also any clinical implications defined.

Apart from ancrod, which has to be given by infusion, there are no drugs available that selectively lower fibrinogen concentrations. However, several fibrates lower concentrations as well as modifying lipid profiles, for which they were originally introduced. If any clinical benefits of bezafibrate could be apportioned between its effects on fibrinogen and on lipids we would be able to clarify the part played by fibrinogen in altering the risk of coronary heart disease. The lower extremity arterial disease event reduction trial of bezafibrate was carried out in men with lower extremity arterial disease to establish any benefits.

	Methods

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The trial was carried out in men on the lists of 85 practices throughout the United Kingdom in the Medical Research Council's general practice research framework and in nine hospital vascular clinics. Recruitment started in 1992 and was completed in 1998. Follow up ended in September 2001. Identification of men with possible lower extremity arterial disease, eligibility criteria, and the recruitment process including blood tests at entry and during the trial have been described elsewhere⁵ (http://cvm.controlled-trials.com/content/2/4/195). Active treatment was bezafibrate 400 mg daily (as Bezalip Mono, Roche) for men with creatinine plasma concentrations <135 µmol/l. The placebo group received tablets identical in appearance. Men with creatinine concentrations of 135-149 µmol/l at entry took 400 mg on alternate days.

Details about follow up and ascertainment of end points are available elsewhere.⁵ All deaths were notified from the NHS central register. Details on non-fatal events were unavailable for only 21 (1.3%) men.

Analysis
The primary end point was the combination of all coronary heart disease events (non-fatal and fatal) and all strokes. We classified all coronary events and fatal and non-fatal events of coronary heart disease and of stroke separately as secondary end points. We calculated that we could detect a reduction of 30% in the primary end point due to bezafibrate in 1500 men at 5% level of significance with 80% power.⁵ Analysis of results on clinical end points was on an intention to treat basis. We used entry characteristics in Cox regressions to estimate relative risks.

	Results

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Recruitment
Of about 3200 men invited to attend the first or screening visit, 2505 did so. The 1568 patients finally randomised represent 86% of the 1816 eligible participants, and their characteristics are given in table 1, which shows that the two randomised groups were similar. At entry, concentrations of fibrinogen and lipids were not grossly abnormal. The median follow up period was 4.6 years (range 3.1 to 7.8 years). About 70% of person years were spent on allocated treatment (see the full version of this paper on bmj.com). The proportions who withdrew were similar in the two groups. However, significantly more men in the placebo group withdrew because they started a drug treatment that was incompatible with bezafibrate, nearly always a statin, and significantly more men in the active treatment group were withdrawn because of raised creatinine concentrations.

There was no effect of treatment on the combined incidence of coronary heart disease and stroke, with 150 and 160 events in those in the active and placebo groups, respectively (table 2 and figure). Of the secondary end points, only non-fatal coronary heart disease events occurred significantly less often in the active treatment group than in the placebo group (table 2).

View larger version (27K): [in this window] [in a new window]   Proportion of men who experienced end points during trial: totals at baseline were 783 in active treatment group and 785 in placebo group

In men aged <65 years at entry bezafibrate substantially reduced the incidence of coronary heart disease, principally of non-fatal events (0.13, 95% confidence interval 0.03 to 0.56). Also, all coronary events, fatal and non-fatal combined, were 62% lower than in the placebo group (0.38, 0.20 to 0.72).

The Edinburgh claudication questionnaire assesses severity of claudication by recording whether pain occurs only when the patient is walking up hill or hurrying or if it also occurs both then and when the patient is walking at an ordinary pace on the level. Bezafibrate resulted in a significant improvement from baseline at one, two, and three years though not thereafter (see bmj.com).

	Discussion

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We found that bezafibrate had no significant effect on our primary end point of coronary heart disease and stroke combined. For various possible reasons ("healthy volunteer" effect, variability of data for determining the required sample size, increased statin use in the placebo group) the incidence of primary end points was less than 60% of that estimated. In particular, there were far fewer non-fatal events than we expected. This is unlikely to have been due to incomplete ascertainment as the methods for identifying and reporting end points were identical to those in other trials in the framework,^6-8 in which the proportions of fatal and non-fatal episodes have been as expected. Apart from chance, one possibility is a particularly high case fatality from heart attacks in these men with lower extremity arterial disease. Another is that two thirds of the men were taking platelet anti-aggregating agents, nearly all as aspirin, which may reduce non-fatal more than fatal events. ^{6 9}

There were more strokes and deaths from all causes in those on active treatment than on placebo treatment, though neither of these differences was significant. However, there was a significant reduction of about 40% in the secondary end point of non-fatal coronary events among those allocated to active treatment. Besides our trial, two other trials of fibrates^10-12 have shown greater treatment effects on non-fatal than on fatal events, though the Israeli bezafibrate infarction prevention trial did not show a significant reduction (9%) in all coronary events.¹¹ Two trials that used gemfibrozil, which has different properties compared with bezafibrate and fenofibrate, showed that it significantly reduced the incidence of clinical end points. ^{13 14}

Bezafibrate increases homocysteine concentrations,¹⁵ and high concentrations are an important risk factor for vascular disease. A further trial could usefully see whether the concurrent use of folic acid and bezafibrate would allow its beneficial effects on fibrinogen and lipid profiles to reduce the risk of heart attacks and strokes to a worthwhile extent.

	Acknowledgments

We thank the nurses and doctors in the general practice research framework, other colleagues, and members of the data monitoring and ethics committee (see full details on bmj.com).

Contributors: See bmj.com

	Footnotes

Competing interests: Trial tablets supplied free of charge by Boehringer-Mannheim.

Funding: Medical Research Council and British Heart Foundation.

This is an abridged version; the full version is on bmj.com

	References

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1.	Danesh J, Collins R, Appleby P, Peto R. Association of fibrinogen, C-reactive protein, albumin, or leukocyte count with coronary heart disease: meta-analysis of prospective studies. JAMA 1998; 279: 1477-1482[Abstract/Free Full Text].
2.	Resch KL, Ernst E, Matrai A, Paulsen HF. Fibrinogen and viscosity as risk factors for subsequent cardiovascular events in stroke survivors. Ann Intern Med 1992; 117: 371-375.
3.	Banerjee AK, Pearson J, Gilliland EL, Goss D, Lewis JD, Stirling Y, et al. A six year prospective study of fibrinogen and other risk factors associated with mortality in stable claudicants. Thromb Haemost 1992; 68: 261-263[Web of Science][Medline].
4.	Meade TW. The epidemiology of atheroma, thrombosis and ischaemic heart disease. 3rd ed. In: Bloom AL, Forbes CD, Thomas DP, Tuddenham EGD, eds. Haemostasis and thrombosis. Edinburgh: Churchill Livingstone, 1994:1199-1227.
5.	Meade TW. Design and intermediate results of the lower extremity arterial disease event reduction (LEADER) trial of bezafibrate in men with lower extremity arterial disease. Curr Control Trials Cardiovasc Med 2001; 2: 195-204.
6.	MRC General Practice Research Framework. Randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk. Lancet 1998; 321: 129-141.
7.	Medical Research Council working party. MRC trial of treatment of mild hypertension: principal results. BMJ 1985; 291: 97-104.
8.	MRC working party. Medical Research Council trial of treatment of hypertension in older adults: principal results. BMJ 1992; 304: 405-412.
9.	Steering Committee of the Physicians Study Research Group. Final report on the aspirin component of the ongoing physicians study. N Engl J Med 1989; 321: 129-135[Abstract].
10.	BIP Study Group. Rationale and design of a secondary prevention trial of increasing serum high-density lipoprotein cholesterol and reducing triglycerides in patients with clinically manifest atherosclerotic heart disease (the bezafibrate infarction prevention trial). Am J Cardiol 1993; 71: 909-915[CrossRef][Web of Science][Medline].
11.	BIP Study Group. Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease. Circulation 2000; 102: 21-27[Abstract/Free Full Text].
12.	Committee of Principal Investigators. Cooperative trial in the primary prevention of ischaemic heart disease using clofibrate. Heart J 1978;1069-118.
13.	Frick MH, Elo O, Haapa K, Heinonen OP, Heinsalmi P, Helo P, et al. Helsinki heart study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. N Engl J Med 1987; 317: 1237-1245[Abstract].
14.	Bloomfield Rubins H, Robins SJ, Collins D, Fye CL, Anderson JW, Elam MB, et al, for the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. N Engl J Med 1999; 341: 410-418[Abstract/Free Full Text].
15.	Jonkers IJAM, de Man FHAF, Onkenhout W, van der Laarse A, Smelt AHM. Implication of fibrate therapy for homocysteine. Lancet 1999; 354: 1208.

(Accepted 8 August 2002)