Bezafibrate Infarction Prevention Study - BIP

Description:

The goal of the trial was to evaluate treatment with the fibric acid derivative bezafibrate compared with placebo in patients with coronary artery disease.

Hypothesis:

Bezafibrate would be more effective in preventing death or myocardial infarction (MI).

Study Design

  • Placebo Controlled
  • Blinded
  • Randomized
  • Parallel

Patients Screened: 15,524
Patients Enrolled: 3,090
Mean Follow Up: 16 years
Mean Patient Age: 60 years
Female: 9%

Patient Populations:

  • Patients 45-74 years of age with a history of MI and/or angina
  • Total cholesterol 180-250 mg/dl, triglyceride <300 mg/dl, LDL-C <180 mg/dl, and HDL-cholesterol <45 mg/dl

Exclusions:

  • Congestive heart failure (New York Heart Association class III-IV)
  • Unstable angina within the last 3 months
  • Coronary artery bypass grafting or percutaneous transluminal coronary angioplasty within the last 6 months
  • Cerebrovascular disease
  • Insulin-dependent diabetes
  • Contraindications to use of bezafibrate

Primary Endpoints:

  • Nonfatal MI, fatal MI, or sudden death

Secondary Endpoints:

  • Unstable angina
  • All-cause mortality
  • Cardiovascular mortality
  • Stroke

Drug/Procedures Used:

Patients with coronary artery disease were randomized to bezafibrate (n = 1,548) versus placebo (n = 1,542).

Concomitant Medications:

At baseline, the use of aspirin was 71%, angiotensin-converting enzyme inhibitor was 12%, beta-blocker was 38%, calcium antagonist was 50%, and nitrate was 51%.

Principal Findings:

Overall, 3,090 patients were randomized. The mean age was 60 years, 9% were women, body mass index was 27 mg/m2, prior MI was present in 79%, mean total cholesterol was 212 mg/dl, triglyceride was 145 mg/dl, high-density lipoprotein cholesterol (HDL-C) was 35 mg/dl, and low-density lipoprotein cholesterol (LDL-C) was 148 mg/dl.

At a mean follow-up of 6.2 years, the primary endpoint, fatal or nonfatal MI or sudden death, was 13.6% in the bezafibrate group versus 15.0% in the placebo group (p = 0.26). For individual outcomes, all-cause mortality was 10.4% versus 9.9% (p = 0.62), MI was 9.7% versus 11.2%, and stroke was 4.6% versus 5.0% (p = 0.66), respectively for bezafibrate versus placebo. There was no difference in adverse events, including cancer, between the treatment arms.

At 16 years, the cumulative incidence of death was 35.3% in the bezafibrate group versus 37.9% in the placebo group (p = 0.12). With multivariate analysis, there was a marginally significant 11% reduction in mortality with the use of bezafibrate (p = 0.06). This benefit was most pronounced among those with >8 mg/dl increase in HDL-C (hazard ratio [HR] 0.78, p = 0.008) versus those with <8 mg/dl increase (HR 0.95, p = 0.43).

Interpretation:

Among coronary artery disease patients with a mean HDL-C of 35 mg/dl and a mean LDL-C of 148 mg/dl, the use of bezafibrate for approximately 6 years was not associated with a reduction in adverse events during this initial follow-up period. When follow-up was extended to 16 years, there was a marginally significant reduction in mortality with the use of bezafibrate. This benefit was most pronounced among those with greater than 8 mg/dl increase in HDL-C. Unfortunately, very few women were studied in this trial.

In current practice, the patients represented in this trial (prior MI and LDL-C >100 mg/dl) would have been primarily treated with a statin medication. It is unknown what the comparative effects of a fibrate medication versus a statin medication versus the combination of these two medications would be in these patients.

The VA-HIT trial studied patients with coronary artery disease, who had low HDL-C (≤40 mg/dl), and LDL-C (≤140 mg/dl). That trial documented a 22% reduction in death or MI with the use of gemfibrozil. Further studies examining HDL rising with fibrate medications are necessary.

References:

Goldenberg I, Boyko V, Tennenbaum A, Tanne D, Behar S, Guetta V. Long-term benefit of high-density lipoprotein cholesterol-raising therapy with bezafibrate: 16-year mortality follow-up of the bezafibrate infarction prevention trial. Arch Intern Med 2009;169:508-14.

The BIP study group. Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease. Circulation 2000;102:21-7.

Presented at the European Society of Cardiology, Vienna, 1998

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Lipid Metabolism, Nonstatins

Keywords: Cholesterol, Myocardial Infarction, Stroke, Multivariate Analysis, Follow-Up Studies, Body Mass Index, Gemfibrozil, Death, Sudden, Lipoproteins, Bezafibrate, Triglycerides


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