Determining the Efficacy and Tolerability of CETP Inhibition With Anacetrapib - DEFINE

Nov 17, 2010
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Author/Summarized by Author:
Anthony A. Bavry, MD, MPH, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
Merck Research Laboratories
Date Presented:
01/01/2010
Date Published:
01/01/2010
Date Updated:
11/17/2010
Original Posted Date:
11/17/2010
References

Description:

The goal of the trial was to evaluate treatment with the cholesteryl ester transfer protein (CETP) inhibitor anacetrapib compared with placebo among patients with coronary heart disease (CHD).

Hypothesis:

Anacetrapib will safely improve lipid parameters.

Study Design

  • Placebo Controlled
  • Randomized
  • Blinded
  • Parallel

Patient Populations:

  • 18-80 years of age
  • CHD or CHD risk-equivalents
  • LDL-C 50-100 mg/dl on statin therapy
  • HDL-C <60 mg/dl
  • Triglycerides ≤400 mg/dl

    Number of screened applicants: 2,757
    Number of enrollees: 1,623
    Duration of follow-up: 76 weeks
    Mean patient age: 63 years
    Percentage female: 22%

Exclusions:

  • Severe chronic heart failure
  • Uncontrolled hypertension
  • Cardiac arrhythmias
  • MI, percutaneous coronary intervention, coronary artery bypass grafting, unstable angina, or stroke within previous 3 months
  • Active or chronic hepatobiliary or hepatic disease
  • Severe renal impairment
  • Treatment with warfarin or CYP3A4 inhibitors or inducers

Primary Endpoints:

  • Percent change from baseline in LDL-C at 24 weeks

Secondary Endpoints:

  • Percent change from baseline in LDL-C at week 76
  • Percent change from baseline in HDL-C, non-HDL-C, apolipoprotein (apo) B, and apo A-I at 24 and 76 weeks
  • Blood pressure
  • Electrolytes
  • Composite of cardiovascular death, nonfatal MI, stroke, and hospitalization for unstable angina

Drug/Procedures Used:

Patients with CHD (or CHD risk equivalents) were randomized to anacetrapib 100 mg daily (n = 811) versus placebo (n = 812).

Concomitant Medications:

Patients were required to be treated with a statin medication.

Principal Findings:

Overall, 1,623 patients were randomized. In the anacetrapib group, the mean age was 63 years, 22% were women, mean body mass index was 30 kg/m2, 55% had prior CHD (45% had CHD risk-equivalents), 53% had diabetes, mean low-density lipoprotein cholesterol (LDL-C) was 81 mg/dl, and mean high-density lipoprotein cholesterol (HDL-C) was 41 mg/dl.

At 24 weeks, LDL-C was reduced from 81 to 45 mg/dl in the anacetrapib group versus 82 to 77 mg/dl in the placebo group, a 38% greater reduction with anacetrapib (p < 0.001); HDL-C was increased from 41 to 101 mg/dl versus 40 to 46 mg/dl (p < 0.001), a 138% greater increase. Benefits were sustained to 76 weeks.

Cardiovascular death, myocardial infarction (MI), unstable angina, or stroke occurred in 2.0% of the anacetrapib group versus 2.6% of the placebo group (p = 0.40). The prespecified primary safety analysis used a Bayesian approach, and the event distribution provided 94% confidence to exclude a torcetrapib-like 25% increase in cardiovascular events. Cardiovascular death was 0.5% versus 0.1%, nonfatal MI was 0.7% versus 1.1%, unstable angina was 0.1% versus 0.7%, and stroke was 0.6% versus 0.6%, respectively. All-cause death, MI, unstable angina, stroke, or revascularization occurred in 3.3% of the anacetrapib group versus 5.3% of the placebo group (p = 0.048). Revascularization occurred in 1.0% versus 3.5% (p < 0.001), respectively.

Blood pressure remained the same in both groups. Drug-related adverse events occurred in 11.4% versus 10.7% (p = NS), liver enzymes >3x upper limit of normal occurred in 0.1% versus 1.0% (p = 0.019), myalgias occurred in 4.0% versus 3.5% (p = 0.61), and rhabdomyolysis occurred in 0 versus 0.3% (p = 0.16) of patients treated with anacetrapib versus placebo, respectively.

Interpretation:

Among patients with CHD treated with statin therapy, the use of the CETP inhibitor anacetrapib was highly effective in improving the lipid profile compared with placebo. This agent markedly reduced LDL-C and raised HDL-C. There were no apparent safety concerns with this agent unlike torcetrapib, which is associated with increased blood pressure, as well as increased deaths and cardiovascular events. This agent may improve clinical outcomes; therefore, large clinical trials are warranted.

References:

Cannon CP, Shah S, Dansky HM, et al., on behalf of the DEFINE Investigators. Safety of anacetrapib in patients with or at high risk for coronary heart disease. N Engl J Med 2010;363:2406-2415.

Presented by Dr. Christopher Cannon at the American Heart Association Scientific Sessions, Chicago, IL, November 17, 2010.

Keywords: Myocardial Infarction, Stroke, Follow-Up Studies, Quinolines, Blood Pressure, Rhabdomyolysis, Lipoproteins, LDL, Cholesterol Ester Transfer Proteins, Body Mass Index, Liver, Lipoproteins, HDL, Triglycerides, Diabetes Mellitus, Oxazolidinones, Myalgia


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