Effect of ACAT inhibition on the progression of coronary atherosclerosis

N Engl J Med. 2006 Mar 23;354(12):1253-63. doi: 10.1056/NEJMoa054699.


Background: The enzyme acyl-coenzyme A:cholesterol acyltransferase (ACAT) esterifies cholesterol in a variety of tissues. In some animal models, ACAT inhibitors have antiatherosclerotic effects.

Methods: We performed intravascular ultrasonography in 408 patients with angiographically documented coronary disease. All patients received usual care for secondary prevention, including statins, if indicated. Patients were randomly assigned to receive the ACAT inhibitor pactimibe (100 mg per day) or matching placebo. Ultrasonography was repeated after 18 months to measure the progression of atherosclerosis.

Results: The primary efficacy variable analyzing the progression of atherosclerosis--the change in percent atheroma volume--was similar in the pactimibe and placebo groups (0.69 percent and 0.59 percent, respectively; P=0.77). However, both secondary efficacy variables assessed by means of intravascular ultrasonography showed unfavorable effects of pactimibe treatment. As compared with baseline values, the normalized total atheroma volume showed significant regression in the placebo group (-5.6 mm3, P=0.001) but not in the pactimibe group (-1.3 mm3, P=0.39; P=0.03 for the comparison between groups). The atheroma volume in the most diseased 10-mm subsegment regressed by 3.2 mm3 in the placebo group, as compared with a decrease of 1.3 mm3 in the pactimibe group (P=0.01). The combined incidence of adverse cardiovascular outcomes was similar in the two groups (P=0.53).

Conclusions: For patients with coronary disease, treatment with an ACAT inhibitor did not improve the primary efficacy variable (percent atheroma volume) and adversely affected two major secondary efficacy measures assessed by intravascular ultrasonography. ACAT inhibition is not an effective strategy for limiting atherosclerosis and may promote atherogenesis. (ClinicalTrials.gov number, NCT00268515.).

Trial registration: ClinicalTrials.gov NCT00185042.

Publication types

  • Clinical Trial, Phase III
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cardiovascular Diseases / epidemiology
  • Cholesterol / blood
  • Coronary Artery Disease / diagnostic imaging
  • Coronary Artery Disease / drug therapy*
  • Coronary Artery Disease / pathology
  • Coronary Vessels / diagnostic imaging
  • Coronary Vessels / pathology
  • Disease Progression
  • Female
  • Humans
  • Indoleacetic Acids / adverse effects
  • Indoleacetic Acids / therapeutic use*
  • Male
  • Middle Aged
  • Sterol O-Acyltransferase / antagonists & inhibitors*
  • Treatment Failure
  • Ultrasonography, Interventional


  • Indoleacetic Acids
  • Cholesterol
  • pactimibe
  • Sterol O-Acyltransferase

Associated data

  • ClinicalTrials.gov/NCT00185042