Effect of ACAT inhibition on the progression of coronary atherosclerosis.
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.).
Nissen
Steven E
SE
Department of Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland, OH 44195, USA. nissens@ccf.org
Tuzcu
E Murat
EM
Brewer
H Bryan
HB
Sipahi
Ilke
I
Nicholls
Stephen J
SJ
Ganz
Peter
P
Schoenhagen
Paul
P
Waters
David D
DD
Pepine
Carl J
CJ
Crowe
Tim D
TD
Davidson
Michael H
MH
Deanfield
John E
JE
Wisniewski
Lisa M
LM
Hanyok
James J
JJ
Kassalow
Laurent M
LM
D002318:Cardiovascular Diseases / Q000453:epidemiology; D002784:Cholesterol / Q000097:blood; D003324:Coronary Artery Disease / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology; D003331:Coronary Vessels / Q000000981:diagnostic imaging / Q000473:pathology; D018450:Disease Progression; D005260:Female; D006801:Humans; D007210:Indoleacetic Acids / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors*; D017211:Treatment Failure; D018084:Ultrasonography, Interventional
D007210:Indoleacetic Acids; D002784:Cholesterol; C509302:pactimibe; D002785:Sterol O-Acyltransferase