ACAT inhibition and progression of carotid atherosclerosis in patients with familial hypercholesterolemia: the CAPTIVATE randomized trial.
BACKGROUND
Inhibition of acyl coenzyme A:cholesterol acyltransferase (ACAT), an intracellular enzyme involved in cholesterol accumulation, with pactimibe was developed to assist in the prevention of cardiovascular disease.


OBJECTIVE
To evaluate the efficacy and safety of pactimibe in inhibition of atherosclerosis.


METHODS
A prospective, randomized, stratified, double-blind, placebo-controlled study (Carotid Atherosclerosis Progression Trial Investigating Vascular ACAT Inhibition Treatment Effects [CAPTIVATE]) of 892 patients heterozygous for familial hypercholesterolemia conducted at 40 lipid clinics in the United States, Canada, Europe, South Africa, and Israel between February 1, 2004, and December 31, 2005. Study was terminated on October 26, 2005.


METHODS
Participants received either 100 mg/d of pactimibe (n = 443) or matching placebo (n = 438), in addition to standard lipid-lowering therapy.


METHODS
Carotid atherosclerosis, assessed by ultrasound carotid intima-media thickness (CIMT), at baseline, 12, 18, and 24 months. Maximum CIMT was the primary end point and mean CIMT the secondary end point.


RESULTS
Because pactimibe failed to show efficacy in the intravascular coronary ultrasound ACTIVATE study, the CAPTIVATE study was terminated prematurely after a follow-up of 15 months. After 6 months of treatment with pactimibe, low-density lipoprotein cholesterol increased by 7.3% (SD, 23%) compared with 1.4% (SD, 28%) in the placebo group (P = .001). The carotid ultrasonographic scans of the 716 patients with at least 2 scans and obtained at least 40 weeks apart were analyzed. Maximum CIMT measurements did not show a pactimibe treatment effect (difference, 0.004 mm; 95% confidence interval [CI], -0.023 to 0.015 mm; P = .64); however, the less variable mean CIMT measurement revealed an increase of 0.014 mm (95% CI, -0.027 to 0.000 mm; P = .04) in patients administered pactimibe vs placebo. Major cardiovascular events (cardiovascular death, myocardial infarction, and stroke) occurred more often in patients administered pactimibe vs placebo (10/443 [2.3%] vs 1/438 [0.2%]; P = .01).


CONCLUSIONS
In patients with familial hypercholesterolemia, pactimibe had no effect on atherosclerosis as assessed by changes in maximum CIMT compared with placebo but was associated with an increase in mean CIMT as well as increased incidence of major cardiovascular events.


BACKGROUND
clinicaltrials.gov Identifier: NCT00151788.
Meuwese
Marijn C
MC
Department of Vascular Medicine, Academic Medical Center, PO Box 22700, 1100 DE Amsterdam, The Netherlands.
de Groot
Eric
E
Duivenvoorden
Raphaël
R
Trip
Mieke D
MD
Ose
Leiv
L
Maritz
Frans J
FJ
Basart
Dick C G
DC
Kastelein
John J P
JJ
Habib
Rafik
R
Davidson
Michael H
MH
Zwinderman
Aeilko H
AH
Schwocho
Lee R
LR
Stein
Evan A
EA
D015415:Biomarkers / Q000097:blood; D002340:Carotid Artery Diseases / Q000097:blood / Q000000981:diagnostic imaging / Q000517:prevention & control*; D018450:Disease Progression; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000097:blood / Q000188:drug therapy*; D000960:Hypolipidemic Agents / Q000627:therapeutic use*; D007210:Indoleacetic Acids / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors*; D014463:Ultrasonography
D015415:Biomarkers; D004791:Enzyme Inhibitors; D000960:Hypolipidemic Agents; D007210:Indoleacetic Acids; C509302:pactimibe; D002785:Sterol O-Acyltransferase