Carotid Atherosclerosis Progression Trial Investigating Vascular ACAT Inhibition Treatment Effects - CAPTIVATE

Mar 17, 2009
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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:
Daiichi Sankyo Pharma Development
Date Published:
01/01/2009
Date Updated:
03/17/2009
Original Posted Date:
03/17/2009
References

Description:

The goal of the trial was to evaluate treatment with the acyl coenzyme A: cholesterol acyltransferase inhibitor (ACAT) pactimibe compared with placebo in patients with familial hypercholesterolemia.

Hypothesis:

Pactimibe would be more effective in reducing carotid intima-media thickness (CIMT).

Study Design

  • Placebo Controlled
  • Randomized
  • Blinded
  • Parallel

Patients Screened: 1,200
Patients Enrolled: 881
Mean Follow Up: 15 months
Mean Patient Age: 55 years
Female: 41%

Patient Populations:

  • Patients with familial hypercholesterolemia and carotid atherosclerosis
  • Age 40-75 years for men or 45-75 years for women
  • LDL cholesterol >100 mg/dl and triglyceride <500 mg/dl
  • Carotid atherosclerosis was defined as maximum CIMT >0.7 mm up to 2.5 mm on ultrasound examination

Exclusions:

  • High-grade carotid artery stenosis or occlusion
  • Symptomatic heart failure
  • Cardiovascular event in the last 3 months
  • Diabetes
  • Uncontrolled hypertension

Primary Endpoints:

  • Maximum CIMT in the same arterial segment with scans performed at least 40 weeks apart

Secondary Endpoints:

  • Mean change in CIMT
  • Lumen diameter and wall compliance of the common carotid arteries
  • Change in inflammatory and oxidative markers
  • Change in lipid profiles
  • Clinical and laboratory adverse events
  • Incidence and time to first occurrence of a cardiovascular event

Drug/Procedures Used:

Patients with familial hypercholesterolemia and carotid atherosclerosis were randomized to 100 mg daily of pactimibe (n = 443) versus placebo (n = 438).

Concomitant Medications:

Approximately 96% of participants received statin medications during the study. Statin medications were used for at least 24 months in 80% and in the remaining participants, they either were not prescribed or they were used for less than 24 months.

Principal Findings:

Overall, 881 patients were randomized. The mean age was 55 years, 41% were women, 41% were former smokers, and mean body mass index was 28 kg/m2. The mean follow-up was 15 months.

At 6 months, low-density lipoprotein (LDL) cholesterol increased 7.3% with pactimibe versus 1.4% with placebo (p = 0.001). The change in high-density lipoprotein (HDL) cholesterol was -0.5% versus 0.6% (p = 0.23), and triglycerides was 2.8% vs. 6.1% (p = 0.18), respectively, for pactimibe versus placebo.

The primary outcome, change in maximum CIMT at 12 months, was increased 0.017 mm with pactimibe versus 0.013 mm with placebo (difference = 0.004 mm, p = 0.64). Change in mean CIMT at 12 months was increased 0.019 mm versus 0.005 mm (difference = -0.014 m, p = 0.04), respectively for pactimibe versus placebo.

One or more serious clinical or laboratory adverse events (10.0% vs. 7.7%, p = 0.24), cardiovascular death, myocardial infarction (MI), or stroke (2.3% vs. 0.2%, p = 0.01), cardiovascular death (0.7% vs. 0.2%, p = 0.62), MI (1.4% vs. 0%, p = 0.03), and stroke (0.2% vs. 0%, p = 0.99), respectively for pactimibe versus placebo.

Interpretation:

Among patients with familial hypercholesterolemia and carotid atherosclerosis, the ACAT inhibitor pactimibe failed to reduce CIMT. There was no change in maximum CIMT at follow-up, although mean CIMT progressed more with pactimibe compared with placebo. LDL cholesterol increased more with pactimibe. Serious adverse events were similar between the groups, although there were more major adverse cardiovascular events with pactimibe. This composite outcome was mainly influenced by a higher rate of MI with pactimibe.

The current study was terminated early after the parallel ACTIVATE trial reported no benefit with the use of pactimibe. The ACTIVATE trial examined the effect of pactimibe on coronary artery disease progression by serial intravascular ultrasound examinations. In a third trial (A-PLUS), avasimibe was found to increase plaque burden and LDL cholesterol.

Taken together, these results to date show that ACAT inhibitors result in harm by increasing LDL cholesterol, plaque burden, and major adverse cardiovascular events. This underscores the importance of clinical trial evaluation of investigational drugs since animal studies documented the benefits of this class of medications.

References:

Meuwese MC, de Groot E, Duivenvoorden R, et al. ACAT inhibition and progression of carotid atherosclerosis in patients with familial hypercholesterolemia: The CAPTIVATE randomized trial. JAMA 2009;301:1131-9.

Keywords: Coronary Artery Disease, Myocardial Infarction, Stroke, Carotid Intima-Media Thickness, Hyperlipoproteinemia Type II, Carotid Artery Diseases, Sulfonic Acids, Sterol O-Acyltransferase, Cholesterol, Body Mass Index, Indoleacetic Acids, Carotid Stenosis, Triglycerides


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