ACAT Inhibition on the Progression of Coronary Atherosclerosis - ACTIVATE

Nov 15, 2005
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Date Presented:
01/01/2005
Date Published:
01/01/2006
Date Updated:
11/15/2005
Original Posted Date:
11/15/2005
References

Description:

The goal of the trial was to evaluate treatment with pactimibe, a novel enzyme acyl-coenzymeA:cholesterol transferase (ACAT) inhibitor, compared with placebo on change in atheroma volume among patients with symptomatic coronary artery disease.

Hypothesis:

Treatment with pactimibe will be associated with less disease progression compared with placebo among patients with coronary artery disease.

Study Design

Study Design:

Patients Enrolled: 534
Mean Follow Up: 18 months
Mean Patient Age: Mean age 60 years
Female: 31

Patient Populations:

Symptomatic coronary artery disease with stenosis >20% on coronary angiography

Primary Endpoints:

Change in percent atheroma volume at 18 months

Secondary Endpoints:

Change in absolute atheroma volume at 18 months in the total segment and in the most diseased 10 mm segment

Drug/Procedures Used:

Patients were randomized to treatment with pactimibe (100 mg per day for 18 months) (n=266) or placebo (n=268). Patients underwent IVUS at baseline and 18 month follow-up. Among the 534 patients randomized in the trial, 408 patients had baseline and 18 month IVUS available.

Principal Findings:

At baseline, LDL cholesterol was 95 mg/dL, HDL cholesterol was 43 mg/dL, and CRP was 3 mg/L. There was no significant difference between groups in change in CRP or LDL at 18 month follow-up, with final LDL 86.4 mg/dL in the placebo group (-3.4 mg/dL vs baseline) and 91.3 mg/dL in the pactimibe group (+0.6 mg/dL vs baseline; p=0.15).

The primary endpoint of change in percent atheroma volume at 18 months did not differ by treatment group, with progression in both groups (0.59 for placebo vs 0.69 for pactimibe, p=0.77). For the secondary endpoint of change in absolute total atheroma volume, the placebo group had a 5.6 mm3 regression while the pactimibe group had a 1.3 mm3 regression (p=0.03). Likewise, in the 10 mm segment with the greatest disease, the placebo group had a 3.2 mm3 regression of absolute atheroma volume while the pactimibe group had a 1.3 mm3 regression (p=0.01). Results were similar in the subgroup analysis.

Among the clinical events, there was no difference in the composite of cardiovascular death, non-fatal MI, stroke, hospitalization for unstable angina, or coronary or carotid revascularization (26.5% vs 23.8%, p=0.53) or any component of the clinical composite endpoint.

Interpretation:

Among patients with symptomatic coronary artery disease, treatment with the novel ACAT inhibitor pactimibe was not associated with a reduction in atherosclerosis progression compared with placebo at 18 month follow-up.

While there was no difference in the primary endpoint, there was actually more disease regression with placebo than with pactimibe in the secondary endpoints of absolute atheroma volume. Given these pro-atherogenic findings with pactimibe, the future of ACAT inhibition as a target treatment for atherosclerosis is unclear, although it is possible that changes in the balance between ACAT 1 and ACAT 2 inhibition could produce different results.

References:

Nissen SE, et al. Effect of ACAT Inhibition on the Progression of Coronary Atherosclerosis. N Engl J Med 2006;354:1253-63.

Presented by Dr. Steven E Nissen at the American Heart Association Scientific Session, Dallas, Texas, November 2005.

Keywords: Cholesterol, Coronary Artery Disease, Stroke, Atherosclerosis, Plaque, Atherosclerotic, Coronary Angiography, Transferases, Indoleacetic Acids, Constriction, Pathologic, Hospitalization, Disease Progression


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