Carotid Atherosclerosis Progression Trial (CAPTIVATE)
Carotid Atherosclerosis Progression Trial (CAPTIVATE)
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.
Pactimibe would be more effective in reducing carotid intima-media thickness (CIMT).
Patients with familial hypercholesterolemia and carotid atherosclerosis were randomized to 100 mg daily of pactimibe (n = 443) versus placebo (n = 438).
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.
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/m. 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.
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.
Placebo controlled. Randomized. Blinded. Parallel.
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).
Drugs/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/m. 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.
Conditions
Arteriosclerosis
Carotid stenosis
Prevention
Therapies
Medical
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%
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
Patient Population
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
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