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Investigation of Lipid Level Management Using Coronary Ultrasound to Assess Reduction of Atherosclerosis by CETP Inhibition and HDL Elevation - ILLUSTRATE – Presented at ACC 2007
Description:
The goal of the trial was to evaluate the effect of treatment with torcetrapib, a cholesteryl ester transfer protein (CETP) inhibitor, in addition to atorvastatin compared with atorvastatin alone on disease progression among patients with coronary disease.
Study Design
Study Design:
Patients Enrolled: 1,188
Mean Follow Up: 24 months
Mean Patient Age: Mean age, 57 years
Female: 30
Patient Populations:
Age 18-75 years, clinically indicated cardiac catheterization showing ≥1 stenosis on angiography with ≥20% narrowing, and if the target vessel had less than 50% obstruction throughout a segment of 40 mm or longer
Exclusions:
Left main coronary artery with >50% obstruction, blood pressure >140/90 mm Hg despite treatment, triglyceride >500 mg/dl, or creatinine >1.7 times the upper limit of normal
Primary Endpoints:
Change in percent atheroma volume
Secondary Endpoints:
Normalized total atheroma volume, and change in atheroma volume in the most diseased 10 mm segment
Drug/Procedures Used:
Following a 4- to 10-week run-in phase in which all patients were treated with atorvastatin titrated to achieve a low-density lipoprotein (LDL) level of 85-115 mg/dl, patients were randomized in a double-blind manner to treatment with torcetrapib (60 mg; n = 591) in addition to atorvastatin compared with atorvastatin alone with matching placebo (n = 597). Intravascular ultrasonography was performed at baseline and at 24 months.
Principal Findings:
Mean atorvastatin dose was 23 mg in both groups. High-density lipoprotein (HDL) cholesterol at follow-up was higher in the torcetrapib group than the atorvastatin alone group (72.1 mg/dl vs. 43.9 mg/dl, p < 0.001); LDL levels were lower in the torcetrapib group (70.1 mg/dl vs. 87.2 mg/dl, p < 0.001). Median C-reactive protein levels at follow-up were higher in the torcetrapib group than the atorvastatin alone group (1.8 mg/l vs. 1.5 mg/l, p = 0.02).
Systolic blood pressure was higher at follow-up in the torcetrapib group (126.4 mm Hg vs. 122.0 mm Hg, p < 0.001), as was diastolic blood pressure (76.0 mm Hg vs. 74.3 mm Hg, p < 0.001), representing an increase in blood pressure in the torcetrapib group of 6.5/2.8 mm Hg.
The primary endpoint of change from baseline in percent atheroma volume did not differ between treatment groups (0.12% for torcetrapib vs. 0.19% for atorvastatin alone, p = 0.72), nor did change in atheroma volume of the most diseased 10 mm segment (-4.1 mm3 for torcetrapib vs. -3.3 mm3 for atorvastatin alone, p = 0.12). Reduction in normalized total atheroma volume was greater in the torcetrapib group compared with atorvastatin alone (-9.4 mm3 vs. -6.3 mm3, p = 0.02).
All-cause death occurred in 1.4% of the torcetrapib group and 1.0% of the atorvastatin alone group. The composite of death from coronary heart disease, nonfatal myocardial infarction (MI), nonfatal stroke, hospitalization for unstable angina, or coronary revascularization did not differ between groups (21.0% for torcetrapib vs. 19.6% for atorvastatin alone). Blood pressure-related adverse events occurred more frequently in the torcetrapib group (23.7% vs. 10.6%), as did an increase in blood pressure of >15 mm Hg (9.0% vs. 3.2%).
Interpretation:
Among patients with coronary disease, treatment with the CETP inhibitor torcetrapib in addition to atorvastatin therapy was not associated with a difference in change in percent atheroma volume compared with atorvastatin alone at 24-month follow-up.
Torcetrapib was effective in raising HDL in the present study. However, there was no effect on atherosclerosis progression, despite having the expected impact on increasing HDL and lowering LDL. Commercial development of torcetrapib was recently stopped after a large trial showed an increase in mortality with torcetrapib, along with an increase in blood pressure. The present study, while much smaller than the other trial, did not show a difference in mortality with torcetrapib, but there were only 14 deaths in the trial. The study did show an increase in blood pressure with torcetrapib.
The cause for the increase in mortality is not known at this time, as full results of the safety trial have not yet been presented or published. It is also not known if the increase in blood pressure and mortality is a class effect of the CETP inhibitors or if it is specific to torcetrapib.
References:
Nissen SE, Tardif JC, Nicholls SJ, et al. Effect of torcetrapib on the progression of coronary atherosclerosis. N Engl J Med 2007;356:1304-16.
Presented by Dr. Steven E. Nissen at the American College of Cardiology Annual Scientific Session, New Orleans, LA, March 2007.
Keywords: Myocardial Infarction, Stroke, Follow-Up Studies, Plaque, Atherosclerotic, Atherosclerosis, Cardiac Catheterization, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Quinolines, Lipoproteins, Coronary Disease, Blood Pressure, Heptanoic Acids, Constriction, Pathologic, Pyrroles, Cholesterol, C-Reactive Protein, Cholesterol Ester Transfer Proteins, Ultrasonography, Interventional, Disease Progression
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