Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events - ILLUMINATE - Presented at AHA 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 clinical events among patients at high risk for cardiovascular events.

Study Design

Study Design:

Patients Enrolled: 15067
Mean Follow Up: Median follow-up 550 days
Mean Patient Age: Mean age 61.3 years
Female: 22

Patient Populations:

Age 45 to 75 years; either history of cardiovascular (CV) disease, including MI, stroke, acute coronary syndrome, unstable angina, peripheral vascular disease, and cardiac revascularization, 30 days to 5 years before screening, or type 2 diabetes without previous CV disease who met American Diabetes Association criteria or were receiving hypoglycemic agents.

Exclusions:

Evidence of an unstable medical condition; life expectancy <5 years; LDL cholesterol level <100 mg/dl if the patient was not receiving a lipid-altering drug; CV event during the run-in period or uncontrolled hypertension or if the LDL cholesterol target level had not been reached at the end of the run-in period.

Primary Endpoints:

Major cardiovascular event, defined as death from coronary heart disease, nonfatal myocardial infarction (MI), stroke, or hospitalization for unstable angina.

Secondary Endpoints:

Individual components of the primary endpoint, death from any cause, and the change from baseline in LDL and HDL cholesterol levels.

Drug/Procedures Used:

Following a 4 to 10 week run-in period of lifestyle counseling and atorvastatin treatment if needed, titrated to achieve LDL levels <100 mg/dl, patients were randomized in a double-blind manner to torcetrapib plus atorvastatin (n = 7,533) or atorvastatin plus placebo (n = 7,534). The trial was to continue for a mean follow-up of 4.5 years.

Principal Findings:

The trial was discontinued early after median of 550 days of follow-up at the recommendation of the Data Safety Monitoring Board due to an increase in events in the torcetrapib group.

At study entry, 46% of patients had a prior MI and 69% of patients had been revascularized. Diabetes was present in 44% of patients and 7% had heart failure.

The increase in high-density lipoprotein (HDL) cholesterol at 12 month follow-up was greater in the torcetrapib group than the atorvastatin alone group (+34.2 mg/dl vs. +0.5 mg/dl, p < 0.001). Likewise, reductions in LDL levels were greater in the torcetrapib group (-21.5 mg/dl vs. +0.9 mg/dl, p < 0.001). Systolic blood pressure at 12 months increased by 5.4 mm Hg in the torcetrapib group and 0.9 mm Hg in the atorvastatin alone group, p < 0.001). Diastolic blood pressure also increased to a greater degree with torcetrapib (+2.0 mm Hg vs. -0.1 mm Hg, p < 0.001). Increases were also observed in sodium, bicarbonate, and aldosterone in the torcetrapib group.

The primary endpoint of major cardiovascular event was higher in the torcetrapib group than the atorvastatin alone group (6.2% vs. 5.0%, HR 1.25, p = 0.001). All-cause mortality occurred more frequently in the torcetrapib group (1.2% vs. 0.8%, HR 1.58, p = 0.006), with a directional increase in both CV death (n = 49 vs. n = 35) and non-CV death (n = 40 vs. n = 20).

To further explore the impact of the increase in blood pressure with torcetrapib on mortality, additional post-hoc analysis was conducted. Converse to what would be expected, patients with an increase in SBP ≤2.5 mm Hg actually had more deaths than patients with an increase in SBP >2.5 mm Hg (1.5% vs. 0.9%). Mortality was also higher in those with a greater decrease in potassium (1.5% vs. 1.0% for those with vs. without a decrease ≥0.1 mmol/L) and a greater increase in bicarbonate (1.5% vs. 0.9% for those with vs. without an increase >0.7 mmol/L).

Interpretation:

Among patients at high risk for cardiovascular events, treatment with the CETP inhibitor torcetrapib in addition to atorvastatin therapy was associated with an increase in the primary endpoint of major cardiovascular events and an increase in mortality compared with atorvastatin alone.

Torcetrapib was highly effective in raising HDL in the present study, as well as lowering LDL. The prior ILLUSTRATE study showed no effect on atherosclerosis progression with torcetrapib, despite having the expected impact on increasing HDL and lowering LDL. The increase in blood pressure observed in the trial was expected to explain in part the increase in mortality, but further analysis of the data showed that those with a greater increase in systolic blood pressure actually had a lower mortality rate than patients with less of an increase in blood pressure. The increase in mortality appeared to be in both cardiovascular and non-cardiovascular causes. Another possible explanation for the increase in mortality raised by the investigators was the increase in aldosterone, or potentially an adverse effect of the CETP inhibition itself, although the conclusive cause is not known.

References:

Barter PJ, et al. Effects of Torcetrapib in Patients at High Risk for Coronary Events. N Engl J Med 2007;357:2109-22.

Presented by Dr. Philip J. Barter at the American Heart Association Annual Scientific Session, Orlando, FL, November 2007.

Clinical Topics: Acute Coronary Syndromes, Dyslipidemia, Heart Failure and Cardiomyopathies, Vascular Medicine, Atherosclerotic Disease (CAD/PAD), Lipid Metabolism, Nonstatins, Novel Agents, Statins, Acute Heart Failure

Keywords: Life Style, Follow-Up Studies, Sodium, Diabetes Mellitus, Type 2, Counseling, Blood Pressure, Cholesterol, Stroke, Acute Coronary Syndrome, Atherosclerosis, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Clinical Trials Data Monitoring Committees, Quinolines, Heptanoic Acids, Peripheral Vascular Diseases, Pyrroles, Potassium, Cholesterol Ester Transfer Proteins, Bicarbonates, Heart Failure, Hypoglycemic Agents, Lipoproteins, HDL


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