Monday, November 5, 2007

AHA - 2007: The ILLUMINATE trial, final analysis

Final results presented on cholesterol drug trial stopped in December

Late-Breaking Clinical Trials News Release 10

ORLANDO, Nov. 5 – Final analysis of a cholesterol drug trial that was halted early was presented as a late-breaking clinical trial at the American Heart Association’s Scientific Sessions 2007.

The ILLUMINATE trial was designed to test whether torcetrapib, in combination with atorvastatin, reduces major cardiovascular disease events when compared to atorvastatin alone.

But the trial was terminated in December 2006 because of “an imbalance of mortality and cardiovascular events” associated with the use of the drug. In the terminated trial, a 60 percent increase in deaths was observed among patients taking torcetrapib and atorvastatin versus those taking atorvastatin alone. The results did suggest any question about the safety of atorvastatin, a well-established therapy.

Torcetrapib is a cholesteryl ester transfer protein (CETP) inhibitor. CETP inhibitors are a class of drugs that increase blood levels of the “good” high density lipoprotein cholesterol (HDL-C).

Between August 2004 and December 2005, researchers randomized 15,067 men and women, ages 45-75 years old who were at high risk for cardiovascular disease events and eligible for statin treatment. Patients were considered high risk because of prior coronary heart disease, peripheral vascular disease, symptomatic carotid artery disease, or type 2 diabetes.

The use of torcetrapib in the ILLUMINATE trial was associated with: a predicted substantial (72 percent) increase in HDL-C (“good” cholesterol) and decrease (25 percent) in LDL-C (“bad” cholesterol); increased systolic blood pressure by 5.4 mmHg, decreased serum potassium, and increased serum sodium, bicarbonate and aldosterone (p<0.001 for each). An excess of major cardiovascular disease events (HR 1.25; p=0.001; 95% CI [1.09,1.44]) and deaths (HR=1.58; p=0.006; 95% CI [1.14,2.19]) was observed with torcetrapib use. The excess of deaths included both cardiovascular, and non-cardiovascular causes. Serious adverse events were reported by 16.4% and 15.0%, respectively, of subjects in the trorcetrpib with atorvastatin group and atorvastatin-only group (p=0.02).

“The adverse clinical outcome associated with the use of torcetrapib may have been the consequence of this off-target pharmacology,” said Philip Barter, M.D., Ph.D., lead investigator of the study and professor at The Heart Research Institute in Sydney, Australia. But the possibility of an adverse effect of CETP inhibition cannot be excluded by the results of the randomized trial.

“Post-hoc exploratory analyses are underway in an attempt to inform the design of any future studies aiming to investigate the potential clinical benefit of CETP inhibition,” Barter said.

Support for this study was provided by Pfizer.

Statements and conclusions of study authors that are presented at American Heart Association scientific meetings are solely those of the study authors and do not necessarily reflect association policy or position. The American Heart Association makes no representation or warranty as to their accuracy or reliability.


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