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Posted by on Jul 8, 2008 in Cardiology, Pharma

Negative Lipitor Data Raise Doubt About CIMT

Negative Lipitor Data Raise Doubt About CIMT

The utility of measuring carotid intima-media thickness (CIMT) in studies of cholesterol-lowering medications may be dubious, given the recent, unexpected results of Pfizer’s atorvastatin (Lipitor) in the CASHMERE trial. According to a recent Dow Jones Newswire report, market analyst Robert Hazlett discovered the negative results of the placebo-controlled trial at clinicalstudyresults.org and issued a report last week, which questioned the usefulness of CIMT for assessing the efficacy of cholesterol-lowering drugs.

In the 12-month, multicenter study of nearly 400 postmenopausal women,* the change in mean CIMT (the primary endpoint) with atorvastatin 80 mg/d (2.9%) was not significantly different from that with placebo (2.5%). However, secondary endpoints, as expected, showed statistically significant reductions in total cholesterol, LDL cholesterol, and triglyceride levels with atorvastatin. Lipitor was initially FDA approved in 1996 for hypercholesterolemia and indicated in 2004 to reduce the risk of clinical cardiac events and stroke.

The negative CIMT data in CASHMERE, by extension, may justify the continued use of the combination of simvastatin/ezetimibe (Vytorin; Schering-Plough/Merck), despite the widely publicized, negative CIMT results from the ENHANCE trial. (However, there are currently no data demonstrating a risk reduction of cardiac events with Vytorin use. These endpoints are being assessed in the ongoing IMPROVE-IT study). The Dow Jones report suggests that both CASHMERE and ENHANCE may have failed to show changes in CIMT thickness with treatment, because of the relatively low burden of arterial disease in enrollees at baseline. Tabulated below are the baseline mean CIMT data from both studies, which can be compared with the mean maximum CIMT measurements (from 12 carotid sites) in the METEOR trial of rosuvastatin (Crestor; AstraZeneca) in “low-risk” individuals. The METEOR trial did show a statistically significant, placebo-controlled effect of rosuvastatin on CIMT over 2 years.

Trial

Baseline CIMT, mm (SD)

Placebo

Active Drug

CASHMERE

0.699 (0.12)

0.682 (0.10)

ENHANCE

0.70 (0.13)

0.69 (0.64)

METEOR

1.15 (0.19)

1.17 (0.20)

In the extensive coverage of the ENHANCE trial, Schering-Plough and others alternatively suggested that a substantial percentage of the CIMT measurements in the study were either biologically implausible or missingthereby calling into question the study’s final, negative results.

CASHMERE = Carotid Atorvastatin Study in Hyperlipidemic Postmenopausal Women: A Randomised Evaluation of Atorvastatin Versus Placebo; ENHANCE = Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression; IMPROVE-IT: Improved Reduction of Outcomes: Vytorin Efficacy International Trial; METEOR = Measuring Effects on Intima-Media Thickness: An Evaluation of Rosuvastatin.

* Belgium, 12 centers; France, 54 centers; The Netherlands, 3 centers. Fasting LDL, 130-190 mg/dL; triglyceride level, 4 g/L. Dropout rate: atorvastatin, 32.8%; placebo, 22.3%.

HT: Pharmalot

bmartin (1127 Posts)

A native East Tennessean, Barbara Martin is a formerly practicing, board-certified neurologist who received her BS (psychology, summa cum laude) and MD from Duke University before completing her postgraduate training (internship, residency, fellowship) at the Hospital of the University of Pennsylvania in Philadelphia. She has worked in academia, private practice, medical publishing, drug market research, and continuing medical education (CME). For the last 3 years, she has worked in a freelance capacity as a medical writer, analyst, and consultant. Follow Dr. Barbara Martin on and Twitter.