New York, NY - A small but intriguing clinical trial has shown that atorvastatin (Lipitor, Pfizer) was no more effective than placebo in slowing the progression of atherosclerosis [1]. Over the course of the 12-month study, investigators observed no difference between atorvastatin and placebo in the mean change in carotid intima-media thickness (IMT) in postmenopausal women with moderate hypercholesterolemia.

BMO Capital Market analyst Robert Hazlett unearthed the unpublished Carotid Atorvastatin Study in Hyperlipidemic Postmenopausal Women (CASHMERE) study on the website ClinicalStudyResults.org. The study included 192 postmenopausal women randomized to atorvastatin 80 mg and 206 women randomized to placebo. The study was completed in July 2006.

Hazlett issued a research note about the study last week, which was picked up by Dow Jones reporter Peter Loftus. [1] As reported by Dow Jones, Hazlett said the study raises questions about the IMT imaging technique when used in certain patient populations. With the wealth of data supporting the clinical effectiveness of atorvastatin, the "question is not the agent in this study, because we know Lipitor works," said Hazlett. The new atorvastatin data, writes Loftus, "provide ammunition to defenders of rival cholesterol drugs Vytorin [simvastatin/ezetimibe] and Zetia [ezetimibe]."

The controversial Effect of Combination Ezetimibe and High-Dose Simvastatin vs Simvastatin Alone on the Atherosclerotic Process in Patients with Heterozygous Familial Hypercholesterolemia (ENHANCE) trial was published this year and, like CASHMERE, showed that despite reductions in LDL-cholesterol levels, there was no significant difference in changes in IMT with combination simvastatin/ezetimibe when compared with simvastatin alone.

It does raise the question about whether or not IMT is a reliable surrogate end point for clinical events.

Dr Antonio Gotto (Weill Medical College of Cornell University, New York, NY) told heartwire that atorvastatin has been proven to reduce clinical events in primary and secondary prevention, so the CASHMERE trial raises the question that the imaging modality doesn't truly capture the effectiveness of lipid-lowering agents in certain patients, including those studied in ENHANCE.

"This is a placebo-controlled study, so ENHANCE had an even higher threshold to overcome," said Gotto. "It does raise the question about whether or not IMT is a reliable surrogate end point for clinical events. Either we're not studying the right patient population, or the technique is not consistent with clinical events." Moreover, Gotto believes there is no reason to expect that ezetimibe won't reduce hard clinical end points, such as MI and death, because of the significant reductions in LDL cholesterol beyond those achieved with statin therapy.

When asked what the CASHMERE results mean, however, others were critical of the study, saying they do not believe the study provides support for Vytorin or Zetia or that IMT is flawed based on these results.

"To say that this study reflects on ENHANCE in any way is a huge stretch of the imagination," Dr James Stein (University of Wisconsin Medical School, Madison) commented to heartwire. "Since when did the medical community start listening to financial analysts? It is a good thing they don't practice medicine and don't conduct research."

Stein said he is critical of CASHMERE and any subsequent comparisons with ENHANCE for a number of reasons. The biggest problem with the study is the short duration of 12 months, which he said is a very short time to show a change in IMT, especially in a group with a low predicted rate of change. "The vast majority of IMT studies are two to three years long, occasionally shorter in higher-risk groups," he said. Patients in CASHMERE were young, mean age 56 years, and had high HDL cholesterol levels (mean 67 mg/dL) and normal triglycerides, so they would be expected to progress slowly regardless of their intermediate LDL-cholesterol levels (approximately 160 mg/dL). Any intervention would need much more time to show a benefit, said Stein.

To say that this study reflects on ENHANCE in any way is a huge stretch of the imagination.

Asked about his thoughts on the CASHMERE study, lead ENHANCE investigator Dr John Kastelein (Academic Medical Center, Amsterdam, the Netherlands) told heartwire his thoughts are very simple: "Baseline IMTs in the CASHMERE participants were thin, and therefore no therapy is able to show improvement." Kastelein earlier postulated this was one of the reasons there was no observed benefit in ENHANCE—that because the familial-hypercholesterolemia (FH) patients were so well treated, the addition of Vytorin was unable to yield any additional benefit on IMT. Merck recently stopped the ACHIEVE trial, a two-year study of niacin/laropiprant in FH patients, for the same reason.

Dr Harlan Krumholz (Yale University School of Medicine, New Haven, CT), who appeared on a special panel at the American College of Cardiology (ACC) 2008 Scientific Sessions to discuss the ENHANCE findings when they were presented in March, told heartwire that he shares similar concerns about the small patient numbers, short duration, and high dropout rate in CASHMERE. Moreover, the issue with ezetimibe, he said, is not with ENHANCE but rather that it highlighted how little is known about the net effects of ezetimibe beyond its lowering of LDL.

"This is where people get confused. They want to say that ENHANCE was weak and flawed and so we should go back to prescribing it with abandon, but the study changed practice because it made us realize that the exuberance for the drug had far outreached the evidence to support it," said Krumholz. "We simply do not have evidence of its clinical benefit and should be cautious with it until we know what it does. . . . I wish it were as simple as seeing what a drug does to LDL, but unfortunately it is not."

The 18 000-patient IMPROVE-IT study—designed to specifically determine whether or not ezetimibe reduces clinical events—is on track for completion in 2012. The study is chaired by Dr Eugene Braunwald of the TIMI Study Group and cochaired by Dr Robert Califf (Duke Clinical Research Institute, Durham, NC).