FDA, drug companies under collateral fire for ENHANCE by panel at ACC
Panel at ACC discuss Vytorin results. Source: Wall Street Journal  
Harlan M. Krumholz, MD, took some time to warm up, but by the time he had finished commenting on the meaning of the ENHANCE results, he lambasted the drug companies for their marketing tactics and the FDA for its propensity to approve drugs without thorough outcomes data.

Krumholz, who spoke on Sunday at the American College of Cardiology meeting, was part of a group of industry experts commenting on the trial on behalf of the ACC. Other members were Patrick T. O'Gara, MD, from Boston; Joseph V. Messer, MD, from Chicago; and Rick A. Nishimura, MD, from Rochester, Minn. Krumholz is from New Haven, Conn.

Krumholz pointed to several previous statin studies that showed an association with less progression of atherosclerosis. In the ENHANCE study, no such association was found for the combination of simvastatin (Zocor, Merck) and ezetimibe (Zetia, Schering-Plough), marketed as Vytorin, as measured by carotid intima-media thickness (CIMT).

“Sometimes negative studies can provide important insights,” he said. “You’ve just seen a negative trial that should change practice. Yes—change practice—especially the way we in this country have prescribed ezetimibe.”

Lead author of the ENHANCE study, John J.P. Kastelein, MD, who also spoke on Sunday, suggested three reasons for no increase in CIMT: ezetimibe could have no vascular benefit despite the observed reduction in LDL cholesterol level; there was a faulty measurement technique; or the study population had too low a risk.

The last reason holds some credence as the study population for ENHANCE had been on aggressive statin therapy for at least 10 years, giving the drug enough time to decrease atherosclerosis progression to an equilibrium that would essentially not change further in the short duration of ENHANCE.

Kastelein, from the department of vascular medicine at the Academic Medical Center, Amsterdam, the Netherlands, admits to such a possibility, as do B. Greg Brown, MD, from the University of Washington School of Medicine, Seattle and Allen J. Taylor, MD, the Uniformed Services University of the Health Sciences, Bethesda, Md., in an accompanying commentary to the published study (NEJM 2008;358[14] 1504-1507).

Krumholz said that critics may opine the reasons for these findings, “but the most likely explanation we keep coming back to is that in this study the compound did not work.”

He said that this study provides “no new evidence to support the use of this drug” and that it “moves us to more uncertainty about the benefit of this drug.”

Krumholz reminded the audience that ezetimibe is a new drug with novel mechanisms—first in class, and that there are no outcomes studies for it. But if the effect of lowering LDL was enough to gain approval from the FDA, isn’t that standard enough for practitioners? No, it is not, he said.

The panel provided several examples to illustrate its point. First, it is known that hormone replacement therapy reduces LDL, but it is not associated with better cardiovascular outcomes. Second, when Pfizer combined atorvastatin (Lipitor) with torceptrapib, LDL was remarkably lowered, but outcomes were worse for the combination arm compared to the atorvastatin alone group (that study was halted).

Krumholz blamed the rush to prescribe Vytorin on the drug’s aggressive marketing campaign. Within four years of its introduction, 15 percent of all prescriptions included ezetimibe. In Canada, which had no such marketing campaign, the number falls to 3 percent.

What is known about the effects of Vytorin on people’s health? It is possible that when the outcomes studies for Vytorin are completed in 2012 they will show the drug to be an effective intervention to reduce cardiovascular risk. “The ENHANCE results make that less likely, but it’s not impossible,” Krumholz said.

It could be that ezetimibe is just “an expensive placebo and its principle harm is that it drains precious resources from our health care system.” The ENHANCE study makes this a more likely possibility, he added.

Or the drug could be harmful, even though it is well tolerated and the liver enzymes are good. “We can’t say for sure if there is an increase risk for death, MI or another important health problem,” Krumholz said.

Krumholz concluded that it’s unfortunate that the industry will not know the answers until 2012, when the outcomes studies are concluded.

“It’s not right we get this far down the line with so much uncertainty,” he said.

The panel recommended prescribing statins, especially those with favorable outcomes data. “Let’s stay with the evidence.”

Merck and Schering-Plough funded the ENHANCE study.

Regarding the panel discussion, Schering-Plough CEO Fred Hassan said the scientific process was hijacked because there were no opposing viewpoints and no questions taken from the audience, according to an April 2 article in Bloomberg. He also said that Krumholz was biased because he once served as a consultant to lawyers suing Merck.

Krumholz said his involvement with Merck’s painkiller Vioxx had been disclosed before and that it did not matter because the panel’s statement was a consensus, according to Bloomberg.

In other controversy surrounding Vytorin, Congress in January had questioned whether monetary contributions from Merck/Schering-Plough influenced the ACC’s soft response to the initial release of the ENHANCE results. That probe by Congress is part of broader committee investigation into the research and marketing of Vytorin, according to the New York Times.

Merck and Schering-Plough have come under fire for taking roughly 21 months to release the ENHANCE study results after its April 2006 completion, with critics suggesting they were delayed because the companies knew they would be negative and wanted to protect the sales growth for Vytorin and Zetia.