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Learning the Lessons of ENHANCE

How negative trial findings can — and should — change practice

With the release of the ENHANCE trial, public attention has focused once again on the clinical role of ezetimibe, the wisdom of approving drugs based on their effect on cholesterol, the impact of marketing, the ethical behavior of investigators and pharmaceutical companies, and the validity of the central dogma about lowering cholesterol.

In the U.S., ezetimibe was introduced in October 2002. It was the first in its class to be approved, and its approval was predicated on its ability to lower cholesterol. ENHANCE, initiated in August 2002 by Merck and Schering-Plough (the manufacturers of the study drugs), was intended to show that combination therapy with a statin plus ezetimibe has a favorable effect on the progression of atherosclerosis.

Attention to this trial escalated in the fall of 2007, when news reports questioned whether publication of the results from ENHANCE, which was completed in April 2006, was being delayed. Subsequent reports indicated that the sponsors were going to change the primary endpoint of the trial based on recommendations from an unidentified panel of experts. Ultimately, the contemplated change was not made, perhaps in response to unfavorable press and congressional scrutiny. In the Wall Street Journal (March 24, 2008), the principal investigator was quoted as saying he was relieved that the endpoint was not changed, raising questions about who was really in charge of the study. On January 14, 2008, in response to a congressional inquiry, Merck and Schering-Plough released some information about ENHANCE, prompting concerns about the efficacy of ezetimibe in slowing the progression of atherosclerosis.

On March 30, 2008, the formal analysis of ENHANCE was presented at the annual meeting of the American College of Cardiology, and the article, along with two editorials, was published in the New England Journal of Medicine. The study shows that, compared with simvastatin alone, simvastatin plus ezetimibe combined therapy effectively reduced LDL cholesterol and C-reactive protein levels in patients with familial hypercholesterolemia; but the improvements in LDL cholesterol and CRP were not accompanied by improvement in the primary endpoint of change in the mean carotid-artery intima–media thickness or in a secondary endpoint of change in the mean femoral-artery intima–media thickness. In fact, although the between-group differences in these endpoints were nonsignificant, they favored simvastatin alone. These surprising results have led experts to propose many possible explanations, but the most obvious possibility is that cholesterol lowering by ezetimibe does not retard the progression of atherosclerosis. There is much to learn from this study.

Clinical Implications

This study should change practice. Although not definitive, it increases our uncertainty about the clinical value of this novel drug. Without some evidence of improved outcomes associated with its use, ezetimibe should be relegated to a last option for patients who need medication for hypercholesterolemia, and, even in these cases, it is reasonable for clinicians and their patients to wait for further information before considering it. We simply do not have enough information to determine whether this drug effectively reduces risk (although ENHANCE lowers the likelihood of this), is an expensive placebo, or even causes harm. Although ezetimibe is widely assumed to be safe, there are no large randomized studies that allow us to appraise whether it increases cardiovascular risk. ENHANCE was not designed to assess safety. We just do not know.

Drug Approval

The study also raises questions about the use of cholesterol levels as the basis for regulatory approval of a drug with a novel mechanism. The recent experience with torcetrapib (Journal Watch Cardiology Nov 5 2007), the cholesterol ester transfer protein inhibitor that raised HDL levels and lowered LDL levels but inexplicably increased mortality in clinical trials, also emphasizes the need for outcomes studies. Drugs that improve laboratory results may not always confer the presumed clinical benefits on patients. Drugs that are approved strictly on the basis of improved markers should carry strong label wording about the limits of the evidence.

Marketing

Ezetimibe was heavily marketed to physicians and consumers in the U.S. More than $200 million was spent in 2007 on direct-to-consumer advertising for Vytorin, the combination of simvastatin and ezetimibe. Even without outcomes data, Vytorin’s sales increased dramatically. Promotional expenditures for ezetimibe per 100,000 persons were four times higher in the U.S. than in Canada, which does not allow direct-to-consumer advertising and requires more oversight of drug availability. Annual sales of the drug in the U.S. may have reached $5 billion at their peak. Had U.S. adoption rates of ezetimibe matched Canadian rates, the savings in healthcare costs would have been $1.5 to $2.0 billion. What exactly was achieved at that price is not clear.

Ethical Behavior

The ruckus about ENHANCE started with concerns about a delay in the trial’s publication and a proposed switching of endpoints. It is clear that the sponsors had a heavy influence on the trial’s conduct. Moreover, the trial did not have an independent steering committee or a data safety and monitoring board. What transpired behind closed doors is not yet known, but delay was certainly in the companies’ interest, and it is not clear whether publication of the study could have and should have been timelier than it was. We may soon learn more from the congressional investigation into this issue; nevertheless, these events raise questions about studies that are administered by companies with strong financial interests in their outcomes and that do not include mechanisms to insulate their conduct from such interests. With so much money — and so many lives — at stake, it is critical that the design of such studies ensure timely publication and public confidence in the results.

LDL Hypothesis

Finally, ENHANCE raises questions about the cholesterol hypothesis — that what matters in risk reduction is that you lower cholesterol, regardless of how. The popular media have now seized the issue. A cover story in Business Week attracted considerable attention. Clearly, it is not all about cholesterol. Drugs may have unanticipated effects that contravene the anticipated direct benefit of cholesterol reduction on atherosclerosis progression (mechanisms that may be at play in ezetimibe) or other effects that offset benefits in patient outcomes (as appear to be present in torcetrapib). In any case, these findings reveal that we still have much to learn about cholesterol, statins, and risk reduction. For clinicians, this study does not provide enough information to refute the large body of evidence supporting the use of many drugs, especially statins, for the treatment of hypercholesterolemia in patients who need them (remembering that diet and exercise should not be overlooked). Nor will this study change the fundamental recommendations about cholesterol reduction in guidelines for prevention of cardiovascular disease, although it may change some specific recommendations about drugs that have or do not have supporting evidence. The lesson here may be that the mechanism of improving lipids may make a difference in outcomes.

Bottom Line

These results will stimulate much discussion about their implications and about the conduct of the study that generated them. From a practical perspective, the findings push ezetimibe to the back of the line of cholesterol-lowering drugs, and perhaps, for some people, out of the line altogether. Personally, I believe that there is not enough evidence to support its use or to reassure me about its safety. I admit that I am influenced by our recent experience with torcetrapib and by my general predisposition to want evidence to support treatment decisions. At the very least, these findings indicate that, for patients who need medication, we should maximize statin treatment before we turn to another agent. The ENHANCE study also emphasizes the importance of clinical research and the need for more information about the effects of our treatment strategies on patients, not just on their lab values. In ezetimibe’s case, we will not have that information for several years. In the meantime, a strong negative finding from this trial of the surrogate endpoint of arterial thickness should be enough to dampen our enthusiasm for a heavily marketed drug.

Harlan M. Krumholz, MD, SM

Published in Journal Watch Cardiology March 30, 2008

Reader Remarks:

Review and add to remarks on this article

• Lessons from ENHANCE
  Edward Jardini MD, Templeton, CA, 31 Dec 2009 12:00 PM EST
  Bravo, Dr. Krumholz. You have raised excellent questions about the influence of comercial interests on clinical trials and community practice.... [more]

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