Controversies Surround Heart Drug Study

The long-anticipated release of results from a clinical trial designed to evaluate a combination therapy intended to prevent progression of atherosclerosis—results which, in fact, found no beneficial effect—has riled the cardiology community, led to lawsuit filings, and seized the attention of government regulators.

The trial pitted Vytorin, a combination of ezetimibe (Zetia, Schering-Plough Corporation, Kenilworth, NJ) and simvastatin (Zocor, Merck & Co Inc, Whitehouse Station, NJ), against simvastatin alone in patients with heterozygous familial hypercholesterolemia. After 2 years, the investigators found no statistically significant difference between treatment groups on the primary end point of mean change in the carotid intima-media thickness—a surrogate marker of atherosclerosis. An analysis of a secondary end point, the reduction of low-density lipoprotein cholesterol (LDL-C), found that ezetimibe/simvastatin achieved a significantly greater decrease in LDL-C compared with simvastatin alone.

Called ENHANCE (Effect of Ezetimibe Plus Simvastatin Versus Simvastatin Alone on Atherosclerosis in the Carotid Artery), the trial was sponsored by a joint venture with Merck and Schering-Plough Pharmaceuticals. This multinational double-blind trial randomly assigned 720 patients to receive ezetimibe/simvastatin or simvastatin alone.

These findings, released on January 14, came amid growing controversy about the nearly 2-year delay in reporting the results after the trial's conclusion in April 2006. Some physicians questioned whether the medication should now be in use; others in the cardiology community urged caution in overinterpreting the results, noting that larger trials due for completion in a few years should better answer efficacy and safety questions. Regardless of the medical debate, this delay, during which sales of Vytorin generated billions of dollars in annual sales, has raised eyebrows among some congressional leaders who began an investigation in December of last year.

Also dogging the study were reports of actions by the trial sponsors that prompted the House Committee on Energy and Commerce to investigate whether the companies attempted to manipulate the findings. According to a statement released on January 14 by Committee Chairman John D. Dingell (D, Mich) and Rep Bart Stupak (D, Mich), chairman of the Subcommittee on Oversight and Investigations, “Merck and Schering-Plough attempted to change the study end points, and thus the study results, prior to the public release of the results,” they noted. “According to the companies, this change was recommended by an unnamed advisory panel,” a group that excluded the trial's primary investigator, John Kastelein, MD, PhD, of the Academic Medical Center in Amsterdam, the Netherlands.

In addition, the companies failed to release findings from small safety studies involving ezetimibe only and delayed in registering the ENHANCE trial, listing the study in the National Institutes of Health's online trial registry (ClinicalTrials.gov [http://www.clinicaltrials.gov]) only after the study was concluded rather than prior to enrollment of patients. The International Committee of Medical Journal Editors requires that “all clinical trials be entered in a public registry before the onset of patient enrollment, as a condition of consideration for publication.”

Merck/Schering-Plough dismissed these concerns, saying the study's release was delayed due to the unexpected time it took to interpret about 40 000 ultrasound images used to measure intima-media thickness. The companies added that the expert panel was created to expedite analysis of the data. The panel suggested measuring just 1 point of the carotid artery instead of the 3 stated in the initial study design; the recommendation was not adopted. They also said the delay in registering the trial with ClinicalTrials.gov was just an oversight, and that they did not think the ezetimibe safety studies were scientifically important enough for publication.

But the companies' dismissal of criticisms of the trial has not mollified critics of how the joint venture handled ENHANCE.

“It was of great concern that the study ended 2 years ago, and it's only now that the information is being heard,” said Jerry Avorn, MD, professor of medicine, Harvard Medical School, and chief of the Division of Pharmacoepidemiology and Pharmacoeconomics at Brigham and Women's Hospital in Boston. “These are companies that do trials all the time, and it's hard to accept the fact that they said the analysis was more complicated than they expected, which resulted in the delay.”

Dingell and Stupak are also bothered by the ENHANCE timeline. The representatives began an investigation December 11 into the delay of the study's results. And on January 16, following the release of ENHANCE data, they sent a pointed letter to the heads of Merck and Schering-Plough. “Given the frequency of Vytorin advertisements, it concerns us that a study showing that Vytorin provides no increased benefit was not issued for nearly 2 years while direct-to-consumer advertisements were carried on the airwaves,” they noted in the letter. “This situation raised concerns that the drug companies and their advertising agencies profited at the significant expense of patients' health.”

The timing issue has also prompted the filing of numerous class-action lawsuits hoping to recapture billions of dollars spent on ezetimibe/simvastatin and probes by some states' attorneys general into various aspects surrounding the release of the ENHANCE data.

Proponents of ezetimibe/simvastatin were quick to defend the combination therapy, saying the trial was a small imaging study of a special patient group affecting about 0.2% of the population. However, Steven Nissen, MD, chairman of the Department of Cardiovascular Medicine at the Cleveland Clinic Foundation, is concerned about the medical implications. Nissen suggested that physicians stop prescribing ezetimibe/simvastatin and treat high LDL-C levels through intensive statin therapy, adding ezetimibe for the most resistant cases.

“The ENHANCE trial was well designed and executed and did not show benefit, with trends going in the wrong direction,” Nissen said, referring to the fact that intima-media thickness was slightly greater in the ezetimibe/simvastatin group compared with the group receiving simvastatin alone, although the difference did not meet statistical significance. “At this point it remains uncertain, 6 years after the drug was initially marketed, whether ezetimibe really accomplishes what it should.” Unlike statins, which lower cholesterol by blocking an enzyme used in its synthesis, ezetimibe works by preventing the absorption of cholesterol in the intestine. But while trials have shown it lowers cholesterol, no studies published to date have demonstrated that it actually reduces the risk of myocardial infarction or stroke.

However, the American Heart Association (AHA) and the American College of Cardiology (ACC) urged cautious interpretation of ENHANCE results. In separate statements issued a day after release of the trial data, both organizations said the ENHANCE findings deserved serious thought and follow-up and that physicians and patients should not make prescription decisions based just on this study that focused on surrogate end points (such as carotid intima-media thickness and LDL-C levels) instead of clinical outcomes (such as cardiovascular events and mortality).

The AHA and ACC also said 3 major clinical trials involving about 20 000 participants are examining ezetimibe/simvastatin's effect on cardiovascular and all-cause mortality and stroke and should provide more definitive evidence for the efficacy of the combination therapy. Results from these studies—IMPROVE-IT (Examining Outcomes in Subjects With Acute Coronary Syndrome: Vytorin [Ezetimibe/Simvastatin] vs Simvastatin), SHARP (Study of Heart and Renal Protection), and SEAS (Simvastatin and Ezetimibe in Aortic Stenosis)—should be known around 2011.

Daniel W. Jones, MD, AHA president, added that current guidelines state that elevated LDL-C is the primary target of cholesterol-lowering therapy and that LDL-C–lowering therapy reduces the risk for cardiovascular disease. “This particular study doesn't change the application of the guidelines,” said Jones, who is also vice chancellor for health affairs and dean of the School of Medicine at the University of Mississippi Medical Center in Jackson.

But Nissen disagrees. “If ENHANCE had shown benefits for Vytorin, it would have been trumpeted as a landmark trial,” Nissen said, adding that the patient population in the trial, those with heterozygous familial hypercholesterolemia, was specifically chosen because maximum benefit would be expected in such patients.

The firestorm of criticism surrounding the ENHANCE results prompted Merck/Schering Plough to issue a press release January 25 that defended its actions. “While the ENHANCE trial was time-consuming and took longer than originally anticipated to complete, our companies acted with integrity and good faith in connection with the trial,” said Thomas Koestler, PhD, president, Schering-Plough Research Institute.

Yet another issue the controversy has thrust into the spotlight is the use of surrogate end points in clinical trials to gain approval for new drugs. Although the US Food and Drug Administration (FDA) can call for postmarketing studies to determine if a medication approved on the basis of a surrogate end point ultimately shows a clinical benefit (or even potential harm), years may elapse before such evidence is available. At a January 25 press conference announcing a review of ezetimibe/simvastatin based on the ENHANCE preliminary results, FDA officials defended approval of the drug on the basis of its ability to lower LDL-C without evidence of improving cardiovascular outcomes, noting that lowering LDL-C is a cornerstone in current therapy approval.

Still, Avorn said the ENHANCE study has planted a seed of doubt surrounding surrogate end points.