Whitehouse Station/Kenilworth NJ - The results of the long-awaited and controversial ENHANCE trial, finally announced today, have shown no benefit of the combination of ezetimibe (Zetia, Merck/Schering-Plough Pharmaceuticals) and simvastatin (sold together as Vytorin, Merck/Schering-Plough Pharmaceuticals) over simvastatin alone.

The trial, which has been dogged with controversy in recent months, was conducted in 720 patients with heterozygous familial hypercholesterolemia and showed no significant difference in the primary end point—mean change in the intima media thickness (IMT) measured at three sites in the carotid arteries—between patients treated with ezetimibe/simvastatin 10/80 mg vs patients treated with simvastatin 80 mg alone over a two-year period.

At baseline, the mean carotid IMT measurement for the ezetimibe/simvastatin group was 0.68 mm and for the simvastatin-80-mg group was 0.69 mm. There was also no statistically significant difference between the treatment groups for each of the components of the primary end point, including the common carotid artery. Key secondary imaging end points showed no statistical difference between treatment groups.

These results will be a huge disappointment to Merck and Schering-Plough. Ezetimibe, which has a complementary action to the statins, preventing the intestinal absorption of cholesterol and generally adding an extra 20% LDL reduction to that seen with statins alone, is a relative newcomer to the cholesterol market but is already generating blockbuster sales, said to be in the region of $5 billion. That is despite the fact there have been no outcome data available on the drug.

The ENHANCE trial is the first major study to be conducted with ezetimibe, which is why the results were so eagerly anticipated. Although it is not a clinical-outcome study, carotid ultrasound studies monitoring the effects of drug therapy on atherosclerotic plaque are seen as reliable surrogates and normally predict whether a drug will be effective in lowering cardiac events. The results were originally expected to be reported about a year ago, and this had led to much speculation in recent months that they were being delayed as they were negative, although this was denied by the companies and the lead investigator.

Further results from the ENHANCE trial show that the overall incidence rates of treatment-related adverse events, serious adverse events, or adverse events leading to discontinuation were generally similar between treatment groups. There were no cases of rhabdomyolysis. Both medicines were generally well tolerated.

As expected, ezetimibe was associated with a larger reduction in LDL cholesterol.

And there were no differences in cardiovascular events between the two groups in the trial, which was not powered to assess cardiovascular clinical-event outcomes.

There were no noncardiovascular deaths or incidents of resuscitated cardiac arrests in the ENHANCE trial.

Merck/Schering-Plough are stressing that this was a surrogate-end-point trial, and they are currently conducting three large outcomes trials with ezetimibe/simvastatin that involve more than 20 000 high-risk patients, including the more-than-10 000-patient IMPROVE-IT trial. No incremental benefit of ezetimibe/simvastatin on cardiovascular morbidity and mortality over and above that demonstrated for simvastatin has been established, they note.

The ENHANCE trial used digitized single-frame ultrasound technology for imaging purposes. There were 357 patients randomized to ezetimibe/simvastatin and 363 to simvastatin. The study collected more than 30 000 carotid artery and 10 000 femoral artery images from these patients. Single-frame ultrasound images were analyzed from the right and left carotid arteries at three sites (the common carotid, the internal carotid, and the carotid bulb) and at numerous time points (baseline and six, 12, 18, and 24 months). Images from the right and left common femoral arteries were analyzed at these same time points as well.

Following this announcement today, two physicians interested in this field have taken very different views of the results.

Dr Steven Nissen (Cleveland Clinic, OH) commented to heartwire that the ENHANCE results were a big surprise and a big disappointment. "The data show no benefit for ezetimibe on top of simvastatin. In fact, the data on both the rate of progression of atherosclerosis and cardiovascular events are trending in the wrong direction. This is a pretty clear failure. Physicians should now stop using ezetimibe or Vytorin except as a last resort."

But Dr Robert Harrington (Duke Clinical Research Institute, Durham, NC), who is involved in one of the large clinical-outcome trials under way with the drug, does not believe the ENHANCE study should provoke such a strong reaction. "Dr Nissen's suggestion about a moratorium on ezetimibe is rather alarmist, given that this was just an imaging study, and an imaging study should not change clinical practice. So for me, whatever way it went, I would not have been blown away by results from this trial," he told heartwire.

But Nissen was adamant about the importance of the ENHANCE results. "We need to see some evidence of benefit before we use this drug. And this study shows clearly that the drug doesn't work. This is despite a large LDL reduction in a population who should have shown a large benefit, as FH is driven by LDL. This result is surprising, because until now lowering LDL has been a very reliable indicator of benefit in both slowing atherosclerosis progression and reducing cardiovascular events. But this mechanism for lowering LDL has never been tested before. It may be that ezetimibe is doing something else that is counteracting the benefit of the LDL lowering. We will not know for sure until we see the outcome studies. They should definitely continue. But doctors should stop using ezetimibe until these results are in."

Nissen, who conducts imaging studies using intravascular ultrasound (IVUS), says that carotid IMT trials such as ENHANCE are normally very reliable at predicting cardiovascular outcomes. "The FDA gives label claims for CIMT studies. In fact, they recently awarded a claim to rosuvastatin based upon an IMT study," he said. He added that John Kastelein, the lead investigator of ENHANCE, is one of the world's experts in this type of study.

Kastelein himself told heartwire he "could not discuss ENHANCE until it is published in a peer-reviewed journal," and, rather than referring journalists to Kastelein for additional comment, which would be the normal procedure, Schering-Plough has been directing the media to physicians conducting the large clinical-outcome trials with the drug.

Harrington is involved in the IMPROVE-IT study, which is comparing simvastatin 40 mg plus ezetimibe 10 mg with simvastatin 40 mg alone in patients with a recent ACS event. The trial has recruited about 10 000 patients so far and will continue for at least two more years before results are available.

Harrington: "Not much has changed"

Harrington does not believe that major clinical decisions should be made on the basis of ENHANCE, as it is not a clinical-outcome study. "ENHANCE is just a biomarker study. Whatever the results were—even if they had been positive—I would still have said we have to wait for the clinical-outcome trials before making our minds up about this drug. The imaging guys all say these imaging studies are predictive of clinical events, but they would say that, wouldn't they? To prove that a biomarker is a true surrogate is actually very difficult, and I do not believe that IMT or IVUS meet the criteria for surrogate markers in this setting," he said.

The imaging guys all say these imaging studies are predictive of clinical events, but they would say that, wouldn't they?

Harrington added: "So I would say not much has changed. If you liked ezetimibe before ENHANCE because it lowers LDL, I would think you would carry on using it. But if you were of the opinion that you would rather wait for clinical-outcome results before prescribing it, then there is nothing in this trial to change your mind about that."

Harrington also pointed out that the ENHANCE trial included a very different patient population from those who would typically take the drug. "ENHANCE included a group of 700 FH patients at risk of atherosclerosis because of high lipid levels and a focus on one particular segment of their vasculature. This is biologically interesting but not definitive in terms of what will happen to clinical events in a patient population more representative of clinical practice. To me, these results just raise my interest even more in the clinical-outcome studies. They are now going to be even more important."

ENHANCE has been dogged with controversy for several months now over delayed reporting of results and discussions on possibly changing the primary end point. At one point, an outside "expert committee" was brought in to advise on possible changes to the trial, which were in the end never made. And the trial attracted the attention of a US government House committee, which wrote to Merck and Schering-Plough about "withholding of clinical trial data that may significantly affect the medical management of hypercholesterolemia."

And the way in which the results are being reported is also raising eyebrows. Harrington commented: "More interesting from my point of view is that all the data from this study seem to have been reported in a press release. The press seems to have pushed the sponsor to really yank the whole scientific process away from the investigators and put all the data out there. That seems to have violated the normal scientific process, whereby the detailed results are usually held back to be reported at a scientific meeting."

The ENHANCE study has been submitted as an abstract to be presented at the upcoming American College of Cardiology (ACC) meeting in March. But Harrington said he did not think the ACC would be pleased that so many of the results had already been reported. "One could imagine that there could be quite a lively discussion about this whole process at the ACC," he said. He also said it was "strange" that Kastelein was not commenting on the study.

Asked by heartwire about these issues, Schering-Plough said: "Prof Kastelein is looking forward to presenting the results of ENHANCE at the ACC meeting in March," and "given the growing level of scientific interest in the ENHANCE trial, we determined it was best to move forward and communicate these results at this time in order to end speculation about the results of the study."