ENHANCE results yield disappointment for ezetimibe

January 14, 2008   Sue Hughes

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.

ENHANCE: Primary end point

End point
Ezetimibe plus simvastatin
Simvastatin alone
p

Change in mean carotid IMT after 2-y treatment (mm)
0.0111
0.0058
0.29

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.

Huge disappointment
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.

More details
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.

ENHANCE: Adverse events

Adverse events
Ezetimibe plus simvastatin, n (%)
Simvastatin alone, n (%)

Consecutive elevations of serum transaminases (>3 times the upper
limit of normal)
10/356 (2.8)
8/360 (2.2)

Elevated creatine phosphokinase (>10 times the upper limit of normal)
4/356 (1.1)
8/360 (2.2)

Creatine phosphokinase >10 times the upper limit of normal associated
with muscle symptoms
2/356 (0.6)
1/360 (0.3)

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

ENHANCE: LDL values at baseline and % reduction after treatment

Ezetimibe plus simvastatin
Simvastatin alone
p

Baseline LDL (mg/dL)
319
318
NS

Reduction after 2-y treatment (%)
58
41
<0.01

Cardiovascular events similar
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.

ENHANCE: CV events

Event
Ezetimibe plus simvastatin, n
Simvastatin alone, n

CV death
2/357
1/363

Nonfatal MI
3/357
2/263

Nonfatal stroke
1/357
1/363

Revascularization
6/357
5/363

To download tables as slides, click on slide logo below

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

Larger outcome trials under way
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.

What now for ezetimibe?
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.

Nissen: "The drug doesn't work"
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, who 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."

Study racked with controversy right up to the end
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."