ENHANCE Results Yield Disappointment for Ezetimibe

Sue Hughes

January 14, 2008

January 14, 2008 (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

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.

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