Is ezetimibe/simvastatin no better than simvastatin alone? Lessons learned and clinical implications

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Further supporting this view, in a previous trial by Dr. Kastelein’s group in patients with familial hypercholesterolemia, 34 giving simvastatin 80 mg for 2 years decreased the intima-medial thickness by .081 mm ( P < .001), compared with 0.0058 mm in ENHANCE (a 14-fold difference). In the previous trial, the baseline measurement was 1.07 mm (vs 0.68 mm in ENHANCE), and the extent of the change was significantly associated with the baseline measurement (r = .53, P < .001) but not with the change in LDL-C levels.

This is powerful evidence that, in two similar studies that used the same methodology and the same drug, the thinner arteries in the ENHANCE trial are by far the most likely explanation for the lack of change with the addition of ezetimibe to high-dose simvastatin. The METEOR trial enrolled only patients who had never received statins and whose carotid intima-media was thicker than 1.2 mm. In retrospect, a similar design would have been preferable for ENHANCE. 35


For Merck/Schering-Plough, missed opportunities

Although Dr. Krumholz (the spokesman for the ACC panel discussion) and I disagree on the clinical implications of the ENHANCE trial, we do agree on an important point. Dr. Krumholz posed the question that if the LDL-C-lowering hypothesis was already proven for ezetimibe, why was the ENHANCE trial conducted? After 6 years on the market, the efficacy of ezetimibe on cardiovascular outcomes should already have been established. It should not take this long to determine the clinical outcome benefit for a drug.

Merck/Schering-Plough’s outcome program for ezetimibe was inadequately designed to demonstrate the clinical value of this novel compound. Rather than assuming the LDL-C-lowering hypothesis was already established, they conducted another “lower-is-better” trial with the carotid intima-media thickness as the end point, and they succeeded only in raising doubt about the benefits of ezetimibe rather than showing that dual therapy is at least equivalent to high-dose statin therapy.

A preferable approach would have been to compare the effects of a statin in low doses plus ezetimibe vs high-dose statin monotherapy on either surrogate or hard outcomes. If the low-dose statin/ezetimibe combination, which should lower the LDL-C level as much as high-dose statin monotherapy, could provide similar or better outcomes with fewer side effects, this trial would change our practice.

One had hoped that dual therapy, by reducing both intestinal cholesterol absorption and hepatic synthesis of cholesterol, would improve outcomes by modifying postprandial chylomicron composition or by reducing plant sterol absorption. 36 Unfortunately, other outcome trials of ezetimibe/simvastatin will not provide an answer regarding the potential advantages of dual therapy. The SEAS study is comparing the number of clinical events in patients with aortic stenosis who receive ezetimibe/simvastatin or placebo; SHARP is being conducted in patients with chronic kidney disease. Although both groups of patients have high rates of coronary events, these trials will not address whether adding ezetimibe provides additional benefits. In fact, if the results of these trials turn out neutral, as in ENHANCE, then ezetimibe will be blamed for potentially offsetting the benefits of simvastatin, and if the trials show a benefit, the simvastatin component of ezetimibe/simvastatin will be given the credit.

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