Commentary

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

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Although the six-site measurement appears to be good for predicting coronary events and evaluating therapies, the measurement in the common carotid arteries appears to be a more reliable surrogate end point for predicting both benefit and harm from antiatherogenic agents. However, trials of statins and other lipid-lowering therapies that assessed clinical events have shown that the reduction in risk associated with a given reduction in cholesterol is similar regardless of the mechanism by which cholesterol is lowered. 33 Therefore, the LDL-C level is far superior as a marker of clinical benefit.

Theory 3: Previous statin treatment affected the ENHANCE results

By far the most likely explanation for the neutral findings in ENHANCE is that the patients were so well treated before entry that it was impossible to detect a difference between the two treatment groups in carotid intima-media thickness at the end of the study. Eighty percent of the patients had received statins previously, and at baseline the mean intima-media thickness of the common carotid arteries was only 0.68 mm. 1 In contrast, most other trials required a thickness greater than 0.7 mm for entry.

The two main reasons for selecting a population with familial hypercholesterolemia were the assumptions that these participants would have a greater-than-average carotid intima-media thickness at baseline and that they would show an above-average progression rate, even on high-dose statin therapy. 4 Both of these assumptions were incorrect: the baseline thickness was normal and the progression rate was negligible in both groups.

Figure 1. Top, in the ASAP extension study, the carotid intima-media thickness did not decrease further after 2 years of treatment with high-dose atorvastatin. This may explain the lack of regression in the RADIANCE (middle) and ENHANCE trials (bottom), in which most patients had already been on long-term statin therapy.
The ENHANCE trial design was based on the smaller ASAP trial, 28,29 which found a significant reduction in progression of carotid intima-media thickness with atorvastatin (Lipitor) in high doses compared with simvastatin in lower doses. However, the ASAP patients had to have had a common carotid intima-media thickness greater than 0.7 mm to enter. A follow-up study after the initial treatment period 29 showed minimal subsequent progression (0.005 mm/year) with atorvastatin 80 mg/day ( Figure 1 ), suggesting that further lowering of LDL-C may have minimal impact on the progression of carotid intima-media thickness after a period of statin treatment. Since 80% of the ENHANCE patients were previously treated with statins, adding ezetimibe to high-dose simvastatin therapy may have been unlikely to affect the progression of carotid intima-media thickness.

Accordingly, the high prevalence of statin pretreatment and the near-normal carotid intima-media thickness at baseline may have prevented the 16.5% greater reduction in LDL-C due to ezetimibe from producing a difference in progression over 24 months of treatment. This conclusion is supported by the long-term follow-up results from ASAP, RADIANCE 1, and CAPTIVATE, all of which showed that in patients with familial hypercholesterolemia well treated with statins, progression of carotid intima-media thickness is negligible. 30,31

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