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Experts discuss ENHANCE trial data, implications for clinical practice

Wednesday, April 02 2008 | Comments
Evidence Grade 0 What's This?
By Courtneay Parsons

The addition of ezetimibe to simvastatin significantly reduces LDL cholesterol levels relative to simvastatin alone, but the combination does not offer additional benefit with respect to slowing the progression of atherosclerosis, 24-month ENHANCE trial data suggest. As a result of these findings, the trial investigators and other experts are encouraging a return to therapies that are known to be effective, such as statins, fibrates, and resins, at least until data from clinical outcomes studies with ezetimibe become available.

The trial included individuals with heterozygous familial hypercholesterolemia who had LDL cholesterol levels >=210 mg/dL after a 6-week placebo run-in period. The participants were randomized to receive simvastatin 80 mg plus placebo (n=363) or simvastatin 80 mg plus ezetimibe 10 mg (n=357). The primary outcome measure was the change in mean carotid artery intima-media thickness (cIMT) after 24 months of treatment. The participants underwent B-mode ultrasonography at baseline (2 scans), during treatment (3 scans), and at endpoint (2 scans).

During 2 years of treatment, LDL cholesterol dropped from 318 mg/dL to 193 mg/dL in the simvastatin-only group and from 319 mg/dL to 141 mg/dL in the combination-therapy group, yielding a relative reduction of 16.5% with combination therapy (P<.01). Similarly significant reductions were also observed for high-sensitivity C-reactive protein (hs-CRP) and apolipoprotein B.

However, there were no significant between-group differences in the primary outcome measure or any of the secondary outcome measures. The mean change in cIMT was 0.0058 mm in the simvastatin-only group, compared with 0.0111 mm in the combination-therapy group (P=.29). In addition, there were no significant between-group differences in subgroup analyses, including an analysis of patients who were statin-naive at baseline and an analysis that stratified patients by baseline artery thickness. There were also no significant differences observed in longitudinal analyses that evaluated changes in the outcome measures with time.

There were no safety issues observed with combination therapy. Both treatments were well-tolerated and had safety profiles consistent with their product labeling.

Dr. John Kastelein, lead investigator of the ENHANCE trial, suggested 3 possible explanations for the apparent lack of additional benefit with combination therapy.

First, he proposed that the measurement technique used in the study might not be sufficient to accurately reflect changes in atherosclerotic burden. However, given the completeness of the data (88% for the primary endpoint), the high intraclass correlation coefficients (0.92 at baseline and 0.93 at endpoint), and the small standard deviations (0.053 mm and 0.056 mm, respectively), he suggested that this is a highly unlikely explanation for the findings.

Second, Dr. Kastelein suggested that the ENHANCE trial population might have been at too low a risk for the study to detect a differential response to the 2 treatments. The rate of pretreatment with statin therapy in the ENHANCE trial was high (approximately 81% of patients), which might have made it difficult to detect an effect of additional therapy.

Third, Dr. Kastelein proposed that the lack of added benefit with ezetimibe might be because the drug has no effect on the change in IMT, in spite of its effects on LDL cholesterol and hs-CRP. There is some evidence to suggest that the effects of statins are not restricted to LDL cholesterol, he explained, and these lipid-independent effects could play an important role in producing a vascular benefit.

Speaking on behalf of an expert panel, Dr. Harlan Krumholz, a professor of medicine at Yale University School of Medicine and director of the Yale-New Haven Hospital Center for Outcomes Research and Evaluation, proposed that the third reason is the most likely explanation for the trial findings.

"This is just one study of ezetimibe and one that employed measurements of arteries and not clinical endpoints, but this study provides no new evidence to support use of this drug and it moves us to more uncertainty about the benefit of this drug," he commented.

Dr. Krumholz added that these findings are likely to have a substantial impact on the treatment of hypercholesterolemia, particularly in the United States, where prescriptions for ezetimibe and the ezetimibe-simvastatin combination have increased dramatically since the approval of ezetimibe in 2002.

He stressed that lowering LDL cholesterol remains an important goal of treatment for these patients. However, he added that the ENHANCE trial data indicate that simply lowering LDL cholesterol might not be sufficient; the pharmacologic means by which it is lowered might be important as well. He added that other drugs, such as hormone replacement therapies, have been shown to lower LDL cholesterol even though they do not improve cardiovascular outcomes.

Clinical outcomes trials with ezetimibe are still under way, and these studies might still show a benefit with the drug, Dr. Krumholz acknowledged. However, until these data are released, he and the other panel members urged physicians to return to statins and other therapies, such as fibrates and resins, which have been shown to be effective.

"For those who have failed these therapies, and this should be a relatively small group, the question is whether we should use ezetimibe," he added. "This will likely remain unresolved until the outcomes studies are available. Until then, we will not know the net effect. We know that there's a reduction of LDL [cholesterol]; we don't know what it translates into. It's an unfortunate predicament that we find ourselves in with these patients."

He added that the ENHANCE trial underscores the need for clinical outcomes studies to be conducted prior to a drug's approval rather than after it has been adopted as a standard treatment option.

"It's not right that we're this far down the line with so much uncertainty," Dr. Krumholz concluded. "We need to understand the effect of new drugs on people, and relying on a drug's effect on a single lab test may not tell the whole story. We have learned this lesson before. It seems like we may need to learn it again."

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Comments

Steve NeSmith writes:
Very interesting article!


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