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ENHANCE panel advises cardiologists to use statins, scale back ezetimibe use
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CHICAGO — The American College of Cardiology panel discussion of the ENHANCE data caused a flurry of media attention and sparked controversy about the late release of the trial results.
“This is a negative trial that should change practice. Yes, change practice, especially given the way that we … have been prescribing ezetimibe,” Harlan Krumholz, MD, SM, professor of medicine and epidemiology and public health at Yale, said during the panel discussion at the ACC 57th Annual Scientific Sessions held here.
“The consensus of the ACC panel was that physicians should try to maximize use of statins and reserve ezetimibe for patients who respond inadequately to statins or cannot tolerate statins. I concur with the panel’s recommendations,” Steve Nissen, MD, chairman of the Department of Cardiovascular Medicine at the Cleveland Clinic Foundation, told Cardiology Today.
In the Effect of Combination Ezetimibe and High-Dose Simvastatin vs. Simvastatin Alone on Atherosclerotic Process in Patients with Heterozygous Familial Hypercholesterolemia (ENHANCE) trial, John J.P. Kastelein, MD, PhD, professor of medicine at the University of Amsterdam, and colleagues randomly assigned 720 patients aged 30 to 75 years to 80 mg simvastatin (Zocor, Schering-Plough, Merck; n=363) or 10 mg ezetimibe (Zetia, Merck) plus 80 mg simvastatin (n=357; Vytorin, Schering-Plough, Merck) to determine the combination’s effect on the progression of atherosclerosis in patients with heterozygous familial hypercholesterolemia. Kastelein presented the complete data of the trial, which was followed by the panel discussion.
Panel discusses ENHANCE
“This trial is not a referendum on the established health benefits of LDL cholesterol lowering, especially in our high-risk patients and especially with statin medications. This point, we believe strongly, needs to be clarified and reinforced with those of our patients who may have become confused by some of the recent coverage of this trial,” Patrick T. O’Gara, MD, vice chairman of clinical affairs in the department of medicine at Brigham and Women’s Hospital, said during the discussion.
“When outcome studies are finally finished, we may recognize that this drug is, in fact, an effective intervention for our patients, that it reduces cardiovascular risk. The ENHANCE results make that less likely, but it is not impossible,” Krumholz said during the discussion.
Other concerns
Senator Charles Grassley of Iowa, a ranking member of the U.S. Senate Committee on Finance, issued letters on March 31, 2008 to Schering-Plough and Merck, as well as the ACC, questioning money spent to promote ezetimibe-simvastatin, and contributions the companies made to the ACC.
“In keeping with our mission, the ACC strongly believes that meticulous attention must be given to ensure appropriate policies and mechanisms are in place to ensure that development of educational content and scientific policy positions are never compromised or influenced by industry relationships,” ACC Chief Executive Officer Jack Lewin, MD, replied in a letter response.
Lewin said the ACC recognized the concerns surrounding the delayed release of the ENHANCE data, and the ACC was “pleased to be able to provide a scientific venue to discuss the complete data from this study, and a forum to discuss the implications of the study on behalf of our members and their patients.”
Complete data presented
In addition to the panel discussion, Kastelein presented the complete ENHANCE data.
The researchers screened 1,180 patients with familial hypercholesterolemia between August 2002 and April 2004 to compare the change in carotid-artery intima–media thickness between the two groups.
Compared with the simvastatin monotherapy group, patients in the combined-therapy group had higher BMI (P=.047), a higher rate of hypertension (P=.09) and a lower rate of MI (P=.06). In each group, about 80% of patients previously received statins, according to the study.
In the simvastatin monotherapy group, the researchers reported a 0.0058±0.0037 mm change in carotid artery intima–media thickness, compared with 0.0111±0.0038 mm in the combination therapy group (P=.29). As predicted, LDL levels at the completion of the study were 4.98±1.56 mmol/L in the simvastatin group and 3.65±1.36 mmol/L in the combination therapy group (a between-group difference of 16.5%; P<0.01).
Though the combination therapy caused a decrease in LDL levels, the primary outcome measure — the change in mean carotid artery intima-media thickness — was not met. The researchers offered three possible explanations for the absence of a reduction in IMT:
- Ezetimibe has no vascular benefit, despite the reduction in LDL.
- Changes in atherosclerosis were not accurately revealed by the measurement technique.
- The population studied had too low a risk to detect any response from either intervention.
The researchers concluded that it is unknown why the combination did not have an effect on intima-media thickness; further studies are needed.
“I believe that future drug approvals based upon ‘surrogate endpoints’ will require clinical outcome trials to be performed promptly, perhaps started even before drug approval. If that had happened with ezetimibe, we would have the answers by now,” Nissen, who is a member of the Noninvasive Imaging section of the Cardiology Today Editorial Board, said in an interview.
“For clinicians who may have employed this medication before exhausting options with statins, the strongest recommendation we can make on this panel is: Turn back to statins, especially those with favorable outcomes data. These are remarkable drugs, we know they lower risks and we need to go back to what works; let’s stay with the evidence,” Krumholz concluded.
The study results of the study were also published in an online-first edition of the New England Journal of Medicine. – by Stacey L. Adams
Editor’s note: I agree that ezetimibe should be used only in patients who can’t get to their LDL and non-HDL goals on a potent statin alone or in patients who cannot tolerate a high enough dose of a statin because of side effects. However, it is likely that the reason the ENHANCE trial did not show a benefit of ezetimibe is that 80% of the patients had been on statin therapy and that 50% had been on agressive lipid lowering therapy for many years. Thus, there was probably little lipid laden material left to be resorbed.
Unfortunately, a few prominent cardiologists kept referring to a “doubling of plaque growth” that was seen in the study. We know that there was only .005 mm nonsignificant difference between the groups. The results were certainly not “shocking,” as one of my colleagues was fond of saying. What is needed in our discussions with the media is more equanimity and more equipoise.
Personally, I think that MRI of the carotid arteries will prove to be much more reliable than IVUS or carotid IMT in assessing future drug development. The recent ORION trial showed that rosuvastatin did not change carotid plaque volume or size, but it did lower the lipid rich necrotic core by 40%.
IVUS trials are limited by the fact that 20-25% of patients do not return for a follow-up study. In ENHANCE, 20% of the measurements needed to be discarded. We do not have the inherent bias with MRI.
– Roger S. Blumenthal
Cardiology Today Editorial Board member
For more information:
- Kastelein J. The ENHANCE study: What do we know? and panel discussion. Special topics 404. Presented at: American College of Cardiology 57th Annual Scientific Sessions; March 29-April 1, 2008; Chicago.
- Kastelein J, Akdim F, Stroes E, et al. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med. 2008;358:1431-1443.