ENHANCE Trial Data Release: NLA Statement to Members

The results of the Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) trial were recently published in the New England Journal of Medicine¹ and also publicly presented at the annual American College of Cardiology (ACC) meeting on March 30. The National Lipid Association (NLA) offers the following opinion and advice to its membership with respect to this trial.*

What clinicians should consider
The NLA stresses the importance of getting patients to low-density lipoprotein cholesterol (LDL-C) treatment targets as identified in the National Cholesterol Education Program, Adult Treatment Panel III (NCEP ATP III) guidelines.^2,3 Lowered levels of LDL-C are associated with corresponding reductions in cardiovascular disease (CVD) risk, as has been demonstrated in studies of both primary and secondary prevention. Nothing in this study has changed our position about the necessity for lipid lowering or the need to treat patients to established NCEP goals.

Therefore, we emphasize the following for patients with dyslipidemia:

• Intensive reduction of LDL-C and non-high-density lipoprotein cholesterol (HDL-C) to ATP III-recommended guidelines.
• Emphasis on therapeutic lifestyle changes in all patients.
• When additional LDL-C lowering is needed to reach cholesterol targets, pharmacotherapy should be considered and statins are the first drugs of choice. The patient should be titrated to his/her goals for LDL cholesterol as per current guidelines. If optimal statin therapy does not achieve these goals, additional therapy may be needed. Options include bile acid sequestrants, niacin, fibrates and cholesterol absorption inhibitors, with the proper choice reflecting both the benefits and risks of these therapies.

Conclusion
ENHANCE was an imaging study designed to examine regression by carotid intima-media thickness (CIMT) measurements in a select population of familial hypercholesterolemia (FH) patients with a mean LDL-C baseline of 317 mg/dL after a 6-week washout. The results demonstrated no measurable CIMT impact by the addition of ezetimibe to a maximal statin dose. Using ezetimibe in combination with a statin can be a reasonable course of treatment if the patient is unable to reach their LDL-C target on optimal statin dosage alone or if the patient is either statin intolerant or cannot tolerate more than a low dose statin. Some signers of this document feel that bile acid sequestrants should be considered before ezetimibe is used due to their successful use in clinical trials.

What patients need to know
The recent ENHANCE study did not reveal a safety issue with ezetimibe. Moreover, ezetimibe lowered LDL-cholesterol as expected. Your physician will always consider the primary target of lowering LDL-C to approved guideline levels based on risk assessment and will use the best combination of lipid-lowering agents to achieve these goals. If you are taking ezetimibe (contained in Zetia and Vytorin), your physician is attempting to get your LDL-C level within the ranges stated in the guidelines. Our advice is to discuss with your doctor and/or your health professional the options to best achieve your treatment goals.

Further comments and references
The ENHANCE study examined the possibility that ezetimibe added to simvastatin 80 mg could enhance regression or slow the rate of progression of arterial plaque. Patients were followed over a 24-month period with measures taken at intervals using imaging technology designed to measure carotid arterial wall thickness. The study found similar rates of plaque progression in the simvastatin and the simvastatin-ezetimibe groups.

Although no significant CIMT regression was seen in the selected population of 720, the majority of whom (over 80%) had previously been treated for FH with statin therapy, no adverse outcomes were seen, either. As for the remaining 20 percent of patients, the population sample size is likely too small to be relevant. The ongoing IMPROVE-IT trial is tracking a patient base of 18,000 patients and will evaluate the effect of statin monotherapy versus combination therapy with ezetimibe on cardiovascular outcomes. While the results of IMPROVE-IT will not be available until 2012, the study will answer many of the questions raised by ENHANCE.⁴

Therefore, it is the opinion of the NLA that the ENHANCE study results provided little insight to the benefit or non-benefit of statin and ezetimibe combinations in this patient group because of problematic study design, especially with regard to patient selection: there were no pre-washout criteria for CIMT or LDL-C level. This was a high-risk population that did not attain treatment targets, and furthermore, the pre-washout lipid values and pre-study lipid lowering treatments of subjects were not included in the data collected for the ENHANCE study. So we may never know the exact details of their treatments prior to entering ENHANCE.

Although this trial showed no benefit in reducing carotid IMT by the combination of simvastatin and ezetemibe, it did show that ezetimibe lowered LDL-C and apo B as expected. The ENHANCE trial demonstrated a 16% greater reduction in LDL-C in the combination group compared to the simvastatin-alone group over the 24-month period as well as an 18% greater reduction in hs-CRP.

We can look to an earlier study, Effects of Atorvastatin and Simvastatin on Atherosclerosis Progression (ASAP)⁵ that was conducted by one of the authors of ENHANCE for clues regarding the ENHANCE findings. To be eligible for ASAP, there were minimal requirements for baseline values of LDL-C (> 173 mg/dL) and carotid IMT (> 0.7 mm). The reason was that change in response to therapy is correlated with baseline values of these two parameters. In the ASAP design paper, much attention is paid to pre-treatment cholesterol levels in relation to IMT. See section re: "Cholesterol Years Score." In ENHANCE, patients had to have an LDL-C >210 mg/dL after washout of prior therapy, but there was no minimal requirement for IMT thickness.

In the Kastelein group's simvastatin study,⁶ simvastatin, 80 mg/day, reduced IMT significantly in FH patients. So in ENHANCE, why did simvastatin, 80 mg/day, fail to reduce IMT in FH patients with the same mean age as in this prior study of the same dose of the same drug in patients with the same hereditary lipid disorder? One possible explanation is the difference in IMT thickness at baseline.

In the ASAP outcome publication⁵ and in the simvastatin study described above, the biggest predictor of change in IMT in response to statin therapy was baseline IMT (r=0.53, simvastatin study; r=041, ASAP). The Kastelein group is recognized for case finding of FH patients in the 1990s.⁷ In this paper they state that after they identified most FH patients in Holland, the percent treated rose from 39% to 91%; and that was by 2001. In the same year the ASAP publication cited above stated that adult FH patients should be treated to decrease LDL-C by a minimum of 45%. So it is reasonable to assume that the Dutch ENHANCE patients had been aggressively treated well before enrollment began.

References

1. J Kastelein MD, F Akdim MD, E Stroes MD, et al. Simvastatin with or without Ezetimibe in Familial Hypercholesterolemia.(http://content.nejm.org/cgi/content/full/NEJMoa0800742) New Engl J Med 2008 358:1431-1443.
2. National Cholesterol Education Program. Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Final Report. Circulation 2002;106:3143-3421.
3. Grundy SM, Cleeman JI, Meraz CNB, et al. Implications of recent clinical trials for the National Cholesterol Program Adult Treatment Panel III guidelines. Circulation 2004;110:227-239.
4. B.G. Brown MD, A Taylor MD. Does ENHANCE Diminish Confidence in Lowering LDL or in Ezetimibe? (http://content.nejm.org/cgi/content/full/NEJMe0801608) New Engl J Med 2008 358:1504-1507.
5. Smilde TJ, van Wissen S, Wollersheim H, Trip MD, Kastelein JJP, Stalenhoef AJP. Effect of aggressive versus conventional lipid lowering on atherosclerosis progression in familial hypercholesterolemia (ASAP): a prospective, randomised, double-blind trial. Lancet 2001;357:577-81.
6. PR Nolting, E de Groot, AH Zwinderman, RJ Buirma, MD Trip, JJ Kastelein Regression of carotid and femoral artery intima-media thickness in familial hypercholester. Arch Int Med 163:1837-41(2003).
7. Umans-Eckenhausen M, Defesche J, Sijbrands E, Screeder R, Kastelein J. Review of first 5 years of screening for familial hypercholesterolaemia in the Netherlands. Lancet 2001;357:165-68.

Author Disclosures:

Thomas P. Bersot, MD
Dr Bersot has received speaker honoraria from Merck & Co, Merck-Schering Plough, and Abbott Laboraties. He has been a consultant for Merck & Co, Merck/Schering-Plough, and Abbott Laboratories

Vera Bittner, MD
Dr Bittner has received grants from Pfizer Inc., Atherogenics, Merck & Co., NIH-Abbott, and CV Therapeutics.
She has been a consultant for Pfizer Inc., CV Therapeutics, and Reliant Pharmaceuticals.

Jerome D. Cohen, MD
Dr Cohen has received speaker honoraria from Abbott Laboratories, King, Merck & Co., and Novartis. He has been a consultant for Bayer and Merck & Co.

Michael H. Davidson, MD
Dr Davidson has received speaker honoraria from Abbott Laboratories, AstraZeneca, Kos Pharmaceuticals, Merck & Co., Merck/Schering-Plough, Pfizer Inc., Reliant Pharmaceuticals, Inc., Sankyo Pharma and Takeda Pharmaceuticals, and research grants from Abbott Laboratories, AstraZeneca, Kos Pharmaceuticals, Merck & Co., Merck/Schering-Plough, Pfizer Inc., Reliant Pharmaceuticals, Inc., Roche Pharmaceuticals, Sankyo Pharma, and Takeda Pharmaceuticals. He has been a consultant for Abbott Laboratories, AstraZeneca, Kos Pharmaceuticals, Merck & Co., Merck/Schering-Plough, Pfizer Inc., Reliant Pharmaceuticals, Inc., Roche Pharmaceuticals, Sankyo Pharma, Sumitomo Pharmaceuticals and Takeda Pharmaceuticals.

Anne C. Goldberg, MD
Dr Goldberg has received speaker honoraria from Merck & Co. and Merck/Schering-Plough and research grant support from Kos Pharmaceuticals, Pfizer Inc., Sankyo Pharma, AstraZeneca, Merck & Co., Takeda Pharmaceuticals, Abbott Laboratories, Reliant Pharmaceuticals, and Sanofi-Aventis. She has been a consultant for Unilever and Abbott Laboratories.

Peter H. Jones, MD
Dr Jones has received speaker honoraria from Abbott Laboratories, AstraZeneca, Merck, and Pfizer. He has been a consultant for Abbott Laboratories, and AstraZeneca.

James McKenney, PharmD
Dr McKenney has received speaker honoraria from AstraZeneca. He has been a consultant for Abbott Laboratories, Aegerion, AstraZeneca, Merck & Co, and Daiichi Sankyo.

Jennifer G. Robinson, MD
Dr Robinson has received speaker honoraria from Merck/Schering-Plough, and grants from Abbott, Aegerion, Bristol-Myers Squibb, Daiichi-Sankyo, Hoffman La Roche, Merck & Co., Merck/Schering-Plough, Pfizer Inc., and Takeda. She has been a consultant for Astra-Zeneca, Merck.

Neil J. Stone, MD
Dr Stone has received speaker honoraria for educational, not promotional activities from Abbott, Merck & Co., Schering-Plough and Unilever. He wrote a case history for the CCMD educational website supported by a consortium of companies led by Pfizer, Inc. He has been a consultant for Abbott, Merck & Co., Schering-Plough, and Unilever (honoraria donated to AHA).