Dr Alan Begg discusses the latest results from the ENHANCE trial and their implications for the use of ezetimibe

The debate on the benefits of lipid lowering and what drugs to use has been stimulated by the recent online publication of the results of the ENHANCE (ezetimibe and simvastatin monotherapy on atherosclerosis progression in familial hypercholesterolaemia) trial.1 This study was completed 2 years ago, but the results have only now been made available on the manufacturers’ website.1 This release is in response to a US congressional investigation into why the trial results had not been published.2 However, it is likely that the trial will be presented in abstract form at the American College of Cardiology Scientific Meeting in March 2008.1

ENHANCE trial results

The trial involved 720 patients with heterozygous familial hypercholesterolaemia. It measured the effect on the change in carotid intima-media thickness (IMT) between patients treated with ezetimibe/simvastatin 10/80 mg or simvastatin 80 mg over a 2-year period. At the end of 2 years, although there was a significant difference in low-density lipoprotein (LDL) cholesterol lowering between the two treatment groups (58% versus 41% for the ezetimibe/simvastatin and simvastatin groups, respectively), there was no difference between the treatment groups in terms of their mean carotid IMT.

Carotid intima-media thickness and atherosclerosis

Carotid IMT, which is easily measured by B-mode ultrasound, is a marker for early atherosclerosis and has been used to assess its extent and progression.3 An increased carotid IMT has been shown to be associated with an increased risk of acute myocardial infarction and stroke over a 6-year period.4 In the Monitored Atherosclerosis Regression Study (MARS), the cholesterol intake, body mass index, and smoking history were all related to the progression of carotid IMT.5

Of the atherosclerosis regression trials, the ASTEROID trial (a study to evaluate the effect of rosuvastatin on intravascular ultrasound-derived coronary atheroma burden)6 has received the most recent publicity. The 507 patients in this trial, who received rosuvastatin 40 mg, significantly reduced both their LDL-cholesterol levels and also percent atheroma volume in their coronary arteries as measured by intravascular ultrasound. Although not directly comparable to the ENHANCE study, the ASTEROID trial suggested that a high-dose statin such as rosuvastatin 40 mg could possibly lead to a regression of the atheroma burden in the coronary arteries. This effect did not appear to happen in the carotid arteries in the ENHANCE study, either with the statin or the combination therapy.

The NICE Technology Appraisal 132

The results of the ENHANCE trial, if they had been available, are unlikely to have influenced the recently published NICE Technology Appraisal 132 on Ezetimibe for the treatment of primary hypercholesterolaemia.7 It recommended the use of ezetimibe in certain circumstances to a similar group of patients to that recruited to the ENHANCE trial with familial hypercholesterolaemia, as well as patients with non-familial hypercholesterolaemia. The use of ezetimibe was sanctioned by the NICE guidance if the patient was intolerant to statin therapy or if the use of statins was contraindicated. Ezetimibe may be co-administered with initial statin therapy if LDL cholesterol is not controlled after titration of the statin or if titration is not indicated.7 The NICE Appraisal Committee based its recommendation on the fact that ezetimibe effectively lowered LDL cholesterol and that it is a reduction in LDL cholesterol that is associated with improved CVD outcomes. NICE was aware of the absence of any clinical benefit of lipid lowering with ezetimibe and that as yet we do not have data on adverse effects related to its long-term use. What the ENHANCE study has confirmed is that ezetimibe is well tolerated either as a monotherapy or in combination with simvastatin with similar overall incidence rates of treatment-related adverse events, serious adverse events, or adverse events leading to discontinuation between the two groups in the trial.


For GPs, it is important that they are aware that the ENHANCE trial is an imaging study and not a clinical outcome study. The use of a surrogate marker such as carotid IMT does not inform us as to whether a drug is clinically effective or not. Three outcome trials using ezetimibe/simvastatin are ongoing:

  • The IMPROVE-IT trial (examining outcomes in subjects with acute coronary syndrome: ezetimibe/simvastatin versus simvastatin), which is enrolling over 10,000 patients is estimated to complete in January 2011)8
  • The SHARP trial (study of heart and renal protection) is evaluating 9000 patients with chronic kidney disease to monitor lowering of LDL cholesterol with a combination of ezetimibe and simvastatin, with time to first major vascular event being the primary endpoint9
  • The SEAS trial (simvastatin and ezetimibe enhances aortic stenosis) will monitor mortality and morbidity in patients with aortic stenosis who are being treated with ezetimibe and simvastatin.10

Any change in clinical practice should await the results of these trials.

  1. Schering-Plough Press Release, Monday 14 January 2008: www.sch-plough.com/schering_plough/news/release.jsp?releaseID=1095943
  2. Lenzer L. Unreported cholesterol drug data released by company. Br Med J 2008; 336: 180–181.
  3. Amato M, Montorsi P, Ravani A et al. Carotid intima-media thickness by B-mode ultrasound as surrogate of coronary atherosclerosis: correlation with quantitative coronary angiography and coronary intravascular ultrasound findings. Eur Heart J 2007; 28 (17): 2094–2101.
  4. O’Leary D, Polak J, Kronmal R et al. Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. N Engl J Med 1999; 340 (1): 14–22.
  5. Markus R, Mack W, Azen S, Hodis H. Influence of lifestyle modification on atherosclerotic progression determined by ultrasonographic change in the common carotid intima-media thickness. Am J Clin Nutr 1997; 65 (4): 1000–1004.
  6. Nissen S, Nicholls S, Sipahi I et al; ASTEROID Investigators. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA 2006; 295 (13): 1556–1565.
  7. National Institute for Health and Care Excellence. Ezetimibe for the treatment of primary (heterozygous-familial and non-familial) hypercholesterolaemia. Technology Appraisal 132. London: NICE, 2007.
  8. http://clinicaltrials.gov/show/NCT00202878
  9. http://www.bermancenter.org/studiestrials/kidney/sharp_abstract.html
  10. www.msd.no/content/downloads/KyotoSept2003Poster.pdfG