Position paper from the NYU Center for the Prevetion of Cardiovascular Disease on the ENHANCE trial and its implications for the use of ezetimibe:

On April, 3, 2008 an article called “Simvastatin with or without Ezetimibe in Familial Hypercholesterolemia (also known as the Enhance Trial) was published.  This clinical trial was a 2 year study comparing high dose Simvastatin (80mg) to high dose Simvastatin 80mg and 10mg of Ezetimibe in 720 patients with a genetic disorder (familial hypercholesterolemia) in which patients have very high cholesterol levels and very high LDL cholesterol levels (average LDL cholesterol level in this group was 318mg/Dl. while normal levels in the general population are usually below 130mg /dl.).  The  study measured the thickness of the lining of the carotid arteries (also known as Carotid intima-media thickness or C-IMT) over 2 years  as a measure of progression of vascular injury or atherosclerosis.  The study showed several major findings:

1. Over the two years of follow up, there was no difference in the rate of increase in the thickness of the carotid artery lining (C-IMT) between the two groups.
2. There was no difference in drug related side effects between the two groups.
3. There was no difference in the incidence of cardiovascular events between the two groups (although the number of patients and the number of events that occurred were not large enough to draw any statistically significant conclusions about the risk of cardiovascular events).

This study has generated a considerable amount of controversy about the use of Ezetimibe (marketed as Zetia  and the combination of Simvastatin and Ezetimibe together, marketed as Vytorin.) In spite of the comments in the press and by radio and TV commentators, the study did not show any adverse effects from the addition of Ezetimbe to Simvastatin (Vytorin).  There has been a wealth of clinical trial data showing that in almost all trials, no matter how one lowers cholesterol (Small intestinal bypass operations, bile acid binding resins, high dose Niacin or Statin drugs), there has been a major reduction in the incidence of heart attack and stroke.  This study was not powered or intended to determine whether the addition of Ezetimibe to a statin will have a benefit on cardiovascular events and thus it was no surprise, that this study showed no change in the cardiovascular event rate when Ezetimibe was added to Simvastatin in spite of the additional reduction in cholesterol and high sensitivity C Reactive protein (HS-CRP).

What was interesting about this trial however, was that there was no impact of the rate of progression of C-IMT (which in other studies has been shown to correlate with the amount of vascular disease and a good surrogate marker for risk of future cardiovascular events) with the addition of Ezetimibe in spite of the beneficial changes in the lipid profile.  One possibility is that there may have been some unknown but negative effect of lowering cholesterol with ezetimibe which theoretically could have neutralized or prevented some of the beneficial effects of cholesterol lowering or more likely the case, that the patient group being treated is this study was unusual and may not be representative of most patients with very elevated cholesterol levels or even most patients for whom cholesterol drugs would be prescribed.  When one looks carefully at the patients treated in this study was stands out is that in spite of their having cholesterol levels over 400mg/dl and LDL levels of 318-319mg/dl (not unusual values for patients with this genetic abnormality but very unusual for most patients), the C- IMT values before initiation of the treatment were normal (C-IMT values of 0.70).  The C-IMT values in this group were much lower than other patients described in other similar studies in this type of patient population.  To reach middle age with no significant vascular changes in the carotid arteries in this patient population would be very unusual and suggested that these patients had already been treated very aggressively prior to the entry into the study.  They had to have stopped all cholesterol lowering drugs for 6 weeks before being randomized to the Simvastatin or Simvastatin plus Ezetimibe treatment groups which would explain the very high cholesterol levels when entering the study.  So, if their carotid arteries were already normal, would we expect to see them become more normal with one treatment vs the other with additional cholesterol lowering?  Probably not!  The slight changes that were seen in both groups were consistent with normal ageing which may not be dependent on cholesterol levels and thus it is hard to see how one might have expected to see a difference when comparing the changes in C-IMT between the two groups.

After all of the discussion in the media and in medical forums has died down, we believe we can say the most reasonable message that we can “take–home” from the ENHANCE trial would be:

1.  There is not data in the ENHANCE trial that would contradict the wealth of clinical trial data that cholesterol lowering an effective way to reduce risk of cardiovascular events (heart attack and stroke).
2.  The ENHANCE trial did show; the addition of ezetimibe to simvastatin was associated with 16% further reduction in LDL-cholesterol and a 27% reduction in HS-CRP with no increase adverse drug related side effects and no significant increase in cardiovascular events.
3.  The patient population in the study was very unusual (normal C-IMT in spite of having a genetic defect associated with very high cholesterol levels) was not typical for most patients treated with cholesterol lowering drugs or even patients with this familial heterozygous hypercholesterolemia.
 4.  There are large scale clinical trials currently in progress,  with adequate size and statistical power to answer the question that we really need to answer – whether additional cholesterol lowering with the addition of Ezetimibe translates into a reduction in cardiovascular events (similar to that which we have seen in almost all other previously published clinical trials). Until these trials are completed, we should continue to use Ezetimibe in a manner consistent with the recommendations of the American Heart Association, American College of Cardiology and the National Lipid Association.

These recommendations stress that the primary modality that should be used for patients that need drug therapy to reduce cardiovascular should be Statins.  These drugs should be used in the maximum tolerated doses in any particular patient, which have been shown to be safe and effective in previously published clinical trials.  If the patient’s cholesterol levels are not at goal on Statin therapy alone, then it is reasonable to add a second drug to get additional cholesterol lowering (the two most effective choices specifically approved by the FDA for this purpose would be Ezetimibe or a bile acid binding resin).