I am writing this in response to the concerns of many of my patients who are taking Vytorin and Zetia to lower cholesterol levels.  We have received many calls expressing concern about the implications of continuing to take Vytorin (ezetimibe/simvastatin) or Zetia (ezetimibe alone).

The ENHANCE trial:
     On March 30th the results of the ENHANCE trial were presented at the annual meeting of the American College of Cardiology.  To summarize, it was a small study of 720 patients with Heterozygous Familial Hypercholesterolemia - a genetic abnormality that causes extremely high levels of LDL cholesterol.  Only 0.2% of all patients with high cholesterol levels have this severe type.  These patients had an average LDL cholesterol before treatment of 318.  After 2 years of taking high dose Vytorin (ezetimibe/simvastatin) or generic Simvastatin alone, there was no significant change in the thickness of plaque in the wall of the carotid arteries in the Vytorin group compared with the Simvastatin group - even though there was a significant reduction of LDL levels in the patients receiving Vytorin.  There was also no significant difference in the rate of heart attacks, strokes, the need for stents/bypass operations or cardiac-related deaths.  So, this study didn't show any benefit in reducing the thickness of the carotid artery wall.  Importantly, it also didn't show any increased side effects or complications of taking Vytorin either.

What does this mean?
     Frankly, I'm not sure.  The ENHANCE trial showed no difference in using Vytorin over Simvastatin.  This is a relatively small study that examined the patients with the worst type of high cholesterol.  It showed that in these people, lowering the LDL cholesterol further than that achieved with generic Simvastatin alone had no effect.  However, the investigators looked at the outcome of a measure of the thickness of the carotid artery wall.  The study wasn't designed with enough patients over a longer period of time to measure what really matters.  What is important are outcomes that effect the general health and lives of people - heart attacks, strokes, the need for stents/bypass operations or cardiac-related deaths.  Also, to generalize this study of patients with the "worst of the worst" high cholesterol to the general population of people with lower cholesterol levels may not be valid.  So, one cannot say that this study necessarily applies to our usual patients with mild to moderately increased lipid levels.
     The results really don't make sense in the setting of what we believe that we have previously known about the causes of heart disease - that lowering total cholesterol and LDL levels will decrease the risk of heart attacks, strokes and cardiovascular disease.  However, it may well be that statin medications have positive cardiovascular effects that go beyond their ability to reduce LDL cholesterol, and that Vytorin and Zetia lack or even block those effects.  Statins like Simvastatin, Lovastatin, Pravastatin and Lipitor have repeatedly been shown to lower cholesterol by 35% to 60% in most patients and have also been proven to reduce heart attacks.  Zetia and Vytorin, which work by a different mechanism, reduce cholesterol levels an additional 15% to 20%, but have never shown a further reduction in heart attacks.  Reducing plaque growth is crucial, because plaque formation, known as atherosclerosis, can lead to the blockages and blood clots that cause heart attacks and strokes.  That is why the trial's finding is worrisome.  Clearly, reducing the progression of atherosclerosis is a critical step in the prevention of cardiac events and that did not happen in the ENHANCE trial.
     The ENHANCE trial was an imaging study and not a clinical-outcome study. The pharmaceutical companies,  Merck and Schering-Plough recently began two large clinical studies intended to test whether the combination of Zetia and statin drugs actually reduces heart attacks and strokes when compared with statins alone. But the data from those studies will not be available until at least 2012.  Conclusions really cannot be made until the large clinical-outcome studies are presented.  Without data from outcomes studies for Zetia and Vytorin, no one can be certain if the drugs help or hurt patients.  In the meantime, based on good current evidence, the concensus recommendation from the American College of Cardiology meeting is that statin medications and others such as niacin be used first to lower lipid levels.  Zetia and Vytorin may be used - but as a last resort.

My concerns:
     I have several ethical and societal concerns about the study.  First, I question why Merck and Schering-Plough withheld the results of the ENHANCE trial for almost 2 years.  Had it not been for the efforts of Rep. John Dingell (D-Mich.), Rep. Bart Stupak (D-Mich.) and Sen.Chuck Grassley (R-Iowa) the results would still be unknown and may have never been released.  Secondly, the drug companies apparently tried to change the endpoints of the study after it was completed.  This suggests scientific dishonesty from a company attempting to suppress negative results.  Clearly, the release of the results would hurt sales and decrease the companies stock values.  Third, the logical question is why should patients take very expensive medications, Vytorin 10/80 (ezetimibe/simvastatin) $100/month or Zetia 10 mg (ezetimibe) $93/month, if there is no additional benefit over the much cheaper generic Simvastatin 80 mg at $33/month?

What to do now?
     First and most importantly, if you are being treated for high cholesterol with Vytorin or Zetia, please continue to take them.  The worst possible action that one could take at this time would be to abruptly stop taking the medications.  I intend to discuss the implications of taking these medications with all patients during our next medical management office visit.  After considering individual situations we may decide to make a change or leave the medications unchanged.  Please remember that the final answer on the status of Zetia and Vytorin won't be known until at least 2012.

For more information on the ENHANCE study please visit CardioSource from the American College of Cardiology.