Vytorin Results Disappointing, Experts Say Don't Panic
Featured ArticleMain Category: Clinical Trials / Drug Trials
Also Included In: Cholesterol; Statins; Cardiovascular / Cardiology
Article Date: 16 Jan 2008 - 3:00 PDT
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The American College of Cardiology (ACC) has issued a statement yesterday, 15th January, asking patients taking the cholesterol busting drugs Zetia (ezetimibe) and Vytorin (ezetimibe and simvastatin combined) not to panic and to talk to their doctors about the impact of the disappointing trial results on their treatment.
The statement follows news released on Monday, 14th January, by drug companies Merck and Schering-Plough Pharmaceuticals, that the ENHANCE trial testing the effect of Vytorin (ezetimibe and simvastatin combined) against an older drug, now available in generic form, Zocor (simvastatin alone), showed that the combination drug Vytorin, which is quite expensive, was no better at reducing artery clogging than the older and cheaper statin.
ENHANCE stands for Effect of Combination Ezetimibe and High-Dose Simvastatin vs. Simvastatin Alone on the Atherosclerotic Process in Patients with Heterozygous Familial Hypercholesterolemia.
The ACC said the study deserves "serious thought and follow-up". The overall rate of cardiac events was nearly the same in both drug groups, and both drugs were generally well tolerated, they said. The differences in mean change in the intima-media thickness (IMT) between the Zocor (simvastatin) and Vytorin (ezetimibe and simvastatin) group was 0.006 versus 0.011 mm. IMT is a measure of the thickness of artery walls, and changes in this measure shows how much plaque has built up.
They said patients should not stop taking the drug on the basis of these results, the situation is not urgent, and they should talk to their doctor about any concerns they have. More research is needed before firm conclusions can be made about the risks and benefits of statin alone versus statin plus ezetimibe, said the ACC.
720 patients with heterozygous familial hypercholesterolemia (inherited high cholesterol from one of their biological parents) participated in the ENHANCE study. Over the two years of the study, there was no significant difference in the ability of the two drugs to slow the growth of plaque in carotid arteries supplying blood to the brain.
When news of the trial was released, there were several media reports saying that the trial showed there was no benefit from the more expensive combination drug Vytorin compared to simvastatin alone, which is now available as a much cheaper generic (used to be known under the brand Zocor).
But the ACC recommended in a press release that "major clinical decisions not be made on the basis of the ENHANCE study alone".
They also noted that the trial is an imaging study (looking at the thickness of the artery walls), and was not designed to assess clinical outcomes. Final conclusions should not be drawn until three larger trials, which are assessing clinical outcomes, publish their results within the next two or three years, said the ACC.
The ACC recommends that Zetia (ezetimibe) is still a "reasonable option for patients who are currently on a high dose statin but have not reached their goal". It is also a reasonable option for patients with low tolerance for statins, or who can only tolerate a low statin dose.
Meanwhile the market has reacted to the news of the ENHANCE trial. Shares in Schering-Plough, who make Vytorin, which accounts for two-thirds of the company's profits, fell for a second day running yesterday, Tuesday. Analysts are saying the more expensive combination drug offers no real benefits over the cheaper statin only version, and that doctors will now think twice before prescribing it.
Another issue that is being reported in connection with this trial is the possibility that the drug companies may have sat on the results. The two year trial ended in April 2006. According to a report by Reuters news agency, Congress is planning to investigate how the two companies handled the release of the study's results, calling the delay a "suspiciously long time".
Click here for the American College of Cardiology (ACC).
Click here for more information on the ENHANCE trial results (cardiosource.com).
Sources: ACC press release, cardiosource.com, Reuters.
Written by: Catharine Paddock
Copyright: Medical News Today
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Misguided War On Cholesterol
posted by Duane Graveline MD MPH on 17 Jan 2008 at 4:45 amCholesterol fighters of the world are now doing their best to explain what to them is inconceivable – a study by Merck/Schering-Plough Pharmaceuticals failed to perform as predicted. In this study they had pitted Zocor and Vytorin against the atherosclerotic menace of familial hypercholesterolemia, using relative plaque thickness (IMT) of major blood vessels as their primary indicator of success. For 24 months they had watched for progress and unhappily had been unable to see a significant difference evolving between the Vytorin and Zocor groups. After behind the scenes’ deliberation about the possibility of changing endpoints, with rumors reaching all the way to Congress, finally the lid is off and media feasting has begun. Even some of the ardent supporters of cholesterol lowering drugs attempted to distance themselves from this ENHANCE study with its dependence on direct observation of atherosclerotic plaque.
As most of you know, Vytorin is nothing but good old Zocor to which has been added Zetia, a non-statin cholesterol lowering drug, acting on the gut absorption rather than on cholesterol synthesis. They did get much lower LDL cholesterol levels with Vytorin in this study but it made no discernible difference. The implication is that LDL cholesterol lowering is not the key in atherosclerosis treatment or prevention. Even the validity of our national cholesterol guidelines and the competence of the men who draw up these guidelines now is called into serious question. This is what is causing great pain among these national and international leaders in the cholesterol war. This should not have happened, they think. They have said for years that LDL cholesterol must be lowered at all costs. This is what we all have been told for decades. Is something wrong here?
What is wrong is that these people with the anti-cholesterol philosophy are far better talkers than listeners. Had they been listening these past 10 years they would know that a growing number of people in our scientific community have been aware for years that cholesterol is irrelevant to the atherosclerotic process. Inflammation is the cause. Cholesterol is nothing but an innocent bystander drawn into the plaques as part of our natural healing. I have said before that labeling cholesterol as causative to atherosclerotic simply because it is there is roughly equivalent to blaming firemen for fires because they are there. For four decades we physicians have been bombarded with this drivel. What has confused these statin advocates is the dual nature of statin drug effects on the human body.
Yes, statins are reductase inhibitors that reduce cholesterol synthesis through mevalonate pathway inhibition. (Unavoidably, statins also must decrease the synthesis of CoQ10, dolichols, selenoprotein and normal phosphorylation at the same time, but that is another story). What we have learned only in the past decade is that statins are also powerful anti-inflammatory agents, exerting this effect via nuclear factor kappa B inhibition. We now know it is this anti-inflammatory effect of statin that is beneficial in atherosclerosis control, for atherosclerosis is an inflammatory disease.
The ENHANCE study simply helps to prove the irrelevance of cholesterol. This study shows rather dramatically that 80 mg of Zocor , however it is combined, is equivalent in effect and the addition of Zetia’s cholesterol reduction does nothing more than sell Zetia.
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