ENHANCE - At Best, No Benefit From Vytorin or Zetia
The ENHANCE study has engendered considerable controversy because, while the study was concluded almost two years ago, the release of its results has been greatly (and famously) delayed. As noted here a few weeks ago, there has been a strong and growing suspicion that the trial did not come out the way the sponsors wanted it to, and that the delay has been for the purpose of trying to salvage something positive before releasing the results. Indeed, this suspicion recently has led to an investigation by Congress.
As I commented on December 17, "..... the fact that the endpoints of the trial were apparently changed after the study was concluded, followed by the fact that apparently now they have been changed back, is strong evidence that the data is being vigorously manipulated. And if the data's being manipulated, one could naturally conclude that the data, analyzed as originally intended, is unfavorable to Vytorin. Which, just as naturally, raises the final question: Are the results "merely negative" (that is, Vytorin appears no more beneficial than simvatatin alone), or are they "really negative" (that is, Vytorin is substantially worse than simvastatin alone)?" Today's release of data begins to answer this question.
The ENHANCE study enrolled 720 patients who were randomized to receive either Vytorin, or simvastatin alone. As an endpoint, investigators looked at the growth of plaques on arterial walls (using non-invasive ultrasound imaging). The trial was expected to show that patients on Vytorin would have less plaque growth than patients taking simvastatin alone.
However, the data released today showed no benefit for Vytorin over simvastatin. In fact, while the results were not statistically significant, patients on Vytorin had more plaque growth than patients taking only simvastatin. (The arterial wall thickness increased by 0.0111 mm for Vytorin, but only by 0.0058 mm for simvastatin alone - a ratio of nearly 2:1.) There did not appear to be any difference in side effects, or in the incidence of cardiovascular events among the two groups. (The results are currently buried pretty deeply on the sponsor's site. Here's a direct link to the press release.)
It's way too early to judge just how much the proverbial waste matter is going to hit the fan - this data has only been out a couple of hours. However, there's a lot to draw the public's attention here, including a) the alleged hanky-panky in manipulating the data; b) the delay of 2 years in releasing the data (during which the sponsors were selling an estimated $5 billion in Zetia and Vytorin); c) the interest Congress has already shown in the behavior of the sponsors, and d) the already accumulating inflammatory statements in the press. (The famous pharmaceutical gadfly Dr. Nissen is already being quoted in the New York Times as saying that the results are shocking, that nobody should be taking these drugs unless all other cholesterol drugs have failed, and that taking these drugs will increase their risk). As a result, it is exceedingly likely that patients now taking Zetia and Vytorin will, at the very least, have lots of questions for their doctors.
It is worth noting, therefore, that the results reported so far for the ENHANCE trial should not be immediately alarming. There is no evidence of worse clinical outcomes for patients taking Vytorin. Furthermore, while the plaques appeared to grow more for patients in the Vytorin group than in the simvastatin group, in fact plaque growth was very small in both groups.
The bottom line is that this study appears to show no compelling reason for patients to take ezetimbe (either Zetia or Vytorin), at least unless their cholesterol levels cannot be controlled with other measures. But at the same time, being on the drugs right now is not something that needs to be dealt with as an emergency. Talk to your doctors about whether you really need to be on them.
The biggest widespread harm caused by Vytorin, judging from the data available so far, is probably to pocketbooks - Vytorin is far, far more expensive than simvastatin alone, which is now available as a cheap generic drug. And while it's probably not a "harm," those commercials comparing your Uncle Harry to a plate of pancakes and eggs are among the most annoying I've seen. We can only hope that, thirty seconds after releasing their press statements today, the sponsors of ENHANCE canceled all those commercials. In which case the ENHANCE trial will have yielded positive results after all.
Comments
Wow interesting !!!
But there is on question remaining …
What was the LDL baseline and how low did the patients get in the two groups ?
Previous studies with statins have shown that you need to get a very low ldl in order to show a plaque reduction
Did they reach that Ldl target in the Enhance study ?
LDL targets were apparently reached. There was a 58% reduction in LDL with Vytorin, and a 41% reduction with simvastatin alone.
DrRich
New story on CT about Blumenthal. Good read. Nice story Richard- never read any of your stuff before.. Cardiology News- Roger Blumenthal
The ENHANCE trial is likely another red herring as the beneficial pleiotropic effects of statins are more than likely what afford the marginal favorable actions of statins in combatting heart disease. These actions would include statin’s increase in nitric oxide production, decreased smooth muscle proliferation, decreased thromboxane formation, increased NF-Kappa-B production (decreased inflammation)and perhaps others (Vitamin D analogue? antioxidant?). These pleiotropic effects can be had other ways without a concomitant lowering cholesterol, a molecule the body needs and loves, especially the brain.
I have a question. Is it really necessary to have your LDL under 2.0? My LDL is 2.07 mmol/L and HDL 2.31 mmol/L . My cardiologist wants me to take Ezetrol to get the LDL under 2.00 but I had severe side effects and have stopped with it. I have had a double bypass 4 years ago. Could somebody give me some advise please? Thank you, Marijke.
OK, so plaque wasn’t reduced significantly - was the HDL lowered? The test group was VERY small considering the # of people that take statins. Many, many people cannot take statins due to the liver damage that statins cause, which Zetia does not…..
The absolute resolution of the best ultrasound equiptment is between 0.11 and 0.07 mm. How can anyone claim to have measured intima-medial thickness to 0.0058 mm ? Obviously this study needs to be reviewed by people familiar with the technology as well as the pharmacology. How can you say “results were not statistically significant…a ratio of nearly 2:1″?
The ratio is irrelevant because the numbers are statistically insignificant.
“ENHANCE - At Best, No Benefit From Vytorin or Zetia”. Very reckless to draw such firm conculsions. I am fearful patients reading this will take it upon themselves to modify therapy and have adverse outcomes. The surrogate marker of intimal thickness (in the absence of statistical significance) and insufficient power for meaningful outcomes data… No conclusions can be drawn here- period. Your write up was entertaining and I enjoyed reading it, HOWEVER lay people surfing the net for information about their medications may come across your article and make inappropriate decisions. One of the other respondants makes a great point regarding limitations of the accuracy and precision of methodologies for determining intimal wall changes. It is bad science to imply (as you did) that intimal changes in this study are meaningful given the fact that random chance cannot be ruled out.
BTW I like the Vytorin commercials. Almost as good as the Lipitor commercials of overly confident people tripping at inopportune moments. I would shed no tears though if ALL direct to consumer advertising of prescription drugs was pulled. Very detrimental to optimal (and economically sound) patient care.
-rtg
I would agree with Tim that the statements made are reckless and worry patients unnecessarily. The study was underpowered. To get meaningful data there must be thousands of patients over a longer period of time. How many patients have heterozygous familial hyperlipidemia in your practice? We can not assume that results in this group can carry over to normal patients. We do not know the significance of IMT measurements. Why would you say that Vytorin is no more beneficial than Simvastatin? Shouldn’t we keep our eye on the ball? The ball is lower LDL reduces events. Vytorin reduced LDL by 58% compared to Simvastatin at 41%. I feel bad for patients who will come back in 6 months after being taken off their Vytorin and whose LDL’s are up then. How many medical legal events am I willing to risk? None. I am not making these strong statements to patients. And some wonder why orphan drug efforts are fewer and fewer. Why are we assuming wrong doing? The end points were not changed and changed back. Read the chronology.
It is available - ask your rep. I think there is something smoking in the woodpile at the Cleveland Clinic.
I am so confused about this. I saw an article on another about.com site and I will quote part of it.
“Cholesterol Drug May Cause Depression
Tuesday February 19, 2008
The Food and Drug Administration (FDA) has approved a product label change for the cholesterol-lowering drugs Zetia (ezetimibe) and Vytorin (ezetimibe/simvastatin), adding depression as a possible side-effect.
In February 7th and 8th letters to the drugs’ co-marketers, Schering-Plough Corp. and Merck & Co., the FDA said depression will be added to the section of the drugs’ package insert concerning adverse reactions in post-marketing experience. The new language also will be included in a section of the patient package inserts listing possible side effects of the drugs.
Vytorin is a combination of Zetia and simvastatin. Simvastatin is marketed by Merck under the brand Zocor.
Vytorin and Zetia have been in the news lately because of a recently released study showing that there is no benefit from using either drug. The labeling changes, however, do not appear to be related to this study.
http://depression.about.com/ ”
I suffer from clinical depression, high cholesterol, diabetes, migraines, degenerative disc disease, arthritis, sleep apnea, and other physical problems. I am now on this medicine, I was originally on Lipitor and was changed to Vytorin a few months ago. I take anti-depressants with a cocktail of other psych meds (total of 4 psych meds) plus over a dozen of meds for my physical problems which includes prescription for vitamins.
Will Vytorin increase my symptoms of clinical depression? I have noticed lately that something is just not right with me because I am now having depressing mood swings. Could this be the Vytorin messing around with my seratonin?
“And while it’s probably not a ‘harm,’ those commercials comparing your Uncle Harry to a plate of pancakes and eggs are among the most annoying I’ve seen.”
Amen to THAT!
These patients were heterozygous familial which represents exactly 0.2% of the population. Thats 1 in 500 people suffer from this genetic abnormality and is not seen in the typical patient.
I look this results with caution. I think that I have more questions than answers. If simvastatin is effective, eztimibe isn’t? What is the real target to reduce plaque? Can I transfer this results for major events? It’s too early to get conclusions about risk of death or AMI, but it’s important to make questions and search answers.