The Controversial Vytorin Trial Ends In Failure
22 CommentsBy Ed Silverman // January 14th, 2008 // 8:39 am
Since November, Schering-Plough and Merck have scrambled to explain a two-year delay in releasing results of a trial designed to boost the profile of their Vytorin cholesterol med. Meanwhile, the drugmakers took a beating for changing the primary endpoint, failing to include the lead investigator in the decision and a reluctance to name members of an allegedly independent panel to review the data (and it wasn’t really independent, either).
Today, they released the results and the findings are hardly surprising - There was no statistically significant difference between treatment groups on the primary endpoint, including the common carotid artery, according to a statement. And key secondary imaging endpoints showed no statistical difference between treatment groups. The study was designed to determine whether Vytorin - which combines Zetia and Zocor - was more effective in reducing the growth of plaque in blood vessel walls more than Zocor.
Initially, the companies had said they would measure the thickness of plaque in two arteries - the carotid, which runs through the neck and supplies the brain with blood, and the femoral, which runs through the hips and supplies the legs. However, the alleged difficulties in assessing ultrasound techniques and images was the reason given for the delays and change in endpoints. [UPDATE: Cleveland Clinic's Steve Nissen tells Bloomberg News there should be a moratorium on using Vyotrin: "Compared with generic simvastatin, Vytorin is expensive and it adds no benefits.'']
Known as the Enhance trial, an abstract will presumably be on display at the American College of Cardiology meeting in March. A belated note: There was a consolation prize for the drugmakers - Vytorin did show a statistical difference in lowering LDL, or bad cholesterol.
Hank
In the meantime, there has been the question of whether combining zetia with a atatin is assocciated with additional problems at a statistically significant level. Do we have any new clues on this?
BDM
It shouldn’t be a surprise to anyone at this point that this trial is negative. Ezetimibe added to simvastatin did not have any beneficial impact on the progression of atherosclerosis. In fact, although not statistically significant, it appears that atherosclerosis progressed about twice as fast in the group that took ezetimibe on top of simvastatin. Only time, and lots of it, will tell if this means anything for the incidence of events. In the meantime, Merck and Schering-Plough will no doubt be laughing all the way to the bank, to the tune of $5 billion per year!
BAC
Obviously, there’s no “enhancement” of the effects of generic simvastatin by adding the new, expensive drug ezetimibe. If anything, the results are worse in the group that got ezetimibe.
The consolation prize means nothing because in medicine it’s “show me” the evidence rather than “tell me” your theory. If healthcare payers have their way, it’ll be Vytorin off the formulary and Zetia relugated to “statin intolerant” patients. It will save them a boat-load of money and cost Merck and Schering-Plough a bundle. The flagship is taking on water fast. Can sinking be far behind?
BPW
Now Congress needs to really close in on these bozos for delaying negative results in order to continue to make bundles of money. I wonder how many times Fred Hassan and Carrie Cox said “No, not yet, because we have to hit our 2007 numbers.”
Former Chronic Fatiguer
BDM - If you see this, can you provide a reference for:
“In fact, although not statistically significant, it appears that atherosclerosis progressed about twice as fast in the group that took ezetimibe on top of simvastatin. ”
Thank you. (I understand not stat signif means what it says!)
BDM
Hi Chronic Fatiguer,
The rates of progression are in the press release that was issued by Schering-Plough and Merck. The p value is 0.29 so no definitive conclusions can be made, but the data leans heavily in favor of smvastatin alone.
BDM
Dr. Remulac
I love being able to say “told ya so”!!! Once again proving the age-old “blind squirrel” theory. Seriously, managed care and PBMs should be looking at this study in the context or previous data/guidelines and relegate Zetia to use in truly statin-intolerant patients (third-line after Niaspan or bile-acid sequestrants which both have regression/outcomes data) and Vytorin should be limited to second- or third-line therapy in patients who need further LDL-C despite maximally tolerated doses of a generic statin (lova, prava, or simva). Although Lipitor and Crestor have at least some positive outcomes data or progression of atherosclerosis data, they are much more expensive than Vytorin. The world needs to wake-up and realize that there are diminishing returns in driving LDL-C lower and lower, and that after a generic statin is onboard, the next Rx should be for niacin!!
AV Block
Come on!
The study consisted of only 720 patients or so - are you sure that this study is generalizable to the wider population? Importantly, the scientific inquiry is still ongoing, with larger, better powered clinical trials.
This study did not demonstrate a statistically significant difference (wrt primary endpoint). But in light of the larger clinical trials, it is premature to conclude that Vytorin is no better than Zocor.
Dr. Remulac
The study was appropriately powered to detect a difference in the primary endpoint, hence the N=720. It is not generalizable to the overall general population, but it is to the several million patients worldwide with heterozygous FH (about 500,000 in the US). I always marvel when people choose to ignore currently available evidence and instead choose to support a therapy simply because it is under investigation in other large studies. The power of suggestion……if it’s worth investigating in all those people, then it must be worth using now!
jan Klodner
I am confused! If it is assumed that High Cholesterol is the main cause for dangerous plaque buildup AND Zetia reduces Cholesterol (the news reports don’t deny this and, case in point, it has reduce mine significantly), I would ASSUME that the reduction in my Cholesterol would reduce or eliminate plaque buildup. Am I missing something here? I dont recall ANY claims of these drugs that they remove plaque. I assumed if you do not have HIGH CHOLESTEROL, plaque build is minimal and what WAS there naturally dimishes.
zetia news | Info trend it
[...] The Controversial Vytorin Trial Ends In Failure [...]
Andreas K
Am i the only one who reacted to the fact that LDL dropped yet no benefit shown?
L Cheng
What we need are outcome results, not carotid IMT results which could be quite variable and U/S tech dependent. Trial pop of 720 doesn’t impress me as being adeq powered. S Nissen of Cleveland Clinic doesn’t impress me with his proposed ban on use of vytorin. Afterall he trusted meta-analysis using trials as short as 8 weeks in his condemnation of avandia, while receiving grant money in ongoing actos trials; and then explaing comparing apples and oranges in his conclusion was reasonable. He should realize this fact: we use vytorin 10/10 in place of zocor 40 mg or lipitor 20 mg which many pts could not tolerate due to side effects and get similar LDL lowerings effects and probably similar outcome.
Tomas
Cheng,
So what are we supposed to do - wait until the companies take their good old time getting us the event results? First due in 2009, then 2010, now 2011 and maybe 2015 before it’s all over. In the meantime, at least $20-30 billion will be spent on drugs that have proven nothing. Oh wait, VBig Pharma wants us to trust them. These drugs will be good for you. And they’ll only cost you a small fortune. Steve Nissen is a little controversial, but he’s not that far off. Why pay bundles for something when you can get by spending pennies a day on something just as good. The payers will be asking the same questions.
dwight m
I agree with l cheng, if low doses of vytorin have the same outcome as high doses of statin, the liver and muscle adverse reaction risk may be reduced,thereby being a better choice of treatment. However, if an increase in plaque or even the same amount of plaque is found in the vessels the treatment may be flawed. Also, people should be alert to the fact that statins may decrease co-enzyme Q-10 and weaken the heart muscle,bringing on possibe cardiovascular events…….
Dave
I’m a preventive cardiologist and have been doing cardiovascular risk factor management on my patients for over 20 years. Lovastatin and simvastatin were the two worst statins for patients to tolerate. Unfortunately, rosuvastatin is next. The two best are atorvastatin for efficacy and pravastatin for safety. If you want the most bang for your buck, then generic pravastatin is your choice! It also has some of the best eveidence for event reduction in all types of situations.
AV Block
Dr. Remulac,
Come on… get real. this 720 patient trial was not powered to detect differences in cardiovascular mortality. that to me is the bottom line… you’re overinterpreting the data. also, 500,000 people in the US pale in comparison to the numbers who would benefit from cholesterol-lowering drugs.
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James Robinette
I have been taking Vytorin for several years. Three weeks ago I had 2 major heart attacks and required quadruple bypass heart surgery. Two main arteries were over 90% blocked and the two smaller arteries were 85-90% blocked. The bottom line is the Vytorin failed it’s promise and in my opinion is a failure.
CV MD
Hi James,
Unfortunately, you have advanced obstructive disease that no medication can reverse or cure. These drugs are designed to primarily treat those who have 30-70% occlusion more than anything else so that events can be reduced. Even in the most ideal circumstances, only about 40% of heart attacks acn be prevented. There is still much work to be done.
Best wishes for a non-eventful recovery.
Dr. Hans J. Kugler, PhD
Excellent discussion points! Lots of logic!
Yet, it’s all the same, all over again. Just different drug names!
News item in newspapers - - accompanied by 2-page ads for Vytorin - - - for several days. Drug company keeps making billions!
Like the LANCET (2006;368:451-58) Antiretroviral Therapy Cohort Collaboration:
20,000 AIDS patients: HAART has no - zilch - effect on death rate from AIDS up to one year. “Ah,” some drug company shareholder will say, “but if antiretroviral drugs are taken longer than 1 year?” Answer: death rate goes up. Dah!
When diagnosed HIV-positive, some people sell everything to by (at $ 5,000 to 8,000/mo.) these - ineffective drugs.
Lots of newspaper ads, publicity “ask your doctor,” and ignoring data - - - and the mega-billion-dollar HAART drug sales continue.
Could it be that all this HIV=AIDS is wrong?
Powerpoint lecture at http://www.duesberg.com.
That the - - only statstical chlesterol/heart disease connections - - are mostly wrong - - - and taking the drugs isn’t worth it?
antiagingforme.com