The Vytorin Anomaly: ‘You’ve Got To Be Worried’
25 CommentsBy Ed Silverman // July 26th, 2008 // 8:35 am
Earlier this week, the SEAS trial showed Vytorin did not help people with a heart-valve disease avoid further heart problems by reducing cholesterol. Instead, the trial found the med yielded a higher risk of developing and dying from cancer - 102 patients taking Vytorin developed cancer, compared with 67 on placebo. And of those, 39 on Vytorin died from cancer, compared with 23 taking placebo.
The lead investigator Terje Pedersen of Ulleval University Hospital in Oslo called this a “disturbing finding,” but chalked it up to chance. And Richard Peto, an Oxford University epidemiologist, said a separate analysis comparing SEAS data with two other ongoing studies, one of which he runs, found the cancer link wasn’t “credible.” He called it a “bizarre hypothesis.”
Merck and Schering-Plough, which jointly market Vytorin, are distributing a letter to any doctor who asks that says “the cancer finding in SEAS is likely to be an anomaly…that does not support an association with Vytorin.” But some prominent heart specialists seem reluctant to discount the cancer risk out of hand.
“Obviously, if you see it in one study, even if it’s not statistically significant, you’ve got to be worried,” oncologist Ezekiel Emanuel of the National Institutes of Health tells USA Today. “Maybe this has a biological mechanism we don’t know anything about.”
“Your first reaction is, ‘Is it just a chance finding?’ Then you see it in a second trial, and say, ‘Whoa, can this be true? What’s the science here?’ ” Allen Taylor, chief of cardiology at Walter Reed Army Medical Center, tells the paper.
“The cancer deaths were a surprising finding and I am skeptical of the effect. However, I am not entirely reassured by the other trials,” Yale University cardiologist Harlan Krumholz writes us. “Although a statistical analysis was not presented, it would seem that this is unlikely due to chance particularly if you do a statistical test that is just assessing whether the drug increases risk (that is, we are not testing for whether it protects against cancer).
“They do not provide enough information for the audience to make this calculation. It is true that they report that the number of fatal and non-fatal cancers is similar in IMPROVE-IT and SHARP (the two other large Vytorin trials ), but that just means that they had a concerning finding and the data from IMPROVE-IT and SHARP are mixed and do not dismiss the finding.
“From a mechanism standpoint I am not sure how it could occur, why it would affect all cancers, and why it would not increase over time. But what we have is a finding of an increase in cancer deaths that was then also shown in two other studies. Maybe a blip, but certainly not something that can be ignored.”
For another take on the issue, take a look at GoozNews
Justice in MI
As I’ve written, it’s definitely a signal - whether significant is unclear.
I’m recalling the concern about a relationship between statins and cancer early on. While the largest studies don’t seem to have borne this out, I’m wondering if there wasn’t speculation about mechanism then?
Thom
The cancer finding is probably an anomaly. Who knows? Of course, if the trial had a cancer protective signal, you’d better believer the companies would send out several press releases to breathlessly announce the results.
The real issue is that we have two trials — ENHANCE and SEAS — where we find NO evidence that Vytorin provides any cardiovascular protection.
The choice is obvious — stick with cheaper statins.
Condor
The always-on-point PM, over at Gooznews, had a very-good SEAS wrap-up piece, yesterday:
http://www.gooznews.com/archives/001125.html
A very-worthy read.
Namaste
NR
“The choice is obvious — stick with cheaper statins”.
Why of course, take the cheaper carcinogenic!
Let no one doubt that pharma and its employees will kill to profit.
The medical profession and industry wonder why we consumers take it to lawyers. It is only the law that protects us from ethics-for-sale stooges, and that, not very well.
LILLI
NR Thank you for YOUR response– Statins are Statins and it does not matter if they are less expensive. Statins remind me of the antidepressant medications. Money Making medications, the medical profession not reporting the serious dangerous probems that medications are causing. Doctors are not required to report side effects from medications,only if they volunteer. I like to know who is directing our government?—the elected officals or the medical profession, healthcare industries, hospitals, medical and pharmacueitcal lobbyists and of course the BIG PHARMA
Jeffrey Clark, CEO of Beaker.com - The Online Community for Life Sciences Professionals
Both the evidence & the negative PR are stacking up against SP & Merck in this instance. I will leave the scientific debate to those who are the experts; however, the court of public opinion (or consumer marketing) also count greatly in this instance. While DTC marketing can sway a patient population toward a particular medicinal brand, repeated stories like this can be equally effective in forcing that same group to shy away from one.
bob
Statins have been studied and restudied for well more than a decade, if there is a cancer issue the zetia may be the culprit
Justice in MI
Condor - Thanks for the link to Gooz. Useful perspective.
Anonymous
As for cheaper statins. The question seems to continue to be framed as “Is Vytorin no better than Generic Zocor”
One thing that tends to be overlooked, especially related to Enhance, is Generic Zocor/Simvastain did not get the job done!!! Patients continued to see progression of the most prevalent and fatal disease doctors routinely treat, accounting for 1/4 of all deaths in 2004.
There are options available for greater reductions in LDL from statin therapy than generics provide. The body of evidence suggest for every 1 mm/dl reduction of LDL equates to a 1% reduction of risk for an event.
For low risk uncomplicated statin therapy, Generics are a great option if they get the patient to goal. But as risk factors increase, the disease process is accelerated. As one doctor shared with me, Stroke really can be a fate worse than death.
NR
“Patients continued to see progression of the most prevalent and fatal disease doctors routinely treat, accounting for 1/4 of all deaths in 2004.”
Could it be, Anonymous, that lowering cholesterol does zip toward decreasing cardiovascular mortality, because cholesterol is not the problem?
“The body of evidence suggest for every 1 mm/dl reduction of LDL equates to a 1% reduction of risk for an event.”
What a sentence. Anybody any idea what it says? Anyone…?
Note to self: must help Ed get better commenters.
NR
Hi Lilli.
Marilyn Mann
I am posting a link to Condor’s blog, where an interesting discussion is going on:
http://shearlingsplowed.blogspot.com/2008/07/more-rigorous-reviews-of-seas-are.html
Doc
NR,
There is no doubt that statins reduce CV events and total mortality. Multiple studies have shown this in both primary and secondary prevention. West of Scotland, 4S, AFCAPs/TEXCAPS, TIMI-22 or PROVE-IT, CARE, etc.
Statins are not without side effects like any drug, but they have played a sig role in reducing CV disease around the world.
Zetia? Who knows? But statins, yes the generic cheap ones have saved many from devastating events.
Marilyn Mann
Great article by Matt Herper on some of the scientific issues:
http://www.forbes.com/healthcare/2008/06/30/cholesterol-schering-vytorin-biz-healthcare-cx_mh_0630cholesterol.html
elliottg
NR: “Note to self: must help Ed get better commenters.”
Stop commenting. Definitely will increase the average quality of commenters around here. Obviously, you don’t believe in the validity of the numerous studies that show the benefits of statins. Progression of the fatal diseases that statins treat is pretty natural. It’s called getting older. Nobody claimed that they were a fountain of youth - those claims are reserved for the arthritis and ED DTC ads.
Justice in MI
Thanks for the Forbes reference, Marilyn. I was especially curious about this bit:
“But Liao argues that Zetia might actually make this inflammation worse and therefore may have less benefit at preventing heart attacks or even, theoretically, cause some harm.”
Elsewhere in Matt’s piece, it says that crp appears to be reduced by adding zetia. Do you or anyone have speculations about by what mechanism zetia might act to increase inflammation?
Thanks for anyone’s thoughts.
Former pharma Marketing Exec
What’s missing in the studies for Vytorin is the information that is needed about the patient population in detail. What are their life styles, where to they live? Do we know for certain that any of the cancers that developed while on Vytorin were not present beforehand? No, we don’t know because for many of them we do not even have bio markers to effectively test if they are present. After the fact, is there or was there any bio material from the patient/subjects in the clinical trial to go back and do DNA and epigenetic analysis? I haven’t read if any of this was done.
Right now all we can say is there was an increase in cancer that was above what we the normal population of incidence of cancer.
What percentage of the patients in the studies had high cholesterol due to genetics rather than poor health habits? It is becoming more and more evident that poor nutrition habits and poor exercise habits lead to higher incidences of cancer. Patients with high cholesterol, unless it is genetic are at a higher risk for cancer already.
What is really distrurbing is that both Merck and SP want to send out letters essentially “blowing off” the cancer incidence data. That is unacceptable and completely unethical in my view, because we haven’t established why this is occurring.
So, we have a drug that hasn’t really shown any benefit to do what it was originally designed to do, and a higher incidence in cancer in the patient subjects who took it.
That people are being asked to “overlook” these important facts is just plain wrong.
Ther perfect storm!!!
Marilyn Mann
Hi Justice in Michigan,
I can give the general concept of what Dr. Liao means. Statins inhibit HMG-CoA reductase which causes less cholesterol to be synthesized by the body. This is part of the mevalonate pathway which also produces something called Rho-kinase, which has inflammatory vascular effects. By inhibiting HMG-CoA reductase, statins also decrease production of Rho-kinase.
When ezetimibe decreases cholesterol absorption, that causes the body to synthesize more cholesterol to try to make up for it. HMG-CoA reductase activity increases, which causes Rho-kinase to increase. So ezetimibe counteracts some of the antiinflammatory effects of statins. Hope that helps.
For a recent review article, see Chao-Yung Wang, Ping-Yen Liu and James K. Liao, Pleiotropic effects of statin therapy: molecular mechanisms and clinical results, Trends in Molecular Medicine, Vol. 14, Issue 1, January 2008, pages 37-44.
Justice in MI
Many thanks, Marilyn - That clarifies a good deal for me.
Marilyn Mann
Another link to Condor’s blog — he imbedded the videos of the debate between Drs. Taylor and Stein:
http://shearlingsplowed.blogspot.com/2008/07/of-rough-seas-and-mcluhans-you-know.html
I recommend this editorial by Dr. Taylor in the July Cleveland Clinic Journal of Medicine:
http://www.ccjm.org/ccjm_pdfs_toc/July08_Taylor.pdf
Practicing Doc
The cancer findings in SEAS are what they are. From the data I’ve seen reported, the findings met significance from a statistical point of view (p<0.05). It’s very troubling that MSP is seeking to wash this away with a letter stating their interpretation of the finding. We know that statins have CV benefits. We don’t know if Zetia (or the addition of it to simvastatin in Vytorin) does anything beneficial for morbidity or mortality. I’m not using it until I see good data from IMPROVE-IT.
Jack2
FPME in a RANDOMIZED, PLACEBO-CONTROLLED trial you don’t A) worry about the lifestyle of patients going into the trial because the study was randomized*, and B) you don’t need to check if the risk was “above what we [sic] the normal population of incidence of cancer” because the trial was placebo-controlled - you just need to compare to the placebo-group - that’s why they’re there. You did work in pharma right?
Merck and SP - did your stats correct for multiplicity? I’d also say JiM makes a good point - clearly it is a signal.
*After the trials done, you do double-check the demographics of both groups to make sure your randomization was good - and both populations were equal.
Piper
For a more informed take on ENHANCE, vs. Dr. Taylor’s editorial in the CCJ, I recommend Dr. Davidson’s recent write-up, which can also be found in this month’s CCJ: http://www.ccjm.org/ccjm_pdfs_toc/July08_Davidson.pdf
SP 2
Davidson is in SP’s back pocket! Everything he says must be taken with a grain of salt. Any patient who takes ezetimibe after hearing about SEAS is playing Russian roulette with their body. The results were statistically significant and cannot simply be dismissed as “occurring by chance.” That’s why statistics exist!!!!
Marilyn Mann
There is a possible way ezetimibe might increase cancer risk, discussed August 11 on Gooznews. Ezetimibe reduces absorption of plant sterols, aka phytosterols. Plant sterols are thought to have anticancer properties. By lowering blood levels of plant sterols in the treatment group, ezetimibe may have increased cancer risk.