Merck, Vytorin & Questionable Oxford Researchers
24 CommentsBy Ed Silverman // November 22nd, 2010 // 9:23 am
Call it the Vytorin Scandal, Part Two. Last month, we learned that University of Oxford researchers, who were running a trial of the Vytorin cholesterol pill in 9,438 people with chronic kidney disease, attempted to change the composite endpoint, which would make it easier to show positive results. Merck, however, resisted, having absorbed the lessons three years ago when controversy erupted after an attempt to move the primary endpoint prompted lawsuits and investigations (see this).
Over the weekend, the next shoe fell. The Oxford researchers and Merck released results of the latest trial, called Sharp, which ran more than four years and was designed to test whether Vytorin could help prevent cardiovascular disease in people with chronic kidney disease. The trial found that 15 percent of Vytorin patients and 18 percent of patients on a placebo had a heart attack, stroke, stent procedure, or cardiovascular death. This amounts to a 16 percent reduction in risk, which Merck prominently noted in its (press release).
The Oxford press release, though, told a different and very skewed story. In their own statement, the researchers trumpted that “around a quarter of all heart attacks, strokes, and operations to open blocked arteries could be avoided in people with chronic kidney disease by using the combination of ezetimibe (Zetia) and simvastatin (Zocor) to lower blood cholesterol levels.” Where did this figure come from? They offered a scenario based on a pie-in-the-sky outcome that would presumably result if each patient had taken Vytorin for the entire trial (see the last line of the last slide).
At the same time, they never mention the primary endpoint. Moreover, the Oxford researchers maintain that Vytorin is more beneficial than Zocor, or simvastatin, alone. “The Sharp results,” they write, “are also relevant to people who don’t have chronic kidney disease.” But that turns out to be a fallacy. Why? The Sharp trial fails to offer such a conclusion, because the trial primarily compared Vytorin with a placebo.
As Harlan Krumholz, a Yale University School of Medicine professor, writes us: The study “leaves open the two questions that needed answering: whether statins or lipid lowering by other means is effective in patients undergoing dialysis - and whether (Zetia) adds to the risk reduction of a statin. The trial cannot answer these questions since there was too small a dialysis group to determine whether this strategy was effective in that group alone - and there was no comparison with a statin. So it is impossible to know if the combination of simvastatin and (Zetia) provided any additional benefit to a statin by itself…Overall, it is a study that will leave many confused about its implications for practice.”
Ironically, it was Merck (and Schering-Plough, its former Vytorin partner that is now owned by Merck) that was hammered for distortions when the scandal first erupted. Now, the Oxford researchers stand accused of questionable conduct. “The ‘breathless’ Oxford press release sent to media in advance of the presentation was highly misleading and resulted in many news stories that distorted the benefits of this therapy and minimized its risks,” Steve Nissen of the Cleveland Clinic Foundation writes us, adding that, among Vytorin patients, there was higher all cause mortality (24.6 percent versus 24.1 percent), more hemorrhagic strokes (45 vs. 37), and more cancer deaths (150 vs. 128). As CardioBrief puts it: “It’s a model of a press release that tries to manipulate the reader to adopt its view of the trial and ruthlessly suppresses all information and perspective that doesn’t support its view.”
Wall Street wags, meanwhile, view the results as a pleasant surprise, at least for Merck…
They “were about as good as they could have been,” writes Sanford Bernstein analyst Tim Anderson in a note. And Leerink Swann analyst Seamus Fernandez wrote in his own note that regulators will probably approve Vytorin for the additional indication. Nonetheless, the upside is likely to be modest, given that Vytorin was damaged by the scandal and faces a big challenge next year when generic Lipitor debuts. Even the results of Merck’s Improve-It trial, which directly compares Vytorin to simvastatin in patients with acute coronary syndrome, may not make much difference because the outcomes won’t be known until 2013, writes Deutsche Bank’s Barbara Ryan.
truth
Shame on Harlaln. The esrd and statin question has been answered. 2 major industry trials, 4d and Aurora.) No benefit and the stat sign risk of hemorhagic stroke in 4d. Do no harm.
Condor
Fabulous, Ed!
Let’s file this under “isn’t it (doubly) ironic“:
On last Tuesday morning, in Chicago, at the AHA Science Sessions — Oxford (and these same researchers!) won the role as the principal investigators (or PIs, for short), on a massive new Merck cholesterol management study, involving hundreds of millions of dollars of reallocable expense burns, 30,000 patient, multi-center, multi-continent, eight year study — called “REVEAL“ — to evaluate the efficacy of Merck’s CETP inhibitor candidate, Anacetrapib. One has to wonder whether the below is how they “won the business” — perhaps worth as much as $50 million in revenue-net-of-expenses, to Oxford — over all the otherwise “well-qualified” universities around the globe. . . .
Indeed, how. did. that. happen — exactly?
Recall also that Dr. James Stein, an independent University of Wisconsin cardiologist, believes that most, if not all, of the SHARP result may be the work of simple. cheap. generic. statins. Indeed. Spin away, ye Brits!
We’ll keep you posted — as ever. [Do go back and read Yale University's Dr. Harlan Krumholz (another independent's voice), on the Anacetrapib DEFINE results -- in view of the above (alleged) shenanigans. Makes sense to me -- when the rest of the story has outed.]
Namaste
randy brown
well is crestor better than the generic simvastatin?
they have never answered that either, but does anyone criticize them for doing multiple outcome trials without ever answering the most important question?
Former BP
SHARP results are dull. In this patinet population, the overall effect of using Vytorin was about half the overall effect of Zocor in 4S, reported in the mid 90s. In 2010, did we really learn anything from this trial. Since Zocor has repeatedly been demonstrated to be effective, why didn’t they stick with the Vytorin vs. Zocor comparison. Given the 16-17% difference between Vytorin and placebo, it probably would not have had a chance against Zocor in this trial. IMPROVE-IT results are badly needed.
CV MD
Nobody should be impressed by the poor showing of Vytorin in the SHARP trial. In fact, given what simvastatin has done by itself in multiple studies in the past, one has to wonder if ezetimibe didn’t reduce the effectiveness of simvastain in this trial. In my mind, Zetia and Vytorin remain dubious drugs.
Mike Utterback
Ed,
Has Merck ever done anything to discredit you in any way? Your writings always seem to suggest that.
Reality
It seems that Merck has been taking the low road for the past several years. I believe that this is why they have been under scrutiny and criticism. It’s a shame that this has happened to a once-great company that used to be the envy of the industry and was well-respected across industries.
vince
An interesting look at the business in the Atlantic …http://www.theatlantic.com/magazine/archive/2010/11/lies-damned-lies-and-medical-science/8269/
Ed Silverman
Hi Mike Utterback,
Sorry for the delay in responding, but I was immersed in some other things. Anyway, the short answer to your question is ‘no.’
I don’t know why you have that impression that anyone has tried to discredit me. The Vytorin and Gardasil controversies have been just that - controversies. And so the coverage is going to reflect the difficulties Merck faces. And as I noted in this post, Merck appears to have played it straight with its latest Vytorin press release. The real issue here was with the Oxford release, not Merck.
On the other hand, I’ve also tracked other developments that have been a plus for Merck, such as the results from the CETP inhibitor just last week…
http://www.pharmalot.com/2010/11/merck-cholesterol-pill-passes-a-big-hurdle/
Then there was the lawyer for the Fosamax plaintiff who was sanctioned for over-the-top courtroom behavior that upset Merck attorneys not just the judge, as well as victory in a trial last May…
http://www.pharmalot.com/2010/10/manic-fosamax-lawyer-is-sanctioned-for-singing/
http://www.pharmalot.com/2010/05/merck-wins-second-fosamax-trial/
I’ve also posted a couple of items in recent weeks about the arbitration with J&J over Remicade. You can do a search if you wish.
In short, there have been a fair amount of posts about Merck that have covered a great many topics and reveal successes and setbacks. That’s par for the course, though.
I hope this helps,
ed
Samba
The results of SHARP were not faithfully represented by the Oxford “trialists” and their role as independent scientists is forever tarnished if not invalidated. A truthful look at the data show the results on real CVD outcomes is minimal. The reporting of lipid values and changes is untruthful as well, with the “trialists” reporting a minimal LDL change for comparison to the outcomes effect. The cancer death findings are very concerning. The bias is apparent. Anything to the right of the null effect line is ignored by oxford. Anything to the left is overstated. Collins and the Oxford group are shameful marketers, disguised as trial scientists.
randy brown
i believe millions of patients are given lipitor for ACS for about the same benefit that vytorin showed in this trial.
so why is one standard of care and the other is irrelevent?
vince
There was a very interesting study in the
“Eur Heart J. 2010 Jun 6. ” Ezetimibe alone or in combination with simvastatin increases small dense low-density lipoproteins in healthy men: a randomized trial.” which concluded
……” In healthy men, treatment with ezetimibe alone is associated with the development of a pro-atherogenic LDL subfraction profile. Potentially atheroprotective effects of simvastatin are offset by ezetimibe. This study is registered with ClinicalTrials.gov, identifier no. NCT00317993. PMID: 20525999
Condor
For Randy Brown:
Um, because Vytorin® costs between 50 and 100 times MORE than a genric statin, that’s why. In 2011, Lipitor® goes generic — then it will truly be irrelvant.
http://shearlingsplowed.blogspot.com/2010/11/reiterating-dr-james-steins-central.html
Sheesh.
Namaste
Truth
The citation that Vince mentions from the Eur Heart J is very interesting. In my opinion, the efficacy of Vytorin in SHARP is quite weak. If there are adverse effects on LDL particles, this could be a potential reason why. It has been realized more and more recently that they are extremely important for fueling the progression of atherosclerosis that ultimately leads to unstable plaque and cardiovascular events. In fact, they appear to be much more important than the traditional measurement and calculation of cholesterol and LDL-C, respectively. If ezetimibe increases their numbers, this cannot be good. The information in the referenced article is not widely known in the US, but it should be.
randy brown
regarding particle size: i have not yet seen a study designed to measure the effects of altering particle size and its impact on CV outcomes.
With any drug.
Also, it appears (?) that particle number may be gaining more traction than particle size. the combination lowers particle size more than a statin alone.
so there are questions remaining for many different issues and for most, if not all, the different drugs.
why is crestor being used so much, when it has not been show to provide any benefit above simvastatin?
why is lipitor used instead of simvastatin? didn’t meet primary endpoint in head to head comparison.
questions remain for ALL lipid lowering medicines.
randy brown
sorry combo lowers particle number more than statin
Truth
Do you have a reference for the combo effects on particle number? Most compounds that increase small low-density lipoproteins raise low-density lipoprotein particle concentrations. Thanks.
EddieVos
Total, good/bad, size matters, apoB/A: it’s all nonsense to make a bad theory stick. The irony: the LDL particle with most cholesterol would be healthiest [the large 'bouyant' type that is] and why would a 10% difference in LDL diameter matter anyhow?
Put LESS trans-fat, ox-chol [dried yolk, beef jerky, crispy bacon], Advanced Glycation Endproducts but MORE omega-3, carotenoids, Q10, tocopherols in the LDL and you have a vital healthy transport vehicle.
Question: how many ‘lipidologists’ and drug reps can dance on an LDL particle?
Answer: that just depends on the money available to make them dance.
The cholesterol hypothesis was ‘flat hearth’ since GV Mann in 1977 NEJM.
If you want references why LOW cholesterol means early death, look at ref’s 4-13 in Medline 20470020, itself a good ref, or try Medline 15006277.
Statins are minor nitroglycerin mimics with some non-fatal benefit, ezetimibe is a simple ‘gut inhibitor’ without such action. Time to turn the page however the money has not run out yet.
Reality
Genetics is much more important for the development of heart disease than the food that an individual eats. Some people could be vegans and still have a markedly elevated cholesterol leading to damage in their arteries. For those people, medicines like statins definitely help.
EddieVos
Dear Reality, genes, I submit, are only important in most of us because of the micro/minor nutrients we DON’T eat, for example the 677 TT allele [the TTerrible gene]: just go to http://www.ncbi.nlm.nih.gov/pubmed and do a search for ” TT allele homocysteine ” This gene effect, as can others, can be compensated for by ingesting a multivitamin.
Before food processing, families with genetically high cholesterol lived LONGER [Kastelein, Sijbrands], i.e. it’s the “biochemical environment”, the nutrients that we DON’T get, that appear to make your genetics play either a protective or detrimental role.
It is thought that only 1 : 1000 cases genetics are truly harmful, the rest has gone extinct over the millions of years we had to refine the genome.
In practice, doctors like to tell people ‘it’s genetic’ when they really mean ‘I don’t know’ and want to send you on your way.
EddieVos
P.S. your ‘vegans’ are often the group with sky high homocysteine, with, in India, Hcy levels about 2 to 3 times they are on N. American omnivores of the same age.
If that is the long-term issue, how could statins help vegans live longer?
industry insider
Eddie, I like your lipidologist joke. It reminds me of the question: “How many psychiatrists does it take to change a light bulb?. Answer: “It depends on how much the light bulb wants to change”.
industry insider
Would someone please explain to me, if the simvastatin labeling require that patients with severe chronic renal failure (such as the GFR of 25 in SHARP) be started at a dose of 5 mg/day how a dose of 20 mg/day as was used in SHARP will be adopted into clinical practice?. Instead of using this fixed dose combination I would start with a combination of Zetia and simvastatin 10/5, then titrate up the simvastatin to the 20 mg dose used in SHARP if the patient could tolerate it. As a general rule I don’t like fixed dose combination products because of this reason.
EddieVos
Insider, thanks for that joke compliment and thanks for yours. Happy thanksgiving.
As you know, I’m no fan of statins, certainly not in end stage renal, as per AURORA’s 10 mg/d Crestor failure in ALL departments. http://www.nejm.org/doi/full/10.1056/NEJMoa0810177
My summary:
http://www.health-heart.org/CRESTOR-rosuva_JUPITER-in-perspective.gif