Does A Lipitor Study Give Vytorin A Boost?
17 CommentsBy Ed Silverman // July 7th, 2008 // 4:16 pm
A study showing Pfizer’s Lipitor cholesterol med was no better than a placebo in slowing artery thickening may raised questions about the imaging technique used both in that trial and in the controversial Enhance study that prompted doubts about the effectivness of Vytorin, Dow Jones writes.
The results of the so-called Cashmere study were unexpected because previous studies have shown that Lipitor reduces the risk of heart attacks and cardiovascular events. And in a research note issued last Thursday, BMO Capital Markets analyst Robert Hazlett says this calls into question the reliability of the study’s imaging technique when used in certain patient populations.
Moreover, the new Lipitor data may provide ammunition to those who defend Vytorin and Zetia, which are marketed jointly by Schering-Plough and Merck, the newswire writes. Why? The Cashmere study was designed to use the same imaging technique as the Enhance study, which showed Vytorin was no better than Zocor at slowing artery thickening.
In both studies, patients at the start of the trial had relatively low artery disease, possibly because of prior treatment with cholesterol drugs. That may explain why the drugs were unable to show a significant benefit that was measured by CIMT, an imaging technique known as carotid intima-media thickness, which is a noninvasive ultrasound test, Dow Jones writes.
One key difference between Lipitor and Vytorin, however, is that there are still no data proving that Vytorin reduces the risk of heart attacks more than Zocor, but that previous studies did reach that conclusion about Lipitor.* A large trial designed to test Vytorin’s effect on outcomes won’t be completed until 2012 (read about that here).
However, the study, which you can read here, has some limitations - it was based on a small patient population that wasn’t a high-risk group for cholesterol, and there was a high rate of discontinuation. Another note - it hasn’t been published in a peer-reviewed journal.
The Cashmere study evaluated the effect of Lipitor on CIMT in nearly 400 post- menopausal women with moderately high levels of bad cholesterol. Roughly half were given an 80-milligram dose of Lipitor - the highest available dose - daily for up to 12 months, and the other half took a fake pill, or placebo. Patients’ artery thickness was measured at the beginning and end of treatment by CIMT tests.
The study found “no statistically significant treatment difference” between Lipitor and placebo in changes in artery thickness. Thickness increased 2.9% in the Lipitor group and 2.5% in the placebo group.
Lipitor did show a significant decrease in bad cholesterol levels versus placebo, however. People taking Lipitor experience side effects such as muscle pain and kidney infection problems. A higher percentage of Lipitor users discontinued treatment due to side effects than in the placebo group.
BMO’s Hazlett noted that the patients in both the Enhance and Cashmere studies had relatively low artery thickness at the start of the trials, when compared to patients in some other CIMT trials.
“The Cashmere results should…call into question the validity and reliability of the CIMT trials and endpoints, especially when issues such as disease severity, hypertension, and even trial conduct (to name a few), appear to confound results,” he wrote. “By extension, Cashmere could also lead to a reassessment of ENHANCE, with the notion that the less disease burdened patients, not the drugs, may be to blame for the result.”
* UPDATE: We scratched out that line because it was, unfortunately, incorrect. There is no comparative data, such as a head-to-head trial, showing a reduction in heart disease for Lipitor compared with Zocor.
ANOTHER UPDATE: In a follow-up piece, TheHeart.org quotes two docs - James Stein of the University of Wisconsin and a member of the infamous Enhance panel of experts - and Yale University’s Harlan Krumholz, who debunked Enhance at the American College of Cardiology symposium this spring, criticized the Cashmere study and noted the issue raised by Hazlett minimizes the key questions surrounding Vytorin’s effectiveness.
Dan
I don’t know about giving Vytorin a ‘boost’, but people may question thier cholesterol management a little better now.
Paul G
Ed,
To your credit, you opened your blog lines when Enhance first came out. At that point, many (including myself) called into question the value of this imaging technique.
Clearly, these products reduce hospitalizations and save lives (including the zocor component of Vytorin). They did not show benefit on a deficient test, so what?!
Ed Silverman
Hi Paul G,
Well, this just seemed like an interesting wrinkle in the whole affair, for better or worse, so I thought I’d put it out there for general consumption. I wasn’t trying to make any particular point, though.
Cheers
ed
Nathan
It’s interesting to me that the news didn’t seem to effect the Schering or Merck stock price today. I would have thought that this news would give them a nice bump. It seems somewhat obvious that investors, media, and academics over-reacted to the ENHANCE study. It could well be that the drug is as effective or more effective than Lipitor. Unfortunately we won’t know until 2012 from what I understand…
pharma pr hack
Isn’t that a little back asswards, our drug didn’t perform as expected because the patients were less diseased.. But we are trying to get the largest amount of patients possible on the drug so we are pushing it as a preventative medication.
Maybe it is really time to take a strong look at the corollary and science behind statins period for the majority of the population. In pushing out pills to everyone in the world, as a cure-all versus targeting those who are really in need - pharma is continually increasing their liability, diminishing side effects and just practicing very short-sighted business strategy.
Doc
The majority of CV events occur in vessels less than 50% occluded. Lipitor has already shown sig reductions in CV events - the hardest endpoint. It may be nice to show less arterial thickening, but event reduction is the goal. There have been studies to show an advantage to lower LDL reductions vs moderate reductions. Vytorin, if it wants a real place must complete its head to head trial with CV events as the endpoint.
Anonymous
The CASHMERE study was underpowered, only lasted 12 months, and had a high discontinuation rate. I view it as inconclusive, and don’t think it changes anything about ezetimibe. Although CASHMERE did not show an effect for atorvastatin, other imaging trials have shown an effect for statin v. placebo or high dose statin v. low dose statin. ENHANCE is still the best evidence we have on ezetimibe, since we don’t have data on its effect on clinical endpoints, and won’t for several years.
Marilyn Mann
Sorry, did not intend to be anonymous, that last comment was from me.
anonymous
LOWER IS BETTER!!! KEEP IT SIMPLE. PERIOD.
pharma pr hack
I’m sorry Doc but are there studies out there which aren’t cherry picked meta-analysis from managed care files that show Lipitor reduces CV events?
Marilyn, thank you very much for the insight. You noted the high discontinuation rate- all these trials are small periods of time but we are talking about individuals taking these medications preventatively for years.
When does the cost of outweighing an event that may or may not ever happen to you get figured in the equation? Specifically the side-effects and quality of life issues.
Bruce
The whole concept of cholesterol is way too simplistic. Its not all about a number. Lower may not mean anything. There are many elderly with no events living late into life with high LDL and their HDL is out of “norm”. They conveniently ignore this when they talk about their theories.
I am not saying don’t use statins, but I am saying I would not rush to put children on them. Lifestyle management is still the best approach.
Doc
Pharma pr hack,
Read the TIMI-22 study. Lipitor reduces CV events and death. CV event reduction is also in the FDA approved label for Lipitor.
Or read the 4S study with simvastatin, it is indicated to reduce total mortality.
Vytorin needs an outcome study that shows sig CV event reduction, then they can market it appropriately.
Dingle
Ed,
In your post above you write “there are still no data proving that Vytorin reduces the risk of heart attacks more than Zocor, but that previous studies did reach that conclusion about Lipitor.” I don’t recall Lipitor having shown an outcomes benefit vs. Zocor. They just added outcomes to their label last year, and I believe that was a study vs. placebo. What study are you referring to?
Thanks.
pharma PR hack
Doc, First paragraph of the TIMI-22 study pasted below- you’ll note two things:
1) it reduces risk - not actual events.
I can reduce the risk of auto accidents by taking the bus; It doesn’t mean I am a better driver or I won’t wreck - just lowers the probability.
2) These “reduced risk benefits” are truly limited to high risk populations for exisiting disease — not every joe smoe out there currently taking a statin.
3) the organ damage done by long term use of statin along with other drugs isn’t just a probability but a certainty. Maybe a closer looks should be taken at targeting medications for those currently in need versus preventing possible effects at the cost/certainty of creating damage.
http://www.timi.org/files/shows/prove%20it%20article%20cpc.pdf
Lowering cholesterol levels can reduce
the risk of coronary events in highrisk
patients and in those with chronic
CHD. Current ACC/AHA guidelines recommend
that lipid levels are managed through
diet, or by treatment with lipid-lowering
drugs such as statins, if LDL-C levels are
130 mg/dL. Although previous studies
suggest that the percentage decrease in
cholesterol levels is important in reducing
risk at high baseline LDL-C levels, there is
currently no evidence to demonstrate thatreducing cholesterol levels below 100
mg/dL in the majority of patients has additional
benefit.
Doc
PR Hack,
TIMI-22 was not a placebo controlled study as we know. It was vs pravastatin, however there was an absolute reduction in actual CV events using Lipitor vs using pravastatin. The Kaplan Mier curves do represent a relative risk reduction, but there was an absolute reduction in CV events also.
I do not know any practitioner who prescribes statins in patients that are not indicated for them. Your ‘certainty’ of organ damage is not proven. The use of statins has prevented many more CV events and death than any organ damage. Of course when drugs are used in combination, physicians must watch for side effects. But to say there is ‘certainty’ of organ damage is irresponsible, at best.
Curious
I’m curious as to why Merck & Shering Plough have been beaten up by EVERYONE in the media and even had congressional investigation because results of Enhance were not available for approx. 2 yrs. I understand CASHMERE (Pfizer) was completed 2 yrs ago - where’s the upset? Where’s the congressional investigation? Is Nissen going to demand everyone stop their Lipitor now too? Pfft!
dr stat
Generally, the blog does better. It fails to present the obvious. This is an additional piece of evidence, an apparently suppressed by PFE, that statins in women are not cardioprotective. This is not an obscure view, but shared by the many in the unconflicted health services research community.