January 17, 2008.
Delays and Suppression of Clinical Trial Study Results: A Tale of Two Deceptions
This has been an interesting week for medical news. First there was the announcement that the cholesterol lowering drug Vytorin (which combines Zetia (ezetimibe) with the statin Zocor (simvastatin)) does not prevent the development of atherosclerotic plaque better than Zocor alone. If anything Vytorin is worse for plaque than Zocor alone. And in spite of the fact that Vytorin reduces cholesterol to lower levels than Zocor, it isn’t better at preventing heart attacks and strokes. It didn't take long for a statement from the American Heart Association
to come sliding through the fax machine at the Emory Department of Cardiology stating that lowering cholesterol is good and that patients should not stop taking their medicines.
The obvious conflict of interest that AHA gets a million dollars a year from Merck and Schering-Plough was quickly pointed out... but denied all around. Now we have
daily full page ads in the NYT invoking us not to stop taking our Vytorin (I sing the ads in my head to the tune of the song by Journey "Don't stop believing, hang on to that feeling").
Scientists have known for years that LDL cholesterol reduction isn’t the only game in town when it comes to preventing heart attacks. Statins probably prevent heart attacks in other ways besides lowering cholesterol, and decreasing your cholesterol level doesn’t necessarily prevent a heart attack. But the cholesterol numbers game is great for marketing, especially when you can sell a drug like Vytorin to patients who didn’t get their cholesterol down with a statin alone. And when Vytorin costs over two dollars a pill and simvastatin costs less than a dollar. But what is most disturbing about this morality play is that the manufacturers, Merck and Schering-Plough, delayed publicizing the study results for almost two years. That was worth a couple of billion dollars of sales that they wouldn’t have gotten if doctors and patients knew how useless Vytorin was compared to the much cheaper generic statins.
This week in The New York Times, an article raised this issue and asked, is lowering cholesterol really the key to heart attack prevention? The article was written as if no one had ever considered the question before. And yet it was only last year Pfizer’s new drug, Torcetrapib, which lowers “bad” LDL cholesterol and raises “good” HDL cholesterol, was shown to actually increase the risk of fatal heart attacks. For years scientists in the cardiology field have known that cholesterol lowering is not the only mechanism by which statin drugs work to prevent heart attacks. They act on inflammatory pathways and by other means that are not fully understood. Why has this news been slow to disseminate to the public? Since half of Americans over age 35 have an LDL cholesterol that is in the elevated range, and since these drugs definitely lower LDL cholesterol, it is easier to sell them on that basis. In fact, Zetia got approved solely on the basis of its ability to get LDL levels down. The FDA didn’t require the manufacturer to prove that it did what we want it to do, that is prevent heart attacks.
And before we get too excited about generic simvastatin, consider how many people with multiple risk factors need to be treated for five years to save one from a heart attack. About 250. That means a risk of heart attack reduction of about 0.2%. And with the risk of muscle pain that doesn't go away right away ("That Statin is Killing My Tennis Game"). Put that stuff in your own damn drinking water.
Statin drugs modestly reduce rate of heart attack in men without heart disease...
...but they won't save your life (sorry).
Here is another example game of the numbers game run amuck: bone mineral density (BMD) testing
("Ladies, Don't Fall Into the BMD Rat Maze"). BMD testing is used to screen for osteoporosis, and drugs like Fosamax can certainly drive up BMD. The FDA approves drugs for osteoporosis based on their ability to increase bone mineral density (BMD), not based on their ability to do what we want, which is prevent fractures. Since half of women in their 70s meet criteria for osteoporosis, focusing on screening and treatment of BMD spurs drug sales. However, the increase in BMD as a result of most of these drugs is not necessarily in the part of the bone that matters. For example, one of the drugs the FDA approved, Miacalcin (calcitonin), has no positive effect on fractures.
The point is that the focus on the cholesterol and BMD number adds to the confusion of healthcare consumers and presents a distorted view of the safety and efficacy of medications. Marketing gone wild has led to a situation where half of Americans take prescription medications, and at 100,000 per year the number of deaths from prescription dwarfs those from street drugs.
Often the distortions associated with how well a drug works results from the fact that the clinical trial study data is never published. For example, analysis of data from studies of 12 antidepressant medications showed that data from 37 of 38 clinical trials that were viewed as having positive results by the FDA were published in medical journals. Out of 36 trials viewed by the FDA as negative, 22 were not published, and 11 were published in a way that made their outcome look positive (even though the FDA didn’t think it was). This means that if you look at the medical literature, you would think that 94% of the studies show that antidepressants work, when in fact only 51% were positive.
Some will argue that it is difficult to get studies published with negative results, or that people don’t get as excited about them. The implication is that negative studies are not as important as positive studies, but that simply isn’t true. We need all of the data related to drugs, not a selective sampling that presents a biases picture. And the fact is that you can always find a journal to publish negative results from large, important studies such as those reported on here. Holding back a negative study results creates a biased view of the efficacy of a drug, so that doctors, and thus the public, don’t have a good idea about how well it really works. Spinning the numbers, whether it’s the cholesterol or BMD numbers game, is not in the interest of healthcare consumers.
January 16, 2008.
ZETIA, SCHMETIA
Recently some unsettling news has come from the FDA about the risks of the cholesterol lowering medication Vytorin (a combination of Zetia (Ezetimibe) and the statin drug Zocor (simvastatin)). Data from the Enhance trial that was not previously revealed by the manufacturer, Merck/Schering-Plough, showed that the combination drug did not reduce atherosclerotic plaque any better than the generic statin drug, simvastatin, when given alone. In fact, if anything Vytorin seemed to make atherosclerotic plaque worse, although it had a greater effect on lowering cholesterol. Vytorin has also been associated with an alarming increase in risk of liver damage. In addition, the Zetia that is in Vytorin has never been shown to reduce the risk of heart attacks or strokes. And Vytorin, at $2.84 a pop, as well as Zetia ($2.63) costs a heck-of-a-lot more than simvastatin, which is less than a dollar per pill.
Doctors use cholesterol lowering drugs to get cholesterol down to normal levels. However just because a drug lowers cholesterol levels doesn’t mean it will do what patients care about most, that is save your life, or even reduce the risk of heart attacks and strokes.
The most commonly prescribed drugs to lower cholesterol, the statins, include Lipitor, Zocor, Crestor, Mevacor, and Pravachol. Statins lower LDL cholesterol by blocking an enzyme that churns out LDL cholesterol in the liver, called HMG CoEnzymeA reductase. Thirteen million prescriptions are written for statins every year. Ezetimibe (Zetia) is a drug that blocks absorption of LDL cholesterol by the small intestine, thus lowering LDL cholesterol levels in the blood. Zetia acts on cells lining the small intestine to interfere with their uptake of cholesterol.
If we followed the recommendations of the experts, cholesterol lowering drugs would be given to every American with an LDL of greater than 130 mg/dL over age 45. Since half of Americans over age 35 have an LDL greater than 130 that would mean that almost half of all Americans or 100 million people should, theoretically, be taking statins. Since a year of statins costs up to $3000, that would cost $300 billion a year. Comparing national guidelines for who should take a statin across different countries, the guidelines which called for the most liberal use of statins (you guessed it, the U.S.) which called for 25% of the population to be on statins, saved no more lives than the guidelines for one of the most restrictive countries, New Zealand, which would treat 13% of the population.
For healthy males without a history of heart disease and without risk factors for heart disease (smoking, hypertension, family history of heart disease, familial hypercholesterolemia, hypertension, obesity and diabetes), there isn’t any evidence that cholesterol lowering drugs are helpful in terms of preventing heart attacks and strokes. For men with risk factors, the majority of the studies show that they may prevent heart attacks but don’t decrease your risk of dying. Cholesterol lowering does not prevent heart attacks in women without heart disease or in men without heart disease who are over the age of 70.
And taking a statin won’t prevent you from having a heart attack or dying if you have heart disease. It only slightly lowers your risk, by about 0.2% per year.
The only study to show that statins reduce risk of death in patients without heart disease showed that although after 15 years men taking Pravachol had fewer deaths (106 versus 135 on placebo), there was a 51% increase in prostate cancer. Other studies have shown a slight increase in the risk of cancer, especially with the use of high dose statins to bring cholesterol down to very low levels. Statins can also cause liver damage, depression, memory problems, and joint pain. They can also cause damage to the muscle tissue which results in muscle pain. In rare cases this can lead to a breakdown of the muscle tissue which results in kidney failure. Zetia can headache, dizziness, diarrhea, muscle and joint pain, and more rarely jaundice, gall stones or inflammation of the pancreas.
Bottom line? The drugs you are taking to prevent heart disease may not be as useful as you think, and in some cases may be doing more harm than good. Let the buyer beware.
October 12, 2007. 3:07 p.m.
I am Having Trouble Dealing with Reality.
This week I discussed the HPV vaccine Gardasil and
a new study of the long-term effects of the statin Pravachol on this site
as well as make some posts on the topics of Gardasil and
Pravachol under related stories by Ed Silverman at pharmalot.com. This
got a response from John Mack, author of the Pharma Marketing Blog, who said I was
"Obviously biased against the pharmaceutical industry" but went on to
highlight the little gem I found (increased prostate cancer) which was
overlooked in the story by AP who said it was "safe".
I then got into an extended back and forth debate in the comments
section of pharmalot.com with someone named Reality about my critiques of
the risks of Gardasil and statins.
These exchanges caused me to spend some time in self-reflection
(don't panic, I'm a psychiatrist, I can fix myself if something goes wrong).
Did the back in forth with Reality mean that I was in conflict with Reality?
Or that I am even in denial of Reality? I reflected on the admonitions
of my agent, Susan Arellano, and the writer Karen Kelly and
editors from Avery/Penguin who have worked with me, to have a neutral and balanced tone.
After my period of self-reflection (no side effects or adverse events, don't worry)
my conclusion was that anything that deviated from an industry supported
press release could be seen as "biased" by those who authored the
original press releases. But that doesn't mean that those comments
should not be heard. I also discovered in my self-reflection that I got a kick out of getting responses
from pharma blogger (yes I will do a podcast with you) and Reality, and the fact that my brother
made a post on pharmalot.com about a Bill Maher segment right after
I did.
Researchers of the West of Scotland Coronary Prevention Study (WOSCOPS)
published a 15 year followup study of their patients who were
originally randomized to the statin pravastatin versus placebo for five years.
They reported a 25% reduction in coronary events and a statistically
significant reduction in mortality. The original
study was designed as a primary prevention study, although the authors
stacked the deck in favor of positive results by including only men with
high LDL cholesterol (>174) and with multiple risk factors, not the average
guy who walks into the doctor's office. The original study reported a 2.2%
reduction in heart attacks, which although statistically significant is
not overwhelming. All cause mortality was 135 on placebo and 106 with pravastatin,
which they reported as statistically non-significant in the
original paper (correct me if I'm wrong) but in the current paper
is re-reported as p value of 0.04 (what gives, guys?). They gave no
report of CCK elevation, indicative of muscle damage, in which a three
fold increase in dangerous elevations were seen in the original study
with pravastatin. What is more concerning, there was a statistically
significant increase in prostate cancer which went up as the years progressed;
since most clinical trials last five years there is always the concern about
long-term outcomes like cancer that can take years to progress.
Prostate cancer developed in 89 on pravastatin versus 59 on placebo, a 51% increase,
which is much greater than the 25% decrease in heart attacks.
The authors stated that the increase was "probably due to
chance and not causally related". A similar ruse was given for
the finding from PROSPER of a 25% increase in cancer, where the
authors said that it was due to "the play of chance". However, since
a recent meta-analysis looking at all trials combined showed that high
dose statins cause a statistically significant increases in cancer, I
think it is time for these researchers to start playing by the
rules of statistics, i.e. don't use statistics only when
it goes in your favor.
October 6, 2007. 8:49 p.m.
Should I Give My Wife a Statin? Do I Dare To Eat a Peach?
I shall wear white flannel trousers and walk upon the beach.
You may have read that heart disease is under diagnosed in women,
and that they are missing potential treatments that could save their lives.
For instance, in the May 10, 2004, edition of Newsweek, it was
reported that heart disease is a “grave threat to women’s health,
but no one needs to take it lying down. Statin drugs (Zocor, Lipitor, Pravachol and others)
can slash a woman’s heart-attack risk by more than a third—just
as they do in men… should you be taking one of these medications?”
The answer is—probably not. In a study that combined all of the available
information on women from the different clinical trials, the authors
found no reduction in heart attacks or mortality in women with high
cholesterol who did not have a history of heart disease.
That means that if you are a woman with high cholesterol who does
not have a history of heart disease, you should not take a statin.
But what if my cholesterol is elevated? You might ask. Just because
your cholesterol is high, and statins reduce it, doesn’t mean it will
prevent heart attacks or death. As seen in the ALL-HAT study, LDL
cholesterol came down with statins, but there was no reduction in mortality.
At this time there is no evidence that statins save the lives of women even
f they have a history of heart disease. For women who are post-menopausal
with heart disease, although the Heart Protection Study showed a reduction in
heart attacks (with no reduction in mortality), more studies, including ASCOT,
LIPID, and PROSPER, did not show any benefit. The 4S study found a 12% increase
in overall mortality for women, even though there was a 24% reduction in heart
disease related mortality. The CARE study showed a 12 fold increase in breast
cancer in women, which may explain the increased overall mortality in spite of
the reduced cardiac mortality. For women without heart disease or pre menopausal
women (even with risk factors) there is no proven benefit to taking statins.
Yet, that did not stop a national consortium of experts on women’s health
sponsored by the American Heart Association, National Institute of Health, and a
wide range of other organizations, from advocating statins for women without heart disease.
I was playing tennis today in the Atlanta Lawn Tennis Association (ALTA) league,
and my doubles partner developed pain in his calf muscle. It turns out that this was a recurring problem,
which he had linked to statin use (for lowering cholesterol). Statins in fact can cause
damage to the muscle cells, leading to muscle pain, or myopathy. When extreme this damage is called
rhabdomyolosis, as I explain in my book Before You Take That Pill,
a condition in which protein is released from the muscles which can clog the kidneys and cause
kidney failure and even death. I have had many healthy young men complain of the same side effect
on statins. If you don't have a history of heart disease and few risk factors other than
elevated cholesterol, you shouldn't take a statin. In the case of my tennis partner
since he had this rare condition he actually responds very well to statins
since his condition is caused by an alteration of the HMG Coenzyme A reductase receptor
which is corrected by statins, which are HMG Coenzyme A reductase receptor inhibitors,
so he should try a lower dose of a less potent statin.
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