Here we go again. If you haven’t yet heard the news from the American Heart Association meeting that was held in New Orleans yesterday, here is Bloomberg’s report on a medical breakthrough that, some say, will “change the way we practice medicine.”
Bloomberg, Nov. 9: “AstraZeneca Plc’s Crestor [a cholesterol-lowering medication] slashed the risk of heart attack, stroke and death by nearly half in people with normal or low cholesterol in a study, potentially opening a way to save the lives of thousands of seemingly healthy people.”
I like that last phrase: “seemingly healthy people.” As we all know, there are no truly healthy people. Even if you think you might be healthy—you’re worried. You know there is probably something wrong with you.
Here, I can’t help but think of “The Last Well Person.” This was the title of an “Occasional Note” that Tennessee physician Clifton Meader wrote for The New England Journal of Medicine in 1994. His fiction was set in the not-too-distant future, and focuses on a 53-year-old professor of freshman algebra at a small college somewhere in the Midwest. He is…you guessed it, the very last healthy American. Using advanced medical screening, physicians have found something wrong with everyone else.
Now medical science is catching up with Meader’s science fiction. It’s beginning to look as if all of should be taking Crestor, or some other cholesterol-lowering drug (a.k.a. a statin) even if we don’t have high cholesterol.
The trial of Crestor reported at the AHA conference yesterday, showed the effect of the drug on patients who did not suffer from high levels of “bad” cholesterol—but did show high levels of a protein called CRP. It turns out that CRP is a marker for inflammation. It is tied to heart risk even in “well” people with no additional symptoms. At the moment, Crestor is approved by U.S. regulators only to lower bad cholesterol. Now, it appears that it also reduces inflammation, and other statins may have the same effect.
As a result, some experts say the study supports broad use of a
high-sensitivity CRP test to find people who may be falsely assured by
low cholesterol levels that they are protected from trouble.
High-sensitivity CRP tests are available just like cholesterol lab
tests, and some insurers will cover the cost.
Bloomberg cannot help but gush: if enough people are tested,
the news “may help double Crestor’s yearly sales to $6.33 billion by
2015, expand the $34 billion market for all cholesterol-lowering
medicine and prevent 50,000 heart complications a year, analysts and
doctors said. The results suggest an additional 6 million men over age 50 and woman over age 60, the group studied, should take the drugs.
“‘Half of heart attacks and strokes happen among apparently
healthy men and women with normal or even low levels of cholesterol,’” observes Paul Ridker, the lead investigator from Harvard Medical School in Boston. “‘We as physicians simply cannot assume our patients are at low risk just because they have low cholesterol.’”
There you go. Just because you look healthy and feel healthy doesn’t
mean you are healthy. (Ridker, by the way, holds a "use patent" on CRP
testing for heart disease risk. According to NPR, “he says the patent hasn’t affected his judgment and that the data speaks for itself.”)
Ridker’s statement reminds me of an ad from New York City’s Memorial Sloan Kettering Hospital that ran in the New York Times :
The early warning signs
of colon cancer
~~~~~~~~~~~~~~~~~~~~~~
You Feel Great
You Have a Healthy Appetite
You’re Only 50.
Drs. Steve Woloshin, Lisa Schwartz and H. Gilbert Welch reproduce this ad at the very beginning of their excellent new book: Know Your Chances: Understanding Health Statistics (How To See Through the Hype in Medical News, Ads and Public Service Announcements).
They use the ad (which looks like a tombstone) to illustrate
how health care advertising can leave you “with an exaggerated sense of
risk” The ad “says that you need to worry: if you feel well, you may
have colon cancer.”
Then there is this message: “Colon Cancer will strike about 150,000
Americans.” Of course, to make sense of this statement, you need to ask
“150,000 out of how many?” The answer is 150,000 out of 300 million—or
just 0.5 percent of the population.
Putting the Numbers in Context
Know Your Chances is all about putting the numbers describing
risks and benefits in context. And this is what Americans need to do
when they hear the news stories about Crestor. Should everyone be
tested for CRP? If it turns out your CRP levels are high should you
start downing Crestor, “just to be safe? “
In an editorial in the current issue of the New England Journal of Medicine,
Mark Hlatky, a professor of medicine at Stanford University takes a
closer look at the Cresetor study. On the one hand, “The relative risk
reductions achieved with the use of statin therapy in [the study] were
clearly significant,” Hlatky writes. In other words, when you compare
the placebo group to the group that took the medication, you find that
the percentage who suffered “hard cardiac events” was indeed cut in
half.
But then he goes on to examine “absolute differences” in risk—which involves looking at the actual number of people who benefited,
while also considering the possible side effects and other costs of
taking the medication. When you put the numbers in that context, you
find that the risk/benefit equation looks quite different.
First, while the headlines tell you that the drug slashed the
combined number of heart attacks , strokes and deaths in half—what that
really means is that the number who suffered one of these “adverse
events” was pared from 1.8% (157 out of 8901 patients who received a
placebo) to .9% (83 of the 8901 patients who took Crestor).
Hlatky sums up the medical miracle: “120 participants were treated
for 1.9 years to prevent one event.” 120—that’s the number of subject
researchers needed to treat in order to spare one person a stroke or a
heart attack. (Note, not all adverse events led to death.) For more on
“number needed to treat,” to find one patient who benefits, see Niko’s
excellent post here on Health Beat.
Here is the question you have to ask yourself: would you want to
take this drug for the rest of your life based on the possibility that
you might be the 1 out of 120 who benefits? It depends.
First, it depends on how you feel about the side effects. The
patients who took Crestor showed “significantly higher glycated
hemoglobin levels and incidence of diabetes,” Hlatky points out (3.0%,
vs. 2.4% in the placebo group). Translation: There were 270 cases of
diabetes among patients who took Crestor compared with 216 among those
on placebo.
Moreover, NPR reports that “Sidney Wolfe, of the Public Citizen’s
Health Research Group, is concerned about studies showing a [general]
increase in the incidence of diabetes in people on statins.” This study confirms that concern.
This is not the only side effect associated with cholesterol-lowering
drugs like Crestor. As we have reported on Health Beat in the past,
many patients suffer deep muscle pain, and among patients over 60, some
suffer memory loss that can mimic Alzheimer’s.
Finally,
Hlatky observes, since the trial ended after 1.9 years, we know nothing
about the long-term safety of lowering the cholesterol levels of
patients who were not showing high levels in the first place. Subjects
taking Crestor showed LDL cholesterol had fallen to 55 mg per deciliter
(1.4 mmol per liter), This is lower than cholesterol levels achieved
in any other trial. “Long-term safety is clearly important in
considering committing low-risk subjects without clinical disease to 20
years or more of drug treatment” Hlatky adds.
Then there is the cost of Crestor—roughly $3.45 per day. Medicare or
your insurer would pick up the tab. But as we all know, that means that
we all will pay for the drug in the form of higher insurance
premiums, higher Medicare co-pays, or reduced Medicare benefits.
Finally, it seems to me you that have to ask yourself, just how many
different pills are you , a relatively healthy person, willing to take
for twenty years, usually without knowing anything about low-term
risks, in the hope that you will be the 120, or the 1 in 100, or the 1
in 300 who benefits?
To its credit, the Wall Street Journal reports
that not all Wall Street analysts are convinced that AstraZeneca,
Crestor’s manufacturer, has hit the ball out of the park: “In a note to
investors, Timothy Anderson of Sanford C. Bernstein” observed “that
physician adoption of the data could be tempered by questions over the
safety of aggressive long-term treatment of patients with normal
cholesterol.”
Kudos to Anderson.
There are, after all, easier, less expensive ways, to ward off heart
attacks and stroke. For example: “Do all things in moderation.” No
risks there; and no side effects.
Or, try to reduce the stress in your life. You might begin by reading Know Your Chances. I’ll talk more about this fact-filled, funny and very persuasive book in part 2 of this post.
The thing that always troubles me with studies like this is how the percentage of those be protected is calculated.
Heart incidents went down from 1.8% to 0.9% over the two year period (I guess). So on an annual basis this would be a change of 0.45%.
Now you have to multiply this by the number of years the average person is expected to be at risk to get some sort of lifetime figure.
Similarly 150,000 cases of colon cancer is per year, so over a decade it is 1.5 million a much more worrisome figure.
A meaningful statistic would be what are your chances of avoiding some disease over your lifetime compared with the chances of suffering some adverse side effect.
I’m troubled, as are you, that they stopped the study early. Not only does this avoid the question of whether the drug is safe over the long term, but it also avoids testing for whether it remains effective.
We know that many cancer drugs, for example, only work for a limited period of time and then the disease becomes resistant.
Perhaps, along with everything else on his plate, Obama can convene a new group which will work out guidelines for what is acceptable for research from an ethical and scientific standpoint.
All that has to happen is for the FDA to adopt these new guidelines and refused to pass drugs which have faulty studies submitted. If the drug firms can’t market it, they will clean up their acts in a hurry.
Robert–
I thought about the fact that if you take the drug for 20 years instead of 2, you would be more likely to benefit.
But over 20 years, you also have to factor in the likelihood that you die of something else before ever
having a “hard cardiac event) Give that they seem to be recommending that 50-60 year olds being taking the drug, it’s pretty likely that, over 20 years, many will die of something else.
Secondly, you are also more likely to suffer side effectors from Crestor if you take it over 20 years.
The deep muscle pain, which is most common, is very painful and explains why a great many patients take themselves off statins.
On Colon cnacer (and other causes of death) Schwartz and Willoshon’s book has a great table that lets you look up your age, and see what the chances are that you will die of colon cancer of the next 10 years
(based on your sex, age and whether you ever smoked)
This may give you a better feel for just how rare it is. I you’re a 50-year-old man, your chances of dying of colon cancer over the next 10 years is 1 in 1,000.
By contrast, if you smoked, your chances of dying of lung cancer are 14 in 1000 your chances of dying of something in the next 10 years are 69 in 1000 (37 in 1000 if you never smoked
Basically, not smoking is the most important thing you could do–far more important than colonoscopies, statins, and all of the diagnostic testing in the world. (One problem with the testing is that, even if they detect the disease early on, that doesn’t mean they can cure you.)
They stopped the test early because the fact that Crestor had reduced teh number of adverse events by half (from 1.8% of placebo group to .9% in those who got Crestor) made
them feel it would be unethical to continue giving people placebo.
They also wanted to end the study to get the prodcut on the market . . .and of course, the longer you run a study, the more likely you are to discover side effects and risks.
I tend to agree with you. I would not be enthusiastic about taking a drug when we know nothing about long-term risks. But we do this all of the time.
And from the drug-makers pont of view, they can “sell” the product to doctors, the public and the media just by using phrases like “slashed in half” And by not making it quite clear that we’re not talking about 50% fewer deaths, just 50% fewer adverse events.
Of course having a heart attack if not pleasant. But it can be a use-ful wake-up call to change your diet, etc. . ..
We definitely need a new FDA that is fully funded and has teeth.
But we also have to recognize that as long as the American ppublic deeply believes that the newest, most expensive innovation can save them, they are going to protest if the FDA becomes more deliberate and selective about what it lets on the market . . .
Public education will be crucial to intelligent health care reform.
Median BMI of people in trial was 28.3; nearly one-third clinically obese; 41 percent had metabolic syndrome. None offered counseling for reversing risk factors. Trial author called his subjects “apparently healthy.”
The discussion that flows from this study will be fascinating.
Who gets to decide if the benefit from getting on crestor (or possibly any statin) after this study is worth it? The government? The insurance company? The patient and his/her doctor? Whomever is paying?
Gets to some fundamental issues, for sure, regarding who makes decisions on our health care as individuals.
merrill & pcb
Thanks for your comments.
Merrill– yes some very questionable stuff going on in terms of how they
picked patients for the trail. (Everyone interested in this topic–I urge you to see Merrill’s post on http://www.goozenews.com
pcb-
Right now, Medicare tends to agree to cover anything the FDA approves.
And then private insurers follow Medicare’s lead–and pass the cost on to us in the form of higher premiums. (Medicare passes the cost along in the form of higher co-pays and deductibles.)
Maybe, in the next administration, Medicare will get much more selective in deciding what to cover. The Comparative Effectiveness Insitute that
Congress is talking about creating would pull together unbiased reserach that should help Medicare do just that.
Again, private insurers would follow suit.
This is how these coverage decisions really should be made–by reserachers and physicians working at the federal level who have no financial interest in the outcome.
Then, if individual doctors and patients want to ignore the medical evidence and go ahead with more expensive, ineffective or marginally effective treatments, they will be free to do that. But the patient will have to pay out of pocket.
If the study holds up to scrutiny (a big if), it will be difficult for Medicare (and private insurers) not to cover statin use in those with elevated CRP, given the numbers in the trial. Not sure the public would stand for it. Calls of rationing, money over lives, etc would be pretty loud I think. A lot of stuff already covered (screening, diabetes meds, etc) have less compelling evidence, and are the standard of care.
completely overlooked in many of these discussions about taking any prescription drug for 20 years+ is the issue of “patient compliance”. From a policy perspective, even if this turns out to be the heart disease equivalent of floridation, if the plan is still to deliver it orally, day by day, don’t we want to think about compliance? access? disparities? etc.
I have a practical issue with this. I use the CRP pretty regularly for its usual indication–a marker for inflammation that usually means infection. It’s a very sensitive test, with a high false positive rate. So how can one be sure (serial testing, maybe?) that an elevated CRP doesn’t mean an occult infection or localized inflammation somewhere.
Diana & pcb–
Thanks for weighing in.
Diana-
You write “even if this turns out to be the heart disease equivalent of floridation, if the plan is still to deliver it orally, day by day, don’t we want to think about compliance? access? disparities? etc”
All excellent points. If this is indeed a huge medical breakthrough, then providing Crestor( or a generic equivalent) to everyone in a way that would mean that everyone would have access should be a public health priority–as flouridation was.
But since the days when we put flouride in the water, we have come to think about health and mor healthcare more and more in terms of individuals, and less and less in term of pubic health.
IF we want to improve hte health of the nation in an
affordable, equitable, sustainable way, we need to once again think collectively–as we did not only when we put flouride in the water, but when we gave polio vaccines to everyone.
It’s worth noting that Dr. Jonas Salk, who invented the polio vaccine, never filed for a patent on it. To do so, he suggested, “would be like trying to put a patent on sunlight.”
He wanted the vaccine to be available to everyone, which it was.
Of course polio is an infectious disease, so everyone benefited by everyone being vaccinated.
But stress, I would argue, also is an infectious disease. Think of road rage, not to mention alcholics who self-medicate to reduce stress–and then get behind the wheel of a car. , ,
Investments in public health –which includes investments in public education, safe playgrounds and parks in inner cities, a new approach to the war on drugs– all of this would make life in the U.S. less stressful, and more
healthful, for everyone.
pcb–
Unfortunately, even if the study doesn’t hold up,
the media and the publc will demand coverage for Crestor.
The media and the public will never hear
about the many questions raised about the study. Most mainstream media won’t cover it. This is why we now cover so many ineffective treatments.
But, I should add, the Internet is now doing a much better job of raising skeptical questions–and doing it in a timely fashion, just when the mainstream media is trumpeting a “miracle cure.”
As more people read blogs–and as more and more physicians, nurses,
and other health care professionals become involved in the blogosphere (writing and reading blogs) the harder it is going to be to hype
the new,new thing.
Chris–
Thanks for the comment.
From what you say, if the CRP test has false positive rate there would be no way to be sure that an elevated CRP didn’t mean an occult infection or localized inflammation somewhere . . .
I suppose serial testing would be the answer, which means more expense, more doctor’s visits for what still looks like a fairly slim chance of benefit, danger of side effects and unknown long term risks.
It’s interesting that none of enthusiastic media reports mentioned the high false positive rate (or at least none that I read).
Chris–
Thanks for your comment.
Form what you say, if the the test has a high false positive rate, and is very sensitive, there would be no way to know whether an elevated CRP means a localized inflammation.
I suppose serial testing would be the answer, but this only adds to the expense the number doctors’ visits needed when the chance of benefit remains relatively slim, the danger of side effects real, and long term risks unknown.
It’s interesting that none of the enthusiastic media reports mentioned the high false positive rate (at least none that I read)
I agree that we have a strong tendency to treat patients too aggressively in the U.S. Comparative effectiveness research can’t come soon enough, in my opinion. That said, I wonder how a Comparative Effectiveness Institute would score Crestor’s impact on heart disease risk vs. both alternative statin drugs and lifestyle changes as well as on a cost per QALY basis.
I think heart disease is different from other medical conditions in a couple of important respects. First, it’s, by far, our #1 killer as it is in most or all other developed countries as well. Second, it often kills instantly and without warning people with no prior heart disease history or symptoms. In that context, the notion of cutting risk in half, even from a comparatively small base, has understandable appeal. By contrast, if there were a drug that significantly reduced the risk that apparently healthy people would later develop, say, diabetes, arthritis, or osteoporosis, I don’t think it would create anywhere near the same level of enthusiasm or excitement.
Barry–
If I’m not mistaken, accidents, are the biggest killer.
Certainly, for middle-aged and younger people, accidents are the biggest threat.
For people 25-45, their chances of dying in an accident over the following ten years (up to 55) are signifcantly higher than their chanceds of dying to heart attack or stroke (This assumes they are not smokers. Smokers will succumb to lung disease first, heart disease after that.
See Know Your Chances– the new book I’ve been talking about. An excellent appendix at the back.
It’s only when you get plder that the chances of death by heart attadck or stroke mounts.
Moreover, we do have some control over death by heart attack and stroke: diet, exrcise and avoiding stress.
Individuals really don’t have any control over so many other things that could happen to them as they age–from Alzheimer’s to arthiritis.
This means, to me, that our emphasis on heart disease may be misplaced.
Those diseases that kill people when they are quite young (various cancers) plus those that
that torment them and their loved ones when they are quite old (various forms of senile dementia, including Alzheimer’s) seem much crueler.
It is promising to see that this type of PR blitz is being greeted with a bit more skepticism that was the norm in the past.
An example from DailyKos:
http://www.dailykos.com/story/2008/11/10/8425/8807/894/658140
And one from “US News and World Report”:
http://health.usnews.com/articles/health/heart/2008/11/11/6-ways-to-reduce-inflammation–without-a-statin-or-a-heart-test.html
Robert–
Thanks for the links.
And good for U.S. News, cautioning its readers:
“So, some experts say, if you have high CRP but are otherwise healthy, “go slow,” and consider all the benefits and risks of statins before you decide to take them.”
I’m not as surprised by Dr. STeve B on Daily Kos (who sometimse comments here); in general good blogs are more skeptical of medical miracles than the mainstream press . . .
anyone still following this thread definitely needs to read Dr. Rich’s insights over at the Covert Rationing Blog.
http://covertrationingblog.com/general-rationing-issues/limiting-crestor
i am a writer and practitioner with special interest in public health issues so i think i know what you are thinking, thanks for sharing ….