Call for Caution in the Rush to Statins- New York Times

November 18, 2008
Well
A Call for Caution in the Rush to Statins
By TARA PARKER-POPE

Is it time to put cholesterol-lowering statin drugs in every medicine cabinet?

Judging by recent headlines, you might think so. Last week heart researchers reported that millions of healthy people could benefit from taking statins even if they don't have high cholesterol.

Although many doctors hailed the study as a major breakthrough, a closer look at the research suggests that statins (like Crestor, from AstraZeneca, and Lipitor, from Pfizer) are far from magic pills. While they clearly save lives in people with a previous heart attack or other serious heart problems, for an otherwise healthy person the potential benefit remains small.

Many doctors who believe in using statins for heart disease say they needn't be given to healthy patients. Instead, they say, the focus should remain on encouraging healthful behavior and screening for traditional risk factors like high blood pressure and cholesterol.

"Statins have many biological effects that appear to be quite meaningful," said Dr. Valentin Fuster, director of the heart program at Mount Sinai Medical Center in Manhattan and past president of the American Heart Association. "But I don't think the answer is a magic drug to prevent disease. The answer is to change behavior."

Still, the latest study, called Jupiter, is sure to fuel interest in a blood test for something called C-reactive protein, or CRP. The test, which can cost $20 to $50, measures inflammation. Studies have shown that patients with high CRP are at higher risk for heart attack, even if they have normal cholesterol.

The researchers sought out men 50 and older and women 60 and older who had elevated CRP but not high cholesterol. The goal was to determine whether statins could improve their health.

But of nearly 90,000 people who were screened, only 17,802 were selected. That means 80 percent of the recruits were excluded for a variety of reasons — another inflammatory condition like arthritis, medication use, high blood pressure, a history of cancer and so on.

"If you extrapolate that, it means there are not all that many people exactly like those who were studied," said Dr. Nieca Goldberg, director of the women's heart program at New York University Langone Medical Center.

"But I can see a lot of people will be wanting a CRP test," she went on. "My greatest concern is that there will be many people who don't fit the criteria of the study, but based on this they will get blood tests and statin therapy."

And because of the way the Jupiter results were reported, many healthy people are likely to get an exaggerated view of statins' benefits. While the investigators reported an impressive-sounding 50 percent reduction in the risk of serious heart problems among the statin users, in reality everyone in the study had a low risk to begin with.

Only 1.8 percent of the subjects who took a placebo had a major cardiovascular problem during the study period. Among statin users, 0.9 percent did. In other words, the absolute risk of a serious cardiovascular problem (as opposed to the relative risk) was reduced by less than one percentage point.

"Absolute differences in risk are more clinically important than relative reductions in risk in deciding whether to recommend drug therapy," The New England Journal of Medicine noted in an editorial accompanying a report on the study.

An important indicator of the usefulness of a drug is the "number needed to treat," a measure of how many people needed to take a pill for just one person to be helped. There is disagreement about what Jupiter showed. The New England Journal editorial concluded that treating 120 people for about two years would help one person. The study authors, using different criteria, came up with a figure of 95.

Some researchers think the number is actually much lower. Extrapolating the data to five years, the study's authors concluded that just 25 healthy people would need to take a statin to prevent one serious heart problem.

As a result, some doctors say they will start testing for CRP and will offer statin therapy to patients whose levels are high.

"This was definitely a pretty stunning result," said Dr. Steven E. Nissen, chairman of cardiovascular medicine at the Cleveland Clinic. "I, for one, will be checking CRP in more patients. If it's elevated, we will be treating them."

Doctors said one worrisome trend did emerge in the study. In the statin group, 3 percent of the people developed diabetes during the study period, compared with 2.4 percent in the placebo group.

Moreover, because the study was stopped early (so those in the placebo group could begin taking statins for their presumed heart benefits), it did not yield much insight into the drugs' long-term safety. Nor is it clear that the early benefit shown in the statin group would have held up over a longer period or whether other risks might have emerged.

"This study does not indicate that we should be putting statins in the drinking water or fortifying cereal with statins," said Dr. Goldberg, of N.Y.U. "There are millions of people who haven't gone in and even gotten their cholesterol checked, but everybody wants the new thing. They want to believe the new thing will be the total answer."

well@nytimes.com

http://www.nytimes.com/2008/11/18/health/18well.html?8dpc=&pagewanted=print

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More analysis questioning the Crestor Study

While the New York Times, National Public Radio and all the usual uncritical media promoters of pharmaceutical "miracles" are touting the results of using statins to treat people with "normal" cholesterol levels, there are a few analysts carefully shifting through the actual data and context. Merrill Goozner of Gooznews is one of our defenders against hype, here is what he is saying about the Crestor study.
Duncan



November 09, 2008
CRP -- The Next Chapter in Medical Waste?

The latest study on statins and heart disease, which appeared in the New England Journal of Medicine website yesterday and in all the major papers this morning, is worth a second look, not because of what it says about heart disease, which is mildly interesting at best, but because of what it reveals about profit-driven medical research and how it contributes to making the U.S. health care system the most bloated and wasteful in the world.

The randomized clinical trial, code-named Jupiter, involved giving a statin drug or placebo to 17,802 "apparently healthy men and women" (their words) with normal cholesterol but elevated levels of a biomarker for inflammation called C-Reactive Protein (CRP). Did it reduce CRP levels, and did that reduce heart attacks, strokes and, most importantly, sudden death from cardiovascular disease?

The answer to both those questions is yes. But before we go to the data, the first thing you need to know about this trial is that its lead investigator, Paul Ridker of Brigham and Women's Hospital in Boston, owns a patent on the $20 test that measures CRP, and the trial was funded by AstraZeneca, whose $3.45-per-day or $1,250-per-year statin (rosuvastatin or Crestor), was used in the trial. If they can get two million more "apparently healthy men and women" on rosuvastatin, it's an additional $2 billion-plus in sales for AstraZeneca. If they can test 10 million people to find the estimated two million with elevated CRP levels (they had to screen nearly 90,000 people to find the 17,800 eligible for the trial), it's $200 million in test sales, which, if the royalty is only 1 percent, amounts to a hefty $2 million a year in extra income for Dr. Ridker.

I don't mention these conflicts of interest to cast doubt on the validity of the data presented in the NEJM paper. Rather, it puts me, as it should all analyzers of this trial, on guard to see if there were any flaws in its construction, biases in its analysis, or slants in its presentation. The answer to all three of those questions is yes.

First let's take a look at these "apparently" healthy people (men over 50 and women over 60). The median body mass index for the group was 28.3, which means more than half were significantly overweight. Indeed, a third were categorized as obese, which isn't surprising since 41 percent had metabolic syndrome, a suite of conditions that suggests the person is well down the road to developing Type II diabetes.

This profile raises some disturbing questions about the ethical oversight of this trial. Were these trial participants offered counseling about lifestyle changes necessary to avoid developing diabetes, which is recommended for people with metabolic syndrome? The methods section suggests they were only offered the right to participate in the trial, which involved taking a drug that might prevent a heart attack because they had heightened levels of CRP.

The data monitoring committee overseeing the trial stepped in to halt it once it became apparent there would be a statistically significant reduction in cardiovascular events. Where were they when the protocols were being written? Why didn't they step in at the beginning to insist that the at-risk portion of this patient population be offered the best available treatment (diet and exercise counseling) for their condition (metabolic syndrome)?

This oversight becomes even more glaring when we look at one of the more disturbing findings of the trial, noted in an accompanying editorial but "not adjudicated" by the study's endpoint committee. The group on rosuvastatin developed diabetes at a higher rate than the group given a placebo, 3.0 percent versus 2.4 percent, an increase of six-tenths of a percentage point.

Keep the size of that percentage in mind as I now turn to the actual benefits of giving the statin for elevated CRP. While the overall rate of cardiovascular incidents fell from 2.8 percent to 1.6 percent by giving the statin, the number of so-called hard events -- heart attacks and strokes, including those that were fatal -- fell from 1.7 percent in the placebo group to 0.9 percent in the statin group, a drop of eight-tenths of a percentage point.

In other words, for every person who didn't get a serious cardiovascular event, three-quarters of a person got diabetes.

We can look at the benefits another way -- in terms of the number of people who need to be treated to avoid a serious event. In this trial, 120 patients had to be treated for 1.9 years to prevent one serious cardiac event. Remember what rosuvastatin costs? $1,250 a year. That's $285,000 per event prevented just for the statin pills. The physician visits, CRP tests and lab work add additional thousands more. Can you imagine how many heart attacks and strokes could be prevented if that money were targeted at people who are truly at risk of heart disease (the obese, smokers, hypertensives, diabetics) to help them modify their lifestyles and get treatment for their underlying conditions?

There's one other curious element in the trial data. In table 4, Ridker and his fellow authors report that the number of "serious adverse events" in both arms of the trial was almost exactly equal: 15.2 percent in the statin arm versus 15.5 percent in the placebo arm. Presumably, all cardiovascular events (2.8 percent and 1.6 percent, respectively) were included in this total.

On the one hand, I'm not surprised that one in seven trial participants suffered a serious health event during the two years of this trial. The median age of this predominantly overweight group was 66, with some as old as 90.

But what were those other serious events? Alas, the study is silent on this point. I, for one, would like to have seen that data published since the raw number suggests that at the end of the day, both of these groups fared almost exactly the same. In other words, giving a statin to people with elevated CRP did nothing to improve this population's overall health.

So there you have it. A possibly unethical trial with marginal results gets trumpeted in the media as showing "wide benefit" (New York Times). Based on the laudatory quotes coming from the leaders of the American College of Cardiology, this off-label use of statins will quickly find its way into clinical practice guidelines and drug compendia. Within a few years, health care payers will be forking over billions more dollars to the statin drug makers in the name of preventing heart disease.

Meanwhile, our health care outcomes -- including cardiovascular disease -- will still rank somewhere between Romania and Poland. Health care costs will still be rising at twice the rate of overall inflation. And those truly at risk of heart disease still won't be getting the counseling that might save their lives.
Posted by gooznews at November 9, 2008 10:44 PM


http://www.gooznews.com/archives/001243.html

http://snipurl.com/5mq69

Crestor for Healthy People: A Deeper Analysis

Duncan here: If you listened to Morning Edition this morning you
would have heard an absolutely gushing piece of news about the use of
statins (specifically, Crestor) and reduction of heart attacks and
strokes in people with low cholesterol. Now if you just like your
news to be almost completely positive then go here:

http://www.npr.org/templates/story/story.php?storyId=96941206

If you would like a more skeptical view that analyzes the actual
statistics and raises a few questions about taking Crestor at $1200
for the rest of your life, then read below. It is a piece written by
Maggie Mahar author of Money-Driven Medicine and Bull Market as well
as head honcho at the Health Beat Blog.

November 10, 2008

Advice for the “Seemingly Healthy”: Know Your Chances (Part I)

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.

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