Another rigged drug trial? What’s the truth behind the latest Crestor research…

I spent last Thursday at the APRIL Conference – Adverse psychiatric side effects of medicines: What’s our responsibility? I particularly enjoyed Dr Ben Goldacre’s (Bad Science) presentation entitled ‘How drug trials are rigged’.

I was reminded of his talk just this morning as I woke to be greeted by news stories about the latest study into a drug called Crestor – stories such as Wonder drug hope for heart patients and NEW WONDER HEART PILL THAT MAY SAVE MILLIONS

Millions of potential heart patients were handed a lifeline last night… a new cholesterol-lowering drug has proved so successful in trials that doctors want to speed it on to the market… the statin was found to dramatically cut illness and death rates in one of the largest studies ever conducted…the results were so surprising that the trial was stopped more than a year early so work could start on making the drug available to patients.

WOW

However all is not what it might seem, a quick search on the internet found this article about the ‘research’:

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.

And those truly at risk of heart disease still won’t be getting the counseling that might save their lives.

So – is this new ‘research’ actually research – or just another piece of drug marketing?

I’ll leave you to make up your mind, I couldn’t possibly comment!

One Response to “Another rigged drug trial? What’s the truth behind the latest Crestor research…”

  1. jeffrey dach md Says:

    It appears that journalists have a short memory.

    Only four year ago, Dr. David Graham, associate director in the FDA’s Office of Drug Safety gave senate testimony that Crestor was one of five drugs with safety concerns. The drug causes muscle breakdown and renal failure.

    Surprisingly, the Jupiter study declared there were no adverse side effects from Crestor. Or at least the adverse effects in the drug group was the same as the placebo group. This is hard to believe since the FDA has issued two advisory warnings about the adverse side effects of Crestor, and a public interest group represented by Sidney Wolfe (Public Citizen) petitioned the FDA to have Crestor banned because of side effects. In addition, Crestor is one of the strongest statins and has the worst adverse effect profile.

    To read more…
    http://jeffreydach.com/2008/11/14/crestor-jupitor-crp-and-heart-attack–by-jefffrey-dach-md.aspx


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