On March 31, 2008, pharmaceutical giant AstraZeneca trumpeted the early closing of its so-called JUIPITER trial of a cholesterol-lowering drug (statin), Crestor. The results after only two years yielded "unequivocal evidence" of the drug's effectiveness, the trial concluded, and the company argued that it could not be withheld from anyone who was well and had normal cholesterol levels but had an elevation in another normal blood constituent, the C-reactive protein (CRP).
I am the skeptical physician who is unwilling to let anyone test my cholesterol until I see unequivocal data that taking a statin yields meaningful benefit for me. Now AstraZeneca wants me to get my CRP measured so that I can swallow Crestor if it's elevated.
On Nov. 9, 2008, the results of JUPITER were published in the online edition of the New England Journal of Medicine.
I knew there was a devil in the details. Let me flush it out for you.
AstraZeneca invested a great deal in this Herculean drug trial. They contracted with physicians in over 1,300 centers in 26 countries to recruit subjects. Some 90,000 were screened and nearly 18,000 enrolled.
At each center, half the recruits were randomly assigned to swallow a placebo pill, the other half Crestor. The intent was to monitor this army of volunteers for five years to see if the groups differed in their incidence of any of the following: heart attack, stroke, hospitalization for unstable angina or for surgery on their coronary arteries and death from cardiovascular causes.
JUPITER, as is true for all modern trials, had an oversight committee charged with breaking the code periodically to see if the volunteers on Crestor were fairing better or worse than the volunteers on the placebo. The JUPITER oversight committee comprised luminaries in the world of cardiology who, like nearly all the principal JUPITER trial investigators, had declared financial involvements with the industry that serves the cardiovascular enterprise, many with AstraZeneca.
After 1.9 years, the oversight committee sounded the alarm when they noted a highly statistically significant 56 percent reduction in the incidence of these feared outcomes. The trial was terminated; AstraZeneca trumpeted the benefit of Crestor and stockholders took notice.
A reduction of 56 percent is hard to ignore -- at first blush. It conjures up an image of marshalling 100 soldiers armed with Crestor and 100 not so armed to assault the cardiovascular monster for two years, at the end of which 56 of the Crestor soldiers are the only ones left standing.
If that were true, I'd have my CRP tested today. But that's not even close to truth.
At the end of two years, about 2 percent of study participants suffered a cardiovascular event. On Crestor, 1.6 percent suffered one of the cardiovascular events, whereas it was 2.8 percent of those not afforded Crestor -- a difference of 1.2 percent.
However, not all these people were in the trial all of the first two years; they entered at different times reflecting the vagaries of recruitment. A more accurate reflection that takes this into account is to calculate for every 100 how many would have suffered one of the cardiovascular outcomes in a year in the trial. This event rate for any of the events (the "composite outcome") is 0.77 on Crestor and 1.36 without Crestor.