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BLOG: November 2008

JUPITER statin study: another BP's snow job?

In case you were wondering why is this medical study named JUPITER (Justification for the Use of Statins in the Prevention: an Intervention Trial Evaluating Rosuvastatin), the reason is probably that it has something in common with Jupiter, the planet. They both revolve around something big. Jupiter the planet revolves around Sun; for its part, JUPITER the study, as all the indications point to, revolves around Big Pharma.

It doesn't come as much of a surprise, considering that it is being sponsored by AstraZeneca, one of the world's largest pharmaceutical conglomerates manufacturing, among many others, the statin drug Crestor (rosuvastatin calcium) used in the study.

It all started back in March this year, when the news broke out that AstraZeneca has halted its study initiated in 2003, after only 1.9 years averaged per participant (with the total of 8901 participant enrolled in each, treatment and control group, 5 years per participant planned), due to "unequivocal evidence" of beneficial effect of Crestor treatment in reducing cardiovascular mortality in those with normal cholesterol level and elevated CRP (C-reactive protein, indicator of internal inflammation).

The centerpiece study figures are: rosuvastatin group had LDL ("bad") cholesterol lower by 50%, CRP by 37% and mortality from cardiovascular causes by 47%.

In celebratory tone, study results were  presented (Rosuvastatin to Prevent Vascular Events in Man and Woman with Elevated C-Reactive Protein, Ridker et al., New England Journal of Medicine, Nov. 20, 2008) as being opening new horizons in the fight against cardiovascular disease. As expected, it was followed with the anticipation of a significant increase in the number of Crestor prescriptions.

The media reports that nearly 90% of physicians surveyed see the study as a positive development, and its results anything from compelling to impressive.

What's the problem with those remaining 10%, or so, of physicians? Are they just attention-hungry spoilers, or there may be some other reason they are not jumping on the bandwagon like so many others? After all, study results are wholeheartedly accepted and greeted by - among others - American Hearth Association, and hailed as a "ground-breaking trial that will change the paradigm of cardiovascular prevention".

Let's hear what do these physicians have to say...

Make yourself comfortable, because the list is rather long, and thought-provoking.

 #1  - It is irresponsible, unprofessional and unacceptable by any acceptable standard for medical profession to terminate any study early, except when there is evidence of danger to participants; especially so for a study that proposes a long-term preventive treatment (which in this particular case may last decades). It is perfectly possible that the results at the end of 5-year period would have been different, less favorable, even negative, or that adverse effects would outweigh the benefit.

#2 - Even with the early ending, study's result indicate significantly higher incidence of diabetes among those taking rosuvastatin than in the placebo group (25%, or 3% vs. 2.4%, respectively).

#3 - No longer-term data for health consequences of lowering LDL cholesterol to an average 55mg/dL, as a result of the treatment, has been obtained, nor it is available from another reliable source; considering that, prompt initiatives following the study to revise and lower government's safe LDL cholesterol level recommendations are outright irresponsible, and very obviously motivated primarily by the financial interest of drug manufacturers.

#4 - The study has been stopped not only before the proposed long-term rosuvastatin treatment has been proven to be safe in the longer-term, but also before proving any long-term benefit.

#5 - Even if the study was ended as planned, which would have made its results more reliable, it

wouldn't provide justifiable basis for making a general
blanket recommendation for rosuvastatin treatment,

considering that more than 80% of those screened for the participation were rejected, most of them due to elevated LDL ("bad") cholesterol, or CRP. More so considering that both, elevated LDL cholesterol and CRP are only two among a number of risk factors for cardiovascular disease, and that the study did not relate mortality numbers to the individual LDL/CRP levels.

#6 - At the moment when it was stopped, the study was showing significant relative risk reduction in rosuvastatin group (83 vs. 157 deaths from cardiovascular causes, or 47% lower than in placebo group); but what is more important in deciding whether or not to recommend any therapy is the absolute risk reduction. And it is very low: 0.93% (83 out of 8900 in the treatment group) vs. 1.76% (157 out of 8900 in the placebo group). The difference of 0.83% translates into 120 patients needed to treat for 2 years (NNT=100/%differential=120) for one life saved. Taking the numbers for total deaths, the difference drops to 0.55% (NNT=182). These numbers

do not give reasonable, nor factual basis to conclude that rosuvastatin treatment is the most efficient preventive treatment
for reducing the risk of cardiovascular disease available.

#7 - Looking at the mortality figures from other than cardiovascular causes, they are actually higher in the rosuvastatin group (115) than placebo group (90). In other words, while the study's beginning indicates that a few people will live longer - at least within two years, or so - if taking rosuvastatin, more than 1/3 as many will die sooner. Not exactly reassuring statistics. Graphs supplied in the NEJM article clearly show that the curves for total mortality are much closer together for the two groups than those for cardiovascular mortality alone. This directly indicates that the mortality from other causes is higher in the rosuvastatin group. In fact, the curves for total mortality for rosuvastatin and placebo groups had started merging shortly before the study was discontinued. One has to wonder:

Wasn't it the real reason to stop the study?

Near-even total mortality figures - and, of course, possible higher total mortality with rosuvastatin - would have been a kiss of death to its prospects as a preventive treatment.

#8 - Also, looking at the figures for myocardial infraction (MI), you can see that the numbers are lower for rosuvastatin group only for "any" MI; the MI mortality figure is actually higher in rosuvastatin group by 50% (9 vs. 6), another important piece of information conveniently brushed aside in celebrating study results.

#9 - Competing interests are evident at the very top: study's lead author, who is also the chair of the steering committee, is a co-inventor of the hs-CRP (high-sensitivity CRP) test, licensed to AstraZeneca. A bit deeper, AstraZeneca would enormously benefit from opening a huge CRP-lowering market for rosuvastatin, after statins in general have shown no preventive benefits, and recent studies (CORONA trial, 2007) showed no benefits from rosuvastatin for high-risk patients either. Can it be trusted to sponsor a study that should decide if its own product - at $3.5 a day significantly more expensive than other statins, and more so than natural alternatives - is the one most suitable for the preventive treatment? Not in the real world.

#10 - Statin group had higher rate of both, myopathy (weakening of the heart muscle) and cancer, qualified by study authors as "not significant". Just how many cancers and long-term degenerative diseases in general one can expect in less than two years? The fact that they are showing after as little as 1.9 years is a legitimate reason for concern.

 The above are the main objections and questions raised by some physicians in regard to the JUPITER statin study. Seems that AstraZeneca has a tiny age-old problem: money can buy anyone, but can't buy all the people all the time. No one's that rich.

What also needs to be clarified is whether or not the results were affected by the participant profile in the two study groups. For instance:

14% of all participants reported taking aspirin, which also lowers CRP;

over 40% had metabolic syndrome (increased risk of developing heart disease, stroke and diabetes, as a result of cumulative health/lifestyle factors);

it is known that drop-out rate is high for statins, due to their unpleasant short-term side effects - was this properly accounted for when comparing the numbers for the treatment group vs. placebo?

Were participants falling into one of these three, as well as other relevant categories, near-evenly distributes in the treatment and placebo group?

Of course, a properly conducted study should have all that handled in the appropriate manner; nevertheless, and for that very reason, it still needs to be acknowledged.

What even these physicians critical of the study don't mention is the very central question: assuming that lowering CRP levels is beneficial for reducing the risk from cardiovascular disease - and most will agree it is - are there better, safer, more effective CRP-lowering alternatives to rosuvastatin? The short answer is: yes, and the list is rather longish.

 But in order to be really efficient at this, we are yet to understand specific mechanisms through which inflammation promotes cardiovascular disease. Before we do, no one can claim to have a working long-term preventive measure. Following article focuses in more detail on the subject of inflammation and cardiovascular disease.