AstraZeneca’s Crestor Trial: More Hype Than Benefit

All this hype about the preventative aspects of AstraZeneca’s (AZN) Crestor study published in Sunday’s New England Journal of Medicine. Looking at Table 3 (“Outcomes”) shows only 49 fewer people died on Crestor than taking a placebo in a population of 17,802 study participants. Even less impressive, there were only 109 fewer participants who had a first time cardiac event taking Crestor versus the placebo.

It’s easy to tout percentage differences such as the endlessly reiterated 44% benefit of Crestor versus placebo, but that statistic is meaningless considering the infinitesimal number of actual events. Less than 400 cardiac events (2.2%) and under 450 total deaths (2.5%) were experienced in this extremely large study group. Given the side effects caused by statins which can necessitate additional medical treatment, it’s hard to justify the cost/benefit of medicating when the risks of this population are so low for cardiac events.

It’s fitting that the Crestor study is called Jupiter. Just like the largest planet in our solar system, AstraZeneca has big plans to expand Crestor sales to people with normal cholesterol profiles who have elevated levels of C-reactive protein (CRP) not caused by inflammatory conditions such as arthritis. Since 50% of all heart attacks occur in people with normal cholesterol levels, AstraZeneca believes CRP could be a factor in causing cardiovascular events. The Jupiter trial was fully funded and sponsored by AstraZeneca. 11,001 “apparently healthy” 60+ year old men and 6,801 50+ women with normal cholesterol profiles and no history of cardiovascular disease, but with elevated CRP levels participated. The study was divided equally between those taking Crestor and those taking a placebo. The five year study trial was halted early with a midpoint of 1.9 years of treatment. Crestor comes in 5, 10, 20, and 40 mg dosage levels. Study participants taking Crestor took the 20 mg dosage which according to information on the Crestor website, is for patients “with marked hypercholesterolemia, and aggressive lipid targets.”

This seems a bit extreme for the characteristics of this study group. Dr. Paul Ridker, a cardiologist at Harvard Medical School and Brigham and Women’s Hospital, led the Jupiter study and presented the results at yesterday’s annual scientific meeting of the American Heart Association. Dr. Ridker is an inventor of CRP-related patents held by Brigham. Dr. Ridker and his New England Journal co-authors have received grants and other fees from AstraZeneca. AstraZeneca is hoping the Jupiter study results will influence government- recommended cholesterol guidelines to be expanded next year to increase the number of prescriptions for Crestor.

Marketing Crestor specifically for elevated CRP will require the FDA to approve a label change which is not likely to happen until 2010, if at all. While Pfizer (PFE) is seeing reduced economic value in reinvesting in its cholesterol franchise (Lipitor), AstraZeneca appears to be pumping as much air in the cholesterol bubble as it can muster.

Disclosure: none

Comments

[alec.elliott:]

HELLO,
How come authors do not mention ABSOLUTE risk reduction ?
Did you notice they are less than 1% ?
You do notice death reduction is significant (18000 patients makes it easier) but is it relevant (0.5%)?

The early stoppage has no justification even pre-planned, since the placebo group patients were not harmed by treatment and it is hardly justified to decide they should all be statin treated based on just one study. It is a short time to detect potential more relevant benefits (beyond 1% in absolute risk) or late side effets (mental status deterioration and cancer require a little more time to appear).

One point makes me feel uncomfortable:
The way the authors naively try and conceal the fact there is no difference in fatal strokes or myocardial infarction in table 3 : this is ridiculous , anyone can make the maths. This is lousy data presentation spinning. Why should they do that?

Another point:
More diabetes cases, but the authors try and minimise this, stating
"minimal difference in the median glycated hemoglobin value (5.9% and 5.8%, respectively;P = 0.001)." So when that does not suit you , a significant result is tagged "minimal" ; And indeed it is minimal. They say mean glucose was not difference. But this and the glycated hemoglobin level are irrelevant to the matter of diabets. Diabetes is a qualitative diagnosis, you are or you are not diabetic. The elevated glyc. haemoglobin or glucose levels from the diabetes diagnoses are very unlikely to impact on the average values for the group. I also call this a dishonest presentation.

Hence I see in this paper where a lot of money (incentives) are at stake, some indications of a biased presentation.

Now I acknowledge there are some significant results, but :

1- When I calculate the absolute risks (that they don't indicate, why ? ) I see nothing impressive , less than 1% reductions if i'm not mistaken (absolute risk is real life, relative risk is well known and shamefully accepted in great journals as a way to enhance a result's appearance). Someone is trying to impress us. If they don't give the absolute risk then they are not satisfied with it, this is the logical conclusion.

2- When I read there aren't more muscle complaints with the statin, I am amazed. Really ? Is this consistant with what is previously known?

3 -When I compare this with the benefits of a healthy way of life (real Cretan diet or equivalent, not just olive oil, physical activity, not smoking) well I don't exactly remember the figures but (I don't have the figures to hand, so I hope I'm not wrong) if I remember well the order of magnitude of the benefits is much higher for no or little cost and extended benefits (bones, cancer , weight, glucose tolerance). This should have been mentionned in the discussion.

4- My opinion on the early interim analysis is that it was unwarranted as stated above, and it feels like a gambler who leaves the table early after a lucky hand. With more time, the results could have been more convincing with better improvements in absolute risk . With less time there is a lesser risk for side effects such as cancer or cognitive decline may be detected.

It is a pity and in my opinion, unethical, that this study was not carried out longer.
This and the aforementionned reasons make me feel someone is trying to manipulate me. This casts doubts on the study.

2008 Nov 11 06:50 PM