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Discussing the simvastatin trial PROSPER

Martin Sturman
Eddie Vos

Marshall Deutsch

Eddie Vos

Malcolm Kendrdick

Eddie Vos

Uffe Ravnskov

Malcolm Kendrick

Martin Sturman¨

Jørgen Vesti-Nielsen

 

28. Nov 2002 

Martin Sturman
This week  Lancet: Shepherd,J, et al  Prevastatin in Elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial Vol 360;1623- Nov. 23,2002 in which it is concluded that "Prevastatin given for 3 years reduced the risk of coronary disease in elderly individual. PROSPER therefore extends to elderly individuals the treatment strategy currently used in middle aged people."  http://www.thelancet.com/journal/vol360/iss9346/full/llan.360.9346.talking_points.23262.1  There was an editorial comment published in the same issue.

Not only is the editorial comment a bit ambivalent "Given that the overall reduction in vascular events in PROSPER is not highly statistically significant,... ",  the notorious p value, as is too commonly the case, is used to test for significant significance.  No careful estimates of systematic bias are given, but most important of all -if you accept their methodology- while deaths from coronary disease, stroke, and vascular disease were apparently reduced in the treatment group, these deaths were balanced by Increased deaths from cancer and non-vascular causes. See Table 2, Endpoints of Prosper, pg. 1625 

I am aware Uffe, Paul Rosch, and others have already commented extensively on the statin controversy, but I wonder if others of our group  would like to comment on this particular paper, especially the mathematically and epidemiologically-minded  with the idea that this article is a classic Pro Statin piece, which shares many of the defects of previous articles on the subject, all of which should be again reassessed and critiqued in another New article to be submitted by The Club.   

Here is the full paper: http://pdf.thelancet.com/pdfdownload?uid=llan.360.9346.original_research.23196.1&x=x.pdf

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Eddie Vos
This is an e-mail I sent to a good friend of mine at Bristol-Myers Squibb with my take on things re PROSPER: "Few Prosper, Nobody Benefits".

Bonjour J...,
Not happy news for Pravachol: in high risk for "vascular disease" [24% of the assessed population] men/women, mean age 75, n=2891 on drug, 3.2 years later overall SURVIVAL in statin group: 89.7%, vs. 89.7% in placebo. My guess: ~$9m/US in drug cost alone to find only 8 fewer deaths, and significantly more cancer. From reading the abstract, one would never guess the outcome since mortality is not mentioned.  The "combined endpoint" masked other effects, including harm in other areas of health. 

In this study LDL was lowered by 34%.  This study joins most other statin studies that are all of short duration.  25% more new diagnosis of cancer in statin group.  There was no assessment if "patients" liked the overall effect of the drug vs. placebo, e.g. muscle pain, etc. Unfortunately this is, in my reading of the studies, the general trend for statins.

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Marshall E. Deutsch
Unless it is particularly desirable to die from one cause rather than another, total mortality is of more interest than is mortality from any given cause. After all, sky-diving without a parachute will decrease one's chance of dying from cancer, but its effect on all-cause mortality precludes recommending it as an intervention.

The control group in the PROSPER study contained 805 current smokers among 2913 subjects, while the intervention group contained only 753 smokers among 2891 subjects. Since 306 members of the control group died from all causes, compared with 298 members of the (smaller) Pravastatin group, it seems likely that the difference may be a result of the difference in the number of smokers. Bear in mind that 60% of excess deaths among smokers are caused by heart disease- lung cancer causes only 13%, and is so widely recognized as caused by smoking only because smoking increases its incidence twentyfold, while heart disease is common even in the absence of smoking.-
 
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Eddie Vos
Hello Marshall, Good points.  I find it shocking that 20 authors endorse an abstract that explains away a significantly greater new cancer incidence in elderly by invoking a meta-analysis with younger subjects and that the line: "Pravastatin had no significant effect on cognitive function or disability." did not go on to read ".. or on overall mortality." The fact that the difference in mortality was the same [+/-0.1%] was not mentioned in the abstract despite the stated aim ".. Our aim was to test the benefits of pravastatin treatment...".   The study would have benefited had the mean levels of creatine kinase been reported since loss of strength and muscle damage can occur before 10x "higher than normal" creatine kinase. 

The Discussion part of the study does not mention overall mortality either but it does touch on the observation that the "greatest benefit" in cardio-endpoints appears in [is limited to] the lower tertile of HDL [i.e. an area where niacin has a greater numerical effect than statins]. 

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Malcolm Kendrick
Is anyone here prepared to state that statins cause cancer? If so, it may be time to hit the BMJ (they seem to listen to me for some strange reasons) and say that this is the case. I still feel the need for a causal biological mechanism, but the evidence is looking pretty clear-cut, and worrying. 

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Eddie Vos
Gentlemen,  I would agree that Lancet is the more appropriate place for a reaction but BMJ is more open and accessible. I'll try and post this response on eBMJ shortly after this Thursday's appearance of the BMJ current issue

(See Rapid Response on http://bmj.bmjjournals.com/cgi/eletters/321/7267/983#29001 )

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Uffe Ravnskov
I agree - this paper should be commented. The scaring fact is that cancer was significantly (on the figure, but not in the table ?!) increased. The authors are eager to explain away this finding by performing a meta-analysis of all clinical statin trials (excluding, of course and as usual, EXCEL, where the increased mortality in the treatment group was borderline significant, but the authors didn't mention anything about the cause of death).

But this is a meaningless way of belittling the findings. The crucial question is: which types of cancer would we expect to see as the first sign of carcinogenecity. The answer is of course, those that are most easily detected, eg. skin cancers (4S and HPS), and cancers that already are present (operated breast cancers in CARE). Next crucial question: which types of patients would we expect to get cancer in the first place. And the answer to that question is of course: the elderly (PROSPER).

(See rejected letter by Ravnskov U, Rosch PJ, Langsjoen PH, Kauffman JM, McCully KS, entitled Evidence from the simvastatin trials that cancer is a probable long-term side effect.)

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Malcolm Kendrick
It does seem that statins increase the risk of cancer. But how? Without a causal hypothesis any association can be more easily dismissed. A t one time cholesterol lowering was clearly associated with increase death from accidents and violence. This was dismissed, primarily, because no-one could see any biological causal link. The link was, possibly, that cholesteral is used to create synapses in the brain, and without them brain function could well be altered in a way that may lead to more 'reckless' behaviour. The synapse connection was not known when the first studies were done, and now the association seems to have been forgotten about.  

As for cancer, I think there need to be a clear hypothesis put forward linking statins with cancer, otherwise people will just keep dismssing it. (Perhaps there is a hypothesis already, I just don't happen to have heard of it)

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Martin Sturman
Dear Malcolm - I politely disagree that a "without a causal hypothesis any association can be more easily dismissed."  Without getting into the argument about "what is (scientific) truth?", I think we are all stuck on the horns of a semantic dilemma:  When does association become causation?  Because of poor statistical power and the insistence of medical editors for the statement of the P-value, a vast confusion abounds, especially in our Soft Science of medicine, that statistical is equivalent to clinical signficance.  In this particular study, the fact that the two groups are treated and untreated, are not consistently matched to avoid strong selection bias (the excess of smokers alone in the untreated group is noted.) 

The medical literature is rife with misunderstandings of the null hypothesis.Here is a quote on the subject from Introductory Medical Statistics 2nd Ed. Mould, RF, Adam Hilger publishers1989:" If H has not been rejected at a given level of probability then we must assume that is has been accepted.  However, this really implies not proven-because we are working in terms of probability.What acceptance means is that if the hypotheses is in fact false, then the experiment was not able to detect it at the established level of significance."

I'm not much of a mathematician, but have developed over the years a profound mistrust of  the majority of clinical trials, not only the cholesterol lowering trials, but other drug and clinical trials.  If we could gather some good statisticians and probability specialists together, I suspect it could be shown that the majority of such trials are biased, misleading, or worthless.  Fertile field for some fellow "hard scientists."  This is where the cholesterol hypothesis and other hypotheses must be attacked, at their statistical claims.So much in our journals has given bull feces a bad name.

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Jørgen Vesti-Nielsen
The statins promote angiogenesis. Cancers need angiogenesis in order to spread. Elderly people have a much higher incidence of cancers of all types. A lot of the elderly must already have growing tumours, albeit still not giving symptoms. It stands to reason that statin treatment in the elderly must be connected with a higher incidence of cancer of all types, promoting the growth of tumours already there.

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