By Jerome Burne
The statin saga – do they help or harm? – took a fascinating new turn on Sunday when statin supremo Professor Sir Rory Collins confessed to the Express that he hadn’t actually done the analysis needed to uncover the true side-effect rate.
If you’ve been following this pharmacological soap, your response when you heard this was probably first amazed laughter, followed by outrage at the breath-taking hypocrisy and then, after a brief reflection, alarm at the implications.
The hilarity was prompted by the fact that for years Sir Rory has been telling everyone that statins are virtually side effect free. The outrage is because he has defended this belief, which now turns out to be far from firmly based, in ways that have nothing to do with the norms of scientific disagreement. (For background detail, go to the drop down menu “categories” at the top of this page and select “statins”).
Last summer, when a couple of articles in the British Medical Journal suggested the true side-effect figure was much higher than he was claiming, he gave an interview to the Guardian warning that thousands would die if doctors kept “creating misleading levels of uncertainty” about statins. Making people “unjustifiably suspicious” of these drugs, he said, was going to lead to deaths because people would stop taking them.
Reports of side-effects ignored for years
In fact he had no data other than what the drug companies had published – a suspect source of information. His team had only looked at the risk of cancer and serious muscle damage. They had so far ignored years of reports from doctors and patients of serious muscle pains, diabetes, cataracts, memory loss, brain fog and declining libido. So the basis for those charges of killing patients was….?
The alarm was then triggered by Sir Rory’s assumption that he was a suitable and fit person to head a new and belated analysis of the data on side effects. A telling reason why he shouldn’t do it is that he thinks the purpose “is to convince the public that statins were safe.” Now there’s a guarantee of impartiality. Later I’ll come to several others reasons why he should be kept well away from any attempt to assess statin risks.
Sir Rory heads a large and very influential, but little known outside medical circles, unit at Oxford called CTT (Cholesterol Trialists Collaboration) which holds a unique and enormous collection of drug company data. It has all the raw material gathered in the 28 or 29 large statin trials (just one trial can generate 100,000 pages) and it regularly publishes complex meta-analyses on their effects. It nearly always finds that statins are beneficial.
In fact it was one of these big CTT meta-analyses published in the Lancet in 2010 that persuaded NICE to recommend prescribing statins for another seven or eight million people in the UK last summer. The critical articles in the BMJ formed part of a campaign objecting to this extension. Other experts have made serious criticisms of the way the CTT estimated statin benefits, described below.
Risk of diabetes greater than heart protection
The issue of side-effects is a crucial part of any decision to recommend drugs for prevention, such as statins or blood pressure pills, because lots of people have to take them for one person to benefit. There is no point in handing out a drug to prevent heart attacks if only 1 in 200 of the people taking it will benefit when 1 in 50 or even 1 in 100 will suffer serious side effects.
In fact the risk, in certain patients, of developing statin induced diabetes is larger than the chance that the drug will protect you from a non-fatal heart attack, according to a new independent analysis – details below.
So Sir Rory’s admission makes it very hard to understand how his Lancet paper could have formed the basis for the decision to double the number of healthy people eligible for the drug, who were at even lower risk of heart disease than those already getting them, without having a realistic picture of the risk of side effects.
If Disney made a movie of the statin saga the Oxford CTT unit would be a vast, turreted Dracula style castle, the retreat of Sir Rory, a strict and austere man who conducted fiendishly complicated calculations on the mounds of data he kept stored in locked underground chambers. Occasionally the thick studded main door would creak open and another pronouncement on the benefits of statins would be handed out to be published in the local journal.
Lower the drawbridge at Castle Collins
The astonishing thing about Castle Collins, which has only very recently become widely known, is that the data it holds on statins really is kept secret. Now everyone from the editor of the BMJ to the head of the Commons health committee are calling for the drawbridge to be let down and the shutters opened to allow light and independent inspectors into its secret chambers.
The secrecy dates back to an agreement between CTT and the pharmaceutical companies in 1995 – in return for being given the raw data on the trials (what is published in a scientific journal is actually only a very bald summary) the CTT would not allow any other researcher to see them on the ground of commercial confidentiality. It is a deal that is no longer acceptable, given what we now know about the ability of companies to fudge and spin trials to produce favourable results.
Another result of the secrecy is a great deal of confusion about where the side effect data on statins actually is. Two years ago – before the great NICE expansion of prescribing – there had been an opportunity to do an assessment of side effects of the sort Sir Rory is at last proposing. The respected Cochrane Collaboration was doing a review of statins and buried in the foot notes is revealing exchange about the gap between the super low CTT estimate of side effects and the higher rate reported by others.
Side-effect data goes missing
Professor Harriet Rosenberg of the Health and Society Program at York University in Toronto thought one way to find out which side was right would be for the Cochrane Reviewers to examine the raw patient data but they said they couldn’t get it. “It’s not clear if the AE (adverse events) data was withheld from the Cochrane reviewers (by CTT) or were not collected in the original trials,” she wrote.
According to the lead author of the review Dr Shah Ebrahim, the CTT didn’t actually have the data. “Full disclosure of all the adverse events by type and allocation from the RCTs is now really needed,” he replied “as the CTT does not seem to have these data.”
What more damning indictment of the secrecy surrounding Castle Collins can there be? Over 20 years after these powerful drugs were introduced and doctors encouraged to keep handing them out to more and more people, not only has a proper analysis of the side effects found in clinical trials still not been done but senior people in one of the top drugs watchdogs doesn’t even know where the relevant data is.
However the mists that constantly swirl around the turrets of Castle Collins needn’t prevent us getting a reliable fix of the risks and benefits of statins. One useful study has just come out that tells you how many people need to take a statin for one person to benefit (known as NNT- numbers needed to treat) and how many for one to be harmed (NNH – numbers needed to harm).
Diabetes risk greater than heart protection
It is posted on a site called theNNT.com which is run by Professor David Newman director of clinical research at Mt. Sinai School of Medicine in New York, together with doctors at St. Luke’s-Roosevelt Hospital Center in New York City. Last month they put up an analysis which set out the risks and benefits of statins taken for five years by people who hadn’t had a heart attack but who were at high risk – most had conditions such as high blood pressure and/or diabetes or smoked.
Their risk of a heart attack (25% over the next 10 years) was much higher than the risk level that NICE decided should make people eligible (10% over ten years). That means that you would expect them to show up as getting more benefit than the lower risk NICE group.
The results were stark and simple.
NNT: Lives saved – 0
Preventing a heart attack – 1/104
Preventing a stroke – 1/154
NNH: Developed diabetes – 1/100
Muscle damage – 1/10.
In other words you are more likely to develop diabetes if you take a statin for five years than you are to avoid a heart attack and it won’t make you live any longer.
Statin benefits over-estimated
Now this is far from the final word. As Professor Newman sets out very clearly there are always problems with reviews like these that combine the data from lots of trials (meta-analyses) but it is just the sort of analysis that CTT relied on.
There is the issue of how good the individual trials were, how well they recorded side effects and assumptions made by the reviewers and so on. This study also doesn’t deal with the side-effect question in any detail – nothing about rate of muscle pains (as opposed to damage), memory problems, cataracts, brain fog and such like.
Newman concludes that deciding to take a statin when you haven’t had a heart attack “may be best left to individual preference,” because, he goes on to say, ”we believe the benefits are best-case and the harms may well be underestimated.” As far as the apparent greater risk of diabetes is concerned, he says it is more important to avoid diabetes “a chronic conditions with serious long term morbidity …than a single event such as a heart attack or stroke.”
Newman acknowledges that the conclusions of NNT.com don’t square with the CTT results but explains that it is because the Oxford group uses a unique method of calculating benefit, which his group doesn’t agree with, and which, he says, “provides potential advantage to the groups taking statins.”
Statistical magic gives statins their shine
Certainly the way Newman describes CTT approach makes it sound distinctly odd. The standard way of analysing a clinical trial is straightforward. You look at the benefit in the group getting the pill and see if it is better or worse than those getting the placebo. What Sir Rory and his CTT team do is to compare the placebo group with those getting a statin but, and this is the important bit, only with those who lowered their cholesterol the most.
In other words the placebo group is compared with those who respond best to the drug. This could be because of their genes, or because they take the pill very regularly or because they exercise more. Whatever the reason, this method seems very unlikely to tell doctors and patients anything useful about how people in general are going to respond to statin drugs.
These days when regulation of institutions needs to be seen to be tough, independent and done in the interests of customers, the idea that Sir Rory himself is the best person to ferret out the side effect data from the dungeons of Castle Collins, or possibly to prise it out of the grip of the drug companies, is very implausible.
Let’s have a clean sweep. Hand the job over to the Cochrane Collaboration possibly headed by Professor Peter Gotzsche, whose forensic and dogged examination of Tamiflu provided a much clearer evaluation of the drug than the company was providing.
Just after this post went up a paper was published showing yet another way statin researchers manipulate statistics to make very iffy trial results look really positive. The authors, David M. Diamond, a professor of psychology, molecular pharmacology and physiology at the University of South Florida, and Dr. Uffe Ravnskov, an independent health researcher and an expert in cholesterol and cardiovascular disease, show how the minimal actual benefit – one fewer heart attack among a 100 on statins – can be presented as a benefit of 30-50%. An explanation of the magic can be found here:
Diamond and Ravnskov conclude that while a a pill that promises a longer, heart attack-free life has great appeal, statins only have a small impact on heart disease while their adverse effects ‘are far more substantial than is generally known.’