Doctoring Data

I am pleased to announce that my book is finally written and edited and available to buy, on-line at http://doctoringdata.co.uk

The full, formal launch will not be until next year. But for those who cannot wait (hopefully several hundred million people), you can pre-order it now on a restricted print run. First come, first served as they say.

It has been a mighty effort to write, and I hope that people can both enjoy reading it, and feel that they have learned something by so doing. I am but your humble servant.

Eskimos and nose bleeds

I have been studying heart disease for many, many, years now and I have read hundreds of different hypotheses as to what causes it. When I say heart disease, I mean the build-up of atherosclerotic plaques (narrowings) in the arteries. This can happen in the heart, the blood vessels leading to the brain, the aorta, the femoral arteries etc. etc. Usually followed by the formation of a blood clot over the plaque – leading to death.

I have read a hundred theories as to why this happens. From infective agents, to lack of micronutrients, to stress, copper deficiency and on and on. I have read theories suggesting that plaques are actually healthy adaptations, that heart attacks happen before the blood clot blocks arteries, causing the heart attack. That atherosclerosis has nothing to do with dying of heart disease – the Japanese, with a very low rate of heart disease, are just as likely to have atherosclerosis as anyone else.

In amongst this cacophony I have searched for the one factor that is consistent, and I have found nothing. Yes, mainstream medicine is still fixated on the LDL/cholesterol hypothesis. But it is perfectly simple to find population with low LDL/cholesterol levels and stratospheric rates of heart disease. Russians and Australian aboriginals spring to mind. Equally you can find populations with high LDL/cholesterol levels and very low rates of heart disease e.g. the Swiss or the French.

This leads us to the concept of necessary and/or sufficient. By this I mean a factor may be necessary for a disease to develop. Yet that factor cannot cause the disease alone. Koch demonstrated this by drinking water full of the cholera bacillus. He did not get cholera, because he was otherwise fit and healthy. He stated that a healthy person could fight off cholera, but if you were unhealthy it could kill you.

Thus, the cholera bacillus is ‘necessary’ to get cholera, but not ‘sufficient’ – on its own. The host needs to be compromised in some way.

So, are there even any ‘necessary’ if not ‘sufficient’ factors for heart disease that have been identified? The answer is quite clearly no. Many people have died of heart disease without a single identified risk factor. In short, there is no single factor that is necessary, or sufficient, to cause heart disease.

This is why heart disease is now considered ‘multifactorial.’ It has many different causes that all, sort of, act together – in some yet to be fully defined way. Whilst this must be true, to a certain extent, the concept of multifactorial allows anyone to say virtually anything, and nothing can either be proved, or disproved.

A skeptic:        ‘Here is a population with a low LDL/cholesterol level and a high rate of heart disease.’

An expert:       ‘Ah, that is because they have a low HDL level, they lightly cook their vegetables, they have a Mediterranean diet, they drink red wine, they [insert any one of three hundred different factors here].’

This type of discussion becomes utterly pointless after a while. You cannot, ever, get anywhere. It is like attacking the Hydra. Chop one head off and another two grow. Which is why we now have, just to look at blood lipids: good cholesterol, bad cholesterol, small and dense bad cholesterol, lightly and fluffy bad cholesterol, the good/bad cholesterol ratio, ‘dyslipidaemia’, high triglycerides, LDL particle number, and on and on. Try pinning anything down and it simply fragments in front of your eyes. Currently you cannot disprove the LDL/cholesterol hypothesis as it has become the perfect shape shifter.

Which means that I decided many years ago not to waste my time on attempting to argue against the LDL/cholesterol hypothesis too often, and pointlessly. Instead I searched for the factor that is necessary to cause heart disease. The factor that is consistent, where there are no contradictions. No need for adaptations, additions, sub-theories, sub-sub-theories.

I have to report that I never found one. Yes, it is true. There is no single factor that is either necessary, or sufficient, to cause heart disease. None. Or at least none yet identified. In truth, I do not think that such a factor ever will be found. Actually I am certain that this will be so.

The reality is that you have to move away from causal factors and start thinking about processes. Here, I believe, is where the answers lie. When you start thinking about process, you can understand why the Eskimos suffer a lot of nose bleeds, and had (when eating their traditional diets), a rate of heart disease that was….zero.

You can also understand why warfarin – an anticoagulant – protects against strokes, but does not protect against heart attacks. Whereas aspirin, which is also an anticoagulant, primarily protects against heart disease.

Yes, Eskimos, nosebleeds and heart disease. And yes, I do know that they are now called Inuit. But I still like Eskimo as it conjures up positive images in my brain.

P.S. A small prize for anyone who can correctly answer the warfarin/aspirin conundrum.

What is T?

Some questions puzzle me, and I search for the answer. For a number of years I am trying to establish. ‘What is T?’ My wife helpfully remarked that it is a drink with jam and bread. Ho, ho.

Moving swiftly on. My question relates to the concept of Number Needed to Treat (NNT). The NNT is a figure widely used in medicine as an outcome measure. It means how many people do you need to treat ‘T’ to achieve a benefit of some kind. The benefit can be many different things, for example: pain relief, curing a chest infection, improving pain and mobility following a hip replacement.

In these cases the ‘T’ is pretty clear cut. You have a medical problem and you intervene in some way to make it better, or cure it. But what is the ‘T’ when you are in the world of preventative medicine? If you are trying to stop something happening e.g. a heart attack, stroke, pulmonary embolism, or death, can you call preventing such things a form of ‘treatment?’

In reality, in preventative medicine, the ‘T’ turns into something else. It has become ‘P’, as in prevent. But treating and preventing are not the same thing, and you can’t use them interchangeably.

If you have a chest infection and I give you antibiotics then I have, in most cases, treated the infection. On the other hand, if you have a high blood pressure and I ‘treat’ it, all I have done is the lower the blood pressure. I have not immediately done anything else. A high blood pressure causes no symptoms, and there is nothing to be treated – other than future risk.

In fact, if lowering the blood pressure were a form of treatment, the NNT would be very nearly one, in that I will lower the blood pressure in almost every case where I prescribe a drug. But the NNT does not refer to the effect on blood pressure lowering; it refers to the number of people you need to treat to prevent, say, a stroke, by lowering the blood pressure.

As I hope is clear, in preventative medicine, the NNT should really be the NNP.

So what, you may think. Everyone working in this area knows that the NNT is really an NNP. You just need to know that when we use the term NNT, we are really talking about the number needed to treat to ‘prevent’ an event. Yes, this is true. However, the underlying problem with nomenclature does not disappear if we change NNT to NNP. The focus simply shifts to the word prevent itself. To prevent something means to stop it happening – forever.

Now, let us imagine death.

Can we prevent death? No, clearly we cannot. We do not make people immortal by lowering their blood pressure. All we can do, the very best we can possibly do, is to increase life expectancy – by some amount. Which means that prevention does not actually mean prevention. When we look at death as an outcome, prevention can only mean life extension. Or, turning this the other way round, the amount of time by which we delay something from happening.

At this point, I hope it has become clear that ‘T’ in preventative medicine has almost nothing to do with ‘treating.’ We treat nothing, we prevent nothing, we simply delay. At least that is all we can do with death. It is possible that we may prevent things such as non-fatal strokes, although we don’t really know, because we do not usually follow people up for long enough to be certain.

Why is this important? It is important for the following reason. When many clinical trials finish, and there is a difference in the number of deaths between the treatment and placebo arm, it is claimed that the difference represents lives that have ‘been saved.’ Which is another way of saying that death has been prevented which is, in turn, a different way of saying that death has been treated. NNT.

To give an example of how this work in real life I shall switch to statins and the Heart Protection Study (HPS)

Heart Protection Study
HPS1

This graph shows the ‘mortality’ curves for the statin and placebo arms. At the start of the trial everyone is alive, 100% in both groups. Five years later, the end of the study, 92.6% of those in the statin arm were still alive, and 90.8% of those in the placebo arm were still alive. A difference of 1.8%.

This was presented, in the HPS press-release, as follows:

‘In this trial, 10 thousand people were on a statin. If now, an extra 10 million high-risk people worldwide go onto statin treatment, this would save about 50,000 lives each year – that’s a thousand a week.’ http://www.ctsu.ox.ac.uk/~hps/pr.shtml
This is a very clear statement. Treat ten million people, and you will save 50,000 lives per week. But are these lives actually saved. No, of course not. Below, I have re-drawn the graph and extended both ‘survival’ lines by a year. We now have a year six.

HPS2

As I hope is clear, by year six, if we assume the lines continue along their previous trajectory, every single extra person who was alive in the statin arm, compared to the placebo arm, is now dead. Thus 1.8% of people did not have their lives ‘saved’. In fact, the average increase in survival time for these 1.8% was approximately six months. [Half of the 1.8% would have died after six months, which give you the mean/average].

So what is ‘T’ in this case. It is certainly not treatment, prevention, or number needed to treat to prevent death. Nor is it 1.8% of lives saved. It is a life extension of six months, for 1.8%.

Or, to put this another way. If you treat one hundred people at very high risk of heart disease (secondary prevention) with statins, what you are achieving is the following:

• 1.8 will live, on average, an extra 6 months.
• 98.2 will gain no benefit

What is ‘T?’ What indeed. Not perhaps what you first thought. T, at present, is taken to mean treatment. With preventative medicine treatment is taken to mean prevention, and prevention is taken to mean lives saved. But you cannot save a life, all you can do is extend life.

So, when someone says….

‘In this trial, 10 thousand people were on a statin. If now, an extra 10 million high-risk people worldwide go onto statin treatment, this would save about 50,000 lives each year – that’s a thousand a week.’

…they are talking nonsense.

In very short summary. NNT is a widely used treatment outcome, and it guides both clinical and economic decisions on what drugs should be used, or not used. It is a pity that in preventative medicine, NNT is meaningless, because ‘T’ has no value attached to it. Indeed, it might as well be a drink with jam and bread.

Can we believe any medical research – at all?

I have now finished my book, to be called ‘Doctoring Data.’ It has taken a long time to write, mainly because I had to bring together hundreds of different strands of thinking and research. Each strand seemed to get longer and longer as I attempted to pursue them to the end. In many cases I never really found the end.

Some ideas just keep stretching away forever and I had to give up, or else the book would have become a million pages long. And I was told three hundred and ten was to be my limit – or something like that. As if my genius could be contained to a mere hundred thousand words, or so.

Anyway, the main purpose of the book was to look at medical research and data, and try to make some sense of it for those who are interested in looking beyond a medical headline. The book was, at least in part, inspired by a paper written by John Ionnadis.

It was entitled ‘Why most published research findings are false.’ You can easily find it on the internet by searching the title. It is currently the most downloaded paper in recent medical scientific literature

The shortest summary of his paper is, as follows:

Moreover, for many current scientific fields, claimed research findings may often be simply accurate measures of the prevailing bias.’ J Ionnadis.

How can it be, you may think, that most published research is false? Surely research is the one area of human endeavour where bias and dogma are ruthlessly hunted down and destroyed. A scientific finding is a scientific finding….is it not? Did Francis Bacon die in vain?

As Dogbert might say. Hahahahahahahahahahaha!

Or you might be best to pay attention to the quote from Friedrich Nietzsche. ‘There are no facts, only interpretations.’ Of course, he was a bit bonkers, but there is an awful lot of truth to what he said. Especially in medical research. Facts are the most tricky little blighters to get hold of. Interpretation, however, that is stated as fact all over the place

Surely, though, we have ways to ensure that research is pure and objective, such as peer-review. A system of using respected ‘experts’ to check and approve papers before publication. This will weed out papers that are flawed, will it not. Well, here is what Richard Horton (editor of the Lancet) has to say on peer-review:

The mistake, of course, is to have thought that peer review was any more than a crude means of discovering the acceptability — not the validity — of a new finding. Editors and scientists alike insist on the pivotal importance of peer review. We portray peer review to the public as a quasi-sacred process that helps to make science our most objective truth teller. But we know that the system of peer review is biased, unjust, unaccountable, incomplete, easily fixed, often insulting, usually ignorant, occasionally foolish, and frequently wrong.’

There we are, nice and reassuring to know that peer-review is such a fabulous system. As for the quality of published research itself, here is one of my favourite quotes by Drummond Rennie, at the time the Deputy Editor of the Journal of the American Medical Association.:

‘There seems to be no study too fragmented, no hypothesis too trivial, no literature citation too biased or too egotistical, no design too warped, no methodology too bungled, no presentation of results too inaccurate, too obscure, and too contradictory, no analysis too selfserving, no argument too circular, no conclusions too trifling or too unjustified, and no grammar and syntax too offensive for a paper to end up in print.’

A view supported from a slightly different angle by Dr Marcia Agnell, who was the editor of the New England Journal of Medicine for two decades. This was, and remains, the single most powerful and influential medical journal in the world. At least it is, when it comes to citations and impact factor:

“It is simply no longer possible to believe much of the clinical research that is published, or to rely on the judgment of trusted physicians or authoritative medical guidelines. I take no pleasure in this conclusion, which I reached slowly and reluctantly over my two decades as an editor of The New England Journal of Medicine.” Dr Marcia Agnell

Here is a further view on the issue by Richard Smith, editor of the BMJ for many years. He wrote this in his blog:

Twenty years ago this week the statistician Doug Altman published an editorial in the BMJ arguing that much medical research was of poor quality and misleading. In his editorial entitled, “The Scandal of Poor Medical Research,” Altman wrote that much research was “seriously flawed through the use of inappropriate designs, unrepresentative samples, small samples, incorrect methods of analysis, and faulty interpretation.” Twenty years later I fear that things are not better but worse…

…The poor quality of much medical research is widely acknowledged,” wrote Altman, “yet disturbingly the leaders of the medical profession seem only minimally concerned about the problem and make no apparent efforts to find a solution.”

Altman’s conclusion was: “We need less research, better research, and research done for the right reasons. Abandoning using the number of publications as a measure of ability would be a start.”

Sadly, the BMJ could publish this editorial almost unchanged again this week. Small changes might be that ethics committees are now better equipped to detect scientific weakness and more journals employ statisticians. These quality assurance methods don’t, however, seem to be working as much of what is published continues to be misleading and of low quality. Indeed, we now understand that the problem doesn’t arise from amateurs dabbling in research but rather from career researchers.’

So, Ionnadis states that most research findings may often be simply accurate measures of the prevailing bias. Current and past editors of the three most respected and powerful medical journals in the world confirm that medical research is warped, biased and flawed and, in many cases simply not believable.

Would this be very evidence used by NICE* to tell us which drugs to use – for example. Why, yes it would be. So be afraid, be very afraid. For an idiotic politician (sorry for the tautology) recently made this announcement1.

‘A Labour government could reduce variation in access to drugs and procedures by making it mandatory for commissioners to follow national clinical guidelines, Andy Burnham has revealed.’ Andy Burnham was, at one time Secretary of State for Health. His is now shadow secretary of state for health. So, if the UK votes for Labour, it will mandatory for all doctors to follow the guidelines based on the evidence that comes from clinical trials.

Oh Joy.

*NICE stands for the National Institute for Care and Health Excellence. It is supposed to review all evidence for various healthcare areas and decree what is best practice. What NICE says tends to get taken up in many, many, other countries as their views are widely respected and acted upon.

1: http://www.hsj.co.uk/news/exclusive-labour-could-make-nice-guidance-mandatory/5076286.article

My father

My father died recently, so I have been rather busy with other things. I wrote a short eulogy to him and I thought I would share it, and my memories of him, on my blog. I am not certain that this is the ‘done’ thing, but I am doing it anyway. I sort of feel the need to share it with those who are kind enough to read my blog.

My father was not a man who suffered fools gladly. In fact his favourite expression was BF, as in, bloody fool. We were all, at times, BFs. I am sure I was referred to as a BF on more occasions than I ever knew. Politicians were most certainly all BFs.

But beneath the façade of referring to everyone and most of their actions as those of a BF was a man who would, after he had finished his obligatory two minute rant, then do all that he possibly could to help someone out.

Crashed your car….you BF….then he would fix it. Needing help… he would invite foreign students into his house for the night. At heart he was, basically, a big softie. A velvet fist in a steel glove. He would forgive anyone anything – in the end.

I remember he used to sing a little song at times. At the time I never knew where it came from. Some of you may recognise it. It is incredibly rude, and incredibly sad. This is the chorus – which is the only bit I heard him sing.

It’s the same the whole world over,

It’s the poor that get the blame,

It’s the rich that get the pleasure,

Ain’t it all a bloody shame

This never seemed, to me, to be a favourite song of a man who did not care deeply about the world, and who would like to see it become a better place.

Yes he could be irascible – we all know that. Yes, he could be difficult and argumentative… and we all most certainly all know that. Yes, he too, he was a fully functioning BF at times, with bells and whistles, and there were most certainly moments when he drove me – and everyone else – completely mad. But my thoughts and memories now are almost entirely positive. As I think are those of everyone else gathered here.

As we know he did many, many things. A man of great energy and boundless enthusiasm for life. Whilst I was thinking about writing this short eulogy I remember a quote about Winston Churchill that I think best sums up my father.

When you first meet him, you see all his faults. It takes a lifetime to appreciate his virtues.

Silence was the stern reply

I thought I should share with you, a letter written to Professor Sir Rory Collins by a reader of my blog. Mr David Bailey. Of course I have ensured that I have his permission to re-print this here.

He sent the letter to me some time after he wrote to Professor Sir Rory Collins. I told I thought it was very well written and interesting. But then, as a confirmed statin/cholesterol geek, I think everything about statins is interesting [More meds please nurse].

Anyway, David Bailey wrote the letter, with the following cover note to me:

Malcolm,

I followed your GOOGLE link in your latest blog, and of course I found Sir Rory’s email address! I sent him the following letter, but I didn’t explicitly CC you, because I thought he might be less likely to take me seriously!

I hope perhaps a few of your other readers will do the same, but I don’t intend to suggest this on your blog – I don’t want this to seem organised.

All the best,

———————————————————

I replied

David

Excellent letter.

The reply will be, as follows

Dear Mr Bailey,

Thank you for you letter. Professor Sir Rory Collins is unable to respond to personal issues of this type. Message ends….

Still a good letter though. Could I put it on my blog in a couple of weeks, once you fail to gain any response at all?

Malcolm

———————————————————

That is the background, here is the letter. It is typical of many hundreds that I receive from people suffering severe and significant statin related adverse effects. In virtually every case their doctor has dismissed the adverse effects as even existing.

When, rarely, their doctor has accepted they are having adverse effects they have NEVER, according to those who write to me, made any attempt to inform the authorities that their patient has suffered a statin related adverse effect. Medwatch in the US, the Yellow Card system in the UK…

Dear Sir Rory,

I am not a medical doctor, though I have a PhD in chemistry, but I am writing to tell you of my experiences taking Simvastatin.

As I understand it, you are of the opinion that statin side effects are rare, and not important when weighed against the chance to avoid cardiovascular events.

I took Simvastatin for 3 years, and for most of that time I suffered no obvious side effects. I felt extremely positive towards this drug, because although I have not had a stroke or heart attack, anything that reduced the risk seemed like a good idea.

The side effects started rather suddenly – with extreme cramps in my right leg, which was weakened by polio when I was a child. I naturally thought I was getting Post Polio Syndrome (PPS) – a problem that I understand has no specific test. Because there was some delay before I could see a specialist, and I was struggling as my symptoms got worse, I decided to stop my Simvastatin as a precaution because I remembered that it could cause ‘muscle pains’. By that time my leg was extremely painful in the muscles and the knee joint, and it had weakened further so that my right foot would drop as I walked – potentially causing me to trip on it.

By the time I saw a polio specialist, I was not diagnosed with PPS because the symptoms were receding – I got no specific diagnosis. As I continued to improve, I decided to restart my Simvastatin, assuming that it had had nothing to do with my problems, and within a week I could feel the symptoms returning.

All in all, I stopped Simvastatin 3 times, and each time the symptoms started to reduce after a delay of about a week, and returned after I restarted the drug!

Had I not realised that Simvastatin might be causing my problems; I think I might have ended up confined to a wheelchair in considerable pain, still taking the drug! As it was, once I gave up on Simvastatin, I recovered completely over a period of about 9 months.

Of course, my situation was a bit special, but I discovered from informal discussions with others in their late 50’s and 60’s that maybe half had had problems with statins, or knew someone else who had! Some had simply discarded their tablets without discussing it with their GP, others had been given prescriptions for a succession of different statins, and had trouble with all!  One man had suffered muscle cramps and severe memory problems – both reversed after he stopped taking statins.  These were personal contacts, but of course, the internet is overflowing with stories of statin side-effects. I realise that the internet may encourage such stories, but when I combine them with my own experience and those of others I know, I am very concerned that you are so ready to endorse an even wider use of statins in people who are currently well.

I would particularly like to draw your attention to the following aspects of my case:

1)           My side effects took 3 years to manifest themselves – making it less obvious what was happening.

2)          Only my polio leg was affected, which suggests that statin side effects may start in a part of the body already damaged in some other way. This must give particular concern because it suggests that there are people out these suffering statin side effects and still taking the drug!

3)          Because I was very positive about the value of Simvastatin, it is hard to attribute what happened to me as a nocebo effect. Furthermore, the fact that I tried stopping the drug several times and observed the symptoms recede each time, means that I can be essentially certain that my troubles were indeed caused by Simvastatin!

After this experience, I have read around the entire subject of statins, cholesterol levels, and saturated fats. What I read disturbs me greatly.

1)            The evidence against saturated fats is weak except for one graph by Ancel Keys, who cherry picked his data to ‘prove’ the result he wanted!

2)           Cholesterol in the blood (or LDL/HDL) seems far less well correlated with heart attacks than I would have expected.

3)           Even though statins also block the synthesis of Co-Enzyme Q10, doctors do not seem to be warned to combine statin treatment with this supplement.

4)           Many medical researchers are concerned by the consequences of taking statins – some even suggest that statin induced muscle damage may be responsible for a rise in the incidence of heart failure in recent years!

We live in an age of openness, and I really think it would help if you debated your views with medical critics – verbally or in written form. Simply repeating that statins are safe and good for you (I paraphrase slightly) doesn’t seem to be sufficient.

Sincerely yours,

David Bailey

‘You are killing my patients’ – again

[Bring it on]

A few months ago I was part of a group that wrote a letter to the National Institute of Health and Care Excellence (NICE) criticising their proposed guidance on the use of statins in primary prevention. I drafted the letter and it was signed by such people as the President of the Royal College of Physicians, past president of the Royal College of Physicians etc. This was not, in short, a group of fringe lunatics.

It caused a bit of a stir, and generated a considerable amount of air time. After receiving the letter, NICE reviewed their guidance and decided that they had been perfectly correct to promote the use of statins in primary prevention in the UK after all. NICE, in effect, judged NICE, and found itself not guilty of anything. Well, that’s one of the benefits of being judge, jury and executioner all wrapped up together in one body.

This letter, and the dismissal of all its points, followed a nasty outbreak of hostilities in which Professor Abramson and Dr Malhotra had been attacked by Rory Collins for publishing separate, but related, papers in the BMJ. These papers suggested that adverse effects from statins were quite common. Professor Rory Collins demanded retraction of the articles and also attacked the editor of the BMJ very publically. Generating articles such as this one:

‘Professor Sir Rory Collins, from Oxford University, said he believes GPs and the public are being made unjustifiably suspicious of the drug, creating a situation that has echoes of the MMR vaccine controversy.

The academic, one of the country’s leading experts on the drug, is particularly unhappy with the British Medical Journal (BMJ), which has run well-publicised articles by two critics of statins that he argues are flawed and misleading.

“It is a serious disservice to British and international medicine,” he said, claiming that it was probably killing more people than had been harmed as a result of the paper on the MMR vaccine by Andrew Wakefield. “I would think the papers on statins are far worse in terms of the harm they have done.”’ 1

Stung by this attack, the BMJ brought together an independent panel in response to Rory Collins criticism. The result, as reported by Forbes, was as follows:

“As previously reported, Rory Collins, a prominent researcher and head of the Cholesterol Treatment Trialists’ (CTT) Collaboration, had demanded that The BMJ retract two articles that were highly critical of statins. Although The BMJ issued a correction for both papers for inaccurately citing an earlier publication and therefore overstating the incidence of adverse effects of statins, this response did not satisfy Collins. He repeatedly demanded that the journal issue a full retraction of the articles, prompting The BMJ’s editor-in-chief, Fiona Godlee, to convene an outside panel of experts to review the problem.

The report of the independent statins review panel exonerates The BMJ from wrong doing and said the controversial articles should not be retracted:

“The panel were unanimous in their decision that the two papers do not meet any of the criteria for retraction. The error did not compromise the principal arguments being made in either of the papers. These arguments involve interpretations of available evidence and were deemed to be within the range of reasonable opinion among those who are debating the appropriate use of statins.”

In fact, the panel was critical of Collins for refusing to submit a published response to the articles:

“The panel noted with concern that despite the Editor’s repeated requests that Rory Collins should put his criticisms in writing as a rapid response, a letter to the editor or as a stand-alone article, all his submissions were clearly marked ‘Not for Publication’. The panel considered this unlikely to promote open scientific dialogue in the tradition of the BMJ.””2

In short, Professor Sir Rory Collins was told that he was utterly wrong to demand retraction of the papers, and that by refusing to take part in an open discussion was trying to strangle scientific debate.

That, if you like sets the scene. A scene whereby anyone who dares to criticise statins, even a prestigious journal such as the BMJ itself, is subjected to vitriolic attacks and a demand for silence. Rory Collins tried to keep all correspondence with Fiona Godlee secret, which kind of backfired on him. Hoorah. Type ‘Rory Collins and Fiona Godlee e-mails’ into Google, and you can see for yourself.

Of course, things have not stopped here. The ‘statinators’ although briefly thwarted in their initial attack on Abramson, Malhotra and the BMJ – and less directly me – have switched track. The British Cardiovascular Society (which you will not have heard of), have decided to run a survey of their members. They are trying to gather information about the damaging impact of the articles, and the letter to NICE:

Here is an e-mail which was sent to all members:

The British Cardiovascular Society is keen to know of any potential adverse effect on cardiovascular disease prevention which may have resulted from recent media stories and articles such as those published in the BMJ (1,2) and in an open letter to NICE (3). 
We would be grateful if members would complete this short survey. Your response will be anonymous and the link below is unique to you allowing you to complete the survey once only. 
The survey closes on 30th September and results will be made available subsequently on the BCS Website and in the BCS newswire.

References

(1) Abramson JD, Rosenberg HG, Jewell N, Wright JM. Should people at low risk of cardiovascular disease take a statin? BMJ 2013; DOI:10.1136/bmj.f6123.
(2) Malhotra A. Saturated fat is not the major issue. BMJ 2013; DOI:10.1136/bmj.f6340
(3) http://www.nice.org.uk/News/Press-and-Media/nice-responds-to-criticisms-of-its-draft-guidance-on-statins
PLEASE CLICK HERE TO COMPLETE THE SURVEY 

Now, why would they be doing this? I do not think it is that difficult to work it out. The BCS is trying to gather evidence that the articles by Abramson, Malhotra and the open letter to NICE have caused harm to patients. They will be asking their members if they know of people who have stopped taking statins, or who will not go on statins, because of what they have read in the BMJ and suchlike.

Once they have done this, they will then extrapolate the raw figures to the entire population of the UK, in order to claim that ‘Thousands have died.’ Abramson will be attacked, along with Malhotra and the BMJ. I will get a few attacks as well for drafting the letter to NICE. This is a very unsubtle variation of the ‘You’re killing my patients’ tactic which is regularly used to silence any who dares criticise currently medical opinion.

At this point you may be wondering what the British Cardiovascular Society (BCS) may be, and could it possibly have any conflicts of interest with the pharmaceutical industry? Well, of course it does. The BCS is heavily reliant on the industry for its very existence. I would say totally reliant, but such bodies do not reveal detailed financial information.

However, you can start looking at what they charge for sponsorship at their conference, and begin to multiply. For example, if you want an exhibition stand at said conference, here is what you pay for an Option 1 stand3.

Option 1 – £33,500 + VAT
To include:

  • Stand – 8mx8m (64msq) island site
  • Full Page Colour advert in Heart Journal
  • Table (10 guests) at BCS Annual Dinner (Tuesday 3 June)
  • 4 x Conference Badges (company name only so transferable)
  • 20 x Stand/Exhibition Badges
  • 50 word entry in the Conference Programme and on the website
  • Opportunity to purchase additional adverts in Heart Journal

with up to a 50% discount of card rate

The BCS helpfully explains the benefits of exhibiting:

Why Exhibit?

The BCS Annual Conference is the most highly attended and respected cardiovascular event in the UK. The Exhibition is a crucial component to the success of BCS event, enabling cardiologists, physicians, scientists, physiologists and nurses to keep up to date with innovative and developing technologies, pharmacology, diagnostic equipment, educational materials and more.

Access over 2,300 cardiovascular healthcare professionals face to face – including top cardiologists, physicians, scientists, physiologists and nurses

Promote and demonstrate products and services directly to key cardiovascular healthcare professionals and gain first-hand feedback

Associate your brand/company with the Society for Cardiovascular Care – the British Cardiovascular Society

Introduce new products/services and test the market

Opportunity to network with industry peers

Of course there are other sponsorship opportunities, such as Advertising in the BCS Conference Programme, which will set you back another £10K:

Advertising in BCS Conference Programme

A copy of the Conference Programme is given to each delegate upon arrival to the event. This is the perfect opportunity to reinforce your presence and support of the BCS Annual Conference 2014.

Inside Front Cover: £2,000 + vat (exclusive)

Inside Back Cover: £2,000 + vat (exclusive)

Outside Back Cover: £2,000 + vat (exclusive)

Double Page: £2,000 + vat

Single Page: £1,200 + vat

There are limited opportunities available

I could go on, but I think you get the general drift. The BCS are funded and supported by the pharmaceutical industry. An industry that is not, currently, that bothered about statins – as the patents have run out. But it is an industry that remains extremely interested in the whole idea of lowering cholesterol. Which remains THE multi-multi-billion dollar market.

Any attack on statins threatens the foundations of this market, one that has been painstakingly constructed over the last thirty years. Keeping the cholesterol lowering idea alive, vibrant, and expanding, will make it far simpler to sell the next generation of cholesterol lowering agents that are currently lurking in the wings, engines purring.

To cut a long story short, the forthcoming attack by the BCS can be considered, to all intents and purposes, an attack by the pharmaceutical industry on anyone who dares to suggest that drugs lowering cholesterol may not be such a brilliant idea. So when you see the headlines in the newspapers damning and rubbishing Aseem Malhotra, John Abramson, and me (and a few others), you now know exactly where this attack originated, and why. Knowledge is, as they say, power.

References:

1: http://www.theguardian.com/society/2014/mar/21/-sp-doctors-fears-over-statins-may-cost-lives-says-top-medical-researcher

2: http://www.forbes.com/sites/larryhusten/2014/08/02/no-retraction-for-you-review-panel-exonerates-medical-journal-in-statin-kerfuffle/

3: http://www.bcs.com/pages/exhibition_09.asp?PageID=497&NavCatID=86

Reality control

“And if all others accepted the lie which the Party imposed – if all records told the same tale – then the lie passed into history and became truth. “Who controls the past,” ran the Party slogan, “controls the future: who controls the present controls the past.” And yet the past, though of its nature alterable, never had been altered. Whatever was true now was true from everlasting to everlasting. It was quite simple. All that was needed was an unending series of victories over your own memory. “Reality control,” they called it: in Newspeak, “doublethink.” 1984

In my first book, the Great Cholesterol Con, I included a passage about Ancel Keys by Henry Blackburn, a colleague and admirer of Keys. It points out that Ancel Keys was humiliated by George Pickering at a meeting of the WHO in Geneva 1954 discussing the new ‘epidemic’ of heart disease. The quote from Henry Blackburn finishes thus:

My theory is that Keys was so stung by this event that he left the Geneva meeting intent on gathering the definitive evidence to establish or refute the Diet-Heart theory. Out of this single, moving, personal experience – so my theory goes – came the challenge, the motivation, the implantation of the Seven Countries Study.’

As I wrote in the book. ‘So there you have it. As a result, Ancel Keys stormed off, put together a huge research budget, hired a staff of thousands, did his study and was the able – in objective ‘scientific speak,’ of course – to say ‘I told you so, I told you so. Nyah, nyah, nyah.’ Not, as I pointed out, the best possible motivation for a research project.

Of course you are going to have to take my word on the exact events described. For, shortly after my book was published, this passage was removed from the University website it was on, never to be seen again. Cause and effect, who can say? But it does raise an important issue. If there is no record of a thing happening – did it happen? If you control the historical record, what is truth?

In the age of the Internet you might think it is more difficult to hide the historical record, but in some ways it is easier. If something only exists on a server somewhere, all you need do is delete it and it is gone – forever. Unless you ensure that you archive it yourself – something I did not do with the Henry Blackburn quote.

At this point you may wonder where this is all going. Well, for some years, I have used statistics from the European Heart Survey which looks at data from nearly a million people. The latest version is here http://www.bhf.org.uk/publications/view-publication.aspx?ps=1002098. This is very impressive bit of research, and is full of good stuff. For a few years I have included statistics from this study to produce tables such as the one below (See table).

guessinggame

The table makes it very clear that saturated fat intake has absolutely nothing to do with the rate of CHD deaths in any country in Europe. In fact, in general, the association is completely inverse i.e. the more saturated fat you eat, the lower the rate of coronary heart disease (CHD). Twenty times as low in France, as Georgia, despite the French eating three times as much saturated fat. This, of course, completely contradicts everything you have ever read about the impact of saturate fat on heart disease.

Jerome Burne, a friend and colleague, and medical journalist, wanted to use a couple of my tables for his blog. So I sent them over. He pointed out that my data was from the 2008 survey. In the latest 2012 survey – it take some time for the data to be published – the figures on saturated fat intake have simply gone. They are no longer published at all.

I hurriedly went back to the search the 2008 data to make sure that this had not been wiped from the record. They have not, although it is rather more difficult to find. I have now stored these data on my computer, and archived them. For I suspect that these data on saturated fat intake will gradually disappear from the historical record.

Of course, I am going to write to the researchers in charge of the European Heart Statistics and ask them why, of all the data, the data on saturated fat no longer features. Why have they done this? I strongly suspect I know the answer, and I suspect that you do to.

I am going to write although I already know the type of answer I will get. It will be some complete fudge, not answering the question but saying something along the lines of ‘Our panel of International Experts constantly review the data that we include and make decisions based on priorities that are determined by many different factors. For various reasons not all data are included, but we are always working to ensure that everything is done to provide the most useful and up to date information. Unfortunately, it is not possible to enter a discussion on specific issues.’ Beep, message ends.

It has long amused me the European Heart Statistics – if you look through them carefully – contradict almost everything we have ever been told about the causes of heart disease. Of course they are now somewhat less contradictory, because they have removed the data on saturated fat.

“Day by day and almost minute by minute the past was brought up to date. In this way every prediction made by the Party could be shown by documentary evidence to have been correct; nor was any item of news, or any expression of opinion, which conflicted with the needs of the moment, ever allowed to remain on record. All history was a palimpsest, scraped clean and reinscribed exactly as often as was necessary.” 1984

Watch this

Someone I have come to know recently is Dr David Newman, Director of Clinical Research in Mount Sinai University, New York. He has been a great thorn in the flesh of the ‘statinators’ recently. He runs a website called http://www.thennt.com/ I recommend that everyone goes and has a look at it.

He is very concerned about providing information to the public that they can understand about various medical interventions. His work is excellent, he is clear, passionate and (nearly) 100% correct about everything.

He gave a talk called ‘The truth that lasts’ and you can catch it on you tube here. https://www.youtube.com/watch?v=UCk_vTkS6bU

For those of you, who have not had a heart attack or stroke, and are on statins, or are bullied into going onto statins, I suggest that you watch this. It is seventeen minutes long, and will be the most valuable seventeen minutes you have spent in your life.

Best wishes.

The planet Vulcan

I love reading about the history of science. In part, because I think you can learn so much about the process of thinking itself. Especially when it goes wrong. More especially when you are looking at the process of immunisation.

Immunisation is something that Karl Popper was particularly interested in. Popper was a scientific philosopher who is a bit of a hero of mine (when I can actually understand what he is saying). Amongst many other things, he was interested in the techniques used by scientists to protect favoured scientific hypotheses, which he called ‘immunisations’.

An immunisation is essentially a way of explaining why a fact, which appears to contradict a favoured hypothesis, does not actually contradict it at all. For example, when it was found that the orbit of the planet mercury could not be explained by classical Newtonian physics, a mathematician called Le Verrier postulated that there must be another, smaller, planet inside the orbit of Mercury that was affecting Mercury’s orbit. The planet Vulcan.

Vulcan was invisible – primarily because it did not exist. But for many years the invisible and non-existent planet served its purpose. It protected classical Newtonian physics from a potential contradiction, or refutation. Or, to be more blunt, of being simply wrong. In this case, scientists were quite happy to believe in invisible non-existent things, if the alternative was to cast aside a hallowed hypothesis.

Of course, this is just one of thousands of examples whereby unwelcome facts have been simply swatted aside, or immunised against. It is not just the Catholic Church that refuses to look through telescopes.

Vulcan, although just one example, does provide a good case study of a widely used form of immunisation tactic, the ‘ad-hoc’ hypothesis. An ad-hoc hypothesis is a secondary hypothesis that is bolted on to the side of the main hypothesis in order to defend it, or protect it. A more recent example of this can be seen in the Global warming debate.

It has been noted that global temperatures have not increased by much, if at all, in the last 15 years. This, however, is not viewed as a contradiction to the hypothesis of man-made global warming. Why not? Because it is argued that the oceans are taking in the excess heat, and trapping it. This process has held back the degree of global warming that had been predicted by the experts.

I am not going to debate whether or not this is true. I am just using it as a more recent example of an ‘ad-hoc’ hypothesis which came into existence to protect the central hypothesis. I would further add that ad-hoc hypothesis are not always wrong. They can very often be right. Le Verrier, prior to inventing the planet Vulcan, had predicted the presence of the plant Neptune due to irregularities in the orbit of Uranus.

However, if you read his works, you will know that Popper was not a fan of ad-hoc hypotheses. He felt that a good hypothesis should be fully predictive of future ‘events’ without the need for additional explanations, adaptations, or suchlike.

He did not state how many ad-hoc hypotheses it took before you had to admit defeat. One, ten, a hundred, a thousand? No-one can give you a clear cut figure, but the more of them there are, the less likely it is your central hypothesis was correct in the first place. The phenomenon of adaptation/immunisation had been recognised many years before Popper.

‘A nice adaptation of conditions will make almost any hypothesis agree with the phenomenon. This will please the imagination, but does not advance our knowledge.’ J Black 1803

I have recently been pondering the ad-hoc hypothesis once more in relation to heart disease. For I suspect that never in the history of science has a central hypothesis had so many ad-hoc hypotheses bolted on to it. Indeed, we have now reached the point where ad-hoc hypotheses have had ad-hoc hypotheses bolted onto them, to protect the ad-hoc hypotheses themselves from being refuted.

Just to look at one example. There are a number of drugs that have been developed to raise High Density Lipoproteins (HDL), the supposed ‘good’ cholesterol. A few of them also lower LDL ‘bad’ cholesterol at the same time. Billions have been spend on this class of drugs known as ‘trapibs’ . The first of these was Torcetrapib.

At this point I should probably remind you that the ‘good’ cholesterol hypothesis was only created as an ad-hoc hypothesis to explain why some/many people with high total cholesterol levels do not suffer from heart disease. ‘It’s because they have a high HDL level.’

The logic here was obvious, if horribly facile. Raise the HDL and reduce the risk of heart disease. Anyway, ignore the chasms of logic, along came the ‘trapibs’, which were going to take over from statins:

‘Hailed as a potential blockbuster that could take Lipitor’s place, torcetrapib was a cholesteryl-ester transfer protein inhibitor (CEP-T inhibitor) designed to increase good cholesterol and lower bad cholesterol. Development of the drug began in 1990 with clinical trials starting nine years later. But it wasn’t until 2006 that Pfizer got close to submitting the drug to the FDA. The company touted torcetrapib as the answer to its near-term pipeline woes, predicting the potential blockbuster could make up for billions of dollars in lost Lipitor sales when that drug went off patent in 2011.’

Well, torcetrapib certain raised HDL by about 50%, and lowered LDL by about 10%. So, what could possibly go wrong?

‘What went wrong: In late 2006, the walls came crashing down around the company. Pfizer announced in December that it was halting development of it’s prized Phase III asset. The decision came after an independent Data Safety Monitoring Board recommended terminating the study because of an imbalance of mortality and cardiovascular events. Results from a 15,000-person trial showed that patients taking torcetrapib with Lipitor experienced excess deaths than those taking Lipitor alone. Not long after torcetrapib demise, Pfizer announced that it was cutting 10,000 jobs. The company spent $800 million developing the drug.’ http://www.fiercepharma.com/special-reports/pharmas-biggest-flops/torcetrapib-pharmas-biggest-flops

What went wrong was the Torcetrapib increased cardiovascular deaths about around 50% (relative increase in risk). Several other ‘trapibs’ have since come, failed, and slunk from the playing field, taking many billions down the drain with them. Yes, I know, you have never heard of them. At the risk of sounding rather big-headed, I predicted their total and abject failure long before the results of the clinical trials came out.

Now, there are those of us i.e. me who would suggest that this blows a hole in the entire good, bad, cholesterol hypothesis. But no. Why not? Because it was found that torcetrapib raised the blood pressure, and lowered potassium levels. This, it seems, was enough to explain the massive rise in CV mortality. Well, quite reasonable, you might say. Yes, but the rise in BP was minute, and the drop in potassium was equally minute. This could explain, perhaps, a 5% rise (at most) in CV mortality. Which should have been overwhelmed by the massive rise in HDL, and drop in LDL.

But no-one was going to look too closely into the figures themselves. An ad-hoc hypothesis had been found. The ‘experts’, rather than questioning the central good/bad cholesterol hypothesis simply bolted on the ‘BP rise, potassium falls’ ad-hoc immunisation device and moved on.

So, here we have an ad-hoc hypothesis, bolted onto an ad-hoc hypothesis, bolted onto the central hypothesis. We have another planet inside the invisible planet Vulcan, to explain why it is so difficult to find the planet Vulcan.

As you can see, the games played to protect the cholesterol hypothesis are, literally, endless. I am not sure when the games end? Perhaps they never do. Very clever people, given enough time and money can, it seems, twist reality round and round, inside out and upside down forever. I would call the process vulcanisation, but I think that has something to do with rubber.

What is a conflict of interest anyway?

Whilst away on my holidays I have been watching the battle between the BMJ and Professor Sir Rory Collins. A couple of years ago I watched the battle between Professor Sir Rory Collins and the Cochrane Collaboration. A month ago I was taking part in the battle between various professors and cardiologists and Professor Sir Rory Collins.

He, as you probably know, thinks statins are wonder drugs that should be prescribed to almost everyone. Actually, that is not entirely true. He doesn’t believe they should be prescribed to almost everyone. He believes that they should be prescribed to everyone.

He thinks statins have no adverse effects at all. In fact, they actually make people feel better when they take them. He viciously attacks anyone who might dare to suggest otherwise, and has accused them of killing people by frightening them off taking these uniquely lifesaving medications. This has been the basis of his attacks over the last couple of years.

Now, he might really believe all this to be true. In fact, I think he probably does. Of course, he might not believe it to be true, but he is just saying it anyway. One of the great frustrations of life is that you can never know what another person is really thinking. You can guess all you like, but it is only ever a guess.

The problem that we have here is that Professor Sir Rory Collins runs a unit called the Clinical Trials Service Unit at Oxford. This unit has received nearly £300m ($500m) in funding from pharmaceutical companies over the years. Without this funding, his unit would be very much smaller. It probably would not exist at all.

Now, you could say that this makes Professor Sir Rory Collins utterly dependent on pharmaceutical company funding, and therefore you should not believe a single word that he has to say about anything to do with statins, and other such drugs. He is completely corrupted.

You could counter argue that this is a ridiculous stance to take. His is a highly motivated and ethical researcher who works with the industry, purely in order to develop effective medicines that will help humanity. After all he is both a Sir and a Professor.

You could say that his Knighthood and professorship are completely irrelevant, and simply ask the following question. Why does he say he has no conflicts of interest to declare. Why does he state that he receives no money from industry. Why has he never admitted to the association between himself, the CTSU, of which he is a director, and £300m in drug company funding? Why does he never disclose these financial interests? Why not, indeed?

His argument, I believe, is the following. If the pharmaceutical industry pay the CTSU, who then pay him, he is not actually being paid any money directly by the pharmaceutical industry. So he has no conflicts of interest to declare. Discuss. [Shouldn’t take long].

Whether or not you think his is conflicted (and I do), this discussion leads into a rather more complicated area. What is the purpose of declaring that you have a conflict of interest in the first place? What does it matter if you are paid money by someone else who has a vested interest in making sure that certain things are said, and done.

Now, you may think the answer is simple. If Professor Sir Rory Collins states he has a conflict of interest e.g. the unit he runs is paid £300m by the industry, we can then….. We can then…..We can then what?

Believe nothing that he says about statins. Believe everything that he says. Believe most of what he says. Believe a bit of what he says. The problem is that there are only two rational positions here.

  • Believe everything
  • Believe nothing

How can you believe most, or a bit, of what Professor Sir Rory Collins says? Which bits could you ignore, which bits could you pay attention to? How could you possibly know? The answer is that you cannot.

Which then leads onto the next question. Why do medical journals, and suchlike, demand that researchers, lecturers and authors declare their conflicts of interest? What does this achieve? If having a conflict means that the author/researcher is biased, then surely the article cannot be published – as the journal is accepting a biased piece of work. Believe me, properly done, bias is impossible to spot. It’s like hearing the dog that didn’t bark.

On the other hand, if conflicts of interests mean nothing. In that you can have financial conflicts of interest, but this makes no difference to anything you say or do – why bother demanding that the conflicts of interests are declared.

In short, I cannot see what declaring a conflict of interest achieves.

Man on the Street 1: ‘Oh, I see Professor Sir Rory Collins unit has received £300m in funding from the pharmaceutical industry. Most interesting. However, this clearly makes no difference to anything he has to say on the matter.’

Man on the Street 2: ‘Oh, I see that Professor Sir Rory Collins unit has received £300m in funding from the pharmaceutical industry. Clearly he is corrupt and biased and I shall pay no attention to any he has to say.’

Man on the Street 3: …. ‘I shall believe 82% of what he has to say.’

Man on the Street 4: …..’I shall believe 23% of what he has to say.’

Which of the men on the street has the right idea? There is no way to tell, without becoming a mind reader. At present, when it comes to conflicts of interest, we just have a gigantic fudge. So long as people declare their conflicts they are then free, it seems, to do anything they like. Carry out research, write papers, sit on guideline committees, advise the Government and NICE. Declaring the interest…what? Makes the possibility of bias disappear?

But what should really happen. My view is relatively simple. I have said it before, and will say it again. If you get paid money by the pharmaceutical industry then, fine. I have no problem with that. Good for you. Buy that luxury ski chalet in the Alps if you want. Indoor swimming pools are lovely things to have. Have both – you will certainly be able to afford it.

However, once you have taken the money, directly or indirectly, you should not be allowed to sit on guidelines committees e.g NICE. Nor should you be allowed to educate your fellow doctors on best forms of drug treatment, or act as a Government advisor on healthcare matters – or suchlike. Because you are, even if you don’t think you are – and get very angry with anyone who suggests that you might be – biased.

This nettle needs to be grasped, and it needs to be grasped soon. I am not a great believer in absolutist positions, as they tend to block the compromises that are necessary for things to work in life. However, when it comes to conflicts of interest I think that the only possible position to take is absolutist. If you are paid money by the pharmaceutical industry, you cannot be appointed to a position that allows you to influence how drugs are used. End of.

Immovable Object

I have not been blogging much recently. One of the reasons is that I have been involved with a group of doctors and professors who have been fighting against the latest guidelines on primary prevention of cardiovascular disease which were due to be announced in July. We have had, as I knew, precisely no effect.

Here is the latest NICE guidance that was announced, today 18th July 2014. The committee having ignored any and all criticism:

Taking further steps to tackle the risk from heart attacks and strokes

NICE has today published its final updated guidance on the steps needed to prevent thousands of people from becoming ill and dying prematurely from heart attacks, strokes and peripheral arterial disease. NICE says doctors should consider many more people to be at risk of cardiovascular disease (CVD) which causes 1 in 3 deaths in the UK (180,000 each year).

NICE advises that the threshold for starting preventive treatment of these conditions should be halved from a 20% risk of developing CVD over 10 years to a 10% risk. Prevention includes stopping smoking, reducing alcohol consumption, taking exercise and eating a healthy diet. Once these factors have been addressed, the guidance says high intensity statin therapy should be offered.

People can be at risk from CVD because of factors they cannot change including their age, sex, ethnicity, and family history. The guidance recommends that risk factors which can be addressed should be managed.

Professor Mark Baker, Director of the Centre for Clinical Practice at NICE, says: “To make progress in the battle against heart disease and stroke, we must encourage exercise, improve our diets still further, stop smoking, and where appropriate offer statins to people at risk.

“Doctors have been giving statins to ‘well people’ since NICE first produced guidance on this in 2006. We are now recommending the threshold is reduced further. The overwhelming body of evidence supports their use, even in people at low risk of cardiovascular disease. The effectiveness of these medicines is now well proven and their cost has fallen.

“The weight of evidence clearly shows statins are safe and clinically and cost effective for use in people with a 10% risk of CVD over 10 years. “We’re not saying that everyone with a 10% or greater risk of CVD within 10 years needs to take a statin. The guideline recognises the importance of choice in preventing CVD and that this should be guided by information on the trade-off between benefits and risks.”

By recommending a systematic approach to identifying those at risk of CVD, the guideline will enable people to access treatments to address that risk by reducing their cholesterol levels. It will also provide further clarity for practitioners in primary and secondary care about how to manage patients both with and without pre-existing cardiovascular disease.

NICE recommends that people are assessed (using the QRISK2 calculator) for their risk of developing cardiovascular disease using measurements including whether or not they smoke, their cholesterol levels, blood pressure, and body mass index. The calculator then provides a percentage risk of developing CVD in the next 10 years. “This new guideline complements the NHS Health checks programme in helping to identify people at future risk of developing cardiovascular disease at a stage at which lifestyle modification can make a significant difference “says Guideline Development Group Chair Dr Anthony Wierzbicki. “It updates and simplifies treatment protocols for people with established CVD, with diabetes or kidney disease so that these people can derive maximum benefit from lipid-lowering therapies.”Liz Clark, a lay member of the Guideline Development Group, said:

“One of the key challenges is how to convince people who feel well that they need to make substantial lifestyle changes or that they benefit from lifelong drug treatment. This requires high quality information and communication on the benefits and risks of these therapies and this is reflected in the guideline.

“The guideline therefore places patients centrally in any decision making about their management and it emphasises the need to address all CVD risk factors in combination. “It highlights the need for doctors to encourage people to participate in reducing their CVD risk. For example, it recommends that doctors assess a person’s readiness and confidence to make changes to their diet, level of physical activity and smoking and alcohol consumption, as well as taking long-term medication. It also recommends that people are involved in developing a shared management plan.”

So, up to 17 million people in the UK will now be taking statins for the rest of their lives. Well, of course, we will never get anywhere near this number. After about a year 50% of people stop taking their statins – I wonder why. A lot of people will refuse to take them in the first place. But millions and millions will take these drugs for many years.

This is clearly, and absolutely, nuts. My major fear, as I tell anyone, is not that statins have a lot of adverse effects – which they do. You can always stop taking them and the adverse effects go away. If, that is, the effects are not permanent.

I have heard enough testimony from patients, and people who e-mail me, and reviewing FDA Medwatch (the system for picking up drug related adverse effects in America) to believe, one hundred per cent, that many people have been left permanently disabled from taking statins.

My personal belief is that the true burden of damage that will be caused by millions of people taking statins, forever, is very heavy. Every individual case of irreversible neuropathy, or muscle wasting, or degenerative neurological condition, or suchlike, is dismissed as anecdote by the great and the good – and the NICE. ‘Statins don’t do that.’ Is what I hear.

Well, part of me hopes that statins really don’t do that. But, frankly, I don’t believe it. I believe that mass statination of the entire adult population is an absolute medical disaster. I shall continue the fight.

Another backlash begins

Recently I was the author, and co-signee, of a letter sent to NICE (the National Institute for Care and Health Excellence) asking that their recommendations on primary prevention of cardiovascular disease should be withdrawn. Mainly the advice on the use of statins for those at low risk of a heart attack, or stroke. Those in the UK may have seen a bit a stir in the media.

Others who signed this letter included: Sir Richard Thompson, Chairman of the Royal College of Physicians, Dr. Clare Gerada, past president of the Royal College of General Practitioners and Dr. Kailash Chand – deputy chairman of the British Medical Association. [I have included this letter for you to read, if you wish]

So, we are not talking about a bunch of mavericks here – apart from me, of course. When people who are as much a part of the ‘establishment’ as this are willing to put their names to such a letter then you know that people are getting very concerned. Very concerned indeed.

NICE wrote back to me saying that their guidance was completely wonderful and that nothing should change [I paraphrase, but not by much]. This was pretty much as expected. However, in parallel with this letter, the organisation that represents all GPs in the UK (the General Practitioner’s Committee of the BMA) voted unanimously to reject the NICE guidelines. This happened in May.

Now, very recently, the Annual Representative Meeting (ARM) of the British Medical Association debated the NICE guidelines. The motion put to the meeting was,as follows:

‘This meeting believes that in any advisory committee of NICE, when guidance on any drug is issued it must be made clear that none of the members must have a financial interest in pharmaceutical companies which manufacture the drugs’.

Here is the speech made by Kailash Chand to the meeting:

‘Chairman, Representative Body (RB). This is a chosen motion for a purpose. Some of you will have been very concerned about the general direction of travel by NICE, others will have been concerned simply by the issue of conflict of interest.’

This motion calls for clarity in the role of the pharmaceutical companies and their relationship with those individuals who hold positions of considerable influence on the advisory committees of the NICE, which describes and defines what many consider to be best practice.

This motion is NOT seeking to discredit people who advise NICE or indeed to diminish the Institute itself, which has a vital role in interpreting complex modern clinical evidence.

In fact, it is precisely because we should value the Guidance provided by NICE, that it is absolutely essential for it to carry the TRUST and complete CONFIDENCE of the profession. Guidance which has the power to influence our everyday practice, and against which many of us are performance managed must be based on the highest principles of INTEGRITY and TRANSPARENCY.

It is possible that those involved in an advisory capacity to NICE believe that they are able to manage their conflicts of interest, but it is absolutely imperative that NICE should not only be free of even subliminal influence from the pharmaceutical industry, but perhaps even more importantly, be SEEN to be completely independent and not reliant on partial data disclosure of pharmaceutical industry trial data.

Today, we see a lack of confidence from the profession in NICE’s capacity to analyse data and provide reliable advice, when only selective trial information from drug trials is made available.

Recently, the conference of LMCs unanimously passed a motion calling upon NICE to defer a decision to recommend a reduction of the threshold for prescribing statins for primary prevention in the general population.

The BMJ, the Cochrane Institute and indeed this Conference last year called upon the pharmaceutical companies to release ALL data, as a means to increase transparency and to allow more independent verification of results. In fact NICE itself has joined this coalition to call for access to this data, yet continues to place itself in a position of advising with access to only limited information – the pharmaceutical industry have widely ignored these calls for transparent disclosure.

We know that pharma sponsored trials are twice as likely to produce positive results for a drug, and we also know that only half of trials are available in a published form for peer review. This excludes trials which may be stopped prematurely or have end points altered by the sponsors.

Earlier this year the Cochrane Review concluded that the early evidence which had shaped the advice from NICE before the Flu pandemic, had been flawed and had resulted in an exaggerated impression of the usefulness of these medications. The absence of transparency in the process by which data was released and then interpreted has been deeply regrettable. Some have called it a gross betrayal.

So, please support this motion. It is a call for NICE to review its methods where advisory boards may be populated by individuals with links to industry. NICE needs to recognise that those of us tasked to implement its guidance must have full confidence in the transparency and integrity of those individuals providing advice. NICE must be beyond reproach. It should not just be SEEN to be independent, it MUST be independent.

Otherwise its advice which most of us have to implement or adhere to, will continue to affect the lives of millions of patients.

I move.’

This motion was passed unanimously.

Once again, NICE is under fire. This time from the entire medical profession, and those who represent them. It seems that doctors are deeply concerned about the medical evidence. They feel it has been corrupted, and that those who sit on the guideline committees are, themselves, under the influence of the pharmaceutical industry.

Hoorah. Will anything change? I shall keep throwing rocks, or course. Now a few more powerful rock throwers are joining in. Perhaps the citadel will crumble.

Letter sent to NICE:

Professor David Haslam, Chairman
National Institute for Health and Care Excellence
10 Spring Gardens
London, SW1A 2BV

cc. The Right Honourable Jeremy Hunt, MP
Secretary of State for Health
Department of Health
Richmond House                                                                                                                                         79 Whitehall
London, SW1A 2NS

10th June. 2014

Concerns about the latest NICE draft guidance on statins

Introduction:

We are concerned about your draft guidance on CV risk for discussion and debate. We would ask for a delay until our concerns are addressed. Whilst we agree with much of the guidance, our concerns focus on six key areas: medicalization of healthy individuals, true levels of adverse events, hidden data, industry bias, loss of professional confidence, and conflicts of interest

The draft guidance recommends offering statin treatment for the primary prevention of CVD to people who have a 10% or greater 10-year risk of developing CVD.

1. Medicalisation of five million healthy individuals.

Firstly, we believe that the benefits in a low risk population do not justify putting approximately five million more people on drugs that will then have to be taken lifelong.

The important questions for clinicians and for patients include: (1) does treatment of elevated cholesterol levels with statins in otherwise healthy persons decrease mortality or prevent other serious outcomes? (2) What are the adverse effects associated with statin treatment in healthy persons? (3) Do the potential benefits outweigh the potential risks? Recent papers have suggested that statin therapy should not be recommended for men with elevated cholesterol who are otherwise healthy.2

Furthermore, Atorvastatin 20mg is also recommended as the first-line treatment. This appears counter intuitive, as Atorvastatin has never been demonstrated to reduce mortality for primary prevention any clinical study. (3b)

2. Conflicting levels of adverse events

In emphasising the cost per Quality Adjusted Life Year (QALY), NICE is clearly making a major assumption that the key issue is mortality reduction, and that statins lead to very few adverse effects. We would question this very strongly.

The levels of adverse events reported in the statin trials contain worrying anomalies. For example, in the West of Scotland Coronary Prevention Study (WOSCOPS, the first primary prevention study done), the cumulative incidence of myalgia was 0.06% in the statin arm, and 0.06% in the placebo arm3.

However, the METEOR study found an incidence of myalgia of 12.7% in the Rosuvastatin arm, and 12.1% in the placebo arm4. Whilst it can be understood that a different formulation of statin could cause a different rate of myalgia, it is difficult to see how the placebo could, in one study, cause a rate of myalgia of 0.06%, and 12.1% in another. This is a two hundred fold difference in a trial lasting less than half as long.

Furthermore, the rate of adverse effects in the statin and placebo arms of all the trials has been almost identical. Exact comparison between trials is not possible, due to lack of complete data, and various measures of adverse effects are used, in different ways. However, here is a short selection of major statins studies.

AFCAPS/TEXCAPS: Total adverse effects losartan 13.6%: Placebo 13.8%

4S: Total adverse effect simvastatin 6%: Placebo 6%

CARDS: Total adverse effects atorvastatin 25%: Placebo 24%

HPS: Discontinuation rates simvastatin 4.5%: Placebo 5.1%

METEOR: Total adverse effects rosuvastatin 83.3%: Placebo 80.4%

LIPID: Total adverse effects 3.2% Pravastatin: Placebo 2.7%

JUPITER: Discontinuation rate of drug 25% Rosuvastatin 25% placebo. Serious Adverse events 15.% Rosuvastatin 15.5% placebo

WOSCOPS: Total adverse effects. Pravastatin 7.8%: Placebo 7.0%

Curiously, the adverse effect rate of the statin, it is always very similar to that of placebo. However, placebo adverse effect rates range from 2.7% to 80.4%, a thirty fold difference.

3. Hidden data

Without access to the raw data, it is difficult to understand how statin related adverse events, and placebo related adverse events can mirror each other so precisely, whilst the absolute rates can vary thirtyfold (almost three thousand per cent). These data most certainly require analysis by a third party with appropriate expertise.

A further serious concern is that the data driving NICE guidance on statins comes almost entirely from pharmaceutical company funded studies. Furthermore, these data are not available for review by independent researchers, only those who work for the Oxford Cholesterol Treatment Trialists Collaboration (CTT).

The CTT has commercial agreements with pharmaceutical companies which apparently means that they cannot release data to any other researchers who request to see it. Which, in turn, means that the latest reviews of the data by NICE and also by the Cochrane group are totally reliant on the CTT 20121 meta-analysis analysis of this concealed data?

4. Industry bias

The overdependence on industry data raises concerns about possible biases. Extensive evidence shows that industry funded trials systematically produce more favourable outcomes than non- industry sponsored ones.5,6

Notably, only one major non-industry funded study on statins has been done. ALLHAT-LLP. The main findings were summarised: ‘Although pravastatin has been shown in multiple large clinical trials to reduce CHD morbidity and mortality, NO benefit was demonstrated in ALLHAT-LLT, the largest clinical event trial of pravastatin published to date.’ (6b)

True levels of adverse events

We are also concerned that the rate of adverse effects in post-marketing studies is, in most cases, far higher than that found in the pre-marketing studies. In part this is due to the fact that the clinical trial populations studied in premarketing trials are highly selected. Furthermore, industry sponsored trials include pre-randomisation run-in periods where those who fail to tolerate statins are excluded.RCT patientsmay therefore not represent the population that will actually take the drugs in the real world. RCTs may thus grossly underestimate adverse effects such as myopathy or cognitive impairment,7 and fail to detect drug interactions e.g. amlodipine and statins.

Important findings from some other non-industry sponsored studies

A double blind randomised controlled trial that compared 1016 low risk patients receiving simvastatin 20 mg or pravastatin 40 mg with placebo showed that both drugs had a significant adverse effect on energy/fatigue exercise score with 40% of women reporting reduced energy or fatigue with exertion.9 Reducing exercise capacity in a healthy group when physical inactivity is a major contributor to the development of cardiovascular disease is extremely counterproductive.

A large observational study involving 153,840 postmenopausal women aged between 50 and 80 years enrolled in the Women’s Health Initiative study found that statins were associated with a 48% increased risk of developing diabetes.8

Potential psychiatric symptoms including depression, memory loss, confusion, and aggressive reactions have also been associated with statin use.(10)

Erectile dysfunction, to take another significant adverse effect, is not mentioned in the statin trials. Yet, when it was specifically looked for, around 20% of men appeared to be affected.(11)

5. Loss of professional confidence

We are also concerned that GPs feel that this guidance is a ‘step too far. It is instructive to note that a survey of 511GPs carried out by Pulse magazine revealed that ‘….almost six out of ten (57%) oppose the plan to lower the current 10-year risk threshold for primary prevention, while only 25% support it. Furthermore, 55% would not personally take a statin or recommend a family member does so based on a 10% 10-year risk score.’ (11b)

More recently the General Practitioners Committee (GPC), which negotiates on behalf of GPs in the UK passed the following resolution: ‘In light of the Cochrane review of the effectiveness of antiviral influenza treatments, the GPC will request that NICE refrain from recommending a reduction to the current treatment threshold for primary prevention of cardiovascular disease with statin therapy unless this is supported by evidence derived from complete public disclosure of all clinical trials’ data’ (11c)

Asking GPs to meet targets that they feel uncomfortable with risks a damaging split within the profession, and a loss of confidence among the public, who are likely to recognise increasingly that GPs are being asked to prescribe statins despite feeling it is inappropriate.

6. Conflicts of Interest (real and perceived)

We are also seriously concerned that 8 members of NICE’s panel of 12 experts for its latest guidance have direct financial ties to the pharmaceutical companies that manufacture statins. Furthermore, some members of the guideline panel are also involved in next generation, more expensive, cholesterol lowering drugs, which are not yet on the market. If cholesterol lowering becomes established in low risk people, the indications for these new cholesterol lowering drugs such as the ApoB Antisence drugs and PCSK9 inhibitors will probably expand as well. We feel that parties with industry conflicts should not be participants in generating recommendations regarding drug use that will influence medical care across the population.

We fear that the CTSU could be perceived as having a major conflict of interest in the area of cardiovascular disease prevention/lipid modification, which has an impact on the Unit’s perceived objectivity. We strongly urge that other researchers, for example, the Cochrane Stroke Group and Cochrane Heart Group, should be able to scrutinize and assess all the data that the CTT has utilised over the years to produce their extremely influential studies.

CTT is a part of the Clinical Trials Service Unit (CTSU) in Oxford, which has carried out many very large studies on statins, and other lipid modification agents with pharmaceutical company support, and has received hundreds of millions in funding over the years. To consider just one such study (REVEAL). REVEAL is being funded by Merck Sharp & Dohme, which developed anacetrapib. A grant of £96 million towards the cost of this multi-million dollar study has been provided to the University of Oxford.

We are concerned that financial conflicts of interest and major commercial bias may have corrupted the database on statins, resulting in an underestimate of the incidence of statin side-effects. Unless all of the data are made available it is impossible to establish a cost per QALY, as there may be DALYs [disability adjusted life years] not accurately accounted for.

We call for all of the data from the clinical trials to be made available to credible researchers, for example, the Cochrane Stroke and Heart Groups. We believe that there is a need for a more robust post-marketing analysis of suspected adverse effects from statins prescribed in a community setting.

To conclude we urge you to withdraw the current guidance on statins for people at low risk of cardiovascular disease until all the data are made available. The potential consequences of not doing so are worrying: harm to many patients over many years, and the loss of public and professional faith in NICE as an independent assessor. Public interests need always to be put before other interests, particularly Pharma.

Yours Sincerely

Sir Richard Thompson, President of the Royal College of Physicians

Professor Clare Gerada, Past Chair of the Royal College of General Practitioners and Chair of NHS Clinical Transformation Board

Professor David Haslam, General Practitioner and Chair of the National Obesity Forum

Dr J S Bamrah, Consultant Psychiatrist and Medical Director of Manchester Mental Health and Social Care Trust

Dr Malcolm Kendrick, General Practitioner and Member of the British Medical Association’s General Practitioners sub- Committee

Dr Aseem Malhotra, London Cardiologist.

Dr Simon Poole, General Practitioner

David Newman, Assistant Professor of Emergency Medicine and Director of Clinical Research, Mount Sinai School of Medicine, New York

Professor Simon Capewell, Professor of Clinical Epidemiology, University of Liverpool

 

References (may require site registration or membership to access)

1: Mihaylova B, Emberson J, Blackwell L, Keech A, Simes J, Barnes EH, Voysey M, Gray A, Collins R, Baigent C: ‘The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials.’ Lancet. 2012 Aug 11;380(9841):581-90. May 17.

2: Redberg RF, Katz MH. Healthy Men Should Not Take Statins. JAMA. 2012;307(14):1491-1492. doi:10.1001/jama.2012.423.

3: http://www.nejm.org/doi/full/10.1056/NEJM199511163332001#t=articleDiscussion

(3b) http://www.health-heart.org/Pfizer’s49LipitorStudies.PDF

4: John R. Crouse, MD; Joel S. Raichlen, MD; Ward A. Riley, et al: ‘Effect of Rosuvastatin on Progression of Carotid Intima-Media Thickness in Low-Risk Individuals With Subclinical Atherosclerosis’: The METEOR Trial JAMA. 2007;297(12):1344-1353. doi:10.1001/jama.297.12.1344

5: Smith R. Conflicts of interest: how money clouds objectivity. J R Soc Med 2006;99:292-7.

6: Bekelman JE, Li Y, Gross CP. Scope and impact of financial conflicts of interest in biomedical research: a systematic review. Jama 2003;289:454-65.

(6b) http://www.lipidsonline.org/commentaries/cme_pdf/commentary_039.pdf:

7: Mansi I, Mortensen E. The controversy of a wider statin utilization: why? Expert Opin Drug Saf 2013:12:327-37.

8: Culver AL, Ockene IS, Balasubramanian R, Olenzki BC, Sepavich DM, Wactawski-Wende
J, et al. Statin use and risk of diabetes mellitus in postmenopausal women in the Women’s
Health Initiative. Arch Intern Med 2012;172:144-52.

9: Tatley M, Savage R. Psychiatric adverse reactions with statins, fibrates and ezetimibe implications for the use of lipid-lowering agents. Drug Safety 2007;30:195-201.

10: Golomb BA, Evans MA, Dimsdale JE, White HL. Effects of Statins on Energy and Fatigue With Exertion: Results From a Randomized Controlled Trial. Arch Intern Med. 2012;172(15):1180-1182. doi:10.1001/archinternmed.2012.2171.

11: Solomon H1, Samarasinghe YP, Feher MD, et al: ‘Erectile dysfunction and statin treatment in high cardiovascular risk patients.’ Int J Clin Pract. 2006 Feb;60(2):141-

(11b) http://www.pulsetoday.co.uk/clinical/therapy-areas/cardiovascular/majority-of-gps-reject-nice-proposals-to-extend-statins-to-millions-more/20005985.article#.Ux3eGPmKVcY

(11c) http://webappmk.doctors.org.uk/Session/2779737-8NrQN5n75yPDD0RVnLZy-aoqmids/MIME/INBOX/125049-02-B/News%2014%20-%2022%20April%202014.pdf

Calling All Physicians: The Salt ‘Debate’ Must Stop

My last blog highlighted the bully boy tactics used to silence critics of mainstream medicine. Normally by threatening anyone who dares question the experts of ‘killing patients’, or words to that effect. It is a well-worn tactic which, surprisingly, seems to work every time.

‘If you dare to question breast cancer screening, women will die.’

‘If you question the use of statins, millions will die.’

‘If you….’ well you get the general gist.

There are of course slightly more subtle versions of this. However, when a medical ‘expert’ deigns to address mere mortals, we know what they mean when they say ‘The salt ‘debate’ must stop.’ What they are saying, albeit indirectly, is that if you don’t stop questioning what I say, millions will die. Maybe billions…..over the years, perhaps an entire Google.

On this note, several different people pointed me at a recent debate at the conference of the European Society of Hypertension (ESH) and the International Society of Hypertension (ISH) in Athens. Well, not a debate really, more of a tirade. Here is one part of the report

‘Any “controversy” over whether dietary salt is a cause of heart disease and stroke is the result of weak research methodology or commercial interference, Dr Norm Campbell (Libin Cardiovascular Institute of Alberta, Calgary) and Dr Graham MacGregor (Wolfson Institute of Preventive Medicine, London, UK) argued here….’1

I shall translate their statement. If you do not believe that excess salt consumption is a cause of heart disease and stroke you are a flawed and misdirected scientist (weak research methodology), or you are corrupt (commercial interference). No other explanation is, of course, possible. You are either an idiot, or corrupt, and therefore – by definition – should be ignored. Or perhaps stoned to death for being an unbeliever.

Ah well, that put me in my place. Along with anyone else who dares to disagree with the mighty Norm Campbell and Graham MacGregor. Now Graham MacGregor makes great play of the fact that grubby commercial companies are pushing hard to get us to put more salt in his food. He, of course, has no commercial affiliations.

Hold on. Is he not on the board of the Blood Pressure Association? An organisation that receives funding from various different sources……

You may like to know that we have been very fortunate to have received substantial funding from a number of organisations who have helped the Association get off the ground. These Founder Members are listed below:2

  • Astra-Zeneca UK Limited
  • Bristol-Myers Squibb Pharmaceuticals Limited
  • Merck Sharp & Dohme Limited
  • The Community Fund
  • Omron Healthcare UK Limited
  • Pfizer Limited
  • Servier Laboratories Ltd
  • Solvay Healthcare Limited

Would some of these companies not be pharmaceutical companies? Would some of them make tablets to lower blood pressure? Well, gosh, let me think….

Astra-Zeneca, just to look at the first company on the list. They make:

  • Candestartan
  • Lisinopril
  • Felodipine
  • Metoprolol
  • Atenolol

Well, that’s only five blood pressure lowering agents. Which means that Astra-Zeneca clearly have little interest in blood pressure lowering….not. If you were being a little cynical, you would think that an organisation almost entirely funded by pharmaceutical companies might be considered to have a dog in this fight? You might think that Graham MacGregor could, just possibly, have a little conflict of interest going on. No, surely not.

As for Norm Campbell.

‘Dr. Norm Campbell has given talks sponsored by Bayer, Sanofi Aventis, Biovail, Bristol Myers Squibb, Pfizer, Novartis and Merck Frosst and also has been on advisory boards for Novartis, Pfizer, Servier, Boehringer Ingelheim and Schering Plough.’ 3

As per usual. Seek the commercial conflicts, and ye shall find. You don’t get to be the sort of professor who gets to stand up, command the stage, and intone your words of wisdom at an international medical conference without a little background helping hand from a few pharmaceutical companies. Anyway, what were these two saying about commercial interference again? Difficult to think with the sound of all these cash registers ringing in my ears.

Of course, if confronted, these two will state that all the money they receive goes to charity, or that any funding makes no difference to what they say….or suchlike. As Robbie Burns once remarked. ‘Oh wad some power the giftie gie us, to see ourselves as others see us.’

You, are corrupt because you have accepted money from a commercial source; I, on the other hand, am not. Because I am a superior being incapable of being tainted by money.’

However, the main point here is the fact that we have more bully boy tactics going on. Two ‘grand fromages’ take the stage to beat the opposition into pulp.

‘When a member of the audience pointed to the PURE analysis showing that most of the world eats much higher levels of sodium than those recommended by most international organizations, MacGregor and Campbell leaped on this as an example of a study that had radically failed to measure salt in an appropriate fashion, even devising a new “formula” to estimate salt intake because even spot urine testing had been inadequate. “Please let [PURE principal investigator Dr] Salim Yusuf [McMaster University, Hamilton, ON] know that he should stop using spot urine analysis,” MacGregor said curtly.’

I do hope that everyone in the audience made their own minds up about what they were hearing. I suspect the reporter had their own view, by including the word ‘curtly’.

May I make, yet another, plea for medical experts to stop, cease and desist, attempting to bully into submission anyone who dares disagree with them. It is demeaning.

References (may require site registration or membership to access)

1: http://www.medscape.com/viewarticle/826970?src=emailthis

2: http://www.surgerydoor.co.uk/advice/living-with/living-with-high-blood-pressure/what-blood-pressure-association-do-for-you/

3:http://archive.cme.mcgill.ca/html/videos/2009.rural_en/20090923_JacquesGenest/homeblank.html

You are killing patients

(Who me?)

Debate in science is essential. You would hope it were the very lifeblood of progress. One would also hope that researchers could disagree with each other in frank and open debate. But it has become increasingly obvious to me that if you criticise the experts in medical research you can expect a very rough ride indeed. You certainly risk being stomped into silence.

I have witnessed this quite a lot recently, and have found that the ‘stomping’ game is very simple. If a critic of an area of mainstream medicine seems to be gaining some traction with the public, they are very rapidly accused of ‘killing patients’ by various professors a.k.a. ‘experts.’

Sadly, it has become an article of faith that ‘experts’ cannot be argued with. For they have attained the status of demi-gods. Recently, I was reading an article about Daniel Kahneman, Nobel Prize winner in economics. He was discussing the irrationality of the financial system. He made many interesting points. For example:

The way scientists try to convince people is hopeless because they present evidence, figures, tables, arguments, and so on. But that’s not how to convince people. People aren’t convinced by arguments, they don’t believe conclusions because they believe in the arguments that they read in favour of them. They’re convinced because they read or hear the conclusions from people they trust. You trust someone and you believe what they say. That’s how ideas are communicated. The arguments come later.’

Slightly later on, he talks about his own belief in global warming:

‘Why do I believe global warming is happening? The answer isn’t that I have gone through all the arguments and analysed the evidence – because I haven’t. I believe the experts from the National Academy of Sciences. We all have to rely on experts.’

We all have to rely on experts? So says Daniel Kahneman. A man whom I generally greatly admire. In this case though, I could not disagree more violently. In one breath he states that people aren’t convinced by arguments; they’re convinced because they read or hear conclusions from people they trust. Then he says that we all have to rely on experts. But he does not link these two thoughts together to ask the obvious question. Just how, exactly, did the experts come to their conclusions?

By listening to people they trust? And who might they be? Other experts presumably. And how did they come to their conclusions….by listening to other experts. And how did they come to their conclusions. Hold on, it seems we are trapped in a loop of self-reinforcing logic. There is no escape.

In this area, I tend more to go along with Professor David Sackett:

According to the founder of Evidence Based Medicine experts are hindering the healthy advancement of science.

Writing in this week’s British Medical Journal (BMJ), Canadian-based researcher, David Sackett, said that he would “never again lecture, write, or referee anything to do with evidence based clinical practice”. Sackett is not doing this because he has ceased to believe in evidence based clinical practice but, as the BMJ comments, because he is worried about the power of experts in stifling new ideas and wants the retirement of experts to be made compulsory.

Sackett claims that the prestige of experts (including himself) gives their opinions far greater persuasive power than they deserve on scientific grounds alone.”Whether through deference, fear, or respect, others tend not to challenge them, and progress towards the truth is impaired in the presence of an expert,” he writes.

He also argues that expert bias against new ideas operates during the review of grant applications and manuscripts. “Reviewers face the unavoidable temptation to accept or reject new evidence and ideas, not on the basis of scientific merit, but on the extent to which they agree or disagree with the public positions taken by experts on these matters.” 1

My rather cynical view is that experts can be compared to those men (usually men) who have grabbed hold of the microphone at the front of a mob during a protest march. With this simple act they have managed to gain status and authority. Shortly after they become spokesmen for the revolutionary movement, then leaders…then despots.

However, most newspapers, journalists, television producers never ask they question, how did an expert become an expert – what makes them so. Instead, they are completely in the thrall of the ‘expert, and greatly fear their power. Which means that when an eminent professor loads and fires the ‘you’re killing patients’ gun, all hell breaks loose and panic stalks the land. Journalists, newspaper editors, TV producers and suchlike quiver in fear. They instantly retract everything they have ever published on the matter, and promise never to do it again.

The example of Andrew Wakefield is familiar to all. He stands accused of causing the deaths of thousands of children. Fewer people have probably heard to Peter Gotzsche, who is a professor and head of the Nordic Cochrane Collaboration (yet, not an expert). He has long been a critic of a breast cancer screening. Which has not endeared him to many who work in that field. He is regularly accused of killing thousands of women.

He was forwarded a copy on e-mail by a colleague. It has been written to one of his greatest critics Lazlo Tabar by another ‘expert’. It contained this section – which I have reproduced in full from Professor Gotzsche’s book ‘Mammography screening, truth lies and controversy’

‘What is remarkable to me is that this man (i.e. Dr G) calls himself a scientist since he obviously and knowingly ignores the scientific method in order to further his own agenda, whatever that may be. I cannot believe he is so intellectually deficient that he cannot grasp the plethora of evidence that so strongly supports the benefits of screening. What then drives him so blindly in his crusade to convince us that all the world is flat? To become infamous as a contrarian, standing lonely on the curvature of the as he denies is spinning under his feet? Or is it something even more petty? An all-consuming hatred and jealousy of Lazlo Taber, whose impeccable trial facilitated by meticulous Swedish record keeping and a socialist society provides a setting unparalleled in the world for a scientific trial? What is tragic and make G’s ravings sinister is that I am sure his influence has resulted in women’s unnecessary deaths somewhere in the world. The Scandinavians are known for their fair-minded, progressive concern for women, as well as for their intellectual integrity. IN this regard, PG is certainly a Nordic contrarian.’ [G or PG in this case refers to Peter Gotzsche]

Well, that’s very pleasant. However the part that I wish to draw attention to is this short section…’I am sure his influence has resulted in women’s unnecessary deaths somewhere in the world.’ A difficult statement to either prove, or disprove – I would think. However, the weapon is familiar ‘You are killing patients.’

On pretty much the same lines, I reproduce two short sections from a letter written to Dr Uffe Ravnskov by Professor John Kastelein (A big noise in CV research). He is objecting to Ravnskov’s view that raised cholesterol does not cause heart disease:

‘If this was a joke, I could have laughed about your statements heartily, but they are in fact criminal and bordering on the insane….. I insist that you refrain from any advice to any patient anymore. You are lucky not to live in the Netherlands. I would have dragged you to court.’

Once again, a nice polite scientific debate. Accusing someone of being criminal bordering on the insane. More recently, you will have noted the successful attempt to crush the Australian Catalyst programmes. One of which criticised the diet heart/cholesterol hypothesis. The second program was critical of the ever increasing prescribing of statins. I mentioned it in my last blog

The controversial Catalyst program on statins and heart disease, The Heart of the Matter, was attacked by health experts even before it aired last year.

The presenter of ABC radio’s Health Report, Norman Swan, warned “people will die” as a result of the TV program’s messages about heart medications.

Swan, whose criticism of the program has been vindicated by the independent Audience and Consumer Affairs Unit report, had said the program made him “really angry” because it might affect Indigenous Australians, who are especially likely to suffer from high cholesterol.’

Once again the ‘you’re killing patients’ gun was prepped and fired to pretty devastating effect. Both programmes were pulled from the air with humble apologies all round. Even the first episode ‘dietary villains’ was pulled,which was found to contain no errors at all. Guilt by association I suppose.

A similar battle is being fought in the UK between the statin experts, and those who would criticize them. It has been going on for some time. In 2011 the Cochrane Collaboration published a report very critical of the benefit of statins in low risk/primary prevention patients.

Professor Sir Rory Collins, the most eminent statin expert took great affront, and started to pick the paper apart, claiming it was highly dangerous and damaging. At one point claiming it was far more dangerous than Andrew Wakefield’s Lancet paper.

I quote from 2011:

In public health terms it is potentially a far more serious misinterpretation than that of Wakefield and the MMR in the Lancet.’2

He doesn’t state that the Cochrane collaboration is killing patients directly, but by using the example of Wakefield, we know exactly what he means. ‘You are killing patients.’

Professor Collins has warmed to this theme more recently. As you may be aware he has been attacking the BMJ recently for publishing articles about statins which claim that they have significant side-effects. He vehemently protests that they have virtually none. I quote him again, this time from the Guardian:

“It is a serious disservice to British and international medicine,” Collins told the Guardian at the time, claiming that the alarm caused was probably killing more people than had been harmed as a result of the paper on the MMR vaccine by Andrew Wakefield. “I would think the papers on statins are far worse in terms of the harm they have done.”3

He has been recently followed on this theme by Professor Magdi Yacoub (A famous heart surgeon, now retired from this job). Who is pressing the ‘you’re killing patients’ button with great enthusiasm.

Hey guys, engage in scientific debate, or shut up. Accusing people of killing patients is a terrible and horrible insult, and should play no part in any discussions of this sort. It is the tactics of the playground bully. Yes, I mean you.

References (may require site registration or membership to access)

1:http://www.abc.net.au/science/news/health/HealthRepublish_124166.htm

2: http://webappmk.doctors.org.uk/Session/3366252-XXkGXnwQtec5BtkDi3av-aoqmidr/MIME/Trash/146856-02-B/collins%20statins%20exchange%20with%20cochrane.pdf

3: http://www.theguardian.com/society/2014/may/15/statins-bmj-statement-professor-collins-side-effects

Catalyst crushed?

“A lie gets halfway around the world before the truth has a chance to get its pants on.”
Winston Churchill

ABC takes down Catalyst heart disease episodes after review criticism

Controversial TV program on cholesterol-lowering statins found to have breached editorial standards1

And that, as the Guardian reported, seems to be pretty much that. Here is some of the accompanying text.

‘Two episodes of the TV science program Catalyst will be removed from the ABC’s website after an internal review found the program had breached editorial standards on impartiality.

The controversial Catalyst program on statins and heart disease, The Heart of the Matter, was attacked by health experts even before it aired last year.

The presenter of ABC radio’s Health Report, Norman Swan, warned “people will die” as a result of the TV program’s messages about heart medications.

Swan, whose criticism of the program has been vindicated by the independent Audience and Consumer Affairs Unit report, had said the program made him “really angry” because it might affect Indigenous Australians, who are especially likely to suffer from high cholesterol.’

If this was all you had heard about the matter you would assume that ABC had done a very shoddy job, with sloppy and potentially dangerous reporting. Well, this is all very interesting. However, if you were to criticise sloppy reporting you could start with the Guardian report itself.

To begin with there were two programs, covering different issues, one of which had nothing to do with statins at all. However, the Guardian headline suggests there were two episodes ‘on statins and heart disease’. Not true. The first episode discussed whether or not saturated fat consumption caused heart disease. This episode was called ‘dietary villains’. It had nothing whatsoever to do with statins. The internal review found that this episode contained no errors. (Yet still it is being taken down?)

The second mistake the Guardian made is to accept Norman Swan’s statement that Indigenous Australians are especially likely to ‘suffer from high cholesterol’. Well this is complete rubbish. In one of the very few studies to report cholesterol levels in this population, published in the BMJ, the average cholesterol levels were very low (around 4.4.mmo/l)2. Lower than in any Western country.

Really, dear Guardian reporter, you ought to check your facts before writing such stuff – as should Norman Swan. But hey, checking facts is very time consuming, I think you will find. Moving on, I should also point out that you cannot ‘suffer’ from high cholesterol as there is no level of cholesterol that causes any symptoms. Mind you, if it were possible to ‘suffer’ from high cholesterol then the Swiss, with an average cholesterol level of 6.4mmol/l, would be suffering mightily. [Instead of having an extremely low rate of heart disease.]

Blimey, a few short paragraphs, and this article is already full of cock-ups. Of course, if you decide to go through anything with a fine toothcomb you will be able to pick up all sorts of errors. Writing scientific stuff is not easy. There is always a choice between absolute factual accuracy and providing the broader picture.

There is another choice between which facts to include, and which to exclude. Because of these inevitable tensions, and difficulties, if you want to attack any study, article, TV program, you will always find some traction. Sure as eggs is eggs, any program criticising statins was bound to be attacked mercilessly. Dr Uffe Ravnskov, a long time statin critic, had his book burned live, on air, in a Finnish TV studio. Part of a highly scientific debate, no doubt.

As a disclosure of interest, I did help the programme’s producer, and presenter, Dr Maryanne Demasi with questions and background information whilst she was putting the Catalyst programs together. I tried to give her as much factual information as possible. The day after the programmes came out, I wrote her this e-mail on 31st October 2013:

Maryanne,

Just seen part II. Brilliant, well done…….. I feel a sense of pride being able, in a small way, to help you put this together.

I now hope that you are viciously attacked, because that means you have won. (And it also means that thincs has won). Be ready – I suspect the attacks have already started.

She wrote back on the 4th of November:

Malcolm

OMG!! I am getting attacked in the media. They’re out for blood!!

Where do I hide??!!

Since then, the attacks have been relentless, from many directions. Page after page of criticism from the National (Australian) Heart Foundation (NHF). Withering attacks by the likes of Norman Swan – who seems to have set himself up at the ultimate arbiter of science in Australia. Somehow or other. Despite the fact that he believes people ‘suffer’ from high cholesterol, and has no idea about risk factors for heart disease in Indigenous Australians.

These attacks were battered backwards and forwards until my brain began to overheat. I provided supportive information to counter the criticism. As did several others. Point after point was refuted. It became quite exhausting.

Eventually, it seems ABC effectively caved in and removed the programmes. Why, I am not sure. The judgements on the programmes were almost entirely supportive – with a single exception, which I shall get to. Here, for example, was the commentary on the first programme on the link between saturated fat and heart disease.

Accuracy and impartiality

Episode 1 – ‘Dietary Villains’

The role of dietary saturated fats in heart disease has been controversial since the theory was first postulated at the beginning of the twentieth century. Notwithstanding the lack of definitive proof, mainstream medical organisations such as the National Heart Foundation (NHF) believe there is enough good quality evidence to recommend a diet low in saturated and trans fats…

In our view, the program could have done a better job of teasing out the mainstream perspective to leave audiences better informed.

However, in our assessment this did not amount to a breach of the impartiality standard in the first episode because judgements about impartiality require a number of factors to be weighed. While there were problems with structure and tone:

1. The factual information in the program was accurately presented and the reporter has demonstrated that she diligently sought and considered a variety of views on the subject. No material inaccuracy has been demonstrated by any complainant.

2. The principal perspectives were presented.

3. Neither position was endorsed by the program.

4. Neither perspective was misrepresented.

5. The nature of the program necessitated that the unorthodox theory was given more time and explanation. The Code does not require that they receive equal time, nor that every facet of every argument is presented.

As an important aside, I find it fascinating that the committee accepted that there is no ‘definitive proof’ that saturated fats cause heart disease. Check.

Yet, in a complete rupture of logic, the report stated that the ‘National Heart Foundation believe there is enough good quality evidence to recommend a diet low in saturated and trans-fats.’

Well, if there is enough good quality evidence, there must be, by definition, definitive proof. Either one statement is correct, or the other. They cannot both be, as they are mutually contradictory. This I am afraid is the level of thinking that goes on here. As expected, there is no criticism of the National (Australian) Heart Foundation for recommending a diet for which where is no ‘definitive proof.’ ‘It’s okay, they believe there is enough good quality evidence, and they are good chaps. So that is good enough for me.’

This is the usual kowtowing to the experts. If the roles had been reversed, Catalyst would have been crucified for promoting dietary advice based on nothing at all. Yet, the NHF are completely let off the hook with this pathetic statement.

‘Notwithstanding the lack of definitive proof, mainstream medical organisations such as the National Heart Foundation (NHF) believe there is enough good quality evidence to recommend a diet low in saturated and trans fats.’

Hang your heads guys. What is sauce for the goose should also be sauce for the gander.

And what of other ‘complaints.’ Here is another judgement, from this very, very, long document:

Did the program incorrectly state that it had sought comment from Merck Sharp & Dohme?

Complaint

Catalyst reported that it sought comment from MSD. MSD says that no contact was made.

Assessment

Catalyst has provided emails demonstrating that it approached MSD for responses to a number of detailed questions. MSD replied that it would not comment on the specific questions and stated only that:

‘MSD is committed to ethical research and abides by the principals of good clinical practices. All clinical trials and their protocols undergo review by hospital ethics committees.’

We are satisfied that Catalyst contacted MSD for comment and they declined to provide specific responses to allegations.

Conclusion – No breach of section 2.1.

Basically, MSD lied. They complained that no-one had sought any comment from them. It turned out this was nonsense, they were simply telling porkies. Any criticism of the company? No.

Here is another of the complaints:

Undue favouring of the perspective that saturated fats do not cause heart disease by raising cholesterol – part I – Code of Practice sections 2.2 and 4.5

Complaint

The hypothesis that eating saturated fats can increase cholesterol levels which in turn can cause heart attacks is widely accepted by the medical community and is the basis for most official dietary advice. Some medical researchers and physicians believe the hypothesis is flawed – Catalyst presented and examined their criticisms.

Complaints, including from the National Heart Foundation, allege the analysis lacked balance and omitted critical evidence…..

Assessment

We are satisfied on the basis of our review that the program’s scepticism towards the diet-heart hypothesis was not unjustified and its presentation of an alternative approach did not amount to an undue favouring of that approach.

Conclusion – No breach of section 4.5, no breach of 2.1

Are you getting some sense of what happened here? In point after point, it turns out that the Catalyst programmes had not, in any way, got anything wrong. Nothing, zip, nada. If you are so inclined, you can read the whole report3. To save you the trouble I have pulled out all the complaints, and added in the conclusions in as concise appendix as I can manage. [There is also a short appendix to make it clear what the Codes of Practice mean].

COMPLAINTS

[There were a total of twelve separate complaints, looking at seventeen possible breaches of editorial standards]

1: Ancel Keys’ population studies were misrepresented – Part I – Code of Practice section 2.2

Conclusion – No breach of section 2.2

2: Mediterranean Diet & The Lyon Diet Heart study – Part I – Code of Practice section 2.2 (Did the program accurately describe the Lyon Diet Heart study?)

Conclusion – No breach of 2.2

3: Misrepresentation of the composition of margarine in Australia – Part I – Code of Practice sections 2.1 & 2.2

Conclusion – No breach of section 2.2

4: Inaccurate description of the structure of polyunsaturated and saturated fats – Part I – Code of Practice section 2.1

Conclusion – No breach of section 2.1

5: Misrepresentation of the National Heart Foundation & Dr Grenfell – Part I – Code of Practice section 2.2

Conclusion – No breach of section 2.2.

6: Undue favouring of the perspective that saturated fats do not cause heart disease by raising cholesterol – part I – Code of Practice sections 2.2 and 4.5

Conclusion – No breach of section 4.5, no breach of 2.1

7: Misrepresentation of the 4S trial data – Part II – Code of Practice section 2.2

Conclusion – No breach of section 2.1 or 2.2

8: Merck Sharp & Dohme (MSD) – Part II – Code of Practice section 2.1 (Did the program incorrectly state that it had sought comment from Merck Sharp & Dohme?)

Conclusion – No breach of section 2.1.

9: Unfair characterisation of Australia’s medicines industry – Part II – Code of Practice sections 2.1 & 4.5

Conclusion – No breach of section 2.1 or 4.5.

  1. Failure to provide material context by not disclosing the commercial interests of some of the experts featured – Parts I & II – Code of Practice section 2.2

Conclusion – No breach of section 2.2.

  1. Failure to provide material context in relation to use of statins and undue favouring of view that statins do more harm than good – Part II – Code of Practice 2.2, 4.5 and 7.6

Did the program unduly favour an anti-statin viewpoint in its presentation of the evidence for the benefits and harms of statins?

Conclusion – Breach 4.5; No breach 2.2; No breach 7.6 (4.5 Do not unduly favour one perspective over another.)

  1. The program falsely claimed that the National Heart Foundation had ‘signed off’ on Catalyst’s evidence (PM 31/10/13) – Code of Practice sections 2.2 & 4.4

Conclusion – corrective action required, no breach 4.4

Twelve complaints about seventeen possible breaches of conduct, one upheld (I don’t think I have ever written anything that accurate in my life). There was another part of the report where the judgment is so weird that I cannot understand it. I defy anyone else to understand it either. You can read the whole report if you wish, and see what you think.

It seems to be saying that stratifying risk in primary prevention of heart disease is something that is contentious, but a lot of doctors believe in it, so it should have been mentioned. Something with no evidence to support it, that happens to be believed in by a number of doctors, should be presented as what….the truth? That bit is bonkers. It seems they thought they should say something, but descended into gibberish.

When you get down to it, the judgement is that there was a single breach. Represented thus:

‘The program’s treatment of use of statins in secondary prevention focused solely on mortality benefits in a way that reinforced the view that statins were overprescribed and their benefits exaggerated. The principal relevant perspective that statins have wider benefits for this group was not properly presented. This perspective was necessary to a fair understanding of the pros and cons of statin use in this group.’

Turning this into English. What the committee believe they found was the second Catalyst program ‘Cholesterol drug war’ did not mention that statins have benefits on non-fatal outcomes e.g. non-fatal heart attack, and non-fatal stroke. By failing to mention this point it was judged that the program gave a misleading perspective on the overall benefits of statins (in secondary prevention).

And that, ladies and gentlemen, is that. Perhaps not quite the crushing indictment you thought. Now, you must remember that this committee was starting from scratch, knowing bugger all about the area of statins and heart disease. Given this, they didn’t do too badly. But on the point about non-fatal strokes and non-fatal heart attacks they failed to spot the Elephant in the room. An Elephant that I need to describe to you.

Pharmaceutical companies hide data

The elephant in the room is that, when it comes to data on statins (and most other drugs), we are completely reliant on pharmaceutical companies to provide it. Increasing attempts have been made to get them to release all the data they have, but this has proven virtually impossible. Recently, we have seen a battle over the Roche drug Tamiflu:

‘The British Medical Journal (BMJ) has alleged that pharmaceutical giant Roche is deliberately hiding clinical trial data about the efficacy of oseltamivir (Tamiflu) in patients with influenza. The journal says global stockpiling and routine use of the drug are not supported by solid evidence and alleges that Roche concealed neurological and psychiatric adverse events associated with the neuraminidase inhibitor drug.

In an open letter from Fiona Godlee, MD, editor-in-chief of BMJ, to Professor John Bell, FRS, HonFREng, PMedSci, Regius Professor of Medicine at Oxford University in the United Kingdom and a Roche board member, published online October 29, Dr. Godlee reminds Bell of concerns that were initially voiced in 2009 about the reliability of Tamiflu research.

At that time, BMJ published an updated Cochrane review of neuraminidase inhibitors in healthy adults. That study “took the view that, since eight of the 10 [randomized controlled trials] on which effectiveness claims were based, were never published, and because the only two that had been published were funded by Roche and authored by Roche employees and Roche-paid external experts, the evidence could not be relied upon,” Dr. Godlee writes.’ [From medline, needs registration to view]

To quote the Cochrane collaboration on this matter:

“Patients around the world are being harmed because clinical decisions on their health care are skewed by the absence of clinical trials data,” said Mark Wilson, CEO of The Cochrane Collaboration, in announcing this new partnership. “For 20 years The Cochrane Collaboration has been working to give clinicians, researchers and patients the best possible evidence-based information to help them make informed decisions, and it is a scandal that we still do not have access to all trials data so that we can be confident in our conclusions…”4

Many people find it difficult to believe that companies just hide the data. But they did, and do, and shall do into the future, I would imagine. The 4S study, the single most positive study on statins ever done, by a long way, is more than slightly worrying in this respect. To quote from a blog by Dr Walter Ferneyhough, discussing the 4S study:

‘Did I mention the study bias. Well, it was funded by Merck (the pharmaceutical responsible for simvastatin (a.k.a. Zocor)), was monitored by the Scandinavian subsidiaries of Merck, and the data analysis was performed by Merck. A financial disclosure (conflicts of interest) of the researchers were not given, which is odd, since most studies provide this information.’5

If you believe that there is no possibility that the industry might present biased data, or fail to provide data that is not positive about their products, then you can sleep soundly in your bed…..you poor deluded fool. The reality is that negative studies are not published. Even when a study is positive the ‘raw’ data are held by the pharmaceutical companies. They release what they like, and keep secret what they like. Perfectly legal, so I am reliably informed.

When it comes to statins, this is highly significant when it comes to the issue of Serious Adverse Event (SEA) data. To explain this in a bit more detail, because the terminology here is confusing.

Drugs can cause adverse effects e.g. flushing, pain, headaches. These are known as drug related adverse effects. They are commonly called side effects, but this is inaccurate. A side effect can be positive, or negative.

On the other hand there are Serious Adverse Events (SAEs). SAEs include deaths. They also include nasty things such as a non-fatal MI, or a non-fatal stroke. Things that could be prevented by a statin. So that is good news for statins. However, an SAE could also be an episode of Rhabdomyolysis, or liver damage requiring hospitalisation, or Transient Global Amnesia, or tendon rupture. These could be caused by the statin, and would therefore be bad news for statins.

As you can see, after mortality, SAEs are the next best measure of how beneficial, or harmful, a product might be. Whilst pharmaceutical companies are delighted for us to have the data on positive SAEs, they are completely silent on the data on negative SAEs. Here is what the Cochrane collaboration first had to say on the matter, after they tried to get hold of the data from the statin trials:

Are SAEs reported in the major lipid-lowering trials?

SAE data were sought in the major placebo-controlled trials published up to September, 2001 using statins (5 trials)3-7 or fibrates (5 trials).8-12 Remarkably, only one study, the AFCAPS trial,3 reported total % SAEs in the treatment and placebo groups. In this study, lovastatin was compared with placebo in patients without cardiovascular disease (primary prevention). Similar total % SAEs were reported for the lovastatin, 34.2%, and placebo groups, 34.1% (RR = 1.0 [0.94-1.07]). What this indicates is that the 1.4% absolute risk reduction in total MI or CV death (see Table Letter #27) has been negated by an absolute risk increase in other SAEs. No information is provided as to what these other SAEs might be. The only other trial that reported anything approximating SAEs was the coronary drug project (CDP), a secondary prevention trial. This trial reported the percentage of patients ever hospitalized at 5 years: 55.1% for clofibrate and 52.4% for placebo (RR = 1.05 [0.99-1.12]).

Later on, they had this to say:

‘How can CHD (Coronary Heart Disease) SAEs decrease, but not total SAEs?

All CHD events are SAEs and are counted in both categories. Therefore a reduction in major CHD SAEs should be reflected in a reduction in total SAEs. The fact that it is not suggests that other SAEs are increased by statins negating the reduction in CHD SAEs in this population. A limitation of our analysis is that we could not get total SAE data from all the included RCTs. However, we are confident that the data from the 6 missing RCTs would not change the results, because they represent only 41.2% of the total population and include ALLHAT-LLT10, where one would not expect a reduction in total SAEs; in that trial there was no effect on mortality or cardiovascular SAEs.6

Yes, these reports from the Cochrane collaboration are getting a bit old now. But so are the placebo controlled statin trials, the ones that are used to support all the guidelines on the use of statins. So, when you get down to it, the fact is this. Serious adverse events are simply not reported from the major statins trials, the data are not released.

Which means that the data that are reported are completely skewed. Yes, statins (in secondary prevention) can reduce non-fatal MI and non-fatal strokes. But they increase other unpleasant things by approximately the same amount.

Now, let me take you back to the judgement on the Catalyst program.

‘The program’s treatment of use of statins in secondary prevention focused solely on mortality benefits in a way that reinforced the view that statins were overprescribed and their benefits exaggerated. The principal relevant perspective that statins have wider benefits for this group was not properly presented. This perspective was necessary to a fair understanding of the pros and cons of statin use in this group.’

The committee that sat in judgement of the Catalyst programme was, in my opinion, very fair in the vast majority of what they said. But on this issue they got it terribly wrong. I cannot really blame them, for they probably cannot believe that critical trial data on SEAs are simply withheld. It cannot even be seen by independent researchers.

Because you probably do not believe that this can possibly be true either, I am about to do something that I possibly should not. I have taken advice from a number of people on this, and the views are contradictory. I am about to reveal e-mails that I was sent, and I have not sought permission to do so. Frankly, I know that if I did I would never get permission from all the parties involved [as you will understand once you have read them]. However, I think they are of such enormous importance that people should know they exist, in order to make their own minds up.

The e-mails come from the following discussion. Whilst making the Catalyst programme, Maryanne Demasi contacted Professor Colin Baigent from the Cholesterol Treatment Triallists Collaboration (CTT). The CTT are Oxford based group that hold all the data from the statin trails (Exactly how much, and in how much detail, I have no idea). They are hugely influential, and their meta-analyses form the basis for guidelines on the use of statins around the world. In the UK, the latest NICE guidance will be based entirely on them.

I have known for some time that the CTT will not release the data that they hold, to anyone. But when I speak to journalists they don’t really believe me, much eye-rolling occurs. So, please read on, and find out the truth for yourself. [The only editing I have done to this e-mail trail is to remove all contact details, apart from the address of the CTSU which can be easily found]. You can amuse yourself by spotting the point where the lawyers get involved in drafting the e-mails.

 

To: Enquiries at CTT
From: Maryanne
Sent: 22 September 2013 05:05
Subject: URGENT COMMENT NEEDED PLEASE: ABC TV AUSTRALIA

Hi, I am a medical reporter for ABC TV AUSTRALIA and I am doing a report on statins in primary and secondary prevention.

I have interviewed Harvard Dr John Abramson about the over use of statins within the population and also the lack of transparency of data when it comes to clinical trials.

In the interview he mentions the CTT collaborators being one group who have access to individual data but will not share their data with the public or other researchers even though they’ve been asked.

Prof Rita Redberg from University of California San Francisco supports these statements.

I would like a comment from CTT collaboration regarding Dr Abramson’s and Prof Redberg’s statements please?

Why has the CTT Collaborations refused to release all the data requested of them?

Kind Regards
Maryanne Demasi
Producer
ABC TV AUSTRALIA

 

To: Maryanne Demasi
From: Colin Baigent – CTT
Date: Mon, 23 Sep 2013 21:37:01 +0000
Subject: FW: URGENT COMMENT NEEDED PLEASE: ABC TV AUSTRALIA

Dear Maryanne

Drs Abramson and Redberg are incorrect in stating that the Cholesterol Treatment Trialists’ (CTT) Collaboration has not shared data on the effects of statin therapy in healthy people. Comprehensive analyses of the effects of statins in people at low risk of heart disease or stroke were published (and widely publicised) in the Lancet in 2012, and directly addressed questions about the balance of benefits and risks of statins in such people. The work showed clearly that statins are of net benefit even among those with no previous history of cardiovascular disease.

I would be pleased to discuss this issue with you over the telephone if this would be helpful. I can be reached on +44…

Colin Baigent
Professor Colin Baigent
MRC Scientist & Hon Consultant in Public Health

Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU)
Richard Doll Building
Old Road Campus
Roosevelt Drive
Oxford OX3 7LF

 

To: Rita Redberg and John Abramson
From: Maryann
On Sep 23, 2013, at 2:51 PM

Hi Rita and John,

Both of you mentioned in the interviews that the CTT collaborators don’t give full access to their data to public but the deny this. Please see below and respond as soon as possible please?

Many thanks

 

To: Maryanne Demasi
From: John Abramson
24/09/2013

To: Maryanne, Jim Wright

Maryanne,I have forwarded this to Jim Wright, who is the Co managing director of the Therapeutics Initiative in British Columbia. He has direct experience re ctt data sharing. I do not want to speak for him, but I believe he will be interested in the email below from Dr. Baigent.

Best wishes,
John

 

To: Maryanne Demasi
From: Rita Redber
24/09/2013

Publishing data that they have analyzed is NOT at all the same as giving full access to the public, or to other researchers. In whatever they publish, they maintain control and access to their data, the analyses etc. I am referring to the fact that CTT will not make their data available to any colleagues and other researchers who wish to study risks and benefits of statins. THe CTT data is not accessible publicly.

Rita

 

To: Colin Baigent
From: Maryanne Demasi
24 September 2013 00:50

Hi Colin, thanks for your time. 

I wasn’t referring to the published data, its the unpublished data. Dr Redberg has been specific:

“Publishing data that they have analyzed is NOT at all the same as giving full access to the public, or to other researchers. In whatever they publish, they maintain control and access to their data, the analyses etc. I am referring to the fact that CTT will not make their data available to any colleagues and other researchers who wish to study risks and benefits of statins. THe CTT data is not accessible publicly.”

Comment?

Cheers
 Maryanne

 

To: Maryanne
From: Colin Baigent
Tue, 24 Sep 2013 10:44:01

Dear Maryanne

This is again incorrect. The trials participating in the Collaboration contributed their data to the combined database on the understanding that the data would be held securely and that analyses would be  discussed and agreed by the collaborators before they are conducted. We meet annually, and discuss proposals for new analyses at those meetings. We welcome suggestions for new analyses from scientists who are not formally part of the Collaboration. If, after discussion, such proposals are felt to be scientifically worthwhile (and are feasible) they are conducted by the Secretariat, and the work is shared with collaborators (which then includes those who proposed the analyses).  It is important to recognise that data from participating trials are not owned by the Collaboration, but remain the property of the trial sponsors, so we are not able to provide unlimited access to the combined database. We do, however, provide a mechanism through which the data can be utilised for public benefit.

I hope this is helpful.

Colin Baigent

 

To: Colin Baigent
From: Maryanne Demasi
24 September 2013 13:26

Hi Colin,

Thanks for your moments. I just want to be clear about how i interpret your email.

The data from the clinical trials is “owned” by the trial sponsors – the statin manufacturers.

Hence, the CTT researchers can’t give full disclosure of the data to the public because the trial owners won’t allow them to? Correct?

Maryanne

 

To: Maryanne Demasi
From: Colin Baigent
Date: Tue, 24 Sep 2013 12:30:22

Dear Maryanne

No, this is again incorrect. I think it may be more efficient if you were to call me so that I can explain the process to you. If you wish to speak then I can be reached at the direct line below.

Colin Baigent

 

To: Rita Redberg, Jim Wright, John Abramson
From: Maryanne
Date: Tue, 24 Sep 2013 22:32:28

Hi Dr Redberg, Dr Abramson and Dr Wright

I wrote to the CTT collaborators (Colin Baignet) a second time specifying that its is the “unpublished” data that they are withholding.  His email is below.  Is it possible that I am asking the wrong CTT collaborators?

Am I missing something?

Regards

Maryanne

 

To: Colin Baigent
From: Maryanne Demasi
Tue, 24 Sep 2013 22:09:39

Unfortunately, I don’t have access to a work phone as its late here in Oz.  Also, our lawyers will want to see all these emails to ensure there hasn’t been a misunderstanding or misrepresentation of your position.  I will have to further clarify further with Prof Redberg, Dr John Abramson and Dr Jim Wright from the Therapeutics Initiative in Canada who all claim that the CTT collaborators do not give full disclosure of their data to the public and other researchers.  They have gone on record with this so the matter must be clarified.

Can you explain why they would say something like this?

Maryanne

 

To: Maryanne Demasi
From: Colin Baigent
Tue, 24 Sep 2013 17:02:23

Dear Maryanne

The CTT secretariat has agreement with the principal investigators of the trials and, in those instances where trial data were provided directly by the drug manufacturers,  with the companies themselves, that individual trial data will not be released to third parties.  Such an agreement was necessary in order that analyses of the totality of the available trial data could be conducted by the CTT Collaboration: without such an agreement the trial data could not have been brought together for systematic analysis. Such analysis has allowed the CTT Collaboration to conduct and report all of the analyses on efficacy and safety that have been sought directly or indirectly by others (eg by Dr Redberg in her papers on the efficacy and safety of statins in primary prevention, and in questions raised by the Cochrane Collaboration). Hence, the CTT Collaboration has made available findings that would not otherwise have emerged.

I would be very happy to ring you at whatever time is convenient for you in order to help you to understand our approach, and then address in writing any residual concerns. It would be a shame if we were not able to speak as this would be the most effective way of explaining things.

Please let me know where and some times when I can reach you, and I will endeavour to telephone.

Colin Baigent

 

To: Colin Baigent
From: Maryanne Demasi
24 Sep 2013, at 22:41

Hi Colin,

I am happy to talk to you.  Ive just arrived at work but understand if its too late in London to call you?!

I have to be honest.  I’m not sure why you keep saying my interpretation of the situation is incorrect because the way I read your last email, it tells me that “individual trial data will not be released to third parties”. (that is a direct quote from the email).

I completely understand the reasons why the CTT can not release this information but the purpose of this correspondence was to confirm that the comments of Prof Redberg, Dr Abramson and Dr Wright were factually correct – that they were not making false statements.

They explained that this is the problem with the data from clinical trials – that drug companies “own” the information and will only release what they want rather than having full disclosure of all the data to the public.

Regards

Maryanne Demasi

 

PHONE CALL WITH COLIN BAIGENT NOTES

I had a follow up conversation with Colin.  He stressed that while the CTT made an agreement with the drug companies not to give full disclosure of the individual data to third parties, the CTT had a very important role in providing doctors with the best information available.  He hoped that my report did not undermine the workings of the CTT.

 

To: Maryanne Demasi
From: Jim Wright
26/09/2013

To: Maryanne Demasi

The truth is that Colin agreed for me to send a student to do that analysis in 2007.  When the student Michelle Wong arrived there he would not let her have access to the data and do the analysis.  We would have done the analysis differently and had a better idea of whether the benefits outweighed the harms in low risk people.  I am not convinced by their 2012 analysis, which is based on little or no harm.

Kind regards,

Jim Wright
Editor-in-Chief
Therapeutics Letter

 


Postscript

So now you know that no-one can see the data. Now you also know that the criticism of the Catalyst programme was unfounded. Balance on the ‘non-mortality’ data on statins is impossible as the data on SEAs are hidden. Yes, know the things that statins can prevent e.g. non-fatal heart attacks, but we do not know the equal and opposite things they cause.

The reality is that, if you all did present the data on non-fatal CV events prevented with statins, you would be presenting catastrophically flawed data. Biased, and unbalanced. Yet, Catalyst is told that this is what they should have done.

I know that nothing anyone says will make any difference to ABC now. They just want the attacks to go away. However, I hope that a few thousand more people are now aware of the truth of this matter.

References (may require site registration or membership to access)

1: http://www.theguardian.com/media/2014/may/12/abc-takes-down-catalyst-heart-disease-episodes-after-review-criticism

2: http://bmjopen.bmj.com/content/3/1/e002308.long

3: http://about.abc.net.au/wp-content/uploads/2014/05/Catalyst-Heart-of-the-Matter-ACA-Investigation-Report.pdf

4: http://www.cochrane.org/features/cochrane-signs-alltrials-initiative-campaign-registration-and-reporting-all-clinical-trials

5: http://www.drfernyhough.ca/Cardiovascular%20disease/files/tag-cardiovascular.html

6: http://www.ti.ubc.ca/newsletter/serious-adverse-event-analysis-lipid-lowering-therapy-revisited

 

 

 

Salt is good for you

One of the most pervasive and stupid things that we are currently told to do is to reduce salt intake. This advice has never been based on controlled clinical studies, ever. Yet, as with the cholesterol myth, the dogma that we should all reduce salt intake has become impervious to facts. I find that the ‘salt hypothesis’ is rather like a monster from a 1950s B movie. Every time you attack it with evidence it simply shrugs it off and grows even stronger.

Very recently, a study was done in Australia looking at salt intake. Actually it looked at sodium intake, not salt intake. I find this interesting, as no-one that I know eats sodium. In fact, it would be interesting to see someone try. To quote from Wikipedia

‘Sodium is generally less reactive than potassium and more reactive than lithium. Like all the alkali metals, it reacts exothermically with water, to the point that sufficiently large pieces melt to a sphere and may explode; this reaction produces caustic sodium hydroxide and flammable hydrogen gas.’

Consuming two grams sodium would likely cause you to explode, splattering sodium hydroxide over the walls. Along with various organs and other body parts.

So why do people talk about sodium consumption? I have never really worked this one out. But it does make things rather confusing. The latest guidelines suggest we should consume less than 2300mg of sodium a day, even as low as 1500mg. Go on, try it. Any idea how much salt (NaCl) that would be? Any idea how much salt you consume every day? No, thought not.

Yes, we have been given guidelines that are totally meaningless, and impossible to follow. In fact 2300mg of sodium is roughly 6000mg of salt (NaCl). So why are we not advise to eat six grams of salt a day? I have no idea. Perhaps someone can tell me. What is this sodium nonsense? [Not that anyone has any idea what six grams of salt even looks like poured out of a salt shaker – I know, I have tried this several times.]

Of course, when I started looking into this area, I went at it sideways. If we eat salt we are eating both sodium, and chloride. You cannot have one without the other. So I became interested in the chloride issue, not the sodium. We are always warned about sodium, but no-one ever mentions chloride levels. Is there any evidence that high chloride consumption is bad for us?

This is an area mostly defined by silence, and zero research. But I have found a few papers looking at chloride levels in the blood and, guess what? They have all found that a low chloride level is associated with a higher mortality. Here is one such, entitled ‘Serum chloride is an independent predictor of mortality in hypertensive patients.’

‘Low, not high Serum Chloride- (<100 mEq/L), is associated with greater mortality risk independent of obvious confounders. Further studies are needed to elucidate the relation between Cl- and risk.’  (view here)

There you go. Having a low chloride level makes it more likely you will die early. Yet, having a high level of sodium consumption makes is supposed to kill you? And you cannot eat sodium without eating chloride at the same time. Go figure. You mean you can’t?

Anyway, to return to the, not yet published Australian study, here is what they found.

‘In a multivariate-adjusted model, those who consumed less than 3000 mg of sodium per day had a 25% increased risk of all-cause mortality and cardiovascular events compared with those who consumed between 4000 mg and 5990 mg/day (reference group).’ [1]

The guidelines tell us to eat less than 2300mg of salt. At this level, if we use the Australian data, overall mortality will be increased by 25%. Excellent advice then. And this is not just one contradictory study. Several other trials have clearly demonstrated that reducing salt intake significantly increases mortality in high risk patients. Particularly those with heart failure, where it would be expected that salt reduction would have the greatest benefit. Yet the trials showed the exact opposite.

As explained in the Journal Stroke. The section I have quoted below is taken from a reply to an article entitled “Reducing Sodium Intake to Prevent Stroke: Time for Action, Not Hesitation” In this article Appel, the author, argues strongly that we must, absolutely must, reduce sodium intake. In reply, three cardiologists make the following points:

‘In regards to patient-oriented outcomes, Appel dismisses randomized trials in patients with heart failure as irrelevant because of the unconventional treatment approach of the investigators. Yet these trials—showing increases in hospitalizations and mortality with low-sodium intake versus normal-sodium intake—tested identical diets in intervention and comparison arms with the only difference being the level of ingested sodium (making these trials more relevant than DASH-Sodium and other trials Appel cites). Also, Appel fails to cite 3 relevant heart failure trials, all consistently show harm with reduced sodium intake.’ [2]

In short, Appel, along with most ‘experts’ in this area had dismissed evidence he did not like.

The simple fact is this. If you strip out all the data on salt consumption there is considerably more, and considerably more powerful data, suggesting a strong link between low salt consumption and increased mortality than the other way around.

In reality, you can eat just about as much salt as you can stand – without harm. (Unless you have damaged kidneys and/or very high blood pressure)

How can I possibly state this? Well, a very wise Swedish professor pointed something out to me a few years ago. If a patient is very ill in hospital and cannot eat, or drink, they will have a drip put up to replace fluids. This very often contains 0.9% NaCl. Or nine grams of salt per litre. Quite often the patient will have two litres of this replacement fluid a day – which is (as you may have figured) 18 grams of salt.

So, we quite happy to give critically ill patients 18 grams of salt per day to help them get better – which has no discernable effect on their blood pressure, or anything else. Yet we tell people that they cannot eat more than six grams a day. Ho, ho. You earthlings are so funny.

References (may require site registration or membership to access)
[1] http://www.medscape.com/viewarticle/824749?src=emailthis
[2] http://webappmk.doctors.org.uk/Session/1405533-8qblkO84E9hsUXe6OUa4-aoqmidt/MIME/INBOX/125637-02-B/Stroke-2014-DiNicolantonio-STROKEAHA.114.005067.pdf to be published soon

The dog that did not bark

Sorry that I have been a bit quiet recently. Just been finishing off my latest book ‘The dangerous book for grown-ups.‘ [Plug]. Anyway, I most amused to see the latest headline from a study that appeared in my inbox. I felt I had to comment.

‘Onglyza offers unparalleled confidence in a broad range of patients with Type 2 diabetes, delivering effective glycaemic control, without the worry of increased risk of CV events.’ This headline was from a site called MDLinx that pushes stuff at me – whether I want it to or not. Actually I did subscribe, as I am always interested in what the pharmaceutical industry is saying about itself.

Onglyza by the way is one a range of new drugs designed to lower blood sugar levels in diabetes. It works in a complicated fashion. However, the bottom line is that is increases insulin release – mainly after mealtimes. Onglyza also goes by the generic name saxagliptin.

Anyway, to return to the main point here. We have this wonderfully positive headline about a new trial on Onglyza, and what could be wrong with that, you may ask yourself? Well, once upon a time, it was assumed that if you lowered that blood sugar you would also reduce the risk of cardiovascular disease. Heart attacks and strokes mainly. This was because a raised blood sugar (or type II diabetes) is seen a very strong risk factor of cardiovascular disease.

Which means that you would kind of expect that if you lowered blood sugar using Onglyza, you might also see a reduction in heart attacks and strokes. instead we have a headline proudly announcing that doctors need not worry about Onglyza increasing cardiovascular risk. My but life does move on.

So what the bloody hell does it do then, exactly? Well, there is much concern that it might increase the risk of pancreatic cancer.  Anything more? Well, here from Wikipedia:

In February 2012, Bristol-Myers/Astra Zeneca distributed additional safety information on saxagliptin use in South Africa. The package insert is to be edited for South Africa. Contraindications will now include a history of sensitivity to saxagliptin (or another DPP4 inhibitor) as well as pancreatitis. Spontaneously-reported adverse events in South Africa have included anaphylaxis, angioedema and acute pancreatitis.

In a cardiovascular outcomes trial, saxagliptin treatment let to a small but statistically significant increase in the risk of being hospitalized for heart failure. http://en.wikipedia.org/wiki/Saxagliptin

Blimey, is there nothing this drug cannot do? Well, one thing it does not do, hooray, is that it does not actually increase the risk of cardiovascular disease. Just as well really, otherwise every effect that Onglyza has would seem to be completely negative. Heart failure, pancreatitis, possibly even pancreatic cancer.

We have reached an interesting point in drug development when the fact that a drug designed to prevent a disease (CV disease) is hailed for not causing an increase in that very disease. Has this really become the limit of our ambitions.

Having thought about this for a while I decided to create my new generic headline that pharmaceutical companies can feel free to use if they wish. Are there no limits to my generosity?

‘A groundbreaking study has found that (insert name of drug here) does not kill people from the disease it is supposed to be preventing. Internationally famous opinion leader (insert name of opinion leader here) says this is a landmark study and strongly recommends that (insert name of drug here) should become the drug of choice for (insert name of disease here)

 

 

$9Bn – open a bottle of Bollinger please

Don’t worry it’s only $9Bn

Last week I noticed that Takeda, and Lilly had just been fined $9bn.

A US jury has fined Takeda and Eli Lilly $9 billion (£5.4 billion) for causing a man’s bladder cancer with their diabetes drug Actos (pioglitazone). The verdict came down hard on the companies after the case unearthed evidence that Japanese company Takeda had deleted emails, at least one of which raised concerns over Actos’ safety. ‘This serves as a wake-up call to those pharmaceutical companies that cut corners and hide or distort the facts rather than openly testing and educating about their drugs,’ Mark Lanier, who represented the plaintiffs, tells Chemistry World.

Takeda was unable to produce files for 46 clinical and sales employees, 38 of which were deleted after it ordered documents be preserved in 2002 ahead of legal action over Actos. ‘The breadth of Takeda leadership whose files have been lost, deleted or destroyed is, in and of itself, disturbing,’ wrote Judge Rebecca Doherty in a January ruling.  http://www.rsc.org/chemistryworld/2014/04/missing-emails-safety-risk-actos-takeda-eli-lilly-fine

I think that most industries would be somewhat shocked at a fine this big, and this truly was a whopper. However, it follows a pattern of massive fines. GSK was fined $3Bn in 2011 for suppressing clinical trial data on increased suicide risk in children, among many other activities, such as paying kickbacks to doctors. Pfizer was ordered to pay $2.3Bn in 2009 for a series of illegal activities, from mis-branding drugs, to bribery and corruption. AstraZeneca had to shell out $523 million in 2010 for illegally marketing Seroquel for use in children. Roche is accused of hiding data on Tamiflu, GSK is embroiled in corruption cases in China and elsewhere. Merck was hit with a $670 million fine over Medicare fraud in 2007. Eli Lilly shelled out $1.4Bn for illegal marketing in 2009…….etc.

These are vast fines, and the activities exposed are very disturbing indeed. Suppressing data on drugs causing cancer, or suicide, is very serious indeed. You would think these fines would be punitive, but clearly they are not. Or they wouldn’t keep happening. Perhaps the companies just see this as the price of doing business?

Say you have a drug that is making $5Bn a year in profit, and half of that profit comes from illegal marketing, or hiding data. It is not difficult to work out that after only five years, you have made an extra $12.5Bn in profit. I assume it takes at least five years for any case to come to court – probably far, far, longer. (Takeda, it seems, started suppressing data as far back as 1993)

I suppose the equation here is very simple, if dreadful. If you get fined a paltry £1Bn for hiding data, then you have made an extra $11.5Bn in profit from acting illegally. Even if you get fined $9Bn, you are still in the money. (Sales of pioglitzazone were very nearly £5Bn in 2010, so this is not an abstract discussion).

In short, if you do not possess a moral compass, and you are only interested in maximizing profit, it makes perfect sense to market your drugs illegally, pay bribes to doctors, suppress data on increased cancer risk – and all the rest of the corrupt and illegal activities that have been exposed in the courts. Why would you not? Any fine you have to pay is going to be smaller than the increased profit.

In my opinion the only real ‘why you would not‘ is if you, the CEO of Takeda, or Merck, or Pfizer can actually be sent to jail if it turns out that the company was acting illegally on thier watch. At present, the greater the profit, the greater the CEO bonus. Fines will usually arrive long after you have left the company, with a massive pay off, and a pat on the back for your great work in boosting shareholder value.

I think it would concentrate the mind if the CEO or Takeda, or Merck, or Pfizer knew that they would go to prison for a long time, if the company they run, or ran, is found guilty suppressing data. At present we are, effectively, rewarding corrupt behavior by pharmaceutical companies. Which is why there have been so many huge fines; and why I predict that there will be many more.

Currently, the situation is one of extreme moral hazard. A pharmaceutical company makes far more money acting illegally, than acting legally. If the activity is exposed, no-one goes to prison and no-one is personally bankrupted. All that is required is  to set aside enough money to pay the fine, if it ever arrives. ‘Don’t worry, dear shareholders, it’s only $9Bn.’ Phew, and I thought profits would be damaged.’

Conflict of Interest at the CTT?

What is a conflict of interest? One definition is thus: ‘A conflict of interest is a set of circumstances that creates a risk that professional judgement or actions regarding a primary interest will be unduly influenced by a secondary interest.’

Or, in my simple world. ‘Someone pays you money. You then say or do things that you would not have said or done, if they hadn’t.’ The secondary interest doesn’t have to be directly monetary. It could be a promise of a promotion, or an invitation to be chairman of an important committee, or a chance to meet someone famous, or watch a world cup final, or suchlike.

However, for the sake of keeping things simple, we are talking about money here. We are talking about pharmaceutical companies paying money to medical ‘experts’, who may then say or do things that they would not otherwise have said or done.

The first problem is, thus. How do you know they would not have said or done it anyway? If the dairy industry paid me a million pounds to say ‘Dairy foods do not cause heart disease.’ This would be a bonus. Because it is what I believe, it is what I say already, and you really don’t need to pay me a million pounds to say it. [Although I am open to offers].

However, if I was paid a million pounds and I then said ‘dairy foods to do not cause heart disease’, and you discovered that the dairy industry had paid me a million pounds, what would you think? I know exactly what you would think. ‘I trusted him, now it turns out he is just lining his wallet, the same as everyone else.’ Some would state this more vehemently than others. However, any reputation that I have would never be the same again. There would always be that loss of trust. That doubt.

The people we admire and trust the most do not take backhanders. Pity.

For many years, pharmaceutical companies paid doctors ‘honoraria’, which is just a posh word for money. The doctors happily stuffed said honoraria into their bank balances, and no-one seemed much bothered. You did not need to declare any financial interests, and the only limitation on how much you got paid was your perceived value to the companies.

Your value was measured in a few different ways:

1. Ability to influence other doctors – your status as an ‘opinion leader’
2. Your quality as a speaker at meetings and/or ability to set up and run clinical trials
3. Your influence within the healthcare system i.e. do you advise Governments on treatment, do you sit on committees that advice NICE, or the Food and Drugs Administration (FDA)
4. Your position on Guideline committees. Can you play a key role in writing the guidelines that other doctors have to follow e.g. drug x a must be used first line in all patients with condition y.

These things are, of course, all linked. As an expert you start on rung one and two, and then move onto three and four. Your progress up this ladder requires very close links with the industry. You cannot influence other doctors if you haven’t done research, and it is very difficult to do research without industry funding. If not impossible.

At a certain point in the process, you become exceedingly important to the industry. In fact there are companies who support the pharmaceutical industry whose entire raison d’etre is to manage Key Opinion Leaders (KOLs).

According to Dan Mintze, senior director, heartbeat experts, “The management of KOLs needs to be broader than identifying, segmenting, influence mapping and working with clinicians in order for products to gain clinical approval. Rather a comprehensive KOL solution which includes the identification and appropriate engagement of KOLs who impact market access decisions e.g. KOLs who serve as Government or payer advisory board members (see figure 3) should be adopted.” Such pharma-KOL engagement will lead to the development of value messages that can help pharma to access the market faster, gain quicker product adoption, and increase bottom line performance.’ [my words in bold]  Original PDF here

The more you increase bottom line performance, the more you are worth, and the more you get paid. Strangely, some left-wing commies a.k.a ‘people’ began to object to this cosy relationship. A bit too much potential for the situation whereby… a primary interest will be unduly influenced by a secondary interest.

Luckily this problem was instantly solved, amid scenes of wild rejoicing, by ensuring that doctors who did major studies, or wrote articles and suchlike, must disclose their conflicts of interest. Once this had been done there was nothing to worry about, ever again. [joke]
Although, what we are supposed to do with a disclosure of interest has never really been explained. As a Swedish doctor wrote to me:

‘While we are at this: I have often wanted to ask the purpose of revealing possible/probable conflicts of interest. Just what are we supposed to do with that editorial caveat? Does it mean the data might be suspect? If the editors want us to know it is suspect then why do they publish it?

If it means we should interpret the data with caution, can someone tell me how one is to be cautious. Does it mean one believes none of it or does one believe some of it? If the latter then which part do we believe and/or which do we not believe. Just how are we supposed to judge these things, after having been warned to beware?

Indeed, what are we supposed to do? The other problem is that, whilst doctors are meant to declare their conflicts, quite often they do not. Here is an addendum taken from the Journal of the American Medical Association.

It was in response to an article which was written by a number of authors, who did not see to need report any of their conflicts. Some eagle eyed readers wrote in to complain, and the journal responded thus [I put in bold those companies who would have benefitted financially from the original paper]:

Unreported Financial Disclosures in: ‘Association of LDL Cholesterol, Non–HDL Cholesterol, and Apolipoprotein B Levels With Risk of Cardiovascular Events Among Patients Treated With Statins: A Meta-analysis.’

….the following disclosures should have been reported: “Dr Mora reports receipt of travel accommodations/meeting expenses from Pfizer; Dr Durrington reports provision of consulting services to Hoffman-La Roche, delivering lectures or serving on the speakers bureau for Pfizer, and receipt of royalties from Hodder Arnold Health Press; Dr Hitman reports receipt of lecture fees and travel expenses from Pfizer, provision of consulting services on advisory panels to GlaxoSmithKline, Merck Sharp & Dohme, Eli Lilly, and Novo Nordisk, receipt of a grant from Eli Lilly, and delivering lectures or serving on the speakers bureau for GlaxoSmithKline, Takeda, and Merck Sharp & Dohme; Dr Welch reports receipt of a grant, consulting fees, travel support, payment for writing or manuscript review, and provision of writing assistance, medicines, equipment, or administrative support from Pfizer, and provision of consultancy services to Edwards, MAP, and NuPathe; Dr Demicco reports having stock/stock options with Pfizer; Dr Clearfield reports provision of consulting services on advisory committees to Merck Sharp & Dohme and AstraZeneca; Dr Tonkin reports provision of consulting services to Pfizer, delivering lectures or serving on the speakers bureau for Novartis and Roche, and having stock/stock options with CSL and Sonic Health Care; and Dr Ridker reports board membership with Merck Sharp & Dohme and receipt of a grant or pending grant to his institution from Amgen. (original JAMA correction here.)

As you can see, Paul Ridker had board membership with Merck Sharp and Dohme, and simply forgot the mention it. The authors’ collective punishment? Well, you have just seen it. Essentially, there is no punishment. A bit of momentary embarrassment, soon forgotten. [Although not by everybody, guys].

However, the steady pressure for doctors to provide disclosures of interest has had one major impact. It has made it a bloody site more difficult to know where the conflicts of interest might actually lie.

For it has been decreed….I don’t know who decreed, or agreed it, that if you are paid money directly by a pharmaceutical company, or say a PR company working for the industry, you have a financial conflict of interest that you must/should declare.

However, if you work for an organisation such as the Cleveland Clinic, or the Clinical Trials Research Unit (CTSU) in Oxford things are different. The clinic is paid money by the industry, and then the clinic pays you. This means that you are not conflicted in any way. You need not declare anything. Why?

I don’t know who stated that this is acceptable. As with most things in this area we are in a shadow world full of ghostly apparitions that elude your grasp. ‘They said it was fine.’ And who, exactly, are they. There is no oversight committee here, no investigations carried out, no rulebook, no punishment. Just a very woolly gentlemen’s agreement amongst the great and the good of medical research.

However, because it has been agreed, in some mysterious way, that ‘second hand’ payments are fine, it means that those working at the Cleveland Clinic, the CTSU, and suchlike, feel able to state that they have no financial conflicts – at all. Even if the organisation they work for earns hundreds of millions, or billions, in industry funding.

If those working at the CTSU do, somehow, find themselves working directly with the industry, they now give any money they might have eared to charity. To quote their rules on the matter:

Guidelines for CTSU staff with respect to honoraria and any
other payments offered and share ownership

——-

d: If an honorarium is declined, the intended CTSU recipient can still mention that a
corresponding amount might be donated to a specific charity.

A corresponding amount to a specific charity. What charity?

‘I guess if I had any advice for reporters, I would say, ask your local university if they’ve set up any associated [non-profit organizations]; many universities have an associated charity or foundation through which they solicit donations from corporate sponsors to support medical research. Find out about who those corporate sponsors are. Unfortunately, many universities set up these associated charities and foundations in such a way that they don’t have to disclose much publicly – ask about that, you know, try to push.’  (original article here)

Push away, but I don’t expect you will get very far.

Anyway, we are now supposed to believe that highly qualified and very influential KOLs, who work at the CTSU in Oxford, carry out work on behalf pharmaceutical companies for no payment, whatsoever. This is just charity work. Helping impoverished pharmaceutical companies is the same, really, as helping starving orphans in Africa.

Strangely, it appears that the CTSU doesn’t mind in the least that their staff are spending large chunks of their professional life helping pharmaceutical companies – out of the goodness of their hearts. The CTSU gets nothing; the pharmaceutical companies get nothing, other than a warm glow in their hearts. Meanwhile a ‘specific charity’ is doing rather well. Whatever that specific charity may be?

Of course the CTSU itself does rather well from the industry. Just for carrying out one of their many studies, REVERSE, they received £96million ($155million) from Merck Sharp and Dohme.

Yet, despite the huge sums of industry money sloshing about in the CTSU there are absolutely no conflicts of interest going on here. We are told this by none other than the CTSU itself. No-one is paid money directly by the industry in any way. So that is fine.
As Robbie Burns said: ‘O, wad some Power the giftie gie us to see oursels as others see us. It wad frae monie a blunder free us.’

As a sort of footnote to this blog, you may be interested to know that the Cholesterol Treatment Triallists Collaboration (CTT) in Oxford is probably the most influential organisation in directing the management of CV disease around the world.
The ACC/AHA guidelines launched last year in the US are based on the latest CTT meta-analysis; as are the latest NICE guidelines in the UK. The Cochrane Collaboration, which is also highly influential world-wide, changed their guidance on the use of statins in primary prevention, based on the CTT meta-analysis.

In short, if you want to identify a group of KOLs who can truly increase ‘bottom line performance’, you will not find any organisation more powerful than this. Best of all, CTT have absolutely no conflicts of interest with the pharmaceutical industry either. If you want to contact the CTT about any of this, you can e-mail them at: CTT@ctsu.ox.ac.uk