Tag Archives: Guidelines

Guidelines kill 800,000

57 Replies

A few days ago a friend sent me this headline by e-mail.

‘Guideline Based on Discredited Research May Have Caused 800,000 Deaths In Europe Over The Last 5 Years.’

I would replace the word ‘May’ with these two words ‘almost certainly.’ You would think, would you not, that if any other event in the world, at any time, had killed eight hundred thousand people, this would be front page headlines around the world for weeks, probably months, maybe even years.

Governments would spring into action, those guilty dragged into court. Thousands would protest in the streets, petitions would be signed, laws passed.

The reality is, I am willing to bet, that you have never even heard of this gigantic scandal. It will not have appeared in any national television programme, or newspaper. The blogosphere is also, almost totally silent.

Eight hundred thousand people. Please let that figure sink in for a few moments. If you dropped a major thermonuclear device on Manchester (UK) and killed every single living person, this would be roughly equivalent. If you laid the corpses end to end, the line of dead people would stretch from John O Groats to Land’s End (the entire length of the UK). Walking briskly each day, it would take you two months to pass them.

Think on that.

To an extent the actual guidelines themselves are not the most important thing here. They are now in the process of being changed (although they have not yet been changed). Nobody can be brought back to life, those who could have died – are dead. The issue here is that the processes leading to the creation of guidelines, that have almost certainly killed 800,000 people, are still in place, with no prospect of any change.

Those who have read this blog may be aware of my distaste for medical guidelines, and my concerns about their impact. I wrote an earlier blog called ‘Who shall guard the guardians.’ This outlined some of the problems, but even I was overwhelmed by the sheer scale of deaths involved when guidelines go wrong. I could have worked it out, but never did.

Guidelines are based on evidence, and evidence is based on clinical trials. And major clinical trials are, almost without exception, paid for, run, and controlled by the pharmaceutical industry. The great and good of medicine, the ‘Key Opinion Leaders’ KOLs, who put together the guidelines will almost all have very close connections with the industry. In some cases they will have been paid millions by pharmaceutical companies.

Whether they think so, or not, these opinion leaders are biased. Biased in favour of pharmaceutical products that are promoted through biased research, and launched on an unsuspecting world. And there is no-one out there to check what these KOLs and guideline committees are doing. If, to pluck a name from the air, the European Society of Cardiology (ESC) decides to create a guideline committee, how do they do it?

They choose a chairman, who will be on one of their committees. A well regarded, sound chap, with expertise in the area. He, very rarely she, will then decide on which of his friends and colleagues would be most suitable to be committee members.

They will have a few meetings, gather the evidence together, decide on what best practice should be, and produce their guidelines. No other organisation checks on them, or their decision making, or their conflicts of interest. Or, indeed, the evidence itself.

Yet, when the guidelines come out, many countries will slavishly follow them. They will form the basis for instructions to their medical services. Doctors who fail to follow the guidelines can be censured, or lose their jobs. They virtually carry the force of law.

Something this powerful and important and critical to medical care is dealt with in an almost completely cavalier fashion. Which is, frankly, inexcusable.

I suppose you are wondering what these guidelines were? Well, they were on the use of beta-blockers to protect the heart during surgery. To see more on this story go to the Forbes website

I cannot send you to the article published in the European Heart Journal, because one hour after going up on their website, it was pulled. Here is the comment from the authors of this paper, Graham Cole and Darrel Francis, on the decision of the Editor to disappear the article.

‘Our article is a narrative of events with a timeline figure and a context figure. We had not considered it to contain scientific statements, but we admit that it does multiply together three published numbers.

It is not an analysis of individual trials considering design, molecule, dose and regimen. We published last year the formal meta-analysis under stringent peer review in Heart and addressed the questions, including dosing, in that paper and associated correspondence.

The first of our two EHJ articles merely says that our community, which races to take credit when research-led therapy improves survival, must be equally attentive to the possibility of harm.  The leverage of leadership means the magnitude of either may be far from trivial.

Where our article relayed numbers, we made clear that alternative values were possible. The focus for readers was on how serious the consequences can be when clinical research goes wrong.

We thank Prof Lüscher for highlighting the scientifically important point that the pivotal trial, DECREASE I, has not been retracted by NEJM because the investigative committee did not recommend this. Unfortunately the committee could not have done so, because DECREASE I was outside its brief, displayed on the first text page of the first committee report. Can readers suggest why DECREASE I, from the same trial family, was exempted from inquiry?

We admire Prof Lüscher’s diligence in sending for peer review what we thought was merely multiplication. We await the review of the pair of articles. The first narrated one instance of a pervasive problem. The second suggests what each of us can do to reduce recurrences.

We respect the process Prof Lüscher has set in motion. We ask readers to join with us, and the journal, in maximizing the reliability of clinical science for the benefit of patients.’

Well, I am really glad that this article is being sent for peer review, because – as we know – peer review is a jolly good thing. To quote Richard Horton, Editor of the Lancet:

‘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.’

Let me just repeat that last bit. Peer-review is:

….biased, unjust, unaccountable, incomplete, easily fixed, often insulting, usually ignorant, occasionally foolish, and frequently wrong.

Frankly, I wouldn’t hold my breath waiting for peer-review on this matter.

I suppose you may also be wondering how the problem with these guidelines came to light. Well, it turns out that the chairman of the guidelines committee was Prof Don Poldermans. A man who has now been booted out of his job at Erasmus Hospital in the Netherlands for making up his research. The very research that was used to create these guidelines.

Don Polderman’s also had financial conflicts of interest with Merck, Pfizer, Novartis and Medtronic. To name but four. (One conflict of interest statement can been seen here).

Anyway, here is a summary of what has happened:

      • Don Poldermans had financial conflicts of interest with several pharmaceutical companies
      • Con Poldermans carried out corrupt research, supporting the use of pharmaceutical products
      • Don Poldermans was the chairman of an ESC committee that recommended widespread use of drugs to protect the heart during surgery
      • Widespread use of drugs to protect the heart during surgery has killed 800,000 people over 5 years in Europe (alone)
      • The paper outlining the scale of deaths has been pulled by the ESC

I hope the hell there are no more Don Poldermans out there…..but you would have to be a brave man to think so. Personally, I believe there is an endemic problem with bias and corruption in medical research, and we should be very afraid indeed.

What is your ‘Statin by date’?

111 Replies

Somewhat to my chagrin, I filled in my risk factors into the new ACC/AHA guidelines on cardiovascular disease prevention. I now find that I should have started statins eight weeks ago. Naughty, naughty, me. My blood pressure was a bit higher than the calculator liked 138/82, my cholesterol quite a bit higher at 6.0mmol/l.

Which means that I have already passed the 7.5% ten year risk score. O….M…..G. (I think my picture makes me look a bit younger than I am, although it was only taken last year – honest)

What to do?

I am now well beyond my ‘Statin by date.’ No longer can I be healthy without taking a statin. By the way, a friend came up with the concept of ‘statin by date.’ It did make me laugh, conjuring up the image of a sell by date on a can of baked beans. Or maybe Logan’s run. If you remember that film, once you reached the age of, I think it was thirty, you had to leave the colony as you had reached your sell by date.  ‘No this is not au-revoir…. It is goodbye.’

Can I be reassured that my parents are both alive and healthy in their late eighties. My grandmother, on my mother’s side, lived to one hundred and two. No idea about my father’s side. WWII did for both my grandparents on that side.

Can I feel comfort in the fact that I play squash three times a week, go to the gym twice a week and walk when I can? Mind you all of this is wiped out by my excess consumption of alcohol I suppose – unfortunately. Also, I am in the overweight category with a BMI, of 28. But wait, isn’t the entire English rugby team obese, using the BMI. Must be all the training and muscle bulk that does it. Yes, the jolly old BMI.

No, I thought I was a pretty healthy chap. I have no real risk factors for heart disease at all. A resting pulse rate of 48, a reasonable blood pressure……

In truth I feel terribly sorry for the Swiss. They have the highest average cholesterol level in Europe at 6.4mmol/l (250mg/dl in those inconvenient US units). Surely the entire nation must be put on statins straight away. But, hold on, wait just one gosh darned minute. Don’t they have the second lowest rate of heart disease in Europe?

Why yes, they do. Only beaten by the French. Who have an average cholesterol levels higher than most other countries, they also eat the most saturated fat in Europe, and yet they have the lowest rate of heart disease. About one quarter that of the UK and US. I wonder how the ACC/AHA calculator works for them? Perhaps not that well.  Ah oui, bonne chance. Zey must be, ‘ow you say ‘une paradox’. (Or would that be ‘un paradox’)

As you can tell I think I am grasping at straws. Who am I to attempt to stand against the massed intellectual power of the ‘experts.’ The reality is that I feel the breath of the grim reaper on the back of my neck, scythe in hand. I am now eight weeks past my statin by date, and I am not taking statins. The clock ticks in the background, I can sense the disapproval of cardiologists around the world weighing heavily upon me.

‘Forgive me father, for I haven’t statined.’

Who shall guard the guardians?

32 Replies

(Quis custodiet ipsos custodes?)

Mainstream medicine increasingly relies on Guidelines. Well, they are called guidelines, but increasingly they carry the force of law. In many countries if you try to practice outside the wise and infallible guidelines you may lose your license to practice medicine. In the US, you may well be dragged into court, and if you have not been following the guidelines, you will be sued. You can even be gaoled (or jailed, as we say in the UK).

In short, guidelines are very serious and important things indeed, and they now rule medicine with a rod of steel. In the UK up to 50% of general practice time is spend ensuring that all patients are constantly monitored to ensure that various guidelines are rigorously followed. Is the BP low enough, the cholesterol low enough, have you checked blood sugar levels etc.

But where do guidelines come from – exactly? Who gives people the right to sit on guideline committees? What are the entrance requirements? Who shall guard the guideliners?

The answer is, perhaps shockingly, that there are almost no rules to this. If a group, such as the National Institutes for Health in the US, decides to set up a committee to decide on, for example, what is the healthy level for cholesterol lowering, what happens? They ask a number of Key Opinion Leaders to join the committee. In this case the NCEP (National Cholesterol Education Programme – which is a committee, not a programme).

In 2004 this committee decided that cholesterol levels should be lowered far more aggressively than in the past. Based on, as far as I could see, very flimsy evidence.  Could it be that that committee was, in some way, biased in favour of cholesterol lowering companies?  A number of people, including me, demanded to see if any of the eight invited members of this hugely important committee had financial conflicts.

With much reluctance, the conflicts were revealed (I have highlighted, in bold, the companies who marketed cholesterol lowering agents at the time.) See below

ATP III Update 2004:  Financial Disclosure of NCEP members

Dr. Cleeman: (Chairman) has no financial relationships to disclose.

Dr. Grundy: has received honoraria from Merck, Pfizer, Sankyo, Bayer, Merck/Schering-Plough, Kos, Abbott, Bristol-Myers Squibb, and AstraZeneca; he has received research grants from Merck, Abbott, and Glaxo Smith Kline.

Dr. Bairey Merz: has received lecture honoraria from Pfizer, Merck, and Kos; she has served as a consultant for Pfizer, Bayer, and EHC (Merck); she has received unrestricted institutional grants for Continuing Medical Education from Pfizer, Procter & Gamble, Novartis, Wyeth, AstraZeneca, and Bristol-Myers Squibb Medical Imaging; she has received a research grant from Merck; she has stock in Boston Scientific, IVAX, Eli Lilly, Medtronic, Johnson & Johnson, SCIPIE Insurance, ATS Medical, and Biosite.

Dr. Brewer: has received honoraria from AstraZeneca, Pfizer, Lipid Sciences, Merck, Merck/Schering-Plough, Fournier, Tularik, Esperion, and Novartis; he has served as a consultant for AstraZeneca, Pfizer, Lipid Sciences, Merck, Merck/Schering-Plough, Fournier, Tularik, Sankyo, and Novartis.

Dr. Clark: has received honoraria for educational presentations from Abbott, AstraZeneca, Bristol-Myers Squibb, Merck, and Pfizer; he has received grant/research support from Abbott, AstraZeneca, Bristol-Myers Squibb, Merck, and Pfizer.

Dr. Hunninghake: has received honoraria for consulting and speakers bureau from AstraZeneca, Merck, Merck/Schering-Plough, and Pfizer, and for consulting from Kos; he has received research grants from AstraZeneca, Bristol-Myers Squibb, Kos, Merck, Merck/Schering-Plough, Novartis, and Pfizer.

Dr. Pasternak: has served as a speaker for Pfizer, Merck, Merck/Schering-Plough, Takeda, Kos, BMS-Sanofi, and Novartis; he has served as a consultant for Merck, Merck/Schering-Plough, Sanofi, Pfizer Health Solutions, Johnson & Johnson-Merck, and AstraZeneca.

Dr. Smith: has received institutional research support from Merck; he has stock in Medtronic and Johnson & Johnson.

Dr. Stone: has received honoraria for educational lectures from Abbott, AstraZeneca, Bristol-Myers Squibb, Kos, Merck, Merck/Schering-Plough, Novartis, Pfizer, Reliant, and Sankyo; he has served as a consultant for Abbott, Merck, Merck/Schering-Plough, Pfizer, and Reliant.

http://www.nhlbi.nih.gov/guidelines/cholesterol/atp3upd04_disclose.htm

Of course, as people have stated to me, the mere fact that there were seventy two financial conflicts of interest does not mean that the guidelines themselves were biased. But you know what, I don’t believe it. Imagine if eight Supreme Court judges, ruling on any issue, had seventy two direct financial conflicts of interest to do with that issue…..Well, the outcry would never end.

Yet doctors, it seems, are beyond any suspicion – of any sort. There is not the slightest possibility that any doctor would ever do anything wrong….We are, after all, superior beings. ‘But, what’s that you say skippy…. hold on.’

‘Despite a 2-year-old scandal discrediting key evidence, current guidelines relying on this evidence have not been revised. As a result of physicians following these guidelines, some researchers say, it is possible that thousands of patients may have died each year in the UK alone. It is unlikely that a true understanding of the damage will ever be known…..

The guidelines, which were published in 2009, were based on analyses of the available trials. The strongest evidence came from the DECREASE family of trials, which appeared to strongly support perioperative beta-blockade, and one other large trial, POISE, which raised concerns that beta-blockers might lead to an increase in deaths

In 2011, however, faith in the reliability of the DECREASE trials was shattered as a result of a scientific misconduct scandal centering on the principal investigator of the studies, the now disgraced Dutch researcher Don Poldermans. The issue was further complicated because, in addition to his key role in the trials, Poldermans was the chairman of the committee that drafted the guidelines.’ http://cardiobrief.org/2013/07/31/european-heart-guidelines-based-on-disgraced-research-may-have-caused-thousands-of-deaths/

Oh well, maybe not.

The fact is that, wherever you look, guidelines are being developed by doctors who have widespread conflicts of interest. And if you go a step further back to review the studies that the guidelines are based on, they are run by, and written up by, doctors who have enormous conflicts of interest. Although sometimes, these conflicts are just…well, forgotten about.

For example, a few opinion leader were ‘named and shamed’ by the Journal of the American Medical Association, when someone pointed out that a number of the authors of the original paper they wrote might just have slipped up in declaring their conflicts:

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. http://jama.ama-assn.org/content/307/16/1694.3.full?etoc

Not a bad little list. As you can see, Dr Ridker had board membership with Merck Sharp and Dohme…… a company that has made billions from selling statins. Now, here is he is authoring a paper on the benefit of statins (which will be used to develop guidelines on cholesterol lowering), and he simply forgot about this conflict of interest. As for the others, well, they’re also busy people; things must have just slipped their minds, such as thirty three separate financial conflicts.

For this terrible crime against the integrity of medical science, none of them can ever again do medical research, or author a medical paper, or sit on guideline committees. Cue, mad cackling laughter. As you may expect, absolutely nothing happened at all, apart from the publication of that statement you in the Journal in the American Medical Journal (JAMA).

I am sorry, but the system of developing guidelines is, frankly, bust. It has been for many years, but it is a very big and dangerous looking nettle to grasp, and no-one, currently has the will to do it.

Someone, somewhere, needs to ensure that guidelines, and the evidence they are based on, and the interpretation of that evidence, is of the highest quality – and free from potential bias, and financial conflicts of interest. We are about as far from this happy state of affairs as I am from being invited onto any guideline committee, ever, anywhere.

And that, my friend, is a very, very long way away indeed. You would need to Hubble telescope to see across distances as vast as that.