$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

Another point of view

As someone who considers myself to be a scientist, I thought I should present another view to you on statins. This piece (a transcript of a talk) can be seen on Medscacpe1.

Please read on, and see what you think of his arguments:

I am Dr. Frank Veith, Professor of Surgery at New York University Medical Center and the Cleveland Clinic. Today I am going to talk about what I call the “statin witch hunt” and why, despite it, we should give more patients statin drugs.

The question of whether to give statins to more healthy patients is one of considerable interest to the public and considerable debate in both the medical community and the lay press. In November, the American College of Cardiology (ACC) and the American Heart Association (AHA) released their long-awaited new guidelines on the treatment of blood cholesterol to reduce the risk for adult atherosclerosis. T

This guideline, among other recommendations, guided physicians to expand the number of patients being treated with statin drugs. The guideline was greeted with many objections in both the medical community and the lay press. Most notable was a November 14 New York Times op-ed by 2 respected experts, Drs. John Abramson and Rita Redberg, titled “Don’t Give More Patients Statins.”

Other New York Times articles about Drs. Paul Ridker and Nancy Cook, and another by Gina Kolata, expressed similar reservations about the ACC/AHA guideline recommendation to broaden statin administration. All three of these New York Times articles were part of what I call the “statin witch hunt” which has generated much confusion among the public.

The op-ed by Drs. Abramson and Redberg makes the case that the recent ACC/AHA cholesterol guideline is incorrect to advocate the expansion of statin usage to more patients because such expansion “will benefit the pharmaceutical industry more than anyone else.” They state that the guideline’s authors were not “free of conflict of interest.” In addition, they claim that “18% or more” of statin recipients “experience side effects” and that the increase in statin administration will largely be in “healthy people” who do not benefit and who would be better served by an improved diet and lifestyle.

Although the latter is true for everyone, Drs. Abramson and Redberg convey the wrong message. Statins are the miracle drug of our era. They have proven repeatedly and dramatically to lower the disabling and common consequences of arteriosclerosis — most prominently heart attacks, strokes, and deaths in patients at risk. Statins avoid these vascular catastrophes not only by lowering bad blood lipids but also by a number of other beneficial effects that stabilize arterial plaques.

 They have minimal side effects, most of which are benign. In several controlled studies, the patients who did not receive statins had an incidence of side effects equal to those who received them. Serious side effects are rare and manageable. Moreover, healthy patients are only healthy until they get sick. Many individuals over the age of 40 take a daily aspirin.

Statins are far more effective than aspirin in preventing the heart attacks and strokes that often occur unexpectedly in previously “healthy people.” Clearly it would be worthwhile for such healthy people to take a daily statin pill with few side effects, if it would lower their risk for such vascular catastrophes and premature death.

In contrast to what is implied in the Abramson-Redberg article, these drugs are an easy way for people to live longer and better, and statins cannot be replaced with a healthy lifestyle and diet — although combining the latter with statins is a good thing.

Lastly, with respect to the comments about the pharmaceutical industry benefiting from statin prescriptions, and the guideline authors’ conflicts of interest, both are less important than patient benefit, which has been demonstrated dramatically and consistently in many excellent and well-controlled statin trials. Moreover, most statins are now generic, so the cost for obtaining these miraculous drugs need not be prohibitive, and the guideline’s authors are experts who are eminently qualified to write them.

The statin witch hunt is a bad thing, and more patients should be on statin medication. I am Dr. Frank Veith, and that is my opinion.

1: http://www.medscape.com/viewarticle/822145?nlid=51963_1985&src=wnl_edit_medn_card&spon=2

(You will need to subscribe to Medscape to see the talk, and transcript. It is fairly straightforward to gain access. The site is www.medscape.com It is one of the biggest medical websites.)

I though you should know if Frank Veith has any conflicts of interest. He works at the Cleveland Clinic, so he probably doesn’t, as most of the medical experts who work there state that they give all of their income from working with the pharmaceutical industry to charity. Steven Nissen, a man of whom you may have heard me speak on a regular basis, is the chairman of Cardiovascular medicine at the Cleveland Clinic.

Here, for example, is Steven Nissens conflict of interest statement

Dr Steven Nissen
Medical Director
Cleveland Clinic Cardiovascular Coordinating Center

Dr. Nissen has received grant/research support from AstraZeneca Pharmaceuticals, Atherogenics; Eli Lilly and Co., Lipid Sciences, Pfizer Labs, Sankyo Pharma, sanofi-aventis, and Takeda Pharmaceuticals North America with all reimbursement directed to the Cleveland Clinic Cardiovascular Coordinating Center; and has been a consultant for Abbott Laboratories, AstraZeneca Pharmaceuticals, Atherogenics, Bayer Corp., Eli Lilly and Co., Forbes Medi-tech, GlaxoSmithKline Pharmaceuticals, Haptogard, Hoffman-LaRoche, Isis Pharmaceuticals, Kemia, KOS Pharmaceuticals, Kowa Optimed, Lipid Sciences, Merck/Schering Plough, Novartis Pharmaceuticals Corp., Novo-Nordisk, Pfizer Labs, Protevia, Roche Pharmaceuticals, Sankyo Pharma, sanofi-aventis, Takeda Pharmaceuticals North America, Vasogenix, Vascular Biogenics, Viron Therapeutics, and Wyeth Pharmaceuticals, all fees are paid directly to charity with no reimbursement paid to Dr. Nissen; and has served on the speakers’ bureaus of AstraZeneca Pharmaceuticals and Pfizer Labs, all fees are paid directly to charity with no reimbursement paid to Dr. Nissen.

Cleveland Clinic physicians and scientists may collaborate with the pharmaceutical or medical device industries to help develop medical breakthroughs or provide medical education about recent trends. The collaborations are reviewed as part of the Cleveland Clinic’s procedures. The Cleveland Clinic publicly discloses payments to its physicians and scientists for speaking and consulting of $5,000 or more per year, and any equity, royalties, and fiduciary relationships in companies with which they collaborate. The Cleveland Clinic requires its doctors to approve the public disclosures of their scientific collaborations with industry. As of 3/21/2014 the review process regarding Dr. Veith’s disclosure had not been completed. Patients should feel free to contact their doctor about any of the relationships and how the relationships are overseen by the Cleveland Clinic. To learn more about the Cleveland Clinic’s policies on collaborations with industry and innovation management, go to our Integrity in Innovation page.

Although now dead, the Cholesterolosaurus will march on

A meta-analysis including 530,525 people, partly funded by the British Heart Foundation, and published in the Annals of Internal Medicine has just come to this conclusion:

Conclusion: Current evidence does not clearly support cardiovascular guidelines that encourage high consumption of polyunsaturated fatty acids and low consumption of total saturated fats1.

Or to put it another way, there is no evidence that saturated fat consumption has anything, whatsoever, to do with causing heart disease, or strokes. Once again I get to say ‘I told you so.’ Ah, the four most satisfying words in the English language. That is, when arranged in that particular order.

So, eat butter, drink milk, and throw away the horrible sugar-loaded low fat yoghurt. Go to France and enjoy the highest saturated fat diet in Europe and you, too, can enjoy the French rate of heart disease. Yes, of course, the lowest in Europe.

But now what happens? You see, the entire edifice of the cholesterol hypothesis is held together by two links in a chain. Link one is that saturated fat consumption raises cholesterol levels. Link two is that raised cholesterol levels then cause heart disease.

Various ‘experts’ have simplified this to the very simple equation:

A (saturated fat in the diet) > B (high cholesterol levels) > C (heart disease)

This is the cholesterol hypothesis, or the lipid hypothesis, and it has driven medical thinking for the last sixty years.

I have had it painstakingly explained to me, by very clever people, exactly how saturated fat raises cholesterol levels. Indeed, you will find ‘evidence’ for this almost universally accepted fact in literally thousands of clinical studies. Here is what Wikipedia has to say on the matter

There are strong, consistent, and graded relationships between saturated fat intake, blood cholesterol levels, and the mass occurrence of cardiovascular disease. The relationships are accepted as causal2.’

Okay, let us accept that eating saturated fat does raise cholesterol levels. However, if consumption of saturated fat does not increase the rate of heart disease then….. Then raised cholesterol levels can have nothing whatsoever to do with causing heart disease. Just keep chasing the implications of that statement around in your head for a while.

So what happens now? We now have a cholesterol/lipid hypothesis that just had its head blown off. Yet, it still continues to wander about, unaware that it is actually dead.

As everyone knows you can chop the head off a chicken and it can wander about for years. I was also informed, when I was an open-mouthed child, that you could shoot a dinosaur through the head and it would continue to blunder about for some time, the rest of its body blissfully unaware that it was actually dead.

Well, the cholesterol hypothesis has just been shot dead, but I suspect it will continue to rampage about, stomping on puny humans for many years, before it finally keels over and admits that it is dead.

But I say, farewell Cholsterolosaurus. You are now a deceased hypothesis. Gone to meet your maker. You just don’t know it yet. Because the people that believe in you do not understand logic.

1: http://annals.org/article.aspx?articleid=1846638
2: http://en.wikipedia.org/wiki/Saturated_fat

A ghost in the machine

I suppose most people missed this story about life expectancy in the UK. If you didn’t pick it up, this article comes from the Doctors net website. A site for doctors registered to practice medicine in the UK.

Life expectancy fall alarm 14/02/2014

The life expectancy of England’s elderly population has fallen for the first time, it was reported last night. Women at the age of 75 can expect to live a little less longer than they would have at the beginning of the decade, according to new figures.

The figures for 2012 are still provisional and represent a reduction of two and half months in life expectancy for women at the age of 75.There was no change in life expectancy for men, who could expect to live 11.3 years.

The Department of Health calculations, obtained by the Health Service Journal, show that life expectancy for women at that age fell from 13.2 years to 13 years. The figures may reflect the growing problems of caring for an elderly population – or simply growing numbers of elderly people.

John Newton, of Public Health England, told the journal: “Life expectancy reflects what has happened in people’s lives, and these people were born in wartime, when there were profound changes in diet. We have seen an unprecedented increase in life expectancy and it’s possible that is coming to an end.

“But we do also expect fluctuation. As we have an older population, the proportion of deaths that will fluctuate due to flu and cold weather is greater.

So it seems that life expectancy in the UK is falling amongst elderly women, and it is staying stationary for elderly men. Which is rather the opposite of what was supposed to happen, and reverses many years of increasing life expectancy.

Why is this happening? Ten years ago the UK Government embarked upon the most expensive, and extensive, initiative ever undertaken in preventative medicine. The Quality Outcome Framework (QoF). This was launched with a great fanfare.

QoF is a system whereby GPs have to screen the entire population for conditions such as diabetes, high blood pressure, chronic kidney disease, high cholesterol, etc. etc.

Once any early stage diseases had been picked up, treatment is instigated. Then there is regular monitoring to ensure that targets for blood pressure lowering, blood sugar control, and suchlike were met. This system has cost billions upon billions of pounds.

It was supposed to stop people dying prematurely from diseases, or conditions that could be properly ‘treated’ and ‘controlled.’ Because the elderly are, by the nature of being elderly, far more likely to have various early stage diseases, and are therefore at highest risk, this is the population that has been most tightly monitored and ‘treated’.

I work, part-time, in Intermediate Care. A unit where elderly people who have had an accident, broken a hip, or suffered other acute illnesses are cared for. Our job is to get them as fit as possible to return home. There are nurses, physiotherapists, occupations therapists, and me, sorting out underlying medical conditions such as anaemia. Some patients arrive from the community, others from hospital.

I did a small audit last year, and found that the average number of drugs that our patients are taking when they arrive in the unit is ten point three. That is, ten point three different drugs. Some of which are taken three or four times a day. So, a total of twenty or thirty tablets a day, in many cases.

This is the very definition of polypharmacy. And how much harm could polypharmacy do? Well here is a study from Israel, looking a study where people in nursing homes had drugs discontinued [They stopped as many drugs as was considered ethical]. Here is the abstract of the paper.

The war against polypharmacy: a new cost-effective geriatric-palliative approach for improving drug therapy in disabled elderly people.

Background:

The extent of medical and financial problems of polypharmacy in the elderly is disturbing, particularly in nursing homes and nursing departments.

Objectives:

To improve drug therapy and minimize drug intake in nursing departments.

Methods:

We introduced a geriatric-palliative approach and methodology to combat the problem of polypharmacy. The study group comprised 119 disabled patients in six geriatric nursing departments; the control group included 71 patients of comparable age, gender and co-morbidities in the same wards. After 12 months, we assessed whether any change in medications affected the death rate, referrals to acute care facility, and costs.

Results:

A total of 332 different drugs were discontinued in 119 patients (average of 2.8 drugs per patient) and was not associated with significant adverse effects. The overall rate of drug discontinuation failure was 18% of all patients and 10% of all drugs. The 1 year mortality rate was 45% in the control group but only 21% in the study group (P < 0.001, chi-square test). The patients’ annual referral rate to acute care facilities was 30% in the control group but only 11.8% in the study group (P < 0.002). The intervention was associated with a substantial decrease in the cost of drugs.

Conclusions:

Application of the geriatric-palliative methodology in the disabled elderly enables simultaneous discontinuation of several medications and yields a number of benefits: reduction in mortality rates and referrals to acute care facilities, lower costs, and improved quality of living.

The first thing to say here is that, if there ever was a ‘war’ against polypharmacy, then polypharmacy won a long time ago…at least in the UK.

For those who find scientific papers somewhat opaque, the key point from this paper is the following

The one year mortality in those who did not have their medications reduced was 45%

The one year mortality in those who did have their medications reduced was 21%

This is a fifty three per cent absolute reduction in overall mortality risk in a year. Which is a better figure than I have seen for any drug intervention, ever, anywhere. So it would seem that the best possible drug treatment discovered…. is to stop taking drugs. As an added bonus you save lots of money, and make the patient feel much better, all at the same time.

Just one paper? No, of course not. There are a number of different studies demonstrating that discontinuing medication in the elderly is a good thing to do. A review paper in the Journal of the American Medical Association (JAMA) came to the following conclusions:

‘The finding that simultaneous discontinuation of many drugs is not associated with significant risks and apparently improves quality of life should encourage physicians to consider testing this in larger RCTs (randomised controlled studies) across a variety of medical cultural settings. Polypharmacy may have different faces in different countries or clinics but there is no doubt that the problem is global. This approach has international relevance; it combines our best existing evidence with patient-focused care while actively avoiding extrapolation from inappropriate populations where no evidence exists for treatment in elderly patients.’

In fact, I cannot find any evidence that polypharmacy, however you define it, does anything but harm. In the face of such evidence what did the UK authorities decide to do? Why, they set about create a system designed to drive the biggest explosion of polypharmacy ever seen. What else would you expect them to do?

So why has the mortality gone up in the elderly population in the UK? Well, I know where I would put my money. On the very system designed to stop them dying in the first place.

The pharmaceutical industry now controls NHS policy – hoorah.

I noticed the other day that the pharmaceutical industry have managed to achieve something they could surely once only have dreamed of. Creating policy documents. Here is the offending headline from the Guardian newspaper:

NHS hires drugmaker-funded lobbyist

As the secondary headlines say:

‘Conflict of interest concerns as Specialised Healthcare Alliance (SHCA), funded by pharmaceutical companies, advises NHS England.’

A lobbying organisation with links to some of the world’s biggest pharmaceutical companies and medical equipment firms has been asked by NHS bosses to write a report that could influence health policy, it has been reported.’

It seems lobbying is now ‘so five minutes ago.’ Who needs a lobbyist when this organisation, the Specialised Healthcare Alliance (SHCA), which is entirely bought and paid for by the pharmaceutical industry, has been commissioned to write a report on funding specialised services for the NHS.  Services worth £13,000,000,000.00p (£13Bn/$20Bn) per year.

The article does point out, though, that we are misguided to think that this could be in any way an issue. For John Murray, the director of the SHCA, a lobbyist, and author of the report, has made it clear that:

.…..there was no link between his lobbying business and the SHCA other than providing secretariat services and said the SHCA “never takes a position on particular products or treatments in any of its activities”.

John (Pinocchio) Murray’s nose is now in the Guinness Book of Records for being the longest nose ever recorded on a human being, at seven point three miles. He is a lobbyist, paid for by pharmaceutical companies, and his organisation never takes a position on particular products…..hahahahahahahahahaha. Well then, sack him immediately for being useless…. sack him for failing to do what he is handsomely paid to do.

The final part of this newspaper report, which I savoured, is the following:

‘James Palmer, clinical director of specialised services at NHS England, said he was aware of Murray’s role as a lobbyist but “there are no opportunities for lobbying in the process of forming clinical policy”.’

This, of course, is true. There are no opportunities for lobbying in this particular process of forming clinical policy. Once a lobbyist starts to write clinical policy, they have moved well past the annoying requirement to lobby anyone. For the lobbyist has now managed to become the very person that they should be paid to lobby.

Instead of trying to influence someone who may not listen to him, he can just talk to himself…. Imagine that this short section of imagined dialogue is like Smeagol talking to Gollum in Lord of the Rings (Smeagol and Gollum are, or course the same person):

John Murray: ‘We must put the following phrase into the report, my precious. A “clear commitment” to “disinvest in interventions that have lower impact for patients” in favour of “new services or innovations”.

John Murray: “But why would you like me to put this in the report, wont this harm the hobbits? Hobbits have been kind to me…yes they have.”

John Murray: ‘I needs it in the report you fool. I represent precious pharmaceutical companies that are bringing new products onto the market. We needs to ensure that there will plenty of money to pay for them. So they must stop paying for stupid old fashioned treatments…yes, they must, foolish Hobbits.’

John Murray: ‘But won’t the kind Hobbits be worried this will just look like lobbying.’

John Murray: ‘Don’t be so stupid. How can the nasty Hobbits accuse me of lobbying? I am their friend, and I am trying to help them…yes I am.. Yes John Murray likes the friendly Hobbits. John Murray want to help the Hobbits, yes he does.’

John Murray: ‘You are so clever Smeagol, our master will be pleased.’…….

Duchess: ‘You’re thinking about something, my dear, and that makes you forget to talk. I can’t tell you just now what the moral of that is, but I shall remember it in a bit.’

“Perhaps it hasn’t one,” Alice ventured to remark.

“Tut, tut, child!” said the Duchess. “Everything’s got a moral, if only you can find it.”

A sorry little patient tale

Working as a GP in England becomes increasingly difficult as the drive to put more and more people on statins gathers pace. Virtually every day I see a patient taking statins who is suffering a clear adverse effect.

I know that this is a very biased sample, because patients in the area know that I am ‘the doctor who writes stuff about statins.’ So there is a degree of self-selection going on here. People who think they may be having adverse effects choose to see me.

However, there is another degree of self-selection going on here. When I see that a patient is on statins, I tend to be on high alert for any mention of statin related adverse effects. Whilst most other doctors happily dismiss such things as: tiredness, memory loss, joint pains, muscle pains depression, irritability, impotence, stomach pains, skin rashes and the like as ‘nothing to do with statins.’ I tend to think the statin may be the cause.

I then usually say. Stop the statin for a couple of months and see what happens to your, tiredness, memory loss, joint pains etc etc. Very often these symptoms go away. Then what? Then the practice statin prescribing statistics start to look quite bad. The senior partner (who is pretty sympathetic to my cause), has had words. The practice is losing money. I have had to ‘exempt’ more and more patients from the cardiovascular disease indicators.

The prescribing lead from the local Clinical Commissioning Group has also had words. It is clear that my non-prescribing of statins is very much frowned upon. Although nothing concrete has yet happened, the pressure to conform cranks up. At times I wonder why I bother. Should I just focus my anti-statin efforts at a more global level? Writing articles, lecturing, speaking to journalists, writing books, and the like. .What difference can I make with a few patients in the practice?

Yesterday, however, I saw a lady who had been admitted to hospital with severe abdominal pains. So severe that she had scans, tests, and was very nearly taken down to surgery for an exploratory operation. Did she have galls stones, appendicitis, cancer? Nothing could be found.

She was discharged with strong painkillers, and follow-up appointments were arranged. She came to see me between Christmas and the New Year to get more painkillers to tide her over. I suggested that the statin may be causing her stomach pain, and that she should stop them, which she did.

Guess what. Of course, the stomach pains have gone. She also reported that she’d had three episodes of Transient Global Amnesia whilst taking statins. This is where your memory goes, you wonder about as if in a fugue, and can remember nothing of what went on. She had not reported these episodes to anyone, but since being made aware that stains can cause them, she now knows what happened.

Since stopping the statins she also reports that her energy levels are back to normal, and that she feels human again. Her life, her quality of life, has returned.

After thanking me for helping her, she then asked. ‘What do you think I should do, doctor. Should I go back on them again, the other doctors say that I should, but I don’t want to.

Please sign

I just got this as an e-mail this morning.

Friends,

I’ve just heard that companies like Coca-Cola, Nestle and others will be able to claim their products are ‘healthier’ thanks to a new EU regulation on using fructose. But consuming high levels of fructose is a leading cause of obesity around the world.

This decision was made by the EU Food Standards Agency in Parma, Italy. We need to push back on food industry lobbying by demanding the EU Food Standards Agency thinks again.

Can you sign this petition demanding the EU Food Standards Agency thinks again?

http://action.sumofus.org/a/eu-fructose/

So, now, it will be claimed that Coca-Cola is a health food. You really couldn’t make this stuff up, could you? Or if you did you would be accusing of stretching credibility far beyond breaking point.

Anyway, if you feel you can, I would hope that you can sign this petition. It takes about thirty seconds.

For those of you who sometimes feel that big business is now running the world, whilst Governments jerk up and down on their strings. ‘All citizens must now drink Coke for a healthy and fulfilling life…’

“In a way, the world−view of the Party imposed itself most successfully on people incapable of understanding it. They could be made to accept the most flagrant violations of reality, because they never fully grasped the enormity of what was demanded of them, and were not sufficiently interested in public events to notice what was happening. By lack of understanding they remained sane. They simply swallowed everything, and what they swallowed did them no harm, because it left no residue behind, just as a grain of corn will pass undigested through the body of a bird.”  1984

Please protect the community

The primary functions of government are to maintain order, settle conflicts, and protect the community. So I am told.

Generally I am a small state man. In fact I refer to myself, when I don’t think anyone important is listening, as an anarchist. I believe that humans should be allowed as much freedom as is possible, without being allowed to seriously harm others. Rules and regulations and bureaucracy are not really my thing. So I am achingly reluctant to demand that the State gets involved in creating yet another agency, or add to its powers in any way.

But sometimes the State must intervene to carry out one of its three primary functions. Namely, to ‘protect the community.’

Where Governments around the world have to step in, right now, is to gain proper control of the creation of medical guidelines. Something that they have spectacularly failed to do, up to now.

As you may be aware, a row is rumbling under the surface about European guidelines on the use of beta-blockers in surgical operations, guidelines that were based on corrupt research. Doctors following these guidelines have probably killed 800,000 people. Give or take.

Some people have written into this blog stating that the numbers cannot be that high, and that the calculations are probably wrong. They were not my calculations, I hasten to add. My view on this is that many many thousands have certainly died unnecessarily. It doesn’t really matter if it was one hundred thousand, five hundred thousand, or eight hundred thousand.

How many would be acceptable?

The answer is, of course, none. But when guidelines go wrong the potential for killing hundreds, thousands, or even millions, is always there. If, for example, your guidelines state that fifty per cent of the population must take a drug for a condition, and these guidelines are wrong, you can kill millions,.

Recently, I did the back of a fag packet calculation on the number of people who were killed by the advice that patients must be managed with six weeks of strict bed rest after a heart attack. Here is some advice from that era: ‘The patient is to be guarded by day and night nursing and helped in every way to avoid voluntary movement, or effort.’ Thomas Lewis.

According to my figures, and I am not going into them here, strict bed rest for six weeks after a heart attack killed fifteen million people worldwide. Yes, fifteen million. More than died in the fighting in the first and second world wars added together.

This, I hope, gives you some idea of the potential death toll when medical guidance goes wrong. Given this, you would hope that the process that leads to the creation of guidelines would be checked, and double checked, then triple checked, then monitored.

You would also hope that the evidence underpinning the guidelines was free from bias, and corruption. Furthermore, that all data – positive or negative – would be freely available, with no possibility of hiding anything away. You would also hope that those creating the guidelines had no possible conflicts of interest.

The fact is that NONE of these things are true. We have a system that is almost perfectly free from scrutiny of any sort. Many, if not most, guidelines are based on trials that are designed, set up and run by the pharmaceutical companies. They own and control the data, and are under no obligation to let anyone else see it, if they don’t want to. Negative data are regularly buried, never to see the light of day.

A few brave souls e.g. Ben Goldacre, Fiona Godlee (editor of the BMJ), and Peter Gotzsche have been demanding that all clinical trial data are made available for scrutiny, but almost nothing has happened. Currently Roche are refusing to release data on their flu drug Tamiflu. Various studies remain unpublished, no data released. The UK Govt. seems powerless to act. Or maybe it just doesn’t want to, with so much money at stake.

Last year AbbVie and InterMune, two drug companies, took legal action against the European Medicines Agency to stop them releasing any data from clinical studies, and to ensure that no trials data could made available, anywhere, to anyone, ever again. I like to think I helped to kick this monstrous and terrible legal action into touch. But, companies still do everything in their power to ensure that data will not, ever, be released.

Then we have the enormous problem that that ‘experts’ chosen to write guidelines work hand in glove with the pharmaceutical industry. The US guidelines on cholesterol lowering written in 2004 were put together by nine people. Here is a conflict of interest statement. I have put this up before, but I think it bears almost endless repetition:

ATP III Update 2004:  Financial Disclosure

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

Those companies that I have marked in bold sell (or at the time sold) statins and/or other cholesterol lowering medications. A mere eight members (the chairman was employed by the NIH who was not allowed close ties with industry), and we have almost seventy direct financial conflicts of interest with companies who made, and sold, cholesterol lowering agents.

How we can possibly allow doctors with enormous financial conflicts of interest to create guidelines that will be followed around that world, and will affect hundreds of millions (in this case billions) of people….How can this possibly be allowed.

We currently have a system of guideline creation that relies on three things being true, if they are to be sare – all three things:

1: That the clinical trial data are not corrupt, or biased

2: That negative data are made available when requested

3: That the medical experts tasked with creating the guidelines are completely unaffected by their financial conflicts of interest

The fact is that none of these critical requirements are followed….even remotely.

How many other guidelines out there are wrong, damagingly wrong, and horrifyingly wrong? How many millions of people are being put at risk by a system that is wide open to corruption, and bias? I have not the slightest idea, but I suspect many….

The public are most certainly not being protected. We have put the foxes in charge of the chicken coop, with entirely predictable results. Time for the farmer to pull out the shotgun and start blasting away. Time for the state to start doing what it is there to do. Namely, ‘protect the public.’

Guidelines kill 800,000

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.

How to kill a hypothesis

“Why do people insist on defending their ideas and opinions with such ferocity, as if defending honour itself? What could be easier to change than an idea?” J.G. Farrell.

When the orbit of Neptune was found to be irregular, and not to follow classical Newtonian physics, it was suggested that, perhaps, the laws of physics may break down in deep space. Others, rather more pragmatically, suggested that there was another planet out there, interfering with the orbit of Neptune. It was just too far out, and dim, to be seen.

That planet, no longer called a planet, was Pluto. Once observed, it accounted for the distortions in the orbit of Neptune.

When the orbit of Mercury was found to be irregular, and not to follow classical Newtonian physics, it was suggested that there was another invisible planet orbiting closer to the sun. This planet was named Vulcan.

Of course there was no planet Vulcan. The reason why classical Newtonian physics did not accurately predict the orbit of Mercury is because the mass of the sun bent time and space. Classical Newtonian physics had to be replaced by Einstein’s theory of relativity.

What does this tell us?

It tells us that it is very difficult to know if an apparently contradictory observation actually refutes a scientific theory. It also tells us that you can use ad-hoc hypotheses (there is another planet out there) to support a cherished central hypothesis, and that this is a valid scientific technique.

But at what point do you have to admit defeat? How many contradictory observations can you dismiss before you must accept that the game is up, and that your hypothesis is wrong?

I think about this a lot. Mainly with regard to the cholesterol hypothesis, or the diet-heart hypothesis, or whatever term is now current. I have seen evidence that directly refutes this hypothesis again and again and again and….indeed…again.

If anyone wishes to debate this issue with me, I can produce far more evidence contradicting it, than supporting it. Yet still it stands, untouched. In fact I would suggest more people believe in this hypothesis than at any time in human history. Billions of people also take statins to lower their cholesterol levels. As you can imagine, this is more than a little frustrating.

How can you convince people that this hypothesis is wrong? I have tried in many, many, different ways. As have other members of THINCS (The International Network of Cholesterol Skeptics).

Yes, I have helped to convince many thousands of people that cholesterol has nothing to do with heart disease, or cardiovascular disease, or atherosclerosis, or unstable atherosclerotic plaques…

Indeed, stepping sideways for a moment, one of the major difficulties in this area is that the terminology shifts and swirls in front of you, making it impossible even to pin down what you are talking about.

At one time the experts were quite happy to tell us that a raised cholesterol level caused heart disease. Now we have ‘good’ cholesterol and ‘bad’ cholesterol, and ‘light and fluffy’ bad cholesterol and ‘small and dense’ bad cholesterol (which really should be called ‘evil’ cholesterol, I suppose). We have the ratio of good to bad cholesterol, apob-100 levels, particle numbers, sub-fractions of good cholesterol, dyslipidaemia, LDL particle size, or number,  or…..the list goes on and on.

How can you argue against a scientific hypothesis when the damned thing will not stay still from day to day?

That, however, is a bit of a side-issue, although I have come to realise that this constant creation of new types of cholesterol, and sub-fractions, and ratios, is all part of the game that is played to protect the cholesterol hypothesis from refutation. How can you refute a hypothesis that can change into any shape it likes? Answer, you can’t.

Anyway, in my efforts to work out how to change ideas in the wider population I have spent a great deal of time looking at the history of scientific thought. I wanted to gain any insights I could into how people managed to kill off hypotheses in the past.

As part of my education I have tried not to get too depressed by fellow thinkers on the subject. Such as Max Plank, who said:

‘A scientific truth does not triumph by convincing its opponents and making them see the light, but rather because its opponents eventually die and a new generation grows up that is familiar with it.’

In short, his view is that you should forget trying to convince people. They will never, ever, change their minds. Max Plank, by the way, was the man who published Einstein’s special theory of relativity (against great opposition).

Another of my scientific heroes is Wilfred Trotter. A man you are unlikely to have come across. Unfortunately, however, he was not much help either:

‘The mind likes a strange idea as little as the body likes a strange protein and resists it with similar energy. It would not perhaps be too fanciful to say that a new idea is the most quickly acting antigen known to science. If we watch ourselves honestly we shall often find that we have begun to argue against a new idea even before it has been completely stated.’

I could fill hundreds of pages with quotes saying the same type of thing. Essentially, people love the ideas they have grown up with, and become deeply emotionally attached to them. Changing them is painful; they dislike and fear new ideas and, will bring forth all the powers of their intellect to do so.

Things are made all the more difficult when you try to convince people who have spent large amounts of their professional life studying a specific area. When someone has become an ‘expert’ in something, and their reputation, and position of authority, is inextricably linked to a certain hypothesis, you are not just attacking an idea, you are attacking them. As noted by Leo Tolstoy:

‘I know that most men, including those at ease with problems of the greatest complexity, can seldom accept even the simplest and most obvious truth, if it be such as would oblige them to admit the falsity of conclusions which they have delighted in explaining to colleagues, which they have proudly taught to others, and which they have woven, thread by thread, into the fabric of their lives.’ Leo Tolstoy

Despite all of this being rather depressing, it has all helped me to establish one clear rule. Do not bother trying to convince people who are ‘experts’ in heart disease that the cholesterol hypothesis is wrong. It is a complete waste of time and energy. The only people who can be convinced are inquisitive people who do not have too much invested in this particular hypothesis.

I have also worked out another rule. Facts are almost completely ineffective at convincing people of anything. Recently, I was reading an article on 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.’

Once again, if this is true, what can be done? How to change ideas…..

I leave you at this point with a small section of dialogue from the film Inception:

Dom Cobb: ‘What is the most resilient parasite? A bacteria? A virus? An intestinal worm?’

Arthur: ‘Uh, what Mr. Cobb is trying to…’

Dom Cobb: ‘An idea. Resilient, highly contagious. Once an idea has taken hold of the brain it’s almost impossible to eradicate. An idea that is fully formed, fully understood. That sticks, right in there somewhere.’

[he points to his head]

The cholesterol hypothesis is one of the most resilient parasites of all. How to kill it off? All suggestions welcome.

Is medical research now beyond redemption?

Below, I have copied an entire article from the BMJ, written by Dr Des Spence, who is a fellow Scottish GP. We communicate from time to time, and share a general view that medicine is heading in a very unfortunate direction with overdiagnosis and over-treatment/polypharmacy becoming a massive problem.

This is driven, in the main part, by the pharmaceutical industry. An industry that would like to see the entire population of the world taking medication every day….. forever. To achieve this they have, effectively, grabbed hold of medical research and twisted it to their own ends.

Anyway, please read this article. It encapsulates much of what I feel, and I believe it needs a wider audience [I have added a few comments into the text to ensure that I am not breaching copyright]

Evidence based medicine (EBM) wrong footed the drug industry for a while in the 1990s. We could fend off the army of pharmaceutical representatives because often their promotional material was devoid of evidence. But the drug industry came to realise that EBM was an opportunity rather than a threat. Research, especially when published in a prestigious journal, was worth more than thousands of sales representatives. Today EBM is a loaded gun at clinicians’ heads. “You better do as the evidence says,” it hisses, leaving no room for discretion or judgment. EBM is now the problem, fuelling overdiagnosis and overtreatment.

[This is now a major problem for GPs who are increasingly measured and monitored, and funded, according to how accurately we follow guidelines mk comment]

You see, without so called “evidence” there is no seat at the guideline table. This is the fundamental “commissioning bias,” the elephant in the room, because the drug industry controls and funds most research. So the drug industry and EBM have set about legitimising illegitimate diagnoses and then widening drug indications, and now doctors can prescribe a pill for every ill.

[As you can imagine, this makes it difficult not to prescribe statins mk comment]

The billion prescriptions a year in England in 2012, up 66% in one decade, do not reflect a true increased burden of illness nor an ageing population, just polypharmacy supposedly based on evidence. The drug industry’s corporate mission is to make us all sick however well we feel. [Absolutely true mk comment] As for EBM screening programmes, these are the combine harvester of wellbeing, producing bails of overdiagnosis and misery.

Corruption in clinical research is sponsored by billion dollar marketing razzmatazz and promotion passed off as postgraduate education. By contrast, the disorganised protesters have but placards and a couple of felt tip pens to promote their message, and no one wants to listen to tiresome naysayers anyway.

[Speaking as a tiresome naysayer I could not agree more mk comment]

How many people care that the research pond is polluted, with fraud, sham diagnosis, short term data, poor regulation, surrogate ends, questionnaires that can’t be validated, and statistically significant but clinically irrelevant outcomes? Medical experts who should be providing oversight are on the take. Even the National Institute for Health and Care Excellence and the Cochrane Collaboration do not exclude authors with conflicts of interest, who therefore have predetermined agendas. The current incarnation of EBM is corrupted, let down by academics and regulators alike. [If anyone has any suggestion how to improve regulation, please let me know mk comment]

What do we do? We must first recognise that we have a problem. Research should focus on what we don’t know. We should study the natural history of disease, research non-drug based interventions, question diagnostic criteria, tighten the definition of competing interests, and research the actual long term benefits of drugs while promoting intellectual scepticism. If we don’t tackle the flaws of EBM there will be a disaster, but I fear it will take a disaster before anyone will listen.

[There have already been many disasters, but nobody has yet listened mk comment]

Original article can be found here

Sorry about the intrusive comments, but I don’t want the BMJ jumping up and down on me – especially as they are the only major journal that seems keen to criticize the industry.

What Des Spence is saying, is what I have been saying for some time now. Evidence Based Medicine (EBM) could have been a great thing – so long as it was not enforced too rigidly. But the evidence has been manipulated and corrupted all the way along the line. EBM is now almost completely broken as a tool to help treat patients.

Some years ago I stated that I no longer believe in many research papers that I read. All I tend to do is look at the authors, look at the conflicts of interest, look at the companies who sponsored the study, and I know exactly what the research is going to say – before I have even read the paper.

I have also virtually given up on references. What is the point, when you can find a reference to support any point of view that you want to promote? Frankly, I do not know where the truth resides any more. I wish to use evidence, and the results of clinical studies, but I always fear that I am standing on quicksand when I do so.

We are at a crisis point. Medical research today (in areas where there is money to be made) is almost beyond redemption. If I had my way I would close down pubmed, burn all the journals, and start again, building up a solid database of facts that we can actually rely on – free from commercial bias. But this is never, ever, going to happen.

Happy New Year.

 

The state of the NHS today

It’s a beautiful thing, the destruction of words.’ 1984

I still do work for the National Health Service (NHS), although not full time. Over the years, and especially the last few years, it has become an increasingly depressing, target driven, soulless place. When I re-read 1984 recently, virtually every page resonated with the type of management nonsense that rains down upon us each day. Particularly the way that language is distorted into meaningless ‘party’ slogans.

The more we are told that our healthcare trust is ‘meeting and exceeding’ targets, the more the word ‘doubleplusgood’ springs to mind, and I also know that we are, clearly, in big trouble.  The greater the trumpet blast of triumphal news, the worse that things become. War is Peace, Failure is Success, Lies are Truth.

One thing that particularly sticks in my craw, are the pictures of happy staff members that adorn various PR brochures. The production of which seems immune from financial pressures of any kind. They are written in a distorted management language that uses thousands of words, whilst their meaning remains almost perfectly obscure.

A recent example of how dispiriting they are was encapsulated by a recent brochure I received through the post. It had a picture of two nurses on the front. They looked as if they had both won several millions pounds on the lottery.  Their faces a picture of almost uncontrollable glee.

When I opened it, I found that this was a brochure informing all nurses, and doctors, that we would have to pay considerably more money into our pensions. In addition, we were going to receive a much lower pension, at a greater age, than we had been told we were getting in the past. Oh joy, oh joy.

I would have said the picture on the front cover was ironic, but NHS management do not do irony. We are continually exhorted, in a ‘Unite workers of the Soviet Union’ sort of a way, to be smiling and happy in our glorious tractor factory. A frowning worker is a worker who clearly does not love the party with sufficient fervour. A frowning workers needs re-education.

Ah yes, each year we produce more tractors to sell all around the world, with a song in our heart, and a spring in our step. Each five years we are set a new, joyous, production targets. Each year everything, we are told, gets better. The statistics tell us so. Each year, we can see with our own eyes, things are getting worse. I suppose people who do not work in the NHS may feel a certain echo of all of this in their work place.

Whilst mulling over this seemingly unstoppable drive from relying on professionals to be professionals; towards target driven, dehumanising, wearisome micro-management and meaningless jargon. I came across a post on Doctorsnet.uk. A website for UK registered doctors. It was written by a doctor A Boyle, and I thought it should be shared more widely.  (I asked for, and got, his permission to do so).

What I wanted, and what I got?

I wanted to help old people
I got frailty assessments on incomplete information

I wanted to save lives from PEs*
I got VTE2 assessments

I wanted to diagnose the cause of acute confusional states
I got dementia screening on frightened old people at 3am

I wanted to spend my career constantly improving my knowledge
I got mandatory training

I wanted to perform cutting edge research
I got GCP3

I wanted to critically evaluate my performance
I got the audit department asking for a meaningless action plan

I wanted role models to inspire me
I got multi-source feedback forms

I wanted to teach the next generation
I got work based assessment emails

I wanted to be competent
I got competencies

I wanted to be good at difficult procedures
I got cannula care records and central access teams

I wanted to keep people alive, safe and comfortable
I got the four hour target, breach reports, and observation wards to fudge the targets

A.  Boyle

And Amen to that. And a happy Christmas to you all. Sorry if this seems a little off-beam from my normal musings, but I felt the need to get it off my chest.

*PEs = Pulmonary Emboli (clots in the lungs)
2: VTE = Venous Thromboembolism (assessment). VTs can break off and travel to the lungs.
3: GCP = Good Clinical Practice

How to avoid dementia

Most of us fear that we may develop dementia as we get older. I fear that I may have got it already, as my memory for names becomes even worse. One piece of good news is that, for around one third of people, it may be possible to prevent dementia simply by taking three forms of vitamin B. Vitamin B6, B12 and folic acid.

The research work on this was done at Oxford University, and was published earlier this year. I received a copy of the study about a month ago, and I read it with great interest. The key statements from the abstract are, as follows:

‘Our results shows that B-vitamin supplementation can slow the atrophy of specific brain regions that are a key component of the AD processes and that are associated with cognitive decline.

….we go further by demonstrating that B vitamin reduces, by as much as seven fold, the cerebral atrophy in those grey matter (GM) regions specifically vulnerable to the AD (Alzheimer’s Disease) process.’

Some of you may know that Jerome Burne blogged about this a while ago, which is what attracted my interest in the first place. It immediately fired me into instant action. Several weeks later I got hold of the full paper, which was published in the proceedings of the National Academy of Sciences. It is entitled: ‘Preventing Alzheimer’s disease-related gray matter atrophy by B-vitamin treatment.’ Sorry to say that you have to pay to get the entire manuscript.

This study built on earlier work which also demonstrated a significant reduction in brain shrinkage using vitamin B(s) (at lower doses). The brain images themselves look particularly impressive, even to my untrained eye, with far less atrophy to see in the vitamin B treated group.

Unfortunately, this benefit only seems to be available those people who had a high level of homocysteine in their blood in the first place. A level found in about one third of the population.  For the other two thirds, taking vitamins does not seem to help.

Why do vitamin B(s) have this beneficial effect in this group?  Well, it has been known for a long time that people with high homocysteine levels are more prone to developing dementia. It is also known that B-vitamins lower the level of homocysteine the blood (look up Wikipedia if you want more detail on this complex area). However, just because a high level of homocysteine is found in people with dementia, does not mean that it truly is cause. It may be an innocent bystander. An association, rather than a cause.

However, the Oxford group, by lowering homocysteine and slowing brain atrophy, have gone a long way to prove that homocysteine does seem to be an actual cause of dementia. At least in about one third of people who have high levels in the first place. More importantly, the risk of dementia can be significantly reduced using a simple regime of B vitamins. A regime that appears to have no adverse effects – apart from a small degree of damage to the bank balance.

Why, you might ask, is no-one doing anything about this? Last week our glorious UK health secretary, Jeremy Hunt, announced that he was, sorry, we were, going to defeat dementia in twelve years’ time. Or some other such nonsense figure that he plucked from out of thin air. Did he mention research into vitamin B? No, he did not. Why not? Possibly because no-one made him aware of this research. Probably because he has no interest in dementia other than as a career enhancing, five minute, sound bite. He is such a busy, busy, man. Tomorrow he will be curing cancer. Sorry, we will be curing cancer.

A further important reason for the deafening silence in this area is because pharmaceutical companies cannot make money out of vitamins. Vitamins cannot be patented; therefore any profit margin is far too puny to be of interest to them. Which means that there will be no funding from the pharmaceutical industry to support any further research into B vitamins.

Even worse, if vitamins do work to reduce dementia this will significantly erode any pharmaceutical industry profits to be made. In commercial parlance vitamins would be called – ‘the competition’.

And what do we do to ‘the competition’ boys and girls?

We crush it sir?

‘Yes, that’s right, we crush it like an insect under our boot, don’t we boys and girls. Using any means possible……lock and load.’

I am sure a few Grima Wormtongues, sorry pharmaceutical company lobbyists, have already been whispering in various ears, denigrating this vitamin B research. ‘Very preliminary, not very convincing, we need a new approach, you need to support us, the pharmaceutical industry, only we can find a cure…….my precious…..’

Trust in me, just in me
Shut your eyes and trust in me
You can sleep safe and sound
Knowing I am around
Slip into silent slumber
Sail on a silver mist
Slowly and surely your senses
Will cease to resist
Trust in me, just in me
Shut your eyes and trust in me

(Kaa, the python the Jungle Book)

Wake up, wake up!

Of course Vitamin B is not a miracle cure for all forms of Dementia. In fact it is not a cure – in any recognised sense of that word. All that vitamin B(s) can do is to significantly slow the process of brain shrinkage. Once you have lost brain tissue, it does not come back.

In addition, these vitamins only work in about a third of the population, and only for Alzheimer’s Disease.  There are other causes of dementia, and vitamin B compounds will have no effect on them, at all. However, right now, it looks like by far best thing we have got. In fact, it is the only thing we have got. Alzheimer’s meds can slightly improve symptoms, but have no impact on the underlying disease process.

On the other hand, for the sake of a relatively simple blood test, and spending a couple of hundred pounds (or dollars) on vitamins a year, or however much they actually cost you, this decision is a no-brainer (sorry, couldn’t resist the pun).

Indeed, it is such an obvious thing to do that I have started to offer the blood test at my own clinic. (Yes, I suppose this counts as a Disclosure of Interest). Mainly because no-one in the NHS is the slightest bit interested. So someone had to do it.

The daily doses of vitamin B in this study were:

20mg vitamin B6
500mcg vitamin B12
800mcg folic acid

These are considerably higher than the recommended daily allowance (RDA) for these vitamins. But the RDAs for almost all vitamins were established as a bare minimum, many years ago, using virtually zero evidence. They remain unchangeable by any means known to man. I call them the ‘ten vitamin commandments,’ which have been engraved upon stone.

Until a group of idiots…sorry experts, decides to study the benefits of various vitamins in greater depth, we are going to be stuck with RDAs that make no sense, and will certainly not help you to delay, or even prevent, dementia. Until then, get a blood test to check homocysteine levels. Providing, that is, you can find anyone to do it. Then, if it is high, take vitamin B(s).  They can do you no harm, but they could do you a hell of a lot of good. Which is my kind of preventative medicine.

A farewell to statins – part two

And so it begins:

‘ …..a Pfizer rep confirmed to me that they were now telling all GP’s that statins do have side-effects and shouldn’t be prescribed anymore but to prescribe the new post-statin drugs…………. how two-faced can you get!!!!’

This was in an e-mail from a friend and supporter of mine, who has close contacts with the pharmaceutical industry.

Well, if you are going to challenge the dominant position of statins, the first thing that you have to do is to attack them. What is the best line of attack? Go after their greatest weakness, which is that they cause serious adverse effects, and damage the quality of life of many people. Something I have been saying for a long, long, time.

For years the experts have informed us that this is utter rubbish, statins are wonder-drugs, and adverse effect free. All of a sudden, now that the pharmaceutical industry is about to launch new cholesterol lowering agents, we are suddenly going to find that, why, after all, statins do cause a whole range of nasty adverse effects.

If you want to see exactly how this is going to be done, watch this discussion on Medscape.  The Medscape site needs a password, however you can get one fairly simply. In this ‘educational’ discussion we see three professors talking about the new cholesterol lowering agents that are soon to arrive. The dreaded PCSK9-inhibitors.

The names of these three professors are Prof Christie Ballantyne, Prof Stephen Nicholls and – yes, you guessed it – Prof Steven Nissen. Is there a new cardiovascular drug in development that he does not get involved with?

The first part of the discussion focusses entirely on the terrible problem of people being statin intolerant; people being unable to take high doses of statins, and the high burden of adverse-effects from statins.

A slide is shown from the PRIMO observational study showing that 15% of people taking atorvastatin have significant adverse effects, and 20% of those taking simvastatin suffer significant adverse effects. These, of course, are the two statins with by far the greatest market share. My, what a coincidence.

The discussion then opens out into the worrying problems with statins causing both diabetes and cognitive dysfunction (something vehemently denied for many, many years). Ballantyne was particularly eloquent on these issues.

The entire tone is one more of sorrow than anger. ‘Statins….great drugs….hate to see them go, but you know, their time is passing.’ Professor wipes a small tear from his eye at the thought.

I watch this stuff with a kind of morbid fascination. The marketing game is on, billions are about to be spent pushing PCSK9-inhibitors. The Key Opinion Leaders who tirelessly promoted the wonders of statins, and who told us that they were virtually side-effect free, are now singing a completely different tune.

Here is what one the panellists Prof Christie Ballantyne had to say about statin adverse effects in his book ‘Dyslipidemia & Atherosclerosis Essentials 2009’. This can be found on page 91, under the heading Adverse Effects and Monitoring.

Statins are very well tolerated with infrequent and reversible adverse effects. In large placebo controlled studies the frequency of adverse effects was similar to placebo (2-3%).’

Here, however, is what he said in March 2013

“Some people have hereditary disorders and have extremely high LDLs. And so the statin has some efficacy but not enough to get them down as low as they’d like.  Then some people have less response than others, and we don’t understand all of that. Some of that may be genetic. And it turns out there’s an even probably larger group of people that have a hard time taking a high dose of a statin.”

Even though statins are safe for most people, there are those that can’t take them because they experience side effects.

Many people complain of some muscle pain, soreness, weakness, excessive fatigability.  There’s some slight increase in diabetes also. That can occur with high dose statins, and some people [who] say that they may have problems with their nerves or cognition.”1

Well, that is all nice and consistent. Finally, here he is on Sunday 8th Dec, quoted as part of a discussion on the new AHA/ACC guidelines.

“Clearly, the focus is to get people on statins,” said Dr. Christie Mitchell Ballantyne, the chief of cardiology and cardiovascular research at Baylor College of Medicine, in Houston. “But if someone has seen four doctors and tried six statins and tells me they can’t take them, what am I going to do? Tell them they are a failure?”

Ballantyne said he would give such patients a non-statin drug, despite the guidelines.’2

….Ballantyne said he would give such patients a non-statin drug, despite the guidelines.’ I wonder what he could possibly mean by this. Perhaps George Orwell had it right.

‘Four legs good, two legs bad’……becomes….’Four legs good, two legs better.’

“The creatures outside looked from pig to man, and from man to pig, and from pig to man again; but already it was impossible to say which was which.”

[A farewell to statins – Part three will arrive at some point.]

P.S. Please watch the video clip soon, as I suspect it may not last very long after this blog.

1: http://www.houstonpublicmedia.org/articles/1362665170-Promising-Baylor-Research-Reduces-Bad-Cholesterol.html

2: http://www.staradvertiser.com/news/20131114_New_cholesterol_advice_startles_even_some_doctors.html

You absolutely cannot be healthy any more – it’s official

I have been waiting for some time now before it became officially impossible to be healthy. In recent years the boundaries of health have been inexorably squeezed tighter and tighter. Recently, they snapped shut. The land of the healthy now no longer exists. Tis but a memory.

I wondered if it would be cholesterol that would obliterate health first, but it turned out to be blood pressure. This was pretty much second favourite in my book.

As with many areas of ‘health’ the definition of a healthy blood pressure has fallen and fallen. A few years ago we had go to the stage of a condition known as pre-hypertension. A state of having a high blood pressure that wasn’t really high, but represented an ill-defined danger of some sort. This pressure was set at 115/75mmHg. Far lower than the average blood pressure in the Western World.

However, with the latest CV prevention guidelines (yes, them again) we have managed to get the optimal systolic blood pressure down to 90mmHg. Underneath, you will see a little graph that I created using the CV risk tool. The tool can be downloaded here:

So you can check out for yourself that what I am saying is true.

CV event risk in next 10 years vs systolic BP

I put in figures for a healthy male, and then only changed the blood pressure level. As you can see, as the blood pressure goes up, the risk of a CV event goes up, and vice-versa. Going from 90mmHg to 150mmHg causes your risk to go up from 2.6% to 6.5%. A 250% increase in relative risk. What this tells us is that 90mHg represents the absolutely optimum blood pressure. Anything higher and your risk increases, and it increases quite steeply.

By definition, this means that a systolic blood pressure of 90mHg is ‘healthy’ and anything above this becomes increasingly ‘unhealthy.’ Now it has to be said that a systolic blood pressure of 90mmHg is low. Pretty damned low. Indeed, I have been asked to check patients out because their systolic BP was 90mmHg, and the nurse was rather worried about them.

I can hardly blame the nurse for this, because the definition of hypotension (dangerously blood pressure), is…yes, you guessed it, a systolic blood pressure of 90mmHg and lower. You can check this ‘fact’ on the National Institutes of Health site.

This means that we have reached a situation whereby a systolic blood pressure lower than 90mmHg increases risk; and a blood pressure higher than 90mmHg increases risk. I suppose you could say that anyone with a blood pressure of exactly 90mmHg is healthy, so the land of health still exists as a microscopically thin sliver of habitable area. But for all intents and purposes, health has gone.

Can it really be true that there is no such thing as a healthy blood pressure?

In order to believe this you have to believe in the linear or log-linear model. A model that can, to a major degree, be laid at the feet of a certain Jeremiah Stamler. He stated that ‘the relation of SBP (systolic blood pressure) to risk of death is continuous, graded, and strong, and there is no evidence of a threshold.’  In short, as BP goes down, risk goes down, and there is no lower limit beyond which this is not true. Well, until you reach 90mmHg, it seems.

This idea is based on mathematics, whereby Stamler took all the studies he could find, matched BP with risk, and then created his perfect curve. You can see how this type of thing is done by looking at a curve created by matching writing score vs. reading score. [I took this example from the internet1]. The dots may seem all over the place, but there is a trend from bottom left to top right.

The curve is a linear model, which smooths out all of the data variations. Excel spreadsheet will even calculate a curve like this for you, if you have a graph with dots which may seem completely random.

log_tr1

In the world of hypertension, the log-linear model rules.

‘This(the log linear model) is the paradigm for the relationship of all cardiovascular risks to blood pressure, and forms the foundation of the current guidelines for hypertension.’ These words from the European Heart Journal in the year 2000, since then the paradigm has not changed, and neither has the model. The latest CV guidelines are based on it.

How could it be otherwise? Do you really think anyone has done a study lowering blood pressure from 100mgHg to 90mmHg? If so, think again. In fact the model was first created from the Framingham study data. This is the world’s longest running, and most cited, study on cardiovascular disease. It has been running since 1948 in a town called, unsurprisingly, Framingham in the US.

Now, this would be all fine and jolly – if the model were actually correct.

In 1980 Ancel Keys, who is not my favourite ever person it must be said, looked at the Framingham data.  He concluded that the linear model, in terms of the relationship between overall and coronary heart disease was unjustified.

Twenty years after this, a group of statisticians from UCLA looked at the data again. And here is what they said:

‘Shockingly, we have found that the Framingham data in no way supported the current paradigm to which they gave birth. In fact, these data actually statistically reject the linear model. This fact has major consequences. Statistical theory now tells us that the paradigm MUST be false for the target population of the study.’2

Was this paper refuted? No, not exactly….

“The National Institutes of Health’s National Heart, Lung, and Blood Institute (NHLBI) issued a statement regarding Port’s findings saying that they found it “thought provoking” but “After careful review of this study, the NHLBI finds that it does not offer a basis for changing the current hypertension guidelines.”

End of.

Which means that we are here. A world where health was finally extinguished by using a mathematical model. A perfect world for the pharmaceutical industry. Everyone is ill, and all shall have medications, for ever.

‘Can you do Addition?’ the White Queen asked. ‘What’s one and one and one and one and one and one and one and one and one and one?’

‘I don’t know,’ said Alice. ‘I lost count.’

 

1: http://goo.gl/ZlJ7tO

2: Port S. et al: ‘There is a non-linear relationship between mortality and blood pressure.’ European Heart Journal (2000) 21, 1635-1638

The most unpronounceable failure yet

Every day a billion things pop into my inbox, and I find my thought dragged this way and that. Mainly, what should I blog on next, and can I be bothered…..so much wine to be drunk.

However, I thought I should give everyone a quick head up on VARESPLADIB. This is the first and last time you are going to hear of this drug, so listen up. The first thing I would like to draw your attention to is the list of authors

Stephen J. Nicholls, MBBS, PhD; John J. P. Kastelein, MD, PhD; Gregory G. Schwartz, MD, PhD; Dianna Bash, RN; Robert S. Rosenson, MD; Matthew A. Cavender,MD, MPH; Danielle M. Brennan, MS; Wolfgang Koenig, MD; J.Wouter Jukema, MD, PhD; Vijay Nambi, MD, PhD; R. Scott Wright, MD; Venu Menon, MD; A. Michael Lincoff, MD; Steven E. Nissen, MD; for the VISTA-16 Investigators 1

Notice anything. Ah yes, Steven Nissen appears once again on a major study. He certainly gets about does our Steven. Another name that means much to me, but nothing to you, is John P Kastelein….he gets about too. Hardly a day passes without these guys running a major clinical trial, and then writing about it. I think they must have been cloned in the past to get through so much work.

Anyhoo,  enough of them. What is, or was, VARESPLADIB, and why should you care. Here from the study itself.

‘Varespladib methyl is a nonspecific pan-sPLA2 inhibitor with favorable effects on atherosclerotic lesions in animal studies. Initial studies demonstrated that varespladib reduced levels of sPLA2-IIA by morethan 90%,in addition to lowering low-density lipoprotein cholesterol (LDL-C) and C-reactive protein (CRP) in patients with stable coronary disease and ACS.’

So now you know. Or maybe not.

Stripped to its basics, varespladib (which I shall PLAD) is an anti-inflammatory drug specifically designed to reduce the inflammatory cascade that is thought to be a major cause/risk factor for heart disease. Not only that, but it reduces LDL ‘bad/naughty cholesterol’ and C reactive protein too – a sign of inflammation in the arteries. Possibly CRP may even be a cause of CHD… in truth you might think it is a cause, if you are idiot.

Some years ago I wrote that we should await the C-reactive protein lowering agents. On the basis that a high CRP levels had been identified as ‘risk factor’ for heart disease. I wasn’t sure if it would happen, but I suspected it would. I predicted that lowering CRP would be a complete and utter waste of time.

Inflammation cannot, I have always said, be the cause of anything. Inflammation is the way that the body heals itself. If you cut yourself you will develop a red and inflamed area around the cut, otherwise known as inflammation. The inflammation did not cause the cut, the cut caused the inflammation.

However, such is the idiotic thinking in heart disease research that various people, led by Paul Ridker, decreed that inflammation causes heart disease (and not the other way around). They then decreed that if you could lower the inflammation that the risk of heart disease would fall. The noise in the background is the mad stampede of pharmaceutical companies rushing off to find drugs to block the inflammatory pathway, lower CRP, and cure heart disease.

Enter PLAD. Here we have a drug that lowers inflammation, lowers CRP, and as an extra added bonus  lowers LDL ‘bad/naughty’ cholesterol, so it should provide a triple benefit. And guess what we find:

‘At a prespecified interim analysis, including 212 primary end point events, the independent data and safety monitoring board recommended termination of the trial for futility and possible harm.’

The conclusions:

‘In patients with recent ACS (acute coronary syndrome – a heart attack to you and me), varespladib did not reduce the risk of recurrent cardiovascular events and significantly increased the risk of MI. The sPLA2inhibition with varespladib may be harmful and is not a useful strategy to reduce adverse cardiovascular outcomes after ACS.’

I am sure that there are a whole new bunch of anti-inflammatory agents out there, being trialled as I write this. I am also sure that they will fail. Hey guys, you could save billions if you read my stuff.

Now, repeat after me. Blocking inflammation blocks healing. Block healing and you die. End of. Time for a glass of wine.

1: Varespladib and Cardiovascular Events in Patients With an Acute Coronary Syndrome The VISTA-16 Randomized Clinical Trial. JAMA. doi:10.1001/jama.2013.282836

A farewell to statins – part one

In the end I knew that statins would be overthrown. Their time, like the dinosaurs would come to an end.  I also knew it would be nothing to do with me, or any of the other critics. Nor would it have anything to do with the fact that their terrible burden of adverse effects finally came to light.

No, it would be because their patents ran out, which meant that the big pharmaceutical companies could not make eye-watering profits from them anymore. Inevitably, therefore, they would be replaced. Indeed, for years I have watched, with varying degrees of amusement, the unending efforts to unearth the ‘new’ statins. The wonder drugs to be taken by everyone, for the rest of their lives. The ones that will make billions for the pharmaceutical companies, and several millions for the key opinion leaders promoting them.

Steven Nissen had a go with apoA-1 Milano. This is a little story you may want to look up on Wikipedia.  Basically, a small village was found in Italy (near Milan) where people had very low rates of heart disease, and they also had very low levels of HDL ‘good’ cholesterol.

Turning science on its head, it was therefore decreed that their HDL must be especially ‘good’ at preventing heart disease. [Rather than accept that HDL had bugger all to do with heart disease]. So attempts were made to synthesize their form of HDL, then inject it into patients. This was done in small scale clinical studies.

So brilliantly did Nissen sell the results of these studies that a start-up company called Esperion, which funded the trials, was sold to Pfizer for over a billion dollars on the back of the results. If you want to find out more, the HDL synthesized was called ETC-216, not apoA-1 Milano.

This is what Steven Nissen had to say about the trials.

The fact that you can actually pull major amounts of plaque out of the artery in five or six weeks is an epiphany,” Nissen says. H. Bryan Brewer, chief of the molecular disease branch at the National Heart, Blood & Lung Institute, adds: “Quite to everyone’s surprise, this indicates that we might be able to be much more successful in a shorter period of time than we thought possible.”

By golly it all sounds very exciting, does it not.  Pulling significant amounts of plaque out of artery walls, in six weeks! This is quite amazing, what a brilliant drug. In truth, though, that quote was from 2003. Has anything since happened since to this magical plaque munching HDL? Is it now on the market, saving lives? Well, as you ask, the answer is no.

However, several other HDL raising agents have also been developed in the last few years. Unfortunately, they also raised the risk of heart attacks and strokes – then disappeared. Torcetrapib, dalcetrapib, anacetrapib…. A yes, anacetrapib, not quite gone yet.

Anacetrapib has a knock-your-socks-off effect on HDL and a jaw-dropping effect on LDL,” said Chris Cannon in an AHA press release.  He also said “The lipid effects are jaw dropping in both directions,” Yes, indeed, they were.  Although I am not sure that ‘jaw dropping’ and ‘knock your socks-off’ are truly scientific terms.

But then Forbes ran this headline on the 22nd October

Merck Heart Drug Runs Into New Worry.’ 1

As an aside, you can find out far more about drugs in development by reading Forbes magazine than you will ever get from the scientific journals.

Anyway, I wouldn’t bet the house on anacetrapib as I suspect it will soon follow the other ‘trapibs’ into an early grave. But never mind, Lilly has yet another HDL raising agent waiting in the pipeline, evacetrapib. What is it with these unpronounceable names, and why don’t these companies just give up? However, perhaps this one has a better shot than most, because as Steven Nissen said of dalcetrapib…

Dalcetrapib was always a long shot,” said Steven Nissen, chairman of cardiovascular medicine at the Cleveland Clinic. “The worry all along was that it wouldn’t have enough effect to produce a benefit,”

Then, as he went on to say of evacetrapib

We got everything we could hope for from this drug, and maybe more,” remarked study co-author Steven Nissen, adding that “we are going to move evacetrapib forward as rapidly as possible” into a late-stage trial.” Gosh, he is running a study on evacetrapib too.  He was also lead investigator for Torcetrapib2.

That Steven Nissen, what a busy chap he is?  Wasn’t he the one who said about the new cardiovascular prevention guidelines.  “The evidence was never there” for the LDL targets, he said. Past committees “made them up out of thin air,” he added.  Why yes, I think he was.

Anyway. They have tried raising HDL…fail. They have tried a different way of lowering LDL using ezetimibe. It lowered LDL, and has had absolutely no effect on cardiovascular disease…fail. They have tried combing different HDL raising agents with statins….fail.

You know, you might even begin to think that raising HDL wasn’t that good an idea. Billions have been thrown this target, everything has miserably failed. It is also interesting that LDL lowering agents, other than statins, have failed to have any impact on cardiovascular disease. Has this had any effect on the lipid hypothesis? You must be joking.

Given this litany of disastrous drugs trials, why do I now believe that statins are about to be overthrown? What agents could be out there that are going to sweep them into the dustbin of history.

Clearly it cannot be an agent that lowers LDL even more than statins. Can it? Well, Steven Nissen has recently said the following about LDL lowering. This quote is in connection to new drugs being developed3.

 “….it matters how you lower cholesterol, not just by how much.”

It matters how you lower cholesterol, not just by how much….. Interesting.  Well, if cholesterol does cause heart disease, then it doesn’t really matter how you lower it, does it? The only question is, by how much? Or is Steven Nissen trying to say something else?

As a further aside, if you want to know where the really big bucks are being spent in cardiovascular research, and what is in the pipeline, all you need to do is follow Steven Nissen’s pronouncements. He is the weather vane. You don’t need to be a weather man to know which way the wind is blowing.

…… (to be continued)

 

1: http://www.forbes.com/sites/matthewherper/2013/10/22/merck-heart-drug-runs-into-new-worry/

2: http://online.wsj.com/news/articles/SB10001424052702304363104577389353232022644

3: http://www.forbes.com/sites/johnlamattina/2013/09/05/esperions-novel-approach-to-lowering-cholesterol-will-it-be-successful/