Author Archives: Dr. Malcolm Kendrick

About Dr. Malcolm Kendrick

Malcolm Kendrick is a Scottish doctor and author of The Great Cholesterol Con (2008). He has been a general practitioner for over 25 years and has worked with the European Society of Cardiology.

COVID Update – Focus on Vitamin D

28th April 2020

I have found, I suspect like almost everyone else, that it is almost impossible to keep track of what is going on with COVID. Stories swirl and multiply, and almost everyone seems to be trying to get something out of it. People are claiming miracle cures and success – but it is difficult to verify any such claims.

The normal rules of research (flawed though they often are) have completely flown out of the window. It is like the wild west, with snake oil salesmen announcing wonderful products that not only cure COVID, but every other disease… I mean every other disease, known to man.

You sir, you look like an intelligent man, a man who understands science. A man who can see that my wonderful potion can cure almost every ailment that befalls man. Baldness, wrinkled skin, impotence, COVID…

‘A vaccine you say sir, of course, I shall have one ready and done in four months, start to finish … safety sir, did you mention safety? No need for such things, vaccines are always safe, never caused anyone any harm. Never a single case of any problems.’

‘Narcolepsy sir… sounds like nonsense, never heard it. Guillain-Barré sir. My, we have been at the medical dictionary haven’t we? In my opinion, if you can’t spell it, you don’t need to worry about it. Sounds French to me anyway – and you can’t trust the French, can you?

‘The WHO sir… what’s that you say? It may be that you can get infected twice. So how is any vaccine going to work. Well, I must say sir that vaccines are far more effective at creating immunity than getting the actual infection. Everyone knows that sir… what do you mean utter bollocks. I can tell you that a vaccine will always work, every time, guaranteed one hundred per cent effective, or your money back.’

‘Bill Gates is behind it all sir you say, pushing for mandatory vaccines for all diseases. You think it’s like something out of 1984. Well, Mr Gates is an expert in viruses sir, is he not…His operating system did allow a massive attack on IT systems in the NHS in 2017 sir. Now, if you will excuse me, I have more snake oil to sell… tatty bye sir, and good luck to you.’

‘Roll up, roll up.

Which takes me to vitamin D. Which is my miracle cure for COVID.

I know that, in the West, the medical profession, hates vitamins with a passion. Those who promote vitamins are the very personification of woo, woo medicine. They have no proven beneficial effects they rant and on, and on. Insult and attack.

However, as I have been known to point out, the ‘vit’ in vitamin, stands for vital. As in, if you don’t take them, you die. So, they do kind of have important beneficial effects on the human body. Of course, I know the counter argument, which is not that vitamins are not necessary, of course they are, even doctors agree with that. The battle is about the optimal level for health.

We are told that almost everyone has sufficient vitamin intake from the food they eat, and that anything above that intake just creates expensive urine. In addition, some vitamins can be dangerous in excess. We have seen up to one death a year, in some cases.

Leaving the battles about vitamins to one side, what are the optimal levels of various vitamins? The answer is no-one really knows … for sure. The central problem here is that, when vitamins were first isolated, their deficiencies were creating major and obvious health problems. A lack of vitamin C caused scurvy – leading to death.

A lack of vitamin B1 a.k.a. thiamine led to Beriberi, with nerve and muscle damage and wasting and death. A severe lack of vitamin B12 lead to nerve damage, anaemia, weakness and death.

So, the focus was very much on finding the dose of vitamins required to prevent these serious health problems. However, no-one was particularly interested in looking beyond this bare minimum, to try and establish what level of a vitamin is associated with optimal health. For example, what are long term effects on cancer and heart disease – for example. Or prevention of infections.

Looking specifically at vitamin D, the major and immediate health problem caused by a lack of vitamin D is on bones. Without vitamin D, calcium is not absorbed properly and the bones become thin and brittle. Children with low vitamin D develop rickets, bent bones that do not grow properly.

Once the level of vitamin D required to protect the bones was established, that was pretty much seen as job done. However, is it better for health to have higher levels. Can we be optimally healthy with, what many believe, to be a low vitamin D level?

More importantly right now, does a higher level of vitamin D enable you to fight off infections such as influenza and COVID? Of course, as I stated at the beginning, in the middle of the COVID maelstrom, people are claiming everything about everything.

So, I am going to take you back to 2008 to look at Virology Journal – yes, this is about as mainstream as you can possibly get in the world of virus research. The article was called ‘On the epidemiology of influenza.’ If you want to get your mind blown, read it 1.

It set out to answer seven questions:

    1. Why is influenza both seasonal and ubiquitous and where is the virus between epidemics?
    2. Why are the epidemics so explosive?
    3. Why do epidemics end so abruptly?
    4. What explains the frequent coincidental timing of epidemics in countries of similar latitudes?
    5. Why is the serial interval obscure?
    6. Why is the secondary attack rate so low?
    7. Why did epidemics in previous ages spread so rapidly, despite the lack of modern transport?

Yes, I realise COVID is not Influenza, but past research on influenza is about as close as you can get. Cutting to the chase, of a very long article, the authors concluded the reason why flu was far more common in winter, is because people have much lower levels of Vitamin D.

Below is their graph of vitamin D levels in the UK, at different times of the year.

VitD1

These researchers then looked at what happened to people who took vitamin D supplements all year round. One group took placebo, one group took 800 international units (IU) a day – and one group took 800 IU per day but 2000 IU a day in the final year of the trial. Below is a graph of what they found.

VitD2

To put this another way, of those 104 subjects who took 2,000 IU of vitamin D every day, only one got a cold or influenza in the entire year.

Perhaps more importantly, if you do get infected with influenza, vitamin D (especially D3) has a potent effect on protecting endothelial cells. And damage to endothelial cells appears to be a key mechanism by which COVID creates the most severe, and potentially fatal, symptoms. Here is a section from the paper ‘Dietary Vitamin D and Its Metabolites Non-Genomically Stabilize the Endothelium.

‘Vitamin D is a known modulator of inflammation. Native dietary vitamin D3 is thought to be bio-inactive, and beneficial vitamin D3 effects are thought to be largely mediated by the metabolite 1,25(OH)2D3…

Our data suggests the presence of an alternative signaling modality by which D3 acts directly on endothelial cells to prevent vascular leak. The finding that D3 and its metabolites modulate endothelial stability may help explain the clinical correlations between low serum vitamin D levels and the many human diseases with well-described vascular dysfunction phenotypes.’ 2

In short, it seems Vitamin D stops you getting infected with viruses and, even if you do get infected, it helps to mitigate the worst effects. This could explain results from a, not yet published study, looking at the severity of COVID infections vs. the level of Vitamin D in the blood 3.

VitD3

On the face of it, remarkable benefits. However, they fit with what is already known about the benefits of vitamin D on influenza.

Further supporting the role of vitamin D in COVID, it has been recognised in many countries that those with dark skin are more likely to get infected, and die, from COVID. Here from the Guardian (UK newspaper).

I am not alone in being alarmed at the preponderance of deaths from COVID-19 among those with dark skin (UK government urged to investigate coronavirus deaths of BAME doctors, 10 April). While COVID-19 is likely to magnify the effect of social deprivation, I don’t think this is the whole story.

Vitamin D is needed for many reasons, including correct functioning of the immune system. It is converted to its active form by the action of sunlight on the skin. This is impeded by having dark skin and leads to low levels of vitamin D. Supplementing with vitamin D3 at 5000iu daily corrects this deficiency, and it is now an urgent need for all people with dark skin (and most with white). There is a reasonable chance that vitamin D replacement could help reduce the risk we are seeing playing out so tragically in the BAME community 4.

So, what do we know?

  1. Dark skinned people are more likely to die from COVID
  2. Dark skinned people are more likely to have low vitamin D levels 5
  3. Vitamin D supplements protect against colds and flu – and hopefully COVID
  4. Higher levels of Vitamin D should be able to mitigate the damage caused by COVID

The increased risks of low vitamin D levels on COVID seem dramatic, and the benefits of supplementation with vitamin D could be just as dramatic. I have been going out into the sun wherever possible in the last month. I take Vitamin D3 supplements 4,000 units a day. I strongly advise everyone else to do the same.  It is snake oil, and it is free (if provided by the sun).

The only problem I see is that I cannot make any money out of this at all. Oh well. Perhaps I should claim to be making a vaccine, that could earn me billions.

1: https://virologyj.biomedcentral.com/articles/10.1186/1743-422X-5-29

2: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0140370

3: https://www.grassrootshealth.net/blog/first-data-published-COVID-19-severity-vitamin-d-levels/

4: https://www.theguardian.com/society/2020/apr/10/uk-coronavirus-deaths-bame-doctors-bma

5: https://academic.oup.com/jn/article/136/4/1126/4664238

The Anti-lockdown Strategy

21st April 2020

Unfortunately, it seems that COVID-19 has infected everyone involved in healthcare management and turned their brains into useless mush.

Lockdown has two main purposes. One, to limit the spread of the virus. Two, and most important, to protect the elderly and infirm from infection – as these are the people most likely to become very ill, end up in hospital, and often die. [In my view, if we had any sense, we would lockdown/protect the elderly, and let everyone else get on with their lives].

However, the hospitals themselves have another policy. Which is to discharge the elderly unwell patients with COVID directly back into the community, and care homes. Where they can spread the virus widely amongst the most vulnerable.

This, believe it or not, is NHS policy. Still.

Yes, you did just read that. COVID-19 patients, even those with symptoms, are still to be discharged back home, or into care homes – unless unwell enough to require hospital care e.g. oxygen, fluids and suchlike. If this is not national policy, then the managers are telling me lies.

In fact, it does seem to be policy, although the guidance from the UK Government is virtually incomprehensible1. I have read it a few times and I fail to fully understand it – or partially understand it. I tried reading it upside down, and it made just about as much sense.

I wrote about this situation in my last blog, as the impact of COVID of care homes was becoming apparent – even to politicians. I thought that someone, somewhere, might have realised the policy of flinging COVID positive patients – or patients who may have COVID – out of hospital, and into care homes, might prove a complete and utter disaster.

I now call care homes COVID incubators. Places where the disease can grow and multiply, happily finding new host after new host. Not so happily for the residents.

Equally, sending people home is further complete madness. Sending them home to somewhere that, very often, contains another elderly and frail person. Normally a husband or a wife. Did anyone think through the consequences of this? Clearly not. Do you think the other person in the house may be at risk? Really, you think. Surely not, knock me down with a feather…

If there is not another elderly partner in the house, there will usually be carers who come in to look after the freshly discharged COVID positive patients. These carers will have almost no protective equipment. Even if they do, they will be lifting and moving the patient around, washing them, taking them to the toilet… in very close proximity. The chances of getting infected are very, very, high.

These carers will then go and visit other elderly, vulnerable patients scattered around the community. They become the perfect vectors to spread the virus far and wide, amongst the exact group of people that we are trying to protect.

I have been doing a lot of jumping up and down about this over the last few days. The hospital trusts appear incapable of understanding the argument. ‘Clear the hospital, clear the hospital’… are the only words they seem capable of uttering.

The hospitals, I point out repeatedly, have been cleared. Wards are standing empty, corridors echoing. The first peak has also been passed – even if no-one dares admit it. So why are we continuing to fling COVID positive patients out into the community? Why? Why? Why?

Because it is national policy’. Squawk. ‘Because it is national policy’. Squawk. ‘Pieces of eight, pieces of eight.’

The entire nation has been locked down. Do not travel, stay two meters apart, do not go outside blah, blah. Meanwhile we have the perfect anti-lockdown policy in place for the very people we are mostly supposed to be protecting. There are two parallel universes here.

If you wanted to create a system most perfectly designed to spread COVID amongst the vulnerable elderly population, you may well have come up with the current one. Infect people with COVID in hospital, and then scatter them into care homes and the rest of the community. Making sure that you infect all the carers on the way.

As Albert Einstein said. ‘Two things are infinite, the universe and human stupidity… and I’m not so sure about the universe.’

Thud… the noise of my head hitting the desk in utter frustration.

1: https://www.gov.uk/government/publications/COVID-19-guidance-for-stepdown-of-infection-control-precautions-within-hospitals-and-discharging-COVID-19-patients-from-hospital-to-home-settings/guidance-for-stepdown-of-infection-control-precautions-and-discharging-COVID-19-patients

Care homes and COVID19

17th April 2020

The government’s disregard of care home residents – old, sick people, acutely vulnerable to COVID19 – has been scandalous.

As a GP, I regularly visit care homes. At one I visit, they recently had eight residents who died in a week, probably from coronavirus. But there’s no testing, so who could possibly know…

When COVID struck, many things were not known, and could not possibly have been predicted. The transmission rate, the case fatality rate, the best way to treat those infected.

However, it was very clear, very early on, that COVID was killing the elderly in far greater numbers than anyone else. In Italy, the early figures released revealed that the average age of death was seventy-nine. The figures were slightly higher in Germany, and around eighty years old in pretty much every other country.

Equally, it was known that amongst the elderly who were dying, almost all of them had other serious medical conditions. Heart disease, high blood pressure, diabetes, chronic pulmonary disease and suchlike. This is often known in my line of work as “multimorbidity.”

In a world of uncertainty, one thing stood out. Which is that the unwell elderly were the ones who were most likely to die. Equally, they were the ones most likely to end up in hospital, potentially overwhelming the health services. As happened in Italy and Spain.

Ergo, you would think that someone, somewhere in the UK government, would have asked the obvious question. Where do we have the greatest concentrations of elderly, frail, people with multimorbidity? Could it possibly be that they are being looked after in care homes around the country?

Nursing homes, residential homes, care homes. They are all pretty much the same thing nowadays. Nursing homes tend to look after those with greater health needs, and they must have registered nurses looking after patients, but the distinctions have become blurred.

Many care homes are also specialised in looking after the elderly with dementia. In the UK, they are called EMI units [elderly mentally infirm]. These represent a particular problem in that residents tend to wander about from room to room.

So, in care homes we potentially had the perfect storm for the pandemic. They are full of elderly and infirm and highly vulnerable people. Environments where it is often impossible to isolate residents, and staff who have never been adequately trained in isolation measures. Equally, whilst relatives cannot visit hospitals, care homes have been continuing to allow them in.

It is not as if the warning signs were not there, flashing red.

What was the government’s strategy for dealing with nursing homes?  It has been, up until the last couple of days, to make things even worse. The instructions from the Dept of Health have been to send patients diagnosed with COVID out of hospital, and back into care homes, with instructions to “barrier nurse” them, a term for a set of stringent infection control techniques.  Care homes were informed that they could not refuse to take the residents back.

All of which means that the staff end up attempting to barrier nurse COVID positive patients with flimsy surgical masks, no eye protection, no gowns and gloves that, in my case, disintegrate rapidly and are almost completely useless. Until very recently, nursing home staff, in many homes, were told not to wear masks, and this was true even when there were COVID positive patients in the home.

The focus, the entire focus, has been to clear patients out of hospitals, waiting for the deluge of patients. This has been so effective that, in my area of Cheshire, the local hospitals have never been so empty.

There are wards with no patients in them. The shiny new Nightingale hospital in London, with four thousand beds, apparently had, so I am informed, just nineteen patients in it last weekend. Yet still the pressure still comes down: get patients out of hospital and back into care homes.

At the same time, all the effective personal protective equipment (PPE) has been directed to hospitals and hospital wards. Care homes have been almost unable to access anything. I scavenge what I can before I visit. I keep being told that things have improved. By those who haven’t seen a patient – or the inside of a care home – for years.

I have also watched patients go down very rapidly and die. COVID is a strange disease that kills people in a way that I have never witnessed before. In some cases, very quickly. I have tried to suggest that hospitals are the best place to look after potentially infectious people, not care homes. No-one has been interested.

Now, of course, the disaster is unfolding. The entirely predictable disaster. Here, from The Guardian:

‘Care home leaders have accused the government of vastly underestimating the deaths of elderly people from coronavirus, as they warned the disease may be circulating in more than 50% of nursing homes and mortality is significantly higher than official figures.

Operators of several large care providers accused the government of not paying enough attention to the tragedy unfolding in residential settings across England, as figures from three of the largest chains show 620 deaths from COVID-19 in recent weeks.’

As I mentioned earlier, in one care home that I visit, they recently had eight deaths in seven days. Were these COVID deaths? Who knows for sure. No-one was tested. No-one is tested. The staff are not tested. I have patients who have died quickly. What do I put on the death certificate? COVID? Well I cannot, not really, because I have no idea if they had COVID or not.

It seems clear that many, many, COVID deaths in care homes will not even be registered as COVID deaths, so the figures are almost certainly worse here than are being reported.

I think we all recognise that the COVID pandemic has hit the country with great force, and that the Government has had to react at great speed. You can agree or disagree with some of the actions. However, one thing that stands out is that complete and utter abject failure to grasp the impact of COVID on care homes.

The actions taken, so far, have made the problem far, far, worse. All the thinking and resources have been directed to the NHS. Meanwhile, the residents and the staff of nursing homes have been, effectively, thrown in front of a bus. On Thursdays, while others have been clapping the NHS, I have been clapping for the unsung heroes of this epidemic. The care home staff.

A Good Cause

15th April 2020

I have known Steve Bennett for a few years now. He became a convert to the high fat low carb world (primal living and eating) and has set up Primal Living to promote this dietary message to the world, using his considerable financial muscle to do so.

In the midst of lockdown, he is running a series of youTUBE programmes, and interviews, discussing a number of topics, and from the resultant publicity he is hoping to gain donations to food banks – which are really struggling at the moment. He will match donations up to £100,000 to do this.

I hope you can watch some of the programmes. I hope you can donate, if you feel able. I am appearing on a couple of the shows. I think this is a very good cause. I support Steve Bennett and his team in the endeavour. Below is a slightly amended press release…

THE FOOD BANK SHOW – YouTube channel: The Primal Living.

Guests on the shows include politician Tom Watson and Dr Aseem Malhotra and Dr Malcolm Kendrick – amongst others (we are also waiting for conformation of singer Liam Payne – Liam is a huge supporter of food banks). The show will also be connecting live to the Trussell Trust, who with their army of amazing volunteers keep many of our food banks operational.

Every morning thereafter, we will be broadcasting live on youTUBE providing food and health advice. Steve Bennett The Food Bank Show host will be joined by doctors, medical experts and chefs, many of whom contributed to his latest health book FAT and Furious. Together – they will be taking your questions from around the country and additionally during the shows we will video link to food banks across the UK and discover new ways we can all help offer support.

With fast food chains closed, we want to seize this opportunity to reshape the eating habits of our nation and improve everyone’s health and whilst we are doing this together –  help feed those most in need during this crisis.

Join Steve and his family, as they put on a truly interactive show and please encourage everyone you care and love to join them too.

Further Info

  • We aim to generate as many donations to the Food Banks as possible. Steve Bennett is going to match donations up to the first £100,000.
  • People can donate via a text or a justgiving page.
  • The show has 3 aims;
    • Help viewers learn about how to eat healthily
    • Raise money for foodbanks, with our partnership with the Trussell Trust
    • Entertain people
  • 2% of UK families currently rely on food banks, but the virus has resulted in fewer donations and fewer volunteers being able to help.
  • After keeping social distance and washing hands, the next best thing we can do to help our immune and defences is to be metabolically healthy, this will be discussed at detail in the shows.
  • Most vulnerable are those with metabolic syndrome. In Italy while the average age of death was 81, the average person who died suffered from 2.7 underlying chronic medical conditions. Including High blood pressure, cancer, diabetes. Lowering blood pressure, reversing diabetes, high sugar levels, can happen quickly with the right advice and that is the message the doctors will be promoting.
  • In Wuhan, more than 60% of people who died, or had serious complications had high blood pressure or type 2 diabetes.
  • UK over 60% adults are overweight or obese. Only 17.4% of American adults are metabolically healthy.

For more information contact:

Contact the Show Writers Nick.Davies@primalliving.com  or Poppy Hadkinson poppy@primalliving.com
Jack Bennett Show Producer JB3015@bath.ac.uk
The Show Host Steve Bennett Steve@tggc.com

The lockdown is NOT a way of beating this virus

12th April 2020

Several politicians, including Keir Starmer, the opposition Labour Party leader, have been demanding to know the exit strategy for the lockdown. “We should know what that exit strategy is, when the restrictions might be lifted and what the plan is for economic recovery to protect those who have been hardest hit,” he said last week.

This is an entirely valid question, but the Government cannot have an exit strategy, unless they have an overall strategy. One follows directly from the other.

And there are only four possible strategies:

To eradicate the virus from the entire population by enforcing lockdown. Or to enforce lockdown until there is an effective treatment. Or to enforce lockdown until there is a vaccine. Or to enforce lockdown to slow the spread of the virus, so as to prevent the NHS from being overwhelmed.

Eradication is virtually impossible with such a highly infectious disease. Even if the UK was successful, if other countries were not, keeping Covid-19 out would require border closures for years, maybe decades. Endless checks on planes, boats, lorries, cars. Constant testing and restrictions. It is almost certain that the virus would still slip through. This does not seem a viable option.

What about finding an effective treatment? The chances are vanishingly small. Influenza, a very similar virus, has been around for decades, and no game changing medications have yet been found.

As for a vaccine? This solution is so distant that it does not really exist. It will be a minimum of eighteen months before an effective vaccine can be developed, then tested, then produced in sufficient quantities to be of any use. Waiting for eighteen months before releasing lockdown would be socially and economically impossible. We would be committing national suicide.

Ergo, there is only one overall strategy that can be followed. Control the spread to avoid overwhelming the NHS. This has never been made explicit, but the Government has, albeit indirectly, told us that this is exactly what they are doing.

In the last few days, a letter was sent to all households, signed by Prime Minister Boris Johnson, before he too succumbed to the disease. It was entitled “Coronavirus – stay at home; protect the NHS, save lives.” It contained this key passage:

“If too many people become seriously unwell at one time, the NHS will be unable to cope. This will cost lives. We must slow the spread of the disease, and reduce the number of people needing hospital treatment in order to save as many lives as possible.

The key sentence is the first. If too many people become seriously unwell at one time.

This fits with the initial UK strategy. Contain, delay, research, mitigate. The UK has passed through “contain” and is now in “delay and mitigate”. Research sits in the background and may, or may not, provide a solution.

However, delay and mitigate doesn’t mean that people will not become infected and die. It just means that the NHS will not be overwhelmed by a massive wave of people getting ill at the same time. We are simply, it should be made clear, trying to control the “peak”, which now may likely be a series of “peaks”.

At present, ministers are not admitting this. They are presenting lock-down as a way of “beating this virus.” In order to enforce lockdown, they are haranguing and scaring the population into compliance.

Covid-19 is being presented as a deadly killer that does not discriminate. Young, old, we are all at risk of contracting this dreadful disease. Every night, the television news has story after story of young people who have been infected, and who have died. In fact, very, very few people under 20 have died so far. I believe it was five, at the end of last week.

There is hardly anything said about the fact that the average age of death is around eighty, that the vast, vast, majority of those dying are old (92% are aged over sixty) The great majority of them have several other serious medical conditions.

The reality is that for anyone younger than about sixty, Covid-19 is only slightly more dangerous than suffering from influenza. The infection fatality rate (IFR) currently stands at around 0.2% in those countries doing the most testing. This figure will inevitably fall, once we can identify those who were infected but had no symptoms.

By avoiding this more reassuring message, by frightening everyone into compliance, the Government has painted itself into a corner. How can they say to people that, last week you couldn’t drive two miles to walk in the countryside, or go to the beach, or go to a restaurant, or lie in a park sunbathing, in order to prevent the spread of this deadly killer disease …but this week you can?

Worse than that, when cases begin to rise again, about a month after lockdown is relaxed, we will all have to lock down again, to prevent the next surge? How will the public respond to this? I don’t know, but I expect that it is going to be extremely difficult, if not impossible, to force everyone back into lockdown again.

By this point, millions will have been financially crippled and will be desperate to work, if their jobs still exist. Thousands of businesses will have fallen over, bankrupt. Hundreds of thousands of operations, and cancer treatments, will have been postponed and cancelled. I have already warned that it’s possible, perhaps even likely, that many more people could as a result of the lockdown than will die from coronavirus.

That great harm is being done by it was made clear in an article last week in the Health Service Journal:

“NHS England analysts have been tasked with the challenging task of identifying patients who may not have the virus but may be at risk of significant harm or death because they are missing vital appointments or not attending emergency departments, with both the service and public so focused on covid-19.

“A senior NHS source familiar with the programme told HSJ: “There could be some very serious unintended consequences [to all the resources going into fighting coronavirus]. While there will be a lot of covid-19 fatalities, we could end up losing more ‘years of life’ because of fatalities relating to non-covid-19 health complications.”

It may well seem that all this suffering was…well, for what, exactly? To simply prevent a surge of cases. This government, all governments, must be honest about this and admit that in the longer term we cannot prevent almost everybody getting infected and acknowledge that a proportion of those infected will die.

When lockdown restrictions are lifted this does not mean that the virus has gone. It does not mean that people cannot infect each other.  It does not mean we can simply carry on as before. It means that we have kept the first surge under control.

So, what is the exit strategy? The answer is that we don’t have one. We have a strategy of delay and mitigation which will continue until… when? Until everyone has been infected? Until we have an effective treatment? Until we have an effective vaccine? Until enough people have been infected that we have achieved herd immunity?

The Government must tell us the truth and be clear about what end point they are seeking to achieve. Only then can we have an exit strategy. One thing for sure is that this lockdown is not a way to defeat the virus.

COVID. ‘With’ ‘Of’ or ‘Because of’

6th April 2020

Here is a section from the Health Service Journal (HSJ) in the UK, discussing the current fears of NHSE (NHS England). The article is behind a paywall.

NHS England is an executive non-departmental public body of the Department of Health and Social Care. NHS England oversees the budget, planning, delivery and day-to-day operation of the commissioning side of the NHS in England as set out in the Health and Social Care Act 2012>/p>

Exclusive: NHSE to act over fears covid-19 focus could ‘do more harm than virus’

‘NHS England analysts have been tasked with the challenging task of identifying patients who may not have the virus but may be at risk of significant harm or death because they are missing vital appointments or not attending emergency departments, with both the service and public so focused on covid-19.

A senior NHS source familiar with the programme told HSJ: “There could be some very serious unintended consequences [to all the resource going into fighting coronavirus]. While there will be a lot of covid-19 fatalities, we could end up losing more ‘years of life’ because of fatalities relating to non-covid-19 health complications.

“What we don’t want to do is take our eye off the ball in terms of all the core business and all the other healthcare issues the NHS normally attends to.

“People will be developing symptoms of serious but treatable diseases, babies will be born which need immunising, and people will be developing breast lumps and need mammograms.”…

Nuffield Trust deputy director of research Sarah Scobie said it was “a considerable worry that people are keeping away from routine and urgent health services, and also from emergency departments”.

She added: “The PHE (public health England) data suggests there could be significant problems already developing for heart disease related conditions patients, for example. Attendances relating to myocardial infarction at emergency departments have dropped right down, whereas ambulance calls in relation to chest pain have gone right [up].

I suppose my first response would not be one of great surprise. In fact, it confirms what I have been saying for some time. When the great Swine Flu epidemic (that killed hardly anyone) created the last pandemic crisis in the UK, exactly the same thing happened. If, whatever you were suffering from, wasn’t Swine Flu, it didn’t seem to matter.

In my small part of the world a small but significant number of people were diagnosed with Swine Flu. This was done over the phone, by poorly trained operatives. These people were then prescribed the (almost entirely useless Tamiflu), they then died. It turned out that they had other conditions that could, and would, have been properly treated had we not been overcome by a massive over-reaction to Swine Flu. They died because of swine flu.

Last week, in Intermediate Care, we sent two patients into the local hospital who were seriously ill. They were both sent back almost immediately. They both died. Yes, they were ill, and may have died anyway. But I believe they should both have been admitted, and treated, and they could both still be alive. They died because of COVID.

Ambulance crews are under very heavy pressure not to admit anyone unless absolutely necessary. Some of those, not admitted, will die.

These people, all these people, are dying ‘because of’ COVID. Because of the fact that almost the entire focus of the NHS is now on COVID – to the virtual exclusion of anything else.

Our local hospital now has more empty beds than at any time in history. Elective surgery has stopped, to free up resources. There is enormous managerial pressure to clear more and more people out of hospital, out of Intermediate Care beds, back home with little support available. Some of them will die because of this.

My last blog focussed on the economic costs of the reaction to COVID. My argument was that economics, and health, do not exist in isolate bubbles. Harm to the economy will result in harm to health and vice-versa.

Equally, if you spend all your healthcare resources trying to treat one thing, everything else will suffer, because resources are not infinite. At present we have virtually shut down the NHS to deal with COVID.

I saw several patients yesterday while I was working in “out of hours”, who were not critically ill, but they were ill. Two of them, I felt, really needed to be followed up. A girl with weight loss over the last three months, a man with clear signs in his chest that could have been malignant.

They will not be followed up any time soon. If at all.

At present there is a lot of discussion about how we are categorising deaths from COVID. Anyone who dies, having been diagnosed with COVID, is considered to have died of COVID. Even if they died of something else. The died with COVID, not of COVID.

There is, I believe, an even greater immediate problem here. Which is those who are dying because of COVID. This is not just me saying this, this is NHS England:

While there will be a lot of covid-19 fatalities, we could end up losing more ‘years of life’ because of fatalities relating to non-covid-19 health complications.”

For many years, there has been an old medical joke. It will not make you laugh out loud, but it goes like this.

The operation was a success, unfortunately the patient died.’

A Health Economic perspective on COVID-19

29th March 2020

The current COVID pandemic has brought a very thorny and difficult issue to the forefront. How much money should we, as a society, spend on keeping people healthy/alive? No-one has ever fully got to grips with this question, but it has never been more important than now.

The reason why I say this is that the US Govt has set aside two trillion dollars to deal with the crisis, in the UK it is over three hundred and fifty billion pounds, which is almost three times the current yearly budget for the entire NHS. Is this a price worth paying?

I know that some people will instantly dismiss such a question as being cold-hearted, and simply stupid. ‘You cannot put a value on a human life.’ Is an argument that I have heard many times, almost whenever health economics is discussed.

The counter argument is that – if funds are not limitless – then we should focus on doing things whereby we can do the most good (save the most lives) for the least possible amount of money. Or use the money we have, to save the most lives. In fact, this is why the National Institute for Health and Care Excellence (NICE) was established.

NICE reviews interventions and decides whether they provide value for money. The economic term for this is cost-effectiveness. This work is complex and often relies on assumptions that can be difficult to verify.

However, keeping this as simple as possible, NICE tries to compare healthcare interventions against each other by using a form of ‘currency’ called the cost per QALY.  A QALY is a Quality Adjusted Life Year. One added year of the highest quality life would be one QALY.

People with conditions such as cancer, or severe heart disease, or who are suffering from chronic pain can be considered to have a quality of life less than one. For the sake of argument, we can say that their quality of life is 50%. Thus, one year of additional life gained for them, would have a value of 0.5 of a QALY.

It also needs to be borne in mind that not everything that is measured using a QALY, relates to saving, or extending, lifespan. For example, someone could have chronic hip pain, and a quality of life of 0.5. Then they have a hip replacement, and their pain goes away, their quality of life can improve from 0.5 to 1. If they live another twenty years, they will have gained 20 x 0.5 QALYs = 10 QALYs.

Obviously, things can get significantly more complicated than this, and the validity of the measured quality of life is a matter of considerable debate.

However, the fundamental question as always, comes down to the following. How much are we willing to pay for one QALY? [How much can you afford to pay for one QALY?] Not just the NHS, but the country as a whole? The current answer, in the UK, is that NICE will recommend funding medical interventions if they cost less than £30,000/QALY. Anything more than this is considered too expensive.

This figure is not set in stone and can vary depending on circumstances. Interventions for young children tend to get more spent per QALY, and powerful lobbying groups can bring pressure to bear on that figure.

However, the figure of £30,000 is generally accepted – if not widely publicised.

Which means that, if we are going to spend £350,000,000,000.00 in the UK, on managing the coronavirus, how many QALYs do we need to get back? The simple answer is to divide three hundred and fifty billion by thirty thousand. Which leaves us with slightly more than eleven and a half million (11,666,666).

To put it in more stark terms. In order to spend three hundred and fifty billion pounds, we require a return on investment of eleven point six million QALYs. If not, NICE would reject it.

[For those who think this an impossible/inhuman calculation, you always have to consider how many other lives could be saved, how much other suffering, or death, could be prevented, by spending three hundred and fifty billion pounds in another way. Because that is what you are really trying to work out].

Are we likely to achieve this level of benefit? Of course, any attempt to model this requires several assumptions to be made. However, the model we can use in this case only has four variables, two of which are (pretty much) known. The variables are:

  • How many people will die?
  • What is the average age of death?
  • What is the average reduction in life expectancy in those who die?
  • What is the average quality of life of those who die?

[In truth, average age of death is only needed to calculate the average reduction in life expectancy.]

So, for example

  • 500,000 die
  • Average age at death 78.5
  • Average reduction in life expectancy 3 years
  • Average quality of life of those who die 0.7

QALYs lost: 500,000 x 3 x 0.7 = 1,050,000

Using these figures, if we spend three hundred and fifty billion pounds – in the hope of reducing the ‘QALYs lost’ figure to zero, then each QALY will have cost £333,000. Which is more than eleven times the maximum cost that NICE will approve.

Of course, people will immediately object to this model, and for valid reasons. How do we know how many will die, how do we know the average quality of life of those who die, how do we know the average reduction in life expectancy?

In fact, we do know two things with reasonable accuracy. First, we can be pretty certain about the average age of death, and we can also be fairly clear on the average quality of life of those who have died.

What is less certain is how many will die, and the average life expectancy of those who have died. At this point we need to look at the ‘variables’ in the model in a little more detail. This is UK only.

Number who may die

The 500,000 figure for possible deaths, that I used in the calculation above, is the absolute upper range of the numbers that have been proposed, and it comes from modelling that was developed by the Imperial College in London. Their modelling has been since used around the world to guide Government responses. 1

On the other hand, the UK Government has used an estimated 250,000, for the upper limit of deaths – if nothing is done to prevent spread. Other figures have been much lower, but I am going to use 500,000 as the maximum, and 250,000 as the ‘most likely number’ in this model.

My minimum figure will be 20,000, as this has recently been suggested by the same Imperial research group. It seems low.

Average age of death

In Italy – which has had the greatest number of deaths – the average age at death is 78.5. This is comparable with age of death in other countries. I am going to use this as a non-variable 2.

Average reduction in life expectancy

This is more complicated. Using Italy, again, the average life expectancy is 82.5 years (both men and women). However, if people die aged 78.5, this does not mean you have reduced life expectancy by 3 years.

The average life expectancy in Italy, at birth, is 82.5 years. However, once you reach 78.5, you can expect another eight or nine years of additional life. [You will have avoided car crashes, early cancer, suicide and suchlike which reduce the ‘average’ life expectancy of the entire population].

On the other hand, those who are dying of COVID have multiple medical conditions. On average they have three serious underlying problems such as: diabetes, COPD, heart disease, previous stroke, active cancer and suchlike.

Which means that these 78.5-year olds do not have a life expectancy of eight or nine years. It will be far less. How much less? This is virtually impossible to calculate. I am going to estimate a half – or 4.5 years (an average).

Which means that, in this model, my lower figure of years of life lost will be three years. My upper figure is nine years and my ‘most likely’ figure 4.5 years.

Average quality of life of those who die

Again, this is difficult to establish. However, studies have been done to work out the ’reported’ quality of life in those with multimorbidity. Perhaps the most accurate figure I could find with that elderly people with three underlying serious health problems have a quality of life of 0.8.3

Using different figures in the model

Having put figures to the likely range of the variables, we can look at the cost per QALY in various scenarios. I am only going to look at three. ‘Best case’ ‘Most likely’ and ‘Least benefit.’

Best case

I am going to start by inputting the figures that would provide the greatest possible gain in QALYs. This is 500,000 deaths prevented, and an average gain in life expectancy of nine years [This assumes all 500,000 lives will be ‘saved’ with the actions taken]. Quality of life is kept constant at 0.8.

The calculation is:

500,000 x 9 x 0.8 = 3,600,000 QALYs

Which gives a cost per QALY of £97,200 [£3,5Bn ÷ 3.6m]

Most likely

We can then run the ‘most likely’ scenario, which is 250,000 deaths prevented, with an average gain in life expectancy 4.5 years.

250,000 x 4.5 x 0.8 = 900.000 QALYs

Which gives a cost per QALY of £388,888 [£3.5Bn ÷ 900K]

Least benefit

Finally, we can tun the ‘least benefit’ scenario, which is 20,000 deaths prevented, with an average gain in life expectancy of 3 years.

20,000 x 3 x 0.8 = 48,000 QALYs

Which give a cost per QALY of £7,291,666 [£3.5Bn ÷ 48K]

As you can see, none of these models achieves a cost per QALY that would be approved by NICE.

Disability Adjusted Life Years

I fully recognise that looking at human life in from this purely economic perspective can seem harsh, almost inhumane. Can we really stand back and watch an elderly person ‘drown’ as their lungs fill up with fluid ‘Sorry, we are not spending money on more ventilators, because it is not cost-effective.’ Or suchlike.

However, there is also a health downside associated with our current approach. Many people are also going to suffer and die, because of the actions we are currently taking. On the BBC, a man with cancer was being interviewed. Due to the shutdown, his operation is being put back by several months – at least. Others with cancer will not be getting treatment. The level of worry and anxiety will be massive.

Hip replacements are also being postponed and other, hugely beneficial interventions are not being done. Those with heart disease and diabetes will not be treated. Elderly people, with no support, may simply die of starvation in their own homes. Jobs will be lost, companies are going bust, suicides will go up. Psychosocial stress will be immense.

In my role, working in Out of Hours, we are being asked to watch out for abuse in the home. Because we know that children will now be more at risk, trapped in their houses. Also, partners will suffer greater physical abuse, stuck in the home, unable to get out. Not much fun.

Which means that we are certainly not looking at a zero-sum game here, where every case of COVID prevented, or treated, is one less death. There is a health cost.

There is also the impact of economic damage, which can be immense. I studied what happened in Russia, following the breakup of the Soviet Union, and the economic and social chaos that ensued. There was a massive spike in premature deaths.

In men, life expectancy fell by almost seven years, over a two to three-year period. A seven-year loss of life expectancy in seventy million men, is forty-nine million QALYs worth. It is certainly a far greater health disaster than COVID can possibly create.4

In Lithuania, the impact of the break-up of the Soviet Union was also dramatic, and damaging. Below is a graph, looking purely at deaths from cardiovascular disease. As you can see, starting in 1989 (when the Berlin wall fell) there was an enormous spike, representing hundreds of thousands of premature deaths. These same spikes, in death and disease, were seen across most countries in the former Soviet Union. 5

These, the downsides, can be calculated, using the figure that is the opposite of the QALY, which is the DALY. The Disability Adjusted Life Year. Or, to put it another way, how much harm are you causing with your interventions? I am not doing this calculation here, because it would have about ten thousand variables and would take far too long.

Despite this, the message here is that severe damage to an economy does not simply affect bank balances, it can be deadly. If we look at the result of social deprivation in the UK, the effect is (potentially) immense

This was highlighted in a review by Michael Marmot, who studied two areas of Glasgow. Lenzie, which was rich, whilst the other area, Calton, was poor (socially deprived). The findings were stark:

…we can see this in Glasgow. When we published the report of the WHO Commission on Social Determinants of Health (CSDH) in 2008, I drew attention to stark inequalities in mortality between local areas of Glasgow: life expectancy of 54 for men in Calton, compared with 82 in Lenzie.’ 6

A twenty-eight-year difference in life expectancy between people living approximately five miles apart. The difference? Money.

This, I hope, puts into some perspective the discussion on cost per QALY. I framed it, to start with, as a discussion about money, but it is not really about money. Health does not exist in some bubble, sitting apart from the rest of society. Health and wealth are closely interrelated.

Which means that I fear that we are taking actions that could, in the longer term, if we are not very careful, result in significantly more deaths than we are trying to prevent.

Even if we restrict the analysis purely to the cost per QALY and narrow the ‘health’ analysis purely to COVID, and deaths from COVID, it remains difficult to justify spending £350 billion pounds to control a single disease.

I know that many people will violently disagree with this analysis and will think I am some cold-hearted fiend. ‘People are dying, we must do absolutely everything we can. No matter how much it costs.’ ‘What would you say if it was your mother…’ and suchlike.

Well, I have spoking to my mother, who is 92. Her view is that she has lived long enough. She thinks the Government actions are a ridiculous over-reaction. She is going out shopping and chatting to friends… she will take no advice on the matter.

So, what would I do if it was my mother that is dying? I will say that she made her choice, and who am I to argue with it.

1: https://www.imperial.ac.uk/news/196234/covid19-imperial-researchers-model-likely-impact/

2: https://www.epicentro.iss.it/coronavirus/bollettino/Report-COVID-2019_20_marzo_eng.pdf

3: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5818872/

4: https://en.wikipedia.org/wiki/Health_in_Russia

5: https://www.bhf.org.uk/informationsupport/publications/statistics/european-cardiovascular-disease-statistics-2012

6: https://journals.sagepub.com/doi/full/10.1177/1403494817717433

COVID – 19 update

22nd March 2020

I thought I should do a quick update on COVID-19, as some interesting and important information has been published in Italy. Looking at deaths in various age groups, underlying conditions etc.

It can be seen here https://www.epicentro.iss.it/coronavirus/bollettino/Report-COVID-2019_20_marzo_eng.pdf

Points of greatest importance

  • Far more men are dying than women, with a ratio of around 3:1 – reasons unknown
  • Mean age at death is 78.5 years (women slightly older than men)
  • 2% of those dying had no comorbidities (other diseases e.g. heart disease, diabetes, cancer)
  • ~50% had three or more comorbidities.

Symptoms

  • 1% were coughing up blood (haemoptysis)
  • 8% had diarrhoea
  • 40% had a cough
  • 73% had difficulty breathing (dyspnoea)
  • 76% had a fever.

[5.7% were admitted with no symptoms at all – not clear what they came in with. Presumably admitted with something else, then developed the symptoms later]

What did they die of?

96.5% died of acute respiratory distress syndrome.

‘Acute respiratory distress syndrome (ARDS) occurs when fluid builds up in the tiny, elastic air sacs (alveoli) in your lungs. The fluid keeps your lungs from filling with enough air, which means less oxygen reaches your bloodstream. This deprives your organs of the oxygen they need to function.

ARDS typically occurs in people who are already critically ill or who have significant injuries. Severe shortness of breath — the main symptom of ARDS — usually develops within a few hours to a few days after the precipitating injury or infection.

Many people who develop ARDS don’t survive. The risk of death increases with age and severity of illness. Of the people who do survive ARDS, some recover completely while others experience lasting damage to their lungs.1

Treatment is with oxygen and ventilation but has a low success rate in the very elderly.

Deaths under 50 years of age

To date (March the 20th), 36 of 3200 (1.1%) COVID-19 positive patients under the age of 50 have died. In particular, 9 of these were younger than 40 years, 8 men and 1 woman (age range between 31 and 39 years). For 2 patients under the age of 40 years, no clinical information is available; the remaining 7 had serious pre-existing pathologies (cardiovascular, renal, psychiatric pathologies, diabetes, obesity).

There do not seem to have been any deaths below the age of thirty.

ACE-inhibitors and Angiotensin Receptor Blockers (ARBs)

There has been much debate as to whether or not ACE-inhibitors (angiotensin converting enzyme inhibitors) and ARBs may increase the risk of death [these drugs are widely used to lower blood pressure]. This is because COVID-19 appears to enter the body through ACE2 receptors – found in high concentrations in the lungs and can cause upset to the neurohormonal system where ACE, and ACE receptors, play an important role.

The data from Italy is that:

‘Before hospitalization, 36% of COVID-19 positive deceased patients followed ACE-inhibitor therapy and 16% angiotensin receptor blockers-ARBs therapy. This information can be underestimated because data on drug treatment before admission were not always described in the chart.’

That is 52% who were on one, or the other (it is very rare for anyone to be on both). That was clearly, as they state, an underestimate. Possibly a considerable underestimate.

Knowing this, it is important to know how many (elderly people) take either of these drugs, to see if there is a correlation between taking them and dying from COVID-19. The figures from Italy are not clear at all. However, the latest data on prevalence of high blood pressure in the adult Italian population was, around 52% (This is an absolute maximum).2

However, the number of people known to have had their high blood pressure recorded by their general practitioner is around 20% 3 . Which means that most people with high blood pressure are not treated with anything.

Bringing these figures together, it can be estimated that a maximum of 10% of the Italian population are taking antihypertensive medications. These figures may be a little out of date, and these data are not specifically for the age group of, around, 80 years of age. Here the figures on diagnosis of hypertension, and use of antihypertensives will probably be higher, possible double.

So, we can say that 10% of the adult population is treated for hypertension, and that this may be around 20% in those aged around 80. Taking the figures one step further, it is estimated that about 67% of those who take antihypertensive in Italy use ACE-inhibitors, or ARB. 4

Bringing all of these figures together, it is likely the average percentage of eighty-year olds taking an ACE, or ARB is

67% of 20% of 52%x 2 = 14.0%

Which means that amongst 80-year olds ~14% are taking one, or other, of these drugs.

I cannot say either of these figures in carved in stone and I believe 14% is probably a overestimate. I wish there were more fully accurate figures to be had. So, what does this mean?

It means that:

  • A (probable) maximum of 14% of the elderly population in Italy are taking ACE-inhibitors/ARBs
  • A minimum of 52% of people in Italy who are dying from COVID-19 are taking ACE-inhibitors/ARBs.

Which suggests you are four times as likely to die from COVID-19 if you are taking one of these drugs, prior to contracting the virus. This, of course, does not take into account confounding variables – many of which are currently unknown. By a confounder I mean that people taking these drugs may have more comorbidities, such as heart disease, diabetes etc.

However, it remains a very strong signal, and I do not think it can be ignored, particularly in the light of the knowledge that the COVID-19 virus has a significant impact on the ‘ACE system’.

On this basis I would strongly recommend that elderly people, with any comorbidity, who is taking an ACE-inhibitor/ARB should look to change their antihypertensive treatment to something else – whilst the threat from COVID-19 is high.

I should point out this runs contrary to the advice from the authors of a study in the European Heart Journal 20th March:

SARS-CoV2: should inhibitors of the renin–angiotensin system be withdrawn in patients with COVID-19?

‘In conclusion, based on currently available data and in view of the overwhelming evidence of mortality reduction in cardiovascular disease, ACE-I and ARB therapy should be maintained or initiated in patients with heart failure, hypertension, or myocardial infarction according to current guidelines as tolerated, irrespective of SARS-CoV2. Withdrawal of RAAS inhibition or preemptive switch to alternate drugs at this point seems not advisable, since it might even increase cardiovascular mortality in critically ill COVID-19 patients.’ https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehaa235/5810479

It should be borne in mind though, that their advice does acknowledge that they had no evidence about the number of people who were taking ACE-inhibitors, or ARBs, who then died. The data from Italy came out a day after the EHJ article was published.

Of course, no-one can be certain about what exactly is happening. I cannot be certain, but the signal from Italy on ACE-inhibitors and ARBs, seems very strong, and concerning. Based on it, I think my advice would be to change medication, if possible.

Stating this, I am aware that most GPs will not change anything, unless they get instruction from the acknowledged experts. Unfortunately, this is likely to take far more time than many people actually have.

1: https://www.mayoclinic.org/diseases-conditions/ards/symptoms-causes/syc-20355576

2: https://www.escardio.org/static_file/Escardio/Subspecialty/EACPR/Country%20of%20the%20month/Documents/italy-country-of-the-month-full-report.pdf

3: https://www.nature.com/articles/jhh200914

4: https://academic.oup.com/ajh/article/25/11/1182/115788

CORONAVIRUS [COVID-19]

18th March 2020

I thought I should say something about the coronavirus for readers of this blog. I need to state that the situation is fast moving, facts are changing, and I am not asking anyone to go against any current medical advice.

Here, I am simply providing advice that I believe, currently, may be of benefit to people out there. I am acutely aware that there is controversy swirling about, but I will not promote anything that can cause any significant harm – but may cause significant good.

I have tended to look back a few years in time for some evidence, because current, emerging evidence is subject to massive bias and controversy, with various vested interests getting involved. The ‘older’ evidence has not been done in a rush and is therefore more measured.

1: Anti-inflammatories (NSAIDs)

COVID-19 appears to impact the lungs more than any other organ and COVID-19 can be thought of as a ‘viral’ community acquired pneumonia. There has been evidence for several years that anti-inflammatory agents e.g. ibuprofen, naproxen (NSAIDs) may worsen community acquired pneumonia. As highlighted in this 2017 paper:

‘Non-steroidal Anti-inflammatory Drugs may Worsen the Course of Community-Acquired Pneumonia: A Cohort Study:

CONCLUSIONS:

Our findings suggest that NSAIDs, often taken by young and healthy patients, may worsen the course of CAP with delayed therapy and a higher rate of pleuropulmonary complications.’ 1

There is now anecdotal evidence, particularly from France, that patients who take NSAIDs do considerably worse. It has been suggested they may lead to an increased death rate.

ADVICE: Avoid NSAIDs if possible

2: Vitamin C

Vitamins always cause massive controversy, and the mainstream medical community tends to be highly critical of the use of vitamins. However, vitamin C has been found to have many, many, positive impacts on the immune system. It also protects the endothelium lining blood vessels – thus preventing/delaying passage of pathogens from the bloodstream.

I include the full abstract from the 2017 paper ‘Vitamin C and Immune Function.’ It contains a great deal of medical jargon, but I have highlighted the most important parts.

Vitamin C contributes to immune defense by supporting various cellular functions of both the innate and adaptive immune system. Vitamin C supports epithelial barrier function against pathogens and promotes the oxidant scavenging activity of the skin, thereby potentially protecting against environmental oxidative stress.

Vitamin C accumulates in phagocytic cells, such as neutrophils, and can enhance chemotaxis, phagocytosis, generation of reactive oxygen species, and ultimately microbial killing. It is also needed for apoptosis and clearance of the spent neutrophils from sites of infection by macrophages, thereby decreasing necrosis/NETosis and potential tissue damage.

The role of vitamin C in lymphocytes is less clear, but it has been shown to enhance differentiation and proliferation of B- and T-cells, likely due to its gene regulating effects. Vitamin C deficiency results in impaired immunity and higher susceptibility to infections. In turn, infections significantly impact on vitamin C levels due to enhanced inflammation and metabolic requirements.

Furthermore, supplementation with vitamin C appears to be able to both prevent and treat respiratory and systemic infections. Prophylactic prevention of infection requires dietary vitamin C intakes that provide at least adequate, if not saturating plasma levels (i.e., 100–200 mg/day), which optimize cell and tissue levels. In contrast, treatment of established infections requires significantly higher (gram) doses of the vitamin to compensate for the increased inflammatory response and metabolic demand.’ 2

In short, Vitamin C can help prevent respiratory infections. It can also help to treat established infections, although much higher doses are required. This seems to fit with emerging Chinese data which appears to be showing considerable success with high dose intravenous Vitamin C in treating coronavirus.

It is unlikely that anyone working in the medical system in the West will agree to using high dose Vitamin C as part of any management plan. However, if your loved one is extremely ill in hospital I would recommend speaking to the doctors and asking if this can be added.

Whilst it is possible that vitamin C may prove ineffective, it also does no harm. Those who are currently attacking the use of Vitamin C and attacking those who believe vitamin C may be beneficial are, I believe, mainly concerned with their personal reputations.

ADVICE: Take at least 2g of Vitamin daily C to ‘prevent’ infection, probably more like 5g. Increase the dose to at least 10g if you are suffering symptoms.

3: ACE-inhibitors/ARBs

COVID-19 appears to enter the body using the ACE2 receptor (found on the surface of many cells, particularly in the lungs. Also found in high concentrations in the heart and kidneys.

Because of its affinity to ACE2 receptors (and the more widespread Renin Aldosterone Angiotensin System or “RAAS”) COVID-19 is causing upset with the whole system – in complex ways. The system itself is complex.

To remind those of a more technical bent, here is the system:

 

I wished to make it clear that if COVID-19 impact on the RAAS system, trying to work out the resultant abnormalities, is not easy.

There are two main drugs that are designed to lower blood pressure by ‘interfering’ with the RAAS system. ACE-inhibitors (angiotensin converting enzyme inhibitors), and ARBs (angiotensin II receptor blockers). They are very widely prescribed.

Some people have suggested that these drugs should be stopped. Others have suggested that they should be continued. You may be able to see why the advice is contradictory, given all the possible interactions.

However, it does seem the COVID-19 creates hypokalaemia (a low blood potassium level). A rising potassium level indicates recovery from the virus. This is probably due to interference with the hormone Aldosterone due to degradation of many ACE-receptors in the body.

ADVICE – currently not enough information to provide any advice on ACE-inhibitors and ARBs. However, increased consumption of potassium, if symptomatic, can be advised. Dose?

People who eat large amounts of fruits and vegetables tend to have a high potassium intake of approximately 8000 to 11,000 mg/d,’ 3

So, up to Ig a day appears perfectly safe, and if more is being lost through the kidneys with COVD-19, there appears to be little danger of overdosage.

4: Chloroquine and Hydroxychloroquine

These drugs normally used to treat/prevent malaria (and are also used to treat various ‘immune’ disease). However, they have been found to be effective in treating other viruses and seem to have been highly effective against COVID-19 4. These drugs will only be available as part of medical management. They cannot be bought over the counter (in any country, as far as I know).

If you, or a loved one, is seriously ill, I would urge you to ask for – one or the other – to be used. Hydroxychloroquine has fewer side effects (drug related adverse effects)

ADVICE – Ask for one of these drugs if you, or a loved one, is seriously ill with COVID-19.

5: Vitamin D

This one is simple. Vitamin D has important effects on the immune system 5. A low vitamin D level in the winter is almost certainly why flu epidemics occur in the winter months. [Vitamin D is synthesized in the sun by the action of sunlight].

ADVICE – take at least 2000iu vitamin (preferably D3) daily.

I hope some people have found this useful. If anything I have written here proves to be wrong, or dangerous, I will change it. However, I am working on the basis here of ‘first, do no harm.’ The worse thing that any of this advice can do, I believe, is to NOT work.

1: https://www.ncbi.nlm.nih.gov/pubmed/28005149

2: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5707683/

3: https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/485434

4: https://www.connexionfrance.com/French-news/French-researcher-in-Marseille-posts-successful-Covid-19-coronavirus-drug-trial-results

5: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3756814/

The Great Placebo scandal

25th February 2020

In this blog I am going to have a closer look at an issue that has niggled away at me for a long time. Placebos. In part I was stimulated to write on this following an article that Maryanne Demasi published on the CrossFit site ‘Sometimes a placebo is not a placebo.’ 1

There are many, many different issues about placebos. Most of which people don’t even consider. Such as, is there really such a thing as the placebo effect? And if there is, how come we haven’t managed to sort out what it actually might be? I know most people reading this will retort. ‘Of course, there’s a placebo effect. It’s a known thing.’ Personally, I am not so sure. Like many known things it begins to fall apart under a bit of critical examination.

For example:

‘Whether you know you’re taking a placebo pill or not, it will still have a beneficial effect, new research has revealed. Scientists from Harvard University and the University of Basel prescribed a group of minor burn victims with a “treatment” cream, telling only some of them that it was a placebo. After the cream was applied, both groups reported benefits, despite the placebo cream containing no medicine.

The study goes against traditional medical thinking surrounding the placebo effect, which has always revolved around the idea that it was necessary to deceive patients in order for “sugar pills” to be clinically effective.’ 2

In short, you get the placebo effect whether you know, or don’t know, that you are receiving a placebo. Which kind of blows a major hole in rationale underpinning double-blind, placebo controlled clinical trials.

However, I am not exploring that particular rabbit hole today.

Today I am going to look at the question. What is in a placebo? You may well believe you know the answer to this. A placebo is an inert formulation containing no active ingredients.

This is a reasonable assumption to make as the medical definition of a placebo, as taken from the Merriam-Webster medical dictionary, is:

‘1a: a usually pharmacologically inert preparation prescribed more for the mental relief of the patient than for its actual effect on a disorder

b: an inert or innocuous substance used especially in controlled experiments testing the efficacy of another substance (such as a drug)’

A few years ago, I was speaking to an investigative journalist from the Netherlands who was trying to get hold of the placebo tablets used in a particular clinical trial. He wanted to establish exactly what was in them, and if they were truly inert. No such luck, these placebos were very carefully guarded, as was any information about what they contained.

He gave up, but I did file his tale in my mind, recognising this was something that needed to be looked in greater detail at some point in the future. Can it be true that placebos are not actually inert?

Surely, it’s possible to ask the pharmaceutical company running the trial what’s in the placebo. Well, you can try. To quote a section of Maryanne’s article

‘The process of obtaining regulatory documents, however, is by no means straightforward. In fact, it is often complicated and time consuming. I have made multiple appeals to a European drug regulator (Medicines Evaluation Board) to obtain information (Certificate of Analysis) regarding the ingredients of a placebo used in a controversial statin study (JUPITER trial), but so far, they have fallen on deaf ears. So, too, have my requests to the trial’s lead investigator, Dr. Paul Ridker.

Medical journals will need to take responsibility and insist that published papers report on the methodological details of “inactive” placebos. Recently, Shader of Clinical Therapeutics stated, “It will no longer be sufficient to simply indicate that a placebo was used.”

“We will require that a full description of any placebo or matched control used in a clinical trial be given in the Methods section. This means that color; type (capsule or pill or liquid); contents (e.g, lactose), including dyes; taste (if there is any); and packaging (e.g, double-dummy) must be noted,” he stated. “We are instituting this change as part of our ongoing effort to facilitate replication of findings from trials. All too often this valuable information is omitted from published trial results.”

In short, you can’t find out what is contained within the placebos. Or at least, it is exceedingly difficult – to impossible.

This is very disturbing indeed, because it has become increasingly clear that placebos are often far from inactive or inert. In fact, they often contain some quite unpleasant substances. For example, here from an article in Medical News Today

‘The authors outline an example where a particular placebo skewed the results of several studies. In studies that investigated oseltamivir, which people may know by its brand name Tamiflu, scientists often added dehydrocholic acid to the placebo.

Dehydrocholic acid has a bitter taste, as does oseltamivir. The researchers chose to add this chemical to the placebo so that the participants would not know whether they had received the active drug or the placebo.

However, both dehydrocholic acid and oseltamivir cause gastrointestinal side effects. When scientists attempted to calculate the rate of gastrointestinal side effects due to oseltamivir, they compared them with side effects from the placebo.

As the placebo also caused these types of symptoms, scientists underestimated the overall gastrointestinal side effect rate for oseltamivir.3

Essentially, and you may find this rather shocking, a company doing a clinical trial can stick almost any nasty substance they like into a placebo and tell no-one. There are no regulations to prevent this happening, or at least none that I can find.

From time to time, however, the secret ingredients are revealed, or discovered, such as dehydrocholic acid. Here is Maryanne on the Gardasil (HPV) vaccine. In this case the ‘secret ingredient’ in the placebo was also identified.

‘In trials of the human papilloma virus (HPV) vaccine, participants were told they were either receiving a “vaccine or placebo.” The vaccine manufacturer defines a placebo as an “inactive pill, liquid, or powder that has no treatment value.”

However, participants in the placebo group did not receive an inactive substance of no treatment value. “Instead,” RIAT researchers state in the BMJ, “they received an injection containing amorphous aluminium hydroxyphosphate (AAHS), a proprietary adjuvant system used in the Gardasil vaccine to boost immune response.” 4

[RIAT = Restoring invisible and abandoned trials. Good people]

This is worrying. Many of those who are concerned about the potential for vaccine damage, believe it may well be the amorphous aluminium hydroxyphosphate (AAHS) itself which is the substance that can cause the adverse effects seen with many vaccines.

If both placebo, and vaccine, contain this adjuvant, then… it’s a free pass for the vaccine. In order to hide adverse effects with the vaccine, the placebo contained the substance suspected to cause adverse effects. Anyone who thinks that is remotely acceptable needs a long hard look in the mirror…

However, important thought it may be, it is time to move onto my favourite subject, statins – and placebos. For years I been highly suspicious of the adverse effect rates seen in the statin clinical trials. My concerns, and the concerns of others, formed part of a letter written to the then Health Secretary (Jeremy Hunt), and also to the National Institute for Health and Care Excellence 5

Here was the section on adverse events:

  1. Conflicting levels of adverse events

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

The levels of adverse events reported in the statin trials contain worrying anomalies. For example, in the West of Scotland Coronary Prevention Study (WOSCOPS, the first primary prevention study done), the cumulative incidence of myalgia was 0.6% in the statin arm, and 0.6% in the placebo arm*

However, the METEOR study found an incidence of myalgia of 12.7% in the Rosuvastatin arm, and 12.1% in the placebo arm

Whilst it can be understood that a different formulation of statin could cause a different rate of myalgia, it is difficult to see how the placebo could, in one study, cause a rate of myalgia of 0.6%, and 12.1% in another. This is a twenty-fold difference in a trial lasting less than half as long*.

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

However, here is a short selection of major statins studies.

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

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

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

HPS: Discontinuation rates simvastatin 4.5%: Placebo 5.1%

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

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

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

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

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

How can the adverse effects of placebo range from 2.7% to 80.4%? Yes, there can be differences in the way that adverse effects are recorded, and that could explain, perhaps a five-fold difference – being extremely generous. But a thirty-fold difference?

Also, how can it be possible that the adverse effects of the placebo, and the statin, are always, almost exactly the same, in all trails – no matter the absolute figure. I believe that this could not possibly occur unless:

  • The placebos in each trial were carefully formulated to cause adverse effects at the same rate as the statin
  • The statistics on adverse effects were manipulated

Neither possibility should fill anyone with joy, nor confidence in the regulatory systems.

I have raised this issue with a number of different people, but they all seem determinedly disinterested. I suppose that if either of my two statements are true, it means that the entire database of randomised double-blind placebo-controlled trials can no longer be trusted. This is not a nettle to be grasped. It is a fifty-thousand-volt power line with a sign reading ‘Danger of Death!’ attached.

I can well understand the reluctance to investigate. However, I do not believe that we can possibly allow the formulation of placebos to remain a well-kept secret in future, current, or past trials.

If my suspicions about placebos are wrong, then can someone please prove me wrong.

*in the letter I had calculated this figure wrongly. It was not 0.06%, it was 0.6%. So, I have changed the text in the blog to reflect that.

1: https://www.crossfit.com/health/sometimes-a-placebo-is-not-a-placebo

2: https://www.independent.co.uk/life-style/health-and-families/placebo-pills-work-no-medication-know-even-treatment-study-harvard-basel-a7969716.html

3: https://www.medicalnewstoday.com/articles/326505#Problems-with-placebos

4: https://www.bmj.com/content/346/bmj.f2865/rr-7

5: https://www.nice.org.uk/Media/Default/News/NICE-statin-letter.pdf

A podcast you may want to listen to

9th February 2020

The good thing about having different ideas about diet, obesity, diabetes and heart disease and suchlike, is that you get to meet with such interesting people. Steve Bennett is one such. He set up successful businesses, that have nothing whatsoever to do with health, and only came to diet and health from his own interest and passion.

He then established a brand called Primal Living, based on eating food that we used to eat in the past. Woolly mammoths and suchlike and avoiding processed foods and carbs. In addition taking supplements that have been removed from our diet by the mass food manufacturing industry. It has improved his own health, and the health of many others.

He is, essentially, on the same pathway as Aseem Malhotra, Tim Noakes, Ivor Cummins, Zoe Harcombe, Gary Taubes, David Unwin – and anyone else who has looked at diet, and health, and possess a fully functioning brain.

They have all – we have all – recognised that the current dietary guidelines are complete dangerous bunk, doing harm rather than providing benefit.

He was also good enough to allow me to outline my ideas on CVD, and the process of CVD, which his team has put together into a podcast. It can now be seen here https://podcasts.apple.com/gb/podcast/fat-furious/id1495158540

As always, I feel I have not really explained things as well as I can, but I hope you find it interesting, and I would welcome feedback and constructive criticism. I would further recommend looking at the other podcasts under the ‘Fat and Furious’ banner.

Coronary artery calcification (CAC)

17th January 2020

I thought I should write a blog on coronary artery calcification (CAC), as it has become the latest hot topic. CAC scans, and CAC scoring are now increasingly popular, and the results are worrying lots of people who wonder what they mean, and exactly how worried they should be. I get many e-mails on this issue from people who have been scared witless, or another word ending in***tless, by having a high CAC score.

What is coronary artery calcification

Coronary artery calcification (CAC) is the deposition of calcium in artery walls. It represents the final stages in the life cycle of some/many/most atherosclerotic plaques. At the risk of oversimplification, it is generally accepted that atherosclerotic plaques go through four stages

  • Small
  • Bigger
  • Vulnerable
  • Calcified

Forget small and bigger. The important ones are vulnerable and calcified. What is a vulnerable plaque? It is a plaque that reaches a certain size (undefined) containing an almost liquid core, with a thin cap. If this thin cap ruptures, it exposes the liquid core to the bloodstream triggering a major blood clot than can fully block a coronary artery and cause a myocardial infarction.

This is generally described as plaque rupture. If it happens in an artery in the neck, a carotid artery, the clot will normally not be big enough to block the artery. But it can break off and head up into the brain, causing a stroke.

Which means that it is these ‘vulnerable’ plaques that are dangerous, and these are often not calcified, and therefore cannot be seen on a CAC scan.

Over time, assuming the vulnerable plaques do not rupture and kill you, some of them (all of them?) shrink down in size, become more solid and start to calcify. At which point they are less likely to rupture and may be considered relatively benign.

Calcification of areas of damage in the body is not restricted to atherosclerotic plaques. Almost any damaged area in the body, that is not perfectly repaired, is likely to calcify to some extent or another. Scars tend to be white, and the white is calcium.

At the extreme end of calcification is a condition called myositis ossificans, whereby almost any damage ends up becoming bone. With damaged muscle turning into bone. This does not end well.

Anyway, assuming you have plaques developing and growing in your arteries, they will in time calcify. Or at least some of them will. Are some people genetically more likely to get calcification than others? Almost certainly.

Some things are known to increase the rate of calcification. Statins, for example. Here from the Cleveland clinic:

  • Patients with coronary artery disease (CAD) who are treated with statins experience an increase in coronary calcification, an effect that is independent of plaque progression or regression.
  • Paradoxically, high-intensity statin therapy is associated with the largest increases in coronary calcification despite promoting atheroma regression 1

With statins the plaques get smaller and the calcium load gets bigger.

Another drug that whacks up the rate of calcification is warfarin (often called coumadin in the US).

‘The vitamin K antagonist, warfarin, is the most commonly prescribed oral anticoagulant. Use of warfarin is associated with an increase in systemic calcification, including in the coronary and peripheral vasculature. This increase in vascular calcification is due to inhibition of the enzyme matrix gamma-carboxyglutamate Gla protein (MGP). MGP is a vitamin K-dependent protein that ordinarily prevents systemic calcification by scavenging calcium phosphate in the tissues.’ 2

High intensity exercise also stimulates CAC.

‘Emerging evidence from epidemiological studies and observations in cohorts of endurance athletes suggest that potentially adverse cardiovascular manifestations may occur following high-volume and/or high-intensity long-term exercise training, which may attenuate the health benefits of a physically active lifestyle. Accelerated coronary artery calcification, exercise-induced cardiac biomarker release, myocardial fibrosis, atrial fibrillation, and even higher risk of sudden cardiac death have been reported in athletes.’ 3

An interesting mix, I think.

  • Statins increase calcification
  • Warfarin increases calcification
  • Intense exercise increases calcification

Yet, all three reduce the risk of dying of cardiovascular disease. Yes, even statins – a bit.

But, let’s turn this around for a second. If you have no calcification in your arteries, you have a greatly reduced risk of dying of cardiovascular disease. Which means that calcification can be both good, and bad? Yes, you are right, this area is not straightforward at all.

Even if you look at non-calcified atherosclerosis, or pre-calcified atherosclerosis, the picture is complex.

For many years I have studied the Masai villagers, on and off. They are fascinating because, amongst Masai males, the diet almost entirely consists of cholesterol and saturated fat – or at least it did. Nowadays, I believe it is more McDonalds and Subway.

Despite their previous super-high saturated fat and cholesterol diet, their cholesterol levels were the lowest of any population studied. However, they developed atherosclerosis at around the same rate as any Western male of the same age.

Added to this, and just to make things even more complicated, there were no recorded cases of any male Masai villagers dying of CVD. Which made me think, at one time, that atherosclerosis and death from CVD must be unrelated phenomenon.

You think not? Here, for example, is a study on the Masai from 1971 by George Mann (who helped to set up the Framingham Study and then became a trenchant critic of the cholesterol hypothesis).

Atherosclerosis in the Masai

‘Do the Masai not develop atherosclerosis or do they have it but remain immune to occlusive disease because of some other protective circumstances? The question was answered with autopsy material collected over a five-year period. The Masai do have atherosclerosis but they are almost immune to occlusive disease.’ 4

Now, if we bring these facts together, what do they tell us. At the risk of running the thinking too fast, these facts tell us that atherosclerosis, calcified or not, is necessary for someone to die from CVD. However, it is not sufficient, by itself, to cause death from occlusive disease.

In epidemiology this is the well-recognised concept of ‘necessary but not sufficient’. It actually applies to many/most diseases. For example, you cannot get TB, or die of TB, without infection with the tuberculous bacillus. However, you can be exposed to the bacillus and not have TB.

Why, because your immune system fought it off. Which means that the tuberculous bacillus is necessary but not sufficient, to cause infection and death from TB. As a slight aside, one sign of TB is calcified nodes in the lungs. Which can mean that you have active TB. Alternatively, it can mean that you had active TB, which has now been cleared out, leaving only calcification.

Turning back to atherosclerosis, and using the Masai as one example, it is clear that you can get atherosclerosis, and calcified atherosclerosis, and not die of CVD, or even have an increased risk of CVD. Why, because other factors are required to kill you. Which is why it can be said that atherosclerosis is necessary, but not sufficient, to cause heart attacks and strokes.

To put this another way, you are exceedingly unlikely to die from an acute blockage to an artery without any atherosclerosis [or at least this is vanishingly rare], but just having atherosclerosis is not sufficient to cause heart attacks and strokes.

Which means that for example, if your atherosclerosis is (only) caused by intense exercise you are at no significant increased risk of dying CVD. In this case your calcified atherosclerosis is not sufficient to cause CVD.

‘A new study of mostly middle-aged men in JAMA Cardiology found the most avid exercisers—averaging eight hours per week of vigorous exercise—did indeed show greater levels of coronary artery calcium (CAC). Nevertheless, they were less prone to dying over the average follow-up period of 10.4 years compared to men who exercised less, suggesting they can safely continue their workout regimens. 5

However, if your CAC score has gone through the roof because of say: diabetes, smoking, steroid use, air pollution, heavy metal toxicity, high Lp(a), lack of various nutrients etc. then you are at great risk of dying of CVD, and you need to do something about it.

Further complications

At one time atherosclerosis was defined as either athero…sclerosis, or arterio…sclerosis, in acknowledgement that there seem to be two distinct and different type of …sclerosis in your arteries. This concept seems to have fallen by the wayside.

This may be a mistake. Some years ago, the AHA tried to define all the different types of lesion* that could be found in arteries. The report was so big, that it got split in two 6.7. Then it got ever bigger, and then they gave the project up. The reports are long, and mind splittingly boring. One of them was a ‘twenty cups of coffee’ read. Followed by three Red Bulls.

(*lesion = abnormal thing)

What I learned, I think, in the moments when I was still conscious, was that atherosclerotic plaques are most certainly not all the same. Which lead me to think that we should attempt to bring back arteriosclerosis as a concept.

By which I mean the idea that some plaques develop, primarily, in response to biomechanical stress – such as is caused by physical exercise. On the other hand, some plaques develop in response to factors that independently damage the endothelium – such as a high blood sugar level, or smoking. With the addition of high clotting factors.

Whilst all plaques are now called atherosclerotic plaques, they do not all look the same, and they probably do not act the same. The arteriosclerotic lesions are thinner and more fibrous, they have no real lipid core and are very unlikely to rupture. They are, still, sometimes called fibroatheroma.

On the other hand atherosclerotic lesions are thicker, have a lipid core, more likely to narrow the artery and are also more likely to rupture, causing an occlusive blockage – leading to a stroke and/or heart attack.

Which is why the Masai (the most heavily exercising population on the planet – at the time) had …sclerosis yet remained ‘almost immune to occlusive disease’. Which is also why people who exercise intensely can develop …sclerosis and calcification but are not at an increased risk of dying of CVD.

However, both arterio and athero… sclerosis can calcify. So, they (probably) look much the same on the CAC san.

Moving on, again.

Sensitivity and specificity

Getting back to the CAC test, and what it means. The next issue is one that plagues all screening tests. Namely, what is the sensitivity, and what is the specificity? Something I always get the wrong way around in my head, then I must go back and look it up, to get it clear again.

To explain. A perfect screening test is one that is 100% sensitive and 100% specific. No test has ever achieved that, and I doubt any test ever will.

Sensitivity means, how good is the test at picking up that someone with the disease is identified as having the disease. Specificity means, how good is the test at making sure that people who do not have the disease are accurately told that they do not.

If we look at breast cancer, the first sign of breast cancer can often be that a woman feels a lump in her breast. However, many things that are not breast cancer, can cause a lump in the breast. Let us say 50% of palpable lumps are not breast cancer. If this is true, then the specificity of manual examination of the breast, in detecting breast cancer, would be 50%.

What of mammography? While it is clearly much better than manual palpation (from a sensitivity point of view) many cancers that cannot be felt, can still be seen on a scan, but it is actually worse from a specificity point of view.

This is because many/most ‘abnormal’ things seen on a mammogram will turn out to be benign. Sensitivity and specificity are often inversely related.

Some things sit in an intermediate area. In breast cancer screening a lot of women are told they may have breast cancer, but what has been detected is an abnormality called ductal carcinoma in situ (DCIS). This is something that may, or far more likely may not, progress to become a significant breast cancer. Should it be treated, or not?

The specificity problem is a problem for almost all screening tests. You have managed to find something abnormal on your test. Is it really abnormal? Does it need treatment? Would it have been better not to have found this ‘abnormality’ at all.

This is not a simple argument. Although it is usually presented in the most black and white terms if you question the breast cancer screening programmes. ‘Do you want women to die of breast cancer?’ Is a statement I have often heard from the pro-screening side. How does one answer this? ‘Well, of course I do. I see it as my role, as a doctor, to ensure that as many women as possible die from breast cancer.’

The real debate, of course, is far more complex and nuanced. Do the harms of finding benign abnormalities (with all the anxiety, further investigations, possible mastectomies etc. that this causes) outweigh the benefits of finding breast cancer at an early stage? Currently, the answer seems to be … yes.

If you want a far more detailed review of this area, you could buy the book ‘Mammography Screening’ by Peter Gøtzsche.

‘If Peter Gøtzsche did not exist, there would be a need to invent him … It may still take time for the limitations and harms of screening to be properly acknowledged and for women to be enabled to make adequately informed decisions. When this happens, it will almost entirely due to the intellectual rigour and determination of Peter Gøtzsche.’ Iona Health President RCGP (Royal College of General Practitioners)

Screening and scanning always seems a fantastic idea. Pick up a disease early, then you can treat it, even cure it. Presented in this, the simplest form, who could argue against it?

But it is not simple, in medicine very few things are. Breast cancer screening – in fact most cancer screening programmes – are far from black and white. You can argue for them, you can argue against them.

And, at present, cancer screening programmes are much better than CAC screening, for many other reasons. I will only deal with the most important one. Which is that… We don’t know what to do about the finding!

If you find a small, early stage, not yet spread anywhere, breast cancer you can remove it. It is gone, never to return. But what are you going to do with calcified plaques? You certainly can’t remove them. You do not know if they are going to rupture. They probably won’t. If you manage to stop the calcification getting worse, are you doing any good. Who knows? What caused them in the first place?

It is not even the calcified plaque that is the problem. The calcified plaque is only really a marker for earlier stage vulnerable plaques. If these start to calcify, this is probably a good thing, but whilst calcification is going on, the CAC score will be getting worse – while your risk of suffering a myocardial infarction is falling.

Sensitivity and specificity, false positives – and CAC scans (Pandora’s box)

My first general comment here is that you should never start screening and scanning until you are extremely certain, based on strong evidence, that you understand the natural history of the disease you are screening for.

Also, that you fully understand what the results of your test mean. And that you have an effective treatment for any abnormality you find.

These criteria are all missing with CAC scans.

Yes, a negative scan – no calcium detected – has reassurance value. If you have no calcium in your arteries, you almost certainly do not have any type of …sclerosis in your arteries. So, your risk of CVD is low.

However, positive scans, like positive mammograms, will include a very high number of false positives. Then what? You have been told you have significant calcification in your arteries. But it is ‘good’ calcification, or ‘bad’ calcification. Are you at increased risk, or not? This, no-one can tell you, for sure.

Equally, if you have calcification in your arteries, what are you going to do about it? Take statins… that makes it worse. Do more exercise…. that makes it worse. If you don’t know why you have calcification in the first place, it becomes impossible to take steps to do anything about it.

This is somewhat analogous to having a genetic test to discover if you have Huntington’s Chorea – if one of your parents had it. Do you want to find out that you have a disease – which will kill you – that you can do absolutely nothing about?

In a similar way should you have a test for Alzheimer’s, to find out if you are going to get the disease. Do you really want to know that you are going to have a terrible and devastating disease, and that there is nothing that can be done to prevent it?

In fact, CAC scans meet most of my criteria for ‘a bloody awful test that should not be done.’ It may or may not mean anything, there is no clear guidance as to what you can do about it if it is positive, and it spreads fear and anxiety in many, many, people. I should know, my inbox is stuffed with e-mails from people terrified by their CAC score.

Recommendations

My first recommendation is that, if you have not had a CAC scan, do not have one.

My second recommendation is that, if you have had a CAC scan, and it shows no calcification, good. Do not have another one.

If, however, you have had a CAC scan and it shows significant calcification. What then? What then indeed? You may want to read this paper: ‘Non-invasive vulnerable plaque imaging: how do we know that treatment works?’

‘Atherosclerosis is an inflammatory disorder that can evolve into an acute clinical event by plaque development, rupture, and thrombosis. Plaque vulnerability represents the susceptibility of a plaque to rupture and to result in an acute cardiovascular event. Nevertheless, plaque vulnerability is not an established medical diagnosis, but rather an evolving concept that has gained attention to improve risk prediction. The availability of high-resolution imaging modalities has significantly facilitated the possibility of performing in vivo regression studies and documenting serial changes in plaque stability. This review summarizes the currently available non-invasive methods to identify vulnerable plaques and to evaluate the effects of the current cardiovascular treatments on plaque evolution.’ 8

It will, at least, give you some idea of the other forms of investigation that are available.

Or, you might want to read this one: ‘New methods to image unstable atherosclerotic plaques.’

‘Atherosclerotic plaque rupture is the primary mechanism responsible for myocardial infarction and stroke, the top two killers worldwide. Despite being potentially fatal, the ubiquitous prevalence of atherosclerosis amongst the middle aged and elderly renders individual events relatively rare. This makes the accurate prediction of MI and stroke challenging. Advances in imaging techniques now allow detailed assessments of plaque morphology and disease activity.

Both CT and MR can identify certain unstable plaque characteristics thought to be associated with an increased risk of rupture and events. PET imaging allows the activity of distinct pathological processes associated with atherosclerosis to be measured, differentiating patients with inactive and active disease states. Hybrid integration of PET with CT or MR now allows for an accurate assessment of not only plaque burden and morphology but plaque biology too.

In this review, we discuss how these advanced imaging techniques hold promise in redefining our understanding of stable and unstable coronary artery disease beyond symptomatic status, and how they may refine patient risk-prediction and the rationing of expensive novel therapies.’ 9

The key words in that abstract are ‘hold promise.’

My final recommendation is that we should NOT be doing CAC scans, until it can be proved in a well conducted clinical trial, that we can do something positive and beneficial about the findings.

Yes, a ‘negative’ CAC is reassuring. This, however, must be set aside against the psychological damage caused by a ‘positive’ CAC scan. At present we are playing a form of psychological Russian Roulette. Half the population walks away reassured, half the population reels away, scared witless.

Also, often puzzled and disappointed. I have lost count of the number of people who have written to me saying that they: don’t smoke, exercise regularly, are not overweight, have low cholesterol levels, do not have high blood pressure, do not have high blood sugar levels, etc. etc. yet they have a terrifyingly high CAC score. What should they do?

Well, what can they do?

I don’t know. Because I don’t know what the test means. Not for sure. Not enough to provide any advice that I can be certain is right. Some boxes are better left unopened, however tempting it may be to peek inside.

Just because you can do something does not mean that you should.

1: https://consultqd.clevelandclinic.org/plaque-paradox-statins-increase-calcium-in-coronary-atheromas-even-while-shrinking-them/

2: https://www.amjmed.com/article/S0002-9343(15)30031-0/pdf

3: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6132728/

4: https://thescienceofnutrition.files.wordpress.com/2014/03/atherosclerosis-in-the-masai.pdf

5: https://www.cardiovascularbusiness.com/topics/lipids-metabolic/intense-exercise-protective-even-cac

6: https://pdfs.semanticscholar.org/cff1/77c1afc2cd00f6db27cf498cb1d05933ec55.pdf

7: https://www.ahajournals.org/doi/full/10.1161/01.CIR.92.5.1355

8: https://academic.oup.com/ehjcimaging/article/15/11/1194/2399586

9: https://www.atherosclerosis-journal.com/article/S0021-9150(18)30135-7/pdf

 

 

Another new study

23rd December 2019

Another new study

Question: If a tree falls in the forest, and there’s nobody around to hear, does it make a sound?

This is a philosophical question that has been around for some time. I shall change it slightly to the following: “If a journal publishes a study, and it doesn’t make a noise, can it make a difference?”

A couple of weeks ago the Lancet published a ridiculous study with the snappy title:

‘Application of non-HDL cholesterol for population-based cardiovascular risk stratification: results from the Multinational Cardiovascular Risk Consortium.’

Which created headlines around the world – most of which failed to understand the difference between LDL (‘bad’ cholesterol) and non-HDL cholesterol. Which may, or may not, have been deliberately done.

This study was reported as saying that twenty-five-year olds should get their cholesterol checked, because raised cholesterol is far more damaging, at a young age, than previously thought. All based on, pretty much nothing at all. I critiqued it in my last blog. It was, to use a word I rather like … bilge!

Then another study came out last week to which I was pointed by a reader of this blog… thanks. It had the even snappier title:

‘Association between hyperlipidaemia and mortality after incident acute myocardial infarction or acute decompensated heart failure: a propensity score matched cohort study and a meta-analysis.’ 1

You know that title really does not scream ‘READ ME!’ What is it about medical journals, and medical writing, which demands all enthusiasm and interest is sucked out, leaving only the driest, of dry, husks. I call it mummified prose.

What I first noticed was that it did not appear to make any headlines, anywhere, at all. Of course, making enough noise to be heard, in today’s jittery, overloaded information world, takes a lot of money and effort. Which is why the Lancet study got blanket coverage. Someone, somewhere, will have been paid a lot of money to ensure that it happened.

The money was paid because there are people who stand to make billions and billions from increased cholesterol testing, including younger people, and suggesting that “raised” cholesterol must be ‘treated’ from an ever-younger age. Perhaps you would like to guess who those people may be.

On the other hand, the study ‘Association between hyperlipidaemia and mortality after incident acute myocardial infarction or acute decompensated heart failure: a propensity score matched cohort study and a meta-analysis.’ could result in the loss of billions and billions.

Because what they found, was that, after an acute myocardial infarction (AMI), and in people with acute decompensated heart failure (ADHF) – normally caused by a previous MI – the higher the LDL level, the lower the overall mortality. They called a higher LDL level hyperlipidaemia (HLP), but it was a high LDL a.k.a. ‘bad’ cholesterol.

The ‘association’ of which they spoke, is in the exact opposite direction to that in the Lancet study. Just to repeat their main finding. Those with higher LDL levels lived the longest. Full stop, exclamation mark.

They set the study up to consider the following questions – I make no excuses for the jargon here:

‘We postulated that if a diagnosis of HLP [Hyperlipidaemia] decreases the mortality after AMI or HF [Heart Failure], then, it also lessens the magnitude of mortality risks associated with other competing comorbidities.

We tested this hypothesis, separately, in large cohorts of patients hospitalised for incident AMI and acute decompensated HF (ADHF). To compare patients with and with no HLP, we assembled 1:1 balanced groups using propensity score-matching for each study condition.

Our objectives were three-fold:

(1) to estimate the association of HLP with all-cause mortality among patients with AMI or ADHF,

(2) to determine the extent to which the association between other competing comorbidities and mortality is modified by HLP

(3) and to provide risk estimates for mortality associated with HLP after incident AMI or HF through systematic review and meta-analyses of published and current study data to place the current findings in the context of published literature.’

Here were the main results. First for those diagnosed with AMI:

  • In matched patients, mortality was significantly lower among patients with Hyperlipidaemia (HLP) versus those with no Hyperlipidaemia (HLP)
  • Overall mortality 2182 (50.2%) vs 2718 (62.5%)
  • 5.9 vs 8.6 deaths/100 person-years of follow-up, p<0.0001.

Next for those diagnosed with acute decompensated heart failure (ADHF):

  • In matched patients, mortality was significantly lower among patients with HLP versus those with no HLP
  • Overall mortality 1687 (58.6%) vs 1948 (67.7%)
  • 12.4 vs 16.3 deaths/100 person-years of follow-up, p<0.0001.

You may have noted that the mortality rate in these patients was very high. For those with ADHF, and lower cholesterol levels (LDL levels), the mortality rate was 16.3 deaths per 100 person years. That is a sixteen point three per-cent death rate per year. One in six.

This, therefore, is a super, exceptionally high-risk population. It is also a super exceptionally high-risk secondary CV prevention population. The exact group where statins are purported to do the most good – through the specific action of lowering LDL levels.

At this point, a short detour. I know any cardiologist reading this will be thinking – or has been taught to think: “Yes, but low cholesterol is a sign of other serious conditions, such as cancer. Ergo, it is not the low cholesterol that is damaging, it is the other underlying conditions”.

This ‘fact’ been stated for many years – without a single scrap of evidence to support it.

It was Stamler who first came up with this ‘apologia’ for much contradictory evidence about low LDL levels and increased mortality. Like many things in medicine it is universally believed, without any supportive evidence. It is true that in a very few cases, late stage terminal cancer, and late stage liver failure, the LDL levels can drop. Otherwise … nothing.

However, these researchers made sure they adjusted for this, non-existent, factor anyway.

‘Our findings were adjusted for cancer and numerous other Clinical Conditions.’

What were the conclusions of this study? Well, they were exceptionally carefully worded.

‘The findings of this study, if validated, should reinforce the importance of HLP in predicting long-term mortality after index AMI or ADHF and potentially provide guidance for subsequent management. HLP can readily be diagnosed and help recognise AMI and HF patients with lower long-term mortality.

In these patients, clinical care should not focus on certain lipid targets; rather evidence based secondary prevention strategies should be initiated.

Conversely, patients with AMI and ADHF without HLP may be considered to have increased risk for early mortality and potentially alert providers for close monitoring during hospitalisation and after discharge. Both categories of patients would profit from thoughtful tailored programme with distinctive goals of care for existing CCs.’

Let me cut to the key comment in that passage. That is, the comment regarding those patients who had HLP:

Clinical care should not focus on certain lipid targets

Clinical care should not focus on certain lipid targets

Clinical care should not focus on certain lipid targets

I thought it was so good, I should say it thrice, for that makes it true. According to Lewis Carroll anyway.

“Just the place for a Snark!” the Bellman cried,

   As he landed his crew with care;

Supporting each man on the top of the tide

   By a finger entwined in his hair.

“Just the place for a Snark! I have said it twice:

   That alone should encourage the crew.

Just the place for a Snark! I have said it thrice:

   What I tell you three times is true.”

Of course, the comment is couched in such diplomatic language that I am not absolutely sure what is meant by it, although I am pretty sure.

On that basis, I shall wind up the emotion of the language somewhat. ‘These poor people, who are dreadfully ill, who have suffered the agony of a heart attack, or severe heart failure, fare so much better when they have a high LDL level. So, for pity’s sake, I beseech thee in the name of God, do not try to lower their LDL level you mad fools. Aaaaaarrrrrrrrggggghhhhh! Gasp, bonk.’

Maybe a touch too emotive? Oh well – after reading too many clinical papers, the temptation to shout become irresistible. Creeping around in the grey and lifeless world of the passive voice is not really my style. Science should not be a place of hushed diplomacy. Science should be lively and stimulating, nay argumentative. If you’ve got something to say, shout it out. Fight for it and debate it properly.

Anyway, my original question was the following. ‘If a journal publishes a study, and it doesn’t make a noise, can it make a difference?’ The answer is, almost certainly, no. Hopefully, however, I have now made a bit of noise, and maybe this study can make a bit of difference.

1: https://bmjopen.bmj.com/content/bmjopen/9/12/e028638.full.pdf

The Lancet Study

11th December 2019

Several people have asked me to comment on a recent Lancet paper ‘Application of non-HDL cholesterol for population-based cardiovascular risk stratification: results from the Multinational Cardiovascular Risk Consortium.’ which made headlines around the world. Here – for example – from the BBC website:

What did the researchers find?

People should have their cholesterol level checked from their mid-20s, according to researchers. They say it is possible to use the reading to calculate the lifetime risk of heart disease and stroke.

The study, in The Lancet, is the most comprehensive yet to look at the long-term health risks of having too much “bad” cholesterol for decades. They say the earlier people take action to reduce cholesterol through diet changes and medication, the better.

They analysed data from almost 400,000 people from 19 countries and found a strong link between bad-cholesterol levels and the risk of cardiovascular disease from early adulthood over the next 40 years or more.

They were able to estimate the probability of a heart attack or stroke for people aged 35 and over, according to their gender, bad-cholesterol level, age and risk factors such as smoking, diabetes, height and weight, and blood pressure.

Report co-author, Prof Stefan Blankenberg, from the University Heart Center, Hamburg, said: “The risk scores currently used in the clinic to decide whether a person should have lipid-lowering treatment only assess the risk of cardiovascular disease over 10 years and so may underestimate lifetime risk, particularly in young people.” 1

The Daily Mail in the UK was a bit more excitable in its reporting

‘Adults ‘should have their cholesterol checked at 25’ because slashing it in the mid-30s can drastically reduce the risk of heart attacks and strokes

Researchers predicted huge 30-year risk profiles for heart disease and stroke, they found higher cholesterol in under-45s is more dangerous than in over-60s Even young people with healthy lifestyles ‘may benefit from knowing their risk.’ 2

My first thought, as always, is to look for the conflict of interest statement, just so you know how independent the researchers may be and make an estimate of potential bias.

My second thought was that this study did not look at cholesterol levels, or HDL levels, it looked at non-HDL cholesterol. An interesting thing to study. This is every form of liver derived lipoprotein that is not HDL, otherwise known as ‘good cholesterol’ or simply high-density lipoprotein.

Part of the reason for not looking at LDL, is that LDL is very rarely measured, or reported. Because the only way to measure LDL accurately is through ultracentrifuge, which is time consuming and expensive. Normally, the LDL levels are simply estimated using the Friedwald equation. To quote from the UK GP Notebook

‘… the ultracentrifugal measurement of LDL is time consuming and expensive and requires specialist equipment. For this reason, LDL-cholesterol is most commonly estimated from quantitative measurements of total and HDL-cholesterol and plasma triglycerides (TG) using the empirical relationship of Friedewald et al.(1972).

[LDL-chol] = [Total chol] – [HDL-chol] – ([TG]/2.2) where all concentrations are given in mmol/L (note that if calculated using all concentrations in mg/dL then the equation is [LDL-chol] = [Total chol] – [HDL-chol] – ([TG]/5))3

*TG = triglyceride

This means that the researchers will not have had any data on LDL levels for most people. The difficulty of directly measuring LDL is the reason why the risk calculators used in the UK and US do not even include LDL. These calculators are Qrisk3 https://qrisk.org/three/ and cvriskcalculator http://www.cvriskcalculator.com/

So, it is important to note that this was not a study on LDL levels. Instead, it was a study on non-HDL levels. Which changes it into something completely different than was reported. Obviously, non-HDL levels bear some relationship to LDL, in that a higher LDL level will tend to raise the overall non-HDL cholesterol level.

However, and very importantly, non-HDL also includes the triglyceride (TG) level. Or at least the TG level divided by 2.2. This is important because a high triglyceride (TG) level, divided by 2.2 or not, is a strong indicator of insulin resistance, which leads to type II diabetes. Here is what WebMD has to say on the matter

‘High TG’s signals insulin resistance; that’s when you have excess insulin and blood sugar isn’t responding in normal ways to insulin. This results in higher than normal blood sugar levels. If you have insulin resistance, you’re one step closer to type 2 diabetes.’ 4

Insulin resistance, whether or not it has developed into type II diabetes, greatly increases your risk of both CVD and overall mortality, as outlined in the paper. ‘Triglyceride–to–High-Density-Lipoprotein-Cholesterol Ratio Is an Index of Heart Disease Mortality and of Incidence of Type 2 Diabetes Mellitus in Men.’

‘This study shows that a high TG/HDL-C ratio in men is a predictor of mortality from CHD and CVD. The TG/HDL-C ratio had a significant and higher HR [hazard ratio] for mortality from CHD and CVD than was found for the TyG index [fasting blood sugar]. These 2 measures, TG/HDL-C ratio and TyG index, similarly predicted incidence of type 2 diabetes, but the HR associated with a high TG/HDL-C seems to make the ratio a preferred single parameter of measurement.’ 5

You will get no argument from me that a high triglyceride level is going to indicate the underlying metabolic catastrophe that is insulin resistance. This, in turn, is going to greatly increase the risk of CVD and early death. But this will have nothing to do with the LDL level. So, it has nothing to do with ‘bad’ cholesterol. Instead is to do with triglycerides.

Therefore, this study is like looking at people who smoke, and who eat red meat, then stating that red meat consumption and smoking cause lung cancer. You have arbitrarily rammed two things together without making any effort to decided which causes what. Scientific nonsense.

There also some massive statistical problems with this study. Where, for example is overall mortality? Not mentioned. Not mentioned means it will not have been significant. Also, the use of a very wide and fuzzy ‘combined end-point.’ I have written about this many times, in many different places. It is a game played to claim statistical significance, where none really exists.

To try and explain as quickly as possible. The most powerful end-point is overall mortality i.e. how many people were dead in either group. Or, to be more positive, how many people were alive in either group.

After this come end-points of decreasing importance. For example, how many people died of CVD. This is clearly important, but if more people died of CVD in one group, yet they were less likely to die of cancer, the overall mortality could remain the same in both groups – even if CVD mortality were lower in one.

Group one

  • CVD deaths 150
  • Cancer death 150
  • Total deaths/mortality 300

Group two

  • CVD deaths 180
  • Cancer death 120
  • Total deaths/mortality 300

Net benefit = zero. But such results can often be hailed as a massive success for, say, a drug. For example, the ‘FOURIER’ study on Repatha (injectable LDL lowering agent) was hailed as a great success, despite overall mortality being higher in the Repatha arm. How, you may think, was this possible?

Well, the Fourier study had five end-points. Known as a ‘combined end-point’. [Mortality was not one of them.] The primary end point was the combined total of:

  • Cardiovascular death
  • MI (myocardial infarction)
  • Stroke
  • Hospitalization for unstable angina
  • Coronary revascularization

How can you have five different end-points as a primary end point? Well, you just can… apparently. 6

What you may notice, or maybe not, is that three of these are clinical events: cardiovascular death, MI and stroke. Two of them are clinical decisions. To admit someone to hospital for unstable angina, and to carry out a coronary revascularisation. Revascularisation is, essentially, putting in a stent to keep a coronary artery open.

So, the second two end-points are potentially subject to significant clinical bias. If someone has a low non-HDL cholesterol level, the decision may well be to not admit to hospital for unstable angina, and to not carry out coronary revascularisation. Why, because the physicians think they are protected by their low cholesterol.

[Guess which end-point dragged the FOURIER study into statistical significance.]

You think that clinical decisions are all objective. Then ask yourself why all clinical trials, wherever possible, are double-blinded (neither the patient or the doctor knows who is taking the drug, or the placebo)? This double blinding is considered essential to remove clinical bias. No blinding, bias introduced.

Even if you look at MIs and strokes, this diagnosis is less certain than you might wish. I have had many patients where it is entirely unclear if they have actually had a stroke or a heart attack. With a small stroke it is often, simply a guess. Low cholesterol, I guess not a stroke. High cholesterol, I guess that it is.

Just in case you think I am now talking nonsense, as I was writing this blog, I was sent a BBC report of a clinical trial done on stents in the US, which stated that stents were as safe as bypass surgery, with regard to MIs. However, the researchers decided to use a completely different system for diagnosing MI…

‘The trial called Excel started in 2010 and was sponsored by big US stent maker, Abbott. It was led by eminent US doctor Gregg Stone and aimed to recruit 2,000 patients. Half were given stents and the other half open heart surgery. Success of the treatments was measured by adding together the number of patients that had heart attacks, strokes, or had died.

The research team used an unusual definition of a heart attack, but had said that they would also publish data for the more common “Universal” definition of a heart attack alongside it. There is debate around which is a better measure and the investigators stand by their choice.

In 2016, the results of the trial for patients three years after their treatments were published in the prestigious New England Journal of Medicine. The article concluded stents and heart surgery were equally effective for people with left main coronary artery disease.

But researchers had failed to publish data for the common, “Universal” definition of a heart attack. Newsnight has seen that unpublished data and it shows that under the universal definition, patients in the trial that had received stents had 80% more heart attacks than those who had open heart surgery.

The lead researchers on the trial have told Newsnight that this is “fake information7

When is a heart attack not a heart attack? When it is measured by investigators in the clinical study – who have financial conflicts of interest.

Another problem is that, if you carry out a coronary artery revascularisation, there is a fifty per cent chance of triggering a heart attack. Usually pretty small and not clinically significant – but an MI, nonetheless. So, for each two additional revascularisations, you may get one more MI. Which further skews the statistics. [Not an issue in the FOURIER study where only the first event was counted].

Anyway, I hope you are getting the general message that a quintuple combined endpoint is, primarily, nonsense. Full of potential bias, particularly in an observational study. As the Lancet study was.

Finally, because I have run out of energy to spend another minute looking at this study, there is the issue of Lipoprotein(a). Otherwise known as Lp(a). This too forms part of the non-HDL cholesterol measurement.

Lp(a) and LDL are identical apart from the fact that Lp(a) has an additional protein attached to the side called apolipoprotein(a). This protein has a critical role in blood clotting and therefore Lp(a) can be viewed as a pro-coagulant agent – makes the blood clot bigger and more difficult to break down. Higher levels have long been linked to an increased risk of CVD.

Just to choose one quote from many thousands of studies about Lp(a): ‘Lipoprotein (a) and the risk of cardiovascular disease in the European Population: results from the BiomarCaRE consortium.’

Elevated Lp(a) was robustly associated with an increased risk for MCE (major cardiovascular events) and CVD in particular among individuals with diabetes. 8

Yes, you will have spotted the link with diabetes a.k.a. insulin resistance. So, a higher triglyceride level, added to raised Lp(a), further increases the risk of CVD.

So, with non-HDL cholesterol and Lp(a) we have another massive confounding factors built into the measurement. Again, I absolutely cannot disagree that raised Lp(a) increases the risk of CVD. I have written about it many, many times. Non-HDL cholesterol is a measure that contains Lp(a) within it…. You probably get the drift by now.

The whole paper, in my opinion, is complete nonsense. Assumptions, built on bias, built on a measure that has nothing much to do with LDL, or ‘bad’ cholesterol. Zoe Harcombe did a more forensic dissection of the paper. I like her ending:

‘The researchers assumed that a 50% reduction in non-HDL cholesterol could and would be achieved. The researchers assumed that a mathematical formula for risk reduction could be applied to that assumed 50% reduction in non-HDL cholesterol. The researchers’ assumed formula included the variable “number of years of treatment” and hence the formula produced a higher number, the earlier treatment started. The assumptions made it so.

The final paragraph of the paper stated: “However, since clinical trials investigating the benefit of lipid-lowering therapy in individuals younger than 45 years during a follow up of 30 years are not available, our study provides unique insights into the benefits of a potential early intervention in primary prevention.”

No, it doesn’t.’

Yet, there was no controlled clinical trial data to back this all up. There are only models and assumptions. Yet it made headlines around the world, as such stuff always does. Not only that, it made the wrong headlines.

As the BBC website stated: ‘The study, in The Lancet, is the most comprehensive yet to look at the long-term health risks of having too much “bad” cholesterol for decades’ Bad cholesterol is the bonkers, unscientific term that is used to describe LDL. This study did not look at ‘bad’ cholesterol… Scientific journalism at is finest.

My analysis. Crumple, throw, bin… forget.

1: https://www.bbc.co.uk/news/health-50648325

2: https://www.dailymail.co.uk/health/article-7751603/People-cholesterol-checked-25-lowering-slash-heart-disease-risk.html

3: https://www.gpnotebook.co.uk/simplepage.cfm?ID=x20030114211535665170

4: https://www.webmd.com/cholesterol-management/diabetes#1

5: https://jim.bmj.com/content/62/2/345

6: https://ahajournals.org/doi/10.1161/CIRCULATIONAHA.118.034309

7: https://www.bbc.co.uk/news/health-5071515

8: https://academic.oup.com/eurheartj/article/38/32/2490/3752512

What causes heart disease – part 67 – The Blood Brain Barrier

10th November 2019

The Blood Brain Barrier

Here I am going backwards in time and space to try and explain, from a different angle, a fundamental problem with the LDL/cholesterol hypothesis. In doing so I hope to again make clear why I am certain the entire process of cardiovascular disease (CVD) requires a complete re-think.

In a medical school long, long ago, on a planet far, far, away, I was part of a small group teaching session on cardiology… Aberdeen 1980, actually. I have mentioned this event before, a critical moment in my life. The tutor was Dr Elspeth Smith, who was researching heart disease at the time. Research that, to my chagrin, I knew little about until several years later, when I began more detailed research into cardiovascular disease.

At one point in the tutorial, Dr Smith stated that LDL (low density lipoprotein) cannot get past, or through, the endothelium. At that time, I hadn’t much of a clue what LDL was, and very little idea about the endothelium. However, something about the intensity of her comment created an itch, one that I have spent very nearly forty years scratching.

I say this because, if LDL cannot get past the endothelium, then the widely accepted, and supposedly primary causal mechanism of heart disease, must be wrong!

Just to remind you that the central mechanism underpinning the ‘cholesterol hypothesis’ has always been that LDL leaks out of the blood past, or through, the endothelium, and into the arterial wall behind.

This then stimulates a whole series of downstream processes whereby you end up with thickenings in the artery wall narrowing the artery – known as atherosclerotic plaques. The higher the LDL level, the faster the leakage? I put a question mark there, because I don’t think I have ever seen this stated explicitly – I suppose it is implied as self-evident.

Clearly, however, if LDL cannot pass through the endothelium – the single layer of cells that lines all artery walls – then the ‘cholesterol hypothesis’ is a busted flush. Which is sort of interesting in a ‘hold the front page’ sort of fashion. ‘LDL hypothesis completely wrong – shock horror.’ Dr Elspeth Smith explains that LDL cannot get through the endothelium. Experts around the world, agree, and look for other explanations for heart disease.

This is a headline that I must have missed.

At this point you may be thinking, how do we get from LDL, and the endothelium, to the Blood Brain Barrier (BBB), which is the title of this blog. Well, are you sitting comfortably? Then I shall begin, at the end, with the blood brain barrier itself.

All doctors are taught there is a barrier between the bloodstream and the brain called the Blood Brain Barrier (BBB). Very few know what it actually consists of, other than that there is a barrier, of some kind, that prevents various things from entering the brain at will.

A barrier between the blood and the brain is critical because the brain is a highly delicate organ, which copes very badly with noxious substances, such as bacterial toxins. Which makes the BBB essential for life. However, it can become a problem if you have, for example, a brain tumour and the doctors want to give you chemotherapy. Because most anti-cancer drugs cannot get past the BBB. Some drugs can, most can’t.

However, a certain number of things must enter our brains, or we would almost instantly die. Glucose, for example. If our brain cannot get enough glucose, we go into a coma, then die. We also need amino acids (the building block of proteins), some fats and vitamins and suchlike.

Clearly, therefore, the BBB needs to be a selective barrier. It must block some things, but allow entry – and exit – of those substances that are required for brain function. Ethanol from malt whisky, for example, distilled from glucose. Well it is essential for my life anyway – in moderation obviously … obviously.

At this point you may be thinking, we are getting further and further away from LDL and heart disease, but please bear with me on this, because it does all come together at the end.

Next question, what is the BBB? The answer is that it is comprised of endothelial cells that are tightly bound to each other, and have a strong support structure underneath called the basement membrane. This membrane keeps the endothelial cells wrapped even more closely, further protecting them from any possible disruption.

This ‘tight’ binding of endothelial cells means that anything that wants to get into the brain must first pass through an endothelial cell. As you may imagine, this is an extraordinarily complicated and tightly controlled process. Substances in the blood cannot flow down a concentration gradient and straight through an endothelial cell.

LDL, for example, can only enter a cell, if there is an LDL receptor on the cell wall. The LDL links onto the receptor and then LDL and the receptor (the ‘LDL receptor complex’) is dragged inside the cell in a process known as ‘endocytosis.’

It does not matter what the concentration of LDL in the blood is – without a receptor, LDL is unable to gain entry to a cell. If it cannot get in, it cannot pass through. This is why the concentration of LDL becomes very high in Familial Hypercholesterolaemia (FH).

In this condition there is a lack of LDL receptors on all cells in the body, so LDL cannot easily enter cells, therefore the concentration in the blood rises very high.

Proof, if proof were needed, that LDL cannot ‘escape’ from the bloodstream and find refuge in the artery wall, or any other tissue. No matter what the concentration in the blood. Osmosis and/or diffusion of LDL through any cell is biologically impossible.

Therefore, getting back to the BBB, for substances to move through the BBB they first must be ‘endocytosed’ and then need to be shuttled through the cell via an active transportation system. This is known scientifically as ‘transcytosis.’ Literally, transport through the ‘cytoplasm’ where cytoplasm is the name for the jelly-like substance that fills up cells.

Once the substance has been transcytosed through the cell it must be ejected out through the cell membrane on the opposite side. Another complex process known as exocytosis.

Not everything needs a receptor to enter a cell. However, nothing gets in without the cell controlling the entry and exit. Even individual ions (charged atoms), tiny as they are, must pass through ‘gates’, or channels, to get into a cell. Calcium, sodium, potassium etc.

Their passage is carefully monitored and controlled. If this were not the case, you would instantly die. If a cell loses control of its internal environment it is either dying – or dead. See under, hyponatremic encephalopathy (for those with a scientific bent).

It has been argued that LDL molecules do not need to pass through endothelial cells, they can simply slip through the ‘cracks’ between endothelial cells. I have seen this argument used as to why ‘small dense LDL’ can cause CVD because, in this form, it is small enough to get through the cracks between the endothelial cells.

The problem with this hypothesis is that, first, small dense LDL is almost exactly the same size as normal LDL. Second, and most important, there are no cracks, or gaps, between the endothelial cells in our arteries – or the BBB. Endothelial cells in large arteries are bound together very tightly indeed. They are linked together by zips, buttons, and super-glue, then welded to create what is called a ‘tight junction’.

You can Google ‘tight junctions’ under ‘images’ to see how complex they are. There are over twenty protein bonds, sealing any gap shut. Tight junctions are so tight that they, too, can prevent the entry and exit of single ions. So, there is absolutely no way through for LDL here, either. For a quick size comparison, if a human were the size of an ion, an LDL molecule would proportionately be around the size of a super tanker.

In short, the idea that LDL can simply leak through the endothelium and into the artery wall behind requires that several key mechanisms – required for life – do not exist.

As I hope you can now see, Elspeth Smith was quite correct. LDL cannot pass through the endothelium. At least it cannot pass through a healthy endothelium, and nor can anything else either. Unless, unless the endothelium enables its passage.

Complication number one – yes, there is always a complication.

As blood vessels get smaller and smaller, like the branches on a tree, the endothelium changes dramatically. As arteries shrink down to became arterioles, then capillaries, the endothelium is no longer an impenetrable barrier.

In these very small blood vessels, the endothelium develops holes (fenestrations). Gaps also appear between individual endothelial cells, and the supporting basement membrane becomes loose. What you have is more like a sieve than a castle wall.

This ‘sieve like’ quality allows substances to move in and out of arterioles and capillaries, almost at will. Which, of course, makes perfect sense. There is little point in blood arriving at, say, the kidneys, where various waste products are removed, if it was all stuck behind an impenetrable endothelial barrier. The blood would flow into your kidneys, then flow out again, unchanged. This is not a good recipe for life.

So, yes, in the very small blood vessels, the endothelium allows the free passage of substances. But absolutely not in the larger blood vessels. If the blood simply leaked out as it passed through larger blood vessels, it would never reach the smaller blood vessels, nor get back to the heart again. It would be like having a garden hose that was full of holes along its entire length. Nothing would reach the sprinkler head.

Anyway, bringing some strands together here, the endothelium lining the large arteries has the same impenetrable structure as the endothelium lining the BBB, and therefore represents a barrier. Substances just cannot leak through this – and that includes LDL.

But can things be transcytosed through? More specifically, can LDL transcytose through it? Because, if it can, this would be a possible mechanism in support of the cholesterol hypothesis. Although, once again, you have to ask the question, why would the body have a system for actively transporting LDL through the endothelium and into the artery wall underneath. What would be the purpose of such a system? To cause atherosclerosis?

The mystery of this question is further deepened by the fact that the larger blood vessels in the body are supplied with nutrients via their own, small, blood vessels known as vasa vasorum. Literally, blood vessels of the blood vessels. These are arterioles, and capillaries, that penetrate/permeate the vessel wall.

These very small blood vessels, lying within the artery wall, have fenestrations (holes) and loose junctions that allow the free movement of LDL – in an out of artery walls. So, any LDL in the bloodstream can quite easily enter the artery – and exit the artery (and the veins) – without having to cross any barrier at all.

Which raises a further conundrum for the cholesterol hypothesis. Why would LDL that enters the artery wall, via the vasa vasorum, cause no problems. Whilst the LDL – that is claimed to enter the artery wall by forcing itself past the endothelium – creates atherosclerotic plaques. Same artery wall, same LDL.

Which then raises another question. Why do atherosclerotic plaques only form in artery walls? Why not everywhere else, within every other organ and tissue in the body. If LDL, once it leaves the bloodstream, is so destructive, acting as the focus for plaque development, why doesn’t it cause plaques within the liver, or the kidneys, or the muscles, or the gut. Only, it seems, in artery walls. [Please don’t say xanthelasma, until you have thought very carefully about it]

Strange…

But to get back on track. I wanted to see if I could answer a final question. We know that LDL cannot simply flow through endothelial cells, nor can it squeeze between non-existent gaps. But can it be actively transported through? Because, if it cannot, then this is the final nail in the cholesterol hypothesis. There is, literally, no way past. Elspeth Smith was quite correct.

[Other than via the vasa vasorum, obviously. However, veins have more vasa vasorum than arteries, so this if this is the route for LDL to enter blood vessel walls, then veins should have more atherosclerosis than arteries, which they do not. In fact, veins never develop atherosclerosis – ever.]

So, deep breath.

I wanted to know if LDL could get past the BBB. If not, then it could not get past the endothelium in the larger arteries either, end game. This is the sort of question to which you would think there should be a straightforward, yes or no answer. It took me a long time to find a definitive answer.

I did know that the brain manufactures its own cholesterol, because cholesterol is absolutely vital for brain function. Neurones are wrapped in myelin/cholesterol sheaths. New synapses have a very high proportion of cholesterol in them, and animal work has shown that – without cholesterol – new synapses cannot be made.

‘Brain cholesterol accounts for a large proportion of the body’s total cholesterol, existing in two pools: the plasma membranes of neurons and glial cells and the myelin membranes  Cholesterol has been recently shown to be important for synaptic transmission, and a link between cholesterol metabolism defects and neurodegenerative disorders is now recognized.’ 1

This ‘brain’ cholesterol is synthesized in support cells, known as glial cells. These cells surround neurones and nourish neurones, and the cholesterol is transported about in its own lipoprotein called Apo E.

So, on initial analysis, it did seem unlikely that the brain would have developed its own, specific, cholesterol manufacturing capability if it could simply absorb it from the bloodstream. As it turns out, and as I eventually discovered, the brain cannot absorb LDL from the bloodstream.

‘… the blood brain barrier (BBB) prevents the uptake of lipoprotein-bound cholesterol from the circulation.’ 1

In quick summary here, the brain requires cholesterol, yet the BBB prevents it from entering the brain. Which means that an intact endothelium can completely block the passage of LDL Which means that LDL cannot get past, or through, the endothelium. Elspeth Smith was quite right.

But what did she think caused CVD, or atherosclerosis, or atherosclerotic plaques – or whatever term is currently in vogue? Well, this is one thing that she wrote about the matter:

‘After many years of neglect, the role of thrombosis in myocardial infarction is being reassessed. It is increasingly clear that all aspects of the haemostatic (blood clotting) system are involved: not only in the acute occlusive event, but also in all stages of atherosclerotic plaque development from the initiation of atherogenesis to the expansion and growth of large plaques.’ 2

She believed, as I have been trying to outline for a few years now, that to start atherosclerosis, you need to damage the endothelium, then a blood clots forms, then we are on the pathway to the final occlusive thrombosis (a blood clot that completely blocks an artery).

She believed, as I believe, that LDL has no part to play in this process. It does not, because it cannot. If you believe in the ‘thrombogenic’ hypothesis, you cannot believe in the LDL hypothesis, and vice-versa.

Which hypothesis is correct?  Well, it is certainly true that the LDL hypothesis is currently in the ascendancy. But science is not, thankfully, a popularity contest like Strictly Come Dancing. Science is built on facts. Well, it is eventually. The fact is that the LDL hypothesis requires a central fact to be true but which can be proven to be wrong.

Elspeth Smith proved it to be wrong over fifty years ago, but no-one was listening. She was a hero, and I intend to do all that I can to ensure that it is her name, not that of Ancel Keys, that will echo through the history of CVD research. Because she was a true scientist. Whereas he….

Next time, why LDL also cannot damage the endothelium.

1: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4837572/#:~:text=The%20CNS%20cholesterol%20is%20transported,%2C%2039%20kDa)%20and%20lipids.&text=Lipid%2Dpoor%20particles%20(for%20example,ApoE%20levels%20in%20the%20brain.

2: https://www.sciencedirect.com/sdfe/pdf/download/eid/1-s2.0-0049384894900493/first-page-pdf

What causes heart disease – a summary

9th October 2019

But not by me

Following a podcast by Ivor Cummings, where I bored him for an hour and a half on what causes CVD*, a journalist that I know well, Jerome Burne, had a go at summarising the ‘thrombogenic’ hypothesis. I thought this was brave of him. I consider him a friend and an ally.

Of course, this is the Readers Digest version and, by necessity, misses out a great deal of the detail. However, I would be grateful if readers of this blog, go have a look on Jerome’s site and see what you think. Leave comments if you feel the urge.

I told him that I could not really comment on it, because I know this whole are so well that I cannot look at it the way a naïve reader could. Or, to put it another way, does it make any sense to an interested and intelligent reader coming across these ideas for the first time.

The blog can be found here: http://healthinsightuk.org/2019/10/08/cholesterol-is-innocent-how-the-real-killers-were-tracked-down/

*Ivor Cummings/Fat emperor podcast:

Or you can view it on Ivor’s site here

What causes heart disease part 66

5th October 2019

How does lead cause CVD?

Following my last blog, several people asked the question. How does lead cause CVD – or atherosclerotic plaques? What is the mechanism of action? It’s a good question, one that I think I have answered before, at least in part. However, I think there is real value in going over it again.

First, I want to highlight some of the more general thinking about causes of CVD, I believe this is important as well, in order to see how lead fits in, and where my interest in lead came from.

For many, many, years now I have been trying to create a unified hypothesis about cardiovascular disease. A journey I thought I would never finish. Mainly, I now realise, because I kept coming across ever more ‘factors’ that had a role in CVD. This meant that – although I couldn’t quite work out why at first – I was running into the impossible, and unsolvable, problem.

246 factorial

The unsolvable problem is a direct result of the number of possible interactions between all the risk factors that have been identified.

To try and explain this further, I shall start with the latest UK risk factor calculator which is called Qrisk3. The previous one was Qrisk2. Qrisk3 can be found on-line here https://qrisk.org/three/ You can play with it to your heart’s content. Qrisk3 has moved on considerably from Qrisk1 and 2. It now incorporates twenty different factors.  If you strip them out of the algorithm they are, in no particular order:

  • Age
  • Sex
  • Smoking
  • Diabetes
  • Total cholesterol/HDL ratio
  • Raised blood pressure
  • Variation in two blood pressure readings
  • BMI
  • Chronic kidney disease
  • Rheumatoid arthritis
  • Systemic Lupus Erythematosus (SLE)
  • History of migraines
  • Severe mental illness
  • On atypical antipsychotic medication
  • Using steroid tablets
  • Atrial fibrillation
  • Diagnosis of erectile dysfunction
  • Angina, or heart attack in first degree relative under the age of 60
  • Ethnicity
  • Postcode

As a quick side-track, it amuses me that LDL is not in there – yet HDL is.

Now, you may think that this appears to be a relatively short list. At first sight it does not appear a complex task to fit these factors together into a coherent model. A twenty-piece jigsaw puzzle – at most?

Not so. The reality is that, if you view the model of CVD as twenty independent and unconnected risk factors, the number of possible interactions, or pieces, you need to analyse becomes mind-boggling.

Just to give you an idea of the scale of the maths involved here. You have twenty different risk factors, and you do not know how the connections between them work. Every risk factor can, potentially, interact with all the others – independently. This means that the possible combinations you must analyse is twenty factorial.

Calculating factorials is, on one hand, very straightforward. You simply multiply each factor, by all of the other factors, in turn. Thus, twenty factorial = 20 x 19 x 18 x 17 x 16 etc.

The result of multiplying 20 x 19 x 18 x 17 x 16 etc. is you end up with the following number: 432,902,008,176,640,000. Which is the number of different possible combinations between twenty factors. Rounding this figure up slightly, that equates to four hundred and thirty-three quadrillion. Which is a lot. And it gets far worse than that.

As far back as 1981, a paper was published outlining 246 different risk factors involved in CVD 1. Today, there would be far more, several thousand at least. However, even by 1981 the number of possible combinations was already incomprehensibly huge. I say this because 246 factorial is:

980360372638941007038951797078339359751464353463061342202811188548638347461066010066193275864531994024640834549254693776854464608509281547718518965382728677985343589672835884994580815417004715718468026937051493675623385569404900262441027874255428340399091926993707625233667755768320823071062785275404107485450075779940944580451919726756974354635829128751944137276448671023801110260206915547825809239994946405007360000000000000000000000000000000000000000000000000000000000

Yes, to my amazement, there is a website which will calculate factorials for you. You don’t think I worked that out myself do you? I would have definitely got bored and made several mistakes on the way. Therefore, I have no idea if this figure is right or wrong, but it seems to be in the right sort of ballpark.

There is no way to even describe a number that big, and it would certainly make for some jigsaw puzzle. In truth what we have here represents a figure so huge that you cannot possibly do anything with it. It has fifty-seven zeros before you even get to another number. At least I think it is fifty-seven, I may have lost count.

How long would it take to feed in the data on all these risk factors, run the combinations, and see if you can establish how they all fit together? That would take as close to an infinite amount of time as makes no practicable difference. Even with the latest Google quantum computer.

Thinking about things in this way, I came to realise that unearthing risk factor, after risk factor, after risk factor, was not going to make it easier to work out the cause of CVD. It was making it impossible.

The other word for impossible, I came to realise, is ‘multifactorial’.

Multifactorial = a word commonly used by cardiologists to prevent any discussion as to the real causes of CVD. In conversation on this issue, I silently change the word multifactorial to ‘246-factorial’, just to remind myself what a stupid concept it is to call a disease multifactorial. Then to believe that, by doing so, you have explained anything. ‘So, how do the factors all fit together?’ I mutter, imaging a number so vast that it is beyond comprehension.

Then I may quote Poincaré at them.

Science is built up of facts, as a house is built of stones; but an accumulation of facts is no more a science than a heap of stones is a house.’ Henri Poincaré.

Because multifactorial also effectively = a pile of stones. Well done, you have found thousands of stones, and carefully piled them ever higher, but this gets no nearer to constructing a house. To build a house you need to know how all the stones join up. You need a plan my friend.

Which starts to bring me, in a roundabout way, back to lead.

As regular readers of this blog will know, I ripped up the multifactorial model of CVD and tried to replace it with a process model. The plan of the house, if you like. I was no longer interested in finding endless risk factors, then chucking them on the pile. I wanted to know the process – or processes – involved.

In the end I stripped it down to three main elements. Basement, walls, roof.

  • Endothelial damage (damage to the lining of artery walls)
  • Formation of a blood clot
  • Repair

Or at least I stripped it down to three main processes – going wrong. Because this triad is all quite normal, and healthy. It is only when endothelial damage and clot formation accelerate, or repair is sub-optimal, that CVD/atherosclerosis will develop.

So, the simplest possible model is: rate of damage > rate of repair = CVD

Using the three-process model I began a different search. Starting with things that could damage the endothelium. I cast the net far and wide. Of course, it is more difficult to do the searching this way. Where do I begin? Do you just start thinking of things that might be damaging, and hope for the best? You will find yourself wandering all over the place. At least I did. Although it is quite an interesting journey – for a geek.

Bringing some structure into my search strategy, I decided that heavy metals were something that could not be doing any good to the human body. Mercury, lead, cadmium, and suchlike. Gold? Gold doesn’t seem to do much, one way or another. It was used to treat rheumatoid arthritis at one time. As for the others – not great. Lots of damage to health.

But do they damage the endothelial lining of the artery wall? Well, yes, they do. Looking at lead, here is a passage from the paper: ‘Mechanisms of lead-induced hypertension and cardiovascular disease.’

I admit that it is far too jargon heavy for most people. But I enjoyed it and I reproduced it in full because, what we have here, is the perfect storm. Many mechanisms I have previously mentioned in my long and winding series on what causes heart disease can be found here. Including many I did not mention because they were just too technical. I have put in bold some of the more important mechanisms:

‘Lead is a ubiquitous environmental toxin that is capable of causing numerous acute and chronic illnesses. Population studies have demonstrated a link between lead exposure and subsequent development of hypertension (HTN) and cardiovascular disease. In vivo and in vitro studies have shown that chronic lead exposure causes HTN and cardiovascular disease by promoting oxidative stress, limiting nitric oxide availability, impairing nitric oxide signaling, augmenting adrenergic activity, increasing endothelin production, altering the renin-angiotensin system, raising vasoconstrictor prostaglandins, lowering vasodilator prostaglandins, promoting inflammation, disturbing vascular smooth muscle Ca2+ signaling, diminishing endothelium-dependent vasorelaxation, and modifying the vascular response to vasoactive agonists. Moreover, lead has been shown to cause endothelial injury, impede endothelial repair, inhibit angiogenesis, reduce endothelial cell growth, suppress proteoglycan production, stimulate vascular smooth muscle cell proliferation and phenotypic transformation, reduce tissue plasminogen activator, and raise plasminogen activator inhibitor-1 production.’ 2

So, there you go. Not just one mechanism of action, but twenty-one different processes that lead can cause CVD. Fifteen ways of damaging the endothelium, four that inhibit repair, and two mechanisms for making blood clots more difficult to get rid of, as highlighted in the final passage… reduce tissue plasminogen activator, and raise plasminogen activator inhibitor-1 production.’

Tissue plasminogen activator (TPa) is the enzyme that activates the breakdown of blood clots. TPa converts plasminogen to plasmin, and plasmin then chops fibrin to bits, thus shaving down blood clots. Plasminogen activator inhibitor-1 is a substance that inhibits the action of tissue plasminogen activator (TPa = the clot buster, often given to patients after a heart attack or stroke).

Clearly, if you reduce TPa, and increase TPa inhibition, you end up with a blood clot that is very difficult to get rid of and is thus more damaging.

So, when people ask, have you got a mechanism of action to explain how lead causes CVD I say (rather smugly), no, I have got twenty-one. In truth, I have found quite a few more, but twenty-one is probably enough to be getting on with. One thing I have found is that once you start looking at all the potential processes, there seems almost no end to this stuff. It stretches in all directions.

Big fleas have little fleas upon their backs to bite ’em,

And little fleas have lesser fleas, and so, ad infinitum.

And the great fleas, themselves, in turn, have greater fleas to go on;

While these again have greater still, and greater still, and so on

Anyway, getting back on track, I started to look for factors, causal agents, whatever is the best name for them, that can impact on one of three processes:

  • Endothelial damage (damage to the lining of artery walls)
  • Formation of a blood clot
  • Repair

This is how I got to lead, only to discover that there was a huge body of research linking lead to CVD… that I had been completely unaware of. My analogy was that of a round the world sailor bumping into Australia and wondering why no-one had bothered to tell him it was there. ‘It’s pretty big, you know.’

Looking at things, by starting with one of the three processes, is also how I came across the evidence on sickle cell disease (SCD). I reasoned that sharp pointy red blood cells (sickled cells) hammering through the blood vessels would create serious damage to endothelial cells.

When I started looking, I found that, in some studies, SCD increases the (relative risk) of CVD by fifty thousand per cent. Yes, you did read that right. Fifty thousand per cent. With none of the other ‘established’ risk factors present.

Which makes SCD a ‘sufficient’ cause of CVD. In fact, it is the only sufficient cause I have ever found – in that it can lead to atherosclerosis in the blood vessels in the lungs, where the blood pressure is pretty low.

Which means that, with SCD, you don’t even need a high blood pressure. SCD can cause CVD all by itself. If you can find any other factor that can do that – let me know. For a more in-depth discussion on causation, and the concept of ‘sufficient’ see this article: https://jech.bmj.com/content/55/12/905.long

Then, I thought, what else causes damage to the endothelium. I ended up looking at a group of diseases known as ‘vasculitis’. Itis means, inflammation, as in tonsillitis, appendicitis. So, vasculitis means inflammation of the vascular system, by which I mean inflammation of the lining of the blood vessels. By which I mean, damage (and repair) to the lining of the blood vessels. Remember, inflammation = repair.

There are many different forms of vasculitis, most of which are not really thought of as being ‘vasculitis.’ For example, Rheumatoid arthritis, and Systemic Lupus Erythematosus. These conditions cause inflammation in many different places, but they also cause vasculitis. You may have noticed that both also appear on the Qrisk3 calculator.

Other forms of vasculitis, or diseases where vasculitis is an important part of the spectrum of abnormalities include:

  • Scleroderma
  • Sjogren’s
  • Erythema nodosum
  • Takayasu’s arteritis
  • Kawasaki’s disease

I think they all have great, evocative names:

All these forms of vasculitis are associated with a greatly increased risk of CVD. You can look this up yourself, if you want. In fact, children who suffer Kawasaki’s can die of myocardial infarctions (MIs), aged five. They have a brief, super-accelerated, form of endothelial damage that lasts a few weeks. Some can then end up with large aneurysms (balloon-like swellings) in their coronary arteries. These can burst, causing a MI.

So, not an entirely conventional MI. Nor conventional atherosclerosis. However, if you think of an aneurysm as a late stage abnormality in atherosclerosis [which most are] then in Kawasaki’s we can get from endothelial damage, to an aneurysm, in a month. Something that normally takes about sixty years to develop.

Three stones to make a wall

Lead, sickle cell disease, vasculitis.

In one sense it could be said that I have been discussing three completely unrelated things here. Lead, sickle cell disease, vasculitis. In another sense I hope you can see that these three ‘factors’ are related to CVD. Not by what they are, but by what they do. The damage they cause… the process.

They all fit very neatly into the walls of the house that are called ‘endothelial damage’. How else can you explain how three such disparate things can possibly cause exactly the same disease.

I must admit that this breakthrough in my thinking, from causes to process, was not mine. It was entirely due to one man. Professor Paul Rosch. We were discussing stress (strain) and CVD and he was critiquing a presentation I had given.

I shall paraphrase his comment. ‘Very good, you have given us the what, but not the how.’ Yes, very simple, when you think of it that way. What he was really asking was, what is the process? Since then, I have often wondered why have others not gone down this route?

I then realised that the problem, the great problem in all research into CVD, is that very early on it was decreed that LDL/cholesterol causes CVD. Therefore, all thinking, and any hypothesis on CVD required that LDL sat at the centre.

To my mind this is like opening a two-thousand-piece jigsaw puzzle and deciding, straight away, that one big piece – LDL/cholesterol – sits at the centre, and the other pieces must be made to fit around it.

Well, perhaps it does have a (small role) to play in CVD, but it most certainly does not sit and the centre. But if you keep it there, you distort the entire puzzle and make it impossible to complete. The pieces must be forced into place. Hammered down, or twisted into extreme shapes.

This, though, is where CVD research currently sits. Thousands of pieces are lying about the board. A few of them have been fitted together, here and there. As for the whole puzzle, it is doomed to failure, because the wrong piece is taking up the key position. Unfortunately, if you are a ‘serious’ CVD researcher, who wants to get grants for research, you can’t move it.

What I found if that you chuck that piece away, and start again, then everything becomes clear. The puzzle can be made to fit into one of these three processes:

  • Endothelial damage (damage to the lining of artery walls)
  • Formation of a blood clot
  • Repair

Lead, for example. Lead makes no sense as a significant risk factor using conventional thinking. It doesn’t raise BP, it doesn’t raise LDL, it doesn’t cause diabetes, it simply does not fit. So, it has become, essentially, ignored. But how can you ignore something that may be responsible for four hundred thousand deaths per year, in the US alone? Most of them CVD deaths?

The answer is that you cannot.

1: https://www.atherosclerosis-journal.com/article/0021-9150(81)90122-2/abstract

2: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2519216/

What causes heart disease part 65 – Lead again

23 September 2019

Lead again

I am returning to lead, the heavy metal. Not the verb to lead, or a noun – such as a dog lead. Yes, English is complicated, with the same word meaning several different things, which can lead to confusion.

I am indebted to Leon Vd Berg for bringing my attention to another paper about lead that I had missed. Which is slightly surprising as I tend to look for such papers. However, such is the daily avalanche of medical publications that it is literally, impossible to keep up.

There are several things about the paper that I found fascinating. However, the first thing that I noticed was that…. it hadn’t been noticed. It slipped by in a virtual media blackout. It was published in 2018, and I heard nothing.

This is in direct contrast to almost anything published about diet. We are literally bombarded with stories about red meat causing cancer and sausages causing cancer and heart disease, and veganism being protective against heart disease and cancer, and on and on. Dietary articles often end up on the front page on national newspapers.

Here is one such headline from the Daily Mail 7th August 2019

‘Eating chicken instead of steak, lamb or sausages ‘slashes a woman’s risk of developing breast cancer by 28%’

Mind you, here is another headline from the Daily Mail 8th Sept 2019

Chicken ’causes cancer’: Oxford University scientists say people who eat poultry are at increased risk of developing deadly disease.’

Tricky thing eating chicken. It can cause and prevent cancer simultaneously. You read it here first.

However, the point I wish to make is not so much the utter nonsense and constant contradictions of dietary studies. Nor is it the fact that the increased, and decreased risk in such studies, is minute. Sitting well within the boundaries of reasonable chance. Which is why you keep getting contradictory studies.

Researcher one:      ‘I just threw a head – all throws of a coin must be heads.’

Researcher two:       ‘No, sorry, I just threw two tails – most throws of a coin end up tails

Researcher one:      ‘Hold on, forget your tails, I just go four more heads – in a row – most throws end up heads, not tails.’

The correct term for this is idiot research, and those who do it are – primarily – idiots. However, none of this nonsense is really important. The point I am trying to make here is that this type of dietary research hogs the limelight.

It seems that whatever else Ancel Keys did not achieve – scientific truth and accuracy, for starters – he most certainly did manage to convince almost everyone in the World that diet is the single most critical important factor for health.

In years gone by, people ate food because they enjoyed eating it. This still happens in France. Imagine that. Nowadays every meal comes with implied fearmongering, and high-level criticism. Are you destroying the world or not – you evil scum.

‘Hold on, it’s only a bacon sandwich. With a fried egg and a bit of cheese grated on top…. Yes, I suppose you’re right, I am personally responsible for the destruction of the Amazonian rain forest. Forgive me father, for I have sinned.’

Destruction of the planet is only one aspect of eating, it’s also destruction of your health – with added moral judgement. If you go to Slimming World, you can eat various tasteless stuff, but you are allowed ‘sins.’ A sin would be something you really like eating, but it is so deadly, that it is a sin to eat it. Chocolate, for example. Get thee behind me Satan.

I don’t understand how anyone manages to eat anything nowadays. I have almost given up eating salads because someone will always remark ‘Oooooh, that’s healthy.’

My reply used to be. ‘I am not eating it because it is healthy, I am eating it, because I enjoy it.’ Nowadays I just grunt in a vaguely non-threatening way. I do not say. ‘No, a healthy meal would be a full English breakfast with bacon, eggs, sausages, fried bread. a few more sausages and a bit of lard melted on top.

I do not say this because, in truth, almost all diets are perfectly healthy. Vegetarian, paleo, keto, vegan (with a few essentially nutrients thrown in, so you don’t die), HFLC, etc. In fact, the only non-healthy diet would be the one recommended by all the experts around the world.

Namely, High carb, low fat (HCLF). The ‘eat well plate’, ‘the food pyramid’ – whatever it is now called. Stay away from that, and you will be fine.

Rule one of diet.       Everything the ‘experts’ recommend, is wrong.

Rule two:                   Eat food you enjoy – and enjoy eating

Rule three:                Eat food that looks like food

Rule four:                   Cook your own meals – when possible

Rule five:                   Try fasting from time to time

Rule six:                     That’s it

Where was I? Oh yes, lead. The heavy metal. The thing that, unlike diet, makes no headlines whatsoever, the thing that everyone ignores. Here is one top-line fact from that study on lead, that I missed:

‘Our findings suggest that, of 2·3 million deaths every year in the USA, about 400 000 are attributable to lead exposure, an estimate that is about ten times larger than the current one. 1

Yes, according to this study, one in six deaths is due to lead exposure. I shall repeat that. One in six. Eighteen per cent to be exact, which is nearer a fifth really.

Of course, this study is observational, with all the usual caveats associated with such studies. Indeed, many people commenting on this blog have stated that correlation [found in such studies] does not mean causation. I think you will find that this does not include me – although I may have said it by mistake. It is true that correlation does not mean causation, up to a point. However, once that point has been reached, causation can be considered proven.

For example, in observational studies, smokers were found to have fifteen times the risk of lung cancer. That is a powerful enough correlation to prove causation – beyond any reasonable doubt. There is no point in setting up a controlled clinical trial to prove this. In fact, any such trial would be completely unethical.

The question is, at what level of increased risk/correlation can causality be accepted. There is no absolute clear-cut answer to this Life ain’t black and white. However, most epidemiologists will tell you that unless the odds ratio (OR) is above two, you cannot attempt to claim causality. Too much noise, too many possible confounders.

Which means (deep breath, waiting for statisticians to attack this mercilessly) you need to find that a ‘factor’ is associated with at least a doubling of risk, before you do not simply crumple up the published paper and throw it in the bin.

Most dietary studies get absolutely nowhere near two. We have risks such as one point one (1.10), or one point three. One point three (1.3) is a thirty per-cent increase in risk. Here for instance is a review of red meat and colo-rectal cancer

‘As a summary, it seems that red and processed meats significantly but moderately increase CRC risk by 20-30% according to these meta-analyses.’  2

Figures like this, from an observational study, mean only one thing. Crumple, throw, bin. Remember also, they are only looking at one form of disease colo-rectal cancer (CRC).  The impact on overall mortality (the risk of dying of anything) would be minuscule, if it could even be found to exist at all. Of course, overall mortality is not mentioned in that CRC paper. Negative findings never are.

So, on one side, we have papers (that make headlines around the world) shouting about the risk of red meat and cancer. Yet the association is observational, tiny, and would almost certainly disappear in a randomised controlled trial, and thus mean nothing.

On the other we have a substance that could be responsible for one sixth of all deaths, the vast majority of those CVD deaths. The odds ratio, highest vs lowest lead exposure, by the way, depending on age and other factors, was a maximum of 5.30 [unadjusted].

Another study in the US found the following

‘Cumulative lead exposure, as reflected by bone lead, and cardiovascular events have been studied in the Veterans’ Normative Aging Study, a longitudinal study among community-based male veterans in the greater Boston area enrolled in 1963. Patients had a single measurement of tibial and patellar bone lead between 1991 and 1999. The HR for ischemic heart disease mortality comparing patellar lead >35 to <22 μg/g was 8.37 (95% CI: 1.29 to 54.4).’ 3

HR = Hazard Ratio, which is similar, if not the same to OR = Odds Ratio. A Hazard Ratio of 8.37, means (essentially) a 737% increase in risk (Relative Risk).

Anyway, I shall repeat that finding a bit more loudly. A higher level of lead in the body leads to a seven hundred and thirty-seven per cent increase in death from heart disease. This is, in my opinion, correlation proving causation.

Looking at this from another angle, it is true that smoking causes a much greater risk of lung cancer (and a lesser but significant increase in CVD), but not everyone smokes. Therefore, the overall damage to health from smoking is far less than the damage caused by lead toxicity.

Yet no-one seems remotely interested. Which is, in itself, very interesting.

It is true that most Governments have made efforts to reduce lead exposure. Levels of lead in the children dropped five-fold between the mid-sixties and the late nineties. 4 Indeed, once the oil industry stopped blowing six hundred thousand tons of lead into the atmosphere from vehicle exhausts things further improved. Lead has also been removed from water pipes, paint, and suchlike.

However, it takes a long old time from lead to be removed from the human body. It usually lingers for a lifetime. Equally, trying to get rid of lead is not easy, that’s for sure. Having said this, chelation therapy has been tried, and does seem to work.

‘On November 4, 2012, the TACT (Trial to Assess Chelation Therapy) investigators reported publicly the first large, randomized, placebo-controlled trial evidence that edetate disodium (disodium ethylenediaminetetraacetic acid) chelation therapy significantly reduced cardiac events in stable post–myocardial infarction (MI) patients. These results were so unexpected that many in the cardiology community greeted the report initially with either skepticism (it is probably wrong) or outright disbelief (it is definitely wrong).3

Cardiologists, it seems from the above quotes, know almost nothing about the subject in which they claim to be experts. Just try mentioning glycocalyx to them… ‘the what?

Apart from a few brave souls battling to remove lead from the body, widely derided and dismissed by the mainstream world of cardiology, nothing else is done. Nothing at all. We spend trillions on cholesterol lowering, and trillions on blood pressure lowering, and more trillions on diet. On the other hand, we do nothing active to try and change a risk factor that kicks all the others – in terms of numbers killed – into touch.

Funny old world. Is it not?

Next time, back to diet, because everyone knows how important diet is…. Only joking.

1: https://www.thelancet.com/journals/lanpub/article/PIIS2468-2667(18)30025-2/fulltext

2: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4698595/

3: https://www.sciencedirect.com/science/article/pii/S0735109716015989

4: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1240871/pdf/ehp0110-000563.pdf

Review of statins needed

7th September 2019

In the UK, it has been decided that high intensity statins can now be sold over the counter to people – no prescription required. The European Society of Cardiology has decreed that there is no normal level for cholesterol, the lower the better. It goes on, and on.

However, there are some glimmers of light, occasionally. Aseem Malhotra, and I, wrote a letter to Sir Norman Lamb MP. Chairman of the Science and Technology Select Committee – at his request – asking for a review of statins, and safety issues.

It was reported in the few news outlets that had any space left after Brexit. You can see the video on Sky with Aseem, here


(or here is the link to YouTube… https://www.youtube.com/watch?v=RxCO9iiJYDw)

The letter is below.

Sir Normal Lamb MP

Chairman, Science and Technology Select Committee
29/08/2019

Dear Norman,

Re: The need for an independent reappraisal of the effects of statins

Statins are the most widely prescribed class of drugs in the UK.[1] They were designed to lower the blood cholesterol (LDL) level and therefore prevent cardiovascular disease.

Publications based on clinical trials have reported reductions in cardiovascular disease in people at high and low risk, and also a very low rate of side effects (drug-related adverse events).

It has been widely claimed that statins have therefore been responsible for the considerable reduction in the cardiovascular disease seen over the past 30 years both in the UK  and the rest of the Western World,[2] but there is evidence that refutes this claim. An ecological study using national databases of dispensed medicines and mortality rates, published in 2015, concluded: ‘Among the Western European countries studied, the large increase in statin utilisation between 2000 and 2012 was not associated with CHD mortality, nor with its rate of change over the years.[3] In the UK, despite far greater statin prescribing, the rate of cardiovascular disease has been rising for the past four years.[4]

In the absence of an analysis of the clinical trial data carried out by an independent group with full access to the raw data in the form of “clinical study reports”, there is good reason to believe that the benefits of statins have been ‘overhyped’ especially in those at low risk of cardiovascular disease, and the potential harms downplayed, unpublished, or uncollected.

Positive spin on the benefits of statins

It is well recognised that ‘positive spin’ is used to ‘hype’ the results from clinical trials. This should not happen but is widespread. According to one review: ‘Clinical researchers are obligated to present results objectively and accurately to ensure readers are not misled. In studies in which primary end points are not statistically significant, placing a spin, defined as the manipulation of language to potentially mislead readers from the likely truth of the results, can distract the reader and lead to misinterpretation and misapplication of the findings.’[5]

The authors continued: ‘This study suggests that in reports of cardiovascular RCTs with statistically nonsignificant primary outcomes, investigators often manipulate the language of the report to detract from the neutral primary outcomes. To best apply evidence to patient care, consumers of cardiovascular research should be aware that peer review does not always preclude the use of misleading language in scientific articles.’ [5]

As one example of such positive spin in relation to statins, the lead author of the JUPITER trial, Paul Ridker, writing in a commentary in the journal Circulation, summarised apparently statistically significant benefits between statin and placebo:

 The JUPITER trial was stopped early at the recommendation of its Independent Data and Safety Monitoring Board after a median follow-up of 1.9 years (maximum follow-up 5 years) because of a 44% reduction in the trial primary end point of all vascular events (P<0.00001), a 54% reduction in myocardial infarction (P=0.0002), a 48% reduction in stroke (P=0.002), a 46% reduction in need for arterial revascularization (P<0.001), and a 20% reduction in all cause mortality (P=0.02).’ [6]

Picking up on these figures, another well-known cardiologist wrote in equally positive terms: ‘Data from the 2008 JUPITER Trial suggest a 54 percent heart attack risk reduction and a 48 percent stroke risk reduction in people at risk for heart disease who used statins as preventive medicine. I don’t think anyone doubts statins save lives.’[7]

In fact in the JUPITER trial there was no statistically significant difference in deaths from cardiovascular disease among those taking rosuvastatin compared with placebo. There were 12 deaths from stroke and myocardial infarction in both groups among those receiving placebo, exactly the same number as in the rosuvastatin arm.[8] So the results of this clinical trial do not support claims that statins save lives from cardiovascular disease. This dissonance between the actual results of statin trials and the way they are reported is widespread.[9]

Other studies, looking at whether statins increase in life expectancy have found that, in high risk patients, they may extend life by approximately four days, after five years of treatment.[10] Doubts have also been raised about the claims of benefit in otherwise healthy people aged over 75, in whom statins are now being actively promoted.[11]

An overview of systematic reviews that examined the benefits of statins using only data from patients at low risk of cardiovascular disease found that those taking statins had fewer events than those not taking statins. However, when the results were stratified by the patients’ baseline risk, there was no statistically significant benefit for the majority of outcomes.[12] In conclusion, the absolute benefits in people at low risk are relatively small. If the 2016 guidelines are implemented in full, large numbers of otherwise healthy people will be offered statins, it has been estimated that 400 will need to take statins for five years to prevent one person from suffering a cardiovascular event.[13]

This information is not routinely given to patients, or indeed doctors who prescribe statins, and both doctors and patients therefore tend to have false expectations of the benefits of statins. Clinical guidelines call for shared decision making, including informing patients of the actual likelihood of benefits and risks, but this rarely occurs. There are also obvious questions in relation to value-for-money and the efficient use of finite healthcare budgets.

Side effects/adverse effects underplayed

There has been a heated debate about the adverse effects of statins. On one side, it is claimed that the rate of adverse effects is extremely low, affecting fewer than one in a thousand people.[14] Other studies have suggested adverse events are common, with up to 45% of people reporting problems.[15]

Attempts to resolve this important controversy have been hampered by the fact that  the data on adverse effects reported in the clinical trials are not available for scrutiny by independent researchers. The data from the major trials of statins are held by the Cholesterol Treatment Triallists Collaboration (CTT) in Oxford and they have agreed amongst themselves not to allow access by anyone else.[16] Many groups, have called for access to these data, but so far, this has not been granted.[17]

It is not even clear whether the CTT themselves have all the adverse effect data, since the relevant Cochrane Review Group does not seem to have had access to them. According to Professor Harriet Rosenberg of the Health and Society Program at York University: “It’s not clear if the AE (adverse events) data was withheld from the Cochrane reviewers (by CTT) or were not collected in the original trials.”[18]

When asked the lead author of the Cochrane review, Dr Shah Ebrahim, the CTT did not have the data. “Full disclosure of all the adverse events by type and allocation from the RCTs is now really needed, as the CTT does not seem to have these data.”[18]

Release of the data would undoubtedly help answer the question on how and whether the trials collected data on the most common side effects of muscle pain, weakness or cramps.

Summary

Rather than mass prescription based on incomplete and selective information, patients and the public deserve an objective account so that individuals can make their own informed decisions.

We believe there is now an urgent need for a full independent parliamentary investigation into statins:

  • a class of drug prescribed to millions in the UK and tens of millions across the world.
  • which, based on the publications available, have had their benefits subjected to significant positive spin, especially among people at low risk of cardiovascular disease, and their potential adverse effects downplayed
  • where independence would mean review of the complete trial data by experts with no ties to industry and who have not previously undertaken or meta-analysed clinical trials of statins.

Among the signatories to this letter, there are a range of views: some of us are deeply sceptical of the benefits of statins, others are neutral or agnostic. But all are strongly of the view that such confusion, doubt and lack of transparency about the effects of a class of drug that is so widely prescribed is truly shocking and must be a matter of major public concern.

Yours Sincerely,

Dr Aseem Malhotra, NHS Consultant Cardiologist and Visiting Professor of Evidence Based Medicine, Bahiana School of Medicine and Public Health, Salvador, Brazil.

Dr John Abramson, Lecturer, Department of Healthcare Policy, Harvard Medical School

Dr JS Bamrah CBE, Chairman, British Association of Physicians of Indian Origin.

Dr Kailash Chand OBE, Honorary Vice President of the British Medical Association  (signing in a personal capacity)

Professor Luis Correia, Cardiologist, Director of the Centre of Evidence Based Medicine, Bahiana School of Medicine and Public Health, Salvador Brazil. Editor in Chief, The Journal of Evidence Based Healthcare

Dr Michel De-Lorgeril, Cardiologist, TIMC-IMAG, School of Medicine, University of Grenoble-Alpes, Grenoble, France.

Dr David Diamond, Cardiovascular Research Scientist, Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, Florida, USA

Dr Jason Fung, Nephrologist and Chief of the Department of Medicine, The Scarborough Hospital, Toronto, Canada and Editor in Chief of the Journal of Insulin Resistance.

Dr Fiona Godlee, Editor in Chief, The BMJ

Dr Malcolm Kendrick, General Practitioner

Dr Campbell Murdoch, General Practitioner, NHS England Sustainable Improvement Team, Clinical Adviser

Professor Rita Redberg, Cardiologist, University of California, San-Francisco.

Professor Sherif Sultan, President, International Vascular Society

Sir Richard Thompson, Past President, The Royal College of Physicians

Professor Shahriar Zehtabchi, Editor in Chief, TheNNT.com, and Professor and Vice Chairman for Scientific Affairs Research, SUNY Downstate Health Science University, Brooklyn, New York

1: https://www.bhf.org.uk/informationsupport/treatments/statins

2: https://www.sciencedirect.com/science/article/pii/S1933287415004493

3: https://bmjopen.bmj.com/content/6/3/e010500

4: https://www.bhf.org.uk/what-we-do/news-from-the-bhf/news-archive/2019/may/heart-and-circulatory-disease-deaths-in-under-75s-see-first-sustained-rise-in-50-years

5: https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2732330

6: https://www.ahajournals.org/doi/full/10.1161/CIRCOUTCOMES.109.868299

7: https://utswmed.org/medblog/statins-debate/

8: https://www.nejm.org/doi/full/10.1056/NEJMoa0807646

9:https://www.researchgate.net/publication/272189007_How_statistical_deception_created_the_appearance_that_statins_are_safe_and_effective_in_primary_and_secondary_prevention_of_cardiovascular_disease

10:  https://bmjopen.bmj.com/content/5/9/e007118

  1. Armitage J, Baigent C, Barnes E, Betteridge DJ, Blackwell L, Blazing M, et al. Efficacy and safety of statin therapy in older people: a meta-analysis of individual participant data from 28 randomised controlled trials. The Lancet. 2019;393(10170):407-15.
  2. Byrne P, Cullinan J, Smith A, Smith SM. Statins for the primary prevention of cardiovascular disease: an overview of systematic reviews. BMJ Open. 2019; 9(4):[e023085 p.]. Available from: https://bmjopen.bmj.com/content/bmjopen/9/4/e023085.full.pdf.
  3. Byrne P, Cullinan J, Gillespie P, Perera R, Smith SM. Statins for primary prevention of cardiovascular disease: modelling guidelines and patient preferences based on an Irish cohort. Br J Gen Pract. 2019. Available from: https://doi.org/10.3399/bjgp19X702701.

14: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)31357-5/fulltext

15: https://www.lipid.org/nla/usage-survey

16: https://www.ctsu.ox.ac.uk/research/ctt

17: https://www.bmj.com/campaign/statins-open-data

18: http://healthinsightuk.org/2015/02/19/keep-statin-supremo-away-from-the-missing-side-effect-data/

 

Will this have any impact, on anything. We must keep bashing away, until the nonsense about cholesterol – has gone.

What causes heart disease part 64 – Not changing your mind

22 August 2019

‘A new 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.’ Max Plank.

Perhaps the greatest challenge facing anyone who has a new idea is the sheer difficulty of getting anyone to change their mind. About anything. This difficulty is compounded if a committee, or any group of people, has to change their minds. Not only do they have to change their mind, they must make a public admission that they were wrong.

Many years ago, I was in contact with a geologist Thomas Gold. Yes, don’t worry, you have never heard of him. Neither had I. It was simply an honour that having read some of my ramblings he chose to reach out for a few on-line chats. Sadly, he is now dead.

He was a maverick. In the nineteen fifties he had been repeatedly thrown out of the American Geological Society for being a vigorous promoter of the tectonic plate hypothesis. Namely, that the Earth’s surface is make up of vast plates that glide about above the mantle. Not so much gliding as grinding very slowly.

Of course, this is now universally accepted as being true. Not so sixty years ago, when anyone mentioning tectonic plates was considered a dangerous fool, who understood nothing about geology, or science. Oh yes, indeed.

However, Thomas Gold did not stop with tectonic plates, he also promoted the abiotic theory of oil generation. I think he also came up with the idea of neutron stars as well. Anyway, getting back to abiotic oil generation, he did not believe that oil was created when trees – or other organic matter – died, rotted, went underground and was, gradually converted to oil.

He believed that oil was generated spontaneously within the Earth’s core. To quote:

‘Gold’s theory of oil formation, which he expounded in a book entitled The Deep Hot Biosphere, is that hydrogen and carbon, under high temperatures and pressures found in the mantle during the formation of the Earth, form hydrocarbon molecules which have gradually leaked up to the surface through cracks in rocks. The organic materials which are found in petroleum deposits are easily explained by the metabolism of bacteria which have been found in extreme environments similar to Earth’s mantle. These hyperthermophiles, or bacteria which thrive in extreme environments, have been found in hydrothermal vents, at the bottom of volcanoes, and in places where scientists formerly believed life was not possible. Gold argues that the mantle contains vast numbers of these bacteria.

The abiogenic origin of petroleum deposits would explain some phenomena that are not currently understood, such as why petroleum deposits almost always contain biologically inert helium. Based on his theory, Gold persuaded the Swedish State Power Board to drill for oil in a rock that had been fractured by an ancient meteorite. It was a good test of his theory because the rock was not sedimentary and would not contain remains of plant or marine life. The drilling was successful, although not enough oil was found to make the field commercially viable. The abiotic theory, if true, could affect estimates of how much oil remains in the Earth’s crust.’ 1

There you go. You have never heard of this before – ever. I think I can pretty much guarantee this. Neither had I. But I loved it. It was utterly and completely different to everything I had been told. Is it right, or is it wrong? No idea. I ain’t no geologist. Worth exploring as an idea though, surely.

What I do know, from speaking to Thomas is that almost all of his peers instantly rejected his ideas out of hand. Why? Because it didn’t fit with the knowledge they had been brought up with. Custom is king …

For many years it was taught that bacteria could not live in the human stomach. It was too hostile, too acidic. So, when it was proposed that a bacterium (H. Pylori), living in the stomach, could be an important cause of stomach ulcers, the idea was pretty much dismissed out of hand.

Warren and Marshall eventually proved that the scientific consensus on this matter was utter nonsense. This despite being attacked viciously from all sides. They eventually won the Nobel prize for their work where they were specifically praised for battling on in the face of implacable hostility. It is clear that had Warren not been a cussed swine, they could easily have given up, worn down by the opposition.

Had Max Plank not decided to publish some wild and whacky papers in his journal ‘Physics’, from a patent clerk, it is perfectly possible we may never have heard of a certain Albert Einstein.

When people ask me why do you think people cling onto the cholesterol hypothesis with such tenacity, is this vast conspiracy driven by the pharmaceutical industry? I expect most of them think I will say yes. I mean, obviously, there is a vast conspiracy going on to protect profits from cholesterol lowering.

However, the main reason why people cling to ideas is the natural human response – which is to reject new ideas out of hand.

“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.”  Wilfred Trotter

Ooh, I do like Wilfred Trotter. Here is another one of his:

‘The truly scientific mind is altogether unafraid of the new, and while having no mercy for ideas which have served their turn or shown their uselessness, it will not grudge to any unfamiliar conception its moment of full and friendly attention, hoping to expand rather than to minimize what small core of usefulness it may happen to contain.’

What has this to do with heart disease, you could ask? The answer is: almost everything.

1: https://enviroliteracy.org/energy/fossil-fuels/abiotic-theory/