Cholesterol and Suicide

Cholesterol and suicide

Society is engrained with the false idea that cholesterol is bad. This is the result of the diet–cholesterol–heart hypothesis that has been held to be the cause of the 20th century pandemic of coronary heart disease (CHD). It is not true.

But if “cholesterol is bad”, it means that our blood levels of cholesterol should be reduced, and this is emphasised by the cholesterol evangelists, who tell us “the lower the better”. This applies to people who consider themselves to be normal, and as a result we spend $20 billion each year on statin medications.

If we look just at CHD, we can see from the immensely important Framingham study that it is only in men below the age of 50 that a high blood level of cholesterol predicts an early death from CHD in the following 30 years. At the age of 50 itself the risk of death is very low.

If we look beyond CHD, we do not find that high blood level of cholesterol is a disadvantage, and in respect of many conditions it can be a significant advantage. Such conditions are mainly infections – pneumonia, post-operative infections, AIDS.

The Framingham study and the others are observational studies. These are very important as science and medicine starts with observation. Absolute conclusions cannot be assumed at this stage, and “proof” is a concept that becomes philosophical. 

Traffic in Beijing, 1994

Suicide

An interesting and clearly important study has recently been published and it concerns people who have died as a result of suicide, fatal self-harm.

The authors are from Beijing, and the paper is published in the Journal of Psychiatry and Neuroscience  (2016; volume 41). 

The study is a meta-analysis, a compilation of 65 published studies which met strict criteria for inclusion.

Those studied included patients with suicidal behaviour, patients without suicidal intent, and healthy controls.

The results are summarised as follows:

• the average (mean) serum cholesterol (total) level of suicidal patients was significantly lower than those of non-suicidal patients and healthy controls;
• when compared with controls, patients with violent suicide attempts had higher serum cholesterol level differences than those with non-violent suicide attempts;
• the serum LDL-Cholesterol level of suicidal patients was significantly lower than those of non-suicidal patients and healthy controls (LDL is regarded as the “bad” cholesterol);
• suicidal patients had significantly lower serum HDL-Cholesterol level than non-suicidal patients and healthy controls (HDL is regarded as the “good” cholesterol);
• the association between lower serum cholesterol levels and suicide was stronger in participants younger than 40 years than in older participants in most analyses; 
• compared with the highest serum total cholesterol level, a lower serum total cholesterol level was associated a 112% higher risk of suicide, including a 123% higher risk of suicide attempt and an 85% higher risk of suicide completion.

The figures show the lower cholesterol levels in suicidal patients. There was no significant difference between the average cholesterol levels in non-suicidal patients and healthy controls.

Relatively low cholesterol levels in suicidal patients compared to healthy controls

Relatively low cholesterol levels in suicidal patients compared to non-suicidal controls

A comment from the authors, but not an observation from the study:

“an increasing number of reports raise the possibility that statins, a class of lipid-lowering agents, may be associated with deleterious cognitive, mood and behavioural adverse effects, including violence, depression and suicide, which have been attributed to the effect of statins’ cholesterol level reduction on brain function.”

Turpan (below sea level), central China 

Conclusions

Conclusions from an observational study must be restrained. 

There is an inverse relationship between blood level of cholesterol and risk of suicide.

The nature of the relationship between low blood cholesterol and a higher risk of suicide can only be speculative, and I am not prepared to speculate.


The studies reviewed in this meta-analysis appeared to have identified the blood cholesterol levels of suicidal patients close to the time of suicide. A better approach would have been to record the cholesterol levels of a large population sample, and then follow up for a number of years and identify whether to not suicide has taken place. At that time cholesterol levels of those committing suicide could be compared to controls. Unfortunately this would require the surveillance of a very large number of people over several decades. The logistics and cost of such study would be prohibitive, and it is not likely to happen. If it were to be conducted, then the expected timescale would seriously reduce the value of the study: the concern is now, not in 2050! The long-term Framingham study does not appear to have recorded suicide death in relation to blood cholesterol levels.

The one conclusion that we can reach from the study outlined in this Post is that the dogmas that “cholesterol is bad” and must be “reduced as low as possible” are distinctly wrong.

There is much more to be learned about cholesterol and its metabolic importance, including its influence on brain function and behaviour. Unfortunately the false dogma that "cholesterol is bad" stands in the way of constructive research.

Shopping in Beijing, 1994

Statins – $20 billion per year should be spent differently

Statins – sense at last, in the Journal of the American Medical Association

Art Deco in Los Angeles

JAMA November 13th 2016

This edition of JAMA is devoted to the subject of statins, and the role of statins in the prevention of coronary heart disease (CHD). It is important to think of statins in terms of the prevention of CHD, and not just as a mechanism of reducing the blood level of cholesterol.

Many readers must wonder why I almost alone appear to be not just a sceptic of the diet–cholesterol–heart hypothesis, but also of low fat diets, the testing of blood cholesterol levels as a routine procedure, and the prescribing of statins for people who consider themselves to be normal. 

You might be surprised or even delighted to learn that I am not alone. The edition of JAMA November 13th 2016 is a landmark event and it provides very strong support for my rather heterodox views.

I have pointed out in previous Blog Posts that the alleged great benefit of statin drugs is an illusion. More than that, it is a giant conspiracy.

The most important paper in this edition of JAMA was the Editorial, summarising the other papers.

Statins for Primary Prevention 

The Debate Is Intense, but the Data Are Weak 

Rita F. Redberg, MD, MSc; Mitchell H. Katz, MD 

Rita F Redberg MD MSc is professor of medicine and director of Women's Cardiovascular Services in the division of cardiology at the University of California, San Francisco Medical Center.

Mitchell H Katz MD is the Director of the Los Angeles County Health Agency and the Director of the Los Angeles County Department of Health Services, the United States' second largest municipal hospital system. 

Dr Rita F Redberg

Dr Mitchell H Katz

I will present to you some of the important points made by Redberg and Katz.

“The evidence for treating asymptomatic persons with statins does not appear to merit a grade B or even a grade C recommendation.”

In general, recommendations for a given treatment can be strong (A), weak (C) or intermediate (B).   The editors judged the evidence presented to justify the use of statins in normal people to be less than weak.

“The report estimated an absolute benefit for use of statins of 0.40% for all-cause mortality and 0.43% for cardiovascular mortality and indicated that the absolute benefit was greater for patients at greater baseline risk.”

This is important because the editors are using the absolute measurement of risk reduction rather that proportionate risk reduction. I have indicated previously the importance of this. An example of the misleading nature of proportionate risk is that if a risk decreases from two in a million to one in a million, it can be expressed as a 50% reduction (proportionate) or one in a million (absolute). Absolute reduction gives real-world estimate, but proportionate sounds much more dramatic and is more likely to be a newspaper headline. The dramatic but misleading usual expression of a "20%" reduction of deaths with statin therapy is more realistically presented as 0.4%.

“Benefits of any preventive therapy accrue according to risk of disease (greater benefit in higher-risk patients), the harms of therapy usually distribute equally over all risk levels. Thus, persons at low risk have little chance of benefit but equal chance of harms and thus are more likely to have a net harm.” 

Someone at high risk is more likely to benefit from any preventative measure than someone at low risk. However the incidence of any side-effects will be the same in both. In people at low risk of CHD, there is a greater chance of side effects of statins than of benefit.

“The evidence base for harms of statins, despite the introduction of these drugs more than 20 years ago, is incomplete.”  

It was in the 1990s that statin drugs were introduced, but only on a very small scale compared to today. The clinical trials undertaken at that time did not publish any details of side-effects (untoward effects). Whether or not side-effects were recorded is not known to the general medical-scientific community. However such data might be held by the pharmaceutical companies that sponsored the trials and who have ownership of the results.

“Other studies have estimated that closer to 20% of statin users have muscle problems.”

This is denied by statin evangelists, without documentary support. The side-effects are rarely more than mild, but commonly troublesome. Ads above, the data have not been released.

“The actual trial data are largely held by the Cholesterol Treatment Trialists’ Collaboration on behalf of the industry sponsor and have not been made available to other researchers, despite multiple requests over many years.” 

I have mentioned in a previous post the Cholesterol Treatment Trialists’ Collaboration (CTTC), headed by Sir Rory Collins. This group of self-interested so-called medical scientists dominate cholesterol and statin publications, mainly through The Lancet. Only this group has access to the original data from the various trials – with the exception of WOSCOPS (the West of Scotland Trial), which  released all data in a second paper, outlined in a previous post. If side-effect data were collected in the trials, then the CTTC will have access but have not released them. The suppression of evidence by the CTTC is a crime. Being a private organisation, it is not subject to the Freedom of Information Act.

“The decision aid [available from the Mayo Clinic website] shows that of 100 people who take a statin for 5 years, only 2 of 100 will avoid a myocardial infarction, and 98 of the 100 will not experience any benefit.” 

This conforms to what I have stated. In the WOSCOPS trial, the five year death rate was 4.1% in the control group and 3.2% in the group treated with a statin. This was Scotland in the 1980s, about the world’s highest incidence of CHD deaths. Of 100 men (at the time high risk) taking pravastatin every day for five years, one did not die. 

“There will be no mortality benefit for any of the 100 people taking the medicine every day for 5 years.”

This is more recent than WOSCOPS. As the incidence of CHD death has fallen through natural processes (the development of immunity), small benefit of statins has become much smaller. A zero benefit of statins is an approximation. Calculated that at present, out of 100 men taking a statin daily for five years, the death reduction will be “0.19 men”, in other words 1 death delayed for every 500 “treated”.

“At the same time, 5 to 20 of the 100 will experience muscle aches, weakness, fatigue, cognitive dysfunction, and increased risk of diabetes.” 

This indicates that the overall disadvantages outweigh the advantages of this statin “treatment” (the statin is not really treating anything), but as the disadvantages are not fatal, the cost–benefit is judgmental.

“The US Food and Drug Administration issued safety label changes in 2012 stating that “Information about the potential for generally non-serious and reversible cognitive side effects (memory loss, confusion, etc.) and reports of increased blood sugar and glycosylated hemoglobin (HbA1c) levels [diabetes] has been added to the statin labels.” 

Although the statin evangelists such as Collins minimise or even trivialise the untoward effects of statins, the US FDA takes this seriously and the industry has had to accept this (reluctantly).

“The rate of statin use for primary prevention among persons older than 79 years had increased from 8.8% in 2000 to 34.1% in 2012.”

The criticism is that  this major increase of statin use in effectively normal people is uncritical and at a time when the risk of CHD death is very much lower than previously.

“There are unintended consequences of the wide-spread statin use in healthy persons.” 

The excess of untoward effects over benefit has already been noted, but the authors continue:

“People taking statins are more likely to become obese and more sedentary over time than non-statin users, likely because these people mistakenly think they do not need to eat a healthy diet and exercise as they can just take a pill to give them the same benefit.”

This is an interesting observation that is new to me. It demonstrates how unexpected effects can occur, and the importance of careful observation. 

“The task force evidence report estimated that to prevent one death from any cause over a 5-year period, 244 patients would need to take a statin daily.” 

The importance of this is that the NNT (the number needed to treat to prevent one endpoint, in this case death). This measure of benefit has been carefully avoided in the publications of clinical trials, and commentaries by the CTTC. The NNT is high in younger people and in women, and greater in men in in older age-groups. The actual number depends on these facts, which are not always expressed.

“The global market for statins has been estimated to be a staggering $20 billion annually in the last decade. For that kind of investment, better data on risks and benefits should be required.” 

This enormous sum of money could be used in other forms of health care. It is thus not just the cash but the opportunity cost: what health care benefits could be achieved by the expenditure of $20 billion each year? Only a careful and critical assessment of the possible benefit of statins could lead to a sensible debate about how $20 billion should be spent.

“Evidence that the medication will lead to a better quality of life, longer life, or both. Such evidence is lacking for statins in primary prevention.”

This lack of evidence of benefit suggests that the $20 billion would be better spent in other areas of health care.

The defunct hypothesis

The use of statins is underpinned by the diet–cholesterol–heart hypothesis which cannot be sustained and it should be abandoned. Unfortunately is so well established within society, nutrition, government, industry and medicine that it is effectively impossible to dislodge it. As Thomas Kuhn has pointed out in his interesting book "The Structure of Scientific Revolutions", an existing paradigm, no matter how unsafe, will not be abandoned until a better hypothesis becomes accepted.

Science is pragmatic, not absolute. The best and accepted answer to a problem will change as more evidence becomes available, or as existing evidence is scrutinised in more detail and with greater objectivity.

There are those who regard the “success” of the statin trials as “proof” of the diet–cholesterol–heart hypothesis. This is unjustified. First, in the trials only the taking of a statin was controlled and cholesterol was not controlled. Second, the very marginal benefit of statins gives little confidence in the hypothesis. When we take into account the fact statin benefit was unrelated to cholesterol-lowering, the hypothesis was not supported at all (data from WOSCOPS; data from other trials has not been released). 

There is a desperate need for a change in the paradigm of the causation of CHD. But if not the absurd diet–cholesterol–heart hypothesis, what alternative is there? I have described my strong preference, that the cause of the 20th century epidemic of CHD could only have been an environmental biological agent – a micro-organism the identity of which is not conclusive.

The problem is that conclusion might never be reached, but this is generally the pattern of science. Pragmatism is necessary because absolute proof is elusive. The conclusive demonstration of a microbiological causation of CHD would require the inoculation of “volunteers”, with follow up for the rest of their lives, for more than 50 years. 

A further problem is that volunteers of today will have inherited immunity to the causative micro-organism. It is the development of population (“herd”) immunity that will have brought the epidemic to an end. There is unlikely to be an animal model.

So we are stuck with a defunct hypothesis and it is backed up by a $20 billion per year industry. This is what we pay for statins given to normal people, and it is money that should be spent on much more worthwhile medical care.

Art Deco in Los Angeles

Cholesterol, Statins, and the Council of Nicaea

Cholesterol, Statins, and the Council of Nicaea

The Council of Nicaea, 325AD (Western painting)

A research paper might have a long list of authors, especially in the times of advanced scientific technology and many sites of collaboration. This is expected, and it is important to include the names of all those who contribute to the research. A characteristic of research papers from The Large Hadron Collider at CERN, France and Switzerland, is that there are usually hundreds of authors, and according to New Scientist (September 24th 2016) the first author has always, until very recently, been Georges Aad (by now very famous) as the authors have been listed alphabetically. 

When it comes to review articles, we might expect more than one author, perhaps just two or three. And so it was very surprising to come across a review article in a recent edition of The Lancet that had 28 authors. The first author is Professor Sir Rory Collins from Oxford University. After the first three authors, the next 24 appear to be in alphabetical order, with Professor Sir Richard Peto given the final place on the list.

Why does a review article require so many distinguished authors? 21 are professors and so they are obviously past the stage in their professional careers that requires their names to appear on as many publications as possible. What can be the purpose of a review article that requires so many distinguished authors?

The title of the paper is:

Interpretation of the evidence for the efficacy and safety of statin therapy 

Rory Collins, Christina Reith, Jonathan Emberson, Jane Armitage, Colin Baigent, Lisa Blackwell, Roger Blumenthal, John Danesh, George Davey Smith, David DeMets, Stephen Evans, Malcolm Law, Stephen MacMahon, Seth Martin, Bruce Neal, Neil Poulter, David Preiss, Paul Ridker, Ian Roberts, Anthony Rodgers, Peter Sandercock, Kenneth Schulz, Peter Sever, John Simes, Liam Smeeth, Nicholas Wald, Salim Yusuf, Richard Peto 

The Lancet (September 8th 2016 on line)

It might be thought that we have heard enough of statins being wonder-drugs saving countless thousands of lives. What's new? – Nothing! 

The randomised controlled trials were published several years ago and statins are the most widely prescribed drugs in the world. Why is it necessary for such a review to be published in The Lancet at this stage?

The stated aim at the start of the paper is expressed as follows: "This Review is intended to help clinicians, patients, and the public make informed decisions about statin therapy for the prevention of heart attacks and strokes."

I doubt if many clinicians will read this paper (30 pages) and its references (307). It is tedious and far from an easy read. To expect patients and the general public to read it is ridiculous. 

The statin trials are based on the diet–cholesterol–heart hypothesis, which is far from robust. The statin trials are therefore not objectively simple drugs trials, but are seen by the evangelists of the hypothesis to be strengthening the cholesterol–heart hypothesis itself (the diet component appears to be quietly dropped). 

We usually see in the title “Cholesterol-lowering with statins….”, which links the two variables. Statin medication is carefully controlled in the trials and is randomly allocated to half of the participants. But the cholesterol effect is not controlled: it is just observed in response to the statin medication.

There are many cholesterol sceptics, and I am one. By this I mean that the proposal that cholesterol causes coronary heart disease (CHD) does not stand up to serious scrutiny. Nor does it follow that statins are of benefit because of their undoubted cholesterol-lowering effect.

A paper of mine was published in The Lancet  (Lancet. 2006 Jul 1;368(9529):83-6) a number of years ago, questioning the way in which statins are helpful, the mechanism likely to be other than cholesterol-lowering. I drew an analogy with the treatment of epilepsy a century ago. At that time it was thought that epilepsy was caused by excessive masturbation (no-one defined "excessive"). The logical treatment was therefore bromide, the purpose being to suppress sexual fantasy and arousal. The treatment worked, but for reasons disconnected from the logic (bromide was later replaced by phenobarbitone, a sedative and anticonvulsant). Similarly, the idea that cholesterol causes CHD led to a logical treatment with cholesterol-lowering remedies. Of these only statins have been found to be effective, but this is empirical treatment and its effectiveness cannot be assumed to result from the logical indication.

Scepticism of the diet–cholesterol–heart hypothesis does not please Collins, the current leading exponent of the dogma. By the use of 28 distinguished authors and 30 pages of the prestigious Lancet, the paper is clearly designed to intimidate  and silence sceptics.

This sort of thing has happened before the present time.

The Council of Nicaea

During the first 300 years of Christianity, there were many different churches, many different books about Jesus and the events subsequent to his crucifixion. All were probably contented, that is until Christianity was hijacked by the Roman Empire. In 313AD the emperor Constantine the Great put an end to the persecution of Christians and he himself embraced the religion. It became the official religion of the Roman Empire in 380AD (the Edict of Thessalonica).

Emperor Constantine (statue at York Minster, UK)

However this gave no regard to the fact that different people or churches had different views of Christianity. Constantine declared himself the head of the Christian Church, not just the Emperor of the Roman Empire but also the “Emperor of Christianity”. If his authority was to be respected then the church must be unified.

To achieve this he convened the ecumenical Council of Nicaea in 325AD, with about 300 bishops being present. It was what we would call today a “consensus conference”. The result was the Nicaean Creed (the "consensus statement") which stated the official view of Christianity. The Creed was of course supported by a ruthless treatment of heretics in the western church.

The Council of Nicaea, Eastern icon

There was also a problem with the many books about Jesus and subsequent events in the first century of the present era. Many were rejected and considered to heretical, and following their destruction or disappearance, heterodox views were suppressed and lost. Aspects of what  must be regarded as the “truth” were hidden from the public domain and only few people know of those that have survived.

The paper by Collins et al in The Lancet is not unlike The Nicaean Creed (but much longer), and the 28 authors are not unlike the Council of Nicaea. The objective is clearly to suppress heterodox views and to bring to an end dissent of the diet-cholesterol-heart hypothesis. And also of course to bring to an end any debate or discord over the extensive and uncritical use of statins (“statins for all by the age of 50” - The Lancet).

The true benefit of statins

As we will see, statin drugs are of undoubted benefit, but there remains concern as to how much benefit. Does everyone benefit or just a few? There are side-effects; these can be troublesome but not dangerous. Do the benefits outweigh the side-effects?

The side-effects are uncommon, as the Lancet paper describes at great lengths. There are those who feel that the side-effects outweigh the benefits, but the paper strongly disagrees with this. The main side-effect is muscle pains, troublesome but not serious. It would be as well to know what the benefits are. 

The thrust of the paper is that all reliable evidence comes from the controlled clinical trials. The first section of the paper was to review the purpose and conduct of clinical trials in general, not really relevant to the alleged purpose of the paper but designed to strengthen authority. 

The paper also warns against using information obtained from observational studies – only the clinical trials are to be regarded as important sources of information. Unfortunately, the original data from the trials are held by the pharmaceutical companies that commissioned them.

CHD risk reduction

A lot of numbers are presented in the paper but the origins of them are far from clear. A 20% reduction in death rate from CHD is mentioned several times and although this is actually correct, it requires a level of understanding that was not presented in the paper. The various clinical trials of statins have shown that this proportional death rate reduction is consistent, at between 20% and 25%. This of course begs the question of “What is the death rate that is being reduced? 25% of what?” 

When it comes to the absolute reduction of death rate, the paper mentions a measure the origin of which is not clear. The absolute effect is assessed indirectly by the mmol/L reduction of LDL cholesterol. 

Remember that cholesterol is attached to protein in the blood and is found in three major forms: low density lipoprotein (LDL, “bad” cholesterol) very low density lipoprotein (VLDL, small in amount and not of major importance), and high density lipoprotein (HDL, the “good” cholesterol). The Lancet paper refers to LDL cholesterol, as is usual in more recent studies.

Cholesterol is in reality a poor indicator of CHD risk, and in the important forty-year Framingham Study (which will never be repeated) it is only applicable to men below the age of fifty. Figure 1 shows that 30 year survival is best (82%) in men aged 31–39 with the lowest blood levels of cholesterol (less than 4.7mmol/L) and worst (67%) in the those with the highest cholesterol (greater than 6.8mmol/L)

Figure 1 Cholesterol and survival, men age 31–39

Although blood level of cholesterol predicts the risk of death in the younger men, in older men there is no difference in 30 year survival based on the blood level of cholesterol. This is shown clearly in Figure 2. 

Figure 2: cholesterol and survival, men age 56–65

It is only to be expected that survival is much less in men aged 56–65 than in those aged 31–39. In the older age group, only 10% survived 30 years, that is to the age of 90. The survival curves are the same in all cholesterol groups.

The Framingham paper states:

The graph in Figure 1 (younger men) is used by cholesterol enthusiasts as a basis to predict a reduction of CHD deaths or events based on the reduction of blood cholesterol by statin therapy. The result in young men is usually extrapolated to older men and to women.

Figure 1 provides the basis for the use of absolute reduction of CHD deaths/events (improved survival) per mmol/L reduction of LDL-cholesterol. However the Framingham study was observational and so predictions based on it should be cautious.

This expression of a reduction of CHD deaths/events by statin therapy based on cholesterol-lowering is indirect and it is far from clear in the statin trials. It is a prediction. Unfortunately, and probably by design, the original data from the various trials are not generally available. The data are held by the pharmaceutical companies that commissioned the trials, and they have not been released despite frequent requests from independent academics led by the British Medical Journal.

West of Scotland

WOSCOPS

The first published statin trial of the primary prevention of CHD deaths using statin drugs was conducted in the West of Scotland: the West of Scotland Coronary Prevention Study, known as WOSCOPS. It was published  in 1995, but there was an important second paper published in 1998. This contained a great deal of original data, the equivalent of which has not been made available in the publications from the statin trials published later. 

WOCOPS was a randomised controlled trial of pravastatin involving 6595 men aged 45–64 years with an average blood cholesterol level 7 mmol/L (272 mg/deciliter), and followed up for 4.9 years. The men recruited into the trial had no previous clinical features of CHD – it was a primary prevention trial.

At the end of the study period, 4.1% of those in the placebo control group had died, and 3.2% in the pravastatin treated group. Pravastatin appeared therefore to be effective. It is important that there is a reduction of total deaths, as the easiest way to reduce only CHD deaths would be to cause an increase in deaths from something else.

The results show both definite coronary events and definite plus suspected coronary events. For the purpose of this brief analysis I will use the “definite + suspected” data. 

Deaths from definite + suspected CHD were 1.9% in the placebo group and 1.3% in the pravastatin group. Non-fatal MI occurred in 7.8% of the control group and  5.8% in the pravastatin group. Again effectiveness of statin therapy.

The absolute benefit from statins

The absolute reduction of all-cause death was 4.1% - 3.2% = 0.9%, approximately 1%. The absolute reduction in CHD death was 1.9% - 1.3% = 0.6%. The absolute reduction of non-fatal MI was 7.8% - 5.8% = 2%.

This is all simple and straightforward. The data is clearly presented in the WOSCOPS paper and it can followed easily. It logically means that for every 100 men aged between 45 and 64 years in the West of Scotland given pravastatin for five years, just one did not die as a result of the pravastatin (from 1% absolute reduction). It required 170 (from 0.6%, 100/0.6) to be treated to prevent one specific CHD death, and 50 (from 2%, 100/2) to prevent one non-fatal MI. 

These simple calculations can be expressed as the “number needed to be treated” (NNT) to achieve one endpoint, in this case death, CHD death or non-fatal MI. This is the best measure of effectiveness of a medical treatment, favoured by health economists but not by pharmaceutical companies.

This clear and simple approach to assessing effectiveness is not presented in the  paper by Collins and colleagues.

Proportional reduction of deaths

A 0.6% reduction in CHD death does not sound very dramatic, nor does a 2% reduction of non-fatal MI. They would certainly not be good for the marketing of statins. Therefore the pharmaceutical companies, and the research doctors and statisticians who they support or effectively employ, express benefit as the proportional reduction of death or other event rate. This was used in the paper by Collins and colleagues.

The proportional reduction is the proportion of expected deaths that did not occur in the treated group. It is calculated from the absolute death rate reduction in the treated group divided by the death rate in the placebo (control) group:  

1.9% - 1.3% / 1.9% 

and then expressed as a percentage, therefore 

0.6% / 1.9% = 32%

This widely-used calculation involves taking a percentage of a percentage, which is mathematically unsound.

We see a 32% reduction of CHD deaths in WOSCOPS. By a similar calculation we can arrive at 25% reduction in all-cause deaths, slightly higher than the 20% in most subsequent statin trials. 32% and 25% sound to be much more dramatic than 1%. However it begs the question, 32% or 25% of what? 

The answer is a 32% and 25% reduction of the current CHD and all-cause death rates in people not taking statins. If the current death rate is high we can expect a significant population benefit, but if the death rate is low there will be very little benefit.

As the death rate from CHD goes down (a good thing), the NNT goes up (a bad thing). There must be point at which the NNT is so high that statin medication for healthy individuals ceases to be of benefit to the population.

In the West of Scotland in the 1980s (the time of recruitment into WOSCOPS) the total death rate in middle-aged men was 4.1% after five years, as we have seen in the control population. This is 0.8% per year, and it equates to 800 per 100,000 per year. 

The background CHD death rate of these men in the West of Scotland in the 1980s was 1.9% after 5 years, or 0.4% per year (again from the control population). This is 400 per 100,000 per year. We can therefore see that half of all deaths in this age-group and in this location at this time were due to CHD. This was the epidemic at its greatest.

Scotland today - the utility of statins

Here we meet a problem. The calculation of the death rate from the specific group studied in WOSCOPS does not immediately translate into the data that comes from national statistics. In 1970 the peak death rate of 600 per 100,000 in Scotland was age-standardised, whereas WOSCOPS presented raw data that had not been manipulated for the purpose of national and international comparisons.

WOSCOPS, like other trials was snapshot, and we must look elsewhere if we wish to see any change in CHD deaths with time.

Figure 3: Changing CHD mortality in the UK, 1971–2013

We can see in Figure 3 (from the Scottish Office) that the age standardised male death rate from CHD in Scotland has fallen from 500 per 100,000 at the time of recruitment to WOSCOPS in the 1980s to 150 per 100,000 in 2013. This equates in 2013 to 0.15% per year CHD deaths, 0.75% at five years. 

We can expect statins to reduce the 2013 death rate at five years by 25%, from of 0.75% to 0.56%. The absolute reduction is therefore 0.19%. We can round this to 0.2% and the NNT is therefore 500 (0.2 x 500 = 100). This means that in 2013 in Scotland, 500 men aged 45–64 would need to take a statin for five years for one death to be delayed (immortality is not an option).  

The NNT would be about 1000 for women of that age whose death rate from CHD is about one half that of men. It would be much greater for men in their 40s than for men in their 60s. If the annual death rate in men at the age of 40 were 0.015% rather than 0.15%, the NNT would be 5,000 and for women 10,000. 

The age range of recruits into WOSCOPS was between 45 and 64 years. This is a wide age range. At present in the UK the risk of CHD death in men in the 55–64 age group is three times higher than in the 45–54 age group. This would mean a three times greater NNT. In the age group 35–44 the CHD death rate is one-ninth than in 55–64 age group, with a corresponding nine times greater NNT. This would be 18 times greater in women age 35–44, about 10,000. Hopefully not many healthy younger women are taking a statin.

The NNT is the true measure of the benefit of statins (or any other medication), and it is against this that the disadvantage of side effects must be balanced. 

The price of statins and the cost of benefit

There is also the financial cost to be considered. The present cost of 500 men treated for five years must be borne by the one who benefits and does not die during the five years. At the time of WOSCOPS only propriety pravastatin was available, the price being approximately £1 per tablet. For an NNT of 200 to prevent one CHD death the cost would have been £365,000, perhaps judged to be good value for money at that time. For reduction of all-cause death the cost would have been half that, £180,000 (there were slightly fewer trauma deaths in the pravastatin group).

The price of a non-proprietary 40mg pravastatin tablet is now £0.066. With the present CHD death rate and an NNT of 500, the cost of preventing one male CHD death is £60,000 (giving the statin at about the age of 60 years). To prevent a female CHD death, £120,000. Whether or not this is good value for money is a matter of judgement, but it must be balanced against other competing health-care costs and financial pressures.

In the younger women (35–44) with an NNT of 10,000, prevention (delay) of one death would cost £2.4 million! 

The elderly paradox

We have seen that one conclusion of the Framingham Study was that blood level of cholesterol did not determine life expectancy in men (and women) above the age of 50 years.

Other observational studies have shown a lack of positive association between blood levels of cholesterol and survival in the elderly (see previous Post). Some studies, and particular those from Paris, Honolulu and Connecticut, have shown that a high cholesterol level does not provide a survival disadvantage, and perhaps gives a longer survival. If despite this statins give an advantage, it would not be in keeping with the cholesterol hypothesis. Statins are prescribed only on the basis of blood level of cholesterol: in The Lancet, Collins et al make this clear.

The paper discussed this apparent paradox arguing that there is no paradox. It is stated that the elderly with low cholesterol levels had cancer or some other near-fatal condition. This was excluded in the various studies. However the subjects in these studies would have been frail as they had lost their independence and they were living in residential accommodation. 

To refute the suggestion that blood level of cholesterol is not a determinant of survival in the elderly, or even that a high level might be an advantage, Collins and colleagues referred to a British Medical Journal paper from 1994. This paper investigated the possibility that a low blood level of cholesterol might be related to certain disease states and found a weak association only with brain haemorrhage. However the paper (observational) did not stratify the populations or samples according to age and it did not not mention age-groups. Similarly it did not measure life expectancy, which is the measure in the more recent cholesterol–survival observations in the elderly.

This paper was misrepresented by Collins and his 27 colleagues. I wonder how many of the authors had actually read the paper (and its 309 references) to which their names were added.

CHD death reduction and cholesterol lowering.

The Lancet paper did not use the simple direct method of calculating benefit, but the cholesterol-lowering transposition. The second WOSCOPS data gives insight into this. 

The study divided the subjects taking pravastatin into five groups (quintiles) based on the change in the blood level of cholesterol during the study. The observed death rate for each group enabled an assessment of the relationship between death rate and cholesterol-lowering. The results are shown in Figure 4.

Figure 4: WOSCOPS CHD event rate based on change in cholesterol with pravastatin

In the first group (left) there was no change in the blood level of cholesterol (percent change = 0). This was at first puzzling, but it became clear that the men in this group had not actually taken the pravastatin, or at least not reliably. Compliance can be checked in most trials today by detecting randomly the blood level of the drug, but this was not possible in WOSCOPS. We can see that this group, who appeared not to have taken the pravastatin, had the highest death rate of the five groups.

In the other four quintiles there was lowering of cholesterol, by 12%, 24%, 31%, 39%. The tablets had been taken and blood levels of cholesterol had fallen by these amounts. The death rate was reduced in all groups, but unexpectedly by about the same amount. There was clearly no association between the quantity of cholesterol-lowering and reduction of CHD death rate. This is clear from Figure 5, which removes the group in which there was no change in cholesterol (statin not taken). 

Figure 5: lack of association between cholesterol lowering and CHD events

This detail of data has not been made available from the other statin trials. It is ignored in the meta-analysis of Collins and colleagues, the Cholesterol Treatment Trialists’ (CTT) Collaboration. Most publications of CTT appear in The Lancet, perhaps an editorial bias by this journal.

Conclusion

Not only has the truth been hidden from public view in this long and tedious Lancet paper but its highly prestigious multitude  of authors is clearly designed to suppress dissent. 

I would recommend the two WOSCOPS papers (1985, 1988) as they are good examples as to how trial data should be presented, and then a deeper understanding of the data processing. It was an objective trial but its example was not followed subsequently.

The conclusion of the authors of WOSCOPS (1988) reads:

“Analysis of the relationship in WOSCOPS between the pravastatin induced fall in LDL cholesterol and reduction in CHD risk did not yield the predicted result…. fall in LDL cholesterol failed to be a significant predictor of risk reduction….the influence of pravastatin on CHD risk could not be completely explained by the reduction in LDL cholesterol….the benefit seen with pravastatin treatment, although obviously linked to a decrease in LDL, cannot be explained by this alone.”

This heresy has now been suppressed, but it must not be forgotten. It is one of the major factors that invalidates the diet–cholesterol–heart hypothesis. 

WOCOPS was transparent but subsequent statin trials made certain that much data remains concealed.