Saturday, 17 February 2018

Multiple Sclerosis, micro-organism and the Sun - the link becomes more plausible

West of Scotland: John Lowrie Morrison – Jolomo

Multiple sclerosis (MS) is a well-recognised disabling and often ultimately fatal neurological disease that affects young adults. Its cause is not known. 



The "Cause"

The cause of MS is said to be "auto-immune", which means that inflammatory processes are involved with immune reactions. However "auto-immune" can only be a mechanism of disease and not a true cause.


Figure 1. MRI scan of brain showing multiple deep seated sclerotic lesions as light grey patches



The cause of a disease is its prime mover, the initiator of the disease process. It is invariably identified from the epidemiology of the disease, its distribution within society and the world. Examples are cigarette smoking and lung cancer, aniline dyes and bladder cancer, contaminated water and cholera, family patterns and genetic conditions. In particular, clues arise from changes in the incidence of the disease and its spread in time or geography.

It has been known for many years that the geographical incidence of MS (new cases per year) varies considerably. It is very rare south of the European Alps, and its incidence is much higher in Northern Europe. The world's highest incidence appears to be in the West of Scotland.


Figure 2. Geography of MS, higher incidences in darker colours
We have seen this pattern previously. The epidemiology of MS is remarkably similar to that of coronary heart disease (CHD). The link is likely to be a common susceptibility rather than specific cause.

I have previously stated my contention that CHD is due to one or more micro-organisms, the identity of which we cannot yet be certain, or of which we are completely ignorant. Although a number of micro-organisms are likely to be responsible for background sporadic CHD, a specific single micro-organism must have been responsible for the 20th century epidemic. So it is for influenza: a number of strains can cause the illness over many years, but a specific strain is responsible for an epidemic.

Epidemics

Epidemics give important clues as to causation, whether a micro-organism or a chemical poison. Epidemics are never due to genetic factors.
Figure 3. Location of the Faroe Islands in the North Atlantic
Epidemics of MS have been described in the Faroe Islands in the Northern Atlantic during World War 2. Previously MS was thought to be unknown in the isolated Faroe Islands, but in 1943 there were 23 new cases, in a population of only 25,000. There were subsequently smaller epidemics of 10, 10 and 12 cases.


Figure 4. Faroe Islands
These small but significant epidemics followed the establishment of RAF (Royal Air Force) bases on the Faroe Islands. The purpose of these was to provide air support for war-time shipping convoys crossing the North Atlantic.

In the absence of alternatives, it was thought that the epidemics must have resulted from transmission of a micro-organism from the staff of the RAF who were stationed on the islands. The identity of the micro-organism could not be established at that time, and it has not been stablished subsequently.
Figure 5. RAF Bristol Blenheim bomber as was stationed on the Faroe Islands
The transmission of micro-organisms around the world is well-known. The sea voyage of Christopher Columbus to the West Indies in 1492 made land-fall in what is now known as the Dominican Republic. 90% of the population were shortly to die from smallpox, contracted from the crew. Smallpox was unknown in the Americas and the populations had no immunity (that is inherited or "herd" immunity). 

In return the crew brought syphilis from the Americas to Spain, and thus to Europe. It ravaged the population, which had no immunity, and it was four hundred years before the microbial cause was identified.

MS in the Armed Forces of the UK

New evidence has just become available, supporting the transmissible nature of MS and the likelihood that it is due to a micro-organism. 

It has been identified that the incidence of MS is much higher in former members of the armed forces (military) than in the general population. 



The incidence of MS in this study has been based on deaths, rather than true incidence (new cases per year) or prevalence (number of cases at a moment in time) of the condition. However MS tends to be ultimately fatal and so death rate is a useful measure.


The study was based on 3,688,916 deaths in the UK among men aged 20–74 years. Occupations of the deceased had been recorded and there were 26,507 whose last recorded occupation was "military". There were 7485 deaths from MS, and 129 of these were in the military group.

Therefore in the general population dying during a period of 30 years, 7485 out of 3,688,916 deaths were the result of MS, and in those who had been in the armed forces 129 out of 26,507 their death  was the result of MS. 

These findings can be expressed the Proportional Mortality Ratio (PMR). The PMR standardises the frequency of deaths in the overall population at 100. This is compared to the subgroup under investigation. A PMR in the subgroup greater than 100 indicates that the cause of death is more common, and a PMR less than 100 indicates that it is more rare.


Table. Proportional (Standardised) Mortality Rate of MS in former military workforce
[The mathematical process of standardisation is quite simple. To standardise the population PMR at 100, the mathematical formula is 100  0.002029 0.002029 = 100. To find the relative PMR of military personnel the formula will be 100 x   0.004867 /   0.002029 = 240.]

We can see in the table that the PMR for MS in former armed forces workers is 240, which is of course two and a half times that of the general population.

This is a major difference in incidence, much higher in people who had been in the armed forces. Why should this be?

Transmission of a biological agent

There appears to be no explanation in terms of chemical exposure, as the difference remained unchanged during each of the three decades included in the study.

The authors felt that the only plausible explanation concerned the fact that members of the armed forces live and work closely together during many years. This implies a transmissible agent as the cause. Person to person transmission is usually a biological agent, a micro-organism.

Is there a reason why MS could not be due to a micro-organism? The answer is "no". There is no competing putative cause, and the experience of the Faroe Islands and the UK military is strong. Direct transmission studies in humans would hardly be ethical and animal inoculations are unlikely to work. Whereas tuberculosis could be transmitted to a variety on animals, this experience does not extend to many other disease–animal experiments.

One of the problems of research into MS is the lack of available pre-mortem biopsy material, the disease being located deep within the brain. The cerebro-spinal fluid (CSF) is readily available for sampling, but it is not as useful as affected brain tissue.

There have been previous suggestions of a micro-organism causing MS, spirochetes and cytomegalovirus, but without transmission studies the identification of a causative organism is unlikely to be conclusive. 

There is the precedent of neuro-syphilis, which leads to the clinical syndromes of the dementing condition general paralysis of the insane (GPI) and also the disabling condition tabes dorsalis (TD). Both manifestations of neuro-syphilis are chronic and ultimately fatal, rarely seen today but a very major health problem a century ago. It was about 350 years before the neurological condition was linked to the primary sexually transmitted infection, and a further 50 years before the causative spirochaetal organism Treponema pallidum was identified. Unethical and effectively criminal human transmission studies were undertaken in the mid-20th century, before medical ethics was established. Such  conclusive studies cannot be undertaken today.

Geography and the Sun

The geography of MS fits in with a microbiological cause. An increasing incidence of disease with increasing distance from the equator (in both hemispheres) indicates a simple latitude factor, the incident sunlight energy at ground level. There is further evidence of the importance of vitamin D in the development of MS. There is a seasonal effect: the highest incidence is in people born in the spring. This means that the later stages of gestation would have been during the winter when sun intensity is at its lowest.


Autumn/winter birth gives lower risk of MS
Figure 6. Month of Birth and risk of MS in the UK
It is known that vitamin D enhances immunity. A failure of full immunity results in greater susceptibility to infection. We can therefore appreciate that whereas MS is extremely rare in countries such as Italy and Greece, the world's highest incidence is in the West of Scotland (tuberculosis and CHD are similar). Even further north in the Faroe Islands immunological defence would be low but MS only occurred when the causative micro-organism arrived in 1943.


The further away from the equator you live, the greater the risk of MS

Links:

MS in the Faroe Islands
https://www.ncbi.nlm.nih.gov/pubmed/371519

MS deaths in UK armed forces
https://academic.oup.com/occmed/article/67/6/448/3872312/Mortality-from-multiple-sclerosis-in-British

Risk of MS and month of birth http://www.bmj.com/content/330/7483/120





Tuesday, 16 January 2018

High blood cholesterol gives a survival advantage



High cholesterol is good


Previous Posts have shown that the existing dogma that "a high level of cholesterol in the blood is bad" is only true in men below the age of 50 years. In women of this age, the blood level of cholesterol is of no value in determining coronary risk or life expectancy.

The most important source of information is the 30 year follow-up of the observational US Framingham study, published in 1987. The conclusion (effectively ignored) is as follows:



The study did not extend beyond the age of 70 years and so the conclusion is limited. However other studies have shown that beyond this age a high cholesterol level is associated with the best survival. There are three important studies showing this that I have reviewed previously: the Paris study, the Honolulu study, and the Stamford (USA) study. There are several other studies showing the same thing. 

New evidence

Now there is a further study, this from the Aging Research Centre at the Karolinska Institute – Stockholm University.

Serum total cholesterol and risk of cardiovascular and non-cardiovascular mortality in old age: a population-based study 
Liang et al. BMC Geriatrics (2017) 17:294 DOI 10.1186/s12877-017-0685-z 

The study involves the observation of 3090 adults aged 60 years or above, from a population cohort. The average length of follow-up was 7.2 years, that is 23,196 person-years of observation. During this time 1059 participants died, 34.3%.

Compared with those who were still alive at the end of follow-up, and after controlling for age, those who died during follow-up were:

  • older, 
  • less likely to have a university education, 
  • less likely to be former smokers or current smokers (surprising), 
  • more likely to be physically inactive, 
  • more likely to have a lower level of total cholesterol, 
  • more likely to have diabetes, 
  • more likely to have cognitive impairment, 
  • more likely to have mobility limitation. 

Whether or not the participants died or did not die did not differ significantly: 

  • in the male/female proportion,
  • in the prevalence of heavy alcohol drinking, 
  • in the prevalence of obesity, 
  • in the prevalence of hypertension,
  • in use of cholesterol-lowering  medications. 
For the purpose of survival analysis all the participants were divided into three groups based on the blood level of cholesterol at the onset of the study: 

  • less than 5.18mmol/L, 
  • 5.18 to 6.21, 
  • greater than 6.21.

The results are displayed in Figure 1.

Figure 1. All cause mortality based on blood cholesterol level

It is clear in Figure 1 that the highest mortality rate (71.8 per 1000 person-years) is in those with the lowest blood levels of cholesterol, less than 5.18 mmol/L. The lowest mortality rate (35.6 per 1000 person-years) is in those with the highest blood levels of cholesterol, half the death rate than in those with the lowest cholesterol. Why is this not publicised?.

Statin effect

During the past 20 years an increasing number of the population have been commenced on long-term cholesterol-lowering therapy, and especially statins. This has added a complication to cholesterol-related observation studies, but it is good to see that such studies continue, demonstrating an academic scepticism of the often-stated dogma that “The lower cholesterol the better”. My recent Post of evolocumab shows that this simply is not true, but it is as well that other people think the same as I do.

An important point is that a low level of cholesterol in an individual can be a “natural” level, a person-characteristic, or it can be the result of statin or other cholesterol-lowering medication in someone with a naturally higher level.

In the Stockholm study the participants are divided into whether or not they take statins (and other cholesterol-lowering medications), but statin intervention was not part of the study: it was purely observational.

In the results we see mortality displays for all the participants (as in Figure 1), those not taking cholesterol-lowering medications, and those who during the study were taking cholesterol-lowering medications (mainly statins).

We also see analysis of all-cause mortality, cardio-vascular disease (CVD) mortality, and non cardio-vascular disease mortality.

All cause mortality

Figure 2 shows all-cause mortality, the most important outcome measure.
Figure 2. Mortality from all causes related to blood cholesterol level

We can see a similar pattern to Figure 1, but it is a little more complicated.  The blue columns, all participants, are as in Figure 1. But we see in addition the division between those not taking statins (green) and those were taking statins (yellow).

The first group of three columns concerns those with low cholesterol (<5.18). We can see that those not taking statins (green column) have the highest mortality. This is a natural low cholesterol and it is clear that it gives a distinct survival disadvantage – it is a bad thing.

But the yellow column, those taking statins, does not really tell us very much. These participants would have a natural cholesterol significantly higher, but we do not have the information, we do not know the pre-statin cholesterol level. 

We can see in the second group (5.18–6.21) and the third group (>6.21) that having a higher cholesterol is associated with a lower mortality rate, a survival advantage, compared to the first group. The participants in the yellow column of first group (those taking statins) would have a similar natural cholesterol level to the second and third groups.

Cardiovascular mortality

In Figure 3 we can see the same analysis but looking at death from cardio-vascular disease (CVD) – strokes and heart attacks.

Figure 3. Cardiovascular mortality related to blood cholesterol level

The pattern is the same. Those with the lowest blood level of cholesterol have the highest mortality, the opposite of what we have been told. Those taking statins (yellow) in the first group would have a natural cholesterol as in the higher cholesterol groups, and therefore have a similar lower mortality rate. 

Non-cardiovascular mortality

Finally we see in Figure 4 mortality due to to causes other than cardio-vascular disease. Such conditions would be cancers or  pneumonia. 

Figure 4. Non-cardiovascular mortality related to blood cholesterol level
The pattern is the same, but course the number of deaths is lower in the subgroups than in the total numbers shown in Figure 2.

Low cholesterol is not a good thing, but if the low cholesterol is because of taking statins, then the mortality rate is similar to those with higher levels of cholesterol.

Conclusion

This is another good quality study that demonstrates clearly, and contrary to what we are generally told, that a high cholesterol level in the blood is a good indicator for a longer than average life expectancy.

Why are we not told this? The information has been available for many years but it has been suppressed. 

There are so many vested interests in perpetuating the myth that cholesterol is effectively poisonous, killing us in proportion to its level in the blood. This is the basis of many academic careers and the rationale of cholesterol-lowering medications, especially statins. 

The self-appointed and powerful Cholesterol Treatment Trialists’ (CTT) Collaboration controls public and government policy, and falsely perpetuates the identity of cholesterol as the "cause" of heart disease and premature death. 

We can see that this is wrong.

In a person over the age of 60 years, a high blood cholesterol is clearly a good thing. Correspondingly a low blood cholesterol level gives a serious survival disadvantage. However this is only true if the low cholesterol level is "natural". 

If low blood cholesterol is the result of statin or other cholesterol-lowering medication, then there is no survival disadvantage and there is no need for concern.

We can conclude that it is not really the cholesterol level of the blood that determines future health and survival, but what we might regard as "the constitution" of the individual that is responsible that natural cholesterol level.







Friday, 5 January 2018

PURE study - vegetables are good

PURE - Fruit, Vegetables, and Legumes 

We have already looked at the large multinational Prospective Urban Rural Epidemiology (PURE) study. The objective of the study was investigate the dietary advice to which we have been subjected during the past half-century. 

The first paper concentrated on fats and carbohydrate. The conclusion was that dietary fat advice has been wrong: a higher proportion of the fat intake of the diet is associated with a lower rate of total deaths, cardiovascular disease (CVD) events, and CVD death. A higher proportion of  carbohydrate intake is associated with worse health outcomes.

Reducing total food intake might be necessary weight control, but reduction of the proportion on calories from fat, although encouraged officially, is not correct.




The second PURE publication in The Lancet is devoted to the relationship between health outcomes and intakes of fruit, vegetables and legumes. 135,335 individuals from 18 countries were included in this analysis. The countries included 3 high-income (Canada, Sweden, and United Arab Emirates), 11 middle-income (Argentina, Brazil, Chile, China, Colombia, Iran, Malaysia, occupied Palestinian territory, Poland, South Africa, and Turkey) and 4 low-income countries (Bangladesh, India, Pakistan, and Zimbabwe). 


The investigation of fats and carbohydrate in the first paper looked at the relative proportions of each in the diet. Inevitably therefore, if the proportion of fat was reduced (on advice), then the proportion of carbohydrate must increase, and vice versa.

The second paper is different in this respect. It looks at the consumption of fruit, vegetables and legumes in absolute measures, the actual amount consumed. 

Because of the large number of participants in the study from many countries, it was not possible to measure the amounts in mass units (eg grams). The measurement used was simply the number of portions per day, recognising that the size of a protion would vary from one person to another. 

Results

During a median follow­-up of 7·4 years, there were 4784 major cardiovascular disease events. Greater fruit, vegetable, and legume intake was associated with a lower risk of major cardiovascular disease events.
Overall, higher total fruit, vegetable, and legume intake was inversely associated with major cardiovascular disease, myocardial infarction, cardio­-vascular mortality, non-­cardiovascular mortality, and total mortality when adjusted for age.
Life expectancy, heart disease, and consumption of fruit, vegetables and legumes
Figure 1
The overall results can be seen in Figure 1 above, a rainbow graph that can be broken down into its constituent parts.

For example, in Figure 2 we see just total deaths. 


Figure 2
The group with the lowest intake of fruit, vegetables and legumes (<1 portions per day), we see a relatively high death rate from total deaths (all causes) of 8% during the study period, compared to 3% in those who consume more than 3 portions per day.

If we look again at Figure 1, we see the pale blue bars which represent cardiovascular events. We can see that there are 4% cardiovascular events in the consuming up to 5 portions of fruit, vegetables and legumes per day, compared to 3% in those in the groups consuming more than  5 portions per day.

All morbidity and mortality events are higher in this with the lowest consumption of fruit, vegetables and legumes.

It is interesting to look at the geographical variations of consumption of fruit, vegetables and legumes. The total amounts can be seen in Figure 3.


Figure 3 Geographical variation of consumption of fruit, vegetables and legumes
The highest consumption is in the Middle East, and this is due to a particularly high consumption of fruit.
It is also found that people who consumed more fruits, vegetables and legumes had higher education, higher levels of physical activity, lower rates of smoking, and higher energy, red meat and white meat intake, and were more likely to live in urban areas. 

Summary

A greater fruit, vegetable and legume intake is associated with a lower risk of major cardiovascular disease, myocardial infarction, cardiovascular mortality, non­-cardiovascular mortality, and total mortality in the analyses adjusted for age 
In this study,  3·2 servings is equivalent to 400 g of fruit, vegetables and legumes per day. Many dietary guidelines in North America and Europe recommended intake ranging from 400 to 800 g/day, but for most individuals in poorer countries in other continents these targets are unaffordable .

The study indicates that even three servings per day (375 g/day) show benefit against non­-cardiovascular and total mortality, and indicate that optimal health benefits can be achieved with a more modest level of consumption, an approach that is likely to be much more affordable. 

Mechanism

The PURE study is observational and it does not try to investigate the possible ways in which diet might influence human health.  It is a public health investigation, to look for empirical ways in which diet can be recommended to improve health and survival. A high fruit, vegetable, and legume diet can be encouraged without understanding the mechanism of benefit.
Several mechanisms have been proposed to explain the lower risk of cardiovascular disease with higher consumption of fruits, vegetables, and legumes. This would include cereals as a diet high in fibre has been related to lower CHD risk, but there is no conclusion as to mechanism.











Sunday, 10 December 2017

PURE - Is this the end of 50 years of dietary advice? It should be.



Several of my Posts have been to expose the absurdity of the diet-cholesterol-heart hypothesis, which has dominated healthy diet advice during more than half a century.

The relationships between diet, cardiovascular disease, and death are topics of major public health importance, and subjects of great controversy.
In European and North American countries, the most enduring and consistent diet advice is to restrict saturated fatty acids, by replacing animal fats with vegetable oils and complex carbohydrates
During the past fifty years there has been little questioning of the theory; the advice to reduce dietary cholesterol and fats continues unchecked. However there have been many studies that have have shown that the diet component of the theory is not sustainable, but the results of these studies have failed to make an impact on popular belief.

The view of a growing number of scientists is that advice to restrict saturated fatty acids is “largely based on selective emphasis on some observational and clinical data, despite the existence of several randomised trials and observational studies that do not support these conclusions”

The PURE study

A large study was recently published in The Lancet. It is known as the Prospective Urban Rural Epidemiology (PURE) study. It investigated the health outcomes of 135,335 individuals aged 35–70 years of age, followed for an average of 7.4 years.

The study was undertaken in 18 countries. These included 3 high-income (Canada, Sweden, and United Arab Emirates), 11 middle-income (Argentina, Brazil, Chile, China, Colombia, Iran, Malaysia, occupied Palestinian territory, Poland, South Africa, and Turkey) and 4 low-income countries (Bangladesh, India, Pakistan, and Zimbabwe). 





Dietary patterns were recorded in detail. The subjects were divided into five groups (quintiles) for diet category, Quintile 1 being the lowest 20% of specific intake, and Quintile 5 the highest 20% intake.

The study documented 5796 deaths and 4784 major cardiovascular disease events.  The main morbidity/mortality categories were total deaths, cardiovascular (CVD) deaths, major CVD events, myocardial infarction (heart attack, MI), and stroke.

Findings

The study was complex in that a great deal of data were recorded and presented in the Lancet paper. I cannot present all the data in this review, but I will concentrate on the two major diet groups of saturated fat and carbohydrate.

The study does not record the absolute consumption of food and its constituents, but just proportions. In other words, if fat intake is reduced then the proportion of carbohydrate inevitably increases, and vice versa. 

Dietary Fats 
higher proportions of fat in the diet are linked to lower death rates
Figure 1. Fat intake association with mortality and morbidity

In the “rainbow” Figure 1, we can see on the horitontal x-axis of the graph the 6 categories of morbidity and mortality. Each category or group needs to examined separately. Within each group are the quintiles of fat intake, the lowest on the left and the highest on the right. Each quintile has its own colour, and the legend is shown at the top.

The vertical y-axis indicates the incidence of deaths or major events, incidence per 1000 person-years.

Let us first look at “total mortality”, the first group.  shows a decline in mortality with increasing fat intake, from 7 events per 1000 person-years in quintile 1 to  4.2 events in quintile 6.

We can also see the same pattern in respect of  “major CVD”, “stroke”, and “non-CVD deaths”. There is no effect on MI and CVD deaths.

It appears that there is no detriment to a high proportion of the diet being saturated fats, and there is a significant advantage in respect of total and non-cardiovascular mortality. This is not what we have been led to expect.

Dietary carbohydrate


Now we will turn to dietary carbohydrate and its relationship to mortality and cardiovascular illness.


This is summarised in Figure 2, which looks like Figure 1 but the results different.

higher proportions of carbohydrate in the diet are linked to higher death rates
Figure 2. Carbohydrate intake association with mortality and morbidity

Within the group of “total mortality” we can see that as the proportion of carbohydrate increases from quintile 1 to 5, the mortality rate increases. 

There is a similar but less significant pattern for major CVD events, stroke and non-CVD deaths.

There are no effects on MI and CVD deaths.

In respect of total mortality, non-cardiovascular deaths and major CVD events, a high proportion of carbohydrates in the diet is not a good thing.

Conclusions

During the past 50 years dierty advice reduce the fat content of our diet has inevitably increased the carohydrate proportion. Therefore advice to reduce fat intake, and therefore increasing proportion from carbohydrate, is likely to have increased deaths and major events, the opposite of the intention of public health advice.

The dietary component of the diet–cholesterol–heart hypothesis has perhaps been quiety side-lined by the cholesterol “experts”. But the cholesterol – heart component continues and despite evidence to the contrary it underpins the pharmacological “treatment of cholesterol”. Cholesterol now seems to be a disease in itself.

In the PURE study a higher proportion of total fat  intake and each type of fat was associated with a lower risk of total mortality .
Higher saturated fat intake was associated with lower risk of stroke. 
Total fat and saturated and unsaturated fats were not significantly associated with risk of myocardial infarction or cardiovascular disease mortality. 
Higher carbohydrate intake was associated with an increased risk of total mortality but not with the risk of cardiovascular disease or cardiovascular disease mortality. 

The authors conclude with this statement:
“Global dietary guidelines should be reconsidered in light of the consistency of findings from the present study, with the conclusions from meta-analyses of other observational studies and the results of recent randomised controlled trials.”

Will we see any change of official diet policy?














Wednesday, 1 November 2017

Evolocumab - cholesterol myth and vested interests



There is a new medicine now available for lowering cholesterol and thereby intended to prevent deaths from coronary heart disease (CHD).

Evolocumab

A few short-term trials have been published that have demonstrated that evolocumab (evo-locu-mab) lowers the blood level of cholesterol very significantly, beyond the effect of statins. But a demonstration of clinical benefit is much more important, especially as we know, that despite what we are told, cholesterol-lowering is not related to reduction in CHD death rate.

Evolocumab is produced by the pharmaceutical company Amgen (see below). It is a monoclonal antibody that inhibits “proprotein convertase subtilisin–kexin type 9 (PCSK9)” and it thereby lowers low-density lipoprotein (LDL) cholesterol levels in the blood. Metabolic details are not important to us at present. There are now many monoclonal antibody medications, ending in -mab, and used in a variety of clinical settings. They need to be given by injection or infusion and they are expensive. They can be dangerous.


The Clinical trial



A randomised controlled clinical trial (RCT) has now been published in the prestigious New England Journal of Medicine (the FOURIER study). 

The study was of 27,564 patients, aged between 40 and 85 years, with known atherosclerotic cardio-vascular disease, with blood LDL-cholesterol level 1.8 mmol/L (70mg per decilitre) or above, and already receiving statin therapy. The study took place in 49 countries.

The subjects were randomly allocated to receive either evolocumab  (13,784) by injection every two weeks (or every month in higher dose) or placebo (presumably saline) by injection (13,780).

The primary outcome endpoint in the trial was "a composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization”. The secondary endpoint was "a composite of cardiovascular death, myocardial infarction, or stroke”. 

Outcomes

There was a large reduction in blood level of cholesterol in the treated group, by 59% compared to those receiving placebo. But did this translate into clinical benefit?

At first sight, “yes”. There was a reduction of endpoints in those receiving evolocumab compared to placebo.




These results represent proportionate reductions of 9.8% and 7.4% respectively. This sounds good, but I have previously criticised clinical trial results for displaying proportionate changes rather than absolute changes, which better represent the real world. 

The absolute reductions of both primary and secondary event rates are 1.5% (11.3 - 9.8% and 7.4 - 5.9%). This means that 67 people (100 / 1.5) would need to be treated for about one year to prevent just one end-point. 67 is therefore the Number Needed to Treat (NNT) to achieve this.

Deaths

What we are not told in the summary becomes more interesting than what we are told, but the details can be found in the full paper. 

The composite endpoints mix deaths with non-fatal events, and this is a dubious method of analysis. There is in fact a slight excess of deaths in the evolocumab treated group than in the placebo group, but this is hidden within the composite bundle of events.

The strange thing is that the trial was stopped prematurely, when the median duration of treatment was just 22 weeks, and when the subjects recruited later had been in the trial for just a very short time. The initial plan had been to continue the trial for 4 years duration of treatment, and so why had it been stopped so early? The reason given is that at 48 weeks from the onset of the trial the result had shown a benefit from evolocumab – that is in the composite bundle analysis. 

But at 48 weeks (the longest time that a subject had been in the trial) there was a slight excess of deaths in the evolocumab group, deaths from any cause and also deaths from cardiovascular disease.





The excess of deaths was small and when the trial was stopped it had not reached statistical significance. It would require 1000 people to receive the medication for about one year for one excess death to occur. But after 4 years (when the trial was planned to end) it almost certainly would have reached statistical significance. Premature ending of the trial avoided this likely serious and negative conclusion.

Conflicts of Interest

We must ask ourselves: is the trail really objective and honest? The trial results were presented with significant “spin”, that is the political ploy of presenting bad news as good news, in this case as the composite endpoints. The spin was enabled by the process of the "bundle of composite endpoints", in which deaths were lost.

The names of the authors of the paper are shown above. A look at some of their details (showing declared conflicts of interest) will give a clue as to whether they might not be objective. Amgen is the pharmaceutical company  that manufactures evolocumab.

RPG reports grants and personal fees from Amgen, during the conduct of the study; grants and personal fees from Amgen, Daiichi-Sankyo, and Merck; and personal fees from Amarin, American College of Cardiology, Angel Med, Beckman-Coulter, Boehringer Ingelheim, Bristol- Myers Squibb, CVS Caremark, GlaxoSmithKline, Janssen, Lexicon, Portola, Pfizer, Regeneron, Sanofi-Aventis, St Jude, and Stealth Peptides, outside from the submitted work. 

TRP reports grants and personal fees from Amgen, during the conduct of the study; and personal fees from Amgen, Sanofi, Merck, Boehringer-Ingelheim, and The Medicines Company, outside the submitted work. 

GMDF reports grants and personal fees from Amgen, during the conduct of the study; grants and personal fees from Amgen and MSD; grants from Boton Scientific; and fees from LivaNova and Sima Tau, outside the submitted work. 

ZAG reports personal fees from Amgen and Sanofi, during the conduct of the study. 

RC reports grants from Pfizer– International Atherosclerosis Society; and personal fees from MSD, Bayer, Amgen, Boehringer Ingeslheim, Sanofi, AstraZeneca, NovoNordisk, Servier, and Kowa, outside the submitted work. 

IG-B reports personal fees and non-financial support from Amgen and Sanofi; and personal fees from Eli Lilly, Regeneron, and Aegereon, outside the submitted work. 

JL-M reports personal fees and non-financial support from Amgen and Sanofi; personal fees from MSD and Laboratorios Dr Esteve, outside the submitted work. 

FM reports grants, personal fees, and non-financial support from Amgen, MSD, Sanofi, AstraZeneca, and Pfizer, during the conduct of the study. 

BRO reports personal fees from Amgen, during the conduct of the study; participation on a data safety monitoring board for Accera; and grants from Long Term Care Group, Merck, Eli Lilly, TauRx, Janssen, Biogen, Avid, and Hoffman-La Roche, outside the submitted work. 

EK reports grants from Amgen during the conduct of the study; and grants from Amgen and AstraZeneca, outside the submitted work. 

ALP is an employee of and holds stocks in Amgen. RS is an employee of Amgen and, as such, has received salary, bonus, stock or stock options, health insurance, and benefits; and is identified as an inventor on at least one pending patent application owned by Amgen relating to evolocumab. SMW is an employee of Amgen; and has a patent for evolocumab issued to Amgen. 

ACK reports grants and personal fees from Abbott, and Mylan; and personal fees from Amgen, AstraZeneca, and Pfizer, outside the submitted work. 

PSS reports grants and personal fees from Amgen, during the conduct of the study; grants and personal fees from Pfizer, outside the submitted work; and that he is the recipient of a National Institute for Health Research Senior Investigator Award and receives support from the Biomedical Research Centre Award to Imperial College Healthcare NHS Trust. 

MSS reports grants from Abbott Laboratories, Clinical Diagnostics, Daiichi-Sankyo, Gilead, GlaxoSmithKline, Roche Diagnostics, Takeda, Novartis, Poxel, Eisai, Genzyme, and Pfizer; grants and personal fees from Amgen, AstraZeneca, Intarcia, Merck, Janssen Research Development, The Medicines Company, and MedImmune; and personal fees from Alnylam, CVS Caremark, Lonis, Cubist, Esperion, and MyoKardia, outside the submitted work. 

J- GP, KT, and FS declare no competing interests. 

The expression “He who pays the piper calls the tune” comes to mind.

We can see the remarkable extent to which academic doctors can be funded by the pharmaceutical industry. This must influence the way which their findings are reported. 

We must also remember that when a pharmaceutical company funds a clinical trial (as in this case) the company will "own" the data and have a veto over the presentation of findings.

The economics of pharmaceutical development

There is a real problem in respect of pharmaceutical development in general and evolocumab in particular.

The development of any pharmaceutical agent today will cost a minimum of $1 billion, and there is always the possibility that the agent might fail because of unforeseen side-effects. The $1 billion needs to be recovered from sales, and the price of the medication will depend on the predicted number of prescriptions. 

Statins provide an example of the ideal. They are taken by millions of well people every day for many years. The huge volume of sales will result in low unit price or vast profits, or both. In 2001 cerivastatin had to be withdrawn because of untoward effects (muscle damage) resulting in a large financial loss to the company (Bayer). 

A contrast would be a new antibiotic, and there are not any. Excluding their animal growth-enhancing use, an antibiotic is given for only a few days for an individual person. The low volume of sales will mean that the price of a tablet or injection will be very high, and this will inevitably inhibit use. The £1 billion development cost is not likely to be recovered from sales. As new antibiotics are considered to be in the public interest, the debate is whether antibiotic development should be funded by pharmaceutical companies or governments.

The economics of evolocumab

The cost of production of a mono-clonal antibody such as evolocumab will be very high. The price was fixed in 2016 at £170.10 for a 140mg pre-filled pen or syringe (excluding VAT). This equates to £4422.60 per year, and £6123.60 for the alternative dose of 420mg each month.

The cost of prevention of one primary event would be £4422.60 x 67 (NNT) x 1 (assuming one year treatment), which  is £296 314 ( $394 035, €338 687). It is a matter of judgement as to whether this sum of money is good value to prevent a non-fatal episode of illness, knowing that death will not be prevented.

Stroke

A non-fatal stroke is an illness that most people dread as it can lead to long-term disability. It is therefore important to look at stroke prevention within the bundle of “composite end-points”.


The number of deaths from stroke differs very little between the two groups. The number is not actually important if total deaths are effectively the same. Changing the cause of death within a given time-scale is not the objective of medicine.


In respect of non-fatal stroke we see a small advantage from evolocumab. 1.9 - 1.5 = 0.4%, which means that 4 non-fatal strokes can be prevented by 1000 people taking evolocumab for about one year, or 1 non-fatal stroke prevented by 250 people taking evolocumab for one year (NNT = 250).

The economics of this is derived from £4477.6 x 250 x 1, which is £1 119 400 ( $1 489 211, €1 279 474). I would suspect that most people would be of the opinion that spending about a million pounds / dollars / euros to prevent a non-fatal stroke would not be good value for money.

Pharmaceutical company considerations

It would be necessary for about 23,000 people to be treated for ten years to recover the £1 billion development cost. This does not include the costs of marketing. The recovery of all the costs would be required to provide a dividend to shareholders and to fund the development of the next product. The stakes are high and it must be important for economic reasons for evolocumab to be taken into widespread clinical practice.

Clearly it is essential for a trial of clinical effectiveness to be successful and to be published, ideally in a prestigious journal. And so we see the publication in the New England Journal of Medicine. The spin indicates success. Conclusions do not reflect results.

Conclusions

There was no “saving of lives”, no matter how many patients might be treated and no matter how many injections of evolocumab might be given. Prevention (delay) of death is by far the most important outcome measure and other cholesterol-lowering trials have identified this. 

A 59% reduction of cholesterol had no mortality benefit, which is against the predictions of the cholesterol-heart hypothesis. The frequently repeated message is that cholesterol-lowering is associated with an arithmetic reduction of CHD deaths, and this is clearly not true. It is also clear from the WOSCOPS statin trial.

Evolocumab has no effect on mortality, perhaps marginally increasing it. It is the same with ezetimibe – distinct lowering of cholesterol but no effect on mortality. Statins slightly reduce mortality and this effect has no relationship to the quantitative reduction of cholesterol. 

The economics of pharmaceutical development is highly vulnerable.

Will the providers of health care, individuals or pre-payment insurance organisations (whether or not government based) be prepared to fund evolocumab?