Saturday, 31 August 2019

The Polypill - statistical spin and amplification of benefit


Many people in the world are taking medications of various sorts to improve their health and duration of life, most of these "medications" being futile. Life is at present longer and healthier than has ever been known. We are increasingly free of disease and as a result old age is the expectation for most of us.

But food enthusiasts of various sorts try to persuade us that changing diet can make our lives even better and longer. And there are of course many others who can make money out of our almost universal health pessimism, and our remarkable optimism in the power of medicines and special diets. Although the 20th century epidemic of high mortality coronary heart disease has now come to an end, we are still under pressure to take medications to prevent it.

Many people who are well and disease-free take statins. Many take aspirin. High blood pressure is constantly redefined so as to make more of us have hypertension. Pharmaceutical consumption without need increases, although of course it is necessary for economic growth. 

The polypill
If vast numbers of people are taking four tablets per day (statin, aspirin and two to lower blood pressure) it might make life easier for these medications to be combined into just one tablet. This “polypill” has been developed, containing aspirin, atorvastatin, hydrochlorothiazide, and either enalapril or valsartan. Even though the component medications might have been approved, combinations require a separate approval by the pharmaceutical regulating authority, and this requires additional clinical trials. 

The polypill trial
The clinical trial of the polypill has now been undertaken in Iran, and it has rather cleverly been called  the PolyIran study. The results were reported very recently in The Lancet, which appears to give special priority to articles promoting cholesterol and statins.  

The study involved 3417 subjects allocated to advice care only,  and 3421 subjects advice plus polypill. The subjects were aged between 50 and 75 years and the duration of follow-up was five years. 

Deaths
There were 222 total deaths in the advice only group, this being  6.5% of the 3417 subjects.

There were 202 total deaths in the advice plus polypill group, this being 5.9% of the 3421 subjects

The difference is 0.6%, meaning that almost 200 (precisely 167) people would need to take a daily polypill for five years to prevent one death during this time. The polypill was effective in preventing death, but it is doubtful that a person prescribed it for five years for the purpose of preventing death would take it knowing that there is a 99.4% chance of it not preventing death.

Cardiovascular events
During follow-up, there were: 

301 (8.8%) non-fatal major cardiovascular events in those who received advice only, and 

202 (5.9%) non-fatal major cardiovascular events in those receiving advice plus polypill. 

The difference is 2.9%, the absolute reduction of event rates, meaning that the polypill was effective in the prevention of major cardiovascular events.

The spin
The absolute reduction of events by 2.9% does not sound to be very dramatic, and so statistical manipulation follows. 2.9% must be expressed as a proportion of 8.8%.

Once again we can see statistical spin, using the dubious method of taking percentages of percentages. 

(8.8-5.9)/8.8 expressed as a percentage = 33%. This sounds much better and this is what was appeared in the press, for example in The Guardian August 22nd 2019.

This spin amplifies the benefit of the polypill from 2.9% to 33%, by a factor of more than ten.

NNT
A useful expression of effectiveness is the NNT, the Number Needed to Treat in order to achieve one clinical benefit, We see in respect of the polypill that for death this is 167.

The paper expressed the NNT for the prevention of cardiovascular events as being 34.5 (100/2.9). This is correct and it means that if 34.5 people take the polypill for five years, one will not experience a major cardiovascular event. The value of this in clinical practice requires an informed discussion between doctor and patient, in this case a disease-free normal person.

Primary prevention only: 
By this is meant subjects without a history of cardiovascular disease. Within the discussion section we find: 

“The PolyIran study showed that the use of polypill resulted in around a 40% reduction in the risk of major cardiovascular events in individuals without a history of cardiovascular disease”.

It is not easy to identify the origin of the 40%, but it can be obtained from Table 2. 

737 of the subjects had a history of pre-existing cardiovascular disease, but the majority 6101 did not have. 

Of those without a history of cardiovascular disease (primary prevention) and receiving advice only, 229 out of 3068 experienced a cardiovascular event during the study, that is 7.5 %. 

Of those without a history of cardiovascular disease and receiving advice plus polypill, 136 out of 3033 experienced a cardiovascular event, 4.5%.

Thus the absolute benefit was a reduction of 7.5-4.5 = 3% in cardiovascular events in those receding the polypill.

More spin
A 3% reduction in events is not very dramatic. How can this number be increased?

The statistical manipulation becomes the expression of 3% as proportion of 7.5%. This is (7.5-4.5)/7.5 expressed as a percentage = 40%. 

40% reduction sound much better than 3%, amplification of effect by a factor of 13.

As I have expressed in a previous Blog post, statistical spin of this sort is disgraceful manipulation designed to mislead the general public and their medical advisors. The expression of proportionate over absolute benefit should be stopped.


Reference:
Gholamreza Roshandel, Masoud Khoshnia, Hossein Poustchi et al.  Effectiveness of polypill for primary and secondary prevention of cardiovascular diseases (PolyIran): a pragmatic, cluster-randomised trial.  Lancet 2019; 394: 672–83.






Tuesday, 11 June 2019

Food and Health – Statistics and Lies

Is highly processed food bad for us?
Can we believe the statistics that are presented to us?


Shopping: a large range of ready-made meals
We live in an era of “dietism”. There are many books and articles on how various aspects of our food are responsible for all sorts of illnesses and threats to our longevity. I have pointed out previously that the past fifty years, since 1970, have seen a major and apparently spontaneous (that is "natural") decline in deaths from coronary heart disease, the end of the greatest epidemic of the 20th century. However this occurred at a time during which we have seen the emergence of “fast food”, that many people regard as “junk food”, and also our supermarkets have become stocked with  food that has been prepared in factories. The food is imaginative and it tastes good. But is it bad for us? Despite such allegations, how is it that the proportion of our population living beyond the 90th birthday continues to increase? Are we not in reality healthier than ever?


Statin trial

Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, Macfarlane PW,
McKillop JH, Packard CJ, for the West of Scotland Coronary Prevention
Study Group. Prevention of coronary heart disease with pravastatin in
men with hypercholesterolemia. N Engl J Med. 1995;333:1301–1307.

We are also in an era of distorted statistics. I have illustrated previously that we are told from the WOSCOPS study (reference above) that pravastatin reduces the risk of death at eight years by 25%, but the reality is that the reduction was just 1%. The absolute reduction in death rates was from 4% to 3%. The 25-fold amplification of the result is manipulative, quoting proportionate reduction in death rate in place of absolute reduction. This means presenting the numerator without reference to the denominator. 

The absolute reduction of 1% tells us clearly that if 100 high-risk men take pravastatin daily for eight years, then the life of one of them will be prolonged. The proportionate reduction of 25% gives no useful information as the denominator is ignored. It is a manipulation to enable sales.

Let me illustrate this manipulation further.

Diet study from Paris

On May 30th 2019 there was a press release in the UK, appearing in many national newspapers and on radio transmissions. It stated that:


The press release indicted an increase of cardiovascular disease by 12% when the proportion of highly processed food in the diet of 105,000 individuals rose from 10% to 20%. Incidentally, is this an increase of 10% or of 100%? 

Read on for further understanding.

It is necessary to look at the original data, some of which was provided in an expansion of the press release in The Guardian, and it is of course found in the original paper in the British Medical Journal.

The study was of 105,000 adults age 18 or greater, and the follow-up was for five years. For the purpose of analysis the population studied was divided into four groups based on the proportion of highly processed food in the diet.



Results

The cardiovascular disease rate in the highest quartile of consumption of highly processed food was 277 per 100,000. This is the usual way of presenting health statistics.

For the lowest quartile of highly processed food consumption the disease rate was 242 per 100,000.

There was thus a higher disease rate in those consuming a diet relatively high in processed food. But how much higher?

Let us note the simple calculation:

277 - 242 = 35

This would appear to be non-controversial. It indicates that if 100,000 people consume a high processed food diet, then 35 more of them will develop cardiovascular disease compared to a similar group with a lower consumption of highly processed food. 

35 out of 100,000  = 0.035 out of 100  =  0.035%

If you are one of the 100,000 would an increased risk of 0.035% make you change your diet? The answer is probably “No”.

If this were the stated result of the study, it would almost certainly be ignored by the media. There would be no press release and the authors would remain in obscurity with no fame and little prospect of future research grants. The cost of the study was not stated but the paper had 13 authors and no doubt many unrecorded assistants and clerical staff employed over 10 years. This would suggest a cost of at least £/€/$ 1.5 million.

The Spin

Turning bad news into good news is a process called “spin”, frequently used by politicians. Enter statistical manipulation.

I have presented absolute proportions, and these enable us to understand the real world, how the results of the study affect "me" as an individual. We now need to look as to how the result is translated into “proportionate” changes.

The increase in disease rate is from 242 to 277, a difference of 35. This number is presented as proportion of 242.

35 / 242 = 0.145

and this represents an increase of 14.5% of cardiovascular disease by consuming a diet high in highly processed food.

0.035% represents a change. But using a proportionate result mean that we can use an increase from the lower number or a decrease from the higher number. 

And so alternatively:  35 / 277 = 0.127

which is a 12.7% decrease by having a diet low in highly processed food realise to a high level diet.

Using proportionate figures of 14.5% of 12.7% is much more dramatic than 0.035%, hence widespread newspaper headlines.

Expressing the result of this study as a proportionate rather than an absolute result amplified the diet effect from 0.035% to 12.7%. This is an amplification factor of about 350.

0.035% tells us about the real world, how the health of us as individuals is influenced by our diet. 25% tells us nothing.


This spin is common in medical papers and it ought to stop or be stopped.

Dubious mathematics - changing denominators

Disease incidence per 100,000
We encounter the mathematical effect of manipulating numerators with no reference to the denominator. In this case the numerators were 277 and 242, and the denominator was 100,000. You will see that the manipulation above took no account of the denominator.

Disease incidence per 1000
Let us assume that the denominator was different by a factor of 100:
High consumption group  277 per 1000
Low consumption group   242 per 1000.

The difference of 35 is now per 1000.

35 per 1000 = 3.5 per 100 = 3.5 %.
This is important, a hypothetical effect 100 times greater than the real study result.

But the proportionate calculation would remain just the same:
35 / 242 = 0.145 = 14.5%  or  35 / 277 = 0.127 = 12.7%

Disease incidence per 10,000,000
Let us suppose that the disease incidence is much lower, by a factor of 100. The numerators remain the same but are now found to be per 10,000,000, a much much lower incidence and a therefore a much larger denominator. The results would be:

277 per 10,000,000  and 242 per 10,000,000. 

The difference (numerator) would remain at 35, but now out of 10,000,000.
.
The absolute difference would be 0.00035%. This is a tiny population effect, but if the sample size is big enough it could achieve statistical significance, even though of no health significance.

However proportionate change manipulation still leaves us with 
35 / 242 = 0.145 = 14.5%  or 35 / 277 = 0.127 = 12.7%

Whatever the disease incidence, the answer is always 12.7% (or 14.5%). 

We can therefore see that proportionate results are meaningless in the real world and give no indication of real risk to the individual who is making a choice of what to eat.

Expressing the proportionate result implies a much higher risk than is really the case. It is intended to frighten the public (and their doctors) into taking tablets or altering their life-styles or to produce an impact much greater than it should be.

Is it acceptable to use numerators without reference to denominators?

This type of manipulation is completely outrageous. It should not be allowed in papers published by reputable journals, or any other form of publication. Numerators should not be separated from their denominators. 

I am no mathematician but I learned about numerators, denominators and percentages when I was in my primary school. I was taught that if the numerator is increased or reduced, then the denominator should be changed by the same proportion:

 3/4 = 6/8, not 6/4.  3/4 = 12/16, not 12/4.

The manipulations that we have seen would result in an examination "fail".

Are my salami sandwiches a form of suicide?

Reference:

Srour B, Fezeu LK, Kesse-Guyot E et al. Ultra-processed food intake and risk of cardiovascular disease: prospective cohort study (NutriNet-Santé). BMJ 2019;365:l1451









Friday, 8 March 2019

Epidemic and Endemic Coronary Heart Disease


Influenza is always with us and no doubt always has been. It affects a significant number of people each winter and it can cause deaths, especially of the vulnerable very elderly. This is endemic influenza: it is more or less constant within the population (end- means within). But occasionally the population experiences an epidemic of influenza (epi- means without or outside). This affects a large proportion of the population with a much higher death rate than the endemic form. An epidemic of influenza is due to a new, a mutant, strain of the influenza virus to which we have no immunity. However we develop immunity rapidly, and so the epidemic subsides. 

It is the same with coronary heart disease (CHD) and myocardial infarction (MI).

The two major epidemics of the 20th century

Immediately following the end of World War One in 1918 the population of Europe experienced an epidemic of influenza. It became known as “Spanish Flu”, and as it occurred in all continents it can be described as a pandemic. It affected worldwide about 500 million people and it was responsible for the deaths of up to 100 million. 


War cemetery at the beautiful marble Bodelwyddan Church, North Wales.
The graves are of Canadian soldiers who died from influenza
shortly after the end of World War 1


War grave of one of the many Canadian soldiers
The second major epidemic was that of many deaths from CHD. It was a disease the basis of which started at about the same time as the influenza epidemic, but it had a long latent interval before the occurrence of clinical effects and the large number of deaths. 

We have all been aware of the many deaths from CHD that occurred during the 20th century. I have described how this appeared as a new cause of death during the 1920s, rising exponentially to a peak in about 1970. CHD became by far the major cause of death, and it was clearly a well defined epidemic. Indeed, as it occurred in temperate zones in all continents it was an international pandemic. Although CHD deaths were mainly in people over the age of 70 years, there were many deaths in younger people.


The epidemic of CHD in the USA, 1940 to 2000. Data from W Rothstein.


The peak of the epidemic in 1970

1970 was time of medical drama, the peak of the epidemic of severe high-mortality CHD. At this time I was busy as a young doctor working in emergency hospital medicine and I remember it vividly. There were many patients admitted severely ill with obvious myocardial infarction (MI). They had a high death rate: almost half died before they reached the hospital, and 35% of those admitted died in hospital. 

They were found to be very likely to suffer from the new experience of “cardiac arrest”, later identified as the immediate result of ventricular fibrillation (VF). ECG monitoring, cardio-pulmonary resuscitation (CPR) and defibrillation came into existence; coronary care units had to be invented. But this was in 1970, very different from the present time, or even in 1990.


Case fatality rate after admission to hospital due to MI,
peak of the epidemic and during its decline

This was the greatest epidemic of the 20th century, and also a worldwide pandemic. Over a much longer time-span (fifty years rather than weeks), it was responsible for more deaths than Spanish Flu. Short memories and a long time-scale mean that few people appreciate it as an epidemic, but it was.

CHD before the epidemic

It is likely that CHD existed before the emergence of the epidemic in the mid-1920s. Historical evidence is far from complete as soft tissues such as arteries decompose after death – except when the body is embalmed. Examples of this are found in Egyptian mummies, and evidence of atherosclerotic disease has been identified. Atherosclerosis, hardening of the arteries, is the background of CHD, with plaque disruption and rupture being the precipitating event of MI (“heart attack”). In the ancient Egyptian experience, CHD, although present, could not be identified as the cause of death. 


Cross-section of a critically narrowed coronary artery,
obviously having caused death.
CHD as a disease can be present for many years without it ever causing symptoms or illness, or even death.

During the Korean war (1950–53), autopsies performed on young soldiers killed in action established the presence of arteriosclerotic CHD in almost 80%, and severe disease in almost 20%. This was twenty years before the peak of the epidemic. It demonstrates a long lead time, and had they not been killed in military action they would probably have died at the peak of the epidemic twenty years later, some earlier, some later. The disease process of the epidemic was well established before 1950. In fact by the time of the Vietnam war (1968–78) the prevalence of atherosclerotic disease in soldiers killed in action had fallen by half, and by the time of the Iraq and Afghanistan wars it had almost disappeared.


Evidence of asymptomatic CHD in young US soldiers killed in action in successive wars.
The decline of the disease is obvious.


Chest pain ?cause

In the years following 1970 there were many people who presented to emergency services with chest pain suggestive of MI. The great majority were not ill and they survived. The ECG was normal and blood enzyme tests were also normal. There was thus no objective evidence of MI/CHD, or any other active disease process. This was in the era before the extensive use of coronary artery imaging. 

A large sample of this group of patients with what was called “chest pain ?cause” was identified in Nottingham, UK, and reviewed after the lapse of a few years. After one year none of those whose diagnosis was chest pain ?cause had died, compared to 30% of patients with a diagnosis of MI. This excellent outcome of chest pain ?cause was obviously very reassuring.

CHD since the end of the epidemic

The main feature during the epidemic of CHD was the very high death rate, but the clinical scene is very different now. A patient who presents to the hospital emergency department today with chest pain is likely to have a normal ECG



Normal ECG

The “Q wave MI”, common in 1970, is now extremely rare. During the latter years of the epidemic we would see an abnormal ECG with ST segment elevation even if no Q wave, but at present we find an ECG with neither Q wave nor ST elevation . This is the “non-STEMI” (non-ST elevation myocardial infarction). This means a normal ECG, indicating minimal heart damage, a condition that would have been diagnosed as “chest pain ?cause” in 1970, with an excellent prognosis.


Q wave MI, common in 1970, rare today

Changes in the diagnosis of MI

When the heart muscle is damaged, enzymes are released from the cells into the blood, where they can be detected and used as confirmatory evidence of MI. The enzyme tests used in the 1970s are no longer in use because they lack “sensitivity”. This means that it was possible that some people in the “chest pain ?cause” group had actually experienced a very “mild” MI without it being recognised, ECG and enzyme tests of the day being normal. 

The next development was a new blood test of “troponin”, again detecting chemicals released from damaged heart muscle cells. This was a more sensitive test: it was positive in cases when the ECG was normal and when the older enzyme tests would be normal. This means that more people with “chest pain” would be diagnosed with MI.

And then in the early 21st century, there was the development of the high-sensitivity troponin test, so that even more people with chest pain would be diagnosed with MI. In previous years this diagnosis was not possible: the patient would have discharged with a label of “Chest pain ?cause”, knowing that there was a good outlook and no cause for concern.

Evaluation has shown that there is no need for concern in people diagnosed as “MI” the basis of only elevated high-sensitivity troponin. It creates more “patients” (patient mongering), with no benefit to themselves, but probably much more anxiety, and of course more activity and income for doctors and other health professionals. 

Coronary angiography

In the 1970s coronary angiography was something very new and not available on a wide scale. Today it is a readily available investigation and the number of angiograms has increased dramatically. The purpose is to identify the condition of the coronary arteries (the arteries that supply blood to the heart muscle). 


Diagrammatic representation of the coronary arteries,
showing the presence of disease and narrowing.

At present about 250,000 coronary angiograms are performed each year in the UK. The purpose of the investigation is not to diagnose MI but to assess the degree of coronary artery disease, and a measure of narrowing of coronary arteries. Following angiography, stent insertion is performed if necessary, about 100,000 per year in the UK.

In respect of patients with MI diagnosed in the traditional way, we expect to see critical coronary artery narrowing, perhaps an 80% or greater narrowing. Under this circumstance the insertion of coronary artery stents would be important, the purpose being to prevent further episodes of MI and possible sudden death. 

It is unfortunate that widespread coronary artery stent insertion was not readily available during the epidemic of CHD. Now that it is readily available we find that the epidemic of severe and high-mortality CHD has come to an end. We are in an era of endemic CHD, a disease that might have been with us since antiquity, and which is in a mild form with a low mortality rate. Most MIs would not have been identified in the past, but now they are. 

A diagnosis of MI is followed as soon as possible by coronary angiography, but today coronary artery disease is much milder and severe stenosis is much less common. Nevertheless coronary artery stents are used more than ever, and this has led to criticism concerning overuse of stents when risk of death is low.

The cause of endemic  CHD

Few people seem to be aware that CHD has undergone a major change since the peak of deaths in 1970, mainly because those, like me, who were at the front end in 1970 are no longer in clinical practice. Personal experience forms opinions. But what has happened: what is the reason for this change?

I have expressed previously thoughts on the causation of CHD . First, an epidemic cannot be genetic, and its development is the result of external factors. These could be chemical or biological. Chemicals from cigarette smoke appear to be accelerating rather than the prime mover of CHD. Chemicals in the diet (mainly cholesterol) have been assumed to be the cause, but confirmatory evidence is far from clear: it must be concluded that CHD is not a dietary disease. It has only recently that CHD has been accepted as being an inflammatory disease, and it is most likely that inflammation is driven by infection.

The infection is the result of micro-organisms circulating within the blood stream, a common or even “normal” event, a low-grade bacteraemia. Bacteria can enter the walls of the arteries through the vasa vasorum (the blood vessels of the blood vessels). 


Diagram of the wall of an artery.
The vasa vasorum provide a blood supply to the wall of the artery, in particular to the media, the muscular part of the artery. It is here that the disease process of atherosclerosis begins, NOT from deposition of cholesterol from the blood on to the internal surface of the artery (the intima)

Body defence mechanisms then come into play, so as to control and neutralise the bacterial invasion. The first line of defence is LDL-cholesterol. Although this leads to the accumulation of cholesterol in the artery wall, its purpose is defensive. If the micro-organism is recognised by immune memory, elimination of a bacterium is aided by the mobilisation of immune mechanisms,.

Bacteraemia is common, the result of a wide variety of micro-organisms, some known and some (probably most) not yet identified. It is inevitable that during life we will encounter a large number of bacterial invasions of our arteries, more if our immunity is impaired. As a result we will accumulate the low-grade inflammatory process that becomes atherosclerosis. This might ultimately lead to low-grade endemic CHD.

The cause of the epidemic of CHD

But a high virulence organism might appear, a novel micro-organism to which there is no innate immunity, and this would cause an epidemic. An epidemic arises with the appearance of a new micro-organism, and it later subsides because of the development of immunity, which will be inherited to protect future generations.

When syphilis first came to Europe in the early 16th century, it caused a sexually transmitted disease that appears to have been much more severe than it was 400 years later. It became a long-term epidemic that was often disabling and fatal, as the result of its later neurological and cardiovascular disease processes. Syphilis is due to the bacterium Treponema pallidum, and it was the cause of an epidemic of heart disease which came to an end at about the same time as the emergence of the epidemic of CHD.


Treponema pallidum, a spirochaete,
the cause of syphilis, that can cause serious and fatal heart and arterial disease

Rheumatic fever in Europe became almost extinct during the 20th century. Its origin is far from clear, but its decline was probably spontaneous, helped (as with syphilis) by susceptibility of the causative micro-organism to penicillin. It was another microbial cause of serious and fatal heart disease, due to the bacterium Streptococcus pyogenes.


Streptococcus pyogenes, strings of spherical bacteria (cocci).
The cause of rheumatic heart disease.
The long-term endemic form of CHD is due to a variety of low-pathogenicity bacteria, but the epidemic must have been due to just one micro-organism, almost certainly Chlamydia pneumoniae, or a specific mutant of it.


Chlamydia pneumonia, a tiny and ancient bacterium
that can only survive within the cells of a host.

Chlamydia pneumoniae is usually but not always detected in CHD. Although it is likely to have been the cause of the epidemic of high-mortality CHD, the endemic disease due to a variety of other micro-organisms continued during and after the epidemic. 

Review of the Chlamydia pneumoniae story will follow in a future Blog post.