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The Actuary The magazine of the Institute & Faculty of Actuaries
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Life: Heart of the matter

As one swallow ‘does not make a summer’, so correlation does not imply causation. When actuaries concern themselves with risk factors they try to avoid the confounding of correlation with causation. We need principles to guide us when we suspect a causal relationship exists or when we decide to use a rating factor when underwriting risks. We generally agree that a reasonably strong correlation is a prerequisite for a risk factor in its association with a particular disease, and acknowledge that this does not make the risk factor a cause.

In 1965 Sir Austin Bradford Hill laid out the accepted nine fundamental principles that should guide the practitioner in distinguishing correlation from causation. The most important of these are the strength of association, the existence of a biological gradient (the dose-response relationship) and temporality — the last of which he downplayed at the time. It is, however, vital that the presumed cause precedes the event. The principle of coherence is also important as any presumed causal relationship should not seriously conflict with generally known facts.

We start by looking at correlation within the context of the original lipid hypothesis in relation to the health of our hearts.

Heart health: The lipid hypothesis (the consumption of saturated fat causes heart disease)
This infamous hypothesis was proposed by Ancel Keys in 1953 based on statistics of consumption of saturated fat in six countries (Figure 1).

Figure 1

Keys neglected to disclose that he had selected six countries out of a total of 22 whose data were available to him. His misuse of the data was exposed by Yerushalmy and Hilleboe in 1957 when they published the graph of the full data set (Figure 2).

0811-features-lane-fig-2

When the full data is used, the biological gradient disappears — as does the strength of the association. The lipid hypothesis was consequently modified so that dietary cholesterol became the villain instead of saturated fat.

Many years of research followed but Ancel Keys finally admitted in 1997 that “There’s no connection whatsoever between cholesterol in food and cholesterol in blood. And we’ve known that all along. Cholesterol in the diet doesn’t matter unless you happen to be a chicken or a rabbit”.

So, if saturated fat and cholesterol in the diet do not matter, what does? Clearly, the implication is that it is cholesterol in the blood and the hypothesis has been modified again.

Heart health: The lipid hypothesis continued (high total serum cholesterol with a high LDL/HDL ratio causes heart disease)
It should be noted at this point that this is still a hypothesis. Unfortunately, it is medical orthodoxy and even perhaps dogma that serum cholesterol levels should be managed down. If it were not for the class of drugs called statins this would not be possible, as the human body manufactures virtually all of the cholesterol needed (mainly in the liver) and has mechanisms to regulate the levels of cholesterol. To our knowledge, it appears that no one has yet demonstrated the satisfaction of Sir Austin Bradley Hill’s criteria in relation to this modified lipid hypothesis.

In fact, many people with heart disease have low levels of cholesterol. In the January 2009 edition of American Heart Journal it was reported that, of the 136,905 people admitted to 541 hospitals in the United States with heart attack whose lipid levels were recorded, nearly 75% had “normal” LDL cholesterol levels, which is below 130mg/dl (or 3.4 mmol/l).

There are many statin drug studies that purport to prove that lives will be saved by reducing cholesterol. However, there appears to be no primary prevention study that shows conclusively, in terms of a strong absolute response, that the total mortality end point will be affected by the use of statins. This means that, in most of the study groups, as many people died as in the control groups. What is the use of being saved from heart disease only to die from some other cause? Even worse, higher cholesterol levels appear to be protective against cancer in the longer term and statins have significant and probably under-reported side effects.

Table 1, extracted from a recent study by Hippisley-Cox and Coupland, illustrates the effect of medicating a large proportion of the whole population. The number of conditions is probably under-reported because some symptoms would have been mild and therefore not reported and cases of memory loss may have been ascribed to age-related conditions.

Table 1

 

 

 

 

 

 

 

 

 

 

It is important to note that statins have shown significant benefits in the case of secondary prevention, albeit not necessarily from their effect on cholesterol. Statins have pleiotropic effects; that is to say they have other effects such as anti-inflammatory, plaque-stabilising or anti-coagulant effects. These effects are available at much lower doses than those that are required to aggressively manage down the level of cholesterol and may be the ones preventing further heart attacks in the secondary prevention trials.

Final thoughts
As actuaries we should consider updating our risk calculators to take account of current research and especially look at the age ranges for which cholesterol may still be an appropriate risk factor, especially for women where there appears to be little or no dose response.

We have an obesity epidemic in spite of the accepted wisdom on diet that emerged from flawed science originated by Ancel Keys. We suspect that overconsumption of carbohydrates may have something to do with this, but we also suspect that giving obese people a statin potentially acts to perpetuate the continued epidemic of obesity as it allows them to avoid lifestyle and behavioural changes in the belief that the statin will prevent future heart attacks.

I will continue to enjoy a full English breakfast, shorn of the guilt that this may affect the health of my heart. At my age (50+), and free of heart disease with a cholesterol level higher than the recommended level, I am quite happy not to increase the five-year probability of avoiding a heart attack from 98.2% to 98.8% by taking a statin for five years. The probability that I will avoid nasty side effects is 100%.

Statins are not the swallows heralding a summer free of heart disease for everyone. Arguably, if we do not insist on a proper answer to the question of what really causes heart disease then we may unduly medicate millions of people for little benefit at the danger of making a significant number of them seriously ill.

 

Appendix and footnotes

"Some genuinely testable theories, when found to be false, are still upheld by their admirers - for example by introducing ad hoc some auxiliary assumption, or by reinterpreting the theory ad hoc in such a way that it escapes refutation. Such a procedure is always possible, but it rescues the theory from refutation only at the price of destroying, or at least lowering, its scientific status. (I later described such a rescuing operation as a "conventionalist twist" or a "conventionalist stratagem")"[1].

Most recent findings on the efficacy of statins are derived from meta-studies. The meta-studies combine primary studies and utilise powerful statistical techniques to amplify faint responses and imbue them with credibility. Relative risk reductions rather than absolute risk reductions are widely quoted. If the absolute chance changes from 0.5% to 0.4% we would not be very impressed but the relative change is 20%.

In order to justify primary or preventative healthcare intervention epidemiologists have resorted to meta-analysis - that is to say they have grouped many studies together to increase their statistical power. This can be a dubious technique as it is incredibly difficult to control selection bias and ensure that all studies were carried out under the same constraints. Even then the individuals being studied might not represent the general population.

Cholesterol is a lipid. HDL and LDL are not cholesterol they are lipoproteins (High Density and Low Density Lipoproteins) which transport cholesterol in the blood (lipids are not water soluble). HDL transports cholesterol back to the liver and LDL transports cholesterol to where it is needed in the body. Higher levels of LDL are not intrinsically bad except that they may indicate that something is wrong in the body - for example LDL transporting cholesterol to where damaged blood vessel walls need repair.

Statins interfere with the metabolic pathway for the production of coenzyme Q10 which acts in supplying energy to the body and the heart muscle (this could lead to eventual heart failure). Heart Failure rates have been increasing in the United States.[2]

Statins have pleiotropic effects; that is to say they have other effects such as improvement of endothelial dysfunction, increased nitric oxide bioavailability, antioxidant properties, inhibition of inflammatory responses, and stabilization of atherosclerotic plaques.[3] These effects are available at much lower doses than those that are required to aggressively manage down the level of cholesterol.

Statins are not as well tolerated in the general population as some drug studies would lead us to believe. Documented serious side effects include myopathy (serious muscle damage), renal failure, cataracts, liver dysfunction and loss of memory.[4]

We also note that The Framingham Heart Study (a longitudinal study that informed a lot of our past underwriting) now admits there is no association between dietary fat and heart disease and indeed the association of elevated cholesterol and heart disease is limited to a small segment of the study population.[5],[6]

George Bernard Shaw (died aged 94 from complications resulting from a fall while pruning trees) said "Everything I eat has been proved by some doctor or other to be a deadly poison, and everything I don't eat has been proved to be indispensable for life. But I go marching on".
Sir Austin Bradford Hill said "we should need very strong evidence before we made people burn a fuel in their homes that they do not like or stop smoking the cigarettes and eating the fats and sugar that they do like" [7] He and Sir Richard Doll subsequently went on to produce the strong evidence on smoking[8] but his advice about dietary changes is still apposite.


Garth LaneGarth Lane is a valuation actuary and Solvency II expert at RGA in the UK

 

 


[1] Popper Karl R , Science as Falsification, Conjectures and Refutations (1963)

[2] Liu L, Changes in Cardiovascular Hospitalization and Comorbidity of Heart Failure in the United States: Findings from the National Hospital Discharge Surveys 1980-2006, (2009)

[3] Davignon J, Beneficial cardiovascular pleiotropic effects of statins, Circulation 109(23 Suppl 1):III39-43 (15 June 2004)

[4] Hippisly-Cox J; Coupland C, Unintended effects of statins in men and women in England and Wales: population based cohort study using the QResearch database, BMJ 2010; 340:c2197

[5] Kannel WB et al, Usefulness of the triglyceride-high-density lipoprotein versus the cholesterol-high-density lipoprotein ratio for predicting insulin resistance and cardiometabolic risk (from the Framingham Offspring Cohort), American Journal of Cardiology 101(4):497-501 (15 Feb 2008)

[6] Gordon T et al, High density lipoprotein as a protective factor against coronary heart disease: The Framingham study, The American Journal of Medicine Volume 62, Issue 5 , pages 707-714, (May 1977)

[7] Hill AB, Proceedings of the Royal Society of Medicine, 58 pages 295-300 (1965)

[8] Doll R; Hill, AB, Smoking and Carcinoma of the Lung, British Medical Journal 2 : 739, (1950)