When I was at medical school I remember being lectured on the wonders of hormone replacement therapy (HRT). I was distinctly taught, and without reservation, that women taking HRT had a lower risk of heart disease compared to women ‘going without’. This ‘fact’ turned out to be complete rubbish. Subsequent evidence revealed that HRT actually has the capacity to increase risk of heart disease.
How could we have got it so wrong?
The initial ‘evidence’ on HRT was epidemiological in nature, which meant that it looked at the relationship between HRT/non-HRT use in a population and risk of cardiovascular disease. One fundamental potential problem with these studies relates to what is known as the ‘healthy user’ effect. In short, what this means is that healthier individuals are more likely to be prescribed a drug than sicker people who may already be on multiple medications and prone to side-effects and interactions. So, any ‘benefit’ seen to be associated with a drug may have nothing to do with the drug, and everything to do with the fact that people taking it are inherently healthier.
To untangle all of this, what we need is randomised controlled trials. These trials give essentially equivalent groups the treatment or placebo to assess any potential benefits or harms of the treatment. It’s when these studies were done that we realised that HRT actually increased the risk of heart disease.
The healthy-user effect, though, has not gone away, and is still alive and well in medical research. Here’s another apparent example that concerns cholesterol-reducing drugs known as statins…
In the past, statins have said to help prevent pneumonia (infection in the lung) on the basis of epidemiological studies. However, it is generally the case that frail, elderly individuals, with perhaps complicated health histories are less likely to be prescribed or take statins than healthier individuals. Because of this, when we see lower incidence of infection in those taking statins, we have no idea if it’s the statins, or the fact that these people are generally healthier, or both, that accounts for the reduced infection risk.
One way to get clarity here is to attempt to take into account health status of individuals when performing this sort of analysis. That’s exactly what a team of doctors based in the US did when analysing the relationship between statin use and risk of pneumonia in a study published in 2009 [1]. This more careful analysis revealed that statin use was actually associated with a 26 per cent increased risk of pneumonia. For pneumonia severe enough to require hospitalisation, statin use was associated with a 61 per cent increased risk.
Now, we should not forget that these studies are epidemiological in nature, and cannot be used to prove that statins cause enhanced susceptibility to pneumonia. However, the evidence as it stands is incriminating nonetheless. Further suspicion is raised in the form of evidence which shows that statins have the ability to directly impair the immune system and its ability to resist bacteria [2].
The most comprehensive account of statin side-effects I can find was published last year in the British Medical Journal [3]. Known side-effects of statins include muscle weakness and/or pain (myopathy), liver damage , kidney failure and cataracts. Here, in summary, are the findings of this review:
For every 10,000 women at high risk of CVD [cardiovascular disease] treated with statins, we would expect approximately 271 fewer cases of cardiovascular disease, 8 fewer cases of oesophageal cancer, 23 extra patients with kidney failure, 307 extra patients with cataracts; 74 extra patients with liver dysfunction; and 39 extra patients with myopathy.
For every 10,000 men at high risk of CVD treated with statins, we would expect approximately 301 fewer cases of cardiovascular disease, 9 fewer cases of oesophageal cancer, 29 extra patients with kidney failure, 191 extra patients with cataracts; 71 extra patients with liver dysfunction; and 110 extra patients with myopathy.
This study focused specifically on data relating to individuals deemed to be at high risk of cardiovascular disease. Many individuals who take statins are actually not at high risk of cardiovascular disease. For these, benefits are likely to be significantly lower than those elucidated in this study (while risks are likely to be about the same).
But look at those figures for a moment. Two things jump out to me:
Of 10,000 high-risk individuals, only about 300 will benefit – that’s 3 per cent. That means, of course, 97 per cent will not benefit. The number of people who benefit is roughly matched by those who will get a serious adverse effect. Hands up who wants to take a statin now?
References:
1. Dublin S, et al. Statin use and risk of community acquired pneumonia in older people: population based case-control study. BMJ 2009;338:b2137
2. Benati D, et al. Opposite effects of simvastatin on the bactericidal and inflammatory response of macrophages to opsonized S. aureus. J Leukoc Biol. 2010;87(3):433-42
3. Hippisley-Cox J, et al. Unintended effects of statins in men and women in England and Wales: population based cohort study using the QResearch database BMJ 2010;340:c2197
I would really like to know why and who are the 3% that can benefit? What criteria makes them part of this 3%?
Hi John,
I think your 2nd paragraph summarising “For every 10000 women” should read “For every 10000 men”.
Regards
Why are there two paragraphs starting ‘For every 10,000 women at high risk of CVD treated with statins’ ?
Each paragraph has different numbers of cases but they appear to be saying the same thing !
DrDobbin – well spotted, thanks.
TerryJ – this has been corrected now.
Interesting study. However I would hate to have an anti-statin message ride so heavily on cataracts, as anyone would trade heart disease for the “side effect” of a cataract. More convincing are the studies that demonstrate muscular and progressive dementia issues.
Matt – I would be interested to know more about the muscular and progressive dementia evidence – can you provide citations?
The point about cataracts has a wider application. Patients need good evidence like this to make decisions – and they should be the ones to make that decision, not the doctor. Some patients may feel cataracts would be much worse than a heart attack (I’ve heard plenty of people say “it’s the way he would have liked to have gone” of someone who died of heart attack, but I’ve never heard anyone with anything good to say about progressive blindness). Some people would be appalled at the thought of suffering liver disease or kidney failure and would be far more focussed on that than on other types of outcome. A singer might want to do anything he could to avoid oesophagal cancer, and be thrilled that statins could help, even at the risk of other serious side effects.
Unfortunately, this sort of clear interpretation of data is rarely given to doctors, so they are in no position to pass it on to their patients.
As part of the studies of those who benefit from statins, how may changed to a healthier lifestyle? That change would probably be more beneficial than just taking statins.
I was unable to take statins due to adverse side effects, but I now take Lipantil (fenofibrate) to control cholesterol. I believe it is one of the older prescribed drugs which predated statins. Are there any similar side effects from this?
My husband was healthy Went to heart specialist because of family history of heart disease Was put on statins and other drugs by way of prevention for five years At age 60 he started to become forgetful and was treated for depression Two months ago at age 61 he has been diagnosed with frontal lobe dementia I am looking at a healthy body and a dying mind and my heart is broken I cannot care for him any longer I ceased all that medication. I often wonder if he has not been treated by the heart man would he still be with me today
I look forward to an in depth study of any links between dementia and statins
I think Matt is right. Not just cataracts but everything in the paper shows poor odds ratio, typically 1.3 except for moderate or serious myopathy where the numbers are larger but the absolute incidence is very low. The question I would ask practitioners is the extent to which anecdotal observations on people who stop taking statins because of the muscle effects are borne out in clinical observations. In theory, this is supposed to be benefit of intention-to-treat but I suspect these people may never get into the study.
Dr Briffa,
I found a wealth of information on Dr. Graveline’s site.
http://www.spacedoc.com/statin_side_effects
‘Of 10,000 high-risk individuals, only about 300 will benefit – that’s 3 per cent. That means, of course, 97 per cent will not benefit. The number of people who benefit is roughly matched by those who will get a serious adverse effect. Hands up who wants to take a statin now?’
I don’t want to evaluate the benefits of taking a statin until I understand that risk/benefit analysis. Surely EVERY single decision that an individual makes for health can have a risk/benefit analysis attached – and for that reason, no one would take aspirin, no one would drink wine… because who knows if the risks might apply instead of the benefits!
Of course, statins don’t guarantee that you will never lose your memory or have diabetes, or suffer liver problems. One BENEFIT of taking a statin is the attention paid to lab tests. Do you really think people go to their doctors insisting on regular liver function tests? In the United States, unless there’s a good reason to order those tests, you will pay cash out of pocket (the testing is not justified so no insurance coverage).
This reminds me of giving blood. You must sign a statement that says that you will not hold the Red Cross responsible for x,y, and z after giving blood. Nevertheless, thousands give blood. There is even a cardiac benefit to giving blood – yet I have never seen a risk/benefit analysis!
All of the clinical trials of statins were no doubt conducted on people following the treatment guidelines. The instructions included with Lipitor say it should be combined with a “low-fat, low-cholesterol” diet and all the other statins probably give similar advice. Anyone who follows those directions will probably be increasing their risk of heart disease with or without the drugs. The results would be very different if they were tested on a population eating a natural, healthful, low-carb/high-fat diet.
In fact, I’d wager that a high-cholesterol diet would produce better results without a statin than a low-cholesterol diet with it. Of course, the drug companies would never fund such a study.
There is no doubt in my mind that blood testing and blood analysis is a growth industry.
And there is no doubt that growth industries serve at least tow important functions. They provide salaries that pay mortgages and rents, in addition to placing food upon families tables; and they return profits that contribute a return upon the capital investments that went into founding the labs in the first instance.
Sure, lab testing can provide some important results and feedback from which lessons can be learned, behaviour modified, or intervention prescribed. But there are problems.
The elementary problem is that the (monetary or financial) benefits for those who have ‘invested capital’ in testing, or for those who have a living based upon it, is not strictly associated with the ‘real’ benefits for patients. Benefits for ‘those with dependencies’ are not a strict or reliable ‘proxy’ for the real interests and benefits of patients.
Lab testing can be responsibly directed and helpful, but it does not have to be to be helpful to patients to be determined a success by those with a financial interest in it.
The problem with statins (aside from inevitable side effects) is that they are prescribed off poor and misapplied ‘proxies’.
First, total ‘cholesterol’ is a poor ‘proxy’ predictor of incidence of heart disease. Second, cholesterol has to measured by a ‘proxy’ method that involves measurement, not of cholesterol, but of lipoproteins (LDL, HDL, etc). Lipoprotein counts are a ‘proxy’ method of arriving at a count of cholesterol. Cholesterol is a lipophile that won’t form an aqueous solution. Blood is an aqueous solution, so cholesterol cannot disperse in blood. Lipoproteins are natures’ solution to the problem of distributing lipophilic substances around the the essentially aqueous solution that is blood.
Science is based upon a fundamental philosophy; that one won’t witness an effect that does not have a cause. The inference is that variable ‘effects’ have ’causes’ that result from variables. LDL and HDL are variables whereas the cholesterol that may be found within them is an invariable.
Einstein described madness as the willingness to go about affairs repeating the same old inputs while anticipating different results each time. Variable results should originate from variable inputs.
If the ‘trump card’ of cholesterol orthodoxy has some validity, that the ratio of HDL ot LDL has some bearing on outcome. then the central philosophy of the scientific method ought to major on some variable. Lipoproteins evidently vary form HDL to LDL, or at least something associated with the lipoprotein does, yet cholesterol is a ‘contsant, an invariabble, that can hitch a ride in both. Cholesterol orthodoxy majors on attaching a variable outcome to an invariable constituent, ‘cholesterol’, and it flies in the face of a philosophy fundamental to the very foundation of science. Worse it does this while knowing a variable, the lipoprotein, has some association with variable results.
‘Medical science’, an oxymoron if ever there was one, has lost sight of the presence, benefits, and above all, the limitations of the ‘proxy’ measurement of cholesterol via the ‘proxy’ measurement of lipoproteins. Losing sight of this proxy results that conclusions are opposite to that that would be rational. Cholesterol is a constant that ought not be responsible for a variable outcome. The outcome is a function of the lipoprotein, or of some variable connected with its constituents, and nothing to do with an invariable, such as cholesterol.
I do not care for serum lipoprotein counts as a predictor of risk of heart disease for they are a poor ‘proxy’ for ‘cholesterol’, which in turn is poor ‘proxy’ for heart disease.
I don’t care too much for money either, for money can’t buy me love. Money can be a poor proxy for the things that really matter, and love is just one of those things.
Money has a bearing upon the health of patients; sometimes helpful, and sometimes otherwise. Often-times, money makes treatment or management of symptoms agreeable and economically expedient, at the expense of failure to see or eradicate cause.
If we were prepared to use ‘better money’ we’d see better health outcomes too. Strange, radical, and true.
Dr. Briffa, what is your view of using statins to treat someone with established CVD/CAD (via stress echocardiogram), coupled with high LDL, albeit of the large, fluffy (Pattern A) variety?