Who should take statins? Is heart disease predictable?

Who should take statins.....besides everyone?  I thought a lot about this when I was working on a lecture about predicting disease. The purpose of statins, of course, is to prevent atherosclerotic cardiovascular disease in people at risk (how well they do this is another issue). The challenge is to identify the people 'at risk'.  I wrote about this in July, but I've been playing some more with the ideas and wanted to follow up.

Statins are a class of drug that, in theory, work by lowering LDL (low-denstity lipoprotein) levels. They do this by inhibiting HMG-CoA reductase, an enzyme that has a central role in the production of cholesterol in the liver.  LDL, the so-called 'bad' cholesterol, isn't actually just cholesterol, but has been linked to risk of heart disease because, as a lipoprotein, its job is to transport cholesterol to and from cells.  It is bound to cholesterol.  What's measured when we have our blood drawn for a cholesterol test is LDL-C, the amount of cholesterol bound to LDL particles (LDL-C), as well as HDL-C, the 'good' cholesterol package, which transports LDL-C from cells, leading to lower blood cholesterol levels.  Cholesterol makes plaque and plaque lines and hardens arteries, which occludes them and leads to stroke and heart attack.  Lower the amount of LDL, and you lower the risk of arterial plaque deposits.

The connection between cholesterol and heart disease was first identified in the Framingham Study in the 1950's and 60's, and this lead directly to the search for drugs to lower cholesterol.  Statins were developed in the 1970's and 80's, and after some fits and starts, began to be used in earnest in the late 1980's.  Statins work by inhibiting the liver cells' synthesizing of new cholesterol, that is, cholesterol that isn't due taken in in the diet.

Akira Endo, one of the first scientists to look for cholesterol-lowering compounds, reviewed the history of statins in 2010.  He described the many studies of the effects of these drugs, saying "The results in all these studies have been consistent: treatment with statins lowers plasma LDL levels by 25–35% and reduces the frequency of heart attacks by 25–30%" (Akira Endo, Proc Japan Acad, Series B, 2010).

A systematic review of the literature on the effectiveness of statins was published by the Cochrane Organization in 2012. The review reports, "Of 1000 people treated with a statin for five years, 18 would avoid a major CVD event which compares well with other treatments used for preventing cardiovascular disease."  This suggests, of course, that 982 people took statins with no benefit, and perhaps some risk, as statins are associated with muscle pain, slightly increased risk of type 2 diabetes, liver damage, neurological effects, digestive problems, rash and flushing, and other effects.  But more on this below.

So, who should take statins? 
Until 2013, the recommendation was that anyone with a modest risk, as assessed by the Framingham Risk Calculator (I've read that that means from 6.5% to 10% 10-year risk) would likely be prescribed statins.  The interesting thing, to me, about this risk calculator is that it's impossible to push the risk estimate past "greater than 30%", even at maximum allowable cholesterol, LDL, and systolic blood pressure, and being a smoker on blood pressure medication.  Which means that there's a lot that this calculator can't tell us about our risk of CVD, based on the best risk factors known.

Framingham Risk Calculator

In 2013, the American Heart Association/American College of Cardiology revised their criteria for statins.  Now, they are recommended for people who have had one CVD event in order to prevent another; for people with primary elevations of LDL-C greater than 190mg/dL; people 45-70 years old who have diabetes and LDL-C between 70 and 189mg/dL, and people 45-70 years old with LDL-C between 70 and 189mg/dL and estimated 10-year cardiovascular disease risk of 7.5% or higher.

The first three criteria are straightforward.  If statins lower LDL, and lower LDL lowers risk of ASCVD (artherosclerotic cardiovascular disease), then taking them should be beneficial.  But then we're back to a risk calculator again to estimate 10-year risk.

ACC/AHA

It has been revised.  Now included are ethnicity (well, White, African American or other), and diabetic status (yes/no), and estimated lifetime risk.  And, now it's possible to push 10-year risk up past 70%, which I discovered by playing around with the calculator a bit.  Whether or not it's a more accurate predictor of a cardiovascular event is another question.

Here's the lowest risk I could come up with, 0.1% 10-year risk.  The recommendations offered are not to prescribe statins.

Lowest 10-year risk

Here's the highest risk I could force the calculator to estimate.  Ten-year risk for a female with these risk factors is higher than for a male, but lifetime risk is lower.  That seems strange, but ok, it must reflect association of risk factors including sex with disease at the population level.  

Compared with the Framingham calculator, risk estimation seems to be getting more precise. Or at least bolder, with estimates up in the 70's.  But is the new calculator actually better at predicting risk than the old one? A paper was recently published in JAMA addressing just this question ("Guideline-
Based Statin Eligibility, Coronary Artery Calcification, and Cardiovascular Events," Pursnani et al.) They identified 2435 people from the Framingham study who had never taken statins. Their medical history allowed the authors to determine that, based on the old guidelines, 14% would have been 'statin eligible' compared with 39%, based on the new 2013 guidelines.

Among those eligible by the old guidelines, 6.9% (24/348) developed CVD compared with 2.4% (50/2087) among noneligible participants (HR, 3.1; 95% CI, 1.9-5.0; P less than .001). Under the new guidelines, among those eligible for statins, 6.3% (59/941) developed incident CVD compared with only 1.0% (15/1494) among those not eligible (HR, 6.8; 95% CI, 3.8-11.9; P less than .001).

So, put a whole lot more people on statins, and you prevent an additional very small number of CVD events; 1.0% vs 2.4%.  And, 93% of those ‘eligible’ for statins did not develop disease. Nor, of course, do statins prevent all disease.  Actually, if everyone in the population were covered, statins would be preventing as many events as they could possibly prevent, but in a small minority of the population.  That is, 90+% of people considered to be at 'high-risk' of disease don't go on to develop disease.  Is it worth the side effects and cost to put so many more people on statins to prevent the 1.4% more CVD that these new guidelines are preventing?  Well, heart disease is still the number one killer in rich countries, and 40+% of the population is currently taking statins, so a lot of people have decided that the benefits do outweigh the risks.

Another question, though, is more fundamental, and it concerns prediction.  The calculator seems to now be predicting risk with some confidence.  But, let's take a hypothetical person with a somewhat elevated risk.  Her cholesterol is higher than the person above who's at lowest risk, but that's due to her HDL.  Her systolic blood pressure is high at 180, which is apparently what bumps up her risk, but her 10-year risk is still not over 7.5% so the recommendation is not statins, but lifestyle and nutrition counseling.  (Though, the definition of 'heart-healthy diet' keeps changing, so what to counsel this person with low risk seems a bit problematic, but ok.)

Low enough risk that statins aren't advised.

Now here's the same hypothetical person, but she's now a smoker, on medication to lower her blood pressure (and her b.p. is still high) and she has diabetes.  Her 10-year risk of ASCVD jumps to 36.8%.  This makes sense, given what we know about risk factors, right?  The recommendation for her is high-intensity statins and lifestyle changes -- lose weight, do regular aerobic exercise, eat a heart-healthy diet, stop smoking (easy enough to say, so hard to do, which is another issue, of course, and the difficulty of changing all these behaviors is one reason that statins are so commonly prescribed).

But now I've lowered her total cholesterol by 70mg/dL, which is what statins ideally would do for her.  Even so, the American College of Cardiology/American Heart Association recommendation is for 'high-intensity statin therapy' and lifestyle counseling.  The calculator doesn't know this, but statins have already done everything they are likely to do for her.

So, let's add lifestyle changes.  But, even when she quits smoking, her 10-year risk is 20%.  So let's say we cure her diabetes -- even then, she's still at high enough risk (9%) that 'moderate to high-intensity statins' are recommended.  I'm confused.  I think even the calculator is confused.  It seems there's a fuzzy area where statins are being recommended when what's left to do is, say, lower blood pressure, which statins won't do.  This hypothetical woman probably needs to lower her weight to do that, and statins aren't going to help with that, either, but still they're recommended.  Indeed, one of the criticisms of this risk calculator when it was released in 2013 was that it overestimates risk.  Perhaps so, but it also seems to overestimate the benefit of statins.  

Further, it seems there are a lot of type 1 errors here.  That is, a lot of people are considered 'at-risk' who wouldn't actually develop cardiovascular disease.  Risk of 7.5% means 7.5 of 100 people with a given, equal set of risk factors are expected to develop disease.  That means that 92.5 would not.  And that means that we have a pretty rough understanding of heart disease risk.  The strongest risk factors we know -- smoking, high LDL-C, diabetes and hypertension -- can be expected to predict only a small fraction of events.

And that means that either something else is 'causing' cardiovascular disease in addition to these major known risk factors, or something is protecting people with these risk factors who don't go on to develop disease.  Family history is a good or even the very best single predictor (why isn't it taken into account in these calculators?) which suggests that it's possible that genetic risk (or protection) is involved, but genome wide association studies haven't found genes with large effects.  Of course, family history is highly conflated with environmental factors, too, so we shouldn't simply assume we need to look for genes when family history indicates risk.  Anyway, it's unlikely that there are single genes responsible for ASCVD except in rare families, because that's the nature of complex diseases.  Instead, many genes would be involved, but again as with most complex diseases, they would surely be interacting with environmental risk factors, and we don't yet know understand how to identify or really understand gene by environment interaction.

And then there's the truly wild card!  All of these risks are based on the combinations of past exposures to measured lifestyle factors, but the mix of those and the rise of other new lifestyle factors, or the demise of past ones, means that the most fundamental of all predictors can itself not be predicted, not even in principle!

So, statins are a very broad brush, and a lot more people are being painted with them than in fact need to be.  The problem is determining which people these are, but rather than zoom in with more precision, the updated calculator instead paints a whole lot more people with the brush.  This isn't the calculator's fault.  It's because understanding risk is difficult, ASCVD is a large and heterogeneous category, and prediction is very imprecise -- even for many 'simple' Mendelian disorders.  If ASCVD were caused by a single gene, we'd say it had very low penetrance.  And we'd want to understand the factors that affect its penetrance.  That's the equivalent to where we are with cardiovascular disease.

I was interested to see that the 2013 ACC/AHA Guideline on the Assessment of Cardiovascular Risk says something that I have said so many times that I decided not to say it again in this post.  But, I'm happy to see it elsewhere now.  The guideline committee itself acknowledges the issue, so I'll let them explain the problem of assessing risk as their calculator does.

By its nature, such an approach requires a platform for reliable quantitative estimation of absolute risk based on data from representative population samples. It is important to note that risk estimation is based on group averages, which are then applied to individual patients in practice. This process is admittedly imperfect; no one has 10% or 20% of a heart attack during a 10-year period. Individuals with the same estimated risk will either have or not have the event of interest, and only those patients who are destined to have an event can have their event prevented by therapy.

It's the problem of using group data, which is all we've got, to make clinical decisions about individuals.  It's the meta-analysis problem -- meta-analyses compile data from many individual studies to produce a single result that certainly reflects all the studies, because they were all included in the statistics, but it doesn't represent any of them with precision.  Ultimately, it's the problem that these sorts of inferences must be based on statistical analysis of samples -- collections -- of individuals.  We do not have an easy way around this, including the N of 1 studies currently being proposed.

Finally, here's a meta-thought about all this.  Ken and I were in Finland this month co-teaching a course, Logical Reasoning in Human Genetics, with colleagues, including Joe Terwilliger.  Joe said multiple times, "We suck at finding candidate genes because we don't know anything about biology.  We're infants learning to crawl."  The same can be said about epidemiological risk factors for many complex diseases -- we suck at understanding the causes of these diseases, and thus we suck at prediction, because we don't really understand the biology.

Heart disease - the 7.5% solution?

Statins are in the news again, and not just because of the new PCSK9-based drugs, at least one of which is likely to be approved by the FDA this week, probably for a small class of at-risk patients.  These drugs will drive LDL cholesterol levels through the floor, while generating an estimated 17.8 billion for pharma by the year 2023 (and that's before we even know whether they will reduce risk of heart attack and stroke).

No, this is about your run-of-the-mill class of LDL-lowering statins.  In late 2013, the American Heart Association and the American College of Cardiology recommended new guidelines for determining who should be on statins.

• anyone who has cardiovascular disease, including angina (chest pain with exercise or stress), a previous heart attack or stroke, or other related conditions

• anyone with a very high level of harmful LDL cholesterol (generally an LDL above greater than 190 milligrams per deciliter of blood [mg/dL])

• anyone with diabetes between the ages of 40 and 75 years

• anyone with a greater than 7.5% chance of having a heart attack or stroke or developing other form of cardiovascular disease in the next 10 years.

Risk score is based on the ASCVD calculator, which uses basic data (age, sex, total cholesterol, HDL cholesterol, systolic blood pressure, and smoking and diabetes status) to calculate risk.  Unlike the previous Adult Treatment Panel III (ATP III) guidelines which were based on a target LDL level and risk factors determined by the long-term Framingham heart disease study (using the Framingham Risk Calculator), these new guidelines were based on a risk profile.  With these new guidelines, it was thought that about 13 million additional Americans would benefit from statins, for a total of a third of all Americans.

A study published in the Journal of the American Medical Association last week asks whether these guidelines were better at identifying at-risk individuals than the old ATP III guidelines.  The prospective study followed up 2435 people from the Framingham study who had never taken statins.  Based on the ATP III guidelines, 14% would have been 'eligible' compared with 39%, based on the 2013 guidelines.

The median follow-up was 9.4 (interquartile range, 8.1-10.1) years. There were a total of 74 (3.0%) incident CVD events (40 nonfatal myocardial infarctions, 31 nonfatal strokes, and 3 with fatal CHD) and 43 (1.8%) incident CHD events (40 nonfatal myocardial infarctions and 3 with fatal CHD).

Among those eligible for statin treatment by the ATP III guidelines, 6.9% (24/348) developed incident CVD compared with 2.4% (50/2087) among noneligible participants (HR, 3.1; 95% CI, 1.9-5.0; P less than .001). Applying the ACC/AHA guidelines, among those eligible for statin treatment, 6.3% (59/941) developed incident CVD compared with only 1.0% (15/1494) among those not eligible (HR, 6.8; 95% CI, 3.8-11.9; P less than .001). Therefore, the HR of having incident CVD among statin-eligible vs noneligible participants was significantly higher when applying the ACC/AHA guidelines’ statin eligibility criteria compared with the ATP III guidelines (P less than .001).

That is, according to this study, the 2013 ACC/AHA guidelines identified more people at risk of heart disease than the ATP III guidelines.  That's presumably progress in understanding heart disease risk, and so a good thing. (Does anyone else find the use of the word 'eligible' odd, though?  Like statins are a reward for passing the risk threshold?)

But why don't they ask about family history?  That is one of the most useful bits of data a physician can have about a patient's risk of heart disease (and other things).  Is it too cynical to suggest that acknowledging its usefulness might diminish the importance of what has been learned from the Framingham study?

Less cynically, one reason, though we don't know if the various investigators considered it in this way, is that family history integrates all factors, including those that are being specifically measured (like blood pressure, LDL levels, and so on). Whether they are genetic or environmental, they went into determining whether the relative had heart disease.  So counting family history and LDL, or for that matter, weight and BMI, also not included, may be redundant to an unknown extent.  For risk factors, this would perhaps inflate the apparent risk, but for protective factors the opposite.  But family history is debatably the best single factor, perhaps as important as all the test-battery factors.  At least, it's important to consider why that alone, or that somehow corrected for redundancy, should be a part of all of this.

So, apparently we don't know more about the causes of ASCVD now than we did before 2013, we're just evaluating what we know differently.  So, assuming that statins really do reduce risk of ASCVD, that more people are 'eligible' is thought to be a good thing.  Though, as the JAMA commentary on this article notes in urging increased treatment with statins, "Although a 10-year ASCVD risk threshold of 7.5% or higher might initially seem to be a low threshold, many, indeed most, CVD events occur among the low-risk members of the population."

Wait!  "Low-risk" is defined by us, based on what we know about heart disease!  Our understanding is clearly wrong if all these 'low-risk' people are really high-risk!  Not to mention that there's clearly a huge false-positive pool if a risk estimate of 7.5 out of 100 makes a person eligible for statins!  That means that 92.5 of those 100 people are taking statins even though they weren't going to have a stroke or heart attack.  And, all this means, at least to me, that we really don't understand what causes heart attacks or stroke. The Framingham study identified cholesterol, particularly LDL, as a risk factor, but we're not really sure why, and we don't know what levels are in fact most risky, and people with low LDL can have heart attacks, too.  Statins may or may not work by reducing LDL cholesterol, and lower LDL cholesterol may or may not reduce risk.

And, statins can have serious side effects -- physical as well as the cost burden.  So, if of 100 people taking statins a large majority weren't going to have heart attacks anyway, statins are causing a lot of unnecessary side effects without preventing disease.  Though, to be fair, physicians can't predict the future, and must do their best with the information they have.  They don't know who will or won't have a heart attack, because epidemiology hasn't given them enough information.  They've got to treat people with 7.5% risk as if they are at 100% risk of disease.

So, it's not physicians who are failing here, it's epidemiologists.  But I'll even be fair to epidemiologists -- it's the methods, based on population data and probability (which may not even exist; see our series of posts on this starting here), that are failing.  Epidemiologists are doing their best with what they've got.  We don't know precisely what causes heart attacks, but to prevent them, we've got to treat people with low risk as though they are at high risk, and that's because some people at low risk really are at high risk.

No one has 7.5% of a heart attack.  They have 0% or 100% of a heart attack. Figuring out who is in which group is currently impossible.  What we do know for certain is that putting everyone on statins, as though they have 100% risk is very good for the pharmaceutical companies that make them, and good for people whose heart attack or stroke was prevented, even if we will never know which people these were, and unnecessary and even harmful for everyone else.

This is a lousy way to do medicine.  But it's currently the only way we've got.

Real Truth in Labeling for the new statin replacement

The FDA is about to or just has approve a new cholesterol-fighting drug to supplement or replace statins.  But is it taking all the 'side effects' into account?  Should it?  The new substances (several pharmaceutical outfits apparently have them near to market) inhibit a different genetic pathway from what statins do and can be used to treat high cholesterol in those who can't handle statins, or for whom statins aren't lowering their LDL cholesterol, and may also actually be much more effective even for the current millions who take statins.

These drugs inhibit the action of a gene called PCSK9 and interfere with the liver's detection and response to LDL levels in the body; see the NYT story here from last week for more details about the drugs.  The excited news reports, at least, describe what are truly remarkable reductions in LDL levels without untoward side effects. If these facts stand up to larger or longer term trials and experience, it will be a major pharmaceutical success....in more ways than one.

One immediate issue is the 'usage creep' that almost inevitably seems to follow the appearance of a new drug, and in this case one with fewer side effects and higher efficacy with regard to lowering the most dangerous type of circulating cholesterol (the 'bad', or LDL form). Recommended approval is for use in three groups of patients: those whose high LDL cholesterol can't be lowered sufficiently with statins, those at particularly high risk because of previous heart attack or diabetes and high LDL, and those with high levels of LDL who can't tolerate statins.

But if these agents are as effective as reports suggest, and with less or even no serious side effects, then even if they are initially approved or recommended for just these specific groups, usage will surely expand as the definition of who is 'at risk' expands. Perhaps people whose cholesterol is responding to statins but who don't like the side effects, or someone whose close relative has had heart disease but whose current LDL levels are not high will ask for this treatment as a preventive, or doctors will think 'off label' usage is absolutely proper, assuming no serious side effects. Hell, if the makers are extremely lucky, maybe it will turn out it even treats erectile dysfunction or male-pattern baldness! And then, what about extending to, say, younger ages or even simply to everyone, like putting vitamins in milk or iodine in salt?  This is what we mean by usage creep.

One might reasonably say that this is just what should be done.  Precedent might suggest that eventually we'll find that the agents are less effective than current tests suggest or have some serious long-term but as yet undiscovered downsides.  However, things that can't be known until the drug is used by millions of people for numbers of years.  Making decisions about usage is harder than one might think.

One reason for concern about usage creep is already being mentioned in the blaring news stories about the apparently genuinely major advantages of these compounds.  That is, the obvious issue of the financial mega-bonanza to be reaped by the pharmaceutical firms.  These drugs are going to be very expensive.  The money to be made is certain to encourage usage creep.  Could we expect otherwise?

But worse than just profiteering is that, even with Obamacare available so that presumably even the poor could have access to these beneficial drugs, putting the whole population, so to speak, on these pills for their whole lives, could bankrupt the health-care funding system that is already a heavy burden on society.  It's being suggested that these new pharmaceuticals could simply by themselves eat up any reasonable premium level for health care plans.

But there is another issue, and that relates to truth in advertising and the issue of side effects--and here we don't refer to incomplete data that may be leading to premature approval or anything like that.  Instead, it's more of a philosophical issue:  What does a list of side effects mean, in this case, and what would the whole truth actually be? What should the manufacturer or the FDA tell you so you would be truly better informed when you take the new drugs for the rest of your life, as so many are likely to do, across the developed world?

From the Sanofi website; Sanofi is one of the makers of these statin replacements

What the FDA and medical community doesn't list on the label
The FDA requires that known side effects of drugs be clearly stated on packaging or labeling material, and surely physicians will know about them.  Isn't that right?  It should be, but there is a sleeping tiger here, that apparently nobody has thought about or, if they have, that they've buried so deep you never will realize it.  In fact, there will be huge unstated negative side effects of these new drugs.  Indeed, shouldn't a proper labeling for these new medications include something like the following?:

"WARNING: Use of this product will greatly increase your risk of Alzheimer's Disease and other dementias, arthritis and other muscle and joint diseases, some forms of cancer, diminished vision and hearing, other degenerative disorders, and accidental death."

Of course such truth in labeling won't happen, and the reasons are subtle and if taken seriously would lead us, as a society, to think more deeply about the role of medicine in health, and of the meaning of health, in a real world in which life is finite.  There is no one who can provide 'the' answers to the problems that are raised, and indeed each person would, in principle, provide his/her own answers.

But at least, there should be a societal discussion.  The reason has to do with the concept of 'causation' and the demographic realities in a world of competing causes.  If these drugs lower LDL cholesterol anywhere nearly as much as they seem on present evidence to do, and if the association between LDL cholesterol and heart disease is as linear as is hoped, then that by itself will eliminate or greatly forestall the occurrence of fatal heart disease in those who take them.  But then what?

If people live much longer as a result, they will inevitably get the sorts of diseases that could be included in an empirically correct labeling!  If you don't get heart disease, it is simply obvious that you will get something else, and it is likely to be slower and more progressive than the quick end to life that heart attacks can be.  Note that our warning list did not include some causes, like kidney failure, diabetes, and the like that could be stalled or avoided by lowering LDL cholesterol--so we are being quite conservative here.

The problem is that of what are known as competing causes, and we've written about it before.  It is inevitable that you will die of something.  If not heart disease, something else.  One might say, well, OK, but at least I'll have more years of life before that something-else gets me. This is likely to be true to some extent, but there are two cautions.

First, people with heart disease often have other health issues because by and large heart diseases gets people at older age, and they are more likely to have less healthy lifestyles.  That includes more risky conditions than high cholesterol.  So, these other causes may be lurking just around the corner, so the removal of heart disease may mean that the gain in years might not be very much!

Secondly, other disorders that those saved from heart attacks will eventually get, if they don't have them already, are ones with gradual onset: you become more and more affected over time.  Mental deficiencies, joint and mobility problems, vision and hearing, are clear examples.  And the nature of accelerating risk is that if you slow it down you defer the onset of serious-level symptoms but you also stretch out the decay process at the end: you have more years with more and more serious symptoms before your body finally conks out.

What is 'cause'?
Are we just playing word games here?  Is it accurate to suggest that the new drugs will 'cause' dementia?  Surely the chemical doesn't mess with neurons!  Let's assume that's true and that no such direct molecular effect is ever found. Then the effect of the medication is related to the occurrence of these other traits, but not in a directly causal way.

This raises questions about causation.  It is more than simply saying that correlation is not the same as causation, because while the active mechanisms responsible for, say, Alzheimer's or joint disease, are not affected by the LDL-reducing drugs, they open the way for the former to act because the person lives longer.  Correlations such as the brand of car you drive being associated with some forms of disease arise because both may be the result of income levels and associated dietary habits. The dietary habits, not the type of car, are causes of interest.

But in the case of competing causes of disease, reduction of one is a sort of mechanistic effect, not just a spurious cause.  If a mechanism is changed in a way that allows a different mechanism to proceed for longer times, this is part of the overall mechanism of the related traits.  The chronic late-onset diseases most of us in the rich world die of now are directly the result of so successfully controlling infectious diseases, our previous killers. One definition of cause is that if you remove it, the effect changes, in this case the protective effect, relative to cancer, of dying of a heart attack.

And what if widespread use of these new drugs puts serious pressure on the health care system, so that some treatments will have to be deferred or denied to more people than presently?  Is that so unlikely?  And is that then not a cause of deteriorating health?

And what if it worked miracles and the relative fraction of our population (and the world's population) of wearing-out old people substantially increased?  That puts all sorts of pressures and pinches on everyone else, indeed, even on the normal living needs of the increased elderly segment.

Causation is not so simple and straightforward a notion.

So, what is 'health care'?
The new LDL reducers raise many deep, and deeply important questions.  The point here is to be realistic about disease in our society and have an open consideration of how to deal with the kinds of game-changing environmental or behavioral aspects of our society, and their long shadow of implications.

In a very serious sense, even if indirectly, the new LDL-lowering agents might have disastrous effects for countless numbers of people.  It's a discussion we should be having.  The news media should be leading the way, to force that on the scientists and health system.

Indeed, these issues should force us to consider what, exactly, we even mean by 'medical care' and 'health care'.  How do they relate to each other, and to the idea of 'public health'?

We think these are real, complex, disturbing, serious truths that have no one answer, and that affect individuals as well as society.  This is not a matter of complaining about science, policy or even drug company profits.  It is about profound issues in human life, that should be discussed openly and fully, because they affect everyone's future.

To statin or not to statin, that is the question....or is it?

Last week we all heard about the new recommendations concerning predicting and preventing heart disease.  An online calculator was going to be used to predict risk, based on past experience of a study cohort, and if we were found to be at risk, we'd be advised to start taking statins.  Based on various risk factors -- BMI, whether we smoke, etc., -- the calculator would advise our doctor if our risk of heart disease was greater than 7.5%, and if so, that would trigger the writing of the prescription.  Estimates were that this was going to lead to 1/3 or more of American adults taking statins for the rest of their life.

We had various reasons to question this recommendation, as we wrote then, and that was even before new issues have come home to roost.  As reported in the NY Times yesterday (and in The Lancet today), experts are now showing that the calculator is way over-estimating risk, which would mean millions more people on statins than the generous new guidelines themselves would recommend.    Some leading cardiologists are calling for a halt to implementation of the new guidelines until the calculator issues get sorted. 

But apparently this shouldn't have come as a surprise to the cardiac community -- two Harvard cardiologists, authors of the Lancet paper, warned a year ago that the calculator overestimates risk.  The problem seems to stem from the use of old data to do the estimations. Ten or more years ago more people smoked, and developed cardiovascular disease earlier than they do now.  Risk estimates on that background now overestimate the effect of factors such as blood pressure and cholesterol because additional background factors, also a component of risk, have changed.  That is, there are confounding variables that affect risk, whose frequency in the population have change, but the calculator doesn't take this into account.  

Or at least that's probably the problem.  It may be even more fundamental than that.  Decades ago, a very well-known cardiovascular disease epidemiologist, Reuel Stallones, used to say that heart disease rates had both risen and fallen in the 20th century for reasons that were not understood.  Diet, exercise, smoking, cholesterol, none of the obvious risk factors explained either the rise or the fall, and it's still true.

However, the risk calculator problem raises another truly fundamental issue that pertains to this sort of risk prediction in general, not just to heart disease.  We have several times noted that one essential flaw in the whole concept of risk estimation based on the kinds of studies that are done, is that risk is estimated retrospectively, from a study sample's past experiences, but what we want are prospective risks: yours and mine for the future, not the past.  But future experiences, mainly here involving lifestyle environmental factors, are inherently unpredictable (In case you missed it, that's inherently unpredictable).

The critique of the new recommendations, in an unusual way, showed just this problem.  Risks were estimated for the new calculator from past data, but used to estimate risks subsequently.  However, since lifestyle risk has changed (less smoking, for example) our ultimate experiences can't be adequately predicted from risks based on the earlier experiences of the cohort used to estimate risk.  Whatever would lead properly cognizant epidemiologists to think that things would be different for the real future?

Indeed, this shows the stubbornness of our clinging to kinds of statistical association mechanisms, the belief in big-science, the haste, and so on that plagues much of what is afoot these days.  To a great extent, we do what we know how to do, the problems are very challenging and often risks are small in absolute value so that, with our approach, we do look to very large studies.  But we also stick with this rather than slowing down, taking a deep breath, and really re-evaluating what we face.  This is the issue we often write about: the need for a deep change in our scientific concepts or methodology, not just keeping the research factory humming.

Plus, we already know a better way to prevent heart disease, and that is lifestyle choices, exercise, not smoking, eating more vegetables than fats and meats.  Statins are largely generic drugs now, but they are still an expensive way to prevent illness -- people without disease become patients (see Jim Wood's August post on how he became sick), they are in the medical system, requiring not only drugs for life but testing and follow-up testing and so on.  And, statins aren't benign drugs; they do have side effects, including muscle pain, liver damage, diabetes.  The industry's credibility is at stake now with this calculator issue, but there are other reasons to question their word about going on statins.  

Universal statins: scam....or just honest good luck for Pharma...or what?

The American Heart Association and American College of Cardiology issued new guidelines on Tuesday for reducing risk of heart disease and stroke (the first of five explanations of these new recommendations is offered here).  If you've got a 7.5% risk of heart disease or higher, as measured by their risk calculator (downloadable here), they recommend you go on statins.  This means, according to the panel, that 70 million Americans should now be considering taking these drugs.  This is perhaps 70% more than the number who now take them, and would put at least one third of all adults in the US on this drug.  For life. 

These recommendations have caused quite a ruckus, but perhaps for the wrong reasons. Before Tuesday, people were put on these drugs to lower their LDL cholesterol levels beyond a given threshold, but, confusingly to many, that threshold which we had supposed was a well-established rock-solid risk factor, has now been eliminated!  Before Tuesday, the indication for going on statins was high LDL, but the indications have now been broadened to include other risk factors such as diabetes and obesity.  So, people now taking statins wonder if they should continue, and others wonder if they need to start.  Some doctors commenting on these changes hasten to add that the most important protection against heart disease is a healthy lifestyle -- don't smoke, exercise, lose weight -- but if these can't be accomplished, statins are recommended (see Dr Harlan Krumholz on "The Newshour" on PBS, e.g.).

Wikipedia

But the new recommendation seems strange. First, a word about statins, drugs designed to control circulating lipids (fats), which confer heart-disease risks. They inhibit an enzyme called 'HMG-CoA reductase' which is expressed in liver cells as they produce cholesterol from raw ingredients and secret it into the blood stream.  Lower enzyme activity, lower circulating lipids.  But in fact, there is evidence that for some reason statins target inflammation in irritated arteries and veins, which may be what reduces risk of heart disease rather than any effect on cholesterol, so there is mystery even in the supposed reason for their supposed effectiveness.


Now, according to John Abramson and Rita Redberg in an editorial in the Thursday New York Times, statins aren't actually effective at preventing heart disease.

Statins are effective for people with known heart disease. But for people who have less than a 20 percent risk of getting heart disease in the next 10 years, statins not only fail to reduce the risk of death, but also fail even to reduce the risk of serious illness — as shown in a recent BMJ article co-written by one of us. That article shows that, based on the same data the new guidelines rely on, 140 people in this risk group would need to be treated with statins in order to prevent a single heart attack or stroke, without any overall reduction in death or serious illness.

If the recommendation is not based on evidence that everyone can agree is reliable then, where is it coming from? Partly, we think, it's a reflection of our belief that we're immortal, partly a general belief in the benefits of drug intervention.... and partly it's a reflection of the fact that some of the recommendation-makers have a vested interest in statins.

The first reason, our belief in immortality, is cultural, and of course very natural.  Few of us, even apparently those with strong religious belief in life hereafter, want to test out that belief.  Heart disease is the number 1 killer in the US and most of us don't want to die of it.

The second reason is more problematic. The most reliable way to lower heart disease risk is through diet, exercise and not smoking.  Indeed, lean, fit, non-smoking individuals whose only risk factor is high LDL are generally at low risk of heart disease.  Until this week, the purpose of statins was to lower LDL cholesterol, but that doesn't reliably lower risk of heart disease. So, are statins a good replacement for life-style?  The answer is No.

But what about the vested interest issues?  As Abramson and Redberg say:

The process by which these latest guidelines were developed gives rise to further skepticism. The group that wrote the recommendations was not sufficiently free of conflicts of interest; several of the experts on the panel have recent or current financial ties to drug makers. In addition, both the American Heart Association and the American College of Cardiology, while nonprofit entities, are heavily supported by drug companies. 

This kind of conflict of interest means that one must be highly suspicious.  One might argue that industry reps are the most knowledgeable about the benefits of their product.  If you want to know how to cure a toothache, ask a dentist, after all.  But how are we to judge the motive behind the recommendations?  Corporate-sponsored research is notoriously biased toward findings favoring their sponsor.  This doesn't mean the bias is intentional, but the evidence suggests that often it is.  At least, the corporate-sponsored research the corporate sponsors tell us about is that which favors their product, since they aren't in fact required to report all their results, and often don't.  (This is why Ben Goldacre, physician, writer and epidemiologist, started the AllTrials campaign to require that all clinical trials be registered, and all results be reported, positive and negative.)  So, when the science isn't convincing, and vested interests are involved in decision-making, it's not unreasonable to be suspicious.

Contingency and context
In addition, the related roles of context and contingency are fundamental and important to understand here.  Risk of heart disease is based on the context--genomic and environmental exposures affect the levels of statins and their consequences.  The risk in an individual is contingent on his/her situation at present, and that can change.  This seems so hard for the established system to understand!

Statins have side effects.  Risk of statin-related disease is estimated in the context of current culture.  If that culture changes, then the risks will change and by all that we know, they'll change dramatically.  If the major contexts change--better diets and so on, things we know a lot about--then the overall risk of heart disease will change.  Models can only do so well at estimating the interaction among the various factors (as the above quote suggests).  If people live healthier lives and if physicians actually pay attention to risk calculations, many may be able to go off their statins, or not start on them, as a result.

But how many will actually risk going off?  Will they keep taking, or their physicians not dare to recommend stopping, for various subjective, inertial, or even emotional reasons?  Will drug companies recommend cessation if, say, body weight goes below some value?  Will they fully advertise the fact that if other factors are favorable, to stop buying their product?  What does history--including their history--suggest to you?

And 10 years from now, how accurate will the predictions have been on which lifelong medications are now being recommended?  Will results be contingent, for example, on the current recommendations themselves?   For example, if you're on statins, will you be more likely to take that second helping of fries, feeling protected by the drug?  The Times Op-Ed puts it this way:

Perhaps more dangerous, statins provide false reassurances that may discourage patients from taking the steps that actually reduce cardiovascular disease. According to the World Health Organization, 80 percent of cardiovascular disease is caused by smoking, lack of exercise, an unhealthy diet, and other lifestyle factors. Statins give the illusion of protection to many people, who would be much better served, for example, by simply walking an extra 10 minutes per day.

These are not secret or new issues by any means, but they tend to be overlooked or minimized by a system that tries to be 'objective' based on current data.  The Op-Ed is written by respectable authors, but they are also known skeptics of the over-medicating problem, with its built-in conflicts of interest as we noted above.  So is their skepticism itself a disqualifying issue--does it mean they bias their views in a similar way to having Pharma-supported people on the panel that made the new recommendations?

Clearly, the issues are complex as so many issues related to late-onset disease are.  After all, you don't get a heart attack even at a young age like 40, unless you live to be 40.

Like second-hand smoke?  The real beneficiaries
Smokers get all sorts of diseases, because of the direct effects of the ugly weed.  But those who live in the same house also get diseases, indirectly, courtesy of their smoking cohabitant.  We have just the opposite story here.  The vendors of statins will get filthy rich as a direct result of their recommendations, whether or not they actually prevent heart disease.  And if they do, some other people--maybe the same people--will get even richer as an indirect result of the same recommendations!

If we don't die of heart disease or its associated diseases, we may live longer but that means more of us will get the slower, nastier, very expensive lingering ailments of old age.  The surgeons, retirement homes, cancer and dementia drug-makers will rake it in big-time!

We've written a few times about the subtle, surreptitious problem of competing causes, and this is another manifestation of the problem.  It's largely unavoidable that if you survive the quick-hitting earlier causes of death, you'll last and linger in service to the slower causes.  They're even more expensive.

We would not credit (nor blame) the statin-promoters for the diabolical scheming that would be involved in salivating over the indirect benefits of statin use.  That takes more perception and a longer view than most people, even scientists, usually have.  It is clear that most drug companies, not to mention the scientific research community itself, as we often write, are in for the quick kill, so to speak.