Rose introduces his manifesto with some general philosophical remarks about the need to engage in medical prevention.  Without yet addressing the basis of his preventive theory,  he nevertheless pre-establishes the ultimate conclusions of the book regarding the political dimensions of health care.  In doing so, he reveals a rather relaxed thought process which, to his credit, is conveyed by a very lively and engaging prose .

Dr. G. Rose

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Rose starts by addressing The scope of prevention with what appears to be uncontroversial survey:

Few diseases are the inescapable lot of humanity, for a problem that is common in one place will usually prove to be rare somewhere else.  Cervical cancer is twenty times commoner in Colombia than in Israel, 10 per cent of Indian children die before their first birthday whereas in Western countries 99 per cent of babes survive, and according to UK census figures 3.1 per cent of adults in Wales report that they are permanently sick, compared with only 1.2 per cent of residents in southeast England.  There is no known biological reason why every population should not be as healthy as the best.

Yet the very first statement is a misleading aphorism since arguably no specific disease is impending on all, but certainly death from some disease remains to this day a common denominator for all human beings, a point that prevention zealots seem to frequently overlook.   As we shall see, the sentence is typical of the easy generalizations that punctuate the book and allow Rose to advance his doctrine effortlessly.  The last statement of the paragraph, true enough in theory, points to the main conclusion of the book regarding the political dimension of health care.

Rose continues with a quote from Virchow:

Epidemics appear, and often disappear without traces, when a new culture period has started; thus with leprosy, and the English sweat.  The history of epidemics is therefore the history of disturbances of human culture. (R. Virchow, quoted from Ackerknecht, EH. Therapeutics from the primitives to the 20th century)

Dr. R.Virchow

For a man reputed to have laid the foundation for modern Western medicine, the German pathologist does not display here the greatest analytical rigor.  For no one will deny that changing socioeconomic conditions can lead societies into epidemics if, for example, sanitary conditions become lax, but what of climate or biologic factors? Are these always value-laden or steeped in a socio-cultural chain of causality?  The 1918 flu pandemic hardly spared a country; to invoke “disturbances of human culture” in this case would be a meaningless use of the phrase.

But this insight from the past encourages Rose to see in the recent rise of coronary disease and duodenal ulcers in modern societies a clear indication of an underlying cultural disorder.  He then notes that

The scale and pattern of disease reflect the way that people live and their social, economic, and environmental circumstances, and all of these can change quickly.  This implies that most diseases are, in theory, preventable, but it leaves us with some anxious questions.  Can we control our history, or must we only analyse and observe it?

Rose’s insinuation that we are a society of contemplative philosophers is rather puzzling, except perhaps to justify a call to activism as we shall later see.  He continues:

Is there an ideal way of life which will minimize every threat to health?  Can we hope simultaneously to avoid on the one hand the ills of poverty and the simple life, and on the other hand the ills of affluence and industrialization?

Lamenting “ills of affluence and industrialization” has been a favorite complaint in the progressive repertoire since the days of Jean-Jacques Rousseau.  That life expectancy in the West has increased dramatically throughout the 20th century despite the epidemic of stroke, myocardial infarction, duodenal ulcers and cancer gives the bien-pensants no reason to pause and re-think their assault on material progress through which they hope to achieve their egalitarian ideals.

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Having established (to his satisfaction) that epidemics are primarily socio-cultural events, Rose goes on to ask in the next section Why Seek to Prevent? He begins by contrasting blitheness and prudence:

‘Take no thought of the morrow…sufficient unto the day is the evil thereof (Matthew, Chapter 6, Verse 34).’  This injunction touches a deeply held human feeling that it may be better to live a day at a time rather than to be anxious about distant problems which may never materialize.

Amazingly, Rose takes the biblical admonition against excessive worries as a clear indication that human nature is carefree and present-oriented (on top of contemplative, as we saw earlier)!  He continues with a jab at clinicians:

Doctors often act as though their professional responsibility does not go beyond the sick and the nearly sick (those at imminent risk), and politicians, who influence health more than the doctors, are rarely troubled by thoughts of the distant future.

The unflattering characterization of doctors seems to be part and parcel of the academic epidemiologist’s mindset.  In a similar vein, for example, Henry Blackburn (heir to Ancel Keys and early collaborator of Rose’s) took a swipe at practitioners in a 1976 paper written to attract more funding for coronary prevention:

There is a story about the busy practitioner who, taking a breather along the river bank, heard a man hailing from midstream, drowning.  The physician shed his coat, jumped in the river, pulled the man ashore, revived him, and just as he was standing up, heard another hail from the middle of the stream and saw another man going down. He repeated the process and, while successfully re-animating the second man, heard a third cry.  About this time another physician, a white-coated, epidemiological type, walking along the bank saw the whole scene: the busy, harried physician taking care of a desperate situation, two people recovering, the third crying out desperately for help.  And he murmured out loud, ‘What do you suppose could be pushing those guys in the river upstream?’, to which the busy practitioner replied: ‘Don’t bother me now, can’t you see I have no time to discuss such things!’ as he dived into the river for his next resuscitative effort. This connotes in a real sense the situation in medical practice today, that we are desperately concerned and occupied with taking care of the sick and consequently are insufficiently concerned with trying to keep whatever it is from pushing people into the river.

One cannot help but think that this conception of the physician as hapless and myopic can only have shaped Rose’s theory of prevention which, as we will see, gives to ‘white-coated, epidemiological type’ technocrats free reign to concoct far-reaching management guidelines…

A 'white-coated, epidemiological type'?

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Having made the case that prevention is unduly neglected by people and doctors occupied only with the here-and-now, Rose goes on to consider in the next section The economic argument in support of prevention.  Here Rose rejects economic considerations to justify preventive care, but the reasoning behind his dismissal is rather astonishing.

For example, Rose proposes that saving the life of a child is of no economic benefit because few resources have been invested in the child, and children “cost little to replace.”  And preventing a myocardial infarction, even in an economically productive adult, is likely a net economic loss since society will eventually be saddled with caring for the aging benefiters of the acts of prevention.

…for every death avoided, whether by prevention or treatment, means one extra old person, and old people are economically unproductive whilst at the same time costly, both medically and in their needs for social support.

For someone who extols taking the long view, Rose’s economic focus is decidedly short term!  Granted, Rose tells us he relies here on the instruction of his “economist friends,” but whoever these advisors are, Rose takes their reasoning at face value, questioning neither the soundness nor the morality of their arguments.   In the end, Rose abandons this Spartan and primitive economic theory not because he  disagrees with it but because he finds it to be of no value for the advancement of prevention: “the economic argument for prevention undergoes progressive collapse, for alas the cheapest patient is a dead patient!” he proclaims.

Unperturbed by this cold utilitarianism, Rose moves to higher ground to deliver the ultimate rationale for prevention.  Three pithy sentences comprise the next section entitled The humanitarian argument:

It is better to be healthy than ill or dead.  That is the beginning and the end of the only real argument for preventive medicine.  It is sufficient.

But the Alpha and Omega of prevention according to Rose may be missing an Iota.  The easy dichotomy used to claim the moral high ground neglects the complex reality of the choice proposed: what is health, what is disease, who decides the distinction, what is the cost of prevention, what are the moral and economic trade-offs, is avoiding death or illness always a choice, is it always better not to be dead, can one find value or meaning in illness, what to do about self-inflicted maladies, etc.  For the time being, at least, Rose chooses to ignore these germane considerations.

The conclusion to this first chapter contains an appeal to rise against “our scandalous international and national inequalities in health.”  But who is to wage that war, with what weapons, and against which tangible enemy are left unspecified.  And even if he acknowledges that prevention may have a cost, Rose frames the debate by begging the question:

The achievement of better health implies many kinds of costs which must be paid if we want good preventive medical services, a healthier environment, and better conditions of work, travel, and housing.  If people wish it to be so, these ends can be achieved, but only if they are willing to transfer resources from other uses, peaceful or military.[emphasis mine]

Moral manipulation or scientifically justified call to arms against political disease?  We will begin to explore the foundation of Rose’s strategy in the next post.

The Book (1st ed)

The first fundamental concept in the Rosean strategy is appropriately illustrated on the cover of his book: a series of shifting bell-shaped curves depicting the distribution of disease risk factors in the population.

Rose’s first major point is that for any given disease, the bulk of clinical complications comes not for the minority of people at high risk for the disease (the tail), but from the larger bulk of subjects with risk factor profiles that are within the center of the distribution, closer to the mean.

For example, the vast majority of cases of cardiovascular complication will be explained not by the minority of patients with unequivocally high blood pressure or high cholesterol but by the “mass” of people in the population with more moderate elevations in these risk factors.

Countries with low incidence of cardiovascular complications have risk factor distribution curves which lie to the left of those of countries with higher rates of disease.  Accordingly, an effective public health intervention must aim to shift the entire curve to the left, as it were, rather than “lop-off” the high-risk tail, since the latter approach would have no significant impact on public health statistics.

We will examine the assumptions and reasoning underlying this argument in detail in subsequent posts.  Suffice it to say here that this approach has been widely adopted in cardiovascular prevention circles, as illustrated in the graph below taken from the 7th report of the Joint National Committee on hypertension.

Public health strategy for hypertension (from JNC)

Today, the enthusiasm for population-based reduction of risk factors provides the main impetus for ‘quality’ programs that expect primary care physicians to achieve target reductions in the average risk factor profile of their patients (and to penalize them if they fail to do so).

And beyond cardiovascular disease, Rose is convinced that his preventive strategy can apply to almost any condition: osteoporosis, obesity, hepatitis, neonatal death, depression, lead poisoning, Down syndrome, all display (according to the theory) a risk-outcome relationship that lends itself perfectly to a population shifting strategy:

In fact these concepts apply to the problems of prevention for almost every clinical specialty, as well as in occupational and environmental health and in the control of wider social problems (Rose’s Strategy of Preventive Medicine, 2nd edition, p 110)

The second tenet of Rose’s philosophy is alluded to in the quote above.  Health and diseases have a societal dimension, meaning that socio-economic and cultural conditions play a determining role in the prevalence of risk factors in society.  Accordingly, a man transplanted from Kyoto to Chicago will be subjected to the risk factor profile of his adoptive population and his risk will vary accordingly, frequently without any conscious change in his lifestyle or behavior.

It cannot be denied that socio-economic factors play a role in disease development and occurrence.  Rose was a co-author (with Michael Marmot) of the Whitehall study which demonstrated an inverse relationship between social grade and coronary mortality among British male civil servants even after controlling for known coronary risk factors and access to medical care.

This observation leads Rose and his followers to conclude that some of the societal characteristics that influence health are “emergent” properties of societies and do not simply represent the cumulative effect of individual behaviors.  We will have occasion to examine further the special perspective from which Rose analyzes the social dimension of health.

The third tenet, which derives naturally from the second, is that if social and economic determinants of disease are so important, medical activism must necessarily take on a political form.  This is unequivocally stated in the last paragraph of Rose’s book and re-stated in Marmot’s introduction to the LRB:

The primary determinants of disease are mainly economic and social, and therefore its remedies must also be economic and social.  Medicine and politics cannot and should not be kept apart. (ibid, p. 161)

Since worse health outcomes are invariably correlated to low socio-economic status (the notion that coronary disease is an affliction of wealthy, meat-eating businessmen being now a quaint, long forgotten idea…), Rose’s philosophy is aligned with a broad, dominant movement in public health whose primary stated goal is to ‘reduce health inequalities’—presumably by means other than traditional medicine and public health.

The Manifesto, 2nd ed.

This movement found a home at the WHO, at national public health agencies such as the CDC, within influential advisory organizations such as the Institute of Medicine, and in an increasing number of academic departments like the Health Inequalities Research Institute at the University of Liverpool or the University College of London’s Institute of Health Equity (headed by Michael Marmot himself).

Rose’s ideas are not essential to this cause which is in large part related to liberation theology or its secular equivalent (broadly lumped under the misused term ‘social justice’ and ultimately traceable to the theory of class struggle), but Rose does provide for this movement the cover of a scientific justification.  And by broadening of the scope of medical prevention so widely,  his strategy allows preventive medicine to more openly become a means of achieving political and economic change.  At least, such is its hope.

_________________

Before concluding this overview, I would like to remark that Rose was by no means unaware of any potential difficulty with his proposed strategy.  On the contrary, throughout the book he candidly identifies some of the most obvious objections that might be raised against his population strategy and seems to give those objections a fair hearing.

On close examination, however, it becomes clear that his treatment of counterpoints is primarily rhetorical and mostly superficial.  In the end, the apparent objectivity serves to effectively dismiss any substantial criticism to his theory by allowing him to claim that the objections have been addressed when, at best, they have simply been acknowledged.  We will highlight this as we go through the book.

I am aware of dissenting viewpoints occasionally expressed in the medical literature against certain aspects of Rose’s theory and will refer to them in due time.  By-and-large, though, the objections to Rose’s theory have been spotty.  I hope this series of articles will provide a more thorough re-appraisal of what has become the dominant public health paradigm, and perhaps shake the faith that allows public health authorities to so confidently compel us to move statistical mountains of risk factor prevalence.

You could say to this mountain: 'Move from here to there...' (Mt 17:20)

Some of the problems related to HTE have been outlined by Kravitz et al.,  as we have previously seen, and Kent et al. offered a proposal to mitigate them.  But as we noted, the proposal by Kent et al. assumes a treatment that provides fixed relative risk reduction across the range of risks.  This is displayed in Panel A in the AJC paper:

The thin line is the hypothetical baseline risk-outcome relationship, the bold line is the post-treatment risk-outcome relationship.  In Panel A, the relative risk reduction is constant.  As one moves from lower risk to higher risk, the absolute benefit (vertical difference between the lines) increases.

Diamond and Kaul point to the other 3 panels are possible relationships.  In Panel B, absolute benefit is constant.  This happens when the intervention does not influence any of the variables that determine baseline risk.  They give the example of anti-platelet therapy for stent thrombosis prevention to  illustrate this scenario (it’s not perfect but gives the idea).

Panel C is a case where the intervention improves a variable that determines baseline risk and worsens a variable not included in the risk assessment model.  As a result, absolute risk is reduced only above a certain risk threshold. They use the example of a medication that increases HDL but worsens blood pressure, alluding to torcetrapib or such drugs.  Again, the example is not very good as BP is included in baseline assessment in most models, but it conveys the idea if one only includes the lipid profile in the risk assessment.

Panel D is the opposite situation, where absolute benefit only occurs below a certain threshold because the intervention worsens a variable included in the model but improves one not included.  They do not provide an example, and we can imagine such an example would be difficult to come to.

But the point of these graphs is not to illustrate how various treatments affect outcome based on a given risk assessment scale.  The same graphs can equally show how various baseline risk prediction models could potentially perform (in terms of predicting treatment benefit) when a given treatment is applied.  Depending on how the treatment affects the variables in the variables in the baseline risk models (as discussed above), any of the relationship A-D may be operative.

Examples of baseline risk assessment models that contain different variables are the TIMI risk score and the GRACE registry score.  Theoretically, they may not predict response to a given treatment in the same way.  Assuming that higher risk patients (as identified by one particular scale) have the most to gain may be faulty reasoning.

To further explore how different baseline risk assessment scales can behave differently, Diamond and Kaul take 2 different models of ICU baseline risk that individually seem to perform well (in terms of predicting risk of complications or death):  The APACHE score and the MPM.  They then plot their patient to patient correlation:

The striking lack of patient-to-patient correlation in the prediction score between the 2 models highlights the impact that the specific variables in the model have when we look at  individual cases.  Diamond and Kaul then conclude that in order for a single model to perform robustly, one would need to include so many variables as to make the model most certainly impractical.

To complicate matters even more, bear in mind that the discussion here looks only at predicting a certain outcome or set of outcomes, eg. cardiovascular complications.  It does not address “overall benefit” across multiple outcomes, meaning that Diamond and Kaul do not address any mitigation due to harm from treatment, (so “absolute benefit” in this paper only refers to an absolute reduction in the outcome in question).  Whether risk of harm from treatment is related or not to the variables in the risk model adds yet more layers of complexity.

Unsurprisingly, the authors still manage to remain optimistic about bringing quantitative methods to the bedside (ie. managed care through outcomes research) and caution against those who advocate “Wholesale abandonment of evidence-based guidelines in favor of idiosyncratic clinical judgment.”

So long as medicine is paid for by others, I don’t think guideline writers have much to fear.

Few practicing physicians are aware of who Rose is and what he stands for, but Lloyd-Jones is correct in identifying him as one of the key figures in modern cardiovascular prevention.  Rose’s theory, however, aims much higher than for a simple reduction in cardiovascular events.  It is a far reaching model that seeks reshaping entire health care systems and redefining concepts of health and disease.  And it has found fertile ground at the WHO, the IOM, the NHS, the AHA, the CDC, and the alphabet soup of organizations which direct national health planning in Western countries (and increasingly in the developing world).

Geoffrey Rose was born in 1926 and died prematurely in 1993 of pancreatic cancer, shortly after publishing his Magnum Opus, “Rose’s Strategy of Preventive Medicine.”  He was an eminent epidemiologist who had studied under George Pickering, himself a student of Thomas Lewis, and therefore benefited from a weighty academic pedigree.  Rose claimed that is was Pickering’s insight on the nature of hypertension that was instrumental in shaping his own views about public health (Pickering’s disease definition and the implication for Rose’s theory will be discussed in another post later).

Rose joined the faculty of the London School of Hygiene and Tropical Diseases where he became full professor of epidemiology in 1977.  He took an interest in cardiovascular epidemiology early on and was principal investigator, along with Jeremiah Stamler, of the INTERSALT study.  In 1985, he published his most famous paper, “Sick Individuals and Sick Population,” which articulated his “population strategy” for public health.  But initial expressions of his theory began to appear in earlier articles, notably “Strategy for prevention: lessons from cardiovascular disease” published in 1981.

Judging from his writing, which is simple, elegant, personal, and to the point, Rose was likely a very charming and erudite man.  I encourage interested readers to purchase his book which is short and eminently readable (almost disarmingly so).  The new edition features a preface by 2 colleagues who knew him well and describe a kind and honest person with a brilliant intellect and a contagious curiosity.

I have no doubt he was such an admirable man and his interest for the betterment of his fellow man genuine.  But I also believe that Rose’s ideas were wrong or self-contradictory in many instances, and that his theory, while clearly articulated in his writing, amounts to a confused hodge-podge of attractive propositions that are untenable on either clinical, epidemiological, social, or economic grounds—and sometimes on the basis of common sense alone.

I will explore Rose’s theory in subsequent posts, time permitting.  This effort will by no means be scholarly or exhaustive, but I hope to bring out counterpoints worthy of consideration.  This examination will also likely be a process of peregrination rather than a systematic analysis of the theory, but I will attempt to remain as focused as I can, discussing 1 or 2 points at a time.

This will be slow going…

The Left hailed the new change as “truly remarkable” and an important first step to “break the logjam” of health care deficits, while the Right was quick to denounce the set of instructions as an “ethical game-changer,” a surreptitious undermining of the doctor-patient relationship, or an overt step toward health care rationing.

I have no doubt that the collectivists who hail this “important shift” do so in the hope of promoting a kind of herd medicine which conforms to their vision of a modern health care system.  I am also aware that advocates of central planning have no particular qualms about trampling on the fiduciary duty of doctors to patients, and will embrace the ACP directives as a convenient cover to justify their ill-advised health policies.

Yet Box 4 is a perfectly acceptable set of declarations in-and-of itself.

Physician oaths, whether ancient or modern, have always contained an unqualified pledge to serve the patient.  The service is not expected to be free, but professional ethics imply that the patient’s resources be respected, that the doctor should provide “parsimonious care” (and I have no objection to the use of the term).

But the difficulty arises because for the last 50 years physicians and patients have mindlessly consented to placing their relationship in grave jeopardy.  By allowing and enjoying a medical care paid for by others, they have explicitly entered into a very problematic ménage-à-trois: the doctor, the patient, and the purser.   And if cost-effectiveness is indeed an implicit duty for all physicians, the question becomes: cost-effective for whom?

The ethical dilemma ultimately proceeds from the modern physician serving two masters.  He may well proclaim to love the one and hate the other, to avoid bondage to Mammon he must cleanly cut the tie.

The ACP ethicists miss the elephant in the room when they declare in a paragraph precisely headed “Third Party Evaluations” that

Performing a limited assessment of an individual on behalf of a third party, for example, as an industry employed physician or an independent medical examiner, raises distinct ethical issues regarding the patient–physician relationship. The physician should disclose to the patient that an examination is being undertaken on behalf of a third party that therefore raises inherent conflicts of interest; ensure that the patient is aware that traditional aspects of the patient–physician relationship, including confidentiality, might not apply…

Snyder et al. are oblivious that the warnings they issue pertain to most insurance-paid medicine.  At a fundamental level, all physicians who sign a contract with a third-party payer are ‘industry-employed,’ and that is the crux of the matter.

The rest of the ACP document seems to be standard fare modern day ethics with the expected materialistic or dualistic biases.

Physicians seeking an organization on more solid ethical grounding should look to the AAPS instead and browse its current and old websites.

In the wake of a recent breast implant scandal, French drug regulator AFSSAPS is now the target of a criminal investigation for keeping on the market the anorectic benfluorex (Mediator) which allegedly caused the premature deaths of hundreds if not thousands of French citizens from valvulopathies.  Some AFSSAPS executives have even had their homes searched.  The head of the agency resigned.

The story was reported by Reuters and by the heart.org.  The investigation is taking place after a couple of papers were published claiming that over the course of the last 33 years, Mediator has been responsible for over 1300 deaths from valve disease.   The most recent one is available from Wiley free online, at least for now.

There are several puzzling aspects to this story:

1) The papers in question are clearly 3rd rate, with very liberal data-mining (of the French “medico-administrative” reimbursement database…), no validation, very loose statistical assumptions, and no cogent comparative group.

2) In the US, although similar anorectics have been removed from the market, a fairly intense scrutiny on these agents hasn’t been able to convincingly demonstrate any serious valvular dysfunction (but only showed an increased prevalence of 1-2+ regurgitation that seems to go away after stopping the drug).

3) European regulations are generally looser than in the US (although that is changing rapidly), and France is not known for high profile product liability actions.

4) It is even more remarkable that the regulating agency itself would be a target of the criminal investigation.

The way the papers come up with the 1300 deaths is by establishing the number of excess hospital admissions with a diagnosis of “valve disease” among those exposed to Mediator during an 8-year period,  and then factoring in the expected decrease in life expectancy derived from a Mayo clinic paper.  But the Mayo paper dealt with subjects who had documented, severe chronic valvular regurgitation.

The authors of the French study then extrapolated the mortality effect from the 8-year period to the entire 33 years that Mediator was available in France to come up with 1300 “attributable deaths.”  There was no attempt to estimate the excess mortality that could be anticipated from being obese enough to take the anorectic!

Imagine the same reasoning applied to say, the oral contraceptive pill.  The sacred cow of pharmaceuticals has clearly been shown to increase the risk of hypertension, stroke, myocardial infarction, venous thromboembolism, cervical cancer, and probably breast cancer, among other things.  None of these conditions are particularly benign…Can we venture a guess as to the magnitude of excess “attributable” deaths one could compute using the same methodology as for Mediator?

I’m not expecting to read in the news that the FBI has ransacked the FDA offices any time soon.  For one thing, existing statistical wizardry has exonerated OCPs from causing “overall” excess deaths despite a greater than 2-fold increase in mortality among smokers (some even claim they save lives!).  But I wouldn’t be surprised if bureaucratic logic doesn’t eventually come to undermine the precisely bureaucratic notion that health outcomes can reliably be modeled and produce “actionable” data for regulators to examine.  In the case of Mediator, the action has been to simply take out the regulator.

Baltimore, MD – A malpractice lawyer is accusing Dr John Chung-Yee Wang (Union Memorial Hospital, Baltimore, MD), a member of the committee tasked with stopping improper stenting in Maryland, of improper stenting in his own practice [1].

The Baltimore Sun reports that medical malpractice attorney Jay Miller has filed complaints with the state health claims arbitration office against Wang. Miller alleges that Wang, Dr Mark Midei, and Dr Kourosh Mastali wrongfully stented patient John Bowers in 2005 and 2006, when the three interventionalists were partners in MidAtlantic Cardiovascular Associates, a practice that has since disbanded. Miller also charges that Wang overstated the extent of coronary disease in patient Lorie Skillman to justify implanting a stent (…)

As reported by heartwire, the Maryland Medical Board revoked Midei’s medical license after it determined he repeatedly violated the Medical Practice Act by implanting hundreds of unneeded stents while working at St Joseph Medical Center in Towson, MD. Midei is one of several high-profile cases of alleged overstenting in recent years.

Wang is part of the Technical Advisory Group on Oversight of Percutaneous Coronary Intervention Services, a group of experts tasked by the Maryland Health Care Commission (MHCC) to develop recommendations for legislative changes that would improve oversight of coronary intervention labs in the state. The committee is set to report its findings at a public meeting of the health commission today. “The allegations could cast a shadow over the work of the advisory committee,” the Sun reports. Wang was nominated for the committee by the Maryland chapter of the American College of Cardiology (ACC).

We may recall another period of time when committees played a prominent role in regulating safety and security.

In 1793, Georges-Francois Danton was given the task of leading the French Committee of Public Safety to ensure application of the ideals of Liberté, Egalité, Fraternité.  In the months that followed, the committee prescribed treatment with the “National Razor” to thousands of individuals deemed to be a threat to the revolution.  The bulk of the offenders were initially identified from among the aristocracy and the clergy, but it soon became necessary to also purify the revolutionary ranks from the less ardent supporters of rhetoric.  Soon enough, Danton himself was condemned to the same end that had so many before him had met.

In a letter to the MHCC, SCAI and the Maryland chapter of the ACC criticize the committee’s recommendations for not going far enough [2]. “The draft recommendation to expand MHCC ‘oversight’ to CABG facilities is excessively vague. It is unclear what authority this would give the MHCC. . . Voluntary oversight provides no guarantee that all citizens in Maryland are afforded equal, high-quality healthcare. . . Over time, the risk is that the foundation of peer review weakens. Good hospitals have nothing to hide or fear (bad ones do).”

The ACC, the SCAI and countless committees, commissions, and task forces around the country are fervently working to ensure application of the modern medical ideals of Quality, Equality, and Appropriateness.

May the just God protect us all from the zeal coming out of utopian ideologies.

But since the 1970′s, after clinical trials established the success of anti-hypertensive therapy, and with the growing enthusiasm for “risk-factor modification” and the inexorable rise of population medicine, any attempt to expect rational nomenclature or clarity of thought has seemed increasingly futile.

Instead, we must be impressed by discussions of studies where “Patients were categorized by their mean SBP level over follow-up as very low normal (<120 mm Hg), low normal (120 to <130 mm Hg), high normal (130 to <140 mm Hg), high (140 to <150 mm Hg) and very high (>150 mm Hg). ”

I recently tested myself on a 24-h ambulatory blood pressure monitor.  My SBP varied from 90 to 142 mmHg.

No wonder I was feeling out of sorts.

The issue of patient preference

Kravitz et al. provide 4 categories that determine HTE: 1) variable baseline risk 2) variable response to treatment 3) variable vulnerability to adverse effects 4) variable patient preferences for possible outcomes (utilities).  I command the authors for emphasizing the last category, for it is the most commonly ignored by the EBM movement.  Yet, as the authors put it, “Patient preferences for different health states (utilities) are the ultimate arbiter of treatment success.” (I wouldn’t necessarily go this far).

But after reading the entire article, one gets the sense that Kravitz et al. may be paying no more than lip service to the subjective dimension of medicine.  Utilities are only mentioned twice more in the paper:  on page 672, the casual statement that “The EBM community has incorporated patient values and preferences into the general framework of evidence-based medicine (Sackett et al. 2000),” implies that acknowledging utilities is sufficient treatment of the issue.  And on page 673, in the graphs that demonstrate the interplay of the 3 other categories of HET, the authors “assume that utilities have already been incorporated into the scales for measuring the absolute treatment effect and teatment-related harm,” and deal with this rather substantial methodological problem by simple hand-waving.

More complexity

Kravitz et al. do a great job of graphically illustrating the complex interplay between the 4 categories of variability.  They also do not hide the difficulty that this complexity presents for the application of EBM methods to clinical practice.  But the reality is likely to be even more complex than they describe.  For example, the paper discusses ‘responsiveness to treatment’ and ‘vulnerability to harm’ as being independent categories of variability, when in fact they could be dependent of each other.  A high responder to aspirin may also be more vulnerable to bleeding complications, but not particularly susceptible to allergic reactions.  The complex interplay between responsiveness and vulnerability is unlikely to lend itself easily to quantitative modeling.

Another area that is problematic is the effect of treatment context.  The authors do identify this issue (top of p. 669 and top of p. 671, with reference to paper by Horwitz et al.), but don’t seem to properly gauge the difficulty that this represents for the application of RCT results to the patient at hand.  They also have an optimistic view of how the “genomics era” will help tease out responsiveness and vulnerability issues in individuals (pp. 676, 679).

False dichotomy

Kravitz et al. do an excellent job of identifying and illustrating the problems that blind enthusiasm for RTC results generate.  “Guideline creep” has already had its nefarious effects well documented, as they show (p675) .  But instead, of limiting the discussion to suggesting improvements in study design and interpretation (pp677-78), the authors feel compelled to set up the discussion in terms of a conflict between two mutually exclusive approaches:

How should clinicians proceed? First, they should recognize that even compromised knowledge is better than complete ignorance. Thus, in the absence of information on HTE and ITEs, reliance on average effects as measured in good clinical studies is likely to produce better outcomes than is intuition or habit.

And later on, they again stick it to the Luddites:

Not even the most vehement critics of EBM would advocate a return to “opinion-based” practice grounded solely in pathophysiological reasoning and personal clinical experience (Tanenbaum 1993).

It should be obvious to any one barely familiar with the debate that the skeptics are not arguing against using evidence from clinical research in clinical practice, but against using this evidence as the primary, if not sole determinant of medical decision.  It is not a matter of favoring practice by “intuition” and disregarding RCT results, but a matter of not letting “guideline creep” blind us into cookie-cutter medicine for the masses.  As Hayek may have put it, it’s a matter of defending the value of local and dispersed knowledge against the misguided diktat of a centrally-planned healthcare system.

Your AccuWeather Treatment Plan Is…

The paper is an outstanding overview of the parameters that impact treatment effect.  The authors give the reader a clear sense of the various dimensions of the problem and of the interactions among them.  In many ways, the article formalizes the work of therapeutic clinical reasoning and can help clinicians gain a better appreciation of all the parameters involved.

But in the final analysis,  Kravitz et al.’s recommendations fail to genuinely “promulgate a spirit of humility” but instead promote the notion that quantitative decision rules–imperfect as they are–remain a necessary evil in the conduct of modern medicine.  Their vision for the future?

Continuing advances at the nexus of genomics and medical informatics, however, hold promise for the future. The day may not be far off when a practitioner, using a handheld PDA, or personal digital assistant, will be able to calculate a patient’s baseline susceptibility and prognosis using validated clinical prediction rules; assess responsiveness and vulnerability to a therapeutic agent based on genotyping and measurement of biomarkers; and use this information for a discussion with the patient.

In other words, the physician as weatherman.

It is no wonder that 7 years after the publication of this paper, the ascendancy of outcomes research on the formulation of health policy seems complete, while the “philosophical challenge” raised with such foresight by Sandra Tanenbaum 18 years ago, has been utterly ignored.

HTE is the technical term used to reflect the fact that clinical trials (other than N-of-1 trials) are designed to reach a conclusion about an overall treatment effect, usually reported as relative or absolute risk reduction for the treated population when compared to the control group.  Clinical trial results tell nothing specific about an individual subject’s response to treatment.

Clearly, not everyone enrolled in the treatment arm of a given clinical trial benefits from (or is harmed by) the intervention.  Attempts to sort out who benefits most or least is usually done by dividing the trial population into subgroups, one characteristic at a time (eg. male vs female, old vs. young, hypertensive vs. normotensive, etc.), and by performing a statistical analysis on each subgroup.  Traditional subgroup analyses, however, are fraught with many well known limitations and are not practically useful to help identify those likely to benefit.

In this proposal, Kent et al. begin by making explicit the intuitively evident fact that if one assumes an unchanging relative risk reduction across the board, patients at high baseline risk of developing the outcome will benefit more than those at low baseline risk in absolute terms (table 1 in the paper).  The greater the baseline spread in risk, the greater the spread in benefit.  If harm is included in the analysis, low baseline risk patients may have no demonstrable benefit and may even be harmed (table 2 in the paper).

The authors then make several recommendations.  Chief among them is to tabulate the distribution of baseline risk in each treatment group using some pre-established baseline risk calculator that includes multiple baseline variables (Recommendation #1).  The next recommendation, as anticipated, is to report on the absolute and relative risk reduction according to this baseline risk categorization (Recommendation #2).

The third recommendation is to perform single-variable subgroup analysis on pre-specified variables that have “strong a priori pathophysiological or empirical justification,” ie. not to go on a subgroup fishing expedition.  The number of pre-specified single-variable subgroup analyses should be limited to avoid the “multiple comparison” trap.  Cut-off threshold for baseline single variables should also be pre-specified before the analysis to avoid fishing.

The fourth recommendation is to designate any other single-variable subgroup analysis (non-pre-specified) as exploratory only.

The fifth recommendation is to subject all subgroup analyses to additional testing of heterogeneity (ie. did treatment effect vary between subgroups?) by using a proposed statistical tool (‘interaction test’), and to be mindful of a number of additional statistical caveats.

Will these refinements improve the clinical utility of clinical trials?  It seems that it would, but 3 points come to mind:

1. From a public health standpoint, dealing with heterogenity of treatment effect goes against Geoffrey Rose’s theory for preventive medicine, the dominant paradigm in public health for the last 30 years.  Rose’s argued that more burden of disease is explained by many people with low risk than by small groups with large risk, ergo we must treat everyone.  This “sick population” approach to prevention is still hailed as a major advancement in public health…
2. Drug companies are unlikely to be keen on refining clinical trial results in a way that would reduce “the market size.”
3. Most importantly, the proposal begs the question:  if we are so good at characterizing baseline risk, why include low risk groups in the trial in the first place? (see 1. and 2. )

Affaire à suivre.  All in all, this seems all right to me.  But needless to say, the expected “actionable” outcome from this proposal is more secure employment for the statistician rather than better care for the patient at hand…