Saturday, December 17, 2011

Medical Practice under Scrutiny: How much care is too much?


Medical Practice under Scrutiny: How much care is too much?
By Dr David KL Quek, FRCP, FNHAM, FAsCC, FACC
NHAM Pulse, 2011 (December): 2-6


“Illness is the night-side of life, a more onerous citizenship. Everyone who is born holds dual citizenship, in the kingdom of the well and in the kingdom of the sick.”
~ Susan Sontag[1]

The Illness Metaphor vs. Medicalisation
Susan Sontag’s introspection above encapsulates this very real if unsettling Manichean truism about illness and health in man.  This was recently re-quoted in the frontispiece of Siddhartha Mukherjee’s 2010 book ‘The Emperor of all Maladies’ — a Pulitzer Prize-winning book about cancers and the heroic battles to conquer if not to deflect cancers’ dismal if inescapable trajectories and outcomes.[2]
The narrative on the history and advances of cardiovascular understanding and therapeutics would probably reflect a similar but perhaps with a more positive historiography.* But there has always been that tendency for physicians from time immemorial to over-extend our professional reach and our self-importance, as we insinuate ever deeper into society’s socio-economic web of life. With affairs of the heart, this is even more pronounced!
Sometimes, as physicians we tend to forget that illness is an innate part of man—we will always become ill at some points in our lives. Yet, most of us subconsciously embrace and expect its opposite—health—as a given. Perhaps we have let Medicine’s overarching narrative to reshape our societal psyche into embracing a pervasively systematic but false Nemesis.[3]
Eventually every one of us will die, sometimes suddenly, prematurely, but frequently enough from a drawn-out chronic ailment, which may be subtly quiescent (‘silent killer’) or which may visibly stress, depress, debilitate and occasionally dehumanize us. Illness and loss of health in humans and our patients are why we physicians are here in the first place—patients are our raison d’être.
Healthcare issues now encapsulate some 3 to 17% of mankind’s economic activity, depending on where you are in the globe.[4],[5]  There is that growing conscious demand and push towards ‘good health’ and more accessible health care.[6] Health is regarded as an inherent component of life, and is rightfully demanded as a human right.[7] As physicians, we must serve as the natural guardians and advocates to ensure this, by making every possible effort to improve universal access and coverage for this increasingly out-of-reach ‘commodity’. At the same time we must remain conscientious that we do not create ‘health’ into an unreachable ideal, which can only bilk or disenfranchise the unquenchable demands and expectations of our willing but poorly informed patients at large.[3]
Yet, as we (as doctors) embark on our furious pace of modern medical practice, we embrace sometimes almost blindly all the advances that come our way, not wanting to be left behind in that unrelenting race to keep up with what are new and trendy, in the name of progress. We readily adopt and utilize whatever technological devices and drugs at our disposal, believing that most of these efforts would benefit or even cure our patients, sometimes at huge costs! But in the sum of all things, medicine does work—patients do benefit and perhaps arguably live longer and enjoy better quality of lives.[8]
Why? Because, as doctors we are trained to follow systematic if narrowly prescribed heuristics on how we approach illness, how we deal with it and how we treat it, piecemeal, one at a time.  However, increasingly we have been reminded to look at each patient in as holistic a manner as possible—treat the whole patient, not the diagnosis, we say.
But because medical information is continually growing and evolving we also need to constantly keep abreast—hence, the exhortation to lifelong continuing medical education and learning. Knowledge growth also implies periodic shifting of the goalposts for what are recognized as normal or abnormal, sometimes akin to new wines in old bottles—blood pressure, blood glucose and cholesterol levels are now lowered for normal acceptable ranges.
This necessarily implies treating more patients to achieve lower and lower targets, because there have been growing research data that show that perhaps lower is better—lesser complications, better prognoses, better outcomes, perhaps longer survival, even better quality of life. But some detractors have decried such measures as examples of ‘medicalisation’ of health, calculated to exploit human vulnerabilities and anxieties.[9]
By looking at the patient as a whole, multiple risk profiles and factors also imply that we treat that patient with more therapies than was customary in the past. Most often this approach employs the easiest means—prescribing medications and pills—one on top of the other! This approach remains controversial and is not readily accepted by all. Lifestyle modification and counseling often take backseats in our therapeutic armamentarium because these are either too hard or time-consuming to carry out, too difficult to measure for results, or because they are inadequately reimbursed or not at all!

Risk Factors, Pre-disease & Injudicious Polypharmacy
Barbara Starfield et al., a pioneering advocate of primary care medicine has lamented:
“the progressive lowering of thresholds for ‘pre-disease’, particularly hypertension, serum cholesterol and blood sugar… (where) risk factors are increasingly considered as equivalent to disease… Encouraged by interests vested in selling more medications for ‘prevention’ and more medical devices for testing, the pressure for increasing ‘prevention’ in clinical care directed at individuals is inexorable – even though it is not well supported by evidence in populations of patients…” [10]
Alas, it is precisely this surge in preventive polypharmacy that has prompted so many pharmaceutical companies to aggressively target the medical community with the current deluge of blockbuster drugs in the hope to explicitly ameliorate the perceived harms of concomitant risk factors/illness, but covertly perhaps for greater profits as economic enterprises extraordinaire!
But the physician’s professional need and mandate to keep current and up-to-date also implies, that we become dependent on various modes of learning experiences and sharing. Clinical and scientific research relentlessly redefines our perception and belief systems about illness and health, so much so that we have sometimes delegated some of these learning encounters to affiliates and peripheral agencies. The danger is that, we might have been kept selectively informed by incomplete snippets of ongoing if premature data by the very same aggressive vendors of such cutting-edge advances and innovations—becoming unwitting agent provocateurs of their surreptitious influence and propaganda, i.e. we become too embroiled in possible conflicts of interest. [11]
Dr James Le Fanu warns that “doctors are not just doing more, but prescribing vastly more – an additional 300 million prescriptions a year, half as many again compared to just 10 years ago.” He went on to question the rationale of this modern shift in medical practice: “the merits of a coronary angioplasty in promptly relieving crippling chest pains of angina is self-evident, but the rationale for the majority of those 300 million extra prescriptions is very different.” He estimates that globally, annual pharmaceutical revenues have doubled from US$400 billion to US$800 billion (2.6 trillion Ringgit) over the past 10 years![12]
“This, then, is the Janus face of modern medicine, the most visible symbol of the power of science to banish disease for the benefit of all. But the distinction between the relative contributions of those technical innovations and the pharmaceutical industry to the spiraling costs of healthcare reveals, with great clarity, the origins and harmful consequences of medicalisation – and what indeed is required to control it.”
 ~ James Le Fanu
Perhaps we have become too indiscriminate, too undiscerning, and too gullible even. We appear to have become uncritical on what needs to be critiqued, to be critically analyzed and challenged. We have allowed possibly biased slants of information to imprint, even distort our impressionable minds too easily!
We must learn to acknowledge that we might have been somewhat less than judicious in deciding which are truly best for the patients in front of us! Perhaps we have become seduced by the glamour and the gloss of the pastiche of modern innovations—new drugs and devices, new techniques that titillate our sense of ‘beauty’ and wonder; and perhaps that patchwork assemblage of molding plausible theories into meaningful practices. 
Perhaps, all these newfound concepts go on to strengthen our physician empowerment as society’s singular shamanic autocrats of medical knowledge. Perhaps, these constantly reconstructed patho-physiological models of consistency, of newly discovered molecules, gene-based proteomics, of mechanistic pathways, and biological systems endow upon us that sense of puissance, of control, of demigod status.
There can be no denying that sometimes we may have become enamoured with too much care, in doling out perhaps too many unwarranted tests and therapies, which could arguably satisfy our egotistical self and enrich us personally, certainly more so than our patients. We fail to be our patient’s best advocates, whose interests should really be our unwritten if expected ethical compass.

Patients’ Interests—First and Foremost
Have we failed in our duty to place our patients first and foremost, by possibly sacrificing their dignity, their interests, thereby undermining their safety and long-term health even? Have we fallen victim to our own entangled conflicts of interest, our moral hazard of being less than fully impartial, by unfairly tapping into the patient-doctor information asymmetry, or physician-industry ties and the last-gasp hopes and anguish of many of our less than educated or informed patients?[11]
Yet, perhaps this statement is too harsh as an indictment to our dilemma as specialist healthcare givers.
Let us return to practical considerations as we re-examine our roles as cardiovascular physicians. Increasingly we have been cast as unwitting but willing diagnostic as well as gate-keeping therapists all rolled into one. Some have even labeled us as unremitting purveyors of ever-newer medical devices: expensive drugs, balloons, stents, pacemakers, etc. Cardiac surgeons have rightfully questioned our objectivity, that we might have unfairly usurped our unique position to sequester all manner of revascularisation therapies, particularly emphasizing PCI to the detrimental exclusion of CABG.
Perhaps the increasing development and use of appropriateness and organizational care pathways, consensus cardiology-cardiothoracic team approach, of hybrid procedures and global budget or diagnostic-related groups (DRGs) remuneration models, can reduce the tendency for individual physician decision-making, which tends to bias the physician toward more costly or self-serving procedures.
Despite the availability of clinical care pathways and guidelines (CPGs), their variable interpretation also means differences in emphasis or practice. Many physicians disdain care pathways and CPGs as ‘cookie-cutter’ medicine, and interpret these loosely. They argue that a one-size-fits-all approach cannot apply to differing patient scenarios, best only known to the physician in charge.
By the very nature of PCI being conceptually ‘simpler’ and less invasive, cardiologists have cornered the market so to speak, so much so that our patients appear to prefer our services, although the actual long-term results may be inferior to the initially more disabling bypass surgery.
Most cardiologists these days appear to have become singularly coronary artery disease (CAD) experts, but not much more, sadly. Almost every young aspirant in cardiology wishes to be that interventionist, that doer who can heal, with that magical balloon and stent. It appears that to do more, rather than simply counsel and advice might be more effective—at least, it seems that way. It has been well described that an injection (even if of sham medicine), surgery or any intervention gives greater effects or is perceived of as being more efficacious than some simple pill.[13]
So could it be that we have become too conditioned into believing that all the percutaneous interventions that we have performed on our patients, are but that ersatz veneer of favourable placebo effects, instead of true outcome-evidenced benefits? Hence, could this misconception lead to some of us becoming perhaps a little too reluctant to relinquish control of that patient in need, to someone else (e.g. cardiac surgeon, or heart failure expert) more capable, more adequately, or more appropriately trained than ourselves?
Consider the recent findings of the extended follow-up OAT cohort that showed that delayed routine revascularization during the subacute phase, gave no greater benefit. Long-term clinical events were not reduced after routine PCI in stable patients with a totally occluded infarct-related artery, if there was no severe inducible ischemia.[14]
It is also important to note that performing such PCI in the non-ACS setting, for patients who are symptom-free (silent ischemic heart disease, SIHD) just because of some ECG or imaging changes during stress testing would not be associated with survival benefits or even lessening of potential CV events. For most scenarios of angiographic stenoses (other than significant LMS and/or proximal LAD disease) the recommendations are Class IIB or even III.[15]
PCI versus medical therapy in stable CAD can be summarized as follows:[ 15]
•  PCI reduces the incidence of angina
•  PCI has not been demonstrated to improve survival in stable patients[16]
•  PCI may increase the short-term risk of MI[16],[17]
•  PCI does not lower the long-term risk of MI[18]

We should learn to re-examine our clinical objectivity and soberly address such issues of potential moral hazard for the ultimate benefit of our patients. Our therapeutic decisions should neither be because of our overwhelming paternalistic influence, nor to our subconscious desire to profit personally.
The ACCF/AHA/SCAI guidelines also strongly recommend that every PCI program should operate a quality improvement program that routinely: [15]
a) reviews quality and outcomes of the entire program;
b) reviews results of individual operators;
c) includes risk adjustment;
d) provides peer review of difficult or complicated cases, and
e) performs random case reviews.
They recommend too that every PCI program should participate in a regional or national PCI registry for the purpose of benchmarking its outcomes against current national norms. Perhaps this is the sort of benchmarking that every cardiologist and heart centre must adopt, as we embark on our journey to make our own ACS and PCI Registries more comprehensive and complete.
Medical Screening Dilemmas
The U.S. Preventive Services Task Force has in recent reports pose yet more dilemmas in the way of our clinical practice.[19] The simple rest ECG and the more routinely performed stress ECG of annual medical check-ups, so much a part of cardiology practice, are now considered too indiscriminately over-utilized.
For the symptom-free person, the benefits of these tests appear to have been inadequately studied. Whatever few studies available apparently showed no major benefit for the population at large. The taskforce warns instead of the potential harms of consequential downstream therapies or decision pathways such as more angiography, bleeding complications, radiation exposure, and contrast allergy or nephropathy; more statin use and its possible adverse effects!
This conclusion was somewhat surprising because the pooled evidence actually says otherwise: Abnormalities on resting ECG (ST-segment or T-wave abnormalities, left ventricular hypertrophy, bundle branch block, or left-axis deviation) or exercise ECG (ST segment depression with exercise, chronotropic incompetence, abnormal heart rate recovery, or decreased exercise capacity) were associated with increased risk (pooled hazard ratio estimates, 1.4 to 2.1). Evidence on harms was limited, but direct harms seemed minimal (for resting ECG) or small (for exercise ECG). No study estimated harms from subsequent testing or interventions, although rates of angiography after exercise ECG ranged from 0.6% to 2.9%.”
The main message appears to be quoted from 2 previous studies which state that a small proportion (<1%) of patients have revascularization with coronary artery bypass graft surgery or a percutaneous coronary intervention after screening exercise ECG, despite the risks of these interventions and their lack of benefits in asymptomatic persons.” [20],[21]
So what are we to do, stop screening of symptom-free patients, and perhaps only judiciously target those who need further evaluation based on complaints and not necessarily for global risk assessment? The recent accompanying editorial addresses this conundrum, but did not offer specific solutions, except to urge for more research.[22]
Should we then not perform electrocardiography at all in asymptomatic adults? Apparently so. Chou and others of the Task Force argue that because of this persistent lack of evidence, clinicians should not incorporate screening with resting or exercise electrocardiography into their practices except in the context of clinical trials! This sadly sounds counterintuitive to most of us physicians and cardiologists!
The more plausible American Academy of Family Physicians recommends the following for the asymptomatic patient, that:
“Exercise stress testing may provide valuable prognostic information in asymptomatic men older than 45 years who have risk factors. The higher the number of risk factors, the higher the pretest probability (hyperlipidemia > 6.20 mmol per L, hypertension: systolic > 140 mm Hg or a diastolic >90 mm Hg, smoking, diabetes mellitus, and history of MI or sudden death in a first-degree relative younger than 60 years).[23]
“In asymptomatic patients with diabetes mellitus, there is a higher risk of CAD in the presence of at least one of the following factors: age >35 years, type 2 diabetes >10 years, type 1 diabetes >15 years, microvascular disease e.g. proliferative retinopathy, nephropathy, or autonomic neuropathy. It is recommended that patients with (these) criteria undergo exercise stress testing before embarking on moderate-to high-intensity exercise.”[24]
Currently, the ACCF/AHA/SCAI Guidelines recommend that: In patients entering a formal cardiac rehabilitation program after PCI, treadmill exercise testing is reasonable. But routine, periodic stress testing of asymptomatic patients after PCI without specific clinical indications should not be performed. For cardiac rehabilitation purposes however, medically supervised exercise programs should be recommended to patients after PCI, particularly for moderate- to high-risk patients for whom supervised exercise training is warranted.[25]

Discussion
My malaise with these newer perplexing recommendations or restrictions is not intended to curb or straitjacket medical or cardiovascular practice. But, it is perhaps timely for us to seriously reconsider our own trajectory of clinical practice and professionalism.
Are we not somewhat complicit in inventing some new entities of health ailments, i.e. increasingly medicalising health? What are we trying to achieve as we push the boundaries and contemplate expanding such concepts as pre-diabetes, pre-hypertension and lower and lower acceptable levels of serum LDL-cholesterol, as we tag along more biological markers such as hs-CRP, hs-TNT, BNP, etc.? Already, many other entities such as serum homocysteine, fibrinogen, lipoprotein (a), PSA (arguably), have fallen by the wayside of bumf rather than useful reliable knowledge!
Who indeed do we serve as we trundle along with exciting if unproven new devices, new paradigms of interventionist procedures, as we become increasingly invasive even as we miniaturize our techniques and devices? Does the spirit of medical adventurism justify medicine’s push for cutting-edge innovation and advances? Does potential future benefits and ends for the many, justify the experimental risks as a means for a few and the now?
What about that ‘life sentence’ of medications for life or for as long as deemed necessary? Yes we appear to have many long-term prognostic outcome data that implies sustained therapies for the best effect — extending this or that survival by perhaps weeks or months, on a statistical basis.
But, how much of our patients’ lives are we interfering with and for what quantum of greater good or longer-term benefits, the possible lost opportunity costs and the inconvenience, that background intrusion into their lives? It is precisely this expropriation of health that philosopher Ivan Illich had lamented.[3] Has health become such a scarce even elusive commodity that the common man now has to “depend upon the consumption of Ambrosia”?+
But perhaps more importantly, we need to reignite our medical professionalism. We must become more critical and discerning, as we embrace change and development. We must learn to stand back from and reappraise the increasing use of industry-sponsored spectacles of ‘show-and-tell’ ‘live’ demonstration courses. We must re-evaluate the allure toward more procedures, devices and interventions than perhaps what might truly be necessary medical care, no matter how promising or how technically beguiling these appear to be!
This includes even pharmaceutical junkets, which invariably encourage greater use of newer, more expensive drugs among physicians. But this is not to say that we have to revert back into being Luddites, opposing everything that is new and good. We just have to be more circumspect, judicious, be really objective and evidence-based! We should be imbued with a healthier dose of common-sense skepticism!
The former editor of the British Medical Journal, Dr Richard Smith had this to say when he reviewed the life and work of Ivan Illich following the latter’s death in 2002 from debilitating cancer: “Technology can help, but modern medicine has gone too far — launching onto a godlike battle to eradicate death, pain and sickness. In doing so, it turns people into consumers or objects, destroying their capacity for health.” [26]
We must re-engage with our patients more candidly and transparently, and place them and their interests first and foremost, after all truth telling is one of the universally accepted pillars of ethics and professionalism. We should inform more openly and widely (to include risks, especially material risks peculiar to this or that patient). We should also propose and discuss alternative models of therapies and lifestyle modifications, so that we allow patients to decide on their own, which options to choose from and live by. This is perhaps the modern expectation of patient empowerment and choice.
Already there is declining trust and belief in physicians. We have to reclaim our trust. Dr Alice Jacobs, president of the AHA in 2005 stated that: “This issue is the erosion of trust. Lack of trust is a barrier between our intellectual renewal and our ability to deliver this new knowledge… to the bedside of our patients, and to the public. Trust is a vital, unseen, and essential element in diagnosis, treatment, and healing. So it is fundamental that we understand what it is, why it’s important in medicine, its recent decline, and what we can all do to rebuild trust in our profession.”[27]
“A 2005 U.S. News and World Report cover stated: ‘Who Needs Doctors? Your next doctor may not be an MD and you may be better off.’ Have we finally come this far, where the human touch of the physician can be replaced by healthcare reduced to guidelines, tests, algorithms, procedures, and drugs?”[28]
This is indeed a possible scenario as we move further and further along in that loosening of the physician-patient bond, that ever-widening chasm of information asymmetry, with Internet or email consultations, video computer-assisted medical appointments/consultations, telemedicine, etc. But at the end of every patient-physician encounter, what is still most needed is that caring empathetic relationship, with the physician serving as that trusted health caregiver who can provide the best that modern medical care can offer, in the best interest of the patient, and no one else! Above all, we are called upon to provide medical care well and prudently, no more and certainly no less.




References:


* historiography  the writing of history based on the critical examination of sources, the selection of particular details from the authentic materials in those sources, and the synthesis of those details into a narrative that stands the test of critical examination (Britannica.com).
+ Ambrosia — the divine potion, which gave the gods unending life.


[1] Susan Sontag. Illness as Metaphor. Doubleday, New York, 1978.
[2] Siddhartha Mukherjee. The Emperor of All Maladies: A Biography of Cancer. Scribner, New York, 2010.
[3] Ivan Illich. Medical nemesis. J Epidemiol Community Health 2003;57:919–922. This article is reprinted with permission from Elsevier (Lancet 1974;i:918–21). (http://www.elsevier.com/locate/lancet)
[4] National health accounts [online database]. Geneva, World Health Organization, 2010  (http://www.who.int/nha,
 accessed 23 June 2010).
[5] World health statistics 2010. Geneva, World Health Organization, 2010.
[6] Grossman M. The demand for health. 30 years later: a very personal retrospective and prospective reflection. J Health Economics. 2004; 23:629-636
[7] Leibowitz. A. A. The demand for health and health concerns after 30 years. J Health Economics. 2004;23: 663-671
[8] Bunker JP. Medicine matters after all. J Roy Coll Physicians. 1995;29:105-12
[9] R. Moynihan, I Heath, D. Henry. “Selling Sickness: The Pharmaceutical Industry and Disease-Mongering”, British Med J. 2002; 324:886–891.
[10] Starfield B, Hyde J, Gervas, Heath I. ‘The Concept of Prevention: A Good Idea Gone Astray?’ J Epidemiol Community Health 2008;62:580–583. [doi:10.1136/jech.2007.071027] Quoted by Chan C.K. in ‘M. K. Rajakumar, Primary Care and Population Health’, in An Uncommon Hero, 2011 (in press), pp 308-320.
[12] James Le FanuBeware the 'Janus face’ of modern medicine. The Telegraph, 14 Nov 2011.  http://www.telegraph.co.uk/health/8883956/Beware-the-Janus-face-of-modern-medicine.html
[13] Kaptchuk TJ, Stason WB, Davis RB, et al. Sham device v inert pill: randomised controlled trial of two placebo treatments. BMJ 2006;332: 391–7.
[14] Judith S. Hochman, MD; Harmony R. Reynolds, MD; Vladimı´r Dzˇavı´k, et al. for the OAT Investigators. Long-Term Effects of Percutaneous Coronary Intervention of the Totally Occluded Infarct-Related Artery in the Subacute Phase After Myocardial Infarction. Circulation. 2011;124:00-00. (Published online Oct 24, 2011)
[15] Levine GN, Bates ER, Blankenship JC, et al. 2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. J Am Coll Cardiol. 2011;58:e44–122.
[16] Boden WE, O’Rourke RA, Teo KK, et al. Optimal medical therapy with or without PCI for stable coronary disease (COURAGE). N Engl J Med. 2007;356:1503–16.
[17] Hambrecht R, Walther C, Mobius-Winkler S, et al. Percutaneous coronary angioplasty compared with exercise training in patients with stable coronary artery disease: a randomized trial. Circulation. 2004; 109:1371– 8.
[18] Trikalinos TA, Alsheikh-Ali AA, Tatsioni A, et al. Percutaneous coronary interventions for non-acute coronary artery disease: a quantitative 20-year synopsis and a network meta-analysis. Lancet. 2009;373:911– 8.
[19] Roger Chou, Bhaskar Arora, Tracy Dana, Rongwei Fu, Miranda Walker, and Linda Humphrey. Screening Asymptomatic Adults With Resting or Exercise Electrocardiography: A Review of the Evidence for the U.S. Preventive Services Task Force. Ann Intern Med. 2011;155:375-385.
[20] Aktas MK, Ozduran V, Pothier CE, Lang R, Lauer MS. Global risk scores and exercise testing for predicting all-cause mortality in a preventive medicine program. JAMA. 2004;292:1462-8. [PMID: 15383517]
[21] Cournot M, Taraszkiewicz D, Galinier M, Chamontin B, Boccalon H, Hanaire-Broutin H, et al. Is exercise testing useful to improve the prediction of coronary events in asymptomatic subjects? Eur J Cardiovasc Prev Rehabil. 2006;13:37-44. [PMID: 16449862]
[22] Michael S. Lauer. What Now With Screening Electrocardiography? Ann Intern Med. 2011;155:395-397.
[23] Bruce RA, DeRouen TA, Hossack KF. Pilot study examining the motivational effects of maximal exercise testing to modify risk factors and health habits. Cardiology. 1980;66:111–9.
[24] Diabetes mellitus and exercise. American Diabetes Association.  Diabetes Care. 1997;20:1908–12.
[25] Levine GN, Bates ER, Blankenship JC, et al. 2011 ACCF/AHA/SCAI guideline for percutaneous coronary interventiona report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. J Am Coll Cardiol. 2011;58:e44–122.
[26] Smith R. Limits to medicine. Medical Nemesis: the expropriation of health. J Epidemiol Community Health 2003;57:928.
[27] Alice K. Jacobs. Rebuilding an Enduring Trust in MedicineA Global Mandate. (Presidential Address American Heart Association Scientific Sessions 2004). Circulation. 2005;111:3494-3498.
[28] Brian Olshansky. Placebo and Nocebo in Cardiovascular Health: Implications for Healthcare, Research, and the Doctor-Patient Relationship. J. Am. Coll. Cardiol. 2007;49;415-421.

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