"Piece of My Mind" for the Christmas Issue Please.

MEDICAL PHAINOMENON

Prof. B. M. Hegde
Vice Chancellor,
M.A.H.E. Deemed University,
Manipal-576 119.
India.

"Fear not! Life still------------------
Leaves human effort scope.
But, since life teems with ill,
Nurse no extravagant hope."

-------------------Mathew Arnold
---------------------------Empedocles on Etna.

Greek meaning of the word phainomenon is something that is “brought to light”. It is, probably, the root of the English word phenomenon. In the midst of the medical claptrap, I have been wondering how does a novice get at the truth. Medical textbooks seem to be produced largely from funds coming from the drug industry and/or technology manufacturers. Most of the short-term studies reported in the journals are funded from similar sources. Most of them, on further scrutiny or on larger samples, give the opposite results! The latter rarely get wide publicity, while the original results are being repeatedly dinned into the practising doctors, through the well-oiled pharmaceutical industry sleuths. Many a time the drug manufacturers make use of the “opinion makers” amongst us to do this job for them.

When a patient has symptoms and seeks our help, we have a moral duty to intervene to do our best for him/her, even though the knowledge in that area might be still patchy. However, in an apparently healthy person it is difficult to interfere with drugs and technology, in the fond hope that our interventions would prevent a particular catastrophe, may be, twenty years down the line. In the latter case our intervention must be unequivocally proven to be one hundred per cent safe and effective. Rarely does one come across such a situation!

Most of the asymptomatic, life long, "doctor-thinks-you-have" diseases like mild-moderate hypertension, hyper-lipidaemia, coronary artery blocks, and asymptomatic hyper-glycaemia fall into this category. When it comes to treating asymptomatic individuals, there seems to be a hidden hand of the drug and/or the instrument industry that tries to sell the idea of long term risks of marginally raised blood pressure, glucose intolerance and coronary artery blocks in the four major epicardial vessels, although the area is still quite hazy and is still in the grey zone.

Risk factor hypotheses, based on epidemiological studies, are our biggest bane. “Epidemiology”, wrote Dr. Charles H. Hennekens, of the Harvard School of Public Health, “is a crude and inexact science. Eighty percent are almost all hypotheses. We tend to overstate findings, either because we want attention or more grant money.” (NewYork Times October 11, 1995)1. Epidemiologists have been predicting the unpredictable. 2

With the onset of the placebo-controlled studies, using randomly matched cohorts, researchers thought that the end of history in medical world was written. Today, every drug has to pass through this acid test before being let lose on the gullible public. This does not apply to medical technology, though.

Lately many audits have shown that the findings of the controlled studies need not be true in the larger scenario of millions of patients using the drug in question, in real life situations. The latter are not isolated instances. Most major studies seem to be flawed. Examples are milrinone (PROMISE STUDY), epoprostenol (FIRST STUDY), vesnarinone (VEST STUDY), and amlodipine (PRAISE II STUDY). 3 The other major study is in the field of anti-diabetic drugs (UKPDS), especially insulin and sulphanylureas. 4

The story is no different when it comes to anti-arrhythmic drugs, which at one time were the mainstay of treatment of acute myocardial infarction. The CAST study did really show anti-arrhythmic drugs in very poor light!5 Most of the anti-hypertensive drugs were studied only for the first five years of treatment; longer studies of 20-25 years have shown that the adequately drug controlled hypertensives had significantly higher deaths compared to their normotensive cousins in society!6

Cardiogenic shock remains unchanged over the years despite all the advances. It is the leading cause of death in hospitalized myocardial infarction patients. It remains as common today as it was thirty five years ago! Reperfusion methods, including thrombolysis, seem to have made no impact on the death rate due to cardiogenic shock, which remains at 5-15% deaths in different series. Aggressive reperfusion has only made a dent in the short-term death. There has been little change in the long-term death rate.7

Then came the era of immediate post-infarction revascularisation, which was sold as the panacea to prevent these deaths. A new study, involving nearly 18151 patients from the OASIS registry of the McMaster University in Ontario, Canada, has shown that immediate post-infarction revascularisation resulted in increased stroke rates nearly four times, and the strokes were universally fatal. Bypass surgery was the most important risk factor for strokes. Even the presence of an onsite catheterization laboratory was an independent risk factor for strokes in patients admitted to such hospitals!8

It is, therefore, not surprising that a recent study revealed that well structured long-term observational studies yield equally reliable results, if not better results than the much touted controlled studies that spend millions of dollars. 9

I have a nagging feeling that all is not well with the controlled studies that compare only some aspects of man's phenotype. The major portions of man-his genotype and the all-pervading consciousness (the mind)- are not being taken into consideration in matching the two groups. Although statisticians tell us that randomization is the answer to all questions, the argument does not hold water here. The future predictions in any dynamic system (like the humanbeing) depend only on the total initial knowledge of the organism. Moreover, changing the initial state of the organism need not (and does not) hold good as time evolves. That is why controlled studies have been sending wrong signals.10

Prospective long term observational studies could get better results until such time that we evolve a fool proof system to assess drugs and technology. Until such time the medical profession should be vigilant to keep a watch on the unexpected happenings in the real world of drugs and interventions. Consequently, we may have to confine ourselves to the symptomatic patients and leave the "well" alone for the time being.11 There is, to-date, no unequivocal evidence that our interventions in the asymptomatic stage of any disease, when the body's wisdom is trying to set the machine right, yield long term better results. On the contrary, there are enough pointers that alert us to the possibility of harm from such interventions. One of the meanings of the word "intervene" in the Webster's dictionary is "to go in between with malice"! The divine interventionists should ponder over this seriously.

"Of the terrible doubt of appearances,
Of the uncertainty that we may be deluded….."
Walt Whitman.

The misconception that linear mathematics works in predicting time evolution in any dynamic system has brought us to this pass. Biology is awaiting the discovery of a new mathematical formula, a new paradigm, using non-linear mathematics to unravel the mystery of time evolution in any dynamic system. Until then we better take note of Robert Hutchinson's prayer that goes somewhat like this.

"Lord, Give me deliverance from-----------------------------
Not letting the well alone,--------------------------------------
Treating sick human beings as cases, and-------------
Making my interventions worse than the disease."
-----------------------------------------------Hutchinson.

BIBLIOGRAPHY.

1. Milloy S. Science without sense. Book. 1997, CATO Institute Washington DC.
2. Editorial. Do epidemiologists cause epidemics? Lancet 1993; 341: 993-994
3. Editorial. All that glitters is not gold. Lancet 2000; 355: 1568, 1569, 1575, 1582.
4. McCormack J, Greenhalgh T. Seeing what you want to see in research. BMJ 2000; 320: 1720-23.
5. Naccarelli GV, Wolbrette DL, Dell-Orfano JT et. al. Cardiac arrhythmia suppression trial (CAST Trial). J. Cardiovasc. Electrophysiol. 1998; 9: 864-891
6. Andersson OK, Almgren T, Persson B et. al. Survival in treated hypertension-follow up after two decades. BMJ 1998; 317: 167-171
7. Goldberg RJ, Samad NA, Yarzebski J et al. Temporal trends in cardiogenic shock complicating myocardial infarction. NEJM 1999; 340: 1162-1168.
8. Josefson D. Early bypass surgery increases risk of stroke. BMJ 2001; 323: 185.
9. Concato J, Shah N, and Horwitz RI. Randomized controlled trials, observational studies, and the hierarchy of research designs. N.Engl.J.Med 2000; 342: 1887-1892
10. Firth WJ. Chaos-Predicting the Unpredictable. BMJ 1991; 303: 1565-1568.
11. Hegde BM. To do or not to do-Doctors' dilemma; Plea for proper audit-Editorial. Kuwait Med Jr. 2001; 33(2): 107-110.