[e-drug] Evidence based medicine (cont'd)

[John Urquhart <urquhart@ix.netcom.com>]

E-drug: Evidence based medicine (cont'd)
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George Kibumba is quite correct in expressing skepticism about
'evidence-based medicine'. Like previous fads in medicine, which
have the attribute of a swinging pendulum, this one threatens to
swing to the point of coming off its hinges, to borrow a metaphor
from Bradford Hill.

'Evidence-based medicine' is a term exquisitely crafted to make it
seem criticism-proof. One of its difficulties, however, is that it
derives from specialization, which is a very powerful force that
carries the occupational hazard of myopia, sometimes severe.
Another of its difficulties are the sometimes misleading estimates of
strengths of effects that arise from intent-to-treat analyses of
randomized, placebo-controlled trials. As Alvan Feinstein has
remarked, intent-to-treat analysis may prevent bias, but does not
prevent foolishness, so the implications of this statistical policy,
designed to avoid one particular type of error in judging drug
effectiveness, need to be understood fully in the context of each
study before photocopying them into drug labeling, reimbursement
decisions, or other types of policy that pertain to medical practice.
In particular, the complete censoring of data on trial participants'
exposure to drug by the intent-to-treat policy means that estimates
of effectiveness are diluted by the pharmacological consequences
of prevalent underdosing in ambulatory drug trials (1). Likewise,
dose-dependent drug side-effects are underestimated, but, more
importantly, safety judgments are confounded by the sometimes
hazardous pharmacologic consequences of patient-initiated dosing
interruptions ("drug holidays") from protocol-specified drug
regimens. These hazards include rebound effects, recurrent
first-dose effects, and other nonlinear pharmacodynamic
phenomena that are largely masked by the averaging that provides
'evidence-based' results (1).

One measure of the status of 'evidence-based medicine' are the
efforts to improve statistical analyses of drug trials. Two
conferences this summer on causal inference, one in Gent, Belgium,
and the other in Snowbird, Utah, USA, represent the beginnings of
biostatistical means to find sound analyses of the often informative
results that arise from the observational studies that are imbedded
in every randomized, controlled, ambulatory drug trial. Work along
these and other lines indicates that 'evidence-based medicine'
cannot yet be deemed ne plus ultra, but is amenable to
improvement, and thus has shortcomings, though one would be
hard put to judge that from present cheerleading.

An especially stark difference between trials and practice is the
much longer persistence with chronic-use medicines that usually
occurs in randomized, controlled trials than in everyday medical
practice. The recent work of Catalan and LeLorier (2), reports a
median persistence with statins in routine medical practice of only
173 days, with only a third of patients still taking any statin at 12
months, and only 12% at 5 years. Contrast these findings with the
75-90% of patients still taking statins at the end of the 5th year
after the start of the 4S (3) and the West of Scotland (4)
randomized, controlled trials -- both cited as evidence-based
medicine in fullest flower. But, to gallop off, in the face of this huge
discrepancy in persistence, and proclaim the need to treat a fifth or
so of adults over age 40 with statins, as was done recently by the
US National Heart, Lung & Blood Institute, is certainly economic
folly, and probably medical folly as well -- if the findings of Catalan
and LeLorier are correct, and half give up taking the medicine before
the 6th month. Similarly short persistence with another major,
chronic-use group of medicines -- antihypertensives -- has been
reported by Jones et al. (5) and by Caro et al. (6,7), also in
situations where reimbursement removed substantive economic
obstacle to continuation.

In my youth, I greatly benefitted from having a gifted physics
teacher, Mr. Marshall. He enunciated what I have come to call
"Marshall's dictum", which is: "Things ain't what they seem" --
useful to bear in mind in surveying what presently passes as
'evidence-based' medicine.

John Urquhart, MD, FRCP(Edin)
Professor of Pharmaco-epidemiology
Maastricht University, Maastricht, NL
Chief Scientist, AARDEX Ltd/APREX Corp, Zug CH & Union City,
CA, USA
Professor of Biopharmaceutical Sciences, UCSF, San Francisco
e-mail: urquhart@ix.netcom.com

References:

1. Urquhart J, de Klerk E. Contending paradigms for the
   interpretation of data on patient compliance with therapeutic
   drug regimens. Stat Med 17: 251-267, 1998. 
2. Catalan VS, LeLorier J. Predictors of long-term persistence on
   statins in a subsidized clinical population. Value in Health 3:
   417-26, 2000.
3. Scandinavian Simvastatin Survival Study Group. Randomised
   trial of cholesterol lowering in 4444 patients with coronary
   heart disease: the Scandinavian Simvastatin Survival Study
   (4S). Lancet 344: 1383-9, 1994.
4. Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR,
   MacFarlane PW, McKillop JH, Packard CJ. Prevention of
   coronary heart disease with pravastatin in men with
   hypercholesterolemia. West of Scotland Coronary Prevention
   Group. N Engl J Med 333: 1301-7, 1995.
5. Jones JK, Gorkin L, Lian JF, Staffa JA, Fletcher AP.
   Discontinuation of and changes in treatment after start of new
   courses of antihypertensive drugs: a study of a United Kingdom
   population. BMJ 311: 293-5, 1995.
6. Caro JJ, Salas M et al. Persistence with treatment for
   hypertension in actual practice. Canad Med Assoc J 160:31-8,
   1999.
7. Caro JJ, Speckman JL et al. Effect of initial drug choice on
   persistence with antihypertensive ttherapy: the importance of
   actual practice data. Canad Med Assoc J 160:41-7, 1999.


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