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Owing to the unexpected results of some studies, such as CAST (cardiac arrhythmia suppression trial)1 and the World Health Organization clofibrate trial,2 or the studies with cAMP dependent positive inotropic agents, the results of randomised controlled trials are taken to represent the gold standard for therapeutic decisions (“evidence based medicine”). The information gain increases as one proceeds from anecdotal case reports over series of observations, to case–control studies, cohort studies, small randomised controlled trials and their meta-analyses (the results of which are not confirmed by randomised controlled trials in up to 30%3), large randomised controlled trials, and finally to careful meta-analyses of such trials (Cochrane criteria). Surrogate end points based on the expectation of a beneficial effect may lead to erroneous conclusions; the gold standard involves primary, hard end points—predominantly prolongation of life—which may be quality adjusted.
However, even where the results of large randomised controlled trials show a significant increase in survival, the clinician is still confronted with difficulties, especially with diseases of unknown aetiology and pathogenesis. If the causes of anaemia were not fully understood, a positive result from a study of vitamin B-12 treatment could imply that all anaemic patients should be treated with vitamin B-12.4 Such generalised recommendations are common practice: in the postinfarction period, the benefits of aspirin, β blockers, angiotensin converting enzyme (ACE) inhibitors, statins, and rehabilitation are clearly documented. Each treatment reduces mortality by about 20%. By simple addition, a survival rate of 100% or immortality would result; more correctly a survival rate of 67% can be expected at best. An exact evaluation would have to be based on a comparison of the five different treatments and all their combinations. This is next to impossible, as more than 450 studies would have to be performed.
For diseases with a …