SeriesSubgroup analysis in randomised controlled trials: importance, indications, and interpretation
Introduction
“The essence of tragedy has been described as the destructive collision of two sets of protagonists, both of whom are correct. The statisticians are right in denouncing subgroups that are formed post hoc from exercises in pure data dredging. The clinicians are also right, however, in insisting that a subgroup is respectable and worthwhile when established a priori from pathophysiological principles.”
A R Feinstein, 19981
Randomised controlled trials (RCTs) and systematic reviews are the most reliable methods of determining the effects of treatments.2, 3, 4, 5 However, when trials were first developed for use in agriculture, researchers were presumably concerned about the effect of interventions on the overall size and quality of the crop rather than on the wellbeing of any individual plant. Clinicians have to make decisions about individuals, and how best to use results of RCTs and systematic reviews to do this has generated considerable debate.6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 Unfortunately, this debate has polarised, with statisticians and predominantly non-clinical (or non-practising) epidemiologists warning of the dangers of subgroup analysis and other attempts to target treatment, and clinicians warning of the dangers of applying the overall results of large trials to individual patients without consideration of pathophysiology or other determinants of individual response. This rift, described by Feinstein as a “clinicostatistical tragedy”,1 has been widened by some of the more enthusiastic proclamations on the extent to which the overall results of trials can properly inform decisions at the bedside or in the clinic.23, 24, 25
The results of small explanatory trials with well-defined eligibility criteria should be easy to apply, but generalisability is often undermined by highly selective recruitment, resulting in trial populations that are unrepresentative even of the few patients in routine practice who fit the eligibility criteria.26 Recruitment of a higher proportion of eligible patients is a major strength of large pragmatic trials, but deliberately broad and sometimes ill-defined entry criteria mean that the overall result can be difficult to apply to particular groups,27 and that subgroup analyses are necessary if heterogeneity of treatment effect is likely to occur. Yet despite the adverse effects on patient care that can result from misinterpreted or inappropriate subgroup analyses (table 1), there are no reviews or guidelines on the clinical indications for subgroup analysis and no consensus on the implications for trial design, analysis, and interpretation of subgroup effects, and the CONSORT statement on reporting of trials includes only a few lines on subgroup analysis.28 This article discusses arguments for and against subgroup analyses, the clinical situations in which they can be useful, and rules for their performance and interpretation. Illustrative examples are taken mainly from treatments for cerebrovascular or cardiovascular disease but the principles are relevant to all areas of medicine and surgery.
Section snippets
Arguments against subgroup analysis
“… it would be unfortunate if desire for the perfect (ie, knowledge of exactly who will benefit from treatment) were to become the enemy of the possible (ie, knowledge of the direction and approximate size of the effects of treatment of wide categories of patient).”
S Yusuf et al, 19844
The main argument against subgroup analysis is that qualitative heterogeneity of relative treatment effect (defined as the treatment effect being in different directions in different groups of patients, ie,
Situations in which subgroup analyses should be considered
“The tragedy of excluding cogent pathophysiologic subgroup analyses merely because they happen to be subgroups will occur if statisticians do not know the distinction, and if clinicians who do know it remain mute, inarticulate or intimidated.”
A R Feinstein, 19981
Subgroup analyses should be predefined and carefully justified. Feinstein and others have emphasised the need for determination of pathophysiological heterogeneity, but there are three other indications for subgroup analysis (
Estimation and interpretation of subgroup effects
“Far better an approximate answer to the right question, which is often vague, than an exact answer to the wrong question, which can always be made precise.”
J W Tukey, 1962118
Conclusions
Large randomised controlled trials with broad eligibility criteria and high inclusion rates provide the most reliable data about the effects of treatments, but these should be designed, analysed, and reported in a way that allows clinicians to use the results as effectively as possible in routine practice. Subgroup analyses can be useful if there are widely differing risks of a poor outcome with or without treatment between specific groups, if there are important differences in pathophysiology
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