Curriculum in Cardiology
Subgroups, treatment effects, and baseline risks: Some lessons from major cardiovascular trials

https://doi.org/10.1067/mhj.2000.106610Get rights and content

Abstract

Background The objective of this study was to determine how subgroup analyses are performed in large randomized trials of cardiovascular pharmacotherapy. Methods and Results We reviewed 67 randomized, double-blind, controlled trials involving pharmacotherapy in at least 1000 patients with unstable angina, myocardial infarction, left ventricular dysfunction, or heart failure with clinical outcomes as primary end points, published between 1980 and 1997. Nine had no subgroup analyses but 43 reported on 5 or more subgroups and 31 reported subgroups without formal statistical tests for treatment-subgroup interactions. In most trials, a rationale for subgroup selection was missing. All but 6 focused on single-factor subgroups. Conclusions Trial subgroups should ideally be defined a priori on 2 bases: single-factor subgroups with a strong rationale for biological response modification and multifactorial prognostic subgroups defined from baseline risks. However, single-factor subgroup analyses are often reported without a supporting rationale or formal statistical tests for interactions. We suggest that clinicians should interpret published subgroup-specific variations in treatment effects skeptically unless there is a prespecified rationale and a significant treatment-subgroup interaction. (Am Heart J 2000;139:952-61.)

Section snippets

Methods

Studies published between 1980 and 1997 were identified through a literature search with the use of Medline, BioMedNet,8 and What’s What.9 We included only randomized, double-blind, controlled trials of pharmacotherapy with clinical outcomes as primary end points, published between 1980 and 1997. We excluded trials with <1000 patients to ensure a sizeable number of patients in the selected subgroups.

We recognized that for many trials, publications after the main report may present additional

General use of subgroup analysis

Our main results are summarized in Tables I and II.

. Delineation of subgroups in 67 large trials of cardiovascular pharmacotherapy

 Trial namen (total)IndicationSubgroups
AIMS Long-term effects of intravenous anistreplase in acute MI321258AMITime to Rx, age, sex, SBP, HR, previous MI, previous AP, current smoker, infarct site
AIRE Acute infarction ramipril efficacy study332006CHF after MIAge, sex, days from MI to randomization, AP, HTN, thrombolysis, Rx with ASA, β-blocker, calcium antagonist,

Discussion

Clinicians and statisticians continue to debate the validity of subgroup analyses within randomized controlled trials.5, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 From a practical standpoint, our review of 67 large randomized trials of medical therapy for cardiac disease confirms concerns about current practice regarding subgroup analyses. Subgroups were usually presented without clear prespecification or explanation of the biological rationale for expecting that the treatment effect size would

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    Reprint requests: C. David Naylor, MD, MSB 2109, 1 King’s College Circle, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada M5S 1A8.

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