Curriculum in CardiologySubgroups, treatment effects, and baseline risks: Some lessons from major cardiovascular trials☆
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. Trial name n (total) Indication Subgroups AIMS Long-term effects of intravenous anistreplase in acute MI32 1258 AMI Time to Rx, age, sex, SBP, HR, previous MI, previous AP, current smoker, infarct site AIRE Acute infarction ramipril efficacy study33 2006 CHF after MI Age, 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
References (94)
Can overall results of clinical trials be applied to all patients?
Lancet
(1995)- et al.
Randomised trial of outcome after myocardial infarction in patients with frequent or repetitive ventricular premature depolarisations: CAMIAT: Canadian Amiodarone Myocardial Infarction Arrhythmia Trial Investigators
Lancet
(1997) Within trial variation: a false trial?
J Clin Epidemiol
(1998)Subgroup analysis
Lancet
(1988)The problem of cogent subgroups: a clinicostatistical tragedy
J Clin Epidemiol
(1998)- et al.
Can treatment that is helpful on average be harmful to some patients? A study of the conflicting information needs of clinical inquiry and drug regulation
J Clin Epidemiol
(1996) The use and abuse of subgroup analysis in epidemiological research
Prev Med
(1987)- et al.
Interaction between prognostic factors and treatment
Control Clin Trials
(1983) Long-term effects of intravenous anistreplase in acute myocardial infarction: final report of the AIMS study
Lancet
(1990)Effect of long-term oral anticoagulant treatment on mortality and cardiovascular morbidity after myocardial infarction
Lancet
(1994)
Randomised trial of effect of amiodarone on mortality in patients with left ventricular dysfunction after recent myocardial infarction: EMIAT: European Myocardial Infarct Amiodarone Trial Investigators
Lancet
Fragmin in unstable angina pectoris or in non-Q-wave acute myocardial infarction (the FRIC study): Fragmin in Unstable Coronary Artery Disease
Am J Cardiol
Low-molecular-weight heparin during instability in coronary artery disease
Lancet
GISSI-2: a factorial randomised trial of alteplase versus streptokinase and heparin versus no heparin among 12,490 patients with acute myocardial infarction
Lancet
Clinical trials in thrombolytic therapy: what do they tell us? INJECT 6-month outcomes data
Am J Cardiol
Intravenous magnesium sulphate in suspected acute myocardial infarction: results of the second Leicester Intravenous Magnesium Intervention Trial (LIMIT-2)
Lancet
Effect on mortality of metoprolol in acute myocardial infarction: a double-blind randomised trial
Lancet
Persantine-Aspirin Reinfarction Study, II: secondary coronary prevention with persantine and aspirin
J Am Coll Cardiol
Randomised study of effect of ibopamine on survival in patients with advanced severe heart failure: Second Prospective Randomised Study of Ibopamine on Mortality and Efficacy (PRIME II) Investigators
Lancet
Controlled trial of sotalol for 1 year after myocardial infarction
Lancet
Effect of d-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction: the SWORD Investigators: Survival With Oral d-Sotalol
Lancet
Comparison of intravenous urokinase plus heparin versus heparin alone in acute myocardial infarction: Urochinasi per via Sistemica nell’Infarto Miocardico (USIM) Collaborative Group
Am J Cardiol
An evidence based approach to individualising treatment
BMJ
Large trials with simple protocols: indications and contraindications
Control Clin Trials
What do the overall results of clinical trials and meta-analyses tell us about the efficacy of treatments?
J Nephrol
Avoidance of large biases and large random errors in the assessment of moderate treatment effects: the need for systematic overviews
Stat Med
The analysis of several 2x2 contingency tables
Biometrika
Statistical methods in cancer research, I: the analysis of case-control studies)
What’s what
Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions
N Engl J Med
A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE)
Lancet
Analysis of clinical trial outcomes: some comments on subgroup analyses
Control Clin Trials
Subgroup analysis of clinical trials
Am J Cardiol
Clinical versus statistical considerations in the design and analysis of clinical research
J Clin Epidemiol
Strategies for subgroup analysis in clinical trials: recent results
Cancer Res
Analysis of clinical trial outcomes: alternative approaches to subgroup analysis
Control Clin Trials
Final rule on investigational new drug applications and new drug applications (GENERIC)
Statistical aspects of cancer trials
On wisdom after the event
J Clin Epidemiol
Two new tests associated with analysis of variance
J R Stat Soc [B]
Testing for qualitative interactions between treatment effects and patient subsets
Biometrics
Metoprolol In Acute Myocardial Infarction (MIAMI): a randomised placebo-controlled international trial
Eur Heart J
A consumer’s guide to subgroup analyses
Ann Intern Med
Analysis and interpretation of treatment effects in subgroups of patients in randomized clinical trials
JAMA
Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure
Lancet
The aspirin myocardial infarction study: final results
Circulation
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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.