Subgroup analyses in therapeutic cardiovascular clinical trials: Are most of them misleading?

Hernández, Adrián V.; Boersma, Eric; Murray, Gordon D.; Habbema, J. Dik F.; Steyerberg, Ewout W.

doi:10.1016/j.ahj.2005.04.020

« Previous Next »American Heart Journal
Volume 151, Issue 2 , Pages 257-264, February 2006

Subgroup analyses in therapeutic cardiovascular clinical trials: Are most of them misleading?

This paper was presented in part during the Young Investigator Award in Population Sciences Session, 2004 European Society of Cardiology Conference, 28 August-1 September, Munich, Germany.

Adrián V. Hernández, MD, MSc
- Center for Clinical Decision Sciences, Department of Public Health, Thoraxcenter, Erasmus University Medical Center, Rotterdam, The Netherlands
- Reprint requests: Adrián V. Hernández, MD, MSc, Center for Clinical Decision Sciences, Department of Public Health, Room H Ee 2010, Erasmus University Medical Center, P.O. Box 1738, 3000 DR Rotterdam, the Netherlands.
Eric Boersma, MSc, PhD
- Clinical Epidemiology Unit, Department of Cardiology, Thoraxcenter, Erasmus University Medical Center, Rotterdam, The Netherlands
Gordon D. Murray, PhD
- Division of Community Health Sciences, Public Health Sciences, University of Edinburgh Medical School, Edinburgh, United Kingdom
J. Dik F. Habbema, PhD
- Center for Clinical Decision Sciences, Department of Public Health, Thoraxcenter, Erasmus University Medical Center, Rotterdam, The Netherlands
Ewout W. Steyerberg, PhD
- Center for Clinical Decision Sciences, Department of Public Health, Thoraxcenter, Erasmus University Medical Center, Rotterdam, The Netherlands

Received 8 February 2005; accepted 28 April 2005.

This study was supported by a grant from the Netherlands Organization for Scientific Research (ZON/MW 908-02-117) (The Hague, The Netherlands) (Dr Adrián V. Hernández).

Background

Treatment decisions in clinical cardiology are directed by results from randomized clinical trials (RCTs). We studied the appropriateness of the use and interpretation of subgroup analysis in current therapeutic cardiovascular RCTs.

Methods

We reviewed main reports of phase 3 cardiovascular RCTs with at least 100 patients, published in 2002 and 2004, and from major journals (Circulation, J Am Coll Cardiol, Am Heart J, Am J Cardiol, N Engl J Med, Lancet, JAMA, BMJ, Ann Intern Med). Information on subgroups included prespecification, number, interaction test use, significant subgroups found, and emphasis on findings. We examined appropriateness of reporting and differences according to sample size, overall trial result, and CONSORT adoption.

Results

We selected 63 RCTs, with a median of 496 (range 100-15245) patients. Thirty-nine RCTs were reported with subgroup analyses and 26 with >5 subgroups. No trial was specifically powered to detect subgroup effects, and only 14 RCTs were reported with fully prespecified subgroups. Only 11 RCTs were reported with interaction tests. Furthermore, 21 RCTs were reported with claims of significant subgroups and 15 with equal or more emphasis to subgroups than to the overall results. Subgroup analyses in large RCTs (>500 patients) were reported more often than in small ones (24/30 vs 15/33, P = .005). No differences were found according to overall result (positive/negative) or CONSORT adoption.

Conclusions

Subgroup analyses in recent cardiovascular RCTs were reported with several shortcomings, including a lack of prespecification and testing of a large number of subgroups without the use of the statistically appropriate test for interaction. Reporting of subgroup analysis needs to be substantially improved because emphasis on these secondary results may mislead treatment decisions.