Elsevier

American Heart Journal

Volume 146, Issue 5, November 2003, Pages 839-847
American Heart Journal

Clinical investigation
Is there evidence of implicit exclusion criteria for elderly subjects in randomized trials? Evidence from the GUSTO-1 study

https://doi.org/10.1016/S0002-8703(03)00408-3Get rights and content

Abstract

Background

Some experts have raised concerns about the ability to generalize randomized trials, emphasizing that patients who participate in these studies are often not representative of those seen in clinical practice, particularly in the case of elderly patients. To determine the effect of implicit exclusion criteria on a trial study sample, we compared data from the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO) trial with data from a retrospective registry from selected hospitals, the National Registry of Myocardial Infarction (NRMI), and a nationally representative study of myocardial infarction care, the Cooperative Cardiovascular Project (CCP).

Methods

We compared GUSTO subjects aged 65 years and older who were enrolled in the United States with similarily aged patients in the 2 observational studies who met the trial's eligibility criteria. We examined baseline characteristics, clinical presentation, treatments, procedures, clinical events, and in-hospital mortality rates.

Results

We found modest, although significant, differences between patients in NRMI, CCP, and GUSTO in demographic and clinical characteristics, treatment, and outcome. For example, GUSTO patients were significantly younger (73.1 ± 5.7 vs 74.7 ± 6.8 for NRMI and 75.8 ± 7.2 for CCP), less likely to have Killip class III/IV at presentation (3.1% vs 6.2% for NRMI and 32.7% for CCP), and more likely to receive aspirin (95.5% vs 86.3% for NRMI and 86.5% for CCP) and β-blockers (71.9% vs 43.5% for NRMI and 52.7% for CCP). Overall, NRMI and CCP patients had a lower risk of 30-day mortality after adjustment for demographic, clinical, and hospital characteristics than patients in GUSTO (odds ratio, 0.79; 95% CI, 0.73–0.86 for NRMI; odds ratio, 0.65; 95% CI, 0.59–0.71 for CCP).

Conclusions

Older patients enrolled in a randomized trial without an age restriction had many similarities compared with patients seen in clinical practice. The higher mortality rate of the GUSTO patients does not support the hypothesis that the trial enrolled a healthier cohort than is seen in practice.

Section snippets

GUSTO

The GUSTO trial compared thrombolytic strategies for the treatment of AMI; all 4 treatment arms included at least 1 thrombolytic agent. The trial's eligibility criteria required that patients come to a participating hospital <6 hours after the onset of symptoms, with chest pain lasting at least 20 minutes and accompanied by electrocardiographic signs of ≥l 0.1 mV of ST-segment elevation in ≥2 limb leads or ≥l 0.2 mV in ≥2 contiguous precordial leads. The criteria for exclusion were previous

Patient characteristics

When we applied the GUSTO selection criteria as aforementioned, we found that 20,647 of the NRMI patients and 17,157 of the CCP patients would have been eligible for participation in GUSTO (Table I). The most common reasons why patients in CCP and NRMI would have been excluded from GUSTO were presentation >6 hours after symptom onset and the absence of chest pain or ST-segment elevation on admission.

Of the 41,021 patients who participated in GUSTO, many were <65 years of age (60%) or were

Discussion

Our comparison of patients in GUSTO with those in 2 large, national observational studies demonstrates several important findings. First, the proportion of elderly patients in the community setting who would have been eligible for the GUSTO trial is relatively small (10%–15% of potentially eligible patients), primarily because of 2 exclusion criteria: delayed presentation and the absence of suitable electrocardiographic findings. Among the subgroup of patients in NRMI and CCP who would have met

Acknowledgements

We thank the patients, investigators, and hospitals that participated in GUSTO, NRMI, and CCP.

References (24)

  • N.R. Every et al.

    A comparison of the National Registry of Myocardial Infarction 2 with the Cooperative Cardiovascular Project

    J Am Coll Cardiol

    (1999)
  • P. Jha et al.

    Characteristics and mortality outcomes of thrombolysis trial participants and nonparticipantsa population-based comparison

    J Am Coll Cardiol

    (1996)
  • D. Robinson et al.

    Subject selection biases in clinical trialsdata from a multicenter schizophrenia treatment study

    J Clin Psychopharmacol

    (1996)
  • R.L. Wentzer et al.

    Generalisability of results from randomized drug trialsa trial on animanic treatment

    Br J Psychiatry

    (1997)
  • L.F. Hutchins et al.

    Underrepresentation of patients 65 years of age or older in cancer-treatment trials

    N Engl J Med

    (1999)
  • L.S. Schneider et al.

    Eligibility of Alzheimer's disease clinic patients for clinical trials

    J Am Geriatr Soc

    (1997)
  • A. Britton et al.

    Threats to applicability of randomised trialsexclusions and selective participation

    J Health Serv Res Policy

    (1999)
  • A.L. Greer

    The state of the art versus the state of the science

    Int J Technol Assess

    (1988)
  • R.I. Horwitz

    Complexity and contradiction in clinical trials research

    Am J Med

    (1987)
  • J.H. Gurwitz et al.

    The exclusion of the elderly and women from clinical trials in acute myocardial infarction

    JAMA

    (1992)
  • L.S. Freedman et al.

    Inclusion of women and minorities in clinical trials and the NIH revitalization act of 1993—the perspective of NIH Clinical Trialists

    Control Clin Trials

    (1995)
  • NIH Revitalization Act. Subtitle B. In: Sec. 131–3;...
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    Dr Gross was supported by a Cancer Prevention, Control and Population Sciences Career Development Award (1K078CA-90402) and the Claude D. Pepper Older Americans Independence Center at Yale (P30AG21342).

    The analyses on which this publication is based were performed under contract number 500-99-CT01, titled “Utilization and Quality Control Peer Review Organization for the State of Connecticut,” sponsored by the Centers for Medicare and Medicaid Services, Department of Health and Human Services. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does the mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. The author assumes full responsibility for the accuracy and completeness of the ideas presented. This article is a direct result of the Health Care Quality Improvement Program initiated by the Centers for Medicare and Medicaid Services, which has encouraged identification of quality improvement projects derived from analysis of patterns of care, and therefore required no special funding on the part of this contractor. Ideas and contributions to the author concerning experience in engaging with issues presented are welcomed.

    Guest editor for this manuscript was A. Michael Lincoff, MD, Cleveland Clinic Foundation, Cleveland, Ohio.

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