Udell JA, Wang TY, Li S, Kohli P, Roe MT, de Lemos JA, Wiviott SD. Clinical Trial Participation After Myocardial Infarction in a National Cardiovascular Data Registry. JAMA. 2014;312(8):841-843. doi:10.1001/jama.2014.6217
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Randomized clinical trials of patients with acute myocardial infarction (MI) enroll selected populations, with low enrollment in the United States, raising questions whether findings are generalizable.1,2 We evaluated whether participants in cardiovascular trials are representative of contemporary patients with MI.
The National Cardiovascular Data Registry Acute Coronary Treatment and Intervention Outcomes Network Registry–Get With The Guidelines is an ongoing, voluntary, quality improvement registry of consecutive patients with MI treated at participating centers across the United States. Registry design, inclusion and exclusion criteria, and data definitions have been described.3
Institutional review boards at participating hospitals approved the registry, and informed consent was waived. Trained abstractors determined registry data, including trial participation, in 190 476 patients with MI at 609 registry centers between July 1, 2008, and March 31, 2011.
Patients with missing or incomplete data for classification of trial participation (n = 472) or eligibility (n = 48 869) were excluded. There were no clinically relevant differences between patients included and excluded. Trial participation was defined as patients who provided informed consent and enrolled in a trial during hospitalization, even if the investigational medication, device, or procedure was never initiated.
Among nonparticipants, we determined whether trial exclusion criteria were met for 3 antiplatelet therapy trials in patients with MI during the study period,4- 6 including age younger than 18 years, uncontrolled hypertension (systolic blood pressure >180 mm Hg), stage 5 kidney disease or dialysis-dependent renal failure, cardiogenic shock, major bleeding within 24 hours of presentation, impaired hemostasis (international normalized ratio [INR] >1.5), severe anemia (hemoglobin <10 g/dL), or use of fibrinolytic therapy. Patients were classified as eligible nonparticipants for an MI trial if they met none of the exclusion criteria, as inclusion criteria for these trials were otherwise similar to registry eligibility. Mortality and cardiovascular event rates in participants were compared with eligible and ineligible nonparticipants.
Logistic regression models used generalized estimating equations to determine the multivariable association between trial participation classification and in-hospital outcomes.3 Two-sided P < .05 was considered significant. Statistical analyses were performed with SAS software version 9.3 (SAS Institute Inc).
Among 141 135 registry participants at 466 centers, 4008 (2.8%) were trial participants and 137 127 were eligible (n = 93 274; 68.0%) or ineligible (n = 43 853; 32.0%) nonparticipants. Overall, 255 sites (54.7%) enrolled at least 1 patient; and trial participation (as a proportion of eligible patients) declined each year during the study period (2008: 5.2%; 2009: 4.4%; 2010: 3.8%; and 2011: 3.4%; P<.001 for trend).
Trial participants were younger, with less previous cardiovascular disease, lower predicted risk of mortality, shorter hospital stays, and more frequent treatment with evidence-based therapy than nonparticipants (Table 1).
Common reasons for ineligibility included uncontrolled hypertension (42%), elevated INR (20%), severe anemia (15%), and cardiogenic shock (14%). In-hospital mortality was lowest for trial participants (1.5%), intermediate among eligible nonparticipants (2.5%) (adjusted odds ratio [OR], 1.63 [95% CI, 1.11-2.41]; P = .01), and highest among ineligible patients (8.4%) (adjusted OR, 1.91 [95% CI, 1.29-2.83]; P = .001) (Table 2).
Within this registry, trial participation was infrequent and declined during the study period, yet 2 of 3 patients with MI were potentially eligible for a randomized clinical trial. Trial participants had a lower risk profile and a more favorable prognosis compared with the broader population with MI, particularly patients eligible for but not enrolled in a clinical trial.
Several limitations are noted. A quarter of registry patients enrolled during the study period were not analyzed, primarily due to a missing initial INR measurement or fibrinolytic status. Participating registry hospitals represented approximately 5% of US acute care hospitals, and half of all participating registry hospitals enrolled at least 1 patient in a clinical trial during the study period, potentially limiting extrapolation to nonparticipating hospitals. Information about socioeconomic status, individual trials, and protocol inclusion or exclusion criteria were not available. Lack of information on the specific timing and reason for trial participation at the patient, physician, and hospital level limited determination of the cause for infrequent trial enrollment, such as patients refusing to participate, researchers not enrolling patients, or no trial being conducted at the hospital.
Efforts to improve trial participation are needed to enhance generalizability of results. Nesting trials within existing registries may help meet this goal.
Corresponding Author: Jacob A. Udell, MD, MPH, Women’s College Hospital, University of Toronto, 76 Grenville St, Toronto, ON M5S 1B1, Canada (email@example.com).
Author Contributions: Ms Li had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Udell, Kohli, Roe, Wiviott.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Udell.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Li, Roe.
Obtained funding: Udell, Roe.
Administrative, technical, or material support: Udell, Wang, Kohli, Roe.
Study supervision: Wang, Roe.
Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Udell reported receiving honoraria from the American College of Cardiology Foundation. Dr Wang reported receiving honoraria from the American College of Cardiology Foundation and AstraZeneca; and research funding to Duke Clinical Research Institute from Lilly USA, Daiichi Sankyo, GlaxoSmithKline, and Gilead Science. Dr Kohli reported serving as a consultant to Live and Jeffries Research. Dr Roe reported receiving grants from Eli Lilly & Company, Daiichi Sankyo, sanofi-aventis, the American College of Cardiology, the American Heart Association, and the Familial Hypercholesterolemia Foundation; and personal fees from Merck, Janssen Pharmaceuticals, Regeneron, AstraZeneca, and Amgen outside the submitted work. Dr de Lemos reported receiving lecture honoraria from AstraZeneca; consulting income from Janssen Pharmaceuticals, Diadexus, St Jude Medical, and Roche Diagnostics; and grant support and consulting income from Roche Diagnostics and Abbott Diagnostics. Dr Wiviott reported receiving grants from Arena, AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, Eisai, Eli Lilly, Merck, and sanofi-aventis; and consulting fees from Aegerion, Angelmed, Arena, AstraZeneca, Boston Clinical Research Institute, Bristol-Myers Squibb, Daiichi Sankyo, Eisai, Eli Lilly, ICON Clinical, Janssen, and Xoma. No other disclosures were reported.
Funding/Support: This research was supported by the American College of Cardiology Foundation’s National Cardiovascular Data Registry (NCDR). The Acute Coronary Treatment and Intervention Outcomes Network (ACTION) Registry–Get With The Guidelines (GWTG) is sponsored in part by the partnership between Bristol-Myers Squibb and sanofi pharmaceuticals. Dr Udell was supported in part by a postdoctoral research fellowship from the Canadian Institutes for Health Research and the Canadian Foundation for Women’s Health.
Role of the Sponsors: The study was designed by Drs Udell and Wiviott and approved by the NCDR. The ACTION Registry–GWTG research and publications subcommittee reviewed and approved the proposal and final draft of the manuscript. The funding agency had no role in the conduct of the study; collection, management, analysis, and interpretation of the data; preparation of the manuscript; and decision to submit the manuscript for publication.
Disclaimer: The views expressed in this manuscript represent those of the authors, and do not necessarily represent the official views of the NCDR or its associated professional societies identified at http://www.ncdr.com.
Additional Contributions: We thank Elliott M. Antman, MD (Brigham and Women’s Hospital, Boston, Massachusetts), for review of the manuscript, for which he received no compensation.