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BMJ. 2020 Feb 5;368:l7078. doi: 10.1136/bmj.l7078.

Updating insights into rosiglitazone and cardiovascular risk through shared data: individual patient and summary level meta-analyses.

Author information

1
Department of Environmental Health Sciences, Yale School of Public Health, 60 College Street, New Haven, CT 06510, USA joshua.wallach@yale.edu.
2
Collaboration for Research Integrity and Transparency, Yale School of Medicine, New Haven, CT, USA.
3
Center for Outcomes Research and Evaluation, Yale-New Haven Health System, New Haven, CT, USA.
4
New York University School of Medicine, New York, NY, USA.
5
Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA.
6
Harvey Cushing/John Hay Whitney Medical Library, Yale University, New Haven, CT, USA.
7
Department of Biostatistics, Yale School of Public Health, New Haven, CT, USA.
8
Section of Cardiovascular Medicine and the National Clinician Scholars Program, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.
9
Department of Health Policy and Management, Yale School of Public Health, New Haven, CT, USA.
10
Section of General Medicine and the National Clinician Scholars Program, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.

Abstract

OBJECTIVES:

To conduct a systematic review and meta-analysis of the effects of rosiglitazone treatment on cardiovascular risk and mortality using multiple data sources and varying analytical approaches with three aims in mind: to clarify uncertainties about the cardiovascular risk of rosiglitazone; to determine whether different analytical approaches are likely to alter the conclusions of adverse event meta-analyses; and to inform efforts to promote clinical trial transparency and data sharing.

DESIGN:

Systematic review and meta-analysis of randomized controlled trials.

DATA SOURCES:

GlaxoSmithKline's (GSK's) ClinicalStudyDataRequest.com for individual patient level data (IPD) and GSK's Study Register platforms, MEDLINE, PubMed, Embase, Web of Science, Cochrane Central Registry of Controlled Trials, Scopus, and ClinicalTrials.gov from inception to January 2019 for summary level data.

ELIGIBILITY CRITERIA FOR SELECTING STUDIES:

Randomized, controlled, phase II-IV clinical trials that compared rosiglitazone with any control for at least 24 weeks in adults.

DATA EXTRACTION AND SYNTHESIS:

For analyses of trials for which IPD were available, a composite outcome of acute myocardial infarction, heart failure, cardiovascular related death, and non-cardiovascular related death was examined. These four events were examined independently as secondary analyses. For analyses including trials for which IPD were not available, myocardial infarction and cardiovascular related death were examined, which were determined from summary level data. Multiple meta-analyses were conducted that accounted for trials with zero events in one or both arms with two different continuity corrections (0.5 constant and treatment arm) to calculate odds ratios and risk ratios with 95% confidence intervals.

RESULTS:

33 eligible trials were identified from ClinicalStudyDataRequest.com for which IPD were available (21 156 patients). Additionally, 103 trials for which IPD were not available were included in the meta-analyses for myocardial infarction (23 683 patients), and 103 trials for which IPD were not available contributed to the meta-analyses for cardiovascular related death (22 772 patients). Among 29 trials for which IPD were available and that were included in previous meta-analyses using GSK's summary level data, more myocardial infarction events were identified by using IPD instead of summary level data for 26 trials, and fewer cardiovascular related deaths for five trials. When analyses were limited to trials for which IPD were available, and a constant continuity correction of 0.5 and a random effects model were used to account for trials with zero events in only one arm, patients treated with rosiglitazone had a 33% increased risk of a composite event compared with controls (odds ratio 1.33, 95% confidence interval 1.09 to 1.61; rosiglitazone population: 274 events among 11 837 patients; control population: 219 events among 9319 patients). The odds ratios for myocardial infarction, heart failure, cardiovascular related death, and non-cardiovascular related death were 1.17 (0.92 to 1.51), 1.54 (1.14 to 2.09), 1.15 (0.55 to 2.41), and 1.18 (0.60 to 2.30), respectively. For analyses including trials for which IPD were not available, odds ratios for myocardial infarction and cardiovascular related death were attenuated (1.09, 0.88 to 1.35, and 1.12, 0.72 to 1.74, respectively). Results were broadly consistent when analyses were repeated using trials with zero events across both arms and either of the two continuity corrections was used.

CONCLUSIONS:

The results suggest that rosiglitazone is associated with an increased cardiovascular risk, especially for heart failure events. Although increased risk of myocardial infarction was observed across analyses, the strength of the evidence varied and effect estimates were attenuated when summary level data were used in addition to IPD. Because more myocardial infarctions and fewer cardiovascular related deaths were reported in the IPD than in the summary level data, sharing IPD might be necessary when performing meta-analyses focused on safety.

SYSTEMATIC REVIEW REGISTRATION:

OSF Home https://osf.io/4yvp2/.

PMID:
32024657
DOI:
10.1136/bmj.l7078
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Conflict of interest statement

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: support from the Laura and John Arnold Foundation for the submitted work. In the past 36 months, JDW received research support through the Meta Research Innovation Center at Stanford (METRICS) from the Laura and John Arnold Foundation and through the Yale-Male Clinic Center for Excellence in Regulatory Science and Innovation (CERSI; U01FD005938); ADZ received research support through the Yale-Mayo Clinic CERSI (U01FD005938); MB is currently, or within the last four years has been, a consultant to Eli Lilly, Forest Laboratories, Glaxo, and Lundbeck, all on matters unrelated to the content of this manuscript; HMK received research support through Yale from Johnson & Johnson to develop methods of clinical trial data sharing, from Medtronic and the Food and Drug Administration (FDA) to develop methods for postmarket surveillance of medical devices (U01FD004585), from the Centers of Medicare and Medicaid Services to develop and maintain performance measures that are used for public reporting, received payment from the Arnold & Porter Law Firm for work related to the Sanofi clopidogrel litigation and from the Ben C. Martin Law Firm for work related to the Cook IVC filter litigation, chairs a Cardiac Scientific Advisory Board for UnitedHealth, is a participant/participant representative of the IBM Watson Health Life Sciences Board, is a member of the Advisory Board for Element Science and the Physician Advisory Board for Aetna, and is the founder of Hugo, a personal health information platform; JSR received research support through Yale from Johnson & Johnson to develop methods of clinical trial data sharing, from Medtronic and the FDA to develop methods for postmarket surveillance of medical devices (U01FD004585), from the Centers of Medicare and Medicaid Services to develop and maintain performance measures that are used for public reporting, from the FDA to establish a CERSI at Yale University and the Mayo Clinic (U01FD005938), from the Blue Cross Blue Shield Association to better understand medical technology evaluation, and from the Agency for Healthcare Research and Quality (R01HS022882).

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