Generalizability of randomized controlled trials in heart failure with reduced ejection fraction

Yvonne Mei Fong Lim, Megan Molnar, Ilonca Vaartjes, Gianluigi Savarese, Marinus J.C. Eijkemans, Alicia Uijl, Eleni Vradi, Kiliana Suzart-Woischnik, Jasper J. Brugts, Hans Peter Brunner-La Rocca, Vanessa Blanc-Guillemaud, Fabrice Couvelard, Claire Baudier, Tomasz Dyszynski, Sandra Waechter, Lars H. Lund, Arno W. Hoes, Benoit Tyl, Folkert W. Asselbergs, Christoph GerlingerDiederick E. Grobbee, Maureen Cronin, Stefan Koudstaal

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Abstract

BACKGROUND: Heart failure (HF) trials have stringent inclusion and exclusion criteria, but limited data exist regarding generalizability of trials. We compared patient characteristics and outcomes between patients with HF and reduced ejection fraction (HFrEF) in trials and observational registries. METHODS AND RESULTS: Individual patient data for 16 922 patients from five randomized clinical trials and 46 914 patients from two HF registries were included. The registry patients were categorized into trial-eligible and non-eligible groups using the most commonly used inclusion and exclusion criteria. A total of 26 104 (56%) registry patients fulfilled the eligibility criteria. Unadjusted all-cause mortality rates at 1 year were lowest in the trial population (7%), followed by trial-eligible patients (12%) and trial-non-eligible registry patients (26%). After adjustment for age and sex, all-cause mortality rates were similar between trial participants and trial-eligible registry patients [standardized mortality ratio (SMR) 0.97; 95% confidence interval (CI) 0.92-1.03] but cardiovascular mortality was higher in trial participants (SMR 1.19; 1.12-1.27). After full case-mix adjustment, the SMR for cardiovascular mortality remained higher in the trials at 1.28 (1.20-1.37) compared to RCT-eligible registry patients. CONCLUSION: In contemporary HF registries, over half of HFrEF patients would have been eligible for trial enrolment. Crude clinical event rates were lower in the trials, but, after adjustment for case-mix, trial participants had similar rates of survival as registries. Despite this, they had about 30% higher cardiovascular mortality rates. Age and sex were the main drivers of differences in clinical outcomes between HF trials and observational HF registries.

Original languageEnglish
Pages (from-to)761-769
Number of pages9
JournalEuropean heart journal. Quality of care & clinical outcomes
Volume8
Issue number7
DOIs
Publication statusPublished - 1 Nov 2022

Bibliographical note

Funding Information:
Conflict of interest M.M. reports grants from Bayer AG, outside the submitted work. G.S. reports grant and personal fees from Vifor, grants and non-financial support from Boehringer Ingelheim, personal fees from Societa´ Prodotti Antibiotici, grants and personal fees from AstraZeneca, personal fees from Roche, personal fees from Servier, grants from Novartis, personal fees from GENESIS, personal fees from Cytokinetics, personal fees from Medtronic, grants from Boston Scientific, outside the submitted work. E.V. is

Funding Information:
This study is part of the BigData@Heart project and is funded by the Innovative Medicines Initiative 2 Joint Undertaking (116074). This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation programme and the European Federation of Pharmaceutical Industries and Associations.

Funding Information:
a fulltime employee of Bayer AG, Berlin, Germany. K.S.-W. reports personal fees from Bayer AG, during the conduct of the study; personal fees from Bayer AG, outside the submitted work. J.J.B reports grants from Abbot, outside the submitted work. H.-P.B.-LR reports grants and personal fees from Novartis, grants and personal fees from Vifor, grants and personal fees from Roche Diagnostics, personal fees from AstraZeneca, personal fees from Boehringer-Ingelheim outside the submitted work. V.B.-G. is a fulltime employee of Institut de Recherches Internationales Servier during the conduct of the study. F.C. is a fulltime employee of Institut de Recherches Internationales Servier. C.B. is a fulltime employee of Institut de Recherches Internationales Servier during the conduct of the study. T.D. is a full-time employee of Bayer AG, Berlin, Germany. S.W. is an employee of Vifor Pharma Int. L.H.L. reports personal fees from Merck, personal fees from Sanofi, grants and personal fees from Vifor-Fresenius, grants and personal fees from AstraZeneca, grants and personal fees from Relypsa, personal fees from Bayer, grants from Boston Scientific, personal fees from Pharmacosmos, personal fees from Abbott, grants and personal fees from Mundipharma, personal fees from Medscape, personal fees from Myokardia, grants and personal fees from Boehringer Ingelheim, grants and personal fees from Novartis, outside the submitted work. B.T. is a fulltime employee of Institut de Recherches Internationales Servier, during the conduct of the study. C.G. is a fulltime employee of Bayer AG, Berlin, Germany. M.C. reports personal fees from Vifor Pharma, during the conduct of the study; personal fees from Ava AG, outside the submitted work. The other authors have no conflicts of interest to disclose.

Funding Information:
This study is part of the BigData@Heart project and is funded by the Innovative Medicines Initiative 2 Joint Undertaking (116074). This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and the European Federation of Pharmaceutical Industries and Associations.

Publisher Copyright:
© The Author(s) 2021.

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