Comparison of Investigator-Reported and Centrally Adjudicated Heart Failure Outcomes in the EMPEROR-Preserved Trial.

Background: There is limited published information on outcome adjudication in heart failure (HF) trials, particularly in heart failure with preserved ejection fraction (HFpEF).
Objectives: The study sought to compare investigator reports with clinical events committee (CEC) adjudication and assess the impact of the SCTI (Standardized Data Collection for Cardiovascular Trials) criteria.
Methods: In the EMPEROR-Preserved (EMPagliflozin outcome tRial in Patients with chronic heart Failure With Preserved Ejection Fraction) trial, we compared investigator reports with CEC for concordance, treatment effect on primary composite outcome events and components (first event primary heart failure hospitalization [HHF] or cardiovascular [CV] mortality), prognosis after first HHF, total HHF, and trial duration with and without SCTI criteria.
Results: The CEC confirmed 67.4% investigator-reported events for the primary outcome (CV mortality 82.7%, HHF 66.3%). The HR for treatment effect did not differ between adjudication methods for the primary outcome: investigator reports (HR: 0.77; 95% CI: 0.69-0.87), CEC (HR: 0.79; 95% CI: 0.69-0.90), its components, or total HHFs. The prognosis after the first HHF for all-cause mortality and CV mortality also did not differ between investigator reports and the CEC, nor did investigator reports and HHFs with a different CEC cause. SCTI criteria were present in 92% of CEC HHFs with a similar treatment effect to non-SCTI criteria. The investigator-reported primary events reached the protocol target number 6 months earlier than the CEC (7 months with full SCTI criteria).
Conclusions: Investigator adjudication is an alternative to a CEC with similar accuracy and faster event accumulation in HFpEF. The use of granular (SCTI) criteria did not improve trial performance. Our data suggest that a broader definition of an HHF event could be particularly beneficial in HFpEF clinical trials. (EMPagliflozin outcome tRial in Patients with chronic heart Failure With Preserved Ejection Fraction; NCT03057951).
Competing Interests: Funding Support and Author Disclosures The EMPEROR-Preserved trial was funded by the Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance. Dr Carson has received consulting fees from Boehringer Ingelheim and IQVIA related to work on a clinical events committee during the conduct of the study. Dr Teerlink has received research support from and/or served as a consultant for Amgen, AstraZeneca, Bayer AG, Boehringer Ingelheim, Bristol Myers Squibb, Cytokinetics, Medtronic, Merck, Novartis, Servier, and Windtree Therapeutics. Dr Komajda has received consulting fees from Boehringer Ingelheim related to work on a clinical events committee during the conduct of the study; and personal fees from Novartis, Servier, Amgen, Sanofi, Bayer, AstraZeneca, Lilly, and Torrent. Dr Anand has received consulting fees from Boehringer Ingelheim related to work on a clinical events committee during the conduct of the study; and personal fees from Novartis, Servier, Amgen, Sanofi, Bayer, AstraZeneca, Lilly, and Torrent. Dr Packer has received consulting fees from AbbVie, Actavis, Amgen, Amarin, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Casana, CSL Behring, Cytokinetics, Johnson and Johnson, Eli Lilly and Company, Moderna, Novartis, ParatusRx, Pfizer, Relypsa, Salamandra, Synthetic Biologics, and Theravance; and served on the Trial Executive Committee for the Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance (trial sponsor). Dr Butler has received consulting fees from Boehringer Ingelheim, Cardior, CVRx, Foundry, G3 Pharma, Imbria, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Relypsa, Roche, Sanofi, Sequana Medical, VWave, and Vifor; and served on the Trial Executive Committee for the Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance (trial sponsor). Dr Doehner has received consulting fees from Boehringer Ingelheim related to work on the clinical events committee during the conduct of the study; personal fees from Aimediq, Bayer, Boehringer Ingelheim, Medtronic, Pfizer, Sanofi, Sphingotec, and Vifor Pharma; and research support from the European Union (Horizon2020), the German Ministry of Education and Research, the German Center for Cardiovascular Research, Vifor Pharma, and ZS Pharma. Dr Ferreira has received consulting fees from Boehringer Ingelheim; and served on the Trial Executive Committee for the Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance (trial sponsor). Dr Filippatos has received lecture fees from and/or committee member contributions from clinical trials sponsored by Bayer, Medtronic, Vifor, Servier, Novartis, and Amgen; research support from the European Union; and served on the Trial Executive Committee for the Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance (trial sponsor). Dr Haass has received consulting fees from Boehringer Ingelheim related to work on the clinical events committee during the conduct of the study. Dr Miller has received consulting fees from Abbott, Boehringer Ingelheim, Respicardia, CVRx, Pfizer, and AbbVie. Dr Pehrson has received consulting fees and/or lecture fees from Boehringer Ingelheim, GlaxoSmithKline, Celgene, Bristol Myers Squibb, Bayer, and Johnson and Johnson. Dr Pocock has received consulting fees and payment or honoraria for lectures, presentations, Speakers Bureau service, manuscript writing, or educational events from Boehringer Ingelheim; and served on the Trial Executive Committee for the Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance (trial sponsor). Drs Iwata, Brueckmann, and Gasior are employees of Boehringer Ingelheim. Dr Zannad has received steering committee or advisory board fees from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cardior, CVRx, Janssen, Livanova, Merck, Mundipharma, Novartis, Novo Nordisk, and Vifor Fresenius; and served on the Trial Executive Committee for the Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance (trial sponsor). Dr Anker has received grants and personal fees from Vifor International and Abbott Vascular; personal fees from AstraZeneca, Bayer, Brahms, Boehringer Ingelheim, Cardiac Dimensions, Novartis, Occlutech, Servier, and Vifor International; and served on the Trial Executive Committee for the Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance (trial sponsor).
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