Assessing Benefit in Heart Failure Patients with Reduced Ejection Fraction: Analysis of the VICTORIA Trial Using Novel Prognostic Risk Stratification

Background Randomized controlled clinical trials remain the gold standard for determining efficacy of new heart failure (HF) therapies; however, failure to account for heterogeneity in risk of the primary endpoint(s) may dilute treatment efficacy. The novel 5-step stratified testing and amalgamation routine (5-STAR) methodology addresses these limitations using risk stratification based on treatment-independent associations between baseline covariates and clinical outcomes. We applied the 5-STAR methodology to the original VICTORIA database enriched by relevant ancillary information.

Within the 5-STAR analysis, elastic net Cox regression and a conditional inference tree tool blinded to treatment assignment were used to partition the trial population into risk strata for trial endpoints based on baseline covariates determined to be jointly strongly associated with the risk of the outcome. Core laboratory mechanistic biomarkers and baseline electrocardiographic variables were added to the VICTORIA dataset. After unblinding, treatments were compared for the primary composite endpoint of cardiovascular death or HF hospitalization within each risk stratum: stratum-level results were then averaged for overall inference.

The 5-STAR analysis showed a greater vericiguat treatment effect on the primary composite endpoint than the original prespecified VICTORIA analysis (5-STAR-averaged HR, 95% CI: 0.85, 0.77–0.94 vs 0.90, 0.82–0.98), and on its components (5-STAR-averaged HR, 95% CI: cardiovascular death: 0.79, 0.67–0.93 vs 0.93, 0.81–1.06; HF hospitalization: 0.89, 0.79–1.00 vs 0.90, 0.81–1.00). Five biomarkers (GDF-15, NT-proBNP, albumin, blood urea nitrogen, urate) determined the risk strata across the 3 endpoints.

By developing treatment-independent risk stratification, the 5-STAR methodology attenuates dilution of treatment effects inherent in conventional prognostic risk heterogeneity. This retrospective analysis of VICTORIA revealed greater efficacy of vericiguat on the primary endpoint and its components. GDF-15 was consistently the strongest prognostic risk factor across the composite endpoint and its components of cardiovascular death and HF hospitalization. Clinical Trial Registration ClinicalTrials.gov (NCT02861534). Competing Interest Statement O Connor: Research funding from Merck; consulting fees from Bayer, Dey LP, and Bristol Myers Squibb Foundation. Rathwell: Nothing to report. Mehrotra: Employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. Corda: Employee of Bayer AG. McMullan: Employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. Lam: Research grants from Bayer, National Medical Research Council of Singapore, Boston Scientific, Roche Diagnostic, Medtronic, Vifor Pharma, and AstraZeneca; consulting fees from Merck, Bayer, Boston Scientific, Roche Diagnostic, Vifor Pharma, AstraZeneca, Novartis, Amgen, Janssen Research & Development LLC, Menarini, Boehringer Ingelheim, Abbott Diagnostics, Corvia, Stealth BioTherapeutics, Novo Nordisk, JanaCare, Biofourmis, Darma, Applied Therapeutics, MyoKardia, Cytokinetics, WebMD Global LLC, Radcliffe Group Ltd, and Corpus. Patent PCT/SG2016/050217 pending, and a patent 16/216929 pending and co-founder & non-executive director of eKo.ai. Ezekowitz: Research grants from Bayer, Merck, Servier, Amgen Sanofi, Novartis, Cytokinetics, American Regent, and Applied Therapeutics; consulting fees from Bayer, Merck, Servier, Amgen, Sanofi, Novartis, Cytokinetics, American Regent, and Applied Therapeutics. Piekse: Personal fees from Merck, Bayer Healthcare, Novartis, AstraZeneca, BMS, and Edwards. Minor shares in ICTS (Imaging Clinical Trial Services). Hernandez: Research grants and personal fees from Merck, AstraZeneca, Novartis, and Boehringer Ingelheim; grants from American Regent; personal fees from Bayer, Amgen and Boston Scientific. Anstrom: Research grants from Merck and NIH. Mentz: Research support and honoraria from Abbott, American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim/Eli Lilly, Boston Scientific, Cytokinetics, Fast BioMedical, Gilead, Innolife, Medtronic, Merck, Novartis, Relypsa, Respicardia, Roche, Sanofi, Vifor, Windtree Therapeutics, and Zoll. deFilippi: Research funding to Inova from Abbott Diagnostics, Roche Diagnostics, Siemens Healthineers and Ortho Diagnostics, and consults for FujiRebio, Roche Diagnostics, Siemens Healthineers, and Ortho Diagnostics. Voors: Research grants from Boehringer Ingelheim and Roche Diagnostics; consulting fees from Merck, Bayer, Amgen, AstraZeneca, Boehringer Ingelheim, Cytokinetics, Myokardia, Novartis, Servier, and Roche Diagnostics. Ponikowski: Research grant, consulting fees, speakers bureau for Bayer, MSD, Servier, Novartis, Vifor Pharma Ltd., BMS, Boehringer Ingelheim, Respicardia, AstraZeneca, Cibiem, RenalGuardSolution, Berlin Chemie. Butler: Consulting fees for Abbott, American Regent, Amgen, Applied Therapeutic, AskBio, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardiac Dimension, Cardiocell, Cardior, CSL Bearing, CVRx, Cytokinetics, Daxor, Edwards, Element Science, Faraday, Foundry, G3P, Innolife, Impulse Dynamics, Imbria, Inventiva, Ionis, Lexicon, Lilly, LivaNova, Janssen, Medtronics, Merck, Occlutech, Owkin, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, Pharmain, Pfizer, Prolaio, Regeneron, Renibus, Roche, Salamandra, Sanofi, SC Pharma, Secretome, Sequana, SQ Innovation, Tenex, Tricog, Ultromics, Vifor, and Zoll. Westerhout: Consulting fees from Bayer Canada. Armstrong: Consulting fees from Merck, Bayer, Boehringer Ingelheim and Novo Nordisk; research grants from Merck, Bayer, Boehringer Ingelheim/Eli Lilly and CSL Limited. Clinical Protocols https://clinicaltrials.gov/study/NCT02861534 Funding Statement The VICTORIA trial was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA and Bayer AG. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study is a retrospective analysis from the VICTORIA trial published in the N Eng J Med. [DOI: 10.1056/NEJMoa1915928].(2) The trial protocol was approved by regulatory agencies in the participating countries and institutional review boards or ethics committees at the participating sites. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability Data Availability Statement Requests to access participant-level data from qualified researchers trained in human subject confidentiality protocols and in accordance with the VICTORIA data-sharing charter may be submitted at https://thecvc.ca/victoria/data-sharing/. Non-standard Abbreviations and Acronyms - BUN - blood urea nitrogen - CI - confidence interval - GDF-15 - growth differentiation factor-15 - HF - heart failure - HFrEF - heart failure with reduced ejection fraction - HR - hazard ratio - ICD - implantable cardioverter defibrillator - NYHA class - New York Heart Association Heart Failure Classification System - NT-proBNP - N-terminal pro-B-type natriuretic peptide - 5-STAR - 5-step stratified testing and amalgamation routine