Clinical Implications of Negatively Adjudicated Heart Failure Events: Data From the VICTORIA Study

HomeCirculationVol. 147, No. 8Clinical Implications of Negatively Adjudicated Heart Failure Events: Data From the VICTORIA Study Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBClinical Implications of Negatively Adjudicated Heart Failure Events: Data From the VICTORIA Study G. Michael Felker, Rebecca North, Hillary Mulder, W. Schuyler Jones, Kevin J. Anstrom, Mahesh J. Patel, Javed Butler, Justin A. Ezekowitz, Carolyn Lam, Christopher M. O’Connor, Lothar Roessig, Adrian F. Hernandez, Paul W. Armstrong and for the VICTORIA Study Group G. Michael FelkerG. Michael Felker Correspondence to: G. Michael Felker, MD, MHS, Duke Clinical Research Institute, 300 West Morgan Street, Durham, NC 27701. Email E-mail Address: [email protected] https://orcid.org/0000-0002-5931-1239 Duke Clinical Research Institute (G.M.F., H.M., W.S.J., K.J.A., A.F.H.), Duke University School of Medicine, Durham, NC. Search for more papers by this author , Rebecca NorthRebecca North https://orcid.org/0000-0002-2877-3801 Duke Aging Center (R.N.), Duke University School of Medicine, Durham, NC. Search for more papers by this author , Hillary MulderHillary Mulder https://orcid.org/0000-0003-4838-582X Duke Clinical Research Institute (G.M.F., H.M., W.S.J., K.J.A., A.F.H.), Duke University School of Medicine, Durham, NC. Search for more papers by this author , W. Schuyler JonesW. Schuyler Jones https://orcid.org/0000-0002-7288-9596 Duke Clinical Research Institute (G.M.F., H.M., W.S.J., K.J.A., A.F.H.), Duke University School of Medicine, Durham, NC. Search for more papers by this author , Kevin J. AnstromKevin J. Anstrom Duke Clinical Research Institute (G.M.F., H.M., W.S.J., K.J.A., A.F.H.), Duke University School of Medicine, Durham, NC. Search for more papers by this author , Mahesh J. PatelMahesh J. Patel Merck & Co, Inc, Rahway, NJ (M.J.P.). Search for more papers by this author , Javed ButlerJaved Butler https://orcid.org/0000-0001-7683-4720 Baylor University Medical Center, Dallas, TX (J.B., P.W.A.). Search for more papers by this author , Justin A. EzekowitzJustin A. Ezekowitz https://orcid.org/0000-0002-2724-4086 Search for more papers by this author , Carolyn LamCarolyn Lam https://orcid.org/0000-0003-1903-0018 National Heart Centre Singapore and Duke–National University of Singapore (C.L.). Search for more papers by this author , Christopher M. O’ConnorChristopher M. O’Connor Inova Heart & Vascular Institute, Falls Church, VA (C.M.O.). Search for more papers by this author , Lothar RoessigLothar Roessig Bayer AG, Wuppertal, Germany (L.R.). Search for more papers by this author , Adrian F. HernandezAdrian F. Hernandez https://orcid.org/0000-0003-3387-9616 Duke Clinical Research Institute (G.M.F., H.M., W.S.J., K.J.A., A.F.H.), Duke University School of Medicine, Durham, NC. Search for more papers by this author , Paul W. ArmstrongPaul W. Armstrong https://orcid.org/0000-0002-0460-3445 Canadian VIGOUR Centre, University of Alberta, Edmonton, Canada (J.A.E., P.W.A.). Search for more papers by this author and for the VICTORIA Study Group Search for more papers by this author Originally published20 Feb 2023https://doi.org/10.1161/CIRCULATIONAHA.122.062055Circulation. 2023;147:694–696Centralized adjudication of potential end point events is standard practice in cardiovascular outcome trials designed for regulatory approval of therapeutics. Adjudication minimizes variability and improves the validity of clinical trials by providing standardized blinded ascertainment of potential end point events by clinician reviewers using accepted, prespecified criteria. Published definitions of heart failure (HF) events for event adjudication generally require an inpatient hospital stay that includes a calendar date change as well as specific documentation of at least 1 symptom, 2 physical examination signs, or objective evidence such as elevated natriuretic peptides or pulmonary congestion on chest radiographs and intensified treatment for worsening HF.1 Whereas this definition is highly specific for HF events, some potential HF events may be negatively adjudicated within a clinical trial because of lack of documentation of 1 or more of these elements. In some previous studies, this disparity has created differential findings between investigator-identified HF events and adjudicated HF events.2–4 In VICTORIA (Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction; URL: https://www.clinicaltrials.gov; Unique identifier: NCT02861534), we aimed to evaluate the clinical effect of negatively adjudicated HF events with a high clinical suspicion for HF. VICTORIA was approved by the relevant institutional review committees and all participants provided informed consent. Data will be made available as outlined in the VICTORIA data sharing charter (available at https://thecvc.ca/victoria/data-sharing).The primary results of VICTORIA demonstrated that vericiguat reduced the composite primary outcome of HF hospitalization or cardiovascular death in patients with chronic HF with reduced ejection fraction (ejection fraction <45%, New York Heart Association class II through IV) and a recent (<6 months) worsening HF event.5 VICTORIA used an independent clinical events committee (CEC) whose members were blinded to study treatment to adjudicate all potential end point events using standardized definitions.1 During the adjudication process, reviewers noted events that did not meet the formal adjudication criteria but clinical suspicion for an HF event remained high on the basis of the totality of information available to the reviewers. Although these events were negatively adjudicated for the primary analysis, they were prospectively identified as probable HF (PHF) events.In VICTORIA, there were 2948 total CEC-adjudicated HF events (1402 in vericiguat, 1546 in placebo) and an additional 236 PHF events (99 in vericiguat, 137 in placebo). Inclusion of PHF events resulted in similar findings for the primary end point of time to first HF event or cardiovascular death using Cox proportional hazards models (hazard ratio [HR], 0.90 [95% CI, 0.82 to 0.98]; P=0.02 for CEC HF events versus HR, 0.89 [95% CI, 0.82 to 0.98]; P=0.014 for CEC + PHF events). In evaluating the total HF events using the negative binomial method, the addition of PHF events to the CEC HF events resulted in similar estimates of treatment effect for total HF events (HR, 0.90 [95% CI, 0.83 to 0.1.02]; P=0.10 for CEC HF events versus HR, 0.88 [95% CI, 0.78 to 0.99]; P=0.035 for CEC + PHF events; Figure). The clinical significance of PHF events was generally similar to that for CEC-adjudicated HF events, including similar length of stay (median 7.5 days for PHF versus 8.5 days for CEC HF), in-hospital mortality (10.3% for PHF versus 7.2% for CEC HF), and rates of 30-day postdischarge cardiovascular death or HF rehospitalization (18.4% for PHF versus 24.0% for CEC HF).Download figureDownload PowerPointFigure. Treatment effect of vericiguat on total HF events adjudicated by the CEC and with the addition of PHF events. CEC indicates clinical events committee; HF, heart failure; and PHF, possible heart failure.Despite the value of centralized event adjudication in cardiovascular outcome trials, the lack of sensitivity of the currently used definition for HF events may exclude a meaningful number of probable HF events that could potentially further inform the efficacy of HF therapies. In the current analysis, these events appear to have similar clinical implications and show similar responsiveness to treatment as traditionally adjudicated HF events. The increase in statistical power seen with the inclusion of these events in VICTORIA may not necessarily be present in all cases and the potential value of PHF events should be explored in other studies. These data suggest that modification of currently used end point definitions may increase statistical power and improve efficiency in randomized clinical trials in HF.Article InformationSources of FundingVICTORIA was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, and Bayer.Nonstandard Abbreviations and AcronymsCECclinical events committeeHFheart failureHRhazard ratioPHFprobable heart failureVICTORIAVericiguat Global Study in Subjects with Heart Failure with Reduced Ejection FractionDisclosures Dr Felker reports receiving research grants from the National Heart, Lung, and Blood Institute, American Heart Association, Amgen, Bayer, BMS, Merck, and Cytokinetics; consulting fees from Novartis, Amgen, BMS, Cytokinetics, Medtronic, Cardionomic, Boehringer-Ingelheim, American Regent, Abbott, Astra-Zeneca, Reprieve, Myovant, Sequana, Windtree Therapeutics, and Whiteswell; and serving on clinical events committees or data and safety monitoring boards for Amgen, Merck, Medtronic, EBR Systems, V-Wave, LivaNova, Siemens, and Rocket Pharma. Dr North reports receiving funding from National Institutes of Health Training Grant T32HL079896. H. Mulder reports no disclosures. Dr Jones reports receiving research grants from PCORI and Boehringer Ingelheim. Dr Anstrom reports receiving research grants from Merck and National Institutes of Health. Dr Patel is an employee of Merck & Co. Dr Butler reports receiving consulting fees from Abbott, Adrenomed, Amgen, Array, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CVRx, G3 Pharmaceutical, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Roche, and Vifor. Dr Ezekowitz reports receiving research grants and consulting fees from Bayer, Merck, Servier, Amgen Sanofi, Novartis, Cytokinetics, American Regent, and Applied Therapeutics. Dr Lam reports receiving 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; has patents PCT/SG2016/050217 and 16/216929 pending; and is cofounder and nonexecutive director of eKo.ai. Dr O’Connor reports receiving research funding from Merck and consulting fees from Bayer, Dey LP, and BMS Foundation. Dr Roessig is an employee of Bayer AG. Dr Hernandez reports receiving research grants from Merck, AstraZeneca, Novartis, and Verily and honoraria from Merck, Bayer, Amgen, AstraZeneca, and Novartis. Dr Armstrong reports receiving research grants from Merck, Bayer, Sanofi-Aventis Recherche & Développement, Boehringer Ingelheim, and CSL Limited and consulting fees from Merck, Bayer, AstraZeneca, and Novartis.FootnotesThis manuscript was sent to Harvey White, Guest Editor, for review by expert referees, editorial decision, and final disposition.For Sources of Funding and Disclosures, see page 695.Circulation is available at www.ahajournals.org/journal/circRegistration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02861534.Correspondence to: G. Michael Felker, MD, MHS, Duke Clinical Research Institute, 300 West Morgan Street, Durham, NC 27701. Email michael.felker@duke.eduReferences1. Hicks KA, Mahaffey KW, Mehran R, Nissen SE, Wiviott SD, Dunn B, Solomon SD, Marler JR, Teerlink JR, Farb A, et al. Standardized data collection for cardiovascular trials I: 2017 cardiovascular and stroke endpoint definitions for clinical trials.J Am Coll Cardiol. 2018; 71:1021–1034. doi: 10.1016/j.jacc.2017.12.048CrossrefMedlineGoogle Scholar2. Solomon SD, McMurray JJV, Anand IS, Ge J, Lam CSP, Maggioni AP, Martinez F, Packer M, Pfeffer MA, Pieske B, et al. Angiotensin-neprilysin inhibition in heart failure with preserved ejection fraction.N Engl J Med. 2019; 381:1609–1620. doi: 10.1056/NEJMoa1908655CrossrefMedlineGoogle Scholar3. Pfeffer MA, Claggett B, Lewis EF, Granger CB, Køber L, Maggioni AP, Mann DL, McMurray JJV, Rouleau J-L, Solomon SD, et al. Impact of sacubitril/valsartan versus ramipril on total heart failure events in the PARADISE-MI trial.Circulation. 2022; 145:87–89. doi: 10.1161/CIRCULATIONAHA.121.057429LinkGoogle Scholar4. Felker GM, Butler J, Januzzi JL, Desai AS, McMurray JJV, Solomon SD. Probabilistic readjudication of heart failure hospitalization events in the PARAGON-HF study.Circulation. 2021; 143:2316–2318. doi: 10.1161/CIRCULATIONAHA.121.054496LinkGoogle Scholar5. Armstrong PW, Pieske B, Anstrom KJ, Ezekowitz J, Hernandez AF, Butler J, Lam CSP, Ponikowski P, Voors AA, Jia G, et al. Vericiguat in patients with heart failure and reduced ejection fraction.N Engl J Med. 2020; 382:1883–1893. doi: 10.1056/NEJMoa1915928CrossrefMedlineGoogle Scholar eLetters(0)eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. 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