Development and validation of imaging-free myocardial fibrosis prediction models, association with outcomes, and sample size estimation for phase 3 trials

Background and Aims Phase 3 trials testing whether pharmacologic interventions targeting myocardial fibrosis (MF) improve outcomes require MF measurement that does not rely on tomographic imaging with intravenous contrast. Methods We developed and externally validated extracellular volume (ECV) prediction models incorporating readily available data (comorbidity and natriuretic peptide variables), excluding tomographic imaging variables. Survival analysis tested associations between predicted ECV and incident outcomes (death or hospitalization for heart failure). We created various sample size estimates for a hypothetical therapeutic clinical trial testing an anti-fibrotic therapy using: a) predicted ECV, b) measured ECV, or c) no ECV. Results Multivariable models predicting ECV had reasonable discrimination (optimism corrected C-statistic for predicted ECV ≥27% 0.78 (95%CI 90.75-0.80) in the derivation cohort (n=1663) and 0.74 (95%CI 0.71-0.76) in the validation cohort (n=1578)) and reasonable calibration. Predicted ECV associated with adverse outcomes in Cox regression models: ECV ≥27% (binary variable) HR 2.21 (1.84–2.66). For a hypothetical clinical trial with an inclusion criterion of ECV ≥27%, use of predicted ECV (with probability threshold of 0.69 and 80% specificity) compared to measured ECV would obviate the need to perform 3940 CMR scans, at the cost of an additional 3052 participants screened and 705 participants enrolled. Conclusions Predicted ECV (derived without tomographic imaging) associates with outcomes and efficiently identifies vulnerable patients who might benefit from treatment. Predicted ECV may foster the design of phase 3 trials targeting MF with higher numbers of screened and enrolled participants, but with simplified eligibility criteria, avoiding the complexity of tomographic imaging. Key Question Phase 3 trials targeting myocardial fibrosis (MF) to improve outcomes require MF measurement that does not rely on tomographic imaging with intravenous contrast. So, we developed and validated extracellular volume (ECV) prediction models incorporating clinical data, excluding tomographic imaging. Key Finding Predicted ECV had reasonable discrimination and associated with outcomes. For a hypothetical trial with an ECV ≥27% inclusion criterion, using predicted ECV versus measured ECV would avoid 3940 cardiovascular magnetic resonance (CMR) scans, but require an additional 3052 participants screened and 705 enrolled. Take-home Message Predicted ECV (derived without imaging) associates with outcomes and efficiently identifies vulnerable patients. Predicted ECV may foster phase 3 trials targeting MF with higher numbers of screened and enrolled participants, but simplified eligibility criteria, avoiding the complexity of tomographic imaging. ![Figure][1] For a hypothetical trial requiring 1812 participants with measured ECV ≥27%, 3940 patients would need to undergo screening with CMR. If predicted ECV is used, an additional 3052 patients would need to be screened and an additional 705 patients enrolled, but no patients would require CMR. If no screening is used, an additional 2128 patients would need to be enrolled. ### Competing Interest Statement TM serves as the clinical lead for the National Heart Failure Audit and has received speaker fees from Novartis, AstraZeneca, and Vifor. JB consults for: Abbott, Actimed, American Regent, Amgen, Applied Therapeutic, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardiac Dimension, Cardior, CVRx, Cytokinetics, Daxor Edwards, Element Science, Innolife, Impulse Dynamics, Imbria, Inventiva, Lexicon, Lilly, LivaNova, Janssen, Medtronics, Merck, Occlutech, Owkin, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, Pharmain, Prolaio, Roche, Secretome, Sequana, SQ Innovation, Tenex, and Vifor. JLC has received consulting fees from 4C Medical, Abbott Structural, Alleviant, Anteris, Boston Scientific, Edwards Lifesciences, JenaValve, JC Medical, Medtronic, Novo Nordisk; has received research grant support from Abbott Structural, Allina Health Foundation, JenaValve, NIH/NHLBI. M.C.P has received research funding from Boehringer Ingelheim, Roche, SQ Innovations, Astra Zeneca, Novartis, Novo Nordisk, Medtronic, Boston Scientific, Pharmacosmos, and has participated on trial committees/consulted for Akero, Applied Therapeutics, AnaCardio, Biosensors, Boehringer Ingelheim, Novartis, Astra Zeneca, Novo Nordisk, Abbvie, Bayer, Horizon Therapeutics, Takeda, Cardiorentis, Pharmacosmos, Siemens, Eli Lilly, Vifor, New Amsterdam, Moderna, Teikoku, LIB Therapeutics. CAM has participated on advisory boards/consulted for AstraZeneca, Boehringer Ingelheim and Lilly Alliance, Novartis and PureTech Health, serves as an advisor for HAYA Therapeutics, has received speaker fees from AstraZeneca, Boehringer Ingelheim and Novo Nordisk, conference attendance support from AstraZeneca, and research support from Amicus Therapeutics, AstraZeneca, Guerbet Laboratories Limited, Roche and Univar Solutions B.V. EBS serves on the Scientific Advisory Board of Haya Therapeutics and sits on the BRITISH Trial Steering Committee. The remaining authors declare no competing interests. ### Funding Statement CAM, Advanced Fellowship, NIHR301338 is funded by the National Institute for Health and Care Research (NIHR). The views expressed in this publication are those of the authors and not necessarily those of the NIHR, NHS or the UK Department of Health and Social Care. CAM acknowledges support from the University of Manchester British Heart Foundation Accelerator Award (AA/18/4/34221) and the NIHR Manchester Biomedical Research Centre (NIHR203308). ### 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: Ethics committee/IRB of National Health Service (NHS) Greater Manchester West Research Ethics Committee gave ethical approval for this work. (reference 14/NW/1165) 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 All data produced in the present study are available upon reasonable request to the authors [1]: pending:yes