Randomized clinical trials are the gold standard for establishing the efficacy and safety of cardiovascular therapies. However, current pivotal trials are expensive, lengthy, and insufficiently diverse. Emerging artificial intelligence (AI) technologies can potentially automate and streamline clinical trial operations. This review describes opportunities to integrate AI throughout a trial's life cycle, including designing the trial, identifying eligible patients, obtaining informed consent, ascertaining physiological and clinical event outcomes, interpreting imaging, and analyzing or disseminating the results. Nevertheless, AI poses risks, including generating inaccurate results, amplifying biases against underrepresented groups, and violating patient privacy. Medical journals and regulators are developing new frameworks to evaluate AI research tools and the data they generate. Given the high-stakes role of randomized trials in medical decision making, AI must be integrated carefully and transparently to protect the validity of trial results., Competing Interests: Funding Support and Author Disclosures Dr Cunningham has received support from the KL2/Harvard Catalyst Medical Research Investigator Training program and the American Heart Association (23CDA1052151); and has received consulting fees from Roche Diagnosis, Edgewise Therapeutics, KCK, and Occlutech. Dr Abraham has served as a consultant to Boehringer Ingelheim, CVRx, Impulse Dynamics, Sensible Medical, Vectorious, V-Wave, and Zoll Respicardia. Dr Bhatt has received research grant support to his institution from the National Institutes of Health (NIH) National Heart, Lung, and Blood Institute (NHLBI) and National Institute on Aging, the American College of Cardiology Foundation, and the Centers for Disease Control and Prevention (CDC); and has received consulting fees from the Kinetix Group, Merck, Sanofi Pasteur, and Novo Nordisk. Dr Dunn has served as a scientific advisor to Veri. Dr Felker has received research grants from NIH, Bayer, Bristol Myers Squibb, Novartis, Daxor, Merck, Cytokinetics, and CSL-Behring; has acted as a consultant to Novartis, Bristol Myers Squibb, Cytokinetics, Innolife, Boehringer Ingelheim, Abbott, Sanofi, Regeneron, Myovant, Sequana, Windtree Therapeutics, and Whiteswell; and has served on clinical endpoint committees or data safety monitoring boards for Merck, Medtronic, EBR Systems, Rocket Pharma, V-Wave, and LivaNova. Dr Jain has received consulting fees from Bristol Myers Squibb, ARTIS Ventures, and Broadview Ventures outside of the submitted work. Dr Lindsell has received grants and contracts from the NIH, the U.S. Department of Defense, CDC, Biomeme, Novartis, bioMérieux, AstraZeneca, AbbVie, Entegrion, and Endpoint Health, all outside of the submitted work; has obtained patents for risk stratification in sepsis and septic shock issued to Cincinnati Children’s Hospital Medical Center; has served on data safety monitoring boards unrelated to the current work; has held stock options in Bioscape Digital unrelated to the current work; and has served as Editor-in-Chief of the Journal of Clinical and Translational Science. Mr Mace is an employee of Acorai AB; and has held stock interest in Abbott Laboratories. Dr Martyn has served as an advisor to or has received consulting fees from Fire1, Cleveland Clinic/American Well Joint Venture, Boehringer Ingelheim/Eli Lilly, NIRSense, Novo Nordisk, AstraZeneca, and Apricity Robotics; and has received grant support from Ionis Therapeutics, AstraZeneca, and the Heart Failure Society of America. Dr Shah is an employee of Meta, which had no role in this work or providing financial support. Dr Tison has received research grants from MyoKardia, a wholly owned subsidiary of Bristol Myers Squibb, and Janssen Pharmaceuticals; and is an advisor to Viz.ai and Prolaio. Dr Fakhouri is an employee of the Office of Medical Policy, Center for Drug Evaluation and Research, U.S. Food and Drug Administration; the views expressed in this article are those of the authors and do not necessarily represent the views or policies of the U.S. Food and Drug Administration. Dr Krumholz has received options from Element Science and Identifeye; has received payments from F-Prime for advisory roles; has co-founded and held equity in Hugo Health, Refactor Health, and ENSIGHT-AI; and has been associated with research contracts through Yale University from Janssen, Kenvue, and Pfizer. Dr O’Connor has received consulting fees from Merck, Abiomed, and Zealcare. Dr Solomon has received research grants from Alexion, Alnylam, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Boston Scientific, Cytokinetics, Edgewise, Eidos, Gossamer, GSK, Ionis, Lilly, MyoKardia, NIH NHLBI, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, Theracos, and US2.AI; and has consulted for Abbott, Action, Akros, Alexion, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GSK, Lilly, Merck, MyoKardia, Novartis, Roche, Theracos, Quantum Genomics, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, AnaCardio, Akros, and Valo. Drs Psotka and Fiuzat have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)