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Background: Neurohormonal modulation and afterload reduction are key for treatment of heart failure with reduced ejection fraction (HFrEF). In HFrEF patients with concomitant moderate aortic stenosis (AS), treatment with transcatheter aortic valve replacement (TAVR) may be complementary to guideline-directed medical therapy (GDMT)., Objectives: This study sought to determine whether TAVR for moderate AS provides clinical benefit in patients with HFrEF on top of GDMT., Methods: We performed an investigator-initiated, international, randomized controlled trial in patients with HFrEF on GDMT with moderate AS who were suitable for transfemoral TAVR with a balloon-expandable valve. Patients were randomized 1:1 to TAVR or clinical aortic stenosis surveillance (CASS) with aortic valve replacement upon progression to severe AS. The primary endpoint was the hierarchical occurrence of: 1) all-cause death; 2) disabling stroke; 3) disease-related hospitalizations and heart failure equivalents; and 4) change from baseline in the Kansas City Cardiomyopathy Questionnaire Overall Summary Score analyzed using the win ratio., Results: From January 2017 to December 2022, 178 patients were randomized to TAVR (n = 89) or AS surveillance (n = 89). The mean age was 77 years, 20.8% were female, and 55.6% were in NYHA functional class III or IV. The median follow-up duration was 23 months (Q1-Q3: 12-33 months). A total of 38 (43%) patients in the CASS group (of whom 35 had progressed to severe AS) underwent TAVR at a median of 12 months postrandomization. TAVR was associated with wins in 47.6% of pairs, compared with 36.6% in the CASS group, resulting in a win ratio of 1.31 (95% CI: 0.91-1.88; P = 0.14). At 1 year, TAVR resulted in a greater improvement in the Kansas City Cardiomyopathy Questionnaire Overall Summary Score compared with the CASS group (12.8 ± 21.9 points vs 3.2 ± 22.8 points; P = 0.018)., Conclusions: TAVR was not superior to AS surveillance for the primary hierarchical composite endpoint in patients with moderate AS and HFrEF on GDMT. Preemptive TAVR for moderate AS was safe and may provide clinically meaningful quality-of-life benefits., Competing Interests: Funding Support and Author Disclosures The TAVR UNLOAD trial was funded by an investigator-initiated grant from Edwards Lifesciences. The funder had no role in the study design, data collection or management, or the statistical analyses. The principal investigators had unrestricted access to the study data, wrote the manuscript, and vouched for the accuracy and completeness of the data and for the fidelity of the trial to the protocol. All the authors reviewed and approved the manuscript. Dr Van Mieghem has received grant support from Abbott Vascular, Boston Scientific, Edwards Lifesciences, and Medtronic; and has received advisory fees from Abbott, Boston Scientific, Pulse Cath BV, and Medtronic. Dr Elmariah has received research grants from Edwards Lifesciences and Medtronic; and has received consulting fees from Edwards Lifesciences. Dr Spitzer has held institutional contracts/grants for which he receives no direct compensation from Abbott, Biosensors Europe SA, Boston Scientific, Edwards Lifesciences, Medtronic, Mixin Medtech (Suzhou), Shanghai Microport Medical, NVT GmbH, Philips Healthcare, Pie Medical Imaging, Shanghai Shenqi Medical Technologies, and Siemens Healthcare GmbH. Dr Pibarot has received funding from Edwards Lifesciences, Pi-Cardia, and Cardiac Success for echocardiography core laboratory analyses in the field of transcatheter valve therapies and Medtronic for in vitro analyses, with no personal compensation. Dr Nazif has received consulting fees or honoraria from Medtronic, Boston Scientific, Teleflex, Encompass Technologies, and Opsens Medical; and has received institutional research grants from Edwards Lifesciences, Boston Scientific, Medtronic, and Abbott. Dr Bax has received speaker fees from Abbott and Edwards Lifesciences. Dr Hahn has received speaker fees from Abbott Structural, Baylis Medical, Edwards Lifesciences, Medtronic, Philips Healthcare, and Siemens Healthineers; has held institutional consulting contracts for which she receives no direct compensation from Abbott Structural, Edwards Lifesciences, Medtronic, and Novartis; and is Chief Scientific Officer for the Echocardiography Core Laboratory at the Cardiovascular Research Foundation for multiple industry-sponsored tricuspid valve trials, for which she receives no direct industry compensation. Dr Popma’s spouse is a Medtronic employee. Dr Ben-Yehuda has received consulting fees from Edwards Lifesciences, Medtronic, Cardiovalve, and Bioventrix. Dr Redfors has received consulting fees from Pfizer and Boehringer Ingelheim. Dr Kodali has received grant support, paid to his institution, from Medtronic, Boston Scientific, and Abbott Vascular; has received consulting fees from Abbott Vascular, Claret Medical, Admedus, and Meril Life Sciences; and holds equity options in BioTrace Medical, Dura Biotech, and Thubrikar Aortic Valve. Dr Hermanides has received lecture fees from Abbott Vascular, Amgen, and Novartis. Dr Cohen has received research grant support from Edwards Lifesciences, Abbott, Boston Scientific, Corvia Medical, Philips, Brain-Q, Saranas, Zoll Medical, CathWorks, and ANCORA; and has received consulting fees from Medtronic, Edwards Lifesciences, Abbott, Boston Scientific, Corvia Medical, Impulse Dynamics, AngioInsight, and HeartBeam. Dr Leon has received institutional clinical research grants from Abbott, Boston Scientific, Edwards, and Medtronic. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)