Late-Breaking Science Abstracts and Featured Science Abstracts From the American Heart Association’s Scientific Sessions 2023 and Late-Breaking Abstracts in Resuscitation Science From the Resuscitation Science Symposium 2023

Abraham M Lincoff¹, Kirstine Brown-Frandsen², Helen M Colhoun³, John Deanfield⁴, Scott S Emerson⁵, Sille Esbjerg⁶, Søren Hardt-Lindberg⁷, G. Kees Hovingh⁸, Steven E Kahn⁹, Robert F Kushner¹⁰, Ildiko Lingvay¹¹, Tugce Kalayci Oral⁸, Marie M Michelsen¹², Jorge Plutzky¹³, Christoffer W Tornoee¹⁴, Donna H Ryan¹⁵, The SELECT Trial Investigators; ¹Dept of Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH, ²Business Development, Novo Nordisk A/S, Søborg, Denmark, ³Institute of Genetics and Cancer, Univ of Edinburgh, Edinburgh, United Kingdom, ⁴Dept of Clinical Science, Univ College London, London, United Kingdom, ⁵Dept of Biostatistics, Univ of Washington, Seattle, WA, ⁶Dept of Biostatistics, Novo Nordisk A/S, Søborg, Denmark, ⁷Project Management - 5 CKAD, Novo Nordisk A/S, Søborg, Denmark, ⁸Global Medical Affairs, Novo Nordisk A/S, Søborg, Denmark, ⁹Dept of Medicine, VA Puget Sound Health Care System and Univ of Washington, Seattle, WA, ¹⁰Dept of Medicine and Medical Education, Northwestern Univ, Chicago, IL, ¹¹Dept of Internal Medicine/Endocrinology, UT Southwestern Medical Center at Dallas, Dallas, TX, ¹²Med & Science, Novo Nordisk A/S, Søborg, Denmark, ¹³Cardiovascular Medicine Division, Brigham and Womens Hospital, Harvard Medical School, Boston, MA, ¹⁴Obesity, Liver Diseases and Devices, Novo Nordisk A/S, Søborg, Denmark, ¹⁵Clinical Research, Pennington Biomedical Research Center, Baton Rouge, LA

Background: Semaglutide, a long-acting agonist of the glucagon-like peptide-1 receptor, is approved for use in people with type 2 diabetes and overweight or obesity. It has been shown to reduce the risk of adverse cardiac events in those with type 2 diabetes. Whether semaglutide can reduce cardiovascular risk associated with overweight and obesity in the absence of diabetes is unknown. Methods: In a multicenter, randomized, double-blind, placebo-controlled event-driven superiority trial, we enrolled 17,604 patients 45 years of age or older with pre-existing cardiovascular disease and a body mass index of 27 kg/m2 or greater, but who did not have diabetes. Patients were randomly assigned to receive once weekly subcutaneous semaglutide 2.4 mg or placebo. The primary cardiovascular efficacy endpoint was any component of the composite of death from cardiovascular causes, non-fatal myocardial infarction, or non-fatal stroke in a time-to-first-event analysis. Confirmatory secondary endpoints, assessed in a time-to-first-event analyses and tested in hierarchical order, were death from cardiovascular causes, a heart failure composite of death from cardiovascular causes or hospitalization or urgent medical visit for heart failure, and death from any cause. Supportive secondary endpoints, also assessed in a time-to-first-event analyses but without control for multiplicity, included expanded cardiovascular composite endpoints, individual components of cardiovascular composite endpoints, a composite nephropathy endpoint, progression to diabetes, or progression to prediabetes as diagnosed by glycated hemoglobin levels. Changes from randomization to week 104 in body weight, glycated hemoglobin concentrations, and other cardiovascular risk factors were measured. Results: The trial met its primary objective, with a 20% reduction in the primary endpoint by semaglutide compared with placebo. Details of primary and secondary efficacy endpoints and safety findings will be presented. Conclusions: In patients with pre-existing cardiovascular disease and overweight or obesity, but without diabetes, weekly subcutaneous semaglutide 2.4 mg was superior to placebo in reducing the incidence of major adverse cardiovascular events.

Author Disclosures: For author disclosure information, please visit the AHA Scientific Sessions 2023 Online Program Planner and search for the abstract title.

Stefan K James¹, David Erlinge², Robert F Storey³, Darren K McGuire⁴, Mark de Belder⁵, Kasper Andersen⁶, David Austin⁷, Gabriel Arefalk⁸, David Carrick⁹, Robin Hofmann¹⁰, Stephen P Hoole¹¹, Daniel A Jones¹², Kelvin Lee¹³, Hans Tygesen¹⁴, Peter A Johansson¹⁵, Anna Maria Langkilde¹⁶, Wilhelm Ridderstråle¹⁶, Ehsan Parvaresh Rizi¹⁶, John Deanfield¹⁷, Jonas Oldgren¹; ¹Uppsala Clinical Rsch Cntr, Uppsala Univ, Uppsala, Sweden, ²Dept of Cardiology, Lund Univ, Lund, Sweden, ³Cardiovascular Rsch Unit, Univ of Sheffield, Sheffield, United Kingdom, ⁴Dept of Internal Medicine, UT Southwestern, Dallas, TX, ⁵NICOR, NHS Arden & GEM Commissioning Support Unit, London, United Kingdom, ⁶Dept of Med Sciences, Uppsala Univ, Uppsala, Sweden, ⁷Academic Cardiovascular Unit, The James Cook Univ Hosp, Middlesbrough, United Kingdom, ⁸Thoracic Cntr, Blekinge Hosp, Karlskrona, Sweden, ⁹Institute of Cardiovascular and Med Sciences, Univ of Glasgow, Glasgow, United Kingdom, ¹⁰Dept of Clinical Science and Education, Karolinska Institutet, Stockholm, Sweden, ¹¹Dept of Interventional Cardiology, Royal Papworth Hosp, Cambridge, United Kingdom, ¹²William Harvey Rsch Institute, Queen Mary Univ of London, London, United Kingdom, ¹³Lincolnshire Heart Cntr, United Lincolnshire Hosps NHS Trust, Lincoln, United Kingdom, ¹⁴Dept of Medicine, South Älvsborg Hosp, Borås, Sweden, ¹⁵BioPharmaceuticals Rsch and Development, AstraZeneca, Molndal, Sweden, ¹⁶BioPharmaceuticals Rsch and Development, AstraZeneca, Mölndal, Sweden, ¹⁷Institute of Cardiovascular Sciences, Univ College London, London, United Kingdom

Background: Therapies that could further prevent the development of heart failure (HF) and other cardiovascular (CV) and metabolic events in patients with recent myocardial infarction (MI) represent a large and unmet medical need. Methods: DAPA-MI is a multicenter, parallel-group, registry-based, randomized, double-blind, placebo-controlled phase 3 trial in patients without known diabetes or established chronic HF, presenting with MI and impaired left ventricular systolic function or Q-waves. The primary objective of the trial was to determine, using the win-ratio analytic method, if dapagliflozin 10 mg, given once daily in addition to standard of care therapy, is superior to placebo. The primary outcome was the hierarchical composite outcome of death, hospitalization for HF (HHF), non-fatal MI, atrial fibrillation/flutter, new onset of type 2 diabetes mellitus, HF symptoms as measured by New York Heart Association (NYHA) Functional Classification at last visit, and body weight decrease ≥5% at last visit. Secondary outcomes included time to the first occurrence of HHF or CV death. A registry-based randomized controlled trial (R-RCT) framework allowed for recruitment, randomization, blinding, and pragmatic data collection of baseline demographics, medications, and clinical outcomes using existing national clinical registries (in Sweden and the United Kingdom) integrated with the trial database. Results: The trial enrolled 4017 patients in Sweden and the United Kingdom from December 2020 to March 2023 with a mean age of 63 years. At baseline, approximately 65% had ST-elevation MI, 8% prior MI, and 2% prior stroke. Patients received guideline-directed therapies comprising > 80% use of ACE inhibitors, beta-blockers, statins, and dual antiplatelet therapy. Left ventricular ejection fraction was below 50% in the majority of participants (66%). The outcome results will be available after the deadline of the abstract submission. Conclusions: The DAPA-MI trial was designed to evaluate the effect of dapagliflozin on the incidence of death, HHF, and cardiometabolic outcomes when added to standard of care in patients without diabetes or chronic HF with recent MI and impaired left ventricular systolic function during the index MI hospitalization.

Author Disclosures: For author disclosure information, please visit the AHA Scientific Sessions 2023 Online Program Planner and search for the abstract title.

Jeffrey L Carson¹, Maria M Brooks², Paul C Hebert³, Shaun G Goodman⁴, Marnie Bertolet⁵, P.Gabriel STEG⁶, Bernard R Chaitman⁷, Tabassome Simon⁸, Simone A Glynn⁹, Renato D Lopes¹⁰, Andrew M Goldsweig¹¹, Andrew P Defilippis¹², Jinnette D Abbott¹³, Howard A Cooper¹⁴, William J Kostis¹⁵, Sunil Rao¹⁶, Dean Fergusson¹⁷, Harvey D White¹⁸, Caroline Alsweiler¹⁹, Darrell Triulzi²⁰, Sheryl F Kelsey²¹, Helaine Noveck¹, John H Alexander¹⁰, MINT Investigators; ¹Medicine, Rutgers Robert Wood Johnson Med, New Brunswick, NJ, ²Epidemiology, Biostatistics and Clinical and Translational Science, Univ of Pittsburgh Sch of Public Health, Pittsburgh, PA, ³Medicine, Univ of Montreal, Montreal, Canada, ⁴Medicine, St. Michaels Hosp, Toronto, Canada, ⁵Depts of Epidemiology, Biostatistics, and The Clinical and Translational Science Institute., Univ of Pittsburgh, Pittsburgh, PA, ⁶Département de Cardiologies, Université Paris-Cité, Paris, France, ⁷Medicine, St. Louis Univ, Saint Louis, MO, ⁸Medicine, APHP.Sorbonne Univ, Paris, France, ⁹Div of Blood Diseases and Resources, National Heart Lung Blood Insitute, National Institutes of Health, Bethesda, MD, ¹⁰Medicine, Duke Clinical Rsch Institute, Duke Univ, Durham, NC, ¹¹Medicine, Baystate Med Cntr, Springfield, MA, ¹²Vanderbilt Univ Med Cente, Nashville, TN, ¹³Medicine, Lifespan Cardiovascular Institute, Providence, RI, ¹⁴Medicine, Westchester Med Cntr, Valhalla, NY, ¹⁵Medicine, Rutgers Robert Wood Johnson Med Sch, New Brunswick, NJ, ¹⁶Medicine, NYU Langone Health, New York, NY, ¹⁷Medicine, Ottawa Hosp Rsch Insititute, Ottawa, Canada, ¹⁸Medicine, Te Toka Tumai, Auckland, New Zealand, ¹⁹Medicine, Green Lane Coordinating Cntr, Auckland, New Zealand, ²⁰Pathology, Univ Pittsburgh Sch of Medicine, Pittsburgh, PA, ²¹Epidemiology, Univ of Pittsburgh Sch of Public Health, Pittsburgh, PA

Background: Anemia is common in patients with acute myocardial infarction (MI) and the indications for red blood cell (RBC) transfusion are controversial. Clinical trials suggest that a restrictive transfusion strategy targeting a hemoglobin concentration (Hb) above 7 or 8 g/dL is safe in most clinical settings. However, in patients with MI, the ischemic myocardium is uniquely vulnerable and might benefit from a higher Hb. Methods: MINT is a randomized controlled trial that enrolled patients with ST-segment elevation or non-ST-segment elevation MI consistent with the Third Universal Definition of Myocardial Infarction criteria and anemia. Anemia was defined as a Hb less than 10 g/dL. Participants were randomly allocated to a restrictive or a liberal transfusion strategy. In the liberal transfusion strategy, one unit of RBC’s was administered following randomization and enough RBCs were transfused to maintain the Hb at 10 g/dL or above through hospital discharge or 30 days. In the restrictive transfusion strategy, transfusion was permitted, but not required, only when the Hb was less than 8 g/dL (and strongly recommended when the Hb was less than 7 g/dL) or for ischemic symptoms not controlled with medications. Electrocardiogram, Hb and troponin measurements were made within 24 hours prior to randomization and daily for 3 days. Participants were contacted 30 days following randomization to assess vital status and admission to the hospital or emergency room, and at 6 months to assess vital status. Serial cardiac troponin values during the index admission were reviewed for each patient and suspected post-randomization MIs in the first 30 days adjudicated by a Clinical Events Committee blinded to treatment assignment. All prespecified outcomes were identified from hospital records. The primary trial endpoint was the composite of all-cause mortality and MI through 30 days following randomization. Secondary outcomes included the individual components of the primary outcome, and the composite of all-cause mortality, MI, ischemia driven unscheduled coronary revascularization, or readmission to the hospital for an ischemia related cardiac diagnosis within 30 days. Cause of death was classified as cardiac, non-cardiac, or undetermined. Other trial outcomes included heart failure and infection. Results: We have completed enrollment of 3506 patients from 144 sites from the United States, Canada, France, Brazil, New Zealand and Australia, and locked the database in August 2023. The main results will be available for the meeting with the plan for a simultaneous publication in a major journal. Summary: The MINT trial is the largest trial evaluating transfusion thresholds in patients with MI and will provide high quality evidence to guide transfusion decisions taken every day by clinicians in a wide variety of patients with MI and anemia.

Author Disclosures: For author disclosure information, please visit the AHA Scientific Sessions 2023 Online Program Planner and search for the abstract title.

Christopher Rajkumar¹, Michael Foley¹, Fiyyaz Ahmed-Jushuf¹, Alexandra Nowbar¹, Florentina Simader¹, Sashiananthan Ganesananthan¹, Peter O’Kane², Peter Haworth³, John Davies⁴, Tushar Kotecha⁵, Neil Ruparelia⁶, Helen Routledge⁷, nick curzen⁸, Manas Sinha⁹, Reto Gamma⁴, Rupert Williams¹⁰, Sukhjinder Nijjer¹¹, Gerald Clesham⁴, Lal h Mughal⁷, Jehangir Din¹², Tim Kinnaird¹³, James Spratt¹⁰, Sayan Sen¹¹, Ricardo Petraco¹⁴, Joban Sehmi¹⁵, David J Collier¹⁶, Syed Afzal Sohaib¹⁷, Thomas Keeble⁴, Graham Cole¹, Frank Harrell¹⁸, James Howard¹, Matthew Shun-Shin¹, Darrel Francis¹, RASHA AL-LAMEE¹; ¹National Heart and Lung Institute, Imperial College London, London, United Kingdom, ²Dept of Cardiology, Univ Hosps Dorset NHS Foundation Trust, London, United Kingdom, ³Dept of Cardiology, Portsmouth Hosps Univ NHS Trust, Portsmouth, United Kingdom, ⁴Dept of Cardiology, Essex Cardiothoracic Cntr, Basildon, United Kingdom, ⁵Dept of Cardiology, Royal Free Hosp, London, United Kingdom, ⁶Dept of Cardiology, Royal Berkshire NHS Foundation Trust, Reading, United Kingdom, ⁷Dept of Cardiology, Worcestershire Acute Hosps NHS Trust, Worcester, United Kingdom, ⁸Dept of Cardiology, Univ Hosp Southampton NHS Foundation Trust, Southampton, United Kingdom, ⁹Dept of Cardiology, Salisbury Hosp NHS Foundation Trust, Salisbury, United Kingdom, ¹⁰Dept of Cardiology, St George’s Univ Hosps NHS Foundation Trust, London, United Kingdom, ¹¹Dept of Cardiology, Imperial College Healthcare NHS Trust, London, United Kingdom, ¹²Dept of Cardiology, Univ Hosps Dorset NHS Foundation Trust, Bournemouth, United Kingdom, ¹³Dept of Cardiology, Cardiff and Vale Univ Health Board, Cardiff, United Kingdom, ¹⁴National Heart and Lung Institute, Imperial Colege London, London, United Kingdom, ¹⁵Dept of Cardiology, West Hertfordshire Teaching Hosps NHS Trust, Watford, United Kingdom, ¹⁶William Harvey Heart Cntr, Queen Mary Univ of London, London, United Kingdom, ¹⁷Dept of Cardiology, Barts Health NHS Trust, London, United Kingdom, ¹⁸Dept of Biostatistics, Vanderbilt Univ, Nashville, TN

Introduction: The primary role for percutaneous coronary intervention (PCI) in stable coronary artery disease is angina relief. Whilst unblinded trials have shown PCI to be effective, the first placebo-controlled trial, ORBITA, showed no significant improvement in exercise time in patients with single vessel disease with maximal antianginal therapy. ORBITA-2 tests the placebo-controlled efficacy of PCI for angina relief in patients with single and multivessel disease, with minimum tolerated antianginal therapy. Trial Design: ORBITA-2 was a multicentre, double-blind, placebo-controlled trial conducted in the United Kingdom which randomised 301 patients who fulfilled the following inclusion criterion: (i) angina or angina equivalent symptoms (ii) objective evidence of ischaemia, (iii) single or multivessel disease, and (iv) clinical eligibility for PCI. At enrolment, participants completed angina and quality of life questionnaires and antianginal medications were stopped. Angina episodes were documented daily via a dedicated smartphone application, and antianginal medications were introduced as required for intolerable angina according to a pre-specified protocol throughout the trial. At pre-randomisation, angina and quality of life questionnaires were repeated, and treadmill exercise testing and dobutamine stress echocardiography were performed. Participants then underwent coronary angiography including pre-randomisation invasive physiological assessment. Eligible participants were sedated to a deep level of conscious sedation and randomised 1:1 to receive PCI or placebo. Any antianginal medications initiated in the pre-randomisation period were stopped. All participants were discharged on dual antiplatelet therapy. Subjects then entered a 12 week blinded follow up period in which participants and medical and research teams were blinded to treatment allocation. At follow-up, angina and quality of life questionnaires, treadmill exercise testing and dobutamine stress echocardiography were repeated prior to unblinding and return to routine clinical care. Endpoints: The primary endpoint of ORBITA-2 is a daily angina symptom score. This is an ordinal clinical outcome scale of angina health status derived from the number of episodes of angina reported by the patient on a given day, the units of antianginal medication prescribed on that day, and high level category overrides for unblinding due to intolerable angina, acute coronary syndrome and death. Key secondary endpoints are change in Canadian Cardiovascular Society angina class, Seattle Angina Questionnaire, treadmill exercise time and frequency of antianginal initiation and uptitration. Importance: ORBITA-2 will report the placebo-controlled efficacy of PCI in a real-world population of patients with both single and multivessel stable coronary artery disease. ClinicalTrials.gov: NCT03742050

Author Disclosures: For author disclosure information, please visit the AHA Scientific Sessions 2023 Online Program Planner and search for the abstract title.

Mandeep R Mehra, The ARIES Investigators; Cardiovascular Medicine, Brigham and Womens Hosp, Boston, MA

Background: Left Ventricular Assist Devices (LVADs) prolong survival and improve quality of life in patients with advanced heart failure. Since advent of LVADs, aspirin has been used on presumption that induced platelet activation requires anti-thrombotic therapy. Prior generation pumps were known to require aspirin due to a greater propensity for stroke or pump thrombosis events, however the fully magnetically levitated HeartMate-3 (HM3) LVAD has demonstrated greater hemocompatibility. Whether aspirin can be safely avoided with the HM3 LVAD or if its use contributes to bleeding events remains unknown. ARIES was designed as an international, double-blind, placebo-controlled study of aspirin in HM3 LVAD treated patients with the hypothesis that withdrawal of aspirin from the antithrombotic regimen will preserve safety and efficacy of the HM3 LVAD and may reduce bleeding complications which confer substantial residual risk. Study Design: We randomized patients 1:1 to either vitamin K antagonist with aspirin (100 mg) or vitamin K antagonist with placebo, with target INR between 2.0-3.0. The primary endpoint for this study will be met if the placebo arm is non-inferior to the aspirin arm in the composite of survival free of any non-surgical (any event occurring >14 days post-implant) major hemocompatibility-related adverse event (stroke, pump thrombosis, bleeding, and arterial peripheral thromboembolism) at 1-year. Secondary endpoints include cumulative hemorrhagic and thrombotic events as well as components of the primary endpoint. Patients were excluded from participation if they required temporary or permanent mechanical circulatory support other than the HM3 LVAD after implant or if they required aspirin for reasons other than the HM3 LVAD. The study required 628 patients to achieve >80% power to prove the hypothesis using a non-inferiority margin of 10% with the Farrington-Manning risk difference approach to non-inferiority at a one-sided alpha=0.025 (accounting for a 30% dropout rate). All patients from the United States have also undergone aspirin response assessment by serum thromboxane B2 testing. Patient Population: A total of 628 Patients were randomized at 49 sites in United States, Canada, United Kingdom, Austria, Czech Republic, Italy, France, Kazakhstan, and Australia. Patients were a median age of 60 years (Q1-Q3 49-68), 31% black, 22.5% Women, 45% INTERMACS profile 3, with most implanted as destination therapy intent (60%). Study Completion: Final Study follow up completes on August 18^th,2023, and final analysis will be available by October 6^th, 2023. Study Highlight: ARIES is the first international randomized trial to establish an evidence-based benchmark for anti-thrombotic medical therapy with LVADs to reduce residual risk and enroll an ethnically diverse population across heterogenous healthcare paradigms. (NCT04069156, funded by Abbott (Chicago, IL).

Author Disclosures: For author disclosure information, please visit the AHA Scientific Sessions 2023 Online Program Planner and search for the abstract title.

Christopher S Almond¹, Kevin P Daly², Erin L Albers³, Juan C Alejos⁴, Rebecca K Ameduri⁵, Scott R Auerbach⁶, Lynsey Barkoff⁷, Aliessa R Barnes⁸, Matthew J Bock⁹, Arene Butto¹⁰, Waldemar F Carlo¹¹, Chesney D Castleberry¹², Maryanne Chrisant¹³, Shriprasad R Deshpande¹⁴, William Dreyer¹⁵, Melanie D Everitt¹⁶, Brian D Feingold¹⁷, Selena A Gonzales¹, Seth A Hollander¹⁸, Gloria Klein¹⁹, Ashwin K Lal²⁰, Jacqueline Lamour²¹, JoAnne Lee²², Minmin Lu¹⁹, Irene D Lytrivi²³, Shelley D Miyamoto²⁴, Elfriede Pahl²⁵, David M Peng²⁶, Ann R Punnoose²⁷, Thomas D Ryan²⁸, Tajinder P Singh²⁹, Jennifer A Su³⁰, David L Sutcliffe³¹, Steven Zangwill³², Joseph Rossano³³, Lynn A Sleeper³⁴; ¹Dept of Pediatrics (Cardiology), Stanford Univ, Palo Alto, CA, ²Dept of Pediatrics (Cardiology), Boston Children’s Hosp, Boston, MA, ³PEDIATRIC CARDIOLOGY, Seattle Childrens Hosp, Seattle, WA, ⁴PEDIATRIC CARDIOLOGY, UCLA Mattel Children’s Hosp, Los Angeles, CA, ⁵Pediatric Cardiology, Mayo Clinic, Rochester, MN, ⁶Dept of Pediatrics (Cardiology), Childrens Hosp Colorado, Aurora, CO, ⁷Dept of Pediatrics (Cardiology), Stanford, Palo Alto, CA, ⁸PEDIATRIC CARDIOLOGY, Childrens Mercy Hosp/UMKC, Kansas City, MO, ⁹Dept of Pediatrics (Cardiology), Rady Children’s Hosp, San Diego, CA, ¹⁰PEDIATRIC CARDIOLOGY, Children’s Healthcare of Atlanta, Atlanta, GA, ¹¹Pediatrics, UAB, Birmingham, AL, ¹²PEDIATRIC CARDIOLOGY, Pediatric Cardiology Assoc Austin, Austin, TX, ¹³Pediatric Cardiology, Joe DiMaggio Childrens Hosp, Hollywood, FL, ¹⁴PEDIATRIC CARDIOLOGY, Children’s National Health System, Washington, DC, ¹⁵Pediatric Cardioology, Texas Childrens Hosp, Houston, TX, ¹⁶PEDIATRIC CARDIOLOGY, Children’s Hosp Colorado, Aurora, CO, ¹⁷Pediatrics, UPMC Children’s Hosp of Pittsburgh, Pittsburgh, PA, ¹⁸Dept of Pediatrics (Cardiology), Stanford Univ Med Ctr, Palo Alto, CA, ¹⁹Pediatrics, Boston Children’s Hosp, Boston, MA, ²⁰Pediatric Cardiology, U of Utah Primary Children’s H, Salt Lake City, UT, ²¹Pediatric Cardiology, Mount Sinai, new york, NY, ²²Dept of Pediatrics (Cardiology), Lucile Packard Children’s Hosp Stanford, Palo Alto, CA, ²³Pediatric Cardiology, Columbia Univ Med Cntr, Larchmont, NY, ²⁴PEDIATRIC CARDIOLOGY, Childrens Hosp Colorado, Aurora, CO, ²⁵Pediatric Cardiology, Ann and Robert H Lurie Children’s Hosp, Wilmette, IL, ²⁶PEDIATRIC CARDIOLOGY, Univ of Michigan, Ann Arbor, MI, ²⁷Pediatric Cardiology, Children’s Hosp of Wisconsin, Milwaukee, WI, ²⁸Pediatric Cardiology, Cincinnati Childrens Hosp, Cincinnati, OH, ²⁹Pediatric Cardiology, Boston Childrens Hosp, Waban, MA, ³⁰Pediatric Cardiology, Childrens Hosp of Los Angeles, Los Angeles, CA, ³¹Pediatric Cardiology, Children’s Health Dallas, Dallas, TX, ³²Pediatric Cardiology, Phoenix Childrens Hosp, Phoenix, AZ, ³³Pediatric Cardiology, Children’s Hosp of Philadelphia, Philadelphia, PA, ³⁴Pediatric Cardiology, Boston Children’s Hosp, Boston, MA

Background: There is controversy whether everolimus, a proliferation signal inhibitor, is safe for preventing rejection after cardiac transplantation because of a higher risk of death due to infection when introduced early after heart transplant. It is unknown whether everolimus is safe and effective when introduced 6 months after heart transplant in children and young adults, a population where FDA-approved immunosuppressants have been lacking. Methods: In this investigator-initiated trial funded by the Department of Defense (DoD), subjects aged 0 to 21 years surviving to 6 months after heart transplant were randomized in a 1:1 ratio to everolimus and low-dose tacrolimus (everolimus group, reflecting the primary immunosuppressant) or standard-dose tacrolimus and mycophenolate mofetil (tacrolimus group) and followed for 30 months. The primary efficacy endpoint was the cumulative burden of biopsy-proven acute cellular rejection, cardiac allograft vasculopathy, and chronic kidney disease (CKD) as measured by the Major Adverse Transplant Event (MATE-3) score, a composite ordinal endpoint capturing prevalence and severity. The primary safety endpoint was the MATE-6 score, which included the MATE-3 events plus 3 additional adverse events: serious infection, post-transplant lymphoproliferative disorder (PTLD), and antibody-mediated rejection. The trial was executed by two coordinating centers (Boston Children’s Hospital for data coordination; Stanford/Lucile Packard Children’s Hospital for clinical coordination). Results: Between 2018 and 2020, 211 subjects were randomized at 25 US sites where at randomization the mean age was 8.2±6.3 years (17% infants); 46% were female, 40% were non-White or Hispanic; 50% were transplanted for cardiomyopathy; 16% had donor-specific antibodies, and 51% had public health insurance. During the trial, 40% received everolimus as a liquid preparation. Over 30 months of follow-up, 17% of patients had acute rejection, 26% had cardiac allograft vasculopathy, 24% had serious infection, 3% had CKD and 1.4% had PTLD. Five participants (2%) withdrew or were lost to follow-up. The primary and important secondary endpoints will be available at the time of presentation. Conclusion: TEAMMATE is the first multicenter randomized clinical trial in heart transplantation for children and young adults and evaluates the safety and effectiveness of everolimus and low-dose tacrolimus to prevent transplant complications like cardiac allograft vasculopathy, chronic kidney disease, and rejection. The results have the potential to change the standard approach to immunosuppression for children and young adults and lead to FDA approval of the first rejection prophylaxis regimen for pediatric heart transplantation.

(Supported by DoD W81XWH-17-1-0532, NCT 03386539)

Author Disclosures: For author disclosure information, please visit the AHA Scientific Sessions 2023 Online Program Planner and search for the abstract title.

Neal W Dickert¹, Scott Halpern², Yi-An Ko³, Dan D Matlock⁴, Andrea Mitchell⁵, Sarah Montembeau⁶, Miranda Moore⁷, Alanna A Morris⁸, Birju Rao⁶, Laura Scherer⁹, Candace Speight⁶, Peter Ubel¹⁰, Larry A Allen¹¹; ¹Dept of Medicine, Div of Cardiology, Emory Univ Sch of Medicine, Atlanta, GA, ²Medicine, Univ of Pennsylvania, Merion Station, PA, ³Biostatistics, Emory Univ Rollins Sch of Public Health, Atlanta, GA, ⁴Medicine, Univ Colorado, Aurora, CO, ⁵Medicine, Div of Cardiology, Emory Univ, Atlanta, GA, ⁶Medicine, Div of Cardiology, Emory Univ Sch of Medicine, Atlanta, GA, ⁷Family and Preventive Medicine, Emory Univ, Atlanta, GA, ⁸Medicine, Div of Cardiology, Emory Univ Sch Medicine, Atlanta, GA, ⁹Medicine, Univ of Colorado Sch of Medicine, Boulder, CO, ¹⁰Fuqua Sch of Business, Duke Univ, Durham, NC, ¹¹Medicine, Univ Colorado Denver, Aurora, CO

Background: Guideline-directed medical therapy for heart failure with reduced ejection fraction (HFrEF) can entail high out-of-pocket (OOP) costs, prompting concerns about financial toxicity and access to therapy. Multiple barriers to discussing cost exist. Most directly, OOP medication costs for individual patients are generally unavailable during clinical encounters. The POCKET-COST-HF trial made patient-specific OOP costs available to HFrEF patients and clinicians during encounters to assess the impact of this information on medication discussions and decisions. Design: This trial was conducted at 6 clinics in 2 health systems using a stepped-wedge cluster randomized design, allowing each site to enroll control and intervention patients. Planned enrollment was 240 adult patients with a diagnosis of HFrEF (EF ≤40%). Intervention: Built upon a HFrEF patient activation tool, the EPIC-HF checklist, the study intervention was a checklist of medications approved for treatment of HFrEF either with (intervention group) or without (control group) patient-specific OOP cost estimates for higher cost medications. Estimates were obtained by providing patient pharmacy benefit information to a financial counseling firm. The checklist was provided to patients and clinicians at clinical encounters. Measures and Outcomes: Encounters were audio-recorded, and patients were surveyed 2 weeks post-visit. The primary outcome was cost-informed decision-making, defined by the presence of HF medication cost discussion based on transcript analysis. The primary analysis used a generalized linear mixed (GLM) model including site-specific random intercepts and fixed effects for intervention arm, calendar quarter, and patients’ age, race, sex, financial well-being, and payor status. Secondary outcomes were assessed via sub-coding of transcripts and analysis of survey responses related to medication changes, cost discussions, and views of the encounter and checklist. Results: 247 patients were enrolled from June 2021 through August 2023. Demographic characteristics in intervention and control periods were similar. In the primary GLM model, the rate of cost-informed decision-making was significantly higher in the intervention group than control (68% vs 49%, p =0.021). Baseline rates of cost discussions and the impact of the intervention varied across sites. In encounters where cost discussions were present, fewer discussions in the intervention group involved “contingency plans” for potential costs of medications (16.5% vs 31.9% p= 0.028). Conclusions: Disclosure of comprehensive OOP medication costs to patients with HFrEF modestly increased cost-informed decision-making. Further work is needed to optimize implementation and assess impact on medication choices and longer-term outcomes such as adherence.

Registration: NCT04793880 Funding: AHRQ 1R01HS026081-01

Author Disclosures: For author disclosure information, please visit the AHA Scientific Sessions 2023 Online Program Planner and search for the abstract title.

Jiang He¹, Chuansheng Zhao², Shanshan Zhong², Nanxiang Ouyang³, Lixia Qiao³, Ruihai Yang⁴, Chunxia Zhao⁵, Huayan Liu⁶, Weiyu Teng⁶, Xu Liu⁶, Jessica Spat-Lemus⁷, Chung-shiuan Chen¹, Clara Li⁸, Jeff Williamson⁹, Yingxian Sun³; ¹Dept of Epidemiology, Tulane Univ, New Orleans, LA, ²Dept of Neurology, The First Hosp of China Med Univ, Shenyang, China, ³Dept of Cardiology, The First Hosp of China Med Univ, Shenyang, China, ⁴Dept of Internal Medicine, Hanzhong People’s Hosp, Hanzhong, China, ⁵Dept of Internal Medicine, Tongji Hosp, Tongji Med College of Huazhong Univ of Science and Technology, Wuhan, China, ⁶Dept of Neurology, First Hosp of China Med Univ, Shenyang, China, ⁷Dept of Clinical Psycholog, Montclair State Univ, Montclair, NJ, ⁸Alzheimer’s Disease Rsch Cntr, Icahn Sch of Medicine at Mount Sinai, New York, NY, ⁹Dept of Internal Medicine, Wake Forest Sch of Medicine, Winston-Salem, NC

Background: Dementia is a leading cause of deaths and disability worldwide. Currently, there are no proven interventions that prevent or delay the development of dementia. We tested the effectiveness of intensive blood pressure (BP) lowering intervention on dementia risk among hypertensive patients in rural China. Methods: In this cluster-randomized effectiveness trial, we recruited individuals aged ≥40 years with an untreated BP ≥140/90 mmHg (≥130/80 mmHg for those at high risk for cardiovascular disease or if currently taking antihypertensive medication). We randomly assigned 163 villages to a non-physician community health-care provider-led intervention and 163 villages to usual care. In the intervention group, trained nonphysician community health-care providers initiated and titrated antihypertensive medications according to a simple stepped-care protocol to achieve a systolic BP goal of <130 mmHg and diastolic BP goal of <80 mm Hg with supervision from primary care physicians. The primary cognitive outcome was adjudicated dementia. Secondary cognitive outcomes included adjudicated cognitive impairment, a composite outcome of dementia or cognitive impairment, and all-cause mortality. All clinical events were adjudicated independently by two neurologists blinded to intervention assignments according to a standard protocol. Intention to treat analysis was conducted. Results: At 48 months, the mean systolic and diastolic blood pressures (BP) were 127.6 and 72.6 mmHg in the intervention group, respectively, and 147.7 and 81.0 mmHg in the usual care group. The net change in systolic BP was -22.0 (95% CI -23.4 to -20.6, p<0.0001), and the net change in diastolic BP was -9.3 (-10.0 to -8.7, p<0.0001). The primary outcome of dementia was significantly lower in the intervention group compared to the usual care group (1.12% vs. 1.31% per year; relative risk with intervention: 0.85, 95% CI: 0.76 to 0.95; p=0.0035). Cognitive impairment alone, the composite outcome of dementia or cognitive impairment, death from all causes, and the composite outcome of dementia or deaths were all significantly lower in the intervention group compared to the usual care group (see Table). Serious adverse events (deaths or hospitalizations) were also less frequent in the intervention group. Conclusion: This is the first ever large cluster-randomized effectiveness trial to demonstrate that BP lowering is effective in reducing risk of dementia in patients with hypertension. This proven-effective intervention should be widely scaled up to reduce the global burden of dementia. (ClinicalTrials.gov: NCT03527719)

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JAMIE KITT¹, Rachael Fox², Annabelle Frost¹, Milensu Shanyide³, Katherine L Tucker³, Paul A Bateman³, Katie Surano¹, yvonne kenworthy¹, Annabelle McCourt¹, William Woodward¹, Winok Lapidaire⁴, Miriam Lacharie¹, Mauro Santos⁵, Cristian Roman⁵, Lucy Mackillop⁶, Christian Delles⁷, Basky Thilaganathan⁸, Lucy Chappell⁹, Adam J Lewandowski¹, Richard McManus³, Paul Leeson¹; ¹Radcliffe Dept of Medicine, Univ of Oxford, Oxford, United Kingdom, ²Mercy Hosp for Women, Mercy Hosp for Women, Heidelberg, Australia, ³Nuffield Dept of Primary Care, Univ of Oxford, Oxford, United Kingdom, ⁴Cardiovascular Clinical Rsch Facility, Univ of Oxford, Oxford, United Kingdom, ⁵Institute for Biomedical Engineering, Univ of Oxford, Oxford, United Kingdom, ⁶Nuffield Dept of Women’s Health, Univ of Oxford, Oxford, United Kingdom, ⁷BHF GLASGOW CARDIOVASCULAR RSCH CTR, Univ of Glasgow, Glasgow, United Kingdom, ⁸Maternal-fetal Medicine Unit, St George’s Hosp, London, UK, London, United Kingdom, ⁹King’s College London, King’s College London, London, United Kingdom

Background: Pregnancy hypertension results in adverse cardiac remodeling and higher incidence of hypertension and cardiovascular diseases in later life. We tested the novel hypothesis that improved blood pressure control, as the cardiovascular system recovers postpartum, has long term blood pressure and cardiac benefits for the mother. Methods: A prospective, randomized, open-label, blinded endpoint trial. Eligible participants were aged 18 years or over, with pre-eclampsia or gestational hypertension, who required antihypertensive medication on hospital discharge postnatally. Participants were randomly assigned 1:1 to self-monitoring with physician-optimized antihypertensive titration or usual postnatal care. Primary outcome was 24-hour mean diastolic blood pressure at 9 months postpartum, adjusted for baseline postnatal blood pressure. Secondary outcomes included other ambulatory and clinic blood pressure levels, as well as cardiac and cerebral imaging with magnetic resonance and echocardiography. Results: 220 participants were randomly assigned to intervention (n=112) or control (n=108), of whom 200 (91%) were included in the primary analysis. 24-hour mean diastolic blood pressure, measured at 249 days (SD 16 days) postpartum, was 5.8 mmHg (95% CI 7.4 to 4.2 mmHg, p<0.001) lower in those who had received the intervention vs. usual care. Similarly, 24-hour mean systolic blood pressure was 6.5 mmHg (95% CI 8.8 to 4.2 mmHg, p<0.001) lower in the intervention group. There were parallel improvements in echocardiographic, and cardiac magnetic resonance, measures of cardiac structure and function. Further imaging analysis will be reported in due course. Conclusions: Optimization of blood pressure with self-monitoring and physician-guided titration of antihypertensives during the immediate postpartum period results in lower blood pressure throughout the first-year postpartum and is associated with more favorable cardiac structure and function.

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Deepak K Gupta¹, Cora E Lewis², Krista A Varady³, Yanru Su⁴, Meena S Madhur⁵, Daniel T Lackland⁶, Jared P Reis⁷, Thomas J Wang⁸, Donald M Lloyd-Jones⁹, Norrina B Allen⁹; ¹MEDICINE, Vanderbilt Univ Med Ctr, Nashville, TN, ²Epidemiology, Univ Alabama Birmingham, Birmingham, AL, ³Kinesiology and Nutrition, Univ of Illinois-Chicago, Chicago, IL, ⁴MEDICINE, Vanderbilt Univ Med Cntr, Nashville, TN, ⁵MEDICINE, Indiana Univ, Indianapolis, IN, ⁶Neurology, Med Univ of South Carolina, MT Pleasant, SC, ⁷Epidemiology, National Heart Lung Blood Inst, Bethesda, MD, ⁸MEDICINE, UT Southwestern Med Cntr, Dallas, TX, ⁹Preventive Medicine, Northwestern Univ, Chicago, IL

Background: Dietary sodium recommendations are debated in part due to variable blood pressure (BP) response to sodium consumption. Further, the BP effect of dietary sodium among individuals on antihypertensive medications is understudied, particularly in randomized trials. Methods: Between 2021-2023, we conducted a randomized crossover trial in Coronary Artery Risk Development in Young Adults (CARDIA) study and non-CARDIA participants from Birmingham, AL and Chicago, IL. A total of 213 individuals (age 50-75 years, 65% female, 64% Black, 73% CARDIA) including those with normotension (25%), controlled hypertension (HTN) (20%), uncontrolled HTN (31%), and untreated HTN (25%), attended a baseline visit on usual diet, then completed one-week high- (~2,200 mg sodium added to usual daily diet) and low-sodium (~500 mg daily total) diets in random order. On the last day of each diet 24-hour ambulatory BP monitoring was performed. We quantified differences in average 24-hour systolic BP 1) between individuals randomized first to high- or low-sodium diet, and 2) within individuals between diets, and assessed for variation by HTN status and its treatment. Results: On usual, high-, and low-sodium diets, median systolic BP were 125-, 126-, and 119-mm Hg, respectively. The mean systolic difference between those randomized to high- vs. low-sodium first was 8 mm Hg (95% CI: 4-11), p < 0.001 (Fig 1A), which was largely similar across subgroups (Fig 1B). The median within individual change in systolic BP between high- and low-sodium diet was 7 mm Hg (25^th-75^th percentile: 0-14), p < 0.001, which did not significantly differ by HTN status; p = 0.32 (Fig 2). Compared with usual diet, high-sodium did not raise systolic BP (p=0.16), while low-sodium diet induced any decline in systolic BP in 72% of individuals. Adverse events were mild and reported by 9.9% and 8.0% of individuals while on high- and low-sodium diet, respectively. Conclusions: Compared with usual diet, sodium reduction significantly lowered systolic BP, while addition of sodium did not raise systolic BP. The decline in systolic BP with a low-sodium diet was independent of HTN status and anti-hypertensive medication use, consistent across subgroups, and did not result in excess adverse events.

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George L Bakris¹, Manish Saxena², Anil Gupta³, Fadi Chalhoub⁴, Maxwell Lasko⁵, Yansong Cheng⁶, Nune Makarova⁷, Nitender Goyal⁸, Weinong Guo⁹, Dion H Zappe¹⁰, Akshay S Desai¹¹; ¹Comprehensive Hypertension Cntr, Univ of Chicago Medicine, Chicago, IL, ²William Harvey Heart Cntr, Queen Mary Univ of London, London, United Kingdom, ³NA, Albion Finch Med Cntr, Toronto, Canada, ⁴Jacksonville - South, CNS Healthcare, Jacksonville, FL, ⁵Clinical Pharmacology, Alnylam Pharmaceuticals, Cambridge, MA, ⁶Biostatistics, Alnylam Pharmaceuticals, Wayland, MA, ⁷Global Patient Safety and Risk Management, Alnylam Pharmaceuticals, Belmont, MA, ⁸Clinical Rsch, Alnylam Pharmaceuticals, Cambridge, MA, ⁹Clinical Development, Alnylam Pharmaceuticals, Warren, NJ, ¹⁰Clinical Development - Clinical Rsch, Alnylam Pharmaceuticals, Andover, NJ, ¹¹Cardiovascular Div, Brigham and Women’s Hosp, Boston, MA

Background: Uncontrolled hypertension is a leading cause of morbidity and mortality. Angiotensinogen (AGT) is the most upstream precursor of the renin-angiotensin system, a key pathway in blood pressure (BP) regulation. In a Phase 1 study of patients with hypertension, a single subcutaneous (SC) dose of zilebesiran, an investigational RNA interference therapeutic targeting hepatic AGT synthesis, resulted in dose-dependent reductions in serum AGT and BP persisting for 24 weeks. We now report the primary efficacy and safety analyses of a placebo-controlled, randomized, double-blind, dose-ranging Phase 2 study (KARDIA-1; NCT04936035) of zilebesiran in patients with mild-to-moderate hypertension. Methods: Following antihypertensive washout, patients with a daytime mean systolic BP (SBP) of 135-160 mmHg, assessed by ambulatory BP monitoring, were randomized to a zilebesiran regimen (150, 300, or 600 mg SC once every 6 months [Q6M] or 300 mg SC once every 3 months [Q3M]) or to placebo SC Q3M. Endpoints included the change from baseline to Month 3 (primary) and Month 6 (key secondary) in 24-hour mean SBP. Rescue antihypertensives were permitted after Month 3, and patients receiving rescue medication underwent a 4-week washout before Month 6 assessments. BP assessments with rescue medication were excluded from the analyses. Results: Of 394 randomized patients, 377 (N=302 zilebesiran, N=75 placebo) were included in the primary analysis (24.7% Black, 55.7% men, 77.7% U.S., mean age 56.8 years, baseline 24-hr mean SBP/diastolic BP 141.8/81.8 mmHg). One randomized patient was not dosed; 16 Ukrainian patients were excluded from the analyses. Reductions from baseline in 24-hour mean SBP were significantly greater for all zilebesiran regimens than placebo at Month 3 and Month 6 (p<0.0001, all comparisons; Figure), with consistent reductions in daytime and nighttime SBP. The most common drug-related adverse events (AEs) over 6 months (≥5% patients) were injection site reactions (ISRs, 6.3% zilebesiran, 0% placebo; all mild and transient) and hyperkalemia (5.3% zilebesiran, 1.3% placebo; most mild and transient). No clinically relevant changes in renal or hepatic function were observed. There were 4 drug-related AEs leading to study drug discontinuation in the zilebesiran groups (orthostatic hypotension [2], BP elevation [1], ISR [1]) and 0 in the placebo group. Conclusions: In patients with mild-to-moderate hypertension, single doses of zilebesiran resulted in clinically significant reductions in SBP compared to placebo, with tonic BP control maintained and low rates of AEs reported through 6 months.

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Joshua Aymond¹, Alexandra Sanchez¹, Michael Castine², Michael Bernard¹, Sammy Khatib¹, Aimee Hiltbold³, GLENN POLIN¹, PAUL ROGERS¹, Paari Dominic⁴, Daniel P Morin¹; ¹Electrophysiology, Ochsner Health, New Orleans, LA, ²Cardiology, Ochsner Health, New Orleans, LA, ³Electrophysiology, Ochsner Med Cntr, New Orleans, LA, ⁴Electrophysiology, LSUHSC Shreveport, Shreveport, LA

Background: External direct current cardioversion (DCCV) is a mainstay treatment to restore sinus rhythm in patients with atrial fibrillation (AF). However, a significant portion of the increasingly prevalent obese population fail traditional cardioversion techniques using a single set of defibrillator pads. Failure increases the risk for adverse events related to multiple shocks, as well as loss of cardiac benefits from restoring sinus rhythm. Alternative treatment strategies are lacking. “Dual-DCCV,” in which simultaneous shocks are delivered via 2 sets of defibrillation pads, is potentially a more effective approach. Objective: To assess the efficacy and safety of dual-DCCV compared to single-DCCV in obese patients with AF. Methods: This multicenter randomized controlled trial enrolled patients with obesity (BMI ≥35 kg/m²) and AF who were undergoing elective DCCV. Participants were blinded and randomized 1:1 to single-DCCV or dual-DCCV. Two pairs of electrode patches were placed on all participants regardless of treatment assignment. The single-DCCV group received a 200J shock using the primary electrode pair only. The dual-DCCV group received synchronized shocks using both the primary and secondary electrode pairs, totaling 400J. Failure of the first cardioversion was followed by a maximum of 2 additional dual-DCCV attempts in both groups. The primary endpoint was successful cardioversion to sinus rhythm immediately following the first DCCV. Secondary safety outcomes were monitored. Results: We enrolled and randomized 200 patients (65.5±10.7 years, 73 [37%] female, 39 [20%] Black). The average BMI was 41.2±6.5 kg/m². Cardioversion failed more often with single-DCCV compared to dual-DCCV (14/101 [14%] vs. 2/99 [2%], P=0.002). Dual-DCCV predicted successful cardioversion (OR 16.7 [2.03-137.9], P=0.009) even after backward stepwise correction starting with all variables for which P≤0.2. Following an initially unsuccessful single-DCCV, subsequent shocks (all dual) were successful in all patients: 12/14 following second DCCV and 2/14 following third DCCV. There was no difference in the rating of post-procedure chest discomfort (median in both groups=0/10; P=0.40). There were no complications. Conclusion: In obese patients with AF undergoing DCCV, dual-DCCV results in higher cardioversion success compared to conventional single-DCCV, without any increase in complications.

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Christian T Ruff, AZALEA-TIMI 71 Steering Committee; Director, General Cardiology, Cardiovascular Div, Brigham and Women’s Hospital, Boston, MA

Background: Direct oral anticoagulants (DOACS), are effective in preventing in stroke in patients with atrial fibrillation (AF) and are associated with low rates of life-threatening bleeding, but clinically significantly bleeding still frequently occurs, resulting in the under treatment of patients. Factor XI inhibitors offer the potential for hemostasis-sparing anticoagulation. Abelacimab is a novel, highly selective, fully human monoclonal antibody with dual inhibitory activity against Factor XI and its active form, Factor XIa. Methods: We conducted a randomized, active-controlled study to evaluate the safety and tolerability of two blinded doses of Abelacimab (150mg and 90 mg subcutaneous monthly) compared with open-label rivaroxaban inpatients with AF who were at moderate-to-high-risk of stroke. The primary endpoint was the composite of major or clinically relevant non-major bleeding. The trial was designed to continue until 166 patients experienced a primary endpoint. Results: 1287 patients (median age 74 yrs, 44% women, median CHADS-VASc score 5) were randomized. On Sep 14, 2023, after a median follow-up of ~21 months, the Data Monitoring Committee recommended to stop the trial prematurely due to an overwhelming reduction in bleeding. Conclusions: AZALEA-TIMI71, the largest and longest head-to-head study of a Factor XI inhibitor compared with a DOAC to date, demonstrated a highly significant reduction in bleeding.

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Nina Becher¹, Tobias Toennis², Emanuele Bertaglia³, Carina Blomstrom-Lundqvist⁴, Axel Brandes⁵, Nuno Cabanelas⁶, Melanie Calvert⁷, Alan J Camm⁸, Gregory Chlouverakis⁹, G Andrei Dan¹⁰, Wolfgang Dichtl¹¹, Hans-Christoph C Diener¹², Alexander Fierenz¹³, Andreas L Goette¹⁴, Joris R de Groot¹⁵, Gregory Lip¹⁶, Astrid Hermans¹⁷, Andrzej Lubinski¹⁸, Eloi Marijon¹⁹, Bela Merkely²⁰, Lluis Mont²¹, Ann-Kathrin Ozga²², Kim Rajappan²³, Andrea Sarkozy²⁴, Ulrich Schotten²⁵, Emmanouil Simantirakis²⁶, Panos Vardas²⁷, Vasil Velchev²⁸, Dan Wichterle²⁹, Antonia Zapf³⁰, Paulus Kirchhof³¹; ¹Dept of cardiology, Univ Hosp Hamburg-Eppendorf, Hamburg, Germany, ²Dept of Cardiology, Univ Heart & Vascular Cntr Hamburg, Univ Med Cntr, Univ Med Cntr Hamburg-Eppendorf, Hamburg, Germany, ³Cardiologia, Azienda Ospedaliera di Padova, Padova, Italy, ⁴Cardiology, Faculty of Medicine and Health, Orebro, Sweden, ⁵Dept of Cardiology, Odense Univ Hosp, Odense C, Denmark, ⁶Cardiology, Arrhythmias Unit, Hosp Fernando Fonseca, Amadora, Portugal, ⁷Institute of Applied Health Rsch, Univ of Birmingham, Birmingham, United Kingdom, ⁸Cardiovascular and cell sciences research institute, St. George’s Univ of London, London, United Kingdom, ⁹Biostatistics Lab, Univ of Crete, Crete, Greece, ¹⁰Colentina Univ Hosp, Medicine Univ “Carol Davila”, Bucharest, Romania, ¹¹Dept of internal medicine III, Innsbruck Med Univ, Innsbruck, Austria, ¹²Dept of Neuroepidemiology, Univ Duisburg-Essen, Essen, Germany, ¹³Institute of Medical Biometry and Epidemiology, Univ Medical Centre Hamburg-Eppendorf, Hamburg, Germany, ¹⁴Cardiology, St Vinzenz Hosp, Paderborn, Germany, ¹⁵Dept of clinical and experimental cardiology, Amsterdam Univ Med Cntr, Amsterdam, Netherlands, ¹⁶Liverpool Cntr for Cardiovascular Science at Univ of Liverpool, Univ of Liverpool, Liverpool, United Kingdom, ¹⁷Dept of Cardiology, Univ Maastricht, Maastricht, Netherlands, ¹⁸Dept of Cardiology and internal disease, Med Univ of Gdansk, Gdansk, Poland, ¹⁹Cardiology Div, European Georges Pompidou Hosp, Paris, France, ²⁰Heart and Vascular Cntr, Semmelweis Univ, Budapest, Hungary, ²¹Arrhythmia Unit, Hosp Clinic, de Barcelona, Barcelona, Spain, ²²Dept for medical biometry and epidemiology, Univ Hosp Hamburg-Eppendorf, Hamburg, Germany, ²³Cardiovascular Clinical Rsch Facility, Oxford Univ Hosp - John Radcliffe Hosp, Oxford, United Kingdom, ²⁴Dept of cardiology, Univ Hosp Antwerp, Antwerp, Belgium, ²⁵Depts of Cardiology and Physiology, Univ Maastricht, Maastricht, Netherlands, ²⁶Dept of Cardiology, Heraklion Univ Hosp, Herakleion, Greece, ²⁷Dept of Cardiology, Univ of Crete, Crete, Greece, ²⁸Clinic of Cardiology, MHAT St. Anna AD, Sofia, Bulgaria, ²⁹Dept of Cardiology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic, ³⁰Institute of medical biometry and epidemiology, Univ Med Cntr Hamburg-Eppendorf, Hamburg, Germany, ³¹Dept of Cardiology, Univ Med Cntr Hamburg-Eppendorf, Hamburg, Germany

Background: Oral anticoagulation is often offered to patients with device-detected atrial high-rate episodes (AHRE) lasting ≥24 hours and stroke risk factors. The Non-vitamin K antagonist Oral anticoagulants in patients with Atrial High-rate episodes trial (NOAH-AFNET 6, Kirchhof NEJM 2023) compared anticoagulation with edoxaban to placebo or aspirin 100 mg in patients with AHRE ≥6 minutes duration aged ≥65 years with stroke risk factors. Anticoagulation did not prevent thrombotic events but increased major bleeding or death. Methods: This sub-analysis of the NOAH-AFNET 6 trial analyzed the efficacy and safety of anticoagulation in patients with AHRE lasting ≥24 hours. AHRE ≥24 hours included all patients with at least one core-lab verified AHRE episode lasting ≥24 hours. Outcomes of interest were composites of stroke, systemic embolism, or cardiovascular death (primary outcome); major ISTH bleeding or death (safety outcome); development of atrial fibrillation and other key secondary outcomes. Results. AHRE ≥24 hours were found in 259/2389 patients (11%). Age, sex, and clinical characteristics did not differ by AHRE groups and were balanced in each AHRE group (Table). Patients with AHRE ≥24 hours had more prior AHRE episodes (Table). In patients with AHRE ≥24 hours the primary outcome occurred in 9/132 patients with anticoagulation (4.3%/year) and in 14/127 patients with placebo (6.9%/year). This was not significantly different to the outcome rates in patients with AHRE<24 hours (anticoagulation 70/1062 patients with event (3.2%/year), placebo 80/1068 patients with event (3.7%/year)) (Figure). Anticoagulation led to more ISTH bleeding or death in both AHRE groups (p[interaction]=0.96). Patients with AHRE ≥24 hours developed more atrial fibrillation (76/259 (29.3%)) than patients with shorter AHRE durations (374/2130 (17.6%), p≤0.001). Other outcomes and further analyses by AHRE duration will be reported. Conclusions: In this subanalysis, anticoagulation with edoxaban did not prevent ischemic events in patients with AHRE ≥24 hours. The stroke rate was low with and without anticoagulation, regardless of AHRE duration. Patients with AHRE ≥24 hours may defer anticoagulation until atrial fibrillation is diagnosed by ECG, balancing individual risks of bleeding and stroke.

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Jeff S Healey¹, Renato D Lopes, Sr.², Christopher Granger³, Marco Alings⁴, David H Birnie⁵, Juan Benezet-Mazuecos⁶, JENS COSEDIS NIELSEN⁷, Giuseppe Boriani⁸, Georges Mairesse⁹, Stefan H Hohnloser¹⁰, Francois Philippon¹¹, Valentina Kutyifa¹², Michael R Gold¹³, cecilia M Linde¹⁴, David Conen¹, Julia Erath¹⁵, Philippe Mabo¹⁶, Christiab Sticherling¹⁷, David Wright¹⁸, William F McIntyre¹, Dan Atar¹⁹, Rajibul Mian²⁰, Lizhen Xu²⁰, Lena Rivard²¹, Josef Kautzner²², Marco Proietti²³, Alan J Camm²⁴, Ronald Aronson²⁵, Ignatius Zarraga²⁶, John Ip²⁷, Stuart J Connolly²⁸; ¹Medicine, McMaster Univ, Hamilton, Canada, ²Medicine, Duke Clinical Research, Durham, NC, ³Medicine, Duke Univ, Durham, NC, ⁴Medicine, Amphia Hosp, Breda, Netherlands, ⁵Medicine, Univ of Ottawa Heart Institute, Ottawa, Canada, ⁶Medicine, Hosp Universitario La Luz, Madrid, Spain, ⁷Medicine, Dept of Cardiology, Aarhus N, Denmark, ⁸Medicine, Univ of Modena, Modena, Italy, ⁹Medicine, Cliniques du Sud-Luxembourg, Arlon, Belgium, ¹⁰Medicine, Goethe Univ Theodor Stern Kai, Frankfurt, Germany, ¹¹Medicine, Univ Laval, Quebec, Canada, ¹²Medicine, Univ of Rochester, Rochester, NY, ¹³Medicine, Med Univ South Carolina, Charleston, SC, ¹⁴Medicine, Karolinska Institutet, Stockholm, Sweden, ¹⁵Medicine, J W Goethe Univ, Frankfurt a. M., Germany, ¹⁶Medicine, CHU Rennes France, Rennes, France, ¹⁷Medicine, Univ Hosp Basel, Basel, Switzerland, ¹⁸medicine, 0151 6001457, Liverpool, United Kingdom, ¹⁹Medicine, Univ of Oslo, Oslo, Norway, ²⁰Biostatistics, McMaster Univ, Hamilton, Canada, ²¹Medicine, Montreal Heart Institute, Montreal, Canada, ²²Medicine, IKEM-Dept Cardiology, Prague, Czech Republic, ²³Medicine, Università degli Studi di Milano, Milan, Italy, ²⁴Medicine, St. George’s Univ of London, London, United Kingdom, ²⁵Clinical Development, Bristol Myers Squibb, Lawrenceville, NJ, ²⁶Medicine, Veterans Affairs, Portland, OR, ²⁷Medicine, Sparrow, Okemos, MI, ²⁸Medicine, Mc Master Univ, Hamilton, Canada

Background: Subclinical atrial fibrillation (SCAF) is short-lasting, asymptomatic atrial fibrillation (AF) detected by long-term continuous monitoring by implanted devices, such as pacemakers. Prior cohort studies have shown that SCAF is associated with an increased risk of stroke. However, this risk is lower than with clinical AF, and current guidelines conclude that there is uncertain benefit in treating SCAF with oral anticoagulation. Methods: The Apixaban for the Reduction of Thrombo-Embolism in patients with device-detected Subclinical Atrial fibrillation trial (ARTESIA) enrolled 4012 individuals from 16 countries with SCAF lasting 6 minutes to 24 hours, detected by an implanted pacemaker, defibrillator, or cardiac monitor, and who had additional stroke risk factors. Patients were randomized in a double-blind, double-dummy fashion to apixaban at 5 mg twice daily (2.5 mg twice daily if meeting criteria for dose reduction) or aspirin 80-100 mg once daily and followed for the primary efficacy outcome of stroke or systemic embolism, and for the main safety outcome of major bleeding. Study medication was discontinued, and anticoagulation started if a patient developed clinical AF or SCAF >24 hr. The primary efficacy analysis will be by intention-to-treat, with censoring of follow-up if patients developed clinical AF or SCAF>24 hours. On-treatment analyses will also be performed. Results: The ARTESIA trial completed follow-up in August 2023, after an average patient participation of 4.0 ± 1.7 years. The mean (± SD) age of patients was 76.8 ± 7.6 years and 36.1% were women. Their mean CHA₂DS₂-VASc score was 3.9 ± 1.1 and the median (25^th, 75^th) duration of their longest SCAF episode was 1.47 (0.2, 4.95) hours. The main results of the trial will be ready for presentation at the 2023 American Heart Association Scientific Sessions. Conclusions: ARTESIA is a well-powered, international, randomized trial that will inform physicians and global guidelines about the use of oral anticoagulation for the large proportion of individuals with implanted pacemakers and defibrillators who have SCAF. The results will also have important relevance to the field of AF screening and the management of individuals who have AF detected by long-term monitoring with medical and patient-facing devices.

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Scott B Vafai¹, Patrick A Gladding², Russell Scott³, Jane Kerr³, Jorg Taubel⁴, Jaimini Cegla⁵, Mahmoud Barbir⁶, Steve E Humphries⁷, Verena Karsten¹, Chelsey L Jensen¹, Richard Falzone¹, Troy Lister¹, Leslie E Stolz¹, Amit V Khera¹, Sekar Kathiresan¹, Andrew M Bellinger¹; ¹Verve Therapeutics, Verve Therapeutics, Boston, MA, ²Cardiology, Te Whatu Ora Waitematā and Ascot Hosp, Auckland, New Zealand, ³Endocrine Metabolic Section, New Zealand Clinical Rsch, Christchurch, New Zealand, ⁴Molecular and Clinical Sciences Rsch Institute, St George’s Univ of London, London, United Kingdom, ⁵Div of Diabetes, Endocrinology and Metabolism, Imperial College London, London, United Kingdom, ⁶Cardiology, Royal Brompton and Harefield NHS Foundation Trust, Harefield, United Kingdom, ⁷Cardiovascular Genetics, Univ College London, London, United Kingdom

Background: Cumulative lifelong exposure to circulating low-density lipoprotein cholesterol (LDL-C) is a primary driver of atherosclerotic cardiovascular disease (ASCVD). Despite being at high risk of cardiovascular events, most patients with heterozygous familial hypercholesterolemia (HeFH) and pre-existing ASCVD do not achieve LDL-C targets within the current chronic care model. VERVE-101 is composed of a messenger RNA encoding an adenine base editor and a guide RNA that targets the PCSK9 gene, packaged within a lipid nanoparticle. Preclinical studies in mice and non-human primates (NHPs) demonstrated that a one-time intravenous administration of VERVE-101 can inactivate the PCSK9 gene in the liver with a single and precise DNA base pair change. NHPs treated with VERVE-101 had substantial reductions in LDL-C that remained durable through more than 2 years of follow-up, supporting the potential for a permanent treatment effect. Here we provide interim data from the first clinical trial of VERVE-101 in patients with HeFH and pre-existing ASCVD. Methods: The heart-1 clinical trial (NCT05398029) is a phase 1b, open-label study designed to assess the safety and pharmacodynamic effects of VERVE-101. The single ascending dose escalation part of the trial is ongoing in adults with HeFH with high-risk features, pre-existing ASCVD, and LDL-C not adequately controlled on maximally-tolerated oral therapies. After pre-medication with dexamethasone and antihistamines, VERVE-101 is delivered as a single peripheral intravenous infusion. Participants in the first dose cohort received 0.1 mg/kg, and dose escalation in subsequent cohorts occurred in consultation with an independent data safety monitoring board. Results: Eight male and two female participants with a mean age of 54 years (range, 29 to 69) received VERVE-101 across 4 dose cohorts ranging from 0.1 to 0.6 mg/kg. All 10 participants had HeFH and evidence of ASCVD, 9/10 required revascularization prior to treatment, and 3/10 were unable to tolerate high-intensity statin therapy. The mean LDL-C at screening was 193 mg/dL (range, 107 to 373). Nine participants have reached at least 28 days of follow-up. Safety data and changes from baseline levels of circulating LDL-C and PCSK9 across dose levels will be presented. Conclusions: These interim data will be the first reported results for any in vivo DNA base editing medicine administered to human trial participants. Proof-of-concept demonstration of a clinically meaningful and durable reduction in LDL-C would support further investigation of single-course editing approaches to inactivate PCSK9 for the treatment of ASCVD.

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Steven E Nissen; Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland, OH

Background: Observational and Mendelian randomization studies have associated elevated serum levels of lipoprotein(a) [Lp(a)] with major adverse cardiovascular events including myocardial infarction, stroke, cardiovascular death and an increased risk of developing calcific aortic stenosis. Although several promising therapies are currently in development, no Lp(a)-lowering agents have been approved by regulatory authorities. Lp(a) is an LDL-like lipoprotein particle that consists of an apolipoprotein-B100 covalently bound to apolipoprotein(a) [apo(a)]. The LPA gene encodes for apo(a), and inhibiting LPA mRNA expression via short-interfering RNA (siRNA) technology reduces apo(a) production and lowers circulating levels of Lp(a). Lepodisiran is an LPA-specific siRNA conjugated to N-acetyl-galactosamine that concentrates lepodisiran in hepatocytes to potently and durably reduce hepatic LPA mRNA levels and thereby reduce circulating Lp(a) levels. Objectives: To assess safety, tolerability, pharmacokinetics (PK), and effects on Lp(a) serum concentrations after administration of single doses of lepodisiran, an extended duration siRNA directed at hepatic synthesis of apo(a), an essential component necessary for assembly of Lp(a) particles. Design, Setting, Participants: A single ascending dose trial of lepodisiran was conducted at 5 clinical research sites in the US and Singapore. The study enrolled 48 adults without cardiovascular disease and Lp(a) serum concentrations ≥75 nmol/L or 30 mg/dL. Interventions: Participants were randomized to receive placebo (n=12) or single doses (n=6) of 4, 12,32,96, 304 or 608 mg of lepodisiran administered subcutaneously. Outcomes Measures: Participants were followed until study completion up to 48 weeks. The primary outcome was safety and tolerability. Secondary outcomes included PK of lepodisiran and the change in Lp(a) serum concentrations following administration to a maximum of 337 days (48 weeks). Results: Forty-eight participants were enrolled, mean (SD) age 46.8 (11.6) years, 35% female; 46 completed the trial. A single serious adverse event was reported (fall from bicycle). Peak plasma concentrations of lepodisiran were achieved within 8 hours and undetectable by 48 hours. Median [IQR]) baseline Lp(a) concentrations in nmol/l were 111 (78,134), 78 (50,152), 97 (86,107), 120 (110,188), 167 (124,189), 96 (72,132), and 130 (87,151) for the placebo, 4, 12, 32, 96, 304 and 608 mg treatment groups, respectively. The effect of lepodisiran on concentrations of Lp(a) from baseline to 337 days (48 weeks) will be available for simultaneous publication and presentation at the AHA Scientific Sessions. Conclusions: In this phase 1 study of 48 participants with elevated Lp(a) levels, lepodisiran was well tolerated and produced dose-dependent reductions in serum Lp(a) concentrations. The full study results will be presented.

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Qiang Lv¹, Xin Du¹, Zhifang Wang², Rongjie Huang³, Xiaohong Gao⁴, Yajun Han⁵, Zhuhua Yao⁶, Mingqi Zheng⁷, Suxin Luo⁸, Yue Li⁹, Xiang Gu¹⁰, Changsheng Ma¹, Shimin An¹¹, tingyan zhong¹¹, Ying Wang¹¹; ¹Dept of Cardiology, Beijing Anzhen Hosp, Capital Med Univ, Beijing, China, ²Dept of Cardiology, Xinxiang Central Hosp, Xinxiang, China, ³Dept of Cardiology, The First Affiliated Hosp of Guangxi Med Univ, Nanning, China, ⁴Dept of Cardiology, Beijing Pinggu Hosp, Beijing, China, ⁵Dept of Geriatric Cardiology, Inner Mongolia Autonomous Region People’s Hosp, Hohhot, China, ⁶Dept of Cardiology, Tianjin Union Med Cntr, Tianjin, China, ⁷Dept of Cardiology, The First Hosp of Hebei Med Univ, Shijiazhuang, China, ⁸Dept of Cardiology, The First Affiliated Hosp of Chongqing Med Univ, Chongqing, China, ⁹Dept of Cardiology, The First Affiliated Hosp of Harbin Med Univ, Harbin, China, ¹⁰Dept of Cardiology, Subei People’s Hosp of Jiangsu Province, Yangzhou, China, ¹¹Clinical Rsch and Development, Jiangsu Hengrui Pharmaceuticals Co., Ltd., Shanghai, China

Introduction: Currently available anti-PCSK9 mAbs can effectively reduce LDL-C levels, but require frequent dosing. Recaticimab (SHR-1209) is a novel humanized mAb against PCSK9. In a phase 1b/2 trial, recaticimab as add-on to stable statin showed robust LDL-C reduction with a dosing interval up to Q12W in hypercholesterolaemia patients (pts). REMAIN-2 aimed to further assess long-term use of add-on recaticimab in pts with non-familial hypercholesterolaemia (non-FH) and mixed hyperlipidemia. Methods: REMAIN-2 (NCT04885218) was a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial. Pts with LDL-C ≥2.6 mmol/L (or ≥1.8 mmol/L in pts with ASCVD) on stable moderate or high intensity statin (± cholesterol absorption inhibitors [ezetimibe] or fenofibrate) for ≥4 wks and fasting triglyceride ≤5.6 mol/L, were randomized (2:2:2:1:1:1) to receive recaticimab 150 mg Q4W, 300 mg Q8W or 450 mg Q12W or matching placebo injections for 48 wks. The primary efficacy endpoint was percentage change from baseline to week 24 in calculated LDL-C level. Results: 689 pts (mean age, 55.8 yrs; male, 64.4%; ASCVD history, 69.5%; concomitant ezetimibe 11.2%; mean baseline LDL-C, 2.8 mmol/L) were randomized and treated. Percentage change in LDL-C from baseline to week 24 was significantly more pronounced with recaticimab vs placebo (p <0.0001), with treatment differences of -62.2% (95% CI -67.0 to -57.4), -59.7% (-65.0 to -54.3) and -53.4% (-58.7 to -48.2) for the 150 mg Q4W, 300 mg Q8W, and 450 mg Q12W regimens, respectively. The reductions in LDL-C with recaticimab were maintained through week 48 (Fig 1 & Table 1). Other lipid variable outcomes also favored the recaticimab groups (Table 1). Over 48 weeks, rates of AEs were similar in the recaticimab and placebo groups (84.4% vs. 82.8%). Common AEs (frequency ≥5%) in pts receiving recaticimab were upper respiratory tract infection, hyperuricaemia, urinary tract infection, increased blood CPK, COVID-19 infection, increased ALT, and increased AST. Conclusion: REMAIN-2 demonstrated the efficacy and long-term safety of add-on recaticimab, as an effective therapeutic option with an infrequent dosing interval, in pts with non-FH and mixed hyperlipidemia inadequately controlled on stable statin therapy.

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Michael T Lu¹, Heather Ribaudo², Borek Foldyna³, Markella V Zanni⁴, Thomas Mayrhofer⁵, Julia Karady⁶, Jana Taron⁷, Katie V Fitch⁸, Sara McCallum⁹, Tricia H Burdo¹⁰, Kayla Paradis⁶, Sandeep S Hedgire¹¹, Nandini M Meyersohn¹, Christopher deFilippi¹², Carlos D Malvestutto¹³, Audra Sturniolo⁶, Marissa Diggs⁸, Gerald S Bloomfield¹⁴, Beverly Alston-Smith¹⁵, Patrice Desvigne-Nickens¹⁶, Edgar T Overton¹⁷, Judith S Currier¹⁸, Judith A Aberg¹⁹, Carl J Fichtenbaum²⁰, Udo Hoffmann²¹, Pamela S Douglas²², Steven K Grinspoon⁸; ¹Dept of Radiology, Massachusetts General Hosp, Boston, MA, ²CBAR, Harvard TH Chan Sch of Public Health, Boston, MA, ³Radiology, Massachusetts General Hosp, Boston, MA, ⁴Endocrinology, Massachusetts General Hosp, Waban, MA, ⁵Stralsund Univ of Applied Sci, Stralsund, ⁶Cardiovascular Imaging Rsch Cntr, Massachusetts General Hosp, Boston, MA, ⁷Dept of Radiology, Med Cntr-Univ of Freiburg, Freiburg, Germany, ⁸Metabolism Unit, Massachusetts General Hosp, Boston, MA, ⁹Metabolism Unit, Massachusetts General Hosp, st. petersburg, FL, ¹⁰Dept of Microbiology, Immunology and Inflammation, Temple Univ Lewis Katz Sch, Philadelphia, PA, ¹¹Cardiovascular Imaging Rsch Cntr, Massachusetts General Hosp, Lexington, MA, ¹²Inova, Inova, Falls Church, VA, ¹³Infectious Disease, Ohio State Univ Med Cntr, Columbus, OH, ¹⁴DUKE CLINICAL RESEARCH INSTITUTE, Duke Univ Med Cntr, Durham, NC, ¹⁵Div of AIDS, National Institute of Allergy and Infectious Diseases, Rockville, MD, ¹⁶NHLBI, NHLBI, NIH, Bethesda, MD, ¹⁷North America Med Affairs, Viiv Healthcare, Birmingham, AL, ¹⁸Infectious Diseases, UCLA, Los Angeles, CA, ¹⁹Infectious Disease, Icahn Sch of Medicine, Mt Sinai, New York, NY, ²⁰INTERNAL MEDICINE, Univ of Cincinnati, Cincinnati, OH, ²¹Chief Scientific Officer, Cleerly Health, New York, NY, ²²Cardiology, Duke Univ DUMC, Durham, NC

Background: Cardiovascular disease (CVD) is increased in people with HIV (PWH). Prior studies suggest a unique phenotype of coronary artery disease in HIV, characterized by premature noncalcified plaque and arterial inflammation. In the REPRIEVE trial, pitavastatin reduced major adverse cardiovascular events (MACE) by 35% over median 5.1 years in low-moderate traditional risk PWH compared to placebo. The effect on MACE was beyond that anticipated from LDL reduction alone (median 107 to 74 mg/dL with pitavastatin). The embedded REPRIEVE Mechanistic Substudy investigated statin effects on noncalcified coronary artery plaque on coronary CT angiography (CTA) and inflammatory biomarkers as potential mechanisms for prevention of MACE. Methods: The REPRIEVE Mechanistic Substudy enrolled PWH without known CVD, on antiretroviral therapy (ART), and low-moderate 10-y CVD risk at 31 sites. Coronary CTA and circulating biomarkers of inflammation were obtained at baseline and after 24 months of 1:1 randomization to oral pitavastatin calcium 4 mg/day vs placebo. Primary outcomes were change in noncalcified coronary plaque volume and progression of noncalcified plaque, defined as increase in plaque volume or incident plaque. Outcomes were compared by treatment group, using linear regression adjusted for baseline plaque volume and Mantel-Haenszel estimate of the relative risk, respectively. Results: Of 804 persons (402 pitavastatin, 402 placebo) in this intent-to-treat analysis, the mean age (SD) was 51 (6) years, with 17% female natal sex, 36% Black race, and median (IQR) 10-year CVD risk 4.6% (2.6, 7.0). Median (IQR) time between CTAs was 24.1 (23.9, 24.5) months. Noncalcified plaque volume decreased in the pitavastatin arm vs placebo (mean ∆ (SD) -1.7 mm³ (25.2) vs +2.6 mm³ (27.1); baseline adjusted difference -4.3 mm³ (95% CI -8.6, -0.1), p=0.044; a 7% greater reduction relative to placebo). A larger effect size was seen among the subgroup with plaque at baseline (-8.8 mm³ (95% CI -17.9, 0.4)). Progression of noncalcified plaque was less likely for individuals in the pitavastatin arm (relative risk 0.67 (95% CI 0.52, 0.88), p=0.003). Compared to placebo, pitavastatin led to lower 2-year hs-CRP (pitavastatin 1.70 vs placebo 1.90 mg/L; p=0.021), oxLDL (37.6 vs 48.2 U/L; p<0.001), and Lp-PLA2 (118 vs 142 ng/mL; p<0.001), with a trend towards lower caspase-1 (69.6 vs 74.2 pg/mL; p=0.08). Additional analyses are ongoing and will be ready for presentation at AHA 2023. Conclusions: In persons with HIV at low-moderate CVD risk, 24 months of pitavastatin 4 mg/day reduced the progression of noncalcified coronary plaque volume compared to placebo. Concurrent changes in inflammatory biomarkers suggest mechanistic pathways and potential therapeutic targets for the 35% reduction in MACE in the parent REPRIEVE trial. (ClinicalTrials.gov NCT02344290)

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Jing Li, Jiamin Liu, the ESPRIT Collaborative Group; ¹NCRC, Fuwai Hosp, Beijing, China

Background: Lowering blood pressure (BP) effectively reduces the risk of cardiovascular (CV) events in high CV risk individuals. However, the optimal target of BP lowering remains unclear, particularly in those with diabetes or history of stroke. Methods: ESPRIT trial is a multi-center, open-label, randomized controlled trial. We randomly allocated 11,255 participants who were aged at least 50 years, with an average baseline systolic BP (SBP) within 130 to 180 mm Hg, at high CV risk (established CV disease or at least 2 major CV risk factors) to intensive treatment (SBP target below 120 mm Hg) or standard treatment (SBP target below 140 mm Hg). The primary outcome is a composite of myocardial infarction, coronary or non-coronary revascularization, hospitalization/emergency room visit for heart failure, stroke, or CV death. Secondary CV outcomes include components of the primary composite outcome, all-cause death, and a composite of the primary outcome or all-cause death. The main pre-specified subgroups are defined according to disease status (coronary heart disease, stroke, and diabetes), baseline SBP tertiles. Results: The mean age of the participants was 64.6 (standard deviation [SD], 7.1) years, 41.3% were women; 28.9%, 26.9% and 38.7% had coronary heart disease, history of stroke, and diabetes, respectively. At 1 year of follow-up, the mean SBP was 120.3±10.9 mm Hg in the intensive treatment group and 135.6±9.5 mm Hg in the standard treatment group. During a median of 3.4 years of follow-up, the primary outcome event occurred in 547 participants (9.7%) in the intensive treatment group and 624 (11.1%) in the standard treatment group (hazard ratio, 0.88; 95% confidence interval [CI], 0.78 to 0.99; P = 0.03). Death from cardiovascular causes occurred in 59 participants (1.1%) in the intensive treatment group and in 97 (1.7%) in the standard treatment group (hazard ratio, 0.61; 95% CI 0.44 to 0.84). Death occurred in 160 participants (2.8%) in the intensive treatment group and in 203 (3.6%) in the standard treatment group (hazard ratio, 0.79; 95% CI 0.64 to 0.97). The effects of intensive treatment with respect to the primary outcome were consistent in subgroups of coronary heart disease, stroke, diabetes, and baseline SBP tertiles. Conclusion: Among divisive participants with high cardiovascular risk, intensive treatment reduced risk of major vascular events and death than standard treatment.

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Jiang He¹, Katherine T Mills¹, Erin Peacock², Jing Chen², Farah Allouch¹, Amy K Carreras¹, Siyi Geng¹, Alecia Cyprian³, Gerrelda Davis⁴, Sonja Fuqua⁵, Darie S Gilliam⁶, Angel Greer⁷, Tammy Mitchell⁸, Lea Gray Winfrey⁹, Shondra Williams¹⁰, Gary Wiltz¹¹, Keith Winfrey¹², Hua He¹, Paul K Whelton¹, Marie A Krousel-Wood²; ¹Dept of Epidemiology, Tulane Univ, New Orleans, LA, ²Dept of Internal Medicine, Tulane Univ, New Orleans, LA, ³Southeast Community Health Systems, Southeast Community Health Systems, Zachary, LA, ⁴Louisiana Primary Care Association, Louisiana Primary Care Association, Baton Rouge, LA, ⁵Community Health Cntr Association of Mississippi, Community Health Cntr Association of Mississippi, Jackson, MS, ⁶RKM Primary Care, RKM Primary Care, Clinton, LA, ⁷Coastal Family Health Cntr, Coastal Family Health Cntr, Biloxi, LA, ⁸SWLA Cntr for Health Services, SWLA Cntr for Health Services, Lake Charles, LA, ⁹EXCELth Primary Care, EXCELth Primary Care, New Orleans, LA, ¹⁰InclusivCare, InclusivCare, Avondale, LA, ¹¹Teche Action Clinic, Teche Clinic, Franklin, LA, ¹²NOELA Community Health Cntr, NOELA Community Health Cntr, New Orleans, LA

Objectives: Uncontrolled hypertension and related cardiovascular disease disproportionately affect low-income populations. We aimed to simultaneously test the effectiveness of a multifaceted implementation strategy for intensive blood pressure (BP) intervention and its acceptance, feasibility, and fidelity in low-income patients with hypertension. Methods: Thirty-six Federally Qualified Health Center (FQHC) clinics in Louisiana and Mississippi were randomly assigned to either the multifaceted implementation strategy group or usual care group. A total of 1,272 individuals aged ≥40 years with untreated systolic BP ≥140 mmHg or treated systolic BP ≥130 mmHg were recruited between 06/27/2018 and 07/31/2022. The multifaceted implementation strategy includes provider training, protocol-based treatment using the SPRINT (Systolic Blood Pressure Intervention Trial) intensive BP management algorithm, BP audit and feedback, home BP monitoring, and health coaching on lifestyle change and medication adherence for 18 months. Difference in mean systolic BP change from baseline to 18 months is the primary effectiveness outcome, and fidelity summary score, which measures treatment intensification, medication adherence, home BP measurement, and health education, is the primary implementation outcome. Intention-to-treat analyses were conducted. Results: At baseline, mean age was 58.9 years, 56.7% were women, 63.3% were African American, 76.2% were unemployed, and 73.0% had a family annual income <$25,000. In addition, 41.6% participants had hypertension >10 years, and 93.8% were taking antihypertensive medication. Mean systolic BP was 147.6 mmHg and diastolic BP was 84.7 mmHg. At 18 months, mean systolic BP decreased by -16.0 mmHg from baseline in the intervention group and decreased by -9.1 mmHg in the control group with a net difference of -6.9 mmHg (95% CI -9.6 to -4.1 mmHg, p<0.0001). Mean fidelity summary score was 3.4 in the intervention group and 2.8 in the control group, with a group difference of 0.6 (95% CI 0.5 to 0.8, p<0.001). Intervention effects on secondary and adverse outcomes are shown in the Table. Conclusions: As compared with usual care, the multifaceted implementation strategy significantly improved BP control among low-income patients with hypertension who received healthcare at FQHC clinics. This effective and scalable implementation strategy could be widely adopted to improve hypertension control among low-income populations with hypertension in the US and other countries. (ClinicalTrials.gov Identifier: NCT03483662)

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Alexander C Fanaroff¹, Qian Huang¹, Kayla Clark¹, Laurie Norton¹, Wendell Kellum², Dwight Eichelberger², John Wood², zachary bricker², Andrea G Dooley Wood², Greta Kemmer², Jennifer I Smith², Srinath Adusumalli³, Mary Putt⁴, Kevin Volpp⁵; ¹Medicine, Univ of Pennsylvania, Philadelphia, PA, ²Medicine, Lancaster General Health System, Lancaster, PA, ³Medicine, Hosp of the Univ of PA, Philadelphia, PA, ⁴Biostatistics, Epidemiology, and Informatics, Univ of Pennsylvania, Philadelphia, PA, ⁵Medicine, Univ of Pennsylvania, Philadelphia, PA

Introduction: The majority of U.S. adults with an indication for statin therapy are not prescribed statins at guideline-recommended intensity. Clinicians’ limited time to address preventative care issues is cited as one factor contributing to gaps in statin prescribing. We conducted two pragmatic clinical trials testing the effect of nudges in increasing referrals of appropriate patients to a centralized pharmacy service for lipid management. Methods: Patients were eligible for inclusion if they had an assigned primary care provider (PCP)in a large, community health care system and were not prescribed a high- or moderate-intensity statin despite an indication, identified via an electronic health record (EHR) algorithm. Trial #1 was a stepped wedge trial, conducted at a single practice with randomization at the PCP level, of an interruptive HER message that appeared during eligible patients’ visits and facilitated referral to the pharmacy service. For the first 3 months, no PCPs received the message; for the second 3 months, half were randomly selected to receive the message; and for the last 3 months, all PCPs received the message. Trial #2 was a cluster-randomized trial conducted at 10 practices, with randomization at the practice level. Practices were randomized to usual care or to have eligible patients automatically referred to centralized pharmacy services via a referral order placed in PCPs EHR inboxes for co-signature. In both trials, when a patient was referred to centralized pharmacy services, a pharmacist reviewed the patient’s chart, contacted the patient, and initiated statin therapy if the patient agreed. The primary endpoint of both trials was the proportion of patients prescribed a statin. Results: Overall,1312 patients were enrolled in Trial #1 and 1950 in Trial #2. The mean age was 65.6years, 43.7% were female, and the mean baseline ASCVD risk score was 17.9%. 88%of patients were not prescribed a statin at baseline; the remainder were prescribed a statin at an inappropriately low dose. In Trial #1, there was no difference in the prescription rate of any statin or appropriate-intensity statin between the intervention and control conditions (OR 0.77, 95% CI0.52-1.13 for any statin prescription). In Trial #2, at intervention arm practices, 31.6% of patients at intervention arm practices were prescribed a statin during the study period, compared with 15.2% of patients at usual care practices (OR 2.22; 95% CI 1.47-3.37); 24.8% of patients were prescribed an appropriate dose statin over the course of the study period, compared with 7.7%at usual care practices (OR 6.79; 95% CI 4.00-11.53). Conclusions: A population health management strategy of automated referrals to centralized pharmacy services for lipid management was more effective than usual care in increasing the proportion of patients prescribed a statin, whereas an interruptive visit-based message was not.

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Dike Ojji1, Abigail S Baldridge², IKECHUKWU A ORJI³, Gabriel Shedul⁴, Blessing Akor⁵, Boni Ale⁶, Kasarachi Omitiran⁷, NONYE EGENTI⁸, Helen Eze⁹, Guhan Iyer¹³, Erica Jamro-Comer¹⁰, Namratha Kandula¹¹, Ada Nwankwo¹, Tunde M. Ojo¹, Rosemary Okoli¹, Samuel Osagie¹, Nanna Ripiye¹, Olutobi Sanuade, University of Utah, Salt Lake City, UT, Gabriel Shedul¹, Eugenia N. Ugwuneji Cardiovascular Research Unit¹, Jiancheng Ye², Lisa Hirschhorn¹², Mark D Huffman¹³, on behalf of the Hypertension Treatment in Nigeria Program Investigators⁵; ¹Internal Medicine, Univ of Abuja Teaching Hosp, Gwagwalada, Abuja, Nigeria, ²NORTHWESTERN UNIVERSITY, Chicago, IL, ³Univ of Abuja, Nigeria, Abuja, ⁴Univ of Abuja Teaching Hospital, Abuja, ⁵, ⁶Paris, France, ⁷FCT, ⁸ABUJA, ⁹Abuja, ¹⁰Clifton Park, NY, ¹¹Namratha Kandula, Chicago, IL, ¹²Northwestern Univ, Chicago, IL, ¹³Medicine, Washington Univ in St. Louis, Saint Louis, MO

Background: Strategies are needed to address low hypertension control rates in Nigeria, the most populous country in Africa. Objective: To evaluate effectiveness and implementation of a large-scale, multi-level hypertension program, adapted from the Kaiser Permanent Northern California and World Health Organization HEARTS models, within public primary healthcare centers (PHCs) in the Federal Capital Territory of Nigeria. Methods: Following formative (2019) and pre-implementation (2020) periods, a multi-level strategy bundle was implemented across 60 PHCs in the Federal Capital Territory of Nigeria from January 2021 to June 2023. The bundle included: 1) registration and empanelment, 2) team-based care led by community health extension workers, 3) quarterly site supervision, 4) national treatment protocol emphasizing fixed-dose combination therapy, 5) access to quality essential medicines and technology, and 6) health coaching and home blood pressure monitoring. Patient-level data were collected during index and follow-up visits among individuals with hypertension (>140/90 mmHg). Unadjusted 6-month rolling average hypertension treatment (end-of-visit prescription) and control (<140/90 mmHg) rates are reported. A two-sided p-value <0.05 was used to define statistical significance of temporal trends. Results: Among 20,378 patients, mean (SD) age was 49 (12) years, 68% were female, mean (SD) body mass index was 28 (6) kg/m², and 27% had no formal education. Over the study period125,583 visits were reported. In February 2020 (n=585 patients), the first full month of recruitment, treatment and control rates were 84.0% (95%CI: 83.6, 84.3) and 22.1% (95% CI: 21.6, 22.6), respectively. Implementation and effectiveness outcomes are shown in the Figure, including treatment and control rates of 95.8% (95%CI: 95.8, 95.8) and 55.7% (95%CI: 55.7, 55.8) in June 2023 (n= 1,861 patients). There was consistent increase in implementation of all bundle components during the post-implementation period (p<0.01 for all). Conclusion: A large-scale, multi-level hypertension program led by community health extension workers was successfully implemented and improved hypertension control in the Federal Capital Territory. Trial registration: NCT04158154

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Demilade A Adedinsewo¹, Andrea Carolina M Morales Lara¹, Patrick W Johnson², Mikolaj A Wieczorek², Jennifer Dugan³, Xiaoxi Yao⁴, Zachi I Attia³, Francisco Lopez-Jimenez⁵, Paul A Friedman³, Peter A Noseworthy³, Rickey E Carter², SPEC-AI Nigeria Investigators; ¹Cardiovascular Medicine, Mayo Clinic, Jacksonville, FL, ²Quantitative Health Sciences, Mayo Clinic, Jacksonville, FL, ³Cardiovascular Medicine, Mayo Clinic, Rochester, MN, ⁴Cardiovascular Medicine, Health Care Delivery Rsch, Mayo Clinic, Rochester, MN, ⁵Cardiovascular Medicine, Mayo Clinic Coll Medicine, Rochester, MN

Background: Nigeria has the highest reported incidence of peripartum cardiomyopathy worldwide. A delay in the diagnosis and treatment of cardiomyopathy significantly contributes to excess maternal deaths and severe morbidity. Our goal was to test the hypothesis that an artificial intelligence (AI) based intervention can improve the diagnosis of pregnancy related cardiomyopathy. Methods: We conducted an open-label, randomized, pragmatic clinical trial (NCT05438576) to evaluate the impact of AI-guided screening to detect cardiomyopathy, defined as left ventricular ejection fraction (LVEF) <50% by echocardiography, in an obstetric population in Nigeria. Pregnant and postpartum individuals were enrolled from prenatal clinics and postpartum wards at 6 teaching hospitals in Nigeria and randomized in a 1:1 fashion to usual care or AI screening. The AI screening used a digital stethoscope (Eko DUO) to record a single lead ECG + phonocardiogram in 2 locations across the chest wall and a single lead ECG in the handheld position. The AI arm also had a study-prescribed echocardiogram in order to validate the AI-ECG algorithm in this population. For determination of the primary outcome in the control arm, clinical documentation of systolic dysfunction was used and in the intervention arm, the echocardiogram results were only considered for disease detection if the AI results were positive at time of ECG acquisition. Results: Among 1232 women randomized, 1195 completed baseline assessments (587 in the intervention arm and 608 in the control arm). The median age was 31 years and 39% were in their third trimester. AI-guided screening (digital stethoscope maximum prediction across all locations recorded) was associated with an increase in the diagnosis of cardiomyopathy - LVEF <50% (24/587 vs. 11/608; odds ratio 2.31, 95% CI: 1.12, 4.77; p=0.019). Among participants in the intervention arm, the digital stethoscope had an AUC of 0.95 (95% CI: 0.92, 0.99) for detection of LVEF <50% and 0.98 for detection of LVEF <40% (95% CI: 0.97, 0.99). Conclusion: The study intervention resulted in double the number of cardiomyopathy cases diagnosed in the control arm, suggesting that half are likely under detected with usual care. In pregnant and postpartum women, AI-guided screening improves the diagnosis of pregnancy related cardiomyopathy, a potentially life-threatening and treatable condition.

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William T Abraham¹, Tuvia Ben Gal², Sean Pinney³, Offer Amir⁴, Jean Marc Weinstein⁵, Daniel Murninkas⁶, Zaza Iakobishvili⁶, Chaim Yosefy⁷, Michael Kleiner Shochat⁸, Robert Dragu⁹, Elisha J Ouzan¹⁰, Chaim Lotan¹¹, Elazer Edelman¹², Ilan Shallom¹³, Ronit Haviv¹³, Daniel Burkhoff¹⁴, Stefan D Anker¹⁵; ¹Cardiovascular Medicine, Ohio State Univ, Columbus, OH, ²Cardiology, Rabin Med Cntr, Petah Tikva, Israel, ³Cardiovascular Medicine, Mount Sinai Morningside, New York, NY, ⁴Cardiology, Hadassah Med Cntr, Jerusalem, Israel, ⁵Cardiovascular Medicine, Soroka Univ Med Cntr, Beer Sheva, Israel, ⁶Cardiology, Clalit Health Services, Bat-Yam, Israel, ⁷Cardiology, Barzilai Med Cntr, Ashkelon, Israel, ⁸Cardiology, Hillel Yaffe Med Cntr, Hadera, Israel, ⁹Cardiology, Hagalil Med Cntr, Nahariya, Israel, ¹⁰Cardiology, Hadassah Hebrew Med Cntr, Jerusalem, Israel, ¹¹Cardiology, Hadassah Univ Hosp, Jerusalem, Israel, ¹²Med Engineering, Massachusetts Institute Techology, Cambridge, MA, ¹³NA, Cordio Med, Or-Yehuda, Israel, ¹⁴Cardiology, Cardiovascular Rsch Foundation, New York, NY, ¹⁵Cardiology, Charite Univ, Berlin, Germany

Background: Detecting and preventing worsening heart failure events (HFEs) requiring hospitalization and/or intravenous therapies remains an unmet medical need. The objective of the present study was to develop and validate a practical user-friendly tool for predicting such events in ambulatory heart failure patients well in advance ofthe requirement for hospitalization and/or intravenous therapies. Methods: The Cordio HearO^® system is a remote monitoring system comprised of a smartphone-based mobile speech application (App) and cloud-based computing to detect changes in speech measures (SM) indicative of worsening heart failure. The Cordio HearO^® Community Study was a multicenter, non-interventional, single-arm clinical study that enrolled New York Heart Association Class II and III HF outpatients, irrespective of left ventricular ejection fraction. Using the App, patients recorded 5 sentences daily in their native language. Distinct SM, which may be indicative of heart failure clinical status, were evaluated retrospectively in a training dataset (development group) and prospectively tested in a separate dataset (test group) to evaluate their ability to detect future worsening HFEs requiring hospitalization and/or intravenous therapies. Results: In the development group, 263 patients were enrolled between March 27, 2018 and November 30, 2021 and followed for upto 44 months or 189,406 patient-days. Recordings were provided on 158,024 days (83%). In the test group, 153 patients were enrolled between February 1, 2020, and April 30, 2023 and followed for up to 31 months or 116,372 patient-days. Recordings were provided on 94,202 days (81%). In the development group, of 58first and recurrent HF events in 43 patients, 44 events (sensitivity 76.3% [SE5.8%]; 95% CI: 62.6%-86.1%) were detected prior to the event. Among the 43first events, 35 events (sensitivity 81.4% [SE 5.9%]; 95% CI: 69.8%-93.0%) were detected. In the test group, 14 first and recurrent events occurred in 13patients, and 10 events (sensitivity 71.4% [SE 12.1%]; 95% CI: 40.8%, 90.1%) were detected, and among 13 first events, 10 events (sensitivity 76.9% [SE11.7%]; 95% CI: 54.0%, 99.8%) were detected. In both development and test groups, events were detected approximately 3 weeks in advance, and the unexplained priority notification rate was about 3 notifications per year. Conclusions: This novel speech analysis technology detects future worsening HF events with a high sensitivity and low unexplained notification rate supporting its potential to reduce such events and improve patient outcomes.

Author Disclosures: For author disclosure information, please visit the AHA Scientific Sessions 2023 Online Program Planner and search for the abstract title.

Chin-Sheng Lin¹, CHIN LIN², Wei-Ting Liu³; ¹Dept of internal medicine, Tri-Service General Hosp, Taipei, Taiwan, ²Sch of Medicine, National Defense Med Cntr, Taipei, Taiwan, ³department of medicine, Tri-Service General Hosp, Taipei, Taiwan

Introduction: To equip essential evidence of artificial intelligence-enabled electrocardiography (AI-ECG) in facilitating the management of ST-elevation myocardial infarction (STEMI), this study aimed to assess the impact of AI-ECG on treatment waiting times and diagnostic accuracy in real-world settings. Methods: An open-labelled randomized controlled trial (ClinicalTrials.gov Identifier NCT05118009) was conducted, which enrolled 20 on-duty cardiologists (12 attending physicians and 8 residents). Patients in emergency department and inpatient department were analyzed. The trial analyzed data from May 1, 2022, to April 31, 2023, with dates randomly allocated to either the intervention group (receiving AI-ECG alert) or control group (receiving standard care). The cardiologists on duty comprised one attending physician and up to two residents each day, collectively responsible for catheterization laboratory activation. The primary outcome was the ECG to catheterization laboratory time using Mann-Whitney U test, and secondary outcomes included STEMI related events, clinical outcomes, and diagnostic accuracy. Results: Of 43,176 patients (average age 60, 49.5% male), 145 patients (intervention = 77; control = 68) were finally diagnosed as STEMI based on coronary angiography (CAG-STEMI). The AI-ECG significantly (p = 0.003) reduced the median time of ECG to catheterization laboratory from 52.3 minutes (IQR: 44.1-68.6) to 43.3 minutes (IQR: 29.0-58.3), with more impacts observed in the emergency department [intervention: 43.0 (IQR: 29.6-55.7) vs. control: 52.3 (IQR: 44.1-68.6), p = 0.001]. We demonstrated that the intervention group had significantly fewer (OR: 0.37, 95% CI: 0.14-0.94) non-CAG-validated STEMIs among AI-identified STEMI [7/108 (6.5%)] compared to the control group [16/111 (15.8%)]. Importantly, the beneficial effects were more pronounced in the inpatient department, with the intervention group exhibiting 7 CAG-STEMIs, whereas the control group had only 1 CAG-STEMI (OR: 6.97, 95% CI: 0.86-56.65). No significant differences were observed between the intervention and control groups in CAG-STEMIs, regarding ejection fraction, peak levels of troponin I and creatine kinase, and the length of hospitalization. The AI-ECG exhibited a positive predictive value of 88.0% (95% CI: 81.8%-94.1%) and a negative predictive value of 99.9% (95% CI: 99.9%-100.0%). Conclusion: This trial furnishes evidence of AI-ECG’s effectiveness in mitigating treatment delays and enhancing diagnostic accuracy for STEMI patients.

Author Disclosures: For author disclosure information, please visit the AHA Scientific Sessions 2023 Online Program Planner and search for the abstract title.

Kenneth Chan¹, Elizabeth Wahome¹, Alexios S Antonopoulos¹, Apostolos Tsiachristas², Ed Nicol³, David Adlam⁴, Jonathan Rodrigues⁵, Nicholas Screaton⁶, Attila Kardos⁷, John P GREENWOOD⁸, Milind Y Desai⁹, Henry West¹, Parijat Patel¹, Pete Tomlins¹⁰, Stefan Neubauer¹, Keith M Channon¹, John Deanfield¹¹, Charalambos Antoniades¹²; ¹Div of Cardiovascular Medicine, Univ of Oxford, Oxford, United Kingdom, ²Nuffield Dept of Primary Care Health Sciences & Dept of Psychiatry, Univ of Oxford, Oxford, United Kingdom, ³Royal Brompton and Harefields Hosp, Royal Brompton and Harefields Hosp, London, United Kingdom, ⁴CARDIOVASCULAR SCIENCES, Univ of Leicester, Leicester, United Kingdom, ⁵Dept of radiology, Royal United Hosps Bath, Bath, United Kingdom, ⁶Radiology, Royal Papworth Hosp NHS Foundation Trust, Cambridge, United Kingdom, ⁷Milton Keynes Univ Hosp, Dept of Cardiology, Milton Keynes, United Kingdom, ⁸Cardiology, Leeds Univ and Leeds Teaching Hosps NHS Trust, Leeds, United Kingdom, ⁹Cardiology, Cleveland Clinic Heart and Vascular Institute, Solon, OH, ¹⁰Caristo Diagnostic Ltd, Caristo Diagnostic Ltd, Oxford, United Kingdom, ¹¹Cardiology, Univ College London, London, United Kingdom, ¹²Div of Cardiovascular Medicine, Univ Oxford, Oxford, United Kingdom

Background: Coronary inflammation can be quantified from routine coronary CT angiograms (CCTA) using the Fat Attenuation Index (FAI) score. An artificial intelligence-assisted prognostic model (AI-Risk) that captures the 8-year residual inflammatory risk by integrating CCTA-derived metrics (including FAI Score and plaque burden) and the patient’s clinical risk factors has initially been trained in a US population (CRISP-CT study). We sought to validate the performance of FAI Score and AI-Risk, in a non-US population and evaluate its real-world impact on patient management. Methods: Individuals undergoing CCTA in 7 UK Hospitals (n=40,091) were followed up prospectively for Major Adverse Cardiac Events (MACE; non-fatal myocardial infarction, new onset heart failure, or cardiac death) in the ORFAN study (Study A). In a nested study of 3,393 patients (Study B), we evaluated the prognostic value of FAI Score and performance of AI-Risk (generated by CaRi-Heart platform) over a median (IQR) of 7.7 (6.4-9.1) years. The impact of AI-Risk on clinical management was prospectively assessed in a real-world evaluation in 744 consecutive patients undergoing CCTA for chest pain investigation in 4 UK hospitals (Study C). Results: In study A, MACE occurred in 1,453 (20.1%) patients with obstructive and 3,124 (9.5%) without obstructive CAD (Panel A). In study B, patients with FAI Score in the LAD above the 75^th percentile had 6.7x higher risk of MACE (Panel B) vs those under the 25^th percentile; among those without obstructive CAD, the risk of MACE was still 4.8x higher (Panel C), all independent of risk factors and CAD-RADS2. Similar results were observed for FAI Score in the LCX and RCA (data not shown). Patients identified as high/very high risk by AI-Risk had significantly higher risk of MACE independently from the presence of obstructive CAD (Panels D and E). AI-Risk significantly reclassified patients compared to a clinical risk factors-based risk prediction model (QRISK3) in the whole cohort and those without obstructive CAD (Panel F). In the real-world evaluation, AI-Risk resulted in change of management in 45% of the patients, by triggering statin initiation (24%), statin dose-intensification (13%) or addition of further treatments (e.g. colchicine, 8%). Conclusion: Patients with high coronary inflammation, measured by FAI Score, have substantially higher risk for MACE. The AI-assisted absolute risk prediction algorithm (AI-Risk) leads to reclassification and change of management in a substantial proportion of patients undergoing routine CCTA and can be used as a precision medicine tool.

Author Disclosures: For author disclosure information, please visit the AHA Scientific Sessions 2023 Online Program Planner and search for the abstract title.

Emmanuel Ekanem¹, MANIFEST-10K Consortium, Vivek Y Reddy²; ¹Cardiology, Winchester Med Cntr-Valley He, Winchester, VA, ²Cardiology, Mount Sinai Sch of Medicine, New York City, NY

Background: Pulsed field ablation (PFA) is an emerging atrial fibrillation (AF) ablation energy with some degree of preferentiality to myocardial tissue ablation. Preclinical studies demonstrated no (or little) damage to peri-atrial tissues like the esophagus or phrenic nerve, and no pulmonary vein (PV) stenosis. After CE-Mark certification of a PFA system in March 2021, the MANIFEST-PF Survey of all AF patients receiving PFA in year 2021 (n=1758 at 24 European centers) revealed no esophageal damage or PV stenosis, and phrenic palsy in <0.1%. But, 1) for cryoablation, esophageal fistula only occurred after a few thousand patients were treated, and 2) unforeseen PFA-related adverse events (AEs) may only manifest after many cases. Thus, the retrospective MANIFEST-10K survey was designed to assess safety of PFA in a very large patient cohort (goal >10,000 patients). Methods: A survey to assess AEs was sent to all 116 clinical centers in 20 countries (initial 24 MANIFEST-PF centers + cohort of 92 Expanded centers) performing post-approval PFA with the pentaspline catheter (Farawave, Boston Scientific Inc). From the 24 MANIFEST-PF sites, the initial 1,758 patients were excluded. The center-level data was augmented by queries about specific reported AEs. Results: Data was received from 102 of 116 centers (88% response), with 3.8 operators/site (range 1-11), including 17,068 PFA patients (167/site, range 17-1,277; treated Jan 2022 - Jul 2023): mean age 64.1, female 34.4%, PAF 57.3%/ PerAF 35.5%/ LSPerAF 5.7%/ AFL 1.5%. PFA was under deep sedation (54.2%) or general anesthesia (45.8%). There were no esophageal AEs, PV stenosis or persistent phrenic palsy (transient palsy in 0.06%; Table). Major AEs (1.01%) were pericardial tamponade (0.34%) and vascular AEs (0.31%). Stroke was rare (0.13%), and death occurred in only 0.03%. Unexpected AEs included coronary spasm in 0.16%, and acute renal failure (ARF) due to hemolysis in 0.03%. The initial MANIFEST-PF (N=24) and Expanded (N=78) cohorts had similar rates of major (p=0.79) and minor (p=0.88) AEs - including the rates of tamponade, stroke, vascular AEs and spasm; however, deaths were only observed in the Expanded cohort (0.03% vs 0%). [Further details on deaths, spasm and ARF-hemolysis will be available in Nov 2023.] Conclusion: In this analysis of the majority of patients who have undergone PFA, the safety profile was consistent with preferential tissue ablation: no esophageal AEs or PV stenosis, and phrenic palsy in < 1 in 1000. Mortality was < 1 in 1000, but unexpected AEs (coronary spasm and hemolysis) did occur, albeit rarely, and require further study.

Author Disclosures: For author disclosure information, please visit the AHA Scientific Sessions 2023 Online Program Planner and search for the abstract title.

Alan J Camm¹, Jonathan P Piccini², Marco Alings³, Paul Dorian⁴, gilbert gosselin⁵, James E Ip⁶, Peter R Kowey⁷, Blandine Mondesert⁸, Paco prins⁹, Jean-Francois Roux¹⁰, Bruce Stambler¹¹, Jacob van Eck¹², Nadea Al Windy¹³, Nathalie Thermil¹⁴, Silvia Shardonofsky¹⁵, David Bharucha¹⁶, Denis Roy¹⁷; ¹Clinical Cardiology, St. Georges Univ of London, London, United Kingdom, ²Medicine, Duke Univ Med Cntr, Durham, NC, ³Surgery, Amphia Ziekenhuis, Breda, Netherlands, ⁴Cardiology, Univ of Toronto, Toronto, Canada, ⁵Medicine, Montreal Heart Institue, Montreal, Canada, ⁶Cardiology, Weill Cornell Medicine, New York, NY, ⁷Cardiovascular Rsch, Lankenau Med Cntr, Wynnewood, PA, ⁸Cardiology, Montreal Heart Institute, Montreal, Canada, ⁹Clinical Cardiology, Elkerliek, Rotterdam, Netherlands, ¹⁰Clinical Cardiology, Cntr Hospier Universitaire de Sherbrooke, Sherbrooke, Canada, ¹¹Cardiology, Piedmont Heart of Jasper, Jasper, GA, ¹²Clinical Cardiology, Jeroen Bosch Hosp, ‘s-Hertogenbosch, Netherlands, ¹³Clinical Cardiology, Gelre ziekenhuizen, Gelderland, Netherlands, ¹⁴Clinical Development, Milestone Pharmaceuticals, Montreal, Canada, ¹⁵Med Affairs, Milestone Pharmaceuticals, Montreal, Canada, ¹⁶Med Affairs, Milestone Pharmaceuticals, Charlotte, NC, ¹⁷Medicine, Montreal Heart Institute, Montreal, Canada

Introduction: Atrial fibrillation(AF) is frequently associated with symptomatic episodes of rapid ventricular rate (RVR) despite currently available therapies. Timely treatment of AF-RVR remains a challenge. Patients who present to an emergency department (ED) for AF-RVR are often treated with intravenous drugs to provide quick reduction in RVR and symptoms. Oral drugs taken as-needed do not provide prompt ventricular rate (VR) control. Etripamil nasal spray (NS) is a fast-acting, new chemical entity, non dihydropyridine calcium channel blocker under study in supraventricular tachycardia and AF-RVR. ReVeRA-201 (NCT04467905) was a randomized, double-blind, placebo-control multicenter study of etripamil NS in patients with AF-RVR. Study: ReVeRA was conducted in Canada and The Netherlands with a primary objective to demonstrate superiority of etripamil NS vs placebo in reducing VR in patients with symptomatic AF-RVR. Patients presenting to an ED with AF-RVR were screened and randomized1:1 to receive double blinded etripamil 70 mg NS or placebo NS. Inclusion criteria included age ≥18 y and AF with VR ≥110 bpm prior to drug. ECG monitoring, ≥10 min prior and 6 h after drug, was performed with a 3-channel ambulatory device that allowed discharge from the ED. Re-evaluation occurred after 1 and 7 days. Results: Eighty-seven patients were screened, 56 were randomized and dosed, 27 with etripamil and 29with placebo. The difference between the maximum mean reductions in VR (baseline to nadir) over 60 min, etripamil vs placebo arms, adjusting for baseline VR, was -29.91 (95% CI: -40.31, -19.52; p<0.0001). The greater VR reductions in etripamilvs placebo arms persisted for ≥150 min (Fig. 1). Proportions of patients achieving a VR <100 bpm during the first 60 min were 58.3% in the etripamil arm (median duration 45.5 min) vs 4.0% in the placebo arm (median duration 7min in 1 patient) (p<0.0001). In the etripamil arm 96% and 67% of patients achieved ≥10% and ≥20% reductions in VR in the first 60 min; in the placebo arm, 20% and 0%, respectively. Using the Treatment Satisfaction Questionnaire 9,there was improvement in satisfaction on relief of symptoms (p<0.0001) and treatment-effectiveness (p<0.0001) with etripamil vs placebo. Serious AE’s were rare (1 patient, etripamil arm; 2 patients placebo arm). Conclusion: Etripamil NS significantly reduced VRand improved symptom-relief and treatment-satisfaction, rapidly after drug administration consistent with its pharmacologic profile. These data support development of self-administered etripamil for treatment of AF-RVR. Funding: Milestone Pharmaceuticals, North Carolina, USA & Québec, Canada.

Figure 1. Mean change (±standard error of the mean) in ventricular rate (bpm) from baseline over 180 minutes.

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Pugazhendhi Vijayaraman¹, Parikshit Sharma², Oscar Cano³, S S Shanmuga⁴, Francesco Zanon⁵, Marek Jastrzebski⁶, Jiangang Zou⁷, Mihail G Chelu⁸, Kevin Vernooy⁹, Zachary Whinnett¹⁰, Girish Nair¹¹, Manuel Molina-Lerma¹², Karol Curila¹³, Dipen Zalavadia¹⁴, Lina Marcanthony¹⁵, Andrew M Leong¹⁶, Cicely Dye¹⁷, Sharath Vipparthy¹⁸, Antonius van Stipdonk¹⁹, Ryan Brunetti²⁰, Pawel Moskal²¹, Jerin George⁸, Yusuf Qadeer²², MISHAL Mumtaz²⁰, Jeffrey Kolominsky²³, Syeda Anum Zahra²⁴, Mehrdad Golian²⁵, Faiz Subzposh²⁶, Kenneth A Ellenbogen²⁷, Bengt Herweg²⁸; ¹Cardiac Electrophysiology, Geisinger Heart Institute, Wilkes Barre, PA, ²Cardiology, Rush Univ Med Cntr, Chicago, IL, ³Cardiology, Hosp Universitari i Politècnic La Fe and Cntr de Investigaciones Biomédicas en RED en Enfermedades Cardiovasculares, Valencia, Spain, ⁴Cardiology, Velammal Med College Hosp, Madurai, India, ⁵Cardiology, Santa Maria della Misericordia Hosp, Rovigo, Italy, ⁶Cardiology, First Dep of Cardiology UJ, Krakow, Poland, ⁷Cardiology, 1st Affilicated Hsp, Nanjing, China, ⁸Cardiology, Baylor College of Medicine, Houston, TX, ⁹Cardiology, Maastricht UMC, Maastricht, Netherlands, ¹⁰Cardiology, Imperial College London, London, United Kingdom, ¹¹Cardiology, Univ of Ottawa Heart Institut, Ottawa, Canada, ¹²Cardiology, Hosp Virgen de las Nieves, Granada, Spain, ¹³Cardiology, Dept of Cardiology FNKV, Prague, Czech Republic, ¹⁴Cardiology, Wright Cntr, Wilkes Barre, PA, ¹⁵Cardiology, Santa Maria Della Misericordia Hosp, Rovigo, Italy, ¹⁶Cardiology, Imperial College London, London, United Kingdom, ¹⁷Cardiac Electrophysiology, Rush Univ, Chicago, IL, ¹⁸Cardiac Electrophysiology, Rush Univ Med Cntr, Chicago, IL, ¹⁹cardiology, MUMC and CARIM, Maastricht, Netherlands, ²⁰Cardiac Electrophysiology, Univ of South Florida, Tampa, FL, ²¹cardiac Electrophysiology, Univ Hosp in Krakow, Krakow, Poland, ²²Cardiology, Baylor College of Medicine, houston, TX, ²³Cardiology, VCU, Richmond, VA, ²⁴Cardiac Electrophysiology, Imperial College, London, United Kingdom, ²⁵Cardiology, Ottawa Heart Institute, Ottawa, Canada, ²⁶Cardiology, Geisinger Heart Institute, Wilkes Barre, PA, ²⁷Cardiology, VCU Sch of Medicine, Henrico, VA, ²⁸Cardiology, Univ of South Florida, Tampa, FL

Background: Left bundle branch area pacing (LBBAP) is associated with greater improvement in LV ejection fraction and reduction in death or heart failure hospitalization compared to biventricular pacing (BVP) in patients requiring cardiac resynchronization therapy (CRT). We sought to compare the occurrence of ventricular arrhythmias and new onset atrial fibrillation (AF) among patients with BVP and LBBAP. Methods: This International Collaborative LBBAP Study (I-CLAS) included consecutive patients who underwent BVP or LBBAP for CRT in patients with LVEF≤35% between Jan 2018 to June 2022 at 15 centers. We assessed the incidence of sustained ventricular tachycardia or ventricular fibrillation (VT/VF) and the incidence of new onset AF among patients with no prior h/o AF. Time to sustained VT/VF and time to new onset AF was evaluated using Cox proportional hazards survival model using multivariate analysis. Results: Among 1778 patients undergoing CRT (981 BVP; 797 LBBAP), the occurrence of sustained VT/VF was significantly reduced with LBBAP compared to BVP (3.8% vs 8.9%; HR 2.323; 95%CI 1.382-3.905; p=0.001). The incidence of VT storm (≥3 episodes in 24 hours) was also significantly lower in LBBAP compared to BVP (0.8% vs 2.2%; p=0.012). Among 416 patients with CRT-pacemakers (BVP 149, LBBAP 267), sustained VT/VF occurred in 11 (6.7% vs 0.4%, p<0.001) with subsequent ICD upgrade in 9 patients. Among patients with no prior h/o AF (N=1125), the occurrence of new onset AF >30 seconds was significantly reduced with LBBAP compared to BVP (2.3% vs 8.5%; HR 4.159; 95%CI 2.040-8.479; p<0.001). The incidence of atrial fibrillation lasting >24 hrs was also significantly lower in LBBAP compared to BVP (0.6% vs 3.6%; p<0.001). Conclusions: In this retrospective multi center registry, LBBAP was associated with significantly lower incidence of sustained VT/VF and new onset AF compared to BVP.

Author Disclosures: For author disclosure information, please visit the AHA Scientific Sessions 2023 Online Program Planner and search for the abstract title.

Shinya Fujiki¹, Kenichi Iijima², Yoshihisa Nakagawa³, Kazuyoshi Takahashi⁴, Masaaki Okabe⁵, Kengo F Kusano⁶, Shingen Owada⁷, Yusuke Kondo⁸, Kenichi Tsujita⁹, Wataru Shimizu¹⁰, Hirofumi Tomita¹¹, Masaya Watanabe¹², Koichi Node¹³, Tohru Minamino², EMPA-ICD investigators; ¹Dept of Cardiovascular Biology and Medicine, Niigata Univ Graduate Sch of Med and Dental Sciences, Niigata, Japan, ²Dept of Cardiovascular Biology and Medicine, Juntendo Univ Graduate Sch of Medicine, Tokyo, Japan, ³Dept of Cardiovascular Medicine, Shiga Univ of Med Science, Shiga, Japan, ⁴Dept of Cardiology, Niigata City General Hosp, Niigata, Japan, ⁵Dept of Cardiology, Tachikawa General Hospxx, Niigata, Japan, ⁶DEPT OF CARDIOVASCULAR MEDICINE, NATL CEREBRAL AND CARDIOVASC CENTER, Osaka, Japan, ⁷Dept of Cardiology, Iwate Med Univ Hosp, Iwate, Japan, ⁸Dept of Cardiovascular Medicine, Chiba Univ, Chiba, Japan, ⁹Dept of Cardiovascular Medicine, KUMAMOTO UNIV, Kumamoto, Japan, ¹⁰Dept of Cardiovascular Medicine, NIPPON MEDICAL SCHOOL, Tokyo, Japan, ¹¹Dept of Cardiology and Nephrology, HIROSAKI UNIVERSITY, Hirosaki, Japan, ¹²Dept of Cardiovascular Medicine, Hokkaido Univ Graduate Sch of Medicine, Hokkaido, Japan, ¹³Dept of Cardiovascular Medicine, SAGA UNIVERSITY, Saga, Japan

Background and Aims: Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure and cardiovascular death with type 2 diabetes; however, their effect on arrhythmias is unclear. The purpose of this study was to investigate the effects of empagliflozin on ventricular arrhythmias in patients with type 2 diabetes. Study Design and Methods: The present study was a prospective, multicenter, placebo-controlled, double-blind, randomized, investigator-initiated clinical trial. A total of 150 patients with type 2 diabetes who were treated with an implantable cardioverter-defibrillator or cardiac resynchronization therapy defibrillator (ICD/CRT-D) were randomized to once-daily empagliflozinor placebo for 24 weeks. The primary endpoint was the change in the number of ventricular arrhythmias from the 24 weeks before to the 24 weeks during treatment. Secondary endpoints included the change in the number of appropriate device discharges and other values. Results: In the empagliflozin group, the number of ventricular arrhythmias recorded by ICD/CRT-D decreased by 1.69 ± 21.46 during treatment compared to before treatment, while in the placebo group, the number increased by 1.79±10.67 (Figure 1). The between-group difference in the change in the number of ventricular arrhythmias was -1.07 (95% confidence interval [CI], -1.29 to -0.86; P<0.001)(Table). The change in the number of appropriate device discharges was 0.06±0.70 in the empagliflozin group and 0.27±1.86 in the placebo group (group difference, -1.16; 95% CI, -2.95 to 0.63) (Figure 2, Table). The change in the number of total ventricular premature contractions recorded by Holter monitoring was 19.50 ± 3346.17 in the empagliflozin group and 392.84 ± 2584.89 in the placebo group (group difference, -373.30; 95% CI, -1478.70 to 732.00). Empagliflozin was associated with an increase in blood ketones and hematocrit and a decrease in blood brain natriuretic peptide and body weight (Table). Conclusions: In patients with type 2 diabetes treated with ICD/CRT-D, empagliflozin reduces the number of ventricular arrhythmias compared with placebo.

Author Disclosures: For author disclosure information, please visit the AHA Scientific Sessions 2023 Online Program Planner and search for the abstract title.

Brian P McGrath¹, Natalia Pinilla², DAVID A WOOD³, Kevin R Bainey⁴, Tej Sheth², Erick Schampaert⁵, Jean-Francois Tanguay⁶, Vladimir Dzavik⁷, Robert F Storey⁸, Roxana Mehran⁹, Matthias Bossard¹⁰, Raul Moreno¹¹, Gianluca Campo¹², Sunil Rao¹³, Warren Cantor¹⁴, Shahar Lavi¹⁵, Thenmozhi Mani¹, Helen Nguyen¹⁶, John A Cairns¹⁷, Shamir R Mehta¹⁸; ¹McMaster Univ and Hamilton Health Sciences, Population Health Rsch Institute, Hamilton, ON, Canada, ²McMaster Univ and Hamilton Health Sciences, Population Health Rsch Institute, Hamilton, Canada, ³CARDIOLOGY, Univ of British Columbia, VANCOVER, Canada, ⁴CARDIOLOGY, UNIVERSITY OF ALBERTA, Edmonton, Canada, ⁵CARDIOLOGY, Hôpital du Sacré-Coeur de Montréal, Université de Montréal, Montreal, Canada, ⁶CARDIOLOGY, Montreal Heart Institute, Montreal, Canada, ⁷CARDIOLOGY, UNIVERSITY HEALTH NETWORK, Toronto, Canada, ⁸CARDIOLOGY, UNIVERSITY SHEFFIELD MEDICAL SCHOOL, Sheffield, United Kingdom, ⁹CARDIOLOGY, ICAHN SCHOOL OF MEDICINE MT SINAI, New York, NY, ¹⁰CARDIOLOGY, Luzerner Kantonsspital, Luzern, Switzerland, ¹¹CARDIOLOGY, Univ Hosp La Paz, Madrid, Madrid, Spain, ¹²CARDIOLOGY, Azienda Ospedaliero Universitaria di Ferrara, Ferrara, Italy, ¹³CARDIOLOGY, NYU Langone Health System, New York, NY, ¹⁴CARDIOLOGY, Southlake Regional Health Cntr, Newmarket, Canada, ¹⁵CARDIOLOGY, UNIVERSITY WESTERN ONTARIO, London, Canada, ¹⁶PHRI, Population Health Rsch Institute, Hamilton, Canada, ¹⁷CARDIOLOGY, UNIVERSITY BRITISH COLUMBIA, Vancouver, Canada, ¹⁸CARDIOLOGY, McMaster Univ, Hamilton, On, Canada

Background: In the COMPLETE (Complete vs Culprit-only Revascularization to Treat Multi-vessel Disease After Early PCI for STEMI) trial, complete revascularization in patients with ST-elevation myocardial infarction (STEMI) and multivessel disease (MVD) reduced clinically important outcomes. A non-culprit lesion (NCL) ≥70% in the left anterior descending (LAD) artery has classically been viewed as a higher risk lesion, particularly with involvement of the proximal segment. Whether clinical outcomes in STEMI patients with MVD are influenced by the location of the NCL remains unknown. Objectives: To determine the impact of proximal and mid LAD non-culprit lesion (NCL) location on major adverse cardiovascular outcomes compared with other NCL locations. Methods: The COMPLETE trial randomized 4,041 patients presenting with STEMI and MVD to angiography-guided complete revascularization versus a culprit-lesion only strategy. All coronary angiograms were evaluated in a central core laboratory. Overall, 1,666 patients had proximal or mid LAD NCLs and 2,185 patients had NCLs in other locations. The co-primary outcomes were 1) cardiovascular (CV) death or new myocardial infarction (MI), and 2) CV death, new MI, or ischemia-driven revascularization (IDR). Separate analyses were performed for proximal LAD NCL versus other locations. Results: Patients with LAD NCLs were older (62.5±10.5 vs 61.6±10.9 years, p=0.005) and more likely female (23.2% vs 17.9%, p<0.001). Those with an LAD NCL had higher baseline (16.7±5.6 vs 15.7±7.4, p<0.001) and residual (9.0 vs 4.0, p<0.001) Syntax scores and more often had ≥2 NCLs (33.3% vs 15.9%, p<0.001). For the first coprimary outcome, the benefit of complete revascularization in those with proximal or mid LAD-NCL (7.7% vs 9.2%, HR 0.85; 95% CI 0.61-1.18) and without proximal or mid LAD-NCL (8% vs 11.9% HR 0.65, 95% CI 0.50-0.86) was similar with no evidence of a differential treatment effect (interaction p=0.235). For those patients with a proximal LAD-NCL (7.1% vs 8.8%, HR 0.80; 95% CI 0.44-1.46) versus another location (8% vs 11%, HR 0.72; 95% CI 0.57-0.90), there was also a similar benefit of complete revascularization (interaction p=0.753). Analogous results were observed for the second co-primary outcome. Conclusion: Among patients presenting with STEMI and multivessel CAD, the benefit of complete revascularization in those with and without proximal or mid LAD NCL location was similar, with no evidence of heterogeneity. Our results support complete revascularization regardless of NCL location.

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Derek S Chew¹, Daniel B Mark², Yanhong Li³, Michael Nanna⁴, Michelle Kelsey⁵, Melanie R Daniels², Linda D Davidson-Ray⁶, Khaula N Baloch², Campbell Rogers⁷, Manesh R Patel⁸, Kevin J Anstrom⁹, nick curzen¹⁰, Sreekanth Vemulapalli¹¹, Pamela S Douglas¹², PRECISE Investigators; ¹Cardiac Sciences, Univ of Calgary, Calgary, Canada, ²Medicine, DUKE UNIV MEDICAL CTR, Durham, NC, ³Biostatistics and Bioinformatics, Duke Univ, Durham, NC, ⁴Cardiovascular Medicine, Yale, New Haven, CT, ⁵Medicine, DUKE UNIVERSITY, Durham, NC, ⁶Medicine, Duke Clinical Rsch Institute, Durham, NC, ⁷HeartFlow, HeartFlow, Mountain View, CA, ⁸Medicine, DUKE MEDICAL CENTER, Durham, NC, ⁹Biostatistics, Univ of North Carolina, Chapel Hill, NC, ¹⁰Medicine, Univ of Southampton, southampton, United Kingdom, ¹¹Medicine, duke university, Durham, NC, ¹²Medicine, DUKE UNIVERSITY DUMC, Durham, NC

Background: The Prospective Randomized Trial of the Optimal Evaluation of Cardiac Symptoms and Revascularization evaluated a novel risk-based precision medicine strategy for patients with non-acute symptoms and suspected coronary artery disease (CAD) using deferred testing for low-risk patients and cCTA with selective FFR for non-low risk patients. This strategy reduced the primary composite endpoint (death, non-fatal myocardial infarction, or catheterization without obstructive CAD) by 65% compared to usual testing. Cost and resource use was a prespecified secondary endpoint of the trial. Methods: PRECISE randomized 2103 patients in Europe and North America between December 2018 and May 2021 at 65 outpatient sites. Mean cohort age was 58 years, 50% were female, 84% White/non-Hispanic, and 22% low risk. Chest pain or its equivalent was the presenting symptom for 83%. We prospectively collected detailed resource consumption data from all study participants and hospital cost data from US participants to estimate total medical costs. Results: In the precision arm, 48% had cCTA alone, 31% cCTA with FFR_CT, and 16% had no test. In the usual care arm, 30% had stress echo, 32% stress nuclear, 11% exercise ECG, and 10% had invasive coronary angiography (ICA) as the initial test. Precision strategy patients had 11% fewer tests and 24% fewer ICA but 80% more revascularizations. At 45 days, total costs were similar (Table). Precision care decreased mean per patient diagnostic cost by $249 and increased mean per patient therapeutic costs by $430. At 1 year, precision strategy costs were $5299 vs $4821 for usual testing (mean difference, $478, 95% confidence interval -$889 to $1437, p=0.43) (Table). In sensitivity analysis reducing FFR_CT cost 25% and 50% reduced the mean 1-year difference to $404 and $329, respectively. Conclusions: The precision strategy had similar costs to usual care at 45 days and a non-significant $478 cost difference at 1 year. The current ACC/AHA guideline-endorsed precision evaluation strategies of deferred testing for low-risk patients and cCTA with selective FFR for non-low-risk patients can improve the clinical efficiency of testing for stable symptomatic patients with suspected CAD with little net effect on medical costs.

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Bjorn Redfors¹, Gregg Stone², John H Alexander³, Eric R Bates⁴, Deepak Bhatt⁵, Tulio Caldonazo⁶, Giuseppe G Biondi-Zoccai⁷, Michael E Farkouh⁸, John D Puskas⁹, Mohamed Rahouma¹⁰, Sigrid Sandner¹¹, Mario F Gaudino¹⁰; ¹Cardiology, Univ of Gothenburg, Goteborg, Sweden, ²Medicine, Mount Sinai Med Cntr, New York City, NY, ³Medicine, Duke Clinical Rsch Institute, Durham, NC, ⁴Medicine, Univ of Michigan, Ann Arbor, MI, ⁵Medicine, Mount Sinai Heart, New York, NY, ⁶Cardiothoracic Surgery, Thüringen Heart Cntr - Univ Hosp Jena, Jena, Germany, ⁷Dept of Medico-Surgical Sciences and Biotechnologies, Sapienza Univ of Rome, Rome, Italy, ⁸Medicine, Peter Munk Cardiac Cntr, Toronto, Canada, ⁹Cardiovascular Surgery, Mount Sinai Morningside, New York, NY, ¹⁰Cardiothoracic Surgery, Weill Cornell Medicine, New York, NY, ¹¹Cardiac Surgery, Med Univ of Vienna, Vienna, Austria

Introduction: In the ISCHEMIA trial, an initial invasive (INV) strategy did not significantly reduce the risk of ischemic events over a median follow-up period of 3.2 years. Revascularization was performed in 2054 patients in the INV arm of ISCHEMIA, of whom 1524 (74.1%) were revascularized by percutaneous intervention (PCI) and 530 (25.8%) by bypass surgery (CABG). The two revascularization modalities have different mechanisms and different periprocedural and long-term outcomes and may compare differently to medical therapy. We conducted a post hoc analysis of the ISCHEMIA trial focusing on the early, late and net risks associated with each revascularization procedure. Methods: Patients were first grouped according to randomized arm (INV versus Conservative [CON] strategy). Patients in the INV arm were categorized in the “INV-Medical therapy” group until they underwent revascularization, experienced a primary endpoint event or reached the end of their follow-up; patients who were revascularized without having a preceding primary endpoint event were moved to the INV-PCI or INV-CABG arms from the time of revascularization until end of follow-up or the occurrence of an endpoint event. Adjusted outcomes versus the CON arm were derived using multivariable Cox proportional hazards regression, with time-varying group status for patients in the INV arm (INV-Medical therapy vs. INV-PCI vs. INV-CABG). The primary endpoint was the same of the ISCHEMIA trial (composite of cardiovascular death, protocol-defined myocardial infarction or hospitalization for unstable angina, heart failure or resuscitated cardiac arrest). Results: Revascularization had a net neutral long-term effect on the primary outcome (Table). However, PCI and CABG were both associated with increased early risks and improved late outcomes compared with CON; the early risk was higher with CABG (Table). The two revascularization modalities were associated with a similar reduction of type 1 myocardial infarction. Conclusions: In the ISCHEMIA trial revascularization with both PCI and CABG was associated with improved post-procedural outcomes, benefits that were offset by peri-procedural complications. Revascularization decisions in stable coronary artery disease should consider the relative impact of these early risks and long-term benefits.

ISCHEMIA Trial

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Uwe Zeymer¹, Freund Anne², Taufik Ouarrak¹, Ibrahim Akin³, Steffen Schneider¹, Desch Steffen², Holger Thiele⁴; ¹Medizinische Klinik B, Institut für Herzinfarktforschung, Ludwigshafen, Germany, ²Dept of Cardiology, Heart Cntr Univ of Leipzig, Leipzig, Germany, ³Cardiology, Medizinische Klinik, Mannheim, Germany, ⁴Dept of Cardiology, Univ Leipzig - Heart Cntr, Leipzig, Germany

Background: Patients with cardiac arrest and infarct-related cardiogenic shock represent a very high-risk population with a high in-hospital mortality. Therefore, mechanical circulatory support devices are increasingly used in order to improve outcome. Venoarterial extracorporeal membrane oxygenation also called extracorporeal life support (ECLS) enables full circulatory and respiratory support differentiating it from other devices and might be especially helpful in patients with cardiac arrest. We therefore analysed the subgroup of patients with cardiac arrest enrolled into the randomized ECLS-SHOCK trial. Methods: Patients between 18 and 80 years with acute myocardial infarction complicated by severe cardiogenic shock and planned early revascularization by either percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) were eligible for inclusion into the ECLS-SHOCK trial. Patients with cardio-pulmonary resuscitation > 45 minutes were excluded. Patients were randomized to early ECLS plus optimal medical therapy versus medical therapy alone. The primary endpoint was 30-day all-cause mortality. Safety endpoints were defined as moderate or severe bleeding defined as type 3-5 according to the Bleeding Academic Research Consortium (BARC) criteria, stroke or systemic embolization and peripheral ischemic vascular complications requiring surgical or interventional therapy. Results: Between June 2019 and November 2022, 877 patients were screened at 44 centers in Germany and Slovenia with 420 patients enrolled in the trial. About 75 % of patients had cardiac arrest before randomization. The results for the 30-day primary and secondary outcomes in the subgroup with and without cardiac arrest will be available in November 2023. Conclusions: The subgroup analysis of the randomized ECLS-SHOCK trial will be helpful to define the impact of a routine strategy with ECLS in patients with infarct-related cardiogenic shock and cardiac arrest.

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Yu-Ping Zhou¹, Wei Ma², YUNSHAN CAO³, Jiang Li⁴, Wei Huang⁵, Lan Wang⁶, Dao Wen Wang⁷, Huaqing Duan⁸, Zhen Wang⁹, Jingshan Shen¹⁰, Zhi-Cheng Jing¹¹, Yong Huo²; ¹Dept of Cardiology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Med College Hosp, Beijing, China, ²Dept of Cardiovascular Disease, Peking Univ First Hosp, Beijing, China, ³Dept of Cardiology, Gansu Provincial Hosp, Gansu, China, ⁴Dept of Cardiovascular Medicine, Second Xiangya hospital, Central South Univ, Changsha, China, ⁵Dept of Cardiology, First Affiliated Hosp of Chongqing Med Univ, Chongqing, China, ⁶Shanghai Pulmonary Hosp, Shanghai Pulmonary Hosp Affiliated to Tongji Univ Sch of Medicine, Shanghai, China, ⁷Div of Cardiology, Dept of Internal Medicine, Tongji Hosp, Wuhan, China, ⁸Vigonvita Life Sciences Co.,Ltd, Vigonvita Life Sciences Co.,Ltd, Jiangsu, China, ⁹Lingang Laboratory, Lingang Laboratory, Shanghai, China, ¹⁰CAS Key Laboratory of Receptor Rsch, Shanghai Institute of Materia Medica, Chinese Academy of Sc, CAS Key Laboratory of Receptor Rsch, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Beijing, China, ¹¹Dept of Cardiology, Dept of Cardiology,Guangdong Cardiovascular Institute,Guangdong Provincial People’s Hosp,Guangdong Academy of Med Sciences,Southern Med Univ, Guangzhou, China

Background: Phosphodiesterase type 5 inhibitors have been approved for the treatment of pulmonary arterial hypertension worldwide. TPN171H, a novel phosphodiesterase type 5 inhibitor derived from a natural plant icariin, was reported to have anti-inflammatory and vasodilatory effects in preclinical studies. Objective: To evaluate the acute hemodynamic effects of single oral intake of TPN171H in patients with pulmonary arterial hypertension. Methods: In this multicenter, double-blind, randomized, placebo-controlled and active-controlled, phase 2 trial, we randomly assigned 60 patients with pulmonary arterial hypertension to receive single oral intake of placebo, TPN171H (2.5-mg or 5-mg or 10-mg) or Tadalafil (20-mg or 40-mg). Patients were eligible if they had not been receiving treatments for pulmonary arterial hypertension within 1 month before study entry. Hemodynamic changes were assessed over a subsequent 24-hour observation period. The primary endpoint was the maximum decrease in pulmonary vascular resistance, as a percentage from baseline. The secondary endpoint was the change of pulmonary vascular resistance to systemic vascular resistance ratio at each observation time point, as a percentage from baseline. The safety of TPN171H was also evaluated. Results: Compared to the placebo group, the least square mean differences in the maximum decrease of pulmonary vascular resistance were -16.8% (95% confidence interval [CI], -29.1 to -4.5, p = 0.008) in the TPN171H 5-mg group, -15.4% (95% CI, -28.2 to -2.7, p = 0.019) in the Tadalafil 20-mg group, and -13.3% (95% CI, -25.6 to -0.9, p = 0.036) in the Tadalafil 40-mg group, respectively (Figure 1A). Moreover, the TPN171H 5-mg group, but not both Tadalafil groups, showed a significant reduction in pulmonary vascular resistance to systemic vascular resistance ratio at three observation time points, including 2^nd hour (p = 0.026), 3^rd hour (p = 0.030) and 5^th hour (p = 0.046), compared to the placebo group (Figure 1B). No serious adverse events occurred and the incidence of adverse drug reactions was similar between the TPN171H groups and the placebo group. Conclusion: A single oral intake of TPN171H 5-mg resulted in a reduction in pulmonary vascular resistance in patients with pulmonary arterial hypertension and tended to have a good selectivity for pulmonary circulation. TPN171H has potential to be a novel treatment option for patients with pulmonary arterial hypertension and warrants further investigation. This clinical trial was registered at www.ClinicalTrials.gov (Identifier: NCT04483115).

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GONGXIN HE¹, Hua YAN¹, Fei Guo¹, Hao Wu¹, Kai Hou¹, Changliang Lu¹, Xiubo Tang¹, Wenyuan Fan¹, Jialin CHEN¹, Yuanchao Zhang¹, Zi-Qiang Gu¹, David Nguyen², Javid Ghandehari³, Xiaowu Chen¹; ¹Rsch, Shanghai CureGene Pharmaceutical Co., Ltd, Shanghai, China, ²clinical, Altasciences, Cypress, CA, ³Clinical, Altasciences, Cypress, CA

Clopidogrel is an antiplatelet drug with significant clinical benefits and acceptable safety profile. It is a prodrug that depends mostly on CYP2C19 for activation to its active metabolite H4. However, large fractions of world population carry loss of function CYP2C19 alleles, ranging from a low ~21% in Latino to a strikingly high ~59% in east Asian population. Several clinical studies have shown that clopidogrel efficacy is indeed reduced or lost among these patients. Known as clopidogrel resistance, FDA added a black box warning to the package insert. Despite this issue and wide use of clopidogrel, routine CYP2C19 screening for clopidogrel patients is not performed, putting many patients at risk. Clopidogrel is slow to take effect and not amenable for IV formulation, limiting its clinical use in emergency. To overcome these issues, we have invented a novel antiplatelet drug CG-0255. CG-0255 is a prodrug designed to require only carboxylesterases for metabolizing to its active metabolite, which is identical to clopidogrel active metabolite H4 generated through CYP metabolism. Thus CG-0255 could completely bypass the CYP metabolism issues associated with clopidogrel. CG-0255 is highly soluble, fast acting and can be formulated for both IV and oral administration. Here we report the results of an open label phase I study of CG-0255 to assess safety, tolerability, pharmacodynamics (PK), and pharmacokinetics (PD: inhibition of platelet aggregation, IPA) of IV administration in healthy volunteers. It was a single dose escalation study, 5 cohorts with 6 participants each were given CG-0255 by bolus and/or infusion with different doses. Cangrelor was the positive control. Blood samples for PK/PD analysis were collected pre-dosing and at various time points. VerifyNow was used for IPA measurement. CG-0255 is generally safe and well tolerated. PK analysis shows fast and consistent conversion of CG-0255 to active metabolite H4. PD results indicate that IPA is dose dependent and quick, reaching over 90% IPA in 20 minutes, similar to that of cangrelor. Because CG-0255 is an irreversible inhibitor of platelet P2Y12 receptor, its effect is long lasting. IPA remains high at 24 hours, providing a convenient period to switch patients from IV to an oral antiplatelet drug, which has been a major problem for cangrelor. The CG-0255 IPA is consistent with minimum individual variations. In conclusion, CG-0255 is a novel, fast acting and long-lasting antiplatelet drug. It shares identical metabolite H4 with clopidogrel, but relies only on carboxylesterases for activation. Therefore, the CYP-dependent activation pathway and clopidogrel resistance issue can be avoided. As the only antiplatelet drug available for either IV or oral administration, CG-0255 fills unmet medical needs and will truly benefit patients. Phase I trial of CG-0255 oral administration is ongoing; the results will be reported separately.

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YanLing He¹, Xueping Wu², Andre Serra Roma³, Maggie Markiewicz⁴, Emma Healy¹, Jing-He Yan⁴, Constantine Bitsaktsis⁵, Kenneth Kulmatycki¹, Arvind Kinhikar¹, Tong Zhang¹, Denise Yates⁶, Robert Frost³, David Nguyen⁷, Cesare Russo³, Christopher J ODonnell¹; ¹Translational Medicine, Novartis Institute for BioMed Rsch, Cambridge, MA, ²Biostats, Novartis Institue for Biomedical Rsch, Basel, Switzerland, ³Translational Medicine, Novartis Institute for BioMed Rsch, Basel, Switzerland, ⁴Translational Medicine, Novartis Institute for BioMed Rsch, East Hannover, NJ, ⁵Translational Medicine, Novartis Institute for BioMed Rsch, East Hanover, NJ, ⁶Biomarker, Novartis, Cambridge, MA, ⁷Med, Altasciences, Cypress, CA

Introduction: The natriuretic peptide receptor 1 (NPR1) is the receptor for atrial natriuretic peptide and B-type natriuretic peptide. Activation of NPR1 results in the synthesis of cyclic guanosine monophosphate (cGMP), the second messenger for downstream signaling cascade, leading to a variety of beneficial cardiorenal effects including, but not limited to, blood pressure (BP) lowering, natriuresis and diuresis. XXB750 is a fully human monoclonal antibody, designed to specifically activate the NPR1. In this first-in-human (FIH) clinical study in healthy participants (HP), we assessed the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of XXB750 to demonstrate the mechanism of action of this novel and long acting NPR1 agonist. Methods: We conducted a double-blind, placebo controlled clinical study, and 77 eligible HP were randomly assigned in a 6:2 ratio to receive either a single subcutaneous dose of XXB750 or placebo (8 HP planned in each cohort). Ascending doses of XXB750 were evaluated in 10 dose cohorts: 7 cohorts (1, 3, 10, 30, 60, 120, 240 mg) in HP, one cohort (240 mg) in Japanese descent HP, 2 cohorts (450 and 600 mg) in HP with elevated BP. Endpoints included safety, PK and PD such as cGMP and BP measured by ambulatory blood pressure monitoring (ABPM), all endpoints were measured for up to 91 days. Results: Seventy-seven participants were enrolled and 73 completed the study. Four subjects discontinued due to reasons not related to study treatment. XXB750 was generally safe and well tolerated. XXB750 was slowly absorbed with a Tmax of 4~10 days and a half-life of 15~25 days at ≥60 mg. XXB750 significantly increased plasma cGMP levels and reduced BP at ≥30 mg. Maximum effects on cGMP and ABPM SBP were observed at ~Day 2. Plasma cGMP levels increased by 1.8- to 7.8-fold (p<0.001) at Day 2 at ≥30 mg and remained significantly elevated (p<0.05) by 1.5- to 2.5-fold at ≥60 mg (30 mg:1.3-fold, p=0.115) at Day 28. XXB750 significantly reduced ABPM SBP by 6.6 to 23 mmHg (p<0.01) on Day 2 at ≥30 mg, except the 60 mg cohort (p=0.122). Both the magnitude and duration of SBP lowering effects appeared to be dose dependent. Sustained SBP lowering effects were maintained at Day 28 at ≥120 mg (8~16 mmHg, p<0.05). Effects on DBP were less pronounced, with significant reduction at ≥240 mg at Day 2 (6~11 mmHg, p<0.05). The duration of BP lowering effect data support further clinical studies to assess the efficacy of a once monthly dosing regimen. Transient increases in heart rate were observed at ≥30 mg, but were asymptomatic at doses up to 450 mg. Symptomatic tachycardia (spontaneously resolved) were reported by two HP who received 600 mg. Conclusions: We reported for the first time that a novel long acting NPR1 agonist, XXB750, significantly increases plasma cGMP and reduces BP in a dose-dependent manner in humans. XXB750 has the potential for future development as a novel therapy for cardiovascular diseases.

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Wolfram H Zimmermann¹, Anas Aboud², Felix Bremmer³, Ingo Eitel⁴, Stephan Ensminger², Tim Friede⁵, Buntaro Fujita², Gerd P Hasenfuss⁶, Kristian Hellenkamp⁷, Christoph Herrmann-Lingen⁸, Ahmad-fawad Jebran⁹, Johannes Kowallick¹⁰, Ingo Kutschka¹¹, Tobias Legler¹², Joachim Lotz¹³, Christina Paitazoglou¹⁴, Marius Placzek⁵, Joachim Riggert¹², Monika Sadlonova⁸, Tim Seidler¹⁵, Malte Tiburcy¹⁶; ¹Pharmacology and Toxicology, UNIVERSITY MED CTR GOETTINGEN, Goettingen, Germany, ²Cardiothoracic Surgery, Univ Med Cntr Schleswig-Holstein, Campus Lübeck, Lübeck, Germany, ³Pathology, UNIVERSITY MED CTR GOETTINGEN, Goettingen, Germany, ⁴Cardiology, Univ Heart Cntr Luebeck, Luebeck, Germany, ⁵Medicinal Statistics, Univ Med Cntr Göttingen, Goettingen, Germany, ⁶Cardiology, Univ Med Cntr Göttingen, Gottingen, Germany, ⁷Cardiology, Univ Med Cntr Göttingen, Goettingen, Germany, ⁸Psychosomatic Medicine and Psychotherapy, UNIVERSITY MED CTR GOETTINGEN, Goettingen, Germany, ⁹Cardiothoracic Surgery, UNIVERSITY HOSPITAL GOETTINGEN, Goettingen, Germany, ¹⁰Radiology, Univ Med Cntr Göttingen, Goettingen, Germany, ¹¹Cardiothoracic Surgery, Univ Med Cntr Göttingen, Göttingen, Germany, ¹²Transfusion Medicine, UNIVERSITY MED CTR GOETTINGEN, Goettingen, Germany, ¹³Radiology, UMG Goettingen, Goettingen, Germany, ¹⁴Cardiology, Univ Med Cntr Schleswig-Holstein, Campus Lübeck, Lübeck, Germany, ¹⁵Cardiology, Univ Med Cntr Göttingen, Göttingen, Germany, ¹⁶Pharmacology and Toxicology, UNIVERSITY MEDICAL CENTER, Goettingen, Germany

Remuscularization by epicardial implantation of engineered human myocardium (EHM) from induced pluripotent stem cell-derived cardiomyocytes is explored in a first-in-class, first-in-patient early clinical trial with the aim to improve heart function and symptoms in patients diagnosed with advanced heart failure (NYHA III/IV, EF ≤35%) despite optimal medical, including device (all patients with ICD or CRT-D) therapy. BioVAT-HF is an open label, non-randomized, multi-center registered early clinical trial (NCT04396899). It comprises of dose finding (Part A) and proof-of-concept (Part B) parts with the intention to treat up to 53 patients. Here, we report the completion of dose finding (Part A) with the treatment of 10 patients (age: 62±9 years, 2/8 female/male, 9/1 ICM/DCM, all in NYHA III, EF 24±7%) with up to 12 months follow-up. 2, 2, and 6 patients were treated at the low, mid, and maximal feasible doses of 5, 10, and 20 EHM patches constructed from 200, 400, and 800 million induced pluripotent stem cell-derived cardiomyocytes and stromal cells, representing dose levels of 2±0.1, 4±1.6, and 10±2 million cells/kg body weight. We made the following key observations: (1) no EHM related adverse events, (2) histopathological evidence for vascularized remuscularization in one study subject, which was subjected to successful heart transplantation, (3) dose dependent improvement of NYHA from III to II in all patients at the maximal feasible dose level 3-12 months post implantation, (4) evidence for sustained thickening of the target heart wall, (5) evidence for enhanced ejection fraction at the maximal feasible dose level at 6-12 months after EHM implantation. Three patients died on study with the cause of death not related to the EHM implant. In conclusion, the first-in-class, first-in-patient BioVAT-HF early clinical trial identified a safe maximal dose for epicardial remuscularization in patients with advanced heart failure. Initial signs of efficacy are presently under clinical scrutiny. Data presented as mean±SD.

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Timothy D Henry, II¹, Eugene Chung¹, Monica Alvisi², Ferzin Sethna³, David E Murray⁴, Jay H Traverse⁵, Youjun Chen³, Stacy Webb³, Monika Mittal³, Leigh Ervin⁶, Kaitlyn Walker⁶, Hesham A Sadek⁷, Sheila Mikhail⁸, Kobra Haghighi⁹, Canwen Jiang¹⁰, Richard J Samulski¹¹, Evangelia L Kranias¹², Anna Tretiakova¹³, Roger J Hajjar¹⁴; ¹Cardiology, The Christ Hosp, Cincinnati, OH, ²CHF, ASKBIO, Berlin, Germany, ³Rsch & Development, ASKBIO, Rsch Triangle Park, NC, ⁴Cardiology, Univ of Wisconsin, Madison, WI, ⁵Cardiology, Allina Health Minneapolis Heart Institute, Minneapolis, MN, ⁶Clinical Operations, ASKBIO, Rsch Triangle Park, NC, ⁷Cardiology, Hesham Sadek, Irving, TX, ⁸Chief Executive Officer, ASKBIO, Rsch Triangle Park, NC, ⁹Cardiology, Univ of Cincinnati, Cincinnati, OH, ¹⁰Chief Med Officer, AskBio, Rsch Triangle Park, NC, ¹¹Chief Scientific Officer, ASKBIO, Rsch Triangle Park, NC, ¹²Pharmacology, UNI OF CINCINNATI COLL MEDICINE, Cincinnati, OH, ¹³Rsch, ASKBIO, Rsch Triangle Park, NC, ¹⁴Gene & Cell Therapy Institute, Massachusetts General Brigham, Cambridge, MA

Congestive heart failure (CHF) is a progressive disease in need of innovative therapies. A key characteristic of failing hearts is abnormal intracellular Ca²⁺ handling and increased protein phosphatase 1 activity (PP1). Recent advances in understanding the molecular basis of myocardial dysfunction and gene therapies have resulted in adeno-associated virus-based (AAV) gene therapy clinical trials for heart failure. Inhibition of PP1 by a constitutively active inhibitor-1 (I-1c) has been shown to enhance cardiac function in multiple pre-clinical models of heart failure. We developed a novel cardiotropic and liver de-targeted capsid, AAV2i8, which was rationally designed to overcome poor transduction in cardiac tissue. We completed enrollment in a phase 1 clinical trial for the treatment of non-ischemic cardiomyopathy using the AAV2i8 capsid to deliver a constitutively active I-1c protein to cardiac tissue via a single intracoronary infusion of AAV2i8.I-1c. Eleven patients have received either 3.25E13 (Cohort 1; n=6) or 1.08E14 (Cohort 2; n=5) viral genomes (vg) of AAV2i8.I-1c. Three patients in cohort 1 and all five patients in cohort 2 have completed a 12-month observational period and there have been no investigational product–related serious adverse events in these patients. Among participants in Cohort 1, three patients showed clinically meaningful improvements in left ventricular ejection fraction (LVEF), New York Heart Association score (NYHA), Minnesota Living with Heart Failure Questionnaire (MLHFQ), cardiopulmonary exercise test (pV02 max), and 6 minute walk test (6MWT) at 12 months. The 3 remaining patients in cohort 1 are still within first month post injection. Among participants in Cohort 2, 2 of 4 patients (only 4 of the 5 patients in cohort 2 could be evaluated) showed clinically meaningful improvements in MLHFQ, 2 of 4 showed clinically meaningful improvements in NYHA score, and all 4 showed clinically meaningful improvements in LVEF at 12 months, when compared to baseline. In support of this encouraging early clinical efficacy signal, AAV2i8.I-1c demonstrated high myocardial transduction efficiency at 1.19 vg/dg in a human left ventricular (LV) sample taken 13 months post-intracoronary gene transfer from a patient in cohort 2 during left ventricular assist device (LVAD) placement. Phorphorylation levels of phospholamban were similar to normal hearts. I-1c mRNA was detected at high levels in cardiomyocytes but not in the endothelial cells in the left ventricular sample, while control human heart tissue was negative for I-1c mRNA. Our Phase 1 clinical trial shows that AAV2i8.I-1c delivery is safe and results in positive efficacy outcomes in patients with non-ischemic CHF, and further validates the AAV2i8 capsid as highly cardiotropic when injected through intracoronary means at low doses.

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Mikhail N Kosiborod¹, Subodh Verma², Barry A Borlaug³, Javed Butler⁴, Melanie Davies⁵, G. Kees Hovingh⁶, Mark Petrie⁷, Sanjiv J Shah⁸, Daniél Vega Møller⁹, Thomas Jon Jensen¹⁰, Soren Rasmussen¹¹, Peter Marstrand¹², Hiroshi Ito¹³, Morten Schou¹⁴, Walter Abhayaratna¹⁵, Dalane W Kitzman¹⁶; ¹Dept of Cardiovascular Disease, ST LUKES HEALTH SYSTEM, Kansas City, MO, ²Div of Cardiac Surgery, Li Ka Shing Knowledge Institute of St Michael’s Hosp, Unity Health Toronto, Toronto, Canada, ³Dept of Cardiovascular Medicine, MAYO CLINIC, Rochester, MN, ⁴Dept of Medicine, Baylor Scott and White Rsch Institute, Univ of Mississippi, Atlanta, GA, ⁵Diabetes Rsch Cntr, Univ of Leicester, Leicester, United Kingdom, ⁶Senior Med Officer, MD, PhD, MBA, Prof Global Chief Med Office, Novo Nordisk A/S, Søborg, Denmark, ⁷Sch of Cardiovascular and Metabolic Health, Univ of Glasgow, Glasgow, United Kingdom, ⁸Div of Cardiology, Dept of Medicine, Northwestern Univ Feinberg Sch of Medicine, Chicago, IL, ⁹Vice President, Med & Scientific Affairs, OSCD International Operations - Strategic Office, Novo Nordisk A/S, Søborg, Denmark, ¹⁰International Med Director OSCD and Outcomes, NOVO NORDISK, Søborg, Denmark, ¹¹Biostatistics, Novo Nordisk A/S, Søborg, Denmark, ¹²Pharmaceutical Medicine Physician, Global Med Affairs, Novo Nordisk A/S, Søborg, Denmark, ¹³Dept of General Internal Medicine 3, Kawasaki Med Sch, Okayama, Japan, ¹⁴Dept of Cardiology, Herlev-Gentofte Hosp, Univ of Copenhagen, Herlev, Denmark, ¹⁵College of Health and Medicine, The Australian National Univ, Canberra, Australia, ¹⁶Dept of Internal Medicine, Sections of Cardiovascular Medicine and Geriatrics, Winston Salem, NC

Background: Patients with the obesity phenotype of heart failure (HF) with preserved ejection fraction (HFpEF) experience high burden of symptoms and functional impairment, and a poor quality of life. STEP-HFpEF, the first trial specifically targeting the obesity phenotype of HFpEF, examined the effects of once-weekly semaglutide 2.4 mg versus placebo on HF-related symptoms and physical limitations, body weight (BW), exercise function and inflammation. This pre-specified analysis aimed to investigate effects of semaglutide on 1) the primary and key secondary endpoints across the range of health status at baseline, measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ) and 2) all key KCCQ domains. Methods: STEP-HFpEF randomized 529 participants with symptomatic HF, LVEF >45% and body mass index of >30 kg/m² to once-weekly semaglutide 2.4 mg or placebo for 52 weeks. Key exclusion criteria were prior/planned bariatric surgery, self-reported BW change >11 lbs (5 kg) ≤90 days before randomization, and HbA_1c ≥6.5% or prior history of diabetes. Dual primary endpoints were change from baseline in KCCQ Clinical Summary Score (KCCQ-CSS) and BW. Confirmatory secondary endpoints included change in 6-minute walk distance (6MWD), hierarchical composite endpoint (death, HF events and change in KCCQ-CSS and 6MWD) and change in C-reactive protein (CRP). In this analysis, patients were stratified based on the KCCQ-CSS tertiles at baseline. Effects of semaglutide on the dual primary and confirmatory secondary endpoints were examined across these subgroups. We also evaluated the effects of semaglutide on additional KCCQ domains (Total Symptom Score [including symptom burden and symptom frequency], Physical Limitations Score, Social Limitations Score, Quality of Life Score, and Overall Summary Score). Results: Overall, median KCCQ-CSS was 59 points, consistent with marked symptomatic and functional impairment; median KCCQ-CSS across tertiles was 37, 59 and 77 points, respectively. Baseline characteristics of patients stratified by KCCQ-CSS are shown in the Table. Patients with worse health status were older, had higher BMI and NYHA class, and were more likely to be female and receive treatment with loop diuretics. Outcomes data will be available at the time of presentation. Conclusions: This pre-specified analysis will examine whether the effects of semaglutide vs placebo on the primary and secondary endpoints were consistent across the categories of health status impairment at baseline; and evaluate the effects of semaglutide on all key KCCQ domains.

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Aldostefano Porcari¹, Francesco Cappelli², Christian Nitsche³, Daniela Tomasoni⁴, Giulio Sinigiani⁵, Simone Longhi⁶, Luca Bordignon⁷, Ahmad Masri⁸, Matteo Serenelli⁹, Marcus A Urey¹⁰, Beatrice Musumeci¹¹, Alberto Cipriani¹², Marco Canepa¹³, Roza Badr Eslam¹⁴, Christina Kronberger³, cristina chimenti¹⁵, Mattia zampieri², Valentina Allegro¹⁶, Yousuf Razvi¹⁷, Rishi Patel¹⁸, Adam Ioannou¹⁸, Muhammad U Rauf¹⁹, Aviva Petrie²⁰, Carol Whelan²¹, Michele Emdin²², Marco Metra²³, Marco Merlo⁷, Gianfranco sinagra⁷, Philip Hawkins¹⁸, Scott Solomon²⁴, Julian Gillmore¹⁸, Marianna Fontana¹⁸; ¹National Amyloidosis Cntr (NAC); Div of Medicine, Univ College of London (UCL), Royal Free Hosp NHS Foundation Trust, London, United Kingdom, ²Cardiomyopathy Unit, Careggi Univ Hosp, Univ of Florence, Florence, Italy, ³Div of Cardiology, Dept of Internal Medicine II, Med Univ of Vienna, Vienna, Austria, ⁴Cardiology, ASST Spedali Civili, Dept of Med and Surgical Specialities, Radiological Sciences and Public Health, Univ of Brescia, London, United Kingdom, ⁵Dept of Cardiac, Thoracic and Vascular Sciences and Public Health, Univ of Padua, Padua, Italy, ⁶Cardiology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bolgna, Italy, ⁷Cntr for Diagnosis and Treatment of Cardiomyopathies, Cardiovascular Dept, Azienda Sanitaria Universitaria Giuliano-Isontina (ASUGI), Univ of Trieste, Trieste, Italy, ⁸Knight Cardiovascular Institute, OHSU, Portland, OR, ⁹Cardiologic Cntr, Ferrara Univ Hosp, Porto Recanati, Italy, ¹⁰Dept of Medicine, UC San Diego Med Cntr, La Jolla, CA, ¹¹Dept of Clinical and Molecular Medicine, Faculty of Medicine and Psychology, Sapienza Univ, Rome, Italy, ¹²Dept of Cardiac, Thoracic and Vascular Sciences and Public Health, Univ of Padua, Padova, Italy, ¹³Cardiovascular Unit, Univ of Genoa, Genova, Italy, ¹⁴Div of Cardiology, Med Univ of Vienna, Vienna, Austria, ¹⁵Dept of Cardiovascular/Respiratory Diseases, Nephrology, Anesthesiology, and Geriatric Science, Policlinico Umberto I, Sapienza Univ of Rome, Rome, Italy, ¹⁶Cntr for Diagnosis and Treatment of Cardiomyopathies, Cardiovascular Dept, Cardiovascular Dept, Azienda Sanitaria Universitaria Giuliano-Isontina (ASUGI), Univ of Trieste, Trieste, Italy, ¹⁷Royal Free Hosp, Royal Free Hosp, London, United Kingdom, ¹⁸Royal Free Hosp, National Amyloidosis Cntr, London, United Kingdom, ¹⁹Royal Free Hosp, National Amylodiosis Cntr, London, United Kingdom, ²⁰Univ College of London (UCL), UCL, London, United Kingdom, ²¹National Amyloidosis Cntr (NAC); Div of Medicine, Univ College of London (UCL), Royal Free Hosp, London, United Kingdom, ²²Cardiology Div, Fondazione Gabriele Monasterio, Pisa, Italy, ²³Cardiology Div, Univ of Brescia, Brescia, Italy, ²⁴Cardiovascular Dept, Brigham and Women’s Hosp, Boston, MA

Background and Aims: The aims of this study were to assess the effectiveness and tolerability of sodium-glucose cotransporter 2 inhibitors (SGLT2-i) in patients with transthyretin amyloid cardiomyopathy (ATTR-CM). Methods: A retrospective analysis of all ATTR-CM patients diagnosed and treated with SGLT2-i in 14 centres from 2016-2022 compared with propensity score (PS) matched controls for eleven variables selected a priori based. Results: The ATTR-CM cohort comprised 260 patients treated with SGLT2-i (77±7 years, 85.4% wild-type ATTR-CM, LVEF 44.9±11.2%) and 260 propensity-matched controls. Adequacy of matching was verified by ensuring the standardised differences between groups were <0.10. Discontinuation rate for SGLT2-i was 5%; at 12 months, treatment with SGLT2-i was associated with less worsening of NYHA class, NT-proBNP, eGFR and fewer new initiations of loop diuretic therapy. During a median follow-up of 28 months (IQR16-47), SGLT2-i therapy was associated with lower all-cause mortality (hazard ratio [HR]0.49[95%confidence interval[CI]:0.31-0.77], p=0.002), cardiovascular mortality (HR0.40[95%CI:0.24-0.69],p=0.00093), heart failure (HF) hospitalization (HR0.56[95%CI:0.34-0.92],p=0.022), and the composite outcome of cardiovascular mortality or HF hospitalization (HR0.47[95%CI:0.32-0.69],p=0.00013). Treatment effect on all outcomes was confirmed across the spectrum of ejection fraction (P-interaction >0.05). Conclusions: SGLT2-i treatment in ATTR-CM patients was well tolerated and associated with less worsening of HF symptoms and NT-proBNP, slower decline in eGFR and lower diuretic requirement over time. SGLT2-i treatment was also associated with reduced risk of HF hospitalization, cardiovascular and all-cause mortality, regardless of the ejection fraction. In the absence of randomized trials, these data may inform clinicians regarding the use of SGLT2-i in patients with ATTR-CM.

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Daniel P Judge¹, Francesco Cappelli², Marianna Fontana³, Pablo Garcia-Pavia⁴, Simon Gibbs⁵, Martha Grogan⁶, Mazen Hanna⁷, Ahmad Masri⁸, Mathew S Maurer⁹, Laura Obici¹⁰, Prem Soman¹¹, Kevin M Alexander¹², Xiaofan Cao¹³, Jing Du¹³, Ted Lystig¹³, Jean-François Tamby¹⁴, Suresh Siddhanti¹⁵, Lenny Katz¹⁵, Jonathan C Fox¹⁵, Julian D Gillmore³; ¹Cardiology, Med Univ South Carolina, Charleston, SC, ²Tuscan Regional Amyloidosis Cntr, Careggi Univ Hosp, Florence, Italy, ³National Amyloidosis Cntr, Div of Medicine, Univ College London, Royal Free Hosp, London, United Kingdom, ⁴Heart Failure and Inherited Cardiac Diseases Unit, Dept of Cardiology, Hosp Puerta de Hierro Majadahonda, Madrid, Spain, ⁵The Victorian and Tasmanian Amyloidosis Service, Dept of Haematology, Monash Univ Eastern Health Clinical Sch, Clayton, Australia, ⁶Dept of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, ⁷Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH, ⁸Cardiac Amyloidosis Program, Oregon Health & Science Univ, Knight Cardiovascular Institute, Portland, OR, ⁹Cardiology, Columbia College of Physicians and Surgeons, New York, NY, ¹⁰Amyloidosis Rsch and Treatment Cntr, IRCCS Fondazione Policlinico San Matteo, Pavia, Italy, ¹¹Divison of Cardiology, Univ of Pittsburgh Med Cntr, Pittsburgh, PA, ¹²Cardiovascular Medicine, Stanford Univ, Palo Alto, CA, ¹³Biostatistics, Eidos Therapeutics, affiliate of BridgeBio Pharma, San Francisco, CA, ¹⁴Clinical Development, Eidos Therapeutics affiliate of BridgeBio Pharma, San Francisco, CA, ¹⁵Clinical Development, Eidos Therapeutics, affiliate of BridgeBio Pharma, San Francisco, CA

Background: Acoramidis is a next-generation, oral, near-complete stabilizer of transthyretin (TTR) under development for transthyretin amyloid cardiomyopathy (ATTR-CM). The Phase 3 ATTRibute-CM study demonstrated robust clinical efficacy that was assessed with a hierarchical analysis of all-cause mortality (ACM), cardiovascular hospitalization (CVH), NT-proBNP and six-minute walk test, analyzed according to the Finkelstein-Schoenfeld (F-S) method (p<0.0001). Here we report a survival analysis of the composite endpoint of ACM and CVH. In contrast to the F-S method of the primary endpoint, which employs a hierarchical stepwise sequence of comparisons beginning with ACM for its components, the analysis presented here uses the more traditional Kaplan-Meier Time-to-First Event approach based on the composite endpoint of ACM and CVH. Methods: Details of the study design, eligibility, and baseline characteristics have been reported elsewhere (ESC 2023). Of the 632 subjects randomized, 611 were included in the modified intent-to-treat efficacy analysis of this 30-month study. Analyses of combined ACM/CVH according to F-S method and Kaplan-Meier Time-to-First Event Analysis (Cox proportional hazards model) were performed. Results: The composite of Time-to-First-Event ACM or CVH was reported in 147 (35.9%) and 102 (50.5%) of acoramidis and placebo-treated subjects, respectively, corresponding to a 14.6% absolute risk reduction, and a 36% relative risk reduction, as shown in Figure. The 2-component (ACM/CVH) F-S method was significant (p=0.0182), with a Win Ratio of 1.5 (95% CI: 1.1-2.0).

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Peter R Sinnaeve¹, Alexandra Arias-Mendoza², Oleg V Averkov³, Arsen Ristic⁴, Kevin R Bainey⁵, Robert C Welsh⁶, Kris Bogaerts², Katleen Vandenberghe⁷, Thierry danays, Sr.⁸, Paul W Armstrong⁹, Frans J Van de Werf¹⁰; ¹CARDIOVASCULAR MEDICINE, UZ LEUVEN, Leuven, Belgium, ², ³HOSPITAL 15, Moscow, Russian Federation, ⁴Dept of Cardiology, Univ Clinical Cntr of Serbia, Belgrade, Serbia, ⁵UNIVERSITY OF ALBERTA, Edmonton, Canada, ⁶Cardiology, Robert Welsh, Edmonton, Canada, ⁷Leuven, Belgium, ⁸Boehringer Ingelheim France, Reims, France, ⁹Univ of Alberta, Edmonton, Canada, ¹⁰Cardiovascular Sciences, KU LEUVEN, Leuven, Belgium

ST-Elevation Myocardial Infarction (STEMI) guidelines recommend pharmaco-invasive treatment if timely primary percutaneous coronary intervention (PCI) is unavailable. However, full-dose tenecteplase as part of a pharmaco-invasive strategy is associated with an increased risk of intracranial hemorrhage, especially in older patients. Whether pharmaco-invasive treatment with half-dose tenecteplase is effective and safe in older STEMI patients was studied in the investigator-initiated, open-label, randomized, multicenter STREAM-2 study (NCT02777580) (Figure). As published (Circulation. 2023;148:00-00. DOI: 10.1161), the STREAM-2 30-day composite endpoint of death, shock, heart failure or reinfarction occurred in 12.8% (51/400) of pharmaco-invasive and 13.3% (27/203) of primary PCI patients (RR: 0.96; 95% CI, 0.62 to 1.48). After last angiography, worst-lead ST-resolution ≥50% was seen more frequently (85.2% versus 78.4%, p=0.049), and more resolution of all ST-segment deviations occurred (71% versus 62%, p= 0.03) in the pharmaco-invasive arm. Halving the dose of tenecteplase in a pharmaco-invasive strategy in this early presenting older STEMI population was also associated with better TIMI 3 flow grades at first angiography when compared to primary PCI (54% vs 19%, p<0.001), and nearly identical TIMI 3 flow grades at last angiography (87%). Six intracranial hemorrhages occurred in the pharmaco-invasive arm (1.5%), while none occurred in the primary PCI arm. The incidence of major non-intracranial bleeding was low in both groups (<1.5%). As pre-specified by protocol, all-cause one year mortality and rehospitalization for cardiovascular causes is acquired in all patients surviving the first 30 days. The last patient was randomized in September 2022; as of August 21^st 2023, 95% of patients have completed 1—year follow-up; complete follow-up is expected at the time of presentation. Given the electrocardiographic, angiographic and clinical outcomes we observed at 30-days, (including benefit in PI patients treated < 1 hour symptom onset) one-year mortality rates are expected to be of particular interest in this important clinical trial of older patients with STEMI.

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Goaris Aarts¹, Cyril Camaro¹, Eddy M Adang², Laura Rodwell², Roger van Hout³, Gijs Brok³, Anouk Hoare⁴, Frank de Pooter⁴, Walter De Wit⁴, Etienne Cramer¹, Roland van Kimmenade¹, Eva Ouwendijk⁵, Martijn Rutten⁶, Erwin Zegers⁷, Marc Gomes⁷, Robert-jan M Van Geuns¹, Peter Damman¹, Niels van Royen¹; ¹Cardiology, Radboud Univ Med Cntr, Nijmegen, Netherlands, ²Health Evidence, Radboud Univ Med Cntr, Nijmegen, Netherlands, ³Safety Region Gelderland-Zuid, Ambulance Service, Nijmegen, Netherlands, ⁴Witte Kruis, Ambulance Service, Houten, Netherlands, ⁵Region Boxmeer and Nijmegen, General Practitioner Cntr, Nijmegen, Netherlands, ⁶General Practitioner Cooperative Noord-Limburg, General Practitoner, Venlo, Netherlands, ⁷Cardiology, CWZ, Nijmegen, Netherlands

Background and aims: The healthcare burden of acute chest pain is enormous. In the randomised ARTICA trial we showed that pre-hospital identification of low-risk patients and rule-out of non-ST-segment elevation acute coronary syndrome (NSTE-ACS) with point-of-care (POC) troponin measurement reduces 30-day healthcare costs with a low major adverse cardiac events (MACE) incidence (1). Here we present the final one-year results of the ARTICA trial. Methods: Low-risk patients with suspected NSTE-ACS were randomised to pre-hospital rule-out with POC troponin measurement or emergency department (ED) transfer. Primary one-year outcome was healthcare costs. Secondary outcomes were safety, quality of life and cost-effectiveness. Safety was defined as one-year MACE, consisting of ACS, unplanned revascularisation or all-cause death. Quality of life was measured with EuroQol-5D-5L questionnaires. Cost-effectiveness was defined as one-year healthcare costs difference per quality of life difference. Results: Follow-up was completed in all 863 patients. Healthcare costs were significantly lower in the pre-hospital strategy (€1932±€2784 vs €2649±€2750), mean difference €717 (95% confidence interval [CI] €347 to €1087; P<0.001). In the total population, one-year MACE rate was comparable between groups (5.1% [22/434] in the pre-hospital strategy vs 4.2% [18/429] in the ED strategy; P=0.54). In the ruled-out ACS population, one-year MACE remained low (1.7% [7/419] vs 1.4% [6/417]), risk difference 0.2% (95% CI -1.4% to 1.9%;P=0.79). Quality of life showed no significant difference between strategies. Conclusions: Pre-hospital rule-out of NSTE-ACS with POC troponin testing in low-risk patients is cost-effective, expressed by a sustainable healthcare costs reduction and no significant effect on quality of life. One-year MACE remained low for both strategies.

1. Camaro C, et al. Eur Heart J. 2023;44:1705-1714. doi:10.1093/eurheartj/ehad056.

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Nicolas Danchin, FAST-MI investigators; Cardiology, Hosp European Georges Pompidou, Paris, France

The effect of lipid lowering therapy (LLT) and its intensity after acute myocardial infarction (AMI) has not been specifically assessed in trials in the very elderly. Because mortality, particularly non-cardiovascular mortality is high in this population, the impact on survival of medications such as LLT may not be as clear as in younger patients. Using the 2005, 2010 and 2015 cohorts from the FAST-MI program, we studied the association between prescription and intensity of lipid lowering therapy (LLT) and five-year mortality in patients aged ≥80 years discharged after AMI. Patients and Methods: FAST-MI included consecutive patients admitted for AMI (STEMI or NSTEMI) ≤48 hours form onset over a one-month period every five years from 2005 to 2015 throughout France (> 200 participating centers). A large amount of data was collected and centralized 10-year follow-up is organized by the French Society of Cardiology. All patients aged ≥80 years surviving the acute episode were included and followed for 5 years. High-dose lipid lowering therapy (LLT) was defined as ≥40 mg atorvastatin or equivalent or any combination of statin + ezetimibe. Five-year mortality was analysed according to use and intensity of LLT prescribed at discharge, using Cox multivariate analysis and propensity score matching to adjust for baseline differences. Results: Among the 2,258 patients ≥80 years (mean age 85 ± 4 years; 51% women; 39% STEMI; 58% with PCI), 415 were discharged without LLT (18%), 866 with conventional dose LLT (38%) and 977 with a high-dose LLT (43%). Five-year overall survival was 36%, 47.5% and 58% respectively. Compared with patients without LLT, high-dose LLT was significantly associated with lower five-year mortality (adjusted HR: 0.78, 95%CI: 0.66-0.92; P=0.008), whereas conventional-intensity LLT was not (aHR 0.94, 95%CI: 0.81-1.10, P=0.46). Propensity score-matched cohorts (n= 278 for high-dose LLT and n=278 for no statins) confirmed these results: 5-year survival was 52% with high-dose LLT at discharge and 42% without statins (HR 0.78, 95% CI 0.62-0.98, P=0.036) (Figure). Subgroup analyses showed that the association was stronger in patients with PCI (HR 0.71, 95%CI 0.55-0.92, P=0.009) than in those without PCI (HR 0.88, 95%CI 0.68-1.13, P=0.31), but the interaction was not significant (P=0.82). Conclusion: High-dose lipid lowering therapy at discharge after AMI was associated with reduced all-cause mortality at 5 years in a truly elderly population. These results suggest that high-intensity lipid lowering therapy should not be denied the patients on the basis of very old age.

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Antonio Abbate¹, Benjamin W Van Tassell², vlad bogin³, ROSHANAK MARKLEY⁴, Dmitry Pevzner⁵, Paul C Cremer⁶, Imad Meray⁷, Dmitry Privalov⁸, Angela M Taylor⁹, Sergey Grishin¹⁰, Alina Egorova¹⁰, Ekaterina Ponomar¹⁰, Yan Lavrovsky¹¹, Mikhail Samsonov¹⁰; ¹Dept of Medicine, Univ of Virginia Health System, Charlottesville, VA, ²Dept of Pharmacotherapy & Outcomes Science, Virginia Commonwealth University, Midlothian, VA, ³Medicine, Cromos Pharma, Dallas, TX, ⁴Pauley Heart Center, VCU Health–Virginia Commonwealth University Health, Richmond, VA, ⁵Intensive Care Unit of the Dept of Emergency Cardiology, National Med Rsch Cntr for Cardiology of the Ministry of Healthcare of the Russian Federation, Moscow, Russian Federation, ⁶Dept of Cardiovascular Medicine Heart, Vascular and Thoracic Institute, Cleveland Clinic, Cleveland, OH, ⁷Internal Diseases, PFUR named after Patrice Lumumba, Moscow, Russian Federation, ⁸Cardiology and Intensive Therapy Dept, City Clinical Hosp No. 51 of Moscow Healthcare Dept, Moscow, Russian Federation, ⁹Univ of Virginia, Charlottesville, VA, ¹⁰Med Dept, R-Pharm JSC, Moscow, Russian Federation, ¹¹Protein Therapeutics, R-Pharm Overseas, Inc., La Jolla, CA

Background: Interleukin-1 (IL-1) may play a key role in local and systemic inflammatory responses to myocardial infarction. Prior studies with IL-1 blockers have shown a favorable response for modulating the inflammatory response from myocardial damage. Hypothesis The primary aim was whether treatment with RPH-104, goflikicept, a soluble trap for IL-1α and IL-1β, leads to a reduction in the systemic inflammatory response in patients with STEMI. Methods: In a phase IIa, double-blind, randomized, placebo-controlled trial, a single administration of RPH-104 80 mg (n= 34), RPH-104 160 mg (n=34) and placebo (n=34) were compared in subjects with STEMI, within 24 hours of the onset of chest pain and 12 hours from reperfusion, between December 2020 and October 2022 in 11 centers in the Russian Federation or United States of America. The primary endpoint was the area-under-the-curve for CRP (AUC-CRP) at 14 days. Data are expressed as geometric least square means with a two-sided 95% CI. Results: Mean age was 59 ±12 years, 73/101 (72.3%) were male and 96/101 (95%) were White/Caucasian. Mean times from pain onset and percutaneous coronary intervention to treatment were 10.7 ± 3.9 and 6.3±3.3, respectively, without significant differences between the groups. The AUC-CRP was significantly lower for RPH-104 80 mg (96.72 [70.57; 132.54] mg*days/L) and for RPH-104 160 mg (106.71 [77.53; 146.87] mg*days/L) compared with placebo (178.59 [129.54; 246.21] mg*days/L); representing a 46% reduction for RPH-104 80 mg and and 40% reduction for RPH 160 mg versus placebo. No significant differences in AUC-CRP were seen between the RPH-104 160 mg and 80 mg. There were no significant differences in the incidence of treatment-related adverse events between RPH-104 80 mg (76.5%), 160 mg (73.5%) and Placebo (61.8%)(p=0.588). There were no treatment-related serious adverse events (SAEs) reported in any group.At 12 months, one patient who received placebo (1/34 (2.9%)) and one patient who received RPH-104 80 mg (1/34 (2.9%)) had died. Three patients were hospitalized for cardiovascular causes in placebo (9.1%), 2 (5.9%) in the RPH-104 80 mg group, and 0 (0%) in the RPH-104 160 mg. None of the hospitalizations were attributed to heart failure. The use of loop-diuretics, a surrogate for heart failure, was 8 (24.2%) in placebo, 5 (14.7%) for RPH-104 80 mg, and 6 (17.6%) for RPH-104 160 mg. Conclusions: In patients with STEMI, IL-1 blockade with RPH-104 80 mg or 160 mg significantly reduced CRP compared with placebo, and treatment with RPH-104 appears safe. Additional studies are needed to determine whether reduction in systemic inflammation with RPH-104 translates into a clinical benefit in patients with STEMI.

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Laust E Obling¹, Rasmus Paulin P Beske¹, Martin A Meyer¹, Johannes Grand¹, Sebastian Wiberg², Benjamin Nyholm¹, Jakob Josiassen¹, Frederik T Soendergaard¹, Thomas Mohr³, Anders Damm-Hejmdal⁴, Mette Bjerre⁵, Ruth Frikke-Schmidt⁶, Fredrik Folke⁷, Jacob E Moller¹, Jesper Kjaergaard¹, Christian Hassager¹; ¹Dept of Cardiology, Rigshospitalet, Copenhagen, Denmark, ²Dept of Thoracic Anesthesiology, Rigshospitalet, Copenhagen, Denmark, ³Intensive Care Unit, Herlev-Gentofte Hosp, Hellerup, Denmark, ⁴Emergency Med Services, Emergency Med Services, Copenhagen, Denmark, ⁵Dept of Clinical Medicine, Med/Steno Aarhus Rsch Laboratory, Aarhus, Denmark, ⁶Dept of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark, ⁷Dept of Cardiology, Herlev-Gentofte Hosp, Hellerup, Denmark

Background: Patients resuscitated after out-of-hospital cardiac arrest (OHCA) often suffer from the post-cardiac arrest syndrome, characterized by inflammation and reperfusion injury. Levels of interleukin-6 (IL-6) and neuron-specific enolase (NSE), biomarkers for systemic inflammation and neurological damage, are associated with poor prognosis. Glucocorticoid has strong anti-inflammatory properties and is commonly used, but never tested in OHCA patients. The hypothesis was that early prehospital treatment with high-dose glucocorticoid could mitigate inflammation, and thereby improve outcome in OHCA patients. Aim: To assess efficacy of prehospital high-dose injection of glucocorticoid to reduce systemic inflammation and neurological damage in comatose OHCA patients. Methods: The study was a randomized 1:1, blinded, placebo-controlled, multicenter study. Resuscitated OHCA patients who remained unconscious after return of spontaneous circulation (ROSC) were eligible. The intervention was the glucocorticoid methylprednisolone 250 mg i.v./i.o. administered after a minimum of 5 minutes from ROSC but before hospital arrival or matching placebo. The co-primary endpoint was IL-6 and NSE- blood levels measured daily the first 72 hours of admission. We used mixed-model analyses to evaluate treatment-by-time effects in the two treatment groups. Main secondary endpoints included survival after 180 days, presented with hazard ratios from a univariate- and a predefined multivariable COX regression model. Results: We included 137 patients during an enrollment period of 21 months. Patients were mainly male (85%) with a median age of 66 years (IQR 56, 75). The treatment resulted in markedly reduced IL-6 levels over time (p<0.0001) in the active treatment group, while no difference over time was found in NSE levels between groups (p=0.22), Figure 1. In the glucocorticoid group, 51 (75%) patients survived and in the placebo group 45 (64%) patients, (Univariate model: HR 0.65 (0.35-1.20), p=0.17; Multivariable model: HR 0.33 (0.16-0.71), p<0.01), Figure 2. Conclusion: Prehospital treatment with high-dose glucocorticoid reduced the inflammatory cytokine IL-6 over time in resuscitated OHCA patients without affecting NSE, a biomarker of brain injury.

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Bradley J Petek¹, Timothy W Churchill², Nathaniel Moulson³, Stephanie A Kliethermes⁴, Aaron L Baggish⁵, Jonathan A Drezner⁶, Manesh R Patel⁷, Michael J Ackerman⁸, Kristen L Kucera⁹, David M Siebert⁶, Lauren Salerno⁶, Monica L Zigman Suchsland⁶, Irfan M Asif¹⁰, Joseph J Maleszewski¹¹, Kimberly G Harmon⁶; ¹Knight Cardiovascular Institute, Oregon Health & Science Univ, Portland, OR, ²DIVISION OF CARDIOLOGY, Massachusetts General Hosp, Boston, MA, ³Div of Cardiology and Sports Cardiology, Univ of British Columbia, Vancouver, Canada, ⁴Dept of Orthopedics and Rehabilitation, Univ of Wisconsin Madison, Madison, WI, ⁵Institute for Sport Science, Univ of Lausanne, Lausanne, Switzerland, ⁶Dept of Family Medicine and Cntr for Sports Cardiology, Univ of Washington, Seattle, WA, ⁷Div of Cardiology, Duke Med Cntr, Durham, NC, ⁸Dept of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, ⁹Dept of Exercise and Sport Science, Univ of North Carolina at Chapel Hill, Chapel Hill, NC, ¹⁰Family and Community Medicine, The Univ of Alabama at Birmingham Heersink Sch of Medicine, Birmingham, AL, ¹¹Dept of Laboratory Medicine & Pathology, Mayo Clinic, Rochester, MN

Background: The incidence, causes, and trends of sudden cardiac death (SCD) among young competitive athletes are critical to inform preventive policies. Methods: National Collegiate Athletic Association (NCAA) athlete deaths from 7/1/2002-6/30/2022 were identified through 4 independent databases/search strategies. Autopsy reports and medical history were reviewed by an expert panel to adjudicate causes of SCD. Poisson regression was used to calculate incidence rate ratios (IRR) for 5-year intervals over the 20-year study. Results: A total of 143 SCD cases were identified among 1102 athlete deaths and 9,106,516 athlete-years (AYs). The incidence of SCD among NCAA athletes was 1:63,682 AYs [95% CI 1:54,065, 1:75,010]. Incidence was higher in males compared with females (1:43,348 [95% CI 1:36,228, 1:51,867] vs. 1:164,504 [95% CI 1:110,552, 1:244,787] AYs) and Black compared with White athletes (1:26,704 [1:20,417, 1:34,925] vs. 1:74,581 [1:60,247, 1:92,326] AYs). The highest incidence of SCD was among Division 1 male basketball players (1:8,188; White 1:5,848; Black 1:7,696 AYs). The incidence rate for SCD decreased over the study period (5-year IRR 0.71 [95% CI 0.61,0.82]), whereas the rate of non-cardiovascular deaths remained stable (5-year IRR 0.98 [95% CI 0.94,1.04]; Figure 1A). Autopsy-negative sudden unexplained death (AN-SUD, 19.5%) was the most common post-mortem exam finding, followed by idiopathic left ventricular hypertrophy/possible cardiomyopathy (CM, 16.9%) and hypertrophic CM (12.7%) in cases with enough information for adjudication (118/143, Figure 1B). There were 8 cases of myocarditis, with none attributed to COVID-19 infection. SCD events were exertional in 50% of cases. Exertional SCD was more common among those with coronary artery anomalies (100%) and arrhythmogenic CM (83%). Conclusions: The incidence of SCD in college athletes has decreased. Male sex, Black race, and basketball are associated with a higher incidence of SCD.

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Rachel Lampert¹, Sharlene Day², Barbara Ainsworth³, Matthew Burg⁴, Bradley S Marino⁵, Lisa Salberg⁶, Maite Tome⁷, Dominic J Abrams⁸, Peter F Aziz⁹, Cheryl Barth¹⁰, Cheyanne Bell¹¹, Charles I Berul¹², Johan M Bos¹³, David Bradley¹⁴, David S Cannom¹⁵, Bryan C Cannon¹⁶, Maryann A Concannon¹⁷, Marina Cerrone¹⁸, Richard J Czosek¹⁹, Anne M Dubin²⁰, Jim D Dziura²¹, Christopher C Erickson²², Nathan A Estes, III²³, Susan P Etheridge²⁴, Belinda Gray²⁵, Carla Haglund-Turnquist¹¹, Cynthia James²⁶, Christopher Johnsrude²⁷, Prince Kannankeril²⁸, Alice Lara²⁹, Ian H Law³⁰, Fangyong Li³¹, Mark S Link³², Silvana M Molossi³³, Brian Olshansky³⁴, Peter A Noseworthy³⁵, Elizabeth V Saarel³⁶, Shubhayan Sanatani³⁷, Maully Shah³⁸, Laura Simone¹⁰, Jonathan Skinner³⁹, Gordon F Tomaselli⁴⁰, James S Ware⁴¹, Gregory G Webster⁴², Douglas P Zipes⁴³, Michael J Ackerman¹¹; ¹SECTION OF CARDIOVASCULAR MEDICINE, YALE SCHOOL OF MEDICINE, New Haven, CT, ²Medicine, Univ of Pennsylvania, Philadelphia, PA, ³NA, Arizona State Univ, Phoenix, AZ, ⁴Medicine, Yale Sch of Medicine, West Haven, CT, ⁵Pediatrics, CLEVELAND CLINIC, Cleveland, OH, ⁶NA, Hypertrophic Cardiomyopathy Assoc., Denville, NJ, ⁷Medicine, St George’s Univ, London, United Kingdom, ⁸Pediatrics, Children’s Hosp, Boston, MA, ⁹Pediatrics, Cleveland Clinic, Cleveland, OH, ¹⁰Medicine, Yale Univ, New Haven, CT, ¹¹Pediatrics, Mayo Clinic, Rochester, MN, ¹²CHILDRENS NATIONAL HEALTH SYSTEM, Washington, DC, ¹³Medicine, Mayo Clinic College of Medicine, Rochester, MN, ¹⁴Pediatrics, C.S. Mott Children’s Hosp, Ann Arbor, MI, ¹⁵Medicine, Keck Medicine of USC, Los Angeles, CA, ¹⁶Pediatrics, MAYO CLINIC, Rochester, MN, ¹⁷Medicine, Univ of Michigan Hosp, Ann Arbor, MI, ¹⁸Medicine, NYU SCHOOL OF MEDICINE, New York, NY, ¹⁹Pediatrics, CINCINNATI CHILDRENS HOSPITAL, Cincinnati, OH, ²⁰Pediatrics, STANFORD UNIV SCHOOL MEDICINE, Palo Alto, CA, ²¹Medicine, Yale Sch of Medicine, New Haven, CT, ²²Pediatrics, JOINT DIVISION OF PEDI OF CARDIO, Omaha, NE, ²³Medicine, UPMC, Pittsburgh, PA, ²⁴Pediatrics, PCOS ECCLES BULIDING, Salt Lake Cty, UT, ²⁵Medicine, Royal Prince Alfred Hosp, Camperdown, Australia, ²⁶Medicine, JOHNS HOPKINS UNIVERSITY, Baltimore, MD, ²⁷Pediatrics, Univ of Louisville, Louisville, KY, ²⁸Pediatrics, Vanderbilt Med Sch, Nashville, TN, ²⁹NA, SUDDEN ARRHYTHMIA DEATH SYNDROME FDN, Salt Lake Cty, UT, ³⁰Pediatrics, UNIVERSITY OF IOWA CHILDRENS HOSPITAL, Iowa City, IA, ³¹NA, YCAS, New Haven, CT, ³²Medicine, UTSouthwestern Med Cntr, Dallas, TX, ³³Pediatrics, BCM TEXAS CHILDRENS HOSPITAL, Houston, TX, ³⁴Medicine, U Iowa, Iowa City, IA, ³⁵Medicine, MAYO CLINIC, Rochester, MN, ³⁶Medicine, St. Luke’s Med Cntr, Meridian, ID, ³⁷Pediatrics, British Columbia, Vancouver, Canada, ³⁸Pediatrics, Children’s Hosp of Philadelphia, Philadelphia, PA, ³⁹Pediatrics, Univ of Aukland, Aukland, New Zealand, ⁴⁰Medicine, Albert Einstein College of Medicine, Bronx, NY, ⁴¹Medicine, Imperial College London, London, United Kingdom, ⁴²Pediatrics, Lurie Childrens Hosp, Chicago, IL, ⁴³Medicine, INDIANA UNIVERISTY SCHL MED, Carmel, IN

Background: Whether vigorous exercise increases risk of ventricular arrhythmias (VA) for individuals diagnosed and treated for congenital long QT syndrome (LQTS) remains unknown. Methods: The NIH-funded LIVE-LQTS study prospectively enrolled individuals age 8-60 years with phenotypic and/or genotypic LQTS, from 42 sites in 5 countries from 5/2015 to 2/2019. Participants (or parents) answered physical activity and clinical events surveys every 6 months for 3 years with follow-up completed in 2/2022. Vigorous exercise was defined as > 6 METS for > 60 hours per year. A blinded events committee adjudicated the composite endpoint of sudden death (SD), sudden cardiac arrest (SCA), VA treated by ICD, and likely-arrhythmic syncope. A National Death Index search ascertained vital status for those with incomplete follow up. A noninferiority hypothesis (boundary of 1.5) between vigorous exercisers and others was tested via multivariable Cox regression analysis. Results: Among the 1413 participants (13% <18, 35% 18-25 years, 67% female, 25% with ICDs, 90% genotype positive, 49% LQT1), 91% were treated with either beta-blocker, left cardiac sympathetic denervation, and/or ICD. Fifty-two percent participated in vigorous exercise (55% of these competitively). Thirty-seven individuals experienced the composite endpoint, (including 1 SCA, 1 arrhythmic death in non-vigorous, and 1 SCA in vigorous, groups) with overall event rates at 3 years of 2.6% in the vigorous and 2.7% in the non-vigorous exercise groups. Hazard ratios after adjustment for pre-specified and post-hoc co-variates are shown in the Figure. CIs extended beyond the 1.5 boundary. Neither vigorous or non-vigorous exercise was found to be superior in any group or subgroup. Conclusions: Among individuals diagnosed with phenotypic and/or genotypic LQTS who were risk-assessed and treated in experienced centers, LQTS-associated cardiac event rates were low and similar between those exercising vigorously and those not. Consistent with the low event rate, confidence intervals are wide, and non-inferiority was not demonstrated. Neither vigorous nor non-vigorous exercise was superior in any group. These data further inform shared decision-making discussions between patient and physician regarding exercise and competitive sports participation.

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John Hummel¹, Steven Ullery², Mahmoud Houmsse³, Gery Tomassoni⁴, Devi Nair⁵, Jorge Romero⁶, Joe Hargrove⁷, Kiran Mathews⁸, Zubin J Eapen⁹, Uday Kumar¹⁰, Roxana Mehran¹¹, Javed Butler¹², Jewel IDE Study Investigators; ¹MEDICINE, OSU, Columbus, OH, ²Biostatistics, NAMSA, Northwood, OH, ³Medicine, Ohio State Univ Med Cntr, Dublin, OH, ⁴Medicine, Baptist Health, Lexington, KY, ⁵Medicine, St. Bernards Healthcare, Jonesboro, AR, ⁶Medicine, Brigham and Women’s Hosp, Jamaica Plain, MA, ⁷Medicine, CHI St. Vincent, Little Rock, AR, ⁸Clinical, Element Science, Oakland, CA, ⁹Clinical, Element Science, San Francisco, CA, ¹⁰CEO, Element Science, Inc., San Francisco, CA, ¹¹Medicine, ICAHN SCHOOL OF MEDICINE MT SINAI, New York, NY, ¹²Baylor Scott and White Rsch Institute, Baylor Scott and White, Atlanta, GA

Background: Sudden cardiac arrest (SCA) due to ventricular tachycardia or fibrillation (VT/VF) is a leading cause of death in the US. Wearable cardioverter defibrillators (WCDs) are a viable option to monitor and treat VT/VF. However, traditional WCDs can be uncomfortable, require frequent maintenance, and are inconvenient during activities such as exercise and showering. This has resulted in reduced compliance and avoidable arrhythmic deaths in clinical trials. The Jewel, a novel, low-profile, water-resistant Patch-WCD (P-WCD) with a proprietary machine learning algorithm, was designed to improve the patient experience, resulting in high compliance and more effective protection against SCA. Objective: To demonstrate the safety and efficacy of the Jewel P-WCD. Methods: The Jewel IDE Study was a prospective, single-arm trial, conducted at 30 US sites from January 2022 to May 2023. The study aimed to enroll ≥290 adults at risk for SCA who were not candidates for or refused an implantable cardioverter defibrillator. The primary effectiveness endpoint was to observe <2 inappropriate shocks per 100 patient-months, with a one-sided upper 98% confidence interval (CI). The primary safety endpoint was to observe <15% subjects with clinically significant cutaneous adverse device effects (ADEs), with a one-sided upper 95% CI. The secondary endpoints were to observe ≥1 successful conversion of VT/VF and a compliance of >14.1 hours/day. Results: The study enrolled 305 patients (mean age 57.99 years; 65.2% male, 25.9% non-white), of which 290 had available device data. The inappropriate shock rate was 0.36 shocks per 100 patient-months (upper 98% CI: 1.54). The clinically significant cutaneous ADE rate was 2.30% (upper one-sided 95% CI: 4.27); all events were mild or moderate severity. No device related deaths or serious adverse events were reported. Eight events observed in 6 patients were successfully converted by a single shock. Average compliance was 21.33 hours/day (median: 23.53). Conclusion: The patient-centric Jewel P-WCD is a safe and effective WCD. Compared to other WCDs, the Jewel P-WCD led to high compliance, resulting in a high number of patient saves and no deaths due to non-compliance.

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Jan Belohlavek¹, Tomas Vetrovsky², Tereza Frybova¹, Iulian Gant¹, Miroslav Semerad³, Vaclav Bunc³, Marie Miklikova⁴, Lenka Sujakova⁴, David Pospisil⁴, Jiri Parenica⁴, Jiri Stastny⁵, Martin Griva⁵, Jan Precek⁶, Radek Pelouch⁷, Jiri Vesely⁸, Adela Vojkuvkova⁹, Karolina Hrabcova⁹, Michal Svoboda⁹, Jiri Jarkovsky⁹, Ales Linhart¹, Michal Siranec¹; ¹2nd Dept of Medicine – Dept of Cardiovascular Medicine, First Faculty of Medicine, Charles Univ and General Univ Hosp in Prague, Prague, Czech Republic, ²Sport Sciences–Biomedical Dept, Faculty of Physical Education and Sport, Charles Univ, Prague, Czech Republic, ³Faculty of Physical Education and Sport, Faculty of Physical Education and Sport, Charles Univ, Prague, Czech Republic, ⁴Cardiology Dept, Univ Hosp Brno and Med Faculty of the Masaryk Univ, Brno, Czech Republic, ⁵Dept of Cardiology, Tomas Bata Regional Hosp, Zlin, Czech Republic, ⁶Dept of Internal Medicine I - Cardiology, Univ Hosp Olomouc, Olomouc, Czech Republic, ⁷1st Dept of Internal Medicine – Cardioangiology, Faculty of Medicine in Hradec Kralove, Charles Univ, Prague, and Univ Hosp Hradec Kralove, Hradec Kralove, Czech Republic, ⁸Edumed s.r.o., Edumed s.r.o., Broumov, Czech Republic, ⁹Institute of Biostatistics and Analyses, Institute of Biostatistics and Analyses, Faculty of Medicine, Masaryk Univ, Brno, Czech Republic

Background: Physical activity is pivotal in managing heart failure with reduced ejection fraction (HFrEF), and walking integrated into daily life is an especially suitable form of such physical activity. This study aimed to determine if a 6-month lifestyle walking intervention combining self-monitoring and regular phone counseling improves functional capacity assessed by the six-minute walk test (6MWT) in stable patients with HFrEF compared to usual care. Methods: The WATCHFUL trial was a 6-month, multicenter, parallel-group, randomized, controlled trial recruiting HFrEF patients from six Czech cardiovascular centers. Eligible participants were ≥18 years old with left ventricular ejection fraction <40% and NYHA class II/III symptoms, on guidelines-recommended medication, excluding those exceeding 450m in the baseline 6MWT. Patients in the intervention group were equipped with a Garmin vívofit activity tracker and received monthly phone counseling from research nurses who encouraged them to employ behavior change techniques such as self-monitoring, goal-setting, and action planning to increase their daily step count. The control group patients continued usual care. The primary outcome was the difference between groups in the distance (in meters) walked during the 6MWT at 6 months. Secondary outcomes included daily step count and minutes of moderate-to-vigorous physical activity (MVPA) as measured by the hip-worn Actigraph wGT3X-BT accelerometer, NT-proBNP and hsCRP biomarkers, ejection fraction, anthropometric measures, depression score, self-efficacy, quality of life, and survival risk score. The primary analysis was conducted by intention-to-treat. Results: From 218 screened patients, 202 were randomized (65 years; 22.8% female; 90.6% NYHA II; left ventricular ejection fraction 32.5%; 6MWT 385m; 5071 steps/day; 10.9 minutes of MVPA per day). At six months, no between-group differences were detected for the 6MWT (7.4 m, 95% CI -8.0 to 22.7, p=0.345, N=186). The intervention group increased their average daily step count by 1420 (95% CI: 749; 2091) and daily minutes of MVPA by 8.2 (95% CI: 3.0; 13.3) over the control group. No between-group differences were detected for any other secondary outcomes. Conclusions: While the lifestyle intervention in patients with HFrEF improved daily steps by about 25%, it failed to demonstrate a corresponding improvement in functional capacity. Further research is needed to understand the disconnect between increased physical activity and functional outcomes. Registration: ClinicalTrials.gov (NCT03041610).

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Jeffrey J Goldberger¹, Raul Mitrani², Maureen Lowery¹, Joel Fishman³, carmen baez-garcia¹, Catherine Blandon¹, Ghaith Zaatari¹, alex velasquez¹, Litsa Lambrakos¹, Gianluca Iacobellis¹; ¹Medicine, Univ of Miami, Miami, FL, ²Medicine, Univ of Miami, Miami, FL, ³Radiology, Univ of Miami, Miami, FL

Introduction: Liraglutide is a GLP-1 agonist approved for weight loss. We assessed whether pre-ablation treatment with Liraglutide in addition to standard risk factor modification (RFM) improves outcomes compared to RFM in patients with atrial fibrillation (AF). Methods: In LEAF, 65 patients with BMI≥27 kg/m² who opted for catheter ablation to treat AF were enrolled and randomized to a 3 month pre-ablation period of RFM or RFM plus Liraglutide (RFM+L, titrated to 1.8 mg daily). There were 6 withdrawals. Four enrolled patients opted not to proceed with ablation and 1 patient no longer required ablation as AF resolved after RFM+L. Ablation procedures targeted pulmonary vein isolation (PVI) - only one patient had additional posterior wall isolation. Echocardiograms were used to assess epicardial adipose tissue (EAT) thickness from the parasternal long axis view at enrollment and prior to ablation. Long-term monitoring was used to assess freedom from AF. Results: There were 28 patients in RFM (age 61.8±10.3 years, 29% female) weighing 102.8±17.0 kg (BMI 34.7±4.7 kg/m²) and 31 in RFM+L (age 62.2±8.6 years, 26% female) weighing 109.6±19.5 kg (BMI 37.4±6.4 kg/m²); 80% had persistent AF (PerAF) and 20% had paroxysmal AF with 85% having hypertension, 27% diabetes, and 44% obstructive sleep apnea. CHA₂DS₂-VASc score was 2.4±1.6 and left ventricular ejection fraction was 56.3±10.4%. Median time from enrollment to ablation was 4.5 and 4.0 months in RFM and RFM+L, respectively (p=0.14). For all patients, there was significant pre-ablation reduction in weight (2.8±3.7%, p<0.001) and EAT (0.8±1.6 mm, p<0.001), with no significant difference between RFM and RFM+L (2.1±3.0% vs 3.4±4.1%, and 1.1±1.7 mm vs 0.6±1.5 mm, respectively). Complete PVI was achieved in all but one patient undergoing ablation with two complications (one post-procedure pericarditis, one femoral artery pseudoaneurysm). The figure shows Kaplan-Meier freedom from AF and atrial flutter (AFL) off antiarrhythmic drugs after a 3 month blanking period (1 RFM only patient still taking amiodarone 100 mg daily at 6 months). Conclusion: In a group of obese patients with primarily PerAF, pre-ablation treatment with RFM and/or RFM+L results in weight loss, reduction in EAT. Improved outcomes were observed from PVI ablation with RFM+L versus RFM only. Treatment with RFM and GLP-1 agonists may be useful adjunctive therapy for obese patients with AF.

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Kazuya Hosokawa¹, JUNJI KISHIMOTO¹, Yu TANIGUCHI², Nobutaka Ikeda³, takumi inami⁴, Satoshi Yasuda⁵, Toyoaki Murohara⁶, Masaru Hatano⁷, Yuichi Tamura⁸, Jun Yamashita⁹, Koichiro Tatsumi¹⁰, Ichizo Tsujino¹¹, Yuko Kobayakawa¹², Shiro Adachi¹³, Nobuhiro Yaoita¹⁴, Shun Minatsuki¹⁵, Koji Todaka¹², Keiichi Fukuda¹⁶, Hiroyuki Tsutsui¹⁷, Kohtaro Abe¹, KABUKI investigaors; ¹Dept of Cardiovascular Medicine, Kyushu Univ, Fukuoka, Japan, ²Div of Cardiovascular Medicine, Kobe Univ Hosp, Kobe, Japan, ³Div of Cardiovascular Medicine, Toho Univ, Ohashi Med Cntr, Tokyo, Japan, ⁴Dept of Cardiovascular Medicine, Kyorin Univ Sch of Medicine, Tokyo, Japan, ⁵Dept of Cardiovascular Medicine, Tohoku Univ Graduate Sch of Medicine, Sendai, Japan, ⁶Dept of Cardiology, Nagoya Univ Graduate Sch of Medicine, Nagoya, Japan, ⁷Dept of Cardiovascular Medicine, Graduate Sch of Medicine, The Univ of Tokyo, Tokyo, Japan, ⁸Pulmonary Hypertension Cntr, International Univ of Health and Welfare Mita Hosp, Tokyo, Japan, ⁹Dept of Cardiology, Tokyo Med Univ, Tokyo, Japan, ¹⁰Dept of Respirology, Graduate Sch of Medicine, Chiba Univ, Chiba, Japan, ¹¹Div of Respiratory and Cardiovascular Innovative Rsch, Faculty of Medicine and Graduate Sch, Hokkaido Univ, Sapporo, Japan, ¹²Cntr for Clinical and Translational Rsch, Kyushu Univ, Fukuoka, Japan, ¹³Dept of Cardiology, Nagoya Univ Hosp, Nagoya, Japan, ¹⁴Tohoku Univ Hosp, Sendai, Japan, ¹⁵Univ of Tokyo, Tokyo, Japan, ¹⁶Dept of Cardiology, Keio Univ, Tokyo, Japan, ¹⁷Director, International Univ of Health and Welfare, Okawa, Japan

Background: In patients with chronic thromboembolic pulmonary hypertension (CTEPH), lifelong anticoagulation with vitamin K antagonists is recommended to prevent worsening of CTEPH. More recently, direct oral anticoagulants (DOACs) are more frequently used as an alternative to vitamin K antagonists, despite a lack of evidence from randomized controlled trials. Edoxaban, the most recently approved DOAC, has proven efficacy and safety for venous thromboembolism. The present trial tested whether edoxaban is non-inferior to warfarin, a vitamin K antagonist, in preventing worsening of CTEPH. Methods: The study (ClinicalTrials.gov Identifier: NCT04730037) was a multicenter, randomized, single-blind, warfarin-controlled, non-inferiority trial to evaluate the efficacy and safety of edoxaban in subjects with CTEPH. The inclusion criteria were CTEPH patients (WHO functional class I-III) aged between 20 and 85 years. Eligible patients were randomly assigned to edoxaban group or warfarin group in a 1:1 ratio. Primary end point was the ratio of pulmonary vascular resistance at week 48 to pulmonary vascular resistance at baseline. Secondary end points were incidence of clinical worsening of CTEPH*, changes in WHO functional class, changes in 6-minute walk distance, and changes in NT-proBNP. Safety end point was clinically relevant bleeding defined by the ISTH 2015 criteria (Figure). Results: Recruitment began in March 31, 2021 and ended in March 30, 2023 with 74 patients; 37 were randomized to edoxaban group and 37 to warfarin group. The mean age was 63.6±12.3 years, 62.2% was women, all patients had undergone reperfusion treatment (i.e. pulmonary endarterectomy or balloon pulmonary angioplasty). The database was locked on June 27, 2023, and the primary results will be available for presentation at the AHA 2023 Scientific Session. Conclusion: We will present the primary results of this first multi-center randomized controlled trial in patients with CTEPH to demonstrate whether edoxaban sufficiently prevent worsening of pulmonary hemodynamics and clinical worsening of CTEPH without increasing bleeding risk, compared with warfarin. (Funded by the Japan Agency Medical Research and Development and Daiichi-Sankyo Corp., Ltd.)

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Stefan Stortecky¹, Stephan Windecker², Dik Heg³, Lars Englberger⁴, Alexander Kadner⁵, Nils Kucher⁶; ¹Cardiology, Univ Hosp of Bern, Bern, Switzerland, ²Cardiology, Swiss Cardiovascular Cntr Bern, Bern, Switzerland, ³Clinical Trials Unit, CTU Bern, Bern, Switzerland, ⁴Cardiac Surgery, Univ Hosp of Bern, Bern, Switzerland, ⁵Dept Cardiovascular Surgery, Univ Hosp Bern, Bern, Switzerland, ⁶Angiology, Univ Hosp Zurich, Zurich, Switzerland

Background: Ultrasound-assisted catheter-directed thrombolysis (USAT) and surgical pulmonary embolectomy (SPE) are treatment options for patients with acute pulmonary embolism (PE) at increased risk of right ventricular (RV) failure and death. At this point in time dedicated randomized trials comparing these treatment options are missing. We hypothesized that USAT is non-inferior to SPE regarding the improvement in RV overload and thrombus burden. Methods: In the SPECIAL (registered at clinicaltrials.gov with NCT03218410) randomized single-center, non-inferiority trial, patients with intermediate-high or high risk PE (symptom onset within 14 days) were evaluated by the multidisciplinary PE response team and considered for trial inclusion. Participants were randomly assigned (1:1) to undergo treatment with USAT or SPE using a block randomization scheme, stratified by PE risk. Primary and secondary endpoints were the baseline-to-72hour difference in right to left ventricular dimension (RV/LV) ratio and the Qanadli pulmonary occlusion score by contrast-enhanced chest computed tomography, assessed by a blinded CoreLab. Results: The study was terminated prematurely due to increasingly difficult patient recruitment. Between October 2015 and June 2020, 27 patients (mean age 62.6 years (± 12.4); 26% were women; 85% had intermediate-high risk and 15% high risk PE) were enrolled. The mean reduction in the RV/LV ratio was -0.34 (95%CI -0.50 to -0.18, p<0.001) for USAT and -0.53 (95%CI -0.68 to -0.38, p<0.001) for SPE, which did not meet the pre-specified non-inferiority margin (mean difference 0.152, non-inferiority p-value=0.80, p-value for superiority 0.013). The mean change in the Qanadli pulmonary occlusion score was greater for SPE (mean -11.36, 95%CI -15.27 to -7.44) than for USAT (mean -7.23, 95%CI -9.58 to -4.88), with a mean difference of 5.00 (95%CI 0.44 to 9.56, p=0.032) in favor of SPE. At 3 months, no differences in all-cause death, recurrent PE, stroke and bleeding were observed between the groups. Conclusion: In this first randomized controlled trial, USAT did not meet non-inferiority compared to SPE for early reversal of right ventricular overload. In addition, SPE was more effective than USAT in improving thrombus burden.

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Mary M McDermott¹, Christopher R Martens², Kathryn Domanchuk³, Dongxue Zhang⁴, Michael H Criqui⁵, Luigi Ferrucci⁶, Philip Greenland⁷, Jack Guralnik⁸, Karen Ho⁹, Melina R Kibbe¹⁰, Kate Kosmac¹¹, Donald M Lloyd-Jones¹², Charlotte Peterson¹³, Robert Sufit¹⁴, Lu Tian¹⁵, Stephanie Wohlgemuth¹⁶, Lihui Zhao¹², Christiaan Leeuwenburgh¹⁷; ¹General Medicine, Northwestern Univ, Chicago, IL, ²Dept of Kinesiology & Applied Physiology, Univ of Delaware, Newark, DE, ³Dept of General Medicine, Northwestern Univ, Chicago, IL, ⁴Dept of Internal Medicine, Northwestern Univ, Chicago, IL, ⁵Dept of Preventative Medicine, UCSD, La Jolla, CA, ⁶Div of Intramural Rsch, NIA, Baltimore, MD, ⁷Dept of Preventive Medicine, Feinberg Sch of Medicine, Chicago, IL, ⁸Dept of Epidemiology, Univ of Maryland, Baltimore, MD, ⁹Dept of Surgery, Northwestern Univ, Chicago, IL, ¹⁰Dept of Surgery, Univ of Virginia, Charlottesville, VA, ¹¹Dept of Physical Therapy, Augusta Univ, Augusta, GA, ¹²Dept of Preventive Medicine, Northwestern Univ, Chicago, IL, ¹³Dept of Physical Therapy, Univ of Kentucky, Lexington, KY, ¹⁴Dept of Neurology, Northwestern Univ, Chicago, IL, ¹⁵Dept of Biomedical Data Science, Stanford Univ, Palo Alto, CA, ¹⁶Dept of Aging and Geriatric Rsch, Univ of Florida, Gainesvlle, FL, ¹⁷Dept of Aging and Geriatric Rsch, Univ of Florida, Gainesville, FL

Introduction: Nicotinamide riboside (NR) is a precursor to nicotinamide adenine dinucleotide (NAD+), which increases endothelial nitric oxide synthase, sirtuin1 (SIRT1), and mitochondrial activity. Resveratrol increases binding of NAD+ to SIRT1. Hypothesis: In a double-blind randomized trial, to assess whether, compared to placebo, six months of NR alone and six months of NR + resveratrol, respectively, improved six-minute walk in people with peripheral artery disease (PAD). Methods: PAD participants were randomized to NR 1,000 mgs (N=28), NR 1,000 mgs + resveratrol 125 mgs (N=33), or placebo (N=29) for six months. The two primary comparisons were differences between NR vs. placebo and between NR+resveratrol vs. placebo in change in six-minute walk distance at 6-month follow-up. In this Phase II Trial, statistical significance was pre-specified as a one-sided P value <0.10. Results: Of 90 participants (age: 71.2 years (±9.1), 43 (47.8%) Black, 42 (46.7%) female), 89 (98.9%) completed follow-up. Adjusting for age, sex, race, and baseline six-minute walk, compared to placebo, NR alone significantly improved six-minute walk at 6-month follow-up by 17.6 meters (90% Confidence Interval (CI): +1.77,+∞, P=0.078), while NR + resveratrol did not significantly improve six-minute walk (+3.65 meters, 90% CI:-11.2,+∞, P=0.38). Among people with at least 75% adherence to assigned study pills, NR alone improved six-minute walk by 31.0 meters (90% CI: +13.2,+∞, P=0.014) and NR + resveratrol improved six-minute walk by 26.9 meters (90% CI:+9.1,+∞, P=0.028), compared to placebo. Conclusions: Compared to placebo, NR improved walking performance in people with PAD. Resveratrol did not further increase benefits from NR.

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Lucas Marinho¹, Brendan M Everett¹, Aaron W Aday², Frank L Visseren³, Jean MacFadyen¹, Elaine Zaharris¹, Jorge Plutzky⁴, Peter Libby¹, Jean Charles C Fruchart⁵, Paul M Ridker¹, Aruna D Pradhan¹; ¹Medicine, Brigham and Women’s Hosp, Boston, MA, ²Medicine, Vanderbilt Univ Med Cntr, Nashville, TN, ³Medicine, Univ Med Cntr Utrecht, Utrecht, Netherlands, ⁴Medicine, Brigham and Womens Hosp, Boston, MA, ⁵Medicine, INSERM & THE U545 INSERM, Lille, France

Introduction: While lower extremity ulceration and related gangrene commonly complicate type 2 diabetes (T2D), diminish quality of life and threaten limb loss, no medical therapy to date has demonstrated significant clinical benefit. Incidence rates are increasing and limb ischemia is a contributing factor in the majority of cases with limited revascularization options due to small vessel involvement. Prior data suggest peroxisome proliferator-activated receptor alpha (PPAR-α) agonists can reduce diabetic microvascular complications including minor amputation. We evaluated whether pemafibrate, a potent selective PPAR-α agonist, reduces the incidence of lower extremity ischemic ulceration or gangrene in the setting of a large, multinational, placebo-controlled, randomized clinical trial. Methods: Participants in the PROMINENT study had T2D, mild-to-moderate hypertriglyceridemia (triglyceride level, 200 to 499 mg/dL), low HDL cholesterol levels (≤ 40 mg/dL), received guideline-directed statin therapy (two-thirds on high intensity statins), were randomly allocated to pemafibrate (0.2 mg orally twice daily) or matching placebo and followed for up to 5 years. Data on ischemic ulceration and gangrene were collected at every visit and referred for prospective adjudication. The primary outcome for this secondary analysis was physician-adjudicated incident lower extremity ischemic ulceration or gangrene. Results: 10,497 participants, 15% of whom had a prior history of PAD, were followed for a median period of 3.3 years (IQR: 2.5,4.0). Incident lower ischemic extremity ulceration or gangrene occurred in 35 participants in the pemafibrate group and 56 in the placebo group (HR, 0.63;95% CI, CI 0.41-0.95;p=0.03). Ulcer or gangrene most commonly occurred in the foot or toe (92%). Event rates were highest among individuals with prior diabetic foot disease, followed by history of PAD, established microvascular disease and current smoking. However, there was no heterogeneity of treatment benefit according to these or other known ulceration risk factors (20-40% reductions in most risk factor groups). Conclusions: In patients with T2D, mild-to-moderate hypertriglyceridemia, and low levels of HDL on guideline directed lipid lowering therapy, pemafibrate significantly reduced the risk of lower extremity ischemic ulceration or gangrene, a finding with potential to address a major and growing unmet clinical need that merits further prospective investigation among patients at high risk of developing this disease.

Author Disclosures: For author disclosure information, please visit the AHA Scientific Sessions 2023 Online Program Planner and search for the abstract title.