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Abstract
Originally Published 18 December 2023
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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

Late-Breaking Science: Obesity - Novel Therapeutics and Implications for Population Health

22962: Semaglutide and Cardiovascular Outcomes in Patients With Overweight or Obesity Who Do Not Have Diabetes

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.

Late-Breaking Science: Hot Topics in Management of Coronary Artery Disease/Acute Coronary Syndrome

23437: DAPA-MI - A Registry-Based Randomized Trial of Dapagliflozin in Patients With Acute Myocardial Infarction Without Diabetes

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.

21081: Restrictive versus Liberal Blood Transfusion in Patients With Myocardial Infarction and Anemia: Results of the MINT Trial

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.

22178: Percutaneous Coronary Intervention for Stable Angina (ORBITA-2): A Randomised, Placebo-Controlled Trial

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.

Late-Breaking Science: Heart Failure - VADS, Kids, and Money

22180: Avoidance of Aspirin With Left Ventricular Assist Devices in Advanced Heart Failure: Primary Results of the International, Double-Blind, Placebo-Controlled ARIES HM3 Clinical Trial

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 18th,2023, and final analysis will be available by October 6th, 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.

23364: The TEAMMATE Trial: Everolimus to Prevent Rejection in Children After Cardiac Transplantation

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.

23532: Integrating Cost Into Shared Decision-Making for Heart Failure With Reduced Ejection Fraction: A Trial Providing Out-of-Pocket Costs for Heart Failure Medications During Clinical Encounters

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.

Late-Breaking Science: Using Drugs, Diet and Delivery to Optimize Hypertension Outcomes

23343: Effectiveness of Blood Pressure-Lowering Intervention on Risk of Total Dementia Among Patients With Hypertension: A Cluster-Randomized Effectiveness Trial

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

23145: Long-Term Blood Pressure Control After Physician Optimised Postpartum Blood Pressure Self-Management: The POP-HT Randomised Clinical Trial

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

22998: Effects of Dietary Sodium on Systolic Blood Pressure in Middle-Aged Individuals: A Randomized Order Cross-Over Trial

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 (25th-75th 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.
Author Disclosures: For author disclosure information, please visit the AHA Scientific Sessions 2023 Online Program Planner and search for the abstract title.

23327: Sustained Blood Pressure Reduction With the RNA Interference Therapeutic Zilebesiran: Primary Results From KARDIA-1, a Phase 2 Study in Patients With Hypertension

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

Late-Breaking Science: Shocking Decisions in AFib Care

23030: Efficacy and Safety of Dual Direct Current Cardioversion versus Single Direct Current Cardioversion as an Initial Treatment Strategy in Obese Patients With Atrial Fibrillation

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

24578: Abelacimab, a Novel Factor XI/XIa Inhibitor, vs Rivaroxaban in Patients with Atrial Fibrillation: Primary Results of the AZALEA-TIMI 71 Randomized Trial

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

23329: Efficacy and Safety of Anticoagulation with Edoxaban in Patients With AHRE Durations ≥24 Hours. The NOAH-AFNET 6 Trial

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

23303: Apixaban for the Prevention of Stroke in Patients With Subclinical Atrial Fibrillation

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 (25th, 75th) 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.
Author Disclosures: For author disclosure information, please visit the AHA Scientific Sessions 2023 Online Program Planner and search for the abstract title.

Late-Breaking Science: Future of Lipid Lowering Therapy - Novel Mechanisms and Approaches

23230: Safety and Pharmacodynamic Effects of VERVE-101, an Investigational DNA Base Editing Medicine Designed to Durably Inactivate the PCSK9 Gene and Lower LDL Cholesterol - Interim Results of the Phase 1b heart-1 Trial

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

22198: Efficacy and Safety of Lepodisiran: An Extended Duration Short-Interfering RNA Targeting Lipoprotein (a)

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

21064: Recaticimab Add-On Therapy in Patients With Non-Familial Hypercholesterolaemia and Mixed Hyperlipidemia (REMAIN-2): A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase 3 Trial

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

19497: Effects of Pitavastatin on Coronary Artery Disease and Inflammatory Biomarkers in HIV: Mechanistic Substudy of the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE)

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

Late-Breaking Science: From Local to Global: Achieving Equity in Prevention

23441: Effects of Intensive Blood Pressure Lowering Treatment in Reducing Risk of Cardiovascular Events

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

23460: Effect of a Multifaceted Implementation Strategy on Blood Pressure Control in Low-Income Patients: A Cluster Randomized Trial

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

23096: A Cluster Randomized Trial of Automated Referral to Centralized Pharmacy Services for Evidence-Based Statin Initiation in High-Risk Patients

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

21810: Hypertension Treatment in Nigeria Program: Early Results of a Type 2 Hybrid Effectiveness and Implementation Interrupted Time Series Trial

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

Late-Breaking Science: Artificial Intelligence at the Bedside

23012: Screening for Peripartum Cardiomyopathies Using an Artificial Intelligence Enhanced Digital Stethoscope: A Randomized Clinical Trial

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

23395: Validation of a Speech Analysis Application to Detect Worsening Heart Failure Events in Ambulatory Heart Failure Patients

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.

23523: Artificial Intelligence Enabled Rapid Identification of ST-Elevation Myocardial Infarction Using Electrocardiogram (ARISE): A Pragmatic Randomized Controlled Trial

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.

23077: Novel AI Technology to Improve Risk Stratification of Patients Without Obstructive Coronary Artery Disease Undergoing CCTA: The Oxford Risk Factors and Non-Invasive Imaging (ORFAN) Study

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 75th percentile had 6.7x higher risk of MACE (Panel B) vs those under the 25th 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.

Featured Science: Innovations in EP Care

22916: Multi-National Survey on the Safety of the Post-Approval Clinical Use of Pulsed Field Ablation in 10,000+ Patients (MANIFEST-10K)

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.

23278: Randomized, Controlled Study of the Efficacy and Safety of Etripamil Nasal Spray for the Acute Reduction of Rapid Ventricular Rate in Patients With Symptomatic Atrial Fibrillation (Phase 2, ReVeRA-201)

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

22960: Arrhythmic Risk in Biventricular Pacing Compared to Left Bundle Branch Area Pacing: Results From International Collaborative LBBAP Study (I-CLAS)

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.
Baseline CharacteristicsAll Patients (N = 1778)BVP (n=981)LBBAP (n=797)P valuePatients with no Prior AF (N = 1125)BVP (n=614)LBBAP (n=511)P value
Age, mean (SD)69 (12)68 (12)69 (12)0.3366 (13)67 (12)66 (13)0.56
Female575 (32%)294 (30%)281 (36%)0.02387 (34%)203 (33%)184 (36%)0.3
Hypertension1145 (64%)614 (63%)529 (66%)0.12675 (60%)366 (60%)309 (61%)0.79
Diabetes698 (39%)381 (39%)317 (40%)0.69428 (38%)234 (38%)194 (38%)0.96
Ischemic CMP649 (36%)386 (39%)263 (33%)<0.01400 (36%)252 (41%)149 (37%)<0.01
Nonischemic CMP1029 (58%)550 (56%)479 (60%) 671 (60%)344 (56%)327 (64%) 
LVEF27 (6)26 (6)27 (6)<0.0127 (7)26 (7)27 (6)0.002
Baseline QRS160 (26)160 (24)160 (28)0.63163 (24)162 (23)164 (25)0.21
Atrial FIbrillation650 (37%)364 (37%)286 (36%)0.14    
Author Disclosures: For author disclosure information, please visit the AHA Scientific Sessions 2023 Online Program Planner and search for the abstract title.

20256: Effect of Empagliflozin on Ventricular Arrhythmias in Patients With Type 2 Diabetes Treated With an Implantable Cardioverter-Defibrillator

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.

Featured Science: Coronary Revascularization - Lessons from Impactful Clinical Trials

23511: Left Anterior Descending Non-culprit Lesion Location And Clinical Outcomes In Patients With St-segment Elevation Myocardial Infarction And Multivessel Disease: Results From The Complete Trial

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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22079: Resource Use and Cost Comparisons of a Novel Precision Medicine Evaluation Strategy for Suspected Coronary Artery Disease versus Usual Testing: Results From the PRECISE Randomized Trial

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 FFRCT, 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 FFRCT 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.
Total Costs of Care in the PRECISE Trial
  45-Day Costs(2022 USD)  1-Year Costs(2022 USD) 
 Precision StrategyUsual Care45-Day Difference (95% CI)Precision StrategyUsual Care1-Year Difference (95% CI)
Outpatient testing + invasive procedures501509−8 (−55 to 43)602635−33 (−82 to 20)
Medications4442238737413
Hospital + ED14331245188 (−544 to 659)43103812498 (−861 to 1440)
TOTAL19781796182 (−555 to 661)52994821478 (−889 to 1437)
Author Disclosures: For author disclosure information, please visit the AHA Scientific Sessions 2023 Online Program Planner and search for the abstract title.

23231: PCI or CABG versus Medical Therapy in the ISCHEMIA Trial: A Post Hoc Analysis

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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21018: Impact of Cardiac Arrest Before Randomization on the Efficacy of ECLS in Patients With Infarct-Related Cardiogenic Shock. A Sub-Analysis of the Prospective EClS-Shock Trial

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

Featured Science: New Approaches to CV Therapeutics - First in Human Treatments

23450: Acute Hemodynamic Study Of Oral TPN171H In Patients With Pulmonary Arterial Hypertension: A Multicenter, Randomized, Controlled, Phase 2 Clinical Trial

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 2nd hour (p = 0.026), 3rd hour (p = 0.030) and 5th 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).
Author Disclosures: For author disclosure information, please visit the AHA Scientific Sessions 2023 Online Program Planner and search for the abstract title.

23282: Phase I Result of a Novel Antiplatelet Drug CG-0255 That is Fast-Acting, Long Lasting and Available for Either IV or Oral Administration

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

23281: Safety and Blood Pressure Lowering Effects of a Novel and Long-Acting Natriuretic Peptide Receptor 1 Agonist in Healthy Participants: A First-in-Human Clinical Study

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

23468: Safety And Efficacy Of Induced Pluripotent Stem Cell-derived Engineered Human Myocardium As Biological Ventricular Assist Tissue In Terminal Heart Failure - BioVAT-HF-DZHK20

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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23484: Phase 1 Gene Therapy Trial In Patients With Advanced Heart Failure Using A Novel Cardiotropic AAV Vector Targeting Protein Phosphatase Inhibitor-1

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

Featured Science: HFpEF and Amyloid - It’s Prime Time!

23482: Effects Of Semaglutide On Symptoms, Function And Quality Of Life In Patients With The Obesity Phenotype Of Heart Failure With Preserved Ejection Fraction: The Step-hfpef Trial

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 HbA1c ≥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.
Author Disclosures: For author disclosure information, please visit the AHA Scientific Sessions 2023 Online Program Planner and search for the abstract title.

23010: Sodium-Glucose Cotransporter-2 Inhibitors in Transthyretin Amyloid Cardiomyopathy

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

23519: Acoramidis Improves Clinical Outcomes In Transthyretin Amyloid Cardiomyopathy Patients

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

Featured Science: Novel Approaches in MI - Hype or Hope?

23438: Half-dose Tenecteplase Or Primary PCI In Older Patients With St-elevation Myocardial Infarction: The STREAM-2 One-year Mortality Follow-up Results

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 21st 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.
Author Disclosures: For author disclosure information, please visit the AHA Scientific Sessions 2023 Online Program Planner and search for the abstract title.

23384: Pre-Hospital Rule-Out of Non-ST-Segment Elevation Acute Coronary Syndrome by a Single Troponin Measurement: Final One-Year Outcomes of the ARTICA Randomised Trial

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

23089: Association of Use and Dose of Lipid Lowering Therapy Post Acute Myocardial Infarction in the Elderly With 5-year Survival: The French Registry on ST-Elevation and Non-ST-Elevation Myocardial Infarction (FAST-MI) Registry

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

22966: Interleukin-1 Blockade With RPH-104 (Goflikicept) in Patients With ST-Segment Elevation Myocardial Infarction (STEMI)

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

19479: Prehospital High-Dose Glucocorticoid Treatment for Post-Cardiac Arrest Syndrome Following Resuscitated Out-of-Hospital Cardiac Arrest: The STEROHCA Trial

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

Featured Science: Exercise is Life (and Death) - Approaches in Athletes, Arrhythmias, and Heart Failure

23246: Incidence and Causes of Sudden Cardiac Death in National Collegiate Athletic Association Athletes: A 20-year Study

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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22936: Vigorous Exercise in Individuals With Long QT Syndrome (LQTS): Primary Results of the Prospective, Multinational Lifestyle and Exercise in LQTS (LIVE-LQTS) Study

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

23500: Safety And Efficacy Of The Jewel, A Novel Patch Wearable Cardioverter Defibrillator: Results From The Jewel Investigational Device Exemption Study

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

23392: Effect of a Walking Intervention on Functional Capacity in Patients With Chronic Heart Failure With Reduced Ejection Fraction: The WATCHFUL Trial

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

23465: The Liraglutide Effect On Atrial Fibrillation (LEAF) Study

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

Featured Science: From Artery to Veins - A Fantastic Journey

19524: A Multicenter, Randomized, Warfarin-Controlled Trial of Edoxaban in Patients With Chronic Thromboembolic Pulmonary Hypertension: KABUKI Trial

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

23553: Ultrasound-assisted Catheter-directed Thrombolysis Versus Surgical Pulmonary Embolectomy For Intermediate-high Or High-risk Pulmonary Embolism: A Randomized Phase II Non-inferiority Study

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

19778: Nicotinamide Riboside to Improve Walking Performance in Peripheral Artery Disease: A Randomized Clinical Trial

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

23102: Pemafibrate Reduces Incidence of Lower Extremity Ischemic Ulcer and Gangrene: Evidence From PROMINENT

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.

2023 AHA LATE-BREAKING RESUSCITATION SCIENCE ABSTRACTS

Plenary Session 6: Late Breaking Resuscitation Science and Critical Care Outcomes

112: EMS Agency Practices Associated With Higher Survival Rates for OHCA

Paul S Chan1, Jessica Sperling2, Kimberly Dukes3, Kevin Kennedy4, Marina Del Rios3, Bryan McNally5, Khadijah Breathett6, Saket Girotra7; 1Mid America Heart Institute, Kansas City, MO, 2Duke Univ, Durham, NC, 3Univ of Iowa, Iowa City, IA, 4Saint Luke’s Mid America Heart Institute, Kansas City, MO, 5Emory Univ, Atlanta, GA, 6Indiana Univ, Bloomington, IN, 7Univ of Texas-Southwestern, Dallas, TX
Background: Survival for out-of-hospital cardiac arrest (OHCA) varies across emergency medical service (EMS) agencies, but little is known about which EMS resuscitation response and quality improvement activities are associated with agencies with higher OHCA survival. Methods: Using data from the Cardiac Arrest Registry to Enhance Survival (CARES), we performed a survey of EMS resuscitation practices among 577 EMS agencies with >10 OHCA cases annually between 2015-2019. Using multivariable hierarchical models, we computed risk-standardized survival rates (RSSR) to hospital admission for OHCA at each agency and examined which agency practices were associated with higher RSSRs for OHCA. Results: Overall, 470 (81.5%) EMS agencies completed the survey. Mean RSSR to hospital admission was 27.5 ± 3.6% but varied widely across agencies (range: 16.6%-43.4%). A total of 9 EMS practices across 4 domains (training, data review, airway management and transport) were associated with higher RSSRs. EMS agencies with higher RSSR for OHCA were more likely (P<0.05 for all) to engage in CPR quality improvement, perform frequent assessment (at least every 6 months) of CPR competency, implement recurrent training in use of mechanical CPR devices, use full scenario simulations for initial training and also ongoing training, and conduct frequent (at least every 6 months) simulations to maintain skills. High performing EMS agencies also reported greater use of impedance threshold devices and waveform capnography during resuscitations and were more likely to transport OHCA patients to a designated cardiac arrest or STEMI center (P<0.05 for all). Adoption of at least half (>5) of these 9 practices was more common at EMS agencies in the highest survival quartile for OHCA compared to agencies in the lowest survival quartile (75.4% vs. 47.5%, P<0.001). Conclusions: In a national registry of OHCA, we identified 9 EMS practices associated with higher survival rates for OHCA. Given the wide variability in OHCA survival among EMS agencies, our findings provide initial insights into potential best practices that distinguish top-performing EMS agencies in survival outcomes for OHCA.
Author Disclosures: For author disclosure information, please visit the AHA Scientific Sessions 2023 Online Program Planner and search for the abstract title.
Key Words: Cardiac arrest, Emergency medical services (EMS), Survival

113: Inhaled Nitric Oxide After Resuscitation From Out-of-Hospital Cardiac Arrest

Cameron Dezfulian1, Jonathan Elmer2, Sara M DiFiore3, Nicholas Krehel4, Francis Pike5, Alexandra Weissman3, Kate Flickinger3, Dylan Burbee6, Valeria Altamirano3, Surya Sharma3, Ankur A Doshi7, Francis X Guyette8, Clifton W Callaway9, Jon Rittenberger10; 1Baylor College of Medicine, Houston, TX, 2Univesity of Pittsburgh, Pittsburgh, PA, 3Univ of Pittsburgh, Pittsburgh, PA, 4Univ of Pittsbuirgh, Pittsburgh, PA, 5Indiana Univ - Purdue Univ, Indianapolis, IN, 6Johns Hopkins Univ, Baltimore, MD, 7UPMC, Pittsburgh, PA, 8U of Pittsburgh, Pittsburgh, PA, 9Univ Pittsburgh, Pittsburgh, PA, 10Sayre, PA
Background: Inhaled nitric oxide (iNO) administered after return of spontaneous circulation (ROSC) is neuro- and cardioprotective in experimental models and protective clinically in other ischemia-reperfusion injury. Hypothesis: We hypothesized iNO administered after ROSC from out-of-hospital cardiac arrest (OHCA) improves brain and heart outcomes. Methods: This was a placebo-controlled double-blinded randomized clinical trial enrolling under exception from informed consent. Comatose survivors of OHCA were randomized within 4h of ROSC to 12h x 20 ppm iNO with a 1h wean or nitrogen placebo. The primary outcome was a composite death, poor neurologic function (discharge destination other than home or inpatient rehabilitation) or NYHA class III/IV heart failure at discharge. ClinicalTrials.gov registration NCT03079102. Results: Between 8/21/2017 and 4/25/2020, we screened 577 subjects at 5 centers and randomized 57 (9.9%) to iNO (n=30) or placebo (n=27). One patient (placebo) was withdrawn early and 2 withdrew consent, though the primary outcome was obtained for all. Groups were similar at baseline (Table 1) except for more epinephrine administration in the iNO group. The primary outcome occurred in 16/30 iNO- and 15/27 placebo-treated subjects (Table 2, p=0.87). Survival, favorable neurologic function and performance of activities of daily living were similar between groups at discharge, 30 and 90 days after ROSC. Conclusions: iNO administration did not improve outcomes in comatose OHCA survivors. Limitations include early study termination due to slow enrollment and COVID, and later administration of study drug (between 3-4 hours post-ROSC) in most subjects.
Author Disclosures: For author disclosure information, please visit the AHA Scientific Sessions 2023 Online Program Planner and search for the abstract title.
Key Words: Nitric oxide, Post cardiac arrest care, Cardiac arrest

114: Bag-Valve-Mask Ventilation and Survival From Out-of-Hospital Cardiac Arrest: A Multicenter Study

Ahamed H Idris1, Elisabete Aramendi2, Brian Leroux3, Xabier Jaureguibeitia2, Betty Yang4, Sarah Shaver4, Mary Chang4, Thomas Rea3, Peter Kudenchuk3, Jim Christenson5, Christian Vaillancourt6, Clifton W Callaway7, David D Salcido8, Jonas Carson3, Jennifer Blackwood9, Henry E Wang10; 1UT Southwestern Med Cntr, Dallas, TX, 2Univ of the Basque Country, Bilbao, 3Univ of Washington, Seattle, WA, 4UT Southwestern, Dallas, TX, 5Univ of British Columbia, Vancouver, Canada, 6Univ of Ottawa, Ottawa, Canada, 7Univ Pittsburgh, Pittsburgh, PA, 8Univ of Pittsburgh, Pittsburgh, PA, 9King County EMS, Seattle, WA, 10The Ohio State Univ, Columbus, OH
Background: Few studies have measured ventilation during early cardiopulmonary resuscitation (CPR) before advanced airway placement. Resuscitation guidelines recommend pauses after every 30 chest compressions to deliver ventilations. The effectiveness of bag-valve-mask (BVM) ventilation delivered during the pause in chest compressions is unknown. Goals: to determine (1) the incidence of lung inflation with BVM ventilation during 30:2 CPR and (2) the association of ventilation with outcomes after out-of-hospital cardiac arrest (OHCA). Methods: We studied OHCA patients from six sites of the Resuscitation Outcomes Consortium Trial of Continuous or Interrupted Chest Compressions during CPR. We analyzed patients assigned to the 30:2 CPR arm with ≥ two minutes of thoracic bioimpedance signal recorded with a cardiac defibrillator/monitor. Detectable ventilation waveforms were defined as having a bioimpedance amplitude ≥0.5 Ohm (corresponding to ≥ 250 ml VT) and duration ≥1 sec. We defined a chest compression pause as a break in chest compressions of 3 - 15 sec duration. We compared the incidence of ventilation and outcomes in two groups: patients with ventilation waveforms in <50% of pauses (Group 1) versus those with waveforms in ≥50% of pauses (Group 2). Results: Among 1,976 patients, mean age was 65 years, 66% were male. From the start of chest compressions until advanced airway placement, mean (SD) duration of 30:2 CPR was 9.8 ± 4.9 min. During this period, we identified 26,861 pauses in chest compressions; 60% of patients had ventilation waveforms in <50% of pauses (Group 1, N=1177), and 40% had waveforms in >50% of pauses (Group 2, N=799); Group 1 had a median 12 pauses and 2 ventilations per patient vs. Group 2 had 12 pauses and 12 ventilations per patient. Group 2 had higher rates of prehospital ROSC (40.7% vs. 25.2%, p<0.0001), survival to hospital discharge (13.5% vs. 4.1%, p <0.0001), and survival with favorable neurological outcome (10.6% vs. 2.4%, p <0.0001). These associations persisted after adjustment for confounders. Conclusions: In this study, lung inflation occurred infrequently with BVM ventilation during 30:2 CPR. Lung inflation in ≥50% of pauses was associated with improved ROSC, survival, and survival with favorable neurological outcome.
Author Disclosures: For author disclosure information, please visit the AHA Scientific Sessions 2023 Online Program Planner and search for the abstract title.
Key Words: Cardiopulmonary resuscitation, Ventilation, Prehospital care

115: “The Slope of Death”: Association Between End-Tidal CO2 and Rearrest in Out-of-Hospital Cardiac Arrest

Amanda E Kusztos1, Jason Coult1, Shiv Bhandari2, Thomas Rea1, Heemun Kwok1, Michael R Sayre1, Catherine Counts1, Nicholas J Johnson1; 1Univ of Washington, Seattle, WA, 2Univ of Washington Medicine, Bellevue, WA
Introduction: Up to half of out-of-hospital cardiac arrest (OHCA) patients who achieve return of spontaneous circulation (ROSC) subsequently rearrest, an event inversely associated with survival. End-tidal carbon dioxide (EtCO2) correlates with real-time cardiac output, but during ROSC its association with potential rearrest is unknown. We sought to determine whether the slope or raw values of EtCO2 over a 5-minute period of ROSC was associated with subsequent rearrest. Methods: We performed a retrospective cohort study of intubated OHCA patients who achieved ROSC in Seattle, WA between 2015-2021. Capnography data was annotated with time of ROSC and rearrest, defined as loss of pulse or rhythm compatible with perfusion prior to hospital arrival (if any). Capnography waveform time-series signal peaks were identified using the findpeaks function in MATLAB. In patients with rearrest, we calculated the median and slope of EtCO2 values in the 5-minute interval ending one minute prior to rearrest (Figure). EtCO2 median and slope in non-rearrest (control) patients was calculated during the interval prior to the median rearrest time of the rearrest group. EtCO2 median and slope distributions for rearrest versus control patients were compared using the Wilcoxon rank-sum test. Results: Of the 1390 patients who achieved ROSC and were included in the study, 683 (49%) subsequently rearrested. In rearrest cases, median EtCO2 slope (mmHg/min) [interquartile range] was -1.70 [-3.49, -0.15], versus -0.39 [-1.54, 0.58] for non-rearrest patients (p<0.001). The median EtCO2 (mmHg) [IQR] over the interval was 31 [20-42] in cases with rearrest versus 41 [32-53] in cases without rearrest (p<0.001). Conclusion: Patients with ROSC who subsequently rearrested had a significantly larger decline in EtCO2 and lower median EtCO2 than patients who did not rearrest. Future study should investigate whether such information could be used to provide an earlier opportunity to intervene.
Author Disclosures: For author disclosure information, please visit the AHA Scientific Sessions 2023 Online Program Planner and search for the abstract title.
Key Words: Cardiac arrest, Return of spontaneous circulation (ROSC), Resuscitation

116: Physiologically Guided Cardiopulmonary Resuscitation Using End Tidal Carbon Dioxide and Cerebral Oximetry: A Multi-Site Observation Study

Sam Parnia1, Tara Keshavarz Shirazi2, Jignesh K Patel3, Linh Tran4, NIRAJ SINHA5, Amanda Mengotto1, Shannon Finlay6, Michael McBrine7, Thaddeus Tarpey1, Elise Huppert1, anelly gonzalez1, Jing Xu1, Gavin D Perkins8, Benjamin Bloom9, Jarman Heather9, Rahul Sharma10, Deepak Pradhan9, Charles Deakin11; 1NYU Langone Health, New York, NY, 2New York, NY, 3Stony Brook Med Cntr, Stony Brook, NY, 4Stony Brook Univ Med Cntr, Stony Brook, NY, 5Stonybrook Univ Med Cente, Stonybrook, NY, 6Univ of Iowa, Iowa City, IA, 7Tufts Med Cntr, Boston, MA, 8Univ of Warwick, Coventry, United Kingdom, 9St Georges NHS Trust, London, United Kingdom, 10New York Presbyterian-Weill Cornell, New York, NY, 11Southampton Univ Hosp, Southampton Hampshire, United Kingdom
Background: A method to improve cardiopulmonary resuscitation (CPR) is by physiological targets of brain O2 delivery and circulation quality. We aimed to identify these optimal targets by regional cerebral oxygenation (rSO2) and end tidal carbon dioxide (ETCO2), and combined rSO2/ETCO2 to predict return of spontaneous circulation (ROSC) and survival with favorable neurologic outcomes (Glasgow Outcome Score [GOS]4-5). Methods: 20 site prospective study in-hospital cardiac arrest. Inclusion: age≥18, CPR≥5 mins. Patients had rSO2 and ETCO2 monitoring with consecutive CPR during working hours. Models were developed by classifications and regression trees (CART) involving key clinical (including rhythm, CPR duration), and key parameters of rSO2 and ETCO2: (a) mean, b) min, c) max, d) rate change, e) % CPR time spent >rSO2 30, 40, 50, 60% and f) ETCO2>10,20,30,40mmHg tested separately and combined. The predictive accuracy of CART model was determined by sensitivity, specificity, PPV, NPV and validated using 4-fold cross validation repeated 1000 times. Results: Of 441 recruits, for ROSC the PPV of all rSO2 parameters were 0.8-0.84, highest sensitivity (0.82 95% CI 0.71-0.91) and AUC (0.66, 95% CI 0.65-0.67) was mean rate of rSO2 increase/min. For 10% increase in mean rSO2, the odds of ROSC increased 1.49 (95% CI: 1.24-1.79). All ETCO2 parameters had similar PPVs ~0.83. A 10mmHg increase ETCO2, had OR 2.12 (95% CI: 1.53-2.93) for ROSC. The %CPR time>20 ETCO2 mmHg had highest AUC (0.73; 95% CI 0.72-0.75). Survival GOS4-5: Mean rSO2 >50% during CPR had PPV 0.98 (95% CI: 0.98-0.99) and a 10% increase mean rSO2 had OR 1.77 (95% CI: 1.19-2.63). Spending >40% of CPR time with rSO2 ≥50% had AUC 0.72 (95% CI: 0.70-0.74). Mean ETCO2 >24 mmHg had a PPV of 0.99 (95% CI: 0.98-1.00) and an OR for 10% increase in mean ETCO2 1.62 (95% CI: 1.01-2.60). Spending 2/3 CPR time > 20 mmHg had AUC of 0.69 (95% CI: 0.64-0.74). Combining rSO2 and ETCO2 to predict ROSC and GOS4-5: Using a combined CART model, ROSC was predicted, if rate of rSO2 change >0.6%/min for 2/3 CPR time, or ETCO2 >35 mmHg for > 40% of CPR time. Using those parameters, the AUC for GOS4-5 with this model was 0.81 (95% CI: 0.71-0.88). Conclusion: While ETCO2 and rSO2 parameters can predict ROSC and GOS4-5, combining them provides greater benefit.
Author Disclosures: For author disclosure information, please visit the AHA Scientific Sessions 2023 Online Program Planner and search for the abstract title.
Key Words: Cardiac arrest, Resuscitation, Outcomes

Late Breaking Resuscitation Science Session 1

440: Identifying Differential Benefits From Increased Recognition of Out-of-Hospital Cardiac Arrest Across Key Subgroups in a Registry Cohort (2019 & 2020)

Jacob Hutton1, Boris Sobolev2, Joseph Puyat2, Michael Asamoah-Boaheng2, Jim Christenson1, Brian Grunau1; 1UBC Faculty of Medicine, Vancouver, Canada, 2Canada
Background: Biosensor technologies have been proposed as a solution for unwitnessed out-of-hospital cardiac arrest (OHCA) however it is currently unknown which individuals may benefit the most, which is information that may guide implementation. We sought to identify variability in the projected impact of increased recognition based on the location type of the cardiac arrest. Methods: We included cases from the British Columbia Cardiac Arrest Registry (2019-2020), which includes Emergency Medical Services (EMS)-assessed OHCAs. We estimated the expected additional number of survivors resulting from increasing recognition alone using a bootstrap logistic regression framework and evaluated the expected additional survivors to hospital discharge if all cases had been recognized in Residential, Public, and Semi Public (Airport, Casino, Industrial Site, Healthcare) settings. Results: Of 13,655 EMS-assessed cases, 11,412 were included (6314 EMS-treated, 5098 EMS-untreated). Of the effect attributable to a bystander witness, recognition accounted for 84% (95% CI: 72, 86) of the benefit. If all previously unwitnessed cases were recognized and reported to EMS by biosensors, the largest gains in OHCA survival would be attained among cases occurring in Private locations 257%, 160%, 108%, 247% increases in survival for 0-35; 36-55; 56-65; 65+ age groups, respectively (Figure 1). Conclusion: Methods to improve recognition, such as with biosensor technologies, may lead to substantial improvements in OHCA survival. Given that the largest incremental benefits of increased recognition appear to be in residential locations, fixed-location detection technologies may be worthy of further development, as they may have potential to increase survival across a wide range of age strata.
Author Disclosures: For author disclosure information, please visit the AHA Scientific Sessions 2023 Online Program Planner and search for the abstract title.
Key Words: Cardiac arrest, Targeted therapeutics

441: Are Rurality or Area Deprivation Independently Associated With Variation in Outcomes After Out-of-Hospital Cardiac Arrest?

Amanda West1, Robert Schmicker1, Remle P Crowe2, Lakota Cheek1, Colin Raelson1, Jason McMulllan3, Robert Dunne4, Karen N Adams1, Dana Morse1, Antje Hoering5, Kari Stephens1, Brent Myers6, Graham Nichol1; 1Univ of Washington, Seattle, WA, 2ESO Inc., Cedar Park, TX, 3Univ of Cinncinati, Cinncinati, OH, 4Wayne State Univ, Detroit, MI, 5Cancer Rsch and Biostatistics, Seattle, WA, 6ESO Inc., Austin, TX
Rationale: Large geographic variations in outcomes after out-of-hospital cardiac arrest (OHCA) exist. We assessed whether rurality or area deprivation of the neighborhood where the arrest occurred explain variation in emergency medical services (EMS) outcomes using a contemporary national registry. Methods: This analysis used data collated by ESO Inc. (Austin, TX) to characterize EMS care up to transfer of care to a receiving emergency department (ED)’s providers. This includes health data exchange with participating receiving hospitals so care can be characterized up to hospital discharge. Included were patients with OHCA treated by EMS from January 1, 2022, to Dec 31, 2022. OHCA was defined as receipt of chest compressions or defibrillation. Rurality was assessed using rural-urban commuting area codes, composite measures based on area-level population density, urbanization, and daily commuting. Deprivation was assessed using area deprivation index, a composite measure of area-level socioeconomic disadvantage. The primary outcome was restoration of spontaneous circulation (ROSC) at ED arrival. The association between rurality or area deprivation and outcome was assessed using generalized estimating equations adjusted for patient and EMS treatment characteristics. Results: Included were 82,772 adults with non-traumatic OHCA. These were median age 66 (53, 76) years, 62% male, 21% Black non-Hispanic, 7% Hispanic, 18% first rhythm shockable, 7% in rural locations; 12% in areas with high deprivation. 28% received bystander CPR. EMS arrived in mean 8.8 ± SD 5.8 minutes. 8% had ROSC at ED arrival. Adjusted for patient and EMS characteristics, OHCA in rural vs. suburban or urban areas were less likely to achieve ROSC (odds ratio [OR] (95% confidence interval [CI]) = 0.82 (0.74, 0.90). OHCA in deprived vs. not deprived areas were not less likely to achieve ROSC (OR (95% CI) = 1.00 (0.92, 1.08)). Conclusions: Geographic variations in EMS outcomes after OHCA are significantly associated with rurality but not deprivation. Strategies are needed to reduce geographic disparities in outcomes after OHCA. EMS data collection without additional manual or duplicate data entry can be used to identify opportunities to improve resuscitation care.
Author Disclosures: For author disclosure information, please visit the AHA Scientific Sessions 2023 Online Program Planner and search for the abstract title.
Key Words: Cardiac arrest, Emergency cardiovascular care, Emergency medical services (EMS)

442: The Cerebral and Hemodynamic Effects of Norepinephrine in an Experimental Cardiac Arrest Model

Deborah Jaeger1, Marinos Kosmopoulos1, Christopher Gaisendrees2, Rajat Kalra3, Alexandra M Marquez3, Tahar Chouihed4, Kevin Duarte5, Demetris Yannopoulos1; 1Univ of Minnesota, Minneapolis, MN, 2Cologne, 3Minneapolis, MN, 4CHRU Nancy, Nancy, France, 5CIC-P Nancy, Vandoeuvre-le-Nancy, France
Introduction: Epinephrine (EPI) has been recommended for decades during cardiopulmonary resuscitation (CPR). Other pure α-agonist drugs such as phenylephrine or methoxamine have shown encouraging results on hemodynamic parameters during resuscitation efforts. On the other hand, norepinephrine’s (NE) effect on hemodynamic and cerebral parameters has only been evaluated with extremely high doses. The aim was to assess NE’s cerebral and hemodynamic impact in an experimental model of cardiac arrest. The dose of 1mg of NE was chosen based on the data of a preliminary dose study. Methods: After 3 minutes of untreated ventricular fibrillation, animals underwent 27 minutes of CPR with a mechanical compression device. Nineteen animals were randomized to receive boluses of either 0.5mg of EPI or 1mg NE every 5 minutes. Hemodynamic parameters such as coronary perfusion pressure (CPP), carotid blood flow (CBF) and cerebral perfusion pressure (CePP) were monitored. Results: Hemodynamic parameters did not differ between the two groups at baseline and during CPR. CPP was similar during resuscitation with a mean of 17.3 mmHg (12.8-31.8) in the EPI group and 16.0 mmHg (11.1-37.7) in the NE group, p=0.9. Overall, during CPR, CBF and CePP were lower in the NE group although the difference was not significant: 28.4 mL/min (22.0-54.8) vs 30.8 mL/min (12.2-56.3), p=0.9 and 12.2 mmHg (-8.2-42.2) vs 7.8 mmHg (-2.0-32.0), p=0.4. Return of spontaneous circulation occurred for only 1 animal in the EPI group and 2 in the NE group (Fig 1). Conclusion: 1mg boluses of norepinephrine did not improve hemodynamic parameters such as CPP, CBF or CePP during CPR compared to epinephrine. Further investigations should evaluate different administration options such as the use of a continuous NE infusion.
Figure 1: A. Mean coronary perfusion pressure (CPP) during CPR with Epinephrine and Norepinephrine boluses; B. Mean cerebral perfusion pressure (CePP) during CPR with Epinephrine and Norepinephrine boluses.
Author Disclosures: For author disclosure information, please visit the AHA Scientific Sessions 2023 Online Program Planner and search for the abstract title.
Key Words: Cardiac arrest, Norepinephrine, Hemodynamics

443: Study of Peri-Resuscitation Troponin and Outcomes (SANTO) Proof of Concept

Graham Nichol1, Colin Raelson1, Karen N Adams1, Dana Morse1, Brianne Okerman1, Sophie Morse1, Robert Schmicker1, Atandra Burman2, Jessie Katz2, Jitto Titus3, Nick J Johnson1; 1Univ of Washington, Seattle, WA, 2RCE Technologies Inc., Carlsbad, CA, 3RCE Technologies, Acworth, GA
Rationale: Common causes of out-of-hospital cardiac arrest (OHCA) include a) arrhythmia, b) chronically weakened myocardium, and c) acute coronary occlusion (ACO). Arrhythmia or ACO must be treated rapidly. Strategies to improve systemic perfusion may include extracorporeal membrane oxygenation (ECMO) until percutaneous coronary intervention (PCI) can be performed to correct ACO. Use of ECMO has risks and does not benefit all patients. As well, early PCI may improve outcomes in patients with spontaneous circulation who have ACO. A rapid method of identifying patients with high likelihood of ACO is needed. RCE Technologies Inc. (Carlsbad, CA) is developing Tropsensor for bloodless transdermal measurement of troponin. This uses infrared optical technology. We sought to assess feasibility of use of this device in the emergency department (ED). Methods: This ongoing prospective cohort study is enrolling adults resuscitated from OHCA of presumed cardiac etiology, with spontaneous circulation at ED arrival. The device is applied as soon as feasible after arrival, and as close as possible to a troponin blood draw. A second draw is obtained to observe trends in troponin. Outcomes are feasibility: prop. of patients with device applied and troponin value recorded. Bloodless troponin values were correlated with standard blood-based measures. Results: 5 patients were enrolled as of August 15, 2023. 40% were female. 60% had bystander cardiopulmonary resuscitation. 40% had a shockable rhythm. Tropsensor-based troponin values were available on 4 (80%) of patients. Tropsensor values were correlated with time-adjusted differences in serum troponin values between the two blood draws (Spearman’s ρ = 1; R2 = 0.9681, Figure). Conclusions: Measurement of bloodless troponin values is feasible after OHCA. Bloodless troponin values are highly correlated with serum troponin values. Additional research is required to determine if Tropsensor in the ED or field improves patient outcome.
Author Disclosures: For author disclosure information, please visit the AHA Scientific Sessions 2023 Online Program Planner and search for the abstract title.
Key Words: Acute coronary syndromes, Cardiac arrest

444: Reproducible Pediatric Swine Model of Cardiac Arrest and Extracorporeal Cardiopulmonary Resuscitation

Tiffany S Ko1, Katsunari Terakawa1, Benjamin F Smood1, Julia Slovis1, Richard Melchior1, Takayuki Sueishi1, Rodrigo M Forti1, Yuxi Lin1, Elizabeth Mignogna1, Anthony M Davis1, Sarah Morton1, Danielle Aronowitz1, Audrey Spelde2, Misun Hwang1, Wesley B Baker1, Constantine D Mavroudis1, Ryan W Morgan1, Todd J Kilbaugh1; 1Children’s Hosp of Philadelphia, Philadelphia, PA, 2Hosp of the Univ of Pennsylvania, Philadelphia, PA
Introduction: Increasing use of pediatric extracorporeal cardiopulmonary resuscitation (ECPR) underscores the need for systematic study and optimization of extracorporeal membrane oxygenation (ECMO) therapy to improve persisting neurological morbidity. To this end, we recently reported on the feasibility of a pilot pediatric porcine ECPR model; however, variability in manual CPR performance confounded ECMO outcomes. In this work, we present an updated model employing low-flow ECMO to simulate manual chest compressions. Hypothesis: The use of 30 min of low-flow ECMO “simulated” CPR versus “manual” CPR reduces physiologic variability while maintaining clinically relevant acidosis. Methods: Thirteen pediatric swine (8-12 kg) underwent a pilot ECPR model with 7 min of asphyxia, induction of ventricular fibrillation (VF), and either 30 or 60 min of manual CPR prior to initiation of VA-ECMO. Subsequently, fourteen comparably sized animals underwent an updated ECPR model comprising 8 min of untreated VF and 30 min of simulated CPR using low-flow ECMO (20 ml/kg/min) prior to initiation of full-flow ECMO (70-100 ml/kg/min). Acidosis was assessed by blood gas analysis after 30 min of either manual or simulated CPR; within-group variability in arterial and central venous pH, pCO2, and lactate were compared by two-sample F-test, and absolute values were compared by two-sample T-test. Results: Use of simulated CPR versus manual CPR significantly reduced variability in arterial pH, pCO2, and lactate and venous lactate (F-test, p<0.05) without impacting absolute values (T-test, p>0.05), and resulted in a trending reduction in variability in venous pH and pCO2 (p<0.1). Manual CPR resulted in lower venous pH (mean (SD) = 6.9 (0.1) vs. 7.1 (0.1); p<0.001), but no difference in venous pCO2. Conclusions: Low-flow ECMO simulation of CPR improved model reproducibility while maintaining clinically relevant acidosis to facilitate systematic study of subsequent ECMO support.
Author Disclosures: For author disclosure information, please visit the AHA Scientific Sessions 2023 Online Program Planner and search for the abstract title.
Key Words: Cardiac arrest, Extracorporeal circulation, Hemodynamics

Late Breaking Resuscitation Science Session 2

460: The Influence of Withdrawal of Life-Sustaining Therapy (WLST) on Outcomes in Cardiac Arrest Research: A Systematic Review

Soo Hyun Kim1, Paolo Antonio G. Cervantes2, Sung-Min Cho3, Romergryko Geocadin4; 1Eunpyeong St. Mary’s Hosp, College of Medicine, The Catholic Univ of Korea, Seoul, Korea, Republic of, 2St. Luke’s Med Cntr, College of Medicine, William H. Quasha Memorial, Quezon City, Philippines, 3Baltimore, MD, 4Johns Hopkins Univ, Baltimore, MD
Background: post-cardiac arrest syndrome (PCAS) refers to the complex physiological and neurological changes that occur following successful resuscitation from a cardiac arrest. Withdrawal of Life-Sustaining Therapies (WLST) is a critical decision-making process in the management of patients who have experienced a PCAS. However, the incidence of the withdrawal of life-sustaining therapies and its potential impact on research data interpretation have been poorly characterized. The aim of this systematic review was to assess the reporting and the impact of withdrawal of life-sustaining therapies in randomized clinical trials of PCAS patients. Methods: We searched four databases for randomized controlled trials in adult patients resuscitated after out-of-hospital cardiac arrest. All randomized controlled trials published between 1986 and 2023. Randomized controlled trials in adult patients resuscitated after out-of-hospital cardiac arrest and reported data on mortality. Our primary objective was to assess the proportion of trials reporting the WLST in a publication. Our secondary objectives were to describe the overall mortality rate, the proportion of deaths following the withdrawal of life-sustaining therapies, and to assess the impact of the WLST on trial results. Results: From 8032 citations retrieved, we included 68 randomized trials (n = 16,828, ranging from 17 to 1861 patients). Overall mortality was 50.3% (range = 11%-89%). Withdrawal of life-sustaining therapies was reported in 26% of trials (18/68, 7803 patients in trials) and the crude number of deaths due to the withdrawal of life-sustaining therapies was reported in 22% of trials (15/68, 4340 patients in trials). In these trials, 55% of deaths were associated with the withdrawal of life-sustaining therapies (1282/2330), range 0-96%). Conclusion: Data on the WLST are incompletely reported in randomized controlled trials of adult patients resuscitated after out-of-hospital cardiac arrest. Given the high proportion of deaths due to the WLST in PCAS patients, and the potential of this medical decision to influence the results of clinical trials, instances of WLST should be systematically reported in clinical trials in this group of patients.
Author Disclosures: For author disclosure information, please visit the AHA Scientific Sessions 2023 Online Program Planner and search for the abstract title.
Key Words: Resuscitation, Post cardiac arrest care, Mortality

461: Association of Cumulative Oxygen and Carbon Dioxide Levels With Favorable Neurologic Outcome at Hospital Discharge in Pediatric Cardiac Arrest Survivors: A Prospective Multicenter Cohort Study

Marijn Albrecht1, Rogier C De Jonge1, Jimena Del Castillo2, Andrea Christoff3, Sangmo Je4, Vinay M Nadkarni4, Dana E Niles4, Oliver Tegg3, Kari A Wellnitz5, Corinne M Buysse1; 1Erasmus MC, Rotterdam, Netherlands, 2Hosp General Universitario Gregorio Marañón, Madrid, Spain, 3The Children’s Hosp at Westmead, Syndey, Australia, 4The Children’s Hosp of Philadelphia, Philadelphia, PA, 5Univ of Iowa Stead Family Children’s Hosp, Iowa, IA
Introduction: Studies on the effects of PaO2 and PaCO2 abnormalities in pediatric post-cardiac arrest care (PCAC) on outcome are inconclusive. Aims: To (1) determine whether cumulative PaO2 and PaCO2 exposure in the first 24 h after return of circulation (ROC) is associated with neurologic outcome and (2) assess adherence to PCAC treatment goals (PaO2 75 - 100 mmHg and PaCO2 35 - 45 mmHg). Methods: Prospectively collected data were analyzed from 5 sites from an international multicenter pediatric resuscitation quality collaborative (pediRES-Q). Cardiac arrest patients (2019 - 2022) with ROC, aged > 1 day and < 18 years with ≥ 4 arterial blood gases (ABG’s) over ≥ 12 hours were eligible. Congenital cyanotic heart disease patients were excluded. For each patient, PaO2 and PaCO2 area under the curve (AUC) was calculated per hour, using the trapezoidal method, correcting for time span of available ABGs, and then multiplied by 24 to yield cumulative exposure 0 - 24 h post-ROC. Similarly, PCAC recommendations were calculated as AUC ranges (PaO2 1800 - 2400 mmHg and PaCO2 840 - 1080 mmHg). The primary outcome was survival to hospital discharge with favorable neurologic outcome defined as a Pediatric Cerebral Performance Category 1-3, or no pre-arrest baseline difference. Results: Among 293 included patients (median age 2.6 years (0.4 - 10.9) and ABG’s 11 (8 - 15) per patient), 57% survived to discharge and 76% of survivors had a favorable neurologic outcome. Cumulative PaO2 (median 2664 mmHg (2151 - 3249)) and PaCO2 (median 948 mmHg (853 - 1051)) exposure 0 - 24 h post-ROC are not significantly associated with favorable neurologic outcome in multivariable analysis. Within the same time frame, cumulative PaO2 and PaCO2 remained within recommended ranges for 24% and 58% of patients respectively. Achieving both normoxia and normocabia was observed in 12% of patients. Conclusion: Cumulative PaO2 and PaCO2 exposure in the first 24 h post-ROC is not associated with neurologic outcome in multivariable analysis. Pediatric PCAC normoxia and normocarbia goals were often not met, especially for normoxia. Studies of larger cohorts are needed to determine the (long term) effects of PaO2 and PaCO2 exposure and to examine whether other PCAC therapeutic strategies modulate impact of exposures.
Author Disclosures: For author disclosure information, please visit the AHA Scientific Sessions 2023 Online Program Planner and search for the abstract title.
Key Words: Cardiac arrest, Post cardiac arrest care, Outcomes

462: Survivorship: The Lattest Link of the Chain of Survival. Feasibility of a Follow-Up Program for Patients at Risk of Acquired Brain Damage.

Jimena del Castillo, Laura X Herrera, Maria Vazquez, Almudena Chacón, Raquel Cieza, Jesús López-Herce; Hosp Gregorio Maranon, Madrid, Spain
Introduction: Advances in pediatric intensive care have led to a decrease in mortality. However, this has been associated with an increase in short- and long-term morbidity. Patients admitted to pediatric intensive care units (PICUs) may exhibit severe physical, psychosocial, and neuropsychological problems after discharge. The implementation of a multidisciplinary follow-up of survivors, allows an early diagnosis of these alterations that associate a high social and quality of life impact on patients. Objective: The aim of this project is to assess the feasibility of implementing a follow-up program based on the Dutch guidelines for post-ICU follow-up. Materials: The Dutch guidelines for PICU follow-up were translated and adapted. Patients aged between 1 month and 18 years were included in the program. Follow-up was initiated with patients who presented cardiac arrest (CA), required extracorporeal membrane oxygenation (ECMO) support or ventricular assist devices (VAD). Subsequently, follow-up was extended to patients with stroke, severe traumatic brain injury and convulsive status. A team was formed and consultations were scheduled at 3, 6 and 12 months post-event, and at each age of academic phase change (3 years, 6 years, 12 years and 18 years). Results: From June 2019 to July 2023, 72 patients admitted to the PICU met the criteria for inclusion in the program (CA, ECMO, VAD). 22 patients died before discharge from the PICU and 2 during follow-up (after the first follow-up visit). Out of 48 patients, 83 % were seen for the first follow-up visit, 23 patients attended the second check-up and 9 have attended the third. Psychomotor developmental delay was observed in 18 patients, being severe in 3: 1 patient presented cognitive disorders and 2 patients had altered motor function. During follow-up 5 patients were lost, all of whom live outside the region where the hospital is located. Conclusions: The development of a post PICU follow-up consultation is feasible. Limitations have been identified. Patient loss to follow-up may be due to geographic dispersion. The development of this program has enabled the team to extend follow-up to patients at risk of acquired brain damage.
Author Disclosures: For author disclosure information, please visit the AHA Scientific Sessions 2023 Online Program Planner and search for the abstract title.
Key Words: Outcomes, Pediatric cardiac intensive care, Resuscitation

463: Establishing Team-Based Performance Measures for Objective Assessment During Code Blue Resuscitation

Hannelisa Callisen1, Brigid A Kiley2, Shae Saint Amour3, Jeffrey Lyter1, Laura McRae1, William Vernon Pyles4, Eric J Humphrey4, Aaron Skolnik1, John Fanous1, Ayan Sen1; 1Mayo Clinic Arizona, Phoenix, AZ, 2Phoenix, AZ, 3Mayo Clinic, Phoenix, AZ, 4Mayo Clinic Hosp, Surprise, AZ
Intro: Characteristics of high performing teams are well described, yet remain challenging to train, observe, and objectively track during emergency resuscitations. Contingency teams built from a large pool of personnel, such as those that respond to in-patient ‘code blue’ events, are particularly challenged given the lack of opportunity to work and train together as a cohesive interprofessional unit. Question: In response to in-patient medical emergencies, what team performance elements can be objectively measured for future evaluation and correlation against metrics of patient outcome and systems practice? Aim: While interprofessional team-based scoring systems have been published, most remain focused to specific clinical contexts and action items. Instead, we aimed to establish measurements of team performance with sub-elements that can be observed and objectively quantified throughout a broader context of resuscitation events. Methods: A qualitative approach was taken to develop a list of team-based elements for objective evaluation during such events. Between 2020 and 2022, all code blue events were reviewed monthly by a consistent pre-defined workgroup, using data collected from the electronic health record, quality forms, and ad-hoc conversations with responders of the code blue events. Thematic analysis of problems identified in these meetings resulted in category creation for ‘opportunities for improvement’ (OFI). These were then validated and prioritized according to perceived challenges via feedback from surveys sent to all code team members. Four categories of concern were identified, from which observable sub-elements were determined using high-fidelity code blue simulations. Results: The four OFI of focus were communication, role clarity, situation monitoring, and device/procedure familiarity. An iterative process evaluating failures during simulated code blue events determined 2-4 elements that could be observed and quantified for each of these four categories. Conclusion: Real-time team performance is difficult to objectively assess. A list of observable elements may therefore be useful in measuring team performance during code blue resuscitation and training for future correlation to clinical outcomes.
Author Disclosures: For author disclosure information, please visit the AHA Scientific Sessions 2023 Online Program Planner and search for the abstract title.
Key Words: Resuscitation, Quality improvement, Team

464: Clinical Significance of Ultra-Early Minimum Intensity Projection Images in Out-of-Hospital Cardiac Arrest Survivors: A Preliminary Retrospective Cohort Study

Jin Hong Min1, Jung Soo Park1, You Yeonho2, Kang Changshin2, In Yong Nam2; 1Chungnam National Univ, Daejeon, Korea, Republic of, 2
Background: The minimum intensity projection (MIP) form of susceptibility-weighted imaging (SWI) in brain magnetic resonance imaging (MRI) demonstrates deoxyhemoglobin in traumatic brain injury. MIP emphasizes tissue changes and vessel details. Hypothesis: After hypoxic-ischemic brain injury (HIBI), delayed hyperemia occurs, and cerebral oxygen metabolism diminishes, elevating cerebral oxyhemoglobin levels. MIP findings in HIBI include diminished signals in the cerebral veins, particularly in ultra-early stage of out-of-hospital cardiac arrest survivors (OHCAs). Aims: The aim of this study was to investigate the relationship between diminished venous signals in ultra-early MIP and poor neurological outcomes of OHCAs. Methods: We conducted a retrospective observational study from March 2021-January 2023. The primary outcome was poor neurologic outcome (cerebral performance category [CPC] of 3-5) at 6 months. Diminished venous signals (DVV) were defined as decreased venous vascularity or presence of scattered discrete foci of venous vascularity in the occipital lobe in MIP. We analyzed neurological outcome differences between diminished and normal signals, as well as the relationship between DVV and presence of high-signal intensity (HSI) on ultra-early diffusion-weighted magnetic resonance imaging (DW-MRI). We compared the regions of interest (ROIs) of the occipital and parietal lobes between good and poor neurological outcome groups, using the signal intensity ratio (SIR) for standardization. The reference ROI for calculating the SIR was obtained from the cerebrospinal fluid area. Results: Among 23 patients, 12 had a poor neurological outcome. In the poor neurological outcome group, 9 patients had DVV (p = 0.001); 5 patients showed DVV without HSI on DW-MRI. SIR of the occipital lobe differed significantly between the good and poor outcome groups (p = 0.027). The SIR of the occipital lobe demonstrated an area under the receiver operating characteristic curve value of 0.77 (95% CI: 0.55-0.92) in predicting poor neurological outcomes. In DVV, sensitivity was 75% (95% CI: 43-95%) at specificity was 100%. Conclusions: To predict neurological outcomes of OHCA at ultra-early phase, MIP is considered to be a complementary tool to DW-MRI.
Author Disclosures: For author disclosure information, please visit the AHA Scientific Sessions 2023 Online Program Planner and search for the abstract title.
Key Words: Magnetic resonance neuroimaging, Outcomes, Hypoxia

465: Neurodevelopment Outcomes in Survivors of In-Hospital Cardiorespiratory Failure (Pre Arrest) and Arrest: Experience From a LMIC

Ebor J James, John Daniel, Carloline P, Joshapine V Paripooranam, Samuel Oommen, Vandana P Pande, Jolly Chandan, Sanketh R, Grace Rebekah; 1CMC Hosp, Vellore, India
Objectives: T o assess neurodevelopmental outcome in survivors of in-hospital cardio-respiratory arrest (CRA) or cardio-respiratory failure (CRF). and to study their clinical profile Methods: Children aged between 72hrs - 15 years, with Cardio-respiratory arrest (CRA) OR Cardio-respiratory failure (CRF: those had respiratory failure and hypotensive shock with or without bradycardia) were recruited. Baseline social quotient and global functions were assessed at discharge using POPC/PCPC. At 6 months follow up, neuro development was assessed using GMDS(Griffiths Mental Development Scale 3rdedn.)/BKT (Binet Kamat Test) along with VSMS (Vinland Social Maturity Scale) and data was analysed. Description of clinical profile of the study population was also done. Results: A total of 232 patients survived either a cardiorespiratory arrest (n=172) OR cardiorespiratory failure (60). 56 children among them (CRA 34+CRF 22) survived to hospital discharge. 48 children had a POPC/PCPC of 1 (Good overall performance or Normal). At 6 months follow up of 24 children,15 were found to have good neurological outcome (GQ > 76 by GMDS 3rd edition or IQ >70 by Binet Kamat test) showed improvement or return to baseline pre-morbid neurological status. Nine children have poor neurological outcome. Conclusion: 1. Among the children followed up for neuro developmental assessment, 63%had a good neurological outcome and were able to return to baseline premorbid neurological status. 2. More than 85% children had good overall global performance function at discharge.
Author Disclosures: For author disclosure information, please visit the AHA Scientific Sessions 2023 Online Program Planner and search for the abstract title.
Key Words: Cardiac arrest, Children, Outcomes

466: High Threshold and Narrow Focus for Rapid Response System Activation May Explain Failure of the National Early Warning Score (NEWS) to Reduce Unplanned ICU Admissions and Hospital Mortality

Raul J Gazmuri1, Mylene Apigo2, Ma Lea Martin2; 1Rosalind Franklin Univ, Chicago, IL, 2Captain James A. Lovell Federal Health Care Cntr, North Chicago, IL
Objectives: NEWS is an early warning scoring system widely utilized to identify patients at high risk of adverse outcomes, including cardiac arrest, unplanned ICU admission, and death. NEWS was selected as the standardized system to be included in the new Federal Electronic Health Record throughout the VA enterprise. NEWS can identify patients at risk of these adverse outcomes. However, its implementation with a rapid response system (RRS) has not been proven to reduce the aforementioned adverse outcomes. NEWS is a point-based system assessing blood pressure, pulse rate, respiratory rate, oxygenation, need of oxygen, mental status, and body temperature, recommending specific actions according to total point summation, with RRS activation for ≥ 7 points. We compared the RRS activation performance of NEWS against an RRS activation system developed in our institution that includes 8 additional signs (i.e., new non-invasive mechanical ventilation, chest pain, severe refractory pain, syncope, fall with suspected head injury, repetitive seizures, stroke alert, and condition of concern) operating with a single sign activation. Methods: We analyzed 182 RRS activations from July 1, 2022, to August 21, 2023, and compared the activation thresholds and dispositions that would have occurred using NEWS. Findings: Of the 182 patients that activated our RRS, 122 (67%) were transferred to a higher level of care, including 58 (31.8%) to ICU, mostly from the general medical ward, and 57 (31.3%) to the ED, mostly from our nursing home. Using NEWS, only 10 of the 182 patients (5.5%) reached the ≥ 7-point threshold for RRS activation and 8 were transferred to ICU or ED (P <0.001). Of the remaining 172 patients, 158 scored 0 to 4 points with NEWS, a score classified as “low” and associated with the recommendation to continue monitoring. A total of 245 signs were activated in 182 patients with 99 signs (40.4%) corresponding to signs not included in NEWS (P <0.001). More than one sign was activated in 45 patients. Conclusions: Relative to our single sign activation system, NEWS demonstrated to have a substantially higher threshold for activation with a narrower list of activation signs, which could explain the failure to impact patient outcomes despite its widespread implementation.
Author Disclosures: For author disclosure information, please visit the AHA Scientific Sessions 2023 Online Program Planner and search for the abstract title.
Key Words: Prevention, Cardiac arrest, Performance measurement

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Published online: 18 December 2023
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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
Circulation
  • Vol. 148
  • No. 25

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