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Maria Rosa Costanzo,1 Shahrokh Javaheri,2,3 Piotr Ponikowski,4 Olaf Oldenburg,5 Ralph Augostini,3 Lee R Goldberg,6 Christoph Stellbrink,7 Henrik Fox,8 Alan R Schwartz,6 Sanjaya Gupta,9 Scott McKane,10 Timothy E Meyer,10 William T Abraham3 for the remedē®System Pivotal Trial Study Group1Advocate Heart Institute, Naperville, IL, USA; 2Bethesda North Hospital, Cincinnati, OH, USA; 3The Ohio State University, Columbus, OH, USA; 4Department of Heart Diseases, Medical University, Military Hospital, Wroclaw, Poland; 5Ludgerus-Kliniken Münster, Clemens Hospital, Münster, Germany; 6University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; 7Bielefeld Medical Center, Bielefeld, Germany; 8Clinic for General and Interventional Cardiology Angiology, Herz- und Diabeteszentrum NRW, Ruhr-Universität Bochum, Bad Oeynhausen, Germany; 9University of Missouri-Kansas City School of Medicine, Saint Luke’s Mid-America Heart Institute, Kansas City, MO, USA; 10Respicardia, Inc., Minnetonka, MN, USACorrespondence: Maria Rosa CostanzoAdvocate Heart Institute, Naperville, IL, 60566, USAEmail mariarosa.costanzo@aah.orgBackground: The remedē System Pivotal Trial was a prospective, multi-center, randomized trial demonstrating transvenous phrenic nerve stimulation (TPNS) therapy is safe and effectively treats central sleep apnea (CSA) and improves sleep architecture and daytime sleepiness. Subsequently, the remedē System was approved by FDA in 2017. As a condition of approval, the Post Approval Study (PAS) collected clinical evidence regarding long-term safety and effectiveness in adults with moderate to severe CSA through five years post implant.Methods: Patients remaining in the Pivotal Trial at the time of FDA approval were invited to enroll in the PAS and consented to undergo sleep studies (scored by a central laboratory), complete the Epworth Sleepiness Scale (ESS) questionnaire to assess daytime sleepiness, and safety assessment. All subjects (treatment and former control group) receiving active therapy were pooled; data from both trials were combined for analysis.Results: Fifty-three of the original 151 Pivotal Trial patients consented to participate in the PAS and 52 completed the 5-year visit. Following TPNS therapy, the apnea-hypopnea index (AHI), central-apnea index (CAI), arousal index, oxygen desaturation index, and sleep architecture showed sustained improvements. Comparing 5 years to baseline, AHI and CAI decreased significantly (AHI baseline median 46 events/hour vs 17 at 5 years; CAI baseline median 23 events/hour vs 1 at 5 years), though residual hypopneas were present. In parallel, the arousal index, oxygen desaturation index and sleep architecture improved. The ESS improved by a statistically significant median reduction of 3 points at 5 years. Serious adverse events related to implant procedure, device or delivered therapy were reported by 14% of patients which include 16 (9%) patients who underwent a pulse generator reposition or lead revision (primarily in the first year). None of the events caused long-term harm. No unanticipated adverse device effects or related deaths occurred through 5 years.Conclusion: Long-term TPNS safely improves CSA, sleep architecture and daytime sleepiness through 5 years post implant.Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT01816776.Keywords: central sleep apnea, phrenic nerve stimulation

Because cardiomyopathy can progress to heart failure, no complaint of dyspnea, its major symptom, should be disregarded. Primary care physicians have a pivotal role in diagnosis and the search for reversible causes. [ABSTRACT FROM AUTHOR]

Central sleep apnea (CSA), a rare polysomnographic finding in the general population, is prevalent in certain cardiovascular conditions including systolic and diastolic left ventricular dysfunction, atrial fibrillation, coronary artery disease, carotid artery stenosis, stroke and use of certain cardiac-related medications. Polysomnographic findings of CSA with adverse cardiovascular impacts include nocturnal hypoxemia and arousals, which can lead to increased sympathetic activity both at night and in the daytime. Among cardiovascular diseases, CSA is most prevalent in patients with left ventricular systolic dysfunction; a large study of more than 900 treated patients has shown a dose dependent relationship between nocturnal desaturation and mortality. Multiple small randomized controlled trials have shown mitigation of sympathetic activity when CSA is treated with nocturnal oxygen, continuous positive airway pressure and adaptive servoventilation. However, two early randomized controlled trials with positive airway pressure devices have shown either neutral effect on survival or excess premature mortality in the active treatment arm, compared to untreated CSA. In contrast, the results of the most recent trial using an advanced adaptive servoventilation device showed improved quality of life and no signal for mortality suggesting that treatment of CSA was at least safe. In addition to positive airway pressure devices, multiple medications have been shown to improve CSA, but no long-term trials of pharmacologic therapy have been published. Currently, phrenic nerve stimulation is approved for treatment of CSA, and the results of a randomized controlled trial showed significant improvement in sleep metrics and quality of life., (© The Author(s) 2024. Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: An interatrial shunt may provide an autoregulatory mechanism to decrease left atrial pressure and improve heart failure (HF) symptoms and prognosis., Methods: Patients with symptomatic HF with any left ventricular ejection fraction (LVEF) were randomized 1:1 to transcatheter shunt implantation versus a placebo procedure, stratified by reduced (≤40%) versus preserved (>40%) LVEF. The primary safety outcome was a composite of device-related or procedure-related major adverse cardiovascular or neurological events at 30 days compared with a prespecified performance goal of 11%. The primary effectiveness outcome was the hierarchical composite ranking of all-cause death, cardiac transplantation or left ventricular assist device implantation, HF hospitalization, outpatient worsening HF events, and change in quality of life from baseline measured by the Kansas City Cardiomyopathy Questionnaire overall summary score through maximum 2-year follow-up, assessed when the last enrolled patient reached 1-year follow-up, expressed as the win ratio. Prespecified hypothesis-generating analyses were performed in patients with reduced and preserved LVEF., Results: Between October 24, 2018, and October 19, 2022, 508 patients were randomized at 94 sites in 11 countries to interatrial shunt treatment (n=250) or a placebo procedure (n=258). Median (25th and 75th percentiles) age was 73.0 years (66.0, 79.0), and 189 patients (37.2%) were women. Median LVEF was reduced (≤40%) in 206 patients (40.6%) and preserved (>40%) in 302 patients (59.4%). No primary safety events occurred after shunt implantation (upper 97.5% confidence limit, 1.5%; P <0.0001). There was no difference in the 2-year primary effectiveness outcome between the shunt and placebo procedure groups (win ratio, 0.86 [95% CI, 0.61-1.22]; P =0.20). However, patients with reduced LVEF had fewer adverse cardiovascular events with shunt treatment versus placebo (annualized rate 49.0% versus 88.6%; relative risk, 0.55 [95% CI, 0.42-0.73]; P <0.0001), whereas patients with preserved LVEF had more cardiovascular events with shunt treatment (annualized rate 60.2% versus 35.9%; relative risk, 1.68 [95% CI, 1.29-2.19]; P =0.0001; P interaction <0.0001). There were no between-group differences in change in Kansas City Cardiomyopathy Questionnaire overall summary score during follow-up in all patients or in those with reduced or preserved LVEF., Conclusions: Transcatheter interatrial shunt implantation was safe but did not improve outcomes in patients with HF. However, the results from a prespecified exploratory analysis in stratified randomized groups suggest that shunt implantation is beneficial in patients with reduced LVEF and harmful in patients with preserved LVEF., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03499236., Competing Interests: Dr Stone has received speaker honoraria from Medtronic, Pulnovo, Abiomed, Amgen, and Boehringer Ingelheim; has served as a consultant to Abbott, Daiichi Sankyo, Ablative Solutions, CorFlow, CardioMech, Robocath, Miracor, Vectorious, Apollo Therapeutics, Elucid Bio, Cardiac Success, Valfix, TherOx, HeartFlow, Neovasc, Ancora, Occlutech, Impulse Dynamics, Adona Medical, Millennia Biopharma, Oxitope, HighLife, Elixir, Remote Cardiac Enablement, and Aria; and has equity or options from Cardiac Success, Ancora, Cagent, Applied Therapeutics, Biostar family of funds, SpectraWave, Orchestra Biomed, Aria, Valfix, and Xenter. Dr Stone’s employer, Mount Sinai Hospital, receives research grants from Shockwave, Abbott, Abiomed, BioVentrix, Cardiovascular Systems Inc, Phillips, Biosense-Webster, Vascular Dynamics, Pulnovo, V-wave, and PCORI (via Weill Cornell Medical Center). Dr Lindenfeld has received consulting fees from Abbott, Alleviant, Axon, AstraZeneca, Boston Scientific, CVRx, Merck, Medtronic, Edwards Lifesciences, V-Wave Medical, WhiteSwell, Vascular Dynamics, and Bayer. Dr Rodés-Cabau has received grants from V-Wave, Edwards Lifesciences, Medtronic, and Boston Scientific; received consulting fees from V-Wave Medical, Edwards Lifesciences, and Medtronic; and has received payment for presentations from Edwards Lifesciences and Medtronic. Dr Rodés-Cabau’s employer receives funding for enrollment in clinical trials for V-Wave Medical. Dr Anker serves as a consultant to Abbott Vascular, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Brahms GmbH, Cardiac Dimensions, Cardior, Cordia, CVRx, Inc, Cytokinetics, Edwards Lifesciences, Faraday Pharmaceuticals, GlaxoSmithKline, HeartKinetics, Impulse Dynamics (USA) Inc, Novartis, Occlutech, Pfizer, Regeneron, Repairon, Sensible Medical Innovations Ltd, Servier, V-Wave Medical, Vectorius, and Vifor; and has 2 patent applications regarding MR-proANP (midregional pro-atrial natriuretic peptide) through Brahms GmbH. Dr Anker’s employer Charité University Medicine Berlin has received grants from Vifor (International) Ltd. Dr Zile has consulting contracts for advisory committees with Abbott, Adona Medical, Aria CV, Avery Therapeutics, Inc, Boehringer-Ingelheim, Boston Scientific, Cardiovascular Research Foundation (CRF) Clinical Trials Center, CVRx, Diasol Therapeutics, LLC, EBR, Edwards, Eli Lilly, Endotronix, Medtronic, Merck, Morphic Therapeutics, Novartis, Salubris Biotherapeutics, Sonata, Srnalytics, Inc, V-Wave Medical, and Vectorious. Dr Kar has received grants and contracts from Abbott, Boston Scientific, Medtronic, Edwards Lifesciences, Laminar, and Picardia; has received consulting fees from Abbott, Medtronic, Boston Scientific, and V-Wave Medical; is a member of the executive committee for V-Wave Medical and advisory boards for Abbott, Boston Scientific, Medtronic, and InterShunt; has stock or stock options in PiCardia and Laminar; serves as the co–principal investigator for REAPIR-MR, CHAMPION, and Laminar Pivotal Trial. Dr Holcomb has received support for preparation of this article and has received consulting fees from V-Wave Medical and has received support for meeting attendance. Dr Pfeiffer has received honoraria from Abbott Cardiovascular and AncoraHeart. Dr Pfeiffer’s employer, The Penn State University and The Milton S. Hershey Medical Center, receives funding from V-Wave Medical for serving as the echo core laboratory. Dr Bayes-Genis has received honoraria for presentations from Abbott, AstraZeneca, Bayer, Boehringer Ingelheim, Medtronic, Novartis, Novo Nordisk, Roche Diagnostics, and Vifor. Dr Bax has served on the advisory board for V-Wave and receives reimbursement for serving on the eligibility committee for V-Wave and receives speaker fees from Abbott Vascular and Edwards Lifesciences. Dr Bax’s employer, Leiden University Medical Center, receives research grants from Abbot Vascular, Alnylam, Bayer, Bioventrix, Biotronik, Boston Scientific, Edwards Lifesciences, GE Healthcare, Medtronic, Medis, Novartis, Pfizer, and Pie Medical. Dr Bank has received consulting fees for serving on the advisory board and eligibility committee for V-Wave. Dr Costanzo has received grants or contracts from V-Wave, Bayer, and Alleviant as a site PI; has received consulting fees from Boehringer-Ingelheim, Nuwellis, V-Wave, and Alleviant; participated on DSMB/advisory boards for Merck and Boehringer-Ingelheim; and serves on the board of directors of Nuwellis. Dr Verheye has received consulting fees from Shockwave and Elixir Medical and stock or options for V-Wave and serves on the advisory board and eligibility committee for V-Wave. Dr Roguin serves on the advisory board for V-Wave and receives money for serving on the eligibility committee for V-Wave. Dr Filippatos has received grants from the European Commission; has received honoraria from Bayer, Boehringer Ingelheim, Servier, and Novartis; serves in a fiduciary role for the Heart Failure Association and JACC Heart Failure; serves on trial committees for Medtronic, Bayer, Boehringer Ingelheim, Vifor, Amgen, Servier, Impulse Dynamics, Cardior, and Novo Nordisk; and has received consulting fees from Cardio and Novo Nordisk. Dr Núñez has received consulting fees from Novartis, Boehringer Ingelheim, Bayer, and Novo Nordisk; and receives fees for lecture presentations from Alleviant, AstraZeneca, Boehringer Ingelheim, Bayer, Novartis, Novo Nordisk, Pfizer, Rovi, and Vifor Pharma. Dr Laufer-Perl has received consulting fees from Alleviant Medical and Unipharm; receives payment or honoraria from AbbVie Biopharmaceuticals, Alleviant Medical, AstraZeneca, Boehringer Ingelheim, Novartis, Medison, Novo Nordisk, Bayer, Unipharm, and CTS; received support for attending meetings from Alleviant Medical; is a participant on DSMB or advisory boards for Boehringer Ingelheim, AstraZeneca, and Bayer; and has received institutional grants from Boehringer Ingelheim, AstraZeneca, Pfizer, Novartis, Bayer, and the Israel Cancer Association. Dr Litwin has received grants for patient selection committees for a clinical trial for a different atrial shunt study for Corvia and served in a fiduciary role as associate editor for the Journal of the American Society for Echocardiography. Dr Litwin’s employer, MUSC, receives funding for enrollment in trials for V-Wave Medical and Corvia. Dr Prihadi has received consulting fees from Novartis, Boehringer Ingelheim, Bayer, Abbott, and Astra Zeneca; has received honoraria for presentations from Novartis, Boehringer Ingelheim, AstraZeneca, Menarinin, Vifor, and Novo Nordisk; has received support for attendance at meetings from Pfizer and Bayer; and has participated on advisory boards for AstraZeneca and Novartis. Dr Chung has received consulting fees from Intershunt, Corvia, Medtronic, and Abbott. Dr Price has received consulting fees from Abbott, Boston Scientific, Medtronic, Shockwave, Philips Medical, Alleviant Medical, and Innovheart; has received honoraria for presentations from WL Gore, Abbott, Shockwave, and Philips Medical; has served on DSMB or advisory boards for Axio Research (Portico NG and Vantage Trials); has served on the American College of Cardiology NCDR LAAO Research and Publication Committee; and holds stock or stock options from InterShunt, Indian Welss, Bolt Medical, Atraverse, and Advanced Bifurcation systems. Dr Thohan has received honoraria from Pfizer and Boehringer Ingelheim. Dr Schewel has received consulting fees from V-Wave Medical for proctoring intervention procedures. Dr Eigler has patents issued and planned for V-Wave Ltd and V-Wave Inc; is a shareholder and stock option holder as an employee of V-Wave Medical; is the chief executive officer of V-Wave Medical; and receives compensation in the form of salary, bonus, and stock option grants. Dr Abraham has received honoraria from Impulse Dynamics, Edwards Lifesciences, and Abbott; has received consulting fees from Zoll Respicardia; has stock in V-Wave Ltd; has a patent for mobile ultrawideband radar for monitoring thoracic fluid levels and cardiorespiratory function (publication No. 20210290074); has participated on advisory boards or data safety and monitoring boards for Sensible Medical, WhiteSwell, AquaPass, Cordio Medical, and Boehringer-Ingelheim; and his institution has received a grant from the National Institutes of Health (1 UG3/UH3 HL140144-01; LOFT-HF [Impact of Low Flow Nocturnal Oxygen Therapy on Hospital Readmission/Mortality in Patients with Heart Failure and Central Sleep Apnea]). The other authors report no disclosures.

Aims: Central sleep apnoea (CSA) is present in 20-40% of heart failure (HF) patients and is associated with poor clinical outcomes and health status. Transvenous phrenic nerve stimulation (TPNS) is an available treatment for CSA in HF patients. The impact on HF outcomes is incompletely understood. The win ratio (WR) allows inclusion of multiple endpoint components, considers the relative severity of each component, and permits assessment of recurrent events in evaluation of clinical benefit., Methods and Results: A WR hierarchy was pre-defined for analysis of the HF subgroup of the remedē® System Pivotal Trial. The analysis used three hierarchical components to compare all treated to all control subjects: longest survival, lowest HF hospitalization rate, and ≥2-category difference in Patient Global Assessment at 6 months. Sensitivity analyses were performed substituting Epworth Sleepiness Scale and 4% oxygen desaturation index for the third component, and a 4-component WR hierarchy was also evaluated. Ninety-one HF subjects, 43 receiving TPNS and 48 in the control group, provided 2064 pairwise comparisons. More patients treated with TPNS experienced clinical benefit compared with control (WR 4.92, 95% confidence interval 2.27-10.63, P < 0.0001). There were 1111 (53.83%) winning pairwise comparisons for the treatment group and 226 (10.95%) for the control group. Similarly, large WRs were observed for all additional WR hierarchies., Conclusions: This WR analysis of the remedē® System Pivotal Trial suggests that TPNS may be superior to untreated CSA in HF patients with CSA using a hierarchical clinical benefit endpoint composed of mortality, HF hospitalization, and health status., (© 2024 The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Our comprehension of atrial mechanics, atrial cardiomyopathy and their clinical implications across various cardiovascular conditions has advanced significantly. Atrial interventions can have differing effects on atrial mechanics. With the rapid increase in the use of atrial interventions, it is crucial for investigators and clinicians to acknowledge the potential adverse effects of these interventions on atrial mechanics that might not be clinically significant at the time of interventions. Recognizing the preclinical stage of atrial maladaptation might enable early interventions before the development of irreversible atrial remodeling and clinical manifestation. We review normal atrial function and mechanics, and atrial cardiomyopathy in select cardiovascular conditions. We also summarize and discuss the current evidence of the impact of various atrial interventions on atrial function and mechanics., Competing Interests: Disclosures ML-P has received speaker honoraria from BI, AstraZeneca, Novartis, Pfizer, Novonordisk, Abbvie, Bayer, Medison, V-wave, and Alleviant and has served as a consultant to BI, Astrazeneca and Bayer, receives research grants from BI, AstraZeneca, Novartis, Pfizer, and Bayer. THM is supported by an Investigator grant (2008129) from the National Health and Medical Research Council (Canberra, Australian Capital Territory, Australia). MR has received research support from Corvia and V-Wave paid to the institution. VT is a consultant for Abbott, Impulse Dynamics and Battelle and participated in speaker's bureaus for Pfizer and Boehringer Ingelheim. KB is on the speaker's bureau for Abbott, Pfizer and Novartis and is a consultant for Abbott. FS has received research grants from Amgen and is a consultant for Abbott. AT has received speaker honoraria from Bristol-Myers Squibb. MF is supported by the NIH (1OT2HL156812-01; 1R01HL171305-01) and Doris Duke and has received consulting fees from Abbott, Ajax, Alio Health, Alleviant, Artha, Audicor, AxonTherapies, Bayer, Bodyguide, Bodyport, Boston Scientific, Broadview, Cadence, Cardioflow, Cardionomics, Coridea, CVRx, Daxor, Deerfield Catalyst, Edwards LifeSciences, Echosens, EKO, Feldschuh Foundation, Fire1, FutureCardia, Galvani, Gradient, Hatteras, HemodynamiQ, Impulse Dynamics, Intershunt, Medtronic, Merck, NIMedical, NovoNordisk, NucleusRx, NXT Biomedical, Orchestra, Pharmacosmos, PreHealth, Presidio, Procyreon, ReCor, Rockley, SCPharma, Shifamed, Splendo, Summacor, SyMap, Verily, Vironix, Viscardia, and Zoll. All other authors have no relevant financial disclosures., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Trials evaluating implantable hemodynamic monitors to manage patients with heart failure (HF) have shown reductions in HF hospitalizations but not mortality. Prior meta-analyses assessing mortality have been limited in construct because of an absence of patient-level data, short-term follow-up duration, and evaluation across the combined spectrum of ejection fractions., Objectives: The purpose of this meta-analysis was to determine whether management with implantable hemodynamic monitors reduces mortality in patients with heart failure and reduced ejection fraction (HFrEF) and to confirm the effect of hemodynamic-monitoring guided management on HF hospitalization reduction reported in previous studies., Methods: The patient-level pooled meta-analysis used 3 randomized studies (GUIDE-HF [Hemodynamic-Guided Management of Heart Failure], CHAMPION [CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in NYHA Class III Heart Failure Patients], and LAPTOP-HF [Left Atrial Pressure Monitoring to Optimize Heart Failure Therapy]) of implantable hemodynamic monitors (2 measuring pulmonary artery pressures and 1 measuring left atrial pressure) to assess the effect on all-cause mortality and HF hospitalizations., Results: A total of 1,350 patients with HFrEF were included. Hemodynamic-monitoring guided management significantly reduced overall mortality with an HR of 0.75 (95% CI: 0.57-0.99); P = 0.043. HF hospitalizations were significantly reduced with an HR of 0.64 (95% CI: 0.55-0.76); P < 0.0001., Conclusions: Management of patients with HFrEF using an implantable hemodynamic monitor significantly reduces both mortality and HF hospitalizations. The reduction in HF hospitalizations is seen early in the first year of monitoring and mortality benefits occur after the first year., Competing Interests: Funding Support and Author Disclosures Abbott (Abbott Park, Illinois) funded the CHAMPION, LAPTOP-HF, and GUIDE-HF studies. Dr Lindenfeld has received consulting fees from Abbott, Alleviant, AstraZeneca, Axon, Biotronik, Boston Scientific, CVRx, Edwards Lifesciences, Medtronic, Merck, Vascular Dynamics, Vectorious, and VWave; and has received grants from AstraZeneca. Dr Costanzo is a consultant for Abbott. Dr Zile has received research funding from Novartis; and has been a consultant for Novartis, Abbott, Boston Scientific, CVRx, EBR, Endotronix, Ironwood, Merck, Medtronic, and Myokardia V Wave. Dr Ducharme has received consulting fees from Abbott, Akcea, Alnylam, AstraZeneca, Bayer, Boehringer Ingelheim, Novartis, Pfizer, and Sanofi; and has received grants from AstraZeneca, Bayer, Corvia, Eidos, Novartis, Novo Nordisk, Pfizer, and Servier. Dr Troughton has received research grants from Health Research Council of New Zealand; has received consulting fees from Merck, Bayer, American Regent, and Roche Diagnostics; and has received honoraria payments from Roche Diagnostics. Drs Maisel and Paul are consultants for Abbott. Dr Mehra is a consultant for Natera, Paragonix, Moderna, Janssen, Broadview Ventures, Mesoblast, and Baim Institute for Clinical Research; is a consultant for Abbott; has served on the Clinical Events Committee for GUIDE-HF through the Baim Institute for Clinical Research; and has stock in NuPulseCV, Leviticus, Transmedics, and FineHeart. Dr Sears has received research grants from Medtronic and Zoll; is a consultant for Abbott, Medtronic, and Milestone Pharmaceutical; and has received personal fees from Medtronic and Zoll. Dr Smart has received research grants from Amgen; and is a consultant for Abbott. Dr Johnson, Mr Henderson, and Dr Adamson are full-time employees and shareholders for Abbott. Dr Desai has received institutional research grants from Abbott, Alnylam, AstraZeneca, Bayer, and Novartis; and is a consultant for Abbott, Alnylam, AstraZeneca, Axon Therapeutics, Avidity, Biofourmis, Boston Scientific, Cytokinetics, GlaxoSmithKline, Medpace, Merck, Novartis, Parexel, Regeneron, Roche, and Verily. Dr Abraham has received personal fees from Zoll Respicardia, Cardionomic, WhiteSwell, AquaPass, Cordio, Vectorious, Impulse Dynamics, and Edwards Lifesciences; and has personal equity in V-Wave Medica. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024. Published by Elsevier Inc.)

Acute decompensated heart failure (ADHF) is one of the most common reasons for hospitalizations or urgent care and is associated with poor outcomes. Therapies shown to improve outcomes are limited, however, and innovation in pharmacologic and device-based therapeutics are therefore actively being sought. Standardizing definitions for ADHF and its trajectory is complex, limiting the generalizability and translation of clinical trials to effect clinical care and policy change. The Heart Failure Collaboratory is a multistakeholder organization comprising clinical investigators, clinicians, patients, government representatives (including U.S. Food and Drug Administration and National Institutes of Health participants), payors, and industry collaborators. The following expert consensus document is the product of the Heart Failure Collaboratory convening with the Academic Research Consortium, including members from academia, the U.S. Food and Drug Administration, and industry, for the purposes of proposing standardized definitions for ADHF and highlighting important endpoint considerations to inform the design and conduct of clinical trials for drugs and devices in this clinical arena., Competing Interests: Funding Support and Author Disclosures Dr Lala is a Speakers Bureau member for Abiomed, Cytokinetics, Novartis, and Zoll; and performs contracted research for Merck. Dr Bozkurt has received consulting fees from Amgen, AstraZeneca, Bristol Myers Squibb, scPharmaceuticals, Baxter, Sanofi, Relypsa, Vifor, Roche, and Boehringer Ingelheim; has served on the steering committees of Relypsa and Renovacor; has served on a Clinical Event Committee for Abbott Pharmaceuticals; and has served on the Data Safety Monitoring Board for LivaNova Pharmaceuticals. Dr Burkhoff receives institutional grant support from Ancora Heart, Axon Medical, and Edwards Lifesciences; and receives consulting fees from AquaPass, Axon, BackBeat Medical, BioMind, Corvia Medical, Impulse Dynamics, and Therox/Zoll. Dr Costanzo has served as a Board of Directors member for Nuwellis; has received research grants from Bayer, Novartis, and V-WAVE to the Midwest Cardiovascular Institute; and is an Associated Editor for the Journal of the American College of Cardiology. Dr Felker has received research grants from the National Heart, Lung, and Blood Institute, the American Heart Association, Amgen, Bayer, BMS, Novartis, Daxor, Merck, Cytokinetics, and CSL Behring; has acted as a consultant to Novartis, Amgen, BMS, Cytokinetics, Innolife, Medtronic, Cardionomic, Boehringer Ingelheim, American Regent, Abbott, AstraZeneca, Regeneron, Reprieve, Myovant, Sequana, Windtree Therapeutics, Rocket Pharma, and WhiteSwell; and has served on clinical endpoint committees/data safety monitoring boards for Amgen, Merck, Medtronic, EBR Systems, V-WAVE, and LivaNova. Dr Filippatos is a committee member of trials and registries sponsored by Amgen, Bayer, Boehringer Ingelheim, Medtronic, Novartis, Servier, and Vifor Pharma; is a Senior Consulting Editor for JACC Heart Failure; and has received research support from the European Union. Dr Konstam has been a consultant for FIRE1, Pfizer, Luitpold, Cardurion, Cytogenetics, and Boehringer Ingelheim. Dr McMurray reports payments to his employer, Glasgow University, for his work on clinical trials, consulting, and other activities from Alnylam, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Cardurion, Cytokinetics, DalCor, GSK, Ionis, KBP Biosciences, Novartis, Pfizer, and Theracos; and personal payments from Abbott, Alkem Metabolics, Eris Lifesciences, Hikma, Ionis, Lupin, ProAdWise Communications, Sun Pharmaceuticals, and Servier. Dr Mentz is a consultant to Abbott, Medtronic, Boston Scientific, and Zoll. Dr Metra has received personal fees of minimal amounts in the last 3 years: from Actelion as member of the Data Monitoring Committee of sponsored clinical trials; from Amgen, LivaNova, Servier, and Vifor Pharma as member of Executive Committees of sponsored clinical trials; and from AstraZeneca, Abbott Vascular, Bayer, Boehringer Ingelheim, and Edwards Therapeutics for participation on advisory boards and/or for speeches at sponsored meetings. Dr Solomon has received research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, BMS, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lilly, Mesoblast, MyoKardia, National Institutes of Health/National Heart, Lung, and Blood Institute, NeuroTronik, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, Theracos, and US2.AI; and has served as a consultant for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi Sankyo, GlaxoSmithKline, Lilly, Merck, MyoKardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi Pasteur, DiNAQOR, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, and Akros. Dr Teerlink is a consultant for 3iveLabs, Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cytokinetics, Medtronic, Merck, Novartis, Verily, ViCardia, and Windtree Therapeutics; and has received research grants from 3ive Labs, Abbott, Amgen, AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol Myers Squibb, Cardurion, Cytokinetics, EBR Systems, Edwards, Medtronic, Novartis, V-WAVE, ViCardia, and Windtree Therapeutics. Dr Abraham has received consulting fees from Boehringer Ingelheim, Cardionomic, Zoll Respicardia, scPharmaceuticals, Sensible Medical; Vectorious Salary support from V-WAVE Medical; and has served as a speaker for Edwards Lifesciences. Dr O’Connor has received grant or research support from Merck; and consulting fees from Merck, Bayer, and Abiomed. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Acute heart failure (AHF) represents the most frequent cause of unplanned hospital admission in patients older than 65 years. Symptoms and clinical signs of AHF (e.g. dyspnoea, orthopnoea, oedema, jugular vein distension, and variation of body weight) are mostly related to systemic venous congestion secondary to various mechanisms including extracellular fluids, increased ventricular filling pressures, and/or auto-transfusion of blood from the splanchnic into the pulmonary circulation. Thus, the initial management of AHF patients should be mostly based on decongestive therapies on admission followed, before discharge, by rapid implementation of guideline-directed oral medical therapies for heart failure. The therapeutic management of AHF requires the identification and rapid diagnosis of the disease, the diagnosis of the cause (or triggering factor), the evaluation of severity, the presence of comorbidities, and, finally, the initiation of a rapid treatment. The most recent guidelines from ESC and ACC/AHA/HFSA have provided updated recommendations on AHF management. Recommended pharmacological treatment for AHF includes diuretic therapy aiming to relieve congestion and achieve optimal fluid status, early and rapid initiation of oral therapies before discharge combined with a close follow-up. Non-pharmacological AHF management requires risk stratification in the emergency department and non-invasive ventilation in case of respiratory failure. Vasodilators should be considered as initial therapy in AHF precipitated by hypertension. On the background of recent large randomized clinical trials and international guidelines, this state-of-the-art review describes current pharmacological treatments and potential directions for future research in AHF., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: In patients with symptomatic heart failure (HF) and previous heart failure hospitalization (HFH), hemodynamic-guided HF management using a wireless pulmonary artery pressure (PAP) sensor reduces HFH, but it is unclear whether these benefits extend to patients who have not been recently hospitalized but remain at risk because of elevated natriuretic peptides (NPs)., Objectives: This study assessed the efficacy and safety of hemodynamic-guided HF management in patients with elevated NPs but no recent HFH., Methods: In the GUIDE-HF (Hemodynamic-Guided Management of Heart Failure) trial, 1,000 patients with New York Heart Association (NYHA) functional class II to IV HF and either previous HFH or elevated NP levels were randomly assigned to hemodynamic-guided HF management or usual care. The authors evaluated the primary study composite of all-cause mortality and total HF events at 12 months according to treatment assignment and enrollment stratum (HFH vs elevated NPs) by using Cox proportional hazards models., Results: Of 999 evaluable patients, 557 were enrolled on the basis of a previous HFH and 442 on the basis of elevated NPs alone. Those patients enrolled by NP criteria were older and more commonly White persons with lower body mass index, lower NYHA class, less diabetes, more atrial fibrillation, and lower baseline PAP. Event rates were lower among those patients in the NP group for both the full follow-up (40.9 per 100 patient-years vs 82.0 per 100 patient-years) and the pre-COVID-19 analysis (43.6 per 100 patient-years vs 88.0 per 100 patient-years). The effects of hemodynamic monitoring were consistent across enrollment strata for the primary endpoint over the full study duration (interaction P = 0.71) and the pre-COVID-19 analysis (interaction P = 0.58)., Conclusions: Consistent effects of hemodynamic-guided HF management across enrollment strata in GUIDE-HF support consideration of hemodynamic monitoring in the expanded group of patients with chronic HF and elevated NPs without recent HFH. (Hemodynamic-Guided Management of Heart Failure [GUIDE-HF]; NCT03387813)., Competing Interests: Funding Support and Author Disclosures The GUIDE-HF trial was funded by Abbott. Dr Desai has received institutional research grants from Abbott, Alnylam, AstraZeneca, Bayer, and Novartis; and is a consultant for Abbott, Alnylam, AstraZeneca, Axon Therapeutics, Avidity, Biofourmis, Boston Scientific, Cytokinetics, GlaxoSmithKline, Medpace, Merck, Novartis, Parexel, Regeneron, Roche, and Verily. Dr Maisel has been a consultant to Abbott. Dr Mehra is a consultant for Abbott, Natera, Paragonix, Moderna, Janssen, Broadview Ventures, Mesoblast, and Baim Institute for Clinical Research; has served on the Clinical Events Committee for GUIDE-HF through the Baim Institute for Clinical Research; and holds stock in NuPulseCV, Leviticus, and FineHeart. Dr Zile has been a consultant for Abbott. Dr Ducharme has been a consultant for Abbott. Dr Paul has been a consultant for Abbott. Dr Sears has received research grants from Medtronic and Zoll; is a consultant for Abbott, Medtronic, and Milestone Pharmaceutical; and has received personal fees from Medtronic and Zoll. Dr Smart has received research grants from Amgen; and is a consultant for Abbott. Mr Henderson is employed by Abbott. Dr Johnson is employed by Abbott. Dr Adamson is employed by Abbott. Dr Costanzo has been a consultant for Abbott. Dr Lindenfeld has received research grants from AstraZeneca, Sensible Medical, and Volumetrix; and is a consultant for Abbott, Alleviant Medical, AstraZeneca, Boehringer-Ingelheim, Boston Scientific, CVRx, Edwards Lifesciences, Impulse Dynamics, and V-Wave. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023. Published by Elsevier Inc.)

Background: Hemodynamic-guided heart failure management is a superior strategy to prevent decompensation leading to hospitalization compared with traditional clinical methods. It remains unstudied if hemodynamic-guided care is effective across severities of comorbid renal insufficiency or if this strategy impacts renal function over time., Methods: In the CardioMEMS US PAS (Post-Approval Study), heart failure hospitalizations were compared from 1 year before and after pulmonary artery sensor implantation in 1200 patients with New York Heart Association class III symptoms and a previous hospitalization. Hospitalization rates were evaluated in all patients grouped into baseline estimated glomerular filtration rate (eGFR) quartiles. Chronic kidney disease progression was evaluated in patients with renal function follow-up data (n=911)., Results: Patients with stage 2 or greater chronic kidney disease at baseline exceeded 80%. Heart failure hospitalization risk was lower in all eGFR quartiles ranging from a hazard ratio of 0.35 (0.27-0.46; P <0.0001) in patients with eGFR >65 mL/min per 1.73 m 2 to 0.53 (0.45-0.62; P <0.0001) in patients with eGFR ≤37 mL/min per 1.73 m 2 . Renal function was preserved or improved in most patients. Survival was different between quartiles and lower in quartiles with more advanced chronic kidney disease., Conclusions: Hemodynamic-guided heart failure management using remotely obtained pulmonary artery pressures is associated with lower hospitalization rates and general preservation of renal function in all eGFR quartiles or chronic kidney disease stages., Competing Interests: Disclosures Dr Raval received research support from Abbott. Dr Valika received research support from Abbott. C. Williams is an Abbott employee. Dr Brett is an Abbott employee; Dr Adamson is an Abbott employee and shareholder. Dr Costanzo received research support from Abbott.

Background: Therapy guided by pulmonary artery (PA) pressure monitoring reduces PA pressures and heart failure hospitalizations (HFH) during the first year, but the durability of efficacy and safety through 2 years is not known., Methods and Results: The CardioMEMS Post-Approval Study investigated whether benefit and safety were generalized and sustained. Enrollment at 104 centers in the United States included 1200 patients with NYHA Class III symptoms on recommended HF therapies with prior HFH. Therapy was adjusted toward PA diastolic pressure 8-20 mmHg. Intervention frequency and PA pressure reduction were most intense during first 90 days, with sustained reduction of PA diastolic pressure from baseline 24.7 mmHg to 21.0 at 1 year and 20.8 at 2 years for all patients. Patients completing two year follow-up (n = 710) showed similar 2-year reduction (23.9 to 20.8 mmHg), with reduction in PA mean pressure (33.7 to 29.4 mmHg) in patients with reduced left ventricular ejection. The HFH rate was 1.25 events/patient/year prior to sensor implant, 0.54 at 1 year, and 0.37 at 2 years, with 59% of patients free of HFH during follow-up., Conclusions: Reduction in PA pressures and hospitalizations were early and sustained during 2 years of PA pressure-guided management, with no signal of safety concerns regarding the implanted sensor., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Hemodynamically-guided management using an implanted pulmonary artery pressure sensor is indicated to reduce heart failure (HF) hospitalizations in patients with New York Heart Association (NYHA) functional class II-III with a prior HF hospitalization or those with elevated natriuretic peptides., Objectives: The authors sought to evaluate the effect of left ventricular ejection fraction (EF) on treatment outcomes in the GUIDE-HF (Hemodynamic-GUIDEd management of Heart Failure) randomized trial., Methods: The GUIDE-HF randomized arm included 1,000 NYHA functional class II-IV patients (with HF hospitalization within the prior 12 months or elevated natriuretic peptides adjusted for EF and body mass index) implanted with a pulmonary artery pressure sensor, randomized 1:1 to a hemodynamically-guided management group (treatment) or a control group (control). The primary endpoint was the composite of HF hospitalizations, urgent HF visits, and all-cause mortality at 12 months. The authors assessed outcomes by EF in guideline-defined subgroups ≤40%, 41%-49%, and ≥50%, within the trial specified pre-COVID-19 period cohort., Results: There were 177 primary events (0.553/patient-year) in the treatment group and 224 events (0.682/patient-year) in the control group (HR: 0.81 [95% CI: 0.66-1.00]; P = 0.049); HF hospitalization was lower in the treatment vs control group (HR: 0.72 [95% CI: 0.57-0.92]; P = 0.0072). Within each EF subgroup, primary endpoint and HF hospitalization rates were lower in the treatment group (HR <1.0 across the EF spectrum). Event rate reduction by EF in the treatment groups was correlated with reduction in pulmonary artery pressures and medication changes., Conclusions: Hemodynamically-guided HF management decreases HF-related endpoints across the EF spectrum in an expanded patient population of patients with HF. (Hemodynamic-GUIDEd Management of Heart Failure [GUIDE-HF]; NCT03387813)., Competing Interests: Funding Support and Author Disclosures Funding was provided by Abbott. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: During the coronavirus disease 2019 (COVID-19) pandemic, important changes in heart failure (HF) event rates have been widely reported, but few data address potential causes for these changes; several possibilities were examined in the GUIDE-HF study., Methods and Results: From 15 March 2018 to 20 December 2019, patients were randomized to haemodynamic-guided management (treatment) vs. control for 12 months, with a primary endpoint of all-cause mortality plus HF events. Pre-COVID-19, the primary endpoint rate was 0.553 vs. 0.682 events/patient-year in the treatment vs. control group [hazard ratio (HR) 0.81, P = 0.049]. Treatment difference was no longer evident during COVID-19 (HR 1.11, P = 0.526), with a 21% decrease in the control group (0.536 events/patient-year) and no change in the treatment group (0.597 events/patient-year). Data reflecting provider-, disease-, and patient-dependent factors that might change the primary endpoint rate during COVID-19 were examined. Subject contact frequency was similar in the treatment vs. control group before and during COVID-19. During COVID-19, the monthly rate of medication changes fell 19.2% in the treatment vs. 10.7% in the control group to levels not different between groups (P = 0.362). COVID-19 was infrequent and not different between groups. Pulmonary artery pressure area under the curve decreased -98 mmHg-days in the treatment group vs. -100 mmHg-days in the controls (P = 0.867). Patient compliance with the study protocol was maintained during COVID-19 in both groups., Conclusion: During COVID-19, the primary event rate decreased in the controls and remained low in the treatment group, resulting in an effacement of group differences that were present pre-COVID-19. These outcomes did not result from changes in provider- or disease-dependent factors; pulmonary artery pressure decreased despite fewer medication changes, suggesting that patient-dependent factors played an important role in these outcomes. Clinical Trials.gov: NCT03387813., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Heart transplantation is advocated in selected patients with advanced heart failure in the absence of contraindications. Principal challenges in heart transplantation centre around an insufficient and underutilized donor organ pool, the need to individualize titration of immunosuppressive therapy, and to minimize late complications such as cardiac allograft vasculopathy, malignancy, and renal dysfunction. Advances have served to increase the organ donor pool by advocating the use of donors with underlying hepatitis C virus infection and by expanding the donor source to use hearts donated after circulatory death. New techniques to preserve the donor heart over prolonged ischaemic times, and enabling longer transport times in a safe manner, have been introduced. Mechanical circulatory support as a bridge to transplantation has allowed patients with advanced heart failure to avoid progressive deterioration in hepato-renal function while awaiting an optimal donor organ match. The management of the heart transplantation recipient remains a challenge despite advances in immunosuppression, which provide early gains in rejection avoidance but are associated with infections and late-outcome challenges. In this article, we review contemporary advances and challenges in this field to focus on donor recovery strategies, left ventricular assist devices, and immunosuppressive monitoring therapies with the potential to enhance outcomes. We also describe opportunities for future discovery to include a renewed focus on long-term survival, which continues to be an area that is under-studied and poorly characterized, non-human sources of organs for transplantation including xenotransplantation as well as chimeric transplantation, and technology competitive to human heart transplantation, such as tissue engineering., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

A number of pathologic processes contribute to the elevation in cardiac filling pressures in heart failure (HF), including myocardial dysfunction and primary volume overload. In this review, we discuss the important role of the venous system and the concepts of stressed blood volume and unstressed blood volume. We review how regulation of venous tone modifies the distribution of blood between these 2 functional compartments, the physical distribution of blood between the pulmonary and systemic circulations, and how these relate to the hemodynamic abnormalities observed in HF. Finally, we review recently applied methods for estimating stressed blood volume and how they are being applied to the results of clinical studies to provide new insights into resting and exercise hemodynamics and therapeutics for HF., Competing Interests: Funding Support and Author Disclosures Dr Fudim was supported by the National Heart, Lung, and Blood Institute (NHLBI) (NHLBI K23HL151744), the American Heart Association (grant number 20IPA35310955), Mario Family Award, Duke Chair’s Award, Translating Duke Health Award, Bayer, and BTG Specialty Pharmaceuticals; and has received consulting fees from AxonTherapies, Bodyport, CVRx, Daxor, Edwards LifeSciences, NXT Biomedical, Zoll, and Viscardia. Dr Borlaug has received research funding from the National Institutes of health/NHLBI (R01 HL128526, U01 HL125205), AstraZeneca, Corvia, Medtronic, Mesoblast, GlaxoSmithKline, and TENAX; and has served on the Advisory Board/as a consultant for Merck, Novartis, Lilly, and Novo Nordisk. Dr Shah has consulted for AxonTherapies. Dr Rich is the chief medical officer of Tenax. Dr Burkhoff has received institutional grants from Abiomed, Ancora, and Fire 1; and has received consulting fees from PVLoops LLC and Axon Therapeutics. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Abnormal fluid handling leads to physiologic abnormalities in multiple organ systems. Deranged hemodynamics, neurohormonal activation, excessive tubular sodium reabsorption, inflammation, oxidative stress, and nephrotoxic medications are important drivers of harmful cardiorenal interactions in patients with heart failure. Accurate quantitative measurement of fluid volume is vital to individualizing therapy for such patients. Blood volume analysis and pulmonary artery pressure monitoring seem the most reliable methods for assessing fluid volume and guiding decongestive therapies. Still the cornerstone of decongestive therapy, diuretics' effectiveness decreases with progression of heart failure. Extracorporeal ultrafiltration, an alternative to diuretics, has been shown to reduce heart-failure events., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Aims: In acute heart failure (AHF), changes of venous haemoglobin (Hb) concentrations, haematocrit (Hct), and estimated plasma volume (ePV) have been proposed as surrogates of decongestion. These estimates are based on the theoretical assumptions that changes of Hb concentrations and Hct are driven by the intravascular volume status and that the intravascular Hb pool remains stable. The objective of this study was to assess the relationship of changes of measured plasma volume (mPV) with changes of Hb, Hct, and ePV in AHF., Methods and Results: We studied 36 AHF patients, who received two sequential assessments of mPV, measured red cell volume (mRCV) and measured total blood volume (mTBV) (48 h apart), during the course of diuretic therapy using a novel visible fluorescent injectate (VFI) technique based on the indicator dilution principle. Changes of ePV were calculated based on the Kaplan-Hakim or Strauss formula. AHF patients receiving diuretics (median intravenous furosemide equivalent 160 mg/48 h) displayed a wide range of changes of mPV (-25.4% to +37.0%). Changes in mPV were not significantly correlated with changes of Hb concentration [Pearson's r (r) = -0.241, P = 0.157], Hct (r = -0.307, P = 0.069), ePV Kaplan-Hakim (r = 0.228, P = 0.182), or ePV Strauss (r = 0.237, P = 0.163). In contrast to theoretical assumptions, changes of mTBV were poorly correlated with changes of Hb concentrations and some patients displayed unanticipated variability of mRCV, suggesting an unstable intravascular red cell pool., Conclusions: Changes of Hb or Hct were not reflective of directly measured changes of intravascular volume status in AHF patients. Basing clinical assessment of decongestion on changes of Hb or Hct may misguide clinical decision-making on an individual patient level., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: The aim of this study is to quantify healthcare resource utilization among non-responders to cardiac resynchronization therapy (CRT-NR) by heart failure (HF) events and influence of comorbidities., Methods and Results: The ADVANCE CRT registry (2013-2015) prospectively identified responders/CRT-NRs 6 months post-implant using the clinical composite score. Heart failure event rates and associated cost, both overall and separated for inpatient hospitalizations, office visits, emergency room visits, and observational stays, were quantified. Costs of events were imputed from payments for similar real-world encounters in subjects with CRT-D/P devices in the MarketScan™ commercial and Medicare Supplemental insurance claims databases. Effects of patient demographics and comorbidities on event rates and cost were evaluated. Of 879 US patients (age 69 ± 11 years, 29% female, ischaemic disease 52%), 310 (35%) were CRT-NR. Among CRT-NRs vs. responders, more patients developed HF (41% vs. 11%, P < 0.001), HF event rate was higher (67.0 ± 21.7 vs. 11.4 ± 3.7/100 pt-year, P < 0.001), and HF readmission within 30 days was more common [hazard ratio 7.06, 95% confidence interval (2.1-43.7)]. Inpatient hospitalization was the most common and most expensive event type in CRT-NR. Comorbid HF was increased by diabetes, hypertension, and pulmonary disorders. Over 2 years, compared to CRT responders, each CRT-NR resulted in excess cost of $6388 ($3859-$10 483) to Medicare (P = 0.015) or $10 197 ($6161-$17 394) to private insurances (P = 0.014)., Conclusion: Healthcare expenditures associated with contemporary CRT non-response management are among the highest for any HF patient group. This illustrates an unmet need for interventions to improve HF outcomes and reduce costs among some CRT recipients., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Background: Previous studies have suggested that haemodynamic-guided management using an implantable pulmonary artery pressure monitor reduces heart failure hospitalisations in patients with moderately symptomatic (New York Heart Association [NYHA] functional class III) chronic heart failure and a hospitalisation in the past year, irrespective of ejection fraction. It is unclear if these benefits extend to patients with mild (NYHA functional class II) or severe (NYHA functional class IV) symptoms of heart failure or to patients with elevated natriuretic peptides without a recent heart failure hospitalisation. This trial was designed to evaluate whether haemodynamic-guided management using remote pulmonary artery pressure monitoring could reduce heart failure events and mortality in patients with heart failure across the spectrum of symptom severity (NYHA funational class II-IV), including those with elevated natriuretic peptides but without a recent heart failure hospitalisation., Methods: The randomised arm of the haemodynamic-GUIDEed management of Heart Failure (GUIDE-HF) trial was a multicentre, single-blind study at 118 centres in the USA and Canada. Following successful implantation of a pulmonary artery pressure monitor, patients with all ejection fractions, NYHA functional class II-IV chronic heart failure, and either a recent heart failure hospitalisation or elevated natriuretic peptides (based on a-priori thresholds) were randomly assigned (1:1) to either haemodynamic-guided heart failure management based on pulmonary artery pressure or a usual care control group. Patients were masked to their study group assignment. Investigators were aware of treatment assignment but did not have access to pulmonary artery pressure data for control patients. The primary endpoint was a composite of all-cause mortality and total heart failure events (heart failure hospitalisations and urgent heart failure hospital visits) at 12 months assessed in all randomly assigned patients. Safety was assessed in all patients. A pre-COVID-19 impact analysis for the primary and secondary outcomes was prespecified. This study is registered with ClinicalTrials.gov, NCT03387813., Findings: Between March 15, 2018, and Dec 20, 2019, 1022 patients were enrolled, with 1000 patients implanted successfully, and follow-up was completed on Jan 8, 2021. There were 253 primary endpoint events (0·563 per patient-year) among 497 patients in the haemodynamic-guided management group (treatment group) and 289 (0·640 per patient-year) in 503 patients in the control group (hazard ratio [HR] 0·88, 95% CI 0·74-1·05; p=0·16). A prespecified COVID-19 sensitivity analysis using a time-dependent variable to compare events before COVID-19 and during the pandemic suggested a treatment interaction (p interaction =0·11) due to a change in the primary endpoint event rate during the pandemic phase of the trial, warranting a pre-COVID-19 impact analysis. In the pre-COVID-19 impact analysis, there were 177 primary events (0·553 per patient-year) in the intervention group and 224 events (0·682 per patient-year) in the control group (HR 0·81, 95% CI 0·66-1·00; p=0·049). This difference in primary events almost disappeared during COVID-19, with a 21% decrease in the control group (0·536 per patient-year) relative to pre-COVID-19, virtually no change in the treatment group (0·597 per patient-year), and no difference between groups (HR 1·11, 95% CI 0·80-1·55; p=0·53). The cumulative incidence of heart failure events was not reduced by haemodynamic-guided management (0·85, 0·70-1·03; p=0·096) in the overall study analysis but was significantly decreased in the pre-COVID-19 impact analysis (0·76, 0·61-0·95; p=0·014). 1014 (99%) of 1022 patients had freedom from device or system-related complications., Interpretation: Haemodynamic-guided management of heart failure did not result in a lower composite endpoint rate of mortality and total heart failure events compared with the control group in the overall study analysis. However, a pre-COVID-19 impact analysis indicated a possible benefit of haemodynamic-guided management on the primary outcome in the pre-COVID-19 period, primarily driven by a lower heart failure hospitalisation rate compared with the control group., Funding: Abbott., Competing Interests: Declaration of interests JL has received research grants from AstraZeneca, Sensible Medical, and Volumetrix and is a consultant for Abbott, Alleviant Medical, AstraZeneca, Boehringer Ingelheim, Boston Scientific, CVRx, Edwards, Impulse Dynamics, and VWave. ASD has received research grants from Alnylam, AstraZeneca, Bayer, and Novartis, is a consultant for Abbott and Alnylam, AstraZeneca, Amgen, Biofourmis, Boston Scientific, Boehringer Ingelheim, Cytokinetics, DalCor Pharma, Lexicon, Merck, Novartis, Relypsa, and Regeneron, and has received personal fees from Lupin Pharma and Sun Pharma. KB is a consultant for Abbott and has received personal fees from Pfizer and Novartis. DH is a consultant for Abbott, has received personal fees from Abbott, and has served on advisory boards for Abbott. SRK is a consultant for Abbott and CareDx and has received personal fees from Abbott and CareDx. MRM is a consultant for Abbott, Medtronic, Janssen, Portola, Bayer, Triple Gene, and Baim Institute for Clinical Research, has served on advisory boards for Abbott and Mesoblast, has served on the Clinical Events Committee for GUIDE-HF through the Baim Institute for Clinical Research, and has stock in NuPulseCV, Leviticus, and FineHeart. SFS has received research grants from Medtronic and Zoll, is a consultant for Abbott, Medtronic, and Milestone Pharmaceuticals, and has received personal fees from Medtronic and Zoll. AJS is a consultant for Abbott and has received personal fees from Abbott. FS has received research grants from Amgen and is a consultant for Abbott. MRZ, AD, AM, SP, and MRC are consultants for Abbott. NJ, PS, GG, JH, and PBA are employees of Abbott. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)