Search

Heart failure (HF) and moderate-to-severe mitral regurgitation (MR) with residual elevations in left atrial pressure (LAP) after MitraClip may remain symptomatic and experience subsequent HF readmissions. The V-Wave interatrial shunt system is a permanent interatrial septal implant that shunts blood from the left-to-right atrium and serves to continuously unload the left atrium. Although the V-Wave shunt has previously been studied in patients with HF, the safety and feasibility of its deployment at the time of the MitraClip procedure is unknown. The V-Wave Shunt MitraClip Study (NCT04729933) is an early feasibility study that aims to demonstrate the safety and efficacy of implantation of the V-Wave shunt device at the time of MitraClip procedure. Patients with moderate-to-severe secondary MR with left ventricular ejection fraction 20% to 50% and New York Heart Association functional class III/IV symptoms despite optimal medical therapy, residual mean LAP ≥20 mm Hg after MitraClip, and mean LAP-right atrial pressure difference ≥5 mm Hg are included. The primary safety end point is a composite outcome of all-cause death, stroke, myocardial infarction device embolization, cardiac tamponade, or device-related re-intervention or surgery at 30 days. Patients will be followed up to 5 years. Enrollment is ongoing, with 30-day results expected by the end of 2024. The V-Wave Shunt Mitraclip Study aims to demonstrate the safety and efficacy of the implantation of the V-Wave interatrial shunt device at the time of index MitraClip placement which may serve as an adjunctive method by which continuous left atrial unloading may be achieved., Competing Interests: Declaration of competing interest Dr. Abraham is the Chief Medical Officer of V-Wave Ltd. The remaining authors have no competing interests to declare., (Copyright © 2024. Published by Elsevier Inc.)

Background: Data on the benefits of cardiac resynchronization therapy (CRT) in patients with severe heart failure symptoms are limited. We investigated the relative effects of CRT in patients with ambulatory New York Heart Association (NYHA) IV versus III functional class at the time of device implantation., Methods and Results: In this meta-analysis, we pooled patient-level data from the MIRACLE (Multicenter InSync Randomized Clinical Evaluation), MIRACLE-ICD (Multicenter InSync Implantable Cardioversion Defibrillation Randomized Clinical Evaluation), and COMPANION (Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure) trials. Outcomes evaluated were time to the composite end point of the first heart failure hospitalization or all-cause mortality, and time to all-cause mortality alone. The association between CRT and outcomes was evaluated using a Bayesian hierarchical Weibull survival regression model. We assessed if this association differed between NYHA III and IV groups by adding an interaction term between CRT and NYHA class as a random effect. A sensitivity analysis was performed by including data from RAFT (Resynchronization-Defibrillation for Ambulatory Heart Failure). Our pooled analysis included 2309 patients. Overall, CRT was associated with a longer time to heart failure hospitalization or all-cause mortality (adjusted hazard ratio [aHR], 0.79 [95% credible interval [CI], 0.64-0.99]; posterior probability or P =0.044), with a similar association with time to all-cause mortality (aHR, 0.78 [95% CI, 0.59-1.03]; P =0.083). Associations of CRT with outcomes were not significantly different for those in NYHA III and IV classes (ratio of aHR, 0.72 [95% CI, 0.30-1.27]; P =0.23 for heart failure hospitalization/mortality; ratio of aHR, 0.70 [95% CI, 0.35-1.34]; P =0.27 for all-cause mortality alone). The sensitivity analysis, including RAFT data, did not show a significant relative CRT benefit between NYHA III and IV classes., Conclusions: Overall, there was no significant difference in the association of CRT with either outcome for patients in NYHA functional class III compared with functional class IV.

Clinical trials are vital for assessing therapeutic interventions. The associated data monitoring committees (DMCs) safeguard patient interests and enhance trial integrity, thus promoting timely, reliable evaluations of those interventions. We face an urgent need to recruit and train new DMC members. The HFC (Heart Failure Collaboratory), a multidisciplinary public-private consortium of academics, trialists, patients, industry representatives, and government agencies, is working to improve the clinical trial ecosystem. The HFC aims to improve clinical trial efficiency and quality by standardizing concepts, and to help meet the demand for experienced individuals on DMCs by creating a standardized approach to training new members. This paper discusses the HFC's training workshop, and an apprenticeship model for new DMC members. It describes opportunities and challenges DMCs face, along with common myths and best practices learned through previous experiences, with an emphasis on data confidentiality and need for quality independent statistical reporting groups., Competing Interests: Funding Support and Author Disclosures Dr Fleming has received consulting fees from the National Institutes of Health, the World Health Organization, the Food and Drug Administration, and the pharmaceutical and biotech industry in the design, monitoring, and analysis of clinical trials; and he has received fees for serving on several industry-sponsored Data Monitoring Committees (DMCs). Dr Wittes has received compensation for her membership on several DMCs sponsored by industry, government, and not-for-profit organizations; and has received consulting fees from a variety of pharmaceutical and medical device companies. Dr Bristow is the President/CEO/Director at ARCA biopharma. Dr Rockhold has received consulting fees from Intercept, Clover, and Inventprise; has received compensation for serving on several industry-sponsored DMCs; and holds stock in Clover, GSK, Athira, Spence, Adaptic, and Doctor Evidence. Dr Claggett has received consulting fees from Alnylam, Axon, Cardior, Cardurion, CVRx, Cytokinetics, Intellia, and Rocket. Dr Abraham has received consulting fees from Boehringer Ingelheim, Cardionomic, Zoll Respicardia, scPharmaceuticals, Sensible Medical, and Vectorious; has received salary support from V-Wave Medical; and has served as a speaker for Edwards Lifesciences. Dr Lindenfeld has received consulting fees from Abbott, ADI, Alleviant, Amgen, AstraZeneca, Axon, Boston Scientific, Cordio, CVRx, Cytokinetics, Edwards Lifesciences, Medtronic, Merck, VWave, Vascular Dynamics, Vectorious, and Whiteswell; and has received grants from Analog Devices Inc, AstraZeneca, and Volumetrix. Dr DeMets has received consulting fees from the National Institutes of Health, the U.S. Food and Drug Administration, and the pharmaceutical and medical device industry on the design, monitoring, and analysis of clinical trials; and he has received compensation for serving on several recent industry-sponsored data and safety monitoring committees or steering committees including AstraZeneca, Bristol Meyers Squib, GSK, Merck, Boston Scientific, Medtronic, USONA, LivaNova, AnthosTherapy, ARCA biopharma, Duke Clinical Research Institute, and the Population Health Research Institute of Hamilton Ontario. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: Haemodynamic monitoring using implantable pressure sensors reduces the risk of heart failure (HF) hospitalizations. Patient self-management (PSM) of haemodynamics in HF has the potential to personalize treatment, increase adherence, and reduce the risk of worsening HF, while lowering clinicians' burden., Methods and Results: The VECTOR-HF I and IIa studies are prospective, single-arm, open-label clinical trials assessing safety, usability and performance of left atrial pressure (LAP)-guided HF management using PSM in New York Heart Association class II and III HF patients. Physician-prescribed LAP thresholds trigger patient self-adjustment of diuretics. Primary endpoints include the ability to perform LAP measurements and transmit data to the healthcare provider (HCP) interface and the patient guidance application, and safety outcomes. This is an interim analysis of 13 patients using the PSM approach. Over 12 months, no procedure- or device-related major adverse cardiovascular or neurological events were observed, and there were no failures to obtain measurements from the sensor and transmit the data to the HCP interface and the patient guidance application. Patient adherence was 91.4%. Using PSM, annualized HF hospitalization rate significantly decreased compared to a similar period prior to PSM utilization (0 admissions vs. 0.69 admissions over 11.84 months, p = 0.004). At 6 months, 6-min walk test distance and the Kansas City Cardiomyopathy Questionnaire overall summary score demonstrated significant improvement., Conclusions: Interim findings suggest that PSM using a LAP monitoring system is feasible and safe. PSM is associated with high patient adherence, potentially improving HF patients' functional status, quality of life, and limiting HF hospitalizations., (© 2024 The Author(s). European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Inadequate inclusion in clinical trial enrollment may contribute to health inequities by evaluating interventions in cohorts that do not fully represent target populations., Objectives: The aim of this study was to determine if characteristics of patients with heart failure (HF) enrolled in a pivotal trial are associated with who receives an intervention after approval., Methods: Demographics from 2,017,107 Medicare patients hospitalized for HF were compared with those of the first 10,631 Medicare beneficiaries who received implantable pulmonary artery pressure sensors. Characteristics of the population studied in the pivotal CHAMPION (CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in NYHA Class III Heart Failure Patients) clinical trial (n = 550) were compared with those of both groups. All demographic data were analyzed nationally and in 4 U.S. regions., Results: The Medicare HF cohort included 80.9% White, 13.3% African American, 1.9% Hispanic, 1.3% Asian, and 51.5% female patients. Medicare patients <65 years of age were more likely to be African American (33%) and male (58%), whereas older patients were mostly White (84%) and female (53%). Forty-one percent of U.S. HF hospitalizations occurred in the South; demographic characteristics varied significantly across all U.S. regions. The CHAMPION trial adequately represented African Americans (23% overall, 35% <65 years of age), Hispanic Americans (2%), and Asian Americans (1%) but underrepresented women (27%). The trial's population characteristics were similar to those of the first patients who received pulmonary artery sensors (82% White, 13% African American, 1% Asian, 1% Hispanic, and 29% female)., Conclusions: Demographics of Centers for Medicare and Medicaid Services beneficiaries hospitalized with HF vary regionally and by age, which should be considered when defining "adequate" representation in clinical studies. Enrollment diversity in clinical trials may affect who receives early application of recently approved innovations., Competing Interests: Funding Support and Author Disclosures Abbott provided resources for access and analyses of CMS claims data and demographic information from the CHAMPION trial. Dr Adamson is an employee of Abbott. Dr Echols is a consultant to Abbott. Dr DeFilippis serves on a clinical trial committee for Abiomed. Dr Morris has received research funding from the Agency for Healthcare Research and Quality (HS026081), the American Heart Association, Google, and Merck; and has received consulting fees from Abbott, Acorai, Boehringer Ingelheim, Eli Lilly, Cytokinetics, Edwards Lifesciences, Ionis, Merck, and Regeneron. Dr Bennett has received consulting fees and speaker honoraria from Abbott. Dr Abraham has received consulting fees from Abbott Vascular, AquaPass, Boehringer Ingelheim, Impulse Dynamics, Sensible Medical Innovations, V-Wave, and Zoll Respicardia. Dr Lindenfeld has received consulting and/or research support from Abbott, AstraZeneca, Boehringer Ingelheim, Boston Scientific, CVRx, Edwards Lifesciences, Impulse Dynamics, Merck, Medtronic, V-Wave, Vifor, and Volumetrix. Dr Teerlink has received research support from 3ive Labs, AstraZeneca, Bayer, Boehringer Ingelheim, Cardurion, Cytokinetics, EBR Systems, Edwards Lifesciences, Impulse Dynamics, Kaiser Permanente, LivaNova, Medtronic, Myovant Sciences, the Patient-Centered Outcomes Research Institute, RECARDIO, and V-Wave; and is a consultant for 3ive Labs, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardurion, CorHepta, Cytokinetics, Daiichi-Sankyo, EBR Systems, Edwards Lifesciences, Eli Lilly Impulse Dynamics, JuvLabs, Kaiser Permanente, LivaNova, Medtronic, Myovant Sciences, Novartis, the Patient-Centered Outcomes Research Institute, Pfizer, ReCor Medical, Regeneron, Reprieve, Tectonic, V-Wave, Verily, ViCardia, and Windtree Therapeutics. Dr O’Connor has received research funding from Merck; and has received consulting fees from Bayer and Dey. Dr Connolly is an employee of Abbott. Dr Li is an employee of Abbott. Dr. Vaduganathan has received research grant support from, served on advisory boards for, or has had speaker engagements with American Regent, Amgen, AstraZeneca, Bayer, Baxter Healthcare, Boehringer Ingelheim, Bristol Myers Squibb, Chiesi, Cytokinetics, Lexicon Pharmaceuticals, Merck, Novartis, Novo Nordisk, Pharmacosmos, Relypsa, Roche Diagnostics, Sanofi, and Tricog Health; and has participated on clinical trial committees for studies sponsored by AstraZeneca, Galmed, Novartis, Bayer, Occlutech, and Impulse Dynamics. Dr Batchelor has received consulting fees from Boston Scientific, Medtronic, Edwards Lifesciences, V-Wave, Chiesi, Abbott, and Idorsia; and has received research support from Abbott and Boston Scientific. Dr McCants has received consulting fees and speaker honoraria from Abbott. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Aim: The RESHAPE-HF2 trial is designed to assess the efficacy and safety of the MitraClip device system for the treatment of clinically important functional mitral regurgitation (FMR) in patients with heart failure (HF). This report describes the baseline characteristics of patients enrolled in the RESHAPE-HF2 trial compared to those enrolled in the COAPT and MITRA-FR trials., Methods and Results: The RESHAPE-HF2 study is an investigator-initiated, prospective, randomized, multicentre trial including patients with symptomatic HF, a left ventricular ejection fraction (LVEF) between 20% and 50% with moderate-to-severe or severe FMR, for whom isolated mitral valve surgery was not recommended. Patients were randomized 1:1 to a strategy of delivering or withholding MitraClip. Of 506 patients randomized, the mean age of the patients was 70 ± 10 years, and 99 of them (20%) were women. The median EuroSCORE II was 5.3 (2.8-9.0) and median plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) was 2745 (1407-5385) pg/ml. Most patients were prescribed beta-blockers (96%), diuretics (96%), angiotensin-converting enzyme inhibitors/angiotensin receptor blockers/angiotensin receptor-neprilysin inhibitors (82%) and mineralocorticoid receptor antagonists (82%). The use of sodium-glucose cotransporter 2 inhibitors was rare (7%). Cardiac resynchronization therapy (CRT) devices had been previously implanted in 29% of patients. Mean LVEF, left ventricular end-diastolic volume and effective regurgitant orifice area (EROA) were 31 ± 8%, 211 ± 76 ml and 0.25 ± 0.08 cm 2 , respectively, whereas 44% of patients had mitral regurgitation severity of grade 4+. Compared to patients enrolled in COAPT and MITRA-FR, those enrolled in RESHAPE-HF2 were less likely to have mitral regurgitation grade 4+ and, on average, HAD lower EROA, and plasma NT-proBNP and higher estimated glomerular filtration rate, but otherwise had similar age, comorbidities, CRT therapy and LVEF., Conclusion: Patients enrolled in RESHAPE-HF2 represent a third distinct population where MitraClip was tested in, that is one mainly comprising of patients with moderate-to-severe FMR instead of only severe FMR, as enrolled in the COAPT and MITRA-FR trials. The results of RESHAPE-HF2 will provide crucial insights regarding broader application of the transcatheter edge-to-edge repair procedure in clinical practice., (© 2024 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Women might benefit more than men from cardiac resynchronization therapy (CRT) and do so at shorter QRS durations., Objective: This meta-analysis was performed to determine whether sex-based differences in CRT effects are better accounted for by height, body surface area (BSA), or left ventricular end-diastolic dimension (LVEDD)., Methods: We analyzed patient-level data from CRT trials (MIRACLE, MIRACLE ICD, MIRACLE ICD II, REVERSE, RAFT, COMPANION, and MADIT-CRT) using bayesian hierarchical Weibull regression models. Relationships between QRS duration and CRT effects were examined overall and in sex-stratified cohorts; additional analyses indexed QRS duration by height, BSA, or LVEDD. End points were heart failure hospitalization (HFH) or death and all-cause mortality., Results: Compared with men (n = 5628), women (n = 1439) were shorter (1.62 [interquartile range, 1.57-1.65] m vs 1.75 [1.70-1.80] m; P < .001), with smaller BSAs (1.76 [1.62-1.90] m 2 vs 2.02 [1.89-2.16] m 2 ; P < .001). In adjusted sex-stratified analyses, the reduction in HFH or death was greater for women (hazard ratio, 0.54; credible interval, 0.42-0.70) than for men (hazard ratio, 0.77; credible interval, 0.66-0.89; P interaction = .009); results were similar for all-cause mortality even after adjustment for height, BSA, and LVEDD. Sex-specific differences were observed only in nonischemic cardiomyopathy. The effect of CRT on HFH or death was observed at a shorter QRS duration for women (126 ms) than for men (145 ms). Indexing QRS duration by height, BSA, or LVEDD attenuated sex-specific QRS duration thresholds for the effects of CRT on HFH or death but not on mortality., Conclusion: Although body size partially explains sex-specific QRS duration thresholds for CRT benefit, it is not associated with the magnitude of CRT benefit. Indexing QRS duration for body size might improve selection of patients for CRT, particularly with a "borderline" QRS duration., (Copyright © 2024. Published by Elsevier Inc.)

Aims: Heart failure (HF) outcomes remain poor despite optimal guideline-directed medical therapy (GDMT). We assessed safety, effectiveness, and transthoracic echocardiographic (TTE) outcomes during the 12 months after Ventura shunt implantation in the RELIEVE-HF open-label roll-in cohort., Methods and Results: Eligibility required symptomatic HF despite optimal GDMT with ≥1 HF hospitalization in the prior year or elevated natriuretic peptides. The safety endpoint was device-related major adverse cardiovascular or neurological events at 30 days, compared to a prespecified performance goal. Effectiveness evaluations included the Kansas City Cardiomyopathy Questionnaire (KCCQ) at baseline, 1, 3, 6, and 12 months and TTE at baseline and 12 months. Overall, 97 patients were enrolled and implanted at 64 sites. Average age was 70 ± 11 years, 97% were in New York Heart Association class III, and half had left ventricular ejection fraction (LVEF) ≤40%. The safety endpoint was achieved (event rate 0%, p < 0.001). KCCQ overall summary score was improved by 12-16 points at all follow-up timepoints (all p < 0.004), with similar outcomes in patients with reduced and preserved LVEF. At 12 months, left ventricular end-systolic and end-diastolic volumes were reduced (p = 0.020 and p = 0.038, respectively), LVEF improved (p = 0.009), right ventricular end-systolic and end-diastolic areas were reduced (p = 0.001 and p = 0.030, respectively), and right ventricular fractional area change (p < 0.001) and tricuspid annular plane systolic excursion (p < 0.001) improved., Conclusion: Interatrial shunting with the Ventura device was safe and resulted in favourable clinical effects in patients with HF, regardless of LVEF. Improvements of left and right ventricular structure and function were consistent with reverse myocardial remodelling. These results would support the potential of this shunt device as a treatment for HF., (© 2024 European Society of Cardiology.)

Aims: Carotid baroreflex activation therapy (BAT) restores baroreflex sensitivity and modulates the imbalance in cardiac autonomic function in patients with heart failure with reduced ejection fraction (HFrEF). We tested the hypothesis that treatment with BAT significantly reduces cardiovascular mortality and heart failure morbidity and provides long-term safety and sustainable symptomatic improvement., Methods and Results: BeAT-HF was a prospective, multicentre, randomized, two-arm, parallel-group, open-label, non-implanted control trial. New York Heart Association (NYHA) class III subjects, ejection fraction ≤35%, previous heart failure hospitalization or N-terminal pro-B-type natriuretic peptide (NT-proBNP) >400 pg/ml, no class I indication for cardiac resynchronization therapy and NT-proBNP <1600 pg/ml were randomized to BAT plus optimal medical management (BAT group) or optimal medical management alone (control). The primary endpoint was cardiovascular mortality and HF morbidity; additional pre-specified endpoints included durability of safety, quality of life (QOL), exercise capacity (6-min hall walk distance [6MHWD]), functional status (NYHA class), hierarchical composite win ratio, freedom from all-cause death, left ventricular assists device (LVAD) implantation, heart transplant. Overall, 323 patients had 332 primary events, median follow-up was 3.6 years/patient. Both primary endpoint (rate ratio 0.94, 95% confidence interval [CI] 0.57-1.57; p = 0.82) and components of the primary endpoints were not significantly different between BAT and control. The system- and procedure-related major adverse neurological and cardiovascular event-free rate remained 97% throughout the trial. Symptom improvement (QOL, 6MHWD, NYHA class, all nominal p < 0.001) in the BAT group was durable in time, sustainable in extent. Win ratio (1.26, 95% CI 1.02-1.58) and freedom from all-cause death, LVAD implantation, heart transplant (hazard ratio 0.66, 95% CI 0.43-1.01) favoured the BAT group but did not reach statistical significance., Conclusion: The BeAT-HF primary endpoint was neutral; however, BAT provided safe, effective, and sustainable improvements in HFrEF patient's functional status, 6MHWD and QOL., (© 2024 CVRx and The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Patients with heart failure usually have several other medical conditions that might alter the effects of interventions. We investigated whether the burden of comorbidity modified the clinical response to cardiac resynchronization therapy (CRT)., Methods and Results: Original patient-level data from eight randomized trials exploring the effects of CRT versus no CRT were pooled (BLOCK-HF, MIRACLE, MIRACLE-ICD, MIRACLE-ICD II, RAFT, COMPANION, MADIT-CRT and REVERSE). A prior history of the following comorbidities was considered: episodic or persistent atrial fibrillation (n = 920), coronary artery disease (n = 3732), diabetes (n = 2171), and hypertension (n = 3353). Patients were classified into three groups based on the number of comorbidities: 0, 1-2, or ≥3. The outcomes of interest were time to all-cause mortality and time to the composite outcome of heart failure hospitalization (HFH) or all-cause mortality. Outcomes were evaluated within each comorbidity group using a Bayesian hierarchical Weibull survival regression model. Of 6324 patients, 970 (15%) had no comorbidities, 4052 (64%) had 1-2 and 1302 (21%) had ≥3 comorbidities. The adjusted hazard ratio (aHR) for CRT versus no CRT for all-cause mortality in the overall cohort was 0.79 (95% credible interval [CI] 0.68-0.93) (p = 0.010); for no comorbidities the aHR was 0.54 (95% CI 0.34-0.86), for 1-2 comorbidities was 0.81 (95% CI 0.67-0.97) and for ≥3 comorbidities was 0.83 (95% CI 0.64-1.07) (no significant interaction between CRT and comorbidity burden: p = 0.13). For the endpoint of HFH or all-cause mortality, the aHR for the overall cohort was 0.74 (95% CI 0.65-0.84) (p = 0.001), for no comorbidities was 0.69 (95% CI 0.50-0.94), for 1-2 comorbidities was 0.77 (95% CI 0.66-0.90) and for ≥3 comorbidities was 0.68 (95% CI 0.55-0.82) (no significant interaction between CRT and comorbidity burden: p = 0.081)., Conclusion: In a meta-analysis of patient-level data from eight major trials, the totality of evidence suggests that CRT reduces HFH and/or all-cause mortality even when several comorbid diseases are present., Clinical Trial Registration: NCT00271154, NCT00251251, NCT00267098, NCT00180271., (© 2023 European Society of Cardiology.)

Heart failure (HF) is a complex syndrome traditionally classified by left ventricular ejection fraction (LVEF) cutpoints. Although LVEF is prognostic for risk of events and predictive of response to some HF therapies, LVEF is a continuous variable and cutpoints are arbitrary, often based on historical clinical trial enrichment decisions rather than physiology. Holistic evaluation of the treatment effects for therapies throughout the LVEF range suggests the standard categorization paradigm for HF merits modification. The multidisciplinary Heart Failure Collaboratory reviewed data from large-scale HF clinical trials and found that many HF therapies have demonstrated therapeutic benefit across a large range of LVEF, but specific treatment effects vary across that range. Therefore, HF should practically be classified by association with an LVEF that is reduced or not reduced, while acknowledging uncertainty around the precise LVEF cutpoint, and future research should evaluate new therapies across the continuum of LVEF., Competing Interests: Funding Support and Author Disclosures Dr Ibrahim has received consulting fees from Cytokinetics. Dr McMurray discloses payments to his employer, Glasgow University, for his work on clinical trials, consulting, and other activities: Alnylam, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Cardurion, Cytokinetics, Dal-Cor, GlaxoSmithKline, Ionis, KBP Biosciences, Novartis, Pfizer, and Theracos; and personal payments: Abbott, Alkem Metabolics, Eris Lifesciences, Hikma, Ionis, Lupin, ProAdWise Communications, Sun Pharmaceuticals, and Servier. Dr Lindenfeld has received consulting fees from Abbott, Alleviant, Boston Scientific, Cordio, CRVx, Edwards Lifesciences, Medtronic, Merck, Whiteswell, Vascular Dynamics, and V-Wave. 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 Bristow has served as a director, officer, partner, advisor, consultant, or trustee for ARCA biopharma; has received research grants from the American Heart Association and National Institute of Allergy and Infectious Diseases; and has received personal payments from ARCA biopharma. Dr Butler has received consulting fees from Boehringer Ingelheim, Cardior, CVRx, Foundry, G3 Pharma, Imbria, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Relypsa, Roche, Sanofi, Sequana Medical, V-Wave Ltd, and Vifor; and is a Trial Executive Committee member of the Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance (trial sponsor). Dr Carson has received consulting fees from Boehringer Ingelheim and IQVIA related to work on Clinical Events Committees. Dr Felker has received research grants from the National Heart, Lung, and Blood Institute, 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 Therapuetics, 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 Murillo is an employee and stockholder of UnitedHealth Group. Dr Kondo has received grants from the Uehara Memorial Foundation and the Japanese Heart Failure Society Tsuchiya Foundation for research activity at the University of Glasgow; and has received lecture fees from Ono Pharmaceutical Co, Ltd, Otsuka Pharmaceutical Co, Ltd, Novartis Pharma K.K., AstraZeneca K.K., Bristol Myers Squibb Co, Abiomed Japan K.K., and Boehringer Ingelheim. Dr Solomon has received research grants from Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, BMS, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lone Star Heart, Mesoblast, MyoKardia, National Institutes of Health/National Heart, Lung and Blood Institute, Novartis, Sanofi Pasteur, and Theracos; and has consulted for Akros, Alnylam, Amgen, AstraZeneca, Bayer, BMS, Cardior, Corvia, Cytokinetics, Gilead, GlaxoSmithKline, Ironwood, Merck, MyoKardia, Novartis, Roche, Takeda, Theracos, Quantum Genetics, Cardurion, AoBiome, Janssen, Cardiac Dimensions, and Tenaya. Dr Abraham has received consulting fees from Boehringer Ingelheim, Cardionomic, Zoll Respicardia, scPharmaceuticals, Sensible Medical, and Vectorious; has received 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., (Published by Elsevier Inc.)

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.)

Background: The Breakthrough Devices Program of the US Food and Drug Administration has accelerated the development and evaluation of medical devices for patients with heart failure. One such device is the Optimizer Smart System, which the US Food and Drug Administration approved in 2019., Methods and Results: The Optimizer device was evaluated in a pivotal randomized clinical trial (FIX-HF-5C [Confirmatory Randomized Trial Evaluating the Optimizer System]) that leveraged Bayesian borrowing of external data to reduce the sample size and determine therapeutic device benefit versus continued medical therapy. Bayesian borrowing is explained in the context of the FIX-HF-5C trial, including an overview of the statistical methodologies, regulatory considerations, and interpretations of trial results., Conclusions: The US Food and Drug Administration Breakthrough Devices Program and novel Bayesian statistical methodology accelerated the path to regulatory approval and patient access to a potentially lifesaving device and may serve as a model for future clinical trials.

Despite remarkable improvements in the management of heart failure (HF), HF remains one of the most rapidly growing cardiovascular condition resulting in a substantial burden on healthcare systems worldwide. In clinical practice, however, a relevant proportion of patients are treated with suboptimal combinations and doses lower than those recommended in the current guidelines. Against this background, it remains important to identify new targets and investigate additional therapeutic options to alleviate symptoms and potentially improve prognosis in HF. Therefore, non-pharmacological interventions targeting autonomic imbalance in HF have been evaluated. This paper aims to review the physiology, available clinical data, and potential therapeutic role of device-based neuromodulation in HF., (© 2024 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Introduction: Cardiac implantable electrical devices are able to affect kidney function through hemodynamic improvements. The cardiac contractility modulation (CCM) is a device-based therapy option for patients with symptomatic chronic heart failure (HF) despite optimized medical treatment. The long-term cardiorenal interactions for CCM treated patients are yet to be described., Methods: CCM recipients (n = 187) from the Mannheim Cardiac Contractility Modulation Observational Study (MAINTAINED) were evaluated in the long-term (up to 60 months) for changes in serum creatinine, estimated glomerular filtration rate (eGFR), other surrogate markers of kidney function, and the chronic kidney disease (CKD) stage distribution. With regard to kidney function at baseline, the patients were furthermore grouped to either advanced CKD (aCKD, CKD stage ≥3, eGFR≤59 mL/min/1.73 m2, n = 107) or preserved kidney function and mild CKD (pCKD, CKD stages 1-2, eGFR≥60 mL/min/1.73 m2, n = 80). The groups were compared for differences regarding kidney function, New York Heart Association classification (NYHA), biventricular systolic function, HF hospitalizations and other parameters in the long-term (60 months)., Results: CKD stage distribution remained stable during the entire follow-up (p = 0.65). An increase in serum creatinine (1.47 ± 1 vs. 1.6±1 mg/dL) with a corresponding decline of eGFR (58.2 ± 23.4 vs. 54.2 ± 24.4 mL/min/1.73 m2, both p &lt; 0.05) were seen after 60 months but not before for the total cohort, which was only significant in pCKD patients in terms of group comparison. Mean survival (54.3 ± 1.3 vs. 55.3 ± 1.2 months, p = 0.53) was comparable in both groups. Improvements in NYHA (3.11 ± 0.46 vs. 2.94 ± 0.41-2.28 ± 0.8 vs. 1.94 ± 0.6) and LVEF (24.8 ± 7.1 vs. 22.9 ± 6.6-31.1 ± 11.4 vs. 35.5 ± 11.1%) were likewise similar after 60 months (both p &lt; 0.05). The aCKD patients suffered from more HF hospitalizations and ventricular tachycardias during the entire follow-up period (both p &lt; 0.05)., Conclusions: The kidney function parameters and CKD stage distribution might remain stable in CCM treated HF patients in the long-term, who experience improvements in LVEF and functional status, regardless of their kidney function before. An impaired kidney function might be associated with further cardiovascular comorbidities and more advanced HF before CCM, and could be an additional risk factor of HF complications afterward., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Background: Cardiac resynchronization therapy (CRT) reduces heart failure hospitalizations (HFH) and mortality for guideline-indicated patients with heart failure (HF). Most patients with HF are aged ≥70 years but such patients are often under-represented in randomized trials., Methods: Patient-level data were combined from 8 randomized trials published 2002-2013 comparing CRT to no CRT (n = 6,369). The effect of CRT was estimated using an adjusted Bayesian survival model. Using age as a categorical (<70 vs ≥70 years) or continuous variable, the interaction between age and CRT on the composite end point of HFH or all-cause mortality or all-cause mortality alone was assessed., Results: The median age was 67 years with 2436 (38%) being 70+; 1,554 (24%) were women; 2,586 (41%) had nonischemic cardiomyopathy and median QRS duration was 160 ms. Overall, CRT was associated with a delay in time to the composite end point (adjusted hazard ratio [aHR] 0.75, 95% credible interval [CI] 0.66-0.85, P = .002) and all-cause mortality alone (aHR of 0.80, 95% CI 0.69-0.96, P = .017). When age was treated as a categorical variable, there was no interaction between age and the effect of CRT for either end point (P > .1). When age was treated as a continuous variable, older patients appeared to obtain greater benefit with CRT for the composite end point (P for interaction = .027) with a similar but nonsignificant trend for mortality (P for interaction = .35)., Conclusion: Reductions in HFH and mortality with CRT are as great or greater in appropriately indicated older patients. Age should not be a limiting factor for the provision of CRT., (Copyright © 2023 Elsevier Inc. All rights reserved.)

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.)

Aim: Although education in self-management is thought to be an important aspect of the care of patients with heart failure, little is known about whether self-rated knowledge of self-management is associated with outcomes. The aim of this study was to assess the relationship between patient-reported knowledge of self-management and clinical outcomes in patients with heart failure and reduced ejection fraction (HFrEF)., Methods and Results: Using individual patient data from three recent clinical trials enrolling participants with HFrEF, we examined patient characteristics and clinical outcomes according to responses to the 'self-efficacy' questions of the Kansas City Cardiomyopathy Questionnaire. One question quantifies patients' understanding of how to prevent heart failure exacerbations ('prevention' question) and the other how to manage complications when they arise ('response' question). Self-reported answers from patients were pragmatically divided into: poor (do not understand at all, do not understand very well, somewhat understand), fair (mostly understand), and good (completely understand). Cox-proportional hazard models were used to evaluate time-to-first occurrence of each endpoint, and negative binomial regression analysis was performed to compare the composite of total (first and repeat) heart failure hospitalizations and cardiovascular death across the above-defined groups. Of patients (n = 17 629) completing the 'prevention' question, 4197 (23.8%), 6897 (39.1%), and 6535 (37.1%) patients had poor, fair, and good self-rated knowledge, respectively. Of those completing the 'response' question (n = 17 637), 4033 (22.9%), 5463 (31.0%), and 8141 (46.2%) patients had poor, fair, and good self-rated knowledge, respectively. For both questions, patients with 'poor' knowledge were older, more often female, and had a worse heart failure profile but similar treatment. The rates (95% confidence interval) per 100 person-years for the primary composite outcome for 'poor', 'moderate' and 'good' self-rated knowledge in answer to the 'prevention' question were 12.83 (12.11-13.60), 12.08 (11.53-12.65) and 11.55 (11.00-12.12), respectively, and for the 'response' question were 12.88 (12.13-13.67), 12.22 (11.60-12.86) and 11.56 (11.07-12.07), respectively. The lower event rates in patients with 'good' self-rate knowledge were accounted for by lower rates of cardiovascular (and all-cause) death and not hospitalization for worsening heart failure., Conclusions: Poor patient-reported 'self-efficacy' may be associated with higher rates of mortality. Evaluation of knowledge of 'self-efficacy' may provide prognostic information and a guide to which patients may benefit from further education about self-management., (© 2023 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Adjustment of treatment based on remote monitoring of pulmonary artery (PA) pressure may reduce the risk of hospital admission for heart failure (HF). We have conducted a meta-analysis of large randomized trials investigating this question., Methods and Results: A systematic literature search was performed for randomized clinical trials with PA pressure monitoring devices in patients with HF. The primary outcome of interest was the total number of HF hospitalizations. Other outcomes assessed were urgent visits leading to treatment with intravenous diuretics, all-cause mortality, and composites. Treatment effects are expressed as hazard ratios, and pooled effect estimates were obtained applying random effects meta-analyses. Three eligible randomized clinical trials were identified that included 1898 outpatients in New York Heart Association functional classes II-IV, either hospitalized for HF in the prior 12 months or with elevated plasma NT-proBNP concentrations. The mean follow-up was 14.7 months, 67.8% of the patients were men, and 65.8% had an ejection fraction ≤40%. Compared to patients in the control group, the hazard ratio (95% confidence interval) for total HF hospitalizations in those randomized to PA pressure monitoring was 0.70 (0.58-0.86) (P = .0005). The corresponding hazard ratio for the composite of total HF hospitalizations, urgent visits and all-cause mortality was 0.75 (0.61-0.91; P = .0037) and for all-cause mortality 0.92 (0.73-1.16). Subgroup analyses, including ejection fraction phenotype, revealed no evidence of heterogeneity in the treatment effect., Conclusion: The use of remote PA pressure monitoring to guide treatment of patients with HF reduces episodes of worsening HF and subsequent hospitalizations., Competing Interests: Conflict of interest P.R.D.C., S.P.R., E.B. report no conflict of interest to declare. R.A.d.B. has received research grants and/or fees from AstraZeneca, Abbott, Boehringer Ingelheim, Cardior Pharmaceuticals GmbH, Ionis Pharmaceuticals, Inc., Novo Nordisk, and Roche; and has had speaker engagements with Abbott, AstraZeneca, Bayer, Bristol Myers Squibb, Novartis, and Roche. J.G. has received consulting fees from Applied Therapeutics, Amarin, Boehringer-Ingelheim, Biosensors, Cardialysis, Edwards Lifesciences, MVRx and Whiteswell and reimbursement of travel expenses from Abbott. W.T.A. has received personal fees from Abbott, Boehringer-Ingelheim, Edwards Lifesciences, Impulse Dynamics, Sensible Medical, Vectorious Medical Technolgoies, V-Wave Medical, and Zoll Respicardia. P.S.J. received consulting fees, advisory board fees and lecture fees from Novartis; advisory board fees from Cytokinetics; and grant support from Boehringer Ingelheim. J.J.V.M.M. received payments through Glasgow University from work on clinical trials, consulting and other activities from Alnylam, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Cardurion, Cytokinetics, DalCor, GSK, KBP Biosciences, Novartis, Pfizer and Theracos, and personal payments from Abbott, Hikma, Ionis, Sun Pharmaceuticals and Servier. J.J.V.M.M. and P.S.J. are supported by a British Heart Foundation Centre of Research Excellence Grant (RE/18/6/34217). J.J.B. received independent research grant from Abbott for ISS and has had speaker engagement or advisory boards in the past 5 years with Astra Zeneca, Abbott, Boehringer-Ingelheim, Bayer, Daiichi Sankyo, Novartis and Vifor., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background Left ventricular (LV) global longitudinal strain (GLS) provides incremental prognostic information over LV ejection fraction in patients with heart failure (HF) and secondary mitral regurgitation. We examined the prognostic impact of LV GLS improvement in this population. Methods and Results The COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation) trial randomized symptomatic patients with HF with severe (3+/4+) mitral regurgitation to transcatheter edge-to-edge repair with the MitraClip device plus maximally tolerated guideline-directed medical therapy (GDMT) versus GDMT alone. LV GLS was measured at baseline and 6-month follow-up. The relationship between the improvement in LV GLS from baseline to 6 months and the composite of all-cause death or HF hospitalization between 6- and 24-month follow-up were assessed. Among 383 patients, 174 (45.4%) had improved LV GLS at 6-month follow-up (83/195 [42.6%] with transcatheter edge-to-edge repair+GDMT and 91/188 [48.4%] with GDMT alone; P =0.25). Improvement in LV GLS was strongly associated with reduced death or HF hospitalization between 6 and 24 months ( P <0.009), with similar risk reduction in both treatment arms ( P interaction =0.40). By multivariable analysis, LV GLS improvement at 6 months was independently associated with a lower risk of death or HF hospitalization (hazard ratio [HR], 0.55 [95% CI, 0.36-0.83]; P =0.009), death (HR, 0.48 [95% CI, 0.29-0.81]; P =0.006), and HF hospitalization (HR, 0.50 [95% CI, 0.31-0.81]; P =0.005) between 6 and 24 months. Conclusions Among patients with HF and severe mitral regurgitation in the COAPT trial, improvement in LV GLS at 6-month follow-up was associated with improved outcomes after both transcatheter edge-to-edge repair and GDMT alone between 6 and 24 months. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01626079.

Aims: To investigate the association of cardiac resynchronization therapy (CRT) on outcomes among participants with and without a history of atrial fibrillation (AF)., Methods: Individual-patient-data from four randomized trials investigating CRT-Defibrillators (COMPANION, MADIT-CRT, REVERSE) or CRT-Pacemakers (COMPANION, MIRACLE) were analyzed. Outcomes were time to a composite of heart failure hospitalization or all-cause mortality or to all-cause mortality alone. The association of CRT on outcomes for patients with and without a history of AF was assessed using a Bayesian-Weibull survival regression model adjusting for baseline characteristics., Results: Of 3964 patients included, 586 (14.8%) had a history of AF; 2245 (66%) were randomized to CRT. Overall, CRT reduced the risk of the primary composite endpoint (hazard ratio [HR]: 0.69, 95% credible interval [CI]: 0.56-0.81). The effect was similar (posterior probability of no interaction = 0.26) in patients with (HR: 0.78, 95% CI: 0.55-1.10) and without a history of AF (HR: 0.67, 95% CI: 0.55-0.80). In these four trials, CRT did not reduce mortality overall (HR: 0.82, 95% CI: 0.66-1.01) without evidence of interaction (posterior probability of no interaction = 0.14) for patients with (HR: 1.09, 95% CI: 0.70-1.74) or without a history of AF (HR: 0.70, 95% CI: 0.60-0.97)., Conclusion: The association of CRT on the composite endpoint or mortality was not statistically different for patients with or without a history of AF, but this could reflect inadequate power. Our results call for trials to confirm the benefit of CRT recipients with a history of AF., (© 2023 Wiley Periodicals LLC.)

Aim: Patients with heart failure (HF) often suffer from a range of comorbidities, which may affect their health status. The aim of this study was to assess the impact of different comorbidities on health status in patients with HF and reduced (HFrEF) and preserved ejection fraction (HFpEF)., Methods and Results: Using individual patient data from HFrEF (ATMOSPHERE, PARADIGM-HF, DAPA-HF) and HFpEF (TOPCAT, PARAGON-HF) trials, we examined the Kansas City Cardiomyopathy Questionnaire (KCCQ) domain scores and overall summary score (KCCQ-OSS) across a range of cardiorespiratory (angina, atrial fibrillation [AF], stroke, chronic obstructive pulmonary disease [COPD]) and other comorbidities (obesity, diabetes, chronic kidney disease [CKD], anaemia). Of patients with HFrEF (n = 20 159), 36.2% had AF, 33.9% CKD, 33.9% diabetes, 31.4% obesity, 25.5% angina, 12.2% COPD, 8.4% stroke, and 4.4% anaemia; the corresponding proportions in HFpEF (n = 6563) were: 54.0% AF, 48.7% CKD, 43.4% diabetes, 53.3% obesity, 28.6% angina, 14.7% COPD, 10.2% stroke, and 6.5% anaemia. HFpEF patients had lower KCCQ domain scores and KCCQ-OSS (67.8 vs. 71.3) than HFrEF patients. Physical limitations, social limitations and quality of life domains were reduced more than symptom frequency and symptom burden domains. In both HFrEF and HFpEF, COPD, angina, anaemia, and obesity were associated with the lowest scores. An increasing number of comorbidities was associated with decreasing scores (e.g. KCCQ-OSS 0 vs. ≥4 comorbidities: HFrEF 76.8 vs. 66.4; HFpEF 73.7 vs. 65.2)., Conclusions: Cardiac and non-cardiac comorbidities are common in both HFrEF and HFpEF patients and most are associated with reductions in health status although the impact varied among comorbidities, by the number of comorbidities, and by HF phenotype. Treating/correcting comorbidity is a therapeutic approach that may improve the health status of patients with HF., (© 2023 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Recent guidelines proposed a classification for heart failure (HF) on the basis of left ventricular ejection fraction (LVEF), although it remains unclear whether the divisions chosen were biologically rational. Using patients spanning the full range of LVEF, we examined whether there was evidence of LVEF thresholds in patient characteristics or inflection points in clinical outcomes., Methods: Using patient-level information, we created a merged dataset of 33 699 participants who had been enrolled in 6 randomized controlled HF trials including patients with reduced and preserved ejection fraction. The relationship between the incidence of all-cause death (and specific causes of death) and HF hospitalization, and LVEF, was evaluated using Poisson regression models., Results: As LVEF increased, age, the proportion of women, body mass index, systolic blood pressure, and prevalence of atrial fibrillation and diabetes increased, whereas ischemic pathogenesis, estimated glomerular filtration rate, and NT-proBNP (N-terminal pro-B-type natriuretic peptide) decreased. As LVEF increased >50%, age and the proportion of women continued to increase, and ischemic pathogenesis and NT-proBNP decreased, but other characteristics did not change meaningfully. The incidence of most clinical outcomes (except noncardiovascular death) decreased as LVEF increased, with a LVEF inflection point of around 50% for all-cause death and cardiovascular death, around 40% for pump failure death, and around 35% for HF hospitalization. Higher than those thresholds, there was little further decline in the incidence rate. There was no evidence of a J-shaped relationship between LVEF and death; no evidence of worse outcomes in patients with high-normal ("supranormal") LVEF. Similarly, in a subset of patients with echocardiographic data, there were no structural differences in patients with a high-normal LVEF suggestive of amyloidosis, and NT-proBNP levels were consistent with this conclusion., Conclusions: In patients with HF, there was a LVEF threshold of around 40% to 50% where the pattern of patient characteristics changed, and event rates began to increase compared with higher LVEF values. Our findings provide evidence to support current upper LVEF thresholds defining HF with mildly reduced ejection fraction on the basis of prognosis., Registration: URL: https://www., Clinicaltrials: gov; Unique identifiers: NCT00634309, NCT00634400, NCT00634712, NCT00095238, NCT01035255, NCT00094302, NCT00853658, and NCT01920711., Competing Interests: Disclosures T.K. received speaker fees from Abbott, Ono Pharma, Otsuka Pharma, Novartis, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, and Abiomed. I.S.A. reports receiving fees for serving on a steering committee from AstraZeneca, ARCA Biopharma, Amgen, and LivaNova; fees for serving as chair of a data and safety monitoring board from Boston Scientific; fees for serving on an end point committee from Boehringer Ingelheim; and fees for serving on an advisory board from Zensun. A.S.D. has received grants and personal fees from AstraZeneca during the conduct of the study; personal fees from Abbott, Biofourmis, Boston Scientific, Boehringer Ingelheim, Corvidia, DalCor Pharma, Relypsa, Regeneron, and Merck; grants and personal fees from Alnylam and Novartis; and personal fees from Amgen, outside the submitted work. M.P. reports consulting fees from AbbVie, Akcea, Actavis, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cardiorentis, Daiichi Sankyo, Gilead, Johnson & Johnson, Novo Nordisk, Pfizer, Relypsa, Sanofi, Synthetic Biologics, and Theravance. M.R.Z. reports research funding from Novartis and has been a consultant for Novartis, Abbott, Boston Scientific, CVRx, EBR, Endotronics, Ironwood, Merck, Medtronic, and Myokardia V Wave. M.A.P. reports research grant support through Brigham and Women’s Hospital from Novartis; reports consulting fees from AstraZeneca, Boehringer Ingelheim and Eli Lilly Alliance, Corvidia, DalCor, GlaxoSmithKline, National Heart, Lung, and Blood Institute CONNECTs (Master Protocol Committee), Novartis, Novo Nordisk, Peerbridge, and Sanofi; and has equity in DalCor. S.D.S. has received research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, 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 consulted for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GlaxoSmithKline, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellPro-Thera, Moderna, American Regent, and Sarepta. W.T.A. has received personal fees from Abbott; has received consulting fees from Boehringer Ingelheim, CVRx, Edwards Lifesciences, Impulse Dynamics, and Respicardia; has received salary support from V-Wave Medical; and has received research support from the National Heart, Lung, and Blood Institute, all for studies performed within the heart failure arena. S.J.S. has received either personal or institutional research support from AstraZeneca. C.S.P.L. is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore; has received research support from Novo Nordisk and Roche Diagnostics; has served as consultant or on the Advisory Board/Steering Committee/Executive Committee for Alleviant Medical, Allysta Pharma, Amgen, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, CardioRenal, Cytokinetics, Darma Inc, EchoNous Inc, Eli Lilly, Impulse Dynamics, Intellia Therapeutics, Ionis Pharmaceutical, Janssen Research & Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, Prosciento Inc, Radcliffe Group Ltd, Recardio Inc, ReCor Medical, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics and Us2.AI; and serves as cofounder and nonexecutive director of Us2.AI. P.S.J. reports speakers’ fees from AstraZeneca, Novartis, Alkem Metabolics, ProAdWise Communications, Sun Pharmaceuticals, and Intas Pharmaceuticals; advisory board fees from AstraZeneca, Boehringer Ingelheim, and Novartis; and research funding from AstraZeneca, Boehringer Ingelheim, and Analog Devices Inc. P.S.J.’s employer, the University of Glasgow, has been remunerated for clinical trial work from AstraZeneca, Bayer AG, Novartis, and Novo Nordisk. P.S.J. is a director of Global Clinical Trial Partners Ltd. J.J.V.M. reports payments through Glasgow University from work on clinical trials, consulting, and other activities from Amgen, AstraZeneca, Bayer, Cardurion, Cytokinetics, GSK, KBP Biosciences, and Novartis; and personal consultancy fees from Alnylam Pharma., Bayer, BMS, George Clinical PTY Ltd, Ionis Pharma, Novartis, Regeneron Pharma, and River 2 Renal Corporation. J.J.V.M. receives personal lecture fees from Abbott, Alkem Metabolics, AstraZeneca, Blue Ocean Scientific Solutions Ltd, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge, Emcure Pharma Ltd, Eris Lifesciences, European Academy of Continued Medical Education, Hikma Pharmaceuticals, Imagica Health, Intas Pharma, JB Chemicals & Pharma Ltd, Lupin Pharma, Medscape/Heart.Org, ProAdWise Communications, Radcliffe Cardiology, Sun Pharma, The Corpus, Translation Research Group, and Translational Medicine Academy. He is a director of Global Clinical Trial Partners Ltd. The other author reports no conflicts.

Aims: Stroke is an important problem in patients with heart failure (HF), but the intersection between the two conditions is poorly studied across the range of ejection fraction. The prevalence of history of stroke and related outcomes were investigated in patients with HF., Methods and Results: Individual patient meta-analysis of seven clinical trials enrolling patients with HF with reduced (HFrEF) and preserved ejection fraction (HFpEF). Of the 20 159 patients with HFrEF, 1683 (8.3%) had a history of stroke, and of the 13 252 patients with HFpEF, 1287 (9.7%) had a history of stroke. Regardless of ejection fraction, patients with a history of stroke had more vascular comorbidity and worse HF. Among those with HFrEF, the incidence of the composite of cardiovascular death, HF hospitalization, stroke, or myocardial infarction was 18.23 (16.81-19.77) per 100 person-years in those with prior stroke vs. 13.12 (12.77-13.48) in those without [hazard ratio 1.37 (1.26-1.49), P < 0.001]. The corresponding rates in patients with HFpEF were 14.16 (12.96-15.48) and 9.37 (9.06-9.70) [hazard ratio 1.49 (1.36-1.64), P < 0.001]. Each component of the composite was more frequent in patients with stroke history, and the risk of future stroke was doubled in patients with prior stroke. Among patients with prior stroke, 30% with concomitant atrial fibrillation were not anticoagulated, and 29% with arterial disease were not taking statins; 17% with HFrEF and 38% with HFpEF had uncontrolled systolic blood pressure (≥140 mmHg)., Conclusion: Heart failure patients with a history of stroke are at high risk of subsequent cardiovascular events, and targeting underutilization of guideline-recommended treatments might be a way to improve outcomes in this high-risk population., (© 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 The incidence and implications of worsening renal function (WRF) after mitral valve transcatheter edge-to-edge repair (TEER) in patients with heart failure (HF) are unknown. Therefore, the aim of this study was to determine the proportion of patients with HF and secondary mitral regurgitation who develop persistent WRF within 30 days following TEER, and whether this development portends a worse prognosis. Methods and Results In the COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation) trial, 614 patients with HF and severe secondary mitral regurgitation were randomized to TEER with the MitraClip plus guideline-directed medical therapy (GDMT) versus GDMT alone. WRF was defined as serum creatinine increase ≥1.5× or ≥0.3 mg/dL from baseline persisting to day 30 or requiring renal replacement therapy. All-cause death and HF hospitalization rates between 30 days and 2 years were compared in patients with and without WRF. WRF at 30 days was present in 11.3% of patients (9.7% in the TEER plus GDMT group and 13.1% in the GDMT alone group; P =0.23). WRF was associated with all-cause death (hazard ratio [HR], 1.98 [95% CI, 1.3-3.03]; P =0.001) but not HF hospitalization (HR, 1.47 [ 95% CI, 0.97-2.24]; P =0.07) between 30 days and 2 years. Compared with GDMT alone, TEER reduced both death and HF hospitalization consistently in patients with and without WRF ( P interaction =0.53 and 0.57, respectively). Conclusions Among patients with HF and severe secondary mitral regurgitation, the incidence of WRF at 30 days was not increased after TEER compared with GDMT alone. WRF was associated with greater 2-year mortality but did not attenuate the treatment benefits of TEER in reducing death and HF hospitalization compared with GDMT alone. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01626079.

Background: Although malnutrition is associated with poor prognosis in several diseases, its prognostic impact in patients with heart failure (HF) and secondary mitral regurgitation (SMR) is not understood., Objectives: The purpose of this study was to assess the prevalence and impact of malnutrition in HF patients with severe SMR randomized to transcatheter edge-to-edge repair (TEER) with the MitraClip plus guideline-directed medical therapy (GDMT) vs GDMT alone in the COAPT trial., Methods: Baseline malnutrition risk was calculated using the validated geriatric nutritional risk index (GNRI) score. Patients were categorized as having "malnutrition" (GNRI ≤98) vs "no malnutrition" (GNRI >98). Outcomes were assessed through 4 years. The primary endpoint of interest was all-cause mortality., Results: Among 552 patients, median baseline GNRI was 109 (IQR: 101-116); 94 (17.0%) had malnutrition. All-cause mortality at 4 years was greater in patients with vs those without malnutrition (68.3% vs 52.8%; P = 0.001). Using multivariable analysis, both baseline malnutrition (adjusted-HR [adj-HR]: 1.37; 95% CI: 1.03-1.82; P = 0.03) and randomization to TEER plus GDMT compared with GDMT alone (adj-HR: 0.65; 95% CI: 0.51-0.82; P = 0.0003) were independent predictors of 4-year mortality. In contrast, GNRI was unrelated to the 4-year rate of heart failure hospitalization (HFH), although TEER treatment reduced HFH (adj-HR: 0.46; 95% CI: 0.36-0.56). The reductions in death (adj-P interaction  = 0.46) and HFH (adj-P interaction  = 0.67) with TEER were consistent in patients with and without malnutrition., Conclusions: Malnutrition was present in 1 of 6 patients with HF and severe SMR enrolled in COAPT and was independently associated with increased 4-year mortality (but not HFH). TEER reduced mortality and HFH in patients with and without malnutrition. (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation [The COAPT Trial] and COAPT CAS [COAPT]; NCT01626079)., Competing Interests: Funding Support and Author Disclosures The COAPT trial was sponsored by Abbott. Dr Scotti has served as a consultant for and has received consulting fees from NeoChord Inc. Dr Coisne has served as a consultant for Abbott; and has received speaker fees from Abbott and GE Healthcare. Dr Granada is the Co-Founder of Cephea Valve Technologies (Abbott); and is the CEO of the Cardiovascular Research Foundation. Dr Kar has received grants from Abbott, Boston Scientific, Edwards Lifesciences, and 4TECH; has been a consultant for Boston Scientific, Edwards Lifesciences, Medtronic, and 4TECH; and holds stock options in 4TECH. Dr Lim has received research grant support from Abbott, Boston Scientific, Corvia, Edwards, Medtronic, Trisol, and V Wave; and has received consultant fees from Ancora, Philips, Valgen, and Venus. Dr Cohen has received institutional research grants and consulting fees from Abbott, Edwards Lifesciences, Medtronic, and Boston Scientific. Dr Lindenfeld has received research grant support from AstraZeneca; and has received consulting income from Abbott Vascular, Alleviant, AstraZeneca, Cordio, CVRx, Edwards Lifesciences, Boehringer Ingelheim, Merck, Medtronic, Vascular Dynamics, and V-Wave. Dr Abraham has received research grant support from the National Institutes of Health – National Heart, Lung, and Blood Institute (National Institutes of Health 1 UG3/UH3 HL140144-01, 08/01/18 - 07/31/22, “Impact of Low Flow Nocturnal Oxygen Therapy on Hospital Readmission/Mortality in Patients with Heart Failure and Central Sleep Apnea [LOFT-HF])”; has received consulting income from Abbott Vascular, Boehringer Ingelheim, and Zoll Respicardia; has received speaker honoraria from Impulse Dynamics; and has received salary support from V-Wave Medical. Dr Mack has served as co-primary investigator for the PARTNER trial for Edwards Lifesciences and the COAPT trial for Abbott; and has served as study chair for the APOLLO trial for Medtronic. Dr Asch has received institutional contracts with Abbott, Neovasc, Ancora, Mitralign, Medtronic, Boston Scientific, Edwards Lifesciences, Biotronik, and Livanova. Dr Stone has received speaker honoraria from Medtronic, Pulnovo, and Infraredx; has served as a consultant to Valfix, TherOx, Robocath, HeartFlow, Ablative Solutions, Vectorious, Miracor, Neovasc, Abiomed, Ancora, Elucid Bio, Occlutech, CorFlow, Apollo Therapeutics, Impulse Dynamics, Cardiomech, Gore, Amgen, Adona Medical, and Millennia Biopharma; and has equity/options from Ancora, Cagent, Applied Therapeutics, Biostar family of funds, SpectraWave, Orchestra Biomed, Aria, Cardiac Success, Valfix, and Xenter; his employer, Mount Sinai Hospital, receives research support from Abbott, Abiomed, Bioventrix, Cardiovascular Systems Inc, Phillips, Biosense-Webster, Shockwave, Vascular Dynamics, Pulnovo, and V-wave; and his daughter is an employee at Medtronic. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Heart failure with preserved ejection fraction (HFpEF) represents a highly heterogeneous clinical syndrome affected in its development and progression by many comorbidities. The left ventricular diastolic dysfunction may be a manifestation of various combinations of cardiovascular, metabolic, pulmonary, renal, and geriatric conditions. Thus, in addition to treatment with sodium-glucose cotransporter 2 inhibitors in all patients, the most effective method of improving clinical outcomes may be therapy tailored to each patient's clinical profile. To better outline a phenotype-based approach for the treatment of HFpEF, in this joint position paper, the Heart Failure Association of the European Society of Cardiology, the European Heart Rhythm Association and the European Hypertension Society, have developed an algorithm to identify the most common HFpEF phenotypes and identify the evidence-based treatment strategy for each, while taking into account the complexities of multiple comorbidities and polypharmacy., (© 2023 European Society of Cardiology.)

Background: In the COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation) trial, a central committee of heart failure (HF) specialists optimized guideline-directed medical therapies (GDMT) and documented medication and goal dose intolerances before patient enrollment., Objectives: The authors sought to assess the rates, reasons, and predictors of GDMT intolerance in the COAPT trial., Methods: Baseline use, dose, and intolerances of angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), angiotensin receptor neprilysin inhibitors (ARNIs), beta-blockers, and mineralocorticoid receptor antagonists (MRAs) were analyzed in patients with left ventricular ejection fraction (LVEF) ≤40%, in whom maximally tolerated doses of these agents as assessed by an independent HF specialist were required before enrollment., Results: A total of 464 patients had LVEF ≤40% and complete medication information. At baseline, 38.8%, 39.4%, and 19.8% of patients tolerated 3, 2, and 1 GDMT classes, respectively (any dose); only 1.9% could not tolerate any GDMT. Beta-blockers were the most frequently tolerated GDMT (93.1%), followed by ACEIs/ARBs/ARNIs (68.5%), and then MRAs (55.0%). Intolerances differed by GDMT class, but hypotension and kidney dysfunction were most common. Goal doses were uncommonly achieved for beta-blockers (32.3%) and ACEIs/ARBs/ARNIs (10.2%) due to intolerances limiting titration. Only 2.2% of patients tolerated goal doses of all 3 GDMT classes., Conclusions: In a contemporary trial population with HF, severe mitral regurgitation, and systematic HF specialist-directed GDMT optimization, most patients had medical intolerances prohibiting 1 or more GDMT classes and achieving goal doses. The specific intolerances noted and methods used for GDMT optimization provide important lessons for the implementation of GDMT optimization in future clinical trials. (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation [The COAPT Trial] [COAPT]; NCT01626079)., Competing Interests: Funding Support and Author Disclosures Abbott Laboratories has provided funding for this paper. Dr Cox has received grants from AstraZeneca, and Cumberland Pharmaceuticals; and consulting fees from Roche. Dr Udelson has served on steering committees for Abiomed; and has received consulting fees from Imbria Pharmaceuticals. Dr Lim has received grants from Abbott, Edwards, Medtronic, and Gore; consulting fees from Abbott, Edwards, Keystone Heart, Pipeline, Siemens, Valgen, and Venus; has served on advisory boards for Ancora and Venus; and holds equity in 510Kardiac and Venus. Dr Grayburn has received grant support and consulting fees from Edwards Lifesciences and Neochord; and grants from Boston Scientific, Medtronic, and Tendyne. Dr Mack has the following nonfinancial relationships: he has served as co-primary investigator for the PARTNER Trial for Edwards Lifesciences and COAPT trial for Abbott; and has served as study chair for the APOLLO trial for Medtronic. Dr Abraham has received grants and consulting fees from Abbott. Dr Stone has received honoraria from Terumo, Cook, and Infraredx; consulting fees from Valfix, TherOx, Robocath, HeartFlow, Ablative Solutions, Vectorious, Miracor, Neovasc, Abiomed, Ancora, Elucid Bio, Occlutech, CorFlow, Reva, MAIA Pharmaceuticals, Vascular Dynamics, Shockwave, V-Wave, Cardiomech, and Gore; holds equity/options for Ancora, Cagent, Applied Therapeutics, Biostar family of funds, SpectraWave, Orchestra Biomed, Aria, Cardiac Success, Valfix, and MedFocus family of funds. Dr Lindenfeld has received grants from AstraZeneca; and consulting fees from Abbott, CVRx, Edwards Lifesciences, RESMED, Relypsa, BI, and V-Wave. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Little is known regarding the risk of cerebrovascular events (CVE) in patients with heart failure and severe secondary mitral regurgitation treated with transcatheter edge-to-edge repair (TEER)., Objectives: The study sought to examine the incidence, predictors, timing, and prognostic impact of CVE (stroke or transient ischemic attack) in the COAPT (Cardiovascular Outcomes Assessment of the Mitraclip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation) trial., Methods: A total of 614 patients with heart failure and severe secondary mitral regurgitation were randomized to TEER plus guideline-directed medical therapy (GDMT) vs GDMT alone., Results: At 4-year follow-up, 50 CVEs occurred in 48 (7.8%) of the 614 total patients enrolled in the COAPT trial; Kaplan-Meier event rates were 12.3% in the TEER group and 10.2 in the GDMT alone group (P = 0.91). Within 30 days of randomization, CVE occurred in 2 (0.7%) patients randomized to TEER and 0% randomized to GDMT (P = 0.15). Baseline renal dysfunction and diabetes were independently associated with increased risk of CVE, while baseline anticoagulation was associated with a reduction of CVE. A significant interaction was present between treatment group and anticoagulation such that TEER compared with GDMT alone was associated with a reduced risk of CVE among patients with anticoagulation (adjusted HR: 0.24; 95% CI: 0.08-0.73) compared with an increased risk of CVE in patients without anticoagulation (adjusted HR: 2.27; 95% CI: 1.08-4.81; P interaction  = 0.001). CVE was an independent predictor of death within 30 days after the event (HR: 14.37; 95% CI: 7.61, 27.14; P < 0.0001)., Conclusions: In the COAPT trial, the 4-year rate of CVE was similar after TEER or GDMT alone. CVE was strongly associated with mortality. Whether anticoagulation is effective at reducing CVE risk after TEER warrants further study. (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation [The COAPT Trial] and COAPT CAS [COAPT); NCT01626079)., Competing Interests: Funding Support and Author Disclosures The COAPT trial was funded by Abbott, Inc. Abbott sponsored the trial and provided funding to the Cardiovascular Research Foundation to provide statistical support for this analysis. Dr Abraham was supported by the National Heart, Lung, and Blood Institute (National Institutes of Health 1 UG3/UH3 HL140144-01, 08/01/18-07/31/22, “Impact of Low Flow Nocturnal Oxygen Therapy on Hospital Readmission/Mortality in Patients with Heart Failure and Central Sleep Apnea [LOFT-HF]). Dr Vincent has received research grant support from the Federation Française de Cardiologie, Lille University Hospital, and Medtronic. Dr Kar has received consulting fees from and served on the advisory board for Abbott Vascular Boston Scientific; and has received consulting fees from and owns stock equity in Valcare. Dr Lim has received research grant support from Abbott, Edwards Lifesciences, Medtronic, and Gore; has received consultant fees from Abbott, Edwards Lifesciences, Keystone Heart, Pipeline, Siemens, Valgen, and Venus; has served on the advisory board for Ancora and Venus; and owns equity in 510Kardiac and Venus. Dr Lindenfield has received research grant support from AstraZeneca; and has received consulting income from Abbott Vascular, CVRx, Edwards Lifesciences, RESMED, Relypsa, Boehringer Ingelheim, and V-Wave. Dr Abraham has received consulting income from Abbott Vascular, Boehringer Ingelheim, and Zoll Respicardia; has received speaker honoraria from Impulse Dynamics; and has received salary support from V-Wave Medical. Dr Stone has received speaker honoraria from Medtronic, Pulnovo, Infraredx, Abiomed; has served as a consultant for Valfix, TherOx, Robocath, HeartFlow, Ablative Solutions, Vectorious, Miracor, Neovasc, Ancora, Elucid Bio, Occlutech, CorFlow, Apollo Therapeutics, Impulse Dynamics, Cardiomech, Gore, Amgen, Adona Medical, and Millennia Biopharma; owns equity/options from Ancora, Cagent, Applied Therapeutics, Biostar family of funds, SpectraWave, Orchestra Biomed, Aria, Cardiac Success, Valfix, and Xenter; has a his daughter who is an employee at IQVIA; is employed by Mount Sinai Hospital, which receives research support from Abbott, Abiomed, Bioventrix, Cardiovascular Systems Inc, Phillips, Biosense Webster, Shockwave, Vascular Dynamics, Pulnovo, and V-Wave. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. All rights reserved.)

Background: Transcatheter mitral valve replacement (TMVR) is an emerging therapeutic alternative for patients with secondary mitral regurgitation (MR). Outcomes of TMVR versus guideline-directed medical therapy (GDMT) have not been investigated for this population. This study aimed to compare clinical outcomes of patients with secondary MR undergoing TMVR versus GDMT alone., Methods: The CHOICE-MI registry (Choice of Optimal Transcatheter Treatment for Mitral Insufficiency) included patients with MR undergoing TMVR using dedicated devices. Patients with MR pathogeneses other than secondary MR were excluded. Patients treated with GDMT alone were derived from the control arm of the COAPT trial (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation). We compared outcomes between the TMVR and GDMT groups, using propensity score matching to adjust for baseline differences., Results: After propensity score matching, 97 patient pairs undergoing TMVR (72.9±8.7 years; 60.8% men; transapical access, 91.8%) versus GDMT (73.1±11.0 years; 59.8% men) were compared. At 1 and 2 years, residual MR was ≤1+ in all patients of the TMVR group compared with 6.9% and 7.7%, respectively, in those receiving GDMT alone (both P <0.001). The 2-year rate of heart failure hospitalization was significantly lower in the TMVR group (32.8% versus 54.4%; hazard ratio, 0.59 [95% CI, 0.35-0.99]; P =0.04). Among survivors, a higher proportion of patients were in the New York Heart Association functional class I or II in the TMVR group at 1 year (78.2% versus 59.7%; P =0.03) and at 2 years (77.8% versus 53.2%; P =0.09). Two-year mortality was similar in the 2 groups (TMVR versus GDMT, 36.8% versus 40.8%; hazard ratio, 1.01 [95% CI, 0.62-1.64]; P =0.98)., Conclusions: In this observational comparison, over 2-year follow-up, TMVR using mostly transapical devices in patients with secondary MR was associated with significant reduction of MR, symptomatic improvement, less frequent hospitalizations for heart failure, and similar mortality compared with GDMT., Registration: URL: https://clinicaltrials.gov; Unique identifier: NCT04688190 (CHOICE-MI) and NCT01626079 (COAPT)., Competing Interests: Disclosures Dr Ludwig reports travel compensation from Edwards; speaker honoraria from Abbott; and advisory fees from Bayer. Dr Conradi reports being on the advisory board at Abbott, Medtronic, and Boston Scientific and personal fees from Edwards. Dr Cohen reports research grant and consulting fees from Abbott, Edwards Lifesciences, Boston Scientific, and Medtronic AC; is a proctor at Abbott; and is a speaker at Abbott and General Electric Healthcare. Dr Scotti is a consultant for NeoChord. Dr Abraham reports research grant from the National Institutes of Health–National Heart, Lung, and Blood Institute (National Institutes of Health 1 UG3/UH3 HL140144-01, 08/01/18-07/31/22, LOFT-HF [Impact of Low Flow Nocturnal Oxygen Therapy on Hospital Readmission/Mortality in Patients With Heart Failure and Central Sleep Apnea]); consulting at Abbott, Boehringer Ingelheim, and Zoll; honoraria from Impulse Dynamics; and salary from V-Wave Medical. Dr Ben Ali reports grants from Medtronic and Edwards. Dr Kar reports grants and consulting from Abbott, Boston Scientific, Edwards, and 4TECH and stock at 4TECH. Dr Scott Lim reports grants from Abbott, Boston Scientific, Corvia, Edwards, Medtronic, Trisol, and V-Wave and is a consultant at Ancora, Philips, Valgen, and Venus. Dr Duncan is a consultant at Abbott, Edwards, and Medtronic. Dr Adamo reports personal fees from Edwards and Boston Scientific and grants and honoraria from Medtronic. Dr Muller is on the advisory board at Abbott, Medtronic, and Edwards. Dr Petronio is a consultant at Medtronic, Boston Scientific, and Abbott. Dr Ruge is on the advisory board at Abbott and is a proctor at Abbott and Edwards. Dr Sondergaard reports grants and consulting at Edwards and Medtronic. Dr Adam reports grants and honoraria from Medtronic and personal fees from Boston Scientific and Edwards. Dr Dahle is a proctor/speaker at Abbott and Edwards. Dr Kempfert reports honoraria from Edwards, Medtronic, Abbott, and CryoLife. Dr Garatti is a proctor at Abbott. Dr Schmidt reports honoraria and travel support from Abbott and Cardiovalve. Dr Tang is a proctor/consultant at Medtronic; consultant/advisory board at Abbott; consultant at NeoChord; advisory board at JenaValve; and honoraria from Siemens and EastEnd Medical. Dr Redwood is a proctor at and reports personal fees from Edwards and is on the advisory board at Medtronic. Dr Taramasso is a consultant at Abbott, Edwards, Boston Scientific, Shenqi Medical, Simulands, Occlufit, MTEx, Medira, 4tech, and CoreMedic and reports personal fees from Cardiovalve. Dr Praz is a consultant at Edwards. Dr Fam is a consultant at Edwards, Abbott, and Cardiovalve. Dr Dumonteil is a consultant/proctor at Abbott, Boston Scientific, Edwards, and Medtronic. Dr von Bardeleben reports consulting/honoraria from Abbott, Edwards, and Medtronic and research grants to the university from Abbott and Edwards. Dr Rudolph reports honoraria from Abbott. Dr Reardon is a consultant at Medtronic, Boston, Abbott, and Gore (all funds to the department). Dr Metra reports personal fees from Actelion, Amgen, Livanova, Servier, Vifor Pharma as member of the Executive or Data Monitoring Committees of sponsored clinical trials, AstraZeneca, Abbott, Bayer, Boheringer Ingelhelm, and Edwards Therapeutics for participation to advisory boards and speeches at sponsored meetings. Dr Denti reports personal fees from Abbott and Edwards. Dr Mack reports being a co-Principal Investigator for the PARTNER trial (Placement of Aortic Transcatheter Valve Trial; Edwards) and COAPT trial (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation; Abbott) and is a study chair for the APOLLO trial (Transcatheter Mitral Valve Replacement With the Medtronic Intrepid TMVR System in Patients With Severe Symptomatic Mitral Regurgitation; Medtronic). Dr Hausleiter reports consulting fees, speaker honoraria, and research support to the institution from Abbott and Edwards. Dr Asch reports institutional contracts from Abbott, Neovasc, Ancora, Mitralign, Medtronic, Boston Scientific, Edwards Lifesciences, Biotronik, and Livanova. Dr Latib is on the advisory board at Medtronic, Boston Scientific, Philips, Edwards, and Abbott. Dr Lindenfeld reports grant support from AstraZeneca and consulting at Abbott, Alleviant, AstraZeneca, Cordio, CVRx, Edwards, Boehringer Ingelheim, Merck, Medtronic, Vascular Dynamics, and V-Wave. Dr Modine is a consultant at Abbott, Edwards, and Medtronic. Dr Stone reports honoraria from Medtronic, Pulnovo, and Infraredx; is a consultant at Valfix, TherOx, Robocath, HeartFlow, Ablative Solutions, Vectorious, Miracor, Neovasc, Abiomed, Ancora, Elucid Bio, Occlutech, CorFlow, Apollo Therapeutics, Impulse Dynamics, Cardiomech, Gore, Amgen, Adona Medical, and Millennia Biopharma; and reports equity/options at Ancora, Cagent, Applied Therapeutics, Biostar family of funds, SpectraWave, Orchestra Biomed, Aria, Cardiac Success, Valfix, and Xenter. Dr Stone’s daughter is an employee at Medtronic. Dr Stone’s employer, Mount Sinai Hospital, receives research support from Abbott, Abiomed, Bioventrix, Cardiovascular Systems, Inc, Phillips, Biosense Webster, Shockwave, Vascular Dynamics, Pulnovo, and V-wave. Dr Granada is the President and Chief Executive Officer of Cardiovascular Research Foundation. The other authors report no conflicts.

Aims: In heart failure (HF), implantable haemodynamic monitoring devices have been shown to optimize therapy, anticipating clinical decompensation and preventing hospitalization. Direct left-sided haemodynamic sensors offer theoretical benefits beyond pulmonary artery pressure monitoring systems. We evaluated the safety, usability, and performance of a novel left atrial pressure (LAP) monitoring system in HF patients., Methods and Results: The VECTOR-HF study (NCT03775161) was a first-in-human, prospective, multicentre, single-arm, clinical trial enrolling 30 patients with HF. The device consisted of an interatrial positioned leadless sensor, able to transmit LAP data wirelessly. After 3 months, a right heart catheterization was performed to correlate mean pulmonary capillary wedge pressure (PCWP) with simultaneous mean LAP obtained from the device. Remote LAP measurements were then used to guide patient management. The miniaturized device was successfully implanted in all 30 patients, without acute major adverse cardiac and neurological events (MACNE). At 3 months, freedom from short-term MACNE was 97%. Agreement between sensor-calculated LAP and PCWP was consistent, with a mean difference of -0.22 ± 4.92 mmHg, the correlation coefficient and the Lin's concordance correlation coefficient values were equal to 0.79 (p < 0.0001) and 0.776 (95% confidence interval 0.582-0.886), respectively. Preliminary experience with V-LAP-based HF management was associated with significant improvements in New York Heart Association (NYHA) functional class (32% of patients reached NYHA class II at 6 months, p < 0.005; 60% of patients at 12 months, p < 0.005) and 6-min walk test distance (from 244.59 ± 119.59 m at baseline to 311.78 ± 129.88 m after 6 months, p < 0.05, and 343.95 ± 146.15 m after 12 months, p < 0.05)., Conclusion: The V-LAP™ monitoring system proved to be generally safe and provided a good correlation with invasive PCWP. Initial evidence also suggests possible improvement in HF clinical symptoms., (© 2023 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Data from a 5-year follow-up of outcomes after transcatheter edge-to-edge repair of severe mitral regurgitation, as compared with outcomes after maximal doses of guideline-directed medical therapy alone, in patients with heart failure are now available., Methods: We randomly assigned patients with heart failure and moderate-to-severe or severe secondary mitral regurgitation who remained symptomatic despite the use of maximal doses of guideline-directed medical therapy to undergo transcatheter edge-to-edge repair plus receive medical therapy (device group) or to receive medical therapy alone (control group) at 78 sites in the United States and Canada. The primary effectiveness end point was all hospitalizations for heart failure through 2 years of follow-up. The annualized rate of all hospitalizations for heart failure, all-cause mortality, the risk of death or hospitalization for heart failure, and safety, among other outcomes, were assessed through 5 years., Results: Of the 614 patients enrolled in the trial, 302 were assigned to the device group and 312 to the control group. The annualized rate of hospitalization for heart failure through 5 years was 33.1% per year in the device group and 57.2% per year in the control group (hazard ratio, 0.53; 95% confidence interval [CI], 0.41 to 0.68). All-cause mortality through 5 years was 57.3% in the device group and 67.2% in the control group (hazard ratio, 0.72; 95% CI, 0.58 to 0.89). Death or hospitalization for heart failure within 5 years occurred in 73.6% of the patients in the device group and in 91.5% of those in the control group (hazard ratio, 0.53; 95% CI, 0.44 to 0.64). Device-specific safety events within 5 years occurred in 4 of 293 treated patients (1.4%), with all the events occurring within 30 days after the procedure., Conclusions: Among patients with heart failure and moderate-to-severe or severe secondary mitral regurgitation who remained symptomatic despite guideline-directed medical therapy, transcatheter edge-to-edge repair of the mitral valve was safe and led to a lower rate of hospitalization for heart failure and lower all-cause mortality through 5 years of follow-up than medical therapy alone. (Funded by Abbott; COAPT ClinicalTrials.gov number, NCT01626079.)., (Copyright © 2023 Massachusetts Medical Society.)

Background: The relationship between left ventricular (LV) remodeling and clinical outcomes after treatment of severe mitral regurgitation (MR) in heart failure (HF) has not been examined., Objectives: The aim of this study was to evaluate the association between LV reverse remodeling and subsequent outcomes and assess whether transcatheter edge-to-edge repair (TEER) and residual MR are associated with LV remodeling in the COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation) trial., Methods: Patients with HF and severe MR who remained symptomatic on guideline-directed medical therapy (GDMT) were randomized to TEER plus GDMT or GDMT alone. Baseline and 6-month core laboratory measurements of LV end-diastolic volume index and LV end-systolic volume index were examined. Change in LV volumes from baseline to 6 months and clinical outcomes from 6 months to 2 years were evaluated using multivariable regression., Results: The analytical cohort comprised 348 patients (190 treated with TEER, 158 treated with GDMT alone). A decrease in LV end-diastolic volume index at 6 months was associated with reduced cardiovascular death between 6 months and 2 years (adjusted HR: 0.90 per 10 mL/m 2 decrease; 95% CI: 0.81-1.00; P = 0.04), with consistent results in both treatment groups (P interaction  = 0.26). Directionally similar but nonsignificant relationships were present for all-cause death and HF hospitalization and between reduced LV end-systolic volume index and all outcomes. Neither treatment group nor MR severity at 30 days was associated with LV remodeling at 6 or 12 months. The treatment benefits of TEER were not significant regardless of the degree of LV remodeling at 6 months., Conclusions: In patients with HF and severe MR, LV reverse remodeling at 6 months was associated with subsequently improved 2-year outcomes but was not affected by TEER or the extent of residual MR. (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation [The COAPT Trial] and COAPT CAS [COAPT]; NCT01626079)., Competing Interests: Funding Support and Author Disclosures The COAPT trial was sponsored by Abbott Vascular. Dr Lindman has received investigator-initiated research grants from Edwards Lifesciences. Dr Asch is the director of an academic echocardiography core laboratory (MedStar Health Research Institute) with institutional contracts with Abbott, Neovasc, Ancora, Mitralign, Medtronic, Boston Scientific, Edwards Lifesciences, Biotronik, Foldax, InnovHeart, Polares Medical, and Corcyn. Dr Grayburn has received consulting fees from Abbott Vascular, Edwards Lifesciences, W.L. Gore, Medtronic, and 4C Medical; and has received grant support from Abbott Vascular, Boston Scientific, Cardiovalve, Edwards Lifesciences, W.L. Gore, Medtronic, and NeoChord. Dr Mack has served as a co–primary investigator for the PARTNER trial for Edwards Lifesciences and the COAPT trial for Abbott; and has served as study chair for the APOLLO trial for Medtronic. Dr Bax’s employer, the Department of Cardiology (Leiden University Medical Center), has received research grants from Medtronic, Biotronik, Edwards Lifesciences, and Boston Scientific; and Dr Bax has received speaker fees from Abbott Vascular. Dr Gonzales has received speaker honoraria from Abbott. Dr Barker has received consultant honoraria from Edwards Lifesciences; and is an advisory board member for Medtronic and Boston Scientific. Dr Weissman is the associate director of an academic echocardiography core laboratory (MedStar Health Research Institute) with institutional contracts with Abbott, Neovasc, Ancora, Mitralign, Medtronic, Boston Scientific, Edwards Lifesciences, Biotronik, and Livanova. Dr Abraham has received research grant support from Abbott Vascular and the National Heart, Lung, and Blood Institute; has received consulting income from Abbott Vascular; and has received speaker honoraria from Impulse Dynamics. Dr Lindenfeld has received research grant support from AstraZeneca and VoluMetrix; and has received consulting income from Abbott Vascular, AstraZeneca, Alleviant, Bayer, CVRx, Cytokinetics, Edwards Lifesciences, Boehringer Ingelheim, Merck, Medtronic, Vascular Dynamics, VoluMetrix, and V-Wave. Dr Stone has received speaker honoraria from Medtronic, Pulnovo, and Infraredx; has served as a consultant to Valfix, TherOx, Robocath, HeartFlow, Ablative Solutions, Vectorious, Miracor, Neovasc, Abiomed, Ancora, Elucid Bio, Occlutech, CorFlow, Apollo Therapeutics, Impulse Dynamics, Cardiomech, Gore, Amgen, Adona Medical; and has equity or options in Ancora, Cagent, Applied Therapeutics, the Biostar family of funds, SpectraWave, Orchestra Biomed, Aria, Cardiac Success, Valfix, and Xenter. Dr Stone’s daughter is an employee of Medtronic. Dr Stone’s employer, Mount Sinai Hospital, receives research support from Abbott, Abiomed, Bioventrix, Cardiovascular Systems, Phillips, Biosense Webster, Shockwave, Vascular 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 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aims: Multimorbidity, the coexistence of two or more chronic conditions, is synonymous with heart failure (HF). How risk related to comorbidities compares at individual and population levels is unknown. The aim of this study is to examine the risk related to comorbidities, alone and in combination, both at individual and population levels., Methods and Results: Using two clinical trials in HF - the Prospective comparison of ARNI (Angiotensin Receptor-Neprilysin Inhibitor) with ACEI (Angiotensin-Converting Enzyme Inhibitor) to Determine Impact on Global Mortality and morbidity in HF trial (PARADIGM-HF) and the Aliskiren Trial to Minimize Outcomes in Patients with Heart Failure trials (ATMOSPHERE) - we identified the 10 most common comorbidities and examined 45 possible pairs. We calculated population attributable fractions (PAF) for all-cause death and relative excess risk due to interaction with Cox proportional hazard models. Of 15 066 patients in the study, 14 133 (93.7%) had at least one and 11 867 (78.8%) had at least two of the 10 most prevalent comorbidities. The greatest individual risk among pairs was associated with peripheral artery disease (PAD) in combination with stroke (hazard ratio [HR] 1.73; 95% confidence interval [CI] 1.28-2.33) and anaemia (HR 1.71; 95% CI 1.39-2.11). The combination of chronic kidney disease (CKD) and hypertension had the highest PAF (5.65%; 95% CI 3.66-7.61). Two pairs demonstrated significant synergistic interaction (atrial fibrillation with CKD and coronary artery disease, respectively) and one an antagonistic interaction (anaemia and obesity)., Conclusions: In HF, the impact of multimorbidity differed at the individual patient and population level, depending on the prevalence of and the risk related to each comorbidity, and the interaction between individual comorbidities. Patients with coexistent PAD and stroke were at greatest individual risk whereas, from a population perspective, coexistent CKD and hypertension mattered most., (© 2023 European Society of Cardiology.)

Aims: Low serum albumin levels are associated with poor prognosis in numerous chronic disease states but the relationship between albumin and outcomes in patients with heart failure (HF) and secondary mitral regurgitation (SMR) has not been described., Methods and Results: The randomized COAPT trial evaluated the safety and effectiveness of transcatheter edge-to-edge repair (TEER) with the MitraClip TM plus guideline-directed medical therapy (GDMT) versus GDMT alone in patients with symptomatic HF and moderate-to-severe or severe SMR. Baseline serum albumin levels were measured at enrolment. Among 614 patients enrolled in COAPT, 559 (91.0%) had available baseline serum albumin levels (median 4.0 g/dl, interquartile range 3.7-4.2 g/dl). Patients with albumin <4.0 g/dl compared with ≥4.0 g/dl were older and more likely to have ischaemic cardiomyopathy and a hospitalization within the year prior to enrolment. After multivariable adjustment, patients with albumin <4.0 g/dl had higher 4-year rates of all-cause death (63.7% vs. 47.6%; adjusted hazard ratio 1.34, 95% confidence interval 1.02-1.74; p = 0.032), but there were no significant differences in HF hospitalizations (HFH) or all-cause hospitalizations according to baseline serum albumin level. The relative effectiveness of TEER plus GDMT versus GDMT alone was consistent in patients with low and high albumin levels (p interaction  = 0.19 and 0.35 for death and HFH, respectively)., Conclusion: Low baseline serum albumin levels were independently associated with reduced 4-year survival in patients with HF and severe SMR enrolled in the COAPT trial, but not with HFH. Patients treated with TEER derived similarly robust reductions in both death and HFH regardless of baseline albumin level., (© 2023 European Society of Cardiology.)

Background: Benefit from cardiac resynchronization therapy (CRT) varies by QRS characteristics; individual randomized trials are underpowered to assess benefit for relatively small subgroups., Methods: The authors analyzed patient-level data from pivotal CRT trials (MIRACLE [Multicenter InSync Randomized Clinical Evaluation], MIRACLE-ICD [Multicenter InSync ICD Randomized Clinical Evaluation], MIRACLE-ICD II [Multicenter InSync ICD Randomized Clinical Evaluation II], REVERSE [Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction], RAFT [Resynchronization-Defibrillation for Ambulatory Heart Failure], BLOCK-HF [Biventricular Versus Right Ventricular Pacing in Heart Failure Patients with Atrioventricular Block], COMPANION [Comparison of Medical Therapy, Pacing and Defibrillation in Heart Failure], and MADIT-CRT [Multicenter Automatic Defibrillator Implantation Trial - Cardiac Resynchronization Therapy]) using Bayesian Hierarchical Weibull survival regression models to assess CRT benefit by QRS morphology (left bundle branch block [LBBB], n=4549; right bundle branch block [RBBB], n=691; and intraventricular conduction delay [IVCD], n=1024) and duration (with 150-ms partition). The continuous relationship between QRS duration and CRT benefit was also examined within subgroups defined by QRS morphology. The primary end point was time to heart failure hospitalization (HFH) or death; a secondary end point was time to all-cause death., Results: Of 6264 patients included, 25% were women, the median age was 66 [interquartile range, 58 to 73] years, and 61% received CRT (with or without an implantable cardioverter defibrillator). CRT was associated with an overall lower risk of HFH or death (hazard ratio [HR], 0.73 [credible interval (CrI), 0.65 to 0.84]), and in subgroups of patients with QRS ≥150 ms and either LBBB (HR, 0.56 [CrI, 0.48 to 0.66]) or IVCD (HR, 0.59 [CrI, 0.39 to 0.89]), but not RBBB (HR 0.97 [CrI, 0.68 to 1.34]; P interaction <0.001). No significant association for CRT with HFH or death was observed when QRS was <150 ms (regardless of QRS morphology) or in the presence of RBBB. Similar relationships were observed for all-cause death., Conclusions: CRT is associated with reduced HFH or death in patients with QRS ≥150 ms and LBBB or IVCD, but not for those with RBBB. Aggregating RBBB and IVCD into a single "non-LBBB" category when selecting patients for CRT should be reconsidered., Registration: URL: https://www., Clinicaltrials: gov; Unique identifiers: NCT00271154, NCT00251251, NCT00267098, and NCT00180271.

Background Peripheral artery disease (PAD) and heart failure (HF) often coexist. Whether PAD influences outcomes of transcatheter mitral valve repair (TMVr) in patients with HF and severe secondary mitral regurgitation is unknown. The objectives are to assess the impact of PAD on outcomes of TMVr plus guideline-directed medical therapy (GDMT) versus GDMT alone in patients with HF and secondary mitral regurgitation. Methods and Results The COAPT trial (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation) randomized patients with HF with ≥moderate-to-severe secondary mitral regurgitation to TMVr with MitraClip implant plus GDMT versus GDMT alone. We evaluated the relationship between PAD and 2-year outcomes in the COAPT trial  and examined whether PAD modified the benefits of TMVr. Among 614 patients enrolled, 109 (17.8%) had PAD. By multivariable analysis, PAD was independently associated with 2-year mortality (adjusted hazard ratio [adjHR], 1.51 [95% CI, 1.07-2.15]) but not HF hospitalizations. Compared with GDMT alone, TMVr reduced the 2-year risk of death in patients without PAD (adjHR, 0.42 [95% CI, 0.30-0.60]) but not those with PAD (adjHR, 1.27 [95% CI, 0.72-2.27]; P interaction =0.001). In contrast, TMVr reduced HF hospitalizations consistently in patients with (adjHR, 0.65 [95% CI, 0.35-1.23]) and without (adjHR, 0.42 [95% CI, 0.31-0.57]) PAD ( P =0.76 and 0.64, respectively). Conclusions In patients with HF and severe secondary mitral regurgitation, the reduced mortality with TMVr in the overall COAPT study population was not observed in the subgroup of patients with PAD. However, TMVr reduced HF hospitalizations and improved health status and exercise capacity consistently in patients with and without PAD. Registration Clinical Trial Name: Cardiovascular Outocmes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation (The COAPT Trial); URL: https://www.clinicaltrials.gov/; Unique identifier: NCT01626079. https://clinicaltrials.gov/ct2/show/NCT01626079.interaction =0.22). Improvements in health status and exercise capacity at 2 years with TMVr compared with GDMT alone were similar in degree, irrespective of PAD status ( P interaction =0.76 and 0.64, respectively). Conclusions In patients with HF and severe secondary mitral regurgitation, the reduced mortality with TMVr in the overall COAPT study population was not observed in the subgroup of patients with PAD. However, TMVr reduced HF hospitalizations and improved health status and exercise capacity consistently in patients with and without PAD. Registration Clinical Trial Name: Cardiovascular Outocmes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation (The COAPT Trial); URL: https://www.clinicaltrials.gov/; Unique identifier: NCT01626079. https://clinicaltrials.gov/ct2/show/NCT01626079.

Despite significant advances in the medical management of patients living with heart failure, there continues to be significant morbidity and mortality associated with the condition. There is a growing need for research and development of additional modalities to fill the management and treatment gaps, reduce hospitalisations and improve the quality of life for patients living with heart failure. In the last decade, there has been a rapid rise in the use of non-valvular catheter-based therapies for the management of chronic heart failure to complement existing guideline-directed management. They target well-defined mechanistic and pathophysiological processes critical to the progression of heart failure including left ventricular remodelling, neurohumoral activation, and congestion. In this review, we will explore the physiology, rationale, and current stages of the clinical development of the existing procedures.

Background: As heart failure therapeutic care becomes increasingly complex, a composite medical therapy score could be useful to conveniently summarize background medical therapy. We applied the composite medical therapy score developed by the Heart Failure Collaboratory (HFC) to the Danish heart failure with reduced ejection fraction population to evaluate its external validation including assessing the distribution of the score and its association with survival., Methods: In a retrospective nationwide cohort study, we identified all Danish heart failure with reduced ejection fraction patients alive on July 1, 2018, and assessed their treatment doses. Patients were excluded if they did not have at least 365 days for up-titration of medical therapy prior to identification. The HFC score (range 0-8) accounts for use and dosing of multiple therapies prescribed to each patient. Risk-adjusted association between the composite score and all-cause mortality was examined., Results: In total, 26 779 patients (mean age 71.9 years; 32% women) were identified. At baseline, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker was used in 77%, β-blocker in 81%, mineralocorticoid receptor antagonist in 30%, angiotensin receptor-neprilysin inhibitor in 2%, and ivabradine in 2%. The median HFC score was 4. After multivariable adjustment, higher HFC scores were independently associated with lower mortality (≥median versus

Background: Current treatment of fluid retention in heart failure relies primarily on diuretics. However, adequate decongestion is not achieved in many patients. We aimed to study the feasibility and short-term performance of a novel approach to remove fluids and sodium directly from the interstitial compartment by enhancing sweat rate., Methods: We used a device designed to enhance fluid and salt loss via the eccrine sweat glands. Skin temperature in the lower body was increased from 35 °C to 38 °C, where the slope of the relationship between temperature and sweat production is linear. The sweat evaporates instantaneously, thus avoiding the awareness of perspiration. The primary efficacy endpoint was the ability to increase skin temperature to the desired range. A secondary efficacy endpoint was a clinically meaningful hourly sweat output, defined as ≥150 mL/h. The primary safety endpoint was any procedure-related adverse events., Results: We studied 6 normal subjects and 18 patients with congestion. Participants underwent 3 treatment sessions of up to 4 hours. Skin temperature increased to a median of 37.5 °C (interquartile range, 37.1-37.9 °C) with the median core temperature increasing by 0.2 °C (interquartile range, 0.1-0.3 °C). The median hourly weight loss during treatment was 215 g/h (interquartile range, 165-285; range, 100-344 g/h). In 80% of treatment procedures, the average sweat rate was ≥150 mL/h. There were no significant changes in hemodynamic variables or renal function and no procedure-related adverse events., Conclusions: Enhancing sweat rate was safe and resulted in a clinically meaningful fluid removal and weight loss., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT04578353.

The Heart Failure Academic Research Consortium is a partnership between the Heart Failure Collaboratory (HFC) and the Academic Research Consortium (ARC) composed of patients, academic investigators from the United States and Europe, the U.S. Food and Drug Administration, the National Institutes of Health, payers, and industry. Members discussed the measure, remote capture, and clinical utility of functional and quality-of-life endpoints for use in clinical trials of heart failure and cardiovascular therapeutics, with the goal of improving the efficiency of heart failure and cardiovascular clinical research, evidence generation, and thereby patient quality of life, functional status, and survival. Assessments of patient-reported outcomes and maximal and submaximal exercise tolerance are standardized and validated, but actigraphy remains inconsistent as a potential endpoint. This paper details those discussions and consensus recommendations., Competing Interests: Funding Support and Author Disclosures The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the FDA or the U.S. Department of Health and Human Services. Dr Abraham has received consulting fees from Boehringer Ingelheim and Zoll Respicardia, speaker honoraria from Impulse Dynamics, salary support from V-Wave Medical, and research support from the U.S. National Institutes of Health/National Heart, Lung, and Blood Institute. Dr Filippatos has received consulting income from Boehringer Ingelheim, Medtronic, Novartis, Servier, and Vifor; and has received lecture fees from Merck. Dr Lindenfeld has received consulting fees from Novartis, Abbott, ResMed, V-Wave, CVRx, and Cytokinetics. Dr Ahmad has received consulting fees from Amgen, Cytokinetics, Relypsa, and Novartis. Dr Felker has received research grants from the National Heart, Lung, and Blood Institute, the American Heart Association, Amgen, Merck, Cytokinetics, and Roche Diagnostics; and has received consulting fees from Novartis, Amgen, Bristol Myers Squibb, Cytokinetics, Medtronic, Cardionomic, Relypsa, V-Wave, Myokardia, Innolife, EBR Systems, Arena, Abbott, Sphingotec, Roche Diagnostics, Alnylam, LivaNova, Windtree Therapeutics, Rocket Pharma, and SC Pharma. Dr Kitzman has received consulting fees from AstraZeneca, Bayer, Novartis, Merck, Pfizer, Boehringer Ingelheim, AbbVie, DCRI, and Corvia; has received grant support from AstraZeneca, Bayer, and Novartis; and has stock in Gilead. Dr Lewis has received consulting fees from Novartis; and has received institutional research grant support from Amgen, Novartis, and Sanofi. Dr Mentz has received consulting fees from Abbott, Amgen, AstraZeneca, Bayer, Boston Scientific, Janssen, Luitpold, Medtronic, Merck, Novartis, and Sanofi; and has received research grants from Akros, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, GlaxoSmithKline, Gilead, InnoLife, Luitpold/American Reagent, Novartis, Otsuka, ResMed, and the National Institutes of Health (grants U01HL125511-01A1 and R01AG045551-01A1). Dr Solomon has received research grants from Alnylam, Amgen, AstraZeneca, Bellerophon, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lone Star Heart, Mesoblast, MyoKardia, the National Institutes of Health/National Heart, Lung, and Blood Institute, Novartis, Sanofi Pasteur, and Theracos; and has received consulting fees from Akros, Alnylam, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Cardior, Corvia, Cytokinetics, Gilead, GlaxoSmithKline, Ironwood, Merck Sharpe & Dohme, Novartis, Roche, Takeda, Theracos, Quantum Genetics, Cardurion, AoBiome, Janssen, and Cardiac Dimensions. Dr Teerlink has received consulting fees from Amgen, Bayer, Cytokinetics, Novartis, and Stealth Health; and has received research funding from Abbott, Amgen, Bayer, Bristol Myers Squibb, Novartis, and scPharma. Dr Unger’s employer, Hyman, Phelps & McNamara, has contracts with many companies, some of which are developing treatments for HF. Dr Whellan has received grant support from the National Institutes of Health (grant R01AG045551). Dr Wittes’s employer, Wittes LLC, has contracts with many companies, some of which are developing treatments for HF. Dr Anker has received fees from Abbott, Bayer, Boehringer Ingelheim, Cardiac Dimension, Cordio, Impulse Dynamics, Novartis, Occlutech, Servier, and Vifor Pharma; and has received grant support from Abbott and Vifor Pharma. Dr O’Connor has received grant or research support from Roche Diagnostics and Merck; and has received consulting fees from Merck, Bayer, Bristol Myers Squibb, Abiomed, and Windtree. All other 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.)

Background: The impact of transcatheter edge-to-edge repair (TEER) on the rate and prognostic impact of hospitalizations in patients with heart failure (HF) and severe secondary mitral regurgitation is unknown., Objectives: This study sought to evaluate the effect of the MitraClip percutaneous edge-to edge repair system on fatal and nonfatal hospitalizations and their relationship with mortality in the COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation) trial., Methods: Patients with HF (n = 614) with severe secondary mitral regurgitation were randomized to TEER plus guideline-directed medical therapy (GDMT) versus GDMT alone. Hospitalizations were classified as fatal if death occurred during that hospitalization or nonfatal if the patient was discharged alive., Results: At 2 years, TEER treatment, compared with GDMT alone, resulted in lower time-to-first-event rates of any heart failure hospitalization (HFH) (34.8% vs 56.4%; HR: 0.51; 95% CI: 0.39-0.66) and fatal HFH (6.5% vs 12.6%; HR: 0.47; 95% CI: 0.26-0.85). TEER also resulted in lower rates of all-cause nonfatal and fatal hospitalizations. During the 2-year follow-up period, patients who underwent TEER spent an average of 2 more months alive and out of the hospital than did patients treated with GDMT alone (581 ± 27 days vs 519 ± 26 days; P = 0.002). All HFHs (adjusted HR: 6.37; 95% CI: 4.63-8.78) and nonfatal HFHs (adjusted HR: 1.78; 95% CI: 1.27-2.49) were consistently independently associated with increased 2-year mortality in both the TEER and GDMT groups (P interaction  = 0.34 and 0.39, respectively)., Conclusions: In the COAPT trial, compared with GDMT alone, patients with HF and severe secondary mitral regurgitation undergoing TEER with the percutaneous edge-to edge repair system had lower 2-year rates of fatal and nonfatal all-cause hospitalizations and HFH and spent more time alive and out of the hospital. HFHs were strongly associated with mortality, irrespective of treatment. (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation [The COAPT Trial] and COAPT CAS [COAPT]; NCT01626079)., Competing Interests: Funding Support and Author Disclosures The COAPT trial was sponsored by Abbott. Dr Giustino has received consulting fees (Advisory Board) from Bristol Myers Squibb/Pfizer. Dr Kapadia has received stock options from Navigate Cardiac Structures, Inc. Dr Kar has received consulting fees and served on the advisory board of Boston Scientific; has received consulting fees/stock equity from Valcare; and has received consulting fees from W.L. Gore and Medtronic. Dr Abraham has received research grant support from Abbott Vascular; and has received consulting fees from Abbott Vascular. Dr Lindenfeld has received research grant support from AstraZeneca; and has received consulting fees from Abbott Vascular, AstraZeneca, CVRx, Edwards Lifesciences, Impulse Dynamics, Boehringer Ingelheim, and V-Wave. Dr Lim has received research grant support from Abbott, Edwards, Medtronic, and Gore; has served as a consultant to Abbott, Edwards, Keystone Heart, Pipeline, Siemens, Valgen, and Venus; has served on the advisory boards of Ancora and Venus; and holds equity in 510Kardiac and Venus. Dr Grayburn has received consulting fees from Abbott Vascular, Edwards Lifesciences, W.L. Gore, Medtronic, and 4C Medical; and has received grant support from Abbott Vascular, Boston Scientific, Cardiovalve, Edwards Lifesciences, W.L. Gore, Medtronic, and Neochord. Dr Cohen has received research grant support from Abbott, Medtronic, Edwards Lifesciences, and Boston Scientific; and has received consulting fees from Abbott, Medtronic, Edwards Lifesciences, and Boston Scientific. Dr Asch has institutional contracts with Abbott, Neovasc, Ancora, Mitralign, Medtronic, Boston Scientific, Edwards Lifesciences, Biotronik, and Livanova. Dr Mack has served as coprimary investigator of the PARTNER Trial for Edwards Lifesciences and of COAPT trial for Abbott; and served as study chair for the APOLLO trial for Medtronic. Dr Stone has received speaker honoraria from Medtronic, Pulnovo, Infraredx; has served as a consultant to Valfix, TherOx, Robocath, HeartFlow, Ablative Solutions, Vectorious, Miracor, Neovasc, Abiomed, Ancora, Elucid Bio, Occlutech, CorFlow, Apollo Therapeutics, Impulse Dynamics, Vascular Dynamics, Shockwave, V-Wave, Cardiomech, Gore, and Amgen; and has received equity/options from Ancora, Cagent, Applied Therapeutics, Biostar family of funds, SpectraWave, Orchestra Biomed, Aria, Cardiac Success, Valfix, and Xenter; his employer, Mount Sinai Hospital, has received research support from Abbott, Abiomed, Bioventrix, Cardiovascular Systems Inc, Phillips, Biosense-Webster, Shockwave, Vascular Dynamics, and V-wave; and his daughter is an employee at Medtronic. 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.)

Aims: Patients with heart failure with reduced ejection fraction (HFrEF) are at significant risk of stroke. Anticoagulation reduces this risk in patients with and without atrial fibrillation (AF), but the risk-to-benefit balance in the latter group, overall, is not favourable. Identification of patients with HFrEF, without AF, at the highest risk of stroke may allow targeted and safer use of prophylactic anticoagulant therapy., Methods and Results: In a pooled patient-level cohort of the PARADIGM-HF, ATMOSPHERE, and DAPA-HF trials, a previously derived simple risk model for stroke, consisting of three variables (history of prior stroke, insulin-treated diabetes, and plasma N-terminal pro-B-type natriuretic peptide level), was validated. Of the 20 159 patients included, 12 751 patients did not have AF at baseline. Among patients without AF, 346 (2.7%) experienced a stroke over a median follow up of 2.0 years (rate 11.7 per 1000 patient-years). The risk for stroke increased with increasing risk score: fourth quintile hazard ratio (HR) 2.35 [95% confidence interval (CI) 1.60-3.45]; fifth quintile HR 3.73 (95% CI 2.58-5.38), with the first quintile as reference. For patients in the top quintile, the rate of stroke was 21.2 per 1000 patient-years, similar to participants with AF not receiving anticoagulation (20.1 per 1000 patient-years). Model discrimination was good with a C-index of 0.84 (0.75-0.91)., Conclusion: It is possible to identify a subset of HFrEF patients without AF with a stroke-risk equivalent to that of patients with AF who are not anticoagulated. In these patients, the risk-to-benefit balance might justify the use of prophylactic anticoagulation, but this hypothesis needs to be tested prospectively., Competing Interests: Conflict of interest: T.K. received speaker fees from Abbott, Ono Pharma, Otsuka Pharma, Novartis, AstraZeneca, Bristol-Myers Squibb, and Abiomed. A.T. have no disclosures to report. W.T.A. has received personal fees from Abbott; has received consulting fees from Boehringer Ingelheim, CVRx, Edwards Lifesciences, Impulse Dynamics, and Respicardia; has received salary support from V-Wave Medical; and has received research support from the NHLBI, all for studies performed within the heart failure arena. A.S.D. has received grants and personal fees from AstraZeneca during the conduct of the study; personal fees from Abbott, Biofourmis, Boston Scientific, Boehringer Ingelheim, Corvidia, DalCor Pharma, Relypsa, Regeneron, and Merck; grants and personal fees from Alnylam and Novartis; and personal fees from Amgen, outside the submitted work. K.D. has received honoraria and/or research support from Medtronic, Boston Scientific, St Jude, Biotronik, Sorin, Merck, Novartis, Amgen, Boehringer Ingelheim, AstraZeneca, Pfizer, Bayer, GlaxoSmithKline, Roche, Sanofi, Abbott, Otsuka, Leo, Servier, and Bristol-Meyers Squibb. S.E.I. has served on clinical trial committees or as a consultant to AstraZeneca, Boehringer Ingelheim, Novo Nordisk, Lexicon, Merck, Pfizer, vTv Therapeutics, Abbott, and Esperion; and has given lectures sponsored by AstraZeneca, and Boehringer Ingelheim. L.K. has received financial from AstraZeneca; and personal fees from Novartis and Bristol Myers Squibb as a speaker. M.N.K. has received research grant support from AstraZeneca, and Boehringer Ingelheim; has served as a consultant or on an advisory board for Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Esperion Therapeutics, Janssen, Merck (Diabetes and Cardiovascular), Novo Nordisk, Sanofi, and Vifor Pharma; has received other research support from AstraZeneca; and has received honorarium from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk. F.A.M. has received personal fees from AstraZeneca. Mi.P. reports consulting fees from AbbVie, Akcea, Actavis, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cardiorentis, Daiichi Sankyo, Gilead, Johnson & Johnson, Novo Nordisk, Pfizer, Relypsa, Sanofi, Synthetic Biologics, and Theravance. Ma.P. is supported by the British Heart Foundation Centre of Research Excellence Award (RE/13/5/30177 and RE/18/6/34217þ); has received research funding from AstraZeneca, Boehringer Ingelheim, Boston Scientific, Medtronic, Novartis, Novo Nordisk, Pharmacosmos, Roche, and SQ Innovations; and has served as a consultant and on Clinical Trials Committees for Abbvie, AstraZeneca, Bayer, Boehringer Ingelheim, Cardiorentis, Medtronic, Novartis, Novo Nordisk, Pharmacosmos, Siemens, and Takeda. P.P. has received personal fees from Boehringer Ingelheim, AstraZeneca, Servier, Bristol Myers Squib, Amgen, Novartis, Merck, Pfizer, and Berlin Chemie; and has received grants and personal fees from Vifor Pharma. J.L.R. reports grants and consulting fees from Novartis and consulting fees from Abbott, AstraZeneca, MyoKardia, and Sanofi. K.S. reports honoraria from AstraZeneca, Boehringer Ingelheim, and Novartis. M.S.S. has received grants and personal fees from AstraZeneca during the conduct of the study; and has received grants and personal fees from Amgen, Intarcia, Janssen Research and Development, Medicines Company, MedImmune, Merck, and Novartis; and has received personal fees from Anthos Therapeutics, Bristol-Myers Squibb, CVS Caremark, DalCor, Dyrnamix, Esperion, IFM Therapeutics, Ionis; and has received grants from Daiichi Sankyo, Bayer, Pfizer, Poxel, Eisai, GlaxoSmithKline, Quark Pharmaceuticals, and Takeda outside the submitted work; and is a member of the TIMI Study Group, which has also received institutional research grant support through Brigham and Women’s Hospital from Abbott, Aralez, Roche, and Zora Biosciences. K.S. reports honoraria from AstraZeneca, Boehringer Ingelheim and Novartis. M.R.Z. reports research funding from Novartis and has been a consultant for Novartis, Abbott, Boston Scientific, CVRx, EBR, Endotronics, Ironwood, Merck, Medtronic, and Myokardia V-Wave. S.D.S. has received research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lilly, Mesoblast, MyoKardia, National Institutes of Health/NHLBI, Neurotronik, Novartis, NovoNordisk, Respicardia, Sanofi Pasteur, Theracos, US2.AI; and has consulted for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi Sankyo, GlaxoSmithKline, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi Pasteur, Dinaqor, Tremeau, CellPro-Thera, Moderna, American Regent, and Sarepta. P.S.J.’s employer has been remunerated for his work on clinical trials from AstraZeneca, Bayer, Novo Nordisk, and Novartis. Consulting and speakers fees Novartis, AstraZeneca, Boheringer Ingelheim, research funding Boehringer Ingelheim. J.J.V.M. has received payments through Glasgow University from 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, Theracos Personal lecture fees: the Corpus, Abbott, Hikma, Sun Pharmaceuticals, Medscape/Heart.Org, Radcliffe Cardiology, Servier Director, Global Clinical Trial Partners (GCTP)., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.)

Aims: Guideline-directed medical therapy (GDMT), based on the combination of beta-blockers (BB), renin-angiotensin system inhibitors (RASI), and mineralocorticoid receptor antagonists (MRA), is known to have a major impact on the outcome of patients with heart failure with reduced ejection fraction (HFrEF). Although GDMT is recommended prior to mitral valve transcatheter edge-to-edge repair (M-TEER), not all patients tolerate it. We studied the association of GDMT prescription with survival in HFrEF patients undergoing M-TEER for secondary mitral regurgitation (SMR)., Methods and Results: EuroSMR, a European multicentre registry, included SMR patients with left ventricular ejection fraction <50%. The outcome was 2-year all-cause mortality. Of 1344 patients, BB, RASI, and MRA were prescribed in 1169 (87%), 1012 (75%), and 765 (57%) patients at the time of M-TEER, respectively. Triple GDMT prescription was associated with a lower 2-year all-cause mortality compared to non-triple GDMT (hazard ratio [HR] 0.74; 95% confidence interval [CI] 0.60-0.91). The association persisted in patients with glomerular filtration rate <30 ml/min, ischaemic aetiology, or right ventricular dysfunction. Further, a positive impact of triple GDMT prescription on survival was observed in patients with residual mitral regurgitation of ≥2+ (HR 0.62; 95% CI 0.44-0.86), but not in patients with residual mitral regurgitation of ≤1+ (HR 0.83; 95% CI 0.64-1.08)., Conclusion: Triple GDMT prescription is associated with higher 2-year survival after M-TEER in HFrEF patients with SMR. This association was consistent also in patients with major comorbidities or non-optimal results after M-TEER., (© 2022 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: The impact of mitral valve geometry on outcomes after MitraClip treatment in secondary mitral regurgitation (MR) has not been examined. We therefore sought to evaluate the association between mitral valve geometry and outcomes of patients with heart failure (HF) and secondary MR treated with guideline-directed medical therapy (GDMT) and MitraClip., Methods and Results: Mitral valve geometry was assessed from the baseline echocardiograms in 614 patients from the COAPT trial. The primary endpoint for the present study was the composite of all-cause mortality or HF hospitalization (HFH) within 2 years. Effect of treatment arm (MitraClip plus maximally tolerated GDMT vs. GDMT alone) on outcomes according to baseline variables was assessed. Among 29 baseline mitral valve echocardiographic parameters, increasing anteroposterior mitral annular diameter was the only independent predictor of the composite endpoint of all-cause mortality or HFH [adjusted hazard ratio (aHR) per cm 1.49; P = 0.04]. The effective regurgitant orifice area (EROA) was independently associated with all-cause mortality alone (aHR per cm2 2.97; P = 0.04) but not with HFH, whereas increasing anteroposterior mitral annular diameter was independently associated with HFH alone (aHR per cm 1.85; P = 0.005) but not all-cause mortality. Other mitral valve morphologic parameters were unrelated to outcomes. MitraClip reduced HFH and mortality independent of anteroposterior mitral annular diameter and EROA (Pinteraction = 0.77 and 0.27, respectively)., Conclusion: In patients with HF and severe secondary MR, a large anteroposterior mitral annular diameter and greater EROA were the strongest echocardiographic predictors of HFH and death in patients treated with GDMT alone and with the MitraClip., Competing Interests: Conflict of interest: The present study was funded by Abbott Vascular. The Department of Cardiology of Leiden University Medical Centre has received unrestricted research grants from Abbott, Bayer, Biotronik, Boston Scientific, Edwards Lifesciences, GE Healthcare, and Medtronic. F.N. and S.M.P. received a research grant support from Abbott Vascular. N.A.M. received speaker fees from Abbott Vascular. V.D. received speaker fees from Abbott Vascular, Medtronic, Edwards Lifesciences, MSD, Novartis and GE Healthcare. F.M.A. and N.J.W. are Director and Associate Director of an academic echocardiography core lab (MedStar Health Research Institute) with Institutional contracts with Abbott, Boston Scientific, Edwards Lifesciences, Neovasc, Ancora, Mitralign, MVRx, Innovheart, Polares Medical, Medtronic, Biotronik, Livanova. J.A.L. receives research grant support from AstraZeneca and consulting income from Abbott and Edwards. W.T.A. receives research grant support and consulting income from Abbott. M.J.M. has non-financial relationships with Edwards Lifesciences (co-PI of the PARTNER 3 Trial), Abbott (Co-PI of the COAPT Trial), and Medtronic (study chairman of the APOLLO Trial). G.W.S. has received speaker or other honoraria from Cook, Terumo, QOOL Therapeutics and Orchestra Biomed; has served as a consultant to Valfix, TherOx, Vascular Dynamics, Robocath, HeartFlow, Gore, Ablative Solutions, Miracor, Neovasc, V-Wave, Abiomed, Ancora, MAIA Pharmaceuticals, Vectorious, Reva, Matrizyme, Cardiomech; and has equity/options from Ancora, Qool Therapeutics, Cagent, Applied Therapeutics, Biostar family of funds, SpectraWave, Orchestra Biomed, Aria, Cardiac Success, MedFocus family of funds, Valfix. J.J.B. has received speaker fees from Abbott and Edwards Lifesciences. The remaining authors have no conflicts of interest to disclose., (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: There are limited data on the predictors of death or heart failure hospitalization (HFH) in patients with heart failure (HF) with functional mitral regurgitation (FMR)., Objectives: The aim of this study was to develop a predictive risk score using the COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation) trial database., Methods: In COAPT, 614 symptomatic patients with HF and moderate to severe or severe FMR were randomized to MitraClip implantation plus guideline-directed medical therapy (GDMT) or GDMT alone. A risk score for the 2-year rate of death or HFH was generated from Cox proportional hazards models. The predictive value of the model was assessed using the area under the curve of receiver-operating characteristic plots. Kaplan-Meier curves were generated to estimate the proportion of patients experiencing death or HFH across quartiles of risk., Results: During 2-year follow-up, 201 patients (64.4%) in the GDMT-alone group and 133 patients (44.0%) in the MitraClip group experienced death or HFH (P < 0.001). A risk score containing 4 clinical variables (New York Heart Association functional class, chronic obstructive pulmonary disease, atrial fibrillation or flutter, and chronic kidney disease) and 4 echocardiographic variables (left ventricular ejection fraction, left ventricular end-systolic dimension, right ventricular systolic pressure, and tricuspid regurgitation) in addition to MitraClip treatment was generated. The area under the curve of the risk score model was 0.74, and excellent calibration was present. The relative benefit of MitraClip therapy in reducing the 2-year hazard of death or HFH was consistent across the range of baseline risk., Conclusions: A simple risk score of clinical, echocardiographic, and treatment variables may provide useful prognostication in patients with HF and severe FMR., Competing Interests: Funding Support and Author Disclosures The COAPT trial was sponsored by Abbott. The funder had no role in the study design, data collection, data analysis, data interpretation, or writing of the report. Dr Madhavan has received an institutional grant from the National Institutes of Health/National Heart, Lung, and Blood Institute to Columbia University Irving Medical Center (T32 HL007854). Dr Gray is a consultant for Boston Scientific. Dr Brener is a Speakers Bureau member for AstraZeneca. Dr Lindenfeld has received research grant support from AstraZeneca; and has received consulting income from Abbott Vascular, CVRx, Edwards Lifesciences, RESMED, Relypsa, Boehringer Ingelheim, and V-Wave. Dr Abraham has received research grant support from Abbott Vascular; and has received consulting income from Abbott Vascular. Dr Grayburn has received grant support and consulting fees from Edwards Lifesciences and NeoChord; and has received grant support from Boston Scientific, Medtronic, and Tendyne. Dr Lim has received research grant support from Abbott, Edwards Lifesciences, Medtronic, and Gore; is a consultant for Abbott, Edwards Lifesciences, Keystone Heart, Pipeline, Siemens, Valgen, and Venus; is an advisory board member for Ancora and Venus; and holds equity in 510Kardiac and Venus. Dr Whisenant is a consultant for Edwards Lifesciences, Boston Scientific, Gore, and NeoChord. Dr Mack has served as co–primary investigator for the PARTNER trial for Edwards Lifesciences and the COAPT trial for Abbott; and has served as study chair for the APOLLO trial for Medtronic. Dr Stone has received speaker or other honoraria from Terumo, Cook, and Infraredx; has served as a consultant to Valfix, TherOx, Robocath, HeartFlow, Ablative Solutions, Vectorious, Miracor, Neovasc, Abiomed, Ancora, Elucid Bio, Occlutech, CorFlow, Reva, MAIA Pharmaceuticals, Vascular Dynamics, Shockwave, V-Wave, CardioMech, and Gore; and has equity and options with Ancora, Cagent, Applied Therapeutics, the Biostar family of funds, SpectraWave, Orchestra Biomed, Aria, Cardiac Success, Valfix, and the MedFocus family of funds. 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.)

Background: Differences in clinically important thresholds in patient-reported outcomes measures such as the Kansas City Cardiomyopathy Questionnaire (KCCQ) remain less well-established in patients with heart failure with preserved ejection fraction (HFpEF) versus heart failure with reduced ejection fraction (HFrEF)., Objectives: The purpose of this study was to estimate meaningful thresholds for improvement or deterioration in the KCCQ-Total Symptom Score (TSS) in patients with HFrEF versus HFpEF., Methods: This secondary analysis of EMPERIAL program used anchor- and distribution-based approaches to estimate thresholds for improvement or deterioration in the KCCQ-TSS using Patient Global Impression of Severity (PGIS) as the primary anchor. Mean change in KCCQ-TSS from baseline to week 12 was calculated for each PGIS., Results: A total of 312 HFrEF and 315 HFpEF patients were enrolled. At week 12, mean changes in KCCQ-TSS corresponding to PGIS changes of "any improvement," "1-category improvement," and "1-category deterioration" were 13 ± 17, 12 ± 17, -3 ± 16 points in HFrEF, and 15 ± 18, 13 ± 17, -7 ± 18 points in HFpEF. Threshold for meaningful within-patient change in KCCQ-TSS was ≥9 points in HFrEF and ≥7 points in HFpEF patients. Sensitivity and specificity of ≥9 points/≥7 points change was 0.65 and 0.70 for HFrEF and 0.64 and 0.66 for HFpEF. Cumulative distribution function curves of KCCQ-TSS change from baseline to week 12 showed a shift to higher scores in both HFrEF and HFpEF patients., Conclusions: In the EMPERIAL program, a change in KCCQ-TSS of ≥9 points in HFrEF and ≥7 points in HFpEF represents the minimal clinically important difference for improvement, confirming the broad range of 5-10 points as meaningful thresholds., Competing Interests: Funding Support and Author Disclosures The EMPERIAL trials were sponsored by Boehringer Ingelheim. Dr Butler has received consulting fees from Boehringer Ingelheim, Cardior, CVRx, Foundry, G3 Pharma, Imbria, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, NovoNordisk, Relypsa, Roche, Sanofi, Sequana Medical, V-Wave Ltd, and Vifor. Dr Lindenfeld has received personal fees from Abbott, AstraZeneca, Boehringer Ingelheim, CVRx, Edwards Lifesciences, Impulse Dynamics, and V-Wave Ltd; and has received grants from AstraZeneca, Sensible Medical, and Volumetrix. Dr Abraham has received personal fees from Boehringer Ingelheim; has received consulting fees from Abbott, Respicardia, Sensible Medical, CVRx, and Impulse Dynamics; and has received salary support from V-Wave Ltd. Dr Savarese has received grants and personal fees from Vifor and AstraZeneca; has received grants and nonfinancial support from Boehringer Ingelheim; has received personal fees from Società Prodotti Antibiotici, Roche, Servier, GENESIS, Cytokinetics, and Medtronic; and has received grants from Merck Sharp & Dohme, and Novartis. Drs Salsali, Zeller, and Peil are employees of Boehringer Ingelheim. Dr Filippatos has received Committee Member contributions in trials sponsored by Medtronic, Vifor, Servier, Novartis, and Boehringer Ingelheim. Dr Ponikowski has received personal fees from Boehringer Ingelheim, AstraZeneca, Servier, Bristol Myers Squib, Amgen, Novartis, Merck, Pfizer, and Berlin Chemie; and has received grants and personal fees from Vifor Pharma. Dr Anker has received grants and personal fees from Vifor International and Abbott Vascular; and has received personal fees from Bayer, Boehringer Ingelheim, Novartis, Servier, ID, and Cardiac Dimensions. Dr Khan has reported that he has no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: Heart failure with reduced ejection fraction (HFrEF) remains associated with high morbidity and mortality, poor quality of life (QoL) and significant exercise limitation. Sympatho-vagal imbalance has been shown to predict adverse prognosis and symptoms in HFrEF, yet it has not been specifically targeted by any guideline-recommended device therapy to date. Barostim™, which directly addresses this imbalance, is the first Food and Drug Administration approved neuromodulation technology for HFrEF. We aimed to analyse all randomized trial evidence to evaluate the effect of baroreflex activation therapy (BAT) on heart failure symptoms, QoL and N-terminal pro-brain natriuretic peptide (NT-proBNP) in HFrEF., Methods and Results: An individual patient data (IPD) meta-analysis was performed on all eligible trials that randomized HFrEF patients to BAT + guideline-directed medical therapy (GDMT) or GDMT alone (open label). Endpoints included 6-month changes in 6-min hall walk (6MHW) distance, Minnesota Living With Heart Failure (MLWHF) QoL score, NT-proBNP, and New York Heart Association (NYHA) class in all patients and three subgroups. A total of 554 randomized patients were included. In all patients, BAT provided significant improvement in 6MHW distance of 49 m (95% confidence interval [CI] 33, 64), MLWHF QoL of -13 points (95% CI -17, -10), and 3.4 higher odds of improving at least one NYHA class (95% CI 2.3, 4.9) when comparing from baseline to 6 months. These improvements were similar, or better, in patients who had baseline NT-proBNP &lt;1600 pg/ml, regardless of the cardiac resynchronization therapy indication status., Conclusion: An IPD meta-analysis suggests that BAT improves exercise capacity, NYHA class, and QoL in HFrEF patients receiving GDMT. These clinically meaningful improvements were consistent across the range of patients studies. BAT was also associated with an improvement in NT-proBNP in subjects with a lower baseline NT-proBNP., (© 2022 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)