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Objective We tested whether remote dielectric sensing (ReDS)-directed fluid management reduces readmissions in patients recently hospitalized for heart failure (HF). Background Pulmonary congestion is the most common cause of worsening HF leading to hospitalization. Accurate remote monitoring of lung fluid volume may guide optimal treatment and prevent re-hospitalization. ReDS technology is a quantitative non-invasive method for measuring absolute lung fluid volume. Methods Patients hospitalized for acute decompensated HF were enrolled during their index admission and followed at home for 90days post-discharge. Daily ReDS readings were obtained using a wearable vest, and were used as a guide to optimizing HF therapy, with a goal of maintaining normal lung fluid content. Comparisons of the number of HF hospitalizations during ReDS-guided HF therapy were made, both to the 90days prior to enrollment and to the 90days following discontinuation of ReDS monitoring. Results Fifty patients were enrolled, discharged, and followed at home for 76.9±26.2days. Patients were 73.8±10.3years old, 40% had LVEF above 40%, and 38% were women. Compared to the pre- and post-ReDS periods, there were 87% and 79% reductions in the rate of HF hospitalizations, respectively, during ReDS-guided HF therapy. The hazard ratio between the ReDS and the pre-ReDS period was 0.07 (95% CI [0.01–0.54] p =0.01), and between the ReDS and the post-ReDS period was 0.11 (95% CI [0.014–0.88] p =0.037). Conclusions These findings suggest that ReDS-guided management has the potential to reduce HF readmissions in acute decompensated HF patients recently discharged from the hospital.

BACKGROUNDIn patients with acute heart failure, early intervention with an intravenous vasodilator has been proposed as a therapeutic goal to reduce cardiac-wall stress and, potentially, myocardial injury, thereby favorably affecting patients' long-term prognosis.METHODSIn this double-blind trial, we randomly assigned 2157 patients with acute heart failure to receive a continuous intravenous infusion of either ularitide at a dose of 15 ng per kilogram of body weight per minute or matching placebo for 48 hours, in addition to accepted therapy. Treatment was initiated a median of 6 hours after the initial clinical evaluation. The coprimary outcomes were death from cardiovascular causes during a median follow-up of 15 months and a hierarchical composite end point that evaluated the initial 48-hour clinical course.RESULTSDeath from cardiovascular causes occurred in 236 patients in the ularitide group and 225 patients in the placebo group (21.7% vs. 21.0%; hazard ratio, 1.03; 96% confidence interval, 0.85 to 1.25; P=0.75). In the intention-to-treat analysis, there was no significant between-group difference with respect to the hierarchical composite outcome. The ularitide group had greater reductions in systolic blood pressure and in levels of N-terminal pro-brain natriuretic peptide than the placebo group. However, changes in cardiac troponin T levels during the infusion did not differ between the two groups in the 55% of patients with paired data.CONCLUSIONSIn patients with acute heart failure, ularitide exerted favorable physiological effects (without affecting cardiac troponin levels), but short-term treatment did not affect a clinical composite end point or reduce long-term cardiovascular mortality. (Funded by Cardiorentis; TRUE-AHF ClinicalTrials.gov number, NCT01661634.)

The prevalence of heart failure (HF) has risen in parallel with improved survival in patients after a myocardial infarction and an aging population worldwide. In recent years, new percutaneous therapies have been developed to complement current established treatments for acute/decompensated and chronic HF and minimize risks. In acute presentations, the failure of medical treatment is no longer the end of the road in refractory circulatory shock; the use of mechanical circulatory support devices may be the next milestone in well-resourced health settings. Although evidence in this area is difficult to generate, research networks can facilitate the volume and quality of data needed to further augment the clinician's knowledge. Pulsatile (intra-aortic balloon pump), axial continuous (Impella), or centrifugal continuous pumps (TandemHeart; HeartMate PHP) together with percutaneously implanted extracorporeal membrane oxygenation are radically changing the prognosis of acute HF. Newer percutaneous therapies for chronic HF are based on attractive hypotheses, including left atrial decompression with shunting devices, left ventricle restoration through partitioning devices, or pressure-guided implantable therapies that may help to promptly treat decompensations. To date, only the last has been proved effective in a randomized study. Therefore, thorough research is still needed in this dynamic and promising field.

Resumen La prevalencia de la insuficiencia cardiaca (IC) aumenta paralelamente al envejecimiento poblacional y la mayor supervivencia de los pacientes con infarto de miocardio. Recientemente se han desarrollado nuevas terapias percutaneas con el objetivo de complementar los tratamientos actuales de la IC aguda/descompensada y cronica minimizando los riesgos. En la IC aguda, el fracaso del tratamiento medico ya no puede ser el final de la estrategia terapeutica para el shock cardiogenico, dado el exito de los dispositivos de soporte circulatorio mecanico. A pesar de que la evidencia en esta area es dificil de generar, el pronostico de la IC aguda esta cambiando radicalmente gracias a la investigacion en red sobre dispositivos de flujo pulsatil (balon de contrapulsacion intraaortico), continuo axial (Impella) o continuo centrifugo (TandemHeart; HeartMate PHP) junto con el implante percutaneo de oxigenador extracorporeo de membrana. Las nuevas terapias percutaneas en la IC cronica se basan en atractivas hipotesis como la descompresion de la auricula izquierda (shunts) , la restauracion ventricular (compartimentacion) o la monitorizacion intratoracica de presiones mediante dispositivos implantables que permitan tratar precozmente las descompensaciones. Actualmente solo la ultima se ha probado efectiva en un estudio aleatorizado. Por lo tanto, es necesario estudiar a fondo este dinamico y prometedor campo.

Background: Elevated pulmonary artery (PA) pressures in patients with heart failure are associated with a high risk for hospitalization and mortality. Recent clinical trial evidence demonstrated a direct relationship between lowering remotely monitored PA pressures and heart failure hospitalization risk reduction with a novel implantable PA pressure monitoring system (CardioMEMS HF System, St. Jude Medical). This study examines PA pressure changes in the first 2000 US patients implanted in general practice use. Methods: Deidentified data from the remote monitoring Merlin.net (St. Jude Medical) database were used to examine PA pressure trends from the first consecutive 2000 patients with at least 6 months of follow-up. Changes in PA pressures were evaluated with an area under the curve methodology to estimate the total sum increase or decrease in pressures (mm Hg-day) during the follow-up period relative to the baseline pressure. As a reference, the PA pressure trends were compared with the historic CHAMPION clinical trial (CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in New York Heart Association [NYHA] Functional Class III Heart Failure Patients). The area under the curve results are presented as mean±2 SE, and P values comparing the area under the curve of the general-use cohort with outcomes in the CHAMPION trial were computed by the t test with equal variance. Results: Patients were on average 70±12 years old; 60% were male; 34% had preserved ejection fraction; and patients were followed up for an average of 333±125 days. At implantation, the mean PA pressure for the general-use patients was 34.9±10.2 mm Hg compared with 31.3±10.9 mm Hg for CHAMPION treatment and 32.0±10.5 mm Hg for CHAMPION control groups. The general-use patients had an area under the curve of −32.8 mm Hg-day at the 1-month time mark, −156.2 mm Hg-day at the 3-month time mark, and −434.0 mm Hg-day after 6 months of hemodynamic guided care, which was significantly lower than the treatment group in the CHAMPION trial. Patients consistently transmitted pressure information with a median of 1.27 days between transmissions after 6 months. Conclusions: The first 2000 general-use patients managed with hemodynamic-guided heart failure care had higher PA pressures at baseline and experienced greater reduction in PA pressure over time compared with the pivotal CHAMPION clinical trial. These data demonstrate that general use of implantable hemodynamic technology in a nontrial setting leads to significant lowering of PA pressures.

Background:\ud \ud Although cardiac resynchronization therapy (CRT) is effective for some patients with heart failure and a reduced left ventricular ejection fraction (HFrEF), evidence gaps remain for key clinical and policy areas. The objective of the study was to review the data on the effects of CRT for patients with HFrEF receiving pharmacological therapy alone or pharmacological therapy and an implantable cardioverter-defibrillator (ICD) and then, informed by a diverse group of stakeholders, to identify evidence gaps, prioritize them, and develop a research plan.\ud \ud Methods:\ud \ud Relevant studies were identified using PubMed and EMBASE and ongoing trials using clinicaltrials.gov. Forced-ranking prioritization method was applied by stakeholders to reach a consensus on the most important questions. Twenty-six stakeholders contributed to the expanded list of evidence gaps, including key investigators from existing randomized controlled trials and others representing different perspectives, including patients, the public, device manufacturers, and policymakers.\ud \ud Results:\ud \ud Of the 18 top-tier evidence gaps, 8 were related to specific populations or subgroups of interest. Seven were related to the comparative effectiveness and safety of CRT interventions or comparators, and 3 were related to the association of CRT treatment with specific outcomes. The association of comorbidities with CRT effectiveness ranked highest, followed by questions about the effectiveness of CRT among patients with atrial fibrillation and the relationship between gender, QRS morphology and duration, and outcomes for patients either with CRT plus ICD or with ICD.\ud \ud Conclusions:\ud \ud Evidence gaps presented in this article highlight numerous, important clinical and policy questions for which there is inconclusive evidence on the role of CRT and provide a framework for future collaborative research.

In the COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation) trial, transcatheter mitral valve repair (TMVr) with the MitraClip rapidly improved health status and reduced the long-term risks for death and heart failure (HF) hospitalization in patients with HF and severe secondary mitral regurgitation who remained symptomatic despite maximally tolerated guideline-directed medical therapy (GDMT).The aim of this study was to examine if early health status changes were associated with long-term clinical outcomes in the COAPT population.The association between change in health status (Kansas City Cardiomyopathy Questionnaire overall summary score [KCCQ-OS]) from baseline to 1 month and the composite rate of death or HF hospitalization between 1 month and 2 years in the COAPT trial were evaluated, and whether treatment (TMVr or GDMT alone) modified this association was tested.Among 551 patients with HF and severe secondary mitral regurgitation who were alive at 1 month, those randomized to TMVr were more likely than those randomized to GDMT alone to achieve a ≥10-point improvement in KCCQ-OS from baseline to 1 month (TMVr, 58%; GDMT alone, 26%). Early improvement in KCCQ-OS was inversely associated with the risk for death or HF hospitalization between 1 month and 2 years (p 0.001). When analyzed as a continuous variable, a 10-point increase in KCCQ-OS was associated with a 14% lower risk for death or HF hospitalization (hazard ratio: 0.86; 95% confidence interval: 0.81 to 0.92; p 0.001), with no significant interaction with treatment group (pIn patients with HF and severe secondary mitral regurgitation, a short-term change in disease-specific health status was strongly associated with the subsequent long-term risk for death or HF hospitalization. These findings reinforce the prognostic utility of serial KCCQ-OS assessments to identify patients at risk for poor long-term clinical outcomes in this population. (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation [The COAPT Trial]; NCT01626079).

Aims: To investigate the relationship between heart rate and outcomes in heart failure and reduced ejection fraction (HFrEF) patients in sinus rhythm (SR) and atrial fibrillation (AF) adjusting for natriuretic peptide concentration, a powerful prognosticator. Methods and results: Of 13 562 patients from two large HFrEF trials, 10 113 (74.6%) were in SR and 3449 (25.4%) in AF. The primary endpoint was the composite of cardiovascular death or heart failure hospitalization. Heart rate was analysed as a categorical (tertiles, T1–3) and continuous variable (per 10 bpm), separately in patients in SR and AF. Outcomes were adjusted for prognostic variables, including N-terminal prohormone of B-type natriuretic peptide (NT-proBNP), and also examined using change from baseline heart rate to 1 year (≤ −10 bpm, ≥ +10 bpm, < ±10 bpm). SR patients with a higher heart rate had worse symptoms and quality of life, more often had diabetes and higher NT-proBNP concentrations. They had higher risk of the primary endpoint [T3 vs. T1 adjusted hazard ratio (HR) 1.50, 95% confidence interval (CI) 1.35–1.66; P < 0.001; per 10 bpm: 1.12, 95% CI 1.09–1.16; P < 0.001]. In SR, heart rate was associated with a relatively higher risk of pump failure than sudden death (adjusted HR per 10 bpm 1.17, 95% CI 1.09–1.26; P < 0.001 vs. 1.07, 95% CI 1.02–1.13; P = 0.011). Heart rate was not predictive of any outcome in AF. Conclusions: In HFrEF, an elevated heart rate was an independent predictor of adverse cardiovascular outcomes in patients in SR, even after adjustment for NT-proBNP. There was no relationship between heart rate and outcomes in AF. Clinical Trial Registration: ClinicalTrials.gov Identifiers NCT01035255 and NCT00853658.

Importance: Accurate prediction of risk of death or hospitalizations in patients with heart failure (HF) may allow physicians to explore how more accurate decisions regarding appropriateness and timing of disease-modifying treatments, advanced therapies, or the need for end-of-life care can be made. Objective: To develop and validate a prognostic model for patients with HF. Design, Setting, and Participants: Multivariable analyses were performed in a stepwise fashion. Harrell C statistic was used to assess the discriminative ability. The derivation cohort was Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure trial (PARADIGM-HF) participants. The models were validated using the Aliskiren Trial to Minimize Outcomes in Patients with Heart Failure Trial (ATMOSPHERE) study and in the Swedish Heart Failure Registry (SwedeHF). A total of 8399 participants enrolled in PARADIGM-HF. Data were analyzed between June 2016 and June 2018. Main Outcomes and Measures: Cardiovascular death, all-cause mortality, and the composite of cardiovascular death or HF hospitalization at both 1 and 2 years. Results: Complete baseline clinical data were available for 8011 patients in PARADIGM-HF. The mean (SD) age of participants was 64 (11.4) years, 78.2% were men (n = 6567 of 8399), and 70.6% were New York Heart Association class II (n = 5919 of 8399). During a mean follow-up of 27 months, 1546 patients died, and 2031 had a cardiovascular death or HF hospitalization. The common variables were: male sex, race/ethnicity (black or Asian), region (Central Europe or Latin America), HF duration of more than 5 years, New York Heart Association class III/ IV, left ventricular ejection fraction, diabetes mellitus, β-blocker use at baseline, and allocation to sacubitril/valsartan. Ranked by χ2, N-terminal pro brain natriuretic peptide was the single most powerful independent predictor of each outcome. The C statistic at 1 and 2 years was 0.74 (95% CI, 0.71-0.76) and 0.71 (95% CI, 0.70-0.73) for the primary composite end point, 0.73 (95% CI, 0.71-0.75) and 0.71 (95% CI, 0.69-0.73) for cardiovascular death, and 0.71 (95% CI, 0.69-0.74) and 0.70 (95% CI, 0.67-0.74) for all-cause death, respectively. When validated in ATMOSPHERE, the C statistic at 1 and 2 years was 0.71 (95% CI, 0.69-0.72) and 0.70 (95% CI, 0.68-0.71) for the primary composite end point, 0.71 (95% CI, 0.69-0.74) and 0.70 (95% CI, 0.69-0.72) for cardiovascular death, and 0.71 (95% CI, 0.69-0.74) and 0.70 (95% CI, 0.68-0.72) for all-cause death, respectively. An online calculator was created to allow calculation of an individual’s risk (http://www.predict-hf.com). Conclusions and Relevance: Predictive models performed well and were developed and externally validated in large cohorts of geographically representative patients, comprehensively characterized with clinical and laboratory data including natriuretic peptides, who were receiving contemporary evidence-based treatment.

Aims: The importance of intra-ventricular conduction delay (IVCD), the incidence of new IVCD and its relationship to outcomes in heart failure and reduced ejection fraction (HFrEF) are not well studied. We addressed these questions in the PARADIGM-HF and ATMOSPHERE trials. Methods and results: The risk of the primary composite outcome of cardiovascular death or heart failure hospitalization and all-cause mortality were estimated by use of Cox regression according to baseline QRS duration and morphology in 11 861 patients without an intracardiac device. At baseline, 1789 (15.1%) patients had left bundle branch block (LBBB), 524 (4.4%) right bundle branch block (RBBB), 454 (3.8%) non-specific IVCD, 2588 (21.8%) ‘mildly abnormal’ QRS (110–129 ms) and 6506 (54.9%) QRS

Cardiac contractility modulation, also referred to as CCM™, by the Optimizer Smart device is an innovative intracardiac device-based therapy that has been recently US FDA-approved for the treatment of patients with chronic heart failure, left ventricular ejection fraction (LVEF) between 25 and 45%, QRS

Functional mitral regurgitation (MR) in setting of cardiomyopathy causes significant morbidity and worsened survival. Surgical therapies have failed to demonstrate significant overall benefit for functional MR. More recently, major trials utilizing transcatheter therapies for functional MR have been completed and offer new avenues for intervention. This review evaluates and compares 2 major recent trials designed to test the benefit of edge-to-edge repair using the MitraClip system for severe functional MR. The Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation (COAPT) and Percutaneous Repair with the MitraClip Device for Severe Functional/Secondary Mitral Regurgitation (MITRA-FR) trials were simultaneous trials evaluating the treatment of effect of MitraClip in the setting of severe functional mitral regurgitation. Results of the trials were quite different with COAPT demonstrating substantial clinical benefit including significantly improved survival compared with MITRA-FR in which no clinical benefit was derived. Key differences in the patient population between the COAPT and MITRA-FR trials help to explain the contrasting results between the 2 trials designed to test the same hypothesis. Patients in COAPT had higher severity of MR with less dilated ventricles compared with MITRA-FR. These results will help shape patient selection for who will most benefit from MitraClip therapy. Further transcather mitral valve therapies continue to evolve and will likely offer alternative therapies for MR as technology improves.

The initial cause of worsening heart failure is increased intracardiac and pulmonary pressures. Traditional non-invasive heart failure monitoring strategies that follow surrogates of increased pressures have not reduced heart failure hospitalizations. Pulmonary artery pressure measurements using the implantable CardioMEMS system allow daily remote monitoring and earlier identification of heart failure decompensations. In the CHAMPION trial, remote monitoring with the CardioMEMS Heart Failure system significantly reduced hospitalizations for heart failure, even in patients with numerous comorbidities. For patients with refractory advanced heart failure, mechanical circulatory support can markedly improve the length and quality of life but can also have multiple complications. Implantable hemodynamic monitoring with CardioMEMS may provide clinicians with better information to guide the timing of left ventricular assist device implantation and to improve post-implant care.

Background Cardiac resynchronization therapy (CRT) improves survival in patients with heart failure, reduced ejection fraction (HFrEF) and left bundle branch block (LBBB). However, little is known about the incidence of LBBB in HFrEF and the risk factors for developing this. We addressed these questions in the PARADIGM-HF and ATMOSPHERE trials. Methods We identified 7703 patients with a non-paced rhythm on their baseline ECG, a QRS Results Overall, 313 of 7703 patients (4%) developed LBBB during a mean follow-up of 2.7 years, yielding an incidence rate of 1.5 per 100 py. The rate ranged from 0.9 in those with QRS ≤100 ms to 4.0 per 100 py in patients with QRS 116–129 ms. Other predictors of incident LBBB included male sex, age, lower LVEF, HF duration and absence of AF. The risk of the primary composite endpoint was higher among those who developed incident LBBB vs no incident LBBB; event rates 13.5 vs 10.0 per 100 py, yielding an adjusted HR of 1.43 (1.05–1.96). For all-cause mortality the corresponding rates were 12.6 vs 7.3 per 100 py; HR 1.55 (1.16–2.07) (Table 1). Table 1. Risk of outcomes according to incident LBBB during follow-up No. events Crude rate per 100py Adjusted* HR (95% CI) HF hospitalization or CV death No incident LBBB 2145 10.0 (9.6–10.4) 1.00 (ref.) Incident LBBB 43 13.5 (10.0–18.2) 1.43 (1.05–1.96) All-cause mortality No incident LBBB 1662 7.3 (6.9–7.6) 1.00 (ref.) Incident LBBB 48 12.6 (9.5–16.7) 1.55 (1.16–2.07) Conclusion Among patients with HFrEF, the annual incidence of new-onset LBBB (and a potential indication for CRT), was around 1.5%, ranging from 1% in those with QRS duration below 100 ms to 4% in those with QRS 116–129 ms. Incident LBBB was associated with a much higher risk of adverse outcomes, highlighting the importance of repeat ECG monitoring in patients with HFrEF. Acknowledgement/Funding Novartis

Background Brain natriuretic peptide (BNP) is a well-established predictor of hospitalization and death in patients with heart failure (HF). In the COAPT trial, treatment of patients with HF and secondary mitral regurgitation (SMR) with transcatheter mitral valve repair (TMVr) reduced the 2-year rates of all-cause mortality and HF hospitalization compared with maximally-tolerated guideline-directed medical therapy (GDMT) alone. Whether these improvements in outcomes were reflected in serial changes in BNP levels has not been reported. Purpose Herein, we report the first results of serial changes in BNP levels by treatment group in patients from the COAPT trial. Methods 614 patients with HF and 3+ or 4+ SMR were randomized 1:1 to TMVr + GDMT or GDMT alone. Key inclusion criteria included NYHA functional class II-IVa (ambulatory), ischemic or non-ischemic cardiomyopathy with LVEF 20%-50% and LVESD ≤70 mm. Baseline BNP or NT-proBNP levels were drawn at baseline and at 6 and 12 months. For the present analysis NT-proBNP (pg/ml) values were converted to BNP values (pg/ml) using a ratio of 7 to 1. Results At baseline, mean values of BNP were not significantly different between treatment groups (945 pg/ml vs. 964 pg/ml in the TMVr + GDMT and GDMT groups respectively, p=0.84). At 6 months, mean values of BNP in the TMVr + GDMT group were significantly lower than in the GDMT alone group (690 pg/ml vs 893 pg/ml, p=0.02) but not at 12 months (584 pg/ml vs. 728 pg/ml, p=0.22). By analysis of covariance, BNP decreased to a greater degree after TMVr + GDMT compared with GDMT only at both 6 and 12 months (least squares mean differences of −121 pg/ml and −166 pg/ml respectively, both p Change in BNP level from baseline Conclusions In patients with HF and 3+ or 4+ SMR enrolled in the COAPT trial, reduction of SMR with TMVr reduced BNP compared with maximally-tolerated GDMT only, a change which paralleled the reductions noted in all-cause mortality and HF hospitalizations with TMVr. Acknowledgement/Funding Abbott

Background/Introduction Invasive pressure-guided therapy has been shown to improve outcomes in patients with heart failure (HF). Thus far, only right-sided pressure sensors have shown clinical efficacy and safety. The Vectorious Medical Technologies V-LAP™ is a novel battery-less and wireless left-sided pressure monitoring system, directly assessing left-atrial pressure (LAP) in an ambulatory setting. In pre-clinical studies, it was shown to enable accurate and safe measurement of LAP. We hereby describe the first human experience with the device. Methods The V-LAP left atrial monitoring systEm for patients with Chronic sysTOlic and diastolic congestive heart failuRe first-in-human (VECTOR) study is a prospective, multicenter, single arm, open-label clinical trial to assess the safety, performance and usability of the V-LAP system in patients with heart failure. The V-LAP™ wireless sensor is implanted using a trans-septal access, under angiographic and echocardiographic guidance. The system includes an external unit, which both powers the implant and collects data via radio frequency communication upon activation, designed to be operated on a daily basis. We hereby describe the first cases, implanted in the CardioVascular Center, in Frankfurt, Germany. Results At this point in time, there have been two successful implantations of the V-LAP™, performed in two NYHA Class III patients. Both were admitted repeatedly for exacerbations of HF, and demonstrated elevated NT-ProBNP levels. They were therefore considered appropriate candidates for the monitoring system, to enable optimal medical therapy. The procedure was performed in a trans-femoral, trans-septal fashion, under mild sedation, with a successful implantation of a V-LAP™, and calibration for pressure measurement. There were no complications, data showed accurate LAP reading (Figure 1). Conclusions In the first-in-human cases, the implantation of the novel wireless left atrial pressure sensor V-LAP™ was feasible, safe, and showed good accuracy and precision. We now await both short and long-term efficacy and safety outcomes of the device, with the hopes of optimizing care according to ambulatory LAP data for patients with HF. Acknowledgement/Funding Vectorious Medical Technologies

Heart failure (HF) patients experience a high burden of symptoms and functional limitations, and morbidity and mortality remain high despite successful therapies. The majority of HF drugs in the United States are approved for reducing hospitalization and mortality, while only a few have indications for improving quality of life, physical function, or symptoms. Patient-reported outcomes that directly measure patient's perception of health status (symptoms, physical function, or quality of life) are potentially approvable endpoints in drug development. This paper summarizes the history of endpoints used for HF drug approvals in the United States and reviews endpoints that measure symptoms, physical function, or quality of life in HF patients.

In the COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation) trial among patients with heart failure (HF) and moderate-to-severe (3+) or severe (4+) secondary mitral regurgitation, patients treated with transcatheter mitral valve repair (TMVr) through leaflet approximation had reduced rates of HF hospitalization and mortality compared with guideline-directed medical therapy (GDMT) alone.The purpose of this study was to describe the echocardiographic patient qualification process for the COAPT trial, baseline echocardiographic characteristics, changes over time, and the interaction between treatment group and echocardiographic parameters on clinical outcomes.A novel echocardiographic algorithm was implemented for grading mitral regurgitation severity during the screening process. Standardized echocardiograms were obtained at baseline and during regular follow-up intervals through 2 years, and were analyzed by a core laboratory.A total of 614 patients were randomized to TMVr plus maximally tolerated GDMT or GDMT alone. Mean baseline left ventricular (LV) ejection fraction was 31.3 ± 9.3%, LV end-diastolic volume was 192.7 ± 71 ml, and effective regurgitant orifice area was 0.41 ± 0.15 cmHF patients in the COAPT trial with 3+ or 4+ secondary mitral regurgitation, selected using strict echocardiographic criteria, benefitted from TMVr with reduced 2-year rates of death and HF hospitalization. Strict application of these echocardiographic criteria should enable the COAPT results to be translated to clinical practice. (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation [The COAPT Trial] [COAPT]; NCT01626079).

Lower extremity lymphedema is frequently encountered in the vascular clinic. Established dogma purports that cancer is the most common cause of lower extremity lymphedema in Western countries, whereas chronic venous insufficiency (CVI) is often overlooked as a potential cause. Moreover, lymphedema is typically ascribed to a single cause, yet multiple causes can coexist.A 3-year retrospective analysis was conducted of demographic and clinical characteristics of 440 eligible patients with lower extremity lymphedema who presented for lymphatic physiotherapy to a university medical center's cancer-based physical therapy department.The four most common causes of lower extremity lymphedema were CVI (phlebolymphedema; 41.8%), cancer-related lymphedema (33.9%), primary lymphedema (12.5%), and lipedema with secondary lymphedema (11.8%). The collective cohort was more likely to be female (71.1%; P .0001), to be white (78.9%; P .0001), to demonstrate bilateral distribution (74.5%; P .0001), and to have involvement of the left leg (bilateral, 69.1% [P .0001]; unilateral, 58.9% [P = .0588]). Morbid obesity was pervasive (mean weight and body mass index, 115.8 kg and 40.2 kg/mIn a large cohort of patients treated in a cancer-affiliated physical therapy department, CVI (phlebolymphedema), not cancer, was the predominant cause of lower extremity lymphedema. One in four patients had more than one cause of lymphedema. Notable clinical characteristics included a proclivity for female patients, bilateral distribution, left limb, cellulitis, and nearly universal morbid obesity.

Study Objective To evaluate long-term efficacy and safety of phrenic nerve stimulation (PNS) in patients with moderate-to-severe central sleep apnea (CSA) through 3 years of therapy. Methods Patients in the remedē System Pivotal Trial were observed every 3 months after implant until US Food and Drug Administration approval. At the time of approval and study closure, all patients completed 24 months of follow-up; 33 patients had not reached the 36-month visit. Sleep metrics (polysomnography) and echocardiographic parameters are reported at baseline, 12, 18, and 24 months, in addition to available 36-month sleep results from polygraphy. Safety was assessed through 36 months; however, analysis focused through 24 months and available 36-month results are provided. Results Patients were assessed at 24 (n = 109) and 36 (n = 60) months. Baseline characteristics included mean age 64 years, 91% male, and mean apnea–hypopnea index 47 events per hour. Sleep metrics (apnea–hypopnea index (AHI), central apnea index, arousal index, oxygen desaturation index, rapid eye movement sleep) remained improved through 24 and 36 months with continuous use of PNS therapy. At least 60% of patients in the treatment group achieved at least 50% reduction in AHI through 24 months. Serious adverse events (SAEs) related to the remedē System implant procedure, device, or therapy through 24 months were reported by 10% of patients, no unanticipated adverse device effects or deaths, and all events resolved. No additional related SAEs were reported between 24 and 36 months. Conclusion These data suggest beneficial effects of long-term PNS in patients with CSA appear to sustain through 36 months with no new safety concerns. Trial Registration NCT01816776.

The substantial burden of heart failure has inspired innovation in medical device development for decades, and this development continues to be a touchstone in the success story of combined medical and device therapy. Recently, baroreflex activation therapy, interatrial shunts, and phrenic nerve stimulation have shown promise in treating patients with heart failure. We seek to provide background about the design, function, and early clinical experience with these 3 novel heart failure devices. In addition, an understanding of the individual regulatory journey of these devices, some of which is ongoing, is informative for future device development and clinical use.

Importance Transcatheter mitral valve repair (TMVr) plus maximally tolerated guideline-directed medical therapy (GDMT) reduced heart failure (HF) hospitalizations (HFHs) and all-cause mortality (ACM) in symptomatic patients with HF and secondary mitral regurgitation (SMR) compared with GDMT alone in the Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation (COAPT) trial but not in a similar trial, Multicenter Study of Percutaneous Mitral Valve Repair MitraClip Device in Patients With Severe Secondary Mitral Regurgitation (MITRA-FR), possibly because the degree of SMR relative to the left ventricular end-diastolic volume index (LVEDVi) was substantially lower. Objective To explore contributions of the degree of SMR using the effective regurgitation orifice area (EROA), regurgitant volume (RV), and LVEDVi to the benefit of TMVr in the COAPT trial. Design, Setting, and Participants This post hoc secondary analysis of the COAPT randomized clinical trial performed December 27, 2012, to June 23, 2017, evaluated a subgroup of COAPT patients (group 1) with characteristics consistent with patients enrolled in MITRA-FR (n = 56) (HF with grade 3+ to 4+ SMR, left ventricular ejection fraction of 20%-50%, and New York Heart Association function class II-IV) compared with remaining (group 2) COAPT patients (n = 492) using the end point of ACM or HFH at 24 months, components of the primary end point, and quality of life (QOL) (per the Kansas City Cardiomyopathy Questionnaire overall summary score) and 6-minute walk distance (6MWD). The same end points were evaluated in 6 subgroups of COAPT by combinations of EROA and LVEDVi and of RV relative to LVEDVi. Interventions Interventions were TMVr plus GDMT vs GDMT alone. Results A total of 548 participants (mean [SD] age, 71.9 [11.2] years; 351 [64%] male) were included. In group 1, no significant difference was found in the composite rate of ACM or HFH between TMVr plus GDMT vs GDMT alone at 24 months (27.8% vs 33.1%, P = .83) compared with a significant difference at 24 months (31.5% vs 50.2%, P

Objectives This study investigated the cost effectiveness of early cardiac resynchronization therapy (CRT) implantation among patients with mild heart failure (HF). The differential cost effectiveness between CRT using a defibrillator (CRT-Ds) and CRT using a pacemaker (CRT-P) was also assessed. Background Cardiac resynchronization has been shown to be cost effective in New York Heart Association (NYHA) functional classes III/IV but is less studied in class II HF. The incremental costs of early CRT implementation in mild HF compared with the costs potentially avoided because of delaying disease progression to advanced HF are also unknown. Finally, combined biventricular pacing and defibrillator (CRT-D) devices are more expensive than biventricular pacemakers (CRT-P), but the relative cost effectiveness is controversial. Methods Data from the 5-year follow-up phase of REVERSE (REsynchronization reVErses Remodeling in Systolic Left vEntricular Dysfunction) were used. The economics were evaluated from the U.S. Medicare perspective based on published clinical projections. Results Probabilistic estimates yielded $8,840/quality-adjusted life year (QALY) gained (95% confidence interval [CI]: $6,705 to $10,804/QALY gained) for CRT-ON versus CRT-OFF (i.e., programmed “ON” or “OFF” at pre-specified post-implantation timings) and $43,678/QALY gained for CRT-D versus CRT-P (95% CI: $35,164 to $53,589/QALY gained) over the patient’s lifetime. Results were robust to choice of patient subgroup and alterations of ±10% to key model parameters. An “early” CRT-D class II strategy totaled $95,292 compared with $91,511 for a “late” implantation. An “early” implant offered on average 1.00 year of additional survival for $3,781, resulting in an ICER of $3,795/LY gained. Conclusions This study demonstrates CRT cost effectiveness in mild HF. The incremental CRT-D costs are justified by the anticipated benefits, despite increased procurement costs and shorter generator longevities. “Early” CRT-D implants have essential cost parity with “late” implants while increasing the patient’s survival. (REsynchronization reVErses Remodeling in Systolic Left vEntricular Dysfunction [REVERSE]; NCT00271154 )

Objectives This study sought to determine the effects of abnormal left ventricular (LV) architecture on cardiac remodeling and clinical outcomes in mild heart failure (HF). Background Cardiac resynchronization therapy (CRT) is an established treatment for HF that improves survival in part by favorably remodeling LV architecture. LV shape is a dynamic component of LV architecture on which contractile function depends. Methods Transthoracic 2-dimensional echocardiography was used to quantify changes in LV architecture over 5 years of follow-up of patients with mild HF from the REVERSE study. REVERSE was a prospective study of patients with large hearts (LV end-diastolic dimension ≥55 mm), LV ejection fraction 120 ms randomly assigned to CRT-ON (n = 419) and CRT-OFF (n = 191). CRT-OFF patients were excluded from this analysis. LV dimensions, volumes, mass index, and LV ejection fraction were calculated. LV architecture was assessed using the sphericity index, as follows: (LV end-diastolic volume)/(4/3 × π × r3) × 100%. Results LV architecture improved over time and demonstrated significant associations between LV shape, age, sex, and echocardiography metrics. Changes in LV architecture were strongly correlated with changes in LV end-systolic volume index and LV end-diastolic volume index (both p 15% occurred in more than two-thirds of patients, which indicates considerable reverse remodeling. Conclusions We demonstrated that change in LV architecture in patients with mild HF with CRT is associated with structural and functional remodeling. Mean LV filling pressure was elevated, and the inability to lower it was an additional predictor of HF hospitalization or death. (Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction [REVERSE]; NCT00271154)

Background: Patients with dilated cardiomyopathy often have progressive heart failure with systolic dysfunction, ventricular remodeling and clinical decompensation heralded by elevations of filling...

More than 1 million heart failure hospitalizations occur annually, and congestion is the predominant cause. Rehospitalizations for recurrent congestion portend poor outcomes independently of age and renal function. Persistent congestion trumps serum creatinine increases in predicting adverse heart failure outcomes. No decongestive pharmacological therapy has reduced these harmful consequences. Simplified ultrafiltration devices permit fluid removal in lower-acuity hospital settings, but with conflicting results regarding safety and efficacy. Ultrafiltration performed at fixed rates after onset of therapy-induced increased serum creatinine was not superior to standard care and resulted in more complications. In contrast, compared with diuretic agents, some data suggest that adjustment of ultrafiltration rates to patients' vital signs and renal function may be associated with more effective decongestion and fewer heart failure events. Essential aspects of ultrafiltration remain poorly defined. Further research is urgently needed, given the burden of congestion and data suggesting sustained benefits of early and adjustable ultrafiltration.

The Expedited Access for Premarket Approval and De Novo Medical Devices Intended for Unmet Medical Need for Life Threatening or Irreversibly Debilitating Diseases or Conditions document was issued as a guidance for industry and for the Food and Drug Administration. The Expedited Access Pathway was designed as a new program for medical devices that demonstrated the potential to address unmet medical needs for life threatening or irreversibly debilitating conditions. The Food and Drug Administration would consider assessments of a device’s effect on intermediate endpoints that, when improving in a congruent fashion, are reasonably likely to predict clinical benefit. The purpose of this review is to provide evidence to support the use of 3 such intermediate endpoints: natriuretic peptides, such as N-terminal pro–B-type natriuretic peptide/B-type natriuretic peptide, the 6-min walk test distance, and health-related quality of life in heart failure.

The TRUE-AHF is a randomized, double-blind, parallel-group, placebo-controlled trial which is evaluating the effects of a 48-h infusion of ularitide (15 ng/kg/min) on the short- and long-term clinical course of patients with acute heart failure. Noteworthy features of the study include the early enrolment of patients following their initial clinical presentation (within 12 h), and entry blood pressure criteria and thresholds for the adjustment of drug infusion rates, which aim to minimize the risk of hypotension. The trial has two primary endpoints: (i) cardiovascular mortality during long-term follow-up; and (ii) the clinical course of patients during their index hospitalization. Cardiovascular mortality is evaluated in this event-driven trial by following all randomized patients for the occurrence of death until the end of the entire study without truncation at an arbitrarily determined early time point. The clinical course during the index hospitalization is evaluated using the hierarchical clinical composite endpoint, which combines information regarding changes in symptoms and the occurrence of in-hospital worsening heart failure events and death into a single ranked metric that captures interval clinical events and minimizes the likelihood of missing data and confounding due to intensification of background therapy. The design of the TRUE-AHF trial capitalizes on lessons learned from earlier trials and aims to evaluate definitively the potential benefit of ularitide in patients with acute heart failure.

Aims Haemodynamic-guided heart failure (HF) management effectively reduces decompensation events and need for hospitalizations. The economic benefit of clinical improvement requires further study. Methods and results An estimate of the cost-effectiveness of haemodynamic-guided HF management was made based on observations published in the randomized, prospective single-blinded CHAMPION trial. A comprehensive analysis was performed including healthcare utilization event rates, survival, and quality of life demonstrated in the randomized portion of the trial (18 months). Markov modelling with Monte Carlo simulation was used to approximate comprehensive costs and quality-adjusted life years (QALYs) from a payer perspective. Unit costs were estimated using the Truven Health MarketScan database from April 2008 to March 2013. Over a 5-year horizon, patients in the Treatment group had average QALYs of 2.56 with a total cost of US$56 974; patients in the Control group had QALYs of 2.16 with a total cost of US$52 149. The incremental cost-effectiveness ratio (ICER) was US$12 262 per QALY.Using comprehensive cost modelling, including all anticipated costs of HF and non-HF hospitalizations, physician visits, prescription drugs, long-term care, and outpatient hospital visits over 5 years, the Treatment group had a total cost of US$212 004 and the Control group had a total cost of US$200 360. The ICER was US$29 593 per QALY. Conclusions Standard economic modelling suggests that pulmonary artery pressure-guided management of HF using the CardioMEMS™ HF System is cost-effective from the US-payer perspective. This analysis provides the background for further modelling in specific country healthcare systems and cost structures.

Aims Haemodynamic-guided heart failure (HF) management using directly measured cardiac filling pressures in symptomatic patients is now recommended in the European Society of Cardiology (ESC) Heart Failure Guidelines [Class IIb(B)]. This meta-analysis evaluates all data from completed clinical trials evaluating this approach in patients with HF. Methods and results All trials evaluating the impact of HF management based on haemodynamic monitoring using implantable devices were reviewed using standard search engine methods. PRISMA methods were used to evaluate and screen publications that included an evaluation of an effect on HF hospitalizations. All publications meeting the inclusion criteria were included, and the outcomes data were evaluated using standard meta-analysis methodology. Of 317 publications initially identified, five trials involving 1296 patients with chronic HF met the criteria used in this meta-analysis. Studies included prospective controlled designs, as well as observational studies with historical control. Heterogeneity testing failed to demonstrate instability of analysis due to differences between trials. When compiled, outcomes from these trials favoured remote haemodynamic monitoring with a significant 38% reduction in HF hospitalizations (hazard ratio 0.62, 95% confidence interval 0.50–0.78, P < 0.001). Conclusions Haemodynamic-guided HF management using permanently implanted sensors and frequent filling pressure evaluation is superior to traditional clinical management strategies in reducing long-term HF hospitalization risk in symptomatic patients.

Summary Background Central sleep apnoea is a serious breathing disorder associated with poor outcomes. The remede system (Respicardia Inc, Minnetonka, MN, USA) is an implantable device which transvenously stimulates a nerve causing diaphragmatic contraction similar to normal breathing. We evaluated the safety and effectiveness of unilateral neurostimulation in patients with central sleep apnoea. Methods We recruited patients from 31 hospital-based centres in Germany, Poland, and the USA in this prospective, multicentre, randomised trial. Participants had to have been medically stable for at least 30 days and have received appropriate guideline recommended therapy, be aged at least 18 years, be expected to tolerate study procedures, and willing and able to comply with study requirements. Eligible patients with an apnoea-hypopnoea index (AHI) of at least 20 events per h, tested by a polysomnography, underwent device implantation and were randomly assigned (1:1) by a computer-generated method stratified by site to either stimulation (treatment) or no stimulation (control) for 6 months. The primary effectiveness endpoint in the intention-to-treat population was the comparison of the proportions of patients in the treatment versus control groups achieving a 50% or greater AHI reduction from baseline to 6 months, measured by a full-night polysomnography assessed by masked investigators in a core laboratory. The primary safety endpoint of 12-month freedom from serious adverse events related to the procedure, system, or therapy was evaluated in all patients. This trial is active, but not recruiting, and is registered with ClinicalTrials.gov (NCT01816776). Findings Between April 17, 2013, and May 28, 2015, we randomly assigned 151 eligible patients to the treatment (n=73) or control (n=78) groups. In the analysis of the intention-to-treat population, significantly more patients in the treatment group (35 [51%] of 68) had an AHI reduction from baseline of 50% or greater at 6 months than had those in the control group (eight [11%] of 73; difference between groups 41%, 95% CI 25–54, p Interpretation Transvenous neurostimulation significantly reduced the severity of central sleep apnoea, including improvements in sleep metrics, and was well tolerated. The clinically meaningful effects of the therapy are supported by the concordant improvements in oxygenation and quality of life, making transvenous neurostimulation a promising therapeutic approach for central sleep apnoea. Funding Respicardia Inc.

Background The Parachute is a novel percutaneously implanted ventricular partitioning device (VPD) that has emerged as a safe and feasible treatment option for patients with heart failure following anterior wall myocardial infarction. VPD efficacy is likely dependent on optimal device placement, but to date there are no published data examining the effect of device positioning on patient outcomes. Methods and results We retrospectively identified 32 patients successfully implanted with the Parachute device, all of whom underwent cardiac computed tomography (CCT) at baseline and after 6 months of follow-up. Patients were divided into two groups based on self-reported improvement in New York Heart Association (NYHA) functional class: “not improved NYHA” (n = 12) and “improved NYHA” (n = 20). There were significant differences between both groups with regard to device positioning on follow-up CCT. Compared to patients with “improved NYHA,” patients with “not improved NYHA” had longer distances from device foot to left ventricular apex (8.0 ± 4.9 vs. 2.9 ± 4.6 mm; P = 0.01), and higher lateral angles (18.0 ± 14 vs. 9.1 ± 6.8 degrees; P = 0.02), respectively. There was no significant difference between the two groups in landing zone (45.4 ± 7. vs. 45.1 ± 6.9 mm; P = 0.92) and inferior angle (14.0 ± 11.9 vs. 14.3 ± 10.1 degrees; P = 0.95). There was a numerically larger malapposition area in the “not improved NYHA” group (5.1 ± 4.5 vs. 3.2 ± 2.2 cm2; P = 0.12). Conclusion Quality of Parachute implant impacted clinical outcome, these findings should be applied prospectively in helping operators to achieve optimal implant. © 2016 Wiley Periodicals, Inc.

© Springer-Verlag Berlin Heidelberg 2016, Background Acute heart failure (AHF) with reduced leftventricular ejection fraction (LVEF) is often a biventricular congested state. The comparative effect of vasodilators and inotropes on the right- and/or left-sided congestion is unknown. Methods and results A systematic review, meta-analysis, and meta-regression of AHF studies using pulmonary artery catheter were performed using PubMed, Embase, and Cochrane library. Data from 35 studies, including 3016 patients, were studied. Included patients had a weighted mean age of 60 years, left-ventricular ejection fraction (LVEF) of 24 %, and plasma B-type natriuretic peptide (BNP) of 892 pg/ml. Both the left- and right-ventricular filling pressures were elevated: weighted mean pulmonary artery wedge pressure (PAWP) was 25 mmHg (range 17–31 mmHg) and right atrial pressure (RAP) 12 mmHg (range 7–18 mmHg). Vasodilators and inotropes had similar beneficial effects on PAWP [-6.3 mmHg (95 % CI -7.4 to -5.2 mmHg) and -5.8 mmHg (95 % CI -7.6 to -4.0 mmHg), respectively] and RAP [-2.9 mmHg (95 % CI -3.8 to -2.1 mmHg) and -2.8 mmHg (95 % CI -3.8 to -1.7 mmHg), respectively]. Among inotropes, inodilators, such as levosimendan, have greater beneficial effect on the left-ventricular filling pressure than dobutamine. Drug-induced improvement of PAWP tightly paralleled that of RAP with all studied drugs (r 2 = 0.90, p\0.001). Vasodilators and inotropes had no short-term effect of renal function. Conclusion The left- and right-sided filling pressures are similarly improved by vasodilators or inotropes, in AHF with reduced LVEF.

Central sleep apnoea (CSA) occurs in ∼30-50% of patients with heart failure (HF) with reduced left ventricular ejection fraction (LVEF) and in as much as in 18-30% of patients with preserved LVEF. In HF patients, it is characterized by periodic breathing also known as the Cheyne-Stokes respiration followed by pauses of breathing. Central sleep apnoea remains often unrecognized due to its chronic and insidious incidences. Patients may report excessive daytime somnolence, poor sleep quality, nocturnal angina, recurrent arrhythmias, refractory HF symptoms, or demonstrate abnormal respiratory pattern or apnoeas. The pathogenesis of CSA remains incompletely understood, but changes in CO2 above and below the apnoea threshold play a major role in its pathogenesis. The presence of CSA in patients with HF is associated with some neurohumoral and haemodynamic responses that are detrimental to the failing heart including increased morbidity and mortality. The development of successful therapies targeting CSA and its harmful downstream effects is therefore important. Several different therapies from medications to implantable devices have been tested with varying effects and primarily in small non-randomized and/or single-centre studies. Large studies to date have been disappointing, but therapeutic options targeting the physiology of the disease may herald a new era in understanding and treating CSA.

Objectives This study sought to analyze medical therapy data from the CHAMPION (CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in Class III Heart Failure) trial to determine which interventions were linked to decreases in heart failure (HF) hospitalizations during ambulatory pulmonary artery (PA) pressure-guided management. Background Elevated cardiac filling pressures, which increase the risk of hospitalizations and mortality, can be detected using an ambulatory PA pressure monitoring system before onset of symptomatic congestion allowing earlier intervention to prevent HF hospitalizations. Methods The CHAMPION trial was a randomized, controlled, single-blind study of 550 patients with New York Heart Association functional class III HF with a HF hospitalization in the prior year. All patients undergoing implantation of the ambulatory PA pressure monitoring system were randomized to the active monitoring group (PA pressure-guided HF management plus standard of care) or to the blind therapy group (HF management by standard clinical assessment), and followed for a minimum of 6 months. Medical therapy data were compared between groups to understand what interventions produced the significant reduction in HF hospitalizations in the active monitoring group. Results Both groups had similar baseline medical therapy. After 6 months, the active monitoring group experienced a higher frequency of medications adjustments; significant increases in the doses of diuretics, vasodilators, and neurohormonal antagonists; targeted intensification of diuretics and vasodilators in patients with higher PA pressures; and preservation of renal function despite diuretic intensification. Conclusions Incorporation of a PA pressure-guided treatment algorithm to decrease filling pressures led to targeted changes, particularly in diuretics and vasodilators, and was more effective in reducing HF hospitalizations than management of patient clinical signs or symptoms alone.

The advent of transcatheter aortic valve replacement (TAVR) has revolutionized the treatment of aortic stenosis and established a life-prolonging therapy in patients that are not operative candidates. It is also approved for high-risk surgical candidates and shows effectiveness comparable to surgical aortic valve replacement (SAVR). The inoperable and high-risk groups represent two parallel but partly divergent populations. In those deemed inoperable, decisions revolve around offering TAVR, palliation, or rehabilitation. These are based primarily on the likelihood of procedural success and clinical benefit, with a careful assessment of the source of their debility and features that underlie extreme surgical risk. In patients that are at high-risk for SAVR, determination of the most favorable route of valve replacement is guided by comparative procedural characteristics, the need for coincident interventions, and presumed ability for rehabilitation. These decisions are inherently difficult and currently rely on imperfect but developing risk assessment systems. Given the complexity of these decisions and patient population, the TAVR experience has underscored the value of a multi-disciplinary approach to advanced cardiovascular disease.

Introduction EMPA induces an initial decline in estimated glomerular filtration rate (eGFR) in T2D pts. Although considered hemodynamic and reversible, it may raise concerns in clinical practice. This phenomenon needs to be better understood in pts with HF, beyond T2D. Hypothesis To assess eGFR after starting/stopping EMPA in HF pts with/without T2D in the EMPERIAL (Effect of EMPagliflozin on ExeRcise ability and heart failure symptoms In patients with chronic heArt faiLure)-Reduced and -Preserved trials. Methods Pts with HF (NYHA class II-IV, diagnosed ≥3 months prior), baseline eGFR >20 mL/min/1.73 m2, elevated NT-proBNP, and LVEF ≤40% in EMPERIAL-Reduced and >40% in -Preserved, received placebo (PBO) or EMPA 10mg. Overall and across subgroups by baseline T2D status, eGFR changes were analyzed for pooled EMPA (both EMPERIAL trials) vs PBO using a mixed model repeated measures analysis. Acute renal failure (ARF) incidence was assessed by investigator-reported adverse events (AEs) coded according to the narrow standardized MedDRA query. Results EMPERIAL-Reduced and -Preserved included 312 (156 EMPA, 156 PBO) and 315 pts (157 EMPA, 158 PBO), respectively. At baseline in the pooled data set, 55.6% had T2D. Overall, mean baseline eGFR±SD was 57.6±19.3 mL/min/1.73 m2. PBO-adjusted mean eGFR±SE change from baseline with pooled EMPA was -2.3±0.7 and -3.3±0.8 at Weeks 6 and 12, respectively (Figure A). Change in eGFR±SE from last value on treatment to follow-up was -0.3±0.5 in PBO and +3.9±0.5 in EMPA groups (Figure A). These findings were consistent across subgroups by baseline T2D status (Figure B). Incidence rates of ARF were similar in PBO and EMPA groups (n=9 and n=8; 11.8 and 10.7 per 100pt-years, respectively), and also consistent across subgroups by baseline T2D status. Serious ARF occurred in 4 PBO pts and 1 EMPA pt. Conclusions In HF pts with baseline eGFR down to 20 mL/min/1.73 m2, eGFR dynamics after starting/stopping EMPA and kidney AEs were similar to EMPA's known eGFR change on and off treatment, and kidney safety profile, regardless of T2D status.

The impact of sex on clinical outcomes in patients with heart failure and moderate-severe or severe secondary mitral regurgitation treated with transcatheter mitral valve repair with MitraClip + guideline-directed medical therapy (device) versus guideline-directed medical therapy alone (control) is

Introduction Prevention of acute decompensated heart failure (ADHF) hospitalizations has both medical and economic implications, yet remains an unmet need. Increases in pulmonary and perhaps upper airway fluid content may be detectable remotely by voice analysis. The Cordio HearO™ system is a mobile application with cloud-based computing, designed to identify distinct speech measures (SM) in standard audio recordings which may be indicative of HF clinical status and provide early warning of impending decompensation. Hypothesis Cordio HearO™ speech analysis can identify clinical worsening of heart failure (HF) patients prior to hospitalization. Methods In this ongoing multicenter, observational study, we recruited 173 New York Heart Association Class II-III, stable stage C chronic heart failure patients. The patients recorded five sentences (2-5 sec each) each day in their native language (English, Hebrew, Arabic or Russian), using Cordio HearO™ operating on standard smartphone devices. Patients have been followed for 3 to 23 months. The current analysis explored the association between different SM parameters and episodes of HF decompensation requiring hospitalization. Results A total of 196,610 recordings, collected over 47,376 patient days of follow up were analyzed during which 13 patients required hospitalization for ADHF. 10 (76.9%) (95% CI: 54.02% - 99.83%) of these episodes were detected by Cordio HearO™ software an average of 12.2 (range 8 to 17 days) days prior to admission. The estimated false-positive event rate per year was 1.47 (95% CI: 1.28 - 1.68). Conclusions Cordio HearO™ novel speech analysis technology may be a useful tool in remote monitoring of HF patients, providing an early warning of impending episodes of decompensation, thus having the potential to reduce ADHF hospitalizations and improve patient quality of life and economic outcomes. Ongoing and future studies will continue to define the role of speech measures in the management of heart failure patients.

OBJECTIVES: To investigate sex-based differences in outcomes after mitral valve (MV) surgery for severe ischemic mitral regurgitation (SMR). BACKGROUND: Whether differences in outcomes exist between men and women after surgery for SMR remains unknown. METHODS: Patients enrolled in a randomized trial comparing MV replacement versus MV repair for SMR were included and followed for 2 years. Endpoints for this analysis included all-cause mortality, major adverse cardiovascular and cerebrovascular events (MACCE; defined as the composite of death, stroke, hospitalization for heart failure, worsening NYHA class or MV re-operation), quality of life. (QOL), functional status, and percentage change in left ventricular (LV) end-systolic volume index (LVESVI) from baseline through 2 years RESULTS: Of 251 patients enrolled in the trial, 96 (38.2%) were women. Compared with men, women had smaller LV volumes and effective regurgitant orifice area (EROA) but greater EROA / LV end-diastolic volume ratio. At 2 years, women had higher rates of all-cause mortality (27.1% vs. 17.4%; adjusted hazard ratio [adjHR]: 1.85; 95% confidence interval [CI]: 1.05–3.26; p=0.03) and MACCE (49.0% vs. 38.1%; adjHR: 1.58; 95% CI: 1.06–2.37; p=0.02). Women also reported worse QOL and functional status at 2 years. There were no significant differences in the percentage change over 2 years in LVESVI between women and men (adjβ: −10.4; 95% CI: −23.4 to 2.6; p=0.12). CONCLUSIONS: Women with SMR display different echocardiographic features and experienced higher mortality and worse QOL after MV surgery compared with men. There were no significant differences in the degree of reverse LV remodeling between sexes. CLINICAL TRIALS.GOV

In the COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation) trial, transcatheter mitral valve repair (TMVr) led to reduced heart failure (HF) hospitalizations and improved survival in patients with symptomatic HF and 3+ to 4+ secondary mitral regurgitation (MR) on maximally-tolerated medical therapy. Given the advanced age and comorbidities of these patients, improvement in health status is also an important treatment goal.The purpose of this study was to understand the health status outcomes of patients with HF and 3+ to 4+ secondary MR treated with TMVr versus standard care.The COAPT trial randomized patients with HF and 3+ to 4+ secondary MR to TMVr (n = 302) or standard care (n = 312). Health status was assessed at baseline and at 1, 6, 12, and 24 months with the Kansas City Cardiomyopathy Questionnaire (KCCQ) and the SF-36 health status survey. The primary health status endpoint was the KCCQ overall summary score (KCCQ-OS; range 0 to 100; higher = better; minimum clinically important difference = 5 points).At baseline, patients had substantially impaired health status (mean KCCQ-OS 52.4 ± 23.0). While health status was unchanged over time in the standard care arm, patients randomized to TMVr demonstrated substantial improvement in the KCCQ-OS at 1 month (mean between-group difference 15.9 points; 95% confidence interval [CI]: 12.3 to 19.5 points), with only slight attenuation of this benefit through 24 months (mean between-group difference 12.8 points; 95% CI: 7.5 to 18.2 points). At 24 months, 36.4% of TMVr patients were alive with a moderately large (≥10-point) improvement versus 16.6% of standard care patients (p 0.001), for a number needed to treat of 5.1 patients (95% CI: 3.6 to 8.7 patients). TMVr patients also reported better generic health status at each timepoint (24-month mean difference in SF-36 summary scores: physical 3.6 points; 95% CI: 1.4 to 5.8 points; mental 3.6 points; 95% CI: 0.8 to 6.4 points).Among patients with symptomatic HF and 3+ to 4+ secondary MR receiving maximally-tolerated medical therapy, edge-to-edge TMVr resulted in substantial early and sustained health status improvement compared with medical therapy alone. (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation [The COAPT Trial] [COAPT]; NCT01626079).

Treatment of patients with heart failure with reduced ejection fraction has evolved. Recently, a fully implantable remote hemodynamic monitoring sensor in the pulmonary artery was approved in the treatment of patients at risk of heart failure readmissions. Several novel devices designed to offload the left atrium by creating a small interatrial shunt are being investigated. Cardiac imaging plays a vital role in the selection process, implantation, and monitoring of individuals with such devices. This article discusses in detail various imaging techniques and key clinical points relating to several cardiac devices used in the treatment of patients with heart failure.

The purpose of this study was to compare the effectiveness of bucindolol with that of metoprolol succinate for the maintenance of sinus rhythm in a genetically defined heart failure (HF) population with atrial fibrillation (AF).Bucindolol is a beta-blocker whose unique pharmacologic properties provide greater benefit in HF patients with reduced ejection fraction (HFrEF) who have the betaA total of 267 HFrEF patients with a left ventricular ejection fraction (LVEF) 0.50, symptomatic AF, and the ADRB1 Arg389Arg genotype were randomized 1:1 to receive bucindolol or metoprolol therapy and were up-titrated to target doses. The primary endpoint of AF or atrial flutter (AFL) or all-cause mortality (ACM) was evaluated by electrocardiogram (ECG) during a 24-week period.The hazard ratio (HR) for the primary endpoint was 1.01 (95% confidence interval [CI]: 0.71 to 1.42), but trends for bucindolol benefit were observed in several subgroups. Precision therapeutic phenotyping revealed that a differential response to bucindolol was associated with the interval of time from the initial diagnoses of AF and HF to randomization and with the onset of AF relative to that of the initial HF diagnosis. In a cohort whose first AF and HF diagnoses were 12 years prior to randomization, in which AF onset did not precede HF by more than 2 years (n = 196), the HR was 0.54 (95% CI: 0.33 to 0.87; p = 0.011).Pharmacogenetically guided bucindolol therapy did not reduce the recurrence of AF/AFL or ACM compared to that of metoprolol therapy in HFrEF patients, but populations were identified who merited further investigation in future phase 3 trials.

Sleep-disordered breathing (SDB), including OSA and central sleep apnea, is highly prevalent in patients with heart failure (HF). Multiple studies have reported this high prevalence in asymptomatic as well as symptomatic patients with reduced left ventricular ejection fraction (HFrEF), as well as in those with HF with preserved ejection fraction. The acute pathobiologic consequences of OSA, including exaggerated sympathetic activity, oxidative stress, and inflammation, eventually could lead to progressive left ventricular dysfunction, repeated hospitalization, and excessive mortality. Large numbers of observational studies and a few small randomized controlled trials have shown improvement in various cardiovascular consequences of SDB with treatment. There are no long-term randomized controlled trials to show improved survival of patients with HF and treatment of OSA. One trial of positive airway pressure treatment of OSA included patients with HF and showed no improvement in clinical outcomes. However, any conclusions derived from this trial must take into account several important pitfalls that have been extensively discussed in the literature. With the role of positive airway pressure as the sole therapy for SDB in HF increasingly questioned, a critical examination of long-accepted concepts in this field is needed. The objective of this review was to incorporate recent advances in the field into a phenotype-based approach to the management of OSA in HF.