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

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

Summary Background Previous studies have suggested that haemodynamic-guided management using an implantable pulmonary artery pressure monitor reduces heart failure hospitalisations in patients with moderately symptomatic (New York Heart Association [NYHA] functional class III) chronic heart failure and a hospitalisation in the past year, irrespective of ejection fraction. It is unclear if these benefits extend to patients with mild (NYHA functional class II) or severe (NYHA functional class IV) symptoms of heart failure or to patients with elevated natriuretic peptides without a recent heart failure hospitalisation. This trial was designed to evaluate whether haemodynamic-guided management using remote pulmonary artery pressure monitoring could reduce heart failure events and mortality in patients with heart failure across the spectrum of symptom severity (NYHA funational class II–IV), including those with elevated natriuretic peptides but without a recent heart failure hospitalisation. Methods The randomised arm of the haemodynamic-GUIDEed management of Heart Failure (GUIDE-HF) trial was a multicentre, single-blind study at 118 centres in the USA and Canada. Following successful implantation of a pulmonary artery pressure monitor, patients with all ejection fractions, NYHA functional class II–IV chronic heart failure, and either a recent heart failure hospitalisation or elevated natriuretic peptides (based on a-priori thresholds) were randomly assigned (1:1) to either haemodynamic-guided heart failure management based on pulmonary artery pressure or a usual care control group. Patients were masked to their study group assignment. Investigators were aware of treatment assignment but did not have access to pulmonary artery pressure data for control patients. The primary endpoint was a composite of all-cause mortality and total heart failure events (heart failure hospitalisations and urgent heart failure hospital visits) at 12 months assessed in all randomly assigned patients. Safety was assessed in all patients. A pre-COVID-19 impact analysis for the primary and secondary outcomes was prespecified. This study is registered with ClinicalTrials.gov , NCT03387813 . Findings Between March 15, 2018, and Dec 20, 2019, 1022 patients were enrolled, with 1000 patients implanted successfully, and follow-up was completed on Jan 8, 2021. There were 253 primary endpoint events (0·563 per patient-year) among 497 patients in the haemodynamic-guided management group (treatment group) and 289 (0·640 per patient-year) in 503 patients in the control group (hazard ratio [HR] 0·88, 95% CI 0·74–1·05; p=0·16). A prespecified COVID-19 sensitivity analysis using a time-dependent variable to compare events before COVID-19 and during the pandemic suggested a treatment interaction (pinteraction=0·11) due to a change in the primary endpoint event rate during the pandemic phase of the trial, warranting a pre-COVID-19 impact analysis. In the pre-COVID-19 impact analysis, there were 177 primary events (0·553 per patient-year) in the intervention group and 224 events (0·682 per patient-year) in the control group (HR 0·81, 95% CI 0·66–1·00; p=0·049). This difference in primary events almost disappeared during COVID-19, with a 21% decrease in the control group (0·536 per patient-year) relative to pre-COVID-19, virtually no change in the treatment group (0·597 per patient-year), and no difference between groups (HR 1·11, 95% CI 0·80–1·55; p=0·53). The cumulative incidence of heart failure events was not reduced by haemodynamic-guided management (0·85, 0·70–1·03; p=0·096) in the overall study analysis but was significantly decreased in the pre-COVID-19 impact analysis (0·76, 0·61–0·95; p=0·014). 1014 (99%) of 1022 patients had freedom from device or system-related complications. Interpretation Haemodynamic-guided management of heart failure did not result in a lower composite endpoint rate of mortality and total heart failure events compared with the control group in the overall study analysis. However, a pre-COVID-19 impact analysis indicated a possible benefit of haemodynamic-guided management on the primary outcome in the pre-COVID-19 period, primarily driven by a lower heart failure hospitalisation rate compared with the control group. Funding Abbott.

Background Central sleep apnea is common in heart failure patients. Transvenous phrenic nerve stimulation (TPNS) requires placing a lead to stimulate the phrenic nerve and activate the diaphragm. Data are lacking concerning the safety and efficacy of TPNS in patients with concomitant cardiovascular implantable electronic devices (CIEDs). Objective To report the safety and efficacy of TPNS in patients with concomitant CIEDs. Methods In the remedē System Pivotal Trial, 151 patients underwent TPNS device implant. This analysis compared patients with concomitant CIEDs to those without with respect to safety, implant metrics, and efficacy of TPNS. Safety was assessed using incidence of adverse events and device–device interactions. A detailed interaction protocol was followed. Implant metrics included overall TPNS implantation success. Efficacy endpoints included changes in the apnea-hypopnea index (AHI) and quality of life. Results Of 151 patients, 64 (42%) had a concomitant CIED. There were no significant differences between the groups with respect to safety. There were 4 CIED oversensing events in 3 patients leading to 1 inappropriate defibrillator shock and delivery of antitachycardia pacing. There was no difference in efficacy between the CIED and non-CIED subgroups receiving TPNS, with both having similar percentages of patients who achieved ≥50% reduction in AHI and quality-of-life improvement. Conclusion Concomitant CIED and TPNS therapy is safe. The presence of a concomitant CIED did not seem to impact implant metrics, implantation success, and TPNS efficacy. A detailed interaction protocol should be followed to minimize the incidence of device–device interaction.

Elevation in cardiac filing pressures is the hallmark of acute and chronic heart failure (HF). A number of pathological processes contribute to the elevation in cardiac filling pressures, including myocardial dysfunction and primary volume overload. In this review, we discuss the important role of the venous system and the concepts of stressed blood volume (SBV) and unstressed blood volume (UBV). We review how regulation of venous tone modifies the distribution of blood between these two functional compartments, the physical distribution of blood between the pulmonary and systemic circulations, and how these relate to hemodynamic abnormalities observed in HF. Finally, we review recently applied methods to estimating SBV and how they are being applied to results of clinical studies to provide new insights into resting and exercise hemodynamics and therapeutics for HF.

STUDY OBJECTIVES: Early evidence with transvenous phrenic nerve stimulation (PNS) demonstrates improved disease severity and quality of life (QOL) in patients with central sleep apnea (CSA). The goal of this analysis is to evaluate the complete prospective experience with PNS in order to better characterize its efficacy and safety, including in patients with concomitant heart failure (HF). METHODS: Using pooled individual data from the pilot (n = 57) and pivotal (n = 151) studies of the remedē System in patients with predominant moderate to severe CSA, we evaluated 12-month safety and 6- and 12-month effectiveness based on polysomnography data, QOL, and cardiac function. RESULTS: Among 208 combined patients (June 2010 to May 2015), a remedē device implant was successful in 197 patients (95%), 50/57 pilot study patients (88%) and 147/151 pivotal trial patients (97%). The pooled cohort included patients with CSA of various etiologies, and 141 (68%) had concomitant HF. PNS reduced apnea-hypopnea index (AHI) at 6 months by a median of −22.6 episodes/h (25th and 75th percentile; −38.6 and −8.4, respectively) (median 58% reduction from baseline, P < .001). Improvement in sleep variables was maintained through 12 months of follow-up. In patients with HF and ejection fraction ≤ 45%, PNS was associated with improvement in systolic function from 27.0% (23.3, 36.0) to 31.1% (24.0, 41.5) at 12 months (P = .003). In the entire cohort, improvement in QOL was concordant with amelioration of sleep measures. CONCLUSIONS: Transvenous PNS significantly improves CSA severity, sleep quality, ventricular function, and QOL regardless of HF status. Improvements, which are independent of patient compliance, are sustained at 1 year and are associated with acceptable safety. CITATION: Fudim M, Spector AR, Costanzo M-R, Pokorney SD, Mentz RJ, Jagielski D, Augostini R, Abraham WT, Ponikowski PP, McKane SW, Piccini JP. Phrenic nerve stimulation for the treatment of central sleep apnea: a pooled cohort analysis. J Clin Sleep Med. 2019;15(12):1747–1755.

Background Hemodynamic-guided heart failure (HF) management using pulmonary artery (PA) pressures reduces HF hospitalizations (HFHs) in previously hospitalized HF patients with New York Heart Association (NYHA) class III symptoms. It remains uncertain whether this approach reduces not only HFHs but all-cause mortality and if benefits extend to patients with NYHA class II and IV HF or to those symptomatic patients with elevated natriuretic peptides without recent HFH. Methods GUIDE-HF is a prospective trial with 2 arms enrolling patients with HF regardless of ejection fraction (EF). The randomized arm is a single-blind, randomized, controlled trial of PA pressure-guided therapy in NYHA class II-IV patients (n = 1,000) with either a previous HFH or elevated natriuretic peptides (B-type natriuretic peptide/NT-pro–B-type natriuretic peptide). All consenting subjects will receive an implantable PA pressure sensor (CardioMEMS HF System) followed by randomization to either a treatment group, managed with provider remote access to the hemodynamic data, or a control group, managed without provider access to these data. Subjects in the control group will receive scheduled, scripted, sham contacts from the study team to maintain blinding as to their study group assignment. The primary study end point is the composite of cumulative HF events and all-cause mortality at 12 months. Secondary end points include quality-of-life and functional assessments. The single arm of the trial is an observational arm in which NYHA class III patients (n = 2,600) with either a previous HFH or elevated natriuretic peptides (but no recent HFH) will be implanted with a PA pressure sensor and observed for occurrence of the primary composite end point of cumulative HF events and mortality at 12 months. This arm will test the hypothesis that hemodynamic-guided care is similarly effective in HF patients enrolled on the basis of elevated natriuretic peptide levels but no recent HFH and those with a recent HFH. Conclusions GUIDE-HF is the largest clinical trial of hemodynamic-guided HF management across a broad population of HF patients, with a study design and sample size adequate to examine survival, cumulative HF events, quality of life, and functional capacity.

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

Background Patients with recurring heart failure (HF) following cardiac resynchronization therapy fare poorly. Their management is undecided. We tested remote hemodynamic‐guided pharmacotherapy. Methods and Results We evaluated cardiac resynchronization therapy subjects included in the CHAMPION (CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in New York Heart Association Class III Heart Failure Patients) trial, which randomized patients with persistent New York Heart Association Class III symptoms and ≥1 HF hospitalization in the previous 12 months to remotely managed pulmonary artery (PA) pressure‐guided management (treatment) or usual HF care (control). Diuretics and/or vasodilators were adjusted conventionally in control and included remote PA pressure information in treatment. Annualized HF hospitalization rates, changes in PA pressures over time (analyzed by area under the curve), changes in medications, and quality of life (Minnesota Living with Heart Failure Questionnaire scores) were assessed. Patients who had cardiac resynchronization therapy (n=190, median implant duration 755 days) at enrollment had poor hemodynamic function (cardiac index 2.00±0.59 L/min per m 2 ), high comorbidity burden (67% had secondary pulmonary hypertension, 61% had estimated glomerular filtration rate 2 ), and poor Minnesota Living with Heart Failure Questionnaire scores (57±24). During 18 months randomized follow‐up, HF hospitalizations were 30% lower in treatment (n=91, 62 events, 0.46 events/patient‐year) versus control patients (n=99, 93 events, 0.68 events/patient‐year) (hazard ratio, 0.70; 95% CI, 0.51–0.96; P =0.028). Treatment patients had more medication up‐/down‐titrations (847 versus 346 in control, P P =0.002), and quality of life improvement (Minnesota Living with Heart Failure Questionnaire decreased −13.5±23 versus −4.9±24.8 in control, P =0.006). Conclusions Remote hemodynamic‐guided adjustment of medical therapies decreased PA pressures and the burden of HF symptoms and hospitalizations in patients with recurring Class III HF and hospitalizations, beyond the effect of cardiac resynchronization therapy. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT00531661.

Aims The aim of this study is to quantify healthcare resource utilization among non-responders to cardiac resynchronization therapy (CRT-NR) by heart failure (HF) events and influence of comorbidities. Methods and results The ADVANCE CRT registry (2013–2015) prospectively identified responders/CRT-NRs 6 months post-implant using the clinical composite score. Heart failure event rates and associated cost, both overall and separated for inpatient hospitalizations, office visits, emergency room visits, and observational stays, were quantified. Costs of events were imputed from payments for similar real-world encounters in subjects with CRT-D/P devices in the MarketScan™ commercial and Medicare Supplemental insurance claims databases. Effects of patient demographics and comorbidities on event rates and cost were evaluated. Of 879 US patients (age 69 ± 11 years, 29% female, ischaemic disease 52%), 310 (35%) were CRT-NR. Among CRT-NRs vs. responders, more patients developed HF (41% vs. 11%, P Conclusion Healthcare expenditures associated with contemporary CRT non-response management are among the highest for any HF patient group. This illustrates an unmet need for interventions to improve HF outcomes and reduce costs among some CRT recipients.

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

Increased body fluid volume portends poorer outcomes in both acute and chronic heart failure. Inadequate decongestion, defined as absence of hemoconcentration or increases in serum creatinine, is consistently associated with higher rates of heart failure hospitalizations and cardiovascular mortality. However, available means to identify and quantify abnormal fluid volume, monitor changes during decongestive therapies and determine when an optimal fluid volume has been achieved are poorly understood. In addition, ideal methods to assess extracellular and intracellular fluid status remain elusive. These knowledge gaps lead to unacceptably poor heart failure outcomes, as underscored by the results of many acute heart failure trials in which, regardless of decongestive therapy, only a small minority of patients achieve optimal volume status. The intent of this discussion is to describe methods for the assessment of fluid volume status, compare their relative advantages and limitations and propose research priorities in this area.

Introduction: Pulmonary artery pressure (PAP)-guided treatment reduces heart failure hospitalizations (HFH) in randomized and “real world” studies. Underlying CKD in HF patients portends poorer outcomes. This analysis was performed to determine if benefit of PAP-guided HF therapy persists with increasing CKD severity. Methods: This retrospective cohort study was conducted in NYHA Class III HF recipients of the PAP sensor enrolled in the CardioMEMS Post Approval Study. Patients were subdivided into quartiles of glomerular filtration rates estimated by MDRD equation (eGFR). Rates of HFH 1 year before versus 1 year after PAP sensor implantation were compared across quartiles of eGFR using the Andersen-Gill Cox proportional hazards model, while accounting for competing risk of death, advanced HF therapies, and progression to end-stage kidney disease. Multivariate analysis was performed to identify independent predictors of CKD (baseline eGFR < 90 mL/min/1,73m 2 ) progression. Results: Among 1200 PAP sensor recipients, 1119 had concomitant CKD with CKD stages 3 and 4 occurring in 754 patients (67.4%). In CKD patients, 40.6%, 42.1%, and 17.3%, respectively, demonstrated worse, unchanged, or improved CKD stage. Compared to 12 pre-implant months, HFH rates dropped in 12 months after implant across all eGFR quartiles (Table). PA systolic, diastolic, and mean pressures decreased from baseline to 24 months in all GFR quartiles. The baseline mean PAP as a continuous variable independently predicted CKD progression (OR: 1.027, p= 0.0006). Conclusion: Reduction of HFH by PAP-guided therapy occurred across CKD stages in a large HF population receiving the CardioMEMS sensor after Food and Drug Administration approval. Thus, PAP monitoring enables safe HF therapy optimization even in patients with advanced CKD. Since higher baseline mean PAP independently forecasts CKD worsening, HF patients with this unfavorable hemodynamic value require intensified monitoring.

Central sleep apnea occurs in up to 50% of heart failure patients and worsens outcomes. Established therapies are limited by minimal supporting evidence, poor patient adherence, and potentially adverse cardiovascular effects. However, transvenous phrenic nerve stimulation, by contracting the diaphragm, restores normal breathing throughout sleep and has been shown to be safe and effective. This review discusses the mechanisms, screening, diagnosis, and therapeutic approaches to CSA in patients with HF. In a prospective, multicenter randomized Pivotal Trial (NCT01816776) of transvenous phrenic nerve stimulation with the remedē System, significantly more treated patients had a ≥ 50% reduction in apnea-hypopnea index compared with controls, with a 41 percentage point difference between group difference at 6 months (p

Background: Ambulatory hemodynamic monitoring with an implantable pulmonary artery (PA) sensor is approved for patients with New York Heart Association Class III heart failure (HF) and a prior HF hospitalization (HFH) within 12 months. The objective of this study was to assess the efficacy and safety of PA pressure-guided therapy in routine clinical practice with special focus on subgroups defined by sex, race, and ejection fraction. Methods: This multi-center, prospective, open-label, observational, single-arm trial of 1200 patients across 104 centers within the United States with New York Heart Association class III HF and a prior HFH within 12 months evaluated patients undergoing PA pressure sensor implantation between September 1, 2014, and October 11, 2017. The primary efficacy outcome was the difference between rates of adjudicated HFH 1 year after compared with the 1 year before sensor implantation. Safety end points were freedom from device- or system-related complications at 2 years and freedom from pressure sensor failure at 2 years. Results: Mean age for the population was 69 years, 37.7% were women, 17.2% were non-White, and 46.8% had preserved ejection fraction. During the year after sensor implantation, the mean rate of daily pressure transmission was 76±24% and PA pressures declined significantly. The rate of HFH was significantly lower at 1 year compared with the year before implantation (0.54 versus 1.25 events/patient-years, hazard ratio 0.43 [95% CI, 0.39–0.47], P P Conclusions: In routine clinical practice as in clinical trials, PA pressure-guided therapy for HF was associated with lower PA pressures, lower rates of HFH and all-cause hospitalization, and low rates of adverse events across a broad range of patients with symptomatic HF and prior HFH. Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02279888.

Reduced responsiveness to diuretics is ubiquitous and multifactorial in heart failure and portends poor outcomes. Due to the limitations of current diuretic approaches, there is an enormous unmet clinical need for more effective fluid removal methods in heart failure patients. Novel volume management approaches include veno-venous ultrafiltration, peritoneal-based sodium and water removal methods, controlled diuresis, transvenous renal venous decongestion, catheter-deployed pumps in the descending aorta to increase renal perfusion, device-driven increase of lymphatic flow into the venous system, and catheter-based splanchnic nerve modulation. Overall novel fluid management therapies are at an early stage of development, with some still in pre-clinical trials and others having been studied in first-in-man trials with a small number of subjects. Further investigation of novel fluid management methods should focus on assessment of safety, ease of use, candidates’ selection, reproducibility of effects across heart failure patient populations, and costs.

This article updates the Heart Failure Association of the European Society of Cardiology (ESC) 2007 classification of advanced heart failure and describes new diagnostic and treatment options for these patients. Recognizing the patient with advanced heart failure is critical to facilitate timely referral to advanced heart failure centres. Unplanned visits for heart failure decompensation, malignant arrhythmias, co-morbidities, and the 2016 ESC guidelines criteria for the diagnosis of heart failure with preserved ejection fraction are included in this updated definition. Standard treatment is, by definition, insufficient in these patients. Inotropic therapy may be used as a bridge strategy, but it is only a palliative measure when used on its own, because of the lack of outcomes data. Major progress has occurred with short-term mechanical circulatory support devices for immediate management of cardiogenic shock and long-term mechanical circulatory support for either a bridge to transplantation or as destination therapy. Heart transplantation remains the treatment of choice for patients without contraindications. Some patients will not be candidates for advanced heart failure therapies. For these patients, who are often elderly with multiple co-morbidities, management of advanced heart failure to reduce symptoms and improve quality of life should be emphasized. Robust evidence from prospective studies is lacking for most therapies for advanced heart failure. There is an urgent need to develop evidence-based treatment algorithms to prolong life when possible and in accordance with patient preferences, increase life quality, and reduce the burden of hospitalization in this vulnerable patient population.

Transvenous phrenic nerve stimulation improved sleep metrics and quality of life after 6 months versus control in the remedē System Pivotal Trial. This analysis explored the effectiveness of phrenic nerve stimulation in patients with central sleep apnea after 12 months of therapy. Reproducibility of treatment effect was assessed in the former control group in whom the implanted device was initially inactive for the sixth month and subsequently activated when the randomized control assessments were complete. Patients with moderate-to-severe central sleep apnea implanted with the remedē System were randomized to therapy activation at 1 month (treatment) or after 6 months (control). Sleep indices were assessed from baseline to 12 months in the treatment group and from 6 to 12 months in former controls. In the treatment group, a ≥50% reduction in apnea-hypopnea index occurred in 60% of patients at 6 months (95% confidence interval [CI] 47% to 64%) and 67% (95% CI 53% to 78%) at 12 months. After 6 months of therapy, 55% of former controls (95% CI 43% to 67%) achieved ≥50%reduction in apnea-hypopnea index. Patient Global Assessment was markedly ormoderately improved at 6 and 12 months in 60% of treatment patients.Improvements persisted at 12 months. A serious adverse event within 12 months occurred in 13 patients (9%). Phrenic nerve stimulation produced sustained improvements in sleep indices and quality of life to at least 12 months in patients with central sleep apnea. The similar improvement of former controls after 6 months of active therapy confirms benefits are reproducible and reliable.

Low serum sodium concentration has long been recognized as an established marker of short- and long-term morbidity and mortality in patients with heart failure (HF), and is commonly included in various risk prediction models. Mechanisms leading to hyponatremia (e.g. maladaptive neurohormonal activation) could also lead to concurrent decline in serum chloride levels. Besides, chloride has distinct biological roles (e.g. modulation of renal tubular sodium transporters) that are relevant to the pathophysiology and therapy of HF, making it a potent cardiorenal connector. Several clinical studies have recently reported on a potentially overlooked link between low serum chloride levels and adverse outcomes in patients with a wide variety of HF syndromes, which could indeed be stronger than that of sodium. While evidence on predictive value of chloride is accumulating in various patient populations and settings, the limited available interventional studies have so far yielded conflicting results. It remains to be elucidated whether hypochloremia represents a marker of disease severity and prognosis, or it is an actual pathogenetic mechanism, hence being a potential novel target of therapy. Current ongoing studies are designed to better understand the mechanistic aspects of the role of hypochloremia in HF and shed light on its clinical applicability.

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

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.

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.

A growing number of countries and geographical regions are involved in major clinical trials. Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure is the largest trial in acutely decompensated heart failure (HF) with patients from 5 geographical regions: North America (NA), Latin America (LA), Western Europe (WE), Central Europe (CE), and Asia-Pacific (AP). Data from the 5 geographical, areas were compared including baseline characteristics, medications, 30-day outcomes (mortality and mortality or HF hospitalization), and 180-day mortality. Of the 7,141 study patients, 3,243 (45.4%) were from NA (average of 15.2 patients/site), 1,762 (24.7%) from AP (28.4 patients/site), 967 (13.5%) from CE (20.2 patients/site), 665 (9.3%) from LA (17.1 patients/site), and 504 (7.1%) from WE (14.4 patients/site). There were marked differences in co-morbidities, clinical profile, medication use, length of stay, 30-day event rates, and 180-day mortality by region. Compared with NA, the adjusted risk for death or HF hospitalization at 30 days was significantly lower in CE (odds ratio [OR] 0.46, 95% CI 0.33 to 0.64), WE (OR 0.52 95% CI 0.35 to 0.75), and AP (OR 0.62 95% CI 0.48 to 0:79) and numerically lower in LA (OR 0.77, 95% CI 0.57 to 1.04) with similar results for 180-day mortality. In conclusion, in patients with acutely decompensated HF, major differences in baseline characteristics, treatments, length of the hospital stay, and 30-day HF rehospitalization rates, and 180-day mortality were found in patients enrolled from different, geographical areas. (C) 2016 Elsevier Inc. All rights reserved.

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.

Introduction Hemodynamic monitoring has been shown to reduce admissions for heart failure in both the large randomized CHAMPION Trial (CHMP) and a 1200 patient Post Approval Study registry (PAS). A persistent observation in heart failure (HF) studies is that trial patient populations differ from patients who are treated in clinical practice. After identifying patients who could be propensity matched to the CHMP trial patients, we studied the characteristics and outcomes of the patients who could not be matched. Methods PAS was an FDA mandated registry to determine if results of the CHMP trial could be replicated in clinical practice, as reported previously. Propensity matching was done between CHMP Control and PAS patients. 387 PAS patients could be propensity matched and can be considered “Trial-Type” patients (TT) and 813 were not match able (NM). For each patient group heart failure (HFH) and all-cause (ACH) hospitalization rates at 1 year were compared to the rate in the year prior to enrollment. Results Compared to CHMP Treatment patients, NM patients were older 61.3 vs 71.8, more likely to be female (18.1% vs 39.6%) and have heart failure with normal ejection fraction (HFpEF) (23% vs 55.9%), p Conclusion Of the 1200 patients in the PAS, 67% (813/1200) patients were not match able to typical trial subjects. Nonetheless, these patients with older age, worse renal function, and more hospitalizations still had significant reduction in rates of HFH and ACH during ambulatory hemodynamic monitoring.

Introduction Central sleep apnea (CSA) and heart failure (HF) often present with similar symptoms. Treatment of CSA primarily focuses on management of CSA-related symptoms such as frequent night-time awakenings or arousals, daytime sleepiness and reduced quality of life (QoL). Transvenous phrenic nerve stimulation (TPNS) has demonstrated improvements in sleep metrics and patient reported outcomes (PROs). Hypothethis To identify symptoms experienced by patients with HF and CSA and determine what types of improvements occur in the most symptomatic patients using TPNS. Methods Post-hoc analysis of baseline and 12-month data collected from patients (N = 75) with HF and moderate to severe CSA from the remedē System Pivotal Trial. Responses to questions pertaining to PROs (Epworth Sleepiness Scale [ESS] and Minnesota Living with Heart Failure Questionnaire [MLHFQ]) and clinical symptoms were analyzed to assess impact of TPNS therapy. Results Baseline clinical symptoms including nocturia (72%), reduced exercise capacity (61%), fatigue or weakness (69%), daytime sleepiness (77%), difficulty falling or staying asleep (52%), snoring (56%) and insomnia/fragmented sleep (51%) were reported by over half of the patients. By 12 months, 24%, 41%, 44%, 45%, 51%, 60% and 66% of the patients, respectively, no longer reported these specific clinical symptoms. On the baseline ESS, > = 50% of patients with HF reported moderate to high (2-3 on the scale) chance of dozing while sitting and reading (55%), watching television (56%) and lying down to rest in the afternoon (68%). For these patients with > = moderate at baseline, 71%, 52% and 35%, respectively, improved to less than moderate chance at 12 months. On the MLHFQ, 6/21 questions had > = 50% of subjects report that HF prevented them from living as they wanted moderately to very much (3-5 on the scale). Following 12 months of TPNS therapy, 33% to 71% of subjects improved from > = moderate at baseline to below moderate (Figure). NYHA functional class improved or remained stable in 89% (67/75) of subjects. Conclusion In the most symptomatic patients with CSA and HF, TPNS may improve symptoms and QoL, specifically related to sleep, sleepiness and fatigue. Heart failure patients with these symptoms may benefit from screening and subsequent treatment of CSA with TPNS.

Introduction Sex is often associated with divergent outcomes in cardiovascular disease. Response to pharmacologic and device-based therapy for heart failure (HF) may vary by sex, yet women are often underrepresented in clinical trials. We sought to examine possible sex differences in the response to ambulatory hemodynamic monitoring in clinical practice using the CardioMEMS Post-Approval Study (PAS). Methods The PAS was a prospective, single arm, multi-center, open-label study of 1200 adults (>18 years) with NYHA Class III HF and at least one HF hospitalization (HFH) within 12 months. Changes in PAP over time were stratified by EF ( Results The 452 (38% of total) women enrolled in the PAS were less likely to be white (78% vs. 86%, p Conclusions Women and men enrolled in the PAS had similar reductions from baseline in PAP over 1 year and experienced similar reductions in HFH at one year compared with the year prior. There were no differences in all-cause mortality between women and men when adjusting for baseline covariates. Hemodynamic monitoring provides similar benefit with regard to HF events in both women and men.

Introduction The most common type of central sleep apnea (CSA) breathing pattern in patients with heart failure (HF) is Cheyne-Stokes respiration (CSR). CSR manifests as a cyclical pattern of apnea and hyperventilation, with absence of airflow and respiratory effort followed by hyperventilation in a crescendo-decrescendo pattern. CSR may be a predictor of negative clinical outcomes in HF patients. Purpose Examine the response to transvenous phrenic nerve stimulation (TPNS) in patients with HF and different amounts of CSR. Methods Patients with CSA and HF who participated in the remedē System Pivotal Trial were divided into clinically relevant subgroups based on percentage of sleep in CSR (%CSR: 50%) during their baseline polysomnogram. The subgroups were analyzed for efficacy and safety by randomized group (TPNS vs control [no TPNS]). Epworth sleepiness scale (ESS) was also collected. Results At baseline, higher percentage CSR subgroups had lower left ventricular ejection fraction (median 45% for CSR 50%). Baseline apnea-hypopnea index (AHI) indicated severe CSA in all subgroups. All CSR subgroups receiving TPNS therapy had more than 50% of patients achieve ≥50% reduction in AHI at 6 months (see Table); control response rates were ≤11% in each CSR subgroup. The AHI decreased by ≥21 events/hour in each CSR subgroup on therapy while Control subgroups had little or no improvement. The central apnea index decreased to median ≤3 events/hour in each TPNS CSR subgroup; each control subgroup had median 22-24 events/hour remaining at 6 months. Baseline daytime sleepiness was worse in lower %CSR subgroups, however improved in all subgroups. No apparent relationship existed between %CSR and cardiovascular death in patients using TPNS therapy through 6 months, with the only death being in the 20-50% CSR subgroup; the death was determined not related to device, therapy or procedure by the clinical events committee. Further, 2/22 control subjects with CSR>50% experienced a cardiovascular death compared to 0/12 in the TPNS treated subgroup. Conclusions Transvenous phrenic nerve stimulation can treat CSA in HF patients regardless of the percentage of sleep in CSR and no signal of increased mortality was observed.

Background: Heart failure (HF) is a common, serious disease in the US and Europe. Patients with HF often require treatment for fluid overload, resulting in costly inpatient visits; however, limited...