Effects of sacubitril/valsartan on the functional capacity of real-world patients in Italy: the REAL.IT study on heart failure with reduced ejection fraction.

Background: Heart failure (HF) significantly affects the morbidity, mortality, and quality of life of patients. New therapeutic strategies aim to improve the functional capacity and quality of life of patients while controlling HF-related risks. Real-world data on both the functional and cardiopulmonary exercise capacities of patients with HF with reduced ejection fraction upon sacubitril/valsartan use are lacking. Methods: A multicenter, retrospective, cohort study, called REAL.IT, was performed based on the data collected from the electronic medical records of nine specialized HF centers in Italy. Cardiopulmonary exercise testing was performed at baseline and after 12 months of sacubitril/valsartan therapy, monitoring carbon dioxide production (VCO2) and oxygen consumption (VO2). Results: The functional capacities of 170 patients were evaluated. The most common comorbidities were hypertension and diabetes (i.e., 53.5 and 32.4%, respectively). At follow-up, both the VO2 peak (from 15.1 ± 3.7 ml/kg/min at baseline to 17.6 ± 4.7 ml/kg/min at follow-up, p < 0.0001) and the predicted % VO2 peak (from 55.5 ± 14.1 to 65.5 ± 16.9, p < 0.0001) significantly increased from baseline. The VO2 at the anaerobic threshold (AT-VO2) increased from 11.5 ± 2.6 to 12.5 ± 3.3 ml/kg/min (p = 0.021), and the rate ratio between the oxygen uptake and the change in work (ΔVO2/Δwork slope) improved from 9.1 ± 1.5 to 9.9 ± 1.6 ml/min/W (p < 0.0001). Conclusions: Sacubitril/valsartan improves the cardiopulmonary capacity of patients with HFrEF in daily clinical practice in Italy.

Pharmacoutilization and adherence to sacubitril/valsartan in real world: the REAL.IT study in HFrEF.

AIMS: The current European Society of Cardiology (ESC) guidelines provide clear indications for the treatment of acute and chronic heart failure (HF). Nevertheless, there is a constant need for real-world evidence regarding the effectiveness, adherence, and persistence of drug therapy. We investigated the use of sacubitril/valsartan for the treatment of HF with reduced ejection fraction in real-world clinical practice in Italy. METHODS AND RESULTS: An observational, retrospective, non-interventional cohort study based on electronic medical records from nine specialized hospital HF centres in Italy was carried out on patients with prescription of sacubitril/valsartan. Overall, 948 patients had a prescription of sacubitril/valsartan, with 924 characterized over 6 months and followed up for 12 months. Pharmacoutilization data at 1 year of follow-up were available for 225 patients {mean age 69.7 years [standard deviation (SD) = 10.8], 81.8% male}. Of those, 398 (45.2%) reached the target dose of sacubitril/valsartan of 97/103 mg in a mean time of 6.9 (SD = 6.2) weeks. Blood pressure and hypotension in 61 patients (65%) and worsening of chronic kidney disease in 10 patients (10.6%) were the main reasons for not reaching the target dose. Approximatively 50% of patients had a change in sacubitril/valsartan dose during follow-up, and 158 (70.2%) were persistent with the treatment during the last 3 months of follow-up. A sensitivity analysis (persistence during the last 4 months of follow-up) showed persistence for 162 patients (72.0%). Adherence data, available for 387 patients, showed full adherence for 205 (53%). Discontinuation (102/717 patients, 14.2%) was mainly due to hypotension and occurred after a mean time of 34.3 (SD = 28.7) weeks. During follow-up, out of 606 patients with available data, 434 patients (71.6%) had an HF add-on drug or drugs concomitant with sacubitril/valsartan. HF-related hospitalization during follow-up was numerically higher in non-persistent (16/67 patients, 23.9%) vs. patients persistent to sacubitril/valsartan (30/158, 19%) (P = 0.405). CONCLUSIONS: Real-world data on the use of sacubitril/valsartan in clinical practice in Italy show a rapid titration to the target dose, high therapeutic adherence enabling a good level of therapeutic management in line with ESC guidelines for patients with reduced ejection fraction.

Sacubitril/Valsartan in Heart Failure with Reduced Ejection Fraction: Real-World Experience from Italy (the REAL.IT Study).

Sacubitril/valsartan reduces heart failure (HF)-related hospitalizations and cardiovascular mortality in PARADIGM-HF and has become a foundational treatment for HF with reduced ejection fraction (HFrEF). However, data of its routine real-world use are limited, and evidence from Italian settings is lacking. The REAL.IT study aimed to characterize the demographics, pharmacotherapy, clinical characteristics and outcomes of sacubitril/valsartan-treated Italian patients with HFrEF. Electronic medical records of patients initiating sacubitril/valsartan from October 2016 to June 2019 at nine specialized hospital outpatient HF centers across Italy were reviewed. Overall, 924 adults (mean age 64.5 years, 84.6% male) were included. At baseline, 38.7% had an ischemic HF etiology, 45.9% hypertension, 23.2% atrial fibrillation, 25.4% diabetes mellitus, 26.1% an implantable cardioverter-defibrillator and 31.9% coronary artery bypass grafting. There were no clear patterns of patient selection over time. During follow-up, NYHA class improved in 37.5% of patients after a mean of 5.3 ± 3.8 months; 36.1% and 16.7% of patients were in NYHA class III during characterization and after one year of follow-up, respectively. Left ventricular ejection fraction (LVEF) improved ≥5% in 56.3% of patients at one year; 39.7% had ≥30% reduction of N-terminal pro-B-type natriuretic peptide; 2.2% had hyperkalemia during characterization and 2.6% during follow-up; and 3.8% had hypotension during characterization and 12% during follow-up. A total of 50 (5.8%) of patients had device implantation (ICD/CRT) during follow-up. HF-related hospitalization was recorded in 19.6% of patients during follow-up; 3.8% of patients died, approximately 1.3% from cardiovascular causes. Our real-world data confirm the favorable effectiveness and tolerability of sacubitril/valsartan observed in pivotal randomized controlled trials.

Physiopathology and Diagnosis of Congestive Heart Failure: Consolidated Certainties and New Perspectives.

Volume overload and fluid congestion are a fundamental issue in the assessment and management of patients with heart failure (HF). Recent studies have found that in acute decompensated heart failure (ADHF), right and left-sided pressures generally start to increase before any notable weight changes take place preceding an admission. ADHF may be a problem of volume redistribution among different vascular compartments instead of, or in addition to, fluid shift from the interstitial compartment. Thus, identifying heterogeneity of volume overload would allow guidance of tailored therapy. A comprehensive evaluation of congestive HF needs to take into account myriad parameters, including physical examination, echocardiographic values, and biomarker serum changes. Furthermore, potentially useful diagnostic tools include bioimpedance to measure intercompartmental fluid shifts, and evaluation of ultrasound lung comets to detect extravascular lung water.

Echocardiography to estimate high filling pressure in patients with heart failure and reduced ejection fraction.

AIMS: Echocardiographic assessment of left ventricular filling pressures is performed using a multi-parametric algorithm. Unselected sample of patients with heart failure with reduced ejection fraction (HFrEF) patients may demonstrate an indeterminate status of diastolic indices making interpretation challenging. We sought to test improvement in the diagnostic accuracy of standard and strain echocardiography of the left ventricle and left atrium (LA) to estimate a pulmonary capillary wedge pressure (PCWP) > 15 mmHg in patients with HFrEF. METHODS AND RESULTS: Out of 82 consecutive patients, 78 patients were included in the final analysis and right heat catheterization, and echocardiogram was performed simultaneously. According to the univariable analysis, E wave velocity, the ratio between E-wave/A-wave (E/A, area under the curve [AUC] = 0.81, respectively), isovolumic relaxation time (AUC = 0.83), pulmonary vein D wave (AUC = 0.84), pulmonary vein S/D Ratio (AUC = 0.85), early pulmonary regurgitation velocity (AUC = 0.80), and accelerationa time at right ventricular out-flow tract (RVOT AT, AUC = 0.84) identified with the highest accuracy PCWP > 15 mmHg. They were all tested in multivariate analysis, and they were not independently correlated with PCWP. Tricuspid regurgitation (TR) velocity was measurement with the highest predictive value in identifying PCWP > 15 mmHg (AUC = 0.89), compared with other established parameters such as the ratio between e-wave velocity divided by mitral annular e' velocity (E/e'), deceleration time, or LA indexed volume (LAVi), which all reached a lower accuracy level (AUC = 0.75; 0.78; 0.76). Among strain measures, global longitudinal strain in four chamber view (GLS 4ch), the ratio between e-wave velocity divided by mitral annular e' strain rate (E/e'sr), and LA longitudinal strain at the reservoir phase were helpful in estimating elevated PCWP (AUC = 0.77; 0.76; 0.75). According to multivariable analysis, the following two models had the greatest accuracy in detecting PCWP > 15 mmHg: (i) TR velocity, LAVi, and E wave velocity (receiver operating characteristic [ROC]-AUC = 0.98), (ii) AT RVOT, LAVi and GLS 4ch (ROC-AUC = 0.96). Neither E/A (ROC-AUC = 0.81) nor E/e' (ROC-AUC = 0.75) was an independent predictor when included in the model. The two MODELS were applicable to the entire population and demonstrated better agreement with the invasive reference (91% and 88%) than the guidelines algorithm (77%) regardless of the type of rhythm. CONCLUSIONS: Our suggested echocardiographic approach could be used to potentially reduce the frequency of "doubtful" classification and increase the accuracy in predicting elevated left ventricular filling pressure leading to a decrease in the number of invasive assessment made by right heart catheterization.

Usefulness of regional right ventricular and right atrial strain for prediction of early and late right ventricular failure following a left ventricular assist device implant: A machine learning approach.

BACKGROUND: Identifying candidates for left ventricular assist device surgery at risk of right ventricular failure remains difficult. The aim was to identify the most accurate predictors of right ventricular failure among clinical, biological, and imaging markers, assessed by agreement of different supervised machine learning algorithms. METHODS: Seventy-four patients, referred to HeartWare left ventricular assist device since 2010 in two Italian centers, were recruited. Biomarkers, right ventricular standard, and strain echocardiography, as well as cath-lab measures, were compared among patients who did not develop right ventricular failure (N = 56), those with acute-right ventricular failure (N = 8, 11%) or chronic-right ventricular failure (N = 10, 14%). Logistic regression, penalized logistic regression, linear support vector machines, and naïve Bayes algorithms with leave-one-out validation were used to evaluate the efficiency of any combination of three collected variables in an "all-subsets" approach. RESULTS: Michigan risk score combined with central venous pressure assessed invasively and apical longitudinal systolic strain of the right ventricular-free wall were the most significant predictors of acute-right ventricular failure (maximum receiver operating characteristic-area under the curve = 0.95, 95% confidence interval = 0.91-1.00, by the naïve Bayes), while the right ventricular-free wall systolic strain of the middle segment, right atrial strain (QRS-synced), and tricuspid annular plane systolic excursion were the most significant predictors of Chronic-RVF (receiver operating characteristic-area under the curve = 0.97, 95% confidence interval = 0.91-1.00, according to naïve Bayes). CONCLUSION: Apical right ventricular strain as well as right atrial strain provides complementary information, both critical to predict acute-right ventricular failure and chronic-right ventricular failure, respectively.

The Effects of Sacubitril/Valsartan on Clinical, Biochemical and Echocardiographic Parameters in Patients with Heart Failure with Reduced Ejection Fraction: The "Hemodynamic Recovery".

BACKGROUND: Sacubitril/valsartan has been shown to be superior to enalapril in reducing the risks of death and hospitalization for heart failure (HF). However, knowledge of the impact on cardiac performance remains limited. We sought to evaluate the effects of sacubitril/valsartan on clinical, biochemical and echocardiographic parameters in patients with heart failure and reduced ejection fraction (HFrEF). METHODS: Sacubitril/valsartan was administered to 205 HFrEF patients. RESULTS: Among 230 patients (mean age 59 ± 10 years, 46% with ischemic heart disease) 205 (89%) completed the study. After a follow-up of 10.49 (2.93 ± 18.44) months, the percentage of patients in New York Heart Association (NYHA) class III changed from 40% to 17% (p < 0.001). Median N-Type natriuretic peptide (Nt-proBNP) decreased from 1865 ± 2318 to 1514 ± 2205 pg/mL, (p = 0.01). Furosemide dose reduced from 131.3 ± 154.5 to 120 ± 142.5 (p = 0.047). Ejection fraction (from 27± 5.9% to 30 ± 7.7% (p < 0.001) and E/A ratio (from 1.67 ± 1.21 to 1.42 ± 1.12 (p = 0.002)) improved. Moderate to severe mitral regurgitation (from 30.1% to 17.4%; p = 0.002) and tricuspid velocity decreased from 2.8 ± 0.55 m/sec to 2.64 ± 0.59 m/sec (p < 0.014). CONCLUSIONS: Sacubitril/valsartan induce "hemodynamic recovery" and, consistently with reduction in Nt-proBNP concentrations, improve NYHA class despite diuretic dose reduction.

Additive Value of Biomarkers and Echocardiography to Stratify the Risk of Death in Heart Failure Patients with Reduced Ejection Fraction.

BACKGROUND: Risk stratification is a crucial issue in heart failure. Clinicians seek useful tools to tailor therapies according to patient risk. METHODS: A prospective, observational, multicenter study on stable chronic heart failure outpatients with reduced left ventricular ejection fraction (HFrEF). Baseline demographics, blood, natriuretic peptides (NPs), high-sensitivity troponin I (hsTnI), and echocardiographic data, including the ratio between tricuspid annular plane excursion and systolic pulmonary artery pressure (TAPSE/PASP), were collected. Association with death for any cause was analyzed. RESULTS: Four hundred thirty-one (431) consecutive patients were enrolled in the study. Fifty deaths occurred over a median follow-up of 32 months. On the multivariable Cox model analysis, TAPSE/PASP ratio, number of biomarkers above the threshold values, and gender were independent predictors of death. Both the TAPSE/PASP ratio ≥0.36 and TAPSE/PASP unavailable groups had a three-fold decrease in risk of death in comparison to the TAPSE/PASP ratio <0.36 group. The risk of death increased linearly by 1.6 for each additional positive biomarker and by almost two for women compared with men. CONCLUSIONS: In a HFrEF outpatient cohort, the evaluation of plasma levels of both NPs and hsTnI can contribute significantly to identifying patients who have a worse prognosis, in addition to the echocardiographic assessment of right ventricular-arterial coupling.

NT-ProBNP and hsTnI: A Multistate Survival Analysis in Outpatients with Reduced Left-Ventricular Ejection Fraction.

Heart failure (HF) with reduced ejection fraction (HFrEF) has a well-known epidemic relevance in western countries. It affects up to 1-2% of patients > 60 years and reaches a prevalence of 12% in octogenarian patients. The role of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitive troponin I (hsTnI) in risk stratifying HFrEF patients has been established; at present, evidence is exclusively based on one-time assessments, and the prognostic usefulness of serial biochemical assessments in this population still remains to be determined. We prospectively recruited 226 patients with chronic HFrEF, who were all referred to the Outpatient Clinic of our institution from November 2011 through September 2014. Recruited patients underwent full clinical evaluation with complete history taking and physical examination as well as ECG, biochemical assessment, and standard 2D and Doppler flow echocardiography at the first visit, and then again at each visit during the follow-up, repeated every 6 months. During the follow-up period, cardiovascular (CV) death, which occurred in 16 patients, was not statistically correlated with gender (p = 0.088) or age (p = 0.1636); however, baseline serum levels of NT-proBNP, which were 3 times higher in deceased patients, were significantly related to this clinical event (p = 0.001). We found that NT-proBNP represents a strong and independent predictor of CV outcome; serum levels of hsTnI, which are significantly related to an increased risk of hospitalization, cannot properly predict the relative risk of CV mortality. Our study validates, eventually, the multimarker strategy, which reflects the complexity of the HF pathophysiology.

[The heart failure management in Sicily: cognitive analysis of clinical features.] / La gestione dello scompenso cardiaco in Sicilia: analisi conoscitiva degli aspetti clinici e organizzativi.

INTRODUCTION: Heart failure (HF) is a main issue of modern healthcare system. Patient affected are continuously growing in number and age; therefore, an integrated management between different parts of healthcare system is crucial to optimize outcome and sustainability. So far, little is known about clinical pathways of HF patients in Sicily. METHODS: On initiative of the Regional HF Group of the Italian Association of Hospital Cardiologists (ANMCO), we decided to census all the Cardiology Unit of Sicily. A simple questionnaire elaborated by the group and exploring clinical and organizational matters of HF was sent to the Units. The answer arrived on a voluntary basis. RESULTS: 41/46 Units sent back the filled questionnaire. Five typologies of units were represented, based on complexity [1. Outpatient units; 2. Units without Intensive Care Unit (ICU); 3. Units with ICU; 4. Units with ICU and Cath Lab; 5. Units with ICU, Cath lab and Cardiac Surgery). A dedicated HF unit is present only in half centers, but it is formally recognized solely in 22% of Units. These Units have scarce dedicated staff and activity is predominantly based on personal initiative. Diagnostic and therapeutic tools are used appropriately in most of them, even though congestion is judged mainly through physical exam and echocardiography. Differently from the indications of the guidelines, post discharge titration of therapy lacks in almost 30% of centers. DISCUSSION AND CONCLUSIONS: In Sicily, HF is managed on a plan mainly based on personal initiative. The quality is sufficiently good but a more appropriate and structured organization in particular of the follow-up seems a necessary and improvable requirement in view of quality measurers and economic sustainability of health care.

Modeling Right Ventricle Failure After Continuous Flow Left Ventricular Assist Device: A Biventricular Finite-Element and Lumped-Parameter Analysis.

The risk of right ventricle (RV) failure remains a major contraindication for continuous-flow left ventricular assist device (CF-LVAD) implantation in patients with heart failure. It is therefore critical to identify the patients who will benefit from early intervention to avoid adverse outcomes. We sought to advance the computational modeling description of the mechanisms underlying RV failure in LVAD-supported patients. RV failure was studied by computational modeling of hemodynamic and cardiac mechanics using lumped-parameter and biventricular finite element (FE) analysis. Findings were validated by comparison of bi-dimensional speckle-tracking echocardiographic strain assessment of the RV free wall vs. patient-specific computational strain estimations, and by non-invasive lumped-based hemodynamic predictions vs. invasive right heart catheterization data. Correlation analysis revealed that lumped-derived RV cardiac output (R = 0.94) and RV stroke work index (R = 0.85) were in good agreement with catheterization data collected from 7 patients with CF-LVAD. Biventricular FE analysis showed abnormal motion of the interventricular septum towards the left ventricular free wall, suggesting impaired right heart mechanics. Good agreement between computationally predicted and echocardiographic measured longitudinal strains was found at basal (- 19.1 ± 3.0% for ECHO, and - 16.4 ± 3.2% for FEM), apical (- 20.0 ± 3.7% for ECHO, and - 17.4 ± 2.7% for FEM), and mid-level of the RV free wall (- 20.1 ± 5.9% for echo, and - 18.0 ± 5.4% for FEM). Simulation approach here presented could serve as a tool for less invasive and early diagnosis of the severity of RV failure in patients with LVAD, although future studies are needed to validate our findings against clinical outcomes.

Heart transplant program at IRCCS-ISMETT: Impact of mechanical circulatory support on pre- and post -transplant survival.

BACKGROUND: Heart transplantation (HTx) improves the quality of life and survival in patients affected by end-stage heart failure. The purpose of the current study is to present the patients' clinical data and results of HTx in a single Center of Sicily. Focus on survival after pre and post HTx mechanical circulatory support use will be performed. METHODS: 133 HTx were done from 2004 to the end of 2015.The average donor age was 34±13.5years and the proportion of male donors was 67%. Percentage of use of mechanical circulatory support to bridge patients to HTx was 18%. RESULTS: Overall pre-transplant mechanical circulatory support was not correlated to worse post-transplant prognosis, p=0.757. Severe primary early graft failure requiring extra corporeal membrane oxygenator support strongly impact the early mortality after heart transplantation (p<0.001). CONCLUSIONS: The results of HTx at ISMETT are comparable to those reported in high volume Italian transplant centers as well as in the ISHLT registry. The favorable outcome can be related to focus on multidisciplinary approach, strict recipients' selection and young donor population. Post HTx mechanical circulatory support use in general remains associated with worse post-transplant outcomes. This does not apply to pre-op mechanical circulatory support population.

Diastolic dysfunction diagnosed by tissue Doppler imaging in cirrhotic patients: Prevalence and its possible relationship with clinical outcome.

BACKGROUND: Cirrhotic cardiomyopathy has been characterized by impaired contractile response to stress and/or altered diastolic relaxation, with electrophysiological abnormalities in the absence of known cardiac disease. However, the clinical significance of diastolic dysfunction (DDF) in cirrhotic patients has not been clarified. METHODS: We studied 84 cirrhotic patients with normal systolic function to evaluate the prevalence of DDF using tissue Doppler imaging, and to investigate the possible correlation of DDF with outcomes (hospitalization, death) and with the specific causes of death. RESULTS: The mean follow-up was 10±8months. DDF was diagnosed in 22 patients (26.2%). Patients with DDF more frequently had ascites (90.9% vs. 64.5 %; p=0.026), lower levels of albumin (OR: 5.39; p=0.004), higher NT-proBNP levels, and longer QTc interval (464±23ms vs. 452±30ms; p=0.039). At follow-up, patients with DDF did not have a higher incidence of adverse events in terms of hospitalization and death. CONCLUSIONS: The presence of diastolic dysfunction has not been found to be clearly associated with outcome, and prognosis has been determined primarily by the severity of liver disease.

Thalassemia and heart surgery: aortic valve repair after endocarditis.

Outcome after heart valve surgery in patients affected by thalassemia is an unreported issue and to the best of our knowledge only 7 cases have been described in the literature. Heart valve disease is commonly encountered in thalassemia patients and heart valve replacement carries high risk of prosthesis complications including thrombosis and embolization despite optimal anticoagulation management. We report a successful long-term outcome after a case of aortic valve repair after mycotic valve endocarditis.

ISMETT: An International Collaboration on Organ Transplantation.

The Institute of the Mediterranean for Transplantation and High Specialty Therapies (ISMETT) is a multi-organ transplant and high specialty center located in Palermo, Italy and managed by the University of Pittsburgh Medical Center. Clinical transplant activity started in 1999 and, herein, we illustrate the outcomes achieved over the past 15 years. In total, ISMETT has performed 997 liver transplants (83.9% adults, 16.1% pediatrics) with a significant percentage of liver transplants from cadaver split livers (17%) and partial grafts from living donors (11.5%). Among liver transplant recipients, the overall five-year graft survival was 74.3% in the adult population and 79% in the pediatric population. ISMETT has also performed 419 kidney transplants in total: 211 from cadaveric donors (22 double), 176 from living donors, and 32 combined (19 with liver, 11 with pancreas, and 2 with heart). The 5-year renal graft survival was 82.2% (cadaveric donor) and 92.2% (living donor). More recently, in 2005, ISMETT started pancreas, lung, and heart transplant programs. In total, 16 pancreas transplants have been performed, of which 12 were simultaneous pancreas-kidney transplants, 1 was pancreas after kidney, and 3 were pancreas alone transplants. One pancreatic islet transplant was also performed in a patient who had already undergone kidney transplantation. Patient and pancreas graft survivals at 1 year were 86.7% and 73.3%, respectively, and 80% and 73.3% at five years (pancreas survival is defined as normoglycemia and insulin-independence). Lung transplant has been performed in 133 patients (116 double and 17 single lung). Eleven were pediatric (8% of all transplants). The 1-month, 1-year, and 5-year overall graft survivals were, 93.8%, 81.4%, and 75.6%, respectively. Heart transplantation has been performed in 133 adults (85% were male). Coronary artery disease and cardiomyopathy were the leading underlying heart disease diagnoses leading to transplant. Mechanical support (ventricular assist device or extracorporeal membrane oxygenation) as a bridge to transplant was used in 18% of the heart transplant cases. One-year heart graft survival was 83% and 5-year heart graft survival was 81%.

Obesity: a new pathology to pay attention to in young people.

Obesity in young people is a form of malnutrition that is found more and more in industrialized countries known both for its association with obesity in adult age and the chronic-degenerate pathologies correlated to it. In 1998 in the United States the prevalence of obesity in 4-12 year olds was 22% for the Hispanics and Afro-Americans and 12.3% for the non Hispanic Caucasians Also in children as in adults, the consequence of obesity is hyperinsulinemia, in direct proportion to the body weight. In this review we discuss the effects of hyperinsulinemia and obesity in young people, and evaluated the difference of cardiovascular complication in young and in adults.