Cost-effectiveness of outpatient adherence to recommendations for monitoring of patients hospitalized for heart failure.

AIMS: A set of indicators to assess the quality of care for patients hospitalized for heart failure was developed by an expert working group of the Italian Health Ministry. Because a better performance profile measured using these indicators does not necessarily translate to better outcomes, a study to validate these indicators through their relationship with measurable clinical outcomes and healthcare costs supported by the Italian National Health System was carried out. METHODS AND RESULTS: Residents of four Italian regions (Lombardy, Marche, Lazio, and Sicily) who were newly hospitalized for heart failure (irrespective of stage and New York Heart Association class) during 2014-2015 entered in the cohort and followed up until 2019. Adherence to evidence-based recommendations [i.e. renin-angiotensin-aldosterone system (RAS) inhibitors, beta-blockers, mineralocorticoid receptor antagonists (MRAs), and echocardiograms (ECCs)] experienced during the first year after index discharge was assessed. Composite clinical outcomes (cardiovascular hospital admissions and all-cause mortality) and healthcare costs (hospitalizations, drugs, and outpatient services) were assessed during the follow-up. The restricted mean survival time at 5 years (denoted as the number of months free from clinical outcomes), the hazard of clinical outcomes (according to the Cox model), and average annual healthcare cost (expressed in euros per person-year) were compared between adherent and non-adherent patients. A non-parametric bootstrap method based on 1000 resamples was used to account for uncertainty in cost-effectiveness estimates. A total of 41 406 patients were included in this study (46.3% males, mean age 76.9 ± 9.4 years). Adherence to RAS inhibitors, beta-blockers, MRAs, and ECCs were 64%, 57%, 62%, and 20% among the cohort members, respectively. Compared with non-adherent patients, those who adhered to ECCs, RAS inhibitors, beta-blockers, and MRAs experienced (i) a delay in the composite outcome of 1.6, 1.9, 1.6, and 0.6 months and reduced risks of 9% (95% confidence interval, 2-14%), 11% (7-14%), 8% (5-11%), and 4% (-1-8%), respectively; and (ii) lower (€262, €92, and €571 per year for RAS inhibitors, beta-blockers, and MRAs, respectively) and higher costs (€511 per year for ECC). Adherence to RAS inhibitors, beta-blockers, and MRAs showed a delay in the composite outcome and a saving of costs in 98%, 84%, and 93% of the 1000 bootstrap replications, respectively. CONCLUSIONS: Strict monitoring of patients with heart failure through regular clinical examinations and drug therapies should be considered the cornerstone of national guidelines and audits.

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.

Flexible Approaches Based on Multistate Models and Microsimulation to Perform Real-World Cost-Effectiveness Analyses: An Application to Proprotein Convertase Subtilisin-Kexin Type 9 Inhibitors.

OBJECTIVES: This study aims to show the application of flexible statistical methods in real-world cost-effectiveness analyses applied in the cardiovascular field, focusing specifically on the use of proprotein convertase subtilisin-kexin type 9 inhibitors for hyperlipidemia. METHODS: The proposed method allowed us to use an electronic health database to emulate a target trial for cost-effectiveness analysis using multistate modeling and microsimulation. We formally established the study design and provided precise definitions of the causal measures of interest while also outlining the assumptions necessary for accurately estimating these measures using the available data. Additionally, we thoroughly considered goodness-of-fit assessments and sensitivity analyses of the decision model, which are crucial to capture the complexity of individuals' healthcare pathway and to enhance the validity of this type of health economic models. RESULTS: In the disease model, the Markov assumption was found to be inadequate, and a "time-reset" timescale was implemented together with the use of a time-dependent variable to incorporate past hospitalization history. Furthermore, the microsimulation decision model demonstrated a satisfying goodness of fit, as evidenced by the consistent results obtained in the short-term horizon compared with a nonmodel-based approach. Notably, proprotein convertase subtilisin-kexin type 9 inhibitors revealed their favorable cost-effectiveness only in the long-term follow-up, with a minimum willingness to pay of 39 000 Euro/life years gained. CONCLUSIONS: The approach demonstrated its significant utility in several ways. Unlike nonmodel-based or alternative model-based methods, it enabled to (1) investigate long-term cost-effectiveness comprehensively, (2) use an appropriate disease model that aligns with the specific problem under study, and (3) conduct subgroup-specific cost-effectiveness analyses to gain more targeted insights.

Simple scores to predict 1-year mortality in atrial fibrillation.

BACKGROUND: Traditional scores as CHADS2 and CHA2DS2-Vasc are suitable for predicting stroke and systemic embolism in patients with atrial fibrillation (AF) and have shown to be also associated with mortality. Other more complex scores have been recommended for survival prediction. The purpose of our analysis was to test the performance of different clinical scores in predicting 1-year mortality in AF patients. MATERIAL AND METHODS: CHADS2 and CHA2DS2-Vasc scores were calculated for AF patients of the BLITZ-AF register and compared to R2-CHADS2, R2-CHA2DS2-Vasc and CHA2DS2VASc-RAF scores in predicting 1-year survival. Scores including renal function were calculated both with glomerular filtration rate (GFR) and creatinine clearance. RESULTS: One-year vital status (1960 alive and 199 dead) was available in 2159 patients. Receiver-operating characteristic curves displayed an association of each score to all-cause mortality, with R2(ClCrea)-CHADS2 being the best [area under the curve (AUC) 0.734]. Differences among the AUCs of the eight scores were not so evident, and a significant difference was found only between R2(ClCrea)-CHADS2 and CHADS2, CHA2DS2VASc, (ClCrea)-CHA2DS2-VASC-RAF.All the scores showed a similar performance for cardiovascular (CV) mortality, with CHA2DS2VASc-RAF being the best (AUC 0.757), with a significant difference with respect to CHADS2, CHA2DS2VASc, and (ClCrea)CHA2DS2Vasc-RAF. CONCLUSIONS: More complex scores, even if with better statistical performance, do not show a clinically relevant higher capability to discriminate alive or dead patients at 12 months. The classical and well known CHA2DS2VASc score, which is routinely used all around the world, has a high sensitivity in predicting all-cause mortality (AUC 0.695; Sensit. 80.4%) and CV mortality (AUC 0.691; Sensit. 80.0%). GRAPHICAL ABSTRACT: http://links.lww.com/JCM/A632.

[ANMCO Position paper: States General 2023 - Digital medicine in cardiology: evidence and state of progress in Italy]. / Position paper ANMCO: Stati Generali 2023 ­ La medicina digitale in cardiologia: evidenze e stato di avanzamento in Italia.

Technological innovation provides easily accessible tools capable of simplifying healthcare processes. Notably, digital technology application in the cardiology field can improve prognosis, reduce costs, and lead to an overall improvement in healthcare. The digitization of health data, with the use of electronic health records and of electronic health files in Italy, represents one of the fields of application of digital technologies in medicine. The 2023 States General of the Italian Association of Hospital Cardiologists (ANMCO) provided an opportunity to focus attention on the potential benefits and critical issues associated with the implementation of the aforementioned digital tools, artificial intelligence, and telecardiology. This document summarizes key aspects that emerged during the event.

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.

What about chronotropic incompetence in heart failure with mildly reduced ejection fraction? Clinical and prognostic implications from the Metabolic Exercise combined with Cardiac and Kidney Indexes score dataset.

AIMS: Chronotropic incompetence (CI) is a strong predictor of outcome in heart failure with reduced ejection fraction, however no data on its clinical and prognostic impacts in heart failure with mildly reduced ejection fraction (HFmrEF) are available. Therefore, the study aims to investigate, in a large multicentre HFmrEF cohort, the prevalence of CI as well as its relationship with exercise capacity and its prognostic role over the cardiopulmonary exercise testing (CPET) parameters. METHODS AND RESULTS: Within the Metabolic Exercise combined with Cardiac and Kidney Indexes (MECKI) database, we analysed data of 864 HFmrEF out of 1164 stable outpatients who performed a maximal CPET at the cycle ergometer and who had no significant rhythm disorders or comorbidities. The primary study endpoint was cardiovascular (CV) death. All-cause death was also explored. Chronotropic incompetence prevalence differed depending on the method (peak heart rate, pHR% vs. pHR reserve, pHRR%) and the cut-off adopted (pHR% from ≤75% to ≤60% and pHRR% ≤ 65% to ≤50%), ranging from 11% to 62%. A total of 84 (9.7%) CV deaths were collected, with 39 (4.5%) occurring within 5 years. At multivariate analysis, both pHR% [hazard ratio 0.97 (0.95-0.99), P < 0.05] and pHRR% [hazard ratio 0.977 (0.961-0.993), P < 0.01] were associated with the primary endpoint. A pHR% ≤ 75% and a pHRR% ≤ 50% represented the most accurate cut-off values in predicting the outcome. CONCLUSION: The study suggests an association between blunted exercise-HR response, functional capacity, and CV death risk among patients with HFmrEF. Whether the CI presence might be adopted in daily HFmrEF management needs to be addressed in larger prospective studies.

Chronotropic incompetence is an easy-to-obtain additive parameter for cardiovascular death risk stratification in heart failure with mildly reduced ejection fraction (HFmrEF). Peak heart rate and peak heart rate reserve are associated with exercise capacity in HFmrEF. Peak heart rate and peak heart rate reserve are associated with cardiovascular death in HFmrEF.

LDL Cholesterol Variability Impacts the Prognosis of Patients with Chronic Ischemic Heart Disease: A Real-World Italian Experience.

Epidemiologic, genetic, and clinical intervention studies have indisputably shown that low-density lipoprotein cholesterol (LDL-C) is causal in the development of atherosclerotic cardiovascular disease (ASCVD). However, LDL-C variability could be related to increased ASCVD risk in patients already treated with statins. The aim of the present retrospective real-life study was to assess the prognostic impact of LDL-C variability on all-cause mortality and cardiovascular hospitalizations in patients with stable cardiovascular artery disease. A total of 3398 patients were enrolled and followed up for a median of 56 months. Considering LDL-C < 70 mg/dL as the therapeutical target, during follow-up, the percentage of patients who achieved this goal raised from 20.7% to 31.9%. In total, 1988 events were recorded, of which 428 were all-cause deaths and 1560 were cardiovascular hospitalizations. At the last medical examination, each increase in LDL-C levels of 20 mg/dL corresponded to a 6% raise in the risk of any event (HR 1.06; 95%CI, 1.03 to 1.09). In conclusion, our real-world study supports the hypothesis that a continuous and progressive downward trend in LDL-C levels is needed to achieve and maintain a cardiovascular benefit, at least in secondary prevention.

Heart failure patients with improved ejection fraction: Insights from the MECKI score database.

AIMS: Improvement of left ventricular ejection fraction is a major goal of heart failure (HF) treatment. However, data on clinical characteristics, exercise performance and prognosis in HF patients who improved ejection fraction (HFimpEF) are scarce. The study aimed to determine whether HFimpEF patients have a distinct clinical phenotype, biology and prognosis than HF patients with persistently reduced ejection fraction (pHFrEF). METHODS AND RESULTS: A total of 7948 patients enrolled in the Metabolic Exercise Cardiac Kidney Indexes (MECKI) score database were evaluated (median follow-up of 1490 days). We analysed clinical, laboratory, electrocardiographic, echocardiographic, exercise, and survival data from HFimpEF (n = 1504) and pHFrEF (n = 6017) patients. The primary endpoint of the study was the composite of cardiovascular death, left ventricular assist device implantation, and urgent heart transplantation. HFimpEF patients had lower HF severity: left ventricular ejection fraction 44.0 [41.0-47.0] versus 29.7 [24.1-34.5]%, B-type natriuretic peptide 122 [65-296] versus 373 [152-888] pg/ml, haemoglobin 13.5 [12.2-14.6] versus 13.7 [12.5-14.7] g/dl, renal function by the Modification of Diet in Renal Disease equation 72.0 [56.7-89.3] versus 70.4 [54.5-85.3] ml/min, peak oxygen uptake 62.2 [50.7-74.1] versus 52.6 [41.8-64.3]% predicted, minute ventilation-to-carbon dioxide output slope 30.0 [26.9-34.4] versus 32.1 [28.0-38.0] in HFimpEF and pHFrEF, respectively (p < 0.001 for all). Cardiovascular mortality rates were 26.6 and 46.9 per 1000 person-years for HFimpEF and pHFrEF, respectively (p < 0.001). Kaplan-Meier analysis showed that HFimpEF had better a long-term prognosis compared with pHFrEF patients. After adjustment for variables differentiating HFimpEF from pHFrEF, except echocardiographic parameters, the Kaplan-Meier curves showed the same prognosis. CONCLUSIONS: Heart failure with improved ejection fraction represents a peculiar group of HF patients whose clinical, laboratory, electrocardiographic, echocardiographic, and exercise characteristics parallel the recovery of systolic function. Nonetheless, these patients remain at risk for adverse outcome.

Comparison of discrimination and calibration performance of ECG-based machine learning models for prediction of new-onset atrial fibrillation.

BACKGROUND: Machine learning (ML) methods to build prediction models starting from electrocardiogram (ECG) signals are an emerging research field. The aim of the present study is to investigate the performances of two ML approaches based on ECGs for the prediction of new-onset atrial fibrillation (AF), in terms of discrimination, calibration and sample size dependence. METHODS: We trained two models to predict new-onset AF: a convolutional neural network (CNN), that takes as input the raw ECG signals, and an eXtreme Gradient Boosting model (XGB), that uses the signal's extracted features. A penalized logistic regression model (LR) was used as a benchmark. Discrimination was evaluated with the area under the ROC curve, while calibration with the integrated calibration index. We investigated the dependence of models' performances on the sample size and on class imbalance corrections introduced with random under-sampling. RESULTS: CNN's discrimination was the most affected by the sample size, outperforming XGB and LR only around n = 10.000 observations. Calibration showed only a small dependence on the sample size for all the models considered. Balancing the training set with random undersampling did not improve discrimination in any of the models. Instead, the main effect of imbalance corrections was to worsen the models' calibration (for CNN, integrated calibration index from 0.014 [0.01, 0.018] to 0.17 [0.16, 0.19]). The sample size emerged as a fundamental point for developing the CNN model, especially in terms of discrimination (AUC = 0.75 [0.73, 0.77] when n = 10.000, AUC = 0.80 [0.79, 0.81] when n = 150.000). The effect of the sample size on the other two models was weaker. Imbalance corrections led to poorly calibrated models, for all the approaches considered, reducing the clinical utility of the models. CONCLUSIONS: Our results suggest that the choice of approach in the analysis of ECG should be based on the amount of data available, preferring more standard models for small datasets. Moreover, imbalance correction methods should be avoided when developing clinical prediction models, where calibration is crucial.

Predicting left ventricular functional recovery in ischaemic cardiomyopathy: needs and challenges.

Left ventricular (LV) systolic function is an essential parameter for the evaluation of patients with ischaemic heart disease, and therapeutic choices are significantly driven by LV ejection fraction (LVEF) in the early stage of the disease and during follow-up. After an acute coronary syndrome, ventricular dysfunction may be reversible when caused by transient myocardial stunning. Therefore, the identification of clinical, laboratory, and instrumental predictors of improvement in LV systolic function (in addition to LVEF) is essential for an adequate prognostic stratification. In the setting of chronic ischaemic heart disease, there is no evidence that an improvement in LV systolic function is invariably associated with a better prognosis and LVEF is only one of many parameters that should be considered for the risk stratification. This state-of-the-art review will critically analyse the scientific evidence regarding known predictors of LVEF recovery, trying to elucidate their pathophysiological principles and clinical value.

[Rationale and significance of the Italian Network for Cardiac Amyloidosis]. / Razionale e valore fondamentale della Rete Italiana integrata dell'Amiloidosi Cardiaca.

The perspective on amyloidosis has changed deeply over the last 10 years following major advances in diagnosis and treatment options, especially in cardiac amyloidosis. This intrinsically heterogeneous disease exposes to the risk of fragmentation of knowledge and requires the interaction among experts of different specialties and subspecialties. Suspicion of disease, timely recognition and confirmation of final diagnosis, prognostic stratification, clinical management and therapeutic strategies represent essential steps to be taken. Missing or delaying the diagnosis may have dramatic impact on patient outcome, as in the case of chemotherapy in unrecognized light-chain amyloidosis. Therefore, there is an urgent need for the foundation of an Italian Amyloidosis Network to deal with the challenges of this condition and orient clinical management at national and local levels. The present consensus document aims to provide the rationale and scopes of the Italian Amyloidosis Network, which has been conceived as an organizational framework for professionals managing patients with amyloidosis.

[ANMCO Position paper: Amyloidosis for the clinical cardiologist. A "clinical primer" from the ANMCO Rare Disease Working Group]. / Position paper ANMCO: L'amiloidosi per il cardiologo clinico. Un "clinical primer" dell'Area Malattie Rare ANMCO.

Cardiac amyloidosis, in the three forms of immunoglobulin light chain (AL), transthyretin (ATTR) wild type (ATTRwt) and mutated (ATTRv) amyloidosis, is an increasingly known and recognized disease in the cardiovascular setting. The first stage of the patient's journey is the clinical suspicion of the disease, which is placed, in presence of a hypertrophic phenotype, by the identification of red flags, both extracardiac and cardiac clues whose presence increase the probability of being faced with a patient with this disease. The second stage is represented by diagnosis, which occurs with certainty through the identification of amyloid substance in cardiac tissue. This stage is spotted in wo parts, i.e. disease confirmation and disease etiology definition (AL vs ATTRwt vs ATTRv). However, it is possible in some selected cases to make a diagnosis of ATTR without the need for tissue assessment, in presence of a positive grade 2-3 bisphosphonate scintigraphy and absence of monoclonal component. Once the diagnosis has been made, the third stage is the assessment of prognosis, the fourth is the patient therapy pathway and fifth is the follow-up plan. Prognosis evaluation is based on different staging systems at the onset of the disease, whose applicability in the era of new effective therapies is still to be defined. To date, the transthyretin tetramer stabilizer tafamidis is the only approved treatment for both wild-type and mutant ATTR cardiomyopathy without polyneuropathy, while ATTRv with associated neuropathy can benefit from treatment with patisiran, an inhibitor of hepatic protein synthesis. Therapies for complications and comorbidities, must be addressed individually, due to the lack of specific clinical trials on this category of patients. In fact, it is important to take into consideration the risks linked to the use of some drugs due to the infiltration of the conduction tissue by the amyloid substance, which increases the risk of bradycardia and heart blocks, the tendency towards hypotension and the increased thromboembolic risk. It is also essential to follow the course of the disease and the efficacy of the treatment in affected patients with a standardized follow-up, and to identify early the signs/symptoms of the disease in asymptomatic TTR mutation carriers.This ANMCO position paper on amyloidosis aims to provide the clinical cardiologist with a practical summary of the disease, to accompany the patient with amyloidosis in the various stages of his journey.

Deep-learning-based prognostic modeling for incident heart failure in patients with diabetes using electronic health records: A retrospective cohort study.

Patients with type 2 diabetes mellitus (T2DM) have more than twice the risk of developing heart failure (HF) compared to patients without diabetes. The present study is aimed to build an artificial intelligence (AI) prognostic model that takes in account a large and heterogeneous set of clinical factors and investigates the risk of developing HF in diabetic patients. We carried out an electronic health records- (EHR-) based retrospective cohort study that included patients with cardiological clinical evaluation and no previous diagnosis of HF. Information consists of features extracted from clinical and administrative data obtained as part of routine medical care. The primary endpoint was diagnosis of HF (during out-of-hospital clinical examination or hospitalization). We developed two prognostic models using (1) elastic net regularization for Cox proportional hazard model (COX) and (2) a deep neural network survival method (PHNN), in which a neural network was used to represent a non-linear hazard function and explainability strategies are applied to estimate the influence of predictors on the risk function. Over a median follow-up of 65 months, 17.3% of the 10,614 patients developed HF. The PHNN model outperformed COX both in terms of discrimination (c-index 0.768 vs 0.734) and calibration (2-year integrated calibration index 0.008 vs 0.018). The AI approach led to the identification of 20 predictors of different domains (age, body mass index, echocardiographic and electrocardiographic features, laboratory measurements, comorbidities, therapies) whose relationship with the predicted risk correspond to known trends in the clinical practice. Our results suggest that prognostic models for HF in diabetic patients may improve using EHRs in combination with AI techniques for survival analysis, which provide high flexibility and better performance with respect to standard approaches.

Contemporary Management and Clinical Course of Acute Pulmonary Embolism: The COPE Study.

BACKGROUND: New diagnosis, risk stratification, and treatment strategies became recently available for patients with acute pulmonary embolism (PE) leading to changes in clinical practice and potentially influencing short-term patients' outcomes. RESEARCH QUESTION: The COntemporary management of PE (COPE) study is aimed at assessing the contemporary clinical management and outcomes in patients with acute symptomatic PE. STUDY DESIGN AND METHODS: Prospective, noninterventional, multicenter study. The co-primary study outcomes, in-hospital and 30-day death, were reported overall and by risk categories according to the European Society of Cardiology (ESC) and American Heart Association guidelines. RESULTS: Among 5,213 study patients, PE was confirmed by computed tomography in 96.3%. In-hospital, 289 patients underwent reperfusion (5.5%), 92.1% received parenteral anticoagulants; at discharge, 75.6% received direct oral anticoagulants and 6.7% vitamin K antagonists. In-hospital and 30-day mortalities were 3.4 and 4.8%, respectively. In-hospital death occurred in 20.3% high-risk patients (n = 177), in 4.0% intermediate-risk patients (n = 3,281), and in 0.5% low-risk patients (n = 1,702) according to ESC guidelines. Further stratification in intermediate-high and intermediate-low risk patients did not reach statistical significance, but intermediate-risk patients with sPESI > 0 alone had lower mortality compared to those with one or both among right ventricular dilation at echocardiography or increased troponin. Death or clinical deterioration occurred in 1.5, 5.0, and 9.4% of patients at low, intermediate-low, and intermediate-high risk for death according to ESC guidelines. CONCLUSION: For the majority of patients with PE, contemporary initial management includes risk stratification and treatment with direct oral anticoagulants. In-hospital mortality remains high in intermediate and high-risk patients calling for and informing research focused on its reduction. TRIAL REGISTRATION NUMBER: NCT03631810.

Prognostic Stratification of Clinically Stable Patients with Heart Failure by Echocardiographic Pressure/Volume Loop Model.

BACKGROUND: Pressure/volume (P/V) loops provide useful information on left ventricular performance and prognosis in patients with heart failure (HF) but do not lend themselves to routine clinical practice. The authors developed a noninvasive method to compute individualized P/V loops to predict adverse clinical outcomes in patients with stable HF, which the authors believe can be used clinically. METHODS: A derivation cohort (n = 443 patients) was used to develop an echocardiography P/V loop model, using brachial arterial pressure and trans-thoracic two-dimensional Doppler echocardiographic data. Each patient's P/V loop was depicted as an irregular pentagon, and a centroid was derived for each loop. The centroid distance (CD) from a reference centroid (derived from 101 healthy control subjects) was computed. This model was prospectively applied to 435 patients who constituted the validation cohort. The study end point was a composite of cardiac death or hospitalization for HF among study patients. RESULTS: In the derivation cohort, CD was threefold greater among patients who experienced adverse events than those who did not. During a follow-up period of 30 months (15-45 months), event rates were 35% (72 of 206 patients) and 12% (29 of 237 patients P < .001), respectively, among patients with CD > 33 mL/mm Hg and those with CD ≤33 mL/mm Hg (prognostic cutoff derived by receiver operating characteristic analysis). Multivariate Cox analysis identified CD as an independent predictor of adverse outcome (hazard ratio, 1.61; 95% CI, 1.03-2.50) independently of left ventricular end-diastolic volume, pulmonary capillary wedge pressure, and left ventricular ejection fraction. These conclusions were confirmed in the validation cohort. CONCLUSIONS: The authors propose a method to create a noninvasive P/V loop and its centroid. These data provide useful pathophysiologic and prognostic information in patients with HF.

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.

Is L-PRF an effective hemostatic agent in single tooth extractions? A cohort study on VKA and DOAC patients.

OBJECTIVES: The aim of this clinical observational study was to assess the efficacy of L-PRF as a hemostatic agent in patients under treatment with vitamin K antagonists (VKAs) or direct oral anticoagulants (DOACs). MATERIALS AND METHODS: Patients under oral anticoagulant therapy (VKA or DOACs) who needed a single simple tooth extraction were enrolled. L-PRF plug was positioned inside the alveolus and secured with non-absorbable sutures. Surgical time, pain-VAS, paracetamol intake, intra-operative, post-operative biological complications, and bleeding events have been registered. RESULTS: A total of 112 patients (59 patients for DOAC and 53 for VKA group) were enrolled. Post-operative bleeding was recorded in nine patients (17%) for VKA group and nine patients (15.3%) for DOACs group. None of the patients needed a medical support for managing of bleeding. Seven days after surgery, no cases of post-extractive complications occurred. CONCLUSIONS: The use of L-PRF resulted in limited mild late post-operative bleedings without the need of medical intervention. CLINICAL RELEVANCE: The use of L-PRF can be adopted for an uneventful post-operative curse in anticoagulated patients without chasing their therapy for single tooth extraction.

Prognostic value of echocardiographic evaluation of cardiac mechanics in patients with aortic stenosis and preserved left ventricular ejection fraction.

Left ventricular ejection function (LVEF) is not reliable in identifying subtle systolic dysfunction. Speckle Tracking (ST) plays a promising role and hemodynamic forces (HDFs) are emerging as marker of LV function. The role of LV myocardial deformation and HDFs was investigated in a cohort of patients with aortic stenosis (AS) and normal LVEF. Two hundred fifty three patients (median age 79 years, IQR 73 - 83 years) with mild (n = 87), moderate (n =77) and severe AS (n =89) were retrospectively enrolled. 2D echocardiographic global longitudinal strain (GLS), circumferential strain (GCS) and HDFs were determined. The worsening of AS was associated with raising inappropriate LV mass (p < 0.001) and declined LVEF, despite being in the normal range (p < 0.001). ST and HDFs parameters declined as the AS became severe (p<0.0001, for all). When patients were grouped based on the median of LV endocardial GLS value (> -19,9%) and LV systolic longitudinal force (LVsysLF) value (< 12,49), patients with impaired ST and lower HDFs components had increased incidence of aortic valve replacement (AVR) and worse survival (p <0.024 and p <0.037, respectively). Among ST and HDFs parameters, only LVsysLF was independently associated with AVR and all causes mortality on multivariable Cox regression analysis (HR 0.94; 95% CI 0.89-0.99; p= 0.012). Reduced values of LVsysLF were associated with AVR and reduced survival in AS patients. LVsysLF could provide useful information in the stratification of patients with AS and possibly in the choice of timing for AVR.