Clinical burden and predictors of non-cardiovascular mortality and morbidity in advanced heart failure.

BACKGROUND: The changing demographic of heart failure (HF) increases the exposure to non-cardiovascular (non-CV) events. We investigated the distribution of non-CV mortality/morbidity and the characteristics associated with higher risk of non-CV events in patients with advanced HF. METHODS: Patients from the HELP-HF registry were stratified according to the number of 2018 HFA-ESC criteria for advanced HF. Endpoints were non-CV mortality and non-CV hospitalization. Competing risk analyses were performed assessing the association between HFA-ESC criteria and study outcomes and the additional predictors of non-CV endpoints. RESULTS: One thousand one hundred and forty-nine patients were included (median age 77 years-IQR 69-83). At 6, 12, 18 and 22 months, cumulative incidence of CV vs non-CV mortality was 13% vs 5%, 17% vs 8%, 20% vs 12%, 23% vs 12%, and of CV vs non-CV hospitalization was 26% vs 11%, 38% vs 17%, 45% vs 20%, 50% vs 21%. HFA-ESC criteria were associated with increasing adjusted risk of CV death, whereas no association was observed for CV hospitalization, non-CV death and non-CV hospitalization. Predictors of non-CV death were age, chronic obstructive pulmonary disease, dementia, preserved ejection fraction, >1 HF hospitalization and hemoglobin. CONCLUSIONS: Patients with advanced HF are exposed to high, even though not predominant, burden of non-CV outcomes. HFA-ESC criteria aid to stratify the risk of CV death, but are not associated with lower competing risk of non-CV outcomes. Alternative factors can be useful to define the patients with advanced HF at risk of non-CV events in order to better select patients for treatments specifically reducing CV risk.

Role of ejection fraction in patients at risk for advanced heart failure: insights from the HELP-HF registry.

AIMS: Patients with heart failure (HF) with reduced ejection fraction (EF) (HFrEF), mildly reduced EF (HFmrEF), and preserved EF (HFpEF) may all progress to advanced HF, but the impact of EF in the advanced setting is not well established. Our aim was to assess the prognostic impact of EF in patients with at least one 'I NEED HELP' marker for advanced HF. METHODS AND RESULTS: Patients with HF and at least one high-risk 'I NEED HELP' criterion from four centres were included in this analysis. Outcomes were assessed in patients with HFrEF (EF ≤ 40%), HFmrEF (EF 41-49%), and HFpEF (EF ≥ 50%) and with EF analysed as a continuous variable. The prognostic impact of medical therapy for HF in patients with EF < 50% and EF > 50% was also evaluated. All-cause death was the primary endpoint, and cardiovascular death was a secondary endpoint. Among 1149 patients enrolled [mean age 75.1 ± 11.5 years, 67.3% males, 67.6% hospitalized, median follow-up 260 days (inter-quartile range 105-390 days)], HFrEF, HFmrEF, and HFpEF were observed in 699 (60.8%), 122 (10.6%), and 328 (28.6%) patients, and 1 year mortality was 28.3%, 26.2%, and 20.1, respectively (log-rank P = 0.036). As compared with HFrEF patients, HFpEF patients had a lower risk of all-cause death [adjusted hazard ratio (HRadj ) 0.67, 95% confidence interval (CI) 0.48-0.94, P = 0.022], whereas no difference was noted for HFmrEF patients. After multivariable adjustment, a lower risk of all-cause death (HRadj for 5% increase 0.94, 95% CI 0.89-0.99, P = 0.017) and cardiovascular death (HRadj for 5% increase 0.94, 95% CI 0.88-1.00, P = 0.049) was observed at higher EF values. Beta-blockers and renin-angiotensin system inhibitors or sacubitril/valsartan were associated with lower mortality in both EF < 50% and EF ≥ 50% groups. CONCLUSIONS: Among patients with HF and at least one 'I NEED HELP' marker for advanced HF, left ventricular EF is still of prognostic value.

Characteristics and outcomes of patients with tricuspid regurgitation and advanced heart failure.

AIMS: To evaluate the role of tricuspid regurgitation in advanced heart failure. METHODS: The multicenter observational HELP-HF registry enrolled consecutive patients with heart failure and at least one 'I NEED HELP' criterion evaluated at four Italian centers between January 2020 and November 2021. Patients with no data on tricuspid regurgitation and/or receiving tricuspid valve intervention during follow-up were excluded. The population was stratified by no/mild tricuspid regurgitation vs. moderate tricuspid regurgitation vs. severe tricuspid regurgitation. Variables independently associated with tricuspid regurgitation, as well as the association between tricuspid regurgitation and clinical outcomes were investigated. The primary outcome was all-cause mortality. RESULTS: Among the 1085 patients included in this study, 508 (46.8%) had no/mild tricuspid regurgitation, 373 (34.4%) had moderate tricuspid regurgitation and 204 (18.8%) had severe tricuspid regurgitation. History of atrial fibrillation, any prior valve surgery, high dose of furosemide, preserved left ventricular ejection fraction, moderate/severe mitral regurgitation and pulmonary hypertension were found to be independently associated with an increased likelihood of severe tricuspid regurgitation. Estimated rates of 1-year all-cause death were of 21.4, 24.5 and 37.1% in no/mild tricuspid regurgitation, moderate tricuspid regurgitation and severe tricuspid regurgitation, respectively (log-rank P  < 0.001). As compared with nonsevere tricuspid regurgitation, severe tricuspid regurgitation was independently associated with a higher risk of all-cause mortality (adjusted hazard ratio 1.38, 95% confidence interval 1.01-1.88, P  = 0.042), whereas moderate tricuspid regurgitation did not. CONCLUSION: In a contemporary, real-world cohort of patients with advanced heart failure, several clinical and echocardiographic characteristics are associated with an increased likelihood of severe tricuspid regurgitation. Patients with severe tricuspid regurgitation have an increased risk of mortality.

Guideline-directed medical therapy in severe heart failure with reduced ejection fraction: An analysis from the HELP-HF registry.

AIM: Persistent symptoms despite guideline-directed medical therapy (GDMT) and poor tolerance of GDMT are hallmarks of patients with advanced heart failure (HF) with reduced ejection fraction (HFrEF). However, real-world data on GDMT use, dose, and prognostic implications are lacking. METHODS AND RESULTS: We included 699 consecutive patients with HFrEF and at least one 'I NEED HELP' marker for advanced HF enrolled in a multicentre registry. Beta-blockers (BB) were administered to 574 (82%) patients, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers or angiotensin receptor-neprilysin inhibitors (ACEi/ARB/ARNI) were administered to 381 (55%) patients and 416 (60%) received mineralocorticoid receptor antagonists (MRA). Overall, ≥50% of target doses were reached in 41%, 22%, and 56% of the patients on BB, ACEi/ARB/ARNI and MRA, respectively. Hypotension, bradycardia, kidney dysfunction and hyperkalaemia were the main causes of underprescription and/or underdosing, but up to a half of the patients did not receive target doses for unknown causes (51%, 41%, and 55% for BB, ACEi/ARB/ARNI and MRA, respectively). The proportions of patients receiving BB and ACEi/ARB/ARNI were lower among those fulfilling the 2018 HFA-ESC criteria for advanced HF. Treatment with BB and ACEi/ARB/ARNI were associated with a lower risk of death or HF hospitalizations (adjusted hazard ratio [HR] 0.63, 95% confidence interval [CI] 0.48-0.84, and HR 0.74, 95% CI 0.58-0.95, respectively). CONCLUSIONS: In a large, real-world, contemporary cohort of patients with severe HFrEF, with at least one marker for advanced HF, prescription and uptitration of GDMT remained limited. A significant proportion of patients were undertreated due to unknown reasons suggesting a potential role of clinical inertia either by the prescribing healthcare professional or by the patient. Treatment with BB and ACEi/ARB/ARNI was associated with lower mortality/morbidity.

Impact of malnutrition in patients with severe heart failure.

AIM: The role of malnutrition among patients with severe heart failure (HF) is not well established. We evaluated the incidence, predictors, and prognostic impact of malnutrition in patients with severe HF. METHODS AND RESULTS: Nutritional status was measured using the geriatric nutritional risk index (GNRI), based on body weight, height and serum albumin concentration, with malnutrition defined as GNRI ≤98. It was assessed in consecutive patients with severe HF, defined by at least one high-risk 'I NEED HELP' marker, enrolled at four Italian centres between January 2020 and November 2021. The primary endpoint was all-cause mortality. A total of 510 patients with data regarding nutritional status were included in the study (mean age 74 ± 12 years, 66.5% male). Among them, 179 (35.1%) had GNRI ≤98 (malnutrition). At multivariable logistic regression, lower body mass index (BMI) and higher levels of natriuretic peptides (B-type natriuretic peptide [BNP] > median value [685 pg/ml] or N-terminal proBNP > median value [5775 pg/ml]) were independently associated with a higher likelihood of malnutrition. Estimated rates of all-cause death at 1 year were 22.4% and 41.1% in patients without and with malnutrition, respectively (log-rank p < 0.001). The impact of malnutrition on all-cause mortality was confirmed after multivariable adjustment for relevant covariates (adjusted hazard ratio 2.03, 95% confidence interval 1.43-2.89, p < 0.001). CONCLUSION: In a contemporary, real-world, multicentre cohort of patients with severe HF, malnutrition (defined as GNRI ≤98) was common and independently associated with an increased risk of mortality. Lower BMI and higher natriuretic peptides were identified as predictors of malnutrition in these patients.

Clinical and prognostic implications of heart failure hospitalization in patients with advanced heart failure.

BACKGROUND: Hospitalization is associated with poor outcomes in patients with heart failure, but its prognostic role in advanced heart failure is still unsettled. We evaluated the prognostic role of heart failure hospitalization in patients with advanced heart failure. METHODS: The multicenter HELP-HF registry enrolled consecutive patients with heart failure and at least one high-risk 'I NEED HELP' marker. Characteristics and outcomes were compared between patients who were hospitalized for decompensated heart failure (inpatients) or not (outpatients) at the time of enrolment. The primary endpoint was the composite of all-cause mortality or first heart failure hospitalization. RESULTS: Among the 1149 patients included [mean age 75.1 ±â€Š11.5 years, 67.3% men, median left ventricular ejection fraction (LVEF) 35% (IQR 25-50%)], 777 (67.6%) were inpatients at the time of enrolment. As compared with outpatients, inpatients had lower LVEF, higher natriuretic peptides and a worse clinical profile. The 1-year rate of the primary endpoint was 50.9% in inpatients versus 36.8% in outpatients [crude hazard ratio 1.70, 95% confidence interval (CI) 1.39-2.07, P < 0.001]. At multivariable analysis, inpatient status was independently associated with a higher risk of the primary endpoint (adjusted hazard ratio 1.54, 95% CI 1.23-1.93, P < 0.001). Among inpatients, the independent predictors of the primary endpoint were older age, lower SBP, heart failure association criteria for advanced heart failure and glomerular filtration rate 30 ml/min/1.73 m2 or less. CONCLUSION: Hospitalization for heart failure in patients with at least one high-risk 'I NEED HELP' marker is associated with an extremely poor prognosis supporting the need for specific interventions, such as mechanical circulatory support or heart transplantation.

Frailty according to the 2019 HFA-ESC definition in patients at risk for advanced heart failure: Insights from the HELP-HF registry.

AIMS: Frailty is highly prevalent in patients with heart failure (HF), but a concordant definition of this condition is lacking. The Heart Failure Association of the European Society of Cardiology (HFA-ESC) proposed in 2019 a new multi-domain definition of frailty, but it has never been validated. METHODS AND RESULTS: Patients from the HELP-HF registry were stratified according to the number of HFA-ESC frailty domains fulfilled and to the cumulative deficits frailty index (FI) quintiles. Prevalence of frailty and of each domain was reported, as well as the rate of the composite of all-cause death and HF hospitalization, its single components, and cardiovascular death in each group and quintile. Among 854 included patients, 37 (4.3%), 206 (24.1%), 365 (42.8%), 217 (25.4%), and 29 (3.4%) patients fulfilled zero, one, two, three, or four domains, respectively, while 179 patients had a FI < 0.21 and were considered not frail. The 1-year risk of adverse events increased proportionally to the number of domains fulfilled (for each criterion increase, all-cause death or HF hospitalization: hazard ratio [HR] 1.43, 95% confidence interval [CI] 1.27-1.62; all-cause death: HR 1.72, 95% CI 1.46-2.02, HF hospitalizations: subHR 1.21, 95% CI 1.04-1.31; cardiovascular death: HR 1.77, 95% CI 1.45-2.15). Consistent results were found stratifying the cohort for FI quintiles. The FI as a continuous variable demonstrated higher discriminative ability than the number of domains fulfilled (area under the curve = 0.68 vs. 0.64, p = 0.004). CONCLUSION: Frailty in patients at risk for advanced HF, assessed via a multi-domain approach and the FI, is highly prevalent and identifies those at increased risk of adverse events. The FI was found to be slightly more effective in identifying patients at increased risk of mortality.

Implantable-cardioverter-defibrillator after ST-elevation myocardial infarction: when and how frequently is it implanted and what is the rate of appropriate interventions? Insight from Trieste registry.

BACKGROUND: There are limited data on implantable-cardioverter-defibrillator (ICD) implantation after ST-elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (pPCI). Therefore, we evaluated when and how frequently an ICD is implanted after pPCI, the rate of appropriate ICD interventions, and predictors of ICD implantation. METHODS: We analyzed STEMI patients treated with pPCI at the University Hospital of Trieste, Italy, between January 2010 and December 2019. We cross-matched patients' data with those present in the Trieste ICD registry. RESULTS: Among 1805 consecutive patients treated with pPCI, 3.6% underwent ICD implantation during a median follow-up of 6.7 [interquartile range (IQR) 4.3-9.2] years. At 12 months, the mean number of ICD implantations was 2.3/100 patients [95% confidence interval (95% CI) 1.7-3.1] and remained stable over time (at 24 months: 2.5/100 patients, 95% CI 2.0-3.5 and at 36 months: 2.6/100 patients, 95% CI 2.3-3.8); 83.1% of ICDs were implanted for primary prevention, and more than half (55%) were implanted in patients with ejection fraction more than 35% at the moment of STEMI discharge. The rate of appropriate ICD interventions was 16.9% at a median follow-up of 5.7 years (IQR 3.3-8.3 years) after ICD implantation. At 12 months, the mean number of appropriate ICD interventions was 5/100 patients and 7/100 patients after 24 months. In patients with ejection fraction more than 35% at STEMI discharge (median ejection fraction 43%; IQR 40-48), independent predictors of ICD implantation were male sex, anterior STEMI and troponin peak more than 100 000 ng/dl. CONCLUSION: The rate of ICD implantations after pPCI is low; however, the rate of appropriate ICD interventions is high. A relevant subgroup of patients received ICD implantations at follow-up despite a nonsevere ejection fraction at discharge after STEMI. Among these patients, those with high troponin release deserve strict follow-up and full optimal medical treatment.

Association of Tricuspid Regurgitation With Outcome in Acute Heart Failure.

BACKGROUND: Tricuspid regurgitation (TR) is common in chronic heart failure (HF) and is associated with negative prognosis. However, evidence on prognostic implications of TR in acute HF is lacking. We sought to investigate the association between TR and mortality and the interaction with pulmonary hypertension (PH) in patients admitted for acute HF. METHODS: We enrolled 1176 consecutive patients with a primary diagnosis of acute HF and with available noninvasive estimation of TR and pulmonary arterial systolic pressure. RESULTS: Moderate-severe TR was present in 352 patients (29.9%) and was associated with older age and more comorbidities. The prevalence of PH (ie, pulmonary arterial systolic pressure >40 mm Hg), right ventricular dysfunction, and mitral regurgitation was higher in moderate-severe TR. At 1 year, 184 (15.6%) patients died. Moderate-severe TR was associated with higher 1-year mortality risk after adjustment for other echocardiographic parameters (pulmonary arterial systolic pressure, left ventricle ejection fraction, right ventricular dysfunction, mitral regurgitation, left and right atrial indexed volumes; hazard ratio, 1.718; P=0.009), and the association with outcome was maintained when clinical variables (eg, natriuretic peptides, serum creatinine and urea, systolic blood pressure, atrial fibrillation) were added to the multivariable model (hazard ratio, 1.761; P=0.024). The association between moderate-severe TR and outcome was consistent in patients with versus without PH, with versus without right ventricular dysfunction, and with versus without left ventricle ejection fraction <50%. Patients with coexistent moderate-severe TR and PH had 3-fold higher 1-year mortality risk compared with patients with no TR or PH (hazard ratio, 3.024; P<0.001). CONCLUSIONS: In patients hospitalized for acute HF, the severity of TR is associated with 1-year survival, regardless of the presence of PH. The coexistence of moderate-severe TR and estimated PH was associated with a further increase in mortality risk. Our data must be interpreted in the context of potential underestimation of pulmonary arterial systolic pressure in patients with severe TR.

Ischemic Etiology in Advanced Heart Failure: Insight from the HELP-HF Registry.

In patients with advanced heart failure (HF), defined according to the presence of at least one I-NEED-HELP criterium, the updated 2018 Heart Failure Association of the European Society of Cardiology (HFA-ESC) criteria for advanced HF identify a subgroup of patients with HF with worse prognosis, but whether ischemic etiology has a relevant prognostic impact in this very high-risk cohort is unknown. Patients from the HELP-HF registry were stratified according to ischemic etiology and presence of advanced HF based on 2018 HFA-ESC criteria. The primary end point was a composite of all-cause death and HF hospitalization at 1 year. Secondary end points were all-cause death, HF hospitalization, and cardiovascular death at 1 year. Ischemic etiology was a leading cause of HF, in both patients with advanced and nonadvanced HF (46.1% and 42.4%, respectively, p = 0.337). The risk of the primary end point (hazard ratio [HR] 1.31, 95% confidence interval [CI] 1.09 to 1.58) and all-cause mortality (HR 1.37, 95% CI 1.06 to 1.76) was increased in ischemic as compared with nonischemic patients. The risk of the primary end point was consistently higher in ischemic patients in both patients with advanced and nonadvanced HF (advanced HF, HR 1.50 95% CI 1.04 to 2.16; nonadvanced HF, HR 1.25 95% CI 1.01 to 1.56, pinteraction = 0.333), driven by an increased risk of mortality, mainly because of cardiovascular causes. In conclusion, ischemic etiology is the most common cause of HF in patients with at least one I-NEED-HELP marker and with or without advanced HF as defined by the 2018 HFA-ESC definition. In both patients with advanced and not-advanced HF, ischemic etiology carried an increased risk of worse prognosis.

Detailed Assessment of the "I Need Help" Criteria in Patients With Heart Failure: Insights From the HELP-HF Registry.

BACKGROUND: The "I Need Help" markers have been proposed to identify patients with advanced heart failure (HF). We evaluated the prognostic impact of these markers on clinical outcomes in a real-world, contemporary, multicenter HF population. METHODS: We included consecutive patients with HF and at least 1 high-risk "I Need Help" marker from 4 centers. The impact of the cumulative number of "I Need Help" criteria and that of each individual "I Need Help" criterion was evaluated. The primary end point was the composite of all-cause mortality or first HF hospitalization. RESULTS: Among 1149 patients enrolled, the majority had 2 (30.9%) or 3 (22.6%) "I Need Help" criteria. A higher cumulative number of "I Need Help" criteria was independently associated with a higher risk of the primary end point (adjusted hazard ratio for each criterion increase, 1.19 [95% CI, 1.11-1.27]; P<0.001), and patients with >5 criteria had the worst prognosis. Need of inotropes, persistently high New York Heart Association classes III and IV or natriuretic peptides, end-organ dysfunction, >1 HF hospitalization in the last year, persisting fluid overload or escalating diuretics, and low blood pressure were the individual criteria independently associated with a higher risk of the primary end point. CONCLUSIONS: In our HF population, a higher number of "I Need Help" criteria was associated with a worse prognosis. The individual criteria with an independent impact on mortality or HF hospitalization were need of inotropes, New York Heart Association class or natriuretic peptides, end-organ dysfunction, multiple HF hospitalizations, persisting edema or escalating diuretics, and low blood pressure.

Prognostic impact of the updated 2018 HFA-ESC definition of advanced heart failure: results from the HELP-HF registry.

AIMS: The Heart Failure Association of the European Society of Cardiology (HFA-ESC) proposed a definition of advanced heart failure (HF) that has not been validated, yet. We assessed its prognostic impact in a consecutive series of patients with high-risk HF. METHODS AND RESULTS: The HELP-HF registry enrolled consecutive patients with HF and at least one high-risk 'I NEED HELP' marker, evaluated at four Italian centres between 1st January 2020 and 30th November 2021. Patients meeting the HFA-ESC advanced HF definition were compared to patients not meeting this definition. The primary endpoint was the composite of all-cause mortality or first HF hospitalization. Out of 4753 patients with HF screened, 1149 (24.3%) patients with at least one high-risk 'I NEED HELP' marker were included (mean age 75.1 ± 11.5 years, 67.3% male, median left ventricular ejection fraction [LVEF] 35% [interquartile range 25%-50%]). Among them, 193 (16.8%) patients met the HFA-ESC advanced HF definition. As compared to others, these patients were younger, had lower LVEF, higher natriuretic peptides and a worse clinical profile. The 1-year rate of the primary endpoint was 69.3% in patients with advanced HF according to the HFA-ESC definition versus 41.8% in the others (hazard ratio [HR] 2.23, 95% confidence interval [CI] 1.82-2.74, p < 0.001). The prognostic impact of the HFA-ESC advanced HF definition was confirmed after multivariable adjustment for relevant covariates (adjusted HR 1.98, 95% CI 1.57-2.50, p < 0.001). CONCLUSIONS: The HFA-ESC advanced HF definition had a strong prognostic impact in a contemporary, real-world, multicentre high-risk cohort of patients with HF.

[Italian Society of Cardiology-Italian Society of Nephrology Consensus document: The cardio-renal interaction in the prevention and treatment of cardiovascular diseases - Part I: From cardiovascular risk factors to the mechanisms of cardio-renal syndrome]. / Documento di consenso Società Italiana di Cardiologia- Società Italiana di Nefrologia: Ruolo dell'asse cardio-renale nella prevenzione e trattamento delle patologie cardiovascolari ­ Parte I: Dai fattori di rischio cardiovascolare ai meccanismi di danno cardio-renale.

Chronic kidney disease (CKD) and cardiovascular (CV) disease are highly prevalent conditions in the general population and are strictly connected to each other with a bidirectional interaction. In patients affected by CKD, the leading cause of morbidity and mortality is represented by CV disease, since CKD promotes the atherosclerotic process increasing inflammation, and modifying lipid and bone mineral metabolism. On the other side, a strict relationship exists between CKD and CV risk factors, which are prevalent in nephropathic patients and impose a stringent assessment of the risk of CV events in this population together with an optimized pharmacological approach, complicated by the coexistence of the two pathological conditions. The first part of this consensus document focuses on the mechanisms of cardio-renal damage and on the impact, as well as the management, of the main CV risk factors in the context of CKD.

[Italian Society of Cardiology-Italian Society of Nephrology Consensus document: The cardio-renal interaction in the prevention and treatment of cardiovascular diseases - Part II: From preventive strategies to treatment of patients with cardio-renal damage]. / Documento di consenso Società Italiana di Cardiologia- Società Italiana di Nefrologia: Ruolo dell'asse cardio-renale nella prevenzione e trattamento delle patologie cardiovascolari ­ Parte II: Dalle strategie di prevenzione al trattamento del paziente con coinvolgimento cardio-renale.

Chronic kidney disease and cardiovascular disease are strictly connected each other with a bidirectional interaction. Thus, the prevention of cardio-renal damage, as its appropriate treatment, are essential steps for a correct management of long-term patients' prognosis. Several preventive and therapeutic strategies, pharmacological and not, are now available for cardio-renal damage prevention and treatment, and for the management of its complications. The second part of this consensus document focuses on the management and treatment of cardio-renal damage, directing the attention on the correct use of drugs that may slow renal disease progression, on the application of preventive strategies in case of invasive cardiac procedures with the use of contrast agents, and on the accurate use of cardiological drugs in patients with chronic kidney disease.