Serum potassium abnormalities, renin-angiotensin-aldosterone system inhibitor discontinuation, and clinical outcomes in patients with chronic cardiovascular, metabolic, and renal conditions: A population-based analysis.

BACKGROUND: Renin-angiotensin-aldosterone system inhibitors (RAASIs) play a crucial role in the treatment of several chronic cardiovascular conditions. Nonetheless, hyperkalemia, a frequent side effect, often leads to the discontinuation of RAASIs. The implications of hyperkalemia-driven changes in RAASI medications are poorly understood. METHODS: Population-based, observational, retrospective cohort study. Two large healthcare databases were utilized to identify 77,089 individuals aged 55 years and older with chronic conditions who were prescribed RAASIs between 2015 and 2017 in Southern Barcelona, Spain. We assessed the interplay between serum potassium abnormalities, RAASI management, and their associations with clinical outcomes, adjusting for potential confounders including socioeconomic factors, medical conditions, and potassium levels. RESULTS: The one-year prevalence of hyperkalemia (defined as serum potassium, K+ >5.0 mmol/L) was 17.8 %. RAASI were down-titrated in 16.1 % of these 13,673 patients with K+ levels. Factors linked to a higher likelihood of reducing/discontinuing RAASI after developing hyperkalemia included older age, impaired kidney function, higher potassium levels, and previous hospitalizations. Dose reduction/discontinuation of RAASI after developing hyperkalemia was associated with an increased risk of hospitalization (adjusted hazard ratio [HR] 1.16, 95 % confidence interval [CI] 1.10-1.21) and with increased mortality (HR 1.60, 95 % CI 1.56-1.84). CONCLUSION: In this large, observational study, hyperkalemia was linked to a greater likelihood of discontinuing RAASIs. Down-titration of RAASI was independently associated with unfavorable clinical outcomes such as hospitalization and specially mortality. Although the observational nature of the study, these findings underscore the importance of preventing circumstances that may lead to RAASI down-titration, such as hyperkalemia, as well as preventing hospitalizations and mortality, to ensure RAASI benefits.

Prognostic Value of Soluble AXL in Serum from Heart Failure Patients with Preserved and Reduced Left Ventricular Ejection Fraction.

Heart failure (HF) is classified according to the degree of reduction in left ventricular ejection fraction (EF) in HF with reduced, mildly reduced, and preserved EF. Biomarkers could behave differently depending on EF type. Here, we analyze the soluble form of the AXL receptor tyrosine kinase (sAXL) in HF patients with reduced and preserved EF. Two groups of HF patients with reduced (HFrEF; n = 134) and preserved ejection fraction (HFpEF; n = 134) were included in this prospective observational study, with measurements of candidate biomarkers and functional, clinical, and echocardiographic variables. A Cox regression model was used to determine predictors for clinical events: cardiovascular mortality and all-cause mortality. sAXL circulating values predicted outcome in HF: for a 1.0 ng/mL increase in serum sAXL, the mortality hazard ratio (HR) was 1.019 for HFrEF (95% CI 1.000 to 1.038) and 1.032 for HFpEF (95% CI 1.013 to 1.052). In a multivariable Cox regression analysis, sAXL and NT-proBNP were independent markers for all-cause and cardiovascular mortality in HFpEF. In contrast, only NT-proBNP remained significant in the HFrEF group. When analyzing the event-free survival at a mean follow-up of 3.6 years, HFrEF and HFpEF patients in the higher quartile of sAXL had a reduced survival time. Interestingly, sAXL is a reliable predictor for all-cause and cardiovascular mortality only in the HFpEF cohort. The results suggest an important role for AXL in HFpEF, supporting sAXL evaluation in larger clinical studies and pointing to AXL as a potential target for HF therapy.

Breaking the 30-day barrier: Long-term effectiveness of a nurse-led 7-step transitional intervention program in heart failure.

BACKGROUND AND AIMS: Heart failure (HF) programs successfully reduce 30-day readmissions. However, conflicting data exist about its sustained effects afterwards and its impact on mortality. We evaluated whether the impact of a new nurse-led coordinated transitional HF program extends to longer periods of time, including 90 and 180 days after discharge. METHODS AND RESULTS: We designed a natural experiment to undertake a pragmatical evaluation of the implementation of the program. We compared outcomes between patients discharged with HF as primary diagnosis in Period #1 (pre-program; Jan 2017-Aug 2017) and those discharged during Period #2 (HF program; Sept 2017-Jan 2019). Primary endpoint was the composite of all-cause death or all-cause hospitalization 90 and 180 days after discharge. 440 patients were enrolled: 123 in Period #1 and 317 in Period #2. Mean age was 75±9 years. There were more females in Period #2 (p = 0.025), with no other significant differences between periods. The primary endpoint was significantly reduced in the HF program group, at 90 [adjusted OR 0.31 (0.18-0.53), p <0.001] and at 180 days [adjusted OR 0.18 (CI 0.11-0.32), p <0.001]. Such a decrease was due to a reduction in cardiovascular (CV) and HF hospitalization. All-cause death was reduced when a double check discharge planning was implanted compared to usual care [0 (0%) vs. 7 (3.8%), p = 0.022]. CONCLUSION: A new nurse-led coordinated transitional bundle of interventions model reduces the composite endpoint of all-cause death and all-cause hospitalization both at 90 and 180 days after a discharge for HF, also in high-risk populations. Such a decrease is driven by a reduction of CV and HF hospitalization. Reduction of all-cause mortality was also observed when the full model including a more exhaustive discharge planning process was implemented.

Psychosocial factors partially explain gender differences in health-related quality of life in heart failure patients.

AIMS: There is little information about the influence of gender on quality of life (QoL) in heart failure. The purpose of this study was to evaluate whether the health-related QoL gap between men and women can be explained by the interaction between psychosocial factors and clinical determinants in a real-word cohort of patients with chronic heart failure. METHODS AND RESULTS: We conducted a single-centre, observational, prospective cohort study of 1236 consecutive patients diagnosed with chronic heart failure recruited between 2004 and 2014. To assess QoL, we used the Minnesota Living with Heart Failure Questionnaire (MLHFQ). Female gender was associated with worse global QoL compared to male gender (MLHFQ overall summary score: 49 ± 23 vs. 43 ± 24; P value <0.001, respectively) and similarly had poorer scores in physical and emotional dimensions but scored better on social dimension. In univariate models and in models adjusted for clinical determinants, female gender behaved as a predictor of worse global, physical and emotional QoL, and better social QoL compared with men. In models only including psychosocial determinants and in comprehensive models including all psychosocial and clinical factors, these differences according to gender were no longer significant. CONCLUSIONS: In this study, we have shown that the gap in health-related QoL between men and women with chronic heart failure can be partially explained by the interaction between biological and psychosocial factors. Biological factors are the main drivers of QoL in HF patients. However, the contribution of psychosocial factors is essential to definitively understand the role of gender in this field.

Usefulness of telemedicine-based heart failure monitoring according to 'eHealth literacy' domains: Insights from the iCOR randomized controlled trial.

BACKGROUND: The potential positive effect of electronic health (eHealth)-based heart failure (HF) monitoring remains uncertain mainly in the 'low literacy' or 'computer or digital illiterate' patients. The aim of this study was to determine the effectiveness of a telemedicine (TM)-based managed care solution across literacy levels and information and communications technology (ICT) skills. METHODS: We performed a sub-analysis on the basis of two literacy domains encompassed in the definition of 'eHealth literacy' to the HF-patients included in the 'insuficiència Cardíaca Optimització Remota' (iCOR) randomized study comparing TM vs. usual care (UC) in HF-patients. The primary study endpoint was the incidence of a non-fatal HF event after 6 months of inclusion. The event rates of primary and secondary study endpoints were calculated for each literacy domains and its combination. Cox proportional-hazards regression models were used to evaluate the effect of 'eHealth literacy' dimensions, treatment group and the interaction term 'eHealth literacy' domains by treatment group on study endpoints. RESULTS: The beneficial effect of TM compared to UC strategy was consistent across all literacy domains (p-value for interaction 0.207 and 0.117 respectively). The risk of experiencing a primary event was significantly lower in patients that underwent allocation to the TM arm compared to UC in both clustered in the 'lower literacy' (p-value=0.001) and those allocated to the 'lower ICT skills' (p-value=0.001) subgroup. CONCLUSIONS: Non-invasive eHealth-based HF monitoring tools are effective compared to UC in preventing HF events in the early post-discharge period, regardless of two 'eHealth literacy' domains ('traditional and computer literacy').

The relationship between self-care, long-term mortality, and heart failure hospitalization: insights from a real-world cohort study.

AIMS: The assumption that improved self-care in the setting of heart failure (HF) care necessarily translates into improvements in long-term mortality and/or hospitalization is not well established. We aimed to study the association between self-care and long-term mortality and other major adverse HF events (MAHFE). METHODS AND RESULTS: We conducted an observational, prospective, cohort study of 1123 consecutive patients with chronic HF. The primary endpoint was all-cause mortality. We used the European Heart Failure Self-care Behaviour Scale 9-item version (EHFSCBS-9) to measure global self-care (overall score) and three specific dimensions of self-care including autonomy-based adherence, consulting behaviour and provider-based adherence. After a mean follow-up of 3.3 years, all-cause death occurred in 487 patients (43%). In adjusted analysis, higher EHFScBS-9 scores (better self-care) at baseline were associated with lower risk of all-cause death [hazard ratio (HR) 0.993, 95% confidence interval (CI) (0.988-0.997), P-value = 0.002], cardiovascular (CV) death [HR 0.989, 95% CI (0.981-0.996), P-value = 0.003], HF hospitalization [HR 0.993, 95% CI (0.988-0.998), P-value = 0.005], and the combination of MAHFE [HR 0.995, 95% CI (0.991-0.999), P-value = 0.018]. Similarly, impaired global self-care [HR 1.589, 95% CI (1.201-2.127), P-value = 0.001], impaired autonomy-based adherence [HR 1.464, 95% CI (1.114-1.923), P-value = 0.006], and impaired consulting behaviour dimensions [HR 1.510, 95% CI (1.140-1.923), P-value = 0.006] were all associated with higher risk of all-cause mortality. CONCLUSION: In this study, we have shown that worse self-care is an independent predictor of long-term mortality (both, all-cause and CV), HF hospitalization, and the combinations of these endpoints in patients with chronic HF. Important dimensions of self-care such as autonomy-based adherence and consulting behaviour also determine the risk of all these outcomes in the long term.

Effectiveness of telemedicine in patients with heart failure according to frailty phenotypes: Insights from the iCOR randomised controlled trial.

BACKGROUND: The potential impact of telemedicine (TM) in the monitoring of patients with heart failure (HF) is still uncertain particularly in the frailest patients. The aim of this study was to define the efficacy of a TM-based managed care solution across different HF patient frailty phenotypes. METHODS: We performed a clustering analysis on the basis of 8 frailty-related dimensions to the HF-patients included in the 'insuficiència Cardíaca Optimització Remota' (iCOR) randomised study comparing TM vs. usual care (UC) in HF patients. The primary study endpoint was the incidence of a non-fatal HF event after 6 months of inclusion. The healthcare-related costs in each study group and cluster were also evaluated. The event rates of primary and secondary study endpoints were calculated for each cluster. Cox proportional-hazards regression models were used to evaluate the effect of cluster, treatment group and the interaction term cluster by treatment group on study endpoints. RESULTS: 5 different frailty phenotypes were identified. The positive effect of TM compared to UC strategy was consistent across all frailty phenotypes (p-value for interaction 0.711). The risk of experiencing a primary event was significantly lower in patients that underwent allocation to the TM arm compared to UC (p-value = 0.016). Ultimately, the healthcare costs were significantly reduced in patients allocated to the TM compared to UC in all 5 frailty phenotypes (all p-value < 0.05). CONCLUSIONS: Non-invasive TM-based follow-up tools are effective compared to UC follow-up in preventing HF events in the early post-discharge period, regardless of the 5 frailty phenotypes.

Quality of life and disease experience in patients with heart failure with reduced ejection fraction in Spain: a mixed-methods study.

OBJECTIVES: To gather insights on the disease experience of patients with heart failure (HF) with reduced ejection fraction (HFrEF), and assess how patients' experiences and narratives related to the disease complement data collected through standardised patient-reported outcome measures (PROMs). Also, to explore new ways of evaluating the burden experienced by patients and caregivers. DESIGN: Observational, descriptive, multicentre, cross-sectional, mixed-methods study. SETTING: Secondary care, patient's homes. PARTICIPANTS: Twenty patients with HFrEF (New York Heart Association (NYHA) classification I-III) aged 38-85 years. MEASURES: PROMs EuroQoL 5D-5L (EQ-5D-5L) and Kansas City Cardiomyopathy Questionnaire and patient interview and observation. RESULTS: A total of 20 patients with HFrEF participated in the study. The patients' mean (SD) age was 72.5 (11.4) years, 65% were male and were classified inNYHA functional classes I (n=4), II (n=7) and III (n=9). The study showed a strong impact of HF in the patients' quality of life (QoL) and disease experience, as revealed by the standardised PROMs (EQ-5D-5L global index=0.64 (0.36); Kansas City Cardiomyopathy Questionnaire total symptom score=71.56 (20.55)) and the in-depth interviews. Patients and caregivers often disagreed describing and evaluating perceived QoL, as patients downplayed their limitations and caregivers overemphasised the poor QoL of the patients. Patients related current QoL to distant life experiences or to critical moments in their disease, such as hospitalisations. Anxiety over the disease progression is apparent in both patients and caregivers, suggesting that caregiver-specific tools should be developed. CONCLUSIONS: PROMs are an effective way of assessing symptoms over the most recent time period. However, especially in chronic diseases such as HFrEF, PROM scores could be complemented with additional tools to gain a better understanding of the patient's status. New PROMs designed to evaluate and compare specific points in the life of the patient could be clinically more useful to assess changes in health status.

Atrial Fibrillation in Heart Failure Is Associated with High Levels of Circulating microRNA-199a-5p and 22-5p and a Defective Regulation of Intracellular Calcium and Cell-to-Cell Communication.

MicroRNAs (miRNAs) participate in atrial remodeling and atrial fibrillation (AF) promotion. We determined the circulating miRNA profile in patients with AF and heart failure with reduced ejection fraction (HFrEF), and its potential role in promoting the arrhythmia. In plasma of 98 patients with HFrEF (49 with AF and 49 in sinus rhythm, SR), differential miRNA expression was determined by high-throughput microarray analysis followed by replication of selected candidates. Validated miRNAs were determined in human atrial samples, and potential arrhythmogenic mechanisms studied in HL-1 cells. Circulating miR-199a-5p and miR-22-5p were significantly increased in HFrEF patients with AF versus those with HFrEF in SR. Both miRNAs, but particularly miR-199a-5p, were increased in atrial samples of patients with AF. Overexpression of both miRNAs in HL-1 cells resulted in decreased protein levels of L-type Ca2+ channel, NCX and connexin-40, leading to lower basal intracellular Ca2+ levels, fewer inward currents, a moderate reduction in Ca2+ buffering post-caffeine exposure, and a deficient cell-to-cell communication. In conclusion, circulating miR-199a-5p and miR-22-5p are higher in HFrEF patients with AF, with similar findings in human atrial samples of AF patients. Cells exposed to both miRNAs exhibited altered Ca2+ handling and defective cell-to-cell communication, both findings being potential arrhythmogenic mechanisms.

Iron deficiency contributes to resistance to endogenous erythropoietin in anaemic heart failure patients.

AIMS: Abnormal endogenous erythropoietin (EPO) constitutes an important cause of anaemia in chronic diseases. We analysed the relationships between iron deficiency (ID) and the adequacy of endogenous EPO in anaemic heart failure (HF) patients, and the impact of abnormal EPO on 12-month mortality. METHODS AND RESULTS: We investigated 435 anaemic HF patients (age: 74 ± 10 years; males: 60%; New York Heart Association class I or II: 39%; left ventricular ejection fraction: 43 ± 17%). Patients with EPO higher than expected for a given haemoglobin were considered EPO-resistant whereas those with EPO lower than expected - EPO-deficient. ID was defined as serum ferritin <100 µg/L or 100-299 µg/L with transferrin saturation <20%. EPO-resistant patients (22%) had more advanced HF whereas those with EPO deficiency (57%) were more frequently females and had worse renal function. Lower serum ferritin (indicating depleted body iron stores) was related to higher EPO observed/predicted ratio when adjusted for significant clinical confounders, including C-reactive protein. One year all-cause mortality was 28% in patients with EPO resistance compared to 17% in patients with EPO deficiency and 10% in patients with adequate EPO (log-rank test for the comparison EPO resistance vs. adequate EPO: P = 0.02). When adjusted for other prognosticators, there was still a trend towards increased 12-month mortality in patients with higher EPO level. CONCLUSION: Anaemic HF patients with endogenous EPO deficiency vs. resistance have different clinical and laboratory characteristics. In such patients, ID contributes to EPO resistance independently of inflammation.

Impacto clínico y en costes sanitarios de alteraciones de potasio en pacientes con enfermedades cardiovasculares, metabólicas y renales crónicas / Impact on clinical outcomes and health costs of deranged potassium levels in patients with chronic cardiovascular, metabolic, and renal conditions

Introducción y objetivos Las alteraciones de la potasemia son frecuentes en las enfermedades cardiovasculares crónicas. El objetivo del estudio es evaluar las asociaciones de la hiperpotasemia y la hipopotasemia con eventos clínicos y costes sanitarios en pacientes con insuficiencia cardiaca, enfermedad renal crónica, diabetes mellitus, hipertensión y cardiopatía isquémica. Métodos Estudio longitudinal que incluyó a 36.269 pacientes de un Área de Salud que tuvieran al menos una de las afecciones mencionadas. Se utilizaron bases de datos administrativas, hospitalarias y de atención primaria. Se siguió a los participantes entre 2015 y 2017; estos tenían 55 o más años y al menos 1 medición de potasio. Se utilizaron 4 diseños analíticos para evaluar la prevalencia y la incidencia y el uso de inhibidores del sistema renina-angiotensina-aldosterona. Resultados La hiperpotasemia fue 2 veces más frecuente que la hipopotasemia. En los análisis ajustados, la hiperpotasemia se asoció de manera significativa con un mayor riesgo de muerte por todas las causas (HR de los modelos de regresión de Cox entre 1,31 y 1,68) y con un aumento de las probabilidades de que los gastos anuales de atención sanitaria superen el 85% (OR entre 1,21 y 1,29). Las asociaciones fueron aún mayores en los pacientes hipopotasémicos (HR para la muerte por todas las causas, 1,92-2,60; OR para los gastos de atención sanitaria> percentil 85, 1,81-1,85). Conclusiones Se necesitarían estudios experimentales para confirmar si la prevención de los trastornos del potasio reduce la mortalidad y los gastos sanitarios en estas enfermedades crónicas. Hasta entonces, nuestros hallazgos proporcionan conclusiones observacionales sobre la importancia de mantener normales las concentraciones de potasio. (AU)

Introduction and objectives Potassium derangements are frequent among patients with chronic cardiovascular conditions. Studies on the associations between potassium derangements and clinical outcomes have yielded mixed findings, and the implications for health care expenditure are unknown. We assessed the population-based associations between hyperkalemia, hypokalemia and clinical outcomes and health care costs, in patients with chronic heart failure, chronic kidney disease, diabetes mellitus, hypertension, and ischemic heart disease. Methods Population-based, longitudinal study including up to 36 269 patients from a health care area with at least one of the above-mentioned conditions. We used administrative, hospital and primary care databases. Participants were followed up between 2015 and 2017, were aged ≥ 55 years and had at least 1 potassium measurement. Four analytic designs were used to evaluate prevalent and incident cases and the use of renin-angiotensin-aldosterone system inhibitors. Results Hyperkalemia was twice as frequent as hypokalemia. On multivariable-adjusted analyses, hyperkalemia was robustly and significantly associated with an increased risk of all-cause death (HR from Cox regression models ranging from 1.31–1.68) and with an increased odds of a yearly health care expenditure >85th percentile (OR, 1.21–1.29). Associations were even stronger in hypokalemic patients (HR for all-cause death, 1.92–2.60; OR for health care expenditure> percentile 85th, 1.81–1.85). Conclusions Experimental studies are needed to confirm whether the prevention of potassium derangements reduces mortality and health care expenditure in these chronic conditions. Until then, our findings provide observational evidence on the potential importance of maintaining normal potassium levels. (AU)

Prognostic Value of the Acute-to-Chronic Glycemic Ratio at Admission in Heart Failure: A Prospective Study.

Acute hyperglycemia has been associated with worse prognosis in patients hospitalized for heart failure (HF). Nevertheless, studies evaluating the impact of glycemic control on long-term prognosis have shown conflicting results. Our aim was to assess the relationship between acute-to-chronic (A/C) glycemic ratio and 4-year mortality in a cohort of subjects hospitalized for acute HF. A total of 1062 subjects were consecutively included. We measured glycaemia at admission and estimated average chronic glucose levels and the A/C glycemic ratio were calculated. Subjects were stratified into groups according to the A/C glycemic ratio tertiles. The primary endpoint was 4-year mortality. Subjects with diabetes had higher risk for mortality compared to those without (HR 1.35 [95% CI: 1.10-1.65]; p = 0.004). A U-shape curve association was found between glucose at admission and mortality, with a HR of 1.60 [95% CI: 1.22-2.11]; p = 0.001, and a HR of 1.29 [95% CI: 0.97-1.70]; p = 0.078 for the first and the third tertile, respectively, in subjects with diabetes. Additionally, the A/C glycemic ratio was negatively associated with mortality (HR 0.76 [95% CI: 0.58-0.99]; p = 0.046 and HR 0.68 [95% CI: 0.52-0.89]; p = 0.005 for the second and third tertile, respectively). In multivariable analysis, the A/C glycemic ratio remained an independent predictor. In conclusion, in subjects hospitalized for acute HF, the A/C glycemic ratio is significantly associated with mortality, improving the ability to predict mortality compared with glucose levels at admission or average chronic glucose concentrations, especially in subjects with diabetes.

Impact on clinical outcomes and health costs of deranged potassium levels in patients with chronic cardiovascular, metabolic, and renal conditions.

INTRODUCTION AND OBJECTIVES: Potassium derangements are frequent among patients with chronic cardiovascular conditions. Studies on the associations between potassium derangements and clinical outcomes have yielded mixed findings, and the implications for health care expenditure are unknown. We assessed the population-based associations between hyperkalemia, hypokalemia and clinical outcomes and health care costs, in patients with chronic heart failure, chronic kidney disease, diabetes mellitus, hypertension, and ischemic heart disease. METHODS: Population-based, longitudinal study including up to 36 269 patients from a health care area with at least one of the above-mentioned conditions. We used administrative, hospital and primary care databases. Participants were followed up between 2015 and 2017, were aged ≥ 55 years and had at least 1 potassium measurement. Four analytic designs were used to evaluate prevalent and incident cases and the use of renin-angiotensin-aldosterone system inhibitors. RESULTS: Hyperkalemia was twice as frequent as hypokalemia. On multivariable-adjusted analyses, hyperkalemia was robustly and significantly associated with an increased risk of all-cause death (HR from Cox regression models ranging from 1.31-1.68) and with an increased odds of a yearly health care expenditure >85th percentile (OR, 1.21-1.29). Associations were even stronger in hypokalemic patients (HR for all-cause death, 1.92-2.60; OR for health care expenditure> percentile 85th, 1.81-1.85). CONCLUSIONS: Experimental studies are needed to confirm whether the prevention of potassium derangements reduces mortality and health care expenditure in these chronic conditions. Until then, our findings provide observational evidence on the potential importance of maintaining normal potassium levels.

Study design of Heart failure Events reduction with Remote Monitoring and eHealth Support (HERMeS).

AIMS: The role of non-invasive telemedicine (TM) combining telemonitoring and teleintervention by videoconference (VC) in patients recently admitted due to heart failure (HF) ('vulnerable phase' HF patients) is not well established. The aim of the Heart failure Events reduction with Remote Monitoring and eHealth Support (HERMeS) trial is to assess the impact on clinical outcomes of implementing a TM service based on mobile health (mHealth), which includes remote daily monitoring of biometric data and symptom reporting (telemonitoring) combined with VC structured, nurse-based follow-up (teleintervention). The results will be compared with those of the comprehensive HF usual care (UC) strategy based on face-to-face on-site visits at the vulnerable post-discharge phase. METHODS AND RESULTS: We designed a 24 week nationwide, multicentre, randomized, controlled, open-label, blinded endpoint adjudication trial to assess the effect on cardiovascular (CV) mortality and non-fatal HF events of a TM-based comprehensive management programme, based on mHealth, for patients with chronic HF. Approximately 508 patients with a recent hospital admission due to HF decompensation will be randomized (1:1) to either structured follow-up based on face-to-face appointments (UC group) or the delivery of health care using TM. The primary outcome will be a composite of death from CV causes or non-fatal HF events (first and recurrent) at the end of a 6 month follow-up period. Key secondary endpoints will include components of the primary event analysis, recurrent event analysis, and patient-reported outcomes. CONCLUSIONS: The HERMeS trial will assess the efficacy of a TM-based follow-up strategy for real-world 'vulnerable phase' HF patients combining telemonitoring and teleintervention.

Use of potassium-binder patiromer for up-titration of renin-angiotensin-aldosterone system inhibition therapy in a patient with chronic heart failure and reduced ejection fraction followed in a multidisciplinary integrated chronic care management programme: a case report.

BACKGROUND: Chronic heart failure (CHF) is a growing epidemic. The cornerstone of pharmacological therapy in CHF patients with reduced ejection fraction (HFrEF) is the inhibition of the renin-angiotensin-aldosterone system (RAAS). One of the adverse effects of RAAS blockade is the development of hyperkalaemia, which often limits the optimization of recommended, Class I treatments. In this context, potassium binders patiromer or sodium zirconium cyclosilicate (ZS-9) provide an opportunity to optimize the pharmacological management of these patients. CASE SUMMARY: We present a case report illustrating our real-life experience using the potassium-binder patiromer in a patient with HFrEF, in whom recurrent hyperkalaemia (up to 6.3 mmol/L with low doses of enalapril) was preventing titration of RAAS inhibition therapies. Use of patiromer allowed re-introducing ramipril (subsequently switched to sacubitril/valsartan) and eplerenone. Serum potassium levels remained normal with patiromer 16.8 g/24 h, and the patient's tolerance to patiromer was excellent. DISCUSSION: In patients with HFrEF and recurrent hyperkalaemia, optimal RAAS inhibition is often discontinued. In this context, novel potassium binders such as patiromer or ZS-9 have been shown to be effective in lowering potassium and maintaining normokalaemia, with a good safety profile and patient tolerance, all of which make them promising alternative options. Our preliminary experience suggests that patiromer may be a helpful and well-tolerated treatment option, which may aid in achieving optimal RAAS inhibition in HFrEF patients with recurrent hyperkalaemia. Registries of HFrEF patients will help better understand whether therapies such as patiromer have prognostic benefits through facilitating optimal RAAS blockade.

Real-World Epidemiology of Potassium Derangements Among Chronic Cardiovascular, Metabolic and Renal Conditions: A Population-Based Analysis.

BACKGROUND: The aims of the present analysis are to estimate the prevalence of five key chronic cardiovascular, metabolic and renal conditions at the population level, the prevalence of renin-angiotensin-aldosterone system inhibitor (RAASI) medication use and the magnitude of potassium (K+) derangements among RAASI users. METHODS AND RESULTS: We used data from more than 375,000 individuals, 55 years of age or older, included in the population-based healthcare database of the Catalan Institute of Health between 2015 and 2017. The conditions of interest were chronic heart failure (CHF), chronic kidney disease (CKD), diabetes mellitus, ischemic heart disease and hypertension. RAASI medications included angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, mineralocorticoid receptor antagonists (MRAs) and renin inhibitors. Hyperkalemia was defined as K+ levels >5.0 mEq/L and hypokalemia as K+ <3.5 mEq/L. The prevalence of chronic cardiovascular, metabolic and renal conditions was high, and particularly that of hypertension (prevalence ranging from 48.2% to 48.9%). The use of at least one RAASI medication was almost ubiquitous in these patients (75.2-77.3%). Among RAASI users, the frequency of K+ derangements, mainly of hyperkalemia, was very noticeable (12% overall), particularly in patients with CKD or CHF, elderly individuals and users of MRAs. Hypokalemia was less frequent (1%). CONCLUSION: The high prevalence of K+ derangements, and particularly hyperkalemia, among RAASI users highlights the real-world relevance of K+ derangements, and the importance of close monitoring and management of K+ levels in routine clinical practice. This is likely to benefit a large number of patients, particularly those at higher risk.

Sympathetic activation and outcomes in chronic heart failure: Does the neurohormonal hypothesis apply to mid-range and preserved ejection fraction patients?

BACKGROUND: Sympathetic activity (SA) is increased in patients with heart failure and reduced ejection fraction (HFrEF) and is associated with poor outcomes. However, its clinical implications are less understood in HF with mid-range (HFmrEF) and preserved ejection fraction (HFpEF). We aimed to study SA across left ventricle ejection fraction (LVEF) groups and its association with clinical outcomes. METHODS AND RESULTS: SA estimated by norepinephrine (NE) levels was determined in 742 consecutive outpatients with chronic HF: 348 (47%) with HFrEF, 116 (16%) HFmrEF, and 278 (37%) HFpEF. After a mean follow-up of 15 months, 17% died. Adjusted analyses showed that patients with HFpEF and HFmrEF had lower estimated marginal means of NE levels compared to HFrEF (278 and 116 pg/mL, respectively, vs. 348 pg/mL; p-value=0.005). Adjusted Cox regression analyses showed that high norepinephrine levels independently predicted all-cause mortality (ACM) in all 3 groups. The strongest associations between high NE levels and cardiovascular mortality (CVM) were observed in HFmrEF (HR: 4.7 [1.33-16.68]), while the weakest association was in HFpEF (HR: 2.62 [1.08-6.35]). CONCLUSIONS: Adjusted analyses showed that HFpEF and HFmrEF were associated with lower SA compared to HFrEF. Nevertheless, increasing NE levels were independently associated with ACM and CVM in all three LVEF groups. The strongest association between high NE levels and CVM was present in HFmrEF patients, while the weakest was seen in HFpEF. These findings could explain why the response to neurohormonal therapies in patients with HFmrEF is similar to that of patients with HFrEF rather than with HFpEF.

Use of intravenous iron in patients with iron deficiency and chronic heart failure: Real-world evidence.

INTRODUCTION AND OBJECTIVES: Treatment with intravenous iron in patients with heart failure (HF) and iron deficiency (ID) improves symptoms, however its impact on survival and safety is unknown. We aimed to evaluate the management of ID and anemia with intravenous iron in patients with HF and long-term safety of intravenous iron. METHODS: We evaluated anemia and ID in patients with chronic HF at 3 university hospitals. Anemia was defined using the World Health Organization definition and ID was defined as ferritin <100 ug/L or a Transferrin Saturation <20% if ferritin between 100 and 299 ug/L. We assessed treatment with intravenous iron during follow-up and its association with mortality and HF hospitalizations using multivariate cox regression analysis. RESULTS: We included 2,114 patients, median age 72 years and 57% had reduced left ventricular ejection fraction. ID was present in 55% and ID and anemia in 29%. Treatment with intravenous iron was used in 24% of patients with ID and 34% of patients with ID and anemia. In patients with ID, after multivariate adjustment, treatment with intravenous iron was associated with lower all-cause mortality: HR = 0.38 (0.28-0.56), lower cardiovascular mortality: HR = 0.34 (0.20-0.57) and no differences in HF hospitalizations: HR = 1.15 (0.88-1.50). Similar outcomes were found for patients with anemia and ID. CONCLUSIONS: In a real-world cohort of patients with HF, treatment with intravenous iron was used in one third of patients with ID and anemia and appears safe in mid-term follow-up.

Iron Deficiency: Impact on Functional Capacity and Quality of Life in Heart Failure with Preserved Ejection Fraction.

The effects of iron deficiency (ID) have been widely studied in heart failure (HF) with reduced ejection fraction. On the other hand, studies in HF with preserved ejection fraction (HFpEF) are few and have included small numbers of participants. The aim of this study was to assess the role that ID plays in functional capacity and quality of life (QoL) in HFpEF while comparing several iron-related biomarkers to be used as potential predictors. ID was defined as ferritin <100 ng/mL or transferrin saturation <20%. Submaximal exercise capacity, measured by the 6-min walking test (6MWT), and QoL, assessed by the Minnesotta Living with Heart Failure Questionnaire (MLHFQ), were compared between iron deficient patients and patients with normal iron status. A total of 447 HFpEF patients were included in the present cross-sectional study, and ID prevalence was 73%. Patients with ID performed worse in the 6MWT compared to patients with normal iron status (ID 271 ± 94 m vs. non-ID 310 ± 108 m, p < 0.01). They also scored higher in the MLHFQ, denoting worse QoL (ID 49 ± 22 vs. non-ID 43 ± 23, p = 0.01). Regarding iron metabolism biomarkers, serum soluble transferrin receptor (sTfR) was the strongest independent predictor of functional capacity (ß = -63, p < 0.0001, R2 0.39) and QoL (ß = 7.95, p < 0.0001, R2 0.14) in multivariate models. This study postulates that ID is associated with worse functional capacity and QoL in HFpEF as well, and that sTfR is the best iron-related biomarker to predict both. Our study also suggests that the effects of ID could differ among HFpEF patients by left ventricular ejection fraction.

Impact of telemedicine on the clinical outcomes and healthcare costs of patients with chronic heart failure and mid-range or preserved ejection fraction managed in a multidisciplinary chronic heart failure programme: A sub-analysis of the iCOR randomized trial.

Background: The efficacy of telemedicine in the management of patients with chronic heart failure and left ventricular ejection fraction ≥40% is poorly understood. The aim of our analysis was to evaluate the efficacy of a telemedicine-based intervention specifically in these patients, as compared to standard of care alone. Methods: The Insuficiència Cardiaca Optimització Remota (iCOR) study was a single centre, randomised, controlled trial, designed to evaluate a telemedicine intervention added to an existing hospital/primary care multidisciplinary, integrated programme for chronic heart failure patients. 178 participants were randomised to telemedicine or usual care, and were followed for six months. For the present sub-analysis, only iCOR participants (n = 116) with left ventricular ejection fraction ≥40% were included. The primary study endpoint was the incidence of an acute non-fatal heart failure event, defined as a new episode of worsening of symptoms and signs consistent with acute heart failure requiring intravenous diuretic therapy. The healthcare-related costs in each study group were also evaluated. Results: The incidence of the first occurrence of the primary endpoint was significantly lower in the telemedicine arm (22% vs 56%, p<0.001), with a hazard ratio of 0.33 comparing to the usual care arm (95% confidence interval 0.17­0.64). Telemedicine was also associated with lower mean overall chronic heart failure care-related costs compared to usual care (8163€ vs 4993€, p=0.001). The results were consistent in both left ventricular ejection fraction of 40­49% and left ventricular ejection fraction ≥50% patients. Conclusions: Our results suggest that telemedicine is a promising strategy for the management of chronic heart failure patients with left ventricular ejection fraction ≥40%. These findings should be replicated in larger cohorts.