Clinical profile, management and outcomes of patients with cardiogenic shock undergoing transfer between centers in Spain.

INTRODUCTION AND OBJECTIVES: The aim of this study was to analyze the clinical profile, management, and prognosis of ST segment elevation myocardial infarction-related cardiogenic shock (STEMI-CS) requiring interhospital transfer, as well as the prognostic impact of structural variables of the treating centers in this setting. METHODS: This study included patients with STEMI-CS treated at revascularization-capable centers from 2016 to 2020. The patients were divided into the following groups: group A: patients attended throughout their admission at hospitals with interventional cardiology without cardiac surgery; group B: patients treated at hospitals with interventional cardiology and cardiac surgery; and group C: patients transferred to centers with interventional cardiology and cardiac surgery. We analyzed the association between the volume of STEMI-CS cases treated, the availability of cardiac intensive care units (CICU), and heart transplant with hospital mortality. RESULTS: A total of 4189 episodes were included: 1389 (33.2%) from group A, 2627 from group B (62.7%), and 173 from group C (4.1%). Transferred patients were younger, had a higher cardiovascular risk, and more commonly underwent revascularization, mechanical circulatory support, and heart transplant during hospitalization (P<.001). The crude mortality rate was lower in transferred patients (46.2% vs 60.3% in group A and 54.4% in group B, (P<.001)). Lower mortality was associated with a higher volume of care and CICU availability (OR, 0.75, P=.009; and 0.80, P=.047). CONCLUSIONS: The proportion of transfers in patients with STEMI-CS in our setting is low. Transferred patients were younger and underwent more invasive procedures. Mortality was lower among patients transferred to centers with a higher volume of STEMI-CS cases and CICU.

Developing Cardio-Oncology Programs in the New Era: Beyond Ventricular Dysfunction Due to Cancer Treatments.

Cardiovascular disease is a common problem in cancer patients that is becoming more widely recognized. This may be a consequence of prior cardiovascular risk factors but could also be secondary to the anticancer treatments. With the goal of offering a multidisciplinary approach to guaranteeing optimal cancer therapy and the early detection of related cardiac diseases, and in light of the recent ESC Cardio-Oncology Guideline recommendations, we developed a Cardio-Oncology unit devoted to the prevention and management of these specific complications. This document brings together important aspects to consider for the development and organization of a Cardio-Oncology program through our own experience and the current evidence.

Soluble Transferrin Receptor as Iron Deficiency Biomarker: Impact on Exercise Capacity in Heart Failure Patients.

The soluble transferrin receptor (sTfR) is a marker of tissue iron status, which could indicate an increased iron demand at the tissue level. The impact of sTfR levels on functional capacity and quality of life (QoL) in non-anemic heart failure (HF) patients with otherwise normal systemic iron status has not been evaluated. We conducted an observational, prospective, cohort study of 1236 patients with chronic HF. We selected patients with normal hemoglobin levels and normal systemic iron status. Tissue iron deficiency (ID) was defined as levels of sTfR > 75th percentile (1.63 mg per L). The primary endpoints were the distance walked in the 6 min walking test (6MWT) and the overall summary score (OSS) of the Minnesota Living with Heart Failure Questionnaire (MLHFQ). The final study cohort consisted of 215 patients. Overall QoL was significantly worse (51 ± 27 vs. 39 ± 20, p-value = 0.006, respectively), and the 6 MWT distance was significantly worse in patients with tissue ID when compared to patients without tissue ID (206 ± 179 m vs. 314 ± 155, p-value < 0.0001, respectively). Higher sTfR levels, indicating increased iron demand, were associated with a shorter distance in the 6 MWT (standardized ß = -0.249, p < 0.001) and a higher MLHFQ OSS (standardized ß = 0.183, p-value = 0.008). In this study, we show that in patients with normal systemic iron parameters, higher levels of sTfR are strongly associated with an impaired submaximal exercise capacity and with worse QoL.

Treatment of Slow-Flow After Primary Percutaneous Coronary Intervention With Flow-Mediated Hyperemia: The Randomized RAIN-FLOW Study.

Background ST-segment-elevation myocardial infarction complicated with no reflow after primary percutaneous coronary intervention is associated with adverse outcomes. Although several hyperemic drugs have been shown to improve the Thrombolysis in Myocardial Infarction flow, optimal treatment of no reflow remains unsettled. Saline infusion at 20 mL/min via a dedicated microcatheter causes (flow-mediated) hyperemia. The objective is to compare the efficacy of pharmacologic versus flow-mediated hyperemia in patients with ST-segment-elevation myocardial infarction complicated with no reflow. Methods and Results In the RAIN-FLOW (Treatment of Slow-Flow After Primary Percutaneous Coronary Intervention With Flow-Mediated Hyperemia) study, 67 patients with ST-segment-elevation myocardial infarction and no reflow were randomized to receive either pharmacologic-mediated hyperemia with intracoronary adenosine or nitroprusside (n=30) versus flow-mediated hyperemia (n=37). The angiographic corrected Thrombolysis in Myocardial Infarction frame count and the minimal microcirculatory resistance, as assessed with intracoronary pressure-thermistor wire, dedicated microcatheter, and thermodilution techniques, were compared after study interventions. Both Thrombolysis in Myocardial Infarction frame count(40.2±23.1 versus 39.2±20.7; P=0.858) and minimal microcirculatory resistance (753.6±661.5 versus 993.3±740.8 Wood units; P=0.174) were similar between groups. Thrombolysis in Myocardial Infarction 3 flow was observed in 26.7% versus 27.0% (P=0.899). Flow-mediated hyperemia showed 2 different thermodilution patterns during saline infusion indicative of the severity of the no reflow phenomenon. In-hospital death and nonfatal heart failure were observed in 10.4% and 26.9%, respectively. Conclusions Both treatments showed similar (and limited) efficacy restoring coronary flow. Flow-mediated hyperemia with thermodilution pattern assessment allowed the simultaneous characterization of the no reflow degree and response to hyperemia. No reflow was associated with a high rate of adverse outcomes. Further research is warranted to prevent and to treat no reflow in patients with ST-segment-elevation myocardial infarction. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT04685941.

Impact of ferric carboxymaltose for iron deficiency at discharge after heart failure hospitalization: a European multinational economic evaluation.

AIMS: Iron deficiency (ID) is comorbid in up to 50% patients with heart failure (HF) and exacerbates disease burden. Ferric carboxymaltose (FCM) reduced HF hospitalizations and improved quality of life when used to treat ID at discharge in patients hospitalized for acute HF with left ventricular ejection fraction <50% in the AFFIRM-AHF trial. We quantified the effect of FCM on burden of disease and the wider pharmacoeconomic implications in France, Germany, Poland, Spain and Sweden. METHODS AND RESULTS: The per country eligible population was calculated, aligning with the 2021 European Society of Cardiology (ESC) HF guidelines and the AFFIRM-AHF trial. Changes in burden of disease with FCM versus standard of care (SoC) were represented by disability-adjusted life years (DALYs), hospitalization episodes and bed days, using AFFIRM-AHF data. A Markov model was adapted to each country to estimate cost-effectiveness and combined with epidemiology data to calculate the impact on healthcare budgets. Between 335 (Sweden) and 13 237 (Germany) DALYs were predicted to be avoided with FCM use annually. Fewer hospitalizations and shorter lengths of stay associated with FCM compared to SoC were projected to result in substantial annual savings in bed days, from 5215 in Sweden to 205 630 in Germany. In all countries, FCM was predicted to be dominant (cost saving with gains in quality-adjusted life years), resulting in net savings to healthcare budgets within 1 year. CONCLUSIONS: This comprehensive evaluation of FCM therapy highlights the potential benefits that could be realized through implementation of the ESC HF guideline recommendations regarding ID treatment.

Minimal Clinically Important Differences in 6-Minute Walk Test in Patients With HFrEF and Iron Deficiency.

BACKGROUND: The 6-minute walk test (6MWT) is widely used to measure exercise capacity; however, the magnitude of change that is clinically meaningful for individuals is not well established in heart failure with reduced ejection fraction (HFrEF). OBJECTIVE: To calculate the minimal clinically important difference (MCID) for change in exercise capacity in the 6MWT in iron-deficient populations with HFrEF. METHODS: In this pooled secondary analysis of the FAIR-HF and CONFIRM-HF trials, mean changes in the 6MWT from baseline to weeks 12 and 24 were calculated and calibrated against the Patient Global Assessment (PGA) tool (clinical anchor) to derive MCIDs in improvement and deterioration. RESULTS: Of 760 patients included in the 2 trials, 6MWT and PGA data were available for 680 (89%) and 656 (86%) patients at weeks 12 and 24, respectively. The mean 6MWT distance at baseline was 281 ± 103 meters. There was a modest correlation between changes in 6MWT and PGA from baseline to week 12 (r = 0.31; P < 0.0001) and week 24 (r = 0.43; P < 0.0001). Respective estimates (95% confidence intervals) of MCID in 6MWT at weeks 12 and 24 were 14 meters (5;23) and 15 meters (3;27) for a "little improvement" (vs no change), 20 meters (10;30) and 24 meters (12;36) for moderate improvement vs a "little improvement,", -11 meters (-32;9.2) and -31 meters (-53;-8) for a "little deterioration" (vs no change), and -84 meters (-144;-24) and -69 meters (-118;-20) for "moderate deterioration" vs a "little deterioration". CONCLUSIONS: The MCID for improvement in exercise capacity in the 6MWT was 14 meters-15 meters in patients with HFrEF and iron deficiency. These MCIDs can aid clinical interpretation of study data.

Systematic review and meta-analysis of intravenous iron-carbohydrate complexes in HFrEF patients with iron deficiency.

Iron deficiency (ID) is a common co-morbidity in patients with heart failure (HF). The present meta-analysis evaluates the effect of intravenous (IV) iron-carbohydrate complex supplementation in patients with HF with reduced ejection fraction (HFrEF) and ID/iron deficiency anaemia (IDA). Randomized controlled trials (RCTs) comparing IV iron-carbohydrate complexes with placebo/standard of care in patients with HFrEF with ID/IDA were identified using Embase (from 1957) and PubMed (from 1989) databases through 25 May 2021. Twelve RCTs including 2381 patients were included in this analysis. The majority (90.8%) of patients receiving IV iron-carbohydrate therapy were administered ferric carboxymaltose (FCM); 7.5% received iron sucrose and 1.6% received iron isomaltoside. IV iron-carbohydrate therapy significantly reduced hospitalization for worsening HF [0.53 (0.42-0.65); P < 0.0001] and first hospitalization for worsening HF or death [0.75 (0.59-0.95); P = 0.016], but did not significantly impact all-cause mortality, compared with control. IV iron-carbohydrate therapy significantly improved functional and exercise capacity compared with the control. There was no significant difference in outcome between IV iron-carbohydrate formulations when similar endpoints were measured. No significant difference in adverse events (AE) was observed between the treatment groups. IV iron-carbohydrate therapy resulted in improvements in a range of clinical outcomes and increased functional and exercise capacity, whereas AEs were not significantly different between IV iron-carbohydrate and placebo/standard of care arms. These findings align with the European Society of Cardiology's 2021 HF guidelines, which recommend the consideration of FCM in symptomatic patients with a left ventricular ejection fraction < 45% and ID.

Inequalities by Income in the Prevalence of Cardiovascular Disease and Its Risk Factors in the Adult Population of Catalonia.

Background Understanding the magnitude of cardiovascular disease (CVD) inequalities is the first step toward addressing them. The linkage of socioeconomic and clinical data in universal health care settings provides critical information to characterize CVD inequalities. Methods and Results We employed a prospective cohort design using electronic health records data from all residents of Catalonia aged 18+ between January and December of 2019 (N=6 332 228). We calculated age-adjusted sex-specific prevalence of 5 CVD risk factors (diabetes, hypertension, hyperlipidemia, obesity, and smoking), and 4 CVDs (coronary heart disease, cerebrovascular disease, atrial fibrillation, and heart failure). We categorized income into high, moderate, low, and very low according to individual income (tied to prescription copayments) and receipt of welfare support. We found large inequalities in CVD and CVD risk factors among men and women. CVD risk factors with the largest inequalities were diabetes, smoking, and obesity, with prevalence rates 2- or 3-fold higher for those with very low (versus high) income. CVDs with the largest inequalities were cerebrovascular disease and heart failure, with prevalence rates 2 to 4 times higher for men and women with very low (versus high) income. Inequalities varied by age, peaking at midlife (30-50 years) for most diseases, while decreasing gradually with age for smoking. Conclusions We found wide and heterogeneous inequalities by income in 5 CVD risk factors and 4 CVD. Our findings in a region with a high-quality public health care system and universal coverage stress that strong equity-promoting policies are necessary to reduce disparities in CVD.

Practical Guidance for Diagnosing and Treating Iron Deficiency in Patients with Heart Failure: Why, Who and How?

Iron deficiency (ID) is a comorbid condition frequently seen in patients with heart failure (HF). Iron has an important role in the transport of oxygen, and is also essential for skeletal and cardiac muscle, which depend on iron for oxygen storage and cellular energy production. Thus, ID per se, even without anaemia, can be harmful. In patients with HF, ID is associated with a poorer quality of life (QoL) and exercise capacity, and a higher risk of hospitalisations and mortality, even in the absence of anaemia. Despite its negative clinical consequences, ID remains under-recognised. However, it is easily diagnosed and managed, and the recently revised 2021 European Society of Cardiology (ESC) guidelines on HF provide specific recommendations for its diagnosis and treatment. Prospective randomised controlled trials in patients with symptomatic HF with reduced ejection fraction (HFrEF) show that correction of ID using intravenous iron (principally ferric carboxymaltose [FCM]) provides improvements in symptoms of HF, exercise capacity and QoL, and a recent trial demonstrated that FCM therapy following hospitalisation due to acute decompensated HF reduced the risk of subsequent HF hospitalisations. This review provides a summary of the epidemiology and pathophysiology of ID in HFrEF, and practical guidance on screening, diagnosing, and treating ID.

Health status improvement with ferric carboxymaltose in heart failure with reduced ejection fraction and iron deficiency.

AIM: Intravenous ferric carboxymaltose (FCM) has been shown to improve overall quality of life in iron-deficient heart failure with reduced ejection fraction (HFrEF) patients at a trial population level. This FAIR-HF and CONFIRM-HF pooled analysis explored the likelihood of individual improvement or deterioration in Kansas City Cardiomyopathy Questionnaire (KCCQ) domains with FCM versus placebo and evaluated the stability of this response over time. METHODS AND RESULTS: Changes versus baseline in KCCQ overall summary score (OSS), clinical summary score (CSS) and total symptom score (TSS) were assessed at weeks 12 and 24 in FCM and placebo groups. Mean between-group differences were estimated and individual responder analyses and analyses of response stability were performed. Overall, 760 (FCM, n = 454) patients were studied. At week 12, the mean improvement in KCCQ OSS was 10.6 points with FCM versus 4.8 points with placebo (least-square mean difference [95% confidence interval, CI] 4.36 [2.14; 6.59] points). A higher proportion of patients on FCM versus placebo experienced a KCCQ OSS improvement of ≥5 (58.3% vs. 43.5%; odds ratio [95% CI] 1.81 [1.30; 2.51]), ≥10 (42.4% vs. 29.3%; 1.73 [1.23; 2.43]) or ≥15 (32.1% vs. 22.6%; 1.46 [1.02; 2.11]) points. Differences were similar at week 24 and for CSS and TSS domains. Of FCM patients with a ≥5-, ≥10- or ≥15-point improvement in KCCQ OSS at week 12, >75% sustained this improvement at week 24. CONCLUSION: Treatment of iron-deficient HFrEF patients with intravenous FCM conveyed clinically relevant improvements in health status at an individual-patient level; benefits were sustained over time in most patients.

Responder analysis for improvement in 6-min walk test with ferric carboxymaltose in patients with heart failure with reduced ejection fraction and iron deficiency.

AIM: Improving functional capacity is a key goal in heart failure (HF). This pooled analysis of FAIR-HF and CONFIRM-HF assessed the likelihood of improvement or deterioration in 6-min walk test (6MWT) among iron-deficient patients with chronic HF with reduced ejection fraction (HFrEF) receiving ferric carboxymaltose (FCM). METHODS AND RESULTS: Data for 760 patients (FCM: n = 454; placebo: n = 306) were analysed. The proportions of patients receiving FCM or placebo who had ≥20, ≥30, and ≥40 m improvements or ≥10 m deterioration in 6MWT at 12 and 24 weeks were assessed. Patients receiving FCM experienced a mean (standard deviation) 31.1 (62.3) m improvement in 6MWT versus 0.1 (77.1) m improvement for placebo at week 12 (difference in mean changes 26.8 [16.6-37.0]). At week 12, the odds [95% confidence interval] of 6MWT improvements of ≥20 m (odds ratio 2.16 [1.57-2.96]; p < 0.0001), ≥30 m (2.00 [1.44-2.78]; p < 0.0001), and ≥40 m (2.29 [1.60-3.27]; p < 0.0001) were greater with FCM versus placebo, while the odds of a deterioration ≥10 m were reduced with FCM versus placebo (0.55 [0.38-0.80]; p = 0.0019). Among patients who experienced 6MWT improvements of ≥20, ≥30, or ≥40 m with FCM at week 12, more than 80% sustained this improvement at week 24. CONCLUSION: Ferric carboxymaltose resulted in a significantly higher likelihood of improvement and a reduced likelihood of deterioration in 6MWT versus placebo among iron-deficient patients with HF. Of the patients experiencing clinically significant improvements at week 12, the majority sustained this improvement at week 24. These results are supportive of FCM to improve exercise capacity in HF.

Burden of cardiovascular risk factors and disease in five Asian groups in Catalonia: a disaggregated, population-based analysis of 121 000 first-generation Asian immigrants.

AIMS: To evaluate the burden of cardiovascular risk factors and disease (CVD) among five Asian groups living in Catalonia (Spain): Indian, Pakistani, Bangladeshi, Filipino, and Chinese. METHODS AND RESULTS: Retrospective cohort study using the Catalan Health Surveillance System database including 42 488 Pakistanis, 40 745 Chinese, 21 705 Indians, 9544 Filipinos, and 6907 Bangladeshis; and 5.3 million native individuals ('locals'). We estimated the age-adjusted prevalence (as of 31 December 2019) and incidence (during 2019) of diabetes, hypertension, hyperlipidaemia, obesity, tobacco use, coronary heart disease (CHD), cerebrovascular disease, atrial fibrillation, and heart failure (HF). Bangladeshis had the highest prevalence of diabetes (17.4% men, 22.6% women) followed by Pakistanis. Bangladeshis also had the highest prevalence of hyperlipidaemia (23.6% men, 18.3% women), hypertension among women (24%), and incident tobacco use among men. Pakistani women had the highest prevalence of obesity (28%). For CHD, Bangladeshi men had the highest prevalence (7.3%), followed by Pakistanis (6.3%); and Pakistanis had the highest prevalence among women (3.2%). For HF, the prevalence in Pakistani and Bangladeshi women was more than twice that of locals. Indians had the lowest prevalence of diabetes across South Asians, and of CHD across South Asian men, while the prevalence of CHD among Indian women was twice that of local women (2.6% vs. 1.3%). Filipinos had the highest prevalence of hypertension among men (21.8%). Chinese men and women had the lowest prevalence of risk factors and CVD. CONCLUSIONS: In Catalonia, preventive interventions adapted to the risk profile of different Asian immigrant groups are needed, particularly for Bangladeshis and Pakistanis.

Blood Differential Gene Expression in Patients with Chronic Heart Failure and Systemic Iron Deficiency: Pathways Involved in Pathophysiology and Impact on Clinical Outcomes.

BACKGROUND: Iron deficiency is a common disorder in patients with heart failure and is related with adverse outcomes and poor quality of life. Previous experimental studies have shown biological connections between iron homeostasis, mitochondrial metabolism, and myocardial function. However, the mechanisms involved in this crosstalk are yet to be unfolded. METHODS: The present research attempts to investigate the intrinsic biological mechanisms between heart failure and iron deficiency and to identify potential prognostic biomarkers by determining the gene expression pattern in the blood of heart failure patients, using whole transcriptome and targeted TaqMan® low-density array analyses. RESULTS: We performed a stepwise cross-sectional longitudinal study in a cohort of chronic heart failure patients with and without systemic iron deficiency. First, the full transcriptome was performed in a nested case-control exploratory cohort of 7 paired patients and underscored 1128 differentially expressed transcripts according to iron status (cohort1#). Later, we analyzed the messenger RNA levels of 22 genes selected by their statistical significance and pathophysiological relevance, in a validation cohort of 71 patients (cohort 2#). Patients with systemic iron deficiency presented lower mRNA levels of mitochondrial ferritin, sirtuin-7, small integral membrane protein 20, adrenomedullin and endothelin converting enzyme-1. An intermediate mitochondrial ferritin gene expression and an intermediate or low sirtuin7 and small integral membrane protein 20 mRNA levels were associated with an increased risk of all-cause mortality and heart failure admission ((HR 2.40, 95% CI 1.04-5.50, p-value = 0.039), (HR 5.49, 95% CI 1.78-16.92, p-value = 0.003), (HR 9.51, 95% CI 2.69-33.53, p-value < 0.001), respectively). CONCLUSIONS: Patients with chronic heart failure present different patterns of blood gene expression depending on systemic iron status that affect pivotal genes involved in iron regulation, mitochondrial metabolism, endothelial function and cardiovascular physiology, and correlate with adverse clinical outcomes.

The effect of intravenous ferric carboxymaltose on health-related quality of life in iron-deficient patients with acute heart failure: the results of the AFFIRM-AHF study.

AIMS: Patients with heart failure (HF) and iron deficiency experience poor health-related quality of life (HRQoL). We evaluated the impact of intravenous (IV) ferric carboxymaltose (FCM) vs. placebo on HRQoL for the AFFIRM-AHF population. METHODS AND RESULTS: The baseline 12-item Kansas City Cardiomyopathy Questionnaire (KCCQ-12), which was completed for 1058 (535 and 523) patients in the FCM and placebo groups, respectively, was administered prior to randomization and at Weeks 2, 4, 6, 12, 24, 36, and 52. The baseline KCCQ-12 overall summary score (OSS) mean ± standard error was 38.7 ± 0.9 (FCM group) and 37.1 ± 0.8 (placebo group); corresponding values for the clinical summary score (CSS) were 40.9 ± 0.9 and 40.1 ± 0.9. At Week 2, changes in OSS and CSS were similar for FCM and placebo. From Week 4 to Week 24, patients assigned to FCM had significantly greater improvements in OSS and CSS scores vs. placebo [adjusted mean difference (95% confidence interval, CI) at Week 4: 2.9 (0.5-5.3, P = 0.018) for OSS and 2.8 (0.3-5.3, P = 0.029) for CSS; adjusted mean difference (95% CI) at Week 24: 3.0 (0.3-5.6, P = 0.028) for OSS and 2.9 (0.2-5.6, P = 0.035) for CSS]. At Week 52, the treatment effect had attenuated but remained in favour of FCM. CONCLUSION: In iron-deficient patients with HF and left ventricular ejection fraction <50% who had stabilized after an episode of acute HF, treatment with IV FCM, compared with placebo, results in clinically meaningful beneficial effects on HRQoL as early as 4 weeks after treatment initiation, lasting up to Week 24.

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.

High soluble transferrin receptor in patients with heart failure: a measure of iron deficiency and a strong predictor of mortality.

AIMS: Iron deficiency (ID) is frequent in heart failure (HF), linked with exercise intolerance and poor prognosis. Intravenous iron repletion improves clinical status in HF patients with left ventricular ejection fraction (LVEF) ≤45%. However, uncertainty exists about the accuracy of serum biomarkers in diagnosing ID. The aims of this study were (i) to identify the iron biomarker with the greatest accuracy for the diagnosis of ID in bone marrow in patients with ischaemic HF, and (ii) to establish the prevalence of ID using this biomarker and its prognostic value in HF patients. METHODS AND RESULTS: Bone marrow was stained for iron in 30 patients with ischaemic HF with LVEF ≤45% and 10 healthy controls, and ID was diagnosed for 0-1 grades (Gale scale). A total of 791 patients with HF with LVEF ≤45% were prospectively followed up for 3 years. Serum ferritin, transferrin saturation, soluble transferrin receptor (sTfR) were assessed as iron biomarkers. Most patients with HF (n = 25, 83%) had ID in bone marrow, but none of the controls (P < 0.001). Serum sTfR had the best accuracy in predicting ID in bone marrow (area under the curve 0.920, 95% confidence interval 0.761-0.987, for cut-off 1.25 mg/L sensitivity 84%, specificity 100%). Serum sTfR was ≥1.25 mg/L in 47% of HF patients, in 56% and 46% of anaemics and non-anaemics, respectively (P < 0.05). The reclassification methods revealed that serum sTfR significantly added the prognostic value to the baseline prognostic model, and to the greater extent than plasma N-terminal pro B-type natriuretic peptide. Based on internal derivation and validation procedures, serum sTfR ≥1.41 mg/L was the optimal threshold for predicting 3-year mortality, independent of other established variables. CONCLUSIONS: High serum sTfR accurately reflects depleted iron stores in bone marrow in patients with HF, and identifies those with a high 3-year mortality.

Ferric carboxymaltose for iron deficiency at discharge after acute heart failure: a multicentre, double-blind, randomised, controlled trial.

BACKGROUND: Intravenous ferric carboxymaltose has been shown to improve symptoms and quality of life in patients with chronic heart failure and iron deficiency. We aimed to evaluate the effect of ferric carboxymaltose, compared with placebo, on outcomes in patients who were stabilised after an episode of acute heart failure. METHODS: AFFIRM-AHF was a multicentre, double-blind, randomised trial done at 121 sites in Europe, South America, and Singapore. Eligible patients were aged 18 years or older, were hospitalised for acute heart failure with concomitant iron deficiency (defined as ferritin <100 µg/L, or 100-299 µg/L with transferrin saturation <20%), and had a left ventricular ejection fraction of less than 50%. Before hospital discharge, participants were randomly assigned (1:1) to receive intravenous ferric carboxymaltose or placebo for up to 24 weeks, dosed according to the extent of iron deficiency. To maintain masking of patients and study personnel, treatments were administered in black syringes by personnel not involved in any study assessments. The primary outcome was a composite of total hospitalisations for heart failure and cardiovascular death up to 52 weeks after randomisation, analysed in all patients who received at least one dose of study treatment and had at least one post-randomisation data point. Secondary outcomes were the composite of total cardiovascular hospitalisations and cardiovascular death; cardiovascular death; total heart failure hospitalisations; time to first heart failure hospitalisation or cardiovascular death; and days lost due to heart failure hospitalisations or cardiovascular death, all evaluated up to 52 weeks after randomisation. Safety was assessed in all patients for whom study treatment was started. A pre-COVID-19 sensitivity analysis on the primary and secondary outcomes was prespecified. This study is registered with ClinicalTrials.gov, NCT02937454, and has now been completed. FINDINGS: Between March 21, 2017, and July 30, 2019, 1525 patients were screened, of whom 1132 patients were randomly assigned to study groups. Study treatment was started in 1110 patients, and 1108 (558 in the carboxymaltose group and 550 in the placebo group) had at least one post-randomisation value. 293 primary events (57·2 per 100 patient-years) occurred in the ferric carboxymaltose group and 372 (72·5 per 100 patient-years) occurred in the placebo group (rate ratio [RR] 0·79, 95% CI 0·62-1·01, p=0·059). 370 total cardiovascular hospitalisations and cardiovascular deaths occurred in the ferric carboxymaltose group and 451 occurred in the placebo group (RR 0·80, 95% CI 0·64-1·00, p=0·050). There was no difference in cardiovascular death between the two groups (77 [14%] of 558 in the ferric carboxymaltose group vs 78 [14%] in the placebo group; hazard ratio [HR] 0·96, 95% CI 0·70-1·32, p=0·81). 217 total heart failure hospitalisations occurred in the ferric carboxymaltose group and 294 occurred in the placebo group (RR 0·74; 95% CI 0·58-0·94, p=0·013). The composite of first heart failure hospitalisation or cardiovascular death occurred in 181 (32%) patients in the ferric carboxymaltose group and 209 (38%) in the placebo group (HR 0·80, 95% CI 0·66-0·98, p=0·030). Fewer days were lost due to heart failure hospitalisations and cardiovascular death for patients assigned to ferric carboxymaltose compared with placebo (369 days per 100 patient-years vs 548 days per 100 patient-years; RR 0·67, 95% CI 0·47-0·97, p=0·035). Serious adverse events occurred in 250 (45%) of 559 patients in the ferric carboxymaltose group and 282 (51%) of 551 patients in the placebo group. INTERPRETATION: In patients with iron deficiency, a left ventricular ejection fraction of less than 50%, and who were stabilised after an episode of acute heart failure, treatment with ferric carboxymaltose was safe and reduced the risk of heart failure hospitalisations, with no apparent effect on the risk of cardiovascular death. FUNDING: Vifor Pharma.

Budget impact of ferric carboxymaltose treatment in patients with chronic heart failure and iron deficiency in Spain.

OBJECTIVE: The treatment of iron deficiency (ID) with ferric carboxymaltose (FCM) improves the functional class and quality of life of chronic heart failure (CHF) patients with reduced left ventricular ejection fraction (LVEF), and reduces the rate of hospitalization due to worsening CHF. This study aims to evaluate the budget impact for the Spanish National Health System (SNHS) of treating ID in reduced LVEF CHF with FCM compared to non-iron treatment. METHODS: We simulated a hypothetical cohort of 1000 CHF patients with ID and reduced LVEF based on the Spanish population characteristics. A decision-analytic model was also built using the data from the largest FCM clinical trial (CONFIRM-HF) that lasted for a year. We considered the use of healthcare resources from a national prospective study. A deterministic sensitivity analysis was carried out varying the corresponding baseline data by ±25%. RESULTS: The cost of treating the simulated population with FCM was €2,570,914, while that of the non-iron treatment was €3,105,711, which corresponds to a cost saving of €534,797 per 1,000 patients in one year. Cost savings were mainly due to a decrease in the number of hospitalizations. All sensitivity analysis showed cost savings for the SNHS. CONCLUSIONS: FCM results in an annual cost saving of €534.80 per patient, and would thus be expected to reduce the economic burden of CHF in Spain.

Angiotensin-Neprilysin Inhibition and Renal Outcomes in Heart Failure With Preserved Ejection Fraction.

BACKGROUND: In patients with heart failure, chronic kidney disease is common and associated with a higher risk of renal events than in patients without chronic kidney disease. We assessed the renal effects of angiotensin/neprilysin inhibition in patients who have heart failure with preserved ejection fraction enrolled in the PARAGON-HF trial (Prospective Comparison of ARNI With ARB Global Outcomes in HF With Preserved Ejection Fraction). METHODS: In this randomized, double-blind, event-driven trial, we assigned 4822 patients who had heart failure with preserved ejection fraction to receive sacubitril/valsartan (n=2419) or valsartan (n=2403). Herein, we present the results of the prespecified renal composite outcome (time to first occurrence of either: ≥50% reduction in estimated glomerular filtration rate (eGFR), end-stage renal disease, or death from renal causes), the individual components of this composite, and the influence of therapy on eGFR slope. RESULTS: At randomization, eGFR was 63±19 mL·min-1·1.73 m-2. At study closure, the composite renal outcome occurred in 33 patients (1.4%) assigned to sacubitril/valsartan and 64 patients (2.7%) assigned to valsartan (hazard ratio, 0.50 [95% CI, 0.33-0.77]; P=0.001). The treatment effect on the composite renal end point did not differ according to the baseline eGFR (<60 versus ≥60 mL·min-1·1.73 m-2 (P-interaction=0.92). The decline in eGFR was less for sacubitril/valsartan than for valsartan (-2.0 [95% CI, -2.2 to -1.9] versus -2.7 [95% CI, -2.8 to -2.5] mL·min-1·1.73 m-2 per year). CONCLUSIONS: In patients with heart failure with preserved ejection fraction, sacubitril/valsartan reduced the risk of renal events, and slowed decline in eGFR, in comparison with valsartan. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01920711.