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.

Right Ventricular Ejection Fraction and Beta-Blocker Effect in Heart Failure With Reduced Ejection Fraction.

BACKGROUND: A low right ventricular ejection fraction (RVEF) is a marker of poor outcomes in patients with heart failure with reduced ejection fraction (HFrEF). Beta-blockers improve outcomes in HFrEF, but whether this effect is modified by RVEF is unknown. METHODS AND RESULTS: Of the 2798 patients in Beta-Blocker Evaluation of Survival Trial (BEST), 2008 had data on baseline RVEF (mean 35%, median 34%). Patients were categorized into an RVEF of less than 35% (n = 1012) and an RVEF of 35% or greater (n = 996). We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) within each RVEF subgroup and formally tested for interactions between bucindolol and RVEF. The effect of bucindolol on all-cause mortality in 2008 patients with baseline RVEF (HR 0.88, 95% CI 0.75-1.02) is consistent with that in 2798 patients in the main trial (HR 0.90, 95% CI 0.78-1.02). Bucindolol use was associated with a lower risk of all-cause mortality in patients with an RVEF of 35% or greater (HR 0.70, 95% CI 0.55-0.89), but not in those with an RVEF of less than 35% (HR 1.02, 95% CI 0.83-1.24, P for interaction = .022). Similar variations were observed for cardiovascular mortality (P for interaction = .009) and sudden cardiac death (P for interaction = .018), but not for pump failure death (P for interaction = .371) or HF hospitalization (P for interaction = .251). CONCLUSIONS: The effect of bucindolol on mortality in patients with HFrEF was modified by the baseline RVEF. If these hypothesis-generating findings can be replicated using approved beta-blockers in contemporary patients with HFrEF, then RVEF may help to risk stratify patients with HFrEF for optimization of beta-blocker therapy.

Drug development in oncology and devices-lessons for heart failure drug development and approval? a review.

Heart failure (HF) and cancer are of the most common diseases globally, both associated with significant adverse outcomes and greatly impaired quality of life. Despite those similarities, over the last 15 years, the United States (USA) and European authorities have approved only 5 and 3 new drugs for HF respectively, none using an accelerated process and none for patients with either acute HF (AHF) or with HF and preserved ejection fraction (HFpEF). During the same period, more than 100 new drugs were approved for treatment of various cancers, several receiving accelerated approval. HF drugs in the last 15 years were mostly approved for reduction in mortality, whereas most approved cancer drugs addressed disease progression and surrogate markers. Consequently, the size of the trials in HF were far greater than those in oncology which was associated with lower probability of success. Given the larger study size and smaller probability of approval, pharma progressively reduces the necessary investments in new HF drugs. We suggest for HF drugs be developed, especially those used to treat patients with HFpEF and AHF, consideration of approval based beyond morbidity and mortality on improvements in symptoms and functional capacity and, like oncology, based on measures of disease progression and end organ damage. At the same time, HF drug development should adopt some approaches used in other diseases (such as oncology) focusing on better defining specific phenotypes and defining specific disease-related targets for new drugs.

Cardiopoietic cell therapy for advanced ischaemic heart failure: results at 39 weeks of the prospective, randomized, double blind, sham-controlled CHART-1 clinical trial.

AIMS: Cardiopoietic cells, produced through cardiogenic conditioning of patients' mesenchymal stem cells, have shown preliminary efficacy. The Congestive Heart Failure Cardiopoietic Regenerative Therapy (CHART-1) trial aimed to validate cardiopoiesis-based biotherapy in a larger heart failure cohort. METHODS AND RESULTS: This multinational, randomized, double-blind, sham-controlled study was conducted in 39 hospitals. Patients with symptomatic ischaemic heart failure on guideline-directed therapy (n = 484) were screened; n = 348 underwent bone marrow harvest and mesenchymal stem cell expansion. Those achieving > 24 million mesenchymal stem cells (n = 315) were randomized to cardiopoietic cells delivered endomyocardially with a retention-enhanced catheter (n = 157) or sham procedure (n = 158). Procedures were performed as randomized in 271 patients (n = 120 cardiopoietic cells, n = 151 sham). The primary efficacy endpoint was a Finkelstein-Schoenfeld hierarchical composite (all-cause mortality, worsening heart failure, Minnesota Living with Heart Failure Questionnaire score, 6-min walk distance, left ventricular end-systolic volume, and ejection fraction) at 39 weeks. The primary outcome was neutral (Mann-Whitney estimator 0.54, 95% confidence interval [CI] 0.47-0.61 [value > 0.5 favours cell treatment], P = 0.27). Exploratory analyses suggested a benefit of cell treatment on the primary composite in patients with baseline left ventricular end-diastolic volume 200-370 mL (60% of patients) (Mann-Whitney estimator 0.61, 95% CI 0.52-0.70, P = 0.015). No difference was observed in serious adverse events. One (0.9%) cardiopoietic cell patient and 9 (5.4%) sham patients experienced aborted or sudden cardiac death. CONCLUSION: The primary endpoint was neutral, with safety demonstrated across the cohort. Further evaluation of cardiopoietic cell therapy in patients with elevated end-diastolic volume is warranted.

New strategies for heart failure with preserved ejection fraction: the importance of targeted therapies for heart failure phenotypes.

The management of heart failure with reduced ejection fraction (HF-REF) has improved significantly over the last two decades. In contrast, little or no progress has been made in identifying evidence-based, effective treatments for heart failure with preserved ejection fraction (HF-PEF). Despite the high prevalence, mortality, and cost of HF-PEF, large phase III international clinical trials investigating interventions to improve outcomes in HF-PEF have yielded disappointing results. Therefore, treatment of HF-PEF remains largely empiric, and almost no acknowledged standards exist. There is no single explanation for the negative results of past HF-PEF trials. Potential contributors include an incomplete understanding of HF-PEF pathophysiology, the heterogeneity of the patient population, inadequate diagnostic criteria, recruitment of patients without true heart failure or at early stages of the syndrome, poor matching of therapeutic mechanisms and primary pathophysiological processes, suboptimal study designs, or inadequate statistical power. Many novel agents are in various stages of research and development for potential use in patients with HF-PEF. To maximize the likelihood of identifying effective therapeutics for HF-PEF, lessons learned from the past decade of research should be applied to the design, conduct, and interpretation of future trials. This paper represents a synthesis of a workshop held in Bergamo, Italy, and it examines new and emerging therapies in the context of specific, targeted HF-PEF phenotypes where positive clinical benefit may be detected in clinical trials. Specific considerations related to patient and endpoint selection for future clinical trials design are also discussed.

The effect of intravenous ferric carboxymaltose on health-related quality of life in patients with chronic heart failure and iron deficiency: a subanalysis of the FAIR-HF study.

AIMS: Patients with chronic heart failure (CHF) show impaired health-related quality of life (HRQoL), an important target for therapeutic intervention. Impaired iron homeostasis may be one mechanism underlying the poor physical condition of CHF patients. This detailed subanalysis of the previously published FAIR-HF study evaluated baseline HRQoL in iron-deficient patients with CHF and the effect of intravenous ferric carboxymaltose (FCM) on HRQoL. METHODS AND RESULTS: FAIR-HF randomized 459 patients with reduced left ventricular ejection fraction and iron deficiency, with or without anaemia, to FCM or placebo (2:1). Health-related quality of life was assessed at baseline and after 4, 12, and 24 weeks of therapy using the generic EQ-5D questionnaire and disease-specific Kansas City cardiomyopathy questionnaire (KCCQ). Baseline mean visual analogue scale (VAS) score was 54.3 ± 16.4 and KCCQ overall summary score was 52.4 ± 18.8. Ferric carboxymaltose significantly improved VAS and KCCQ (mean differences from baseline in KCCQ overall, clinical and total symptom scores, P< 0.001 vs. placebo) at all time points. At week 24, significant improvement vs. placebo was observed in four of the five EQ-5D dimensions: mobility (P= 0.004), self-care (P< 0.001), pain/discomfort (P= 0.006), anxiety/depression (P= 0.012), and usual activity (P= 0.035). Ferric carboxymaltose improved all KCCQ domain mean scores from Week 4 onward (P≤ 0.05), except for self-efficacy and social limitation. Effects were present in both anaemic and non-anaemic patients. CONCLUSIONS: HRQoL is impaired in iron-deficient patients with CHF. Intravenous FCM significantly improved HRQoL after 4 weeks, and throughout the remaining study period. The positive effects of FCM were independent of anaemia status.

Cell Therapy Improves Quality-of-Life in Heart Failure: Outcomes From a Phase III Clinical Trial.

Patients with heart failure experience limitations in daily activity and poor quality-of-life. Prospective surveillance of health-related quality-of-life supplemented traditional death and hospitalization outcomes in the multinational, randomized, double-blinded CHART-1 clinical trial that assessed cardiopoiesis-guided cell therapy in ischemic heart failure patients with reduced left ventricular ejection fraction. The Minnesota Living with Heart Failure Questionnaire (MLHFQ), a Food and Drug Administration qualified instrument for evaluating therapeutic effectiveness, was applied through the 1-year follow-up. Cell treated (n = 109) and sham procedure (n = 140) cohorts reported improved MLHFQ scores comparable between the 2 study arms (mean treatment difference with baseline adjustment -3.2 points, P = .107). Superiority of cell treatment over sham in betterment of the MLHFQ score was demonstrated in patients with pre-existing advanced left ventricular enlargement (baseline-adjusted mean treatment difference -6.4 points, P = .009). In this highly responsive subpopulation, benefit on the MLHFQ score paralleled reduction in death and hospitalization post-cell therapy (adjusted Mann-Whitney odds 1.43, 95% CI, 1.01-2.01; P = .039). The potential of cell therapy in addressing the quality-of-life dimension of heart failure requires further evaluation for disease relief.

Urinary Marker Profiles in Heart Failure with Reduced Versus Preserved Ejection Fraction.

BACKGROUND: Recent data suggest different causes of renal dysfunction between heart failure with reduced (HFrEF) versus preserved ejection fraction (HFpEF). We therefore studied a wide range of urinary markers reflecting different nephron segments in heart failure patients. METHODS: In 2070, in chronic heart failure patients, we measured several established and upcoming urinary markers reflecting different nephron segments. RESULTS: Mean age was 70 ± 12 years, 74% was male and 81% (n = 1677) had HFrEF. Mean estimated glomerular filtration rate (eGFR) was lower in patients with HFpEF (56 ± 23 versus 63 ± 23 ml/min/1.73 m2, P = 0.001). Patients with HFpEF had significantly higher values of NGAL (58.1 [24.0-124.8] versus 28.1 [14.6-66.9] µg/gCr, P < 0.001) and KIM-1 (2.28 [1.49-4.37] versus 1.79 [0.85-3.49] µg/gCr, P = 0.001). These differences were more pronounced in patients with an eGFR > 60 ml/min/1.73m2. CONCLUSIONS: HFpEF patients showed more evidence of tubular damage and/or dysfunction compared with HFrEF patients, in particular when glomerular function was preserved.

Differential biomarker expression in heart failure patients with and without mitral regurgitation: Insights from BIOSTAT-CHF.

BACKGROUND: Mitral regurgitation (MR) frequently coexists with heart failure (HF). OBJECTIVES: To better understand potential pathophysiological differences between patients with HF with or without moderate-severe MR, we compared differentially expressed circulating biomarkers between these two groups. METHODS: The Olink Proteomics® Multiplex Cardiovascular (CVD) -II, CVD-III, Immune Response and Oncology-II panels of 363 unique proteins from different pathophysiological domains were used to investigate the biomarker profiles of HF patients from index and validation cohorts of the BIOSTAT-CHF study stratified according to the presence of moderate-to-severe MR or no-mild MR. RESULTS: The index cohort included 888 patients (46%) with moderate-to-severe MR and 1029 (54%) with no-mild MR at baseline. The validation cohort included 522 patients (33%) with moderate-to-severe MR and 1076 (66%) with no-mild MR at baseline. Compared to patients with no-mild MR, those with moderate-to-severe MR had lower body mass index, higher comorbidity burden, signs and symptoms of more severe HF, lower systolic blood pressure, and larger left atrial and ventricular dimensions, in both cohorts. NT-proBNP, CA125, fibroblast growth factor 23 (FGF23) and growth hormone 1 (GH1) were up-regulated, whereas leptin (LEP) was down-regulated in patients with moderate-severe MR versus no-mild MR, in both index and validation cohorts. CONCLUSION: Circulating biomarkers differently expressed in HF patients with moderate-severe MR versus no-mild MR were related to congestion, lipid and mineral metabolism and oxidative stress. These findings may be of value for the development of novel treatment targets in HF patients with MR.

Mineralocorticoid receptor antagonists for heart failure with reduced ejection fraction: integrating evidence into clinical practice.

Mineralocorticoid receptor antagonists (MRAs) improve survival and reduce morbidity in patients with heart failure, reduced ejection fraction (HF-REF), and mild-to-severe symptoms, and in patients with left ventricular systolic dysfunction and heart failure after acute myocardial infarction. These clinical benefits are observed in addition to those of angiotensin converting enzyme inhibitors or angiotensin receptor blockers and beta-blockers. The morbidity and mortality benefits of MRAs may be mediated by several proposed actions, including antifibrotic mechanisms that slow heart failure progression, prevent or reverse cardiac remodelling, or reduce arrhythmogenesis. Both eplerenone and spironolactone have demonstrated survival benefits in individual clinical trials. Pharmacologic differences exist between the drugs, which may be relevant for therapeutic decision making in individual patients. Although serious hyperkalaemia events were reported in the major MRA clinical trials, these risks can be mitigated through appropriate patient selection, dose selection, patient education, monitoring, and follow-up. When used appropriately, MRAs significantly improve outcomes across the spectrum of patients with HF-REF.

Mid-regional pro-adrenomedullin improves disposition strategies for patients with acute dyspnoea: results from the BACH trial.

OBJECTIVES: To assess the value of mid-regional pro-adrenomedullin (MR-proADM) in guiding patient disposition from the emergency department (ED), as one of the key factors of hospital resource utilisation, in undifferentiated patients with acute dyspnoea. METHODS: We used clinical and outcome data from a large international biomarker study (BACH trial) and analysed data of all 1557 patients of the European and US sites presenting with acute dyspnoea. Patients were discharged or transferred from the ED to different levels of care (general ward, monitoring unit, intensive care unit). This original patient disposition was compared with the hypothetical disposition based on an adapted method of net reclassification improvement (NRI), which upgraded or downgraded patients from one level of care to the other based on the MR-proADM test result. RESULTS: MR-pro-ADM was significantly higher in patients who died during the follow-up than in survivors (p<0.0001). When applying the adapted NRI model, 30 additional patients from the European Union (EU) and 55 additional patients from USA were theoretically discharged (increase of 16.5%) if MR-proADM had been used for patient management. The overall NRI, adding up the rates of upgrades and downgrades, in the EU was 16.0% (95% CI 8.2% to 23.9%). A total of n=72 (9.9%) patients changed disposition when adding MR-pro ADM. In the USA, the overall NRI was 12.0% (5.7%-18.4%) and a total of n=81 (11.2%) patients changed disposition. CONCLUSIONS: MR-proADM has the potential to guide initial disposition of undifferentiated ED patients with acute dyspnoea and might therefore be helpful to improve resource utilisation and patient care.

Associations between baseline heart rate and blood pressure and time to events in heart failure with reduced ejection fraction patients: Data from the QUALIFY international registry.

AIMS: A high resting heart rate (RHR) and low systolic blood pressure (SBP) are a risk factor and a risk indicator, respectively, for poor heart failure (HF) outcomes. This analysis evaluated the associations between baseline RHR and SBP with outcomes and treatment patterns in patients with HF and reduced ejection fraction (HFrEF) in the QUALIFY (QUality of Adherence to guideline recommendations for LIFe-saving treatment in heart failure surveY) international registry. METHODS AND RESULTS: Between September 2013 and December 2014, 7317 HFrEF patients with a previous HF hospitalization within 1-15 months were enrolled in the QUALIFY registry. Complete follow-up data were available for 5138 patients. The relationships between RHR and SBP and outcomes were assessed using a Cox proportional hazards model and were analysed according to baseline values as high RHR (H-RHR) ≥75 bpm versus low RHR (L-RHR) <75 bpm and high SBP (H-SBP) ≥110 mmHg versus low SBP (L-SBP) <110 mmHg and analysed according to each of the following four phenotypes: H-RHR/L-SBP, L-RHR/L-SBP, H-RHR/H-SBP and L-RHR/H-SBP (reference group). Compared to the reference group, H-RHR/L-SBP was associated with the worst outcomes for the combined primary endpoint of cardiovascular death and HF hospitalization (hazard ratio [HR] 1.83, 95% confidence interval [CI] 1.51-2.21, p < 0.001), cardiovascular death (HR 2.70, 95% CI 1.69-4.33, p < 0.001), and HF hospitalization (HR 1.62, 95% CI 1.30-2.01, p < 0.001). Low-risk patients with L-RHR/H-SBP achieved more frequently ≥50% of target doses of angiotensin-converting enzyme inhibitors (ACEIs) and beta-blockers (BBs) than the other groups. However, 48% and 46% of low-risk patients were not well treated with ACEIs and BBs, respectively (≤50% of target dose or no treatment). CONCLUSION: In patients with HFrEF and recent hospitalization, elevated RHR and lower SBP identify patients at increased risk for cardiovascular endpoints. While SBP and RHR are often recognized as barriers that deter physicians from treating with high doses of recommended drugs, they are not the only reason leaving many patients suboptimally treated.

Systemic oxidative stress associates with disease severity and outcome in patients with new-onset or worsening heart failure.

BACKGROUND: Oxidative stress may be a key pathophysiological mediator in the development and progression of heart failure (HF). The role of serum-free thiol concentrations, as a marker of systemic oxidative stress, in HF remains largely unknown. OBJECTIVE: The purpose of this study was to investigate associations between serum-free thiol concentrations and disease severity and clinical outcome in patients with new-onset or worsening HF. METHODS: Serum-free thiol concentrations were determined by colorimetric detection in 3802 patients from the BIOlogy Study to TAilored Treatment in Chronic Heart Failure (BIOSTAT-CHF). Associations between free thiol concentrations and clinical characteristics and outcomes, including all-cause mortality, cardiovascular mortality, and a composite of HF hospitalization and all-cause mortality during a 2-years follow-up, were reported. RESULTS: Lower serum-free thiol concentrations were associated with more advanced HF, as indicated by worse NYHA class, higher plasma NT-proBNP (P < 0.001 for both) and with higher rates of all-cause mortality (hazard ratio (HR) per standard deviation (SD) decrease in free thiols: 1.253, 95% confidence interval (CI): 1.171-1.341, P < 0.001), cardiovascular mortality (HR per SD: 1.182, 95% CI: 1.086-1.288, P < 0.001), and the composite outcome (HR per SD: 1.058, 95% CI: 1.001-1.118, P = 0.046). CONCLUSIONS: In patients with new-onset or worsening HF, a lower serum-free thiol concentration, indicative of higher oxidative stress, is associated with increased HF severity and poorer prognosis. Our results do not prove causality, but our findings may be used as rationale for future (mechanistic) studies on serum-free thiol modulation in heart failure. Associations of serum-free thiol concentrations with heart failure severity and outcomes.

The effect of diabetes on the diagnostic and prognostic performance of mid-region pro-atrial natriuretic peptide and mid-region pro-adrenomedullin in patients with acute dyspnea.

Serum mid-regional pro-atrial natriuretic peptide (MR-proANP) and pro-adrenomedullin (MR-proADM) are novel biomarkers for acute heart failure (AHF). Like other AFH biomarkers, the performance of these tests are affected by the presence of clinical variables such as renal failure and obesity. In a substudy of the Biomarkers from Acute Heart Failure Study, we show that diabetes did not influence the performance of these markers with regards to AHF diagnosis or 90-day all cause death. However, in patients without AHF, increased MR-proADM alone was associated with the presence of diabetes.

Hyperuricaemia, chronic kidney disease, and outcomes in heart failure: potential mechanistic insights from epidemiological data.

AIM: To determine if the association between hyperuricaemia and poor outcomes in heart failure (HF) varies by chronic kidney disease (CKD). METHODS AND RESULTS: Of the 2645 systolic HF patients in the Beta-Blocker Evaluation of Survival Trial with data on baseline serum uric acid, 1422 had hyperuricaemia (uric acid ≥6 mg/dL for women and ≥8 mg/dL for men). Propensity scores for hyperuricaemia, estimated for each patient, were used to assemble a matched cohort of 630 pairs of patients with and without hyperuricaemia who were balanced on 75 baseline characteristics. Associations of hyperuricaemia with outcomes during 25 months of median follow-up were examined in all patients and in those with and without CKD (estimated glomerular filtration rate of <60 mL/min/1.73 m(2)). Hyperuricaemia-associated hazard ratios (HRs) and 95% confidence intervals (CI) for all-cause mortality and HF hospitalization were 1.44 (1.12-1.85, P = 0.005) and 1.27 (1.02-1.58, P = 0.031), respectively. Hazard ratios (95% CIs) for all-cause mortality among those with and without CKD were 0.96 (0.70-1.31, P = 0.792) and 1.40 (1.08-1.82, P = 0.011), respectively (P for interaction, 0.071), and those for HF hospitalization among those with and without CKD were 0.99 (0.74-1.33, P = 0.942) and 1.49 (1.19-1.86, P = 0.001), respectively (P for interaction, 0.033). CONCLUSION: Hyperuricaemia has a significant association with poor outcomes in HF patients without CKD but not in those with CKD, suggesting that hyperuricaemia may predict poor outcomes when it is primarily a marker of increased xanthine oxidase activity, but not when it is primarily due to impaired renal excretion of uric acid.

Association of Finerenone Use With Reduction in Treatment-Emergent Pneumonia and COVID-19 Adverse Events Among Patients With Type 2 Diabetes and Chronic Kidney Disease: A FIDELITY Pooled Secondary Analysis.

Importance: Patients with chronic kidney disease and type 2 diabetes have a higher risk of developing pneumonia as well as an increased risk of severe COVID-19-associated adverse events and mortality. Therefore, the anti-inflammatory effects of mineralocorticoid receptor antagonists via blockade of the mineralocorticoid receptor may alter the risk of pneumonia and COVID-19-associated adverse events in patients with chronic kidney disease and type 2 diabetes. Objective: To evaluate whether the selective, nonsteroidal mineralocorticoid receptor antagonist finerenone is associated with protection against pneumonia and COVID-19 adverse events in patients with type 2 diabetes and chronic kidney disease. Design, Setting, and Participants: This secondary analysis used patient-level data from FIDELITY, a prespecified pooled analysis of 2 multicenter, double-blind, placebo-controlled, event-driven, phase 3 randomized clinical trials: FIDELIO-DKD and FIGARO-DKD, conducted between September 2015 and February 2021. Patients in FIDELIO-DKD or FIGARO-DKD with type 2 diabetes and chronic kidney disease (urine albumin to creatine ratio, 30-5000 mg/g, estimated glomerular filtration rate ≥25 mL/min/1.73 m2) were assessed. Data were analyzed from May 15, 2021, to July 28, 2022. Exposure: Patients were randomized to finerenone (10 or 20 mg once daily) or matching placebo. Main Outcomes and Measures: The main outcomes were investigator-reported incidences of treatment-emergent infective pneumonia adverse events and serious adverse events (during and up to 3 days after treatment) and any COVID-19 adverse events. Results: Of 13 026 randomized patients (mean [SD] age, 64.8 [9.5] years; 9088 [69.8%] men), 12 999 were included in the FIDELITY safety population (6510 patients receiving finerenone; 6489 patients receiving placebo). Over a median (range) treatment duration of 2.6 (0-5.1) years, finerenone was consistently associated with reduced risk of pneumonia and serious pneumonia vs placebo. Overall, 307 patients (4.7%) treated with finerenone and 434 patients (6.7%) treated with placebo experienced pneumonia (hazard ratio [HR], 0.71; 95% CI, 0.64-0.79; P < .001). Serious pneumonia occurred in 171 patients (2.6%) treated with finerenone and 250 patients (3.9%) treated with placebo (HR, 0.69; 95% CI, 0.60-0.79; P < .001). Incidence proportions of COVID-19 adverse events were 86 patients (1.3%) in the finerenone group and 118 patients (1.8%) in the placebo group (HR, 0.73; 95% CI, 0.60-0.89; P = .002). Conclusions and Relevance: These findings suggest that mineralocorticoid receptor blockade with finerenone was associated with protection against pneumonia and COVID-19 adverse events in patients with type 2 diabetes and chronic kidney disease. Further clinical studies may be warranted. Trial Registration: ClinicalTrials.gov identifiers: FIDELIO-DKD: NCT02540993; FIGARO-DKD: NCT02545049.

Clinical implications of left atrial changes after optimization of medical therapy in patients with heart failure.

AIMS: Limited data exist regarding the prognostic relevance of changes in left atrial (LA) dimensions in patients with heart failure (HF). We assessed changes in LA dimension and their relation with outcomes after optimization of guideline-directed medical therapy (GDMT) in patients with new-onset or worsening HF. METHODS AND RESULTS: Left atrial diameter was assessed at baseline and 9 months after GDMT optimization in 632 patients (mean age 65.8 ± 12.1 years, 22.3% female) enrolled in BIOSTAT-CHF. LA adverse remodelling (LAAR) was defined as an increase in LA diameter on transthoracic echocardiography between baseline and 9 months. After the 9-month visit, patients were followed for a median of 13 further months. LAAR was observed in 247 patients (39%). Larger baseline LA diameter (odds ratio [OR] 0.90; 95% confidence interval [CI] 0.87-0.93; p < 0.001) and up-titration to higher doses of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (ACEi/ARBs) (OR 0.56; 95% CI 0.34-0.92; p = 0.022) were independently associated with lower likelihood of LAAR. LAAR was associated with an increased risk of the composite of all-cause mortality or HF hospitalization (log-rank p = 0.007 and adjusted hazard ratio 1.73, 95% CI 1.22-2.45, p = 0.002). The association was more pronounced in patients without a history of atrial fibrillation (p for interaction = 0.009). CONCLUSION: Among patients enrolled in BIOSTAT-CHF, LAAR was associated with an unfavourable outcome and was prevented by ACEi/ARB up-titration. Changes in LA dimension may be a useful marker of response to treatment and improve risk stratification in patients with HF.

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.