Association between loop diuretic dose changes and outcomes in chronic heart failure: observations from the ESC-EORP Heart Failure Long-Term Registry

[Abstract] Aims. Guidelines recommend down-titration of loop diuretics (LD) once euvolaemia is achieved. In outpatients with heart failure (HF), we investigated LD dose changes in daily cardiology practice, agreement with guideline recommendations, predictors of successful LD down-titration and association between dose changes and outcomes. Methods and results. We included 8130 HF patients from the ESC-EORP Heart Failure Long-Term Registry. Among patients who had dose decreased, successful decrease was defined as the decrease not followed by death, HF hospitalization, New York Heart Association class deterioration, or subsequent increase in LD dose. Mean age was 66±13 years, 71% men, 62% HF with reduced ejection fraction, 19% HF with mid-range ejection fraction, 19% HF with preserved ejection fraction. Median [interquartile range (IQR)] LD dose was 40 (25–80) mg. LD dose was increased in 16%, decreased in 8.3% and unchanged in 76%. Median (IQR) follow-up was 372 (363–419) days. Diuretic dose increase (vs. no change) was associated with HF death [hazard ratio (HR) 1.53, 95% confidence interval (CI) 1.12–2.08; P = 0.008] and nominally with cardiovascular death (HR 1.25, 95% CI 0.96–1.63; P = 0.103). Decrease of diuretic dose (vs. no change) was associated with nominally lower HF (HR 0.59, 95% CI 0.33–1.07; P = 0.083) and cardiovascular mortality (HR 0.62 95% CI 0.38–1.00; P = 0.052). Among patients who had LD dose decreased, systolic blood pressure [odds ratio (OR) 1.11 per 10 mmHg increase, 95% CI 1.01–1.22; P = 0.032], and absence of (i) sleep apnoea (OR 0.24, 95% CI 0.09–0.69; P = 0.008), (ii) peripheral congestion (OR 0.48, 95% CI 0.29–0.80; P = 0.005), and (iii) moderate/severe mitral regurgitation (OR 0.57, 95% CI 0.37–0.87; P = 0.008) were independently associated with successful decrease. Conclusion. Diuretic dose was unchanged in 76% and decreased in 8.3% of outpatients with chronic HF. LD dose increase was associated with worse outcomes, while the LD dose decrease group showed a trend for better outcomes compared with the no-change group. Higher systolic blood pressure, and absence of (i) sleep apnoea, (ii) peripheral congestion, and (iii) moderate/severe mitral regurgitation were independently associated with successful dose decrease

Is heart failure misdiagnosed in hospitalized patients with preserved ejection fraction? From the European Society of Cardiology - Heart Failure Association EURObservational Research Programme Heart Failure Long-Term Registry.

AIMS: In hospitalized patients with a clinical diagnosis of acute heart failure (HF) with preserved ejection fraction (HFpEF), the aims of this study were (i) to assess the proportion meeting the 2016 European Society of Cardiology (ESC) HFpEF criteria and (ii) to compare patients with restrictive/pseudonormal mitral inflow pattern (MIP) vs. patients with MIP other than restrictive/pseudonormal. METHODS AND RESULTS: We included hospitalized participants of the ESC-Heart Failure Association (HFA) EURObservational Research Programme (EORP) HF Long-Term Registry who had echocardiogram with ejection fraction (EF) ≥ 50% during index hospitalization. As no data on e', E/e' and left ventricular (LV) mass index were gathered in the registry, the 2016 ESC HFpEF definition was modified as follows: elevated B-type natriuretic peptide (BNP) (≥100 pg/mL for acute HF) and/or N-terminal pro-BNP (≥300 pg/mL) and at least one of the echocardiographic criteria: (i) presence of LV hypertrophy (yes/no), (ii) left atrial volume index (LAVI) of >34 mL/m2 ), or (iii) restrictive/pseudonormal MIP. Next, all patients were divided into four groups: (i) patients with restrictive/pseudonormal MIP on echocardiography [i.e. with presumably elevated left atrial (LA) pressure], (ii) patients with MIP other than restrictive/pseudonormal (i.e. with presumably normal LA pressure), (iii) atrial fibrillation (AF) group, and (iv) 'grey area' (no consistent description of MIP despite no report of AF). Of 6365 hospitalized patients, 1848 (29%) had EF ≥ 50%. Natriuretic peptides were assessed in 28%, LV hypertrophy in 92%, LAVI in 13%, and MIP in 67%. The 2016 ESC HFpEF criteria could be assessed in 27% of the 1848 patients and, if assessed, were met in 52%. Of the 1848 patients, 19% had restrictive/pseudonormal MIP, 43% had MIP other than restrictive/pseudonormal, 18% had AF and 20% were grey area. There were no differences in long-term all-cause or cardiovascular mortality, or all-cause hospitalizations or HF rehospitalizations between the four groups. Despite fewer non-cardiac comorbidities reported at baseline, patients with MIP other than restrictive/pseudonormal (i.e. with presumably normal LA pressure) had more non-cardiovascular (14.0 vs. 6.7 per 100 patient-years, P < 0.001) and cardiovascular non-HF (13.2 vs. 8.0 per 100 patient-years, P = 0.016) hospitalizations in long-term follow-up than patients with restrictive/pseudonormal MIP. CONCLUSIONS: Acute HFpEF diagnosis could be assessed (based on the 2016 ESC criteria) in only a quarter of patients and confirmed in half of these. When assessed, only one in three patients had restrictive/pseudonormal MIP suggestive of elevated LA pressure. Patients with MIP other than restrictive/pseudonormal (suggestive of normal LA pressure) could have been misdiagnosed with acute HFpEF or had echocardiography performed after normalization of LA pressure. They were more often hospitalized for non-HF reasons during follow-up. Symptoms suggestive of acute HFpEF may in some patients represent non-HF comorbidities

Aging Impairs Recipient T Cell Intrinsic and Extrinsic Factors in Response to Transplantation

As increasing numbers of older people are listed for solid organ transplantation, there is an urgent need to better understand how aging modifies alloimmune responses. Here, we investigated whether aging impairs the ability of donor dendritic cells or recipient immunity to prime alloimmune responses to organ transplantation.Using murine experimental models, we found that aging impaired the host environment to expand and activate antigen specific CD8(+) T cells. Additionally, aging impaired the ability of polyclonal T cells to induce acute allograft rejection. However, the alloimmune priming capability of donor dendritic cells was preserved with aging.Aging impairs recipient responses, both T cell intrinsic and extrinsic, in response to organ transplantation

A comprehensive characterization of acute heart failure with preserved versus mildly reduced versus reduced ejection fraction - insights from the ESC-HFA EORP Heart Failure Long-Term Registry.

AIMS: To perform a comprehensive characterization of acute heart failure (AHF) with preserved (HFpEF), versus mildly reduced (HFmrEF) versus reduced ejection fraction (HFrEF). METHODS AND RESULTS: Of 5951 participants in the ESC HF Long-Term Registry hospitalized for AHF (acute coronary syndromes excluded), 29% had HFpEF, 18% HFmrEF, and 53% HFrEF. Hospitalization reasons were most commonly atrial fibrillation (more in HFmrEF and HFpEF), followed by ischaemia (HFmrEF), infection (HFmrEF and HFpEF), worsening renal function (HFrEF), and uncontrolled hypertension (HFmrEF and HFpEF). Hospitalization characteristics included lower blood pressure, more oedema and higher natriuretic peptides with lower ejection fraction, similar pulmonary congestion, more mitral regurgitation in HFrEF and HFmrEF and more tricuspid regurgitation in HFrEF. In-hospital mortality was 3.4% in HFrEF, 2.1% in HFmrEF and 2.2% in HFpEF. Intravenous diuretic (∼80%) and nitrate (∼15%) use was similar but inotrope use greater in HFrEF (16%, vs. HFmrEF 7.4% vs. HFpEF 5.3%). Weight loss and estimated glomerular filtration rate improvement were greater in HFrEF, whereas reduction in natriuretic peptides was similar. Over 1 year post-discharge, events per 100 patient-years (95% confidence interval) in HFrEF versus HFmrEF versus HFpEF were: all-cause death 22 (20-24) versus 17 (14-20) versus 17 (15-20); cardiovascular (CV) death 12 (10-13) versus 8.6 (6.6-11) versus 8.4 (6.9-10); non-CV death 2.4 (1.8-3.1) versus 3.3 (2.1-4.8) versus 4.5 (3.5-5.9); all-cause hospitalization 48 (45-51) versus 35 (31-40) versus 42 (39-46); HF hospitalization 29 (27-32) versus 19 (16-22) versus 17 (15-20); and non-CV hospitalization 7.7 (6.6-8.9) versus 9.6 (7.5-12) versus 15 (13-17). CONCLUSION: In AHF, HFrEF is more severe and has greater in-hospital mortality. Post-discharge, HFrEF has greater CV risk, HFpEF greater non-CV risk, and HFmrEF lower overall risk

Hyponatraemia and changes in natraemia during hospitalization for acute heart failure and associations with in-hospital and long-term outcomes - from the ESC-HFA EORP Heart Failure Long-Term Registry.

AIMS: To comprehensively assess hyponatraemia in acute heart failure (AHF) regarding prevalence, associations, hospital course, and post-discharge outcomes. METHODS AND RESULTS: Of 8298 patients in the European Society of Cardiology Heart Failure Long-Term Registry hospitalized for AHF with any ejection fraction, 20% presented with hyponatraemia (serum sodium <135 mmol/L). Independent predictors included lower systolic blood pressure, estimated glomerular filtration rate (eGFR) and haemoglobin, along with diabetes, hepatic disease, use of thiazide diuretics, mineralocorticoid receptor antagonists, digoxin, higher doses of loop diuretics, and non-use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and beta-blockers. In-hospital death occurred in 3.3%. The prevalence of hyponatraemia and in-hospital mortality with different combinations were: 9% hyponatraemia both at admission and discharge (hyponatraemia Yes/Yes, in-hospital mortality 6.9%), 11% Yes/No (in-hospital mortality 4.9%), 8% No/Yes (in-hospital mortality 4.7%), and 72% No/No (in-hospital mortality 2.4%). Correction of hyponatraemia was associated with improvement in eGFR. In-hospital development of hyponatraemia was associated with greater diuretic use and worsening eGFR but also more effective decongestion. Among hospital survivors, 12-month mortality was 19% and adjusted hazard ratios (95% confidence intervals) were for hyponatraemia Yes/Yes 1.60 (1.35-1.89), Yes/No 1.35 (1.14-1.59), and No/Yes 1.18 (0.96-1.45). For death or heart failure hospitalization they were 1.38 (1.21-1.58), 1.17 (1.02-1.33), and 1.09 (0.93-1.27), respectively. CONCLUSION: Among patients with AHF, 20% had hyponatraemia at admission, which was associated with more advanced heart failure and normalized in half of patients during hospitalization. Admission hyponatraemia (possibly dilutional), especially if it did not resolve, was associated with worse in-hospital and post-discharge outcomes. Hyponatraemia developing during hospitalization (possibly depletional) was associated with lower risk

Right heart dysfunction and failure in heart failure with preserved ejection fraction: mechanisms and management. Position statement on behalf of the Heart Failure Association of the European Society of Cardiology

There is an unmet need for effective treatment strategies to reduce morbidity and mortality in patients with heart failure with preserved ejection fraction (HFpEF). Until recently, attention in patients with HFpEF was almost exclusively focused on the left side. However, it is now increasingly recognized that right heart dysfunction is common and contributes importantly to poor prognosis in HFpEF. More insights into the development of right heart dysfunction in HFpEF may aid to our knowledge about this complex disease and may eventually lead to better treatments to improve outcomes in these patients. In this position paper from the Heart Failure Association of the European Society of Cardiology, the Committee on Heart Failure with Preserved Ejection Fraction reviews the prevalence, diagnosis, and pathophysiology of right heart dysfunction and failure in patients with HFpEF. Finally, potential treatment strategies, important knowledge gaps and future directions regarding the right side in HFpEF are discussed

Rationale and design of the ESC Heart Failure III Registry - Implementation and discovery.

AIMS: Heart failure outcomes remain poor despite advances in therapy. The European Society of Cardiology Heart Failure III Registry (ESC HF III Registry) aims to characterize HF clinical features and outcomes and to assess implementation of guideline-recommended therapy in Europe and other ESC affiliated countries. METHODS: Between 1 November 2018 and 31 December 2020, 10 162 patients with chronic or acute/worsening HF with reduced, mildly reduced, or preserved ejection fraction were enrolled from 220 centres in 41 European or ESC affiliated countries. The ESC HF III Registry collected data on baseline characteristics (hospital or clinic presentation), hospital course, diagnostic and therapeutic decisions in hospital and at the clinic visit; and on outcomes at 12-month follow-up. These data include demographics, medical history, physical examination, biomarkers and imaging, quality of life, treatments, and interventions - including drug doses and reasons for non-use, and cause-specific outcomes. CONCLUSION: The ESC HF III Registry will provide comprehensive and unique insight into contemporary HF characteristics, treatment implementation, and outcomes, and may impact implementation strategies, clinical discovery, trial design, and public policy

Patient, hospital and country-level risk factors of all-cause mortality among patients with chronic heart failure: Prospective international cohort study

Background Although many studies have described patient-level risk factors for outcomes in heart failure (HF), health care structural determinants remain largely unexplored. This research reports patient-, hospital- and country-level characteristics associated with 1-year all-cause mortality among patients with chronic HF, and investigates geographic and hospital variation in mortality. Methods and findings We included 9,277 patients with chronic HF enrolled between May 2011 and November 2017 in the prospective cohort study European Society of Cardiology Heart Failure Long Term registry across 142 hospitals, located in 22 countries. Mean age of the selected outpatients was 65 years (sd 13.2) and 28% were female. The all-cause 1-year mortality rate per 100 person-years was 7.1 (95% confidence interval (CI) 6.6–7.7), and varied between countries (median 6.8, IQR 5.6–11.2) and hospitals (median 7.8, IQR 5.2–12.4). Mortality was associated with age (incidence rate ratio 1.03, 95% CI 1.02–1.04), diabetes mellitus (1.37, 1.15–1.63), peripheral artery disease (1.56, 1.27–1.92), New York Heart Association class III/IV (1.91, 1.60–2.30), treatment with angiotensin-converting enzyme inhibitor and angiotensin receptor antagonists (0.71, 0.57–0.87) and HF clinic (0.64, 0.46–0.89). No other hospital-level characteristics, and no country-level healthcare characteristics were associated with 1-year mortality, with case-mix standardised variance between countries being very low (1.83e-06) and higher for hospitals (0.372). Conclusions All-cause mortality at 1 year among outpatients with chronic HF varies between countries and hospitals, and is associated with patient characteristics and the availability of hospital HF clinics. After full adjustment for clinical, hospital and country variables, between-country variance was negligible while between-hospital variance was evident