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Aim: In this subgroup analysis of STRONG‐HF, we explored the association between changes in renal function and efficacy of rapid up‐titration of guideline‐directed medical therapy (GDMT) according to a high‐intensity care (HIC) strategy. Methods and results: In patients randomized to the HIC arm (n = 542), renal function was assessed at baseline and during follow‐up visits. We studied the association with clinical characteristics and outcomes of a decrease in estimated glomerular filtration rate (eGFR) at week 1, defined as ≥15% decrease from baseline. Patients in the usual care group (n = 536) were seen at day 90. The treatment effect of HIC versus usual care was independent of baseline eGFR (p‐interaction = 0.4809). A decrease in eGFR within 1 week occurred in 77 (15.5%) patients and was associated with more rales on examination (p = 0.004), and a higher New York Heart Association class at the corresponding visit. Following the decrease in eGFR at 1 week, lower average optimal doses of GDMT were prescribed during follow‐up (p = 0.0210) and smaller reductions in N‐terminal pro‐B‐type natriuretic peptide occurred (geometrical mean 0.81 in no eGFR decrease vs 1.12 in GFR decrease, p = 0.0003). The rate of heart failure (HF) readmission or death at 180 days was 12.3% in no eGFR decrease versus 18.5% in eGFR decrease (p = 0.2274) and HF readmissions were 7.8% versus 16.6% (p = 0.0496). Conclusions: In the STRONG‐HF study, HIC reduced 180‐day HF readmission or death regardless of baseline eGFR. An early decrease in eGFR during rapid up‐titration of GDMT was associated with more evidence of congestion, yet lower doses of GDMT during follow‐up. [ABSTRACT FROM AUTHOR]

Aims: Patients recently hospitalized for heart failure (HF) often have unstable haemodynamics and experience worsening renal failure, and are at elevated risk for recurrent HF events. In DELIVER, dapagliflozin reduced HF events or cardiovascular death including among patients who were hospitalized or recently hospitalized. Methods and results: We examined the effects of dapagliflozin versus placebo on estimated glomerular filtration rate (eGFR) slope (acute and chronic), 1‐month change in systolic blood pressure, and the occurrence of serious hypovolaemic or renal adverse events in patients with and without HF hospitalization within 30 days of randomization. The 654 (90 randomized during hospitalization, 147 1–7 days post‐discharge and 417 8–30 days post‐discharge) recently hospitalized patients had lower baseline eGFR compared with those without recent HF hospitalization (median [interquartile range] 55 [43, 71] vs. 60 [47, 75] ml/min/1.73 m2). Dapagliflozin consistently reduced the risk of all‐cause (pinteraction = 0.20), cardiac‐related (pinteraction = 0.75), and HF‐specific (pinteraction = 0.90) hospitalizations, irrespective of recent HF hospitalization. In those recently hospitalized, acute placebo‐corrected eGFR reductions with dapagliflozin were modest and similar to patients without recent hospitalization (−2.0 [−4.1, +0.1] vs. −3.4 [−3.9, −2.9] ml/min/1.73 m2, pinteraction = 0.12). Dapagliflozin's effect to slow chronic eGFR decline was similar regardless of recent hospitalization (pinteraction = 0.57). Dapagliflozin had a minimal effect on 1‐month systolic blood pressure and to a similar degree in patients with and without recent hospitalization (−1.3 vs.−1.8 mmHg, pinteraction = 0.64). There was no treatment‐related excess in renal or hypovolaemic serious adverse events, irrespective of recent HF hospitalization. Conclusion: In patients recently hospitalized with HF, initiation of dapagliflozin had minimal effects on blood pressure and did not increase renal or hypovolaemic serious adverse events, yet afforded long‐term cardiovascular and kidney protective effects. These data suggest that the benefit to risk ratio favours initiation of dapagliflozin among stabilized patients hospitalized or recently hospitalized for HF. Clinical Trial Registration: ClinicalTrials.gov NCT03619213. [ABSTRACT FROM AUTHOR]

Aim: The sodium–glucose cotransporter 2 (SGLT2) inhibitor empagliflozin improved clinical outcomes in patients hospitalized for acute heart failure. In patients with chronic heart failure, SGLT2 inhibitors cause an early decline in estimated glomerular filtration rate (eGFR) followed by a slower eGFR decline over time than placebo. However, the effects of SGLT2 inhibitors on renal function during a hospital admission for acute heart failure remain largely unknown. Methods and results: Between 1 and 5 days after a hospitalization for acute heart failure, 530 patients with an eGFR >20 ml/min/1.73 m2 were randomized to 10 mg of empagliflozin or placebo and treated for 90 days. Renal function and electrolytes were measured at baseline, and after 15, 30 and 90 days. We evaluated the effect of empagliflozin on eGFR over time and the impact of baseline eGFR on the primary hierarchical outcome of death, worsening heart failure events and quality of life. Mean baseline eGFR was 52.4 ml/min/1.73 m2 in the empagliflozin group and 55.7 ml/min/1.73 m2 in the placebo group. Empagliflozin caused an initial decline in eGFR (−2 ml/min/1.73 m2 at day 15 compared to placebo). At day 90, eGFR was similar between empagliflozin and placebo. Investigator‐reported acute renal failure occurred in 7.7% of empagliflozin versus 12.1% of placebo patients. The overall clinical benefit (hierarchical composite of all‐cause death, heart failure events and quality of life) of empagliflozin was unaffected by baseline eGFR. Conclusion: In patients hospitalized for acute heart failure, empagliflozin caused an early modest decline in renal function which was no longer evident after 90 days. Acute renal events were similar in both groups. The clinical benefit of empagliflozin was consistent regardless of baseline renal function. [ABSTRACT FROM AUTHOR]

Aims: Physicians are sometimes reluctant to initiate guideline-directed therapy in patients with heart failure and reduced ejection fraction (HFrEF) due to concerns of adverse events. We explored the risk of hypotension, volume depletion, and acute kidney injury (AKI) on sodium-glucose cotransporter 2 (SGLT2) inhibitors in HFrEF populations.Methods and Results: We determined summary risk ratios (RRs) by conducting a meta-analysis on reported aforementioned adverse events on SGLT2 inhibitors from randomized controlled trials. We explored robustness of meta-analyses by computing fragility and/or reverse fragility index (FI or RFI) and its corresponding fragility quotient (FQ or RFQ) for each outcome. A total of 10 050 patients with HFrEF entered the final meta-analysis. Hypotension was reported in 4.5% (219/4836) on SGLT2 inhibitors and in 4.1% (202/4846) on placebo (RR 1.09, 95% confidence interval [CI] 0.91-1.31, p = 0.36). An RFI of 21 and RFQ of 0.002 suggest robust findings for hypotension. Volume depletion occurred in 9.4% (473/5019) on SGLT2 inhibitors and in 8.7% (438/5031) on placebo (RR 1.07, 95% CI 0.95-1.21, p = 0.25), respectively. RFI of 19 and RFQ of 0.001 suggest moderately robust findings for volume depletion. AKI was reported in fewer patients (1.9% [95/4888]) on SGLT2 inhibitors than on placebo (2.8% [140/4899]) providing lower incidence of AKI (RR 0.69, 95% CI 0.51-0.93, p = 0.02). FI of 14 and RFQ of 0.001 suggest moderately robust findings for AKI.Conclusion: Sodium-glucose cotransporter 2 inhibitor therapy is not associated with a clinically relevant risk of hypotension and volume depletion. Its use reduces the risk of AKI. This analysis supports current guideline recommendations on early use of SGLT2 inhibitors. [ABSTRACT FROM AUTHOR]

Aims: Diabetes is associated with a faster rate of renal function decline in patients with heart failure (HF). Sacubitril/valsartan attenuates the deterioration of renal function to a greater extent in patients with diabetes and HF with reduced ejection fraction compared with renin–angiotensin system inhibitors alone. We assessed whether the same may be true in HF with preserved ejection fraction (HFpEF). Methods and results: In the PARAGON‐HF trial in patients with HF and left ventricular ejection fraction of ≥45% (n = 4796), we characterized the effects of sacubitril/valsartan on changes in estimated glomerular filtration rate (eGFR) over a period of 192 weeks, and on the pre‐specified renal composite outcome (eGFR reduction of ≥50%, end‐stage renal disease, or death attributable to renal causes) in patients with (n = 2388) and without diabetes (n = 2408). The decline in eGFR was greater in patients with diabetes than in those without (−2.6 vs. −1.7 ml/min/1.73 m2 per year, p < 0.001), regardless of treatment assignment. Sacubitril/valsartan attenuated decline in eGFR similarly in patients with (−2.2 vs. −2.9 ml/min/1.73 m2 per year, p = 0.001) and without diabetes (−1.5 vs. −2.0 ml/min/1.73 m2 per year, p = 0.006) (pinteraction for difference in eGFR slopes = 0.40). Compared with valsartan, sacubitril/valsartan reduced the renal composite outcome similarly in patients without diabetes (hazard ratio [HR] 0.42, 95% confidence interval [CI] 0.19–0.91) and those with diabetes (HR 0.54, 95% CI 0.33–0.89; pinteraction = 0.59), as well as across a range of baseline glycated haemoglobin (pinteraction = 0.71). Conclusion: Sacubitril/valsartan, compared with valsartan, attenuates the decline of eGFR and reduces clinically relevant kidney events similarly among patients with HFpEF with and without diabetes. [ABSTRACT FROM AUTHOR]

Novel pharmacologic treatment options reduce mortality and morbidity in a cost‐effective manner in patients with heart failure (HF). Undisputedly, the effective implementation of these agents is an essential element of good clinical practice, which is endorsed by the European Society of Cardiology (ESC) guidelines on acute and chronic HF. Yet, physicians struggle to implement these therapies as they have to balance the true and/or perceived risks versus their substantial benefits in clinical practice. Any worsening of biomarkers of renal function is often perceived as being disadvantageous and is in clinical practice one of the most common reasons for ineffective drug implementation. However, even in this context, they clearly reduce mortality and morbidity in HF with reduced ejection fraction (HFrEF) patients, even in patients with poor renal function. Furthermore these agents are also beneficial in HF with mildly reduced ejection fraction (HFmrEF) and sodium–glucose cotransporter 2 (SGLT2) inhibitors more recently demonstrated a beneficial effect in HF with preserved ejection fraction (HFpEF). The emerge of several new classes (angiotensin receptor–neprilysin inhibitor [ARNI], SGLT2 inhibitors, vericiguat, omecamtiv mecarbil) and the recommendation by the 2021 ESC guidelines for the diagnosis and treatment of acute and chronic HF of early initiation and titration of quadruple disease‐modifying therapies (ARNI/angiotensin‐converting enzyme inhibitor + beta‐blocker + mineralocorticoid receptor antagonist and SGLT2 inhibitor) in HFrEF increases the likelihood of treatment‐induced changes in renal function. This may be (incorrectly) perceived as deleterious, resulting in inertia of starting and uptitrating these lifesaving therapies. Therefore, the objective of this consensus document is to provide advice of the effect HF drugs on renal function. [ABSTRACT FROM AUTHOR]

Aims: Vericiguat reduced the primary composite outcome of cardiovascular death or heart failure (HF) hospitalization in patients with worsening HF with reduced ejection fraction (HFrEF) and a lower limit of baseline estimated glomerular filtration rate (eGFR) of 15 mL/min/1.73 m2. We evaluated the relationship between the efficacy of vericiguat and baseline and subsequent changes in renal function. Methods and results: In VICTORIA, core laboratory serum creatinine was measured at baseline (n = 4956) and weeks 16, 32, and 48. Worsening renal function (WRF), defined as an increase ≥0.3 mg/dL in creatinine from baseline to week 16, was assessed via a Cox model with respect to subsequent primary events. Mean age was 69 years, 24% were female, and mean baseline eGFR was 61 mL/min/1.73 m2. During 48 weeks of treatment, the trajectories in eGFR and creatinine with vericiguat were similar to placebo (P = 0.50 and 0.18). The beneficial effects of vericiguat on the primary outcome were not influenced by baseline eGFR (interaction P = 0.48). WRF occurred in 15% of patients and was associated with worse outcomes (adjusted hazard ratio 1.28, 95% confidence interval 1.11–1.47; P < 0.001), but the beneficial effects of vericiguat on the primary outcome were similar in patients with or without WRF (interaction P = 0.76). Conclusion: Renal function trajectories were similar between vericiguat‐ and placebo‐treated patients and the beneficial effects of vericiguat on the primary outcome were consistent across the full range of eGFR and irrespective of WRF. [ABSTRACT FROM AUTHOR]

Aims: In acute heart failure (AHF), assessment of renal function comprises estimation of glomerular filtration rate (eGFR), which does not provide any information about renal sodium/water handling. We describe the interactions between urinary sodium concentration and eGFR to better characterize AHF patients. Methods and results: In 219 patients with AHF, spot urine sodium (UNa+) and eGFR were assessed on admission, day 1 and day 2 of hospitalization. We found no correlation between UNa+ and eGFR (calculated on each consecutive day, as an average of all three values, and as changes from baseline; all P > 0.05). The population was subsequently divided into four profiles based on eGFR (preserved vs. impaired; cutoff of 60 mL/min/1.73 m2) and UNa+ (sodium excreter vs. non‐excreter; cutoff of 60 mmol/L). At day 1, there were 70 (31.9%) patients classified as preserved eGFR/sodium excreter, 37 (16.8%) as impaired eGFR/sodium non‐excreter, 72 (32.9%) as impaired eGFR/sodium excreter, and 40 (18%) as preserved eGFR/sodium non‐excreter. Both sodium non‐excreter profiles were associated with an increased risk of in‐hospital heart failure worsening [odds ratio (OR) 2.8, 95% confidence interval (CI) 1.3–6.4], inotrope use (OR 2.6, 95% CI 1.1–6.7) and rehospitalization due to AHF (OR 3.2, 95% CI 1.6–6.2; all P < 0.05). The preserved eGFR/sodium non‐excreter profile was associated with highest 1‐year mortality (52.5%) and remained an independent prognosticator after adjustment for other prognosticators (hazard ratio 2.9, 95% CI 1.7–5.2; P < 0.0005). Conclusions: In AHF, values of spot UNa+ and eGFR are not interrelated. Concomitant assessment of eGFR and spot UNa+ may be useful for better clinical and therapeutic profiling of patients. [ABSTRACT FROM AUTHOR]

Aims: To characterize the prevalence and clinical relevance of malnutrition in patients undergoing transcatheter tricuspid valve edge-to-edge repair (TTVR).Methods and Results: Overall, 86 consecutive patients (mean age 78 ± 7 years) with moderate-to-severe tricuspid regurgitation (TR) at prohibitive surgical risk were analysed. Mini Nutritional Assessment (MNA), quality of life assessment, 6-min walk test distance and laboratory analyses were performed before and 1 month after TTVR. A total of 43 patients (50%) underwent concomitant transcatheter mitral valve repair. According to MNA, 81 patients (94%) were malnourished or at risk of malnutrition before TTVR. Following TTVR, MNA improved in 64 patients (74%). As compared to patients without MNA improvement, patients with increased MNA score had greater reductions in TR [regurgitation volume -17.0 (interquartile range, IQR -25.0; -7.0) mL vs. -26.4 (IQR -40.3; -14.5) mL, P < 0.001] and inferior vena cava diameter. Only patients with increased MNA score displayed a decrease in N-terminal pro-brain natriuretic peptide levels [-320 (IQR -1294; 105) pg/mL vs. +708 (IQR -342; 2708) pg/mL, P = 0.009], improvements in cholinesterase levels (0.0 ± 11.9 μmoL/L vs. +10.9 ± 16.7 μmoL/L, P < 0.001) and renal function during follow-up. Beneficial effects on quality of life scores and 6-min walk test distance following TTVR were observed exclusively in patients with improvement in MNA. During a median follow-up of 6 months, patients with worsened MNA had an increased risk of death and rehospitalization for heart failure.Conclusion: Nutritional impairment is common and of prognostic importance in patients undergoing TTVR. Hepatorenal function modestly improves after successful TTVR. Further study of extracardiac implications of TR-associated right heart failure is warranted to improve care in this vulnerable patient population. [ABSTRACT FROM AUTHOR]

Aims: Inhibition of sodium-glucose co-transporter 2 (SGLT2) reduces the risk of death and heart failure (HF) admissions in patients with chronic HF. However, safety and clinical efficacy of SGLT2 inhibitors in patients with acute decompensated HF are unknown.Methods and Results: In this randomized, placebo-controlled, double-blind, parallel group, multicentre pilot study, we randomized 80 acute HF patients with and without diabetes to either empagliflozin 10 mg/day or placebo for 30 days. The primary outcomes were change in visual analogue scale (VAS) dyspnoea score, diuretic response (weight change per 40 mg furosemide), change in N-terminal pro brain natriuretic peptide (NT-proBNP), and length of stay. Secondary outcomes included safety and clinical endpoints. Mean age was 76 years, 33% were female, 47% had de novo HF and median NT-proBNP was 5236 pg/mL. No difference was observed in VAS dyspnoea score, diuretic response, length of stay, or change in NT-proBNP between empagliflozin and placebo. Empagliflozin reduced a combined endpoint of in-hospital worsening HF, rehospitalization for HF or death at 60 days compared with placebo [4 (10%) vs. 13 (33%); P = 0.014]. Urinary output up until day 4 was significantly greater with empagliflozin vs. placebo [difference 3449 (95% confidence interval 578-6321) mL; P < 0.01]. Empagliflozin was safe, well tolerated, and had no adverse effects on blood pressure or renal function.Conclusions: In patients with acute HF, treatment with empagliflozin had no effect on change in VAS dyspnoea, diuretic response, NT-proBNP, and length of hospital stay, but was safe, increased urinary output and reduced a combined endpoint of worsening HF, rehospitalization for HF or death at 60 days. [ABSTRACT FROM AUTHOR]

Aims: Neladenoson bialanate is a partial adenosine A1 receptor agonist with demonstrated beneficial effects on cardiac function in animal models. We aimed to assess the dose-response effect of neladenoson bialanate on cardiac structure and function, clinical outcome, and safety in patients with heart failure (HF) with reduced ejection fraction (HFrEF).Methods and Results: PANTHEON was a dose-finding, phase IIb, randomized, double-blind, placebo-controlled trial conducted in 92 centres in 11 countries including 462 patients with chronic HFrEF, randomized to once daily oral dose of neladenoson bialanate (5, 10, 20, 30, and 40 mg) or placebo. The primary endpoints were change from baseline to 20 weeks in left ventricular ejection fraction (LVEF) (echocardiography) and in N-terminal pro-B-type natriuretic peptide (NT-proBNP). Mean age of the patients was 67 years, 17% were female, mean LVEF was 28%, mean NT-proBNP was 2085 ng/L. After 20 weeks of treatment, there was no dose-effect of neladenoson bialanate on changes in NT-proBNP or LVEF (primary endpoints). No effect of neladenoson bialanate was found on left ventricular volumes, high-sensitivity troponin T, or cardiovascular mortality, HF hospitalization, and urgent visits for HF (secondary endpoints). There was a dose-dependent increase in creatinine and cystatin C, and a dose-dependent decrease in estimated glomerular filtration rate and heart rate.Conclusions: In patients with chronic HFrEF, treatment with neladenoson bialanate was not associated with dose-dependent favourable effects on cardiac structure and function, cardiac risk markers, or clinical outcome but was associated with a dose-dependent decrease in renal function.Clinical Trial Registration: ClinicalTrials.gov Identifier NCT02992288. [ABSTRACT FROM AUTHOR]

Aims: Sodium-glucose co-transporter 2 (SGLT2) inhibition reduces heart failure hospitalizations in patients with diabetes, irrespective of glycaemic control. We examined the effect of SGLT2 inhibition with empagliflozin (EMPA) on cardiac function in non-diabetic rats with left ventricular (LV) dysfunction after myocardial infarction (MI).Methods and Results: Non-diabetic male Sprague-Dawley rats underwent permanent coronary artery ligation to induce MI, or sham surgery. Rats received chow containing EMPA that resulted in an average daily intake of 30 mg/kg/day or control chow, starting before surgery (EMPA-early) or 2 weeks after surgery (EMPA-late). Cardiac function was assessed using echocardiography and histological and molecular markers of cardiac remodelling and metabolism were assessed in the left ventricle. Renal function was assessed in metabolic cages. EMPA increased urine production by two-fold without affecting creatinine clearance and serum electrolytes. EMPA did not influence MI size, but LV ejection fraction (LVEF) was significantly higher in the EMPA-early and EMPA-late treated MI groups compared to the MI group treated with vehicle (LVEF 54%, 52% and 43%, respectively, all P < 0.05). EMPA also attenuated cardiomyocyte hypertrophy, diminished interstitial fibrosis and reduced myocardial oxidative stress. EMPA treatment reduced mitochondrial DNA damage and stimulated mitochondrial biogenesis, which was associated with the normalization of myocardial uptake and oxidation of glucose and fatty acids. EMPA increased circulating ketone levels as well as myocardial expression of the ketone body transporter and two critical ketogenic enzymes, indicating that myocardial utilization of ketone bodies was increased. Together these metabolic changes were associated with an increase in cardiac ATP production.Conclusion: Empagliflozin favourably affects cardiac function and remodelling in non-diabetic rats with LV dysfunction after MI, associated with substantial improvements in cardiac metabolism and cardiac ATP production. Importantly, it did so without renal adverse effects. Our data suggest that EMPA might be of benefit in heart failure patients without diabetes. [ABSTRACT FROM AUTHOR]

Background: Current heart failure guidelines recommend target eplerenone dose of 50 mg/day. We have examined the effect of different eplerenone doses based on pre-specified renal function stratification in the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF).Methods and Results: In EMPHASIS-HF, the target dose of eplerenone/placebo was stratified at randomization according to estimated glomerular filtration rate (eGFR): 50 mg/day if eGFR ≥ 50 mL/min/1.73 m2 and ≤ 25 mg/day if eGFR 30-49 mL/min/1.73 m2 . Patients remained within these dose ranges during the trial (as per stratification). The primary outcome was a composite of heart failure hospitalization or cardiovascular mortality. Eplerenone was superior to placebo within each respective eGFR stratum [eplerenone vs. placebo in the eGFR ≥ 50 mL/min/1.73 m2 stratum: hazard ratio (HR) 0.58, 95% confidence interval (CI) 0.45-0.74; and eplerenone vs. placebo in the eGFR 30-49 mL/min/1.73 m2 stratum: HR 0.62, 95% CI 0.49-0.78; Pinteraction  = 0.89]. Despite receiving lower eplerenone doses, patients in the eGFR 30-49 mL/min/1.73 m2 stratum more often had hyperkalaemia, renal failure events, and drug discontinuation.Conclusion: In EMPHASIS-HF the eplerenone dose was stratified according to renal function and the treatment effect was not influenced by renal function: 25 mg/day in patients with eGFR 30-49 mL/min/1.73 m2 was as effective as 50 mg/day in patients with eGFR > =50 mL/min/1.73 m2 . However, patients with impaired renal function experienced more adverse events, despite reveiving lower eplerenone doses. Current guidelines do not recommend tailoring the dose of eplereone according to renal function but the current data suggest they should. [ABSTRACT FROM AUTHOR]

The Heart Failure Association (HFA) of the European Society of Cardiology (ESC) has recently issued a position paper on the role of sodium-glucose co-transporter 2 (SGLT2) inhibitors in heart failure (HF). The present document provides an update of the position paper, based of new clinical trial evidence. Accordingly, the following recommendations are given: • Canagliflozin, dapagliflozin empagliflozin, or ertugliflozin are recommended for the prevention of HF hospitalization in patients with type 2 diabetes mellitus and established cardiovascular disease or at high cardiovascular risk. • Dapagliflozin or empagliflozin are recommended to reduce the combined risk of HF hospitalization and cardiovascular death in symptomatic patients with HF and reduced ejection fraction already receiving guideline-directed medical therapy regardless of the presence of type 2 diabetes mellitus. [ABSTRACT FROM AUTHOR]

Aim: We aimed to study the relationships of loop diuretic dose with renal function and clinical outcomes in patients with chronic heart failure (HF).Methods and Results: Loop diuretic dose at baseline was recorded in patients included in the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA). The relationship to change in estimated glomerular filtration rate (eGFR) over time and to the first occurrence of the composite outcome of cardiovascular (CV) death or hospitalization owing to HF was examined in propensity score matched cohorts. Of the 5011 patients, 2550, 745, and 449 were receiving >80 mg (high), 41-80 mg (medium) and ≤40 mg (low) of loop diuretics in furosemide equivalent daily dosages, respectively, which were used to assemble 229, 385, and 1045 pairs of propensity-matched high, medium, and low dose cohorts. Compared with matched no loop diuretic groups, eGFR declined 0.3 ± 0.2, 0.3 ± 0.3 and 1.2 ± 0.5 mL/min/1.73 m(2) /year in the low-, medium-, and high-dose groups, respectively. Compared with matched no loop diuretic groups, hazard ratios (HR) (95% confidence intervals) for outcome associated with low-, medium- and high-dose groups were 1.71 (1.41-2.06), 1.99 (1.50-2.64), and 2.94 (1.95-4.41), respectively. Higher loop diuretic dose was particularly associated with increased risk for hospitalization owing to HF: HR 4.80 (2.75-8.37), P < 0.001.Conclusions: The use of loop diuretics was associated with a slightly greater rate of decline in eGFR, which did not vary significantly by diuretic dose.Loop diuretic dose was associated with higher risks of (CV) mortality and predominantly hospitalization owing to HF, which appeared to be higher among those receiving higher daily doses. [ABSTRACT FROM AUTHOR]

Background Increases in serum creatinine with renin-angiotensin-aldosterone system ( RAAS) inhibitors can lead to unnecessary discontinuation of these agents. The dual-acting angiotensin receptor neprilysin inhibitor LCZ696 improves clinical outcome patients with heart failure with reduced ejection fraction, and pilot data suggest potential benefit in heart failure with preserved ejection fraction ( HFpEF). The effects of LCZ696 on renal function have not been assessed. Methods and results A total of 301 HFpEF patients were randomly assigned to LCZ696 or valsartan in the PARAMOUNT trial. We studied renal function [creatinine, estimated glomerular filtration rate ( eGFR), cystatin C, and urinary albumin to creatinine ratio ( UACR)] at baseline, 12 weeks, and after 36 weeks of treatment. Worsening renal function ( WRF) was determined as an serum creatinine increase of >0.3 mg/ dL and/or >25% between two time-points. Mean eGFR at baseline was 65.4 ± 20.4 mL/min per 1.73 m2. The eGFR declined less in the LCZ696 group than in the valsartan group (-1.5 vs. -5.2 mL/min per 1.73 m2; P = 0.002). The incidence of WRF was lower in the LCZ696 group (12%) than in the valsartan group (18%) at any time-point, but this difference was not statistically significant ( P = 0.18). Over 36 weeks, the geometric mean of UACR increased in the LCZ696 group (2.4-2.9 mg/mmol), whereas it remained stable in the valsartan group (2.1-2.0 mg/mmol; P for difference between groups = 0.016). Conclusion In patients with HFpEF, therapy with LCZ696 for 36 weeks was associated with preservation of eGFR compared with valsartan therapy, but an increase in UACR. [ABSTRACT FROM AUTHOR]

Aims Anaemia and iron deficiency are constituents of the cardio-renal syndrome in chronic heart failure ( CHF). We investigated the effects of i.v. iron in iron-deficient CHF patients on renal function, and the efficacy and safety of this therapy in patients with renal dysfunction. Methods and results The FAIR-HF trial randomized 459 CHF patients with iron deficiency (ferritin <100 µg/L, or between 100 and 299 µg/L if transferrin saturation was <20%): 304 to i.v. ferric carboxymaltose ( FCM) and 155 to placebo, and followed-up for 24 weeks. Renal function was assessed at baseline and at weeks 4, 12, and 24, using the estimated glomerular filtration rate ( eGFR, mL/min/1.73 m2), calculated from the Chronic Kidney Disease Epidemiology Collaboration ( CKD-EPI) formula. At baseline, renal function was similar between groups (62.4 ± 20.6 vs. 62.9 ± 23.4 mL/min/1.73 m2, FCM vs. placebo). Compared with placebo, treatment with FCM was associated with an increase in eGFR [treatment effect: week 4, 2.11 ± 1.21 ( P = 0.082); week 12, 2.41 ± 1.33 ( P = 0.070); and week 24, 2.98 ± 1.44 mL/min/1.73 m2 ( P = 0.039)]. This effect was seen in all pre-specified subgroups ( P > 0.20 for interactions). No interaction between the favourable effects of FCM and baseline renal function was seen for the primary endpoints [improvement in Patient Global Assessment ( P = 0.43) and NYHA class ( P = 0.37) at 24 weeks]. Safety and adverse event profiles were similar in patients with baseline eGFR <60 and ≥60 mL/min/1.73 m2. Conclusions Treatment of iron deficiency in CHF patients with i.v. FCM was associated with an improvement in renal function. FCM therapy was effective and safe in CHF patients with renal dysfunction. [ABSTRACT FROM AUTHOR]

Aims Aldosterone activation is central to the sodium-fluid retention that marks the progression of heart failure ( HF). The actions of dietary sodium restriction, a mainstay in HF management, on cardiorenal and neuroendocrine adaptations during the progression of HF are poorly understood. The study aim was to assess the role of dietary sodium during the progression of experimental HF. Methods and results Experimental HF was produced in a canine model by rapid right ventricular pacing which evolves from early mild HF to overt, severe HF. Dogs were fed one of three diets: (i) high sodium [250 mEq (5.8 g) per day, n =6]; (ii) standard sodium [58 mEq (1.3 g) per day, n =6]; and (iii) sodium restriction [11 mEq (0.25 g) per day, n =6]. During the 38-day study, haemodynamics, renal function, plasma renin activity ( PRA), and aldosterone were measured. Changes in haemodynamics at 38 days were similar in all three groups, as were changes in renal function. Aldosterone activation was demonstrated in all three groups; however, dietary sodium restriction, in contrast to high sodium, resulted in early (10 days) activation of PRA and aldosterone. High sodium demonstrated significant suppression of aldosterone activation over the course of HF progression. Conclusions Excessive dietary sodium restriction particularly in early stage HF results in early aldosterone activation, while normal and excess sodium intake are associated with delayed or suppressed activation. These findings warrant evaluation in humans to determine if dietary sodium manipulation, particularly during early stage HF, may have a significant impact on neuroendocrine disease progression. [ABSTRACT FROM AUTHOR]

Aims: We studied the characteristics and clinical outcome related to diuretic response and the effects of serelaxin in patients hospitalized for acute heart failure (AHF).Methods and Results: RELAX-AHF was a double-blind, placebo-controlled trial, enrolling 1161 patients admitted to hospital for AHF who were randomized to 48 h i.v infusions of placebo or serelaxin (30 µg/kg per day) within 16 h from presentation. Diuretic response was defined as Δ weight kg/[(total i.v. dose)/40 mg] + [(total oral dose)/80 mg)] furosemide (or equivalent loop diuretic dose) up to day 5. Median diuretic response was -0.42 (-1.00, -0.14) kg/40 mg. A poor diuretic response was independently associated with Western-like region (Western Europe, North America, Israel, and Poland), lower diastolic blood pressure, the absence of oedema, higher blood urea nitrogen, and lower levels of aspartate aminotransferase and potassium (all P < 0.01). Randomization to serelaxin was associated with lower doses of i.v. loop diuretics and slightly less weight loss, resulting in a neutral effect on diuretic response. Worse diuretic response was independently associated both with less relief of dyspnoea, measured with a visual analogue scale (VAS) at day 5 (primary endpoint; P = 0.0002), and with a higher risk of cardiovascular death or rehospitalization for heart failure or renal failure through day 60 (secondary endpoint, P < 0.0001), but not with increased 180-day cardiovascular mortality (P = 0.507).Conclusions: In patients hospitalized for AHF, a poor diuretic response was associated with a poor in-hospital and early post-discharge clinical outcome. Serelaxin had a neutral effect on diuretic response.Trial Registration: NCT00520806. [ABSTRACT FROM AUTHOR]

Aims We studied the relationship between heart rate and renal function and the effects of heart rate reduction with ivabradine in heart failure patients with and without renal dysfunction. Methods and results From the 6505 patients who were randomized in SHIFT, baseline creatinine and at least one follow-up measurement were available in 6160 patients. Median follow-up was 22.9 months. Worsening renal function (WRF) was defined as a creatinine increase of =0.3 mg/dL and =25% from the baseline value. WRF developed in 1029 (17%) patients and was directly related to baseline heart rate, with an incremental risk of 5% for every 5 b.p.m. heart rate increment (P =0.003). WRF was associated with an increased risk of the primary composite endpoint of hospitalization for worsening heart failure or cardiovascular death [hazard ratio (HR) 1.38, P <0.001] and of all-cause mortality (HR 1.42, P <0.001). Ivabradine use was associated with a reduction of the primary composite endpoint in patients both with (HR 0.82, P =0.023) and without renal dysfunction (HR 0.81, P <0.001) at baseline (P for interaction=0.89), and tolerability of ivabradine was comparable in the two groups. No differences were found in changes in renal function over time between ivabradine- and placebo-treated patients. Conclusion In chronic stable systolic heart failure patients, heart rate is directly and independently associated with the risk of WRF, but reduction in heart rate by ivabradine had a neutral effect on renal function during 2 years of follow-up. The beneficial cardiovascular effects and safety of ivabradine were similar in patients with and without renal dysfunction. [ABSTRACT FROM AUTHOR]

Aims The renal arterial resistance index ( RRI) is a measure of renal blood flow obtained by Doppler ultrasonography, which has been demonstrated to reflect both vascular and parenchymal renal abnormalities. The aim of the study was to evaluate clinical correlates and the prognostic relevance of RRI in a group of patients affected by chronic heart failure ( CHF). Methods and results We enrolled 250 CHF outpatients in a stable clinical condition and receiving conventional therapy. Peak systolic velocity and end-diastolic velocity of a segmental renal artery were obtained by pulsed Doppler flow. Then the RRI was calculated. Standard renal function assessment was obtained by the measurement of creatinine serum levels and the estimation of the glomerular filtration rate ( GFR). During follow-up (21.4 ± 11.3 months), 41 patients experienced heart failure progression (hospitalization and/or heart transplantation and/or death due to worsening heart failure). Considered as a continuous variable, RRI was associated with events at univariate [hazard ratio ( HR) 1.14; 95% confidence interval ( CI) 1.09-1.19; P < 0.001] as well as at multivariate Cox regression analysis ( HR 1.08; 95% CI 1.02-1.13; P = 0.004) after correction for independent predictors of the reference model. When the RRI was added to the reference model including GFR, a significant improvement of reclassification according to both category-free net reclassification improvement ( NRI, 47%; 95% CI 13-80%; P = 0.006) and integrated discrimination improvement ( IDI, 0.034; 95% CI 0.006-0.061; P = 0.016) was observed. Conclusions Quantification of arterial renal perfusion provides a new parameter that independently predicts CHF patient outcome, thus strengthening its possible role in current clinical practice in order to better characterize renal function and stratify patients' prognosis. [ABSTRACT FROM AUTHOR]

Aims: Haemoconcentration has been studied as a marker of decongestion in patients with hospitalization for heart failure (HHF). We describe the relationship between haemoconcentration, worsening renal function, post-discharge outcomes, and clinical and laboratory markers of congestion in a large multinational cohort of patients with HHF.Methods and Results: In 1684 patients with HHF with ejection fraction (EF) ≤40% assigned to the placebo arm of the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) trial, absolute in-hospital haematocrit change was calculated as the change between baseline and discharge or day 7 (whichever occurred first). Patient characteristics, changes in renal function, and outcomes over a median follow-up of 9.9 months were compared by in-hospital haematocrit change. Overall, 26% of patients had evidence of haemoconcentration (i.e., ≥3% absolute increase in haematocrit). Patients with greater increases in haematocrit tended to have better baseline renal function. Haemoconcentration correlated with greater risk of in-hospital worsening renal function, but renal parameters generally returned to baseline within 4 weeks post-discharge. Patients with haemoconcentration were less likely to have clinical congestion at discharge, and experienced greater in-hospital decreases in body weight and natriuretic peptide levels. After adjustment for baseline clinical risk factors, every 5% increase of in-hospital haematocrit change was associated with a decreased risk of all-cause death [hazard ratio (HR) 0.81, 95% confidence interval (CI) 0.70-0.95]. Haematocrit change was also associated with decreased cardiovascular mortality or heart failure (HF) hospitalization at ≤100 days post-randomization (HR 0.73, 95% CI 0.71-0.76).Conclusion: In this large cohort of patients with HHF with reduced EF, haemoconcentration was associated with greater improvements in congestion and decreased mortality and HF re-hospitalization despite an increased risk of in-hospital worsening renal function. [ABSTRACT FROM AUTHOR]

Aims To compare the predictive value of estimated renal function calculated by the Chronic Kidney Disease Epidemiology Collaboration (eGFRCKD-EPI), four-variable Modification of Diet in Renal Disease (eGFRMDRD-4), and Cockcroft–Gault [estimated creatinine clearance (eCcr)] equation in terms of all-cause mortality in heart failure. Renal function is an important prognostic factor in heart failure. Established methods of estimating renal function are known to under-/overestimate true function in certain settings. Methods and results A total of 800 systolic heart failure outpatients (mean age 57 ± 11.5 years, 82% male) were studied over a median follow-up of 121 (Q1–Q3: 110–130) months. The highest systematic difference was seen between eCcr and eGFRMDRD-4 [+12.33 points (mean), 95% limits of agreement –22.35 to 47.01; generalized kappa = 0.36]. eGFRMDRD-4 and eGFRCKD-EPI were the most similar [–4.16 points (mean), 95% limits of agreement –11.56 to 3.25; generalized kappa = 0.74]. Up to 35.4% of patients were reclassified into different estimated glomerular filtration rate (eGFR) categories when comparing eGFRCKD-EPI with eCcr and eGFRMDRD-4. eGFRCKD-EPI performed marginally better in terms of predicting all-cause mortality than eGFRMDRD-4, as univariate areas under the time-dependent receiver operating characteristic curves (AUC), marginal and partial proportions of explained variation (PEV), net reclassification improvement (NRI), and the integrated discrimination improvement (IDI) for 5 years of follow-up were significantly higher for eGFRCKD-EPI than for eGFRMDRD-4. Conclusion In this cohort of heart failure patients, eGFRCKD-EPI was marginally better in predicting all-cause mortality than eGFRMDRD-4. Estimated function differed widely between equations and is likely to have an effect on therapy choice. [ABSTRACT FROM PUBLISHER]

Aims Gouty arthritis is a frequent and disabling complication in heart failure patients. This study aimed to investigate which factors are associated with the occurrence of gouty arthritis in these patients. Methods and results A case–control study was performed in heart failure patients (February 2007 to October 2009). Cases were defined as patients with gouty arthritis. Factors that are possibly associated with gouty arthritis and/or heart failure were evaluated. Echocardiographic dimensions and laboratory values including glomerular filtration rate (GFR) and fractional excretion of uric acid (FEUA) were measured. Logistic regression analysis was used to determine crude and adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for possibly associated factors. In total, 188 patients (59 with gouty arthritis) were included. Spironolactone use was associated with a decreased occurrence of gouty arthritis (OR 0.32, 95% CI 0.13–0.77). Independently associated with an increased occurrence of gouty arthritis were hypertensive heart failure (OR 3.6, 95% CI 1.6–8.2), New York Heart Association (NYHA) class III/IV (OR 4.5, 95% CI 1.8–11.0), lower GFR (P < 0.001), and FEUA <4% (OR 3.3, 95% CI 1.4–7.9). Among the four age/gender groups, the strongest association with gouty arthritis was found in men <65 years. Conclusion Our identification of factors that are associated with the occurrence of gouty arthritis makes it possible to develop strategies to improve further the quality of life in heart failure patients. The possible decreased occurrence of gouty arthritis in spironolactone users has to be confirmed in prospective studies. [ABSTRACT FROM AUTHOR]

Aims We aimed to determine the relation between baseline systolic blood pressure (SBP), change in SBP, and worsening renal function (WRF) in acute heart failure (AHF) patients enrolled in the Pre-RELAX-AHF trial. Methods and results The Pre-RELAX-AHF study enrolled 234 patients within 16 h of admission (median 7 h) for AHF and randomized them to relaxin given intravenous (i.v.) for 48 h or placebo. Blood pressure was measured at baseline, at 3, 6, 9, 12, 24, 36, and 48 h and at 3, 4, and 5 days after enrolment. Worsening renal function was defined as a serum creatinine increase of ≥0.3 mg/dL by Day 5. Worsening renal function was found in 68 of the 225 evaluable patients (30%). Patients with WRF were older (73.5 ± 9.4 vs. 69.1 ± 10.6 years; P= 0.003), had a higher baseline SBP (147.3 ± 19.9 vs. 140.8 ± 16.7 mmHg; P= 0.01), and had a greater early drop in SBP (37.9 ± 16.0 vs. 31.4 ± 12.2 mmHg; P= 0.004). In a multivariable model, higher age, higher baseline creatinine, and a greater early drop in SBP, but not baseline SBP, remained independent predictors of WRF. Furthermore, WRF was associated with a higher Day 60 (P= 0.01), and Day 180 (P= 0.003) mortality. Conclusions Worsening renal function in hospitalized AHF patients is related to a poor clinical outcome and is predicted by a greater early drop in SBP. [ABSTRACT FROM AUTHOR]

Aims To investigate the relationship between signs and symptoms of congestion, renal impairment and outcome in chronic heart failure (CHF) patients. Methods and results The Cardiac Insufficiency Bisoprolol Study II included 2647 NYHA class III/IV CHF patients. Congestion was estimated by the presence of elevated jugular venous pressure, orthopnoea, ascites, or oedema. Glomerular filtration rate (eGFR) was estimated using the simplified modification of diet in renal disease (sMDRD) formula. The main outcome consisted of all-cause mortality. Mean age was 61±11 years, 80% of patients were male, and mean eGFR was 77±31 mL/min/1.73 m². A total of 1234 (47%) patients had at least one sign, and 10% of patients had more than three signs of congestion. Mean eGFR was lower in patients with signs of congestion (75±30 vs. 79±31 mL/min/1.73 m², P < 0.001). In multivariable analysis, signs of congestion remained independently related to eGFR (P = 0.012). Mortality rates almost doubled from no signs to three or more signs of congestion (11 vs. 20%, respectively, P < 0.0001). Patients with any signs of congestion also had a worse outcome. Adjusted hazard ratio was 1.42 (1.14-1.77), P , 0.01 for mortality and 1.21 (1.05-1.39), P , 0.01 for the composite endpoint. Conclusion Signs and symptoms of congestion are associated with renal impairment and are independent determinants of prognosis in patients with CHF [ABSTRACT FROM AUTHOR]

Abstract: Renal impairment, as measured by reduced glomerular filtration rate (GFR) and increased urinary albumin excretion (UAE), is prevalent in patients with chronic heart failure (CHF) and is associated with reduced survival. The prevalence of structural tubular damage in CHF is unknown. We investigated 90 CHF patients and 20 age and sex matched healthy controls, and determined estimated GFR, UAE, N terminal-pro brain natriuretic peptide (NT-proBNP) and urinary neutrophil gelatinase associated lipocalin (NGAL) as a marker for tubular damage. CHF patients had significantly lower averaged estimated GFR (64±17 vs 90±12 mL/min/1.73 m2, P <0.0001), but higher NT-proBNP and UAE levels (both P <0.0001). Median urinary NGAL levels were markedly increased in CHF patients compared to controls (175 (70–346) vs 37 (6–58) μg/gCr, P <0.0001). Both serum creatinine (r =0.26, P =0.006) and eGFR (r =−0.29, P =0.002) were significantly associated with urinary NGAL levels as were NT-proBNP and UAE but to a lesser extent. In conclusion, renal impairment in CHF patients is not only characterised by decreased eGFR and increased UAE, but also by the presence of tubular damage, as measured by increased urinary NGAL concentrations. [Copyright &y& Elsevier]