Randomized, double-blind, placebo-controlled, multicentre pilot study on the effects of empagliflozin on clinical outcomes in patients with acute decompensated heart failure (EMPA-RESPONSE-AHF)

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

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure &lt; 100 mmHg (n = 1127), estimated glomerular filtration rate &lt; 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

Prognostic value of heart rate variability and ventricular arrhythmias during 13-year follow-up in patients with mild to moderate heart failure

In contrast to patients with moderate to severe chronic heart failure (CHF), data regarding long-term outcome in patients with mild CHF are scarce. We examined the place of Holter monitoring to study the prognostic value of ventricular arrhythmias and heart rate variability (HRV) in patients with mild to moderate CHF during long-term follow-up. We studied 90 patients with mild to moderate CHF and NYHA class II who had been enrolled in the Dutch Ibopamine Multicenter Trial. At baseline their mean age was 60.5 +/- A 8.0 years, left ventricular ejection fraction (LVEF) was 0.29 +/- A 0.09, and 85% were males. At the start of the study, patients were only using diuretics, while digoxin, and particularly ACE inhibitors and beta-blockers were initiated later. Univariate and multivariate proportional hazard analyses were performed. At baseline 80% of patients were in NYHA class II, and 20% were in class III; their mean age was 60 years, mean LVEF was 0.29, and 85% were men. During a follow-up of 13 years, 47 patients (53%) died. Cardiovascular (CV) death occurred in 39 patients, of which 28 were sudden cardiac death (SCD). For both CV death and SCD, LVEF 20) were independent risk markers. Of the HRV parameters, total power (> 2,500 ms(2)) was an important risk marker for CV death, but not for SCD. The present 13-year follow-up study in 90 patients with mild to moderate CHF showed that ventricular premature beats and HRV may have important value in predicting outcome

Drawbacks and prognostic value of formulas estimating renal function in patients with chronic heart failure and systolic dysfunction

Background - Renal function is an important risk marker for morbidity and mortality in chronic heart failure (CHF) and is often estimated with the use of creatinine-based formulas. However, these formulas have never been validated in a wide range of CHF patients. We validated 3 commonly used formulas estimating glomerular filtration rate (GFR) with true GFR in CHF patients. Furthermore, we compared the prognostic value of these formulas for cardiovascular outcome with that of true GFR during 12 months of follow-up. Methods and Results - In 110 CHF patients (age, 57 +/- 11.7 years; left ventricular ejection fraction, 0.27 +/- 0.09; NYHA class, 2.5 +/- 0.9), we measured (125)I-iothalamate clearance. Cockcroft-Gault (GFR(cg)), Modification of Diet in Renal Disease (MDRD), and simplified MDRD (sMDRD) equations were used as creatinine-based renal function estimations. Furthermore, 24-hour creatinine clearance (CrCl) was determined. CrCl and GFRcg were the most accurate. MDRD was most precise formula, although it was also highly biased. All formulas overestimated in the lower ranges and underestimated in the upper ranges of the GFR corrected for body surface area. The predictive performance of the formulas was best in severe CHF (NYHA classes III and IV). The prognostic value of CrCl and MDRD for cardiovascular outcome was comparable to that of GFR, the sMDRD was slightly less, and the GFR(cg) had a significantly worse prognostic value. Conclusions - In the more severe ranges of CHF, creatinine-based formulas and CrCl corrected for body surface area appeared to be more precise and accurate in estimating true GFR corrected for body surface area. The MDRD formula is the most precise and has a good prognostic value, whereas the sMDRD is slightly less accurate but uses fewer parameters, which makes this formula a practical alternative in clinical practice

Use of cystatin C levels in estimating renal function and prognosis in patients with chronic systolic heart failure

Background Estimates of glomerular filtration rate (GFR), including creatinine and creatinine based formulae, are inaccurate in extremes of GFR and substantially biased in patients with chronic heart failure (CHF). Objective To investigate whether serum cystatin C levels would be a better, more accurate and simple alternative for estimation of GFR and prognosis in CHF. Design Cohort study. Setting Chronic heart failure. Patients, interventions and main outcome measure In 102 CHF patients, the correlation between GFR as estimated by I-125-iothalamate clearance (GFR(IOTH)), the modification of diet in renal disease formula (GFR(MDRD)) and cystatin C was investigated. The combined endpoint consisted of the first occurrence of all cause mortality, heart transplantation or admission for CHF within 24 months. Results Mean age was 58 +/- 12 years; 77% were male. Mean left ventricular ejection fraction was 28 +/- 9%. Mean GFR(IOTH) was 75 +/- 27 ml/min/1.73 m(2), while median cystatin C levels were 0.80 (0.69-1.02) mg/l. GFR(IOTH) was strongly correlated with all renal function estimates, including 1/cystatin C (r 0.867, p<0.001). GFR(IOTH) was better predicted by 1/cystatin C compared to 1/serum creatinine (z-3.12, p-0.002), but equally predicted compared to GFR(MDRD) (z=0.92, p=0.356). Serum 1/cystatin C was a strong independent predictor of prognosis (HR: 2.27 per SD increase, 95% CI 1.12 to 4.63), comparable to GFR(MDRD). Conclusions Cystatin C is an accurate and easy estimate of renal function with prognostic properties superior to serum creatinine and similar to creatinine based formulae in patients with CHF

Decreased cardiac output, venous congestion and the association with renal impairment in patients with cardiac dysfunction

Background: Renal failure in heart failure is related to decreased cardiac output. However, little is known about its association with venous congestion. Aims: To investigate the relationship between venous congestion and glomerular filtration rate (GFR) in patients with cardiac dysfunction. Methods and results: Right atrial pressure (RAP) and cardiac index (CI) were determined by right heart catheterisation in 51 patients with cardiac dysfunction, secondary to pulmonary hypertension. GFR and renal blood flow (RBF) were measured as I-125-lothalamate and I-131- Hippuran clearances, respectively. Mean age was 40 +/- 11 years and 69% of patients were female. GFR was 73 +/- 19 ml/min/1.73 m(2) with a CI of 2.1 +/- 0.7 l/min/m(2). In multivariate analysis, RBF (r=0.664, p Conclusion: RBF is the main factor determining GFR in patients with cardiac dysfunction. Venous congestion, characterised by an increased RAP, adjusted for RBF is also related to GFR. Treatment to preserve GFR should not only focus on improvement of renal perfusion, but also on decreasing venous congestion. (C) 2007 European Society of Cardiology. Published by Elsevier B.V. All rights reserved

Worsening renal function and prognosis in heart failure:Systematic review and meta-analysis

Background: Renal impairment is associated with increased mortality in heart failure (HF). Recently, reports suggest that worsening renal function (WRF) is another predictor of clinical outcome in HE The present study was designed to establish the proportion of patients with HF that exhibits (WRF) and the associated risk for mortality and hospitalization by conducting a systematic review and meta-analysis. Methods and Results: A systematic search of MEDLINE revealed 8 Studies on the relationship between WRF and mortality in 18,634 patients with HE The mortality risk associated with WRF was estimated using random-effects meta-analysis. WRF was defined as an increase in serum creatinine >= 0.2 mg/dL or a corresponding decrease in estimated glomerular filtration rate >= 5 mL.min.1.73 m(2). Subgroup analysis included differentiation between in- and out-hospital patients, degree of WRF and time until end point occurrence. WRF developed in 4,734 (25%) patients and was associated with a higher risk for mortality (odds ratio [OR] = 1.62; 95% confidence interval [CI] 1.45-1.82, P <.001) and hospitalization (OR = 1.30, 95% CI 1.04-1.62, P = .022). The severity of WRF was also associated with greater mortality. Patients with impaired renal function at baseline were more prone to progressive renal function loss. Conclusions: WRF predicts substantially higher rates of mortality and hospitalization in patients with HF

Clinical and prognostic value of advanced glycation end-products in chronic heart failure

Aims Advanced glycation end-products (AGEs) have been proposed as a novel factor involved in the development and progression of chronic heart failure (CHF). We aimed to determine whether plasma levels of N-epsilon-(carboxymethyl)lysine (CML) and N-epsilon-(carboxyethyl)lysine (CEL), two well-known AGEs, are related to the severity and prognosis of CHF. Methods and results A total of 102 CHF patients, aged 58 +/- 12 years, with an average left ventricular ejection fraction of 28 +/- 9% were followed for 1.7 (1.2-1.9) years. NYHA functional class and NT-pro-BNP were used as estimates of the severity of CHF. CML and CEL were determined by LC-MS/MS. CML levels were associated with NYHA functional class (P <0.001) and NT-pro-BNP levels (P <0.001). Survival analysis for the combined end-point of death, heart transplantation, ischaemic cardiovascular event, and hospitalization for heart failure revealed that CML levels predicted outcome, even after adjustment for age, gender, aetiology of CHF, identified risk modifiers, and several known predictors of outcome in CHF. The predictive value of CML subsided after correction for renal function. CEL was not associated with the severity or prognosis of CHF. Conclusion Plasma AGEs, in particular CML levels, are related to the severity and prognosis of CHF. The fact that the relation between CML and prognosis subsided after correction for renal function may suggest that AGE accumulation in renal failure explains part of the prognostic value of renal function in CHF. However, further investigation is warranted to exclude the possibility that CML is just an innocent marker of renal function

Differential associations between renal function and "modifiable" risk factors in patients with chronic heart failure

Reduced glomerular filtration rate (GFR) is strongly associated with reduced survival in patients with chronic heart failure (CHF). Our aim was to determine different pathophysiologic markers that are associated with reduced renal function in CHF. We studied 86 patients with CHF (58 +/- A 12 years, 78% male). GFR and renal blood flow (RBF) were determined by (125)I-Iothalamate and (131)I-Hippuran clearances. Filtration fraction (FF) was calculated. We determined haemoglobin levels, endothelial function, inflammatory status, plasma renin activity (PRA) and N-terminal pro brain natriuretic peptide (NT-proBNP). Urinay albumin excretion (UAE) was measured in 24 h urine. Mean GFR was 74 +/- A 28 ml/min/1.73 m(2). GFR was strongly related to RBF (r = 0.915, P <0.001), FF (r = 0.546, P <0.001), but only weakly to endothelial function and PRA. In multivariate analysis, RBF (r = 0.938, P <0.001), FF (r = 0.786, P <0.001) and haemoglobin levels (r = -0.520, P <0.001) were independently associated with GFR. UAE was mainly dependent on RBF (r = -0.401, P <0.001) and increased exponentially with decreasing RBF. RBF was mainly associated with NT-proBNP (r = -0.561, P <0.001) and PRA (r = -0.422, P <0.001). Reduced GFR is mainly dependent of decreased RBF in patients with CHF. Endothelial function and neurohormonal activation showed only mild associations with GFR. NT-proBNP showed a strong relationship with RBF, and may be used as a marker of reduced renal perfusion