Renal function stratified dose comparisons of eplerenone versus placebo in the EMPHASIS-HF trial.

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.

Antihypertensive effect of the mineralocorticoid receptor antagonist eplerenone: a pooled analysis of patient-level data from comparative trials using regulatory-approved doses.

PURPOSE: Several options are available for the treatment of hypertension; however, many treated patients are still not below blood pressure (BP) target. Eplerenone, a selective mineralocorticoid receptor antagonist, is an approved treatment option for the management of patients with hypertension in a number of countries. This patient-level pooled analysis was conducted to document the efficacy and safety/tolerability of eplerenone at the dosages approved for use in hypertension in comparison to placebo or other approved antihypertensive agents. METHODS: Seventeen Phase III studies conducted in patients with mild-to-moderate hypertension in the Eplerenone Hypertension Clinical Program were reviewed; eleven met the selection criteria. The primary endpoint was change from baseline in seated diastolic BP and seated systolic BP measured at the end of the study. RESULTS: A total of 2,698 patients were included in this per-protocol analysis. In patients treated for at least 6 weeks with a stable dose of eplerenone, doses of 50 mg daily and 100 mg daily were associated with greater reductions of seated systolic BP and seated diastolic BP compared with placebo (P<0.001) and active-controlled studies (P< 0.033). In the analysis of covariance model testing of the contribution of four factors (age, body mass index [BMI], history of cardiovascular disease, and diabetes) on the BP lowering effects of eplerenone, only BMI and age were associated with small though statistically significant changes in BP (<0.2 mmHg). Eplerenone was well tolerated; headache was the most common adverse event for patients in any group. Severe hyperkalemia (serum potassium level >6.0 mmol/L) occurred in up to 0.4% in the eplerenone groups, 0.4% in the placebo group, and 0.1% in the active-control group. CONCLUSION: This patient-level pooled analysis provides robust evidence that eplerenone, at 50 mg or 100 mg daily, was effective in lowering BP in patients with mild-to-moderate hypertension and was well tolerated.

A real-world perspective on the prevalence and treatment of heart failure with a reduced ejection fraction but no specific or only mild symptoms.

Heart failure (HF) is commonly described according to the severity of symptoms, using the New York Heart Association (NYHA) classification, and the assessment of ventricular function, by measuring the left ventricular ejection fraction (LVEF). It is important to acknowledge, however, that the severity of symptoms does not systematically correlate with the level of ventricular systolic dysfunction. Patients with no or only mild symptoms are still at high risk of HF-related morbidity and mortality. The objective of this review was to summarize the prevalence, characteristics, and treatment of patients with chronic HF and mild or no symptoms and to review epidemiological data from three recent registries conducted in Europe. From a clinical practice perspective, patients with a reduced ejection fraction who have only mild symptoms appear to represent a group of patients for whom the provision of adequate medical care is yet to be optimized. While prescription of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and beta-blockers appears to be consistently high, the use of mineralocorticoid receptor antagonists is more variable and does not appear to be in accordance with the latest clinical guidelines. As approximately half of patients with HF and a reduced LVEF have NYHA class II symptoms, significant reductions in morbidity and mortality could be achieved by more comprehensive treatment of this population.

Treatment of heart failure in real-world clinical practice: findings from the REFLECT-HF registry in patients with NYHA class II symptoms and a reduced ejection fraction.

BACKGROUND: Optimal medical therapy (OMT) for patients with chronic heart failure and a reduced ejection fraction (HF-REF) includes angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, ß-blockers, and mineralocorticoid receptor antagonists, plus a diuretic. HYPOTHESIS: We hypothesized that OMT is less often prescribed in HF-REF patients (≤35%) with New York Heart Association (NYHA) class II symptoms compared with those with NYHA class III/IV symptoms. METHODS: This was a cross-sectional, observational, multicenter survey of hospital-based cardiologists, office-based cardiologists, and general practitioners in Germany. RESULTS: Out of a total of 384 patients enrolled, 144 had REF ≤35%. Patients with REF had NYHA class II symptoms in 39.6% (n = 57) and NYHA class III/IV symptoms in 60.4% (n = 87). The REF/NYHA class II group had a higher proportion of males than the REF/NYHA class III/IV group. For angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and ß-blockers, prescription rates were high and comparable between groups. However, prescription rates for mineralocorticoid receptor antagonists were lower compared with other guideline-recommended treatments. Multivariate analyses indicated that OMT prescription was reduced for older patients and increased for patients cared for by an office-based cardiologist. CONCLUSIONS: Given the high proportion of patients with reduced left ventricular systolic function but only minor symptoms, HF-REF appears to be underdiagnosed, and a higher proportion of patients than are currently recognized could potentially be candidates for OMT.

Registry in Germany focusing on level-specific and evidence-based decision finding in the treatment of heart failure: REFLECT-HF.

BACKGROUND: In Germany, care for patients with chronic heart failure (HF) is provided by hospital-based cardiologists (HBC), office-based cardiologists (OBC) and general practitioners (GP). We aimed to compare patient characteristics, diagnostic approaches and therapeutic decisions. METHODS: Multi-centre, cross-sectional, observational survey at 48 physicians. Patients (n = 384) were required to have previously diagnosed HF and NYHA class ≥ II and/or a left ventricular ejection fraction of <50 %. A total of 384 patients were included at 5 HBCs, 26 OBCs and 18 GPs. RESULTS: A mean of 18.8 % of all patients at HBCs practices had heart failure, compared to a smaller proportion of 13.9 and 6.7 % at OBCs and GPs, respectively. Echo facility was available for all HBCs and OBCs, but for 16.7 % of GPs (p < 0.0001 for trend). Patients at HBCs had a higher NYHA class (65.6 % had class III/IV; p < 0.0001) compared to 36.8 % at OBCs and 39.3 % at GPs. Usage of three guideline-recommended pharmaceutical treatments was more than 80 %: diuretics (83.1 %), renin-angiotensin system blocking agents (91.4 %) and betablockers (90.1 %) with no differences between physician groups. Mineralocorticoid receptor antagonists (MRAs, overall 47.7 %) were more frequently prescribed by OBCs (54.7 %; p = 0.0007 for trend) than HBCs (43.8 %) and GPs (31.0 %). Ivabradin was not frequently used (11.0 % at OBCs, 4.9 % at HBCs and 0 % at GPs; p = 0.0163 for trend). The proportion of patients with CRT (8.6 %), ICD (23.5 %) and CABG (23.1 %) was not statistically different between groups. CONCLUSION: REFLECT-HF demonstrates that there are some differences in evidence-based treatment decisions between the three main health services (HBC, OBC and GP) providing care for patients with HF in Germany. Advocating adherence to guideline recommendations and earlier adoption of these evidence-based treatments across all levels of care might further improve patient care.

Crystal structure of a POU/HMG/DNA ternary complex suggests differential assembly of Oct4 and Sox2 on two enhancers.

Members of the POU and SOX transcription factor families exemplify the partnerships established between various transcriptional regulators during early embryonic development. Although functional cooperativity between key regulator proteins is pivotal for milestone decisions in mammalian development, little is known about the underlying molecular mechanisms. In this study, we focus on two transcription factors, Oct4 and Sox2, as their combination on DNA is considered to direct the establishment of the first three lineages in the mammalian embryo. Using experimental high-resolution structure determination, followed by model building and experimental validation, we found that Oct4 and Sox2 were able to dimerize onto DNA in distinct conformational arrangements. We demonstrate that the DNA enhancer region of their target genes is responsible for the correct spatial alignment of glue-like interaction domains on their surface. Interestingly, these surfaces frequently have redundant functions and are instrumental in recruiting various interacting protein partners.

OBF1 enhances transcriptional potential of Oct1.

The POU transcription factors Oct1 and Oct2 bind to DNA in various monomer and dimer configurations. Depending on the DNA sequence to which they bind, the dimers are arranged in configurations that are either accessible (PORE sequence) or inaccessible (MORE sequence) to the B-cell-specific cofactor OBF1 (OcaB, Bob1). As shown previously, the MORE and related sequences (such as the heptamer/octamer motif) are found in immunoglobulin heavy chain promoters. Here we show that the expression of Osteopontin, which contains a PORE sequence in its enhancer region, depends on the presence of OBF1 in B cells. OBF1 alleviates DNA sequence requirements of the Oct1 dimer on PORE-related sequences in vitro. Furthermore, OBF1 stabilizes POU dimer-DNA interactions and overrides Oct1 interface mutations, which abolish PORE-mediated dimerization without OBF1. Our data indicate that the PORE-type Oct1 or Oct2 dimer, rather than the monomer, is the primary target of the cofactor OBF1. Based on our biochemical data, we propose a mode of OBF1-Oct1 dimer interaction, suggesting a novel arrangement of the subdomain connectivities.