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.

Early eplerenone treatment in patients with acute ST-elevation myocardial infarction without heart failure: the Randomized Double-Blind Reminder Study.

AIMS: We aimed to assess the impact of eplerenone on cardiovascular (CV) outcomes in STEMI without known heart failure, when initiated within 24 h of symptom onset. METHODS AND RESULTS: In this randomized, placebo-controlled, double-blind trial, we assigned 1012 patients with acute STEMI and without a history of heart failure to receive either eplerenone (25-50 mg once daily) or placebo in addition to standard therapy. The primary endpoint was the composite of CV mortality, re-hospitalization, or, extended initial hospital stay, due to diagnosis of HF, sustained ventricular tachycardia or fibrillation, ejection fraction ≤40%, or elevated BNP/NT-proBNP at 1 month or more after randomization. BNP elevation was defined as BNP levels or values above 200 pg/mL or NT-proBNP values above 450 pg/mL (in patients aged below 50); above 900 pg/mL (age 50-75 years) or above 1800 pg/mL (patients older than 75). After a mean follow-up of 10.5 months, the primary endpoint occurred in 92 patients (18.2%) in the eplerenone group and in 149 patients (29.4%) in the placebo group [adjusted hazard ratio (HR), 0.58; 95% confidence interval (CI), 0.45-0.76; P < 0.0001]. The primary endpoint was driven by a high BNP/NT-proBNP level (adjusted HR, 0.60; 95% CI, 0.45-0.79; P < 0.0003). Adverse event rates were similar in both groups. Serum potassium levels exceeded 5.5 mmol/L in 5.6 vs. 3.2% (P = 0.09) and were below 3.5 mmol/L in 1.4 vs. 5.6% of patients (P = 0.0002), in the eplerenone and placebo groups, respectively. CONCLUSION: The addition of eplerenone during the acute phase of STEMI was safe and well tolerated. It reduced the primary endpoint over a mean 13 months follow-up mostly because of significantly lower BNP/NT-proBNP levels. Additional studies are needed to clarify the role of early use of MRAs in STEMI patients without heart failure. CLINICAL TRIAL REGISTRATION: NCT01176968.

Heart failure care in the Central and Eastern Europe and Baltic region: status, barriers, and routes to improvement.

Despite improvements over recent years, morbidity and mortality associated with heart failure (HF) are higher in countries in the Central and Eastern Europe and Baltic region than in Western Europe. With the goal of improving the standard of HF care and patient outcomes in the Central and Eastern Europe and Baltic region, this review aimed to identify the main barriers to optimal HF care and potential areas for improvement. This information was used to suggest methods to improve HF management and decrease the burden of HF in the region that can be implemented at the national and regional levels. We performed a literature search to collect information about HF epidemiology in 11 countries in the region (Bulgaria, Croatia, Czechia, Estonia, Hungary, Latvia, Lithuania, Poland, Romania, Serbia, and Slovenia). The prevalence of HF in the region was 1.6-4.7%, and incidence was 3.1-6.0 per 1000 person-years. Owing to the scarcity of published data on HF management in these countries, we also collected insights on local HF care and management practices via two surveys of 11 HF experts representing the 11 countries. Based on the combined results of the literature review and surveys, we created national HF care and management profiles for each country and developed a common patient pathway for HF for the region. We identified five main barriers to optimal HF care: (i) lack of epidemiological data, (ii) low awareness of HF, (iii) lack of national HF strategies, (iv) infrastructure and system gaps, and (v) poor access to novel HF treatments. To overcome these barriers, we propose the following routes to improvement: (i) establish regional and national prospective HF registries for the systematic collection of epidemiological data; (ii) establish education campaigns for the public, patients, caregivers, and healthcare professionals; (iii) establish formal HF strategies to set clear and measurable policy goals and support budget planning; (iv) improve access to quality-of-care centres, multidisciplinary care teams, diagnostic tests, and telemedicine/telemonitoring; and (v) establish national treatment monitoring programmes to develop policies that ensure that adequate proportions of healthcare budgets are reserved for novel therapies. These routes to improvement represent a first step towards improving outcomes in patients with HF in the Central and Eastern Europe and Baltic region by decreasing disparities in HF care within the region and between the region and Western Europe.

Hypo- and hyperglycemia predict outcome in patients with left ventricular dysfunction after acute myocardial infarction: data from EPHESUS.

BACKGROUND: Hyperglycemia predicts death in cardiovascular disease, but intensive glucose-lowering strategies increase mortality rates in diabetes. The present analysis investigated the prognostic value of postadmission blood glucose (BG) concentration on clinical outcomes in high-risk patients with heart failure after acute myocardial infarction. METHODS AND RESULTS: A total of 6,496 patients from the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) were categorized into 4 groups by plasma glucose concentration: ≤4.5 mmol/L (hypoglycemia), 4.5-5.5 mmol/L (normoglycemia), 5.5-8.3 mmol/L (elevated glucose level), and >8.3 mmol/L (severe hyperglycemia). We evaluated the time to all-cause death (primary end point) and time to cardiovascular death or hospitalization (secondary end point). Hypo- and severe hyperglycemia were prevalent in 509 (8%) and 1,588 (24%) patients, respectively. There was a U-shaped relationship between BG level and incidence of all-cause death (11.8% in patients with normoglycemia vs 15.1% and 19.9% in those with hypo- and severe hyperglycemia; P < .001). The incidence of the secondary end point was increased only in hyperglycemic patients (36% vs 23% in normoglycemic patients; P < .001). In multivariate Cox regression analysis, hypoglycemia (hazard ratio [HR] 1.38, 95% confidence interval [CI] 1.06-1.81; P = .002) and severe hyperglycemia (HR 1.52, CI 1.27-1.83; P < .0001) proved to be strong predictors of all-cause death. There was no significant interaction between eplerenone treatment and blood glucose levels regarding clinical outcomes. CONCLUSIONS: In heart failure after acute myocardial infarction, both hypo- and hyperglycemia at the postacute phase identify patients with increased risk of death during long-term follow-up.

Effect of eplerenone on extracellular cardiac matrix biomarkers in patients with acute ST-elevation myocardial infarction without heart failure: insights from the randomized double-blind REMINDER Study.

OBJECTIVE: Aldosterone stimulates cardiac collagen synthesis. Circulating biomarkers of collagen turnover provide a useful tool for the assessment of cardiac remodeling in patients with an acute myocardial infarction (MI). METHODS: The REMINDER trial assessed the effect of eplerenone in patients with an acute ST-elevation Myocardial Infarction (STEMI) without known heart failure (HF), when initiated within 24 h of symptom onset. The primary outcome was almost totally (>90%) driven by natriuretic peptide (NP) thresholds after 1-month post-MI (it also included a composite of cardiovascular death or re-hospitalization or new onset HF or sustained ventricular tachycardia or fibrillation or LVEF ≤40% after 1-month post-MI). This secondary analysis aims to assess the extracellular matrix marker (ECMM) levels with regards to: (1) patients` characteristics; (2) determinants; (3) and eplerenone effect. RESULTS: Serum levels of ECMM were measured in 526 (52%) of the 1012 patients enrolled in the REMINDER trial. Patients with procollagen type III N-terminal propeptide (PIIINP) above the median were older and had worse renal function (p < 0.05). Worse renal function was associated with increased levels of PIIINP (standardized ß ≈ 0.20, p < 0.05). Eplerenone reduced PIIINP when the levels of this biomarker were above the median of 3.9 ng/mL (0.13 ± 1.48 vs. -0.37 ± 1.56 ng/mL, p = 0.008). Higher levels of PIIINP were independently associated with higher proportion of NP above the prespecified thresholds (HR = 1.95, 95% CI 1.16-3.29, p = 0.012). CONCLUSIONS: Eplerenone effectively reduces PIIINP levels when baseline values were above the median. Eplerenone may limit ECMM formation in post-MI without HF.

Aspirin does not reduce the clinical benefits of the mineralocorticoid receptor antagonist eplerenone in patients with systolic heart failure and mild symptoms: an analysis of the EMPHASIS-HF study.

AIMS: It is not known whether concomitant use of aspirin might attenuate the beneficial effects of mineralocorticoid receptor antagonists (MRAs). The purpose of this subgroup analysis was to explore the interaction between baseline aspirin treatment and the effect of eplerenone on the primary efficacy outcomes (composite of hospitalization for heart failure or cardiovascular mortality), its components, and safety markers [estimated glomerular filtration rate (eGFR), systolic blood pressure (SBP), and serum potassium >5.5 mmol/L] in the Eplerenone in Mild Patients Hospitalization and SurvIval Study in Heart Failure trial (EMPHASIS-HF). METHODS AND RESULTS: Patients with chronic heart failure, reduced ejection fraction (HFREF), and mild symptoms were enrolled in EMPHASIS-HF. We evaluated baseline characteristics according to aspirin use. We explored the interaction between aspirin and eplerenone, using Cox proportional hazards models providing adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) and P-values for interaction. Of the 2737 patients randomized, 1605 patients (58.6%) were taking aspirin. The beneficial effects of eplerenone on the primary endpoint were similar in patients not treated (adjusted HR 0.59, 95% CI 0.46-0.75) or treated (adjusted HR 0.71, 95% CI 0.59-0.87) with aspirin at baseline (interaction P-value = 0.19). We did not observe any significant modification of the safety markers by aspirin that was clinically meaningful. CONCLUSION: Aspirin use in patients with chronic systolic heart failure and mild symptoms did not substantially reduce the overall beneficial effects of the MRA eplerenone contrary to what has been described in some studies with ACE inhibitors.

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.

Biomarkers: optimizing treatment guidance in heart failure.

Heart failure is a frequent and life-threatening syndrome which is not only the result of myocardial injury or hemodynamic overload as commonly perceived, but appears to be the result of an interplay among genetic, neurohormonal, inflammatory, and biochemical factors, collectively referred to as biomarkers. Biomarkers can become risk factors in case their therapeutic modification results in an improvement of clinical outcomes. Among those markers identified in patients with heart failure, a number appears to have direct clinical relevance in aiding diagnosis, risk stratification, monitoring therapy, and treating to targets in order to improve clinical outcomes. These include brain natriuretic peptides (e.g., BNP, NT-proBNP), inflammatory markers (e.g., hsCRP), neurohormones (e.g., aldosterone), cardiorenal markers (e.g., cycstatin C), and novel markers (e.g., galectin-3). While their utility to indicate risk is mostly well established, there are less data to establish that a treatment using biomarkers as a guidance results in better outcomes than a more generalized intensified treatment of patients with heart failure. Future directions may involve larger platforms that facilitate to simultaneously analyze hundreds of biomarkers and may help to tailor heart failure therapy on a single patient basis, considering the specific pathogenesis and prognosis. Also from a therapeutic perspective there are data that a single intervention such as aldosterone blockade may affect multiple biomarkers at the same time. Taken together the data indicate that biomarkers are evolving into a valuable addendum to the diagnostic and therapeutic armamentarium.

Blood pressure control in hypertensive patients in Irish primary care practices.

In Ireland, cardiovascular disease is a major cause of death. However, blood pressure (BP) goal achievement is unsatisfactory. The authors aimed to document BP control and increase awareness. A total of 1534 patients were enrolled in the study, with a mean age of 64.7+/-11.9 years (53.8% women). Duration of hypertension was 8.7+/-7.7 years, and 14.6% had diabetes, 13.8% had coronary artery disease, and 40.5% were taking antihypertensive monotherapy. beta-Blockers (39.8%), angiotensin-converting enzyme inhibitors (32.2%), and angiotensin receptor blockers (22.0%) were prescribed most frequently. Mean BP was 136.0+/-6.1 mm Hg/89.5+/-5.0 mm Hg in nondiabetic patients (48.6% <140/90 mm Hg) and 131.0+/-7.4 mm Hg/81.7+/-4.6 mm Hg in diabetic patients (16.7% <130/80 mm Hg). Diet, exercise, and lifestyle modifications (63.5%) were frequently recommended. Increased patient awareness and compliance together with the adherence of physicians to current guidelines and greater willingness to take action in patients with uncontrolled hypertension should help in improving BP control and thus reduce cardiovascular risk.