Practical considerations on the introduction of sacubitril/valsartan in clinical practice: Current evidence and early experience.

The combination of neprilysin inhibitor sacubitril with the angiotensin II receptor 1 blocker valsartan is the first agent from the angiotensin receptor neprilysin inhibitors (ARNI) class authorized for clinical use in heart failure (HF) patients with reduced ejection fraction (HFrEF). Sacubitril/valsartan resulted in 20% reduction in the incidence rate of death or HF hospitalization compared to enalapril in symptomatic HFrEF patients in the seminal PARADIGM-HF trial. As a result, the recently updated European and American HF guidelines granted this agent a class IB indication for the treatment of ambulatory/chronic symptomatic HFrEF patients. However, translating the positive results of trials into true clinical benefit is often challenging. This is particularly true in the case of sacubitril/valsartan, as HF is a heterogeneous syndrome including many severely ill patients who are prone to decompensation, while this new agent comes to replace a cornerstone of current evidence-based HF therapy. In the present paper, we address a number of practical issues regarding the introduction of sacubitril/valsartan and propose an algorithm based on available evidence and early clinical experience.

Temporal trends in epidemiology, clinical presentation and management of acute heart failure: results from the Greek cohorts of the Acute Heart Failure Global Registry of Standard Treatment and the European Society of Cardiology-Heart Failure pilot survey.

AIM: Temporal trends of epidemiological data on acute heart failure (AHF) are limited. We sought to assess changes in epidemiology, clinical presentation and management of AHF in Greece using data from two international registries conducted three years apart. METHODS AND RESULTS: The Acute Heart Failure Global Registry of Standard Treatment (ALARM-HF) and the European Society of Cardiology-Heart Failure (ESC-HF) pilot survey were conducted during 2006-2007 and 2009-2010, respectively. A total of 432 AHF patients were recruited by Greek sites in the two registries (255 in ALARM-HF and 177 in ESC-HF pilot survey). About 60% of patients in both registries presented with acutely decompensated chronic HF and 40% with de novo AHF. The use of life-prolonging, guideline-recommended medications increased over time (pre-admission use of angiotensin-converting enzyme (ACE) inhibitors/ angiotensin receptor blockers (ARBs) from 47% to 60%, beta-blockers from 31% to 65%, aldosterone antagonists from 18% to 45%). Those therapies also increased during hospitalisation in both registries. Patients were treated by cardiologists in >90% of cases during hospitalisation; the main intravenous therapies in both registries were diuretics (94% and 97%), followed by vasodilators (47% and 22%) and inotropes (31% and 20%). The length of hospitalisation remained similar (6-7 days in both registries), while in-hospital mortality dropped from 8.5% in the ALARM-HF to 4.5% in the ESC-HF pilot survey. CONCLUSIONS: A temporal increase in the use of life-prolonging therapies along with an improvement of in-hospital mortality was observed. Clinical profiles, in-hospital management and outcome of AHF patients in Greece were similar to other European countries, despite regional differences in healthcare systems.

Clinical and neurohormonal correlates and prognostic value of serum prolactin levels in patients with chronic heart failure.

AIMS: Hypothalamic axis deregulation is associated with clinical severity and depression in chronic heart failure (CHF). We investigated the relationship of serum prolactin, an indicator of hypothalamic axis function, to neurohomonal/immune activation and depressive symptoms in CHF as well as its prognostic value. METHODS AND RESULTS: Serum prolactin was determined in 180 patients with advanced CHF (aged 65 ± 12 years, mean LVEF 27 ± 7%) along with natriuretic peptides (BNP), inflammatory cytokines, endothelial adhesion molecules, 6 min walk test (6MWT), and the Zung self-rating depression scale (SDS). Patients were followed for all-cause death or hospitalization for cardiovascular reasons for up to 8 months. Prolactin levels were significantly correlated with NYHA class (r = 0.394, P < 0.001), LVEF (r = -0.314, P < 0.001), 6MWT (r = -0.353, P < 0.001), BNP (r = 0.374, P < 0.001), Zung SDS (r = 0.544, P < 0.001), interleukin-6 (IL-6) (r = 0.451, P < 0.001), IL-10 (r = -0.426, P < 0.001), tumour necrosis factor (TNF)-α (r = 0.310, P = 0.001), soluble Fas (r = 0.333, P < 0.001), soluble Fas-ligand (r = 0.517, P < 0.001), soluble intercellular adhesion molecule-1 (ICAM-1) (r = 0.409, P < 0.001), and soluble vascular cell adhesion molecule-1 (VCAM-1) (r = 0.480, P < 0.001). During follow-up, 119 patients (66%) died or were hospitalized for cardiovascular events after a median time of 72 days (range 5-220 days); these patients had higher baseline prolactin levels (10.2 ± 5.7 vs. 6.7 ± 4.3 ng/mL, P < 0.001), and a prolactin value ≥4.5 ng/mL was associated with a higher rate of death or hospitalization (116 ± 7 vs. 181 ± 11 days, P = 0.0001). In multivariate analysis, prolactin levels remained an independent predictor of death or hospitalization (<4.5 vs. ≥4.5 ng/mL; odds ratio, 0.368; 95% confidence interval 0.148-0.913; P = 0.031), along with BNP (P < 0.001) and 6MWT (P = 0.020). CONCLUSIONS: Serum prolactin is associated with neurohormonal/immune activation and depressive symptoms and is an independent predictor of prognosis in advanced CHF.

Acute heart failure in patients with diabetes mellitus: clinical characteristics and predictors of in-hospital mortality.

OBJECTIVE/METHODS: ALARM-HF was an in-hospital observational survey that included 4953 patients admitted for acute heart failure (AHF) in six European countries, Mexico and Australia. This article is a secondary analysis of the survey which evaluates differences in clinical phenotype, treatment regimens and in-hospital outcomes in AHF patients with diabetes mellitus (DM) compared to non-diabetics. The data were collected retrospectively by the investigators, and the diagnosis of AHF (reported at discharge) was based on the definition and classification of ESC guidelines, while the diagnosis of DM was based on medical record (past medical and medication history). RESULTS: This sub-analysis demonstrates substantial differences regarding both baseline features and in-hospital outcome among diabetic and non-diabetic AHF patients. Diabetic patients (n=2229, 45%) presented more frequently with acute pulmonary edema (p<0.001) than non-diabetics, had more often acute coronary syndrome (p<0.001) as precipitating factors of AHF, and multiple comorbidities such as renal dysfunction (p<0.001), arterial hypertension (p<0.001), anemia (p<0.001) and peripheral vascular disease (p<0.001). All-cause in-hospital mortality of diabetics was higher compared to non-diabetics (11.7% vs 9.8%, p=0.01). The multivariate analysis revealed that older age (p=0.032), systolic blood pressure <100mm Hg (p<0.001), acute coronary syndrome and non compliance as precipitating factors (p=0.05 and p=0.005, respectively), history of arterial hypertension (p=0.022), LVEF<50% (p<0.001), serum creatinine >1.5mg/dl (p=0.029), absence of life saving therapies such as ACE inhibitors/ARBs (p<0.001) and beta-blockers (p=0.014) at admission, as well as absence of interventional treatment by PCI (p<0.001), were independently associated with adverse in-hospital outcome. CONCLUSION: Diabetics with AHF have higher in-hospital mortality than non-diabetics despite their intensive treatment regimens (regarding care for HF and ACS), possibly due to underlying ischemic heart disease and the presence of multiple comorbidities.

Plasma B-type natriuretic peptide reduction predicts long-term response to levosimendan therapy in acutely decompensated chronic heart failure.

OBJECTIVE: We sought to identify predictors of long-term response to levosimendan therapy among patients' baseline features and treatment-induced changes in acutely decompensated chronic heart failure (ADHF). METHODS: Ninety-eight consecutive patients [aged 64+/-10 years, New York Heart Association (NYHA) classes III-IV, left ventricular ejection fraction <35%], 69 treated with levosimendan and 29 with standard therapy, underwent a clinical, echocardiographic and biochemical assessment before and after treatment. All patients were subsequently followed for 6 months for death or rehospitalization for ADHF. RESULTS: Compared to standard therapy, levosimendan induced a significant improvement in NYHA class (F=37.529, p<0.001), B-type natriuretic peptide (BNP, F=22.917, p<0.001), left ventricular ejection fraction (F=23.561, p<0.001), transmitral E deceleration time (DT, F=6.499, p=0.013) and E/e ratio (F=10.812, p=0.003). During follow-up, 88 of 98 patients (90%) experienced an event. Event-free survival (days alive and out of hospital) at 6 months was similar in two groups (median, 48 days, log-rank test p=0.6760). In the levosimendan group, treatment-induced percent BNP change was the best predictor of events (OR=0.970, 95% CI=0.954-0.986, p<0.001). A cut-off for BNP change of 58% predicted events with 87% sensitivity and 83% specificity. Event-free survival was longer in patients with a BNP reduction > or =58% (median, 135 versus 43 days, p=0.0001). CONCLUSION: Treatment-induced BNP reduction is an independent predictor of 6-month outcome following levosimendan therapy in ADHF.

Plasma B-type natriuretic peptide and anti-inflammatory cytokine interleukin-10 levels predict adverse clinical outcome in chronic heart failure patients with depressive symptoms: a 1-year follow-up study.

AIMS: To assess the prognostic value of a wide spectrum of neurohormonal and inflammatory markers along with functional status and exercise capacity, in hospitalized chronic heart failure (CHF) patients with depressive symptoms. METHODS AND RESULTS: A total of 300 consecutive hospitalized CHF patients were screened for depressive symptomatology using the Zung self-rated depression scale (SDS). Patients with depressive symptoms (Zung SDS > or = 40) underwent a 6 min walking test, and evaluation of left ventricular ejection fraction, B-type natriuretic peptide (BNP), and plasma inflammatory/anti-inflammatory factors [interleukin (IL)-6, IL-10, tumour necrosis factor-alpha, soluble intercellular adhesion molecule-1, and vascular cell adhesion molecule-1]. Patients were subsequently followed for up to 1 year for major adverse cardiovascular events (MACE, death or hospitalization due to cardiovascular causes). One hundred and fourteen patients (38%) had a Zung SDS > or = 40. One-year event-free survival of these patients was 19% (mean +/- SE, 150 +/- 12 days). In multivariate analysis, only BNP (HR = 1.001, P = 0.002) and IL-10 (HR = 0.864, P = 0.049) were independent predictors of MACE. Using receiver operator characteristics analysis-derived cut-offs, a BNP value of 290 pg/mL predicted MACE with 86% sensitivity and 69% specificity, whereas an IL-10 value of 5 pg/mL predicted MACE with 61% sensitivity and 78% specificity. Event-free survival differed significantly between patients with BNP < 290 pg/mL and IL-10 > 5 pg/mL (261 +/- 44 days) and those with BNP > 290 pg/mL and IL-10 < 5 pg/mL (79 +/- 11 days, P = 0.0001). CONCLUSION: Neurohormonal activation and defective anti-inflammatory properties are independent predictors of long-term outcome in hospitalized CHF patients with depressive symptoms.

Self-assessment of health status is associated with inflammatory activation and predicts long-term outcomes in chronic heart failure.

AIMS: Clinicians lack a generally accepted means for health status assessment in chronic heart failure (CHF). We investigated the correlation between health status and inflammation burden as well as its long-term prognostic value in CHF outpatients. METHODS AND RESULTS: Kansas City Cardiomyopathy Questionnaires (KCCQ) were completed by 137 CHF outpatients (aged 64+/-12 years, mean ejection fraction 27+/-7%). Inflammatory markers [interleukin (IL)-6, IL-10, TNF-alpha, soluble Fas, Fas ligand, ICAM-1, VCAM-1], plasma B-type natriuretic peptide (BNP), 6 min walk test (6MWT), Zung self-rating depression scale, and Beck Depression Inventory were also assessed. Patients were followed for major cardiovascular events (death or hospitalization for disease progression) for up to 250 days. Patients with worse KCCQ-summary (KCCQ-s<50) score had lower 6MWT (P<0.05), and higher BNP (P<0.05) and pro-inflammatory markers (P<0.05) than those with KCCQ-s>or=50. Worse health status was also associated with shorter event-free survival (115+/-12 days for KCCQ-s<50 vs. 214+/-15 days for KCCQ-s>or=50, P=0.0179). Separating patients according KCCQ-functional score (KCCQ-f, cut-off 50) showed similar results. In multivariate Cox regression analysis, only LVEF (HR=0.637, 95% CI 0.450-0.900, P=0.011) and KCCQ-f (HR=0.035, 95% CI 0.002-0.824, P=0.037) were independent predictors of event-free survival at 250 days. CONCLUSION: KCCQ-s reflects neurohormonal and inflammatory burden in CHF. Among studied questionnaires, only KCCQ-f is an independent predictor of long-term event-free survival in CHF.

Clinical and prognostic value of Duke's Activity Status Index along with plasma B-type natriuretic peptide levels in chronic heart failure secondary to ischemic or idiopathic dilated cardiomyopathy.

The Duke Activity Status Index (DASI) provides an accurate estimate of functional capacity in patients with chronic heart failure (HF). The aim of this study was to evaluate the prognostic value of the DASI against well-established prognostic factors in 130 consecutive patients hospitalized for worsening HF symptoms (mean age 64 +/- 12 years, mean left ventricular ejection fraction 26 +/- 7%), followed for 9 months for major cardiovascular events, defined as death or hospitalization for HF decompensation. During follow-up, 77 of 130 patients (59%) experienced major cardiovascular events after a median time of 60 days (range 5 to 220). Patients with eventful courses were in higher New York Heart Association functional classes (p = 0.001) and had shorter 6-minute walking distances (p = 0.041), lower ejection fractions (p <0.001), higher plasma B-type natriuretic peptide (BNP) levels at hospital admission and discharge (both p <0.001), and lower DASI scores (16 +/- 12 vs 25 +/- 17, p = 0.003). In multivariate Cox regression analysis including all these variables, only BNP level at discharge (p = 0.006) and DASI score (p = 0.047) were independently associated with event-free survival. A BNP cutoff of 697 pg/ml predicted future events with 59% sensitivity and 86% specificity, while a DASI score cutoff of 8 had 76% sensitivity and 25% specificity. The combination of the 2 cutoffs predicted events with 33% sensitivity and 95% specificity. Event-free survival was significantly lower in patients with the 2 markers positive (BNP >697 pg/ml and DASI score <8) compared with those with with 2 markers negative (63 +/- 27 vs 183 +/- 15 days, log-rank p <0.0001). In conclusion, functional status assessment by the DASI bears prognostic value, and its combination with plasma BNP may provide quite specific risk stratification in patients with chronic HF.

Usefulness of dobutamine-induced changes of the two-dimensional longitudinal deformation predict clinical and neurohumoral improvement in men after levosimendan treatment in acutely decompensated chronic heart failure.

Levosimendan reduces symptoms and improves hemodynamics in patients with acutely decompensated chronic heart failure (ADCHF). The aim of this study was to investigate (1) the association of changes induced by low-dose dobutamine stress echocardiography in 2-dimensional strain parameters with the corresponding changes in the left ventricular (LV) ejection fraction (EF) and LV outflow tract velocity time integral (VTI) in patients with ADCHF and (2) whether LV contractile reserve assessed by conventional and speckle-tracking echocardiography is associated with clinical and neurohumoral improvement after levosimendan treatment. Twenty-eight consecutive patients with ADCHF (mean age 65 +/- 10 years, mean New York Heart Association class 3.6 +/- 0.3, mean EF 22 +/- 6%) were studied using dobutamine stress echocardiography before 24-hour infusion of levosimendan. The LV EF, VTI, and mean longitudinal, circumferential, and radial strain and strain rate using speckle-tracking imaging were measured. Twenty-one patients (75%) had evidence of contractile reserve (LV EF increase >10% and VTI increase >20% after peak dobutamine dose). Patients with versus without contractile reserve demonstrated greater improvements in New York Heart Association class (mean change -1.0 +/- 0.5 vs -0.5 +/- 0.3, p = 0.01) and reductions in B-type natriuretic peptide levels (-34 +/- 30% vs +4 +/- 31%, p <0.01) 48 hours after treatment. On multivariate analysis, mean longitudinal systolic strain rate reserve (peak longitudinal strain rate minus longitudinal strain rate at rest) was the best predictor of improvement in New York Heart Association class (p = 0.039) and B-type natriuretic peptide level (p = 0.042) after levosimendan among the reserve of LV fractional shortening, the EF, VTI, and longitudinal, circumferential, and radial strain and strain rate. In conclusion, dobutamine-induced changes in longitudinal systolic strain rate are associated with clinical and neurohumoral improvement after levosimendan treatment in patients with ADCHF.

Novel biologic mechanisms of levosimendan and its effect on the failing heart.

BACKGROUND: Calcium sensitizers belong to a new class of cardiac enhancers that stimulate cardiac contractility without causing intracellular calcium overload or increasing myocardial oxygen demand. Levosimendan, the most well-studied calcium sensitizer in the real clinical practice, produces greater hemodynamic and symptomatic improvement in patients with acute heart failure than traditional inotropes. OBJECTIVE: To review the recent experimental and clinical evidence on novel biologic mechanisms explaining the pleiotropic effects of levosimendan on the failing heart. METHODS: A systematic search of peer-reviewed publications was performed on Medline and EMBASE from January 1995 to December 2007. The results of unpublished trials were obtained from presentations at national and international meetings. RESULTS: Levosimendan has a unique dual mechanism of action by enhancing cardiac contractility and causing peripheral vasodilatation. Immunomodulatory and antiapoptotic properties of levosimendan may be an additional biologic mechanism that prevents further cytotoxic and hemodynamic consequences of abnormal immune and neurohormonal responses in acute heart failure, leads to cardioprotection, and beneficially intervenes in the progression of syndrome. Experimental data show that levosimendan exerts its cardioprotective effects through its antioxidant properties and seems to be a potent inhibitor of H2O2-induced cardiomyocyte apoptotic cell death. Clinical data demonstrate that levosimendan does not increase markers of oxidative and nitrosative stress, in contrast to placebo treatment, in advanced chronic heart failure patients. Levosimendan has also been shown to activate mitoK(ATP) channels which are important mediators of ischemic preconditioning. Pharmacological modulation of K(ATP) channels may prove beneficial in patients at risk of myocardial ischemia, particularly those requiring inotropic support. CONCLUSION: Pleiotropic effects of levosimendan appear to have important clinical and prognostic implications in acute heart failure syndromes and ischemic heart disease.

Effects of levosimendan on flow-mediated vasodilation and soluble adhesion molecules in patients with advanced chronic heart failure.

AIM: Endothelial activation and dysfunction may be an important contributor to chronic heart failure (CHF) progression. We sought to investigate whether the calcium sensitizer levosimendan affects beneficially endothelial function and attenuates the deleterious effects of soluble adhesion molecules in patients with advanced CHF. METHODS: Twenty-six advanced CHF patients (mean New York Heart Association class, 2.6+/-0.3; ischemic/dilated, 18/8; mean left ventricular ejection fraction <35%) hospitalized due to syndrome worsening, were randomized (2:1) to receive either a 24-h levosimendan infusion of 0.1 microg/kg/min (n=17) or placebo (n=9). Endothelial function estimated by endothelial-dependent flow-mediated dilatation of the brachial artery (FMD), as well as plasma soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1), were assessed before and 48 h after therapy. RESULTS: Baseline characteristics and medications were well balanced in the two treatment groups. A significant improvement of FMD (6.4+/-4.4% from 4.8+/-3.0%; p<0.05) with concomitant reduction of plasma concentrations of sICAM-1 (231+/-75 pg/ml from 339+/-157 pg/ml; p<0.05) and sVCAM-1 (1134+/-508 pg/ml from 1386+/-602 pg/ml; p<0.05) were observed only in levosimendan treated patients. CONCLUSION: Levosimendan could be an effective treatment in improving the endothelial function and reducing the detrimental adhesion molecule activation in advanced CHF patients.

Effects of levosimendan on quality of life and emotional stress in advanced heart failure patients.

AIM: Levosimendan improves central hemodynamics and symptoms in acutely decompensated chronic heart failure (CHF) patients. However, its effects on quality of life, emotional stress and functional capacity of patients with advanced CHF have not been properly investigated. METHODS AND RESULTS: Sixty-three advanced CHF patients (NYHA III-IV, LVEF<30%) were randomized (2:1) to receive either a 24-h levosimendan infusion of 0.1 mug/kg/min or placebo. Questionnaires addressing quality of life [Kansas City Cardiomyopathy Questionnaire (KCCQ), functional and overall, Duke's Activity Status Index (DASI)] and emotional stress [Zung self-rating depression scale (SDS), Beck Depression Inventory (BDI)], as well as plasma BNP and 6-min walking distance (6MWT as a marker of exercise capacity) were assessed before treatment and at hospital discharge. A significant improvement in NYHA class (2.1 +/- 0.7 from 3.3 +/- 0.7, p < 0.01), 6 MWT (305 +/- 152 from 215 +/- 142 m, p < 0.01) and plasma BNP (598 +/- 398 from 1,078 +/- 756 pg/ml, p < 0.01) was observed post-treatment only in levosimendan-treated group. KCCQ functional (45 +/- 19 from 35 +/- 17%, p < 0.05) and overall (34 +/- 13 from 28 +/- 11%, p < 0.05), DASI (26 +/- 13 from 22 +/- 12, p < 0.05), Zung SDS (38 +/- 12 from 42 +/- 13, p < 0.01) and BDI (11 +/- 6 from 14 +/- 8, p < 0.05) scores also improved in levosimendan-treated patients, while remained unchanged in the placebo group. The hospital length stay was shorter in levosimendan group compared to placebo (3.2 +/- 1.7 versus 5.8 +/- 2.1 days, p < 0.01). Levosimendan-induced BNP reduction was significantly correlated with concomitant increase in 6MWT (r = 0.643, p < 0.001) as well as with the decrease of BDI (r = 0.30, p < 0.05) and Zung SDS (r = 0.25, p = 0.05). CONCLUSION: Levosimendan seems to have a beneficial effect on quality of life, physical activity and emotional stress in advanced CHF patients, reducing concurrently hospitalization length.