Optimization of Evidence-Based Heart Failure Medications After an Acute Heart Failure Admission: A Secondary Analysis of the STRONG-HF Randomized Clinical Trial.

Importance: The Safety, Tolerability, and Efficacy of Rapid Optimization, Helped by N-Terminal Pro-Brain Natriuretic Peptide Testing of Heart Failure Therapies (STRONG-HF) trial strived for rapid uptitration aiming to reach 100% optimal doses of guideline-directed medical therapy (GDMT) within 2 weeks after discharge from an acute heart failure (AHF) admission. Objective: To assess the association between degree of GDMT doses achieved in high-intensity care and outcomes. Design, Setting, and Participants: This was a post hoc secondary analysis of the STRONG-HF randomized clinical trial, conducted from May 2018 to September 2022. Included in the study were patients with AHF who were not treated with optimal doses of GDMT before and after discharge from an AHF admission. Data were analyzed from January to October 2023. Interventions: The mean percentage of the doses of 3 classes of HF medications (renin-angiotensin system inhibitors, ß-blockers, and mineralocorticoid receptor antagonists) relative to their optimal doses was computed. Patients were classified into 3 dose categories: low (<50%), medium (≥50% to <90%), and high (≥90%). Dose and dose group were included as a time-dependent covariate in Cox regression models, which were used to test whether outcomes differed by dose. Main Outcome Measures: Post hoc secondary analyses of postdischarge 180-day HF readmission or death and 90-day change in quality of life. Results: A total of 515 patients (mean [SD] age, 62.7 [13.4] years; 311 male [60.4%]) assigned high-intensity care were included in this analysis. At 2 weeks, 39 patients (7.6%) achieved low doses, 254 patients (49.3%) achieved medium doses, and 222 patients (43.1%) achieved high doses. Patients with lower blood pressure and more congestion were less likely to be uptitrated to optimal GDMT doses at week 2. As a continuous time-dependent covariate, an increase of 10% in the average percentage optimal dose was associated with a reduction in 180-day HF readmission or all-cause death (primary end point: adjusted hazard ratio [aHR], 0.89; 95% CI, 0.81-0.98; P = .01) and a decrease in 180-day all-cause mortality (aHR, 0.84; 95% CI, 0.73-0.95; P = .007). Quality of life at 90 days, measured by the EQ-5D visual analog scale, improved more in patients treated with higher doses of GDMT (mean difference, 0.10; 95% CI, -4.88 to 5.07 and 3.13; 95% CI, -1.98 to 8.24 points in the medium- and high-dose groups relative to the low-dose group, respectively; P = .07). Adverse events to day 90 occurred less frequently in participants with HIC who were prescribed higher GDMT doses at week 2. Conclusions and Relevance: Results of this post hoc analysis of the STRONG-HF randomized clinical trial show that, among patients randomly assigned to high-intensity care, achieving higher doses of HF GDMT 2 weeks after discharge was feasible and safe in most patients. Trial Registration: ClinicalTrials.gov Identifier: NCT03412201.

Patiromer for the management of hyperkalemia in heart failure with reduced ejection fraction: the DIAMOND trial.

AIMS: To investigate the impact of patiromer on the serum potassium level and its ability to enable specified target doses of renin-angiotensin-aldosterone system inhibitor (RAASi) use in patients with heart failure and reduced ejection fraction (HFrEF). METHODS AND RESULTS: A total of 1642 patients with HFrEF and current or a history of RAASi-related hyperkalemia were screened and 1195 were enrolled in the run-in phase with patiromer and optimization of the RAASi therapy [≥50% recommended dose of angiotensin-converting enzyme inhibitor/angiotensin receptor blocker/angiotensin receptor-neprilysin inhibitor, and 50 mg of mineralocorticoid receptor antagonist (MRA) spironolactone or eplerenone]. Specified target doses of the RAASi therapy were achieved in 878 (84.6%) patients; 439 were randomized to patiromer and 439 to placebo. All patients, physicians, and outcome assessors were blinded to treatment assignment. The primary endpoint was between-group difference in the adjusted mean change in serum potassium. Five hierarchical secondary endpoints were assessed. At the end of treatment, the median (interquartile range) duration of follow-up was 27 (13-43) weeks, the adjusted mean change in potassium was +0.03 mmol/l in the patiromer group and +0.13 mmol/l in the placebo group [difference in the adjusted mean change between patiromer and placebo: -0.10 mmol/l (95% confidence interval, CI -0.13, 0.07); P < 0.001]. Risk of hyperkalemia >5.5 mmol/l [hazard ratio (HR) 0.63; 95% CI 0.45, 0.87; P = 0.006), reduction of MRA dose (HR 0.62; 95% CI 0.45, 0.87; P = 0.006), and total adjusted hyperkalemia events/100 person-years (77.7 vs. 118.2; HR 0.66; 95% CI 0.53, 0.81; P < 0.001) were lower with patiromer. Hyperkalemia-related morbidity-adjusted events (win ratio 1.53, P < 0.001) and total RAASi use score (win ratio 1.25, P = 0.048) favored the patiromer arm. Adverse events were similar between groups. CONCLUSION: Concurrent use of patiromer and high-dose MRAs reduces the risk of recurrent hyperkalemia (ClinicalTrials.gov: NCT03888066).

Cardiovascular and kidney outcomes with finerenone in patients with type 2 diabetes and chronic kidney disease: the FIDELITY pooled analysis.

AIMS: The complementary studies FIDELIO-DKD and FIGARO-DKD in patients with type 2 diabetes and chronic kidney disease (CKD) examined cardiovascular and kidney outcomes in different, overlapping stages of CKD. The purpose of the FIDELITY analysis was to perform an individual patient-level prespecified pooled efficacy and safety analysis across a broad spectrum of CKD to provide more robust estimates of safety and efficacy of finerenone compared with placebo. METHODS AND RESULTS: For this prespecified analysis, two phase III, multicentre, double-blind trials involving patients with CKD and type 2 diabetes, randomized 1:1 to finerenone or placebo, were combined. Main time-to-event efficacy outcomes were a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for heart failure, and a composite of kidney failure, a sustained ≥57% decrease in estimated glomerular filtration rate from baseline over ≥4 weeks, or renal death. Among 13 026 patients with a median follow-up of 3.0 years (interquartile range 2.3-3.8 years), the composite cardiovascular outcome occurred in 825 (12.7%) patients receiving finerenone and 939 (14.4%) receiving placebo [hazard ratio (HR), 0.86; 95% confidence interval (CI), 0.78-0.95; P = 0.0018]. The composite kidney outcome occurred in 360 (5.5%) patients receiving finerenone and 465 (7.1%) receiving placebo (HR, 0.77; 95% CI, 0.67-0.88; P = 0.0002). Overall safety outcomes were generally similar between treatment arms. Hyperkalaemia leading to permanent treatment discontinuation occurred more frequently in patients receiving finerenone (1.7%) than placebo (0.6%). CONCLUSION: Finerenone reduced the risk of clinically important cardiovascular and kidney outcomes vs. placebo across the spectrum of CKD in patients with type 2 diabetes. KEY QUESTION: Does finerenone, a novel selective, nonsteroidal mineralocorticoid receptor antagonist, added to maximum tolerated renin-angiotensin system inhibition reduce cardiovascular disease and kidney disease progression over a broad range of chronic kidney disease in patients with type 2 diabetes? KEY FINDING: In a prespecified, pooled individual-level analysis from two randomized trials, we found reductions both in cardiovascular events and kidney failure outcomes with finerenone. Because 40% of the patients had an estimated glomerular filtration rate of >60 mL/min/1.73m2 they were identified solely on the basis of albuminuria. TAKE HOME MESSAGE: Finerenone reduces the risk of clinical cardiovascular outcomes and kidney disease progression in a broad range of patients with chronic kidney disease and type 2 diabetes. Screening for albuminuria to identify at-risk patients among patients with type 2 diabetes facilitates reduction of both cardiovascular and kidney disease burden.

A Clinical Tool to Predict Low Serum Selenium in Patients with Worsening Heart Failure.

Selenium is an essential micronutrient, and a low selenium concentration (<100 µg/L) is associated with a poorer quality of life and exercise capacity, and an impaired prognosis in patients with worsening heart failure. Measuring selenium concentrations routinely is laborious and costly, and although its clinical utility is yet to be proven, an easy implemented model to predict selenium status is desirable. A stepwise multivariable logistic regression analysis was performed using routinely measured clinical factors. Low selenium was independently predicted by: older age, lower serum albumin, higher N-terminal pro-B-type natriuretic peptide levels, worse kidney function, and the presence of orthopnea and iron deficiency. A 10-points risk-model was developed, and a score of ≥6 points identified >80% of patients with low selenium (sensitivity of 44%, specificity of 80%). Given that selenium and iron overlap in their physiological roles, we evaluated the shared determinants and prognostic associates. Both deficiencies shared similar clinical characteristics, including the model risk factors and, in addition, a low protein intake and high levels of C-reactive protein. Low selenium was associated with a similar or worse prognosis compared to iron deficiency. In conclusion, although it is difficult to exclude low selenium based on clinical characteristics alone, we provide a prediction tool which identifies heart failure patients at higher risk of having a low selenium status.

Rationale and design of the AFFIRM-AHF trial: a randomised, double-blind, placebo-controlled trial comparing the effect of intravenous ferric carboxymaltose on hospitalisations and mortality in iron-deficient patients admitted for acute heart failure.

AIMS: Iron deficiency (ID) is a common co-morbidity in heart failure (HF), associated with impaired functional capacity, poor quality of life and increased morbidity and mortality. Treatment with intravenous (i.v.) ferric carboxymaltose (FCM) has shown improvements in functional capacity, symptoms and quality of life in stable HF patients with reduced ejection fraction. The effect of i.v. iron supplementation on morbidity and mortality in patients hospitalised for acute HF (AHF) and who have ID has yet to be established. The objective of the present article is to present the rationale and design of the AFFIRM-AHF trial (ClinicalTrials.gov NCT02937454) which will investigate the effect of i.v. FCM (vs. placebo) on recurrent HF hospitalisations and cardiovascular (CV) mortality in iron-deficient patients hospitalised for AHF. METHODS: AFFIRM-AHF is a multicentre, randomised (1:1), double-blind, placebo-controlled trial which recruited 1100 patients hospitalised for AHF and who had iron deficiency ID defined as serum ferritin <100 ng/mL or 100-299 ng/mL if transferrin saturation <20%. Eligible patients were randomised (1:1) to either i.v. FCM or placebo and received the first dose of study treatment just prior to discharge for the index hospitalisation. Patients will be followed for 52 weeks. The primary outcome is the composite of recurrent HF hospitalisations and CV mortality. The main secondary outcomes include the composite of recurrent CV hospitalisations and CV mortality, recurrent HF hospitalisations and safety-related outcomes. CONCLUSION: The AFFIRM-AHF trial will evaluate, compared to placebo, the effect of i.v. FCM on morbidity and mortality in iron-deficient patients hospitalised for AHF.

Efficacy and Safety of Novel Oral Anticoagulants in Patients With Atrial Fibrillation and Heart Failure: A Meta-Analysis.

OBJECTIVES: This study investigated the efficacy and safety of novel oral anticoagulants (NOACs) in patients with atrial fibrillation (AF) and heart failure (HF) by a meta-analysis. BACKGROUND: AF is quite prevalent in patients with HF. METHODS: Four phase III clinical trials comparing NOACs to warfarin in patients with AF were included. Each patient was defined as affected by HF according to the criteria of the trial in which the patient was enrolled. Pre-specified outcomes were the composite of stroke/systemic embolism (SSE); major, intracranial, and any bleeding; and cardiovascular (CV) and all-cause death. RESULTS: A total of 55,011 patients were enrolled, 26,384 (48%) with HF, and 28,627 (52%) without HF; 27,518 receiving NOACs and 27,493 receiving warfarin (median, 70 years of age; 36% females; follow-up: 1.5 to 2.8 years). Rates of SSE (relative risk [RR]: 0.98; 95% confidence interval [CI]: 0.90 to 1.07]; p = 0.68) and major bleeding (RR: 0.95; 95% CI: 0.88 to 1.03; p = 0.21) were comparable in patients with and without HF. HF patients had reduced rates of any (RR: 0.86; 95% CI: 0.81 to 0.91; p < 0.01) and intracranial (RR: 0.74 95% CI: 0.63 to 0.88; p < 0.01) bleeding but increased rates of all-cause (RR: 1.70 95% CI: 1.31 to 2.19; p < 0.01) and CV death (RR: 2.05 95% CI: 1.66 to 2.55; p < 0.01). NOACs, compared with warfarin significantly reduced SSE and major, intracranial, and any bleeding, regardless of the presence or absence of HF (pinteraction > 0.05 for each). CONCLUSIONS: Patients with AF and HF had increased mortality but reduced rates of intracranial and any bleeding compared with the no-HF patients, with no differences in rates of SSE and major bleeding. NOACs significantly reduced SSE, major bleeding, and intracranial hemorrhage in HF patients. No interactions in efficacy and safety of NOACs were observed between AF patients with and without HF.

A systems BIOlogy Study to TAilored Treatment in Chronic Heart Failure: rationale, design, and baseline characteristics of BIOSTAT-CHF.

AIMS: Despite major improvements in pharmacological and device treatments, heart failure remains a syndrome with high morbidity and mortality, poor quality of life, and high health-care costs. Given the extensive heterogeneity among patients with heart failure, substantial differences in the response to therapy can be expected. We hypothesize that individualized therapy is an essential next step to improve outcomes in patients with heart failure. METHODS: The BIOlogy Study to TAilored Treatment in Chronic Heart Failure (BIOSTAT-CHF) included 2516 patients with worsening signs and/or symptoms of heart failure from 11 European countries, who were considered to be on suboptimal medical treatment. Another 1738 patients from Scotland were included in a validation cohort. Overall, both patient cohorts were well matched. The majority of patients were hospitalized for acute heart failure, and the remainder presented with worsening signs and/or symptoms of heart failure at outpatient clinics. Approximately half of the patients were in New York Heart Association class III, and 7% vs 34% of patients of the index vs validation cohort had heart failure with preserved ejection fraction. According to study design, all patients used diuretics, but owing to the inclusion criteria of both cohorts, patients were not on optimal, evidence-based medical therapy. In the follow-up phase, uptitration to guideline-recommended doses was encouraged. CONCLUSION: By using a novel systems biology approach, incorporating demographics, biomarkers, genome-wide analysis, and proteomics, a model that predicts response to therapy will be developed, which should be instrumental in developing alternative therapies for patients with suboptimal response to currently recommended therapies and thus further improve care for patients with heart failure.

Efficacy and safety of functional electrical stimulation of lower limb muscles in elderly patients with chronic heart failure: A pilot study.

BACKGROUND: Exercise training is an established modality in chronic heart failure. Functional electrical stimulation (FES) is an effective alternative mode of training in patients unwilling or unable to exercise; however, it has not been investigated in elderly patients. We sought to investigate the effects of FES on functional status, quality of life, emotional status and endothelial function in chronic heart failure patients aged 70 years or higher. METHODS: Thirty patients with stable systolic chronic heart failure (mean age 75 ± 3 years, New York Heart Association (NYHA) class II/III, 37%/63%) randomly underwent a six-week FES training programme or placebo. Questionnaires addressing quality of life (Kansas City Cardiomyopathy Questionnaire (KCCQ), functional and overall) and emotional stress (Zung self-rating depression scale (SDS), Beck Depression Inventory (BDI)), as well as endothelial function (flow-mediated dilatation) were assessed at baseline and upon protocol completion. RESULTS: A significant improvement in NYHA class (p=0.005), KCCQ-functional (F=68.6, p for interaction<0.001), KCCQ-overall (F=66.9, p<0.001), BDI (F=66.3, p<0.001) and Zung SDS (F=95.1, p<0.001) was observed in the FES group compared to placebo. Patients in the FES group also had a significant increase in flow-mediated dilatation compared with placebo (F=59.1, p<0.01). FES-induced per cent change in flow-mediated dilatation was significantly correlated with respective per cent change in KCCQ functional (r=0.386, p=0.039). CONCLUSION: In this pilot study, FES effectively improved functional status, quality of life, motional stress and endothelial function in elderly chronic heart failure patients and warrants further investigation in this particular group of patients.

Functional electrical stimulation of peripheral muscles improves endothelial function and clinical and emotional status in heart failure patients with preserved left ventricular ejection fraction.

BACKGROUND: Functional electrical stimulation (FES) improves exercise capacity, quality of life, emotional stress, and endothelial function in chronic heart failure with impaired systolic function. We sought to investigate the effects of FES on the above parameters in patients with preserved ejection fraction (HFpEF). METHODS: Thirty HFpEF patients, 18 female and 12 male, aged 69 ± 8 years, in New York Heart Association class II or III and with mean ejection fraction 63% ± 6%, were randomly (1:1) assigned to a 6-week FES program or placebo. Assessment was performed at baseline and after completion of training protocol and included 6-minute walked distance, quality of life (Kansas City Cardiomyopathy Questionnaire and Minnesota Living with Heart Failure Questionnaire), depressive symptoms (Beck Depression Inventory and Zung self-rated depression scores), B-type natriuretic peptide, endothelial function (flow-mediated dilatation), and left ventricular diastolic function. RESULTS: A significant improvement in 6-minute walked distance (F = 21.61, P = .001), Kansas City Cardiomyopathy Questionnaire summary (F = 8.68, P = .006), Minnesota Living with Heart Failure Questionnaire (F = 6.43, P = .017), Beck Depression Inventory (F = 6.66, P = .015), Zung (F = 6.25, P = .019), and flow-mediated dilatation diameter (F = 11.98, P = .002) was observed in the FES group compared with placebo group; B-type natriuretic peptide also declined but not significantly (F = 0.249, P = .622), and there was a tendency toward lower mitral E/e' wave ratio (F = 3.066, P = .091). CONCLUSION: As in heart failure and reduced left ventricular ejection fraction, FES also improves exercise capacity, quality of life, emotional status, and endothelial function in HFpEF. Given the lack of effective evidence-based therapies in these patients, FES warrants further investigation.

Rationale and design of ARTS: a randomized, double-blind study of BAY 94-8862 in patients with chronic heart failure and mild or moderate chronic kidney disease.

AIMS: BAY 94-8862 is a novel, non-steroidal, mineralocorticoid receptor antagonist with greater selectivity than spironolactone and stronger mineralocorticoid receptor binding affinity than eplerenone. The aims of the MinerAlocorticoid Receptor Antagonist Tolerability Study (ARTS; NCT01345656) are to evaluate the safety and tolerability of BAY 94-8862 in patients with heart failure associated with a reduced left ventricular ejection fraction (HFREF) and chronic kidney disease (CKD), and to examine the effects on biomarkers of cardiac and renal function. Methods ARTS is a multicentre, randomized, double-blind, placebo-controlled, parallel-group study divided into two parts. In part A, oral BAY 94-8862 [2.5, 5, or 10 mg once daily (o.d.)] is compared with placebo in ∼60 patients with HFREF and mild CKD. Outcome measures include serum potassium concentration, biomarkers of renal injury, estimated glomerular filtration rate (eGFR), and albuminuria. Part B compares BAY 94-8862 (2.5, 5, or 10 mg o.d., or 5 mg twice daily), placebo, and open-label spironolactone (25-50 mg o.d.) in ∼360 patients with HFREF and moderate CKD. Outcome measures include the change in serum potassium concentration with BAY 94-8862 vs. placebo (primary endpoint) and vs. spironolactone, safety and tolerability, biomarkers of cardiac and renal function or injury, eGFR, and albuminuria. BAY 94-8862 pharmacokinetics are also assessed. Perspectives ARTS is the first phase II clinical trial of BAY 94-8862 and is expected to provide a wealth of information on BAY 94-8862 in patients with HFREF and CKD, including the optimal dose range for further studies.

Beyond the cardiorenal anaemia syndrome: recognizing the role of iron deficiency.

Growing awareness that heart failure, renal impairment, and anaemia are frequent co-morbidities which can exacerbate one another in a vicious circle of clinical deterioration has led to the concept of the cardiorenal anaemia syndrome (CRAS). The role of iron deficiency within this complex interplay has been less well examined. Scrutiny of data from the recent FAIR-HF trial raises a new hypothesis: is it time for 'CRAS' to be supplemented with new acronyms such as CRIDS (cardiorenal-iron deficiency syndrome) or even CRAIDS (cardiorenal-anaemia-iron deficiency syndrome)? Iron deficiency occurs frequently in heart failure patients with or without anaemia. It not only impairs oxygen transport through reduced erythropoiesis, but adversely affects oxidative metabolism, cellular energetics, and immune mechanisms, and the synthesis and degradation of complex molecules such as DNA. One large observational study in patients with heart failure found iron deficiency to be an independent predictor of death or urgent heart transplantation (hazard ratio 1.58, 95% confidence interval 1.14-2.17, P = 0.005). In the FAIR-HF trial, i.v. iron therapy was associated with significant improvements in physical functioning in iron-deficient patients with heart failure, even in non-anaemic patients in whom haemoglobin levels did not change following i.v. iron administration. Key questions regarding the use of i.v. iron supplementation in the setting of heart failure merit exploration and could readily be answered by appropriately designed clinical trials. It is to be hoped that these important clinical trials are conducted, to permit a more subtle characterization of the patient's pathological condition and interventional requirements.

Iron deficiency predicts impaired exercise capacity in patients with systolic chronic heart failure.

BACKGROUND: Iron is an indispensable element of hemoglobin, myoglobin, and cytochromes, and, beyond erythropoiesis, is involved in oxidative metabolism and cellular energetics. Hence, iron deficiency (ID) is anticipated to limit exercise capacity. We investigated whether ID predicted exercise intolerance in patients with systolic chronic heart failure (CHF). METHODS AND RESULTS: We prospectively studied 443 patients with stable systolic CHF (age 54 ± 10 years, males 90%, ejection fraction 26 ± 7%, New York Heart Association Class I/II/III/IV 49/188/180/26). ID was defined as: serum ferritin <100 µg/L or serum ferritin 100-300 µg/L with serum transferrin saturation <20%. Exercise capacity was expressed as peak oxygen consumption (VO(2)) and ventilatory response to exercise (VE-VCO(2) slope). ID was present in 35 ± 4% (±95% confidence interval) of patients with systolic CHF. Those with ID had reduced peak VO(2) and increased VE-VCO(2) slope as compared to subjects without ID (peak VO(2): 13.3 ± 4.0 versus 15.3 ± 4.5 mL•min•kg, VE-VCO(2) slope: 50.9 ± 15.8 versus 43.1 ± 11.1, respectively, both P < .001, P < .05). In multivariable models, the presence of ID was associated with reduced peak VO(2) (ß = -0.14, P < .01 P < .05) and higher VE-VCO(2) slope (ß = 0.14, P < .01 P < .05), adjusted for demographics and clinical variables. Analogous associations were found between serum ferritin, and both peak VO(2) and VE-VCO(2) slope (P < .05). CONCLUSIONS: ID independently predicts exercise intolerance in patients with systolic CHF, but the strength of these associations is relatively weak. Whether iron supplementation would improve exercise capacity in iron-deficient subjects requires further studies.

Iron deficiency: an ominous sign in patients with systolic chronic heart failure.

AIMS: Beyond erythropoiesis, iron is involved in numerous biological processes crucial for maintenance of homeostasis. Patients with chronic heart failure (CHF) are prone to develop iron deficiency (ID), and iron supplementation improves their functional status and quality of life. We sought to examine the relationship between ID and survival in patients with systolic CHF. METHODS AND RESULTS: In a prospective observational study, we evaluated 546 patients with stable systolic CHF [age: 55 +/- 11 (mean +/- standard deviation) years, males: 88%, left ventricular ejection fraction: 26 +/- 7%, New York Heart Association (NYHA) class (I/II/III/IV): 57/221/226/42]. Iron deficiency was defined as: ferritin <100 microg/L, or 100-300 microg/L with transferrin saturation <20%. The prevalence of ID was 37 +/- 4% [+/-95% confidence intervals (CI)] in the entire CHF population (32 +/- 4 vs. 57 +/- 10%-in subjects without vs. with anaemia defined as haemoglobin level <12 g/dL in women and <13 g/dL in men, P < 0.001). In a multiple logistic model, ID was more prevalent in women, those in the advanced NYHA class, with higher plasma N-terminal pro-type B natriuretic peptide and higher serum high-sensitivity C-reactive protein (all P < 0.05). At the end of follow-up (mean duration: 731 +/- 350 days), there were 153 (28%) deaths and 30 (6%) heart transplantations (HTX). In multivariable models, ID (but not anaemia) was related to an increased risk of death or HTX (adjusted hazard ratio 1.58, 95% CI 1.14-2.17, P < 0.01). CONCLUSION: In patients with systolic CHF, ID is common and constitutes a strong, independent predictor of unfavourable outcome. Iron supplementation may be considered as a therapeutic approach in these patients to improve prognosis.

Functional electrical stimulation is more effective in severe symptomatic heart failure patients and improves their adherence to rehabilitation programs.

BACKGROUND: Functional electrical stimulation (FES) improves exercise capacity and quality of life in chronic heart failure (CHF) patients. However, there is no evidence regarding the effectiveness of this treatment modality according to the severity of CHF. This study compares the effectiveness of FES on exercise capacity, endothelial function, neurohormonal status, and emotional stress in New York Heart Association (NYHA) III-IV versus NYHA II patients. METHODS AND RESULTS: Eighteen NYHA II and 13 age- and sex-matched NYHA III-IV patients with stable CHF (left ventricular ejection fraction <35%) underwent a 6-week FES training program. Questionnaires addressing quality of life (Kansas City Cardiomyopathy Questionnaire, functional and overall), and emotional stress (Zung self-rating depression scale, Beck Depression Inventory), as well as plasma B-type natriuretic peptide (BNP), 6-minute walking distance test (6MWT), and endothelial function (flow-mediated dilatation [FMD]) were assessed at baseline and after completion of training protocol. 6MWT and plasma BNP improved significantly in 2 patient groups (both P < .001) after training program. The improvement of BNP was statistically greater in NYHA III-IV patients posttreatment than in those with NYHA II class (F=315.342, P < .001). Similarly, the improvement of 6MWT was statistically greater in NYHA III-IV group than in NYHA II patients (F=79.818, P < .001). Finally, an FES-induced greater improvement of FMD (F=9.517, P=.004) and emotional stress scores was observed in NYHA III-IV patients in comparison to NYHA II patients. There was a higher proportion of NYHA III-IV patients adhering to the FES training program for additional 3 months compared with the NYHA II group of patients (76.9% vs. 55.6%, P < .001). CONCLUSION: FES might exert a greater beneficial effect on clinical and neurohormonal status of NYHA III-IV patients in comparison to NYHA II patients. This effect may have important clinical relevance leading to increased adherence of severe CHF patients to exercise rehabilitation programs.

Rationale and design of Ferinject assessment in patients with IRon deficiency and chronic Heart Failure (FAIR-HF) study: a randomized, placebo-controlled study of intravenous iron supplementation in patients with and without anaemia.

AIMS: Iron deficiency (ID) and anaemia are common in patients with chronic heart failure (CHF). The presence of anaemia is associated with increased morbidity and mortality in CHF, and ID is a major reason for the development of anaemia. Preliminary studies using intravenous (i.v.) iron supplementation alone in patients with CHF and ID have shown improvements in symptom status. FAIR-HF (Clinical Trials.gov NCT00520780) was designed to determine the effect of i.v. iron repletion therapy using ferric carboxymaltose on self-reported patient global assessment (PGA) and New York Heart Association (NYHA) in patients with CHF and ID. METHODS AND RESULTS: This is a multi-centre, randomized, double-blind, placebo-controlled study recruiting ambulatory patients with symptomatic CHF with LVEF < or = 40% (NYHA II) or < or =45% (NYHA III), ID [ferritin <100 ng/mL or ferritin 100-300 ng/mL when transferrin saturation (TSAT) < 20%], and haemoglobin 9.5-13.5 g/dL. Patients were randomized in a 2:1 ratio to receive ferric carboxymaltose (Ferinject((R))) 200 mg iron i.v. or saline i.v. weekly until iron repletion (correction phase), then monthly until Week 24 (maintenance phase). Primary endpoints are (i) self-reported PGA at Week 24 and (ii) NYHA class at Week 24, adjusted for baseline NYHA class. CONCLUSION: This study will provide evidence on the efficacy and safety of iron repletion with ferric carboxymaltose in CHF patients with ID with and without anaemia.

Excessive vagal response during left atrial ablation in a patient with paroxysmal atrial fibrillation.

Vagal reflexes can be induced by stimulation of select epicardial and endocardial areas of the left atrium. The present report describes the case of a 54-year-old woman with a history of recurrent symptomatic episodes of paroxysmal atrial fibrillation. During radiofrequency application around the left superior pulmonary vein, the patient exhibited an excessive vagal response with a sinus pause of 17 s.

Predictors of atrial fibrillation recurrence in patients with long-lasting atrial fibrillation.

BACKGROUND: Limited data are available on the predictors of atrial fibrillation (AF) recurrence in patients with chronic AF. OBJECTIVES: To evaluate potential clinical, echocardiographic and electrophysiological predictors of AF recurrence, after internal cardioversion for long-lasting AF. METHODS: A total of 99 consecutive patients (63 men and 36 women, mean age 63.33+/-9.27 years) with long-standing AF (52.42+/-72.02 months) underwent internal cardioversion with a catheter that consisted of two defibrillating coils. Shocks were delivered according to a step-up protocol. Clinical follow-up and electrocardiographic recordings were performed on a monthly basis for a 12-month period or whenever patients experienced symptoms suggestive of recurrent AF. RESULTS: Ninety-three patients (93.94%) underwent a successful uncomplicated cardioversion, with a mean atrial defibrillation threshold of 10.69+/-6.76 J. Immediate reinitiation of AF was observed in 15 patients (15.78%) of whom a repeated cardioversion restored sinus rhythm in 13 cases. Early recurrence of AF (within one week) was observed in 12 of 93 patients (12.90%). At the end of the 12-month follow-up period, during which seven patients were lost, 42 of the 86 remaining patients (48.84%) were still in sinus rhythm. Multivariate regression analysis showed that left atrial diameter (OR 1.126, 95% CI 1.015 to 1.249; P=0.025) and mitral A wave velocity (OR 0.972, 95% CI 0.945 to 0.999; P=0.044) were significant and independent predictors of AF recurrence, whereas age, left ventricular ejection fraction and AF cycle length were not predictive of arrhythmia recurrence. CONCLUSION: The present study showed that the left atrial diameter and mitral A wave velocity are the only variables associated with AF recurrence after successful cardioversion.