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Background: In AFFIRM-AHF, treatment of iron deficiency with intravenous ferric carboxymaltose (FCM) reduced the risk of heart failure (HF) hospitalization and improved quality of life (QoL) vs placebo in patients stabilized following an acute HF (AHF) episode, with no effect on cardiovascular (CV) death. Diabetes and iron deficiency frequently accompany AHF. This post hoc analysis explored the effects of diabetes on outcomes in AFFIRM-AHF patients. Methods: Patients were stratified by diabetes yes/no at baseline. The effects of FCM vs placebo on primary (total HF hospitalizations and CV death) and secondary (total CV hospitalizations and CV death; CV death; total HF hospitalizations; time to first HF hospitalization or CV death; and days lost due to HF hospitalizations or CV death) endpoints at Week 52 and change vs baseline in disease-specific QoL (12-item Kansas City Cardiomyopathy Questionnaire [KCCQ-12]) at Week 24 were assessed by subgroup. For each endpoint, the interaction between diabetes status and treatment outcome was explored. Results: Of 1108 AFFIRM-AHF patients, 475 (FCM: 231; placebo: 244) had diabetes and 633 (FCM: 327; placebo: 306) did not have diabetes. Patients with diabetes were more commonly male (61.5% vs 50.9%), with a higher frequency of ischemic HF etiology (57.9% vs 39.0%), prior HF history (77.7% vs 66.5%), and comorbidities (including previous myocardial infarction [49.3% vs 32.9%] and chronic kidney disease [51.4% vs 32.4%]) than those without diabetes. The annualized event rate/100 patient-years with FCM vs placebo for the primary endpoint was 66.9 vs 80.9 in patients with diabetes (rate ratio [RR]: 0.83, 95% CI 0.58–1.81) and 51.3 vs 66.9 in patients without diabetes (RR: 0.77, 95% CI 0.55–1.07), with no significant interaction between diabetes status and treatment effect (pinteraction = 0.76). Similar findings were observed for secondary outcomes. Change from baseline in KCCQ-12 overall summary score was numerically greater with FCM vs placebo at almost all time points in both subgroups, with no interaction between diabetes and treatment effect at Week 24. Conclusions: The clinical and QoL benefits observed with intravenous FCM in patients with iron deficiency following stabilization from an AHF episode are independent of diabetes status. Trial registration Clinicaltrials.gov, NCT02937454 (registered 10.18.2016). [ABSTRACT FROM AUTHOR]

This article discusses the importance of accurately defining iron deficiency (ID) in heart failure (HF) patients. ID is clinically linked to poor exercise tolerance, reduced quality of life, and poor long-term outcomes in HF. The current definition of ID in HF is based on serum ferritin levels and transferrin saturation, but there are limitations to this definition. The article presents a study comparing different ID definitions and their prognostic capabilities in HF patients referred for heart transplantation. The study suggests that the current definition may not be ideal and that new definitions should be explored to better identify patients who would benefit from iron supplementation. However, the study has limitations and further research is needed. [Extracted from the article]

Background: Iron deficiency, with or without anemia, is an adverse prognostic factor in heart failure (HF). In AFFIRM-AHF (a randomized, double-blind placebo-controlled trial comparing the effect of intravenous ferric carboxymaltose on hospitalizations and mortality in iron-deficient subjects admitted for acute heart failure), intravenous ferric carboxymaltose (FCM), although having no significant effect on the primary end point, reduced the risk of HF hospitalization (hHF) and improved quality of life versus placebo in iron-deficient patients stabilized after an acute HF (AHF) episode. These prespecified AFFIRM-AHF subanalyses explored the association between hemoglobin levels and FCM treatment effects. Methods: AFFIRM-AHF was a multicenter, double-blind, randomized, placebo-controlled trial of FCM in hospitalized AHF patients with iron deficiency. Patients were stratified by baseline hemoglobin level (<12 versus ≥12 g/dL). In each subgroup, the primary composite (total hHF and cardiovascular death) and secondary (total hHF; total cardiovascular hospitalizations and cardiovascular death; time to cardiovascular death, and time to first/days lost due to hHF or cardiovascular death) outcomes were assessed with FCM versus placebo at week 52. Sensitivity analyses using the World Health Organization anemia definition (hemoglobin level <12 g/dL [women] or <13 g/dL [men]) were performed, among others. Results: Of 1108 AFFIRM-AHF patients, 1107 were included in these subanalyses: 464 (FCM group, 228; placebo group, 236) had a hemoglobin level <12 g/dL, and 643 (FCM, 329; placebo, 314) had a hemoglobin level ≥12 g/dL. Patients with a hemoglobin level <12 g/dL were older (mean, 73.7 versus 69.1 years), with more frequent previous HF (75.0% versus 68.7%), serum ferritin <100 μg/L (75.4% versus 68.1%), and transferrin saturation <20% (87.9% versus 81.4%). For the primary outcome, annualized event rates per 100 patient-years with FCM versus placebo were 71.1 and 73.6 (rate ratio, 0.97 [95% CI, 0.66–1.41]), respectively, and 48.5 versus 72.9 (RR, 0.67 [95% CI, 0.48–0.93]) in the hemoglobin levels <12 and ≥12 g/dL subgroups, respectively. No significant interactions between hemoglobin subgroup and treatment effect were observed for primary (P interaction=0.15) or secondary outcomes. Changes from baseline in hemoglobin, serum ferritin and transferrin saturation were significantly greater with FCM versus placebo in both subgroups between weeks 6 and 52. Findings were similar using the World Health Organization definition for anemia. Conclusions: The effects of intravenous FCM on outcomes in iron-deficient patients stabilized after an AHF episode, including improvements in iron parameters over time, did not differ between patients with hemoglobin levels <12 and ≥12 g/dL. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02937454. [ABSTRACT FROM AUTHOR]

Aim: Improving functional capacity is a key goal in heart failure (HF). This pooled analysis of FAIR‐HF and CONFIRM‐HF assessed the likelihood of improvement or deterioration in 6‐min walk test (6MWT) among iron‐deficient patients with chronic HF with reduced ejection fraction (HFrEF) receiving ferric carboxymaltose (FCM). Methods and results: Data for 760 patients (FCM: n = 454; placebo: n = 306) were analysed. The proportions of patients receiving FCM or placebo who had ≥20, ≥30, and ≥40 m improvements or ≥10 m deterioration in 6MWT at 12 and 24 weeks were assessed. Patients receiving FCM experienced a mean (standard deviation) 31.1 (62.3) m improvement in 6MWT versus 0.1 (77.1) m improvement for placebo at week 12 (difference in mean changes 26.8 [16.6–37.0]). At week 12, the odds [95% confidence interval] of 6MWT improvements of ≥20 m (odds ratio 2.16 [1.57–2.96]; p < 0.0001), ≥30 m (2.00 [1.44–2.78]; p < 0.0001), and ≥40 m (2.29 [1.60–3.27]; p < 0.0001) were greater with FCM versus placebo, while the odds of a deterioration ≥10 m were reduced with FCM versus placebo (0.55 [0.38–0.80]; p = 0.0019). Among patients who experienced 6MWT improvements of ≥20, ≥30, or ≥40 m with FCM at week 12, more than 80% sustained this improvement at week 24. Conclusion: Ferric carboxymaltose resulted in a significantly higher likelihood of improvement and a reduced likelihood of deterioration in 6MWT versus placebo among iron‐deficient patients with HF. Of the patients experiencing clinically significant improvements at week 12, the majority sustained this improvement at week 24. These results are supportive of FCM to improve exercise capacity in HF. [ABSTRACT FROM AUTHOR]

Aims: Iron deficiency is common in patients with heart failure (HF). In AFFIRM‐AHF, ferric carboxymaltose (FCM) reduced the risk of hospitalisations for HF (HHF) and improved quality of life vs. placebo in iron‐deficient patients with a recent episode of acute HF. The objective of this study was to estimate the cost‐effectiveness of FCM compared with placebo in iron‐deficient patients with left ventricular ejection fraction <50%, stabilised after an episode of acute HF, using data from the AFFIRM‐AHF trial from Italian, UK, US and Swiss payer perspectives. Methods and results: A lifetime Markov model was built to characterise outcomes in patients according to the AFFIRM‐AHF trial. Health states were defined using the 12‐item Kansas City Cardiomyopathy Questionnaire (KCCQ‐12). Subsequent HHF were incorporated using a negative binomial regression model with cardiovascular and all‐cause mortality incorporated via parametric survival analysis. Direct healthcare costs (2020 GBP/USD/EUR/CHF) and utility values were sourced from published literature and AFFIRM‐AHF. Modelled outcomes indicated that treatment with FCM was dominant (cost saving with additional health gains) in the UK, USA and Switzerland, and highly cost‐effective in Italy [incremental cost‐effectiveness ratio (ICER) EUR 1269 per quality‐adjusted life‐year (QALY)]. Results were driven by reduced costs for HHF events combined with QALY gains of 0.43–0.44, attributable to increased time in higher KCCQ states (representing better functional outcomes). Sensitivity and subgroup analyses demonstrated data robustness, with the ICER remaining dominant or highly cost‐effective under a wide range of scenarios, including increasing treatment costs and various patient subgroups, despite a moderate increase in costs for de novo HF and smaller QALY gains for ischaemic aetiology. Conclusion: Ferric carboxymaltose is estimated to be a highly cost‐effective treatment across countries (Italy, UK, USA and Switzerland) representing different healthcare systems. [ABSTRACT FROM AUTHOR]

Aims: We evaluated the relation between baseline and new‐onset atrial fibrillation (AF) and outcomes, and assessed whether vericiguat modified the likelihood of new‐onset AF in patients with worsening heart failure (HF) with reduced ejection fraction in VICTORIA. Methods and results: Of 5050 patients randomized, 5010 with recorded AF status at baseline were analysed. Patients were classified into three groups: no known AF (n = 2661, 53%), history of AF alone (n = 992, 20%), and AF on randomization electrocardiogram (n = 1357, 27%). Compared with those with no AF, those with history of AF alone had a higher risk of cardiovascular death [adjusted hazard ratio (HR) 1.21, 95% confidence interval (CI) 1.01–1.47] without excess myocardial infarction or stroke; neither type of AF was associated with a higher risk of the primary composite outcome (time to cardiovascular death or first HF hospitalization), HF hospitalizations, or all cause‐death. The beneficial effect of vericiguat on the primary composite outcome and its components was evident irrespective of AF status at baseline. Over a median follow‐up of 10.8 months, new‐onset AF occurred in 6.1% of those with no AF and 18.3% with history of AF alone (P < 0.0001). These events were not influenced by vericiguat treatment (adjusted HR 0.93, 95% CI 0.75–1.16; P = 0.51), but were associated with an increase in the hazard of both primary and secondary outcomes. Conclusions: Atrial fibrillation was present in nearly half of this high‐risk population with worsening HF. A history of AF alone at baseline portends an increased risk of cardiovascular death. Neither type of AF affected the beneficial effect of vericiguat. Development of AF post‐randomization was associated with an increase in both cardiovascular death and HF hospitalization which was not influenced by vericiguat. [ABSTRACT FROM AUTHOR]

Volume recruitment from the splanchnic compartment is an important physiological response to stressors such as physical activity and blood loss. In the setting of heart failure (HF), excess fluid redistribution from this compartment leads to increased cardiac filling pressures with limitation in exercise capacity. Recent evidence suggests that blocking neural activity of the greater splanchnic nerve (GSN) could have significant benefits in some patients with HF by reducing cardiac filling pressures and improving exercise capacity. However, to date the long‐term safety of splanchnic nerve modulation (SNM) in the setting of HF is unknown. SNM is currently used in clinical practice to alleviate some forms of chronic abdominal pain. A systematic review of the series where permanent SNM was used as a treatment for chronic abdominal pain indicates that permanent SNM is well tolerated, with side‐effects limited to transient diarrhoea or abdominal colic and transient hypotension. The pathophysiological role of the GSN in volume redistribution, the encouraging findings of acute and chronic pilot SNM studies and the safety profile from permanent SNM for pain provides a strong basis for continued efforts to study this therapeutic target in HF. [ABSTRACT FROM AUTHOR]

Background: Patients with heart failure (HF) and reduced ejection fraction will experience multiple hospitalizations for heart failure during the course of their disease. We assessed the efficacy of dapagliflozin on reducing the rate of total (ie, first and repeat) hospitalizations for heart failure in the DAPA-HF trial (Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure).Methods: The total number of HF hospitalizations and cardiovascular deaths was examined by using the proportional-rates approach of Lei-Wei-Yang-Ying and a joint frailty model for each of recurrent HF hospitalizations and time to cardiovascular death. Variables associated with the risk of recurrent hospitalizations were explored in a multivariable Lei-Wei-Yang-Ying model.Results: Of 2371 participants randomly assigned to placebo, 318 experienced 469 hospitalizations for HF; of 2373 assigned to dapagliflozin, 230 patients experienced 340 admissions. In a multivariable model, factors associated with a higher risk of recurrent HF hospitalizations included higher heart rate, higher N-terminal pro-B-type natriuretic peptide, and New York Heart Association class. In the Lei-Wei-Yang-Ying model, the rate ratio for the effect of dapagliflozin on recurrent HF hospitalizations or cardiovascular death was 0.75 (95% CI, 0.65-0.88), P=0.0002. In the joint frailty model, the rate ratio for total HF hospitalizations was 0.71 (95% CI, 0.61-0.82), P<0.0001, whereas, for cardiovascular death, the hazard ratio was 0.81 (95% CI, 0.67-0.98), P=0.0282.Conclusions: Dapagliflozin reduced the risk of total (first and repeat) HF hospitalizations and cardiovascular death. Time-to-first event analysis underestimated the benefit of dapagliflozin in HF and reduced ejection fraction. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03036124. [ABSTRACT FROM AUTHOR]

Aims: Treatment with sodium–glucose co‐transporter 2 (SGLT2) inhibitors improves outcomes in patients with chronic heart failure (HF) with reduced ejection fraction. There is limited experience with the in‐hospital initiation of SGLT2 inhibitors in patients with acute HF (AHF) with or without diabetes. EMPULSE is designed to assess the clinical benefit and safety of the SGLT2 inhibitor empagliflozin compared with placebo in patients hospitalized with AHF. Methods: EMPULSE is a randomized, double‐blind, parallel‐group, placebo‐controlled multinational trial comparing the in‐hospital initiation of empagliflozin (10 mg once daily) with placebo. Approximately 500 patients admitted for AHF with dyspnoea, signs of fluid overload, and elevated natriuretic peptides will be randomized 1:1 stratified to HF status (de‐novo and decompensated chronic HF) to either empagliflozin or placebo at approximately 165 sites across North America, Europe and Asia. Patients will be enrolled regardless of ejection fraction and diabetes status and will be randomized during hospitalization and after stabilization (between 24 h and 5 days after admission), with treatment continued up to 90 days after initiation. The primary outcome is clinical benefit at 90 days, consisting of a composite of all‐cause death, HF events, and ≥5 point change from baseline in Kansas City Cardiomyopathy Questionnaire total symptom score (KCCQ‐TSS), assessed using a 'win‐ratio' approach. Secondary outcomes include assessments of safety, change in KCCQ‐TSS from baseline to 90 days and change in natriuretic peptides from baseline to 30 days. Conclusion: The EMPULSE trial will evaluate the clinical benefit and safety of empagliflozin in patients hospitalized for AHF. [ABSTRACT FROM AUTHOR]

Background: Intravenous ferric carboxymaltose has been shown to improve symptoms and quality of life in patients with chronic heart failure and iron deficiency. We aimed to evaluate the effect of ferric carboxymaltose, compared with placebo, on outcomes in patients who were stabilised after an episode of acute heart failure.Methods: AFFIRM-AHF was a multicentre, double-blind, randomised trial done at 121 sites in Europe, South America, and Singapore. Eligible patients were aged 18 years or older, were hospitalised for acute heart failure with concomitant iron deficiency (defined as ferritin <100 μg/L, or 100-299 μg/L with transferrin saturation <20%), and had a left ventricular ejection fraction of less than 50%. Before hospital discharge, participants were randomly assigned (1:1) to receive intravenous ferric carboxymaltose or placebo for up to 24 weeks, dosed according to the extent of iron deficiency. To maintain masking of patients and study personnel, treatments were administered in black syringes by personnel not involved in any study assessments. The primary outcome was a composite of total hospitalisations for heart failure and cardiovascular death up to 52 weeks after randomisation, analysed in all patients who received at least one dose of study treatment and had at least one post-randomisation data point. Secondary outcomes were the composite of total cardiovascular hospitalisations and cardiovascular death; cardiovascular death; total heart failure hospitalisations; time to first heart failure hospitalisation or cardiovascular death; and days lost due to heart failure hospitalisations or cardiovascular death, all evaluated up to 52 weeks after randomisation. Safety was assessed in all patients for whom study treatment was started. A pre-COVID-19 sensitivity analysis on the primary and secondary outcomes was prespecified. This study is registered with ClinicalTrials.gov, NCT02937454, and has now been completed.Findings: Between March 21, 2017, and July 30, 2019, 1525 patients were screened, of whom 1132 patients were randomly assigned to study groups. Study treatment was started in 1110 patients, and 1108 (558 in the carboxymaltose group and 550 in the placebo group) had at least one post-randomisation value. 293 primary events (57·2 per 100 patient-years) occurred in the ferric carboxymaltose group and 372 (72·5 per 100 patient-years) occurred in the placebo group (rate ratio [RR] 0·79, 95% CI 0·62-1·01, p=0·059). 370 total cardiovascular hospitalisations and cardiovascular deaths occurred in the ferric carboxymaltose group and 451 occurred in the placebo group (RR 0·80, 95% CI 0·64-1·00, p=0·050). There was no difference in cardiovascular death between the two groups (77 [14%] of 558 in the ferric carboxymaltose group vs 78 [14%] in the placebo group; hazard ratio [HR] 0·96, 95% CI 0·70-1·32, p=0·81). 217 total heart failure hospitalisations occurred in the ferric carboxymaltose group and 294 occurred in the placebo group (RR 0·74; 95% CI 0·58-0·94, p=0·013). The composite of first heart failure hospitalisation or cardiovascular death occurred in 181 (32%) patients in the ferric carboxymaltose group and 209 (38%) in the placebo group (HR 0·80, 95% CI 0·66-0·98, p=0·030). Fewer days were lost due to heart failure hospitalisations and cardiovascular death for patients assigned to ferric carboxymaltose compared with placebo (369 days per 100 patient-years vs 548 days per 100 patient-years; RR 0·67, 95% CI 0·47-0·97, p=0·035). Serious adverse events occurred in 250 (45%) of 559 patients in the ferric carboxymaltose group and 282 (51%) of 551 patients in the placebo group.Interpretation: In patients with iron deficiency, a left ventricular ejection fraction of less than 50%, and who were stabilised after an episode of acute heart failure, treatment with ferric carboxymaltose was safe and reduced the risk of heart failure hospitalisations, with no apparent effect on the risk of cardiovascular death.Funding: Vifor Pharma. [ABSTRACT FROM AUTHOR]

In EMPERIAL-Preserved, 315 patients were treated (157 with empagliflozin, 158 with placebo); in EMPERIAL-Reduced, 311 patients were treated (155 with empagliflozin, 156 with placebo). E. Pfarr, Dr Hauske, Dr Peil, Dr Salsali, Dr Ritter, and Dr Brueckmann are employees of Boehringer Ingelheim. Keywords: chronic kidney disease; diabetes mellitus; heart failure EN chronic kidney disease diabetes mellitus heart failure 1265 1267 3 06/06/22 20211012 NES 211012 Sodium-glucose cotransporter-2 inhibitors elicit an initial decline in estimated glomerular filtration rate (eGFR).[1] This phenomenon may raise concerns in clinical practice, especially for patients vulnerable to kidney dysfunction such as those with heart failure. [Extracted from the article]

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. [ABSTRACT FROM AUTHOR]

The European Society of Cardiology (ESC) has published a series of guidelines on heart failure (HF) over the last 25 years, most recently in 2016. Given the amount of new information that has become available since then, the Heart Failure Association (HFA) of the ESC recognized the need to review and summarise recent developments in a consensus document. Here we report from the HFA workshop that was held in January 2019 in Frankfurt, Germany. This expert consensus report is neither a guideline update nor a position statement, but rather a summary and consensus view in the form of consensus recommendations. The report describes how these guidance statements are supported by evidence, it makes some practical comments, and it highlights new research areas and how progress might change the clinical management of HF. We have avoided re-interpretation of information already considered in the 2016 ESC/HFA guidelines. Specific new recommendations have been made based on the evidence from major trials published since 2016, including sodium-glucose co-transporter 2 inhibitors in type 2 diabetes mellitus, MitraClip for functional mitral regurgitation, atrial fibrillation ablation in HF, tafamidis in cardiac transthyretin amyloidosis, rivaroxaban in HF, implantable cardioverter-defibrillators in non-ischaemic HF, and telemedicine for HF. In addition, new trial evidence from smaller trials and updated meta-analyses have given us the chance to provide refined recommendations in selected other areas. Further, new trial evidence is due in many of these areas and others over the next 2 years, in time for the planned 2021 ESC guidelines on the diagnosis and treatment of acute and chronic heart failure. [ABSTRACT FROM AUTHOR]

Aims: Heart failure (HF) is associated with considerable symptom burden and impairment in physical functioning and quality of life. The sodium-glucose co-transporter 2 inhibitor empagliflozin reduced the risk of HF hospitalisation and cardiovascular death in patients with type 2 diabetes and established cardiovascular disease in the EMPA-REG OUTCOME trial, and could potentially improve congestion symptoms and exercise capacity in patients with HF. We describe the designs of the EMPERIAL-Preserved and EMPERIAL-Reduced trials of empagliflozin in patients with chronic stable HF, with or without type 2 diabetes.Methods: EMPERIAL-Preserved and EMPERIAL-Reduced are randomised, placebo-controlled trials designed to investigate the effects of empagliflozin on exercise capacity and patient-reported outcomes in patients with chronic stable HF with preserved ejection fraction [HFpEF; left ventricular ejection fraction (LVEF) > 40%] and HF with reduced ejection fraction (HFrEF; LVEF ≤ 40%), respectively. In each trial, approximately 300 patients will be randomised 1:1 to receive empagliflozin 10 mg or placebo once daily for 12 weeks. In both trials, the primary endpoint is the change from baseline in 6-min walk test distance at week 12. Key secondary endpoints are the change from baseline in Kansas City Cardiomyopathy Questionnaire total symptom score and change from baseline in dyspnoea score of the Chronic Heart Failure Questionnaire at week 12.Conclusion: The EMPERIAL-Preserved and EMPERIAL-Reduced trials will determine the effects of empagliflozin on exercise capacity and patient-reported outcomes in patients with HFpEF and HFrEF, respectively, and provide insight into the potential of empagliflozin in the treatment of patients with HF.Clinical Trial Registration: ClinicalTrials.gov ID: NCT03448406 (EMPERIAL-Preserved), NCT03448419 (EMPERIAL-Reduced). [ABSTRACT FROM AUTHOR]

10 Giannoni A, Borrelli C, Mirizzi G, Richerson GB, Emdin M, Passino C. Benefit of buspirone on chemoreflex and central apnoeas in heart failure: a randomized controlled crossover trial. Do Cheyne and Stokes have an important message for modern-day patients with heart failure? Do Cheyne and Stokes have an important message for modern-day patients with heart failure?. [Extracted from the article]

Aims: The presence of central sleep apnoea (CSA) is associated with poor prognosis in patients with heart failure (HF). The aim of this analysis was to evaluate if using phrenic nerve stimulation to treat CSA in patients with CSA and HF was associated with changes in HF-specific metrics.Methods and Results: All patients randomized in the remedē System Pivotal Trial and identified at baseline with HF were included (n = 96). Effectiveness data from treatment and former control groups were pooled based on months since therapy activation. Changes from baseline to 6 and 12 months in sleep metrics, Epworth Sleepiness Scale, patient global assessment health-related quality of life, Minnesota Living with Heart Failure Questionnaire (MLHFQ), and echocardiographic parameters are reported. HF hospitalization, cardiovascular death, and the composite of HF hospitalization or cardiovascular death within 6 months are reported by the original randomized group assignment for safety assessment. Sleep metrics and quality of life improved from baseline to 6 and 12 months. At 12 months, MLHFQ scores changed by -6.8 ± 20.0 (P = 0.005). The 6-month rate of HF hospitalization was 4.7% in treatment patients (standard error = 3.3) and 17.0% in control patients (standard error = 5.5) (P = 0.065). Reported adverse events were as expected for a transvenous implantable system.Conclusions: Phrenic nerve stimulation reduces CSA severity in patients with HF. In parallel, this CSA treatment was associated with benefits on HF quality of life. [ABSTRACT FROM AUTHOR]

Aims: In chronic heart failure, proportional pulse pressure (PPP) is suggested as an estimate of cardiac index (CI). The association between CI and PPP in acute heart failure (AHF) has not been described. Methods: This was examined using hemodynamic measurements (from a trial using serelaxin) in 63 stabilized AHF patients. Results: Mean (SD) age was 68 (11), 74% male, mean (SD) ejection fraction (EF) was 33.4% (13.7), mean (SD) CI (L/min/m2) was 2.3 (0.6). CI correlated with PPP (Pearson R = 0.42; p < 0.0001) based on a linear mixed-effects model analysis of 171 pairs of measurements from 47 patients (out of 63) where CI and PPP were measured within 3 min of each other during. Serelaxin treatment did not modify the established correlation between CI and PPP. Time-weighted average CI correlated with time-weighted average PPP (Spearman Rank R = 0.35; p = 0.0051) over the −4 h to 24 h time interval. In a multivariable regression analysis, low PPP was an independent predictor of low CI (p < 0.0001). Conclusions: In patients with AHF after initial clinical stabilization, both baseline and post-baseline CI measurements are positively related to PPP. This was the most closely related non-invasive blood pressure variable to CI. [ABSTRACT FROM AUTHOR]

Background: Iron deficiency is common in patients with heart failure (HF) and is associated with reduced exercise capacity and poor outcomes. Whether correction of iron deficiency with (intravenous) ferric carboxymaltose (FCM) affects peak oxygen consumption [peak VO2], an objective measure of exercise intolerance in HF, has not been examined.Methods: We studied patients with systolic HF (left ventricular ejection fraction ≤45%) and mild to moderate symptoms despite optimal HF medication. Patients were randomized 1:1 to treatment with FCM for 24 weeks or standard of care. The primary end point was the change in peak VO2 from baseline to 24 weeks. Secondary end points included the effect on hematinic and cardiac biomarkers, quality of life, and safety. For the primary analysis, patients who died had a value of 0 imputed for 24-week peak VO2. Additional sensitivity analyses were performed to determine the impact of imputation of missing peak VO2 data.Results: A total of 172 patients with HF were studied and received FCM (n=86) or standard of care (control group, n=86). At baseline, the groups were well matched; mean age was 64 years, 75% were male, mean left ventricular ejection fraction was 32%, and peak VO2 was 13.5 mL/min/kg. FCM significantly increased serum ferritin and transferrin saturation. At 24 weeks, peak VO2 had decreased in the control group (least square means -1.19±0.389 mL/min/kg) but was maintained on FCM (-0.16±0.387 mL/min/kg; P=0.020 between groups). In a sensitivity analysis, in which missing data were not imputed, peak VO2 at 24 weeks decreased by -0.63±0.375 mL/min/kg in the control group and by -0.16±0.373 mL/min/kg in the FCM group; P=0.23 between groups). Patients' global assessment and functional class as assessed by the New York Heart Association improved on FCM versus standard of care.Conclusions: Treatment with intravenous FCM in patients with HF and iron deficiency improves iron stores. Although a favorable effect on peak VO2 was observed on FCM, compared with standard of care in the primary analysis, this effect was highly sensitive to the imputation strategy for peak VO2 among patients who died. Whether FCM is associated with an improved outcome in these high-risk patients needs further study.Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01394562. [ABSTRACT FROM AUTHOR]

Aims: Patients with central sleep apnoea (CSA) often have poor quality of life and are at increased risk of morbidity and mortality. This study sought to evaluate the 12-month clinical outcomes of patients with CSA treated with unilateral transvenous phrenic nerve stimulation in the prospective, multicentre, non-randomized remedē® System pilot study.Methods and Results: Forty-seven patients with CSA were treated with the remedē® System (Respicardia Inc., Minnetonka, MN, USA) for a minimum of 3 months. Sleep-disordered breathing parameters were evaluated by polysomnography (PSG) at 3, 6, and 12-month follow-up. Sleep symptoms and quality of life were also evaluated. Forty-one patients completed all follow-up PSGs and were included in the analysis. At 12 months, there was sustained improvement compared with baseline in the apnoea-hypopnoea index (49.9 ± 15.1 vs. 27.5 ± 18.3 events/h, P < 0.001) and central apnoea index (28.2 ± 15.0 vs. 6.0 ± 9.2 events/h, P < 0.001). Sustained improvement in the oxygen desaturation index (46.1 ± 19.1 vs. 26.9 ± 18.0 events/h, P < 0.001), rapid eye movement sleep (11.4 ± 6.1% vs. 17.1 ± 8.0%, P < 0.001), and sleep efficiency (69.3 ± 16.9% vs. 75.6 ± 17.1%, P = 0.024) were also observed. There were also continued favourable effects on sleepiness and quality of life. Three deaths unrelated to remedē® System therapy and five serious adverse events occurred over 12 months of follow-up.Conclusion: The present study demonstrates that in patients with CSA, unilateral transvenous phrenic nerve stimulation is associated with sustained improvement in key sleep parameters, sleep symptoms, and quality of life over 12 months of follow-up. [ABSTRACT FROM AUTHOR]

Aims Patients with central sleep apnoea (CSA) often have poor quality of life and are at increased risk of morbidity and mortality. This study sought to evaluate the 12-month clinical outcomes of patients with CSA treated with unilateral transvenous phrenic nerve stimulation in the prospective, multicentre, non-randomized remed ·e® System pilot study. Methods and results Forty-seven patients with CSA were treated with the remed·e® System (Respicardia Inc., Minnetonka, MN, USA) for a minimum of 3 months. Sleep-disordered breathing parameters were evaluated by polysomnography (PSG) at 3, 6, and 12-month follow-up. Sleep symptoms and quality of life were also evaluated. Forty-one patients completed all follow-up PSGs and were included in the analysis. At 12months, there was sustained improvement compared with baseline in the apnoea-hypopnoea index (49.9±15.1 vs. 27.5±18.3 events/h, P <0.001) and central apnoea index (28.2±15.0 vs. 6.0±9.2 events/h, P <0.001). Sustained improvement in the oxygen desaturation index (46.1±19.1 vs. 26.9±18.0 events/h, P <0.001), rapid eye movement sleep (11.4±6.1% vs. 17.1±8.0%, P <0.001), and sleep efficiency (69.3±16.9% vs. 75.6±17.1%, P =0.024) were also observed. There were also continued favourable effects on sleepiness and quality of life. Three deaths unrelated to remed·e® System therapy and five serious adverse events occurred over 12 months of follow-up. Conclusion The present study demonstrates that in patients with CSA, unilateral transvenous phrenic nerve stimulation is associated with sustained improvement in key sleep parameters, sleep symptoms, and quality of life over 12months of follow-up. [ABSTRACT FROM AUTHOR]

Background: Central sleep apnoea is a serious breathing disorder associated with poor outcomes. The remedé system (Respicardia Inc, Minnetonka, MN, USA) is an implantable device which transvenously stimulates a nerve causing diaphragmatic contraction similar to normal breathing. We evaluated the safety and effectiveness of unilateral neurostimulation in patients with central sleep apnoea.Methods: We recruited patients from 31 hospital-based centres in Germany, Poland, and the USA in this prospective, multicentre, randomised trial. Participants had to have been medically stable for at least 30 days and have received appropriate guideline recommended therapy, be aged at least 18 years, be expected to tolerate study procedures, and willing and able to comply with study requirements. Eligible patients with an apnoea-hypopnoea index (AHI) of at least 20 events per h, tested by a polysomnography, underwent device implantation and were randomly assigned (1:1) by a computer-generated method stratified by site to either stimulation (treatment) or no stimulation (control) for 6 months. The primary effectiveness endpoint in the intention-to-treat population was the comparison of the proportions of patients in the treatment versus control groups achieving a 50% or greater AHI reduction from baseline to 6 months, measured by a full-night polysomnography assessed by masked investigators in a core laboratory. The primary safety endpoint of 12-month freedom from serious adverse events related to the procedure, system, or therapy was evaluated in all patients. This trial is active, but not recruiting, and is registered with ClinicalTrials.gov (NCT01816776).Findings: Between April 17, 2013, and May 28, 2015, we randomly assigned 151 eligible patients to the treatment (n=73) or control (n=78) groups. In the analysis of the intention-to-treat population, significantly more patients in the treatment group (35 [51%] of 68) had an AHI reduction from baseline of 50% or greater at 6 months than had those in the control group (eight [11%] of 73; difference between groups 41%, 95% CI 25-54, p<0·0001). 138 (91%) of 151 patients had no serious-related adverse events at 12 months. Seven (9%) cases of related-serious adverse events occurred in the control group and six (8%) cases were reported in the treatment group. Seven patients died (unrelated to implant, system, or therapy), four deaths (two in treatment group and two in control group) during the 6-month randomisation period when neurostimulation was delivered to only the treatment group and was off in the control group, and three deaths between 6 months and 12 months of follow-up when all patients received neurostimulation. 27 (37%) of 73 patients in the treatment group reported non-serious therapy-related discomfort that was resolved with simple system reprogramming in 26 (36%) patients, but was unresolved in one (1%) patient.Interpretation: Transvenous neurostimulation significantly reduced the severity of central sleep apnoea, including improvements in sleep metrics, and was well tolerated. The clinically meaningful effects of the therapy are supported by the concordant improvements in oxygenation and quality of life, making transvenous neurostimulation a promising therapeutic approach for central sleep apnoea.Funding: Respicardia Inc. [ABSTRACT FROM AUTHOR]

Aims Anaemia and iron deficiency are constituents of the cardio-renal syndrome in chronic heart failure ( CHF). We investigated the effects of i.v. iron in iron-deficient CHF patients on renal function, and the efficacy and safety of this therapy in patients with renal dysfunction. Methods and results The FAIR-HF trial randomized 459 CHF patients with iron deficiency (ferritin <100 µg/L, or between 100 and 299 µg/L if transferrin saturation was <20%): 304 to i.v. ferric carboxymaltose ( FCM) and 155 to placebo, and followed-up for 24 weeks. Renal function was assessed at baseline and at weeks 4, 12, and 24, using the estimated glomerular filtration rate ( eGFR, mL/min/1.73 m2), calculated from the Chronic Kidney Disease Epidemiology Collaboration ( CKD-EPI) formula. At baseline, renal function was similar between groups (62.4 ± 20.6 vs. 62.9 ± 23.4 mL/min/1.73 m2, FCM vs. placebo). Compared with placebo, treatment with FCM was associated with an increase in eGFR [treatment effect: week 4, 2.11 ± 1.21 ( P = 0.082); week 12, 2.41 ± 1.33 ( P = 0.070); and week 24, 2.98 ± 1.44 mL/min/1.73 m2 ( P = 0.039)]. This effect was seen in all pre-specified subgroups ( P > 0.20 for interactions). No interaction between the favourable effects of FCM and baseline renal function was seen for the primary endpoints [improvement in Patient Global Assessment ( P = 0.43) and NYHA class ( P = 0.37) at 24 weeks]. Safety and adverse event profiles were similar in patients with baseline eGFR <60 and ≥60 mL/min/1.73 m2. Conclusions Treatment of iron deficiency in CHF patients with i.v. FCM was associated with an improvement in renal function. FCM therapy was effective and safe in CHF patients with renal dysfunction. [ABSTRACT FROM AUTHOR]

Abstract: Background: Any increase in heart rate (HR) during daily activities above the ischemic threshold may trigger myocardial ischemia. HR reduction with the I f inhibitor ivabradine has been demonstrated to confer anti-ischemic and antianginal efficacy in patients with stable angina pectoris. This analysis of the ASSOCIATE trial assessed whether the anti-ischemic efficacy and safety of ivabradine were comparable in patients with baseline resting HRs above and below the median. Methods: Patients with chronic stable angina pectoris were randomized to treatment with ivabradine (5 to 7.5mg bid) or placebo for 4months, in addition to atenolol 50mg od. The effect of treatment on exercise tolerance test parameters was analyzed in two groups according to baseline HR: >65bpm (n=418) versus ≤65bpm (n=436) (above and below the median, respectively). Results: Ivabradine reduced resting HR in both groups with placebo-corrected reductions of −9.1 (95% CI −11.0 to −7.3; >65bpm group) and −5.9 (95% CI −7.5 to −4.3; ≤65bpm group) (both P <0.001 versus placebo). Ivabradine reduced heart rate at all stages of exercise (all P <0.001). Improvements in exercise capacity (total exercise duration, time to limiting angina, angina onset, and 1-mm ST segment depression, all P <0.05) were recorded in both HR groups. There were no differences between the two groups in terms of safety. Conclusions: Ivabradine resulted in significant improvements in exercise capacity relative to placebo in patients with stable angina pectoris receiving beta-blocker therapy whether their resting HR was above or below 65bpm. [Copyright &y& Elsevier]

Chronic heart failure (HF) with either reduced or preserved ejection fraction is common and remains an extremely serious disorder with a high mortality and morbidity. Many complications related to HF can be related to thrombosis. Epidemiological and pathophysiological data also link HF to an increased risk of thrombosis, leading to the clinical consequences of sudden death, stroke, systemic thrombo-embolism, and/or venous thrombo-embolism. This consensus document of the Heart Failure Association (EHFA) of the European Society of Cardiology (ESC) and the ESC Working Group on Thrombosis reviews the published evidence and summarizes ‘best practice’, and puts forward consensus statements that may help to define evidence gaps and assist management decisions in everyday clinical practice. In HF patients with atrial fibrillation, oral anticoagulation is recommended, and the CHA2DS2-VASc and HAS-BLED scores should be used to determine the likely risk–benefit ratio (thrombo-embolism prevention vs. risk of bleeding) of oral anticoagulation. In HF patients with reduced left ventricular ejection fraction who are in sinus rhythm there is no evidence of an overall benefit of vitamin K antagonists (e.g. warfarin) on mortality, with risk of major bleeding. Despite the potential for a reduction in ischaemic stroke, there is currently no compelling reason to use warfarin routinely for these patients. Risk factors associated with increased risk of thrombo-embolic events should be identified and decisions regarding use of anticoagulation individualized. Patient values and preferences are important determinants when balancing the risk of thrombo-embolism against bleeding risk. New oral anticoagulants that offer a different risk–benefit profile compared with warfarin may appear as an attractive therapeutic option, but this would need to be confirmed in clinical trials. [ABSTRACT FROM AUTHOR]

Aims: This pilot study aimed to assess the potential benefits of cardiac contractility modulation (CCM) in patients with heart failure with preserved ejection fraction (HFpEF). Methods and results: This was a prospective, multicentre, single‐arm, pilot study of CCM therapy in patients with HFpEF and New York Heart Association (NYHA) class II or III. Echocardiographic parameters were measured by an echo core laboratory to determine study eligibility. After CCM device implantation, patients were followed for 24 weeks. Overall, 47 patients (mean age 74.3 ± 4.4 years, 70.2% female) were enrolled, with left ventricular ejection fraction of 59 ± 4.4%, 63.8% with hypertension, 46.8% with atrial fibrillation, 40.4% with diabetes, 31.9% with at least one heart failure hospitalization in the prior year, 61.7% in NYHA class III, and Kansas City Cardiomyopathy Questionnaire (KCCQ) overall summary score of 48.9 ± 21.7. The primary efficacy endpoint (mean change in the KCCQ overall summary score) improved by 18.0 ± 16.6 points (p < 0.001) and there was an event‐free rate of 93.6% for the primary safety endpoint (device‐ and procedure‐related complications), as adjudicated by an independent physician committee. Conclusion: This pilot study demonstrates that the benefits of CCM may extend to the HFpEF patient population. The significant improvement in health status observed, with no obvious impact on safety, suggests that utilization of CCM for patients with HFpEF could prove to be promising. [ABSTRACT FROM AUTHOR]

Aims The direct effects of adenosine A1 receptor antagonists on haemodynamic parameters in patients with acute heart failure (HF) remain largely unknown. Methods and results We evaluated the haemodynamic effects of the AA1RA rolofylline in 59 HF patients with concomitant renal impairment (estimated creatinine clearance 20–80 mL/min). Placebo or rolofylline 30 mg was administered as a 4 h infusion followed by intravenous (i.v.) loop diuretic administration. Haemodynamic measurements were carried out hourly up to 8 h post-dosing by pulmonary artery catheterization. Urine output, fractional excretion of sodium, potassium, urea, and uric acid, and blood urea nitrogen (BUN) and creatinine levels were also measured. In both groups, the changes from baseline in all haemodynamic indices except mean pulmonary artery pressure (PAP) were not clinically significant. Mean [95% confidence interval (CI)] PAP showed a placebo-adjusted decrease with rolofylline of −1.5 (−4.1, 1.1)mmHg at Hour 4 and −3.5 mmHg (95% CI: −6.2, −0.2) at Hour 8. There was a significant increase with rolofylline in diuresis [placebo-corrected mean (95% CI) change of 68 (20, 116)mL/h at Hour 2–4 and 103 (21, 185)mL/h at Hour 4–8] and in fractional excretion of sodium, potassium, and uric acid. Placebo-corrected changes in plasma levels of creatinine and BUN with rolofylline were non-significant. Conclusion Single administration of rolofylline in patients with HF and impaired renal function produced a slight decrease in mean PAP and consistently increased diuresis and natriuresis without compromising renal function, both before and after administration of i.v. loop diuretics. [ABSTRACT FROM AUTHOR]

Abstract: Therapy has improved the survival of heart failure (HF) patients. However, many patients progress to advanced chronic HF (ACHF). We propose a practical clinical definition and describe the characteristics of this condition. Patients that are generally recognised as ACHF often exhibit the following characteristics: 1) severe symptoms (NYHA class III to IV); 2) episodes with clinical signs of fluid retention and/or peripheral hypoperfusion; 3) objective evidence of severe cardiac dysfunction, shown by at least one of the following: left ventricular ejection fraction<30%, pseudonormal or restrictive mitral inflow pattern at Doppler-echocardiography; high left and/or right ventricular filling pressures; elevated B-type natriuretic peptides; 4) severe impairment of functional capacity demonstrated by either inability to exercise, a 6-minute walk test distance<300 m or a peak oxygen uptake<12–14 ml/kg/min; 5) history of >1 HF hospitalisation in the past 6 months; 6) presence of all the previous features despite optimal therapy. This definition identifies a group of patients with compromised quality of life, poor prognosis, and a high risk of clinical events. These patients deserve effective therapeutic options and should be potential targets for future clinical research initiatives. [Copyright &y& Elsevier]

Objectives: This study sought to investigate whether darbepoetin alfa, an erythropoiesis-stimulating protein (ESP), improves exercise capacity in patients with symptomatic chronic heart failure (CHF) and anemia. Background: Anemia is common in patients with CHF. Methods: In a multicenter, randomized, double-blind, placebo-controlled study, CHF patients with anemia (hemoglobin ≥9.0 to ≤12.0 g/dl) received subcutaneous placebo (n = 22) or darbepoetin alfa (n = 19) at a starting dose of 0.75 μg/kg every 2 weeks for 26 weeks. The primary end point was change in exercise tolerance from baseline to week 27 as measured by peak oxygen uptake (ml/min/kg body weight). Other end points included changes in absolute peak Vo 2 (ml/min), exercise duration, and health-related quality of life. Results: Differences (95% confidence interval) in mean changes from baseline to week 27 between treatment groups were 1.5 g/dl (0.5 to 2.4) for hemoglobin concentration (p = 0.005), 0.5 ml/kg/min (−0.7 to 1.7) for peak Vo 2 (p = 0.40), 45 ml/min (−35 to 127) for absolute peak Vo 2 (p = 0.27), and 108 s (−11 to 228) for exercise duration (p = 0.075). Patients receiving darbepoetin alfa compared with placebo had an improvement in self-reported Patient’s Global Assessment of Change (79% vs. 41%, p = 0.01) but no significant differences in the Kansas City Cardiomyopathy and Minnesota Living with Heart Failure Questionnaire scores. Darbepoetin alfa was well tolerated. Conclusions: In patients with symptomatic CHF and anemia, darbepoetin alfa increased and maintained hemoglobin concentrations and improved health-related quality of life. A trend toward increased exercise time but not peak Vo 2 was observed. (Impact of Darbepoetin Alfa on Exercise Tolerance and Left Ventricular Structure in Subjects With Symptomatic Congestive Heart Failure (CHF) and Anemia; http://clinicaltrials.gov/ct/show/NCT00117234?order = 1; NCT00117234). [Copyright &y& Elsevier]

Abstract: Activation of the immune system and derangement of cardiorespiratory neural control are established elements of the complex pathophysiology of chronic heart failure (CHF). The magnitude of these abnormalities relates to disease progression and mortality. Less clear is the origin of these derangements and the sequence of triggering mechanisms in the course of the natural history of CHF. To date, immune activation and autonomic imbalance have been considered independently; we hypothesise they are closely related. Damaged heart muscle through autonomic afferents triggers functional and structural changes in the central nervous system, in part related to inflammatory processes. The altered function of the autonomic centres is expressed as a reduction of central parasympathetic tone. Diminished cholinergic signalling (mainly nicotinergic) activates inflammation and stimulates immune response. These two phenomena predict prognosis and represent therapeutic targets in the syndrome of CHF. [Copyright &y& Elsevier]

Aims Methods and results Conclusions The effects of initiating sacubitril/valsartan in patients with stable heart failure with reduced ejection fraction (HFrEF) on response to fluid and sodium expansion are unknown.We have explored changes in natriuresis, diuresis, and congestion in response to the administration of intravenous fluid/sodium load in patients with HFrEF before as compared to after the initiation of sacubitril/valsartan. At baseline (before sacubitril/valsartan initiation) and 2 and 3 months after the initiation, patients underwent an evaluation that consisted of three phases of 3 h: the rest phase (0–3 h), the load phase (3–6 h) in which 1 L of intravenous Ringer solution was administered, and the diuretic phase (6–9 h) at the beginning of which furosemide was administered. Overall, 216 patients completed the study. In comparison to baseline values, at 2 and 3 months after sacubitril/valsartan initiation, patients' diuresis and natriuresis in response to Ringer administration significantly increased (mean difference: 38.8 [17.38] ml, p = 0.0040, and 9.6 [2.02] mmol, p < 0.0001, respectively). Symptoms and signs of congestion after the fluid/sodium challenge were significantly decreased at months 2 and 3 compared to baseline. Compared to baseline, there was also an increment of natriuresis after furosemide administration on sacubitril/valsartan (9.8 [5.13] mmol, p = 0.0167). There was a significant decrease in body weight in subsequent visits when compared to baseline values (−0.50 [−12.7, 7.4] kg at 2 months, and −0.75 [−15.9, 7.5] kg at 3 months; both p < 0.0001).The initiation of sacubitril/valsartan in HFrEF patients was associated with improvements in natriuresis, diuresis, and weight loss and better clinical adaptation to potentially decongestive stressors. [ABSTRACT FROM AUTHOR]

ABSTRACT Aims Methods and results Conclusions Although much is known about the usefulness of heart failure (HF)‐specific instruments for assessing patient well‐being, less is known about the value of generic instruments for the measurement of health‐related quality of life (HRQL) in HF. The aim of this study was to assess the relationship between the EuroQol 5‐dimension 5‐level (EQ‐5D‐5L) visual analogue scale (VAS) and index scores, clinical characteristics, and outcomes in patients with HF and the effect of dapagliflozin on these scores.We performed a patient‐level pooled analysis of the DAPA‐HF and DELIVER trials, which investigated the effectiveness and safety of dapagliflozin in patients with HF and reduced ejection fraction (HFrEF) and mildly reduced/preserved ejection fraction (HFmrEF/HFpEF), respectively. Patients reporting higher (better) EQ‐5D‐5L VAS and index scores had a lower prevalence of comorbidities, including atrial fibrillation and hypertension, than patients with a worse score. They were also more likely to have better investigator‐reported (New York Heart Association class) and patient‐self‐reported (Kansas City Cardiomyopathy Questionnaire) health status and lower median N‐terminal pro‐B‐type natriuretic peptide levels. Compared to patients with the lowest scores (Q1), those with higher EQ‐5D‐5L VAS scores had better outcomes: the hazard ratio for the composite of cardiovascular death or worsening HF was 0.81 (95% confidence interval 0.72–0.91) in Q2, 0.74 (0.65–0.84) in Q3, and 0.62 (0.54–0.72) in Q4. The risk of each component of the composite outcome, and all‐cause death, was also lower in patients with better scores. Similar findings were observed for the index score. Treatment with dapagliflozin improved both EQ‐5D‐5L VAS and index scores across the range of ejection fraction.Both higher (better) EQ‐5D‐5L VAS and index scores were associated with better outcomes. Dapagliflozin treatment improved EQ‐5D‐5L VAS and index scores, irrespective of ejection fraction. [ABSTRACT FROM AUTHOR]

Central Illustration. Abbreviation: RSV – Respiratory Syncytial Virus. [Display omitted] • Simultaneous vaccination against RSV and Influenza virus among high-risk heart failure patients is safe. • Only small percentage of patients experienced reactions severe enough to prevent daily activities. • Simultaneous vaccination reduces patients contact with healthcare. The safety of simultaneous vaccination for Respiratory Syncytial Virus (RSV) and influenza in vulnerable high-risk heart failure (HF) patients remains unclear. In an open-label, prospective study, 105 patients received concurrent influenza (Vaxigrip Tetra, season 2023/2024, Sanofi) and RSV (Arexvy, GSK) vaccinations from September 15th to November 17th, 2023. Adverse events were collected on the fourth-day post-vaccination. Overall, the vaccination was well tolerated, with the most common reaction being injection site pain (63 %). General symptoms occurred in 33 % of patients, predominantly fatigue (23 %), myalgia (12 %), and headache (9 %). Grade 3 reactions were observed in 6 % of patients, and a few experienced temperature elevation or flu-like symptoms, managing them with antipyretics. Notably, there were no exacerbations of HF, hospitalizations, or deaths within a week post-vaccination. This study indicates the safety of simultaneous influenza and RSV vaccination in high-risk HF patients, with a low incidence of mild adverse events. [ABSTRACT FROM AUTHOR]

Aims: The safety and effectiveness of the MitraClip device to treat functional mitral regurgitation (FMR) has been tested in previous clinical trials yielding somewhat heterogeneous results in heart failure (HF) patients. Over time, the MitraClip device system has been modified and clinical practice evolved to consider also less severely diseased HF patients with FMR for this therapeutic option. The RESHAPE‐HF2 trial aims to assess the safety and effectiveness of the MitraClip device system on top of medical therapy considered optimal in the treatment of clinically significant FMR in symptomatic patients with chronic HF. Methods: The RESHAPE‐HF2 is an investigator‐initiated, prospective, randomized, parallel‐controlled, multicentre trial designed to evaluate the use of the MitraClip device (used in the most up‐to‐date version as available at sites) plus optimal standard of care therapy (device group) compared to optimal standard of care therapy alone (control group). Eligible subjects have signs and symptoms of HF (New York Heart Association [NYHA] class II–IV despite optimal therapy), and have moderate‐to‐severe or severe FMR, as confirmed by a central echocardiography core laboratory; have an ejection fraction between ≥20% and ≤50% (initially 15–35% for NYHA class II patients, and 15–45% for NYHA class III/IV patients); have been adequately treated per applicable standards, and have received appropriate revascularization and cardiac resynchronization therapy, if eligible; had a HF hospitalization or elevated natriuretic peptides (B‐type natriuretic peptide [BNP] ≥300 pg/ml or N‐terminal proBNP ≥1000 pg/ml) in the last 90 days; and in whom isolated mitral valve surgery is not a recommended treatment option. The trial has three primary endpoints, which are these: (i) the composite rate of total (first and recurrent) HF hospitalizations and cardiovascular death during 24 months of follow‐up, (ii) the rate of total (i.e. first and recurrent) HF hospitalizations within 24 months, and (iii) the change from baseline to 12 months in the Kansas City Cardiomyopathy Questionnaire overall score. The three primary endpoints will be analysed using the Hochberg procedure to control the familywise type I error rate across the three hypotheses. Conclusions: The RESHAPE‐HF2 trial will provide sound evidence on the MitraClip device and its effects in HF patients with FMR. The recruitment was recently completed with 506 randomized patients. [ABSTRACT FROM AUTHOR]

Aim: The EMPULSE (EMPagliflozin in patients hospitalised with acUte heart faiLure who have been StabilizEd) trial showed that, compared to placebo, the sodium–glucose cotransporter 2 inhibitor empagliflozin (10 mg/day) improved clinical outcomes of patients hospitalized for acute heart failure (HF). We investigated whether efficacy and safety of empagliflozin were consistent across the spectrum of left ventricular ejection fraction (LVEF). Methods and results: A total of 530 patients hospitalized for acute de novo or decompensated HF were included irrespective of LVEF. For the present analysis, patients were classified as HF with reduced (HFrEF, LVEF ≤40%), mildly reduced (HFmrEF, LVEF 41–49%) or preserved (HFpEF, LVEF ≥50%) ejection fraction at baseline. The primary endpoint was a hierarchical outcome of death, worsening HF events (HFE) and quality of life over 90 days, assessed by the win ratio. Secondary endpoints included individual components of the primary endpoint and safety. Out of 523 patients with baseline data, 354 (67.7%) had HFrEF, 54 (10.3%) had HFmrEF and 115 (22.0%) had HFpEF. The clinical benefit (hierarchical composite of all‐cause death, HFE and Kansas City Cardiomyopathy Questionnaire total symptom score) of empagliflozin at 90 days compared to placebo was consistent across LVEF categories (≤40%: win ratio 1.35 [95% confidence interval 1.04, 1.75]; 41–49%: win ratio 1.25 [0.66, 2.37)] and ≥50%: win ratio 1.40 [0.87, 2.23], pinteraction = 0.96) with a favourable safety profile. Results were consistent across individual components of the hierarchical primary endpoint. Conclusion: The clinical benefit of empagliflozin proved consistent across LVEF categories in the EMPULSE trial. These results support early in‐hospital initiation of empagliflozin regardless of LVEF. [ABSTRACT FROM AUTHOR]

Aims: Patients with heart failure (HF) and history of myocardial infarction (MI) face a higher risk of disease progression and clinical events. Whether sodium–glucose cotransporter 2 inhibitors may modify clinical trajectory in such individuals remains incompletely understood. Methods and results: The DAPA‐HF and DELIVER trials compared dapagliflozin with placebo in patients with symptomatic HF with left ventricular ejection fraction (LVEF) ≤40% and > 40%, respectively. In this pooled participant‐level analysis, we assessed efficacy and safety outcomes by history of MI. The primary outcome in both trials was the composite of cardiovascular death or worsening HF. Of the total of 11 007 patients, 3731 (34%) had a previous MI and were at higher risk of the primary outcome across the spectrum of LVEF in covariate‐adjusted models (hazard ratio [HR] 1.12, 95% confidence interval [CI] 1.02–1.24). Dapagliflozin reduced the risk of the primary outcome to a similar extent in patients with (HR 0.83, 95% CI 0.72–0.96) and without previous MI (HR 0.76, 95% CI 0.68–0.85; pinteraction = 0.36), with consistent benefits on key secondary outcomes as well. Serious adverse events did not occur more frequently with dapagliflozin, irrespective of previous MI. Conclusion: History of MI confers increased risks of adverse cardiovascular outcomes in patients with HF across the LVEF spectrum, even among those with preserved ejection fraction. Dapagliflozin consistently and safely reduces the risk of cardiovascular death or worsening HF, regardless of previous MI. [ABSTRACT FROM AUTHOR]

In chronic congestive heart failure (CHF) an overactivity of muscle ergoreceptors and peripheral chemoreceptors may lead to an increased ventilatory response to exercise and contribute to the autonomic imbalance. The analysis of heart rate variability (HRV), which is a reliable method of studying autonomic regulations within the cardiovascular system, showed depressed HRV indexes in CHF, but predictors of abnormal HRV pattern in CHF remain controversial. Considering a common mechanism involved in generation of both abnormal ventilation and autonomic dysfunction in CHF, we hypothesized that impaired ventilation may be better than other variables of CHF severity in determining HRV parameters. Seventy-two patients with CHF (57+/-9 years, ejection fraction: 28+/-11%) underwent cardiopulmonary exercise testing; the relation between ventilation and carbon dioxide production (VE/VCO2) was used as an index of the ventilatory response to exercise. Time and frequency-domain measurements of HRV were derived from 24-hour electrocardiographic monitoring. Patients had reduced exercise tolerance with abnormal ventilatory response (peak oxygen consumption [VO2max]: 17.8+/-5.5 ml/kg/min, VE/VCO2: 36.0+/-9.8). Correlations were found between HRV measures and etiology, New York Heart Association (NYHA) functional class, and VO2max, but the strongest relation was observed for VE/VCO2 slope (r values from -0.33 to -0.65, p <0.01). In the multiple regression analysis only VE/VCO2 was found to correlate independently with all HRV measurements. To investigate the role of peripheral chemoreceptor overactivity as the mechanism of autonomic imbalance and the increased ventilatory response to exercise, we assessed peripheral chemosensitivity in 22 patients (mean value of peripheral chemosensitivity: 0.62+/-0.34 L/min/%SaO2, significantly higher than in normal controls, mean value: 0.29+/-0.20 L/min/%SaO2 in our laboratory). The activity of the peripheral chemoreflex inversely correlated with all parameters of HRV. Increased ventilatory response to exercise correlated with depressed HRV measures in patients with CHF better than other clinical variables. An important role of the increased peripheral chemosensitivity in this relation may be relevant, being also a potential link between functional severity and sympathovagal imbalance in CHF. [ABSTRACT FROM AUTHOR]

Examines the chemoreceptor dependence of very low frequency rhythms in advanced chronic heart failure (CHF). Assessment of the ventilatory response to hypoxia in studying peripheral chemosensitivity; Antibaroreflex relationship between the heart rate and systolic blood pressure.

Assesses the use of heart rate variability (HRV) analysis as a prognostic indicator in a large population of ambulatory patients with moderate to severe congestive heart failure (CHF). Predictors of survival; Possible use of HRV in the risk assessment of patients with CHF; Spectral measures of HRV.

Tests for the role of increased peripheral chemosensitivity in the pathogenesis of very low frequency oscillations in chronic heart failure patients. Quantification of total oscillatory power via autoregressive spectral analysis of R-R intervals, blood pressure and respiration; Assessment of ventilatory response to hypoxia during transient inhalations of nitrogen.

Aims: In VICTORIA, vericiguat compared with placebo reduced the risk of cardiovascular death (CVD) and heart failure hospitalization (HFH) in patients enrolled after a worsening heart failure (WHF) event. We examined clinical outcomes and efficacy of vericiguat as it relates to background use of loop diuretics in patients with WHF. Methods and results: We calculated the total daily loop diuretic dose equivalent to furosemide dosing at randomization and categorized these as: no loop diuretic, 1–39, 41–80, 40, and >80 mg total daily dose (TDD). The primary composite outcome of CVD/HFH and its components were evaluated based on TDD loop diuretic and expressed as adjusted hazard ratios with 95% confidence intervals. Post‐randomization rates of change in TDD were also examined. Of 4974 patients (98% of the trial) with diuretic dose information available at randomization, 540 (10.8%) were on no loop diuretic, 647 (13.0%) were on 1–39, 1633 (32.8%) were on 40, 1185 (23.8%) were on 41–80, and 969 (19.4%) were on >80 mg TDD. Patients with higher TDD had a higher rate of primary and secondary clinical outcomes. There were no significant interactions with TDD at randomization and efficacy of vericiguat versus placebo for any outcome (all pinteraction > 0.5). Post‐randomization diuretic dose changes for vericiguat and placebo showed similar rates of up‐titration (19.6 and 20.2/100 person‐years), down‐titration (16.8 and 18.1/100 person‐years), and stopping diuretics (22.9 and 24.2/100 person‐years). Conclusions: Loop diuretic TDD at randomization was independently associated with worse outcomes in this high‐risk population. The efficacy of vericiguat was consistent across the range of diuretic doses. [ABSTRACT FROM AUTHOR]

Aim: Inhibition of microRNA (miR)‐132 effectively prevents and reverses adverse cardiac remodelling, making it an attractive heart failure (HF) target. CDR132L, a synthetic antisense oligonucleotide selectively blocking pathologically elevated miR‐132, demonstrated beneficial effects on left ventricular (LV) structure and function in relevant preclinical models, and was safe and well tolerated in a Phase 1b study in stable chronic HF patients. Patients with acute myocardial infarction (MI) and subsequent LV dysfunction and remodelling have limited therapeutic options, and may profit from early CDR132L treatment. Methods: The HF‐REVERT (Phase 2, multicenter, randomized, parallel, 3‐arm, placebo‐controlled Study to Assess Efficacy and Safety of CDR132L in Patients with Reduced Left Ventricular Ejection Fraction after Myocardial Infarction) evaluates the efficacy and safety of CDR132L in HF patients post‐acute MI (n = 280), comparing the effect of 5 and 10 mg/kg CDR132L, administered as three single intravenous doses 28 days apart, in addition to standard of care. Key inclusion criteria are the diagnosis of acute MI, the development of systolic dysfunction (LV ejection fraction ≤45%) and elevated N‐terminal pro‐B‐type natriuretic peptide. The study consists of a 6‐month double‐blinded treatment period with the primary endpoint LV end‐systolic volume index and relevant secondary endpoints, followed by a 6‐month open‐label observation period. Conclusion: The HF‐REVERT trial may underpin the concept of miR‐132 inhibition to prevent or reverse cardiac remodelling in post‐MI HF. The results will inform the design of subsequent outcome trials to test CDR132L in HF. [ABSTRACT FROM AUTHOR]

Implantable devices form an integral part of the management of patients with heart failure (HF) and provide adjunctive therapies in addition to cornerstone drug treatment. Although the number of these devices is growing, only few are supported by robust evidence. Current devices aim to improve haemodynamics, improve reverse remodelling, or provide electrical therapy. A number of these devices have guideline recommendations and some have been shown to improve outcomes such as cardiac resynchronization therapy, implantable cardioverter‐defibrillators and long‐term mechanical support. For others, more evidence is still needed before large‐scale implementation can be strongly advised. Of note, devices and drugs can work synergistically in HF as improved disease control with devices can allow for further optimization of drug therapy. Therefore, some devices might already be considered early in the disease trajectory of HF patients, while others might only be reserved for advanced HF. As such, device therapy should be integrated into HF care programmes. Unfortunately, implementation of devices, including those with the greatest evidence, in clinical care pathways is still suboptimal. This clinical consensus document of the Heart Failure Association (HFA) and European Heart Rhythm Association (EHRA) of the European Society of Cardiology (ESC) describes the physiological rationale behind device‐provided therapy and also device‐guided management, offers an overview of current implantable device options recommended by the guidelines and proposes a new integrated model of device therapy as a part of HF care. [ABSTRACT FROM AUTHOR]

Despite major advances in pharmacological treatment for patients with heart failure, residual mortality remains high. This suggests that important pathways are not yet targeted by current heart failure therapies. We sought integration of genetic, transcriptomic, and proteomic data in a large cohort of patients with heart failure to detect major pathways related to progression of heart failure leading to death. We used machine learning methodology based on stacked generalization framework and gradient boosting algorithms, using 54 clinical phenotypes, 403 circulating plasma proteins, 36,046 transcript expression levels in whole blood, and 6 million genomic markers to model all-cause mortality in 2,516 patients with heart failure from the BIOSTAT-CHF (Systems BIOlogy Study to TAilored Treatment in Chronic Heart Failure) study. Results were validated in an independent cohort of 1,738 patients. The mean age of the patients was 70 years (Q1-Q3: 61-78 years), 27% were female, median N-terminal pro–B-type natriuretic peptide was 4,275 ng/L (Q1-Q3: 2,360-8,486 ng/L), and 7% had heart failure with preserved ejection fraction. During a median follow-up of 21 months, 657 (26%) of patients died. The 4 major pathways with a significant association to all-cause mortality were: 1) the PI3K/Akt pathway; 2) the MAPK pathway; 3) the Ras signaling pathway; and 4) epidermal growth factor receptor tyrosine kinase inhibitor resistance. Results were validated in an independent cohort of 1,738 patients. A systems biology approach integrating genomic, transcriptomic, and proteomic data identified 4 major pathways related to mortality. These pathways are related to decreased activation of the cardioprotective ERBB2 receptor, which can be modified by neuregulin. [Display omitted] [ABSTRACT FROM AUTHOR]

Sodium-glucose cotransporter-2 (SGLT2) inhibitors are guideline recommended in the management of heart failure (HF). Although these therapies can be initiated even in patients with comorbid chronic kidney disease, some patients may face deterioration of kidney function over time. In this study, the authors sought to examine the safety and efficacy of continuing SGLT2 inhibitors in HF when the estimated glomerular filtration rate (eGFR) falls below thresholds for initiation. Associations between a deterioration of eGFR to <25 mL/min/1.73 m2, efficacy, and safety outcomes and treatment with dapagliflozin were evaluated in time-updated Cox proportional hazard models in a participant-level pooled analysis of the DAPA-HF (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure) and DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure) trials. Among 11,007 patients, 347 (3.2%) experienced a deterioration of eGFR to <25 mL/min/1.73 m2 at least once in follow-up. These patients had a higher risk of the primary composite outcome (HR: 1.87; 95% CI: 1.48-2.35; P < 0.001). The risk of the primary outcome was lower with dapagliflozin compared with placebo among patients who did (HR: 0.53; 95% CI: 0.33-0.83) as well as did not (HR: 0.78; 95% CI: 0.72-0.86) experience deterioration of eGFR to <25 mL/min/1.73 m2 (P interaction = 0.17). The risk of safety outcomes, including drug discontinuation, was higher among patients with deterioration of eGFR to <25 mL/min/1.73 m2; however, rates remained similar between treatment groups including among those who remained on study drug. Patients with deterioration of eGFR to <25 mL/min/1.73 m2 had elevated risks of cardiovascular outcomes yet appeared to benefit from continuation of dapagliflozin with no excess in safety outcomes between treatment groups. The benefit-to-risk ratio may favor continuation of dapagliflozin treatment in patients with HF experiencing deterioration of kidney function. Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure [DAPA-HF]; NCT03036124 ; and Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure [DELIVER]; NCT03619213) [Display omitted] [ABSTRACT FROM AUTHOR]