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CEC indicates clinical events committee; HF, heart failure; and PHF, possible heart failure. Keywords: clinical trial; clinical trials as topic; heart failure EN clinical trial clinical trials as topic heart failure 694 696 3 02/24/23 20230221 NES 230221 Centralized adjudication of potential end point events is standard practice in cardiovascular outcome trials designed for regulatory approval of therapeutics. Footnotes 1 Nonstandard Abbreviations and Acronyms CEC clinical events committee HF heart failure HR hazard ratio PHF probable heart failure VICTORIA Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction 2 This manuscript was sent to Harvey White, Guest Editor, for review by expert referees, editorial decision, and final disposition. [Extracted from the article]

The article discusses common reasons for hospitalization worldwide, and decongestion with loop diuretics is the primary focus of treatment in most patients. Topics include the practice, high-quality data from randomized trials evaluating effective treatment approaches, Diuretic Optimization Strategies Evaluation (DOSE) trial, and means of administration (bolus vs. continuous infusion) in patients hospital ized with heart failure and congestion.

Telephone or digital check-ins, direct to participant drug delivery, and patient-reported end points are all tools that could be used in situations when participants are no longer able to participate in a traditional trial model with scheduled in-person site visits. Keywords: clinical trial protocol; randomized clinical trials EN clinical trial protocol randomized clinical trials 369 371 3 08/02/22 20220802 NES 220802 The clinical research community, like others, has watched the unfolding humanitarian crisis in Ukraine with great concern. One of the most important considerations for a trial during a catastrophe must be the ethics of ongoing trial participation by affected sites and participants. [Extracted from the article]

The article focuses on the advancements in mechanical circulatory support devices for late-stage heart failure, highlighting progressive improvements in device durability and patient outcomes. Topics discussed include the ARIES-HM3 study, demonstrating the noninferiority of avoiding aspirin therapy in patients with a HeartMate 3 LVAD, leading to a substantial reduction in major bleeding events without compromising survival or thrombotic outcomes.

Expansion of extracellular fluid volume is central to the pathophysiology of heart failure. Increased extracellular fluid leads to elevated intracardiac filling pressures, resulting in a constellation of signs and symptoms of heart failure referred to as congestion. Loop diuretics are one of the cornerstones of treatments for heart failure, but in contrast to other therapies, robust clinical trial evidence to guide the use of diuretics is sparse. A nuanced understanding of renal physiology and diuretic pharmacokinetics is essential for skillful use of diuretics in the management of heart failure in both the inpatient and outpatient settings. Diuretic resistance, defined as an inadequate quantity of natriuresis despite an adequate diuretic regimen, is a major clinical challenge that generally portends a poor prognosis. In this review, the authors discuss the fundamental mechanisms and physiological principles that underlie the use of diuretic therapy and the available data on the optimal use of diuretics. [ABSTRACT FROM AUTHOR]

A study published in the European Journal of Heart Failure examined the use of vasodilators in patients with heart failure. The study found that while vasodilators can lower peripheral resistance and increase cardiac output, they may impair diuresis and have little benefit for patients with heart failure who are congested. Observational studies suggest that vasodilators may improve hemodynamics and preserve renal function in patients with acute heart failure, but randomized trials have not shown any clinical benefit. The authors recommend avoiding the use of vasodilators in patients with acute heart failure unless there is a specific reason for their use, and instead focusing on guideline-recommended medical therapy. [Extracted from the article]

Hospitalisation for acute heart failure remains a major public health problem with high prevalence, morbidity, mortality, and cost. Prior attempts to develop new therapies for this condition have not been successful. Nitroxyl (HNO) plays a unique role in cardiovascular physiology by direct post-translational modification of thiol residues on target proteins, specifically SERCA2a, phospholamban, the ryanodine receptor and myofilament proteins in cardiomyocytes. In animal models, these biological effects lead to vasodilatation, increased inotropy and lusitropy, but without tachyphylaxis, pro-arrhythmia or evidence of increased myocardial oxygen demand. BMS-986231 is an HNO donor being developed as a therapy for heart failure, and initial studies in patients with heart failure support the potential clinical value of these physiological effects. In this manuscript, we describe the ongoing phase II development programme for BMS-986231, which consists of three related randomised placebo-controlled clinical trials, StandUP-AHF, StandUP-Imaging and StandUP-Kidney, which are designed to provide evidence of tolerability and efficacy as well as confirm the anticipated physiological effects in patients with heart failure with reduced ejection fraction. These studies will set the stage for the further study of BMS-986231 in future phase III clinical trials. [ABSTRACT FROM AUTHOR]

As previously reported, PARAGON-HF narrowly missed statistical significance for its primary end point (rate ratio, 0.87 [95% CI, 0.75-1.01]; I P i =0.059).[2] It is noteworthy that 28% (566 cases) of potential HF hospitalizations identified by investigators were negatively adjudicated by the CEC. This mean probability for each event was then used in a multiple imputation procedure, creating 1000 imputed data sets with CEC-unconfirmed events included or not based on their probability (random draw from a respective Bernoulli distribution), such that an event with an average probability of 40% would be expected to be included as a HF hospitalization in 400 of 1000 data sets. Keywords: clinical trial; heart failure; hospitalization; probability; sacubitril-valsartan; valsartan EN clinical trial heart failure hospitalization probability sacubitril-valsartan valsartan 2316 2318 3 06/10/21 20210608 NES 210608 Heart failure with preserved ejection fraction is a highly morbid condition with few proven treatment options. [Extracted from the article]

B This article refers to 'Association of time-to-intravenous furosemide with mortality in acute heart failure: data from REPORT-HF' by W. Ouwerkerk I et al i ., published in this issue on pages 43-51. b There are acute cardiovascular conditions in which the speed of treatment is directly correlated with clinical outcomes - most notably, in ST-elevation myocardial infarction ("door-to-balloon time") and in cardiac arrest (time to defibrillation). Early intravenous heart failure therapy and outcomes among older patients hospitalized for acute decompensated heart failure: findings from the Acute Decompensated Heart Failure Registry Emergency Module (ADHERE-EM). Patients in whom an AHF diagnosis is more apparent (thus allowing for prompter treatment) may have an inherently more favourable long-term prognosis than patients with greater diagnostic complexity (resulting in delayed first diuretic doses). [Extracted from the article]

The article discusses aspects of diuretic therapy for heart failure. Topics include the pharmacologic, pharmacokinetic and pharmacodynamic characteristics of loop diuretics, administration of loop diuretics in patients with acute decompensated heart failure, and causes and treatment of diuretic resistance.

Importance: The natriuretic peptides are biochemical markers of heart failure (HF) severity and predictors of adverse outcomes. Smaller studies have evaluated adjusting HF therapy based on natriuretic peptide levels ("guided therapy") with inconsistent results.Objective: To determine whether an amino-terminal pro-B-type natriuretic peptide (NT-proBNP)-guided treatment strategy improves clinical outcomes vs usual care in high-risk patients with HF and reduced ejection fraction (HFrEF).Design, Settings, and Participants: The Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure (GUIDE-IT) study was a randomized multicenter clinical trial conducted between January 16, 2013, and September 20, 2016, at 45 clinical sites in the United States and Canada. This study planned to randomize 1100 patients with HFrEF (ejection fraction ≤40%), elevated natriuretic peptide levels within the prior 30 days, and a history of a prior HF event (HF hospitalization or equivalent) to either an NT-proBNP-guided strategy or usual care.Interventions: Patients were randomized to either an NT-proBNP-guided strategy or usual care. Patients randomized to the guided strategy (n = 446) had HF therapy titrated with the goal of achieving a target NT-proBNP of less than 1000 pg/mL. Patients randomized to usual care (n = 448) had HF care in accordance with published guidelines, with emphasis on titration of proven neurohormonal therapies for HF. Serial measurement of NT-proBNP testing was discouraged in the usual care group.Main Outcomes and Measures: The primary end point was the composite of time-to-first HF hospitalization or cardiovascular mortality. Prespecified secondary end points included all-cause mortality, total hospitalizations for HF, days alive and not hospitalized for cardiovascular reasons, the individual components on the primary end point, and adverse events.Results: The data and safety monitoring board recommended stopping the study for futility when 894 (median age, 63 years; 286 [32%] women) of the planned 1100 patients had been enrolled with follow-up for a median of 15 months. The primary end point occurred in 164 patients (37%) in the biomarker-guided group and 164 patients (37%) in the usual care group (adjusted hazard ratio [HR], 0.98; 95% CI, 0.79-1.22; P = .88). Cardiovascular mortality was 12% (n = 53) in the biomarker-guided group and 13% (n = 57) in the usual care group (HR, 0.94; 95% CI; 0.65-1.37; P = .75). None of the secondary end points nor the decreases in the NT-proBNP levels achieved differed significantly between groups.Conclusions and Relevance: In high-risk patients with HFrEF, a strategy of NT-proBNP-guided therapy was not more effective than a usual care strategy in improving outcomes.Trial Registration: clinicaltrials.gov Identifier: NCT01685840. [ABSTRACT FROM AUTHOR]

Background The oral vasopressin-2 receptor antagonist tolvaptan causes aquaresis in patients with volume overload, potentially facilitating decongestion and improving the clinical course of patients with acute heart failure (AHF). Objectives The TACTICS-HF (Targeting Acute Congestion with Tolvaptan in Congestive Heart Failure) study was conducted to address the acute use of tolvaptan to improve congestion in AHF. Methods The TACTICS-HF study randomized patients (n = 257) within 24 h of AHF presentation in a prospective, double blind, placebo-controlled trial. Patients were eligible regardless of ejection fraction, and were randomized to either 30 mg of tolvaptan or placebo given at 0, 24, and 48 h, with a fixed-dose furosemide regimen as background therapy. The primary endpoint was the proportion of patients considered responders at 24 h. Secondary endpoints included symptom improvement, changes in renal function, and clinical events. Results Dyspnea relief by Likert scale was similar between groups at 8 h (25% moderately or markedly improved with tolvaptan vs. 28% placebo; p = 0.59) and at 24 h (50% tolvaptan vs. 47% placebo; p = 0.80). Need for rescue therapy was also similar at 24 h (21% tolvaptan, 18% placebo; p = 0.57). The proportion defined as responders at 24 h (primary study endpoint) was 16% for tolvaptan and 20% for placebo (p = 0.32). Tolvaptan resulted in greater weight loss and net fluid loss compared with placebo, but tolvaptan-treated patients were more likely to experience worsening renal function during treatment. There were no differences in in-hospital or post-discharge clinical outcomes. Conclusions In patients hospitalized with AHF, dyspnea, and congestion, the addition of tolvaptan to a standardized furosemide regimen did not improve the number of responders at 24 h, despite greater weight loss and fluid loss. (Targeting Acute Congestion With Tolvaptan in Congestive Heart Failure [TACTICS-HF]; NCT01644331 ) [ABSTRACT FROM AUTHOR]

Until recently, the combination of -blockers, renin-angiotensin system inhibitors (angiotensin-converting enzyme inhibitors or angiotensin receptor blockers), and mineralocorticoid receptor antagonists formed the foundation of triple therapy for heart failure (HF). These data are of critical importance, because improving patient-reported outcomes in HF, especially in highly symptomatic patients, is an important goal in drug development. [Extracted from the article]

Background: Omecamtiv mecarbil (OM) is a selective cardiac myosin activator that increases myocardial function in healthy volunteers and in patients with chronic heart failure.Objectives: This study evaluated the pharmacokinetics, pharmacodynamics, tolerability, safety, and efficacy of OM in patients with acute heart failure (AHF).Methods: Patients admitted for AHF with left ventricular ejection fraction ≤40%, dyspnea, and elevated plasma concentrations of natriuretic peptides were randomized to receive a double-blind, 48-h intravenous infusion of placebo or OM in 3 sequential, escalating-dose cohorts.Results: In 606 patients, OM did not improve the primary endpoint of dyspnea relief (3 OM dose groups and pooled placebo: placebo, 41%; OM cohort 1, 42%; cohort 2, 47%; cohort 3, 51%; p = 0.33) or any of the secondary outcomes studied. In supplemental, pre-specified analyses, OM resulted in greater dyspnea relief at 48 h (placebo, 37% vs. OM, 51%; p = 0.034) and through 5 days (p = 0.038) in the high-dose cohort. OM exerted plasma concentration-related increases in left ventricular systolic ejection time (p < 0.0001) and decreases in end-systolic dimension (p < 0.05). The adverse event profile and tolerability of OM were similar to those of placebo, without increases in ventricular or supraventricular tachyarrhythmias. Plasma troponin concentrations were higher in OM-treated patients compared with placebo (median difference at 48 h, 0.004 ng/ml), but with no obvious relationship with OM concentration (p = 0.95).Conclusions: In patients with AHF, intravenous OM did not meet the primary endpoint of dyspnea improvement, but it was generally well tolerated, it increased systolic ejection time, and it may have improved dyspnea in the high-dose group. (Acute Treatment with Omecamtiv Mecarbil to Increase Contractility in Acute Heart Failure [ATOMIC-AHF]; NCT01300013). [ABSTRACT FROM AUTHOR]

Circulating natriuretic peptide measurements have been used extensively over the past 15 years to diagnose and monitor patients with heart failure. We are still learning how complex the dynamics of natriuretic peptides can be in the interpretation of test results in individual patients. Although natriuretic peptide measurements are widely used in practice, there are questions regarding why these peptides may not necessarily track with blood volume or invasive hemodynamic measurements in individual patients. Interpretation of natriuretic peptide measurements will depend on many factors, including special patient populations, obesity, renal function, the state of congestion or decongestion, and whether patients are receiving specific therapies. Natriuretic peptide measurements have clearly revolutionized clinical care for patients with heart failure, but further research should provide insights to help use these measurements to individualize patient care beyond the current guidelines. [ABSTRACT FROM AUTHOR]

Aims: Troponin elevation is common in acute heart failure (AHF) and may be useful for prognostication; however, available data are mixed and many previous studies used older, less sensitive assays. We examined the association between serial measurements of high-sensitivity cardiac troponin T (hs-cTnT) and outcomes in RELAX-AHF.Methods and Results: Hs-cTnT was measured at baseline and days 2, 5, and 14. We assessed the relationship between baseline, peak and peak change hs-cTnT with dyspnoea relief by visual analogue scale, cardiovascular death, or HF/renal hospitalization to 60 days and cardiovascular mortality to 180 days. Models were adjusted for clinical variables and treatment assignment. Whether baseline troponin status affected the treatment effect of serelaxin was assessed using interactions terms. In 1074 patients, the median baseline troponin was 0.033 µg/L, and 90% of patients were above the 99th upper reference limit (URL). Patients with hs-cTnT >median were more likely to be men with ischaemic heart disease, worse renal function, and higher N-terminal pro-brain natriuretic peptide. Higher baseline or peak hs-cTnT and greater peak change were associated with worse outcomes independent of adjustment for covariates, but relationships were generally strongest for 180-day cardiovascular mortality (hazard ratio per doubling of baseline hs-cTnT = 1.36, 95% confidence interval 1.15-1.60). Troponin was most strongly associated with death from heart failure or from other cardiovascular causes. The treatment effect of serelaxin did not differ by baseline troponin levels.Conclusion: Hs-cTnT was elevated above the 99% URL in the majority of AHF patients. Baseline, peak, and peak change hs-cTnT were associated with worse outcomes, with the strongest relationship with 180-day cardiovascular mortality. [ABSTRACT FROM AUTHOR]

Aims Troponin elevation is common in acute heart failure (AHF) and may be useful for prognostication; however, available data are mixed and many previous studies used older, less sensitive assays. We examined the association between serial measurements of high-sensitivity cardiac troponin T (hs-cTnT) and outcomes in RELAX-AHF. Methods and results Hs-cTnT was measured at baseline and days 2, 5, and 14. We assessed the relationship between baseline, peak and peak change hs-cTnT with dyspnoea relief by visual analogue scale, cardiovascular death, or HF/renal hospitalization to 60 days and cardiovascular mortality to 180 days. Models were adjusted for clinical variables and treatment assignment. Whether baseline troponin status affected the treatment effect of serelaxin was assessed using interactions terms. In 1074 patients, the median baseline troponin was 0.033 μg/L, and 90% of patients were above the 99th upper reference limit (URL). Patients with hs-cTnT >median were more likely to be men with ischaemic heart disease, worse renal function, and higher N-terminal pro-brain natriuretic peptide. Higher baseline or peak hs-cTnT and greater peak change were associated with worse outcomes independent of adjustment for covariates, but relationships were generally strongest for 180-day cardiovascular mortality (hazard ratio per doubling of baseline hs-cTnT = 1.36, 95% confidence interval 1.15- 1.60). Troponin was most strongly associated with death from heart failure or from other cardiovascular causes. The treatment effect of serelaxin did not differ by baseline troponin levels. Conclusion Hs-cTnT was elevated above the 99% URL in the majority of AHF patients. Baseline, peak, and peak change hs-cTnT were associated with worse outcomes, with the strongest relationship with 180-day cardiovascular mortality. [ABSTRACT FROM AUTHOR]

The author comments on a review of clinical trials and studies that evaluated natriuretic peptides (NP) as markers of risk in patients with heart failure (HF). He describes the effects of targeting a specific decrease in NP level on treatment outcomes. He also discusses the implications of the results for the inpatient management of HF and the design of randomized controlled trials (RCT).

Background Little is known about mode of death after acute heart failure (AHF) hospitalization. In the RELAX-AHF (Efficacy and Safety of Relaxin for the Treatment of Acute Heart Failure) study, serelaxin, the recombinant form of human relaxin-2, reduced post-discharge mortality at 180 days in selected patients with AHF. Objectives The goal of this study was to assess the effect of serelaxin on specific modes of death in patients with AHF. Methods The RELAX-AHF study randomized 1,161 patients with AHF to 48 h of therapy with intravenous serelaxin or placebo. Patients were followed for vital status through 180 days. A blinded clinical events committee reviewed all deaths and adjudicated a cause of death on the basis of pre-specified criteria. Cox proportional hazard models were used to assess the effect of serelaxin on each mode of death, on the basis of pre-specified groupings of mode of death. Results There were 107 deaths (9.3%): 37 (35%) due to HF, 25 (23%) due to sudden death, 15 (14%) due to other cardiovascular (CV) causes, 19 (18%) due to non-CV causes, and 11 (10%) classified as unknown. The treatment effect of serelaxin was most pronounced on other CV deaths (hazard ratio [HR]: 0.29; 95% CI: 0.12 to 0.73; p = 0.005) and sudden death (HR: 0.46; 95% CI: 0.20 to 1.07; p = 0.065). There was no apparent impact of serelaxin treatment on HF deaths or non-CV deaths. Conclusions In the RELAX-AHF study, the effects of serelaxin on mortality were primarily driven by reduction in mortality from other CV causes and sudden death, without apparent impact on HF deaths. (Efficacy and Safety of Relaxin for the Treatment of Acute Heart Failure [RELAX-AHF]; NCT00520806 ) [ABSTRACT FROM AUTHOR]

Following those important results, how should we manage loop diuretics in HF patients without clinical congestion and low dose of loop diuretics? 6 Dauw J, Martens P, Tersalvi G, Schouteden J, Deferm S, Gruwez H, De Moor B, Nijst P, Dupont M, Mullens W. Diuretic response and effects of diuretic omission in ambulatory heart failure patients on chronic low-dose loop diuretic therapy. Although diuretic discontinuation may be feasible in carefully selected patients, chronic loop diuretics are central to maintaining sodium and fluid balance in many patients with chronic HF. [Extracted from the article]

The article argues over the comment that lack of effect on cardiovascular mortality in GALACTIC-HF is due to an unfavorable effect of omecamtiv mecarbil on myocardial energetics, citing work in a model of acute ischemia in pigs and in whole hearts subjected to cardioplegia. Topics include deficiencies in the experimental approach undermine the conclusions contradictory to the lack of effect of omecamtiv mecarbil; and myocardial oxygen consumption and its inhibition of the resting myosin ATPase.

Aims We examined the prognostic importance of cardiac troponin I (cTnI) in a cohort of patients enrolled in the ASCEND-HF study of nesiritide in acute decompensated heart failure (ADHF). Circulating troponins are a prognostic marker in patients with ADHF. Contemporary assays with greater sensitivity require reassessment of the significance of troponin elevation in HF. Methods and results Cardiac troponin I was measured in a core laboratory in 808 ADHF patients enrolled in the ASCEND-HF biomarkers substudy using a sensitive assay (VITROS Trop I ES, Ortho Clinical Diagnostics) with a lower limit of detection of 0.012 ng/mL and a 99th percentile upper reference limit (URL) of 0.034 ng/mL. Patients with clinical evidence of acute coronary syndrome or troponin >5× the URL were excluded. Multivariable modelling was used to assess the relationship between log(cTnI) and in-hospital and post-discharge outcomes. Baseline cTnI was undetectable in 22% and elevated above the 99th percentile URL in 50% of subjects. cTnI levels did not differ based on HF aetiology. After multivariable adjustment, higher cTnI was associated with worsened in-hospital outcomes such as length of stay (P = 0.01) and worsening HF during the index hospitalization (P = 0.01), but was not associated with worsened post-discharge outcomes at 30 or 180 days. The relationship between cTnI and outcomes was generally linear and there was no evidence of a threshold effect at any particular level of cTnI. Conclusion cTnI is elevated above the 99th percentile URL in 50% of ADHF patients and predicts in-hospital outcome, but is not an independent predictor of long-term outcomes. [ABSTRACT FROM AUTHOR]

Congestion and volume overload are the hallmarks of acute decompensated heart failure (ADHF), and loop diuretics have historically been the cornerstone of treatment. The demonstrated efficacy of loop diuretics in managing congestion is balanced by the recognized limitations of diuretic resistance, neurohormonal activation, and worsening renal function. However, the recently published DOSE (Diuretic Optimization Strategies Evaluation) trial suggests that previous concerns about the safety of high-dose diuretics may not be valid. There has been a growing interest in alternative strategies to manage volume retention in ADHF with improved efficacy and safety profiles. Peripheral venovenous ultrafiltration (UF) represents a potentially promising approach to volume management in ADHF. Small studies suggest that UF may allow for more effective fluid removal compared with diuretics, with improved quality of life and reduced rehospitalization rates. However, further investigation is needed to completely define the role of UF in patients with ADHF. This review summarizes available data on the use of both diuretics and UF in ADHF patients and identifies challenges and unresolved questions for each approach. [Copyright &y& Elsevier]

Abstract: Objective: To determine the correlation between differential white blood cell (WBC) count and characteristics and outcome of acute heart failure (AHF) syndromes. Background: Previous studies suggested that different white blood cell count patterns are related to outcome in patients with heart failure (HF) and other cardiovascular disorders. Methods: Data from all qualifying AHF admissions to a city hospital (n =340) was prospectively collected. Patients were followed from admission up to 6months post-discharge. The relationship between patients'' demographics, clinical and laboratory characteristics and outcome were assessed in relation to WBC count and lymphocyte to WBC ratio (LWR). Results: WBC count >10,100×10 (9)/L (upper tertile) on admission was associated with higher admission blood pressure, lower oxygen saturation, higher heart rate and increased troponin, with no impact on either short-term worsening HF or long-term adverse outcome. Lower LWR was associated with higher BUN and troponin and lower hemoglobin, but not with a distinct clinical presentation. The lower LWR tertile (≤13%) was associated with a 60% increase in worsening HF risk and a substantially higher 1month (15% versus 2%) and 6months mortality (23% vs. 3%) for lowest versus highest quartile (p <0.0001). Conclusions: While increased WBC count is associated with a more “vascular presentation” and certain severity markers, it is not related to worse patient outcome. Low LWR (≤13%) is predictive of worse outcome and higher mortality. It is also associated with certain laboratory abnormalities, but not related to a specific clinical profile. [Copyright &y& Elsevier]

Abstract: Acute heart failure (HF) is the most common diagnosis at discharge in patients aged >65years. It carries a dismal prognosis with a high in-hospital mortality and very high post-discharge mortality and re-hospitalization rates. It is a complex clinical syndrome that cannot be described as a single entity as it varies widely with respect to underlying pathophysiologic mechanisms, clinical presentations and, likely, treatments. It is the aim of this paper to describe some of the main clinical presentations of acute HF. Amongst them, we will consider de novo HF versus acutely decompensated chronic HF, HF caused, and/or worsened, by myocardial ischemia, acute HF with low, normal, or high systolic blood pressure, acute HF caused by lung congestion or fluid retention or fluid redistribution to the lungs, and acute HF with comorbidities (diabetes, anemia, renal insufficiency, etc.). Different pathophysiologic mechanisms and clinical presentations may coexist in the same patient. Identification and, whenever possible, treatment of underlying pathophysiologic mechanisms may become important for acute HF management. [ABSTRACT FROM AUTHOR]

Aims: The prevalence and importance of liver function test (LFT) abnormalities in a large contemporary cohort of heart failure patients have not been systematically evaluated. [ABSTRACT FROM PUBLISHER]

The article discusses the data supporting the efficacy of inotropic therapy for acute heart failure (AHF) patients. It is noted that although these agents improve cardiac output, their use in heart failure has consistently been associated with increased myocardial oxygen demand, cardiac arrhythmias, and mortality. Inotropes such as dobutamine and milrinone act by increasing cyclic adenylate monophosphate and therefore intracellular calcium flux.

Objectives: The goal of this study was to identify potentially novel laboratory markers of risk in chronic heart failure patients. Background: Although a variety of prognostic markers have been described in heart failure, a systematic assessment of routine laboratory values has not been reported. Methods: All 2,679 symptomatic chronic heart failure patients from the North American CHARM (Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity) program had a wide range of laboratory measures performed at a core facility, enabling us to assess the relationship between routine blood tests and outcomes using a Cox proportional hazards model. We then replicated our findings in a cohort of 2,140 heart failure patients from the Duke Databank. Results: Among 36 laboratory values considered in the CHARM program, higher red cell distribution width (RDW) showed the greatest association with morbidity and mortality (adjusted hazard ratio 1.17 per 1-SD increase, p < 0.001). Higher RDW was among the most powerful overall predictors, with only age and cardiomegaly showing a better independent association with outcome. This finding was replicated in the Duke Databank, in which higher RDW was strongly associated with all-cause mortality (adjusted hazard ratio 1.29 per 1 SD, p < 0.001), second only to age as a predictor of outcome. Conclusions: In 2 large contemporary heart failure populations, RDW was found to be a very strong independent predictor of morbidity and mortality. Understanding how and why this marker is associated with outcome may provide novel insights into heart failure pathophysiology. [Copyright &y& Elsevier]

The natriuretic peptides are a family of related hormones that play a crucial role in cardiovascular homeostasis. They have recently emerged as potentially important clinical markers in heart failure. Recent data have suggested an important role for these markers in establishing the diagnosis of heart failure in patients with unexplained dyspnea in both acute care and ambulatory settings. Other clinical uses of the natriuretic peptides, such as screening for asymptomatic ventricular dysfunction, establishing prognosis or guiding titration of drug therapy, are under investigation but have not yet sufficiently been validated for widespread clinical use. [ABSTRACT FROM AUTHOR]

Abstract: Accurate assessment of volume status remains an important clinical goal in the management of patients with heart failure. Although physical examination can provide clues to volume status, its sensitivity and reproducibility are limited. Other noninvasive methods, such as measurement of natriuretic peptides or the use of impedance cardiography, are not well validated. The cardiovascular response to the Valsalva maneuver had been proposed as a simple, inexpensive bedside test for estimating filling pressures in patients with heart failure. Our objective was to summarize and critically evaluate the evidence for the use of the Valsalva maneuver in evaluating volume status in patients with heart failure. Studies have demonstrated a significant correlation between the cardiovascular response to the Valsalva maneuver and invasively measured ventricular filling pressures in patients with clinical heart failure. Although often overlooked in clinical training and practice, the cardiovascular response to the Valsalva maneuver is a potentially useful, noninvasive means of evaluating filling pressures in patients with heart failure. [Copyright &y& Elsevier]

Background: Anaemia is common in heart failure (HF) and associated with higher mortality. Exacerbation of myocardial ischemia in patients with heart failure, coronary disease, and anaemia patients has been suggested as a potential mechanism underlying this association. Aims: The aim of this study was to evaluate the hypothesis that greater CAD severity would exacerbate the adverse effects of anaemia in HF. Methods: We examined data on patients with symptomatic heart failure (NYHA class > or = II) undergoing coronary angiography between 1995 and 2003 (n = 4951). Patients with primary valvular or congenital heart disease were excluded. Cox proportional hazards modeling was used to evaluate the relationship between coronary disease severity (as defined by no. of diseased vessels) and hemoglobin concentration. Results and Conclusions: In patients with symptomatic HF undergoing coronary angiography, we found an interaction between hemoglobin and CAD severity (p = 0.003 for interaction). Contrary to our hypothesis, the mortality hazard associated with anaemia was greatest in patients without CAD and progressively lower with increasing CAD severity. These data suggest that anaemia may exert its effect on HF outcomes through mechanisms beyond simply the exacerbation of myocardial ischemia. [ABSTRACT FROM AUTHOR]

Background: Heart transplantation (HT) is an effective therapy for end-stage heart failure, but its impact is limited by the scarcity of donor organs and stringent selection criteria for both donors and recipients. The creation of an alternate list to match recipients with contraindications to traditional HT with sub-optimal donor organs has been implemented at some centers, but outcomes using this approach are uncertain. Methods: We created an alternate list that matched recipients in whom standard HT was contraindicated with donor organs that had been rejected for use in standard transplantation. Data on patient characteristics and outcomes were compared with a control group of patients transplanted on the standard list over the same time period. Results: Fifty patients received HT on the alternate list, compared with 195 on the standard list. The most common reasons for recipient listing on the alternate list were age >65 years (n = 28) and diabetes with end-organ dysfunction (n = 9). Alternate-list patients were older and more likely to have an ischemic etiology and diabetes mellitus. The most common reasons for allocation of donor organs to alternate-list patients were coronary artery disease (n = 12), positive hepatitis serology (n = 12) or left ventricular (LV) dysfunction (n = 8). Two-year survival was 70% for alternate-list patients compared with 88% for standard-list patients (p = 0.02). Post-transplant morbidity did not differ significantly between the 2 groups except that alternate-list patients were hospitalized more frequently. Conclusions: The use of an alternate list can expand the applicability of HT to patients who would otherwise be denied this therapy. Although associated with greater morbidity and mortality than standard-list HT, alternate-list HT resulted in clinical outcomes that were significantly better than the natural history of end-stage heart failure. [Copyright &y& Elsevier]

We investigated the prevalence of anemia and its relation to clinical events in patients with decompensated heart failure enrolled in the OPTIME-CHF study. Our data demonstrate that anemia is common in patients hospitalized with decompensated heart failure and is associated with a greater number of co-morbid conditions. Lower baseline hemoglobin is associated with risk of short-term adverse clinical outcomes in this population, even after controlling for other baseline differences. [Copyright &y& Elsevier]

: ObjectivesThe goal of this study was to assess the interaction between heart failure (HF) etiology and response to milrinone in decompensated HF.: BackgroundEtiology has prognostic and therapeutic implications in HF, but its relationship to response to inotropic therapy is unknown.: MethodsThe Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-CHF) study randomized 949 patients with systolic dysfunction and decompensated HF to receive 48 to 72 h of intravenous milrinone or placebo. The primary end point was days hospitalized from cardiovascular causes within 60 days. In a post-hoc analysis, we evaluated the interaction between response to milrinone and etiology of HF.: ResultsThe primary end point was 13.0 days for ischemic patients and 11.7 days for nonischemic patients (p = 0.2). Sixty-day mortality was 11.6% for the ischemic group and 7.5% for the nonischemic group (p = 0.03). After adjustment for baseline differences, there was a significant interaction between etiology and the effect of milrinone. Milrinone-treated patients with ischemic etiology tended to have worse outcomes than those treated with placebo in terms of the primary end point (13.6 days for milrinone vs. 12.4 days for placebo, p = 0.055 for interaction) and the composite of death or rehospitalization (42% vs. 36% for placebo, p = 0.01 for interaction). In contrast, outcomes in nonischemic patients treated with milrinone tended to be improved in terms of the primary end point (10.9 vs. 12.6 days placebo) and the composite of death or rehospitalization (28% vs. 35% placebo).: ConclusionsMilrinone may have a bidirectional effect based on etiology in decompensated HF. Milrinone may be deleterious in ischemic HF, but neutral to beneficial in nonischemic cardiomyopathy. [Copyright &y& Elsevier]

: ObjectivesWe sought to evaluate the association between the extent of coronary artery disease (CAD) and survival in patients with symptomatic heart failure (HF) and to create the most prognostically powerful clinical definition of ischemic cardiomyopathy.: BackgroundAn ischemic etiology of HF is known to be a predictor of adverse outcome; however, there is no uniform definition for ischemic cardiomyopathy.: MethodsWe assessed the clinical history and coronary anatomy of patients with symptomatic HF and ejection fraction ≤40% undergoing diagnostic coronary angiography between 1986 and 1999 (n = 1,921). Five classification schemes were tested to identify the most prognostically powerful method for defining the extent of CAD and to develop the best definition of ischemic cardiomyopathy for prognostic purposes.: ResultsA more extensive CAD was independently associated with shorter survival. When the various classification schemes were compared, a modified number-of-diseased-vessels classification, in which patients with single-vessel disease and no prior history of revascularization or myocardial infarction (MI) were classified as nonischemic, provided the most prognostic power. A definition of ischemic cardiomyopathy that incorporated this definition had more prognostic power than the traditional definition.: ConclusionsAngiographically diagnosed ischemic HF is associated with shorter survival than nonischemic HF. A more extensive CAD is independently associated with shorter survival, and patients with single-vessel disease and no history of MI or revascularization should be classified as nonischemic for prognostic purposes. Standardization of the definition of ischemic cardiomyopathy will be useful in the conduct and interpretation of clinical research in HF. [Copyright &y& Elsevier]

Aims Methods and results Conclusion Serelaxin is recombinant human relaxin‐2, a hormone responsible for haemodynamic adaptations and organ protection in pregnancy. In the RELAX‐AHF trial, serelaxin demonstrated reductions in cardiac, renal and hepatic damage. In RELAX‐AHF‐2, organ damage‐related biomarkers were assessed in a biomarker substudy.Patients enrolled within 16 h of presentation for heart failure hospitalization were randomized to 48‐h infusions of either serelaxin (30 μg/kg/day) or placebo, and plasma samples were obtained at baseline, 2, 5, and 14 days in patients participating in the biomarker substudy. Of the 6545 patients analysed in RELAX‐AHF‐2, 1020 (15.6%) patients (mean age 72 ± 12 years; 61% male) were enrolled in the biomarker substudy. Compared to placebo, serelaxin decreased percentage change from baseline in troponin T through day 14 (serelaxin +0.2% vs. placebo +40.3%; p = 0.042), as well as creatinine (−0.8% vs. +5.8%; p = 0.002), cystatin C (+3.8% vs. +8.3%; p = 0.016), and uric acid (+0.8% vs. +7.2%; p = 0.0014) at day 2. The decrease of N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) from baseline to day 2 was greater in serelaxin‐treated patients (−39.8% vs. −27.6%; p = 0.002). Early changes in NT‐proBNP and troponin, but not creatinine, cystatin C and uric acid, were associated with 180‐day mortality. In this substudy population, serelaxin did not reduce 180‐day cardiovascular death (hazard ratio [HR] 0.78; 95% confidence interval [CI] 0.49–1.25; p = 0.30), but significantly reduced worsening heart failure through day 5 (HR 0.55; 95% CI 0.33–0.93; p = 0.027).In this substudy, serelaxin decreased plasma concentrations of cardiac, renal and hepatic injury markers. Changes of most of these markers were associated with cardiovascular mortality. In this pre‐specified biomarker subgroup, serelaxin did not reduce 180‐day cardiovascular mortality but significantly reduced worsening heart failure through day 5. [ABSTRACT FROM AUTHOR]

Randomized clinical trials are the gold standard for establishing the efficacy and safety of cardiovascular therapies. However, current pivotal trials are expensive, lengthy, and insufficiently diverse. Emerging artificial intelligence (AI) technologies can potentially automate and streamline clinical trial operations. This review describes opportunities to integrate AI throughout a trial's life cycle, including designing the trial, identifying eligible patients, obtaining informed consent, ascertaining physiological and clinical event outcomes, interpreting imaging, and analyzing or disseminating the results. Nevertheless, AI poses risks, including generating inaccurate results, amplifying biases against underrepresented groups, and violating patient privacy. Medical journals and regulators are developing new frameworks to evaluate AI research tools and the data they generate. Given the high-stakes role of randomized trials in medical decision making, AI must be integrated carefully and transparently to protect the validity of trial results. [ABSTRACT FROM AUTHOR]