Abstract Background Heart failure (HF) is characterized by perturbations in energy homeostasis and metabolism. The reversibility and prognostic value of circulating markers associated with these ...changes remain unclear. Objectives This study sought to describe the metabolomic profiles of patients along the spectrum of systolic HF, determine their association with adverse outcomes in a clinical trial of HF, and evaluate whether identified metabolites change with treatment for end-stage systolic HF. Methods To assess association of metabolites with clinical outcomes, we evaluated a population of 453 chronic systolic HF patients who had been randomized to exercise training versus usual care. To assess change in metabolites with mechanical circulatory support, 41 patients with end-stage HF who underwent left ventricular assist device (LVAD) placement were studied. Targeted, quantitative profiling of 60 metabolites using tandem flow injection mass spectrometry was performed on frozen plasma samples obtained prior to randomization, as well as prior to and ≥90 days post-placement in the LVAD group. Principal components analysis was used for data reduction. Results Five principal components analysis–derived factors were significantly associated with peak V o2 levels at baseline in fully adjusted models. Of these, factor 5 (composed of long-chain acylcarnitines) was associated with increased risk of all 3 pre-specified clinical trial outcomes: all-cause mortality/all-cause hospitalization, all cause-hospitalization, and cardiovascular death or cardiovascular hospitalization. Individual components of factor 5 were significantly higher in patients with end-stage HF prior to LVAD placement and decreased significantly post-implantation. Conclusions In chronic HF patients, circulating long-chain acylcarnitine metabolite levels were independently associated with adverse clinical outcomes and decreased after long-term mechanical circulatory support. These metabolites may serve as potential targets for new diagnostics or therapeutic interventions. (Exercise Training Program to Improve Clinical Outcomes in Individuals With Congestive Heart Failure; NCT00047437 )
Abstract Heart failure patients are classified by ejection fraction (EF) into distinct groups: heart failure with preserved ejection fraction (HFpEF) or heart failure with reduced ejection fraction ...(HFrEF). Although patients with heart failure commonly have multiple comorbidities that complicate management and may adversely affect outcomes, their role in the HFpEF and HFrEF groups is not well-characterized. This review summarizes the role of noncardiac comorbidities in patients with HFpEF versus HFrEF, emphasizing prevalence, underlying pathophysiologic mechanisms, and outcomes. Pulmonary disease, diabetes mellitus, anemia, and obesity tend to be more prevalent in HFpEF patients, but renal disease and sleep-disordered breathing burdens are similar. These comorbidities similarly increase morbidity and mortality risk in HFpEF and HFrEF patients. Common pathophysiologic mechanisms include systemic and endomyocardial inflammation with fibrosis. We also discuss implications for clinical care and future HF clinical trial design. The basis for this review was discussions between scientists, clinical trialists, and regulatory representatives at the 10th Global CardioVascular Clinical Trialists Forum.
Abstract 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 To address the acute use of tolvaptan to improve congestion in AHF, we conducted the Targeting Acute Congestion with Tolvaptan in Congestive Heart Failure (TACTICS-HF, NCT01644331) study. Methods TACTICS-HF randomized patients within 24 hours 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 hours, with a fixed-dose furosemide regimen as background therapy. The primary endpoint was the proportion of patients considered responders at 24 hours. Secondary endpoints included symptom improvement, changes in renal function, and clinical events. Results A total of 257 patients were randomized. Dyspnea relief by Likert scale was similar between tolvaptan and placebo at 8 hours (25% moderately or markedly improved for tolvaptan vs. 28% placebo, p=0.59) and at 24 hours (50% tolvaptan vs. 47% placebo, p=0.80). Need for rescue therapy was also similar at 24 hours (21% tolvaptan, 18% placebo, p=0.57). The proportion defined as responders at 24 hours (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 to 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 hours despite greater weight loss and fluid loss.
Objectives The study sought to investigate the clinical correlates and prognostic role of anemia and changes in hemoglobin in patients hospitalized for acute decompensated heart failure (AHF). ...Background Anemia is related to a poor outcome in patients with heart failure. In addition, an increase in hemoglobin during hospitalization might be a sign of effective decongestion and therefore related to improved outcome. Methods This is a post hoc analysis of the PROTECT (Placebo-Controlled Randomized Study of the Selective Adenosine A1 Receptor Antagonist Rolofylline for Patients Hospitalized with Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function) study in 1,969 patients with AHF and mild to moderate impaired renal function. Hemoglobin levels were measured daily for the first 4 days and at day 7. The endpoint was 180-day all-cause mortality. Results Anemia at baseline was observed in 50.3% of the patients. During follow-up, 359 patients (18.2%) died. Hemoglobin increased in 69.1% and was associated with a better renal function at baseline and more weight loss, but was associated with a deterioration of renal function (p = 0.01), whereas total dose diuretics was lower in patients with hemoconcentration (p < 0.01). Interaction analysis showed that greater weight loss and better baseline renal function were associated with a more rapid increase in hemoglobin concentration (p < 0.01 for both). The absolute change in hemoglobin (g/dl) independently predicted outcome (hazard ratio: 0.66; 95% confidence interval: 0.51 to 0.86; p = 0.002), whereas baseline hemoglobin levels did not. Conclusions Patients with AHF and preserved renal function are decongested better, as shown by an increase in hemoglobin. A rapid increase in hemoglobin during the first week is independently associated with a favorable outcome, despite a slight decrease in renal function.
Background The postdischarge rehospitalization and death rates are high in patients with acute heart failure (HF) syndromes despite optimization of standard therapy for chronic HF. To the best of our ...knowledge, there has been no systematic analysis of the causes of death and rehospitalization in this patient population. Methods This was a prespecified analysis of adjudicated cause-specific all-cause mortality and cardiovascular (CV) hospitalization in the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) trial, a randomized, double-blind, placebo-controlled study in patients hospitalized with worsening HF and left ventricular ejection fraction ≤40% comparing tolvaptan, an oral vasopressin receptor antagonist to placebo, in addition to standard care. Results Of the 4,133 randomized, there were 5,239 rehospitalizations and 1,080 deaths during a median of 9.9 months. Of all deaths, 41.0% were due to HF, 26.0% due to sudden cardiac death (SCD), 2.6% due to acute myocardial infarction (MI), 2.2% due to stroke, and 13.2% due to non-CV causes. Of all hospitalizations, 39.2% were non-CV, whereas 46.3% were for HF, and a minority of hospitalizations was due to stroke, MI, arrhythmia, or other CV causes. Conclusions Despite close follow-up and evidence-based therapy within a clinical trial, rehospitalization and death remain high. Although most deaths were from HF, one quarter of patients had SCD. In addition, there were almost as many non-CV hospitalizations as HF hospitalizations. Knowledge of the causes of death and rehospitalization may be essential for proper management and early initiation of therapy.
Highlights • We performed an analysis using ESCAPE (Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness) data of patients with invasive hemodynamic data. • ...We examined outcomes of patients with heart failure and with persistent hemodynamic abnormalities. • Final pulmonary capillary wedge pressure was associated with adverse outcomes, but final cardiac index was not.
Abstract Background Data from a cardiopulmonary exercise (CPX) test are used to determine prognosis in patients with chronic heart failure (HF). However, few published studies have simultaneously ...compared the relative prognostic strength of multiple CPX variables. Objectives The study sought to describe the strength of the association among variables measured during a CPX test and all-cause mortality in patients with HF with reduced ejection fraction (HFrEF), including the influence of sex and patient effort, as measured by respiratory exchange ratio (RER). Methods Among patients (n = 2,100, 29% women) enrolled in the HF-ACTION (HF-A Controlled Trial Investigating Outcomes of exercise traiNing) trial, 10 CPX test variables measured at baseline (e.g., peak oxygen uptake V o2 , exercise duration, percent predicted peak V o2 %ppV o2 , ventilatory efficiency) were examined. Results Over a median follow-up of 32 months, there were 357 deaths. All CPX variables, except RER, were related to all-cause mortality (all p < 0.0001). Both %ppV o2 and exercise duration were equally able to predict (Wald chi-square: ∼141) and discriminate (c-index: 0.69) mortality. Peak V o2 (ml·kg–1 ·min–1 ) was the strongest predictor of mortality among men (Wald chi-square: 129) and exercise duration among women (Wald chi-square: 41). Multivariable analyses showed that %ppV o2 , exercise duration, and peak V o2 (ml·kg–1 ·min–1 ) were similarly able to predict and discriminate mortality. In men, a 10% 1-year mortality rate corresponded to a peak V o2 of 10.9 ml·kg–1 ·min–1 versus 5.3 ml·kg–1 ·min–1 in women. Conclusions Peak V o2 , exercise duration, and % ppV o2 carried the strongest ability to predict and discriminate the likelihood of death in patients with HFrEF. The prognosis associated with a given peak V o2 differed by sex. (Exercise Training Program to Improve Clinical Outcomes in Individuals With Congestive Heart Failure; NCT00047437 )
Abstract Objectives In this study, the authors used biomarker profiles to characterize differences between patients with acute heart failure with a midrange ejection fraction (HFmrEF) and compare ...them with patients with a reduced (heart failure with a reduced ejection fraction HFrEF) and preserved (heart failure with a preserved ejection fraction HFpEF) ejection fraction. Background Limited data are available on biomarker profiles in acute HFmrEF. Methods A panel of 37 biomarkers from different pathophysiological domains (e.g., myocardial stretch, inflammation, angiogenesis, oxidative stress, hematopoiesis) were measured at admission and after 24 h in 843 acute heart failure patients from the PROTECT trial. HFpEF was defined as left ventricular ejection fraction (LVEF) of ≥50% (n = 108), HFrEF as LVEF of <40% (n = 607), and HFmrEF as LVEF of 40% to 49% (n = 128). Results Hemoglobin and brain natriuretic peptide levels (300 pg/ml HFpEF; 397 pg/ml HFmrEF 521 pg/ml HFrEF; ptrend <0.001) showed an upward trend with decreasing LVEF. Network analysis showed that in HFrEF interactions between biomarkers were mostly related to cardiac stretch, whereas in HFpEF, biomarker interactions were mostly related to inflammation. In HFmrEF, biomarker interactions were both related to inflammation and cardiac stretch. In HFpEF and HFmrEF (but not in HFrEF), remodeling markers at admission and changes in levels of inflammatory markers across the first 24 h were predictive for all-cause mortality and rehospitalization at 60 days (pinteraction <0.05). Conclusions Biomarker profiles in patients with acute HFrEF were mainly related to cardiac stretch and in HFpEF related to inflammation. Patients with HFmrEF showed an intermediate biomarker profile with biomarker interactions between both cardiac stretch and inflammation markers. (PROTECT-1: A Study of the Selective A1 Adenosine Receptor Antagonist KW-3902 for Patients Hospitalized With Acute HF and Volume Overload to Assess Treatment Effect on Congestion and Renal Function; NCT00328692 )
Abstract Recent clinical trials in patients with heart failure with preserved ejection fraction (HFpEF) have provided important insights into participant selection strategies. Historically, HFpEF ...trials have included patients with relatively preserved left ventricular ejection fraction ranging from 40% to 55% and a clinical history of heart failure. Contemporary HFpEF trials have also incorporated inclusion criteria such as hospitalization for HFpEF, altered functional capacity, cardiac structural and functional abnormalities, and abnormalities in neurohormonal status (e.g., elevated natriuretic peptide levels). Careful analyses of the effect of these patient selection criteria on outcomes in prior trials provide valuable lessons for future trial design. We review recent and ongoing HFpEF clinical trials from a patient selection perspective and appraise trial patient selection methodologies in relation to outcomes. This review reflects discussions between clinicians, scientists, trialists, regulators, and regulatory representatives at the 10th Global CardioVascular Clinical Trialists Forum in Paris, France, on December 6, 2013.
Background Diuretic unresponsiveness often occurs during hospital admission for acute heart failure (AHF) and is associated with adverse outcome. This study aims to investigate determinants, clinical ...outcome, and the effects of nesiritide on diuretic response early after admission for AHF. Methods Diuretic response , defined as weight loss per 40 mg of furosemide or equivalent, was examined from hospital admission to 48 hours in 4,379 patients from the ASCEND-HF trial. As an additional analysis, a urinary diuretic response metric was investigated in 5,268 patients using urine volume from hospital admission to 24 hours per 40 mg of furosemide or equivalent. Results Mean diuretic response was −0.42 kg/40 mg of furosemide (interquartile range −1.0, −0.05). Poor responders had lower blood pressure, more frequent diabetes, long-term use of loop diuretics, poorer baseline renal function, and lower urine output (all P < .01). Randomized nesiritide treatment was not associated with diuretic response ( P = .987). Good diuretic response was independently associated with a significantly decreased risk of 30-day all-cause mortality or heart failure rehospitalization (odds ratio 0.44, 95% CI 0.29-0.65, highest vs lowest quintile, P < .001). Diuretic response based on urine output per 40 mg of furosemide showed similar results in terms of clinical predictors, association with outcome, and the absence of an effect of nesiritide. Conclusions Poor diuretic response early after hospital admission for AHF is associated with low blood pressure, renal impairment, low urine output, and an increased risk of death or rehospitalization early after discharge. Nesiritide had a neutral effect on diuretic response.
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