Search

Objectives The purpose of this study was to investigate the relationship of serum digoxin concentration (SDC) and outcomes in women with heart failure (HF). Background Controversy continues concerning the clinical utility of digoxin in women with HF. Methods Our analysis was retrospective with data from the Digitalis Investigation Group (DIG) trial. The principal study analysis reviewed 4,944 patients with HF due to systolic dysfunction who survived for at least 4 weeks (all 3,366 patients randomized to placebo and the 1,578 of 3,372 patients randomized to digoxin who had serum concentration measured 6 to 30 h [inclusive] after the last dose of study drug at 4 weeks). Results Continuous multivariable analysis demonstrated a significant linear relationship between SDC and mortality in women (p = 0.008) and men (p = 0.002, p = 0.766 for gender interaction). Averaging hazard ratios (HRs) across serum concentrations from 0.5 to 0.9 ng/ml in women produced a HR for death of 0.8 (95% confidence interval [CI] 0.62 to 1.13, p = 0.245) and for death or hospital stay for worsening HF of 0.73 (95% CI 0.58 to 0.93, p = 0.011). In contrast, SDCs from 1.2 to 2.0 ng/ml were associated with a HR for death for women of 1.33 (95% CI 1.001 to 1.76, p = 0.049). Conclusions Retrospective analysis of data from the DIG trial indicates a beneficial effect of digoxin on morbidity and no excess mortality in women at serum concentrations from 0.5 to 0.9 ng/ml, whereas serum concentrations ≥1.2 ng/ml seem harmful.

Heart failure (HF) affects >5 million patients in the United States, and its prevalence is increasing every year. Despite the compelling scientific evidence that angiotensin-converting enzyme inhibitors and beta-blockers reduce hospitalizations and mortality rates in patients with HF, these lifesaving therapies continue to be underused. Several studies in a variety of clinical settings have documented that a significant proportion of eligible patients with HF are not receiving treatment with these guideline-recommended, evidence-based therapies. In patients hospitalized with HF, who are at particularly high risk for re-hospitalization and death, the initiation of beta-blockers is often delayed because of concern that early initiation of these agents may exacerbate HF. Recent studies suggest that beta-blockers can be safely and effectively initiated in patients with HF before hospital discharge and that clinical outcomes are improved. The Initiation Management Predischarge Process for Assessment of Carvedilol Therapy for Heart Failure (IMPACT-HF) trial demonstrated that pre-discharge initiation of carvedilol was associated with a higher rate of beta-blocker use after hospital discharge, with no increase in hospital length of stay. In addition, there was no increase in the risk of worsening of HF. Studies of hospital-based management systems that rely on early (pre-discharge) initiation of evidence-based therapies for patients with cardiovascular disease have also found increases in post-discharge use of therapy and a reduction in the rates of mortality and hospitalization. On the basis of these pivotal studies, the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF) program is designed to improve medical care and education of hospitalized patients with HF and accelerate the initiation of evidence-based HF guideline recommended therapies by administering them before hospital discharge. A registry component, planned as the most comprehensive database of the hospitalized HF population focusing on admission to discharge and 60- to 90-day follow-up, is designed to evaluate the demographic, pathophysiologic, clinical, treatment, and outcome characteristics of patients hospitalized with HF. The ultimate aim of this program is to improve the standard of HF care in the hospital and outpatient settings and increase the use of evidence-based therapeutic strategies to save lives.

Objectives The Initiation Management Predischarge: Process for Assessment of Carvedilol Therapy in Heart Failure (IMPACT-HF) trial was an investigator-initiated study to evaluate if predischarge carvedilol initiation in stabilized patients hospitalized for heart failure (HF) increased the number of patients treated with beta-blockade at 60 days after randomization without increasing side effects or length of hospital stay. Background Beta-blockers are underused in HF. Predischarge initiation may improve the use of evidence-based beta-blockade. Methods The IMPACT-HF was a prospective, randomized open-label trial conducted in 363 patients hospitalized for HF. Patients were randomized to carvedilol initiation pre-hospital discharge or to postdischarge initiation (>2 weeks) of beta-blockade at the physicians' discretion. The primary end point of the study was the number of patients treated with beta-blockade at 60 days after randomization. Secondary end points included the number of patients discontinuing beta-blockade, median dose achieved, and a composite of death, rehospitalization, unscheduled visit for HF, or ≥50% increase in oral diuretic, new oral diuretic, or any intravenous therapy with diuretics, inotropes, or other vasoactive agents. Results At 60 days 165 patients (91.2%) randomized to predischarge carvedilol initiation were treated with a beta-blocker, compared with 130 patients (73.4%) randomized to initiation postdischarge (p Conclusions Predischarge initiation of carvedilol in stabilized patients hospitalized for HF improved the use of beta-blockade at 60 days without increasing side effects or length of stay. Predischarge initiation may be one approach to improve beta-blocker use in this population.

Background Arginine vasopressin is a peptide hormone that modulates a number of processes implicated in the pathogenesis of heart failure. Numerous vasopressin antagonists are currently under development for the treatment of this syndrome. Methods Preclinical and clinical data describing the effects of vasopressin and the vasopressin antagonists on both normal physiology and heart failure were reviewed. Results Through activation of V 1a and V 2 receptors, vasopressin regulates various physiological processes including body fluid regulation, vascular tone regulation, and cardiovascular contractility. Vasopressin synthesis is significantly and chronically elevated in patients with heart failure despite the volume overload and reductions in plasma osmolality often observed in these patients. Vasopressin also appears to adversely effect hemodynamics and cardiac remodeling, while potentiating the effects of norepinephrine and angiotensin II. The selective V 2 and dual V 1a /V 2 receptor antagonists tolvaptan and conivaptan, respectively, substantially increase free water excretion and plasma osmolality, reduce body weight, improve symptoms of congestion, and moderately increase serum sodium concentrations in patients with heart failure who present with symptoms of fluid overload. Tolvaptan effectively normalizes serum sodium concentrations in hyponatremic heart failure patients. Conivaptan significantly reduces pulmonary capillary wedge pressure without affecting systemic vascular resistance or cardiac output. The clinical significance of V 1a receptor antagonism requires further investigation. Conclusions Current preclinical and clinical findings with the vasopressin antagonists appear promising, however further evaluation in phase III clinical trials is necessary to define the role of vasopressin antagonism in the treatment of heart failure.

OBJECTIVES We sought to determine the effect of tezosentan in patients with acute decompensated heart failure (HF) associated with acute coronary syndrome (ACS). BACKGROUND Tezosentan is a dual endothelin receptor antagonist that has been shown to improve cardiac output, decrease pulmonary capillary wedge pressure, and reduce pulmonary and systemic vascular resistance in initial clinical studies in acute decompensated HF. METHODS The Randomized Intravenous TeZosentan (RITZ)-4 study was a multicenter, randomized, double-blinded, placebo-controlled study of tezosentan in patients with acute decompensated HF associated with ACS. A total of 193 patients were randomized to receive tezosentan (25 mg/h for 1 h, then 50 mg/h for 23 to 47 h) or placebo. Patients with evidence of acute decompensated HF and ACS were eligible to participate. The primary end point was the composite of death, worsening HF, recurrent ischemia, and recurrent or new myocardial infarction within 72 h. RESULTS No significant differences were observed between placebo and 50 mg/h tezosentan in the composite primary end point: 24.2% (95% confidence interval [CI] 16.0% to 34.1%) and 28.9% (95% CI 20.1% to 39.0%), respectively (p = 0.5152). Symptomatic hypotension was more frequent in the treatment group. CONCLUSIONS At the doses studied, tezosentan did not result in a significant improvement in the composite primary clinical end point in the RITZ-4 trial. Tezosentan did not demonstrate pro-ischemic effects in this population. Symptomatic hypotension may have resulted in an increased number of adverse events in the treatment group. Further studies with lower tezosentan doses are warranted.

Data from small studies have suggested the presence of platelet abnormalities in patients with congestive heart failure (CHF). We sought to characterize the diagnostic utility of different platelet parameters and platelet-endothelial biomarkers in a random outpatient CHF population investigated in the EPCOT (‘Whole Blood Impedance Aggregometry for the Assessment of Platelet Function in Patients with Congestive Heart Failure’) Trial. Blood samples were obtained for measurement of platelet contractile force (PCF), whole blood aggregation, shear-induced closure time, expression of glycoprotein (GP) IIb/IIIa, and P-selectin in 100 consecutive patients with CHF. Substantial interindividual variability of platelet characteristics exists in patients with CHF. There were no statistically significant differences when patients were grouped according to incidence of vascular events, emergency revascularization needs, survival, or etiology of heart failure. Aspirin use did not affect instrument readings either. PCF correlates very poorly with whole blood aggregometry (r2 = 0.023), closure time (r2 = 0.028), platelet GP IIb/IIIa (r2 = 0.0028), and P-selectin (r2 = 0.002) expression. Furthermore, there was no correlation with brain natriuretic peptide concentrations, a marker of severity and prognosis in heart failure reflecting the neurohumoral status. Patients with heart failure enrolled in the EPCOT Trial exhibited a marginal, sometimes oppositely directed change in platelet function, challenging the diagnostic utility of these platelet parameters and biomarkers to serve as useful tools for the identification of platelet abnormalities, for predicting clinical outcomes, or for monitoring antiplatelet strategies in this population. The usefulness of these measurements for assessing platelets in the different clinical settings remains to be explored. Taken together, opposite to our expectations, major clinical characteristics of heart failure did not correlate well with the platelet characteristics investigated in this study.

The Coumadin Aspirin Reinfarction Study demonstrated that combination treatment with fixed dose warfarin (1 or 3 mg) + aspirin 80 mg was not superior to aspirin 160 mg alone after myocardial infarction for reducing nonfatal reinfarction, nonfatal stroke, and cardiovascular death. In this analysis, we examined the importance of aspirin dose in the protection against the secondary end point of ischemic stroke. The comparison arms for this analysis were warfarin 1 mg + aspirin 80 mg versus aspirin 160 mg. In the Coumadin Aspirin Reinfarction Study, 2,028 patients were randomized to aspirin 80 mg plus warfarin 1 mg, and 3,393 were randomized to aspirin 160 mg alone. A predictive model for ischemic stroke was developed using the Cox proportional-hazards model. A reduced Cox proportional-hazards model was developed to test for the effect of aspirin dose on ischemic stroke in predefined subgroups. The incidence of ischemic stroke was lower in patients treated with aspirin 160 mg than in patients treated with aspirin 80 mg + warfarin 1 mg (0.6% vs 1.1%; p = 0.0534). Age, previous stroke or transient ischemic attack, and aspirin dose were independent predictors of ischemic stroke. In addition, the highest risk patients, those with Q-wave myocardial infarction and male patients, appeared to receive greater benefit from aspirin 160 mg than from aspirin 80 mg + warfarin 1 mg. The results of this secondary analysis suggest that aspirin 160 mg is more effective than aspirin 80 mg + warfarin 1 mg in preventing ischemic stroke in post-myocardial infarction patients.

Metoprolol CR/XL (metoprolol succinate extended-release tablets) is a beta1-selective agent that improved survival and reduced hospitalization among patients with New York Heart Association class II-IV heart failure in a randomized trial. Metoprolol CR/XL differs from conventional metoprolol tartrate with respect to pharmacokinetic and pharmacodynamic properties that may be clinically important in patients with heart failure. A thorough patient evaluation should be performed to determine optimal dosage and titration of this drug, as with any beta-blocker, and to assess the potential for drug-drug or drug-disease interactions. By applying knowledge of drug-specific characteristics and designing therapy for each individual patient, improvement in patient outcomes can be realized with metoprolol CR/XL.

Background: Data from small studies have shown the presence of platelet abnormalities in patients with congestive heart failure (CHF). We sought to characterize the diagnostic utility of platelet function analyzer (PFA-100) in the CHF population. Methods: Blood samples were obtained for measurement of adenosine diphosphate (ADP)/collagen and epinephrine/collagen shear-induced closure time (CT), whole blood aggregation, platelet contractile force, activity of glycoprotein (GP) IIb/IIIa, and P-selectin receptors in 100 consecutive outpatients with CHF. Results: Substantial interindividual variability of platelet characteristics exists in patients with CHF. There were no statistically significant differences when patients were divided by the incidence of vascular events, emergency revascularization needs, survival, or etiology of heart failure. Aspirin use did not affect instrument readings as well. CT correlates well with whole blood aggregometry (r2=.587) and less with GP IIb/IIIa activity (r2=.326). No correlation has been observed for the CT with the platelet-bound P-selectin (r2=.041) and platelet contractile force measures (r2=.028). Conclusions: PFA-100 is indeed capable to serve as a platelet analyzer and may be successfully used as a screening device. However, patients with heart failure enrolled in the EPCOT trial exhibited a marginal, sometimes oppositely directed changes in the platelet function, challenging the diagnostic utility of PFA-100 to serve as a useful tool for the identification of platelet abnormalities, predicting clinical outcomes, or for the monitoring of antiplatelet strategies in this population.

The management of heart failure is complex. Initiating and maintaining drug therapy in patients with heart failure can be challenging. Many factors influence the heart failure syndrome and are important to account for when evaluating these patients. Concomitant diseases such as ischemic heart disease and hypertension may contribute to worsening heart failure, and treatment strategies addressing these conditions should be implemented in affected patients. Concomitant drugs also must be considered. The heart failure population is at risk for drug interactions, both pharmacokinetic and pharmacodynamic, because these patients often take many drugs at the same time. Proactively recognizing potential interactions and modifying a patient's regimen to minimize or avoid adverse effects are important. Many agents are contraindicated in heart failure; thus, avoiding such therapies may significantly affect a patient's outcome. The successful treatment of a patient with heart failure requires careful consideration of many factors, including other diseases, drugs, and social issues. Addressing these factors when treating patients translates into improved pharmaceutical care.

Objective To determine the short-term safety and tolerability of the addition of ecadotril to conventional therapy in patients with mild to moderate heart failure. Methods Fifty ambulatory patients, 18 to 75 years of age, with mild to moderate heart failure, left ventricular ejection fraction ≤35%, taking stable doses of angiotensin-converting enzyme inhibitor, diuretics, and optionally digoxin were enrolled in a randomized, double-blind, placebo-controlled dose-escalation study of ecadotril 50 to 400 mg twice daily versus conventional therapy alone. Results: No increases in deaths, serious adverse events, or dropouts from adverse events were observed for the ecadotril group compared with placebo. The serum measures of neurohormonal activation were highly variable. Changes in signs and symptoms of heart failure, New York Heart Association class, and patient self-assessment of symptoms were not observed with ecadotril therapy; however, the study was not designed to detect differences in these parameters. Conclusion In this small pilot study, ecadotril in doses of 50 to 400 mg twice daily was generally well-tolerated and without severe short-term adverse effects in patients with mild to moderate heart failure. Evaluation of the clinical efficacy and long-term safety of ecadotril and other neutral endopeptidase inhibitors in patients with heart failure requires further study. (Am Heart J 1999;138:1140-8.)

Objective To evaluate clinical characteristics and outcomes of patients with advanced heart failure receiving intravenous continuous dobutamine in the FIRST Trial (Flolan International Randomized Survival Trial). Methods Four hundred seventy-one patients with class IIIb to IV heart failure who were enrolled in the FIRST trial were included. Eighty patients treated with dobutamine at FIRST randomization were compared with 391 patients not treated with dobutamine at randomization. The occurrence of worsening heart failure, need for vasoactive medications, resuscitated cardiac arrest, myocardial infarction, and total mortality were compared between the 2 groups. Results The dobutamine group had a higher occurrence of first event (85.3% vs 64.5%; P = .0006) and a higher mortality rate (70.5% vs 37.1%; P = .0001) compared with the no dobutamine group. Intravenous continuous dobutamine was an independent risk factor for death after adjusting for baseline differences. Conclusions Dobutamine use at the time of randomization was associated with a higher 6-month mortality rate. This effect persisted after adjustment for baseline differences. This analysis challenges the concept that continuous intravenous dobutamine is beneficial to advanced heart failure patients with respect to survival. (Am Heart J 1999;138:78-86.)

Thrombin generation (TG) is an important pathogenic factor in acute coronary syndromes including acute myocardial infarction (AMI). Since the diagnostic utility of TG remains uncertain we sought to determine whether markers of TG may triage patients presenting to the Emergency Department with chest pain. Soluble plasma levels of prothrombin fragment 1+2 (F1+2), and thrombin/antithrombin III complexes (TAT) were determined by ELISA in 80 patients presenting with chest pain to the Emergency Department and compared with 20 controls. There were no differences in TG markers between patients with non-cardiac chest pain and healthy controls. Patients with unstable angina (UA), and congestive heart failure (CHF) did not differ from controls with respect to F1+2, and TAT was elevated in UA patients (6.05 ± 1.15 ng/ml, p = 0.033) when compared with controls (3.34 ± 0.20 ng/ml). Contrary to expectations, TAT levels at presentation with AMI were well below the concentrations observed in patiens with UA and CHF. Moreover, plasma F1+2 levels were significantly lower than in healthy controls (0.84 ± 0.10 ng/ml versus 1.22 ± 0.11, p = 0.026). At the time of presentation to the Emergency Department, F1+2 and TAT failed to suitably triage patients with chest pain. The surprisingly low levels of TG markers in AMI patients before applying intensive therapy and reperfusion strategies deserves further investigation.

C-reactive protein (CRP) levels were measured in a cohort of 96 outpatients with heart failure. Baseline angiotensin-converting enzyme inhibitor plus beta-blocker use were associated with lower levels of CRP; no relation was found between CRP levels and aspirin or statin use.

β-Blockers for the treatment of heart failure are underprescribed in the United States despite the availability of extensive data and the current guidelines that support their use. The ongoing Initiation Management Predischarge Process for Assessment of Carvedilol Therapy for Heart Failure (IMPACT-HF) study was designed to determine if initiation of beta blockade prior to hospital discharge is safe and improves the long-term use of β-blockers. IMPACT-HF is a multicenter, randomized, open-label trial of carvedilol initiated before hospital discharge or to usual care in 363 patients hospitalized for worsening heart failure. The primary end point of the study is the number of patients treated with any β-blocker at 60 days. Secondary endpoints include β-blocker dose achieved and a composite clinical endpoint. The data from the IMPACT-HF trial will provide evidence to evaluate whether in-hospital initiation of β-blocker therapy is effective in improving the long-term use of β-blockers in this population.

There is substantial clinical evidence that the incidence of depression and mortality after acute coronary events are strongly related. As mediators of coronary thrombosis, platelets may represent a link between these events, and could be possibly targeted by therapy with serotonin reuptake inhibitors.

EPIDEMIOLOGY AND PATHOPHYSIOLOGY Nomenclature and Classification of Acute Heart Failure Epidemiology and Scope of the Problem of Decompensated Heart Failure Clinical Profile of the Acute Heart Failure Patient Gender Differences in Epidemiology and Pathophysiology of Advanced Heart Failure Ethnic Differences in Epidemiology and Pathophysiology of Advanced Heart Failure Aging as a Factor in the Epidemiology and Pathophysiology of Advanced Heart Failure Pathophysiology of the Spectrum of Acute Heart Failure: Denovo heart failure Decompensated Heart Failure Advanced Refractory Heart failure Low Output Acute Heart Failure Right-sided Heart Failure and Cor Pulmonale in the Advanced Heart Failure Patient Pathophysiology of Advanced Heart Failure in the Setting of Preserved Systolic Function Hemodynamic Classification of Acute Heart Failure Pathophysiology of the Hepatorenal Syndrome in Acute heart failure DIAGNOSIS AND EVALUATION OF THE ACUTE HEART FAILURE PATIENT Presentation of the Acute Heart Failure Patient: Signs, Symptoms, and Differential Diagnosis Physical Examination of the Acute Heart Failure Patient Assessment of Dyspnea and other Physical Examination Parameters Biologic Markers and Acute Heart Failure Assessment of LV Function in the Advanced Heart Failure Patient Diagnostic Evaluation of the Acute Heart Failure Patient with Systolic Dysfunction (cath, MRI, CXR, ECG) Hemodynamic Monitoring and Acute Heart Failure Non-Invasive Monitoring of the Acute Heart Failure Patient COMORBIDITIES IN THE ACUTE HEART FAILURE PATIENT Arrhythmias and Acute Heart Failure Mechanical Complications in Acute Heart Failure Ischemic Complications of Acute Heart Failure Hypertension Complicating the Patient with Acute Heart Failure Respiratory Failure in Acute Heart Failure Stroke Complicating Acute Heart Failure Psychiatry and Mental Status Changes in Acute Heart Failure Diabetic Complications in Acute Heart Failure Anemia Complicating Acute Heart Failure Thromboembolic disorders in the Patient with Acute Heart Failure TREATMENT STRATEGIES Management of Patients with Acute Heart Failure in the Setting of Preserved Systolic Function IV Nitroglycerin IV Inotropes/Inodilators IV Diuretics IV Nesiritide Antiplatelet Therapy Antithrombin Therapy Antiarrhythmic Therapy Psychosocial Therapy and Acute Heart Failure Pacing AICD EECP Balloon Pump Ultrafiltration Advanced Mechanical Therapy CABG Transplant SVR Cor Cap MVR CPAP In-Hospital Cardiac Rehabilitation in the Acute Heart Failure Patient Adenosine Antagonists and Potassium Sparing Diuretics Aldosterone Antagonists Calcium Sensitizers Vasopressin Antagonists Endothelin Receptor Antagonists ISSUES IN THE MANAGEMENT OF ACUTE HEART FAILURE Advanced Nursing Aspects Managing Pharmacotherapy: Focus on Alterations of Pharmacokinetics, Pharmacodynamics, and Drug Interactions in the Acute Heart Failure Patient Disease Management in the Advanced Heart Failure Patient Economics & Quality of Life in the Advanced Heart Failure Patient Addressing End of Life in the Acute Heart Failure Patient FUTURE DIRECTIONS IN ACUTE HEART FAILURE The Future of Clinical Practice and Clinical Research in Acute Heart Failure

The purpose of this study was to investigate the relationship of serum digoxin concentration (SDC) and outcomes in women with heart failure (HF).Controversy continues concerning the clinical utility of digoxin in women with HF.Our analysis was retrospective with data from the Digitalis Investigation Group (DIG) trial. The principal study analysis reviewed 4,944 patients with HF due to systolic dysfunction who survived for at least 4 weeks (all 3,366 patients randomized to placebo and the 1,578 of 3,372 patients randomized to digoxin who had serum concentration measured 6 to 30 h [inclusive] after the last dose of study drug at 4 weeks).Continuous multivariable analysis demonstrated a significant linear relationship between SDC and mortality in women (p = 0.008) and men (p = 0.002, p = 0.766 for gender interaction). Averaging hazard ratios (HRs) across serum concentrations from 0.5 to 0.9 ng/ml in women produced a HR for death of 0.8 (95% confidence interval [CI] 0.62 to 1.13, p = 0.245) and for death or hospital stay for worsening HF of 0.73 (95% CI 0.58 to 0.93, p = 0.011). In contrast, SDCs from 1.2 to 2.0 ng/ml were associated with a HR for death for women of 1.33 (95% CI 1.001 to 1.76, p = 0.049).Retrospective analysis of data from the DIG trial indicates a beneficial effect of digoxin on morbidity and no excess mortality in women at serum concentrations from 0.5 to 0.9 ng/ml, whereas serum concentrationsor =1.2 ng/ml seem harmful.

Background More than half of all patients with congestive heart failure have preserved left ventricular systolic function. This is particularly common in African American patients, yet there have been few studies examining the long-term natural history of this disorder in African-American and white patients. Methods We studied 2740 white and 563 African American patients with class II to IV symptoms and preserved systolic function (ejection fraction >40) identified in the Duke Cardiovascular Databank from 1984 to1996. Unadjusted and adjusted 5-year survival rate comparisons were performed with Kaplan-Meier and Cox proportional hazards models, respectively. Results The 5-year survival rates were 68% for African American patients and 70% for white patients ( P = .55). However, after adjusting for known risk factors, African American patients had a significantly higher mortality risk than white patients (hazard ratio [HR], 1.34; 95% CI, 1.13–1.60). This racial difference in survival rate was most prominent in patients with a non-ischemic etiology (HR, 1.6; 95% CI, 1.2–2.0) as compared with patients with ischemic heart failure (HR, 1.1; 95% CI, 0.9–1.4). Conclusion Among patients with heart failure and preserved left ventricular systolic function, African American patients have a worse long-term prognosis than white patients. These results are important because of the prevalence of this condition in African American patients and their potential heterogeneous response to many heart failure therapies.

The use of beta-blockers for the treatment of heart failure in the United States is inadequate, despite available data and current guidelines that support their use. The Initiation Management Predischarge: Process for Assessment of Carvedilol Therapy for Heart Failure (IMPACT-HF) study was designed to determine whether initiation of beta-blockade before hospital discharge is safe and effective in improving the 60-day use of beta-blockers in patients with heart failure. IMPACT-HF compared the strategy of the initiation of carvedilol before patients were discharged versus usual care (Heart Failure Society of America guidelines recommend waiting 2 to 4 weeks after hospitalization for heart failure before initiating beta-blocker therapy) in 363 randomized patients with heart failure. The entry criteria were non-restrictive to ensure inclusion of patients reflective of the general heart failure population. The primary end point of the study (the number of patients treated with any beta-blocker at 60 days) was statistically significantly higher in the predischarge group versus the postdischarge group (91.2% vs 73.4%, respectively). Based on the study's results, predischarge initiation may be a successful strategy to improve the use of beta-blocker therapy for patients with heart failure.

Nearly 1 million hospitalizations for chronic heart failure occur yearly in the United States, with most related to worsening systemic congestion. Diuretic use, the mainstay therapy for congestion, is associated with electrolyte abnormalities and worsening renal function. In contrast to diuretics, the vasopressin antagonist tolvaptan may increase net volume loss in heart failure without adversely affecting electrolytes and renal function.To evaluate the short- and intermediate-term effects of tolvaptan in patients hospitalized with heart failure.Randomized, double-blind, placebo-controlled, parallel-group, dose-ranging, phase 2 trial conducted at 45 centers in the United States and Argentina and enrolling 319 patients with left ventricular ejection fraction of less than 40% and hospitalized for heart failure with persistent signs and symptoms of systemic congestion despite standard therapy.After admission, patients were randomized to receive 30, 60, or 90 mg/d of oral tolvaptan or placebo in addition to standard therapy, including diuretics. The study drug was continued for up to 60 days.In-hospital outcome was change in body weight at 24 hours after randomization; outpatient outcome was worsening heart failure (defined as death, hospitalization, or unscheduled visits for heart failure) at 60 days after randomization.Median (interquartile range) body weight at 24 hours after randomization decreased by -1.80 (-3.85 to -0.50), -2.10 (-3.10 to -0.85), -2.05 (-2.80 to -0.60), and -0.60 (-1.60 to 0.00) kg in the groups receiving tolvaptan 30, 60, and 90 mg/d, and placebo, respectively (Por =.008 for all tolvaptan groups vs placebo). The decrease in body weight with tolvaptan was not associated with changes in heart rate or blood pressure, nor did it result in hypokalemia or worsening renal function. There were no differences in worsening heart failure at 60 days between the tolvaptan and placebo groups (P =.88 for trend). In post hoc analysis, 60-day mortality was lower in tolvaptan-treated patients with renal dysfunction or severe systemic congestion.Tolvaptan administered in addition to standard therapy may hold promise for management of systemic congestion in patients hospitalized for heart failure.

A considerable number of patients with reduced systolic function caused by primary or ischemic cardiomyopathy have viable and noncontractile myocardium. This may be related to numerous and perhaps overlapping factors, such as chronic ischemia (stunning/hibernation), neurohormonal abnormalities, oxidative stress, metabolic imbalances, and/or nutritional depletion. Changes in myocardial substrate utilization have adverse effects on the metabolism of the viable but noncontractile myocardium. Shifting the energy substrate preference away from fatty acids and replenishing the tricarboxylic acid cycle components via amino acids rather than via fatty acids would increase adenosine triphosphate production, with positive effects on cellular metabolism. A proposed study design is described and will be piloted through the Effects of Diatrofen on Myocardial Function in Patients with Chronic Heart Failure trial (D-CHF), an evaluation of an oral amino acid supplementation treatment in outpatients with heart failure.

Anemia has recently been recognized as an important comorbid condition and potentially novel therapeutic target in patients with heart failure (HF). Anemia is common in HF patients, with a prevalence ranging from 4% to 55% depending on the population studied. Multiple potential mechanisms of interaction exist between anemia and the clinical syndrome of HF, including hemodilution, inflammatory activation, renal insufficiency, and malnutrition. A growing body of literature from observational databases and clinical trials suggests that anemia is an independent risk factor for adverse outcomes in patients with HF. Although preliminary data suggest that treatment of anemia may result in significant symptomatic improvement in HF, aggressive treatment of anemia may also be associated with increased risk of hypertension or thrombosis. Multiple ongoing studies will provide definitive data on the balance of risks and benefits of anemia treatment in chronic HF.

Background Elevated concentrations of cardiac troponin T (TnT) have been reported in patients hospitalized for decompensated heart failure (HF). We assessed whether elevated TnT levels are associated with the severity, etiology, and prognosis of HF in stable, ambulatory patients. Methods From 1998–1999, we prospectively collected data from 136 ambulatory patients with HF, New York Heart Association functional class II to IV, ejection fraction ≤35%, and no recent unstable angina, myocardial infarction, surgery, or coronary revascularization. Blood was obtained and analyzed by immunoassay for TnT, and patients were followed for 14.0 ± 4.3 months for death or HF hospitalization (primary end point) and other adverse cardiovascular outcomes. Results Thirty-three patients (24%) had an elevated TnT level (≥0.02 ng/mL). Mean TnT concentration did not differ by etiology of HF (0.002 ± 0.03 ng/mL vs 0.02 ± 0.04 ng/mL for ischemic and nonischemic etiologies, P = .25). Compared with patients with normal (undetectable) levels of TnT, patients with elevated TnT were significantly older, had worse functional class, and had poorer renal function. Elevated TnT concentrations were associated with increased relative risks (RR) of death or HF hospitalization (RR 2.7, 95% CI 1.7–4.3, P = .001) and death alone (RR 4.2, 95% CI 1.8–9.5, P = .001) during follow-up. Elevated TnT and New York Heart Association class were significant, independent predictors of death or HF hospitalization. Increased age and serum creatinine concentrations were significant independent predictors of death alone. Conclusions Nearly one fourth of ambulatory patients with chronic HF have ongoing myocardial necrosis as shown by abnormal TnT values, which are associated with increased mortality and morbidity.

The relation of cardiac troponin-I (cTnI) to clinical outcomes was examined in patients with decompensated heart failure and concomitant acute coronary syndrome enrolled into the Randomized Intravenous TeZosentan 4 (RITZ-4) study. RITZ-4 was a multicenter, randomized, double-blind, placebo-controlled trial of the endothelin receptor antagonist tezosentan in patients admitted with acute heart failure and concomitant acute coronary syndrome. One hundred ninety-two patients were enrolled in this study. Patients with baseline cTnI values were included in this analysis, and the relation between cTnI and the composite clinical primary end point of RITZ-4 was evaluated.

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.

The Initiation Management Predischarge: Process for Assessment of Carvedilol Therapy in Heart Failure (IMPACT-HF) trial was an investigator-initiated study to evaluate if predischarge carvedilol initiation in stabilized patients hospitalized for heart failure (HF) increased the number of patients treated with beta-blockade at 60 days after randomization without increasing side effects or length of hospital stay.Beta-blockers are underused in HF. Predischarge initiation may improve the use of evidence-based beta-blockade.The IMPACT-HF was a prospective, randomized open-label trial conducted in 363 patients hospitalized for HF. Patients were randomized to carvedilol initiation pre-hospital discharge or to postdischarge initiation (2 weeks) of beta-blockade at the physicians' discretion. The primary end point of the study was the number of patients treated with beta-blockade at 60 days after randomization. Secondary end points included the number of patients discontinuing beta-blockade, median dose achieved, and a composite of death, rehospitalization, unscheduled visit for HF, oror =50% increase in oral diuretic, new oral diuretic, or any intravenous therapy with diuretics, inotropes, or other vasoactive agents.At 60 days 165 patients (91.2%) randomized to predischarge carvedilol initiation were treated with a beta-blocker, compared with 130 patients (73.4%) randomized to initiation postdischarge (p0.0001). Predischarge initiation was not associated with an increased risk of serious adverse events. The median length of stay was five days in both groups.Predischarge initiation of carvedilol in stabilized patients hospitalized for HF improved the use of beta-blockade at 60 days without increasing side effects or length of stay. Predischarge initiation may be one approach to improve beta-blocker use in this population.

We sought to determine the effect of tezosentan in patients with acute decompensated heart failure (HF) associated with acute coronary syndrome (ACS).Tezosentan is a dual endothelin receptor antagonist that has been shown to improve cardiac output, decrease pulmonary capillary wedge pressure, and reduce pulmonary and systemic vascular resistance in initial clinical studies in acute decompensated HF.The Randomized Intravenous TeZosentan (RITZ)-4 study was a multicenter, randomized, double-blinded, placebo-controlled study of tezosentan in patients with acute decompensated HF associated with ACS. A total of 193 patients were randomized to receive tezosentan (25 mg/h for 1 h, then 50 mg/h for 23 to 47 h) or placebo. Patients with evidence of acute decompensated HF and ACS were eligible to participate. The primary end point was the composite of death, worsening HF, recurrent ischemia, and recurrent or new myocardial infarction within 72 h.No significant differences were observed between placebo and 50 mg/h tezosentan in the composite primary end point: 24.2% (95% confidence interval [CI] 16.0% to 34.1%) and 28.9% (95% CI 20.1% to 39.0%), respectively (p = 0.5152). Symptomatic hypotension was more frequent in the treatment group.At the doses studied, tezosentan did not result in a significant improvement in the composite primary clinical end point in the RITZ-4 trial. Tezosentan did not demonstrate pro-ischemic effects in this population. Symptomatic hypotension may have resulted in an increased number of adverse events in the treatment group. Further studies with lower tezosentan doses are warranted.

We sought to determine whether platelet activity in patients with heart failure is related to an ischemic versus nonischemic etiologic condition, clinical disease severity, or adverse clinical outcomes.Platelet activity may affect outcome in patients with heart failure. A prospective evaluation of the relation of baseline platelet function to etiologic condition, New York Heart Association (NYHA) class, and clinical outcomes has not been previously reported.Ninety-six consecutive outpatients with ambulatory heart failure with an ejection fraction0.40 and NYHA Class II to IV symptoms who presented to the Duke Heart Failure Clinic and 14 healthy control subjects formed the study groups. Baseline characteristics and blood analyzed for thromboxane (Tx) B2, 6-keto PGF(1alpha), platelet contractile force, adenosine diphosphate/collagen shear-induced closure time, whole blood aggregation and CD41, CD31, CD62p, and CD51/CD61 by flow cytometry were determined. Survival status and hospitalizations were determined in the heart failure patient cohort.The median age of patients was 65 years (22% female, 64% white). An ischemic etiologic condition was present in 61% of patients. The population had mild to moderate heart failure: NYHA class I (1%), II (41%), III (46%), and IV (12.5%) and severe ventricular dysfunction (median ejection fraction = 0.20). There were 39 clinical events (7 deaths, 3 cardiac transplants, 29 other first hospitalizations) in 305 median days of observation. Platelet activity, indicated by whole blood aggregation with 5 micromol adenosine diphosphate (P =.04) and Tx B2 (P =.01), was higher in patients with heart failure. Whole blood aggregation was greater than the 90th percentile in 22% of patients with heart failure versus 7% of control subjects. Platelet function did not differ for any of the markers between the ischemic and nonischemic groups and was not affected by antecedent aspirin. There was no relation of NYHA class or the occurrence of events to platelet activity.Platelet activity is heightened in 22% of outpatients with stable heart failure symptoms and is not affected by antecedent aspirin therapy. The degree of platelet activation is similar in ischemic and nonischemic patients with heart failure and is not related to clinical disease severity. Current methods to assess platelet activation do not appear to predict outcome.

Clinicians face daunting challenges when caring for patients who have been hospitalized with exacerbated chronic heart failure. It is generally accepted that hospital admissions for worsening heart failure are highly prevalent, but no consensus has been reached as to how the patients in this population should be categorized. As a result, the true incidence and prevalence of the disease is difficult to determine. In addition, once a patient has been hospitalized with symptoms of worsening heart failure, the attending physician confronts complex treatment decisions. The options available to treat exacerbated heart failure are limited, in contrast to the evidence-based therapies available for the management of chronic heart failure. Chronic heart failure therapy is guided by overwhelming clinical data that support the use of angiotensin-converting enzyme (ACE) inhibition and -blockade to improve long-term clinical outcomes. By contrast, the most commonly prescribed therapies for acute heart failure are diuretics, vasodilators, and inotropes—therapies that have demonstrated they either produce no improvements in long-term outcomes or have harmful clinical effects, or that have been inadequately studied. It is imperative that new therapies for acute heart failure be developed with evidence of clinical benefit from well-designed, randomized, controlled trials. In designing a clinical trial for new therapies for decompensated heart failure, the approach that is taken is different from that in trials for new therapies for chronic heart failure. First, it may be necessary to define the goal of therapy differently. For chronic heart failure, the goal is to prevent progression of the disease and associated adverse clinical outcomes, such as death or rehospitalization. Therapy for an exacerbation of heart failure may also aim to prevent disease progression; however, a novel therapy for the acute setting will only be able to demonstrate its long-term benefits if it can be shown to affect an acute event that worsens disease progression. For example, a therapy for an acute event would be beneficial if it prevents myocardial necrosis caused by progressive ischemia, or an acute coronary syndrome in a patient with left ventricular dysfunction. Conversely, a therapy for the acute setting of heart disease may be harmful if it improves hemodynamic function but is proarrhythmic or increases myocardial oxygen consumption.

randomized, double-blind, placebo-controlled study of the effects of tolvaptan on the acute and chronic outcomes of patients hospitalized with worsening congestive heart failure Mihai Gheorghiade, MD, Wendy A. Gattis, PharmD, Alejandro Barbagelata, MD, Kirkwood F. Adams, Jr, MD, Uri Elkayam, MD, Cesare Orlandi, MD, and Christopher M. O’Connor, MD, for the Acute and Chronic Therapeutic Impact of a Vasopressin Antagonist in Congestive Heart Failure (ACTIV in CHF) Investigators Chicago, Ill, Durham and Chapel Hill, NC, Los Angeles, Calif, Buenos Aires, Argentina, and Baltimore, Md

Discharges for patients hospitalized with heart failure rose from 377,000 in 1979 to 978,000 in 1998, making heart failure the leading discharge diagnosis in the Medicare population in the United States. Currently, 4,800,000 Americans are living with this disease. Approximately 550,000 new cases are diagnosed each year and 200,000 deaths related to heart failure occur annually. Patients admitted to a hospital for the treatment of this disease have readmission rates as high as 30% to 60% within 3 to 6 months after initial discharge. The Survival and Ventricular Enlargement (SAVE) trial demonstrated that once patients with heart failure were hospitalized because of an acute exacerbation, their mortality rate after 4 years increased from 25% to nearly 60%, despite optimal medical management. Inpatient admissions for the treatment of heart failure are increasing in prevalence and are associated with an increased risk of both readmission and subsequent death. The presentations of heart failure that require hospitalization may be classified into 3 categories: 1) newonset heart failure secondary to a precipitating factor such as a large anterior wall myocardial infarction (MI); 2) acute decompensation of chronic heart failure (ADHF); and 3) end-stage or refractory heart failure that responds poorly to medical therapy. This review focuses on acute exacerbations of chronic heart failure (CHF) resulting in hospitalization and discusses medical therapy for and clinical outcomes in patients with this complex clinical syndrome.

Beta blockers have been shown to reduce morbidity and mortality in patients with heart failure without evidence of overt congestion. No data are available describing outcomes of patients admitted with exacerbated chronic heart failure who are receiving beta blockade at the time of admission. The purpose of this analysis was to evaluate clinical outcomes in patients from the Outcomes of the Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-CHF) study who were prescribed beta blockers on admission compared with patients who were not prescribed beta blockers at admission. In all, 212 patients were treated with beta blockers at admission and 737 patients were not. Baseline characteristics were similar between groups, except that patients prescribed beta blockers on admission had slightly higher ejection fractions, fewer New York Heart Association class IV symptoms, and lower heart rates. There was no difference in clinical events between patients who were treated with beta blockers at the time of admission and those who were not. Exploratory analyses suggested that patients whose beta-blocker therapy was discontinued had a higher risk of adverse outcomes, particularly in the subset of patients randomized to milrinone. The data from this nonrandom comparison suggest that continuation of pre-existing beta-blocker therapy is not associated with an increased risk of adverse clinical events in patients admitted with worsening heart failure. These results also suggest that caution should be taken when withdrawing beta blockade in this population.

The utilization of b-blockers for the treatment of heart failure in the United States is inadequate despite the available data and the current guidelines that support their use. The ongoing Initiation Management Predischarge Process for Assessment of Carvedilol Therapy for Heart Failure (IMPACT-HF) study was designed to determine if initiation of beta-blockade prior to hospital discharge is safe and effective in improving the 60-day use of beta-blockers in patients with heart failure. IMPACT-HF is a community-based, multicenter, open-label trial of 375 heart failure patients randomized to carvedilol initiated before their hospital discharge or to usual care (Heart Failure Society of America guidelines that recommend waiting 2-4 weeks after hospitalization for heart failure before initiating beta-blocker therapy). The entry criteria are nonrestrictive to ensure inclusion of patients reflective of the general heart failure population. The primary endpoint of the study is the number of patients treated with any beta-blocker at 60 days. A concurrently ongoing pilot registry will enroll 550 patients, admitted with exacerbated heart failure, in three phases to collect demographic, clinical, treatment patterns, and outcome data. The trial will test the tolerability of beta-blocker initiation in the hospital setting, develop strategies to improve the use of evidence-based medicine in clinical practice, and explore the patient's course from hospital admission through discharge and up to 60 days. The trial data will determine if in-hospital initiation of beta-blocker therapy is effective at improving the long-term use of pharmacologic agents proven to reduce morbidity and mortality.

Chronic heart failure continues to increase in incidence and prevalence despite many pharmacologic advances over the previous decade. Morbidity and mortality remain high, with the number of hospitalizations for worsening heart failure in 1999 approaching 1 million. In addition to investigation of new therapies for the treatment of heart failure, attention must be placed on identifying effective methods for increasing the adoption of proven therapies. First, the potential barriers to implementation of evidence-based medicine must be recognized. Subsequently, strategies to overcome such barriers can be developed. Published guidelines may be helpful in educating practitioners on current standards of care. Other tools may also be considered, and testing the influence of such tools on the implementation of optimal therapy may help the scientific community better understand the factors that influence decision-making among clinicians.

Data from small studies have suggested the presence of platelet abnormalities in patients with congestive heart failure (CHF). We sought to characterize the diagnostic utility of different platelet parameters and platelet-endothelial biomarkers in a random outpatient CHF population investigated in the EPCOT ('Whole Blood Impedance Aggregometry for the Assessment of Platelet Function in Patients with Congestive Heart Failure') Trial. Blood samples were obtained for measurement of platelet contractile force (PCF), whole blood aggregation, shear-induced closure time, expression of glycoprotein (GP) IIb/IIIa, and P-selectin in 100 consecutive patients with CHF. Substantial interindividual variability of platelet characteristics exists in patients with CHF. There were no statistically significant differences when patients were grouped according to incidence of vascular events, emergency revascularization needs, survival, or etiology of heart failure. Aspirin use did not affect instrument readings either. PCF correlates very poorly with whole blood aggregometry (r(2) = 0.023), closure time (r(2) = 0.028), platelet GP IIb/IIIa (r(2) = 0.0028), and P-selectin (r(2) = 0.002) expression. Furthermore, there was no correlation with brain natriuretic peptide concentrations, a marker of severity and prognosis in heart failure reflecting the neurohumoral status. Patients with heart failure enrolled in the EPCOT Trial exhibited a marginal, sometimes oppositely directed change in platelet function, challenging the diagnostic utility of these platelet parameters and biomarkers to serve as useful tools for the identification of platelet abnormalities, for predicting clinical outcomes, or for monitoring antiplatelet strategies in this population. The usefulness of these measurements for assessing platelets in the different clinical settings remains to be explored. Taken together, opposite to our expectations, major clinical characteristics of heart failure did not correlate well with the platelet characteristics investigated in this study.

Objective Data from small studies have shown the presence of platelet abnormalities in patients with congestive heart failure (CHF). We sought to characterize the diagnostic utility of the whole blood aggregometry (WBA) in a random outpatient CHF population. Methods Blood samples were obtained for measurement of whole blood aggregation, shear-induced closure time, platelet contractile force, expression of GP IIb/IIIa, and P-selectin in 100 consecutive patients with CHF. Results Substantial inter-individual variability of platelet characteristics exists in patients with CHF. There were no statistically significant differences when patients were divided by the incidence of vascular events, emergency revascularization needs, survival, or etiology of heart failure. Surprisingly, aspirin use did not affect instrument readings as well. Whole blood aggregometry correlates well with the closure time (r2-0.587), and with GP IIb/IIIa expression (r2-0.435). Significant but less strong correlation has been observed for the WBA with platelet P-selectin expression (r2-0.295), and no correlation was present for the platelet contractile force measures (r2-0.030). Conclusions Despite the fact that patients with heart failure enrolled in the EPCOT trial exhibited marginal, sometimes oppositely directed changes, in their platelet characteristics, whole blood impedance aggregometry is indeed capable to serve as a valuable diagnostic tool, and may be successfully used as an established screening device in this population. Ability of the whole blood aggregometry to predict clinical outcomes, or for the monitoring of anti-platelet agents in CHF patients, will be evaluated in the ongoing clinical trials.

Knowledge of the pathogenesis of congestive heart failure (CHF) has improved greatly in recent years. However, this disease continues to cause one of the highest morbidities and mortalities in the Western world. The pathophysiology of heart failure is complex and much of our understanding revolves strictly around the neurohormonal mechanisms involved. Various pharmacologic interventions have significantly improved morbidity and include ACE inhibitors, beta-blockers, diuretics, and inotropic agents. Yet, no consensus has been reached regarding the use of anticoagulants or antiplatelet agents. It has been suggested that CHF is associated with altered hemostasis, but whether this prothrombotic state contributes to the pathogenesis and progression of the disease is unknown. The purpose of this review article is to discuss our current knowledge of platelet activation, thrombin generation, fibrinolysis, and endothelial dysfunction in CHF patients, and the potential role of anticoagulants and/or antiplatelet agents in preventing these hemostatic abnormalities.

Although the syndrome of heart failure with preserved systolic function may occur in up to 40% of all heart failure patients, the clinical, angiographic characteristics, and long-term outcomes of these patients are poorly understood. We prospectively evaluated 2,498 consecutive patients with New York Heart Association class II to IV symptoms and ejection fractions of >40%, who underwent cardiac catheterization between January 1984 and December 1996 at Duke University Medical Center. The median age for the entire cohort was 63 years; 25% of the population was >71 years old. In addition, 55% of the patients were women, 65% had ischemic heart disease, 28% had a history of diabetes, and 62% had a history of hypertension. The median ejection fraction was 58%. One third of the patients had multivessel disease by coronary angiography. The overall 5-year mortality of the total population was 28%. The independent predictors of mortality (p

Aims: To evaluate the clinical characteristics and long-term outcomes of advanced heart failure patients (NYHA Class IIIb–IV) receiving beta-blocker therapy vs. those patients not receiving beta-blockers at randomization in the FIRST trial, a randomized, double-blind, placebo-controlled trial of epoprostenol vs. usual care in advanced heart failure. Methods and results: The patient population consisted of 471 patients enrolled in FIRST with Class IIIb–IV heart failure, left ventricular ejection fraction (LVEF) of < 30%, advanced hemodynamic abnormalities, and standard pharmacologic treatment of ACE-inhibitor, diuretics, and/or digoxin. The study cohort consisted of 448 patients not receiving beta-blockers and 23 patients receiving beta-blockers at randomization for the FIRST trial. Patients in the beta-blocker group had decreased rates of any clinical event (P = 0.03), worsening heart failure (P = 0.001), and death or worsening heart failure (P = 0.0008) than patients not receiving beta-blockers. After adjusting for prognostically important variables, the favorable effect of beta-blockers on worsening heart failure (P = 0.02) and death or worsening heart failure (P = 0.02) persisted. Conclusion: Patients with advanced heart failure who receive beta-blocker therapy have a lower rate of hospitalization and are less likely to experience worsening heart failure or death at 6 months than patients who are not treated with beta-blockers. These observational data contribute to the growing body of data demonstrating a favorable effect of beta-blockers on clinical outcomes in heart failure.