Relationship of serum digoxin concentration to mortality and morbidity in women in the digitalis investigation group trial: a retrospective analysis.

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 > or =1.2 ng/ml seem harmful.

Anemia as a risk factor and therapeutic target in 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.

Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF): rationale and design.

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.

Racial differences in the outcomes of patients with diastolic heart failure.

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 to 1996. 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.

Predischarge initiation of carvedilol in patients hospitalized for decompensated heart failure: results of the Initiation Management Predischarge: Process for Assessment of Carvedilol Therapy in Heart Failure (IMPACT-HF) trial.

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 > 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 < 0.0001). Predischarge initiation was not associated with an increased risk of serious adverse events. The median length of stay was five days in both groups. 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.

Predischarge initiation of carvedilol in patients hospitalized for decompensated heart failure.

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.

Usefulness of an elevated troponin-I in predicting clinical events in patients admitted with acute heart failure and acute coronary syndrome (from the RITZ-4 trial).

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.

Effects of tolvaptan, a vasopressin antagonist, in patients hospitalized with worsening heart failure: a randomized controlled trial.

CONTEXT: 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. OBJECTIVE: To evaluate the short- and intermediate-term effects of tolvaptan in patients hospitalized with heart failure. DESIGN, SETTING, AND PARTICIPANTS: 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. INTERVENTION: 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. MAIN OUTCOME MEASURES: 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. RESULTS: 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 (P< or =.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. CONCLUSION: Tolvaptan administered in addition to standard therapy may hold promise for management of systemic congestion in patients hospitalized for heart failure.

Effects of amino acid supplementation on left ventricular remodeling in patients with chronic heart failure with decreased systolic function and diabetes mellitus: rationale and design of a magnetic resonance imaging study.

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.

Implications of elevated cardiac troponin T in ambulatory patients with heart failure: a prospective analysis.

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 < or =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 (> or =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.

Effect of angiotensin-converting enzyme inhibitors, beta blockers, statins, and aspirin on C-reactive protein levels in outpatients with heart failure.

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.

Usefulness of anemia as a predictor of death and rehospitalization in patients with decompensated heart failure.

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.

Tezosentan in patients with acute heart failure and acute coronary syndromes: results of the Randomized Intravenous TeZosentan Study (RITZ-4).

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.

Pharmacologic therapy for patients with chronic heart failure and reduced systolic function: review of trials and practical considerations.

Heart failure (HF) is a complex clinical syndrome resulting from any structural or functional cardiac disorder impairing the ability of the ventricles to fill with or eject blood. The approach to pharmacologic treatment has become a combined preventive and symptomatic management strategy. Ideally, treatment should be initiated in patients at risk, preventing disease progression. In patients who have progressed to symptomatic left ventricular dysfunction, certain therapies have been demonstrated to improve survival, decrease hospitalizations, and reduce symptoms. The mainstay therapies are angiotensin-converting enzyme (ACE) inhibitors and beta-blockers (bisoprolol, carvedilol, and metoprolol XL/CR), with diuretics to control fluid balance. In patients who cannot tolerate ACE inhibitors because of angioedema or severe cough, valsartan can be substituted. Valsartan should not be added in patients already taking an ACE inhibitor and a beta-blocker. Spironolactone is recommended in patients who have New York Heart Association (NYHA) class III to IV symptoms despite maximal therapies with ACE inhibitors, beta-blockers, diuretics, and digoxin. Low-dose digoxin, yielding a serum concentration <1 ng/mL can be added to improve symptoms and, possibly, mortality. The combination of hydralazine and isosorbide dinitrate might be useful in patients (especially in African Americans) who cannot tolerate ACE inhibitors or valsartan because of hypotension or renal dysfunction. Calcium antagonists, with the exception of amlodipine, oral or intravenous inotropes, and vasodilators, should be avoided in HF with reduced systolic function. Amiodarone should be used only if patients have a history of sudden death, or a history of ventricular fibrillation or sustained ventricular tachycardia, and should be used in conjunction with an implantable defibrillator [corrected]. Finally, anticoagulation is recommended only in patients who have concomitant atrial fibrillation or a previous history of cerebral or systemic emboli.