Effect of baseline or changes in adrenergic activity on clinical outcomes in the beta-blocker evaluation of survival trial.

BACKGROUND: Adrenergic activation is thought to be an important determinant of outcome in subjects with chronic heart failure (CHF), but baseline or serial changes in adrenergic activity have not been previously investigated in a large patient sample treated with a powerful antiadrenergic agent. METHODS AND RESULTS: Systemic venous norepinephrine was measured at baseline, 3 months, and 12 months in the beta-Blocker Evaluation of Survival Trial (BEST), which compared placebo treatment with the beta-blocker/sympatholytic agent bucindolol. Baseline norepinephrine level was associated with a progressive increase in rates of death or death plus CHF hospitalization that was independent of treatment group. On multivariate analysis, baseline norepinephrine was also a highly significant (P<0.001) independent predictor of death. In contrast, the relation of the change in norepinephrine at 3 months to subsequent clinical outcomes was complex and treatment group-dependent. In the placebo-treated group but not in the bucindolol-treated group, marked norepinephrine increase at 3 months was associated with increased subsequent risks of death or death plus CHF hospitalization. In the bucindolol-treated group but not in the placebo-treated group, the 1st quartile of marked norepinephrine reduction was associated with an increased mortality risk. A likelihood-based method indicated that 18% of the bucindolol group but only 1% of the placebo group were at an increased risk for death related to marked reduction in norepinephrine at 3 months. CONCLUSIONS: In BEST, a subset of patients treated with bucindolol had an increased risk of death as the result of sympatholysis, which compromised the efficacy of this third-generation beta-blocker.

Milrinone versus dobutamine in heart failure subjects treated chronically with carvedilol.

OBJECTIVE: To compare the efficacy of milrinone and dobutamine in patients chronically treated with carvedilol. BACKGROUND: Milrinone and dobutamine are used to manage decompensated heart failure, but their efficacy in patients on beta-blocker therapy was unknown. METHODS: Twenty patients with decompensated heart failure were prospectively enrolled. Inotropic responses to milrinone (12.5, 25 or 50 microg/kg bolus infusions) or dobutamine (5, 10, 15 or 20 microg/kg/min infusions) were evaluated by right-heart catheterization. RESULTS: Milrinone increased cardiac index (2.0-2.6 l/min/m2, P=0.0001) without significantly altering heart rate (70-75 bpm, P=0.19). Milrinone decreased mean pulmonary artery pressure (36-29 mm Hg, P=0.0001), pulmonary capillary wedge pressure (24-18 mm Hg, P=0.0001) and mean arterial blood pressure (78-75 mm Hg, P=0.0002). Left ventricular stroke volume index increased in the milrinone group (31-35 ml/beat/m2, P=0.0001). Dobutamine produced an increase in cardiac index (2.4-3.3 l/min/m2, P=0.0001) only at doses that are not typically used to treat heart failure (15-20 microg/kg/min). At these doses, dobutamine increased heart rate (68-82 bpm, P=0.008), mean systemic pressure (90-117 mm Hg, P=0.0001) and mean pulmonary artery pressure (21-30 mm Hg, P=0.001). Dobutamine did not alter left ventricular stroke volume index or pulmonary capillary wedge pressure. CONCLUSIONS: Dobutamine and milrinone have different hemodynamic effects in patients treated chronically with carvedilol. These differences should be considered when selecting inotropic therapy for decompensated heart failure.

Practical aspects of using beta-adrenergic blockade in systolic heart failure.

Heart failure exacts a severe human and public health toll. In the United States, heart failure afflicts approximately 5 million patients and is responsible for or contributes to 3 million hospitalizations and 300,000 deaths yearly. Physicians can have a major impact on this disease by using effective agents for the treatment of heart failure (particularly angiotensin-converting enzyme [ACE] inhibitors and beta blockers), yet the actual clinical use of these drugs (especially the use of beta blockers by primary physicians) is disappointingly low. Many physicians appear to be reluctant to prescribe beta blockers for two reasons. First, they are concerned about the potential interference of beta blockers with important compensatory mechanisms that support the failing heart and fear that such interference may lead to clinical deterioration. Second, they fail to identify patients with heart failure (especially those with mild or moderate symptoms) or regard such patients as being too well to require additional treatment. These reasons should no longer be used as excuses to avoid the use of these drugs, given the persuasive evidence that beta blockers can improve symptoms and prolong life in patients with heart failure. Instead, physicians must recognize that long-term activation of the sympathetic nervous system primarily exerts deleterious (rather than compensatory) effects in patients with heart failure and that these actions can be antagonized effectively and safely by the appropriate use of beta-blocking drugs.

Optimizing the use of beta-blockers in the effective treatment and management of heart failure: a case study approach.

Today, heart failure is an increasing concern in the United States. Its prognoses are poor and its treatment is a complicated endeavor, because heart failure is not a single disease state. Rather, it is a syndrome with a cyclic pathophysiology composed of multiple mechanisms. Effective case management of heart failure must address each of the many changes involved in this syndrome, and therapy must be individualized, especially because patients with heart failure often require regimens of five or more drugs. In special populations, such as the elderly and/or patients with concomitant diseases requiring added medication, polypharmacy becomes an important issue. Maintaining consistent compliance with the treatment regimen and patient education regarding symptoms of fluid retention can be critical. Currently, beta-blockers, in addition to standard therapy, are recommended as first-line treatment in mild-to-moderate heart failure. The three cases presented in this article illustrate some common scenarios encountered and clinical decisions made when beta-blockers are used in the management of heart failure.

Effect of concomitant digoxin and carvedilol therapy on mortality and morbidity in patients with chronic heart failure.

We retrospectively performed stepwise logistic regression analysis on 1,509 patients with chronic heart failure in 4 multicenter United States studies and 1 Australia-New Zealand study to examine the effect of digoxin in patients randomized to carvedilol or placebo. Patients receiving digoxin had more advanced heart failure, the incidence of hospitalization for any cause and the combination of all-cause death and all-cause hospitalization were the same in the digoxin versus no-digoxin groups.

Clinical use of beta-blockers in patients with heart failure.

Recognition of the role of the sympathetic nervous system in chronic heart failure has resulted in dramatic changes in the way heart failure is viewed, providing strong evidence for the therapeutic role for beta-adrenergic blocking agents. This treatment strategy does not provide short-term hemodynamic improvement and may even worsen symptoms initially. However, beta-blockers can be administered with good or even excellent tolerability by slowly withdrawing adrenergic support to the failing heart. Results of clinical trials have shown that long-term treatment with beta-blockers improves ventricular function and reduces mortality rates in patients with mild-to-moderate heart failure. Although the improvement in ventricular function is a beta-blocker class effect, there are distinct differences in antiadrenergic activity and tolerability among the first-, second-, and third-generation agents. These differences--as well as practical strategies for dose titration and the management of decompensation--are the focus of this article.

Ambulatory ventricular arrhythmias in patients with heart failure do not specifically predict an increased risk of sudden death. PROMISE (Prospective Randomized Milrinone Survival Evaluation) Investigators.

BACKGROUND: Ventricular arrhythmias are a frequent finding in congestive heart failure (CHF) patients and a cause of concern for physicians caring for them. Previous studies have reached conflicting conclusions regarding the importance of ventricular arrhythmias as predictors of sudden death in patients with CHF. This study examined the independent predictive value of ventricular arrhythmias for sudden death and all-cause mortality in PROMISE (Prospective Randomized Milrinone Survival Evaluation). METHODS AND RESULTS: Ventricular arrhythmias were analyzed and quantified by use of prespecified criteria on baseline ambulatory ECGs from 1080 patients with New York Heart Association (NYHA) class III/IV symptoms and a left ventricular ejection fraction

Experience with beta blockers in heart failure mortality trials.

Recent investigations have indicated that chronic heart failure can be reversed with agents that inhibit the reninangiotensin-aldosterone or sympathetic nervous system, such as angiontensin-converting enzyme (ACE) inhibitors and beta blockers. A meta-analysis of clinical trials of ACE inhibition in chronic heart failure reported reductions in mortality ranging from 13 to 33%, but as ACE inhibitors do not block chronic noradrenergic stimulation of the heart, mortality remains unacceptably high. Beta blockers have been shown to increase left ventricular ejection fraction, reduce end-systolic and end-diastolic cardiac dimensions, improve quality of life, and reduce mortality. All-cause mortality in the US Carvedilol trial was reduced 65%, and in MERIT-HF there was a 49% reduction in mortality from heart failure among patients receiving metoprolol CR/XL. MERIT-HF was ended early because of evidence of survival benefit. Although certain effects of beta blockers may be considered class effects, it is not yet clear whether there are differences between beta 1-selective antagonists and nonselective agents. The benefits conferred across differences in disease severity, race, and age should be answered as large ongoing and planned clinical trials of beta blockers are completed.

Effect of selective versus nonselective beta blockade on QT dispersion in patients with nonischemic dilated cardiomyopathy.

We retrospectively examined the electrocardiograms in all of our patients with nonischemic dilated cardiomyopathy and normal sinus rhythm before and after at least 3 months of metoprolol (n = 12), bucindolol (n = 8), carvedilol (n = 6), or no beta blocker (n = 9). Both beta1-selective and nonselective beta-adrenergic blockade reduced QTc dispersion equally in patients with dilated cardiomyopathy.

The role of third-generation beta-blocking agents in chronic heart failure.

Third-generation beta-blocking agents developed for the hypertension market are proving useful in the treatment of chronic heart failure (HF). These compounds share the ancillary property of vasodilation, which improves acute tolerability by unloading the failing left ventricle at a time when beta-adrenergic withdrawal produces myocardial depression. In the case of carvedilol and bucindolol, this allows for the administration of nonselective beta blockade. Because of blockade of both beta 1 and beta 2 adrenergic receptors as well as other properties, these compounds possess a more comprehensive antiadrenergic profile than second-generation, beta 1-selective compounds. For this and potentially other reasons, third-generation beta-blocking agents have theoretical efficacy advantages that have yet to be demonstrated in large-scale trials. Ongoing trials with either second- or third-generation compounds and one trial directly comparing a compound from each class will provide the answer as to whether third-generation compounds have an advantage in the treatment of chronic HF.

Our new understanding of heart failure: the role of beta-blockers in treatment.

Beta-blockers, long considered contraindicated in heart failure, improve left ventricular function in this disease by improving the biology of cardiac myocytes. Whether they improve survival remains to be determined.

Restoring function in failing hearts: the effects of beta blockers.

Until recently, clinical management of congestive heart failure was purely palliative. The drugs used in patients with failing hearts--digoxin, vasodilators, and positive inotropic agents--improved contractility, reversed hemodynamic abnormalities, and enhanced functional status, but they failed to confer a survival benefit. Indeed, the use of inotropic agents often resulted in excess mortality--a paradox explained in part by the pharmacological properties of these agents, which increase production of cAMP, the intracellular messenger for the beta-adrenergic system. The short-term pharmacological benefits of these drugs may be offset by deleterious long-term biological effects on the heart muscle itself. The use of beta-blockers in heart failure is counterintuitive, given that their initial pharmacological effect is to reduce heart rate and contractility in a faltering heart, thus producing an effect diametrically opposed to that of inotropic agents. However, it is becoming more clear that beta-blocker therapy in patients with heart failure not only improves left ventricular function, but may actually reverse pathological remodeling in the heart. Accumulating clinical evidence indicates that these beneficial changes are the result of secondary biological changes in the myocardium rather than a response to the pharmacological effects of the drugs themselves. Mounting evidence suggest that these agents may prolong survival in patients with heart failure, and ongoing clinical trials may soon confirm these preliminary findings.

Medical therapy of chronic heart failure. Role of ACE inhibitors and beta-blockers.

Heart failure has long been considered to have a progressive downhill course leading inexorably to an early demise. This course often occurs silently, in the absence of any obvious cardiac insults. The reason for this is a combination of cell loss, myocyte dysfunction, impaired energetics, and pathologic remodeling of the chamber. Improved clinical outcome should result from strategies that reduce the biologic signals responsible for myocyte growth, dysfunction, and loss and chamber remodeling. Clinicians should no longer attempt to treat chronic heart failure with pharmacologic growth and remodeling process. In time, it may be possible for the clinician to view the treatment of heart failure largely as a matter of improving the biologic function of the myocardium.

Does digoxin provide additional hemodynamic and autonomic benefit at higher doses in patients with mild to moderate heart failure and normal sinus rhythm?

OBJECTIVES: This study sought to examine the hemodynamic and autonomic dose response to digoxin. BACKGROUND: Previous studies have demonstrated an increase in contractility and heart rate variability with digitalis preparations. However, little is known about the dose-response to digoxin, which has a narrow therapeutic window. METHODS: Nineteen patients with moderate heart failure and a left ventricular ejection fraction < 0.45 were studied hemodynamically using echocardiography and blood pressure at baseline and after 2 weeks of low dose (0.125 mg daily) and 2 weeks of moderate dose digoxin (0.25 mg daily). Loading conditions were altered with nitroprusside at each study. Autonomic function was studied by assessing heart rate variability on 24-h Holter monitoring and plasma norepinephrine levels during supine rest. RESULTS: Low dose digoxin provided a significant increase in ventricular performance, but no further increase was seen with the moderate dose. Low dose digoxin reduced heart rate and increased heart rate variability. Moderate dose digoxin produced no additional increase in heart rate variability or reduction in sympathetic activity, as manifested by heart rate, plasma norepinephrine or low frequency/high frequency power ratio. In addition, we did not find that either low or moderate dose digoxin increased parasympathetic activity. CONCLUSIONS: We conclude that moderate dose digoxin provides no additional hemodynamic or autonomic benefit for patients with mild to moderate heart failure over low dose digoxin. Because higher doses of digoxin may predispose to arrhythmogenesis, lower dose digoxin should be considered in patients with mild to moderate heart failure.

Practical guidelines for initiation of beta-adrenergic blockade in patients with chronic heart failure.

Recent developments in the treatment of chronic heart failure have lead to the use of beta blockers to improve ventricular function and symptoms, and to reverse or slow pathologic remodeling of the failing heart. Little practical information exists in the literature on how to initiate this therapy and how to select the proper beta-blocking agent. This editorial examines which beta-blocking agents are best tolerated and why, and describes how best to initiate treatment with these agents.

Hemodynamic effects of the class III antiarrhythmic drug, d-sotalol, in patients with congestive heart failure.

In contrast to Vaughan Williams class I drugs, class III drugs, such as d-sotalol, may not be negative inotropic. These drugs block potassium ion channels and prolong repolarization, theoretically leading to improved contractility. We investigated the hemodynamic actions of acute intravenous administration of 1.5 mg/kg of d-sotalol in 28 patients with congestive heart failure randomized to receive placebo (n = 10) or active drug (n = 18) in a double-blind study. A Swan-Ganz catheter was placed in all patients > or = 16 hours before drug administration. All hemodynamic variables were assessed at baseline and 30 minutes and 1, 2, 4, 8, and 12 hours after administration of the drug. Electrocardiograms were obtained before and 1, 2, 4, and 12 hours after drug administration. The QT interval increased from 370 +/- 9 to 426 +/- 14 ms at 1 hour, whereas the QTc increased from 433 +/- 5 to 470 +/- 12 ms (both p < 0.001). The increase was still statistically significant at 12 hours. There was no change in the placebo group. Although heart rate decreased in the d-sotalol group (84 +/- 2 to 76 +/- 2 at 1 hour, p < 0.001), there were no changes in blood pressure or right atrial pressure. Cardiac index decreased slightly (2.0 +/- 0.2 to 1.9 +/- 0.1 mm Hg), consistent with the lower heart rate. Pulmonary capillary wedge pressure decreased from 18.9 +/- 2.4 to 17.9 +/- 1.9 mm Hg at 1 hour despite reduced cardiac index. We conclude that in contrast to class I, II, and IV antiarrhythmic drugs, d-sotalol exerts no clinically important acute hemodynamic actions at doses that produce electrophysiologic effects.