Early initiation of beta blockade in heart failure: issues and evidence

Despite clinical trials demonstrating that inhibitors of the renin-angiotensin and sympathetic nervous systems can reduce the mortality and morbidity risk associated with heart failure, these drugs have remained underutilized in general clinical practice. In particular, many patients with heart failure due to left ventricular systolic dysfunction fail to receive beta blockers, although this class of drugs, as well as other antihypertensive agents such as angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, are recommended as part of routine heart failure therapy by national expert consensus guidelines. In-hospital initiation of beta-blocker therapy may improve long-term utilization by physicians and compliance by patients through obviating many of the misperceived dangers associated with beta blockade. The following review of the clinical trial data from the Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD) trial, the Metoprolol Controlled-Release Randomized Intervention Trial in Heart Failure (MERIT-HF), the Cardiac Insufficiency Bisoprolol Study II (CIBIS-II), the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) trial, and the Initiation Management Predischarge Process for Assessment of Carvedilol Therapy for Heart Failure (IMPACT-HF) trial on the efficacy, safety, and tolerability of beta blockers indicates that early initiation can be safely achieved and can improve patient outcomes.     

Aldosterone receptor blockers in the treatment of heart failure

Opinion statement Heart failure is associated with neurohormonal activation, including activation of the renin-angiotensin-aldosterone system. Plasma aldosterone levels are elevated in patients with heart failure in spite of the use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers because of angiotensin-independent stimuli for aldosterone production. In addition to its long recognized role in sodium retention, aldosterone has a number of other deleterious effects, including the increase in myocardial and vascular fibrosis and myocardial remodeling in patients with heart failure. Based on strong clinical trial data, low-dose aldosterone receptor blockers are recommended to improve morbidity and mortality in patients with severe chronic heart failure due to left ventricular systolic dysfunction and in patients with heart failure associated with left ventricular systolic dysfunction after acute myocardial infarction, and in patients already on standard therapy including ACE inhibitors (or angiotensin receptor blockers) and β blockers. In view of the potential for serious hyperkalemia with the use of aldosterone receptor blockers, it is essential to monitor serum potassium closely and to adjust the dose of aldosterone antagonists based on serum potassium levels. Close adherence to the dosing regimens used in the clinical trials (RALES [Randomized Aldactone Evaluation Study] and EPHESUS [Eplerenone Post-AMI Heart Failure Efficacy and Survival Study]) is recommended. These agents should not be initiated in patients with severe renal insufficiency and closer monitoring is warranted in those with mild to moderate renal insufficiency or diabetes.     

Heart Failure Management in African Americans: Meeting the Challenge

Heart failure affects 3% of African Americans. The etiology of disease and prognosis for these patients differs substantially from those for non-African Americans. A history of hypertension is associated with development of heart failure more often in African Americans than in non-African Americans and it also appears that target organ involvement is more severe in African Americans with hypertension than in other patient subgroups. Reviewing the results from large-scale clinical end point studies suggests that optimal treatment for heart failure in African Americans may differ from that of their non-African American counterparts. More importantly, concomitant use of β blockers and angiotensin-converting enzyme inhibitors may be as effective in African Americans as in non-African Americans. Utilizing angiotensin–converting enzyme inhibitors alone may not represent ideal therapy. Of the drugs studied, especially among the β blockers, carvedilol may be the most effective to use for this population.     

The role of angiotensin receptor blockers in heart failure

The effectiveness of ACE inhibitors in reducing morbidity and mortality in patients with heart failure is largely attributable to their suppression of angiotensin II production. Despite chronic therapy with ACE inhibitors, angiotensin II levels may be incompletely suppressed and contribute to the high mortality of patients with heart failure. Recently, angiotensin receptor blockers, which block the effects rather than the production of angiotensin II, have become available. Angiotensin receptor blockers have been evaluated as both monotherapy and in combination with ACE inhibitors. In short term studies, angiotensin receptor blocker monotherapy appears to share many of the hemodynamic and clinical features of ACE inhibitors. In a long-term study, the Losartan Heart Failure Survival Study, angiotensin receptor blockers failed to demonstrate any beneficial effect over that seen with ACE inhibitors. The addition of an angiotensin receptor blocker to an ACE inhibitor appears to exert favorable short term hemodynamic, clinical, and neurohormonal effects. Four ongoing trials, Valsartan Heart Failure Trial, Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity, Optimal Therapy in Myocardial Infarction with Angiotensin II Antagonist Losartan study, and Valsartan In Acute Myocardial Infarction study, are evaluating the role of angiotensin receptor blockers either alone or in combination with ACE inhibitors in the management of left ventricular dysfunction. (c)2000 by CHF, Inc.     

Overview of the results of recent beta blocker trials

Results of the studies published or reported within the last 2 years provide convincing evidence that beta-blockers can decrease mortality in patients with chronic symptomatic heart failure because of left ventricular systolic dysfunction. The Cardiac Insufficiency Bisoprolol Study (CIBIS)-II and Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF) trials showed a 34% reduction in all-cause death with bisoprolol and metoprolol therapy in patients with class II-III heart failure. Data from Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS), with a 35% mortality reduction, extended this benefit to class IV patients treated with carvedilol who do not require intravenous diuretics or positive inotropes. Ongoing beta-blocker studies address new topics, such as treatment of older patients, in whom diastolic heart failure may be more common, and direct comparison of different drugs. Although the use of beta-blockers for heart failure tends to increase, implementation of the knowledge from the trials in clinical practice still remains a challenge.     

Contemporary treatment of heart failure: Is there adequate evidence to support a unique strategy for African-Americans? pro position

Clinical trials provide average effects of interventions but are not powered to identify differences in subgroup responses. African-Americans have been under-represented in most previous trials in patients with heart failure. Furthermore, physiologic differences have been demonstrated between African-Americans and whites in the mechanisms and response to therapy in hypertension. Review of previous heart failure trials reveals that African-Americans exhibit less benefit than whites from ACE inhibitors, angiotensin receptor blockers, and at least one β-blocker. In contrast, black patients experienced a greater benefit than white patients from the combination of nitrate and hydralazine. These data emphasize the need for trials in black patients to identify effective therapy. The first such trial, African-American Heart Failure Trial, is currently underway.     

Metoprolol CR/XL in black patients with heart failure (from the Metoprolol CR/XL randomized intervention trial in chronic heart failure)

A subgroup analysis was performed in black patients who participated in the Metoprolol CR/XL Randomized Intervention trial in Congestive Heart Failure trial. Results suggest a beneficial effect of beta blockade and support the use of beta blockers in black patients with clinically stable heart failure and left ventricular dysfunction.     

Angiotensin blockade or aldosterone blockade as the third neuroendocrine-blocking drug in mild but symptomatic heart failure patients

Recent clinical trials have explored whether angiotensin receptor blockers (ARBs) or aldosterone blockade should be added to standard angiotensin-converting enzyme (ACE) inhibitor/beta blocker treatment in heart failure. Both strategies are of some value but it is unclear which strategy should be used first in patients with mild but symptomatic heart failure. The arguments for and against each strategy are discussed. The strongest argument for aldosterone blockade is the consistency in the results of the RALES (Randomized Aldactone Evaluation Study) and EPHESUS (Eplerenone Post-acute Myocardial Infarction Heart Failure Efficacy and Survival Study) studies, but what is lacking is a trial of aldosterone blockade in patients with mild, symptomatic heart failure as such. The strongest argument for ARBs is that the CHARM (Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity) Added trial result was positive in the precise patient population of interest (mild, symptomatic heart failure). The strength of this argument is diminished by the somewhat different results in Val-HeFT (Valsartan Heart Failure Trial). A third possibility is to use neither an ARB nor an aldosterone blocker and arguments can be marshalled for this position also. Clinicians should now assess these various arguments to select what they believe would be best for their patients.     

Use of pulmonary artery catheters in advanced heart failure

PURPOSE OF REVIEW: Randomized trials have demonstrated that use of the pulmonary artery catheter does not improve outcomes in patients with critical illness. Despite this, pulmonary artery catheters continue to be used, especially in heart failure. This review addresses recent clinical trials evaluating the safety and efficacy of the pulmonary artery catheter. It also offers guidelines on when pulmonary artery catheter use could be considered in patients with advanced heart failure. RECENT FINDINGS: A meta-analysis demonstrated that use of the pulmonary artery catheter in critically ill patients had no significant impact on morbidity or mortality. In the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness trial, the addition of the pulmonary artery catheter to careful clinical assessment also had neutral impact. The results of the study are limited, however, by the patient population that was selected for the study, and there still may be a role for the pulmonary artery catheter in advanced heart failure. SUMMARY: Based on the results of the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness trial and the meta-analysis, there is no indication for routine use of pulmonary artery catheters to adjust therapy during hospitalization for decompensation of chronic heart failure. There remain many specific clinical situations in heart failure in which the pulmonary artery catheter may be useful, however.     

Use of beta blockers in patients with post-MI left ventricular dysfunction

Opinion statement β Blockers have been shown to reduce mortality after myocardial infarction (MI) in several large trials. Despite strong evidence supporting the role of β blockers in treating patients after MI, less than half are prescribed these drugs. The majority of studies demonstrating efficacy of β blockers in the treatment of the post-MI patients were conducted at a point in time when left ventricular (LV) dysfunction was considered a strong contraindication to their use. In addition, when these studies were carried out a variety of therapies that are known to improve survival were not yet available. In the present era, β blockers are routinely used to treat patients with heart failure due to systolic dysfunction. Until recently, however, there was uncertainty about their role in the management of patients with LV dysfunction after MI. The recent CAPRICORN (Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction) study demonstrated a significant mortality benefit when carvedilol was added to standard therapy in patients with LV dysfunction after MI. This article reviews information regarding the initiation and maintenance of β blockers in patients with post-MI LV dysfunction.     

Efficacy and safety of carvedilol in patients with chronic heart failure receiving concomitant amiodarone therapy

Background: The β-blocker/vasodilator carvedilol is found to have beneficial effects in patients with chronic heart failure. However, the safety and efficacy of this agent in the presence of concomitant amiodarone therapy has not been previously determined.Methods and Results: We retrospectively analyzed the Australia/New Zealand Carvedilol Heart Failure Research Collaborative Group study of 415 patients with mild to moderate ischemic heart failure where amiodarone was administered as part of the treatment therapy (in 52 patients). After the open-label carvedilol run-in, patients received carvedilol (target dose 25 mg twice daily) or placebo for an average of 19 months. The main adverse events during this double-blind period were worsened heart failure, hypotension/dizziness, bradycardia/ atrioventricular block, and aggravation of angina. By Chi square analysis, carvedilol and amiodarone together were not associated with a greater overall incidence of adverse effects than either drug alone. The beneficial effects of carvedilol on left ventricular ejection that were observed in the main trial were preserved in the presence of amiodarone.Conclusions: Carvedilol is a useful additional therapy for patients with chronic heart failure already receiving amiodarone. Carvedilol can be added to amiodarone in these patients without expectation of increased adverse effects or loss of clinical efficacy.     

Update of REACH-1 and MERIT-HF clinical trials in heart failure. Cardio.net Editorial Team

BACKGROUND: This article reviews the design and results of REACH-1 (Research on Endothelin Antagonism in Chronic Heart Failure) and MERIT (Metoprolol controlled and Extended release, Randomised Intervention Trial in congestive Heart Failure), two recently reported clinical trials that investigated, respectively, the role of a non-selective endothelin antagonist (bosentan) and of a beta-selective blocker for the treatment of heart failure. RESULTS: The REACH-1 trial demonstrated that initiation of bosentan therapy is associated with an increased risk of worsening heart failure. However, long-term therapy with bosentan may have improved symptoms and favourably altered the progression of heart failure. The MERIT-HF clinical trial indicated that beta-blockade using metoprolol confers a significant beneficial effect on total mortality in patients with stable chronic heart failure.     

Treatment of the african-american patient with congestive heart failure

Opinion statement African Americans have a higher burden of cardiovascular disease than white Americans, including a higher prevalence of heart failure. In addition, heart failure in African Americans conforms to a more malignant natural history. Hypertension is most often cited as the sole etiology of heart failure in African Americans. Most of the major trials of pharmacotherapy for the management of chronic heart failure have failed to include significant numbers of African-American patients. Based on the available evidence, there is no reason to withhold standard evidence-based medical therapy for heart failure. Even though there is much controversy as to the efficacy of angiotensin-converting enzyme (ACE) inhibitors and β blockers in African Americans, in the absence of definitive data they should be used. Recently, the combination of isosorbide dinitrate and hydralazine has been demonstrated to improve survival in African Americans with New York Heart Association class III and IV heart failure, and represents an adjunctive treatment option when added to standard medical therapy consisting of ACE inhibitors, β blockers, digoxin, diuretics, and aldosterone antagonists. Emerging evidence suggests that this therapy may be targeting a novel mechanism of heart failure progression (ie, nitric oxide bioavailability) found in African Americans.     

Effect of β-Blockers on β<Subscript>3</Subscript>-Adrenoceptor Expression in Chronic Heart Failure

Objectives To investigate the expression of β₃-adrenoceptors in rats with chronic heart failure, and to explore the effect of β-blockers on β₃-adrenoceptor expression. Materials and methods Thirty-two male Wistar rats were divided into Sham (n = 10) and heart failure (n = 22) groups. The heart failure group was treated with normal saline (Heart Failure Control, n = 6), Metoprolol (n = 8) or Carvedilol (n = 8) for 3 months. Results The left ventricular end systolic pressure (LVESP) and the absolute values of maximal rate of rise and fall of left ventricular pressure (±dP/dt max) in the heart failure group were lower than in the Sham group (P < 0.01), whereas the left ventricular end diastolic pressure (LVEDP) was higher (P < 0.01). The LVESP and dP/dtmax in the Carvedilol group were higher than the Metoprolol group whereas LVEDP was lower (P < 0.01). The left ventricular mass index (LVMI) in the Carvedilol group was less than the Metoprolol and Heart Failure Control groups (P < 0.01). The level of β₃-adrenoceptor expression in the study groups was significantly higher than the Sham group (P < 0.01). β₃-adrenoceptor expression in the Carvedilol group was lower than the Heart Failure Control and Metoprolol groups (P < 0.01). Conclusion β₃-adrenoceptor expression is increased in the failing ventricles in rats. Carvedilol is more effective than Metoprolol for improving the hemodynamics and in attenuating ventricular remodeling after heart failure. Carvedilol, rather than Metoprolol, diminishes β₃-adrenoceptor expression in the failing ventricles.     

Medical Therapy for Acute Decompensated Heart Failure: What Recent Clinical Trials Have Taught Us About Diuretics and Vasodilators

Diuretics and vasodilators have been the cornerstone of heart failure (HF) therapy for decades. Although not shown to reduce mortality, diuretic and vasodilator therapy remain commonplace for treating acute decompensated HF, with diuretics being the mainstay of therapy for the removal of excess fluid in all patients with HF. This article discusses results of recent trials concerning diuretic or vasodilator therapy and HF, including the Diuretic Optimization Strategies Evaluation (DOSE) trial, the Placebo-Controlled Randomized Study of the Selective A1 Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized With Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function (PROTECT), and the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST), as well as results from the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) trial and the Preliminary Study of Relaxin in Acute Heart Failure (Pre-RELAX-AHF).     

Heart Failure and Its Management With β-Blockade: Potential Applications of Once-Daily Therapy

Heart failure (HF) due to left ventricular (LV) systolic dysfunction is a progressive disease beginning with a primary injury that activates compensatory cardiovascular mechanisms including varying degrees of neurohormonal activation. Within the neurohormonal cascade, activation of the sympathetic nervous system is in part responsible for ongoing myocardial injury, progressive LV remodeling, and functional deterioration eventually leading to symptomatic HF. Large randomized clinical trials of certain β-blockers added to standard therapies have shown unequivocal benefits in patients with chronic systolic HF resulting in reduced remodeling, fewer total and cardiovascular deaths, and less risk of hospitalization for worsening HF. Evidence-based clinical guidelines recommend β-blockers as part of the regimen for patients with systolic HF as well as LV dysfunction following myocardial infarction. Based on published clinical trial results, bisoprolol, carvedilol, and sustained-release metoprolol succinate are recommended for systolic HF. Carvedilol, propranolol, and timolol are recommended for post-myocardial infarction LV dysfunction. Unfortunately, these evidence-based therapies are often underused in actual practice. Various strategies to increase β-blocker use in HF have been attempted, including in-hospital initiation of β-blocker therapy. Simplifying dosing regimens may also improve adherence to prescribed medications. Use of controlled-release carvedilol may encourage better adherence in patients with LV dysfunction and help overcome at least one barrier to optimal evidence-based care.     

The Carvedilol and ACE-Inhibitor Remodelling Mild Heart Failure EvaluatioN trial (CARMEN)--rationale and design

Inhibition or reversal of ventricular remodelling in heart failure patients is regarded as of prime importance in the treatment of heart failure and in determining long term outcome. Recent studies have demonstrated that the addition of carvedilol to Angiotensin Converting Enzyme (ACE) inhibitors and other routine heart failure therapy results in a valuable improvement in the clinical status and life expectancy of mild, moderate and severe heart failure patients. ACE inhibitors have become the cornerstone of heart failure therapy. Also, carvedilol in combination with standard therapy (including ACE inhibitors) has demonstrable beneficial effects on left ventricular remodelling. Each new treatment has to be added, this quickly leads to polypharmacy, which may not be necessary and even unwanted in the individual patient, as the pharmacological profile of carvedilol compares favourably to ACE inhibitors, this suggests that it could challenge ACE inhibitors as first-line treatment for heart failure.The CARMEN trial (Carvedilol and ACE-Inhibitor Remodelling Mild Heart Failure EvaluatioN) was designed to compare the effects of carvedilol alone and of carvedilol plus an ACE inhibitor (enalapril) with the effect of an ACE inhibitor alone on different parameters of left ventricular remodelling as well as morbidity and mortality in patients with chronic mild heart failure, thereby allowing conclusions on whether combination therapy may be replaced by the multiple action adrenergic inhibitor carvedilol in the future.     

Angiotensin II receptor blockers in older patients

Older patients with hypertension are often inadequately treated due to misconceptions regarding reasonable goal blood pressures or concerns about treatment side effects. Adequately treating hypertension can yield impressive benefits in terms of improved morbidity and enhanced quality of life in persons of any age. Antagonists of the renin-angiotensin-aldosterone system are especially effective in older persons, many of whom have concomitant conditions such as diabetes mellitus, renal dysfunction, and other cardiovascular risk factors. Treatment with angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers has been shown to improve many of the complications of hypertension, including left ventricular hypertrophy and renal disease. Results of recent key studies such as Losartan Intervention For Endpoint Reduction in Hypertension (LIFE), Valsartan in Heart Failure Trial (Val-HeFT), Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM), and Valsartan in Acute Myocardial Infarction (VALIANT) add to the evidence that angiotensin II receptor blockers are well suited for the treatment of hypertension in older patients. These trials also indicate that they are appropriate therapy for heart failure patients and for patients who have experienced acute myocardial infarction, particularly those who are unable to tolerate an angiotensin-converting enzyme inhibitor.     

Carvedilol in the failing heart.

Patients with chronic heart failure due to left ventricular systolic dysfunction of ischemic or nonischemic etiology have shown improvement in morbidity and mortality with carvedilol therapy. In patients with symptomatic (New York Heart Association class II-IV) heart failure, carvedilol improves left ventricular ejection fraction and clinical status, and slows disease progression, reducing the combined risk of mortality and hospitalization. Despite the overwhelming evidence for their benefit, there continues to be a large treatment gap between those who would derive benefit and those who actually receive the drug. In this article, the pharmacology, clinical trial evidence, and the potential differences between carvedilol and other beta blockers are discussed. Carvedilol provides powerful therapy in the treatment of chronic heart failure caused by a variety of etiologies and in a wide array of clinical settings.