Should beta-blockers be used for the treatment of pediatric patients with chronic heart failure?

In multiple clinical trials, beta-blockers have been shown to significantly improve morbidity and mortality in adults with chronic congestive heart failure, but there is little reported experience with their use in children. Heart failure involves activation of the adrenergic nervous system and other neurohumoral systems in order to maintain cardiovascular homeostasis. These compensatory mechanisms have been shown to cause myocardial damage with chronic activation, which has been hypothesized to be a major contributing factor to the clinical deterioration of adults with heart failure. Studies have demonstrated inhibition of this neurohumoral response and concomitant clinical benefits with beta-blockers. Consequently, beta-blockers have evolved to become an important part of comprehensive medical therapy for congestive heart failure in adults. Pediatric heart failure represents an entirely different spectrum of disease, caused more commonly by congenital heart disease than cardiomyopathy. Surgical palliation and correction are important components of pediatric heart failure therapy, and residual, postsurgical cardiac lesions can lead to chronic heart failure. Although neurohumoral activation in children is similar to that in adults with heart failure, there are important differences from adults in physiology and developmental changes that are especially observed in infants. Current published clinical experience with beta-blocker use in children with heart failure is limited to case series with relatively small numbers of patients. Nevertheless, these series show consistent symptomatic improvement, and improvement in ventricular systolic function in patients with cardiomyopathies and congenital heart disease, similar to findings in adults. Adverse effects were common and many patients in these studies had adverse outcomes (death and/or need for transplantation). One study has noted differences in pharmacokinetics in children compared with adults. However, a multicenter, randomized controlled trial to evaluate carvedilol in pediatric heart failure from systolic ventricular dysfunction is currently ongoing and should help to clarify the efficacy and tolerability of carvedilol in children.     

Beta-blockers in heart failure. The 'new wave' of clinical trials.

There is now considerable clinical trial data to support the use of beta-blockers in patients with congestive heart failure (CHF) due to systolic left ventricular dysfunction. A substantial database has accumulated over the last 20 years supporting the benefits of these agents on ventricular function and clinical status. In addition, morbidity and mortality benefits have been suggested, specifically with the non-selective vasodilating agent, carvedilol. More recently, a "new wave" of clinical trials have been conducted to definitively determine the mortality benefits of beta-blockers in patients with mild to moderate CHF as well as addressing other important clinical questions. These questions include whether the beneficial effects of carvedilol on survival can be reproduced by other agents in prospective, adequately powered studies; whether the benefits of carvedilol in systolic heart failure are due to its beta-blocking properties alone or to a combination of the beta-blocking and ancillary effects of the drug; whether beta-blockers are of benefit in patients with severe New York Heart Association (NYHA) Class IIIB-IV CHF; and, whether beta-blockers are of benefit (additional to ACE inhibitors) in patients with evidence of systolic ventricular dysfunction when commenced in the immediate post-myocardial infarction period. Major studies are currently being undertaken to address the above questions. Most are still underway but 3 studies have recently reported their results: the second Cardiac Insufficiency Bisoprolol Study (CIBIS II), the Research in Left Ventricular Dysfunction Study (RESOLVD), and the Metoprolol CR/XL Randomised Intervention Trial in Heart Failure (MERIT-HF) study. These studies have demonstrated that blockade with beta1-selective, non-vasodilating agents (i.e. bisoprolol and metoprolol) improve survival in patients with CHE Comparison of relative risk reduction in these recent studies with the earlier carvedilol studies raises mechanistic questions, specifically whether non-selectivity, vasodilation and other ancillary properties of carvedilol are critical to its benefit in CHF patients. This question is currently being addressed in the Carvedilol and Metoprolol European Trial (COMET), comparing metoprolol with carvedilol. The beneficial effects of beta-blockers on mortality in patients with mild to moderate CHF have also had major implications in ongoing studies of other agents in this condition. Open-label prescribing of beta-blockers is increasing in these studies and this is having an impact on event rates and thus required duration of administration of study drug. Furthermore, it would now appear unethical to deprive suitable NYHA Class II-III CHF patients of beta-blockers as part of the design of such studies. In conclusion, beta-blockers have now become the most extensively studied class of agents in the treatment of CHF, with a database of over 6000 patients in placebo-controlled studies, and ongoing clinical and mechanistic studies. Despite this, further questions remain regarding the use of these agents in CHF, including their role in the extreme elderly, in patients with diabetes mellitus and in patients with renal impairment.     

The use of carvedilol in pediatric heart failure

Chronic congestive heart failure has become a significant medical burden in the adult and a growing problem in the pediatric age group. While the etiologies of heart failure differ between children and adults, applied medical therapies are generally the same. In this regard, over the last decade, beta-adrenergic receptor blockade has become an important component in drug therapy of congestive heart failure in the adult population. A third-generation beta-blocker, carvedilol, has now been shown in adult trials to be efficacious in the treatment of heart failure and has been shown to be superior to other similarly used beta-blockers. Carvedilol use has been adapted into pediatric heart failure practice although data supporting its efficacy in infants and children are scarce. This review will describe the application of carvedilol in the adult, as it pertains to pediatric practice, review the existing pediatric literature and describe our institution's experience with carvedilol in heart failure therapy.     

Antioxidant properties of carvedilol and metoprolol in heart failure: a double-blind randomized controlled trial

Animal and human studies have shown that carvedilol has significant antioxidant properties compared with other beta-blockers. The objective of this study was to determine if these antioxidant effects are detectable in patients with heart failure and to compare carvedilol with the selective beta-blocker metoprolol. Twenty-four patients with chronic heart failure were randomly assigned to receive either carvedilol or metoprolol in a double-blind control trial for 12 weeks in a University teaching hospital clinic. Blood pressure, heart rate, exercise tolerance, left ventricular ejection fraction, plasma total antioxidant status, erythrocyte superoxide dismutase, and glutathione peroxidase activities were determined at baseline and every 4 weeks up to 12 weeks. The results showed that erythrocyte superoxide dismutase and glutathione peroxidase were significantly reduced in carvedilol treated patients after 12 weeks of therapy, whereas metoprolol had no significant effect, although the clinical improvement over the short-term was similar with both drugs. Thus carvedilol, in addition to improving symptoms in heart failure, also possesses significant antioxidant properties. Whether this additional action influences long-term outcome is at present unknown.     

Tolerability of beta-blockers in outpatients with refractory heart failure who were receiving continuous milrinone

STUDY OBJECTIVE: To investigate the dosing, tolerability, and outcomes associated with the use of concomitant beta-blockers and inotropic therapy in patients with refractory heart failure during the first 6 months of their therapy. DESIGN: Retrospective review. SETTING: University-based, tertiary care heart failure and transplant center. PATIENTS: Sixteen inotrope-dependent outpatients with end-stage refractory heart failure who were receiving continuous intravenous milrinone. Of these patients, 12 also received an oral beta-blocker; the remaining four patients who did not receive beta-blockers served as the comparator group. MEASUREMENTS AND MAIN RESULTS: For each patient, the initial and final study drug doses of continuous intravenous milrinone and oral beta-blocker treatment, when applicable, were recorded over the 6-month period. Mean heart rate, blood pressure, ejection fraction, and oxygen consumption were measured, and 95% confidence intervals were calculated. Serum sodium and creatinine concentrations, as well as the creatinine clearance, were measured. In the 12 patients who received concomitant milrinone and beta-blockers, the mean baseline ejection fraction was approximately 18%, and they received milrinone for 18.6 weeks. Seven patients received carvedilol for 16.1 weeks, and five received metoprolol tartrate for 17.6 weeks. Dosages of the beta-blockers were titrated. Final daily doses were carvedilol 42.8 mg (95% confidence interval 20.3-65.4) and metoprolol 42.5 mg (95% confidence interval 28.0-57.2). Patients continued to receive other standard oral drug therapy for heart failure. One patient discontinued metoprolol and one discontinued carvedilol because of hypotension and/or worsening heart failure. Cardiac adverse events in the concomitant milrinone plus beta-blocker group were heart failure requiring hospitalization in 10 patients and ventricular arrhythmias in one. CONCLUSION: Inotrope-dependent patients with refractory end-stage heart failure tolerated continuous intravenous milrinone plus beta-blockers in addition to diuretics and vasodilators for the 6-month observation period. Beta-blocker dosages were titrated, and three patients achieved the target beta-blocker dosage established for stage A-C heart failure. Additional studies are needed to determine the optimal selection and dosing of drug combinations in this population.     

β受体阻滞剂对慢性心力衰竭患者血浆钠尿肽、心功能和心室重构的影响

目的 探讨美多洛尔和卡维地洛对慢性心力衰竭(CHF)患心脏神经内分泌、心功能及心室重构的影响。方法 CHF患33例，分别予常规治疗(基础组，12例)或加用美多洛尔(美多洛尔组，10例)、卡维地洛(卡维地洛组，11例)治疗3个月。治疗前后用同位素放免法和放免法测定血浆心房钠尿肽、脑钠尿肽(ANP、BNP)水平，心脏彩色多普勒超声诊断仪测量左室结构和心功能；观察治疗前后各组钠尿肽水平、心功能、心室重构的变化及组间差异。结果 (1)3组血浆ANP、BNP水平都显下降(P均＜0．05或0．01)；组间下降程度ANP水平无显差异(F=0．06，P＞0．05)，BNP水平有显差异(F=4．97，P＜0．05)，两β受体阻滞剂组均明显大于基础组(P均＜0．05)，但两组间无显差异(P＞0．05)。(2)两β受体阻滞剂组治疗后NYHA心功能分级均改善(P＜0．05)，肺动脉收缩压下降(P均＜0．05)，其中治疗前左室射血分数＜35％(8例)，治疗后明显上升(P＜0．05)。(3)3组治疗后心脏结构指标无显变化(P＞0．05)。结论 CHF患在常规治疗基础上加用β受体阻滞剂治疗3个月，可显改善心功能，但未观察到对心室重构指标的明显影响及两β受体阻滞剂组疗效的差异。     

Carvedilol in the treatment of chronic heart failure

Along with the angiotensin-converting enzyme inhibitors (ACEIs), the beta-adrenergic receptor blockers have gradually emerged to be standard in the therapy of heart failure. Individual beta-blockers that have been shown to reduce all-cause mortality in patients with heart failure include bisoprolol, metoprolol and carvedilol. Carvedilol distinguishes from the other beta-blockers as being a non-selective beta(1)- and beta(2)-receptor blocker with (1)-receptor blockade effect and anti-oxidant properties. The drug does not have sympathomimetic activity and has vasodilatory effects attributable to its (1)-receptor blockade property. Experimental and clinical studies have confirmed carvedilol's vasodilator, anti-oxidant and anti-apoptotic properties, which may contribute to its effect in reversing cardiac remodelling in animal models and patients with heart failure. These pharmacological properties render carvedilol a potentially useful agent in the treatment of patients with heart failure. Early studies of carvedilol in heart failure have reported beneficial haemodynamic effects but variable effects on exercise tolerance and clinical well being. The large-scale US Carvedilol Heart Failure Program and the Australian/New Zealand Heart Failure Collaborative Research Group reported beneficial effects of carvedilol on mortality, morbidity and clinical well being in patients with mild-to-moderate heart failure. The recently reported but yet unpublished preliminary results of the COPERNICUS study suggest that carvedilol improves mortality and morbidity in patients with advanced heart failure and severe symptoms. At this time, it is unclear whether the ancillary pharmacological properties of carvedilol can be translated to more superior clinical benefit compared to the other beta-blockers. Preliminary studies examining surrogate end points suggest that carvedilol may improve left ventricular ejection fraction (LVEF) more than metoprolol. More conclusive information regarding their relative effects of clinical outcomes will await the completion of the COMET study, which compares the effect of metoprolol and carvedilol on mortality and morbidity, expected at the end of the year 2002.     

Profile of carvedilol controlled-release: a new once-daily formulation of carvedilol

Carvedilol is a third-generation beta(1)- and beta(2)-blocker that also possesses alpha(1)-adrenergic-blocking properties. This compound has: i) shown superior efficacy to certain other beta-blockers in heart failure, ii) can improve myocardial function (e.g., in myocardial infarction) and iii) is the only beta-blocker shown to significantly reduce mortality and morbidity (such as reinfarction and development of heart failure) in postmyocardial infarction patients with left ventricular dysfunction (LVD). The currently available preparation of carvedilol needs to be taken twice daily; however, studies have shown that the need for twice-daily dosing may decrease adherence. A once-daily formulation of carvedilol (controlled release) is expected to become available in 2007. The pharmacokinetic and pharmacodynamic properties of the new formulation are equivalent to the twice-daily formulation. A number of investigations have demonstrated equivalence between the twice-daily and once-daily formulations; thus, carvedilol controlled-release is expected to provide not only the same life-prolonging benefits of twice-daily carvedilol, but also the convenience of once-daily dosing.     

Optimizing treatment of diabetes and cardiovascular disease with combined alpha,beta-blockade

BACKGROUND: Cardiovascular risk factors of the diabetic patient should be treated as aggressively as those of the nondiabetic patient who has had a myocardial infarction. beta-Blockers are established to reduce cardiovascular risk in patients with hypertension, coronary heart disease, and heart failure. Despite this benefit of beta-blockers, physicians have been reluctant to use them in patients with diabetes, in whom they are even more effective, because of the negative effects on carbohydrate and lipid metabolism. OBJECTIVE: This paper reviews (based on a Medline literature search to December 2004) the relationship between diabetes and cardiovascular risk factors, describes the metabolic consequences of insulin resistance, and discusses the impact of different beta-blockers on the treatment of cardiovascular disease in patients with diabetes. RESULTS: There is a large cardioprotective benefit with the use of beta-blockers in patients with diabetes; however, metabolic risks are associated with some beta-blockers. Newer, vasodilating, nonselective beta-blockers do not have the same adverse metabolic consequences observed with earlier beta-blockers. Recent evidence has shown that they have a neutral effect on metabolic parameters and lipid profile. They do not promote insulin resistance and can be used safely in heart failure patients with diabetes. CONCLUSIONS: Nonselective vasodilating beta-blockers, such as carvedilol, may be used in patients with cardiovascular disease and diabetes without the same negative metabolic consequences seen with the use of earlier generation beta-blockers.     

Controlled-Release Carvedilol

? A new once-daily controlled-release (CR) capsule formulation of the nonselective β- and α1-adrenoceptor antagonist carvedilol is now available for use in the treatment of essential hypertension, heart failure (HF), and left ventricular dysfunction following myocardial infarction (MI). ? Carvedilol CR had equivalent β1-adrenoceptor antagonist activity to carvedilol immediate release (IR) in patients with hypertension in terms of the reduction in exercise-induced heart rate. In addition, corresponding dosages of the two formulations demonstrated pharmacokinetic bioequivalence. ? 24-Hour DBP (primary endpoint) and SBP (measured by ambulatory blood pressure monitoring [ABPM]) were reduced to a significantly greater extent with carvedilol CR 20, 40, or 80 mg once daily than with placebo in patients with hypertension in a well designed trial. Carvedilol CR 40 or 80 mg also significantly reduced trough DBP and SBP as measured by both ABPM and office sphygmomanometry in this patient population. ? Preliminary results of a randomized comparison did not find any difference in medication compliance rates between once-daily carvedilol CR and twice-daily carvedilol IR administered over 5 months in patients with HF, which was in part due to a higher than anticipated compliance in the carvedilol IR cohort. ? Carvedilol CR was generally well tolerated in patients with hypertension, mild to severe HF, or left ventricular dysfunction following MI. Headache was the most commonly reported adverse event associated with carvedilol CR in patients with hypertension, but generally was not reported at a higher incidence in carvedilol CR than placebo recipients.     

Update in the management of diastolic heart failure

Diastolic heart failure (DHF) is characterized by the clinical presentation of heart failure in the setting of preserved left ventricular systolic function and evidence of diastolic dysfunction. It is estimated to be present in at least one-third of patients, who represent the signs and symptoms of heart failure, and is especially prevalent among the elderly population. Despite an increasing understanding of the pathophysiology of this disease and the improvement of diagnostic and prognostic assessment, the management of DHF remains to be established. Medical therapy consists of the cautious use of diuretics, and some studies suggested the beneficial role of beta-blockers and calcium antagonists. The rationale of current therapy is largely dependent on understanding the pathophysiology of DHF and observations from clinical trials that included relatively small numbers of patients. Large, multicenter, randomized, controlled studies are needed to define the role of various therapeutic agents in DHF, and whether the prognosis of the disease will be altered. The SWEDIC trial observed that carvedilol treatment in patients with DHF was associated with an improvement in diastolic indices measured by Doppler echocardiography. The CHARM-Preserved trial reported a non-significant reduction of cardiovascular death or admission for heart failure. Other studies which are underway include PEP-CHF and the Hong Kong Diastolic Heart Failure study. They will play a pivotal role in ascertaining the therapeutic efficacy of various agents and will help experts to set up treatment guidelines for this common condition.     

Betaxolol versus carvedilol in chronic heart failure (BETACAR study). Rationale and design.

The use of beta-blockers in heart failure for a long time was regarded as contra-indicated because of their negative inotropic effects. Nevertheless, there is growing evidence that beta-blockers slow down the progression of left ventricular dilatation that characterizes heart failure. In addition changes in left ventricular ejection fraction after several months of beta-blocker treatment appears to have predictive value for survival. This beneficial effect of beta-blockade in chronic heart failure needs to be assessed further. The presumed benefit of beta-blockade with betaxolol (CAS 63659-18-7), a highly selective beta-blocker with long duration of action in chronic heart failure (CHF) will be assessed in BETACAR, a comparative study versus carvedilol (CAS 72956-09-3). The design of this study is provided in this article.     

Different intrinsic activities of bucindolol, carvedilol and metoprolol in human failing myocardium

1. Clinical studies have shown different effects of beta-blockers on the beta-adrenergic system, tolerability and outcome in patients with heart failure. 2. The study examines beta-adrenoceptor-G-protein coupling and intrinsic activity of bucindolol, carvedilol and metoprolol in human ventricular myocardium. 3. Radioligand binding studies ([(125)I]-Iodocyanopindolol) were performed in membrane preparations of human failing and nonfailing myocardium. Functional experiments were carried out in isolated muscle preparations of human left ventricular myocardium from failing hearts. 4. Bucindolol and carvedilol bound non-selectively to beta(1)- and beta(2)-adrenoceptors and exerted guanine nucleotide modulatable binding. Metoprolol was 35-fold beta(1)-selective and lacked guanine nucleotide modulatable binding. 5. All beta-blockers antagonized isoprenaline-induced enhancement of contractility. 6. In preparations in which the coupling of the stimulatory G-protein to adenylate cyclase was facilitated by forskolin, bucindolol increased force of contraction in three and decreased it in five experiments. Carvedilol increased force in one and decreased it in six experiments. Metoprolol decreased force in all experiments by 89. 4+/-2.2% (P<0.01 metoprolol vs carvedilol and bucindolol). The negative inotropic effect of metoprolol was antagonized by bucindolol. 7. It is concluded that differences in intrinsic activity can be detected in human myocardium and have an impact on cardiac contractility. In human ventricular myocardium, bucindolol displays substantially higher intrinsic activity than metoprolol and carvedilol. Bucindolol can behave as partial agonist or partial inverse agonist depending on the examined tissue. 8. Differences in intrinsic activity may contribute to differences in beta-adrenoceptor regulation and possibly to differences in tolerability and outcomes of patients with heart failure.     

ACE inhibitors in pediatric patients with heart failure

This article reviews reports of ACE inhibitor use in pediatric heart failure and summarizes the present implications for clinical practice. Captopril, enalapril, and cilazapril are orally active ACE inhibitors, and widely used in pediatric cardiology, although more than ten other ACE inhibitors have been applied clinically in adults. Effects of ACE inhibitors on the renin-angiotensin-aldosterone system in pediatric patients are similar to those in adults. ACE inhibitors lower aortic pressure and systemic vascular resistance, do not affect pulmonary vascular resistance significantly, and lower left atrial and right atrial pressures in pediatric patients with heart failure. In infants with a large ventricular septal defect and pulmonary hypertension, ACE inhibitors decrease left-to-right shunt in those infants with elevated systemic vascular resistance. ACE inhibitors induce a small increase in left ventricular ejection fraction, left ventricular fractional shortening, and systemic blood flow in children with left ventricular dysfunction, mitral regurgitation, and aortic regurgitation. These beneficial effects usually persist long term without the development of tolerance. Therapeutic trials of ACE inhibitors have been reported in children with heart failure and divergent hemodynamics, including myocardial dysfunction, left-to-right shunt, such as large ventricular septal defect and pulmonary hypertension, aortic or mitral regurgitation, and Fontan circulation.Hypotension and renal failure usually occur within 5 days after starting ACE inhibition or increasing the dose and, in most cases, recovery is seen after reduction or cessation of the drug. With all ACE inhibitors, smaller doses are administered initially to prevent excessive hypotension, and doses are increased gradually to the target dose. Captopril is administered orally, usually every 8 hours. Daily doses range from 0.3 to 1.5 mg/kg in children. Enalapril is administered orally, once or twice a day, and daily doses range from 0.1 to 0.5 mg/kg. Enalaprilat is administered intravenously, one to three times a day, in doses ranging from 0.01 to 0.05 mg/kg/dose.For the treatment of chronic heart failure in children, ACE inhibitors are essential along with other medications including diuretics, digoxin, and beta-blockers (beta-adrenoceptor antagonists).     

Current role of beta-adrenergic blockers in the treatment of chronic congestive heart failure.

Recent findings on the use of beta-adrenergic blockers in patients with congestive heart failure (CHF) are reviewed. CHF is a progressive, debilitating disease that afflicts 4.6 million patients in the United States. Treatment has traditionally consisted of a diuretic, an angiotensin-converting-enzyme (ACE) inhibitor, and digoxin. Despite advances in ACE-inhibitor therapy, the five-year mortality rate remains nearly 50%. Overstimulation of the sympathetic nervous system is believed to contribute to mortality. Beta-blockers have recently been added to the standard of care for patients with New York Heart Association functional class II or III heart failure. Four randomized, double-blind, placebo-controlled clinical trials were recently completed that addressed the benefits of beta-blockers in CHF. The overall mortality rate was reduced 65% by carvedilol, 34% by metoprolol, and 33% by bisoprolol; all these reductions were significant compared with placebo, and the trials were ended early. Bucindolol, however, did not have a significant effect on mortality. These drugs are hepatically metabolized and may require dosage adjustment in hepatically impaired patients. Decompensation of heart failure is another consideration; a beta-blocker should be added only for patients with stable CHF. Dosages must be slowly adjusted to targeted levels. Adverse effects do not differ significantly among beta-blockers. In addition to their effect on mortality, beta-blockers reduce CHF-related morbidity, such as all-cause hospitalization. Carvedilol, metoprolol, and bisoprolol decrease the mortality and morbidity associated with CHF and can be used with limited adverse effects. The choice among these agents does not affect clinical outcomes; bucindolol, however, has proven ineffective.     

Brain natriuretic peptide: Disease marker or more in cardiovascular medicine?

Brain natriuretic peptide (BNP) is predominantly a cardiac ventricular hormone that promotes natriuresis and diuresis, inhibits the renin-angiotensin-aldosterone axis, and is a vasodilator. Plasma BNP levels are raised in essential hypertension, and more so in left ventricular (LV) hypertrophy and heart failure. Plasma BNP levels are also elevated in ischemic heart disease. Attempts have been made to use plasma BNP levels as a marker of LV dysfunction, but these have shown that plasma BNP levels are probably not sensitive enough to replace echocardiography in the diagnosis of LV dysfunction. Pericardial BNP or N-BNP may be more suitable markers of LV dysfunction. Plasma BNP levels are also elevated in right ventricular dysfunction, pregnancy-induced hypertension, aortic stenosis, age, subarachnoid hemorrhage, cardiac allograft rejection and cavopulmonary connection, and BNP may have an important pathophysiological role in some or all of these conditions. Clinical trials have demonstrated the natriuretic, diuretic and vasodilator effects, as well as inhibitory effects on renin and aldosterone of infused synthetic human BNP (nesiritide) in healthy humans. BNP infusion improves LV function in patients with congestive heart failure via a vasodilating and a prominent natriuretic effect. BNP infusion is useful for the treatment of decompensated congestive heart failure requiring hospitalization. The clinical potential of BNP is limited as it is a peptide and requires infusion. Drugs that modify the effects of BNP are furthering our understanding of the pathophysiological role and clinical potential of BNP. Increasing the effects of BNP may be a useful therapeutic approach in heart failure involving LV dysfunction. The levels of plasma BNP are increased by beta-blockers, cardiac glycosides and vasopeptidase inhibitors, and this may contribute to the usefulness of these agents in heart failure. (c) 2001 Prous Science. All rights reserved.     

Carvedilol: a review of its use in chronic heart failure

Carvedilol (Dilatrend) blocks beta(1)-, beta(2)- and alpha(1)-adrenoceptors, and has antioxidant and antiproliferative effects. Carvedilol improved left ventricular ejection fraction (LVEF) in patients with chronic heart failure (CHF) in numerous studies. Moreover, significantly greater increases from baseline in LVEF were seen with carvedilol than with metoprolol in a double-blind, randomised study and in a meta-analysis. Carvedilol also reversed or attenuated left ventricular remodelling in patients with CHF and in those with left ventricular dysfunction after acute myocardial infarction (MI). Combined analysis of studies in the US Carvedilol Heart Failure Trials Program (patients had varying severities of CHF; n = 1094) revealed that mortality was significantly lower in carvedilol than in placebo recipients. In addition, the risk of hospitalisation for any cardiovascular cause was significantly lower with carvedilol than with placebo. Mortality was significantly lower with carvedilol than with metoprolol in patients with mild to severe CHF in the Carvedilol Or Metoprolol European Trial (COMET) [n = 3029]. The Carvedilol Prospective Randomised Cumulative Survival (COPERNICUS) trial (n = 2289) demonstrated that compared with placebo, carvedilol was associated with significant reductions in all-cause mortality and the combined endpoint of death or hospitalisation for any reason in severe CHF. All-cause mortality was reduced in patients who received carvedilol in addition to conventional therapy compared with those who received placebo plus conventional therapy in the Carvedilol Post-Infarct Survival Control in LV Dysfunction (CAPRICORN) trial (enrolling 1959 patients with left ventricular dysfunction following acute MI). Carvedilol was generally well tolerated in patients with CHF. Adverse events associated with the alpha- and beta-blocking effects of the drug occurred more commonly with carvedilol than with placebo, whereas placebo recipients were more likely to experience worsening heart failure. In conclusion, carvedilol blocks beta(1)-, beta(2)- and alpha(1)-adrenoceptors and has a unique pharmacological profile. It is thought that additional properties of carvedilol (e.g. antioxidant and antiproliferative effects) contribute to its beneficial effects in CHF. Carvedilol improves ventricular function and reduces mortality and morbidity in patients with mild to severe CHF, and should be considered a standard treatment option in this setting. Administering carvedilol in addition to conventional therapy reduces mortality and attenuates myocardial remodelling in patients with left ventricular dysfunction following acute MI. Moreover, mortality was significantly lower with carvedilol than with metoprolol in patients with mild to severe CHF, suggesting that carvedilol may be the preferred beta-blocker.     

Rate control in atrial fibrillation: choice of treatment and assessment of efficacy

The clinical relevance and high social costs of atrial fibrillation have boosted interest in rate control as a cost-effective alternative to long-term maintenance of sinus rhythm (i.e. rhythm control). Prospective studies show that rate control (coupled with thromboembolic prophylaxis) is a valuable treatment option for all forms of atrial fibrillation. The rationale for rate control is that high ventricular rates, frequently found in atrial fibrillation, lead to haemodynamic impairment, consisting of a variable combination of loss of atrial kick, irregularity in ventricular response and inappropriately rapid ventricular rate, depending on the type of underlying heart disease. Long-term persistence of tachycardia at a high ventricular rate can lead to various degrees of ventricular dysfunction and even to tachycardiomyopathy-related heart failure. Identification of this reversible and often concealed form of left ventricular dysfunction can permit effective management by rate (or rhythm) control. Although acute rate control (to reduce ventricular rate within hours) is still often based on digoxin administration, for patients without left ventricular dysfunction, calcium channel antagonists or beta-adrenoceptor antagonists (beta-blockers) are generally more appropriate and effective. In chronic atrial fibrillation, long-term rate control (to reduce morbidity/mortality and improve quality of life) must be adapted to patients' individual characteristics to grant control during daily activities, including exercise. According to current guidelines, the clinical target of rate control should be a ventricular rate below 80-90 bpm at rest. However, in many patients, assessment of the appropriateness of different drugs should include exercise testing and 24h-Holter monitoring, for which specific guidelines are needed. In practice, rate control is considered a valid alternative to rhythm control. Recent prospective trials (e.g. the Pharmacological Intervention in Atrial Fibrillation [PIAF] and the Atrial Fibrillation Follow-up Investigation of Rhythm Management [AFFIRM] trials) have shown that in selected patients, rate control provides similar benefits, more economically, in terms of quality of life and long-term mortality. The choice of a rate control medication (digoxin, beta-blockers, calcium channel antagonists or possibly amiodarone) or a non-pharmacological approach (mainly atrioventricular node ablation coupled with pacing) must currently be based on clinical assessment, which includes assessing the presence of underlying heart disease and haemodynamic impairment. Definite guidelines are required for each different subset of patients. Rate control is particularly tricky in patients with heart failure, for whom non-pharmacological options can also be considered. The preferred pharmacological options are beta-blockers for stabilised heart failure and digoxin for unstabilised forms.     

beta-blockers in heart failure: recently completed and ongoing clinical trials

beta-Blockers have emerged as an important therapy in patients with symptomatic left ventricular systolic dysfunction. Early studies demonstrated that beta-blocker therapy improved left ventricular function, reduced neurohumoral activity and reduced heart failure symptoms in these patients. While none of these small studies demonstrated a significant benefit in terms of overall survival, several meta-analyses suggested that beta-blocker therapy could, in fact, reduce mortality in patients with left ventricular systolic dysfunction and mild to moderate heart failure symptoms (New York Heart Association class II or III). Three large, recently completed, trials have confirmed the benefit of beta-blockade in these patients. This report reviews some of the initial clinical studies of beta-blockade in heart failure, examines the findings of the three large multicentre trials and other relevant research. Finally, ongoing trials designed to assess the relative efficacy of different beta-blockers and evaluate the utility of beta-blockade in specific subsets of patients with heart failure are discussed.     

Pharmacotherapy for heart failure with left ventricular dysfunction: beyond angiotensin-converting enzyme inhibitors and beta-blockers

Angiotensin-converting enzyme (ACE) inhibitors and beta-blockers make up the cornerstone of therapy for patients with heart failure involving left ventricular dysfunction. These drug classes have been proven to decrease morbidity and mortality in patients with heart failure. Unfortunately, many patients remain symptomatic and experience disease progression despite taking both an ACE inhibitor and a beta-blocker. Others may be unable to tolerate one or both of these agents. In recent years, several other drug classes have been shown to provide additional morbidity and mortality benefits in patients with heart failure. These include angiotensin II receptor blockers (ARBs), aldosterone antagonists, and the combination of isosorbide dinitrate plus hydralazine. To select the most appropriate drug therapy for patients with heart failure, clinicians should consider results from clinical trials in specific patient populations, adverse-event profiles, tolerability, cost, and dosing regimens.