β-Blockers in Chronic Heart Failure: Considerations for Selecting an Agent
2002; Elsevier BV; Volume: 77; Issue: 11 Linguagem: Inglês
10.4065/77.11.1199
ISSN1942-5546
Autores Tópico(s)Cardiovascular and exercise physiology
ResumoPatients with chronic heart failure have increased sympathetic nervous system activity that contributes to deterioration of cardiovascular function over time. Long-term β-blocker therapy prevents such deterioration through inhibition of this neurohormonal pathway. The impressive survival data collected from several large studies have made β-blockers a component of standard therapy for New York Heart Association class II to III heart failure. Although there are differences in the pharmacological properties of the β-blockers shown to improve morbidity and mortality in heart failure, there is little evidence to suggest that such properties constitute any major advantages in clinical outcome. Carvedilol and extended-release metoprolol succinate are 2 β-blockers currently approved in the United States for the treatment of patients with heart failure. Both agents have shown similar risk reductions in overall and cause-specific mortality; however, no outcome data from a comparative trial are available to support the use of one agent over the other. Regardless of the agent chosen, appropriate dosing and titration of β-blockers are essential for successful therapy. Patients with chronic heart failure have increased sympathetic nervous system activity that contributes to deterioration of cardiovascular function over time. Long-term β-blocker therapy prevents such deterioration through inhibition of this neurohormonal pathway. The impressive survival data collected from several large studies have made β-blockers a component of standard therapy for New York Heart Association class II to III heart failure. Although there are differences in the pharmacological properties of the β-blockers shown to improve morbidity and mortality in heart failure, there is little evidence to suggest that such properties constitute any major advantages in clinical outcome. Carvedilol and extended-release metoprolol succinate are 2 β-blockers currently approved in the United States for the treatment of patients with heart failure. Both agents have shown similar risk reductions in overall and cause-specific mortality; however, no outcome data from a comparative trial are available to support the use of one agent over the other. Regardless of the agent chosen, appropriate dosing and titration of β-blockers are essential for successful therapy. Chronic heart failure (CHF) due to systolic dysfunction is a progressive disease characterized by left ventricular dysfunction and cardiac remodeling.1Packer M Cohn JN Advisory Council to Improve Outcomes Nationwide in Heart Failure Consensus recommendations for the management of chronic heart failure.Am J Cardiol. 1999; 83: 1A-38AAbstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar, 2Sabbah HN The cellular and physiologic effects of beta blockers in heart failure.Clin Cardiol. 1999; 22: V16-V20PubMed Google Scholar Patients with heart failure have increased sympathetic nervous system activity, which initially supports cardiac function through an increase in heart rate, myocardial contractility, and systemic vascular resistance.2Sabbah HN The cellular and physiologic effects of beta blockers in heart failure.Clin Cardiol. 1999; 22: V16-V20PubMed Google Scholar, 3Colucci WS The effects of norepinephrine on myocardial biology: implications for the therapy of heart failure.Clin Cardiol. 1998; 21: I20-I24Crossref PubMed Scopus (50) Google Scholar However, prolonged adrenergic activation leads to down-regulation and desensitization of β-adrenergic receptors. These processes, in turn, cause deterioration of cardiovascular function and exercise tolerance.2Sabbah HN The cellular and physiologic effects of beta blockers in heart failure.Clin Cardiol. 1999; 22: V16-V20PubMed Google Scholar, 3Colucci WS The effects of norepinephrine on myocardial biology: implications for the therapy of heart failure.Clin Cardiol. 1998; 21: I20-I24Crossref PubMed Scopus (50) Google Scholar Additionally, continued exposure to excess norepinephrine contributes to the development of cardiac hypertrophy, arrhythmia, and myocardial cell apoptosis.1Packer M Cohn JN Advisory Council to Improve Outcomes Nationwide in Heart Failure Consensus recommendations for the management of chronic heart failure.Am J Cardiol. 1999; 83: 1A-38AAbstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar Long-term β-blocker therapy prevents such adverse biological effects and reduces cardiac remodeling by inhibiting this neurohormonal pathway. Cardiac remodeling is characterized by progressive ventricular hypertrophy, altered gene expression on cardiac myocytes, and subsequent deterioration in cardiac contractility; it is a strong predictor of adverse clinical outcome. Studies have shown that use of β-blockers in patients with mild to moderate heart failure substantially improves left ventricular ejection fraction (LVEF), symptoms, and overall mortality.4CIBIS-II Investigators and Committees The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial.Lancet. 1999; 353: 9-13Abstract Full Text Full Text PDF PubMed Scopus (4109) Google Scholar, 5MERIT-HF Study Group Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF).Lancet. 1999; 353: 2001-2007Abstract Full Text Full Text PDF PubMed Scopus (4434) Google Scholar, 6Packer M Bristow MR Cohn JN U.S. Carvedilol Heart Failure Study Group et al.The effect of carvedilol on morbidity and mortality in patients with chronic heart failure.N Engl J Med. 1996; 334: 1349-1355Crossref PubMed Scopus (4196) Google Scholar, 7Packer M Coats AJ Fowler MB Carvedilol Prospective Randomized Cumulative Survival Study Group et al.Effect of carvedilol on survival in severe chronic heart failure.N Engl J Med. 2001; 344: 1651-1658Crossref PubMed Scopus (2761) Google Scholar According to professional practice guidelines, β-blockers should be administered to all patients with New York Heart Association (NYHA) class II or III heart failure who are clinically stable while taking a diuretic, an angiotensin-converting enzyme (ACE) inhibitor, and, in some cases, digoxin.8Heart Failure Society of America HFSA guidelines for management of patients with heart failure caused by left ventricular systolic dysfunction—pharmacological approaches.Pharmacotherapy. 2000; 20: 495-522Crossref PubMed Google Scholar Initial randomized trials conducted to evaluate the efficacy of various β-blockers in the treatment of heart failure did not include sufficient sample sizes, had short follow-up durations, and had different primary end points, which make interpretation of their results difficult.9Australia/New Zealand Heart Failure Research Collaborative GroupRandomised, placebo-controlled trial of carvedilol in patients with congestive heart failure due to ischaemic heart disease.Lancet. 1997; 349: 375-380Abstract Full Text Full Text PDF PubMed Scopus (712) Google Scholar, 10CIBIS Investigators and Committees A randomized trial of β-blockade in heart failure: the Cardiac Insufficiency Bisoprolol Study (CIBIS).Circulation. 1994; 90: 1765-1773Crossref PubMed Scopus (1080) Google Scholar, 11Waagstein F Bristow MR Swedberg K Metoprolol in Dilated Cardiomyopathy (MDC) Trial Study Group et al.Beneficial effects of metoprolol in idiopathic dilated cardiomyopathy.Lancet. 1993; 342: 1441-1446Abstract PubMed Scopus (1191) Google Scholar In some studies, LVEF was the primary end point; in other studies, the primary end points were a combination of a mortality (eg, all-cause mortality) and a morbidity component (eg, need for hospitalization or cardiac transplantation).9Australia/New Zealand Heart Failure Research Collaborative GroupRandomised, placebo-controlled trial of carvedilol in patients with congestive heart failure due to ischaemic heart disease.Lancet. 1997; 349: 375-380Abstract Full Text Full Text PDF PubMed Scopus (712) Google Scholar, 10CIBIS Investigators and Committees A randomized trial of β-blockade in heart failure: the Cardiac Insufficiency Bisoprolol Study (CIBIS).Circulation. 1994; 90: 1765-1773Crossref PubMed Scopus (1080) Google Scholar, 11Waagstein F Bristow MR Swedberg K Metoprolol in Dilated Cardiomyopathy (MDC) Trial Study Group et al.Beneficial effects of metoprolol in idiopathic dilated cardiomyopathy.Lancet. 1993; 342: 1441-1446Abstract PubMed Scopus (1191) Google Scholar Although these trials provided no definitive evidence of mortality reduction, they suggested that β-blockers could be used safely in heart failure patients, and the results were sufficiently encouraging to warrant further evaluation.12Carson PE Beta blocker treatment in heart failure.Prog Cardiovasc Dis. 1999; 41: 301-321Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar Two meta-analyses,13Heidenreich PA Lee TT Massie BM Effect of beta-blockade on mortality in patients with heart failure: a meta-analysis of randomized clinical trials.J Am Coll Cardiol. 1997; 30: 27-34Abstract Full Text Full Text PDF PubMed Scopus (344) Google Scholar, 14Lechat P Packer M Chalon S Cucherat M Arab T Boissel JP Clinical effects of β-adrenergic blockade in chronic heart failure: a meta-analysis of double-blind, placebo-controlled, randomized trials.Circulation. 1998; 98: 1184-1191Crossref PubMed Scopus (553) Google Scholar each including more than 3000 patients, have evaluated results of heart failure trials analyzing numerous β-blockers, including bisoprolol, bucindolol, carvedilol, metoprolol, and nebivolol. Both meta-analyses showed a risk reduction (RR) for mortality, hospitalization due to heart failure, and the combined end points of mortality and hospitalizations with β-blocker use. Several larger randomized trials have firmly established the benefits of β-blockers in heart failure, including the US Carvedilol Program and 4 large mortality trials: the Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF), the Cardiac Insufficiency Bisoprolol Study II (CIBIS-II), the BetaBlocker Evaluation of Survival Trial (BEST), and the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) trial (Table 1).4CIBIS-II Investigators and Committees The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial.Lancet. 1999; 353: 9-13Abstract Full Text Full Text PDF PubMed Scopus (4109) Google Scholar, 5MERIT-HF Study Group Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF).Lancet. 1999; 353: 2001-2007Abstract Full Text Full Text PDF PubMed Scopus (4434) Google Scholar7Packer M Coats AJ Fowler MB Carvedilol Prospective Randomized Cumulative Survival Study Group et al.Effect of carvedilol on survival in severe chronic heart failure.N Engl J Med. 2001; 344: 1651-1658Crossref PubMed Scopus (2761) Google Scholar, 15Hjalmarson Å, Goldstein S Fagerberg B MERIT-HF Study Group et al.Effects of controlled-release metoprolol on total mortality, hospitalizations, and well-being in patients with heart failure: the Metoprolol CR/XL Randomized Intervention Trial in congestive Heart Failure (MERIT-HF).JAMA. 2000; 283: 1295-1302Crossref PubMed Scopus (1153) Google Scholar, 16Beta-Blocker Evaluation of Survival Trial Investigators A trial of the beta-blocker bucindolol in patients with advanced chronic heart failure.N Engl J Med. 2001; 344: 1659-1667Crossref PubMed Scopus (981) Google ScholarTable 1Summary of Major Mortality Trials Evaluating β-Blockers in Patients With Heart Failure*BEST = Beta-Blocker Evaluation of Survival Trial; CIBIS-II = Cardiac Insufficiency Bisoprolol Study II; COPERNICUS = Carvedilol Prospective Randomized Cumulative Survival; ER = extended release; LVEF = left ventricular ejection fraction; MERIT-HF = Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure; NYHA = New York Heart Association; RR = risk reduction.Annual mortality rate (%)Studyβ-BlockerNo. of patientsNYHA classLVEF (%)Annual RR vs placebo in all-cause mortality (%)P valueβ-BlockerPlaceboMERIT-HF5MERIT-HF Study Group Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF).Lancet. 1999; 353: 2001-2007Abstract Full Text Full Text PDF PubMed Scopus (4434) Google Scholar, 15Hjalmarson Å, Goldstein S Fagerberg B MERIT-HF Study Group et al.Effects of controlled-release metoprolol on total mortality, hospitalizations, and well-being in patients with heart failure: the Metoprolol CR/XL Randomized Intervention Trial in congestive Heart Failure (MERIT-HF).JAMA. 2000; 283: 1295-1302Crossref PubMed Scopus (1153) Google ScholarER metoprolol succinate3991II-IV≤4034<.0017.211.0CIBIS-II4CIBIS-II Investigators and Committees The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial.Lancet. 1999; 353: 9-13Abstract Full Text Full Text PDF PubMed Scopus (4109) Google ScholarBisoprolol2647III-IV≤3534<.00111.817.3BEST16Beta-Blocker Evaluation of Survival Trial Investigators A trial of the beta-blocker bucindolol in patients with advanced chronic heart failure.N Engl J Med. 2001; 344: 1659-1667Crossref PubMed Scopus (981) Google ScholarBucindolol2708III-IV≤35… †RR for total mortality, 10% (33% placebo, 30.2% bucindolol; P=.13; 2-year follow-up)..1315.017.0COPERNICUS trial7Packer M Coats AJ Fowler MB Carvedilol Prospective Randomized Cumulative Survival Study Group et al.Effect of carvedilol on survival in severe chronic heart failure.N Engl J Med. 2001; 344: 1651-1658Crossref PubMed Scopus (2761) Google ScholarCarvedilol2289III-IV≤2535<.00111.418.5* BEST = Beta-Blocker Evaluation of Survival Trial; CIBIS-II = Cardiac Insufficiency Bisoprolol Study II; COPERNICUS = Carvedilol Prospective Randomized Cumulative Survival; ER = extended release; LVEF = left ventricular ejection fraction; MERIT-HF = Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure; NYHA = New York Heart Association; RR = risk reduction.† RR for total mortality, 10% (33% placebo, 30.2% bucindolol; P=.13; 2-year follow-up). Open table in a new tab The US Carvedilol Program consisted of 4 separate protocols, which were not designed to assess mortality prospectively, and enrolled 1094 patients with mild, moderate, or severe CHF (LVEF ≤35%).6Packer M Bristow MR Cohn JN U.S. Carvedilol Heart Failure Study Group et al.The effect of carvedilol on morbidity and mortality in patients with chronic heart failure.N Engl J Med. 1996; 334: 1349-1355Crossref PubMed Scopus (4196) Google Scholar End points for these studies differed and included hospitalization rate for cardiovascular disease and exercise tolerance. All patients received carvedilol, 6.25 mg twice daily, for a 2-week, open-label, run-in period; patients who tolerated this dose were then randomly assigned to receive carvedilol (to a target maximum dose of 25-50 mg twice daily) or placebo in addition to their current therapies. The safety committee terminated the program early because of a significant RR for mortality (P>.001) observed among patients treated with carvedilol; overall mortality rates were 3.2% and 7.8% in the carvedilol and placebo groups, respectively. The total number of deaths was small: 22 deaths in the carvedilol group and 31 deaths in the placebo group. The mortality benefits observed in this trial were initially questioned because mortality was not a predefined end point in all the protocols and the length of follow-up was short (mean follow-up, 6.5 months).17McMurray JJV Major β blocker mortality trials in chronic heart failure: a critical review.Heart. 1999; 82: IV14-IV22PubMed Google Scholar, 18Pfeffer MA Stevenson LW Beta-adrenergic blockers and survival in heart failure [editorial].N Engl J Med. 1996; 334: 1396-1397Crossref PubMed Scopus (97) Google Scholar In addition, pooling the 4 protocols, which had different inclusion criteria and end points, and the nature of the run-in period (in which patients who could not tolerate carvedilol were excluded) have been criticized.12Carson PE Beta blocker treatment in heart failure.Prog Cardiovasc Dis. 1999; 41: 301-321Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar The outcomes of the US Carvedilol Program provided a strong rationale for conducting large, randomized mortality trials. MERIT-HF was a randomized, double-blind, placebo-controlled study that included 3991 patients with NYHA class II to IV heart failure and an LVEF of 40% or less.5MERIT-HF Study Group Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF).Lancet. 1999; 353: 2001-2007Abstract Full Text Full Text PDF PubMed Scopus (4434) Google Scholar, 15Hjalmarson Å, Goldstein S Fagerberg B MERIT-HF Study Group et al.Effects of controlled-release metoprolol on total mortality, hospitalizations, and well-being in patients with heart failure: the Metoprolol CR/XL Randomized Intervention Trial in congestive Heart Failure (MERIT-HF).JAMA. 2000; 283: 1295-1302Crossref PubMed Scopus (1153) Google Scholar After a 2-week, single-blind, placebo, run-in period, patients were randomized to extended-release (ER) metoprolol succinate at a starting dose of 12.5 mg/d (class III and IV patients) to 25 mg/d (class II patients) or placebo in addition to their conventional therapies. The ER metoprolol succinate dose was doubled every 2 weeks as tolerated up to a maximum target dose of 200 mg/d; doses could be adjusted at the discretion of the investigator. The 2 primary study end points were all-cause mortality and the combined end point of all-cause mortality plus all-cause hospitalization (time to first event). The independent safety committee terminated the trial early, approximately 18 months after start of randomization, because ER metoprolol succinate significantly reduced all-cause mortality. Results showed a 34% RR for all-cause mortality (P>.001, Figure 1) and a 19% RR for total mortality or all-cause hospitalization (P>.001).5MERIT-HF Study Group Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF).Lancet. 1999; 353: 2001-2007Abstract Full Text Full Text PDF PubMed Scopus (4434) Google Scholar The median follow-up at study termination was 12 months. The ER metoprolol succinate therapy resulted in a 31% RR for all-cause mortality or hospitalization for worsening heart failure (P>.001), a 41% RR for sudden death (P>.001), and a 49% RR for death due to worsening heart failure (P=.002).5MERIT-HF Study Group Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF).Lancet. 1999; 353: 2001-2007Abstract Full Text Full Text PDF PubMed Scopus (4434) Google Scholar, 15Hjalmarson Å, Goldstein S Fagerberg B MERIT-HF Study Group et al.Effects of controlled-release metoprolol on total mortality, hospitalizations, and well-being in patients with heart failure: the Metoprolol CR/XL Randomized Intervention Trial in congestive Heart Failure (MERIT-HF).JAMA. 2000; 283: 1295-1302Crossref PubMed Scopus (1153) Google Scholar Several predefined subgroups were analyzed to determine any difference in outcome, including elderly patients, smokers and nonsmokers, and those with a history of hypertension, prior myocardial infarction, or diabetes mellitus5MERIT-HF Study Group Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF).Lancet. 1999; 353: 2001-2007Abstract Full Text Full Text PDF PubMed Scopus (4434) Google Scholar; the benefits observed with ER metoprolol succinate in the overall study population were consistent across all predefined subgroups.15Hjalmarson Å, Goldstein S Fagerberg B MERIT-HF Study Group et al.Effects of controlled-release metoprolol on total mortality, hospitalizations, and well-being in patients with heart failure: the Metoprolol CR/XL Randomized Intervention Trial in congestive Heart Failure (MERIT-HF).JAMA. 2000; 283: 1295-1302Crossref PubMed Scopus (1153) Google Scholar In addition, ER metoprolol succinate significantly reduced the number of all-cause hospitalizations (P=.005) and the total number of days in the hospital due to all causes (P=.004) relative to placebo.15Hjalmarson Å, Goldstein S Fagerberg B MERIT-HF Study Group et al.Effects of controlled-release metoprolol on total mortality, hospitalizations, and well-being in patients with heart failure: the Metoprolol CR/XL Randomized Intervention Trial in congestive Heart Failure (MERIT-HF).JAMA. 2000; 283: 1295-1302Crossref PubMed Scopus (1153) Google Scholar This difference was primarily related to a reduction in the number of hospitalizations for worsening heart failure. A post hoc subgroup analysis of MERIT-HF evaluated patients with NYHA class III and IV heart failure and an ejection fraction less than 25% (n=795).19Goldstein S Fagerberg B Hjalmarson Å MERIT-HF Study Group et al.Metoprolol controlled release/extended release in patients with severe heart failure: analysis of the experience in the MERIT-HF study.J Am Coll Cardiol. 2001; 38: 932-938Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar Treatment with ER metoprolol succinate in this subgroup resulted in significant RRs for total mortality (RR, 39%; P=.009), sudden death (RR, 45%; P=.02), and death due to worsening heart failure (RR, 55%; P=.01) relative to placebo. The ER metoprolol succinate treatment significantly reduced hospitalizations due to worsening heart failure by 45% compared with placebo (P>.001). This subgroup analysis suggests that patients with more severe heart failure had a mortality benefit and reduction in hospitalizations similar to those observed in the overall population of MERIT-HF. CIBIS-II, a randomized, double-blind, placebo-controlled study, included 2647 patients with NYHA class III to IV heart failure and an LVEF of 35% or less.4CIBIS-II Investigators and Committees The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial.Lancet. 1999; 353: 9-13Abstract Full Text Full Text PDF PubMed Scopus (4109) Google Scholar Patients were randomized to receive bisoprolol, 1.25 mg/d (titrated to a maximum target dose of 10 mg/d), or placebo in addition to standard heart failure therapies. The primary study end point was all-cause mortality; secondary end points included all-cause hospitalizations, cardiovascular mortality, and the combined end point of cardiovascular mortality and cardiovascular hospitalizations. The trial was discontinued because of the substantial reduction in total mortality (34%) observed among patients in the bisoprolol group (Figure 2, P>.001).4CIBIS-II Investigators and Committees The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial.Lancet. 1999; 353: 9-13Abstract Full Text Full Text PDF PubMed Scopus (4109) Google Scholar In addition, there were significantly fewer cardiovascular deaths (P=.005) and all-cause hospitalizations (P>.001) reported among patients treated with bisoprolol vs those who received placebo.4CIBIS-II Investigators and Committees The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial.Lancet. 1999; 353: 9-13Abstract Full Text Full Text PDF PubMed Scopus (4109) Google Scholar Thus, the CIBIS-II mortality data are consistent with the data from MERIT-HF. Although a substantial body of evidence in the medical literature supports the use of β-blockers in patients with mild to moderate heart failure, data regarding the long-term safety and efficacy of β-blockers in patients with severe heart failure are limited.8Heart Failure Society of America HFSA guidelines for management of patients with heart failure caused by left ventricular systolic dysfunction—pharmacological approaches.Pharmacotherapy. 2000; 20: 495-522Crossref PubMed Google Scholar The COPERNICUS trial evaluated carvedilol in 2289 patients with severe heart failure and an LVEF of 25% or less.7Packer M Coats AJ Fowler MB Carvedilol Prospective Randomized Cumulative Survival Study Group et al.Effect of carvedilol on survival in severe chronic heart failure.N Engl J Med. 2001; 344: 1651-1658Crossref PubMed Scopus (2761) Google Scholar Patients randomized to carvedilol treatment received an initial dose of 3.125 mg twice daily for 2 weeks, which was doubled at 2-week intervals to a maximum target dose of 25 mg twice daily as tolerated. The Data and Safety Monitoring Board discontinued the trial early because of the mortality benefits observed with carvedilol. Final analysis of the data showed that patients in the carvedilol group had a 35% RR in total mortality (Figure 3, P=.001), with cumulative risk of death at 1 year of 18.5% in the placebo group and 11.4% in the carvedilol group. These data are consistent with the results of MERIT-HF and CIBIS-II and extend the results of β-blocker trials to the sickest group of patients. The post hoc analysis of the MERIT-HF study of a comparable severe heart failure subgroup also supports this conclusion.19Goldstein S Fagerberg B Hjalmarson Å MERIT-HF Study Group et al.Metoprolol controlled release/extended release in patients with severe heart failure: analysis of the experience in the MERIT-HF study.J Am Coll Cardiol. 2001; 38: 932-938Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar The efficacy of bucindolol, a nonselective β-blocker, was evaluated in patients with severe heart failure in the BEST.16Beta-Blocker Evaluation of Survival Trial Investigators A trial of the beta-blocker bucindolol in patients with advanced chronic heart failure.N Engl J Med. 2001; 344: 1659-1667Crossref PubMed Scopus (981) Google Scholar This randomized placebo-controlled study included 2708 patients with NYHA class III to IV heart failure (LVEF ≤35%). Patients were randomly assigned to receive placebo or bucindolol titrated to a target maximum daily dose of 50 to 100 mg twice daily in addition to standard therapies. The primary end point was all-cause mortality. In contrast to previous mortality studies in heart failure, this study was terminated after 2 years because no significant differences were observed between the 2 groups with regard to all-cause mortality. However, a post hoc analysis of causes of death showed a significant decrease in cardiovascular deaths among patients treated with bucindolol (P=.04). Additionally, hospitalization due to heart failure (P>.001) and progression to death or transplantation (P=.04) were significantly reduced in the bucindolol group. Treatment with bucindolol had no significant effect on outcomes such as sudden death, heart failure death, death due to pump failure, and all-cause hospitalization.16Beta-Blocker Evaluation of Survival Trial Investigators A trial of the beta-blocker bucindolol in patients with advanced chronic heart failure.N Engl J Med. 2001; 344: 1659-1667Crossref PubMed Scopus (981) Google Scholar The issue of whether the overall neutral effects with bucindolol are due to specific characteristics of the drug or to specifics of the patient population enrolled in the BEST remains unresolved. Importantly, the results of the BEST indicate that mortality benefits with β-blockers cannot be considered a class effect. β-Blockers are categorized into 3 classes. First-generation agents (eg, propranolol) are nonselective in their blockade of β-adrenergic receptors. Second-generation β-blockers (eg, metoprolol and bisoprolol) are β1-selective and have no ancillary vasodilatory effects. Third-generation agents (eg, carvedilol and bucindolol) are nonselective β-blockers and have ancillary vasodilating properties, attributable to α1-blocking activity in the case of carvedilol.20Bristow MR β-Adrenergic receptor blockade in chronic heart failure.Circulation. 2000; 101: 558-569Crossref PubMed Scopus (939) Google Scholar, 21Kukin IV, ML Are all β blockers the same for heart failure?.Congest Heart Fail. 2000; 6: 153-157Crossref PubMed Google Scholar Three β-blockers, ER metoprolol succinate, carvedilol, and bisoprolol, have proven mortality and morbidity benefits in patients with CHF and therefore can be considered for heart failure treatment. Only ER metoprolol succinate and carvedilol are approved in the United States to treat CHF. Whether differences in the pharmacological properties of these β-blockers have practical importance in determining clinical response and tolerability in heart failure patients is debatable. Currently, no convincing clinical trial data support the preferential use of a nonselective β-blocker over a β1-selective agent in CHF. It has been speculated that comprehensive adrenergic blockade provided by the third-generation agent carvedilol offers some clinical advantage in the treatment of heart failure.20Bristow MR β-Adrenergic receptor blockade in chronic heart failure.Circulation. 2000; 101: 558-569Crossref PubMed Scopus (939) Google Scholar, 22Bristow MR Larrabee P Minobe W et al.Receptor pharmacology of carvedilol in the human heart.J Cardiovasc Pharmacol. 1992; 19: S68-S80Crossref PubMed Scopus (81) Google Scholar, 23Bristow MR Roden RL Lowes BD Gilbert EM Eichhorn EJ The role of third-generation beta-blocking agents in chronic heart failure [published correction appears in Clin Cardiol. 1999; 22: March].Clin Cardiol. 1998; 21: I3-I13Crossref PubMed Scopus (77) Google Scholar, 24Gilbert EM Anderson JL Deitchman D et al.Long-term β-blocker vasodilator therapy improves cardiac function in idiopathic dilated cardiomyopathy: a double-blind, randomized study of bucindolol versus placebo.Am J Med. 1990; 88: 223-229Abstract Full Text PDF PubMed Scopus (242) Google Scholar, 25Gilbert EM Abraham WT Olsen S et al.Comparative hemodynamic, left ventricular functional, and antiadrenergic effect
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