LEADING ARTICLE

Drugs 1999 Aug; 58 (2): 203-210 0012-6667/99/0008-0203/$08.00/0 © Adis International Limited. All rights reserved.

β-Blockers in Heart Failure The ‘New Wave’ of Clinical Trials Henry Krum Clinical Pharmacology Unit, Dept. of Epidemiology & Preventive Medicine and Dept. of Medicine, Monash University, Alfred Hospital, Prahran, Australia

Abstract

There is now considerable clinical trial data to support the use of β-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 β-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 β-blocking properties alone or to a combination of the β-blocking and ancillary effects of the drug; whether β-blockers are of benefit in patients with severe New York Heart Association (NYHA) Class IIIB-IV CHF; and, whether β-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 β1-selective, non-vasodilating agents (i.e. bisoprolol and metoprolol) improve survival in patients with CHF. 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 β-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 β-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 β-blockers as part of the design of such studies. In conclusion, β-blockers have now become the most extensively studied class of agents in the treatment of CHF, with a database of over 6000 patients in

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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 results of 3 of these studies have recently been reported; the second Cardiac Insufficiency Bisoprolol Study (CIBIS II),[13] the β-blocker arm of the Research in Left Ventricular Dysfunction (RESOLVD study)[14] and the Metoprolol CR/XL Randomised Intervention Trial in Heart Failure (MERIT-HF) study.[15] The clinical need for these recent trials and the potential impact of the results of these studies on the management of the heart failure patient will be explored in this brief review.

There is now considerable clinical trial data to support the use of β-blockers in patients with congestive (CHF) heart failure due to systolic left ventricular dysfunction. Since the first, open-label studies were reported by various Swedish groups in the mid-1970s,[1-3] a large number of placebo-controlled trials have confirmed the clinical utility of these agents in CHF. Specifically, single-centre studies have consistently demonstrated improvements in ejection fraction and clinical status in symptomatic patients with this condition.[4-9] The findings of these small studies have in turn led to larger trials to ascertain morbidity and mortality effects of these agents. Early, large-scale trials with β-blockers have indeed suggested morbidity and mortality benefits with these agents.[10-12] However, none of these trials were adequately powered to prospectively assess mortality as a primary endpoint, and a number of important questions regarding the type of βblocker and selection of patient are yet to be answered. Furthermore, because β-blocking agents are a pharmacologically heterogeneous group (table I), it is not clear whether mortality benefits observed with one agent can be attributed to other drugs in the class. For these reasons, and despite the recent approval of carvedilol for heart failure in many countries, a series of clinical trials of β-blockers in CHF were recently initiated. Most of the studies in this ‘new wave’ of clinical trials are ongoing. However,

1. Previous β-Blocker Mortality Trials in Heart Failure Until recently, only 3 large, multicentre studies had been published that examined the effects of β-blockers on morbidity and mortality in CHF. In the Metoprolol Dilated Cardiomyopathy trial[10], there was a trend toward a reduction in mortality and/or need for cardiac transplantation with metoprolol (p = 0.058) in 383 heart failure patients. However, mortality was not reduced in the study (fig. 1). In the first CIBIS trial,[11] which was underpowered in terms of sample size (641 patients) for a primary mortality effect, there was a trend toward a benefit (20% relative risk reduction in mortality) with bisoprolol compared with placebo. Posthoc analysis suggested a greater effect in the nonischaemic group and in those patients with New

Table I. Pharmacological properties of β-adrenoceptor blockers currently being studied in heart failure Agent

β-adrenoceptor antagonist Direct vasodilator selectivity activity

α-adrenoceptor antagonist activity

Intrinsic sympathomimemtic activity

Ancillary propertiesa

Bisoprolol

β1 >> β2

-

-

-

-

Bucindolol

β1 = β2

+

-

?

-

Carvedilol

β1 = β2

+

+

-

++

Metoprolol

β1 >> β2

-

-

-

-

a

Ancillary properties are vasodilatory, anti-oxidant, anti-proliferative and anti-endothelin.

© Adis International Limited. All rights reserved.

Drugs 1999 Aug; 58 (2)

β-Blockers in Heart Failure

Trial

205

N

% Mortality BB Control

OR & 95% Cl

Small trials - Carvedilol - Non-carvedilol

149

4.5%

3.3%

222

7.1%

9.1%

MDC

383

11.9%

11.1%

CIBIS

641

16.6%

20.9%

ANZ

415

9.7%

12.5%

US Multicentre

1094

2.4%

7.1%

CIBIS II

2639

11.8%

17.2%

RESOLVD

769

3.7%

8.1%

MERIT-HF

3991

7.2%

11.0%

Total

6312

8.5%

12.8%

OR = 0.66 95% Cl 0.61-0.71 2p = 0.0005

0

0.5

1.0

1.5

2.0

Fig. 1. Meta-analysis of total mortality outcomes of placebo-controlled β-blocker trials in congestive heart failure. The meta-analysis included all trials involving patients randomised to a β-blocking agent or placebo. For reasons of space, small single-centre trials were grouped as those involving carvedilol or those involving β-blockers other than carvedilol (noncarvedilol). Odds ratios, confidence intervals and significance values were determined using Revman meta-analysis software. ANZ = Australia/New Zealand Heart Failure Research Collaborative Group trial (with carvedilol); BB = β-blocker arm; CI = confidence interval; CIBIS = Cardiac Insufficiency Bisoprolol Study; MDC = Metoprolol Dilated Cardiomyopathy trial; OR = odds ratio; RESOLVD = Randomised Evaluation of Strategies for Left Ventricular Dysfunction study; US Multicentre = US Carvedilol Heart Failure Study Group trial.

York Heart Association (NYHA) Class IV symptoms. More recently, the US multicentre carvedilol study programme[12] (1094 patients) was terminated early by that group’s Data Safety Monitoring Board (DSMB) because of a highly significant 65% mortality reduction with carvedilol compared with placebo when added to standard therapy (i.e. ACE inhibitor, digoxin, diuretic). Patients had symptomatic heart failure and were mainly in NYHA Class II-III. In contrast to the CIBIS study, the magnitude of the benefit was similar in patients with mild or moderate symptoms and whether idiopathic dilated or ischaemic cardiomyopathy was the aetiology of heart failure. Whilst the relative mortality benefits observed in the US multicentre carvedilol study programme were substantial, only a small number of deaths (53 in total) were recorded during the study leading some observers to conclude that definitive mortality benefits with β-blockers had not been ade© Adis International Limited. All rights reserved.

quately demonstrated. Therefore, the mortality results of the US multicentre carvedilol studies were considered by many as hypothesis-generating, rather than hypothesis-testing. In particular, the questions raised by this study included: • can the beneficial effects of carvedilol on mortality be reproduced in prospective, adequately powered studies of β-blockers in heart failure? • are the benefits of carvedilol in systolic CHF due to its β-blocking properties or to a combination of β-blocking and ancillary (i.e. vasodilatory, anti-oxidant, anti-proliferative, anti-endothelin) effects of the drug? • are β-blockers of benefit in patients with severe (NYHA Class IIIB-IV) CHF? • are β-blockers of benefit in patients with evidence of systolic ventricular dysfunction in the immediate post-myocardial infarction (MI) period? Drugs 1999 Aug; 58 (2)

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A number of ongoing and recently completed studies have been specifically designed to formally address these questions. 2. Can the Beneficial Effects of Carvedilol on Mortality be Reproduced in Prospective, Adequately Powered Studies? 2.1 Cardiac Insufficiency Bisoprolol Study II (CIBIS II)

CIBIS II[13] was a follow-up to the first CIBIS study,[11] but in contrast to the CIBIS study, mortality was the primary endpoint. 2647 severely ill patients designated as NYHA Class III (83%) or Class IV (17%) CHF were randomised to bisoprolol, a β1-selective, nonvasodilatory β-blocker, or placebo and followed for an average of 1.3 years. The dosage of bisoprolol was slowly up-titrated to a maximum of 10 mg/day. 62% of patients were less than 65 years of age. All-cause mortality was reduced by 34% in the bisoprolol group compared with placebo [156 (11.8%) versus 228 deaths (17.3%)]. This represented an odds ratio (OR) of 0.66 (95% confidence interval 0.54 to 0.81). The magnitude of this benefit resulted in the study being stopped early by the study’s DSMB as it was thought unethical to deprive patients receiving placebo of the benefits of this drug. Further sub-group analysis established that the majority of the benefit with bisoprolol was attributable to a reduction in sudden death with no significant decrease in pump failure, frequency of MI or other cardiovascular events. In contrast to the first CIBIS study, a greater mortality benefit was observed with bisoprolol in CIBIS II in the ischaemic group and only a nonsignificant trend towards a benefit was observed in patients with NYHA Class IV symptoms. However, the distinction between NYHA Class III and IV patients may be arbitary in CIBIS II as the mortality event rate was relatively low. In addition to the effects on mortality, hospital admissions were lower in the bisoprolol group © Adis International Limited. All rights reserved.

Krum

(33%) than in the placebo group (39.6%). Bisoprolol was well tolerated with a low (5% in both groups) permanent withdrawal rate. In conclusion, this study of β-blockade in heart failure with bisoprolol reported a significant mortality benefit and established a clear role for these agents in improving survival in patients with NYHA Class III heart failure. There will undoubtedly be considerable ongoing debate regarding the magnitude of the mortality benefit in CIBIS II, particularly compared with the 65% relative risk reduction observed in the US multicentre carvedilol studies. CIBIS II established that a pure β-blocking drug is of prognostic benefit in heart failure. However, the greater relative risk reduction observed in the carvedilol studies may be due to the nonselective β-adrenoceptor blockade (in comparison to the β1-selectivity of bisoprolol), lack of β-adrenoceptor upregulation[16] and/or ancillary pharmacological properties of carvedilol. An ongoing study, the Carvedilol and Metoprolol European Trial (COMET), is testing this hypothesis by directly comparing the effects of carvedilol and a β1-selective antagonist metoprolol on morbidity and mortality in patients with CHF.[17] 2.2 Randomised Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD Study)

The RESOLVD study[14] was a pilot trial of candesartan in CHF designed to lead into a larger mortality trial. The study design was complicated: an ACE inhibitor (enalapril) was compared with an angiotensin II receptor antagonist (candesartan cilexitil) or the combination at various dosages. Moreover, patients were secondarily randomised to receive controlled-release (CR) metoprolol or placebo. A total of 426 patients were enrolled in the βblocker arm of the study, the purpose of which was to establish the efficacy of CR metoprolol in heart failure. After 20 weeks of treatment there were fewer deaths in the CR metoprolol group (8 versus 17 in the placebo group). There was however, an excess of heart failure-related hospitalisation in the Drugs 1999 Aug; 58 (2)

β-Blockers in Heart Failure

CR metoprolol group (18 patients) compared with placebo (7 patients), but no overall increase in hospitalisation (35 versus 36 patients). The magnitude of the mortality benefit in this study was similar in terms of relative risk reduction to that in the US multicentre carvedilol studies. However, fewer patients were studied and fewer deaths were recorded (25 in total). Nevertheless, this preliminary data supports the findings of the recently reported prospective mortality study of CR metoprolol in heart failure (the MERIT-HF trial). Furthermore, this trial further supported the CIBIS II observation that a β1-selective agent is of prognostic benefit in heart failure. 2.3 Metoprolol CR/XL Randomised Intervention Trial in Heart Failure (MERIT-HF) Study

The MERIT-HF study was a placebo-controlled mortality study of CR metoprolol in 3991 patients with systolic heart failure (ejection fraction <40%). This study complemented the pilot data obtained in the RESOLVD study. The mortality results of MERIT-HF have recently been published.[15] The study was prematurely terminated by the trial’s DSMB because of a significant mortality benefit with CR metoprolol. A 34% decrease in mortality with metoprolol-CR was reported (145 in the metoprolol group versus 217 in the placebo group). In addition, both sudden death and death from progressive heart failure were significantly reduced (by 41 and 49%, respectively). Predefined subgroup analysis demonstrated consistent mortality benefits in those patients with previous MI, hypertension or diabetes mellitus. Metoprolol appeared to be well tolerated. Further details, such as the impact on hospitalisation, are still awaited. 2.4 Bucindolol Evaluation Study

The Bucindolol Evaluation Study (BEST) is examining the effect of bucindolol on mortality compared with placebo in 2800 patients with symptomatic (NYHA Class III-IV) CHF.[18] © Adis International Limited. All rights reserved.

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Bucindolol is of great interest as it shares many of the pharmacological properties of carvedilol (table I). That is, it is a relatively nonselective βblocker, has vasodilatory activity (similar to carvedilol, although the mechanism is uncertain) and does not cause upregulation of β-adrenoceptors (in contrast to metoprolol which up-regulates β1adrenoceptors).[19] There is some debate as to whether the drug has intrinsic sympathomimetic activity. 3. Are the Benefits of Carvedilol in Systolic Congestive Heart Failure (CHF) Due to its β-Blocker Properties or to a Combination of the β-Blocking and Ancillary Effects of the Drug? 3.1 COMET (Carvedilol and Metoprolol European Trial)

The purpose of COMET is to formally test the hypothesis that treatment with a nonselective βblocker with vasodilating and ancillary properties (i.e. carvedilol) will result in a greater mortality benefit in patients with heart failure than a nonvasodilating, β1-selective agent (i.e. metoprolol). The 2 agents are being compared in a mortality trial in patients with symptomatic NYHA Class II-III CHF. The rationale for this hypothesis is that if catecholamine excess in heart failure contributes to the ongoing pathological ventricular remodelling process, then blockade of both myocardial adrenoceptor sub-types may be necessary to maximise the benefits of sympathetic blockade. Blockade of both receptor subtypes may assume even greater importance in heart failure where there is relative down-regulation of the β1-adrenoceptor compared with the β2 sub-type in the setting of catecholamine excess.[20] However, even if differences in mortality are observed between patient groups assigned to treatment with metoprolol or carvedilol in COMET, this hypothesis cannot be fully ascertained on the basis of adrenoceptor sub-type differences as the Drugs 1999 Aug; 58 (2)

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vasodilator, anti-oxidant and other ancillary effects of carvedilol may also be contributing. 4. Are β-Blockers of Benefit in Patients With Severe (NYHA Class IIIB-IV) CHF 4.1 Carvedilol Prospective Randomised Cumulative Survival Trial (COPERNICUS)

The COPERNICUS study, involving 1800 patients, is addressing the question of β-blockade with carvedilol in patients with severe CHF. It is these patients in whom physicians are most reluctant to commence β-blocker therapy because of concerns regarding the tolerability of these agents (for example, worsening CHF, hypotension, bradycardia etc.). In addition, given the limited life expectancy of such patients, there are legitimate concerns regarding the extended period of time required before symptomatic benefits accrue with βblockers. Why give β-blockers to patients with severe CHF? Certainly, patients with severe symptomatic heart failure are the most dependent on sympathetic activation to maintain systolic cardiac performance. However, these are the patients in whom β-blockade may potentially be of greatest symptomatic and mortality benefit. There is limited data regarding β-blockers in patients with severe CHF. In the US multicentre carvedilol studies, only 105 patients had severe CHF, as defined by a 6-minute walk test, and most of them were treated for only short periods (less than 2 months).[21] These patients roughly conformed to a NYHA Class IIIB-IV clinical symptom subgroup. The trend within this sub-group was towards an improved ejection fraction and a reduction in symptom severity with carvedilol; however, no conclusions regarding morbidity or mortality could be made from the data. In the CIBIS II study,[13] 445 (17%) of the 2647 patients were described as having NYHA Class IV CHF symptoms. 40 of 221 patients (18.1%) died during treatment with bisoprolol versus 55 of 224 (24.6%) placebo recipients. However, this 26% re© Adis International Limited. All rights reserved.

Krum

duction in mortality was not statistically significant. The COPERNICUS study will address this high-risk sub-group in the setting of an appropriately powered mortality study. 5. Are β-Blockers of Benefit in Patients With Evidence of Systolic Ventricular Dysfunction in the Immediate Post-Myocardial Infarction Period? 5.1 Carvedilol Post-Infarction Survival Control in Left Ventricular Dysfunction (CAPRICORN)

The CAPRICORN study is designed to test the hypothesis that carvedilol is superior to placebo when added to ACE inhibitors in patients with evidence of ventricular dysfunction post-MI. It is well known that ACE inhibitors are useful in patients with ventricular dysfunction post-MI as demonstrated in both symptomatic (Acute Infarction Ramipril Efficacy; AIRE) [22] and asymptomatic patients (Survival and Ventricular Enlargement; SAVE).[23] β-blockers are known to prevent sudden death and re-infarction post-MI.[24] Evidence of ventricular dysfunction post-MI has previously been regarded as a contra-indication to the use of β-blockers. However, retrospective analyses of studies in which β-blockers were used post-MI (in the pre-ACE inhibitor era) suggest that the benefits of β-blockade are preserved (or even enhanced) in patients with evidence of ventricular dysfunction post-MI.[25] β-Blockers have never been added to ACE inhibitors in a prospective study design in patients with left ventricular dysfunction post-MI and this is the rationale for the CAPRICORN study. 6. Impact of Recent β-Blocker Trials on Ongoing β-Blocker Studies in CHF The results of the CIBIS II study (section 2.1)[13] most directly impact upon the ongoing COPERNICUS study (section 4.1) as the patient group studied in CIBIS II (moderate to severe symptoms) overlaps with those patients currently being reDrugs 1999 Aug; 58 (2)

β-Blockers in Heart Failure

cruited into COPERNICUS (patients with severe symptoms). However, COPERNICUS was designed to assess patients with extremely impaired heart function who correspond to true NYHA Class IIIB-IV with symptoms of dyspnoea, fatigue at rest or on minimal exertion, as well as having a left ventricular ejection fraction of <25%. Thus, the patient group studied in COPERNICUS is more severely impaired than those in CIBIS II. 7. Impact of Recent β-Blocker Trials on Studies of Other Agents in Heart Failure The results of the CIBIS II[13] (section 2.1) and MERIT-HF (section 2.3) studies and the findings of earlier studies that examined morbidity and mortality [10-12] are influencing ongoing studies of other agents in heart failure. Specifically, openlabel uptake of β-blockers by patients during the course of ongoing studies has important effects on the required patient numbers and/or the required duration of administration to the study drug. For example, in the Valsartan Heart Failure Trial (Val-HeFT), which is examining the effect of valsartan when added to ongoing ACE inhibitor therapy in patients with heart failure, the overall study sample size was recently increased at least in part because of the relatively high level of administration of β-blockers in patients enrolled in the study (currently 25% and increasing). As the most recent (post-CIBIS II and RESOLVD) meta-analysis of β-blockers in heart failure suggests an overall mortality reduction of 34% (fig 1), this will have a substantial impact on the rate of generation of mortality end-points in this study. The uptake of β-blockers in other ongoing CHF studies may under-power the ability of such studies to discern clinically significant mortality differences between active treatment groups. A large phase III trial (Sustained-release Moxonidine for Congestive Heart Failure; MOXCON) addressed the effect of central sympatholysis with moxonidine in patients with symptomatic heart failure in addition to background therapy comprising ACE inhibitors, digoxin and diuretics. In this © Adis International Limited. All rights reserved.

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study, the use of β-blockers was initially prohibited because it was thought that the combined effects of 2 sympathetic blocking agents might be potentially dangerous or limit the ability of the study to detect the effects of moxonidine on clinical outcomes. However, the results of CIBIS II[13] and MERIT-HF raised the ethical issue of denying NYHA Class II-III patients β-blockers and exposing them to an unproven therapy (moxonidine) or placebo. The study was recently terminated because of excess mortality in the moxonidine arm. Nevertheless, the results of the recently completed β-blocker mortality studies suggest that NYHA Class II and III patients cannot now be denied βblocker therapy as part of the study design of ongoing and future clinical trials in heart failure. However, the intriguing clinical question, of whether central sympatholysis can provide additive or even synergistic clinical benefits in the setting of β-blockade, remains to be answered. 8. Conclusion β-Blockers have now definitively been shown to be of prognostic benefit in patients with NYHA Class II-III CHF and are becoming more widely accepted by clinicians as standard pharmacological therapy in such patients who remain symptomatic despite treatment with ACE inhibitors and diuretics. Whilst the central question as to the benefit of β-blockers in heart failure has now been well established, on-going clinical trials are addressing fundamental clinical and mechanistic questions, such as, which agent provides the maximum clinical benefit, and what is the role of these agents in patients with severe NYHA Class IIIB-IV CHF or in the post-MI setting in combination with ACE inhibitors. Other, as yet unanswered questions remain, such as the role of β-blockers in the extreme elderly, in patients with diabetes mellitus and in patients with severe renal impairment. Nevertheless, the new wave of clinical trials should provide us with important additional clinical and mechanistic data with which to make ratioDrugs 1999 Aug; 58 (2)

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nal and evidence-based choices regarding βblocker therapy in heart failure. References 1. Swedberg K. Initial experience with beta blockers in dilated cardiomyopathy. Am J Cardiol 1993; 71: 30C-8C 2. Waagstein F, Hjalmarson A, Varnauskas E, et al. Effect of chronic beta adrenergic receptor blockade in congestive cardiomyopathy. Br Heart J 1975; 37: 1022-6 3. Swedberg K, Hjalmarson A, Waagstein F, et al. Prolongation of survival in congestive cardiomyopathy by beta-receptor blockade. Lancet 1979; I: 1374-6 4. Anderson JL, Lutz JR, Gilbert EM, et al. A randomized trial of low-dose beta blockade therapy for idiopathic dilated cardiomyopathy. Am J Cardiol 1985; 55: 471-5 5. Engelmeier RS, O’Connell JB, Walsh R, et al. Improvement in symptoms and exercise tolerance by metoprolol in patients with dilated cardiomyopathy: a double-blind, randomised placebo-controlled trial. Circulation 1985; 72: 536-46 6. Gilbert EM, Anderson JL, Deitchman D, et al. Long-term βblocker vasodilator therapy improves cardiac function in idiopathic dilated cardiomyopathy: a double-blind, randomised study of bucindolol versus placebo. Am J Med 1990; 88: 223-9 7. Krum H, Sackner-Bernstein JD, Goldsmith R, et al. Doubleblind, placebo-controlled study of the long-term efficacy of carvedilol in severe chronic heart failure. Circulation 1995; 92: 1499-506 8. Metra M, Nardi M, Giubbini R, et al. Effects of short-term and long-term carvedilol administration on rest and exercise hemodynamic variables, exercise capacity and clinical conditions in patients with idiopathic dilated cardiomyopathy. J Am Coll Cardiol 1994; 24: 1678-87 9. Olsen SL, Gilbert EM, Renlund DG, et al. Carvedilol improves left ventricular function and symptoms in chronic heart failure: a double-blind randomised study. J Am Coll Cardiol 1995; 25: 1225-31 10. Waagstein F, Bristow MR, Swedberg K, et al. Beneficial effect of metoprolol in idiopathic dilated cardiomyopathy. Lancet 1993; 342: 1441-6 11. CIBIS Investigators and Committees. A randomised trial of βblockade in heart failure: the cardiac insufficiency bisoprolol study (CIBIS). Circulation 1994; 90: 1765-73 12. Packer M, Colucci WS, Sackner-Bernstein JD, et al. Doubleblind, placebo-controlled study of the effects of carvedilol in patients with moderate to severe heart failure. Circulation 1996; 94: 2793-9 13. CIBIS II investigators and committees. The cardiac insufficiency bisoprolol study II (CIBIS II): a randomised trial. Lancet 1999; 353: 9-13

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14. White M, Rouleau JL, Perick D, et al. on behalf of the RESOLVD Investigators. Effects of metoprolol-CR in patients with ischaemic and dilated cardiomyopathy: the RESOLVD pilot study (phase II) (abstract). Eur Heart J 1998; 19 (Suppl.): 308 15. MERIT-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: 2001-7 16. Bristow MR, Larabee P, Muller-Beckmann, et al. Effect of carvedilol on adrenergic pharmacology in human ventricular myocardium and lymphocytes. Clin Invest 1992; 70: S105-S13 17. Poole-Wilson PH, Remme WJ. COMET: a multicentre randomised double-blind study to compare the effect of carvedilol and metoprolol on mortality and morbidity in patients with moderate or severe congestive heart failure (NYHA IIIV) [abstract]. Cardiovasc Drug Ther 1999 Mar; 13: 24 18. BEST Steering Committee. Design of the beta-blocker evaluation survival (BEST). Am J Cardiol 1995; 75: 1220-3 19. Fowler MB. Controlled trials with beta blockers in heart failure: metoprolol as the prototype. Am J Cardiol 1993; 71: 45C-53C 20. Bristow MR, Hershberger RE, Port JD, et al. β-adrenergic pathways in non-failing and failing human ventricular myocardium. Circulation 1990; 82 (Suppl. I): 12-25 21. Cohn JN, Fowler MB, Bristow MR, et al. Safety and efficacy of carvedilol in severe heart failure. J Cardiac Failure 1997; 3: 173-9 22. AIRE (Acute Infarction Ramipril Efficacy) study investigators. Effect of ramipril on mortaility and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. Lancet 1993; 342: 821-8 23. Pfeffer MA, Braunwald E, Moyé LA, et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction: results of the survival and ventricular enlargement trial. N Engl J Med 1992; 327: 669-77 24. Yusuf S, Peto R, Lewis J, et al. Beta blockade during and after myocardial infarction: an overview of the randomized trials. Prog Cardiovasc Dis 1985; 27: 335-71 25. Chadda K, Goldstein, CK, Byington R, et al. Effect of propranolol after acute myocardial infarction in patients with heart failure. Circulation 1986: 73: 503-10

Correspondence and reprints: Associate Professor Henry Krum, Clinical Pharmacology Unit, Dept. of Epidemiology & Preventive Medicine and Dept. of Medicine, Monash University, Alfred Hospital, Prahran, Victoria 3181, Australia. E-mail: [email protected]

Drugs 1999 Aug; 58 (2)