This report was reviewed for medical and scientific accuracy by Ronald S. Freudenberger, MD, Director of Heart Failure and Transplant Cardiology, Associate Professor of Medicine, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, New Jersey

Expert Commentary and Opinion

Professor John GF Cleland, Department of Cardiology, University of Hull, Kingston upon Hull, United Kingdom; COMET Investigator.

The combination of angiotensin converting enzyme (ACE) inhibitors and β-blockers has halved the two-year mortality of patients with heart failure secondary to left ventricular systolic dysfunction. The results of COMET, the longest and largest clinical trial conducted in patients with heart failure, indicate that treatment with carvedilol reduces mortality by a further 17% (P = .0017) over existing therapy and prolonged median survival by a further 1.4 years compared to metoprolol.¹ This suggests that the benefits of treatment with a β-blocker can be increased by a further 50% by using or switching to carvedilol. No effect was observed on time to first all-cause hospitalization. Further analyses on cause-specific hospitalization, total number of hospitalizations, total days in hospital and effects on symptoms and quality of life are awaited. These are the facts, but why was such a difference in mortality observed? There are many possible explanations with varying degrees of plausibility.

The most obvious and most likely reason for the difference in outcome is the pharmacological differences between the agents used. Carvedilol provides comprehensive anti-adrenergic blockade (β₁-, β₂-and α₁-receptors--all of which are expressed on cardiac myocytes) whereas metoprolol only blocks the β₁-receptor. β₁-receptors mediate much, but not all, of the inotropic, chronotropic and arrhythmogenic effects of sympathetic activation. β₂-receptors also mediate some of the inotropic and chronotropic effects of sympathetic activation. Activation of β₂-receptors may also provoke hypokalemia during sympathetic stress (not good) but also peripheral vasodilatation (potentially good). Blockade of α₁-receptors, which probably also mediate some of the inotropic effects of sympathetic activation, are involved in the hypertrophic response and cause peripheral vasoconstriction, may offset the effects of peripheral β₂-receptor blockade. However, the long-term benefit of α-blockade in heart failure remains unknown. Carvedilol and its metabolites are also powerful antioxidants,² which may confer benefits to patients with heart failure who have increased oxidant stress³ and reduced endogenous antioxidant defenses. The significance of this attribute in treating heart failure remains uncertain at this time but it could potentially be of great importance. Carvedilol, like metoprolol, is also lipophilic, a common attribute of all β-blocking agents for which there is robust evidence of a mortality benefit. Thus of all available β-blockers, carvedilol appears to have the most favorable pharmacological profile for the management of heart failure and there should be no surprise that this translates into greater patient benefits.

Those who have invested much time and energy in trials of β₁-receptor blockers have done a great service to patients and are naturally inclined to defend their trials and criticize the results of COMET. It has been said that the doses of metoprolol and carvedilol are not equivalent. This is very hard to prove one way or another. Simple pharmacokinetics suggest no difference. COMET was planned at a time when only four substantial studies were available (the MDC trial with metoprolol in similar doses and the same formulation used in COMET⁴; CIBIS-I, an inconclusive study of bisoprolol⁵; and two trials of carvedilol - the Australia New-Zealand trial⁶ and the US carvedilol trial⁷), before MERIT-HF⁸ and CIBIS-II⁹ reported. Small differences in the reduction in heart rate and blood pressure with carvedilol and metoprolol were observed but these are more likely to reflect differences in the types of receptor blocked rather than differences in dose. Furthermore, there are, as yet, no compelling data showing an important relationship between dose and long-term outcome with β-blockers.

The difference between carvedilol and metoprolol in terms of mortality is similar to or greater than that between enalapril and placebo in the SOLVD treatment study of heart failure,¹⁰ the effects of coronary artery bypass graft (CABG) surgery compared to medical treatment in a landmark meta-analysis,¹¹ or the effects of statins¹² (Table 1). These studies are widely recognized as being valuable contributions to clinical care. Similar recognition should be given to COMET.

Perspective

Activation of the sympathetic nervous system is one of the hallmarks of heart failure. Sympathetic activation, although increasing cardiac contractility in the short-term has adverse effects on myocardial function in the long-term, contributes to progressive ventricular dilatation (remodelling) and is arrhythmogenic. Unsurprisingly, sympathetic activation predicts a worse outcome. The addition of β-blockers to standard therapy for stable heart failure has gained widespread acceptance, as data from several clinical trials have demonstrated favorable outcomes.^7-9,15 However, it appears that some β-blocking agents, such as bucindolol, are ineffective.¹⁶ This raises the question of whether the large pharmacological differences between β-blockers translates into differences in outcome for patients. More specifically, are the benefits of this class of agent mediated solely by the β₁-receptor or does more comprehensive adrenergic receptor blockade provide additional benefits?

The COMET Trial

The Carvedilol or Metoprolol European Trial (COMET), the largest and longest ever study in chronic heart failure was designed to evaluate whether the different pharmacologic profiles of β-blockers result in different effects on heart failure morbidity and mortality.¹⁷ The agents chosen for the trial have demonstrated efficacy in previous heart failure studies.^7,8,15 Metoprolol is a β₁-selective agent, whereas carvedilol has broad-spectrum activity that includes antagonism of β₁- and β₂-receptors as well as α₁-receptors. The primary results from COMET were reported during Heart Failure 2003,¹ and demonstrated a statistically significant 17% survival benefit for patients treated with carvedilol compared to those patients treated with metoprolol (P = .0017).

"We undertook this trial to assess these 2 drugs, and the trial was done according to how we planned it," advised Principal Investigator Philip A. Poole-Wilson, MD, Simon Marks and British Heart Foundation Professor of Cardiology, Head of the Department of Cardiac Medicine at the National Heart and Lung Institute, Imperial College School of Medicine, London, England.¹⁸ "It does seem to be quite reasonable to conclude that carvedilol is the preferred β-blocker for heart failure."

COMET evaluated β-blocker use in 3029 patients from 15 European countries with New York Heart Association (NYHA) Class II-IV heart failure who remained symptomatic despite treatment with ACE inhibitors and diuretics. The patients were randomized to target doses of carvedilol 25 mg twice daily (n = 1511) or metoprolol 50 mg twice daily (n = 1518) and followed for a mean duration of 58 months. The respective doses were selected based on previous studies suggesting that a dose ratio of 1:2 (carvedilol: metoprolol) achieved a similar heart rate reduction.¹⁷

The primary endpoints of COMET were all-cause mortality and the composite endpoint of all-cause mortality or all-cause hospitalization. Safety was monitored by an independent data and safety monitoring board. All reports of adverse and serious adverse events were recorded irrespective of etiology. Serious adverse events included adverse events that were fatal or life-threatening, required or extended hospital admission, or resulted in persistent or significant disability or incapacity.

Key inclusion criteria included at least one cardiovascular hospital admission during the 2 years prior to study entry, stable heart failure therapy with ACE inhibitors for at least 4 weeks and diuretics (≥40 mg furosemide or equivalent) for at least 2 weeks, and ejection fraction of 35% or less. Exclusion criteria included contraindication to β-blocker therapy (eg, sick sinus syndrome, asthma, chronic obstructive pulmonary disease, peripheral arterial disease, second or third degree atrioventricular block), requirement for intravenous inotropic therapy, current use of calcium channel blockers (diltiazem, verapamil), amiodarone (>200 mg/day) or class-I antiarrhythmic drugs within the 30 days prior to study entry.

The two treatment arms had similar baseline characteristics and were well matched. The incidence of ischemic heart disease, previous myocardial infarction, angina, hypertension, diabetes and stroke were comparable. The mean duration of heart failure was 42 months in each treatment arm with an average ejection fraction of 26%. Pharmacologic therapy for heart failure consisted primarily of diuretics (99%), ACE inhibitors (91%), spironolactone (11%), nitrates (33%), digoxin (59%), aspirin (37%) and warfarin (46%).

At randomization, patients were assigned to receive either carvedilol 3.125 mg twice daily or metoprolol 5 mg twice daily. During the titration phase, the dose of each β-blocker was increased every 2 weeks to the target dose or the maximally tolerated dose.

An analysis of all-cause mortality revealed a total of 512 (34%) patients died in the carvedilol treatment arm compared to 600 (40%) in the metoprolol treatment arm (hazard ratio 0.83, 95% Confidence Interval (CI), 0.74-0.93; P = .0017) or a 17% reduction in mortality due to carvedilol (Table 2). Cardiovascular deaths were 29% and 35% in the carvedilol and metoprolol treatment arms, respectively (hazard ratio 0.80, 95% CI 0.70-0.90; P = .0004). The annualized mortality rate was 8.3% in the carvedilol treatment arm compared to 10.0% in the metoprolol treatment arm. The endpoint of all-cause mortality and all-cause hospital admission showed a slight advantage for carvedilol (74% vs 76%), but the difference did not achieve statistical significance (hazard ratio 0.94, 95% CI, 0.86-1.02; P = .122).

COMET investigators conducted an extensive subgroup analysis that included age, sex, NYHA classification, ejection fraction, heart rate, blood pressure, and diabetes. The reduction in all-cause mortality was similar in direction and magnitude across the predefined subgroups. Additionally, sensitivity analyses confirmed the primary mortality analysis.

The incidence and number of adverse events were fewer in the carvedilol treatment arm despite a slightly longer mean observation time for carvedilol-treated patients (46.8 months vs 45.2 months) due to differences in mortality. Adverse events typically associated with β-blockade were similar between treatment arms. Bradycardia was reported in 144 (10%) carvedilol-treated patients and in 135 (9%) metoprolol-treated patients. Hypotension occurred in 215 (14%) carvedilol-treated patients and 160 (11%) metoprolol-treated patients.

At baseline, the mean heart rates between treatment arms were identical at 81 beats per minute (BPM). After 4 months of treatment, mean heart rate reduction was 13.3 BPM in carvedilol-treated patients compared with 11.7 BPM in metoprolol-treated patients (difference -1.6 BPM, 95% CI, -2.7- -0.6; P<.01). At baseline, the mean systolic blood pressure was identical between treatment arms (126 mm Hg). After 4 months of treatment, the mean decrease in systolic blood pressure in carvedilol-treated patients was 3.8 mm Hg and 2.0 mm Hg in metoprolol-treated patients (difference -1.8 mm Hg, 95% CI, -3.2- -0.4; P = .01). Systolic blood pressure remained slightly but significantly lower in carvedilol-treated patients throughout the trial.

Issues from COMET-Questions and Answers

One question that will likely rise from the results of COMET relates to the comparability of the dosages used in the trial, stated co-presenter Milton Packer, MD, Professor of Medicine, Chief of the Division of Circulatory Physiology at the Columbia University College of Physicians and Surgeons, New York, New York.¹⁹ "Attenuation of exercise heart rate is the gold standard for determining the degree of β₁-blockade," advised Dr. Packer. Continuing, "The best available evidence indicates that maximal or near-maximal β₁-blockade leads to a 20% reduction in exercise heart rate, an effect that is achieved with a metoprolol tartrate dose of 100 mg per day or a carvedilol dose of 50 mg per day, the doses used in COMET."

Another possible issue relates to the use of the immediate-release formulation of metoprolol in COMET (metoprolol tartrate). An earlier trial (MERIT-HF) demonstrated mortality benefits with an extended-release formulation of metoprolol (metoprolol succinate).^8,20 At steady state, the average bioavailability of metoprolol succinate is 77% relative to corresponding doses of immediate-release metoprolol.²¹ However, at therapeutic doses, both immediate-release and extended-release metoprolol have similar relationships with respect to plasma levels and β₁-blockade.^21,22 Moreover, metoprolol tartrate 50 mg twice daily has been shown to produce similar hemodynamic and clinical effects both acutely and chronically as metoprolol succinate 100 mg daily.²³ That being said, there has been considerable debate as to whether the dose of metoprolol used in COMET exerted a similar degree of β₁-blockade to carvedilol.²⁴ Henry J. Dargie, MD, from the Department of Cardiology, Western Infirmary, Glasgow, Scotland has stated that the question of metoprolol dose (100 mg) has to be seriously considered and has further suggested that perhaps a pragmatic trial comparing carvedilol, metoprolol, and even bisoprolol titrated to their maximum individually tolerated doses in a cohort of patients reflective of those encountered in clinical practice would satisfy most clinicians.

"Data from placebo-controlled trials conducted prior to COMET had already suggested an advantage for non-selective β-blockers such as carvedilol," stated Dr. Packer. "Combined results from studies involving post-myocardial infarction patients showed a 31% reduction in mortality among patients treated with agents that had β₂-or α₁-receptor activity in addition to β₁-blockade. That compared with a 21% overall reduction with β₁-selective agents and a 15% reduction for β₁ agents with intrinsic sympathomimetic activity," advised Dr. Packer.

Dr. Packer elaborated, "In placebo-controlled heart failure trials, non-selective agents with or without α₁-receptor activity resulted in a 42% overall risk reduction for mortality. Selective β₁ agents achieved an overall reduction in mortality of 34%, and treatment with β-blockers that had intrinsic sympathomimetic activity led to a 10% reduction in relative risk."

"These data, taken together, strongly suggest that actions beyond β₁-blockade really do make a difference," commented Dr. Packer. Thus, the COMET data make a compelling case for use of a broad-spectrum β-blocker that provides greater antisympathetic activity in heart failure patients.

"The results of the COMET trial indicate that the actions of carvedilol beyond β₁-blockade had a favorable effect on mortality," said Dr. Packer. "If the antisympathetic actions of carvedilol beyond β1-blockade really do make a difference, why would anyone prescribe a β₁-blocker without these additional properties, regardless of dose or formulation?"

References

1. Komajda M, Swedberg K. Challenging Established Treatment Patterns in Chronic Heart Failure. Satellite Symposium held during Heart Failure 2003-European Society of Cardiology and International Society for Heart Research, June 23, 2003, Strasbourg, France.
2. Yue TL, Cheng HY, Lysko PG, et al. Carvedilol, a new vasodilator and beta adrenoceptor antagonist, is an antioxidant and free radical scavenger. J Pharmacol Exp Ther. 1992;263:92-98.
3. Dhalla AK, Singh N, Singal PK. Antioxidant therapy associated with the reversal of oxidative stress delays the pathogenesis of heart failure. Circulation. 1994:90:I-491. Abstract.
4. Waagstein F, Bristow MR, Swedberg K, et al. Beneficial effects of metoprolol in idiopathic dilated cardiomyopathy. Metoprolol in Dilated Cardiomyopathy (MDC Trial Study Group). Lancet. 1993;342:1441-1446.
5. A randomized trial of beta-blockade in heart failure. The Cardiac Insufficiency Bisoprolol Study (CIBIS). CIBIS Investigators and Committees. Circulation. 1994; 90:1765-1773.
6. Randomized, placebo-controlled trial of carvedilol in patients with congestive heart failure due to ischaemic heart disease. Australia/New Zealand Heart Failure Research Collaborative Group. Lancet. 1997;349:375-380.
7. Packer M, Bristow MR, Cohn JN, et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group. N Engl J Med. 1996;334:1349-1355.
8. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet. 1999;353:2001-2007.
9. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomized trial. Lancet. 1999;353:9-13.
10. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. The SOLVD Investigators. N Engl J Med. 1992;327:685-691.
11. Yusuf S, Zucker D, Peduzzi P, et al. Effect of coronary artery bypass graft surgery on survival: overview of 10 year results from randomised trials by the Coronary Artery Bypass Graft Surgery Trialists Collaboration. Lancet. 1994;344:563-570.
12. Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:1383-1389.
13. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Lancet. 1988;2:349-360.
14. Pfeffer MA, Braunwald E, Moye 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. The SAVE Investigators. N Engl J Med. 1992;327:669-677.
15. Packer M, Coats AJ, Fowler MB, et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med. 2001;344:1651-1658.
16. A trial of the beta-blocker bucindolol in patients with advanced chronic heart failure. The Beta-Blocker Evaluation of Survival Trial Investigators. N Engl J Med. 2001;344:1659-1667.
17. Poole-Wilson PA, Cleland JGF, DiLenarda A, et al. Rationale and design of the carvedilol or metoprolol European trial in patients with chronic heart failure: COMET. Eur J Heart Fail. 2002;4:321-329.
18. Poole-Wilson PA. COMET-Results of the Longest and Largest Ever Study in CHF. Challenging Established Treatment Patterns in Chronic Heart Failure. Satellite Symposium held during Heart Failure 2003-European Society of Cardiology and International Society for Heart Research, June 23, 2003, Strasbourg, France.
19. Packer M. Ensuring Efficacy across the Spectrum of CHF-The Impact of Comprehensive Adrenergic Blockade. Challenging Established Treatment Patterns in Chronic Heart Failure. Satellite Symposium held during Heart Failure 2003-European Society of Cardiology and International Society for Heart Research, June 23, 2003, Strasbourg, France.
20. Wikstrand J, Hjalmarson A, Waagstien F, et al. Dose of metoprolol CR/XL and outcomes in patients with heart failure. Analysis of experience in metoprolol CR/XL randomized intervention trial in chronic heart failure (MERIT-HF). J Am Coll Cardiol. 2002;40:491-498.
21. Toprol XL prescribing information [package insert]. AstraZeneca. Available at http://www.astrazeneca-us.com. Accessed August 11, 2003.
22. Abrahamsson B, Lucker P, Olafsson P, et al. The relationship between metoprolol plasma concentration and beta-1 blockade in healthy subjects: a study on conventional metoprolol and metoprolol CR formulations. J Clin Pharmacol. 1990;30(2 suppl):S46-S54.
23. Kukin ML, Mannino MM, Fruedenberger RS, Kalman J, Buchholz-Varley C, Ocampo O. Hemodynamic comparison of twice daily metoprolol tartrate with once daily metoprolol succinate in congestive heart failure. J Am Coll Cardiol. 2000;35:45-50.
24. Dargie HJ. b blockers in heart failure. Lancet. 2003;362:2-3.

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Disclosure
John GF Cleland
Grant/Research Support-AstraZeneca, F. Hoffmann-La Roche Ltd.;
Consultant-AstraZeneca, F. Hoffmann-La Roche Ltd.;
Speakers Bureau-AstraZeneca, F. Hoffmann-La Roche Ltd.

Ronald S. Freudenberger, MD
Shareholder-GlaxoSmithKline;
Speakers Bureau-AstraZeneca, GlaxoSmithKline

This report contains information on commercial products that are unlabeled for use or investigational uses of products not yet approved.

This report is supported by an educational grant from GlaxoSmithKline.

The opinions expressed in this publication are those of the participating faculty and do not necessarily reflect the opinions or the recommendations of their affiliated institutions: University of Medicine & Dentistry of New Jersey; MMC, Inc.; or any other persons. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this publication should not be used by clinicians without evaluation of their patients' conditions, assessment of possible contraindications or dangers in use, review of any applicable manufacturer's product information, and comparison with the recommendation of other authorities. This Cardiology Express Report™ includes discussion of treatment and indications outside of current approved labeling. This Cardiology Express Report™ was made possible through an educational grant from GlaxoSmithKline.

© 2003 Millennium Medical Communications, Inc. and UMDNJ-Center for Continuing and Outreach Education