Data Presented at the Symposium "Following COMET's Trail: Results and Implications of the Largest Head-to-head Mortality Trial of β-blockers in Heart Failure" held during the 7th Annual Scientific Meeting of the Heart Failure Society of America, September 22-23, 2003 in Las Vegas, Nevada.

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

Barry H. Greenberg, MD, Professor of Medicine, University of California, San Diego; Director, Heart Failure/Cardiac Transplantation Program, UCSD Medical Center, San Diego, California

An analysis of secondary endpoints data from the recently published Carvedilol or Metoprolol European Trial (COMET) indicate that treatment with carvedilol in patients with heart failure produced significant reductions in cardiovascular mortality, death from stroke, and new-onset diabetes compared with patients treated with metoprolol. These findings supplement the publication of COMET's primary endpoints, which showed a 17% mortality advantage for carvedilol over metoprolol.¹ With approximately 15,000 patient-years, COMET is the largest head-to-head trial of beta-blockers ever conducted in heart failure.

The results of COMET have generated considerable discussion among specialists in the field of cardiology. While the data unequivocally have shown that carvedilol is superior to metoprolol in terms of overall mortality at the doses and formulations used, debate continues on the dose of metoprolol (50 mg twice a day) as well as the formulation used (tartrate versus succinate).

The purpose of this Cardiology Express Report is to review the data presented on COMET and address some of the issues that continue to generate debate among cardiologists. It is my hope that continued discussion will lead to a consensus that the results of COMET support the concept that carvedilol is clearly superior to metoprolol tartrate (in doses commonly used to treat heart failure patients) in improving the clinical course. The information presented from COMET also supports the concept that the superiority of carvedilol is related to cardiovascular effects beyond those due to blockade of the beta1 adrenergic receptor alone. Overall, the primary and secondary results of COMET provide a compelling rationale for using carvedilol in treating heart failure and it is my hope that the important debate that is being conducted over the results of COMET will ultimately result in better medical treatment for the millions of heart failure patients in the United States (US) and around the world.

Introduction

Traditionally, standard therapy for heart failure has consisted of diuretics, digoxin (Lanoxin) and angiotensin converting enzyme (ACE) inhibitors. However, beta-blockers have been underused in chronic heart failure despite data from several large clinical trials that indicate that with optimal titration and maintenance strategies, beta-blockers are efficacious and well tolerated in heart failure patients indicated Philip A. Poole-Wilson, MD, Professor of Cardiology, Imperial College School of Medicine, University of London, London, England.² Dr. Wilson recited the clinical trials that have demonstrated the efficacy of beta-blockers in reducing morbidity and mortality in heart failure patients—the US Carvedilol heart failure Program (USCP),³ the Cardiac Insufficiency Bisoprolol Study II (CIBIS-II),⁴ the Metoprolol CR/XL Randomized Intervention Trial in chronic Heart Failure (MERIT-HF),⁵ and the Carvedilol Prospective Randomized Cumulative Survival trial (COPERNICUS).⁶ Beta-blockers have different pharmacological profiles and as such, there have been considerable attempts to determine the preferred beta-blocker in treating heart failure.

The COMET Trial

The COMET trial was designed to evaluate whether the different pharmacologic profiles of carvedilol (Coreg) and metoprolol (Lopressor) result in different effects on heart failure morbidity and mortality.⁷ COMET randomized 3,029 patients with NYHA class II-IV CHF to receive carvedilol (target dose 25 mg twice a day) or metoprolol (target doses of 50 mg twice a day). The trial compared dosing regimens of metoprolol and carvedilol that produced similar degrees of beta1-blockade, both at peak and trough. Patients in COMET had a mean age of 62 years and mean ejection fraction of 0.26.

Primary Endpoints

The primary endpoints of COMET were all-cause mortality and the composite endpoint of all-cause mortality or all-cause hospitalization. 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 1). 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 with carvedilol prolonging median survival by 1.4 years. 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).

Dr. Poole-Wilson mentioned that both carvedilol and metoprolol produced a reduction in resting heart rate. Mean heart rate reduction was 13.3 beats per minute (BPM) in carvedilol-treated patients compared with 11.7 BPM in metoprolol-treated patients at 4 months (difference -1.6 BPM, 95% CI, -2.7- -0.6; P<.01). After 4 months, there was no longer a difference between agents; indicating beta blockade was similar between treatment arms.

Secondary Endpoints

The predefined secondary endpoints of COMET were presented by Karl Swedberg, MD, Professor/Chief Physician, The Cardiovascular Institute, Gothenburg, Sweden,⁸ and are illustrated in Table 2.

While the use of carvedilol resulted in significant reductions in mortality and cardiovascular death compared to metoprolol, Dr. Swedberg reported no significant differences were demonstrated in non-cardiovascular deaths between the two treatment arms (hazard ratio 1.078, 95% CI, 0.773-1.502; P = .6592).

The incidence of cardiovascular death, heart transplantation, non-fatal myocardial infarction or worsening heart failure was 49.3% in carvedilol-treated patients compared to 53.7% in metoprolol-treated patients (hazard ratio 0.881, 95% CI, 0.798-0.974; P = .0128) (Table 3). For cardiovascular death or hospitalization for non-fatal acute myocardial infarction, worsening heart failure, unstable angina, atrial fibrillation or ventricular arrhythmia, the difference in relative risk was significant (hazard ratio 0.895, 95% CI, 0.814-0.985; P = .0226) in favor of carvedilol (54.3 vs 58.3%). Further analysis of death or hospitalization for worsening heart failure revealed a significant reduction in carvedilol-treated patients (51.2% vs 55.4%; hazard ratio 0.89, 95% CI, 0.807-0.981, P = .0191). Dr. Swedberg did advise that, because of the long duration of the trial, very high numbers of patient hospitalizations were seen in COMET.

Cardiovascular mortality and death from stroke were highly significantly reduced by carvedilol (Table 4). Commenting on the 22% risk reduction in new-onset diabetes observed in carvedilol-treated patients (hazard ratio 0.778, 95% CI, 0.613-0.989; P = .04), Dr. Swedberg stated, "We do not know whether metoprolol increases the risk of new-onset diabetes or carvedilol controls it."

Concluding, Dr. Swedberg advised the audience, "Today, we have more evidence for comprehensive beta-adrenergic blockade in the treatment of heart failure, resulting in significant reductions in mortality, stroke and new-onset diabetes."

Pharmacological Differences between Beta-blocking Agents

COMET set out to test the hypothesis: do the anti-sympathetic actions of carvedilol beyond beta1-blockade have a favorable effect on survival? Is there a significant difference between carvedilol and metoprolol in the treatment of heart failure? To answer these questions, Milton Packer, MD, Professor of Medicine, Professor of Pharmacology, Chief, Division of Circulatory Pathology, Director, Center for Heart Failure Research, New York-Presbyterian Medical Center, New York, New York outlined the pharmacological differences between beta-blocking agents.⁹ Normal heart tissue functions under beta₁-environment; whereas heart failure converts the circulation from a beta₁—to a beta₁/beta₂/alpha₁—environment. Metoprolol is beta₁-selective, whereas, carvedilol blocks all three receptors, beta₁, beta₂, and alpha₁; reduces the release of norepinephrine in the synapse, as well as exhibiting anti-ischemic and antioxidant effects. Norepinephrine can interact with all three receptors and other cofactors to enhance cardiac cell toxicity.

Dr. Packer addressed a number of questions that have been raised concerning the use of immediate-release metoprolol 50 mg twice a day in COMET. For instance; is immediate-release metoprolol 50 mg twice a day an effective treatment regimen for heart failure? Does immediate-release metoprolol 50 mg twice a day provide the same degree of beta₁-blockade as carvedilol 25 mg twice a day? Is immediate-release metoprolol a less effective beta-blocker than extended-release metoprolol? Dr. Packer outlined evidence to answer these questions:

• Immediate-release metoprolol 50 mg twice a day has been shown to improve ejection fraction, symptoms and exercise tolerance in six placebo-controlled heart failure trials
• The largest trial (MDC¹⁰) showed a 34% reduction in risk of death or need for heart transplantation (P = .058) and in risk of actual transplantation (P = .007)

In response to the dose selection question, Dr. Packer furnished data on the pharmacokinetic and pharmacodynamic responses to immediate-release metoprolol 50 and 100 mg twice a day indicating the degree of beta-blockade by the two doses was the same when measured by percent reduction in the exercise heart rate, "which is the gold standard for measuring beta-blockade", stated Dr. Packer. "Moreover, the dose-response characteristics for immediate-release metoprolol 100 mg, carvedilol 50 mg and bisoprolol 10 mg show that these doses all mediate a 20 percent reduction in exercise heart rates in patients with or without heart failure," advised Dr. Packer.

Another question Dr. Packer discussed was the therapeutic equivalency of immediate-release metoprolol to that of extended-release metoprolol. It is well established that extended-release metoprolol provides continuous delivery of metoprolol throughout the day without peaks and troughs exhibited by immediate-release metoprolol with little variability in plasma levels.¹¹ However, extended-release metoprolol is 30% less bioavailable compared with immediate-release metoprolol, therefore, immediate-release metoprolol 50 mg twice a day is equivalent to 143 mg of extended-release metoprolol once daily.¹¹ However, Dr. Packer cautioned that no assessment of metoprolol plasma levels has been conducted in long-term clinical studies (>7 days).

As further evidence in support of his argument, Dr. Packer cited data from a clinical study that showed similar heart-rate reductions with immediate-release metoprolol 50 mg twice a day in patients with heart failure, both at peak (-23 beats/minute) and trough (-20 beats/ minute).¹² An additional study compared differences between peak and trough effects of long-term immediate-release metoprolol 46 mg twice a day and extended-release metoprolol 115 mg once daily on heart rates.¹³ The study found no differences in fluctuations in heart rates during long-term therapy with the two formulations of metoprolol. "Therefore," concluded Dr. Packer, "we do not know whether extended-release metoprolol 143 mg once daily is superior to immediate-release metoprolol 50 mg twice a day. But, we do know that carvedilol 25 mg twice a day is superior to immediate-release metoprolol 50 mg twice a day." Despite the supportive data, Dr. Packer expected active discussion on these questions to continue for some time.

Questions & Answers: Panel Discussion

Symposium Chair, Barry H. Greenberg, MD, Professor of Medicine, University of California, San Diego; Director, Heart Failure/Cardiac Transplantation Program, UCSD Medical Center, San Diego, California convened a panel discussion asking Drs. Swedberg and Poole-Wilson to comment on the mechanisms responsible for the substantial difference in the relative risk for stroke and new-onset diabetes conferred by carvedilol in COMET.

In response, Dr. Poole-Wilson stated, "The effects on insulin sensitivity are not known. But, I conjecture that some generalized vascular effect may be responsible for it. At the moment, we can't pick out a direct mechanism for it but the beta₂ receptor may have a role to play."

Regarding the risk of stroke, Dr. Swedberg thought that small differences in blood pressure may account for it but "some vascular protection may be responsible and it is difficult to describe a mechanism."

Commenting on the findings of COMET's primary endpoints, Dr. Poole-Wilson stated, "More than six percent absolute difference in mortality can't be ignored. The magnitude of effect is equivalent to the SOLVD study^[14] results. SOLVD helped establishment of ACE inhibitors in the treatment of heart failure. Hopefully, COMET will serve that role for beta-blockers in the treatment of heart failure. COMET is an active control trial with specific mortality reduction with some type of effect beyond beta₁-blockade."

Dr. Greenberg emphasized one important take home message from COMET—that a large number of patients with heart failure are not being treated according to the evidence from large trials like COMET. A survey, by show of hands, revealed that a majority of physicians are prescribing doses of beta-blockers [metoprolol] far below those recommended on the basis of clinical trial results. Adding to that premise, Dr. Poole-Wilson advised, "Based on the presented evidence, if you have new heart failure patients, start them on carvedilol and switch patients on low-dose immediate-release metoprolol to carvedilol, and be pragmatic regarding high-dose extended-release metoprolol."

The panel concluded that carvedilol, with comprehensive beta₁-, beta₂-, and alpha₁-blockade, has significantly greater benefit in reducing mortality compared to metoprolol with beta₁-selective blockade. Moreover, prolonging median survival should establish carvedilol as the preferred beta-blocking agent for patients with heart failure.

Conclusion

COMET provides insights into the advantages of beta-blockade in heart failure and will facilitate translation of research results into clinical practice. The results are very timely, as the utilization of beta-blockers in the treatment of heart failure remains disappointing. The findings of COMET will encourage physicians to prescribe carvedilol to reduce cardiovascular mortality, death from stroke and new-onset diabetes in patients with heart failure.

References

1. Poole-Wilson PA, Swedberg K, Cleland JGF, et al. Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol Or Metoprolol European Trial (COMET): randomised controlled trial. Lancet. 2003;362:7-13.
2. Poole-Wilson PA. COMET: Results from the Largest and Longest HF Study-Part 1. Presented as part of the Symposium "Following COMET's Trail-Results and implications of the Largest Head-to-Head Mortality Trial of β-Blockers in Heart Failure" during the 7th Annual Scientific Meeting of the Heart Failure Society of America, September 22-23, 2003, Las Vegas, Nevada.
3. Packer M, Bristow MR, Cohn JN, et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. US Carvedilol Heart Failure Study Group. N Engl J Med. 1996;334:1349-1355.
4. CIBIS-II Investigators and Committees. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet. 1999;353:9-13.
5. 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;353:2001-2007.
6. 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.
7. Poole-Wilson PA, Cleland JG, Di Lenarda 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.
8. Swedberg K. COMET: Results from the Largest and Longest HF Study-Part 2. Hospitalisations and predefined secondary endpoints. Presented as part of the Symposium "Following COMET's Trail-Results and implications of the Largest Head-to-Head Mortality Trial of β-Blockers in Heart Failure" during the 7th Annual Scientific Meeting of the Heart Failure Society of America, September 22-23, 2003, Las Vegas, Nevada.
9. Packer M. Pharmacological Differences of β-blocking Agents. Presented as part of the Symposium "Following COMET's Trail-Results and implications of the Largest Head-to-Head Mortality Trial of β-Blockers in Heart Failure" during the 7th Annual Scientific Meeting of the Heart Failure Society of America, September 22-23, 2003, Las Vegas, Nevada.
10. 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.
11. Sandberg A, Ragnarsson G, Jonsson UE, Sjogren J. Design of a new multiple-unit controlled-release formulation of metoprolol-metoprolol CR. Eur J Clin Pharmacol. 1988;33(Suppl):S3-S7.
12. Kukin ML, Kalman J, Mannino MM, Buchholz-Varley C, Ocampo O. Beta blockade in congestive heart failure: persistent adverse haemodynamic effects during chronic treatment with subsequent doses. Heart. 1997;78:444-449.
13. Kukin ML, Mannino MM, Freudenberger RS, et al. Hemodynamic comparison of twice daily metoprolol tartrate with once daily metoprolol succinate in congestive heart failure. J Am Coll Cardiol. 2000;35:45-50.
14. 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.

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Disclosure
Barry H. Greenberg, MD
Consultant-GlaxoSmithKline;Speakers Bureau-GlaxoSmithKline

Ronald S. Freudenberger, MD
Speakers Bureau-AstraZeneca, GlaxoSmithKline; Stock Shareholder (directly purchased)-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