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

Expert Commentary

Philip A. Poole-Wilson, MD, FRCP, Professor of Cardiology, National Heart and Lung Institute, Faculty of Medicine, Imperial College, London, England

Results presented at the 53rd Annual Scientific Session of the American College of Cardiology provided further insight into the landmark Carvedilol or Metoprolol European Trial (COMET). The new evidence provided support for the primary finding in COMET that carvedilol had superior efficacy compared to metoprolol tartrate in reducing all-cause mortality in heart failure patients. Compared to metoprolol tartrate, the new data showed an improved survival in patients with heart failure as the result of treatment with carvedilol irrespective of blood pressure reduction,1 reduction in baseline heart rate,² and dose administered.³ The use of carvedilol was associated with lower overall costs⁴ and greater improvements in patient-reported quality of life.⁵ Another report presented at this meeting showed that compared to atenolol, the use of carvedilol in myocardial infarction patients was associated with a significant reduction in predefined cardiovascular endpoints with no difference in global or regional ejection fraction.⁶ Together these findings suggest there are important differences among beta-blocking agents which should be considered when prescribing a beta-blocker for a patient with heart failure.

Traditionally, standard therapy for heart failure has consisted of diuretics, digoxin, and angiotensin-converting-enzyme inhibitors. Despite several large clinical trials that indicate that with optimal titration and maintenance strategies, beta-blockers are efficacious and well tolerated in the treatment of heart failure, beta-blockers are still underused. The efficacy of beta-blockers in reducing morbidity and mortality in patients with heart failure has been demonstrated in the United States Carvedilol Trials Program (USCTP),⁷ the Cardiac Insufficiency Bisoprolol Study II (CIBIS-II),⁸ the Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF),⁹ and the Carvedilol Prospective Randomized Cumulative Survival trial (COPERNICUS).¹⁰ The American College of Cardiology/American Heart Association guidelines for the evaluation and management of chronic heart failure recognize beta-blocker therapy as an integral component of heart failure treatment.¹¹

Until recently, few clinical trials had directly compared the relative safety and efficacy of different beta-blockers in the treatment of patients with heart failure. The COMET trial represents the largest and longest head-to-head clinical trial of beta-blockers ever conducted in patients with heart failure.¹² The publication of COMET's primary endpoints showed a 17% relative risk reduction in terms of mortality for carvedilol over metoprolol tartrate. The median survival was prolonged by 1.4 years. An analysis of secondary endpoints indicated that carvedilol produced significant reductions in cardiovascular mortality, death from stroke, and new-onset diabetes compared with patients treated with metoprolol tartrate.¹³

This Cardiology Forum Report(tm) will examine the latest findings from the COMET trial and related data examining the use of carvedilol for heart failure as presented at the 53rd Annual Scientific Session of the American College of Cardiology.

Physiological Effects of Carvedilol and Relationships to Outcome

Carvedilol Better Protects Against Vascular Events than Metoprolol in Heart Failure: Results from COMET

Remme WJ, Cleland JG, Di Lenarda A, et al for the COMET Investigators.

In COMET, carvedilol had a significantly greater benefit on survival compared with metoprolol tartrate in patients with NYHA Class II-IV heart failure with a 20% reduction in cardiovascular mortality (hazard ratio 0.80; 95% Confidence Interval (CI), 0.7–0.9; P = .0004).¹² An analysis was conducted to evaluate the differentiation of cardiovascular death and the possible contribution of vascular event reduction to the beneficial effects observed with carvedilol.¹⁴ Adjudication of cardiovascular causes of death included sudden death, death due to worsening heart failure, fatal stroke, and other cardiovascular causes of death.

According to COMET investigator Willem J. Remme, MD, PhD, Director of the STICARES Cardiovascular Institute, Rhoon, The Netherlands, "The superior cardiovascular survival might reflect a differential effect on vascular function and myocardial ischemia due to the additional beta-2 and alpha-1-blocking properties of carvedilol, in addition to its antioxidant properties. Moreover, long-term treatment with carvedilol has been shown to improve endothelial function." In the Carvedilol Hibernating Reversible Ischaemia Trial: Marker of Success (CHRISTMAS) trial, carvedilol led to greater improvement in cardiac function in hibernating and ischemic myocardium compared to placebo.¹⁵

In COMET, treatment with carvedilol reduced the risk of sudden death by 19% compared to metoprolol tartrate (hazard ratio 0.81; 95% CI, 0.68–0.97; P = .0216). Death due to worsening heart failure was reduced by 17% in carvedilol-treated patients compared to metoprolol tartrate-treated patients although this did not reach statistical significance (hazard ratio 0.83; 95% CI, 0.67–1.02; P = .0702). Vascular event rates were consistently lower in patients treated with carvedilol. Myocardial infarctions were reported in 69 carvedilol-treated patients (resulting in 21 deaths) versus 94 metoprolol tartrate-treated patients (resulting in 36 deaths) (relative risk 0.71; 95% CI, 0.52–0.97; P = .0333) (Table 1). Cardiovascular death or non-fatal myocardial infarction combined was reduced by 19% in carvedilol-treated patients compared to metoprolol tartrate-treated patients (relative risk 0.81; 95% CI, 0.72–0.92; P = .0007). Stroke occurred in 65 patients treated with carvedilol and 80 patients treated with metoprolol tartrate (relative risk 0.79; 95% CI, 0.57–1.10; P = .1632). Although the difference in stroke incidence did not reach statistical significance, the use of carvedilol did significantly reduce the number of deaths that occurred from a stroke (13 vs 38 for carvedilol vs metoprolol tartrate, respectively, relative risk 0.33; 95% CI, 0.18–0.62; P = .0006). The differences between treatments were maintained throughout the duration of the study.

The baseline patient characteristics for each treatment arm did not differ with respect to any factor that could have influenced the risk of cardiovascular death, including heart rate, blood pressure, NYHA functional class, left ventricular ejection fraction, diabetes, history of stroke, or use of cardiovascular medications, Dr. Remme noted. "Nonetheless, the cardiovascular mortality curves began to diverge during the first year of follow-up and continued to separate throughout the study, resulting in a highly significant 20 percent difference in favor of carvedilol at the end of the trial," explained Dr. Remme.

"Carvedilol significantly reduced the major components of cardiovascular death, such as sudden death and heart failure death, compared to metoprolol. In addition, carvedilol reduced the incidence of myocardial infarction and led to significantly less deaths from stroke compared to metoprolol. The reduction in cardiovascular mortality observed with carvedilol was comparable in all patient subgroups and similar to the overall reduction. These results suggest a protective effect against major vascular events with the use of carvedilol."

Beta-blocker Dose Does Not Influence the Beneficial Effects of Carvedilol Compared to Metoprolol in the Patients with Heart Failure: Results from the Carvedilol or Metoprolol European Trial (COMET)

Metra M, Poole-Wilson PA, Cleland JG, et al for the COMET Investigators.

Doses of beta-blockers utilized in clinical practice are typically lower than doses shown to be of benefit in controlled clinical trials. In order to determine whether the observed outcome differences between carvedilol and metoprolol tartrate were directly related to the dose administered, an analysis was conducted to compare the baseline characteristics and outcomes between patients reaching the target doses of carvedilol and metoprolol tartrate and those who did not.³ The target doses for maintenance therapy were carvedilol 25 mg twice daily and metoprolol tartrate 50 mg twice daily.¹⁶

Four months after randomization (end of uptitration), the mean dose of carvedilol was 41.8 ±14.6 mg daily and 85.0 ±28.9 mg daily for metoprolol tartrate, which represented 75% and 78% of carvedilol-treated and metoprolol tartrate-treated patients receiving their target drug dose, respectively. Among those patients who did not reach their target dose, the mean dose of carvedilol was 17.8 mg daily and 33.7 mg daily for metoprolol tartrate.

Compared to those patients not on target dose, patients receiving target doses were younger (61 ±11 years vs 64 ±11 years), with higher systolic and diastolic blood pressure (128 ±19 mm Hg vs 122 ±19 mm Hg and 78 ±11 mm Hg vs 75 ±11 mm Hg, respectively), higher heart rate (82 ±13 beats per minute vs 79 ±13 beats per minute), a higher prevalence of NYHA functional class II symptoms (55% vs 40%) and a lower prevalence of coronary artery disease (48% vs 61%)(all P<.0001).

Overall, failure to receive the target beta-blocker dose was associated with a significantly worse long-term outcome. At 4 months of treatment, the mortality rate in patients on target dose versus patients not receiving target dose was 29.5% and 43.1%, respectively (hazard ratio 0.61, 95% CI, 0.52–0.70; P<.0001). The mortality reduction achieved with carvedilol was similar to metoprolol tartrate in patients on target dose (25.1% vs 31.7% for metoprolol tartrate; hazard ratio 0.76; 95% CI, 0.65–0.90; P = .0014) and in patients not achieving target dose (36.2% vs 45.2% for metoprolol tartrate; hazard ratio 0.75; 95% CI, 0.59–0.96; P = .0233).

In a multivariate analysis of predictors of death (unadjusted), patients who received the target dose of beta-blocker had a relative risk of 0.61 compared to patients not receiving the target dose (95% CI, 0.52–0.70; P<.0001). After adjustment for variables, treatment with the target dose of beta-blocker reduced the relative risk for mortality by 20% (relative risk 0.80; 95% CI, 0.69–0.94; P = .0055). Randomization to carvedilol (versus metoprolol tartrate) also emerged as an independent predictor of lower mortality (relative risk 0.758; 95% CI, 0.653–0.88; P = .0003)

Concluding his presentation, COMET investigator Marco Metra, MD, Institute of Cardiology at the University of Brescia, Brescia, Italy stated, "The survival benefits of carvedilol were consistent and independent of the dose administered. However, administration of target doses of beta-blocker proved to be an independent predictor of reduced mortality risk."

Lack of Heart Rate Effects on the Mortality Benefits of Carvedilol Compared to Metoprolol in Patients with Heart Failure: Results from the Carvedilol or Metoprolol European Trial (COMET)

Cleland JG, Di Lenarda A, Hanrath P, et al for the COMET Investigators.

Similar to the relationship of change in blood pressure on mortality, the relative effect of heart rate on long-term mortality during COMET was unknown. In order to assess the effect of heart rate on the reduction in mortality, an analysis was undertaken to evaluate the relationship between baseline heart rate and early changes in heart rate on long-term mortality.²

Four months after randomization (end of uptitration), the mean heart rate declined by 13.3 beats per minute in carvedilol-treated patients and 11.7 beats per minute in metoprolol tartrate-treated patients (95% CI, -2.7 to -0.6; P<.01). Patients treated with carvedilol maintained a significantly lower mean heart rate at only 2 more visits compared to metoprolol tartrate (8 and 16 months, P<.01 and P<.05, respectively). Among 2,579 patients reassessed at 4 months, significantly more carvedilol-treated patients had a reduction in heart rate >12 beats per minute from baseline than metoprolol-tartrate treated patients (55% vs 50%, respectively, P = .0033).

Multivariate analysis showed that carvedilol reduced mortality by 19% in patients with a baseline heart rate ≤80 beats per minute (95% CI, 1–34%; P = .0468) and by 29% in patients with a baseline heart rate >80 beats per minute (95% CI, 12–43%; P = .0019). Mortality in carvedilol-treated patients was reduced by 22% in patients with a heart rate ≤68 beats per minute at 4 months compared to metoprolol tartrate-treated patients (95% CI, 4–36%; P = .019) and 23% in those patients with a heart rate >68 beats per minute (95% CI, 5–38%; P = .0171). Two independent factors predictive of increased mortality were treatment with study drug (carvedilol vs metoprolol tartrate) (relative risk 0.758, 95% CI, 0.653–0.88; P = .0003) and a heart rate >68 beats per minute at 4 months (relative risk 1.339; 95% CI, 1.15–1.56; P = .0002).

"Neither baseline heart rate or the magnitude of the change in heart rate from baseline to 4 months predicted long-term survival," reported Dr. Metra. "With regard to the relationship of heart rate to long-term patient survival, the results from COMET differ from other studies in that no significant relationship between baseline heart rate or the magnitude of change from baseline and outcome were observed," continued Dr. Metra. "The mortality differences between carvedilol and metoprolol were maintained independently from heart rate, both at baseline and 4 months, as well as changes in heart rate. There was a very consistent reduction in mortality in patients on carvedilol compared to metoprolol in all subgroups, independent of heart rate. Even in multivariate analysis, treatment with carvedilol was associated with a significant reduction in mortality, independent of heart rate," concluded Dr. Metra.

Blood Pressure Changes Do Not Influence the Beneficial Effects of Carvedilol Compared to Metoprolol in the Patients with Heart Failure: Results from COMET (Carvedilol or Metoprolol European Trial)

Metra M, Di Lenarda A, Hanrath P, et al for the COMET Investigators.

The COMET trial has shown that treatment of heart failure with carvedilol resulted in a reduction in all-cause mortality compared with metoprolol tartrate (relative risk 0.83, 95% CI, 0.74–0.93; P = .0017).12 In order to assess the effect of blood pressure on the reduction in mortality, an analysis was undertaken to evaluate the relationship between baseline blood pressure and early changes in blood pressure on long-term mortality.¹

"There has been some question whether the doses of drug used in COMET were appropriate," commented COMET investigator Christian Torp-Pedersen, MD, Cardiologist, University of Copenhagen, Denmark. "There is general agreement that beta-blockers reduce blood pressure and heart rate. If the mortality difference observed in COMET was dependent on the doses utilized, this may be further evaluated by examining the respective blood pressure and pulse-lowering effect of each medication."

Four months after randomization (end of uptitration phase), the mean systolic blood pressure declined from baseline by 3.8 ±17.4 mm Hg in carvedilol-treated patients compared to 2.0 ±17.7 mm Hg in metoprolol tartrate-treated patients (P = .01). Throughout the study period, patients treated with carvedilol maintained a significantly lower systolic blood pressure at most visits and lower mean diastolic blood pressure at 4, 8, 16, 32, 44, and 52 months.

Among 2,589 patients reassessed at 4 months, a change in systolic blood pressure >3 mm Hg (median value) was observed in 53% of carvedilol-treated patients compared to 48% of metoprolol tartrate-treated patients (P = .0049).

The magnitude of the change in systolic blood pressure did not affect survival as the mortality rate was 31% regardless of the change in systolic blood pressure. Mortality was reduced with carvedilol compared to metoprolol tartrate in patients with systolic blood pressure reduction >3 mm Hg (28% vs 34%, respectively), and <3 mm Hg reduction in systolic blood pressure (28% vs 35%, respectively). The analysis indicated no interaction was found between the effect of carvedilol compared to metoprolol tartrate and the change in systolic blood pressure. Multivariate analysis revealed that a systolic blood pressure >120 mm Hg at 4 months was significantly associated with a lower mortality (relative risk 0.801; 95% CI, 0.678–0.948; P<.0098).

Variables associated with increased mortality were increasing age, male sex, heart rate at 4 months, dose of beta-blocker, lower body weight, NYHA functional class, duration of chronic heart failure, lower left ventricular ejection fraction, previous myocardial infarction, history of diabetes, digitalis therapy, anti-arrhythmic therapy, nitrate therapy, absence of lipid-lowering therapy, lower serum hemoglobin levels, lower serum sodium levels, and higher serum creatinine levels.

"We observed blood pressure through 4 months of therapy and our analysis showed that the relative effect of dose on blood pressure lowering does not explain the difference observed between carvedilol and metoprolol in COMET," explained Dr. Torp-Pedersen. "We are not saying that we have completely resolved this discussion, but we have clarified that which we are able to analyze retrospectively."

Exchange of ß-blocking Therapy in Heart Failure Patients. Experiences from the Post Study Phase of COMET (the Carvedilol or Metoprolol European Trial)

Di Lenarda A, Poole-Wilson PA, Cleland JG, et al for the COMET Investigators.

Withdrawal of beta-blockade is associated with worsening heart failure and an increased risk of cardiac arrhythmias. However, limited information exists about the effects of switching treatments of beta-blockers in patients with heart failure. An analysis was conducted to determine the effects of switching beta-blockers in patients enrolled in COMET.¹⁷ Previous data suggest no early adverse events associated with switching from metoprolol tartrate to carvedilol in patients with chronic heart failure.¹⁸

The study design of COMET called for patients to be followed for maintenance therapy up to 74 months, at which point assigned beta-blocker therapy in patients with stable heart failure was stopped without unblinding and down-titration and immediately replaced by a beta-blocker at a dose equivalent to one-half of their study dose. Investigators were free to choose whichever beta-blocker currently available for the treatment of heart failure (carvedilol, metoprolol tartrate/succinate, or bisoprolol) they considered most appropriate for individual patients. Thereafter, uptitration to the target or maximum-tolerated dose was recommended.

"The switching of therapy was designed as part of the procedural close to COMET," explained Andrea Di Lenarda, MD, Cardiologist, Ospedale di Cattinara, Trieste, Italy. "If patients are to be the recipients of the beneficial outcomes observed with carvedilol in COMET, we needed to test the hypothesis that it is safe and effective to move patients from one beta-blocker to another [carvedilol]."

Of the 1,425 (47%) patients who completed the study on beta-blocker therapy, 1,317 (92.4%) were subsequently switched to a post-study beta-blocker. A total of 1,014 (71.2%) patients were switched to carvedilol, 201 (14.1%) patients were switched to metoprolol tartrate/succinate, and 102 (7.2%) patients to bisoprolol. The remaining 108 (7.6%) patients withdrew from beta-blocker therapy. In switching beta-blockers, 61% of patients received an equivalent dose to their study medication, while 37% received the equivalent of one-half the study dose.

As might be expected, patients who stayed on the same beta-blocker (8.7% for carvedilol, 7.4% on metoprolol tartrate) had fewer adverse events compared to those who switched. The incidence of adverse events for patients who switched from metoprolol tartrate to carvedilol was 14.0% compared to 15.1% in patients who switched from carvedilol to metoprolol tartrate/succinate. The incidence of adverse events for patients who discontinued beta-blocker therapy was 22.2%. Similarly, the incidence of serious adverse events (30-day serious adverse events) was lower in patients staying on the same beta-blocker (2.1% for carvedilol, 3.2% for metoprolol tartrate). The incidence of serious adverse events for patients who switched from metoprolol tartrate to carvedilol was 3.1% compared with 9.4% in patients who switched from carvedilol to metoprolol tartrate/succinate and 11.1% in patients withdrawing from beta-blocker therapy.

Adverse events related to heart failure occurred more frequently in patients switched from carvedilol to metoprolol tartrate/succinate (4.7%) than from metoprolol tartrate to carvedilol (2.3%). Bradycardia and hypotension were reported in <1% of patients.

Investigators concluded that switching from one beta-blocker to another without down-titration is practical, safe, and well tolerated for patients with clinically stable heart failure. Switching patients from metoprolol tartrate to carvedilol resulted in fewer adverse events than switching from carvedilol to metoprolol tartrate/succinate.

"The key point from this analysis is that switching patients from metoprolol to carvedilol is safe and the rate of adverse events is low," advised Dr. Di Lenarda.

Retrospective Study of Risks of Death and Hospitalization and Costs of Inpatient Care in Heart Failure Patients Receiving Carvedilol versus Metoprolol Tartrate

Delea TE, Stanford RH, Hagiwara M, Edelsberg JS, Oster G.

The COMET trial demonstrated improved survival with carvedilol versus metoprolol tartrate in patients with heart failure.¹² However, it is unknown whether this benefit exists under the conditions of typical clinical practice.¹⁹ Because the differences in costs of inpatient care were not examined in COMET, a retrospective observational cohort study was conducted to compare the costs of carvedilol and metoprolol tartrate for the inpatient treatment of heart failure, in addition to the risks of death and hospitalization.⁴

According to lead investigator Thomas Delea, PhD, Policy Analysis Associates Inc, Brookline, Massachusetts, data was obtained from a longitudinal claims database of a large private U.S. health insurer. The database included approximately 3 million members, primarily from Midwestern and Southern states and principally enrolled in Health Management Organization or Preferred Provider Organization (HMO/PPO) health plans. The analysis encompassed claims data from September 1997 to August 2000.

The date of the first insurance claim for carvedilol or metoprolol tartrate (but not both) determined the index date for inclusion criteria. Patients were included if, prior to the index date, they had ≥1 medical claim with a primary diagnosis of heart failure, ≥1 pharmacy claim for an angiotensin-converting-enzyme inhibitor, and ≥1 pharmacy claim for a loop diuretic. Patients were excluded for <12 months continuous eligibility prior to the index date and for age <35 years on the index date. Patients were followed until death, disenrollment from the health plan, or until August 2000.

An equal number of carvedilol- and metoprolol tartrate-treated patients (887 each) met all the criteria for inclusion into the study. Baseline characteristics were generally comparable with the exception of higher rates of hypertension (81.4% vs 67.4%; P<.0001) and renal disease (23.2% vs 16.1%; P = .0002) in metoprolol tartrate-treated patients and higher digoxin use (76.2% vs 51.2%; P<.0001) in carvedilol-treated patients. Dr. Delea noted that time to study events were analyzed using Cox regression to control for differences in baseline characteristics between treatment groups. The individual outcomes of the study were all-cause mortality, hospitalization for heart failure, hospitalization for cardiovascular disease, and all-cause hospitalization. Combined study outcomes included all-cause mortality or hospitalization due to heart failure, all-cause mortality or hospitalization due to cardiovascular disease, or all-cause mortality or all-cause hospitalization. Additional outcomes included heart failure-related, cardiovascular-related and total inpatient care costs.

With a mean follow up of 11 months, comparison of outcomes demonstrated significant advantages for carvedilol in reducing the risk for all-cause mortality (16.5% vs 22.1%; hazard ratio 0.78; 95% CI, 0.61–0.98; P = .0359), cardiovascular hospitalization (27.6% vs 36.8%; hazard ratio 0.72, 95% CI, 0.60–0.86; P = .0004), all-cause hospitalization (43.1% vs 54.1%; hazard ratio 0.77; 95% CI, 0.66–0.89; P = .0006), death or cardiovascular hospitalization (36.5% vs 46.7%; hazard ratio 0.76; 95% CI, 0.64–0.89; P = .0007), and death or all-cause hospitalization (48.5% vs 59.3%; hazard ratio 0.79; 95% CI, 0.69–0.91; P = .0011) (Table 2).

Costs of inpatient care were compared for propensity-matched samples, using Kaplan-Meier estimates. After matching patients for baseline characteristics, inpatients costs were analyzed for 1,128 patients (564 patients for both carvedilol and metoprolol tartrate). Over a 3-year period, total costs, as well as costs associated with heart failure and cardiovascular disease, were consistently lower in patients treated with carvedilol. The total inpatient costs associated with carvedilol treatment was $22,401 compared to $32,911 with metoprolol tartrate (absolute difference $10,510). The inpatient cardiovascular and heart failure costs associated with carvedilol treatment were $8,942 and $4,647, respectively, compared to $16,673 and $5,386 with metoprolol tartrate, respectively.

The analysis also examined the dose of beta-blocker utilized in the community practice. In COMET, the target dose for carvedilol was 50 mg/day and 100 mg/day for metoprolol tartrate.¹² However, the mean doses at onset of maintenance therapy were 42 mg/day and 85 mg/day for carvedilol and metoprolol tartrate, respectively.¹² In the analysis, the mean prescribed doses for patients in the database were 24 mg/day for carvedilol and 70 mg/day for metoprolol tartrate and the mean actual doses received were 14 mg/day for carvedilol and 44 mg/day for metoprolol tartrate, well below levels utilized in COMET.

"The benefits of carvedilol observed in COMET were confirmed in this retrospective, observational study," Dr. Delea concluded. "Carvedilol was also associated with substantially lower costs of inpatient care. The results provide additional support for use of carvedilol versus metoprolol in patients with heart failure in the typical community practice."

Quality of Life

Comparison of the Effects of Metoprolol and Carvedilol on Symptoms, Well-being, and Quality-adjusted Life-years: A Description of the 'Patient-journey' in COMET

Cleland JG, Swedberg K, Di Lenarda A, et al for the COMET Investigators.

The objectives of heart failure therapy are to prolong life, avoid morbidity, and improve or maintain patient well-being, noted John G. Cleland, MD, Professor of Cardiology at the University of Hull and Castle Hill Hospital, Kingston-Upon-Hull, United Kingdom.⁵ Although prolonging life and avoiding morbidity are easily quantifiable outcomes, improvements in well-being or quality of life are more difficult to assess. Improved well-being can equate to improvement in symptoms, prevention of symptom worsening, or avoidance of adverse events associated with pharmacologic treatment. To assess the true effect of treatment, survival and quality of life should be evaluated concurrently.

"It is often said that in treating heart failure, we are prolonging death, not prolonging life," stated Dr. Cleland. "It becomes quite difficult to assess the true impact of a treatment on symptoms or quality of life when it alters mortality. Of course, a treatment that alters mortality will tend to have the biggest impact on the sickest patients. So, it is quite important to be able to integrate both longevity and quality into a single measure. In COMET, data was not assessed according to the quality of longevity achieved in the study. In fact, some measures of morbidity, such as hospitalization rates, showed no difference between treatment groups. Such measures often provide a limited and sometimes misleading impression of quality of life and well-being."

In order to assess the quality of life of patients in COMET, investigators employed "the patient-journey" method of assessment.²⁰ This approach involves an evaluation of heart failure therapy that uses a composite of scoring systems to capture changes in a patient's clinical experience and status.

Based on a 5-point scale, patients were reviewed every 4 months for heart failure symptoms and well-being assessment. Adjustments in symptoms were made for time alive, hospitalization and the need for intensified diuretic therapy. Each patient was assigned a "health state" for each day, based on medical records and self-rated well-being assessment. Dr. Cleland noted that the methodology for the analysis was developed before unblinding of the COMET data.

Patient well-being for each period was assumed to be the mean of the symptom score at the beginning and ending of the assessment period. Patients who died of worsening heart failure were assumed to be in the worst state of well-being on the day of death. Patients who died of other causes were assumed to have well-being scores that were unchanged from the prior assessment. The impact of the diuretic dose was based on an increase ≥40 mg/day of furosemide (or equivalent) and by ≥50% compared to baseline. In such cases, the patient well-being score was reduced by one category, a penalty that could be reversed if the patient's diuretic dose was subsequently decreased. The diuretic penalty was assessed only once, regardless of the number of times the dose might be increased.

Treatment with carvedilol showed a non-significant trend over metoprolol tartrate in change of NYHA functional class (baseline 2.6) with improvement at 4 months (-0.30 ±0.59 with carvedilol, -0.28 ±0.57 with metoprolol tartrate) and plateauing at 2 years (-0.42 ± 0.66 with carvedilol, -0.39 ±0.67 with metoprolol tartrate). Importantly, this improvement occurred despite the survival advantage conveyed by carvedilol that would have been expected to prolong life in a larger number of symptomatic patients. Similarly, symptom scores for breathlessness, fatigue and well-being paralleled these changes observed with carvedilol treatment. Patients treated with carvedilol reported feeling "good" or "very good" for approximately 48% of study days (over 4 years) compared with approximately 45% of patients treated with metoprolol tartrate.

"These scores are not adjusted for mortality," advised Dr. Cleland. "If you assume that mortality is the worst possible score, these scores would be highly significant in favor of carvedilol. Treatment with carvedilol resulted in a lower mortality with no increase in the number of hospital days compared to metoprolol. Carvedilol resulted in greater long-term improvement in well-being and an improved patient-journey. If you analyze the data, one in every eight patients switched from metoprolol to carvedilol will have a 10 percent absolute improvement in their patient-journey over four years, which is notionally equivalent to an extra six months of full well-being," concluded Dr. Cleland.

A Comparison of Adverse Events Occurring with Carvedilol or Metoprolol in the Treatment of Heart Failure: Results from COMET

Lutiger B, Poole-Wilson PA, Hanrath P, et al for the COMET Investigators.

In COMET, carvedilol (25 mg twice daily) was shown to reduce mortality compared to metoprolol tartrate (50 mg twice daily) in the treatment of heart failure.¹² An analysis of adverse events might be expected to reflect this advantageous outcome. The additional alpha-1 and beta-2-blocking properties of carvedilol, which possibly contribute to its survival advantage, may also be reflected in the adverse events profile.

Of 1,511 patients treated with carvedilol, 93.6% experienced an adverse event and 73.9% experienced a cardiovascular adverse event.21 Of 1,518 patients treated with metoprolol tartrate, the corresponding figures were 95.9% and 75.8%, respectively. Despite prolonged survival with carvedilol, serious adverse cardiovascular events occurred less frequently with carvedilol than metoprolol tartrate, and included respectively, sudden death (8.9% vs 12.1%; P = .022), myocardial infarction (4.6% vs 6.1%; P = .0461), unstable angina (3.8% vs 4.9%) and stroke (3.4% vs 4.2%) (Table 3).

Adverse events associated with the magnitude of beta-adrenergic blockade (bradycardia, sinus bradycardia, 1st-, 2nd- and 3rd-degree heart block) were comparable between treatment with carvedilol and metoprolol tartrate.

"This finding addresses the discussion that has occurred about the doses we chose to use in this study," explained Principal COMET Investigator Philip A. Poole-Wilson, MD, FRCP Professor of Cardiology, National Heart and Lung Institute, Faculty of Medicine, Imperial College, London, England. "The fact there was no difference in adverse events attributable to the magnitude of beta-adrenergic blockade, assures me that the doses of carvedilol and metoprolol utilized in COMET were, in terms of their effect of beta-blockade, similar."

Adverse events attributed to alpha-1 and beta-2-blockade for metoprolol tartrate and carvedilol, respectively, included hypo-tension (10.5% vs 14.2%; P<.05), dizziness (11.7% vs 12.4%), postural hypotension (1.3% vs 2.6%; P<.05), syncope (6.3% vs 8.2%; P<.05), and peripheral vascular disease (4.7% vs 4.6%). The incidence of bronchospasm and asthma were very low with both carvedilol and metoprolol tartrate (≤0.6%).

"The analysis of this trial is very difficult. Once the mortality endpoint is reached, one cannot experience an adverse event. This results in a bias toward the medication with the highest mortality rate," explained Dr. Poole-Wilson.

Metabolic adverse events (diabetes mellitus, hyperglycemia, hypo- glycemia, hyperkalemia) were comparable between carvedilol and metoprolol tartrate with the exception of hypokalemia that occurred in 2.0% of carvedilol-treated patients compared to 3.2% in metoprolol tartrate-treated patients (P<.05).

"These adverse event rates reflect an expected outcome based on the pharmacological properties of carvedilol and metoprolol," advised Dr. Poole-Wilson. "The lower number of adverse cardiovascular events associated with carvedilol reflects its beneficial effect on mortality," concluded Dr. Poole-Wilson.

Effects of Carvedilol Compared to Atenolol on Ejection Fraction and Clinical Endpoints after Myocardial Infarction

Jonsson G, Abdelnoor M, Mџller C, Kjeldsen SE, Os I, Westheim A.

Beta-blockers reduce mortality and morbidity in post-myocardial infarction patients.^22-26 However, it is not fully understood whether all beta-blockers have similar and favorable cardiovascular effects. In an effort to address this issue, a randomized, prospective clinical study was conducted to compare the effects of carvedilol and atenolol on global and regional left ventricular ejection fraction, in addition to predefined cardiovascular endpoints in post-myocardial infarction patients.⁶ The results of the study were presented by cardiologist Gisli Jonsson, MD, of the Ulleval University Hospital, Oslo, Norway.

A total of 232 patients were randomized to carvedilol 25 mg twice daily (n = 118; mean dosage 36.2 mg/day) or atenolol 50 mg twice daily (n = 114; mean dosage 72.1 mg/day). No difference in baseline patient characteristics such as age, gender, race, smoking, hypertension, diabetes mellitus, or lipid-lowering therapy was observed. Additionally, there were no differences at baseline regarding infarct localization, reperfusion therapy and acute treatment. The global and regional left ventricular ejection fraction were calculated by gated blood pool scintigraphy at baseline, 3 months, and at the end of the study. Dr. Jonsson reported that 82% of patients had ST segment elevation myocardial infarction.

Global left ventricular ejection fraction was similar between the two treatment groups at all assessments. Mean global left ventri-cular ejection fraction with carvedilol was 55 ±11% at baseline, 57 ±10% at 3 months, and 57 ±10% at 12 months versus 53 ±15%, 56 ±10%, and 56 ±9% with atenolol, respectively. Regional left ventricular ejection fraction did not differ between treatment with carvedilol and atenolol, according to Dr. Jonsson.

Despite the similarity in left ventricular ejection fraction, carvedilol-treated patients had significantly fewer serious cardiovascular endpoints, 90 (76.3%) versus 104 (91.2%) in atenolol-treated patients (relative risk 0.84; 95% CI, 0.74-0.94; P = .002). The principal contributor to the difference in endpoints was the composite of cardiovascular death, non-fatal myocardial infarction, and hospitalization due to congestive heart failure.

"Following acute myocardial infarction, treatment with carvedilol was associated with a reduction in combined cardiovascular endpoints compared to atenolol," indicated Dr. Jonsson. "This difference occurred despite similar global and regional left ventricular ejection fractions. The results suggest that mechanisms other than ventricular remodeling account for the difference in clinical effects between carvedilol and atenolol. We don't know what the mechanisms might be, but oxidative stress is one possible explanation. We have observed significant differences in oxidized low-density lipoprotein between carvedilol and atenolol, and that could explain the difference in outcome, but we are still unsure."

References

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Disclosure

Philip A. Poole-Wilson, MD, FRCP
No significant relationships to disclose.

Ronald S. Freudenberger, MD
Grant/Research Support-SCIOS; Speakers Bureau-AstraZeneca, GlaxoSmithKline, Medtronic, Pfizer; Stock Shareholder (directly purchased)-GlaxoSmithKline

This report contains no information on commercial products that are unlabeled for use or investigational uses of products not yet approved.

Medical Journalist: With the exception of the Expert Commentary, the Medical Journalist for this report was Charles Bankhead.

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 Forum Report(tm) does not include discussion of treatment and indications outside of current approved labeling. This Cardiology Forum Report(tm) was made possible through an educational grant from GlaxoSmithKline.

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