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Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the carvedilol or metoprolol european trial (COMET): randomized controlled trial
Heart Failure/Transplant
additional benefit of carvedilol is unrelated to 1 blockade. Carvedilol now appears to be the beta-blocker of choice in chronic heart failure. KA
Abstracts
Comparison of Carvedilol and Metoprolol on Clinical Outcomes in Patients with Chronic Heart Failure in The Carvedilol or Metoprolol European Trial (COMET): Randomized Controlled Trial
Hemodynamic and Clinical Effects of Tezosentan, an Intravenous Dual Endothelin Receptor Antagonist, in Patients Hospitalized for Acute Decompensated Heart Failure
Poole-Wilson PA, Swedberg K, Cleland JGF, et al., for the COMET Investigators. Lancet 2003;362:7–13.
Torre-Amione G, Young JB, Colucci WS, et al. J Am Coll Cardiol 2003;42:140 –7.
Study Question: Does treatment with carvedilol or with metoprolol tartrate result in better clinical outcomes? Methods and Results: In a multicenter, double-blind and randomized parallel group trial, the authors assigned 1511 patients with chronic heart failure to treatment with carvedilol (target dose 25 mg twice daily) and 1518 to metoprolol (metoprolol tartrate, target dose 50 mg twice daily). Patients were required to have chronic heart failure (NYHA II–IV), previous admission for a cardiovascular reason, an ejection fraction of less than 35% and to have been treated optimally with diuretics and angiotensin-converting enzyme inhibitors unless not tolerated. The primary end points were all-cause mortality and the composite end point of all-cause mortality or all-cause admission. Analysis was done by intention to treat. The mean study duration was 58 months (SD 6). The mean ejection fraction was 0.26 (0.07) and the mean age 62 years (11). The all-cause mortality was 34% (512 of 1511) for carvedilol and 40% (600 of 1518) for metoprolol (hazard ratio 0.83 [95% CI 0.74 – 0.93], p⫽0.0017). The reduction of all-cause mortality was consistent across predefined subgroups. The composite end point of mortality or all-cause admission occurred in 1116 (74%) of 1511 on carvedilol and in 1160 (76%) of 1518 on metoprolol (0.94 [0.86 –1.02], p⫽0.122). Incidence of side-effects and drug withdrawals did not differ by much between the two study groups. Conclusions: The authors concluded that carvedilol extends survival compared with metoprolol. Perspective: Beta-blockers reduce mortality in patients with LV systolic dysfunction and chronic heart failure. This study, the first large RCT in chronic heart failure to directly compare two drugs of the same class, showed lower mortality with carvedilol, a nonselective beta-blocker with alpha1 blocking, antiendothelin and antioxidant properties, than with metoprolol tartrate (“short-acting” metoprolol) a 1-selective beta-blocker. The annualized death rate was reduced from 10% with metoprolol to 8.3% with carvedilol. While some have argued that the metoprolol dosing was too low, the two drugs reduced resting heart rate similarly at nearly all time points and have reduced exercise heart rate (the best measure of 1 blockade) similarly when given at these doses in prior studies, suggesting that the
Study Question: What is the short-term efficacy and safety of intravenous tezosentan, a dual endothelin-receptor antagonist, in patients hospitalized for acute heart failure? Methods & Results: In a double-blind fashion, 292 patients (cardiac index ⱕ2.5 l/min per m2 and pulmonary capillary wedge pressure (PCWP) ⱖ15 mm Hg) were randomized to 24-hour intravenous treatment with tezosentan (50 or 100 mg/h) or placebo. Central hemodynamic variables, the dyspnea score and safety variables were measured. After 6 hours of treatment, significantly greater increases in the cardiac index and decreases in PCWP were observed with both tezosentan dosages than with placebo (mean treatment effects at 0.38 and 0.37 l/min per m2 with 50 and 100 mg/h and ⫺3.9 mm Hg for each dose, respectively; p⬍0.0001). This effect was maintained during the remaining infusion and for ⱖ6 h after treatment cessation. A tendency for an improved dyspnea score and a decreased risk of clinical worsening was observed after 24 hours of treatment with each tezosentan dose. Adverse events, more frequent with tezosentan than with placebo (headache, asymptomatic hypotension, early worsening of renal function, nausea, vomiting) were dose related. Conclusions: Intravenous tezosentan rapidly and effectively improved hemodynamics in these patients. The similar beneficial effects of the two dosages and the increased dose-related adverse events with the higher dosage suggest that the optimal dosing regimen is ⬍50 mg/h. Perspective: A trend toward clinical improvement at 24 hours and, in a post hoc analysis, at 28 days must be considered in the context of an earlier worsening of renal function, and the deterioration in renal function observed in an earlier study in acute heart failure. The hemodynamic improvements achieved with tezosentan complement those previously demonstrated in patients with stable chronic HF. However, the past two decades of drug trials have shown no predictable relationship between drug-induced acute hemodynamic improvements and intermediate or long-term outcomes. We need outcome studies before we can be sure of a true benefit. KA
ACC CURRENT JOURNAL REVIEW Sep/Oct 2003
45
additional benefit of carvedilol is unrelated to 1 blockade. Carvedilol now appears to be the beta-blocker of choice in chronic heart failure. KA
Abstracts
Comparison of Carvedilol and Metoprolol on Clinical Outcomes in Patients with Chronic Heart Failure in The Carvedilol or Metoprolol European Trial (COMET): Randomized Controlled Trial
Hemodynamic and Clinical Effects of Tezosentan, an Intravenous Dual Endothelin Receptor Antagonist, in Patients Hospitalized for Acute Decompensated Heart Failure
Poole-Wilson PA, Swedberg K, Cleland JGF, et al., for the COMET Investigators. Lancet 2003;362:7–13.
Torre-Amione G, Young JB, Colucci WS, et al. J Am Coll Cardiol 2003;42:140 –7.
Study Question: Does treatment with carvedilol or with metoprolol tartrate result in better clinical outcomes? Methods and Results: In a multicenter, double-blind and randomized parallel group trial, the authors assigned 1511 patients with chronic heart failure to treatment with carvedilol (target dose 25 mg twice daily) and 1518 to metoprolol (metoprolol tartrate, target dose 50 mg twice daily). Patients were required to have chronic heart failure (NYHA II–IV), previous admission for a cardiovascular reason, an ejection fraction of less than 35% and to have been treated optimally with diuretics and angiotensin-converting enzyme inhibitors unless not tolerated. The primary end points were all-cause mortality and the composite end point of all-cause mortality or all-cause admission. Analysis was done by intention to treat. The mean study duration was 58 months (SD 6). The mean ejection fraction was 0.26 (0.07) and the mean age 62 years (11). The all-cause mortality was 34% (512 of 1511) for carvedilol and 40% (600 of 1518) for metoprolol (hazard ratio 0.83 [95% CI 0.74 – 0.93], p⫽0.0017). The reduction of all-cause mortality was consistent across predefined subgroups. The composite end point of mortality or all-cause admission occurred in 1116 (74%) of 1511 on carvedilol and in 1160 (76%) of 1518 on metoprolol (0.94 [0.86 –1.02], p⫽0.122). Incidence of side-effects and drug withdrawals did not differ by much between the two study groups. Conclusions: The authors concluded that carvedilol extends survival compared with metoprolol. Perspective: Beta-blockers reduce mortality in patients with LV systolic dysfunction and chronic heart failure. This study, the first large RCT in chronic heart failure to directly compare two drugs of the same class, showed lower mortality with carvedilol, a nonselective beta-blocker with alpha1 blocking, antiendothelin and antioxidant properties, than with metoprolol tartrate (“short-acting” metoprolol) a 1-selective beta-blocker. The annualized death rate was reduced from 10% with metoprolol to 8.3% with carvedilol. While some have argued that the metoprolol dosing was too low, the two drugs reduced resting heart rate similarly at nearly all time points and have reduced exercise heart rate (the best measure of 1 blockade) similarly when given at these doses in prior studies, suggesting that the
Study Question: What is the short-term efficacy and safety of intravenous tezosentan, a dual endothelin-receptor antagonist, in patients hospitalized for acute heart failure? Methods & Results: In a double-blind fashion, 292 patients (cardiac index ⱕ2.5 l/min per m2 and pulmonary capillary wedge pressure (PCWP) ⱖ15 mm Hg) were randomized to 24-hour intravenous treatment with tezosentan (50 or 100 mg/h) or placebo. Central hemodynamic variables, the dyspnea score and safety variables were measured. After 6 hours of treatment, significantly greater increases in the cardiac index and decreases in PCWP were observed with both tezosentan dosages than with placebo (mean treatment effects at 0.38 and 0.37 l/min per m2 with 50 and 100 mg/h and ⫺3.9 mm Hg for each dose, respectively; p⬍0.0001). This effect was maintained during the remaining infusion and for ⱖ6 h after treatment cessation. A tendency for an improved dyspnea score and a decreased risk of clinical worsening was observed after 24 hours of treatment with each tezosentan dose. Adverse events, more frequent with tezosentan than with placebo (headache, asymptomatic hypotension, early worsening of renal function, nausea, vomiting) were dose related. Conclusions: Intravenous tezosentan rapidly and effectively improved hemodynamics in these patients. The similar beneficial effects of the two dosages and the increased dose-related adverse events with the higher dosage suggest that the optimal dosing regimen is ⬍50 mg/h. Perspective: A trend toward clinical improvement at 24 hours and, in a post hoc analysis, at 28 days must be considered in the context of an earlier worsening of renal function, and the deterioration in renal function observed in an earlier study in acute heart failure. The hemodynamic improvements achieved with tezosentan complement those previously demonstrated in patients with stable chronic HF. However, the past two decades of drug trials have shown no predictable relationship between drug-induced acute hemodynamic improvements and intermediate or long-term outcomes. We need outcome studies before we can be sure of a true benefit. KA
ACC CURRENT JOURNAL REVIEW Sep/Oct 2003
45