COREG CR Rx

Mild to Moderate Heart Failure (HF)

• Carvedilol was evaluated in patients with mild to moderate HF in 5 multicenter, placebo-controlled trials, and in 1 active-controlled trial (COMET).

• There were 4 US multicenter, double-blind, placebo-controlled trials which included 1094 patients with NYHA II-III HF and ejection fraction less than or equal to 0.35. Most of the patients were on digitalis, diuretics, and an ACE inhibitor at trial entry. There was an Australia-New Zealand double-blind, placebo-controlled trial which included 415 patients with less severe HF. All patients tolerated a 2-week course of carvedilol 6.25mg twice daily. 

• The primary endpoint was either progression of HF (1 US trial) or exercise tolerance (2 US trial and the Australia-New Zealand trial). 

• Slowing Progression of HF:

• One US multicenter trial (366 subjects) had as its primary end point the sum of cardiovascular mortality, cardiovascular hospitalization, and sustained increase in heart failure medications. Heart failure progression was reduced, during an average follow‑up of 7 months, by 48% (P =.008).

• In the Australia‑New Zealand trial, death and total hospitalizations were reduced by about 25% over 18 to 24 months. 

• In the 3 largest U.S. trials, death and total hospitalizations were reduced by 19%, 39%, and 49%, nominally statistically significant in the last 2 trials. The Australia‑New Zealand results were statistically borderline.

• Functional Measures:

• None of the multicenter trials had NYHA classification as a primary end point, but all such trials had it as a secondary end point. There was at least a trend toward improvement in NYHA class in a l trials.

• Subjective Measures: 

• Health-related quality of life, as measured with a standard questionnaire (a primary end point in 1 trial), was unaffected by carvedilol. However, patients' and investigators' global assessments showed significant improvement in most trials.

• Mortality: 

• Death was not a pre-specified end point in any trial but was analyzed in all trials. Overall, in these 4 US trials, mortality was reduced, nominally significantly so in 2 trials.

The COMET Trial

• The COMET trial included 3029 subjects with NYHA class II-IV heart failure (left ventricular ejection fraction less than or equal to 35%) who were randomly assigned to receive either carvedilol (target dose: 25mg twice daily) or immediate-release metoprolol tartrate (target dose: 50mg twice daily). The mean age of the subjects was approximately 62 years, 80% were males, and the mean left ventricular ejection fraction at baseline was 26%. Approximately 96% of the subjects had NYHA class II or III HF.

• The primary end points were all-cause mortality and the composite of death plus hospitalization for any reason.

• All-cause mortality was 34% in the subjects treated with carvedilol and was 40% in the immediate-release metoprolol group (P =.0017; hazard ratio = 0.83, 95% CI, 0.74-0.93). The effect on mortality was primarily due to a reduction in cardiovascular death. The difference between the 2 groups with respect to the composite end point was not significant (P =.122). The estimated mean survival was 8.0 years with carvedilol and 6.6 years with immediate-release metoprolol.

Severe Heart Failure (COPERNICUS)

• The COPERNICUS trial included 2289 patients with HF at rest or with minimal exertion and LVEF <25% (mean 20%), despite digitalis (66%), diuretics (99%) and ACE inhibitors (89%) who were randomly assigned to receive placebo or carvedilol.

• Patients were up-titrated from a starting dose of 3.125mg twice daily to a maximum tolerated dose or up to 25mg twice daily over 6 weeks.

• The primary end point was all-cause mortality, but cause-specific mortality and the risk of death or hospitalization (tota, CV or HF) were also examined.

• The trial was stopped after a median follow‑up of 10 months because of an observed 35% reduction in mortality (from 19.7% per patient-year on placebo to 12.8% on carvedilol; hazard ratio 0.65, 95% CI: 0.52 to 0.81, P =.0014, adjusted).

• The effect on mortality was principally the result of a reduction in the rate of sudden death among subjects without worsening heart failure. 

• Fewer subjects on carvedilol than on placebo were hospitalized for any reason (372 vs 432, P =.0029), for cardiovascular reasons (246 vs 314, P =.0003), or for worsening heart failure (198 vs 268, P =.0001).

Left Ventricular Dysfunction following Myocardial Infarction

• The double-blind CAPICORN trial included 1959 patients with a recent MI (within 21 days) and LVEF of ≤40%, with (47%) or without symptoms of HF. Patients initially received carvedilol at 6.25mg twice daily then titrated as tolerated to 25mg twice daily. Subjects had to have a systolic blood pressure greater than 90 mm Hg, a sitting heart rate greater than 60 beats per minute, and no contraindication to β‑blocker use.

• All‑cause mortality was 15% in the placebo group and 12% in the carvedilol group, indicating a 23% risk reduction in subjects treated with carvedilol (95% CI: 2% to 40%, P =.03).

• There was also a significant 40% reduction in fatal or non-fatal myocardial infarction observed in the group treated with carvedilol (95% CI: 11% to 60%, P =.01). A similar reduction in the risk of myocardial infarction was also observed in a meta-analysis of placebo- controlled trials of carvedilol in heart failure.

Mild to Moderate Heart Failure (HF)

• Carvedilol was evaluated in patients with mild to moderate HF in 5 multicenter, placebo-controlled trials, and in 1 active-controlled trial (COMET).

• There were 4 US multicenter, double-blind, placebo-controlled trials which included 1094 patients with NYHA II-III HF and ejection fraction less than or equal to 0.35. Most of the patients were on digitalis, diuretics, and an ACE inhibitor at trial entry. There was an Australia-New Zealand double-blind, placebo-controlled trial which included 415 patients with less severe HF. All patients tolerated a 2-week course of carvedilol 6.25mg twice daily. 

• The primary endpoint was either progression of HF (1 US trial) or exercise tolerance (2 US trial and the Australia-New Zealand trial). 

• Slowing Progression of HF:

• One US multicenter trial (366 subjects) had as its primary end point the sum of cardiovascular mortality, cardiovascular hospitalization, and sustained increase in heart failure medications. Heart failure progression was reduced, during an average follow‑up of 7 months, by 48% (P =.008).

• In the Australia‑New Zealand trial, death and total hospitalizations were reduced by about 25% over 18 to 24 months. 

• In the 3 largest U.S. trials, death and total hospitalizations were reduced by 19%, 39%, and 49%, nominally statistically significant in the last 2 trials. The Australia‑New Zealand results were statistically borderline.

• Functional Measures:

• None of the multicenter trials had NYHA classification as a primary end point, but all such trials had it as a secondary end point. There was at least a trend toward improvement in NYHA class in a l trials.

• Subjective Measures: 

• Health-related quality of life, as measured with a standard questionnaire (a primary end point in 1 trial), was unaffected by carvedilol. However, patients' and investigators' global assessments showed significant improvement in most trials.

• Mortality: 

• Death was not a pre-specified end point in any trial but was analyzed in all trials. Overall, in these 4 US trials, mortality was reduced, nominally significantly so in 2 trials.

The COMET Trial

• The COMET trial included 3029 subjects with NYHA class II-IV heart failure (left ventricular ejection fraction less than or equal to 35%) who were randomly assigned to receive either carvedilol (target dose: 25mg twice daily) or immediate-release metoprolol tartrate (target dose: 50mg twice daily). The mean age of the subjects was approximately 62 years, 80% were males, and the mean left ventricular ejection fraction at baseline was 26%. Approximately 96% of the subjects had NYHA class II or III HF.

• The primary end points were all-cause mortality and the composite of death plus hospitalization for any reason.

• All-cause mortality was 34% in the subjects treated with carvedilol and was 40% in the immediate-release metoprolol group (P =.0017; hazard ratio = 0.83, 95% CI, 0.74-0.93). The effect on mortality was primarily due to a reduction in cardiovascular death. The difference between the 2 groups with respect to the composite end point was not significant (P =.122). The estimated mean survival was 8.0 years with carvedilol and 6.6 years with immediate-release metoprolol.

Severe Heart Failure (COPERNICUS)

• The COPERNICUS trial included 2289 patients with HF at rest or with minimal exertion and LVEF <25% (mean 20%), despite digitalis (66%), diuretics (99%) and ACE inhibitors (89%) who were randomly assigned to receive placebo or carvedilol.

• Patients were up-titrated from a starting dose of 3.125mg twice daily to a maximum tolerated dose or up to 25mg twice daily over 6 weeks.

• The primary end point was all-cause mortality, but cause-specific mortality and the risk of death or hospitalization (tota, CV or HF) were also examined.

• The trial was stopped after a median follow‑up of 10 months because of an observed 35% reduction in mortality (from 19.7% per patient-year on placebo to 12.8% on carvedilol; hazard ratio 0.65, 95% CI: 0.52 to 0.81, P =.0014, adjusted).

• The effect on mortality was principally the result of a reduction in the rate of sudden death among subjects without worsening heart failure. 

• Fewer subjects on carvedilol than on placebo were hospitalized for any reason (372 vs 432, P =.0029), for cardiovascular reasons (246 vs 314, P =.0003), or for worsening heart failure (198 vs 268, P =.0001).

Left Ventricular Dysfunction following Myocardial Infarction

• The double-blind CAPICORN trial included 1959 patients with a recent MI (within 21 days) and LVEF of ≤40%, with (47%) or without symptoms of HF. Patients initially received carvedilol at 6.25mg twice daily then titrated as tolerated to 25mg twice daily. Subjects had to have a systolic blood pressure greater than 90 mm Hg, a sitting heart rate greater than 60 beats per minute, and no contraindication to β‑blocker use.

• All‑cause mortality was 15% in the placebo group and 12% in the carvedilol group, indicating a 23% risk reduction in subjects treated with carvedilol (95% CI: 2% to 40%, P =.03).

• There was also a significant 40% reduction in fatal or non-fatal myocardial infarction observed in the group treated with carvedilol (95% CI: 11% to 60%, P =.01). A similar reduction in the risk of myocardial infarction was also observed in a meta-analysis of placebo- controlled trials of carvedilol in heart failure.