Coreg

[Carvedilol]

Among 839 patients with NYHA class II-III heart failure treated for 26 to 52 weeks in 4 US placebo-controlled trials, average left ventricular ejection fraction (EF) measured by radionuclide ventriculography increased by 9 EF units (%) in COREG patients and by 2 EF units in placebo patients at a target dose of 25-50 mg twice daily. The effects of carvedilol on ejection fraction were related to dose. Doses of 6.25 mg twice daily, 12.5 mg twice daily, and 25 mg twice daily were associated with placebo-corrected increases in EF of 5 EF units, 6 EF units, and 8 EF units, respectively; each of these effects were nominally statistically significant.

Left Ventricular Dysfunction Following Myocardial Infarction:

The basis for the beneficial effects of COREG in patients with left ventricular dysfunction following an acute myocardial infarction is not established.

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Hypertension:

The mechanism by which -blockade produces an antihypertensive effect has not been established.

-adrenoreceptor blocking activity has been demonstrated in animal and human studies showing that carvedilol

(1) reduces cardiac output in normal subjects;

(2) reduces exercise-and/ or isoproterenol-induced tachycardia

(3) reduces reflex orthostatic tachycardia.

Significant -adrenoreceptor blocking effect is usually seen within 1 hour of drug administration.

1-adrenoreceptor blocking activity has been demonstrated in human and animal studies, showing that carvedilol

(1) attenuates the pressor effects of phenylephrine;

(2) causes vasodilation

(3) reduces peripheral vascular resistance.

These effects contribute to the reduction of blood pressure and usually are seen within 30 minutes of drug administration.

Due to the 1-receptor blocking activity of carvedilol, blood pressure is lowered more in the standing than in the supine position, and symptoms of postural hypotension (1.8%), including rare instances of syncope, can occur. Following oral administration, when postural hypotension has occurred, it has been transient and is uncommon when COREG is administered with food at the recommended starting dose and titration increments are closely followed (see DOSAGE AND ADMINISTRATION).
In hypertensive patients with normal renal function, therapeutic doses of COREG decreased renal vascular resistance with no change in glomerular filtration rate or renal plasma flow.

Changes in excretion of sodium, potassium, uric acid, and phosphorus in hypertensive patients with normal renal function were similar after COREG and placebo.

COREG has little effect on plasma catecholamines, plasma aldosterone, or electrolyte levels, but it does significantly reduce plasma renin activity when given for at least 4 weeks. It also increases levels of atrial natriuretic peptide.

CLINICAL TRIALS

Congestive Heart Failure:

A total of 3,946 patients with mild to severe heart failure were evaluated in placebo-controlled studies of carvedilol. In the largest study (COPERNICUS), 2,289 patients with heart failure at rest or with minimal exertion and left ventricular ejection fraction <25% (mean 20%), despite digitalis (66%), diuretics (99%), and ACE inhibitors (89%) were randomized to placebo or carvedilol. Carvedilol was titrated from a starting dose of 3.125 mg twice daily to the maximum tolerated dose or up to 25 mg twice daily over a minimum of 6 weeks. Most subjects achieved the target dose of 25 mg.

The study was conducted in Eastern and Western Europe, the United States, Israel, and Canada. Similar numbers of subjects per group (about 100) withdrew during the titration period. The primary end point of the trial was all-cause mortality, but cause-specific mortality and the risk of death or hospitalization (total, cardiovascular [CV], or congestive heart failure [CHF]) were also examined. The developing trial data were followed by a data monitoring committee, and mortality analyses were adjusted for these multiple looks. 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 – 0.81,
p = 0.0014, adjusted) (see Figure 1). The results of COPERNICUS are shown in Table 1.
Table 1. Results of COPERNICUS
End point Placebo
N = 1,133
Carvedilol
N = 1,156
Hazard ratio
(95% CI)
%
Reduction
Nominal p
value
Mortality 190 130 0.65
(0.52 – 0.81)
35 0.00013

Mortality + all
hospitalization
507 425 0.76
(0.67 – 0.87)
24 0.00004

Mortality + CV
hospitalization
395 314 0.73
(0.63 – 0.84)
27 0.00002

Mortality + CHF
hospitalization
357 271 0.69
(0.59 – 0.81)
31 0.000004

Figure 1. Survival Analysis for COPERNICUS (intent-to-treat)
p = 0. 0014
%
Survival

Carvedilol

Placebo

0 3 6 9 12 15 18 21
Months

100
90
80

60
70

0
The effect on mortality was principally the result of a reduction in the rate of sudden death among patients without worsening heart failure.
Patients' global assessments, in which carvedilol-treated patients were compared to placebo, were based on pre-specified, periodic patient self-assessments regarding whether clinical status post-treatment showed improvement, worsening or no change compared to baseline.

Patients treated with carvedilol showed significant improvements in global assessments compared with those treated with placebo in COPERNICUS. The protocol also specified that hospitalizations would be assessed. Fewer patients on COREG than on placebo were hospitalized for any reason (198 vs. 268, p = 0.0001), for cardiovascular reasons (246 vs. 314, p = 0. 0003), or for worsening heart failure (372 vs. 432, p = 0.0029).

COREG had a consistent and beneficial effect on all-cause mortality as well as the combined end points of all-cause mortality plus hospitalization (total, CV, or for heart failure) in the overall study population and in all subgroups examined, including men and women, elderly and non-elderly, blacks and non-blacks, and diabetics and non-diabetics (see Figure 2).

Figure 2. Effects on Mortality for Subgroups in COPERNICUS
Carvedilol was also studied in five other multicenter, placebo-controlled studies.

Four US multicenter, double-blind, placebo-controlled studies enrolled 1,094 patients (696 randomized to carvedilol) with NYHA class II-III heart failure and ejection fraction <0.35. The vast majority were on digitalis, diuretics, and an ACE inhibitor at study entry. Patients were assigned to the studies based upon exercise ability. An Australia-New Zealand double-blind, placebo-controlled study enrolled 415 patients (half randomized to carvedilol) with less severe heart failure. All protocols excluded patients expected to undergo cardiac transplantation during the 7.5 to 15 months of double-blind follow-up. All randomized patients had tolerated a 2-week course on carvedilol 6.25 mg twice daily.

In each study, there was a primary end point, either progression of heart failure (one US study) or exercise tolerance (two US studies meeting enrollment goals and the Australia-New Zealand study). There were many secondary end points specified in these studies, including NYHA classification, patient and physician global assessments, and cardiovascular hospitalization. Death was not a specified end point in any study, but it was analyzed in all studies.

Other analyses not prospectively planned included the sum of deaths and total cardiovascular hospitalizations. In situations where the primary end points of a trial do not show a significant benefit of treatment, assignment of significance values to the other results is complex, and such values need to be interpreted cautiously. The results of the US and Australia-New Zealand trials were as follows:

Slowing Progression of Heart Failure:

One US multicenter study (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 = 0. 008).

In the Australia-New Zealand study, death and total hospitalizations were reduced by about 25% over 18 to 24 months. In the three largest US studies, death and total hospitalizations were reduced by 19%, 39%, and 49%, nominally statistically significant in the last two studies. The Australia-New Zealand results were statistically borderline.

Functional Measures:

None of the multicenter studies had NYHA classification as a primary end point, but all such studies had it as a secondary end point. There was at least a trend toward improvement in NYHA class in all studies. Exercise tolerance was the primary end point in 3 studies; in none was a statistically significant effect found.

Subjective Measures:

Quality of life, as measured with a standard questionnaire (a primary end point in one study), was unaffected by carvedilol. However, patients' and investigators' global assessments showed significant improvement in most studies.

Mortality:

Overall, in these four US trials, mortality was reduced, nominally significantly so in 2 studies.

Left Ventricular Dysfunction Following Myocardial Infarction:

CAPRICORN was a double-blind study comparing carvedilol and placebo in 1,959 patients with a recent myocardial infarction (within 21 days) and left ventricular ejection fraction of 40%, with (47%) or without symptoms of heart failure. Patients given carvedilol received 6.25 mg twice daily, titrated as tolerated to 25 mg twice daily. Patients had to have a systolic blood pressure >90 mm Hg, a sitting heart rate >60 beats/ minute, and no contraindication to -blocker use.

Treatment of the index infarction included aspirin (85%), IV or oral -blockers (37%), nitrates (73%), heparin (64%), thrombolytics (40%), and acute angioplasty (12%). Background treatment included ACE inhibitors or angiotensin receptor blockers (97%), anticoagulants (20%), lipid-lowering agents (23%), and diuretics (34%). Baseline population characteristics included an average age of 63 years, 74% male, 95% Caucasian, mean blood pressure 121/ 74 mm Hg, 22% with diabetes, and 54% with a history of hypertension.

Mean dosage achieved of carvedilol was 20 mg twice daily; mean duration of follow-up was 15 months.

All-cause mortality was 15% in the placebo group and 12% in the carvedilol group, indicating a 23% risk reduction in patients treated with carvedilol (95% CI 2-40%, p = 0.03), as shown in Figure 3. The effects on mortality in various subgroups are shown in Figure 4. Nearly all deaths were cardiovascular (which were reduced by 25% by carvedilol), and most of these deaths were sudden or related to pump failure (both types of death were reduced by carvedilol). Another study endpoint, total mortality and all-cause hospitalization, did not show a significant improvement.

Figure 3. Survival Analysis for CAPRICORN (intent-to-treat)
Figure 4. Effects on Mortality for Subgroups in CAPRICORN

Hypertension:

COREG was studied in two placebo-controlled trials that utilized twice-daily dosing, at total daily doses of 12.5 to 50 mg. In these and other studies, the starting dose did not exceed 12.5 mg. At 50 mg/ day, COREG reduced sitting trough (12-hour) blood pressure by about 9/ 5.5 mm Hg; at 25 mg/ day the effect was about 7.5/ 3.5 mm Hg. Comparisons of trough to peak blood pressure showed a trough to peak ratio for blood pressure response of about 65%. Heart rate fell by about 7.5 beats/ minute at 50 mg/ day. In general, as is true for other -blockers, responses were smaller in black than non-black patients. There were no age-or gender-related differences in response.

The peak antihypertensive effect occurred 1 to 2 hours after a dose. The dose-related blood pressure response was accompanied by a dose-related increase in adverse effects (see ADVERSE REACTIONS).

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