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Carvedilol
See also Beta-adrenoceptor antagonists
General information
Carvedilol is a highly lipophilic non-selective beta-adrenoceptor antagonist with alpha1-blocking action, promoting peripheral vasodilatation. It also has free radical scavenging and antimitogenic effects.
The safety and tolerability profile of carvedilol in heart failure appears to be reassuring [ ]. In trials in patients with congestive heart failure, carvedilol was withdrawn in only about 5% [ ]. The most common adverse reactions were edema, dizziness, bradycardia, hypotension, nausea, diarrhea, and blurred vision. The rate of drug withdrawal was not different among patients under 65 years and among older ones.
The largest trial of carvedilol in patients with heart failure documented only a 5% withdrawal rate in 1197 patients during the open phase that preceded randomization. The major reasons for withdrawal were worsening heart failure (2%), dizziness (1.1%), bradycardia (0.2%), and death (0.5%). Overall, 78% of the patients who entered the trial and were randomized to carvedilol achieved the target dose of 50 mg/day, and withdrawal rates were comparable with carvedilol and placebo (11–14% over 6.5 months of treatment).
The issue of tolerability is particularly important in patients with severe heart failure (NYHA class IV). Unfortunately, so far all trials with carvedilol have failed to recruit a large number of such patients. A retrospective analysis of the tolerability profile of carvedilol in 63 patients with NYHA class IV heart failure showed that non-fatal adverse events while taking carvedilol were more frequent than in patients with class II–III heart failure (43% versus 24%) and more often resulted in permanent withdrawal of the drug (25% versus 13%) [ ]. However, 59% of the patients with class IV heart failure improved by one or more functional class after 3 months of treatment. The conclusion was that carvedilol is a useful adjunctive therapy for patients with NYHA class IV heart failure, but these patients require close observation during the start of treatment and titration of the dose.
In patients with heart failure, amiodarone is often required for the treatment of serious ventricular dysrhythmias. The beneficial effects of carvedilol on left ventricular remodeling, systolic function, and symptomatic status were not altered by amiodarone in 80 patients with heart failure. Adverse effects that necessitated withdrawal of carvedilol were no more frequent in patients taking amiodarone than in those taking carvedilol alone (26% versus 25%) [ ].
In 10 patients with gastroesophageal varices, none having bled, treated with oral carvedilol 12.5 mg/day for 4 weeks, hemodynamic measurements were performed before the first administration and at 1 hour and 4 weeks after [ ]. After acute administration, the hepatic venous pressure gradient was significantly reduced by 23% (from 16.4 to 12.6 mmHg), with a significant reduction in heart rate. After 4 weeks, the hepatic venous pressure gradient was further significantly reduced to 9.3 mmHg. Carvedilol was well tolerated, and only one patient had asymptomatic hypotension. The results of this study suggest that low-dose carvedilol significantly reduces portal pressure without significantly systemic hemodynamic effects. The reduction in portal pressure with carvedilol was larger than that obtained with propranolol, encouraging specific trials of carvedilol for the primary prevention of variceal hemorrhage.
Organs and systems
Cardiovascular
Since the adrenergic system is activated to support reduced contractility of the failing heart, the administration of a beta-blocker in a patient with heart failure can cause myocardial depression. This effect is more marked with non-selective first-generation beta-blockers, such as propranolol. Carvedilol has an acceptable tolerability profile, reducing after-load and thus counteracting the negative inotropic properties of adrenoceptor blockade. While these vasodilatory properties can play a favorable role at the start of treatment, it is less likely that vasodilatation can make a substantial contribution to the long-term effects of third-generation beta-blockers.
Beta-blockers are life-saving in adults with heart failure, but little is known about their value in children and adolescents. The effects of carvedilol, target dose 0.2 or 0.4 mg/kg, in children and adolescents with symptomatic systemic ventricular systolic dysfunction have been prospectively evaluated in a multicenter, double-blind, randomized, placebo-controlled study in 161 children and adolescents [ ]. There was no statistically significant difference between the groups in the composite primary end-point based on the percentage of patients who improved, worsened, or were unchanged. More than 90% of the patients reported at least one adverse event, the most common being upper respiratory tract infections, vomiting, and cough, without differences between placebo and carvedilol. There was worsening heart failure in 11% of the patients in both groups. At variance with results in adults, carvedilol did not significantly improve heart failure outcomes in children and adolescents.
There are concerns about the risks of starting beta-blockers in patients with heart failure, specifically those with severe impairment. The database of the COPERNICUS study, which tested the effects of carvedilol in patients with advanced heart failure, has been evaluated in order to assess the rates of death, hospitalizations, and permanent withdrawal of carvedilol in the first 8 weeks from the start of treatment [ ]. The patients allocated to carvedilol did not have any significant increase in cardiovascular risk compared with those randomized to placebo and carvedilol was associated with fewer deaths, hospitalizations, and drug withdrawals. These data suggest that in patients with advanced heart failure the benefit to harm balance in the first 2 months of treatment is similar to that observed during long-term therapy. These findings should encourage clinicians to use carvedilol in such patients.
Carvedilol has been evaluated in patients with heart failure [ ]. In more than 50% of the patients given carvedilol the dosage could be titrated up to the maximum (50 mg/day). The major reason for missing the target dose was hypotension followed by bradycardia. Carvedilol had to be withdrawn in 21/316 patients (6.6%), in 14 (4.4%) for cardiovascular reasons: six with worsening heart failure, five with hypotension, two with syncope, and one with bradycardia. The most frequent non-cardiovascular reason for withdrawal was chronic obstructive pulmonary disease. Age did not influence tolerability: the rate of discontinuation was similar in patients aged 70 years or older and in younger patients. These data have confirmed in a real clinical context what controlled studies have shown, that carvedilol is generally well tolerated and that the maximum target dose can be reached in a relevant number of patients irrespective of age and severity of heart failure.
As with other alpha-blockers, postural hypotension is quite common with carvedilol, especially in elderly people [ ]. In a comparison of carvedilol with pindolol in elderly patients, postural hypotension occurred even with small doses of carvedilol (12.5 mg) [ ]. The authors concluded that lower starting doses should be used in elderly people, in patients taking diuretics, and in patients with heart failure.
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