Drugs

, Volume 54, Issue 1, pp 161–185

Carvedilol

A Reappraisal of its Pharmacological Properties and Therapeutic Use in Cardiovascular Disorders

Authors

  • Christopher J. Dunn
    • Adis International Limited
    • Adis International Limited
  • Antona J. Wagstaff
    • Adis International Limited
Adis drug Evaluation

DOI: 10.2165/00003495-199754010-00015

Cite this article as:
Dunn, C.J., Lea, A.P. & Wagstaff, A.J. Drugs (1997) 54: 161. doi:10.2165/00003495-199754010-00015

Summary

Synopsis

Carvedilol competitively blocks β1, β2 and α1 receptors. The drug lacks sympathomimetic activity and has vasodilating properties that are exerted primarily through α1-blockade. Animal models indicate that carvedilol confers protection against myocardial necrosis, arrhythmia and cell damage caused by oxidising free radicals, and the drug has no adverse effects on plasma lipid profiles.

Recent data have confirmed the antihypertensive efficacy of carvedilol in patients with mild to moderate essential hypertension. Carvedilol has similar efficacy to other β-blocking agents, calcium antagonists, ACE inhibitors and hydrochlorothiazide. Carvedilol also improves exercise tolerance and ischaemic symptoms in patients with stable angina pectoris. Significant reductions in serious cardiac events after acute myocardial infarction and in frequency and severity of ischaemic events in patients with unstable angina have also been demonstrated.

Interest in the use of carvedilol in patients with congestive heart failure (CHF) has culminated in the publication of a cumulative analysis of data from 1094 patients with mild to severe CHF who participated in the US Carvedilol Heart Failure Study Program (4 trials). After a median follow-up of 6.5 months, a significant overall reduction in mortality relative to placebo (3.2 vs 7.8%) was revealed in patients who had received carvedilol 6.25 to 50 mg twice daily (plus diuretics and ACE inhibitors). All-cause mortality, risk of hospitalisation for cardiovascular reasons and hospitalisation costs were also reduced significantly (by 65, 28% and 62%, respectively) in these trials. In addition, the Australia and New Zealand Heart Failure Research Collaborative Group showed a 26% reduction in the combined risk of death or hospitalisation with carvedilol 12.5 to 50 mg/day relative to placebo after a mean 19-month follow-up period in 415 patients with CHF (relative risk 0.74).

Adverse events with carvedilol appear to be less frequent than with other β-blocking agents, are dosage-related and are usually seen early in therapy. Events most commonly reported are related to the vasodilating (postural hypotension, dizziness and headaches) and the β-blocking (dyspnoea, bronchospasm, bradycardia, malaise and asthenia) properties of the drug. Carvedilol appears to date to have little effect on the incidence of worsening heart failure. Concomitant administration of carvedilol with some medications requires monitoring.

Carvedilol is therefore likely to have a beneficial role in the management of controlled CHF, but further clinical studies are required to show the place of β-adrenoceptor blocking therapy in general in this indication, and the position of carvedilol relative to other similar agents. Carvedilol is also confirmed as effective in the management of mild to moderate hypertension and ischaemic heart disease.

Pharmacodynamic Properties

Carvedilol competitively blocks β1, β2 and α1 adrenoceptors, lacks sympathomimetic activity and has vasodilating properties exerted mainly through α1-blockade. Single oral doses of carvedilol 12.5 to 200mg reduce SBP and DBP with no reflex tachycardia. Significant reductions in blood pressure have been reported, starting 30 minutes after administration, with maximal decreases at 1.5 to 7 hours. Exercise-induced increases in SBP and heart rate are attenuated by the drug, and stroke index and cardiac index are preserved after single doses of 20 to 60mg in healthy volunteers. Cardiac index was reduced after carvedilol 25 mg/day for 6 to 9 months in patients with hypertension.

Carvedilol has been associated with improved myocardial function, particularly improvements in afterload (left ventricular ejection fraction) and decreased left ventricular volumes in patients with left ventricular dysfunction, and regression of left ventricular hypertrophy in patients with mild to moderate essential hypertension.

Carvedilol has demonstrated protective effects against myocardial necrosis and arrhythmia and against cell damage caused by oxidising free radicals in several animal models. The drug also does not adversely affect renal function at dosages of up to 50 mg/day, has antiproliferative effects on intimai tissue and does not affect plasma lipid profiles. Increased insulin sensitivity has been reported with carvedilol 25 to 50 mg/day in a 12-week study in patients with mild to moderate essential hypertension.

Pharmacokinetic Properties

Oral carvedilol shows predominantly linear pharmacokinetics. Absolute oral bioavailability is 20 to 25% and peak plasma concentrations (Cmax) are seen 1 to 2 hours after administration. The terminal elimination half-life has ranged from 2 to 8 hours in clinical studies. There are no significant age-related variations in the pharmacokinetic properties of the drug. Carvedilol is highly lipophilic and protein bound. No dosage alterations are required in patients with renal failure. However, patients with liver dysfunction show stereoselective alterations in metabolism of the drug; this may affect the balance between β- and α-adrenergic effects.

Therapeutic Use

The antihypertensive efficacy of carvedilol 25 to 50 mg/day in patients with mild to moderate essential hypertension is well established. Recent comparative trials have confirmed earlier findings and show carvedilol to be of equivalent efficacy to other antihypertensive agents (notably atenolol, labetalol, pindolol, metoprolol, nitrendipine, hydrochlorothiazide and captopril). A 29-week comparison of carvedilol 12.5 to 50 mg/day with enalapril 10 to 40 mg/day showed similar antihypertensive response rates and quality-of-life effects for both drugs. Enalapril reduced SBP by 5 to 10mm Hg more than carvedilol in this study.

Confirmation of the ability of carvedilol to improve ischaemic and exercise parameters in patients with stable angina pectoris has also been obtained. Carvedilol 25mg twice daily has similar efficacy to nifedipine 20mg twice daily or verapamil 120mg 3 times daily. Angina attack frequency and nitroglycerin (glyceryl trinitrate) consumption were reduced significantly in both groups in the 4-week comparison with nifedipine. In the verapamil study, mean total treadmill exercise time was increased relative to baseline by 15.3% with carvedilol and 13.5% with verapamil.

Intravenous plus oral carvedilol has been associated with significant clinical benefit in a placebo-controlled 6-month study in 151 patients with acute myocardial infarction. Significantly fewer serious cardiac events were associated with carvedilol treatment [17 vs 31 events].

Significant reductions in the frequency and severity of ischaemic events have been reported with carvedilol (50 mg/day for 48 hours) in patients with unstable angina. However, clinical efficacy of the drug in the prevention of restenosis after coronary angioplasty has not been conclusively shown.

Since the publication of the previous review in Drugs in 1993, interest in carvedilol has focused on the potential utility of the drug in congestive heart failure (CHF). A cumulative analysis of data from 1094 patients with mild to severe CHF [New York Heart Association (NYHA) classifications II to IV] who participated in a stratified programme of 4 US clinical studies (the US Carvedilol Heart Failure Study Program) has shown a significant overall reduction in mortality relative to placebo (3.2 vs 7.8%) in patients who received carvedilol 6.25 to 50mg twice daily (plus diuretics and ACE inhibitors) after the programme was terminated early (median follow-up 6.5 months) because of the clear benefit associated with carvedilol treatment. Thus, the risk of death was (significantly) reduced by carvedilol therapy (65% reduction compared with placebo). There was also a significant 28% overall reduction in the risk of hospitalisation for cardiovascular reasons across the 4 trials, and a decrease of 62% in the costs of hospitalisation. Preliminary data from a nonblind follow-up (mean 270 days) in 899 patients from the studies suggest that these survival benefits are maintained with continuing treatment. Results from the mean 19-month follow-up period of another large trial (the Australia and New Zealand Heart Failure Research Collaborative Group’s study in 415 patients with CHF secondary to ischaemic heart disease) showed a 26% reduction in the combined risk of death or hospital admission (all reasons) with carvedilol 12.5 to 50 mg/day relative to placebo.

Improvements in NYHAclass were seen in 5 of the 8 published well controlled studies of carvedilol in patients with heart failure. In contrast, improved ventricular function but no improvements in exercise capacity or NYHA classification were reported after 12 months in the Australia and New Zealand study. Carvedilol had a beneficial effect on disease progression in most well controlled studies.

Tolerability

Adverse events with carvedilol therapy are dosage-related, tend to be seen early in therapy, and are reported to have a lower incidence than is seen with other β-blocking agents. Events most commonly reported are postural hypotension, dizziness and headache (related to the vasodilating properties of the drug) and dyspnoea, bronchospasm, bradycardia, malaise and asthenia (related to β-blockade). From the data published to date, carvedilol appears to have little effect on the incidence of worsening heart failure.

Dosage and Administration

A dosage of carvedilol 12.5mg once daily for 2 days, increased to 25mg daily thereafter and increased to 50mg once daily after 2 weeks if necessary, is recommended for patients with mild to moderate essential hypertension. In patients with stable angina pectoris, a dosage of 25 to 50mg twice daily appears to be appropriate. In patients with controlled CHF, the dosage should be titrated gradually upwards from 3.125 mg twice daily to a maintenance dosage of 25mg twice daily (50mg twice daily if bodyweight is >85kg). No dosage adjustment is required in patients with renal failure. The drug is contraindicated in patients with second or third degree heart block, shock, severe bradycardia, asthma, decompensated heart failure, hepatic impairment or chronic obstructive pulmonary disease. Care should be taken when administering carvedilol to elderly patients, as they are particularly prone to orthostatic hypotension. Drug interactions with β-blocking agents are common but avoidable with regular monitoring where appropriate.

Copyright information

© Adis International Limited 1997