Summary
Abstract
Carvedilol (Dilatrend®) blocks β1-, β2- and α1-adrenoceptors, and has antioxidant and antiproliferative effects. Carvedilol improved left ventricular ejection fraction (LVEF) in patients with chronic heart failure (CHF) in numerous studies. Moreover, significantly greater increases from baseline in LVEF were seen with carvedilol than with metoprolol in a double-blind, randomised study and in a meta-analysis. Carvedilol also reversed or attenuated left ventricular remodelling in patients with CHF and in those with left ventricular dysfunction after acute myocardial infarction (MI).
Combined analysis of studies in the US Carvedilol Heart Failure Trials Program (patients had varying severities of CHF; n = 1094) revealed that mortality was significantly lower in carvedilol than in placebo recipients. In addition, the risk of hospitalisation for any cardiovascular cause was significantly lower with carvedilol than with placebo. Mortality was significantly lower with carvedilol than with metoprolol in patients with mild to severe CHF in the Carvedilol Or Metoprolol European Trial (COMET) [n = 3029]. The Carvedilol Prospective Randomised Cumulative Survival (COPERNICUS) trial (n = 2289) demonstrated that compared with placebo, carvedilol was associated with significant reductions in all-cause mortality and the combined endpoint of death or hospitalisation for any reason in severe CHF.
All-cause mortality was reduced in patients who received carvedilol in addition to conventional therapy compared with those who received placebo plus conventional therapy in the Carvedilol Post-Infarct Survival Control in LV Dysfunction (CAPRICORN) trial (enrolling 1959 patients with left ventricular dysfunction following acute MI).
Carvedilol was generally well tolerated in patients with CHF. Adverse events associated with the α- and β-blocking effects of the drug occurred more commonly with carvedilol than with placebo, whereas placebo recipients were more likely to experience worsening heart failure.
In conclusion, carvedilol blocks β1-, β2- and α1-adrenoceptors and has a unique pharmacological profile. It is thought that additional properties of carvedilol (e.g. antioxidant and antiproliferative effects) contribute to its beneficial effects in CHF. Carvedilol improves ventricular function and reduces mortality and morbidity in patients with mild to severe CHF, and should be considered a standard treatment option in this setting. Administering carvedilol in addition to conventional therapy reduces mortality and attenuates myocardial remodelling in patients with left ventricular dysfunction following acute MI. Moreover, mortality was significantly lower with carvedilol than with metoprolol in patients with mild to severe CHF, suggesting that carvedilol may be the preferred β-blocker.
Pharmacodynamic Properties
Carvedilol competitively blocks β1-, β2- and α1-adrenoceptors. It is nonselective when administered at target dosages (≥25mg twice daily), does not increase β-adrenoceptor density, is devoid of intrinsic sympathomimetic activity and is not associated with high levels of inverse agonist activity. In patients with chronic heart failure (CHF), carvedilol reduces cardiac adrenergic drive; it is not certain if α1-mediated vasodilation is maintained in the long term.
Long-term carvedilol administration (target dosage 25–50mg twice daily) reduced heart rate in patients with CHF. Carvedilol therapy had minimal effect on blood pressure (BP) in two studies and reduced BP by a significantly greater extent than placebo in two other studies. Pulmonary capillary wedge pressure was reduced from baseline by a significantly greater extent with carvedilol than with placebo or metoprolol. Reductions in systemic vascular resistance were seen in some studies but not in others. Significantly greater increases from baseline in left ventricular ejection fraction (LVEF) were seen in carvedilol than in placebo recipients in numerous randomised studies in patients with CHF. In addition, significantly greater increases from baseline in LVEF were seen with carvedilol than with metoprolol in a double-blind, randomised study and in a meta-analysis. Moreover, carvedilol improved diastolic function in patients with symptomatic heart failure and abnormal diastolic function (patients had normal left ventricular systolic function).
Reductions in left ventricular dimensions were seen in carvedilol recipients with CHF (target carvedilol dosage 12.5–25mg twice daily). In addition, combination therapy with carvedilol and enalapril reduced the left ventricular end-systolic volume index by a significantly greater extent than enalapril alone in the Carvedilol ACE Inhibitor Remodelling Mild Heart Failure Evaluation (CARMEN) trial (in patients with mildly symptomatic heart failure). Left ventricular remodelling was also attenuated by a significantly greater extent in carvedilol than in placebo recipients in substudies of the Carvedilol Post-Infarct Survival Control in LV Dysfunction (CAPRICORN) trial (patients also received conventional therapy) and the Carvedilol Heart Attack Pilot Study (CHAPS) [the substudies included patients with left ventricular dysfunction following acute myocardial infarction (MI)].
Administration of carvedilol was associated with reductions in infarct size following temporary occlusion of a coronary artery and reductions in the frequency of ischaemia-induced arrhythmias in various animal models. Some of this cardioprotective effect may be attributable to the antioxidant activity of carvedilol (thought to reside in its carbazol moiety). In in vitro studies, carvedilol inhibited lipid peroxidation and the oxidation of low-density lipoprotein, and prevented the formation of oxygen radicals and the depletion of endogenous antioxidants. Carvedilol also had antioxidant effects in healthy volunteers, patients with hypertension and patients with hypertension and type 2 diabetes mellitus. In several studies, carvedilol had antioxidant activity in patients with CHF, although conflicting results have been seen (thought to be because of the use of different methods to assess antioxidant effects). In addition, carvedilol had anti-apoptotic effects in vitro and in animal studies.
Carvedilol has several other potentially beneficial pharmacodynamic effects. For example, carvedilol had antiproliferative effects on vascular smooth muscle cells in vitro and in animal studies. In patients with CHF, carvedilol had a vasodilatory effect on the renal vasculature, improved endothelial function, increased plasma vascular endothelial growth factor levels and reduced tumour necrosis factor-α and interleukin-6 levels.
Pharmacokinetic Properties
In healthy volunteers and patients with hypertension, carvedilol is rapidly absorbed following oral administration; peak plasma concentrations (Cmax) generally occur 1–2 hours after administration of an oral dose and increase proportionally with increasing dosages. Carvedilol is highly lipophilic and thus is extensively distributed into extravascular tissues. Carvedilol is >95% protein bound and is extensively metabolised in the liver, predominantly by cytochrome P450 (CYP) 2D6 and CYP2C9. Stereoselective first-pass hepatic metabolism results in more rapid clearance of S(−)-carvedilol than R(+)-carvedilol. The plasma terminal elimination half-life (tv1/2β) of carvedilol after oral administration was reported to range from 7–10 hours.
Plasma carvedilol concentrations were increased in adult patients with CHF compared with volunteers, with 50–100% higher values in patients with New York Heart Association (NYHA) class IV heart failure (carvedilol dosage not stated). The ty1/2β and total body clearance were generally similar between the two groups, suggesting that first-pass metabolism of carvedilol is reduced in patients with severe CHF.
No clinically significant changes in the pharmacokinetics of carvedilol were seen in elderly patients with hypertension and no change in dosage is needed in patients with moderate to severe renal insufficiency. However, Cmax (104 vs 24 μg/L) and absolute bioavailability (83% vs 19%) were significantly higher in patients with liver cirrhosis who received a single dose of carvedilol 25mg than in healthy controls who received the drug; the rate of oral clearance was significantly lower in patients with liver cirrhosis than in controls (25 vs 169 L/h).
The pharmacokinetics of R(+)-carvedilol were altered to a greater extent than those of S(−)-carvedilol after coadministration of carvedilol 25–50mg twice daily and fluoxetine 20 mg/day in patients with CHF; however, the interaction did not appear to be of clinical significance. Pharmacokinetic interactions were also observed between carvedilol and rifampicin (rifampin) or cimetidine (attributable to the effects of these comparator drugs on CYP enzymes) and between carvedilol and digoxin in healthy volunteers or patients with hypertension. Mean trough plasma cyclosporin concentrations were modestly increased in renal transplant recipients with chronic vascular rejection who were receiving cyclosporin and carvedilol.
Therapeutic Efficacy
The US Carvedilol Heart Failure Trials Program comprised four double-blind, randomised, placebo-controlled trials (n = 105–366) that enrolled patients with CHF of ischaemic or nonischaemic aetiology that was of varying severity (NYHA class II–IV). Combined analysis of the studies (n = 1094) revealed that all-cause mortality was significantly lower in carvedilol 12.5–100 mg/day than in placebo recipients (3.2% vs 7.8%; relative risk reduction of 65%; p < 0.001) [only 53 deaths overall]. In addition, the risk of hospitalisation for any cardiovascular cause was significantly lower in carvedilol than in placebo recipients (relative risk reduction of 27%; p = 0.036). Carvedilol therapy was associated with improvement from baseline in NYHA class in two of the studies. No significant improvement in submaximal exercise tolerance was seen in three of the studies, although the 6-minute walk distance increased from baseline to a significantly greater extent in carvedilol than in placebo recipients in the fourth. Retrospective analyses of the US Carvedilol Heart Failure Trials Program data revealed that carvedilol had similarly efficacy in Black and non-Black patients with CHF and was effective in patients with CHF and concomitant atrial fibrillation.
The double-blind, randomised Australia/New Zealand Heart Failure Research Collaborative Group trial compared the use of carvedilol (target dosage 25mg twice daily) with that of placebo in patients (n = 415) with CHF of ischaemic aetiology (NYHA class I–III). No significant difference between carvedilol and placebo recipients was seen with regard to most of the clinical outcomes assessed, although the risk of the combined endpoint of death or hospitalisation (secondary endpoint) was significantly reduced by 26% in carvedilol compared with placebo recipients (p = 0.02).
Nonselective blockade with carvedilol (target dosage 25mg twice daily) was superior to selective β1 blockade with metoprolol (target dosage 50mg twice daily) in patients with mild to severe CHF (n = 3029) in the double-blind, randomised, multicentre Carvedilol Or Metoprolol European Trial (COMET). Mortality was significantly lower with carvedilol than with metoprolol (34% vs 40%; p = 0.0017) [hazard ratio 0.83; 95% CI 0.74–0.93]. The annual mortality rate was 8.3% in carvedilol recipients versus 10.0% in metoprolol recipients.
The Carvedilol Prospective Randomised Cumulative Survival (COPERNICUS) trial demonstrated that compared with placebo, carvedilol 25mg twice daily was associated with significant reductions in the risk of all-cause mortality (by 35%; p = 0.0014 adjusted for interim analyses) and the combined endpoint of death or hospitalisation for any reason (by 24%; p < 0.001) in patients with severe CHF (n = 2289; LVEF ≤25%). The beneficial effect of carvedilol was also seen in the subgroup of patients considered to be at the highest risk (i.e. those with recent or recurrent cardiac decompensation or severely depressed cardiac function). Moreover, the magnitude of benefit obtained during the first 8 weeks in COPERNICUS was similar to that obtained throughout the entire study. Additional analyses of the COPERNICUS data revealed that carvedilol had beneficial effects on other clinical endpoints (e.g. the combined rate of death or hospitalisation for a cardiovascular cause and the combined rate of death or hospitalisation for heart failure) and was effective in both Black and non-Black patients, in patients with and without diabetes mellitus, and in patients who did or did not receive concomitant spironolactone.
Administration of carvedilol (target dosage 25mg twice daily) was of benefit in patients with advanced heart failure who had been referred for heart transplantation. In addition, two studies examined the use of carvedilol in patients with idiopathic dilated cardiomyopathy. In one study, carvedilol compared with placebo recipients had a significantly greater improvement in NYHA class and carvedilol recipients had a significant increase from baseline in submaximal exercise duration. In the other study, the incidence of arrhythmias (ventricular ectopic beats and ventricular couplets) was reduced to a significantly greater extent in carvedilol than in metoprolol recipients. However, peak oxygen consumption decreased with carvedilol but increased with metoprolol (p = 0.03).
In the CAPRICORN trial, carvedilol in combination with conventional therapy reduced mortality and inhibited myocardial remodelling to a greater extent than placebo and conventional therapy in patients with left ventricular dysfunction following acute MI. The double-blind, randomised CAPRICORN trial enrolled 1959 stable patients who had experienced a definite MI in the previous 3–21 days. All-cause mortality (one of the two co-primary endpoints) was reduced in carvedilol 25mg twice daily versus placebo recipients (12% vs 15%; relative risk reduction of 23%; p = 0.031). There was no significant between-group difference in the rate of all-cause mortality or hospitalisation for any cardiovascular reason (35% in carvedilol recipients and 37% in placebo recipients), the second co-primary endpoint. Carvedilol, compared with placebo, was associated with a significantly lower frequency of cardiovascular mortality (11% vs 14%; relative risk reduction of 25%; p = 0.024), recurrent nonfatal MI (3% vs 6%; relative risk reduction of 41%; p = 0.014) and the combined endpoint of all-cause mortality or nonfatal MI (14% vs 20%; relative risk reduction of 29%; p = 0.002). Moreover, several secondary analyses of the CAPRICORN trial showed the beneficial effects of carvedilol therapy on additional clinical endpoints (e.g. supraventricular and ventricular arrhythmias).
Cost Considerations
Reductions in the cost of hospitalisation for heart failure or for any cardiovascular cause were seen in carvedilol compared with placebo recipients in a study using data from the US Carvedilol Heart Failure Trials Program. However, this analysis did not include the acquisition cost of carvedilol or the costs associated with drug monitoring. When these costs were included, carvedilol therapy was still associated with cost savings, although the between-group difference was not statistically significant. A modelling study revealed that carvedilol in combination with digoxin, diuretics and ACE inhibitors was a cost effective option compared with digoxin, diuretics and ACE inhibitors alone (incremental cost of carvedilol per life-year saved of $US29 477 [1997 values]). Moreover, in an analysis of data from COPERNICUS, the estimated overall cost of hospitalisation was £3.49 million and £4.24 million in carvedilol and placebo recipients, respectively, and the estimated overall cost of care following discharge was £479 200 and £548 300 in the corresponding treatment groups (currency year not stated).
Tolerability
Carvedilol was generally well tolerated in patients with CHF in randomised, double-blind, placebo-controlled trials. Adverse events associated with the α- and β-blocking effects of the drug (e.g. dizziness, bradycardia, hypotension) occurred more commonly in carvedilol than in placebo recipients with mild to severe heart failure (statistical analysis not reported). Dizziness occurred most frequently during initiation of treatment with carvedilol or during dosage adjustment but resolved either spontaneously or after adjustment of concomitant therapy. Few carvedilol recipients discontinued therapy because of bradycardia, dizziness or nausea (0.4–0.9%). Placebo recipients were more likely than carvedilol recipients to discontinue therapy because of worsening heart failure (statistical analysis not reported).
In COPERNICUS, significantly fewer carvedilol than placebo recipients had permanently discontinued therapy at 1 year (14.8% vs 18.5%; p = 0.02). Overall, the incidence of serious adverse events was significantly lower with carvedilol than with placebo (39.0% vs 45.5%; p = 0.0016). During the first 8 weeks of COPERNICUS, 4.4% of carvedilol recipients and 5.2% of placebo recipients withdrew for any reason other than death, and a similar proportion of carvedilol and placebo recipients withdrew from the study because of worsening heart failure (0.6% vs 0.7%). This shows that initiation of carvedilol therapy was well tolerated.
Carvedilol had similar tolerability to metoprolol in patients with mild to severe CHF in the double-blind, randomised COMET trial. In a smaller double-blind, randomised trial comparing carvedilol with metoprolol in patients with CHF, the most common adverse events occurring during drug titration were dizziness in carvedilol recipients (14.7%) and worsening heart failure in metoprolol recipients (17.3%). Worsening heart failure (8%), symptomatic bradycardia (4%) and hypotension (2.7%) were also reported in carvedilol recipients and hypotension (2.7%), symptomatic bradycardia (2.7%) and dizziness (1.3%) were reported in metoprolol recipients.
Dosage and Administration
Oral carvedilol is indicated for use in patients with mild to severe heart failure to increase survival and reduce the risk of hospitalisation. It is usually administered in combination with ACE inhibitors and diuretics with or without digoxin. In CHF, treatment with carvedilol should be started at a dosage of 3.125mg twice daily; the dosage should then be titrated at intervals of at least 2 weeks to a maximum dosage of 25mg twice daily (the maximum recommended dosage in patients with mild to moderate heart failure who weigh >85kg is 50mg twice daily). In patients who experience a transient worsening of heart failure, vasodilatory symptoms or fluid retention after starting carvedilol therapy, the dosage of diuretics or ACE inhibitors can be adjusted or carvedilol therapy can be modified or temporarily discontinued.
In the US, carvedilol is also approved for the reduction of cardiovascular mortality in patients who are clinically stable following acute MI and who have an LVEF ≤40%, regardless of whether or not they are symptomatic. In these patients, the recommended starting dosage of carvedilol is 6.25mg twice daily. The dosage may be increased after 3–10 days to 12.5mg twice daily and then to the target dosage (25mg twice daily).
Carvedilol therapy is contraindicated in patients with cardiogenic shock, decompensated heart failure requiring the use of intravenous inotropes, bronchos-pasm or asthma, second or third degree atrioventricular heart block, severe bradycardia (unless fitted with a permanent pacemaker) or sick sinus syndrome. The use of carvedilol in patients with hepatic dysfunction (in the UK) or clinically manifest hepatic impairment (in the US) is also contraindicated. Additional contraindications in the UK include obstructive airways disease, severe hypotension, metabolic acidosis and phaeochromocytoma (unless adequately controlled by α blockade).