Published in:
01-03-2005 | Adis Drug Evaluation
Candesartan Cilexetil
A Review of its Use In the Management of Chronic Heart Failure
Authors:
Caroline Fenton, Lesley J. Scott
Published in:
Drugs
|
Issue 4/2005
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Summary
Abstract
Candesartan cilexetil is the orally administered pro-drug of candesartan, a highly selective antagonist of the angiotensin II subtype 1 receptor that mediates the pressor activities of angiotensin II. Candesartan cilexetil is widely used for the treatment of hypertension and has recently been approved in Europe for the treatment of chronic heart failure (CHF) in patients with impaired left ventricular (LV) systolic function.
Results of the CHARM (Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity) programme suggest that oral candesartan cilexetil reduces morbidity and mortality in patients with CHF and LV ejection fraction (LVEF) ≤40%. There are cardiovascular benefits when candesartan cilexetil is administered as an alternative to an ACE inhibitor, or as an add-on to current treatment regimens that include an ACE inhibitor, in symptomatic CHF. While tolerability is generally good, renal monitoring is required. The recent approval of candesartan cilexetil as both add-on and alternative therapy to ACE inhibitors in patients with CHF and impaired LV systolic function recognises the cardiovascular benefits of candesartan cilexetil in both types of treatment regimens.
Pharmacologica Properties
As an angiotensin II-receptor antagonist, candesartan cilexetil acts on the renin-angiotensin-aldosterone system, one of the neurohormonal pathways that is activated in CHF. In patients with CHF not receiving ACE inhibitors, orally administered candesartan cilexetil 8–16mg once daily for up to 43 weeks significantly increased angiotensin II levels, had varying effects on the levels of atrial natriuretic factor and pro-atrial natriuretic peptide and, in combination with enalapril, transiently decreased aldosterone levels.
LVEF, pulmonary capillary wedge pressure and pulmonary artery pressure improved in candesartan recipients with CHF who were not receiving concomitant ACE inhibitors. LVEF also improved with coadministered candesartan plus enalapril and metoprolol. Progressive LV dilatation was reduced with the treatment combination of candesartan and enalapril.
Oral candesartan cilexetil is hydrolysed to candesartan within 1 hour of administration, with oral bioavailability of about 15%. After single or multiple 16mg doses in elderly healthy volunteers, mean times to the maximum plasma concentration (Cmax) were 4.8 and 4.4 hours, and the mean elimination half-life (t1/2β) of a single dose was 12.3 hours. There were no clinically relevant differences between pharmacokinetic parameters in young and elderly healthy volunteers. Most candesartan is eliminated unchanged through urinary and biliary excretion.
Clinically significant differences in pharmacokinetic parameters requiring dosage adjustment occurred with candesartan 12 mg/day (single or multiple doses) in patients with severe renal impairment (increased Cmax, area under the plasma concentration-time curve [AUC] and t12gb values) and after a single dose of 16mg in those with moderate hepatic impairment (increased AUC value).
Therapeutic Efficacy
Oral candesartan cilexetil ≤32mg (mean 23–25mg) once daily significantly improved the combined primary endpoint of cardiovascular death and hospitalisation for worsening CHF in patients with an LVEF ≤40% in CHARM-Added and CHARM-Alternative, two of the three trials in the large (n = 7599) 34- to 41-month CHARM Programme. There was no significant improvement in the same combined primary endpoint in the third component CHARM trial in patients with an LVEF >40% (CHARM-Preserved), although fewer candesartan cilexetil than placebo recipients were admitted for investigator-assessed hospitalisations for worsening CHF (secondary endpoint).
In patients with an LVEF ≤40%, reductions in the combined endpoint were significant compared with placebo whether or not candesartan cilexetil recipients were already receiving ACE inhibitors (CHARM-Added) or were intolerant toACE inhibitors (CHARM-Alternative). In the CHARM-Added trial, the reduction was significant in patients who were receiving a β-adrenoceptor antagonist (β-blocker) at baseline (i.e. triple therapy recipients) and in those receiving the recommended CHF ACE inhibitor dosage, indicating a cardiovascular benefit with maximal neurohormonal blockade.
In patients with CHF and an LVEF ≤40%, cardiovascular deaths and hospitalisations for worsening CHF were significantly less likely with candesartan cilexetil than with placebo, according to results of a prespecified pooled analysis of all patients in the CHARM programme with this degree of LV dysfunction. This analysis demonstrated a decrease in all-cause mortality in candesartan cilexetilversus placebo recipients.
All-cause mortality (primary endpoint) was numerically lower in patients receiving candesartan cilexetil than those receiving placebo in CHARM-Overall (combined results from the three component trials); this did not reach statistical significance. All-cause mortality was affected by the lack of mortality benefit in CHARM-Preserved. Overall, candesartan cilexetil recipients had a higher rate of deaths from cancer than placebo recipients, which contributed to similar non-cardiovascular mortality. However, the incidences of cardiovascular death, hospitalisation for worsening CHF or the combination of these endpoints in CHARM-Overall (secondary endpoints) were significantly lower with candesartan cilexetil than with placebo, as was the incidence of new type 2 diabetes mellitus.
In other trials, candesartan cilexetil significantly improved total exercise time and reduced the likelihood of CHF progression compared with placebo.
Tolerability
Candesartan cilexetil ≤32mg once daily was generally well tolerated, and there was no increase versus placebo in the incidence of cough or angioedema, including in patients previously intolerant to ACE inhibitors. In CHARM-Alternative, in which patients were not receiving ACE inhibitors, the incidence of adverse events with candesartan cilexetil was similar to that with placebo. However, in each of the individual CHARM trials, there were generally significantly more withdrawals for hypotension, increased serum creatinine levels and hyperkalaemia in candesartan cilexetil than placebo recipients, leading to a significantly greater CHARM-Overall withdrawal rate for adverse events in the former (21.0% vs 16.7%) and suggesting that renal monitoring is necessary.