Candesartan Cilexetil, a Novel Angiotensin II Antagonist, Provides Dose-dependent Antihypertensive Effect with Maintained Tolerability

Abstract

Candesartan is a new angiotensin II type 1 (AT 1 ) receptor blocker that binds tightly to and dissociates slowly from the AT 1 -receptor. It is administered as a prodrug, candesartan cilexetil, which is completely converted to the active compound, candesartan, during absorption in the gastrointestinal tract. Placebo-controlled studies have shown that candesartan cilexetil is an effective antihypertensive drug. The individual studies, however, lacked the statistical power to assess the dose-response relationship with high precision. A more precise estimate of the effect of different doses may be achieved by pooling similar studies in a meta-analysis. The primary objective of this meta-analysis was to determine the dose-response relationship for the antihypertensive effect of candesartan cilexetil. Six European randomized, double-blind, placebo-controlled, dose-response studies with candesartan cilexetil were reported by 30 September 1996. These studies enrolled similar patients (primary hypertension with a sitting diastolic blood pressure [DBP] of 95-114 mmHg after a placebo run-in period) and had a similar design (parallel groups and fixed doses). The doses investigated ranged from 2 to 16 mg once daily. All doses were not given in every study, but all studies investigated at least two different doses of candesartan cilexetil. The duration of the double-blind phase varied between studies, but was at least 4 weeks (range: 4-12 weeks). The variable of primary interest was sitting DBP measured 24 h after dose (trough effect). Each dose of candesartan was analysed separately, and compared with placebo data only from those studies in which that dose was given. The analysis was performed using an analysis of covariance model. Placebo-corrected estimated mean blood pressure reductions from baseline (randomization) to the end of the study and the 95% confidence intervals for the true mean reductions were calculated for each dose. In total, 1498 hypertensive patients were randomized, of whom 1482 provided efficacy data and were included in the analysis. The vast majority of patients (99%) were of Caucasian origin. The placebo-corrected reductions in sitting DBP and sitting systolic blood pressure (SBP) achieved with the different doses of candesartan cilexetil are shown in the Table. Reductions in blood pressure were dose-related, and age or gender did not influence the antihypertensive effect of candesartan cilexetil. Furthermore, blood pressure reductions achieved in the standing position were similar to those in the sitting position, i.e. there was no indication of an abnormal orthostatic response during treatment with candesartan cilexetil. Heart rate was not significantly influenced by candesartan cilexetil. Adverse events occurred in a similar proportion of patients treated with placebo or candesartan cilexetil and did not increase with the dose. Candesartan cilexetil was equally well tolerated in young and elderly patients and in men and women. Thus, in European patients with mild to moderate hypertension, candesartan cilexetil provides a clinically significant, dose-dependent, antihypertensive effect in doses ranging from 4 to 16 mg once daily. The optimal maintenance doses of candesartan cilexetil appear to be 8 or 16 mg once daily in most patients. © 2000, Informa UK Ltd All rights reserved: reproduction in whole or part not permitted. All rights reserved.