Phase IV, 8-week, multicenter, randomized, active treatment-controlled, parallel group, efficacy, and tolerability study of high-dose candesartan cilexetil combined with hydrochlorothiazide in korean adults with stage II hypertension

Objective: The objective of this study was to evaluate the efficacy and tolerability of high-dose (32 mg) candesartan in Asians. Methods: In Korean adult patients with stage II hypertension, we evaluated the efficacy and tolerability of candesartan 16 mg/hydrochlorothiazide (HCT) 12.5 mg and candesartan 32 mg/HCT 12.5 mg compared with candesartan 16-mg and 32-mg monotherapy, respectively. This Phase IV, 8-week, multicenter, randomized, active treatment-controlled, parallel group, efficacy, and tolerability study, named CAESAR (Candesartan Effect in Second Stage Arterial Hypertension), enrolled 253 patients with stage II hypertension. Treatment started with either candesartan 16 mg or candesartan 16 mg/HCT 12.5 mg. After 4 weeks, the candesartan dose was forced titrated to 32 mg in both groups. The primary and secondary objectives were to compare the blood pressure (BP) changes after 4 weeks and 8 weeks between candesartan-HCT combination therapy and candesartan monotherapy. The proportion of patients achieving target BP (systolic blood pressure [SBP] <140 mm Hg, but <130 mm Hg for patients with diabetes mellitus or chronic kidney disease; diastolic blood pressure (DBP) <90 mm Hg, but <80 mm Hg for those with diabetes mellitus or chronic kidney disease) after 4 and 8 weeks of therapy was also evaluated. Adverse events were investigated both by spontaneous report by the patient and by the investigators' evaluations in each visit. Laboratory tests were performed at the end of the study to evaluate drug tolerability. Results: Study patients were all Asians, mostly male (65.7%), with a mean (SD) age of 49.4 (10.6) years and a mean body weight of 68.9 (12.1) kg; there were no between-group variances in demographic profiles except that the mean age in the candesartan-HCT group (51.0 [10.2] years) was about 3.2 years higher than that in the candesartan monotherapy group (47.8 [10.7] years; P = 0.02) despite random allocation. A total of 80.4% of the study patients had not been treated before, whereas 19.6% were previously treated and enrolled after 2 weeks of washout period. Baseline sitting systolic/diastolic BPs (SBP/DBP) were 160.7 (13.0)/104.6 (9.5) mm Hg. After 4 weeks, patients treated with candesartan 16 mg/HCT 12.5 mg showed significant decreases in SBP/DBP of 28.7 (17.5)/17.8 (10.2) mm Hg, and those in the candesartan 16 mg monotherapy group showed decreases of 20.5 (14.5)/14.1 (10.1) mm Hg (P < 0.01 between treatments for both SBP and DBP). After forced titration of candesartan from 16 mg to 32 mg at week 8, there was an additional reduction in SBP/DBP of 4.1 (12.7)/3.8 (8.3) mm Hg in the candesartan-HCT combination therapy group and 4.0 (11.6)/2.0 (8.5) mm Hg in the candesartan monotherapy group (P < 0.001 for SBP and DBP in both groups compared with values at week 4). A greater proportion of patients (70.6%) attained the target BP in the candesartan-HCT combination therapy group than in the candesartan monotherapy group (53.2%, P = 0.014). A total of 32 mg of candesartan was well tolerated both in combination therapy with HCT and in monotherapy. Dizziness was the most common adverse event in both groups (5 and 2 patients, respectively). Conclusions: The candesartan-HCT combination was associated with a statistically significant lowering of BP compared with candesartan monotherapy. Clinicaltrials.gov: NCT00621153.