A randomized trial of the efficacy and safety of azilsartan medoxomil combined with chlorthalidone

Michael A Weber, Peter Sever, Attila Juhasz, Andrew Roberts, Charlie Cao, Michael A Weber, Peter Sever, Attila Juhasz, Andrew Roberts, Charlie Cao

Abstract

Introduction: We measured the effects of azilsartan medoxomil co-administered with chlorthalidone 25 mg in stage 2 hypertension.

Methods: Azilsartan medoxomil 40 or 80 mg plus chlorthalidone were compared with placebo plus chlorthalidone once daily in a randomized, double-blind, 6-week trial. The primary endpoint was change from baseline in 24-hour mean systolic blood pressure by ambulatory blood pressure monitoring.

Results: Patients ( N=551; mean age 59 years; 51.7% men) were randomly assigned to placebo plus chlorthalidone ( n=184), azilsartan medoxomil 40 mg plus chlorthalidone ( n=185), or azilsartan medoxomil 80 mg plus chlorthalidone ( n=182). Baseline systolic blood pressures were similar among groups. After 6 weeks, least squares mean (standard error) reductions with azilsartan medoxomil 40 mg and 80 mg plus chlorthalidone were similar in magnitude (-31.7 (1.0) and -31.3 (1.0) mmHg, respectively), but greater than chlorthalidone alone (-15.9 (1.0) mmHg). Hypotension and serum creatinine elevations were more frequent with azilsartan medoxomil plus chlorthalidone than chlorthalidone alone (reversed with drug discontinuation). Notably, plasma potassium reduction of 0.43 meq/L with chlorthalidone was attenuated to 0.13 and 0.05 meq/L by azilsartan medoxomil 40 mg and 80 mg, respectively.

Conclusion: Azilsartan medoxomil 40 mg or 80 mg plus chlorthalidone 25 mg was significantly more efficacious than chlorthalidone alone in reducing blood pressure and was well tolerated. Clinicaltrial.gov , https://ichgcp.net/clinical-trials-registry/NCT00591773 , NCT00591773.

Keywords: Hypertension; angiotensin receptor blockers; azilsartan medoxomil; chlorthalidone; clinical trial.

Conflict of interest statement

Declaration of conflicting interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: MAW is a consultant for Boehringer-Ingelheim, Daiichi Sankyo, Forest, Novartis, and Takeda; PS has received grant income from consultancies from Pfizer and Amgen and consultancy fees from Takeda; AJ and AR are no longer employees of Takeda, though, they were during the time the research was conducted; CC is an employee of Takeda.

Figures

Figure 1.
Figure 1.
Disposition of patients. aFor the purpose of this disposition figure, patients who completed study were calculated as the total number randomly assigned per treatment group minus those who discontinued. bPatients could have had more than one reason for discontinuation; only the primary reason is presented here. AZL-M: azilsartan medoxomil; CLD: chlorthalidone; FAS: full analysis set; PP: per protocol.
Figure 2.
Figure 2.
Clinic and ABPM results for both SBP and DBP. *P<0.001. ABPM: ambulatory blood pressure measurement; AZL-M: azilsartan medoxomil; CLD: chlorthalidone; DBP: diastolic blood pressure; LS: least squares; SBP: systolic blood pressure.
Figure 3.
Figure 3.
Hourly SBP and DBP ABPM data at baseline and week 6. ABPM: ambulatory blood pressure measurement; AZL-M: azilsartan medoxomil; CLD: chlorthalidone; DBP, diastolic blood pressure; LS: least squares; SBP: systolic blood pressure.
Figure 4.
Figure 4.
Proportion of patients achieving BP target at final visit. aP<0.001 based on logistic regression analysis. bP=0.002 based on logistic regression analysis. AZL-M: azilsartan medoxomil; BP: blood pressure; CLD: chlorthalidone; DBP: diastolic blood pressure; SBP: systolic blood pressure.

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