A randomized titrate-to-target study comparing fixed-dose combinations of azilsartan medoxomil and chlorthalidone with olmesartan and hydrochlorothiazide in stage-2 systolic hypertension

William C Cushman, George L Bakris, William B White, Michael A Weber, Domenic Sica, Andrew Roberts, Eric Lloyd, Stuart Kupfer, William C Cushman, George L Bakris, William B White, Michael A Weber, Domenic Sica, Andrew Roberts, Eric Lloyd, Stuart Kupfer

Abstract

Background: Azilsartan medoxomil (AZL-M), an angiotensin II receptor blocker, has been developed in fixed-dose combinations (FDCs) with chlorthalidone (CTD).

Objective/methods: We compared FDCs of AZL-M/CTD 20/12.5 mg once daily titrated to 40/25 mg if needed or AZL-M/CTD 40/12.5 mg once daily titrated to 80/25 mg if needed with an olmesartan medoxomil (OLM)-hydrochlorothiazide (HCTZ) 20/12.5 mg FDC once daily titrated to 40/25 mg if needed in a randomized, double-blind, 8-week study of 1085 participants with clinic SBP 160-190 mmHg and DBP 119 mmHg or less. Titration to higher doses occurred at week 4 if BP was at least 140/90 mmHg (≥130/80 mmHg if diabetes or chronic kidney disease). The primary endpoint was change from baseline in clinic SBP; 24-h ambulatory BP monitoring was also measured.

Results: Greater reductions in clinic SBP from a baseline of 165 mmHg were observed (P < 0.001) in both AZL-M/CTD arms (-37.6 and -38.2 mmHg) versus OLM/HCTZ (-31.5 mmHg), despite greater dose titration in the OLM/HCTZ group. At 8 weeks, both AZL-M/CTD FDCs reduced 24-h SBP more than OLM/HCTZ (-26.4 and -27.9 versus -20.7 mmHg; both P < 0.001), and higher proportions in both AZL-M/CTD groups achieved target BP compared with the OLM/HCTZ group (69.4 and 68.9 versus 54.7%, both P < 0.001). Adverse events leading to drug discontinuation occurred in 6.2, 9.5, and 3.1% with the AZL-M/CTD lower and higher doses, and OLM/HCTZ, respectively.

Conclusion: This large, titration-to-target BP study demonstrated AZL-M/CTD FDCs to have superior antihypertensive efficacy compared with the maximum approved dose of OLM/HCTZ.

Trial registration: ClinicalTrials.gov NCT00846365.

Figures

FIGURE 1
FIGURE 1
Treatments and titration schedule. AZL-M/CTD, azilsartan medoxomil/chlorthalidone; BP target, less than 140/90 mmHg or less than 130/80 mmHg for patients with chronic kidney disease or diabetes; OLM/HCTZ, olmesartan/hydrochlorothiazide.
FIGURE 2
FIGURE 2
Patient disposition. Data are n (%). AZL-M/CTD, azilsartan medoxomil/chlorthalidone; OLM/HCTZ, olmesartan/hydrochlorothiazide. The three most common reasons for permanent discontinuation from the study are listed.
FIGURE 3
FIGURE 3
Change from baseline in SBP at each hour of the 24-h ABPM recording at week 8. Data are mean changes from baseline. ABPM, ambulatory blood pressure monitoring; AZL-M/CTD, azilsartan medoxomil/chlorthalidone; OLM/HCTZ, olmesartan/hydrochlorothiazide.
FIGURE 4
FIGURE 4
Subgroup analyses of clinic SBP by baseline characteristics. AZL-M/CTD, azilsartan-medoxomil/chlorthalidone; eGFR, estimated glomerular filtration rate; OLM/HCTZ, olmesartan/hydrochlorothiazide. Open circles (○) are treatment differences between AZL-M/CTD 20/12.5–40/25 mg and OLM/HCTZ. Closed circles (•) are the treatment differences between AZL-M/CTD 40/12.5–80/25 mg group and OLM/HCTZ. Baseline eGFR categories expressed as ml/min per 1.73 m2. ∗P < 0.05 versus OLM/HCTZ.

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