Safety, tolerability, and efficacy of azilsartan medoxomil with or without chlorthalidone during and after 8 months of treatment for hypertension

Abstract

A phase 3, 26-week, open-label, titrate-to-target study (n=418) assessed the safety of azilsartan medoxomil (AZL-M) alone and with chlorthalidone (CLD), followed by a 6-week, double-blind, placebo-controlled reversal phase with change in clinic diastolic blood pressure (DBP) as the primary endpoint. Target blood pressure (BP) was <140/90 mm Hg (<130/80 mm Hg with diabetes/chronic kidney disease). AZL-M was initiated at 40 mg once a day (QD), force-titrated to 80 mg at week 4. CLD 25 mg QD could be added (weeks 8-22), if required, to reach target, followed by additional antihypertensives from week 12. At the end of the open-label phase, mean change in systolic BP (SBP)/DBP from baseline was -23/-16 mm Hg. The most common adverse events, irrespective of treatment, were dizziness (8.9%) and headache (7.2%). Serious AEs were reported in eight patients (1.9%). Consecutive creatinine elevations ≥50% with values exceeding the upper limit of normal (ULN) were reported in nine (2.2%) patients. All returned to below the 50% threshold; most also returned to below the ULN after drug discontinuation. Mean DBP was maintained through the reversal phase in patients receiving AZL-M, but increased with placebo (difference: -7.8 mm Hg, 95% confidence interval, -9.8 to -5.8; P<.001). AZL-M alone or with CLD showed good long-term safety and stable BP improvements in a titrate-to-target approach. BP improvements caused by AZL-M therapy were safely reversible upon AZL-M withdrawal.

Trial registration: ClinicalTrials.gov NCT00696384.

Figure 1

Study design for the open‐label phase and double‐blind reversal phase. AZL‐M indicates azilsartan medoxomil; QD, once daily; CLD, chlorthalidone.

Figure 2

Mean trough clinic sitting diastolic blood pressure (DBP) (A) and systolic blood pressure (SBP) (B) by study visit (open‐label phase; last observation carried forward). Note that the individual data lines do not represent randomized groups and are in a single cohort, but are presented separately according to treatment received for clarity. AZL‐M indicates azilsartan medoxomil; CLD, chlorthalidone. Data are expressed as mean±standard deviation. The dashed line at week 8 represents the first visit at which patients could additionally have received CLD.

Figure 3

Mean trough clinic sitting diastolic blood pressure (DBP) (A) and systolic blood pressure (SBP) (B) by study visit (double‐blind reversal phase; last observation carried forward). AZL‐M indicates azilsartan medoxomil; CLD, chlorthalidone. Data are expressed as mean±standard deviation.