Andrew Roberts

The Comparative Effects of Azilsartan Medoxomil and Olmesartan on Ambulatory and Clinic Blood Pressure

The current study assesses the antihypertensive efficacy and safety of the investigational angiotensin receptor blocker (ARB), azilsartan medoxomil (AZL‐M), compared with placebo and the ARB olmesartan medoxomil (OLM‐M). This randomized, double‐blind, placebo‐controlled, multicenter study assessed change from baseline in mean 24‐hour ambulatory systolic blood pressure (SBP) following 6u2003weeks of treatment. Patients with primary hypertension (n=1275) and baseline 24‐hour mean ambulatory systolic pressure ≥130 mm Hg and ≤170u2003mm Hg were studied; 142 received placebo and the remainder received 20 mg, 40 mg, or 80u2003mg AZL‐M or 40u2003mg OLM‐M. Mean age of participants was 58±11u2003years, baseline mean 24‐hour SBP was 146u2003mm Hg. Dose‐dependent reductions in 24‐hour mean SBP at study end occurred in all AZL‐M groups. Reduction in 24‐hour mean SBP was greater with AZL‐M 80u2003mg than OLM‐M 40u2003mg by 2.1u2003mm Hg (95% confidence interval, −4.0 to −0.1; P=.038), while AZL‐M 40u2003mg was noninferior to OLM‐M 40u2003mg. The side effect profiles of both ARBs were similar to placebo. AZL‐M is well tolerated and more efficacious at its maximal dose than the highest dose of OLM‐M. J Clin Hypertens (Greenwich). 2011;13:81–88.

Azilsartan Medoxomil Plus Chlorthalidone Reduces Blood Pressure More Effectively Than Olmesartan Plus Hydrochlorothiazide in Stage 2 Systolic Hypertension

Azilsartan medoxomil, an effective, long-acting angiotensin II receptor blocker, is a new treatment for hypertension that is also being developed in fixed-dose combinations with chlorthalidone, a potent, long-acting thiazide-like diuretic. We compared once-daily fixed-dose combinations of azilsartan medoxomil/chlorthalidone force titrated to a high dose of either 40/25 mg or 80/25 mg with a fixed-dose combination of the angiotensin II receptor blocker olmesartan medoxomil plus the thiazide diuretic hydrochlorothiazide force titrated to 40/25 mg. The design was a randomized, 3-arm, double-blind, 12-week study of 1071 participants with baseline clinic systolic blood pressure 160 to 190 mm Hg and diastolic blood pressure ⩽119 mm Hg. Patients had a mean age of 57 years; 59% were men, 73% were white, and 22% were black. At baseline, mean clinic blood pressure was 165/96 mm Hg and 24-hour mean blood pressure was 150/88 mm Hg. Changes in clinic (primary end point) and ambulatory systolic blood pressures at week 12 were significantly greater in both azilsartan medoxomil/chlorthalidone arms than in the olmesartan/hydrochlorothiazide arm (P<0.001). Changes in clinic systolic blood pressure (mean±SE) were −42.5±0.8, −44.0±0.8, and −37.1±0.8 mm Hg, respectively. Changes in 24-hour ambulatory systolic blood pressure were −33.9±0.8, −36.3±0.8, and −27.5±0.8 mm Hg, respectively. Adverse events leading to permanent drug discontinuation occurred in 7.9%, 14.5%, and 7.1% of the groups given azilsartan medoxomil/chlorthalidone 40/25 mg, azilsartan medoxomil/chlorthalidone 80/25 mg, and olmesartan/hydrochlorothiazide 40/25 mg, respectively. This large, forced-titration study has demonstrated superior antihypertensive efficacy of azilsartan medoxomil/chlorthalidone fixed-dose combinations compared with the maximum approved dose of olmesartan/hydrochlorothiazide.

Blood Pressure–Lowering Efficacy of the Fixed‐Dose Combination of Azilsartan Medoxomil and Chlorthalidone: A Factorial Study

J Clin Hypertens (Greenwich). 2012; 14:284–292. ©2012 Wiley Periodicals, Inc.

Effects of combining azilsartan medoxomil with amlodipine in patients with stage 2 hypertension

ObjectiveThe aim of the study was to measure the effects on blood pressure (BP) of the angiotensin receptor blocker azilsartan medoxomil, in 40 and 80 mg doses, combined with 5 mg of the calcium channel blocker amlodipine and to compare these effects with placebo plus amlodipine 5 mg. MethodsThis was a randomized, controlled, double-blind study of 6 weeks’ duration in 566 patients with stage 2 hypertension. The primary endpoint was 24-h systolic BP by ambulatory monitoring. ResultsThe mean age of the participants was 58 years; men and women were equally represented, and baseline 24-h BP (153–154/93 mmHg) and clinic BP (165–166/94–95 mmHg) were similar across the three treatment groups. After 6 weeks, 24-h BP decreased by 25/15 mmHg in both the azilsartan medoxomil/amlodipine 40/5 and 80/5 mg groups. These reductions were each greater than the 14/8 mmHg decrease with placebo plus amlodipine 5 mg (P⩽0.001 for both comparisons). All treatments were well tolerated, and adverse events did not increase with the azilsartan medoxomil doses. Edema or fluid retention was less common in both combination groups (2.6 and 2.7%) than with placebo plus amlodipine (7.6%). ConclusionCoadministration of azilsartan medoxomil with amlodipine was well tolerated and led to meaningful additional BP reductions compared with placebo plus amlodipine.

Safety and tolerability of azilsartan medoxomil in subjects with essential hypertension: a one-year, phase 3, open-label study

Abstract This 56-week phase 3, open-label, treat-to-target study, involving 2 consecutive, non-randomized cohorts, evaluated the safety and tolerability of azilsartan medoxomil (AZL-M) in essential hypertension (mean baseline blood pressure [BP] 152/100u2009mmHg). All subjects (nu2009=u2009669) initiated AZL-M 40u2009mg QD, force-titrated to 80u2009mg QD at week 4, if tolerated. From week 8, subjects could receive additional medications, starting with chlorthalidone (CLD) 25u2009mg QD (Cohort 1) or hydrochlorothiazide (HCTZ) 12.5–25u2009mg QD (Cohort 2), if required, to reach BP targets. Adverse events (AEs) were reported in 75.9% of subjects overall in the two cohorts (73.8% Cohort 1, 78.5% Cohort 2). The most common AEs were dizziness (14.3%), headache (9.9%) and fatigue (7.2%). Transient serum creatinine elevations were more frequent with add-on CLD. Clinic systolic/diastolic BP (observed cases at week 56) decreased by 25.2/18.4u2009mmHg (Cohort 1) and 24.2/17.9u2009mmHg (Cohort 2). These results demonstrate that AZL-M is well tolerated over the long term and provides stable BP improvements when used in a treat-to-target BP approach with thiazide-type diuretics.

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

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.

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

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://clinicaltrials.gov/ct2/show/NCT00591773, NCT00591773

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

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 20/12.5u200amg once daily titrated to 40/25u200amg if needed or AZL-M/CTD 40/12.5u200amg once daily titrated to 80/25u200amg if needed with an olmesartan medoxomil (OLM)-hydrochlorothiazide (HCTZ) 20/12.5u200amg FDC once daily titrated to 40/25u200amg if needed in a randomized, double-blind, 8-week study of 1085 participants with clinic SBP 160–190u200ammHg and DBP 119u200ammHg or less. Titration to higher doses occurred at week 4 if BP was at least 140/90u200ammHg (≥130/80u200ammHg 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 165u200ammHg were observed (Pu200a<u200a0.001) in both AZL-M/CTD arms (−37.6 and −38.2u200ammHg) versus OLM/HCTZ (−31.5u200ammHg), 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 −20.7u200ammHg; both Pu200a<u200a0.001), 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 Pu200a<u200a0.001). 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.