New combination therapy promising approach for hypertension management

American Society of Hypertension 2011 Annual Scientific Meeting and Exposition

NEW YORK — Among patients with stage II systolic hypertension, azilsartan medoxomil, a newly approved angiotensin II receptor blocker, plus chlorthalidone led to greater reductions in systolic blood pressure compared with olmesartan plus hydrochlorothiazide, according to findings presented here at the American Society of Hypertension 2011 Annual Scientific Meeting and Exposition.

According to study investigator William C. Cushman, MD, of the University of Tennessee College of Medicine in Memphis, this was the first large, forced titration study of an angiotensin II receptor blocker fixed-dose combination.

“This [study] gives the maximum comparison in terms of the effectiveness of these products … and demonstrates superior efficacy of the [azilsartan medoxomil-chlorthalidone] fixed-dose combinations compared with [olmesartan-hydrochlorothiazide],” Cushman said in a press conference.

In the phase 3, multicenter, double blind, randomized study, the effects of two doses of azilsartan medoxomil (Edarbi, Takeda Pharmaceuticals) plus chlorthalidone were compared with olmesartan plus hydrochlorothiazide. The study design called for force titrating to maximum doses for all three arms during a 12-week interval: 20 mg azilsartan medoxomil/12.5 mg chlorthalidone to 40 mg azilsartan medoxomil/25 mg chlorthalidone (n=355); 40 mg azilsartan medoxomil/12.5 mg chlorthalidone to 80 mg azilsartan medoxomil/25 mg (n=352); and 20 mg olmesartan/12.5 mg hydrochlorothiazide to 40 mg olmesartan/25 mg hydrochlorothiazide (n=364). Only patients aged at least 18 years and with post-washout clinic systolic BP of between 160 mm Hg and 190 mm Hg were included.

At 12 weeks, the study’s primary endpoint of change in clinic systolic BP favored both the 40/25-mg (–42.5 mm Hg) and 80/25-mg azilsartan medoxomil arms (–44 mm Hg) vs. the olmesartan arm (–37.1 mm Hg; P<.001 for both comparisons). Similarly, change in 24-hour mean systolic BP also favored the 40/25-mg (–33.9 mm Hg) and 80/25-mg azilsartan medoxomil arms (–36.3 mm Hg) compared with the olmesartan arm (–27.5 mm Hg; P<.001 for both).

Overall, adverse events appeared more frequently in the 40/25-mg (71.3%) and 80/25-mg (70.7%) azilsartan medoxomil groups vs. the olmesartan group (60.2%). However, serious adverse events were least common in the 40/25-mg group (0.3%), followed by olmesartan (2.2%) and azilsartan medoxomil 80/25 mg (2.8%).

The study was sponsored by Takeda. – by Brian Ellis

For more information:

Cushman W. LB-OR-03. Presented at: American Society of Hypertension 2011 Annual Scientific Meeting and Exposition; May 21-24, 2011; New York.

Disclosure: In the past 12 months, Dr. Cushman reports receiving grant/research support from Merck, GlaxoSmithKline and Novartis and has consulted for Takeda, Novartis and Noven.

Franz Messerli

This certainly is an impressive study. AZL-M as mono-therapy seems to be an outstanding angiotensin II receptor blocker. It has been shown to lower BP more efficaciously than 40 mg of OLM, which is a very good angiotensin II receptor blocker as we know. However, the exact mechanism why AZL-M is so much more efficacious than other ARBs is not entirely clear.

It is important to consider, though, that there was no placebo arm in this study. There would certainly be a placebo reduction [in systolic BP] of about 10 mm HG. Therefore the BP reduction that was observed with 24-hour BP is much more realistic than the one in the physician's office, but still extremely good.

Another point is that we and others have shown that antihypertensive efficacy of CLD is more powerful than HCTZ. Although this has been established in quite a few studies, it was never documented in a combination. But it is my suspicion that the good anti-hypertensive effects of AZL-M and CLD will most likely be synergistic and may well beat any HCTZ competition.

– Franz Messerli, MD
Professor of Medicine and Director of the Hypertension Program,
St. Luke’s-Roosevelt Hospital, New York

Disclosure: Dr. Messerli has advised/consulted for Daiichi-Sankyo and Takeda and has received grant/research support from Daiichi-Sankyo.

Follow EndocrineToday.com on Twitter.