Diuretic-ARB Combo Best to Lower BP

The trial compared the duo of azilsartan medoxomil (Edarbi) and chlorthalidone with the combination of olmesartan medoxomil and hydrochlorothiazide (Benicar HCT).

According to William Cushman, MD, of the University of Tennessee and the VA Medical Center in Memphis, the results at 12 weeks showed that two different fixed-dose combinations of azilsartan medoxomil and chlorthalidone -- one with 40 mg of the ARB and one with 80 mg -- resulted in reductions of systolic blood pressure, measured in the clinic, that were 5 to 7 mm Hg greater than with the olmesartan combination (P<0.001).  The findings were similar when 24-hour ambulatory blood pressure monitoring measurements were used.

Azilsartan medoxomil was approved as monotherapy in February after clinical trials showed that it was superior to other approved angiotensin receptor blockers, including valsartan (Diovan) and olmesartan (Benicar).

The purpose of the current study was to compare two investigational fixed-dose combinations of azilsartan medoxomil and chlorthalidone with maximum approved doses of the olmesartan-hydrochlorothiazide fixed-dose combination. Titration of the drugs was forced and was not done to meet a specific goal.

Patients in the study had stage 2 systolic hypertension, with a baseline pressure of at least 160 mm Hg, but no higher than 190 mm Hg. The mean age was about 57 and the mean body mass index was about 32 kg/m2.

After a washout period and a two-week placebo run-in, the researchers randomized patients to one of three groups:

Azilsartan medoxomil 20 mg plus chlorthalidone 12.5 mg: 355 patients

Azilsartan medoxomil 40 mg plus chlorthalidone 12.5 mg: 352 patients

Olmesartan 20 mg plus hydrochlorothiazide 12.5 mg: 364 patients

At week four, there was a forced doubling of the dose for the angiotensin receptor blockers, resulting in combinations containing 40 mg and 80 mg of azilsartan medoxomil and 40 mg of olmesartan. At week eight, there was a forced doubling of the diuretics dose, resulting in fixed-dose combinations containing either 25 mg of chlorthalidone (in the azilsartan medoxomil groups) or 25 mg of hydrochlorothiazide.

After 12 weeks, there were substantial reductions in systolic blood pressure measured in the clinic in all three groups: 42.5 mm Hg with the lower dose and 44 mm Hg with the higher dose of azilsartan medoxomil-chlorthalidone and 37.1 mm Hg with olmesartan-hydrochlorothiazide (P<0.001 for both azilsartan medoxomil groups versus the olmesartan group).

The magnitude of the difference between the azilsartan medoxomil groups and the olmesartan group was similar when looking at the measurements from ambulatory blood pressure monitoring. There was also significant separation between the azilsartan medoxomil fixed-dose combinations and the olmesartan combination for diastolic blood pressure.

In general, tolerability was similar between the lower-dose azilsartan medoxomil-chlorthalidone combination (40 mg/25 mg) and the olmesartan-hydrochlorothiazide combination (40 mg/25 mg), with rates of adverse events leading to discontinuation of 8.7% and 7.1%, respectively. The rate was higher with the combination of 80 mg azilsartan medoxomil and 25 mg chlorthalidone (14.8%).

The rate of serious adverse events was low overall, but was elevated in the combination containing the 80-mg dose of azilsartan medoxomil (2.8% versus 0.3% with the lower dose and 2.2% with the olmesartan combination).

Rates of hypokalemia and hyponatremia were low, but slightly higher with the azilsartan medoxomil combinations.

Cushman addressed the use of equal doses of the diuretics in all three fixed-dose combinations even though chlorthalidone has been shown to have greater blood pressure-lowering effects on a per-milligram basis.

He said that, from a scientific perspective, one would use a higher dose of hydrochlorothiazide if the purpose was to compare optimal doses of the diuretics. But, he added, the purpose of the current study was to compare the investigational combinations with what is currently available on the market, and there are no fixed-dose combinations that contain more than 25 mg of hydrochlorothiazide.

Robert Phillips, MD, PhD, of UMass Memorial Medical Center in Worcester, Mass., said the trial was a fair comparison.

"These are the fixed combinations that are out there, so I think it's fair to test what's out on the market, one against another," said Phillips, who is chair of the ASH continuing medical education committee.

Cushman W, et al "Azilsartan medoxomil plus chlorthalidone reduces BP more effectively than olmesartan plus HCTZ in stage 2 systolic hypertension" ASH 2011; Abstract LB-OR-03