Once-daily plasma renin inhibitor aliskiren effective antihypertensive alone or with a thiazide diuretic

The investigative agent aliskiren, the first orally active renin inhibitor, is an effective antihypertensive agent as monotherapy and in combination with hydrochlorothiazide, reported investigators at the 21st annual scientific meeting of ASH.

The investigative agent aliskiren, the first orally active renin inhibitor, is an effective antihypertensive agent as monotherapy and in combination with hydrochlorothiazide, reported investigators at the 21st annual scientific meeting of ASH.

Renin inhibitors offer a new mechanism for inhibiting chronic activation of the renin-angiotensin system (RAS) to reduce blood pressure and the potential to improve outcomes in hypertension and other cardiovascular diseases by interrupting the RAS at its rate-limiting step.

Data from a placebo-controlled study of aliskiren in 216 patients with mild-to-moderate hypertension were presented by Jerry Mitchell, MD, PhD, chairman and CEO of the Texas Center for Drug Development, Houston, Tex.

Aliskiren, at all 3 dose levels, was highly statistically effective at lowering blood pressure. Reductions in mean ambulatory systolic blood pressure were superior to placebo by 11.4 mmHg (150 mg), 10.5 mmHg (300 mg), and 11.7 mmHg (600 mg) (all P<.0001). Reductions in 24-hour ambulatory diastolic blood pressure also were significantly better with all doses of aliskiren compared with placebo (P<.0001).

"Trough-to-peak ratios indicated that there was minimal loss of effect during the 24-hour dosing interval," Dr Mitchell said. Trough-to-peak ratios were 0.64, 0.98, and 0.86 at the 150-, 300-, and 600-mg doses, respectively. "There was no morning surge in blood pressure [with aliskiren]," Dr Mitchell said. "The drug works throughout the 24-hour cycle." Variability in blood pressure and early morning surges correlates with increased risk of cardiovascular events, he said.

Smoothness indices for aliskiren were 0.64, 0.60, and 0.67 from the lowest to highest dosages tested, compared with –0.17 for placebo.

In the study, sustained blood pressure-lowering with aliskiren corresponded to a maintained suppression of plasma renin activity following treatment withdrawal despite continued elevation of renin concentration, which suggests a persistent effect of aliskiren.

In a second trial presented at the ASH meeting, aliskiren in combination with hydrochlorothiazide achieved greater reductions in sitting blood pressure when compared with either monotherapy in a single-blinded study that included 2,776 patients randomized to placebo, aliskiren (75, 150, or 300 mg), hydrochlorothiazide (6.25, 12.5, or 25 mg), or a combination of the 2 drugs for 8 weeks.

Aliskiren produced a dose-dependent reduction in blood pressure, according to lead investigator Alberto Vilamil, MD, from Fundapres, Las-Heras, Buenos Aires, Argentina.

A mean reduction of 21.2/14.3 mmHg in sitting blood pressure was achieved with the aliskiren 300 mg/hydrochlorothiazide 25 mg combination (P<.001 vs placebo).

Combination therapy increased the proportion of responders compared with either monotherapy. The responder rate, defined as a final achieved sitting diastolic blood pressure <90 mmHg or at least a 10-mmHg reduction in sitting diastolic blood pressure, was significantly higher with the aliskiren 300 mg (64%) group and all combinations (55% to 81%) than with placebo (46%).

The incidence of adverse events was similar between the aliskiren and placebo groups and was unrelated to dose. Headache and nasopharyngitis were the most common adverse events in both the placebo and treatment groups, said Dr Vilamil.

Discontinuation because of adverse events occurred in 0% to 4.4% of the aliskiren groups compared with 3.6% of the placebo group.