ATLANTA — Treatment with aliskiren, a drug from a new class of antihypertensive agents, led to safe and effective lowering of blood pressure in a phase III study with 672 patients.
“Aliskiren has the potential to be an important new treatment for hypertension, with placebolike tolerability and sustained, 24-hour action,” Dr. Byung-Hee Oh said in a poster presentation at the annual meeting of the American College of Cardiology.
But what some experts find even more compelling is the potential that ali- skiren might have for preventing end-organ damage because it works by blocking renin, the rate-limiting enzyme for the entire renin-angiotensin-aldosterone system (RAAS). Two existing classes of antihypertensive drugs, ACE inhibitors and angiotensin-receptor blockers (ARBs), also act by inhibiting elements of the RAAS.
“As good as the ACE inhibitors and ARBs have been, there is still some unfulfilled promise. It may be that we need to inhibit the whole RAAS rather than one or two components. The hope is that renin inhibitors can do what the other RAAS-active drugs do, but do it even better,” said Dr. Thomas D. Giles, a professor of medicine at Louisiana State University, New Orleans, and president of the American Society of Hypertension Inc.
Clinical studies are planned to test aliskiren's efficacy for preventing end-organ damage, such as heart or renal failure, in patients with hypertension. In the meantime, Novartis, the company developing aliskiren, has filed a new drug application with the Food and Drug Administration. The company is seeking an indication of blood pressure lowering, based on the study results reported by Dr. Oh and findings from other studies, said a company spokeswoman.
The study run by Dr. Oh and his associates enrolled patients with mild to moderate hypertension (defined as an average diastolic blood pressure of 95–109 mm Hg and an average systolic blood pressure of less than 180 mm Hg) at 68 centers in five countries, including the United States. Patients were randomized to daily treatment with placebo or one of three dosages of aliskiren: 150 mg, 300 mg, or 600 mg once daily. Treatment continued for 8 weeks, and 608 patients completed the full study course.
After 8 weeks of treatment, systolic blood pressure fell by an average of 13.0, 14.7, and 15.8 mm Hg in patients taking 150 mg, 300 mg, and 600 mg of aliskiren, respectively, compared with an average drop of 3.8 mm Hg in the placebo group. Diastolic pressure fell by an average of 10.3, 11.1, and 12.5 mm Hg in the three aliskiren arms, compared with a 4.9 mm Hg decline in the placebo group, reported Dr. Oh, chief of the division of cardiology at Seoul (South Korea) National University.
Substantial reductions in blood pressure were seen after 2 weeks of treatment, and the drops in pressure reached near-maximal levels after 4 weeks and then were maintained out to week 8.
Between 59% and 69% of the patients who were treated with ali-skiren had a drop of at least 10 mm Hg in their diastolic pressure or reached a pressure of less than 90 mm Hg, compared with 36% of patients having this level of decline while on placebo.
Laboratory analyses of serum specimens showed that plasma renin activity fell by an average of 75%–81% in patients treated with aliskiren, compared with a 20% rise in the control group. Despite these drops in activity, the level of plasma renin rose substantially, by 52%–229%, in patients taking aliskiren.
Treatment with aliskiren was generally well tolerated; the overall rate of all reported adverse effects was roughly similar in all four treatment groups. The incidence of serious adverse events was 0, 2.4%, and 1.8% in the three groups taking aliskiren, compared with 0.6% in the placebo group.
Fewer patients discontinued aliskiren because of adverse effects, compared with patients in the placebo group. The most common adverse event associated with aliskiren use was diarrhea, which occurred in 11.8% of patients taking 600 mg daily, compared with rates of 1.2%–1.8% in the other two dosage groups and in patients who received placebo.
Based on these results, aliskiren's side effect profile is “distinctly better than [that of] a lot of other antihypertensive drugs,” said Dr. Giles in an interview. As a result, once aliskiren gets FDA approval, some physicians will probably use it for patients who have not adequately responded to other drugs, and some may be attracted to trying aliskiren as a first-line agent because of its efficacy and good adverse effect profile, said Dr. Giles, who did not collaborate on this study but has been a consultant to, a speaker for, and received research support from Novartis.