BARCELONA — The investigational antihypertensive agent aliskiren, alone or with add-on hydrochlorothiazide, effectively maintained 24-hour blood pressure control in a large, 1-year, phase III clinical trial, Dr. Domenic Sica reported at a joint meeting of the European Society of Cardiology and the World Heart Federation.
Moreover, the drug's strong tissue penetration and long half-life meant that rebound hypertension upon discontinuation was a nonissue. When a subset of participants in the 1,625-patient trial were switched double-blind to placebo for a month following 11 months on aliskiren, their blood pressure (BP) increased only gradually and stayed significantly lower than at baseline, added Dr. Sica, professor of medicine and pharmacology and chairman of clinical pharmacology and hypertension at the Medical College of Virginia, Richmond.
Aliskiren (Rasilez) is a novel once-daily oral agent, first in a new class known as direct renin inhibitors. The drug is now under review by the Food and Drug Administration. Novartis, its developer, anticipates marketing approval by next spring as monotherapy and in fixed-dose combination with hydrochlorothiazide (HCTZ), the physician said in an interview.
The company plans to file for European marketing approval by the end of 2006.
Participants had mild to moderate hypertension and were initially randomized to 150 or 300 mg of aliskiren once daily. The 53% whose blood pressure wasn't adequately controlled on 300 mg/day received add-on HCTZ at 12.5 or 25 mg/day as required.
After 1 year, 86% of subjects were classified as responders, meaning their sitting diastolic BP was below 90 mm Hg and/or at least 10 mm Hg lower than baseline. Patients on monotherapy had mean reductions of 17.4 mm Hg systolic and 13.3 mm Hg diastolic BP. Those on combination therapy with HCTZ averaged reductions of 18.7/12.1 mm Hg.
Particularly impressive was the fact that there were essentially no drug-related side effects, Dr. Sica continued. The incidence and type of adverse events didn't differ between patients on 150, compared with 300 mg of the direct renin inhibitor. And during the double-blind month-long treatment withdrawal phase, the side effects of patients switched to placebo were similar to those who remained on aliskiren monotherapy.
Aliskiren has favorably impressed other investigators as well.
“This is going to be a big drug,” Dr. Charles Kilo predicted in an interview. “It's going to be the drug of choice, probably in combination with the diuretic, because the side effect profile is that of placebo.”
Dr. Kilo, professor of medicine at Washington University, St. Louis, was principal investigator in a 256-patient study he presented at the congress that showed combining aliskiren with ramipril suppressed the undesirable rise in plasma renin typically caused by ACE inhibitor therapy.
In another trial presented at the conference, Mark A. Munger, Pharm.D., reported that adding 150 mg/day of aliskiren to patients whose blood pressure wasn't adequately controlled with 5 mg/day of amlodipine brought their BP down to levels seen in patients switched to amlodipine monotherapy at 10 mg/day—and with far less of the peripheral edema that often limits calcium channel-blocker therapy.
The incidence of peripheral edema was 11.2% in patients on 10 mg of amlodipine, 3.4% with 5 mg amlodipine, and 2.1% with 150 mg aliskiren plus 5 mg amlodipine, according to Dr. Munger, who is a professor of pharmacotherapy at the University of Utah, Salt Lake City.
Dr. Sica said short-term studies indicate aliskiren has a prominent left ventricular hypertrophy-reducing effect and strong compartmentalization in the kidneys. This suggests the drug might provide clinical benefits beyond simply its BP-lowering effect. This possibility will be explored in a series of soon-to-start large clinical trials with cardiac and renal event rates rather than surrogate markers as end points. The studies will include patients who have heart failure, diabetes, or are post MI. Results are 3–5 years away.
All of the aliskiren studies presented at the congress were funded by Novartis.