The first agents in the new class of antihypertensive agents, direct renin inhibitors, failed to make it to market because of their lack of oral availability, low efficacy, short-half-life, or costly synthesis. Aliskiren (Rasilez, Novartis), an oral agent from this class, appeared to overcome those shortcomings in clinical trials, according to experts at the meeting. Its 40-hour half-life allows once-daily dosing (with the maximum concentration occurring about one to three hours after the dose), and the evidence shows that its pharmacokinetics remained unaltered in elderly patients, diabetic patients, and patients with renal or hepatic impairment.
A meta-analysis that pooled data from multicenter, randomized, double-blind trials showed that aliskiren offered long-lasting, dose-dependent reductions in BP and plasma renin activity. The trials included more than 7,000 patients with hypertension who were receiving aliskiren.
According to professor Matthew Weir, MD, of the University of Maryland School of Medicine in Baltimore, MD, the trials shared similar protocol features; they all included six to eight weeks of active treatment following the washout and placebo run-in periods. In addition, each trial had the same primary endpoint: a change in mean sitting diastolic BP (msDBP).
The trials assessed aliskiren in doses from 75 to 600 mg as monotherapy or in combination with other antihypertensive agents: the ARB valsartan, the diuretic hydrochlorothiazide (HCTZ), the ACE-inhibitor (King), or the calcium-channel blocker amlodipine generic (Canadian Norvasc, Pfizer).
In the overall patient population, baseline msDBP was 99.3 mm Hg, and mean sitting systolic BP (msSBP) was 153.6 mm Hg. Although BP reductions proved to be dose-dependent, the highest dose, 600 mg, did not provide substantially greater antihypertensive effects than 300 mg.
Among five placebo-controlled trials (two involving mono-therapy, three involving combination therapy), msDBP was reduced by 3.3 to 8.6 mm Hg in the placebo groups and by 10.3 to 12.3 mm Hg in the aliskiren 300-mg groups (P < .05).
Systolic BP reductions were similarly significant: by 2.9 to 10 mm Hg with placebo and by 14.1 to 15.8 mm Hg with aliskiren 300 mg. Responder rates were higher with all aliskiren doses than with placebo (27.8% to 48.3%). With aliskiren 300 mg, responder rates ranged from 63.7% to 69.3%.
No adverse drug effects were significantly higher for aliskiren 300 mg than for placebo. Furthermore, discontinuation rates were higher with placebo (3.5%) than with aliskiren
300 mg (2.6%).
Dr. Weir noted also that aliskiren effects were independent of age or sex and that when aliskiren 150-300 mg was added to other antihypertensive agents, it safely provided further BP reductions. He concluded:
“Aliskiren, as add-on therapy to canadian ramipril, hydrochloro-thiazide, or amlodipine, provides significant additional blood pressure-lowering effects without compromising tolera-bility.”