Aliskiren effective as part of combination or monotherapy

Drug demonstrated high response rates in combination with hydrochlorothiazide.

Issue: November 2006

BARCELONA — Clinical trials of aliskiren, the first in a new class of antihypertensive agents that block the renin system at its point of activation, demonstrated high response rates in combination with hydrochlorothiazide and efficacy with placebo-like tolerability in a large meta-analysis.

The smaller trial, presented as a poster by Domenic Sica, MD, Medical College of Virginia Commonwealth University Health System, Richmond, enrolled patients randomly to aliskiren (Rasilez, Novartis) 150 mg or 300 mg with dose titration or addition of HCTZ 12.5 mg or 25 mg to those who had failed to achieve a BP goal of less than 140 mm Hg/90 mm Hg on aliskiren monotherapy. After 12 months of therapy, 66.9% of patients in the aliskiren 300 mg/HCTZ 12.5 mg or 25 mg group achieved goal.

Overall, 868 out of 1,928 received the aliskiren and HCTZ together, achieving a mean sitting diastolic BP reduction of 12.1 mm Hg and a mean sitting systolic BP reduction of 18.7 mm Hg.

“If you’re a responder to this drug class, monotherapy often will suffice. If you’re a partial responder, however, adding a diuretic can be expected to move you into a responder category,” Sica said at the World Congress of Cardiology 2006. He also said that there was no evidence of rebound hypertension during a carefully monitored one-month aliskiren withdrawal period at the study’s end.

The meta-analysis included more than 7,000 hypertensive patients enrolled in seven randomized, double blind, multicenter clinical trials of aliskiren. According to Matthew Weir, MD, University of Maryland School of Medicine, Baltimore, all of the trials had six to eight weeks of active treatment and change from baseline in mean sitting diastolic BP as primary endpoint. Baseline mean sitting diastolic BP was 99.3 mm Hg and mean sitting systolic BP was 153.6 mm Hg. Although BP lowering proved to be dose dependent, analysis showed that the highest dose, 600 mg, did not provide substantially greater effects than 300 mg.

The meta-analysis included five placebo-controlled trials (two monotherapy, three combinations) evaluating aliskiren in doses from 75 mg to 600 mg. Combinations included valsartan (Diovan, Novartis), HCTZ, ramipril (Altace, King) or amlodipine.

Mean sitting diastolic BP was reduced by 3.3 mm Hg to 8.6 mm Hg in the placebo groups and by 10.3 mm Hg to 12.3 mm Hg for the aliskiren 300 mg groups (P<.05).

Systolic BP reductions were similarly significant (2.9 mm Hg to 10 mm Hg for placebo, 14.1 mm Hg to 15.8 mm Hg for aliskiren 300 mg). Responder rates were significantly higher across all aliskiren doses compared with placebo (27.8% to 48.3% for placebo, 63.7% to 69.3% for aliskiren 300 mg).

No adverse effects were significantly higher for aliskiren 300 mg than for placebo. Discontinuations due to adverse events were higher in the placebo group (3.5% vs. 2.6% for aliskiren 300 mg). Aliskiren effects were independent of age or gender, Weir said. – by Walter Alexander

Dr. Weir is an ad hoc paid consultant for Novartis.

For more information:

Sica D, Gradman O, Lederballe M, et al. Aliskiren, a novel renin inhibitor, is well tolerated and has sustained BP-lowering effects alone or in combination with HCTZ during long-term (52 weeks) treatment of hypertension.
Weir M, Bush C, Zhang J, Keefe D, Satlin A. Antihypertensive efficacy and safety of the oral renin inhibitor aliskiren in patients with hypertension: a pooled analysis.
Both presented at: World Congress of Cardiology 2006; Sept. 2-6, 2006; Barcelona.