Evaluation of the dose--response relationship of aliskiren, a direct renin inhibitor, in an 8-week, multicenter, randomized, double-blind, parallel-group, placebo-controlled study in adult patients with stage 1 or 2 essential hypertension.
BACKGROUND
Aliskiren is approved for the treatment of hypertension at once-daily doses of 150 or 300 mg by the US Food and Drug Administration and the European Commission. It is generally well tolerated and provides 24-hour, dose-dependent blood pressure (BP) reduction; however, the effect of the 75-mg dose has been inconsistent in previous trials.


OBJECTIVE
This study was designed to assess the efficacy and tolerability of once-daily administration of aliskiren 75 mg and to evaluate the dose-response relationship across all 3 doses of aliskiren (75, 150, and 300 mg).


METHODS
In this 8-week, multicenter, randomized, double-blind, parallel-group, placebo-controlled study, patients aged > or =18 years with stage 1 or 2 essential hypertension entered a 3- to 4-week, single-blind, placebo run-in period. Eligible patients were randomized (1:1:1:1) to receive oral, once-daily doses of aliskiren 75, 150, or 300 mg or placebo. The primary efficacy variable was the change from baseline in mean sitting diastolic BP (msDBP) at the week-8 end point. Tolerability was assessed by monitoring and recording all adverse events (AEs).


RESULTS
A total of 642 patients (mean [SD] age, 52.0 [10.73] years; 60.0% male; 80.8% white; mean body weight, 89.2 [18.4] kg [range, 50-160 kg]) were included in the study. Overall, 576 patients (89.7%) completed the double-blind treatment period. The most frequent reasons for discontinuation were unsatisfactory therapeutic effect (27/642 randomized patients [4.2%]) and AEs (17/642 [2.6%]). At end point, aliskiren 150 and 300 mg significantly reduced msDBP (both, P < 0.001) and mean sitting systolic


CONCLUSIONS
This study found a positive linear dose-response relationship in BP reduction with aliskiren 75, 150, and 300 mg dosed once daily, but only aliskiren 150 and 300 mg provided statistically significant reductions from baseline compared with placebo. All 3 doses of aliskiren were generally well tolerated.
Puig
Juan G
JG
Vascular Risk Unit, Department of Internal Medicine, La Paz Hospital, Madrid, Spain.
Schunkert
Heribert
H
Taylor
Addison A
AA
Boye
Sam
S
Jin
James
J
Keefe
Deborah L
DL
D000284:Administration, Oral; D000328:Adult; D000577:Amides / Q000008:administration & dosage* / Q000009:adverse effects; D000959:Antihypertensive Agents / Q000008:administration & dosage* / Q000009:adverse effects; D001794:Blood Pressure / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005060:Europe; D005260:Female; D005650:Fumarates / Q000008:administration & dosage* / Q000009:adverse effects; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000503:physiopathology; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D015990:Placebo Effect; D012720:Severity of Illness Index; D013997:Time Factors; D016896:Treatment Outcome; D014481:United States; D000092502:Renin Inhibitors
D000577:Amides; D000959:Antihypertensive Agents; D005650:Fumarates; D000092502:Renin Inhibitors; C446481:aliskiren