Published online before print January 12, 2009, doi: 10.1161/CIRCULATIONAHA.107.750745
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(Circulation. 2009;119:417-425.)
© 2009 American Heart Association, Inc.
Hypertension |
Long-Term Antihypertensive Efficacy and Safety of the Oral Direct Renin Inhibitor Aliskiren
A 12-Month Randomized, Double-Blind Comparator Trial With Hydrochlorothiazide
From the Department of Nephrology and Hypertension, University of Erlangen-Nürnberg, Erlangen, Germany (R.E.S.); Department of Nephrology, University Hospital, Essen, Germany (T.P.); Department of Nephrology, Hospital San Agustin, Avilés, Spain (J.G., M.G.); Novartis Pharmaceuticals Corporation, East Hanover, NJ (B.S., M.M.); and Novartis Pharma AG, Basel, Switzerland (N.W., J.B., H.v.I.).
Correspondence to Roland E. Schmieder, MD, Department of Nephrology and Hypertension, University of Erlangen-Nürnberg, Krankenhausstrasse 12, 91054 Erlangen, Germany. E-mail Roland.Schmieder{at}rzmail.uni-erlangen.de
Received November 19, 2007; accepted October 14, 2008.
Background— Diuretics are recommended as first-line agents for the treatment of hypertension. This randomized, double-blind, multicenter study assessed the long-term efficacy and safety of the direct renin inhibitor aliskiren in comparison with the diuretic hydrochlorothiazide in patients with essential hypertension.
Methods and Results— After a 2- to 4-week placebo run-in, 1124 patients (mean sitting diastolic blood pressure [BP] 95 to 109 mm Hg) were randomized to aliskiren 150 mg (n=459), hydrochlorothiazide 12.5 mg (n=444), or placebo (n=221) once daily. Forced titration (to aliskiren 300 mg or hydrochlorothiazide 25 mg) occurred at week 3; at week 6, patients receiving placebo were reassigned (1:1 ratio) to aliskiren 300 mg or hydrochlorothiazide 25 mg. From week 12, amlodipine 5 mg was added and titrated to 10 mg from week 18 for patients whose BP remained uncontrolled. Efficacy variables were analyzed for the intent-to-treat population with the use of the last observation carried forward method. BP reductions (mean sitting systolic BP/mean sitting diastolic BP) were significantly greater with aliskiren- versus hydrochlorothiazide-based treatment at week 26 (–20.3/–14.2 versus –18.6/–13.0 mm Hg; P<0.05) and were also greater at week 52 (–22.1/–16.0 versus –21.2/–15.0 mm Hg; P<0.05 for mean sitting diastolic BP). At the end of the monotherapy period (week 12), aliskiren 300 mg was superior to hydrochlorothiazide 25 mg in reducing BP (–17.4/–12.2 versus –14.7/–10.3 mm H; P<0.001). Adverse event rates were similar with aliskiren- (65.2%) and hydrochlorothiazide-based therapy (61.5%). Hypokalemia was more frequent with hydrochlorothiazide-based therapy than aliskiren-based therapy (17.9% versus 0.9%; P<0.0001).
Conclusions— Aliskiren treatment, both as monotherapy and with optional addition of amlodipine, provided significantly greater BP reductions than the respective hydrochlorothiazide regimens. Aliskiren-based therapy was well tolerated. Direct renin inhibition with aliskiren therefore represents an effective option for the long-term treatment of essential hypertension.
CLINICAL PERSPECTIVE
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