Efficacy and Safety of Crystalline Valsartan/Sacubitril (LCZ696) Compared With Placebo and Combinations of Free Valsartan and Sacubitril in Patients With Systolic Hypertension: The RATIO Study.
We compared the systolic blood pressure (SBP)-lowering efficacy and safety of crystalline valsartan/sacubitril (LCZ696, an angiotensin receptor blocker-neprilysin inhibitor) 400 mg daily against valsartan (320 mg once daily) alone or coadministered with placebo or increasing doses of free sacubitril (50, 100, 200, or 400 mg once daily) to identify the optimal antihypertensive combination dose. This multicenter, double-blinded, 7-arm parallel-group study recruited patients with mild-to-moderate systolic hypertension (office SBP 150-179 mm Hg). Primary-dependent variable was change in office SBP from baseline to week 8. At entry (n = 907), mean age was 61.5 years, sitting office BP 160/90.2 mm Hg, and mean 24-hour ambulatory BP 142/82.1 mm Hg; 852 participants completed the study. At week 8, there were greater reductions in sitting office SBP and 24-hour ambulatory SBP with LCZ696 400 mg than with valsartan 320 mg (-5.7 and -3.4 mm Hg, respectively, P < 0.05 each). The SBP reduction with LCZ696 400 daily was similar to coadministered free valsartan 320 mg and sacubitril 200 mg. Effects were similar in those older and younger than 65 years, and active therapies had adverse event rates similar to placebo. We conclude that crystalline valsartan/sacubitril 400 mg daily (1) is superior to valsartan 320 mg daily for lowering SBP, (2) has similar efficacy to the combination of free valsartan 320 mg plus free sacubitril 200 mg, (3) represents the optimal dosage for systolic hypertension in patients of any age, and (4) is safe and well tolerated.
*Department of Medicine, State University of New York, Buffalo, NY; †Novartis Pharmaceuticals Corporation, East Hanover, NJ; ‡Eisai Inc, Woodcliff Lake, NJ; and §Alcon Laboratories, Inc, (A Novartis Division), Fort Worth, TX.
Joseph L
JL
Izzo
Dion H
DH
Zappe
Yan
Y
Jia
Kudsia
K
Hafeez
Jack
J
Zhang
D000368:Aged; D000613:Aminobutyrates / Q000008:administration & dosage* / Q000009:adverse effects; D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage* / Q000009:adverse effects; D000959:Antihypertensive Agents / Q000008:administration & dosage* / Q000009:adverse effects; D001118:Argentina; D001713:Biphenyl Compounds; D001794:Blood Pressure / Q000187:drug effects*; D004311:Double-Blind Method; D004338:Drug Combinations; D005060:Europe; D005260:Female; D006801:Humans; D006973:Hypertension / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology; D007194:India; D008297:Male; D008875:Middle Aged; D015260:Neprilysin / Q000037:antagonists & inhibitors / Q000378:metabolism; D009656:North America; D011480:Protease Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D056910:Republic of Korea; D013599:Systole; D013777:Tetrazoles / Q000008:administration & dosage* / Q000009:adverse effects; D013997:Time Factors; D016896:Treatment Outcome; D000068756:Valsartan / Q000008:administration & dosage* / Q000009:adverse effects
D000613:Aminobutyrates; D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D004338:Drug Combinations; D011480:Protease Inhibitors; D013777:Tetrazoles; D000068756:Valsartan; D015260:Neprilysin; C549068:sacubitril and valsartan sodium hydrate drug combination