title: Initiating sacubitril/valsartan (LCZ696) in heart failure: results of TITRATION, a double-blind, randomized comparison of two uptitration regimens.
abstract: To assess the tolerability of initiating/uptitrating sacubitril/valsartan (LCZ696) from 50 to 200 mg twice daily (target dose) over 3 and 6 weeks in heart failure (HF) patients (ejection fraction ≤35%).
  
  
  
  A 5-day open-label run-in (sacubitril/valsartan 50 mg twice daily) preceded an 11-week, double-blind, randomization period [100 mg twice daily for 2 weeks followed by 200 mg twice daily ('condensed' regimen) vs. 50 mg twice daily for 2 weeks, 100 mg twice daily for 3 weeks, followed by 200 mg twice daily ('conservative' regimen)]. Patients were stratified by pre-study dose of angiotensin-converting enzyme inhibitor/angiotensin-receptor blocker (ACEI/ARB; low-dose stratum included ACEI/ARB-naïve patients). Of 540 patients entering run-in, 498 (92%) were randomized and 429 (86.1% of randomized) completed the study. Pre-defined tolerability criteria were hypotension, renal dysfunction and hyperkalaemia; and adjudicated angioedema, which occurred in ('condensed' vs. 'conservative') 9.7% vs. 8.4% (P = 0.570), 7.3% vs. 7.6% (P = 0.990), 7.7% vs. 4.4% (P = 0.114), and 0.0% vs. 0.8% of patients, respectively. Corresponding proportions for pre-defined systolic blood pressure <95 mmHg, serum potassium >5.5 mmol/L, and serum creatinine >3.0 mg/dL were 8.9% vs. 5.2% (P = 0.102), 7.3% vs. 4.0% (P = 0.097), and 0.4% vs. 0%, respectively. In total, 378 (76%) patients achieved and maintained sacubitril/valsartan 200 mg twice daily without dose interruption/down-titration over 12 weeks (77.8% vs. 84.3% for 'condensed' vs. 'conservative'; P = 0.078). Rates by ACEI/ARB pre-study dose stratification were 82.6% vs. 83.8% (P = 0.783) for high-dose/'condensed' vs. high-dose/'conservative' and 84.9% vs. 73.6% (P = 0.030) for low-dose/'conservative' vs. low-dose/'condensed'.
  
  
  
  Initiation/uptitration of sacubitril/valsartan from 50 to 200 mg twice daily over 3 or 6 weeks had a tolerability profile in line with other HF treatments. More gradual initiation/uptitration maximized attainment of target dose in the low-dose ACEI/ARB group.
authors.affiliation: Cardiology, Heart Failure and Heart Transplant Unit, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Piazza OMS, 24127, Bergamo, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Senni
authors.affiliation: British Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, UK.
authors.forename: John J V
authors.initials: JJ
authors.lastname: McMurray
authors.affiliation: University Medicine Goettingen, Clinic for Cardiology and Pneumology, Goettingen, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Wachter
authors.affiliation: Hon Reader in Medicine, Brighton and Sussex Medical School, UK.
authors.forename: Hugh F
authors.initials: HF
authors.lastname: McIntyre
authors.affiliation: University Hospital Virgen de Valme, Medicina Interna, Sevilla, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Reyes
authors.affiliation: Outpatient Internal Medicine, Cardiology, Kosice, Slovakia.
authors.forename: Ivan
authors.initials: I
authors.lastname: Majercak
authors.affiliation: Gottsegen Gyorgy, Orszagos Kardiologiai Intezet, Felnott Kardiologiai Osztaly, Budapest, Hungary.
authors.forename: Peter
authors.initials: P
authors.lastname: Andreka
authors.affiliation: MHAT Bratan Shukerov, Cardiology Department, Smolian, Bulgaria.
authors.forename: Nina
authors.initials: N
authors.lastname: Shehova-Yankova
authors.affiliation: Veterans Medical Center -Minneapolis, Minneapolis, MN, USA.
authors.forename: Inder
authors.initials: I
authors.lastname: Anand
authors.affiliation: Cumhuriyet University Medical Faculty Cardiology, Sivas, Turkey.
authors.forename: Mehmet B
authors.initials: MB
authors.lastname: Yilmaz
authors.affiliation: Cardiology Consultants of Orange County, Anaheim, CA, USA.
authors.forename: Harinder
authors.initials: H
authors.lastname: Gogia
authors.affiliation: Hospital Gregorio Maranon, Servicio de Cardiologia, and Universidad Europea y Universidad Complutense, Madrid, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Martinez-Selles
authors.affiliation: Praxis Dr Fischer, Leipzig, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Fischer
authors.affiliation: Kardiologiai Szakrendeles, Nyiregyháza, Hungary.
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Zilahi
authors.affiliation: P.O. Ospedale Valdichiana S. Margherita, U.O. di Cardiologia, Cortona, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Cosmi
authors.affiliation: MHAT Tokuda Hospital Sofia, Clinic of Cardiology and Angio, Sofia, Bulgaria.
authors.forename: Valeri
authors.initials: V
authors.lastname: Gelev
authors.affiliation: Hospital Vall D'Hebron, Cardiology, Paseo Valle de Hebron, Barcelona, Spain.
authors.forename: Enrique
authors.initials: E
authors.lastname: Galve
authors.affiliation: Hospital Virgen de la Victoria, Cardiologia, Campus Universitario Teatinos, Malaga, Spain.
authors.forename: Juanjo J
authors.initials: JJ
authors.lastname: Gómez-Doblas
authors.affiliation: Kardio 1 s.r.o., Lucenec, Slovakia.
authors.forename: Jan
authors.initials: J
authors.lastname: Nociar
authors.affiliation: Letesia s.r.o., Trebisov, Slovakia.
authors.forename: Maria
authors.initials: M
authors.lastname: Radomska
authors.affiliation: Galenum s.r.o., Ambulancia v odbore Vutorne Lekarstvo, Bratislava, Slovakia.
authors.forename: Beata
authors.initials: B
authors.lastname: Sokolova
authors.affiliation: IRCCS San Raffaele Pisana, Rome, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Volterrani
authors.affiliation: Novartis HC Ltd, Hyderabad, India.
authors.forename: Arnab
authors.initials: A
authors.lastname: Sarkar
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Bernard
authors.initials: B
authors.lastname: Reimund
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: Fabian
authors.initials: F
authors.lastname: Chen
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Charney
mesh_terms: D000368:Aged; D000613:Aminobutyrates / Q000008:administration & dosage*; D057911:Angiotensin Receptor Antagonists / Q000008:administration & dosage*; D001713:Biphenyl Compounds; D004311:Double-Blind Method; D004338:Drug Combinations; D005260:Female; D006333:Heart Failure / Q000188:drug therapy*; D006801:Humans; D006947:Hyperkalemia / Q000139:chemically induced; D007022:Hypotension / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D051437:Renal Insufficiency / Q000139:chemically induced; D013777:Tetrazoles / Q000008:administration & dosage*; D016896:Treatment Outcome; D000068756:Valsartan
chemical_list: D000613:Aminobutyrates; D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D004338:Drug Combinations; D013777:Tetrazoles; D000068756:Valsartan; D015260:Neprilysin; C549068:sacubitril and valsartan sodium hydrate drug combination
keywords: ARNI; Heart failure; LCZ696; Sacubitril; Tolerability; Valsartan