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Eur J Heart Fail. 2016 Sep;18(9):1193-202. doi: 10.1002/ejhf.548. Epub 2016 May 12.

Initiating sacubitril/valsartan (LCZ696) in heart failure: results of TITRATION, a double-blind, randomized comparison of two uptitration regimens.

Author information

1
Cardiology, Heart Failure and Heart Transplant Unit, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Piazza OMS, 24127, Bergamo, Italy.
2
British Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, UK.
3
University Medicine Goettingen, Clinic for Cardiology and Pneumology, Goettingen, Germany.
4
Hon Reader in Medicine, Brighton and Sussex Medical School, UK.
5
University Hospital Virgen de Valme, Medicina Interna, Sevilla, Spain.
6
Outpatient Internal Medicine, Cardiology, Kosice, Slovakia.
7
Gottsegen Gyorgy, Orszagos Kardiologiai Intezet, Felnott Kardiologiai Osztaly, Budapest, Hungary.
8
MHAT Bratan Shukerov, Cardiology Department, Smolian, Bulgaria.
9
Veterans Medical Center -Minneapolis, Minneapolis, MN, USA.
10
Cumhuriyet University Medical Faculty Cardiology, Sivas, Turkey.
11
Cardiology Consultants of Orange County, Anaheim, CA, USA.
12
Hospital Gregorio Maranon, Servicio de Cardiologia, and Universidad Europea y Universidad Complutense, Madrid, Spain.
13
Praxis Dr Fischer, Leipzig, Germany.
14
Kardiologiai Szakrendeles, Nyiregyháza, Hungary.
15
P.O. Ospedale Valdichiana S. Margherita, U.O. di Cardiologia, Cortona, Italy.
16
MHAT Tokuda Hospital Sofia, Clinic of Cardiology and Angio, Sofia, Bulgaria.
17
Hospital Vall D'Hebron, Cardiology, Paseo Valle de Hebron, Barcelona, Spain.
18
Hospital Virgen de la Victoria, Cardiologia, Campus Universitario Teatinos, Malaga, Spain.
19
Kardio 1 s.r.o., Lucenec, Slovakia.
20
Letesia s.r.o., Trebisov, Slovakia.
21
Galenum s.r.o., Ambulancia v odbore Vutorne Lekarstvo, Bratislava, Slovakia.
22
IRCCS San Raffaele Pisana, Rome, Italy.
23
Novartis HC Ltd, Hyderabad, India.
24
Novartis Pharma AG, Basel, Switzerland.
25
Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.

Abstract

AIMS:

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%).

METHODS AND RESULTS:

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'.

CONCLUSIONS:

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.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT01922089.

KEYWORDS:

ARNI; Heart failure; LCZ696; Sacubitril; Tolerability; Valsartan

PMID:
27170530
PMCID:
PMC5084812
DOI:
10.1002/ejhf.548
[Indexed for MEDLINE]
Free PMC Article

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