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

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) prece...

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Published in:	European journal of heart failure Vol. 18; no. 9; pp. 1193 - 1202
Main Authors:	Senni, Michele, McMurray, John J.V., Wachter, Rolf, McIntyre, Hugh F., Reyes, Antonio, Majercak, Ivan, Andreka, Peter, Shehova-Yankova, Nina, Anand, Inder, Yilmaz, Mehmet B., Gogia, Harinder, Martinez-Selles, Manuel, Fischer, Steffen, Zilahi, Zsolt, Cosmi, Franco, Gelev, Valeri, Galve, Enrique, Gómez-Doblas, Juanjo J., Nociar, Jan, Radomska, Maria, Sokolova, Beata, Volterrani, Maurizio, Sarkar, Arnab, Reimund, Bernard, Chen, Fabian, Charney, Alan
Format:	Journal Article
Language:	English
Published:	Oxford, UK John Wiley & Sons, Ltd 01-09-2016
Subjects:	Aged Aminobutyrates - administration & dosage Angiotensin Receptor Antagonists - administration & dosage ARNI Biphenyl Compounds Double-Blind Method Drug Combinations Female Heart failure Heart Failure - drug therapy Humans Hyperkalemia - chemically induced Hypotension - chemically induced LCZ696 Male Medical Treatment Middle Aged Neprilysin - antagonists & inhibitors Renal Insufficiency - chemically induced Sacubitril Tetrazoles - administration & dosage Tolerability Treatment Outcome Valsartan Heart failure ARNI LCZ696 Tolerability Valsartan Sacubitril
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Summary:	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.
Bibliography:	Novartis Pharmaceuticals Corporation, USA Appendix S1. Principal investigators (responsible for data collection). Appendix S2. Tolerability in patients switched to open-label sacubitril/valsartan after randomization (treatment failures), study drug discontinuation and overall safety. Table S1. Definition of low-dose and high-dose ACEI/ARB inhibition strata based on pre-study ACEI/ARB total daily dose at screening. Table S2. Hazard rates and ratios for pre-specified AEs, SBP <95 mmHg, and laboratory criteria. Table S3. Discontinuations for AEs during the run-in and post-randomization periods. Table S4. Most common AEs (at least 2% in either uptitration group) in the post-randomized phase. ark:/67375/WNG-HDNM5M2D-D istex:DC5885BA819D87EFB2119B7E609C880EBC183F08 ArticleID:EJHF548 ClinicalTrials.gov Identifier: NCT01922089.
ISSN:	1388-9842 1879-0844
DOI:	10.1002/ejhf.548