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

Senni, M. et al. (2016) Initiating sacubitril/valsartan (LCZ696) in heart failure: results of TITRATION, a double-blind, randomized comparison of two uptitration regimens. European Journal of Heart Failure, 18(9), pp. 1193-1202. (doi: 10.1002/ejhf.548) (PMID:27170530) (PMCID:PMC5084812)

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: McMurray, Professor John
• Authors: Senni, M., McMurray, J. J.V., Wachter, R., McIntyre, H. F., Reyes, A., Majercak, I., Andreka, P., Shehova-Yankova, N., Anand, I., Yilmaz, M. B., Gogia, H., Martinez-Selles, M., Fischer, S., Zilahi, Z., Cosmi, F., Gelev, V., Galve, E., Gómez-Doblas, J. J., Nociar, J., Radomska, M., Sokolova, B., Volterrani, M., Sarkar, A., Reimund, B., Chen, F., and Charney, A.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: European Journal of Heart Failure
• Publisher: Wiley
• ISSN: 1388-9842
• ISSN (Online): 1879-0844
• Published Online: 12 May 2016
• Copyright Holders: Copyright © 2016 The Authors
• First Published: First published in European Journal of Heart Failure 18(9):1193-1202
• Publisher Policy: Reproduced under a Creative Commons License