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

Michele Senni, John J.V. McMurray, Rolf Wachter, Hugh F. McIntyre, Antonio Reyes, Ivan Majercak, Peter Andreka, Nina Shehova-Yankova, Inder Anand, Mehmet B. Yilmaz, Harinder Gogia, Manuel Martinez-Selles, Steffen Fischer, Zsolt Zilahi, Franco Cosmi, Valeri Gelev, Enrique Galve, Juanjo J. Gómez-Doblas, Jan Nociar, Maria RadomskaBeata Sokolova, Maurizio Volterrani, Arnab Sarkar, Bernard Reimund, Fabian Chen, Alan Charney

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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.

Original languageEnglish
Pages (from-to)1193-1202
Number of pages10
JournalEuropean journal of heart failure
Volume18
Issue number9
DOIs
Publication statusPublished - Sep 1 2016

Keywords

  • ARNI
  • Heart failure
  • LCZ696
  • Sacubitril
  • Tolerability
  • Valsartan

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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    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., ... Charney, A. (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), 1193-1202. https://doi.org/10.1002/ejhf.548