Initiating sacubitril/valsartan (LCZ696) in heart failure: Results of TITRATION, a double-blind, randomized comparison of two uptitration regimens
Senni, Michele, McMurray, John J. V., Wachter, Rolf, McIntyre, Hugh F., Reyes, Antonio, Majercak, Ivan, Andreka, Peter, Shehova-Yankova, Nina, Anand, Inder S., Yilmaz, Mehmet B., Gogia, Harinder, Martinez-Selles, Manuel, Fischer, Steffen, Zilahi, Zsolt, Cosmi, Franco, Gelev, Valeri, Galve, Enrique, Gómez-Doblas, Juanjo J., Nociar, Jan, ... Charney, Alan. (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. https://doi.org/10.1002/ejhf.548
|Authors||Senni, Michele, McMurray, John J. V., Wachter, Rolf, McIntyre, Hugh F., Reyes, Antonio, Majercak, Ivan, Andreka, Peter, Shehova-Yankova, Nina, Anand, Inder S., 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 and Charney, Alan|
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.
|Journal||European Journal of Heart Failure|
|Journal citation||18 (9), pp. 1193 - 1202|
|Publisher||John Wiley & Sons Ltd|
|Digital Object Identifier (DOI)||https://doi.org/10.1002/ejhf.548|
|Open access||Open access|
|Page range||1193 - 1202|
|Research Group||Mary MacKillop Institute for Health Research|
© 2016 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
|Place of publication||United Kingdom|
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