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, P. Andréka, 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 Radomska & 6 others Beata Sokolova, Maurizio Volterrani, Arnab Sarkar, Bernard Reimund, Fabian Chen, Alan Charney

Research output: Article

59 Citations (Scopus)

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 - szept. 1 2016

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Heart Failure
Blood Pressure
Angioedema
Hyperkalemia
Angiotensin Receptor Antagonists
Random Allocation
Angiotensin-Converting Enzyme Inhibitors
Hypotension
LCZ 696
Creatinine
Kidney
Serum
Therapeutics

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

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; Andréka, P.; 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.

In: European Journal of Heart Failure, Vol. 18, No. 9, 01.09.2016, p. 1193-1202.

Research output: Article

Senni, M, McMurray, JJV, Wachter, R, McIntyre, HF, Reyes, A, Majercak, I, Andréka, P, Shehova-Yankova, N, Anand, I, Yilmaz, MB, Gogia, H, Martinez-Selles, M, Fischer, S, Zilahi, Z, Cosmi, F, Gelev, V, Galve, E, Gómez-Doblas, JJ, Nociar, J, Radomska, M, Sokolova, B, Volterrani, M, Sarkar, A, Reimund, B, Chen, F & 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, vol. 18, no. 9, pp. 1193-1202. https://doi.org/10.1002/ejhf.548
Senni, Michele ; McMurray, John J V ; Wachter, Rolf ; McIntyre, Hugh F. ; Reyes, Antonio ; Majercak, Ivan ; Andréka, P. ; 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. / Initiating sacubitril/valsartan (LCZ696) in heart failure : results of TITRATION, a double-blind, randomized comparison of two uptitration regimens. In: European Journal of Heart Failure. 2016 ; Vol. 18, No. 9. pp. 1193-1202.
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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-na{\"i}ve 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.",
keywords = "ARNI, Heart failure, LCZ696, Sacubitril, Tolerability, Valsartan",
author = "Michele Senni and McMurray, {John J V} and Rolf Wachter and McIntyre, {Hugh F.} and Antonio Reyes and Ivan Majercak and P. Andr{\'e}ka and Nina Shehova-Yankova and Inder Anand and Yilmaz, {Mehmet B.} and Harinder Gogia and Manuel Martinez-Selles and Steffen Fischer and Zsolt Zilahi and Franco Cosmi and Valeri Gelev and Enrique Galve and G{\'o}mez-Doblas, {Juanjo J.} and Jan Nociar and Maria Radomska and Beata Sokolova and Maurizio Volterrani and Arnab Sarkar and Bernard Reimund and Fabian Chen and Alan Charney",
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TY - JOUR

T1 - Initiating sacubitril/valsartan (LCZ696) in heart failure

T2 - results of TITRATION, a double-blind, randomized comparison of two uptitration regimens

AU - Senni, Michele

AU - McMurray, John J V

AU - Wachter, Rolf

AU - McIntyre, Hugh F.

AU - Reyes, Antonio

AU - Majercak, Ivan

AU - Andréka, P.

AU - Shehova-Yankova, Nina

AU - Anand, Inder

AU - Yilmaz, Mehmet B.

AU - Gogia, Harinder

AU - Martinez-Selles, Manuel

AU - Fischer, Steffen

AU - Zilahi, Zsolt

AU - Cosmi, Franco

AU - Gelev, Valeri

AU - Galve, Enrique

AU - Gómez-Doblas, Juanjo J.

AU - Nociar, Jan

AU - Radomska, Maria

AU - Sokolova, Beata

AU - Volterrani, Maurizio

AU - Sarkar, Arnab

AU - Reimund, Bernard

AU - Chen, Fabian

AU - Charney, Alan

PY - 2016/9/1

Y1 - 2016/9/1

N2 - 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.

AB - 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.

KW - ARNI

KW - Heart failure

KW - LCZ696

KW - Sacubitril

KW - Tolerability

KW - Valsartan

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DO - 10.1002/ejhf.548

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VL - 18

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