Initiating sacubitril/valsartan (LCZ696) in heart failure: results of TITRATION, a double-blind, randomized comparison of two uptitration regimens
Tarih
2016Yazar
Senni, MicheleMcMurray, 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
Gomez-Doblas, Juanjo J.
Nociar, Jan
Radomska, Maria
Sokolova, Beata
Volterrani, Maurizio
Sarkar, Arnab
Reimund, Bernard
Chen, Fabian
Charney, Alan
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AimsTo 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 resultsA 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-naive 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'. ConclusionsInitiation/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.
Kaynak
EUROPEAN JOURNAL OF HEART FAILURECilt
18Sayı
9Koleksiyonlar
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