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

Abstract

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‐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’.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.

Sex Influence on the Efficacy and Safety of Sacubitril/Valsartan

“…In the Prospective comparison of angiotensin receptor neprilysin inhibitor with angiotensin-converting enzyme inhibitor to Determine Impact on Global Mortality and morbidity in Heart Failure (PARADIGM-HF) trial [10], treatment with SV was superior to enalapril in reducing mortality and heart failure readmissions. It should be noted that only 21% of patients included in this pivotal trial and in the TITRATION trial were women [10, 11]. In real life, the proportion of women receiving SV is higher [12].…”

Angiotensin Receptor Neprilysin Inhibitor in Japanese Patients With Heart Failure and Reduced Ejection Fraction ― Baseline Characteristics and Treatment of PARALLEL-HF Trial ―

“…9 The majority (93.3%) of patients in PARALLEL-HF were receiving an ACEI/ARB at a dose equivalent to ≤10 mg enalapril before entering the study. Although the target dose of sacubitril/valsartan was well tolerated in most patients receiving low doses of ACEIs/ARBs in the TITRATION study, 17 the results from the PARALLEL-HF study will provide further insights into the tolerability of the target dose of sacubitril/valsartan in Japanese HFrEF patients, who are associated with lower SBP and receiving lower maintenance doses of ACEIs/ARBs at study entry.…”

Angioedema Spotlight: A Closer Examination of Sacubitril/Valsartan Safety Results

“…4 bitril/valsartan indicated a low risk of angioedema in approximately 650 patients, they were short (only 12 weeks). 6,7 The phase III study, PARADIGM-HF, examined 8442 patients at a median follow-up of 27 months, which helped better estimate angioedema incidence, a secondary safety end point of the trial. 1 Patients with a history of angioedema were excluded from the trial at enrollment.…”