Efficacy and Safety of Sacubitril/Valsartan in Japanese Patients With Chronic Heart Failure and Reduced Ejection Fraction　― Results From the PARALLEL-HF Study ―

Abstract

Background: In the Prospective Comparison of angiotensin receptor neprilysin inhibitor (ARNI) With ACEi to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) study, treatment with sacubitril/valsartan reduced the primary outcome of cardiovascular (CV) death and heart failure (HF) hospitalization compared with enalapril in patients with chronic HF and reduced ejection fraction (HFrEF). A prospective randomized trial was conducted to assess the efficacy and safety of sacubitril/ valsartan in Japanese HFrEF patients. Methods and Results: In the Prospective comparison of ARNI with ACEi to determine the noveL beneficiaL trEatment vaLue in Japanese Heart Failure patients (PARALLEL-HF) study, 225 Japanese HFrEF patients (New York Heart Association [NYHA] class II-IV, left ventricular ejection fraction [LVEF] ≤35%) were randomized (1 : 1) to receive sacubitril/valsartan 200 mg bid or enalapril 10 mg bid. Over a median follow up of 33.9 months, no significant between-group difference was observed for the primary composite outcome of CV death and HF hospitalization (HR 1.09; 95% CI 0.65-1.82; P=0.6260). Early and sustained reductions in N-terminal pro-brain natriuretic peptide (NT-proBNP) from baseline were observed with sacubitril/valsartan compared with enalapril (between-group difference: Week 2: 25.7%, P<0.01; Month 6: 18.9%, P=0.01, favoring sacubitril/valsartan). There was no significant difference in the changes in NYHA class and Kansas City Cardiomyopathy Questionnaire (KCCQ) clinical summary score at Week 8 and Month 6. Sacubitril/valsartan was well tolerated with fewer study drug discontinuations due to adverse events, although the sacubitril/valsartan group had a higher proportion of patients with hypotension. Conclusions: In Japanese patients with HFrEF, there was no difference in reduction in the risk of CV death or HF hospitalization between sacubitril/valsartan and enalapril, and sacubitril/valsartan was safe and well tolerated.

JCS/JHFS 2021 Guideline Focused Update on Diagnosis and Treatment of Acute and Chronic Heart Failure

“…Early and sustained reductions in NT-proBNP from baseline were observed with sacubitril/valsartan compared with enalapril (between-group difference at week 2 of 25.7% [P < .01] and at month 6 of 18.9% [P = .01], favoring sacubitril/valsartan). 60 In contrast, in the PARAGON-HF study involving patients with heart failure retaining LVEF (HFpEF) including Japanese patients, the sacubitril/valsartan group and valsartan group were compared and significant differences were not observed in the composite primary end point of total (first and recurrent) hospitalizations for heart failure and cardiovascular death. However, in a subgroup analysis specified beforehand, significant effects of sacubitril/valsartan were noted in the primary end point, female or a LVEF of 57% or less.…”

“…In the PARALLEL-HF study involving Japanese, a 36-hour washout period, about 3 times longer than the elimination half-life of ACE inhibitors and LBQ657, was set, and no obvious angioedema was observed. 60 For the actual use, it is recommended to discontinue ACE inhibitor administration 36 hours before the initiation of sacubitril/valsartan administration and combination with ACE inhibitors is contraindicated. Amyloid b is known as a substrate of neprilysin.…”

JCS/JHFS 2021 Guideline Focused Update on Diagnosis and Treatment of Acute and Chronic Heart Failure

“…Early and sustained reductions in NT-proBNP from baseline were observed with sacubitril/valsartan compared with enalapril (betweengroup difference at week 2 of 25.7% [P<0.01] and at month 6 of 18.9% [P=0.01], favoring sacubitril/valsartan). 60 In contrast, in the PARAGON-HF study involving patients with heart failure retaining LVEF (HFpEF) including Japanese patients, the sacubitril/valsartan group and valsartan group were compared and significant differences were not observed in the composite primary end point of total (first and recurrent) hospitalizations for heart failure and cardiovascular death. However, in a subgroup analysis specified beforehand, significant effects of sacubitril/valsartan were noted in the primary end point, female or a LVEF of 57% or less.…”

“…In the PARALLEL-HF study involving Japanese, a 36-hour washout period, about 3 times longer than the elimination half-life of ACE inhibitors and LBQ657, was set, and no obvious angioedema was observed. 60 For the actual use, it is recommended to discontinue ACE inhibitor administration 36 hours before the initiation of sacubitril/ valsartan administration and combination with ACE inhibitors is contraindicated. Amyloid β is known as a substrate of neprilysin.…”

DataSheet2.doc

“…Among the 10 studies, one study (United Kingdom HARP-III, 414 patients, 15 of them reported heart failure) assessed CKD patients with an eGFR of 20-60 ml/min/1.73 m 2 , one study [Post-STEMI (Rezq et al, 2021), 200 patients] assessed patients after ST-segment elevation myocardial infarction. Five studies [54.9%, 10,085/ 18,362, PARADIGM (McMurray et al, 2014), PIONEER (Velazquez et al, 2019), EVALUATE (Desai et al, 2019), PRIME (Kang et al, 2019), and PARALLEL (Tsutsui et al, 2021)] assessed patients with HFrEF, while the other three…”