Effects Of Sacubitril/valsartan On Clinical Efficacy During The Vulnerable Period And Short-term Myocardial Remodelingin Patients With Acute Decompensated Heart Failure And Reduced Ejection Fraction

Objective:Patients with acute decompensated heart failure(ADHF)are usually in a vulnerable phase(VP)within 3 months after discharge,during which a high mortality rate and high readmission rate are clinical characteristics.Previous studies have shown that sacubitril/valsartan(S/V)can improve the prognosis of chronic stable heart failure(HF)and reduce n-terminal pro-B-type natriuretic peptide(NT-pro BNP)levels in ADHF patients.However,few studies have been conducted to evaluate the safety and efficacy of S/V in treating ADHF patients.Therefore,This study explores that whether an angiotensin-converting enzyme inhibitor(ACEI)or angiotensin-receptor blocker(ARB)can reduce the rate of death from cardiovascular causes and rehospitalizations for HF compared to S/V treatment in patients with ADHF during the VP and whether it is safe to use S/V early in the VP and throughout the VP;we also observed the effect of S/V on myocardial remodeling in ADHF patients.Methods:According to the inclusion and exclusion standards,patients with ADHF and reduced ejection fraction were successively enrolled in 4research cardiology centres,with a screening period of 1-7 days after admission;left ventricular ejection fraction(LVEF),NT-pro BNP,electrolytes,liver and kidney function and related biomarker levels were evaluated.Patients were divided into the S/V or ACEI/ARB group according to the clinical prescribing information.During hospitalization and after discharge,the doctor titrated the test drug dose according to the patient’s condition and blood pressure.The primary endpoint was the composite of death from cardiovascular causes and rehospitalization for HF within 90 days,the effect of S/V treatment on myocardial remodeling after 12 months,and the secondary efficacy endpoint was changes in the New York Heart Association(NYHA)classification after 90days.The safety endpoint was a composite of worsening renal function,hyperkalaemia,cough,angioneurotic oedema,and symptomatic hypotension within 90 days.Results:From May 2018 to October 2019,a total of 758 patients using S/V or an ACEI/ARB were enrolled,of which 127 were excluded according to the inclusion criteria,631 were included for propensity score matching,and 502patients were included in the data analysis.In total,251 patients who received S/V and 251 patients who received an ACEI/ARB had similar propensity scores and were included and compared.At the follow-up 90 days after discharge,in the S/V group and ACEI/ARB group,the incidences of the primary outcome measure(cardiovascular causes and rehospitalization for HF)were 15.9%and23.5%,respectively(HR,0.650;95%CI,0.435～0.971;P=0.035),the incidences of cardiovascular death were 2.4%and 7.5%,respectively(HR,0.308;95%CI,0.123～0.771;P=0.012),and the incidences of HF rehospitalization were 13.5%and 15.9%(HR,0.811;95%CI,0.513～1.281;P=0.368);the secondary efficacy endpoint of proportion with an improved NYHA grade were 72.1%and 59.8%,respectively(HR,1.303;95%CI 1.097～1.548,P=0.004).At the safety end point in the S/V group and ACEI/ARB group,the incidences of worsening renal function were 11.2%and 10.8%,respectively(RR,1.021;95%CI,0.768 to 1.357;P=0.886);the incidence of hyperkalaemia in both groups was 2.0%(RR,0.992;95%CI,0.530 to 1.855;P=0.886).The incidences of symptomatic hypotension were 8.4%and 5.6%,respectively(RR,1.269;95%CI,0.837 to 1.922;P=0.220);the incidences of cough were 5.6%and 7.6%,respectively(RR,0.859;95%CI,0.632 to 1.168;P=0.368).There was no angioedema in either group.The incidences of test drug withdrawal due to adverse events in the two groups were 5.6%and 4.8%,respectively(RR,1.167;95%CI,0.551 to 2.472;P=0.687).In the subgroup analysis,S/V treatment reduced the composite measure of death from cardiovascular causes and rehospitalizations for HF in patients with ischaemic cardiomyopathy,NYHA class Ⅲ/Ⅳ and the absence of atrial fibrillation.After an average of 315days of S/V treatment,the LVEF increased by 6.0%(P<0.001),left ventricular shortening rate increased by 4.0%(P<0.001),stroke volume increased by 9.8ml(P=0.005),left ventricular anteroposterior diameter decreased by 1.9 mm(P=0.014),left atrial anteroposterior diameter decreased by 2.0 mm(P<0.001),right atrial transverse diameter decreased by 4.0 mm(P=0.025),tricuspid regurgitation area decreased by 2.8 cm~2(P<0.001),mitral regurgitation area decreased by 1.7 cm~2(P<0.001),pulmonary artery pressure decreased by 11.0mm Hg(P<0.001),and the level of tricuspid regurgitation(P=0.007),mitral regurgitation(P<0.001)and aortic regurgitation(P<0.001)improved.The right ventricle transverse diameter(P=0.786),left ventricle end-diastolic volume(P=0.403),E/e’(P=0.117)and aortic regurgitation area(P=0.925)were not significantly affected.Conclusion:Among patients hospitalized with ADHF and a reduced left ventricular ejection fraction,we observed that S/V therapy led to a reduction in the number of deaths from cardiovascular causes and rehospitalizations for heart failure compared to ACEI/ARB therapy alone during the vulnerable phase.Our results support that S/V may be administered early in the vulnerable phase after ADHF and improves NYHA class.S/V may have potential benefits in patients with ischaemic cardiomyopathy,an LVEF≤32.0%,NYHA cardiac function grade Ⅲ/Ⅳ,and non-atrial fibrillation.S/V treatment also improved the myocardial remodeling of ADHF.