Effect Of Simultaneous Versus Sequential Therapy On Cardiac Function And Left Ventricular Remodeling In Heart Failure And Reduced Ejection Fraction

BackgroundChronic heart failure(CHF)is a complex clinical syndrome characterized by impaired systolic and/or diastolic function caused by numerous etiologies.Furthermore,CHF is the decompensated and end stage of various cardiovascular diseases,which caused serious financial burdens and distress.Compare with the estimated prevalence of 1-2%of the worldwide adult population,in a recent Chinese population-based study conducted in 2019,the morbidity of heart failure was 0.97%,which had increased by 44%since 2004.With the intensification of population aging,the incidence of chronic diseases such as coronary heart disease,hypertension,diabetes,and obesity is on the rise.The improvement in the medical level has prolonged the survival period of patients with heart disease,leading to a continuous increase in the prevalence of CHF.At the same time,the mortality of heart failure within 5 years is>50%,even higher than the mortality of some tumors.The combination of β-blocker,Renin-angiotensin system inhibitor(RASi),and mineralocorticoid receptor antagonist(MRA)has long been recommended by guidelines because it can significantly lower the mortality and rehospitalization rate of patients with heart failure.However,the mortality of heart failure is still at a high level,and more optimized treatment options are urgently required for heart failure treatment.In patients with heart failure and reduced ejection fraction(HFrEF),two further pharmacological approaches—inhibition of neprilysin and sodium-glucose cotransporter 2(SGLT2i)—have been shown to improve survival when added to the original’core’ therapies of a RASi,a beta-blocker and an MRA.Sodium-glucose cotransporter-2 inhibitors(SGLT2i)have been shown to reduce the risk of heart failure hospitalization and cardiovascular death in patients with HFrEF in several trials.In the DAPA-HF trial,treatment with the SGLT2 inhibitor dapagliflozin,added to other guideline-directed medical therapy,SGLT2i compared with placebo reduced the composite of cardiovascular death or HF hospitalization by 26%,irrespective of the presence of type 2 diabetes.The benefit in the reduction of HF hospitalization was greater(30%)in these trials.The risk of cardiovascular death was significantly lowered(18%)with dapagliflozin,as was a risk of all-cause mortality(17%).Subsequently,the EMPEROR-Reduced trial found that empagliflozin reduced the combined primary endpoint of CV death or HF hospitalization by 25%in patients with HFrEF.These landmark data argue for the addition of the SGLT2i class to the therapeutic armamentarium for HFrEF.Based on the landmark DAPA-HF trial and the EMPEROR-Reduced trial,quadruple therapy with an β-blocker,RASi/ARNI,MRA,and SGLT2i for patients with HFrEF has been recommended by the 2021 ESC Guideline for the diagnosis and treatment of acute and chronic heart failure.However,prioritizing the initiation of each medication was not specified in the 2021 ESC HF Guideline.Some experts suggested that the drugs should be administered in sequence according to evidence-based evidence.And some experts also suggest that medications may be started simultaneously at initial and then titrated to the target dose or the maximum tolerated.McMurray et al.proposed a "new sequence" algorithm that involves three steps.Step 1:simultaneous initiation of treatment with a beta-blocker and an SGLT2i.Step 2:addition of sacubitril/valsartan,within 1-2 weeks of Step 1.Step 3:addition an MRA,within 1-2 weeks of Step 2,if serum potassium is normal and renal function is not severely impaired.The 2022 AHA/ACC/HFSA HF Guideline recommended that quadruple therapy can be initiated at low doses or started sequentially without achieving target doses before initiating the next medication.The 2022 China’s Expert Consensus on quadruple therapy emphasized that for all patients with HFrEF when hemodynamics is stable without contraindications,the new quadruple therapy should be started as early as possible.However,so far,there is no study investigating the effects of the initiation timing of SGLT2i on left ventricular remodeling and function.Also,there is no evidence-based medical evidence for the above-mentioned therapeutic regimens of quadruple therapy.In this study,we compare the effects of simultaneous and subsequent therapeutic regimens of quadruple therapy on cardiac structure and function in patients with HFrEF.Objectives1.To compare the effects of simultaneous and sequential strategies on cardiac function and recovery of ventricular remodeling in patients with HFrEF.2.To study the effect of simultaneous and sequential strategies on the titration ofβ-blockers and ARNI and the effect on diuretics and digoxin.3.To study the safety of simultaneous and sequential strategies.Methods1.Study populationThis was a single-center non-randomized control study,which was approved by the Ethics Committee of Qilu Hospital of Shandong University(KYLL-202205-027-1).All patients provided informed written consent.Participants were consecutively collected from outpatients and inpatients with new diagnoses of heart failure between May 2020 and May 2021 in Qilu Hospital.1.1 Inclusion criteria included(1)ages range from 18 to 75 years old,(2)validated heart failure with reduced ejection fraction(HFrEF)which refers to LVEF≤40%determined by using transthoracic echocardiography,(3)New York Heart Association(NYHA)functional class Ⅱ to Ⅳ,(4)N-terminal pro-B-type natriuretic peptide(NT-proBNP)of at least 600 pg per milliliter,patients with atrial fibrillation were required to have an NT-proBNP level of at least 900 pg per milliliter,(5)na(?)ve new diagnoses of heart failure based on baseline echocardiography and NT-proBNP within one week and initially received guideline-directed medical therapy,including low dose β-blocker(<1/4 target dose),RASi/ARNI(<1/4 target dose)and MRA with or without SGLT2i.1.2 Exclusion criteria included(1)acute decompensated HF or previous diagnosis of CHF accepted more than 1/4 target dose of β-blocker and RASi/ARNI,(2)acute coronary syndrome or acute cerebral vascular disease within 3 months,(3)cardiomyopathy based on infiltrative/accumulation diseases,muscular dystrophies,reversible causes,hypertrophic cardiomyopathy,pericardial restriction,peripartum,cardiomyopathy caused by chemotherapy within 12 months,(4)HF primarily resulting from congenital heart disease,(5)lost to follow-up after treatment,(6)type 1 diabetes mellitus,(7)systolic blood pressure of less than 95mmHg,(8)estimated glomerular filtration rate of 30mL/min/1.73m2 or less,(9)known untreated tumors.1.3 GroupingPatients were grouped via the prescribing patterns of guideline-directed medical therapy(GDMT)therapies left to the treating physician.Simultaneous group:β-blocker,RASi/ARNI,MRA,and SGLT2i were prescribed to be taken simultaneously;Sequential group:β-blocker,RASi/ARNI,and MRA were administered firstly,followed by SGLT2i after β-blocker and RASi/ARNI were titrated to target dose or maximum tolerated dose.The β-blockers and RASi/ARNI were started at a low dose(initial dose)and titrated based on GDMT in both groups.2 Data collection2.1 Baseline data collectionThe following data,including gender,age,NYHA functional classification,basic vital signs,and important complications(including coronary heart disease,hypertension,diabetes,and atrial fibrillation),were collected at baseline.2.2 Pharmacotherapy interventionGDMT pharmacotherapies,including RASi/ARNI,β-blocker,MRA,and SGLT2i,were initiated once the patient was hemodynamically stabilized and gradually up-titrated to target dose or maximum tolerated recommended doses according to the China HF guideline.2.3 Echocardiogram examinationTwo-dimensional echocardiography(2DE)was performed by Phillip EPIQ7C system(Philips Ultrasound,Bothell,WA,USA)to evaluate the cardiac function and status of left ventricular(LV)remodeling at the baseline and follow-up period.The echocardiographic parameters,such as LVEF,left ventricular end-diastolic Dimension(LVEDD),Left atrium long-axis dimension(LA-1),and the ratio of early diastolic mitral in flow velocity(E)to early diastolic TDI annular velocities’(E/e’),was performed following the American Society of Echocardiography and the European Association of Cardiovascular Imaging guidelines.We used a modified version of Simpson’s rule to calculate LVEF using the biplane method.3 Study outcomes3.1 The primary efficacy measures were changes in LVEDD,LVEF,and left ventricular reverse remodeling(LVRR).3.2 The secondary efficacy measures included titration time,additional echocardiographic measurements LA-ap,RA-1,RV-1,E/e’,PASP,NT-proBNP,and NYHA functional classification.3.3 The safety outcomes were symptomatic hypotension,urinary tract infection,and worsening renal function.4 Follow-upAll participants would be re-evaluated at 12 weeks after treatment,6 months after bothβ-blocker and RASi/ARNI achieved the target dose or maximum tolerated dose,which are defined as the early follow-up,and end point of follow-up respectively.5 Statistical analysesThe Kolmogorov-Smirnov test assessed the normality of continuous data by presenting the mean+standard deviation for normality variables and the median(interquartile range,IQR)for non-normality variables.Percentages were used to express categorical variables.The student’s t-test or the Mann-Whitney U test was used to compare continuous data according to the normality and homogeneity of variance;the χ2 test was used to compare categorical data.We evaluated the association between different initiation strategies and the LVRR using Logistic Regression Analysis,with prespecified covariates of age,gender,and type 2 diabetes at baseline.We performed an analysis of covariance to compare the outcome difference between the two groups with adjustment of baseline values including age,gender,and diabetes status.A two-tailed P value<0.05 was statistically significant.Analysis of the data was performed using SPSS Statistics 26.0(Chicago,IL,USA).ResultsWe retrospectively collected a total of 173 outpatients and inpatients with a new diagnosis of heart failure between May 2020 and May 2021 in Qilu Hospital of Shan dong University,with the last follow-up on February 18,2022.Finally,a total of 101 consecutive patients were included in this study.1.Patient characteristicsThere is no statistically significant difference between the two groups in terms of age,gender,NYHA functional classification,blood pressure,heart rate,and important complications.Besides,echocardiogram parameters(including LVEF,LVEDD,LA-ap,RA-I,RV-1,E/e’,and PASP)were also similar between groups.For SGLT2i,empagliflozin(6.4%)and dapagliflozin(93.6%)were prescribed in the simultaneous group and no one received SGLT2i therapy in the sequential group at baseline.2.Effect of simultaneous initiation with quadruple medical therapy to cardiac function and Left ventricular remodelingCompared with the sequential group,LVEF was significantly improved at the early follow-up,and it have a greater improvement at the end follow-up in the simultaneous group.LVEDD decreased dramatically and continuously in the simultaneous group than in the sequential group.After adjusted by age,gender,and type 2 diabetes,Logistic regression analysis also indicated that simultaneous initiation with quadruple medical therapy significantly facilitated the improvement of LV systolic function and reversion of LV remodeling(OR,2.834[95%CI,1.184 to 6.784];P=0.019).3.Effect of simultaneous initiation with quadruple medical therapy to other echocardiographic parametersThere were no statistically significant differences in other echocardiographic parameters(including LA-ap,RA-1,RV-1,PASP,and E/e’)during the whole follow-up period.4.Pharmacotherapy titrationSimultaneous initiation with quadruple medical therapy facilitated the up-titration of theβ-blockers and RASi/ARNI.After the follow-up period,there were no differences between the two groups with regard to the number of patients achieving target doses.5.Simultaneous initiation with quadruple medical therapy decreased the usage of diureticAt one month,part of the patients had their dose of diuretic reduced,and this happened more frequently in the simultaneous group than in the sequential group.6.Simultaneous initiation with quadruple medical therapy decreased the usage of digoxinAt the end of the follow-up,part of the patients had stopped digoxin,and this happened more frequently in the simultaneous group than in the sequential group.7.Effect of simultaneous initiation with quadruple medical therapy to NYHA functional classificationThe number of patients in NYHA functional classification Ⅰ/Ⅱ increased in both groups over time.The proportion of patients with a NYHA functional classification enhancement(at least one level or greater)was higher at the end of follow-up than that at 12 weeks in both groups.8.Secondary outcomesCompared with the baseline,NT-proBNP was significantly reduced in both groups,but no statistical difference was seen between the groups.There were no inter-group differences in the change in re-hospitalization and other safety events between the two groups.Conclusions1.Among patients with HFrEF treated with quadruple medical therapy,simultaneous initiation resulted in a remarkable improvement in left ventricular remodeling and function.2.Early initiation of SGLT2i shortened the time needed for up-titration of the β-blockers and RASi/ARNI.