A Retrospective Study Of Guideline-Directed Medical Therapy In The Outpatient With Chronic HFrEF And Their Tolerability Of Treatment With ARNI

Thesis I:A Retrospective Study of Guideline-Directed Medical Therapy in the Outpatient with Chronic HFrEFBackgroundHeart failure is the final manifestation of all kinds of cardiovascular diseases,and it is also the "fortress" that has not been broken up to now.Heart failure is characterized by long hospitalization time,high mortality rate,high readmission rate and poor prognosis.The treatment goals of chronic heart failure with reduced ejection fraction（HFrEF）are to improve the quality of life,to prevent or reverse cardiac remodeling,reduce hospitalization rate and mortality of patients.With the further understanding of heart failure,the concept of heart failure treatment is constantly updated.ACEI/ARB/ARNI,β-blocker and MRA,as the"Golden Triangle" drugs for the treatment of heart failure,can effectively prevent or reverse ventricular remodeling,prolong the survival of patients,and obtain high level recommendations in national guidelines.However,the guideline-directed medical therapy（GDMT）in heart failure still has great deficiencies,and the application of neuroendocrine antagonists still has problems such as low utilization rate and low target dose ratio.In a multi-national,multicenter Asian-HF registry in Asia,12.2%of patients received target dose of ACEI/ARB,and 9.7%of patients received target dose of β-blocker.According to the latest REALITY-HF study,56.6%of HFrEF patients were dosed with ARNI,but the proportion of patients reaching the target dose of ARNI at 6 months was only 1.6%.According to national heart failure guidelines,the GDMT should be combined withβ-blocker and ACEI/ARB/ARNI,and gradually titrated to the target dose or maximum tolerated dose.However,there is still a problem in our country that the use rate of β-blocker and ACEI/ARB/ARNI is not high,and the ratio of the target dose is very low.And the problem has not been resolved.The main reason for this problem is that the doctor’s philosophy or the poor tolerance of patients with heart failure to the drugs is still unclear.Multi-national heart failure guidelines emphasize that the dose should reach the target dose or the maximum tolerated dose during the treatment.However,it is not clear whether there is a difference in the effect of β-blocker and ACEI/ARB/ARNI target dose on the improvement of cardiac function in patients compared with the maximum tolerated dose.More research data is still needed to confirm.There are few studies in this area,and all of them are "hard" clinical endpoints such as mortality,and there are no reports of such studies in China.Based on this,we designed this retrospective real-world study.Objective1.To study the ratio of β-blocker and ACEI/ARB/ARNI to the target dose recommended by the guidelines and the improvement of left ventricular remodeling and cardiac function in patients with chronic HFrEF after GDMT.2.To explore the feasibility and safety of using β-blocker and ACEI/ARB/ARNI to achieve target doses in patients with chronic heart failure in China.3.Verify that after optimized medical therapies in patients with chronic HFrEF,whetherβ-blocker and ACEI/ARB/ARNI reach the target dose and reach the clinical maximum tolerated dose are different in the effect of LVEF improvement in patients with heart failure.Materials and MethodsSelected patientsWe collected patients according to inclusion and exclusion criteria.All patients were admitted to the Heart Failure Clinic of Shandong University Qilu Hospital.Inclusion criteria:（1）Meet the diagnostic criteria for chronic heart failure in the China Guidelines for the Diagnosis and Treatment of Heart Failure in 2018:Pre-existing symptoms and/or signs of heart failure,LVEF≤40%,NYHA Class Ⅱ～Ⅳ;（2）Age≥18 years old;（3）Regular outpatient follow-up.Exclusion criteria:（1）The condition is poorly controlled and has developed to terminal heart failure;（2）Complicated with severe hepatic and renal insufficiency（Child-Pugh class C,GFR<30ml/min/1.73m 2）;（3）Complicated with malignant tumor;（4）The patient’s compliance is poor,and regular follow-up in the outpatient department is not possible.Outpatient follow-up management methodsThe selected patients start with low-dose β-blocker and ACEI/ARB/ARNI,and follow up every 2-4 weeks,and gradually adjust the drug dose according to the patient’s symptoms,family self-tested blood pressure and heart rate,until β-blocker and ACEI/ARB/ARNI titrated to the target dose or maximum tolerated dose.The follow-up was 6 months,and the information of each follow-up was entered into the designed electronic form.When the 6-month follow-up time is reached,regardless of whether the target dose or the maximum tolerated dose is reached,we recheck the patient’s laboratory parameters and echocardiography.And we record the results in the electronic follow-up form.The information of visit is recorded in the patient’s outpatient medical record.GroupPatients whose β-blocker and ACEI/ARB/ARNI doses reached the target dose recommended by the guidelines were considered the target dose group.The drug dose when the heart rate is 55～60 beats/min and/or the blood pressure is close to but not lower than 90/60 mmHg is recorded as the maximum tolerated dose.（1）Target dose group:β-blockers and ACEI/ARB/ARNI are all titrated to the target dose recommended by the guidelines;（2）Maximum tolerated dose group:β-blockers and/or ACEI/ARB/ARNI have not been titrated to the target dose recommended by the guidelines but have reached the clinical maximum tolerated dose.Data collection and analysisThe patients’ gender,age,lifestyle,etiology and complications,medications,New York Heart Association（NYHA）heart function classification,blood pressure,heart rate,NT-proBNP,low density lipoprotein cholesterol（LDL-C）,aspartate aminotransferase（AST）,alanine aminotransferase（ALT）,creatinine（Cr）,potassium（K+）,LVEF and/or the left ventricular end-diastolic dimension（LVEDD）is recorded in the follow-up form.At each follow-up,the patients’ symptoms,home self-tested blood pressure and heart rate,laboratory examinations and echocardiographic results and how to adjust the medications are recorded in the outpatient medical records.Establish a database,and use SPSS Statistics 26.0 statistical software to analyze all data.Results1.A total of 317 patients with heart failure were enrolled in our study,their age range is 18～83 years old,of which 2 cases were not treated with β-blocker due to bradycardia（one case was bradycardia,another case was Ⅲ° atrioventricular block）.The remaining patients were treated with β-blocker and ACEI/ARB/ARNI,the drug combination rate was 99.37%,of which the rate of β-blocker reaching the target dose was 61.90%（195/315）.The ratio of ACEI/ARB/ARNI reaching the target dose was 73.81%（234/317）.And the ratio of reaching the target dose of both drugs was 50.16%（159/317）.In this study,a total of 134 patients did not reach the guideline recommended target dose but reached the clinical maximum tolerated dose.24 patients had not adjusted the drug to the guideline recommended target dose or maximum tolerated dose during the 6-month follow-up period.2.Analysis of curative effect after treatment:（1）Echocardiogram:LVEDD was significantly lower than before treatment[57.00（52.00-63.00）mm vs 63.00（57.00-68.00）mm]（P<0.05）.LVEF was significantly higher than before treatment[0.400（0.340-0.530）vs 0.310（0.250-0.360）]（P<0.05）.（2）Laboratory examination:NT-proBNP was significantly lower than before treatment[395（110-855）pg/ml vs 1211（373-3085）pg/ml]（P<0.05）;K+was significantly increased[4.40（4.17-4.67）mmol/L vs 4.30（4.00-4.56）mmol/L]（P<0.05）,but within the normal range.AST,ALT,LDL-C were significantly lower than before treatment（P<0.05）..（3）The patient’s blood pressure and heart rate decreased significantly（P<0.05）.（4）NYHA classification:NYHA class Ⅰ～Ⅱ patients increased significantly compared with before treatment,and NYHA class Ⅲ～Ⅳ patients decreased significantly compared with before treatment（P<0.05）.3.Comparison between the maximum tolerated dose group and the target dose group（1）Baseline data analysis:The maximum tolerated dose group had a lower proportion of males compared with the target dose group（P<0.05）.There was no statistical difference in lifestyle including smoking history and drinking history.There was no significant difference in NT-proBNP,AST,LDL-C,K+,and Cr between the maximum tolerated dose group and the target dose group（P>0.05）.The ALT of the target dose group was higher than the maximum tolerated dose group（P<0.05）,but all were in the normal range.In terms of echocardiography,patients in the maximum tolerated dose group had a smaller LVEDD than the target dose group[60.00（55.00-67.00）mm vs 64.40（60.00-70.00）mm]（P<0.05）.There was no significant difference in LVEF between the two groups[0.315（0.270-0.360）vs 0.300（0.230-0.370）]（P>0.05）.The patient’s SBP was not statistically significant.The DBP of patients in the maximum tolerated dose group was significantly lower than that in the target dose group.The heart rate of patients in the maximum tolerated dose group was significantly slower than that in the target dose group.In terms of the etiology of heart failure,both groups of patients had dilated cardiomyopathy as the main cause.The proportion of patients with dilated cardiomyopathy in the maximum tolerated dose group was lower than that in the target dose group,and the proportion of patients with ischemic cardiomyopathy in the maximum tolerated dose group was higher than that in the target dose group.In terms of basic diseases,the proportion of patients after radiofrequency ablation in the maximum tolerable dose group was significantly higher than that in the target dose group.And the proportion of patients with pulmonary hypertension in the maximum tolerated dose group was significantly lower than that in the target dose group（P<0.05）.There was no significant difference in the proportion of patients with arrhythmia,atrial flutter or atrial fibrillation,coronary heart disease,PCI/CABG surgery,hypertension,type 2 diabetes,renal insufficiency,and sleep apnea between the two groups（P>0.05）.In terms of past medications,the rate of patients in the maximum tolerable dose group who had used β-blocker before enrollment was lower than that of patients in the target dose group（P<0.05）.The ratio of ACEI/ARB/ARNI in patients in the maximum tolerable dose group was lower than that in the target dose group（P<0.05）.In terms of baseline combination medication,there was no statistical difference in the proportion of patients who were combined with MRA,furosemide,digoxin,and SGLT-2 inhibitor between the two groups（P>0.05）.The proportion of patients combined with ivabradine at baselinein maximum tolerated dose group was lower than the target dose group（P<0.05）.In terms of NYHA classification,patients in the maximum tolerated dose group and target dose group were all in NYHA class Ⅱ-Ⅳ,and there was no statistical difference between each class（P>0.05）.（2）Comparison of LV,NT-proBNP changes and LVEF change rates before and after treatment in the maximum tolerated dose group and the target dose group:The △LVEDD,△NT-proBNP,and the change rates of LVEF in the maximum tolerated dose group were not statistically different from those in the target dose group.（3）LVEF improvement rate,heart failure rehospitalization rate within 6 months and NYHA class improvement after treatment in the maximum tolerable dose group and target dose group:After 6 months of standardized heart failure treatment,there was no statistically significant difference in LVEF improvement rate,heart failure rehospitalization rate,and NYHA grade improvement rate of at least 1 grade compared with the previous one in two groups（P>0.05）.（4）Single-factor and multi-factor analysis of LVEF improvement in patients in the maximum tolerated dose group and target dose group:We take the LVEF improvement in patients with heart failure（improvement/unimprovement）as the dependent variable,whether the target dose is reached and other factors that may affect the improvement of LVEF as the independent variables to perform single-factor Logistic regression.The main variables to be studied of whether reach the target dose and the variables that are meaningful in the single-factor analysis（P<0.1）are included in the multivariate regression analysis.It showed that there was no difference in the effect of reaching the target dose on the LVEF improvement compared with reaching the maximum tolerated dose（OR:0.773;95%CI:0.448-1.335;P=0.356）.Conclusion1.This study proves that the tolerability of Chinese heart failure patients to β-blocker and ACEI/ARB/ARNI is well,and it is also safe,effective and feasible.2.In this study,there was no significant difference in the rate of LVEF improvement between the patients who did not reach the target dose of β-blocker and ACEI/ARB/ARNI but reached the maximum tolerated dose at 6 months follow-up compared with the patients who reached the target dose.Thesis Ⅱ:Tolerability of Treatment with ARNI in patients with Chronic HFrEFBackgroundThe PARADIGM-HF study showed that compared with enalapril,the angiotensin receptor-neprilysin inhibitor sacubitril/valsartan is more effective in heart failure.Guidelines recommend ARNI priority for heart failure treatment.Data from many randomized controlled trials have shown that patients treated with ARNI have a stronger reduction in blood pressure than those treated with ACEI/ARB.The dose and speed of ARNI titration are closely related to the blood pressure level of patients with heart failure.Due to various reasons such as the compliance of patients with heart failure,doctors’ concept of guideline-directed medical therapy（GDMT）,and the patient’s own tolerance,the treatment of heart failure is not standardized.The use rate of β-blocker and ACEI/ARB/ARNI and the rate of reaching the target dose recommended by the guidelines are all low.The REALITY-HF study showed that 56.6%of HFrEF patients had adjusted the dose of ARNI,but the proportion of patients who reached the target dose at 6 months was only 1.6%.At present,for Chinese patients with chronic heart failure,ARNI has been used in the Chinese population for a short time compared with ACEI/ARB and the clinical experience is relatively limited.In particular,it is unclear whether the impact of ARNI on blood pressure limits patients ability to reach the target dose recommended by the guidelines.Therefore,we designed this study to clarify the tolerability of treatment with ARNI in Chinese patients with Chronic HFrEF compared with ACEI/ARB.ObjectiveTo verify the tolerability of treatment with ARNI in patients with Chronic HFrEF compared with ACEI/ARB.Materials and MethodsThe inclusion and exclusion criteria and outpatient follow-up management methods for selected patients are as described in Thesis I.Group1.ACEI/ARB treatment group:give patients GDMT based on ACEI/ARB.2.ARNI treatment group:give patients GDMT based on ARNI.Data collection and analysisData collection and statistical methods are as described in Thesis I.On the basis of ThesisⅠ,we collected the symptomatic hypotension of patients during follow-up,and the withdrawal of patients who were difficult to tolerate hypotension.Results1.This study finally enrolled 317 patients.There were 183 patients in the ACEI/ARB treatment group and 134 patients in the ARNI treatment group.2.Comparison of baseline data（1）In the ACEI/ARB treatment group,there were 134 male patients（73.2%）and 49 female patients（26.8%）.In the ARNI treatment group,there were 98 male patients（73.1%）and 36 female patients（26.9%）..（2）Patients in the ACEI/ARB treatment group were significantly older than those in the ARNI treatment group（P<0.05）.（3）There was no statistically significant difference in lifestyle between the two groups.（4）In terms of laboratory examination,the NT-proBNP,AST,ALT,Cr,LDL-C,and K+levels of the ACEI/ARB treatment group and ARNI treatment group were not statistically different（P>0.05）.（5）The left ventricular end-diastolic dimension（LVEDD）in ACEI/ARB treatment group was lower than that in ARNI treatment group[62.00（56.00-67.00）mm vs 64.90（58.00-70.00）mm]（P<0.05）.The left ventricular ejection fraction（LVEF）in ACEI/ARB treatment group was higher than that in ARNI treatment group[0.320（0.270-0.370）vs 0.290（0.210-0.350）]（P<0.05）.（6）Patients treated with ACEI/ARB had higher blood pressure than those treated with ARNI[125（112-137）/77（70-85）mmHg vs 116（105-128）/73（65-80）mmHg]（P<0.05）.But the heart rate was no significant difference（P>0.05）.（7）In terms of the etiology of heart failure,both groups of patients had dilated cardiomyopathy as the main cause.The proportion of dilated cardiomyopathy in the ACEI/ARB treatment group was lower than that in the ARNI treatment group,and the proportion of ischemic heart disease in the ACEI/ARB treatment group was higher than that in the ARNI treatment group.（8）Compared with the ARNI treatment group,the ACEI/ARB treatment group had a higher rate of coronary heart disease and a lower rate of sleep apnea（P<0.05）.There was no significant difference in the proportion of arrhythmias,atrial flutter or atrial fibrillation,after radiofrequency ablation,PCI/CABG,hypertension,type 2 diabetes,renal insufficiency and pulmonary hypertension（P>0.05）.（9）In terms of past medications,there was no statistical difference in the ratios ofβ-blocker,ACEI/ARB/ARNI,MRA and diuretics between the two groups of patients before enrollment.（10）In terms of basic combined medication,the rates of ivabradine and sodium dependent glucose transporters 2（SGLT-2）inhibitors in ACEI/ARB treatment group were significantly lower than those in ARNI treatment group（P<0.05）.There was no significant difference in the rates of MRA,furosemide and digoxin between the two groups.（11）The patients in both groups were NYHA class Ⅱ～Ⅳ.3.Comparison of the efficacy of the two groups of patientsIn the ACEI/ARB treatment group,blood pressure was significantly lower than baseline,and heart rate was significantly slowed down（P<0.05）.Patients’ NT-proBNP and LDL-C levels were significantly lower than baseline in ACEI/ARB treatment group,although K+level was higher than baseline,but still within the normal range;AST,ALT,Cr did not change significantly from baseline.The LVEDD was significantly lower than baseline,and LVEF was significantly higher than before treatment（P<0.05）.In the ARNI treatment group,blood pressure was significantly lower than baseline,and heart rate was significantly slower（P<0.05）.Patients’ NT-proBNP and LDL-C levels were significantly lower than baseline（P<0.05）,and AST,ALT,Cr,K+did not change significantly from baseline（P>0.05）.The LVEDD was significantly lower than baseline,and LVEF was significantly higher than before treatment（P<0.05）.4.The blood pressure of ARNI treatment group was lower than that of ACEI/ARB treatment group[108（97-120）/66（60-72）mmHg vs 117（106-130）/73（65-80）mmHg]（P<0.05）.The decrease of systolic blood pressure in ACEI/ARB treatment group was 8.0（-3.0-18.0）mmHg,and that in ARNI treatment group was 11.0（-2.0～24.0）mmHg.There was no significant difference between the two groups（P>0.05）.The decrease of diastolic blood pressure in ACEI/ARB treatment group was 6.0（-3.0～13.0）mmHg,and that in ARNI treatment group was 5.5（-3.0～13.0）mmHg.There was no significant difference between the two groups（P>0.05）.5.Symptomatic hypotension and drug withdrawal due to intolerance of hypotension occurred in ACEI/ARB treatment group and ARNI treatment group during follow-upThe rate of symptomatic hypotension in ACEI/ARB treatment group was 7.1%.The rate of symptomatic hypotension in ARNI treatment group was 13.4%.There was no significant difference in the rate of symptomatic hypotension between the two groups（P=0.061）.During the follow-up period,there were 0 patient in the ARNI treatment group who stopped the drug because of low blood pressure intolerance,and 1 patient（0.5%）in the ACEI/ARB treatment group stopped the drug because of low blood pressure intolerance.The difference between the two groups was not statistically significant（P=0.391）.6.Comparison of target dose ratio between the two groups at 6-month follow-upAt 6 months of follow-up,there was no difference in the ratio of β-blocker reaching the target dose with two groups of patients（P>0.05）.The rate of ACEI/ARB reaching the target dose was higher than that in ARNI treatment group[139/183（76.0%）vs 95/134（70.9%）,but there was no significant difference between the two groups（P=0.311）.7.Univariate and multivariate analysis of drug tolerance in the two groupsAfter exclusion of confounding factors,ARNI was also better tolerated compared with ACEI/ARB（OR:0.678;95%CI:0.404-1.140;P=0.143）.8.Etiology subgroup analysisWe classified the top three causes of this study:dilated cardiomyopathy,ischemic cardiomyopathy,and structural heart disease into subgroup analysis according to different causes.The results showed that there was no difference in drug tolerance between ARNI treatment group and ACEI/ARB treatment group at different etiological levels.Conclusion1.In this study,for patients with chronic HFrEF,the antihypertensive effect of ARNI is slightly stronger than that of ACEI/ARB.2.In this study,compared with ACEI/ARB,the rate of ARNI reaching the target dose recommended by the guidelines in patients with chronic HFrEF is slightly lower than that of ACEI/ARB.In the real world,the tolerability of treatment with ARNI in Chinese patients with Chronic HFrEF is good.