| BackgroundHeart failure is a serious manifestation or terminal stage of various cardiovascular diseases.The 5-year mortality rate is comparable to malignant tumors,and it is the final battlefield for cardiovascular disease prevention and control.Heart failure is a global public health problem that brings a huge economic and health burden.A total of 64.3 million people worldwide suffer from heart failure;the latest my country’s epidemiological survey released in 2019 shows that there are approximately 13.7 million people with heart failure in China.The treatment of chronic heart failure has undergone a major change since the 1990s,from aiming to improve the hemodynamic status to a long-term repair strategy.As the cornerstone drug for the treatment of heart failure,the "Golden Triangle"program can delay the progression of heart failure and improve the prognosis on the basis of alleviating symptoms.A new type of heart failure treatment drug,sacubitril/valsartan,is the first Angiotensin Receptor Neprilysin Inhibitor(ARNI),which have better effects than RAAS inhibitors alone.The PARADIGM-HF study shows that compared with enalapril,sacubitril/valsartan can further reduce the risk of cardiovascular death in patients with heart failure with reduced ejection fraction(HFrEF)by 20%.Reduce all-cause mortality by 16%and reduce the risk of hospitalization due to heart failure by 21%.Therefore,the ESC and AHA heart failure guidelines regard sacubitril/valsartan as a type I evidence and a level B recommendation as an alternative to RAAS inhibitor therapy in patients with HFrEF.Studies have confirmed that sacubitril/valsartan show a significant dose-dependent benefit in the treatment of heart failure.High-dose sacubitril/valsartan can further improve cardiac remodeling and patient prognosis.Therefore,the guidelines for heart failure recommend the use of target doses of sacubitril/valsartan in order to achieve the greatest clinical and prognostic benefits.In a large randomized clinical trial(RCT),the 12-week target dose rate of sacubitril/valsartan can reach 76%.However,the dosage of sacubitril/valsartan in real-world studies at home and abroad is mostly much lower than the target dosage.In a German real-world study involving 12,082 patients,only 21%of patients received target doses of sacubitril/valsartan.In a domestic single-center study involving 135 patients with heart failure,only 5.9%of patients reached the target dose.Only a few real-world studies have reported successful titrations for more than 50%of patients with heart failure.In view of the fact that the high-dose treatment of sacubitril/valsartan is closely related to the prognosis of patients with heart failure,it is necessary to more comprehensively explore the experience of the successful titration of sacubitril/valsartan in the real world.Therefore,we analyzed more than 200 patients with heart failure included in the heart failure chronic disease follow-up management system,focusing on their clinical characteristics,tolerability,target dose ratio,outcome and prognosis after one year of follow-up.Provide experience in the titration of sacubitril/valsartan.Purpose1.Summarize the experience and methods of titration of sacubatril/valsartan in the real world;2.To verify that the use of sacubitril/valsartan in most heart failure patients in the real world can achieve the target dose recommended by the guidelines,and can get better heart failure prognosis improvement;3.Explore the feasibility and effectiveness of the follow-up management system for heart failure and chronic diseases.methods1.Study populationA retrospective cohort study of heart failure patients who were included in the heart failure follow-up management system and followed up in the outpatient clinics of Professor Ji Xiaoping and Lu Huixia of Qilu Hospital of Shandong University and prescribed sacubitril/valsartan,and conducted a retrospective cohort study on heart failure patients who met the enrollment requirements Carry out outpatient and telephone follow-up.2.Data collectionCollect clinical data of selected patients,including demographic information,heart failure etiology and accompanying diseases,symptoms,vital signs,New York Heart Association(NYHA)grading,medication treatment plan,home self-test blood pressure,heart rate,ultrasound Cardiogram indicators and laboratory indicators,etc.3.Establishment of a follow-up system for chronic heart failureEstablish a heart failure follow-up system through the establishment of the heart failure medical circle in Shandong Province in batches,offline management and follow-up,online follow-up and education,and selection of appropriate follow-up mode.4.Groups4.1 According to the patient’s systolic blood pressure level before starting sacubitril/valsartan treatment,the patients were divided into 3 groups:①The systolic blood pressure<100mmHg is the hypotension group;②100≤systolic blood pressure<140mmHg is the normal blood pressure group;③The systolic blood pressure≥140mmHg is the hypertension group4.2 According to the cause of heart failure,the patients are divided into 2 groups:①Ischemic cardiomyopathy group②Non-ischemic cardiomyopathy group5.Dosage standard5.1 Sacubitril/Valsartan:Target dose:400mg/d;Maximum tolerated dose:The patient is due to symptomatic hypotension or blood pressure lower than 90/60mmHg,hyperkalemia without spironolactone action,deterioration of renal function and other reasons.The dose of batril valsartan cannot be further increased,and the maximum tolerated dose of sacubitril/valsartan that the patient can tolerate and maintain is the maximum tolerated dose.5.2 β-blockers:target dose:Amber Metoprolol acid is 190mg/d,Bisoprolol is 10mg/d,and Carvedilol is 50mg/d;maximum tolerated dose:β-receptor blocker applied when the patient’s resting heart rate reaches 55-60 beats/min Delay dose.6.Statistical analysisAccording to whether it accords with normal distribution,quantitative data are expressed as mean±standard deviation(x±s)or median and interquartile range,using t test or u test to compare quantitative variables;categorical variables are expressed in percentage(%)Expressed and compared with the Chi-square test or Fisher’s exact test.Kaplan-Meier survival curve analysis was used for the primary study endpoint.With P<0.05 as the test standard for whether the difference is statistically significant,all data were analyzed using SPSS 19.0.Results1.Baseline characteristics:A total of 226 patients were enrolled in this study,with an average age of(49.36± 14.42)years old.There were 167 male patients(73.9%).Dilated cardiomyopathy(38.5%)and ischemic cardiomyopathy(27.4%)were the first and second causes of heart failure,respectively.The proportions of patients with NYHAI,Ⅱ,Ⅲ,and Ⅳ levels were 0,43.4%,41.2%,and 15.5%,respectively;the previous prescription rates of β-blockers,ACEI/ARB,spironolactone,and loop diuretics were 52.2%and 38.5,respectively.%,36.7%,25.7%.2.Baseline characteristics of blood pressure group:the average age of patients in the hypotension group is smaller than that of the normal blood pressure group[(43.75±14.59)years vs(51.37±13.86)years,P=0.009],the age of patients in the hypertension group is similar to that of the other two groups There was no statistical difference.The proportion of men in the hypotension group,normal blood pressure group,and hypertension group were 53.1%,87.5%,and 74.7%,respectively(P=0.006).The proportion of patients with diabetes in the hypertension group was higher than that in the normal blood pressure group(40.6%vs 23.4%,P<0.05)and the patients in the hypotension group(40.6%vs 3.1%,P<0.05)(P=0.002).Baseline systolic blood pressure[(150.53± 11.52)mmHg vs(118.49± 10.54)mmHg vs(91.22±5.08)mmHg(P<0.001)]and diastolic blood pressure of patients in the hypertension group,normal blood pressure group and hypotension group 14.31)mmHg vs(74.12± 11.18)mmHg vs(61.22±6.73)mmHg(P<0.001)]were statistically different.There were no significant differences in the heart structure,NT-proBNP,and combined medication among the three groups of patients.3.Baseline characteristics of the etiology group:Compared with the non-ischemic cardiomyopathy group,the average age of patients in the ischemic cardiomyopathy group is older[(60.53± 10.78)years vs(45.42± 12.147)years,P<0.001]A higher proportion of patients with diabetes(40.3%vs 16.5%,P<0.001)and hypertension(56.5%vs 28.5%,P<0.001),baseline LA[(42.94±6.10)mm vs(46.64±8.47)mm,P=0.001]smaller,LVEDD[(58.80±7.06)mm vs(66.10±9.18)mm,P<0.001]smaller,LVEF[(34.81 ±7.60%)vs(28.22±9.46%),P<0.001,P<0.001]higher.There were no significant differences in baseline NT-proBNP concentration,vital signs,and previous medications between the two groups.4.Application status of sacubitril/valsartan:43.8%of patients started sacubitril/valsartan at 100mg/d,24.1%of patients started with 200mg/d,and 22.3%of patients started at 50mg/d Initially,3.6%of patients started with 25mg/d,2.7%with 150mg/d,1.8%with 300mg/d,1.3%with 400mg/d,0.4%with 250mg/d At the end of the study visit,74.3%of the patients reached the target dose,the median time to reach the target dose was 3(Q1-Q2,2-5)months,and 78.5%of the patients reached the maximum tolerated dose.5.The drug titration mode of sacubitril/valsartan:after 3 months of treatment,93.2%(136/146)of the 146 patients on the titration period increased the dose,1.4%(2/146)decreased the dose,5.5%(8/146)Maintain the original dosage;the patients at the titration period at the 6th,9th,and 12th month of treatment are significantly reduced.By the 12th month,the rate of increase,decrease,and maintenance of the original dosage of 25 patients at the titration period is 40%,respectively.(10/25),28%(7/25),32%(8/25).6.Changes in the dose ratio of sacubitril/valsartan:46.4%of patients started sacubitril/valsartan at 100mg/d≤dose≤200mg/d,and 24.6%of patients were treated with 200mg/d≤dose≤ Starting at 300 mg/d;the percentages of patients reaching the target dose at the 3rd,6th,9th and 12th months of treatment were 48.7%,65.0%,73.7%and 69.7%,respectively.7.Changes in LVEF before and after treatment:The median value of LVEF in patients with heart failure at baseline was 30%,and the median value of LVEF in patients at months 3,6,9,and 12 were 40%,42%,43%,and 44,respectively.%(P<0.001),which were increased by 10%,12%,13%,and 14%respectively from the baseline median value.The proportions of complete recovery,partial recovery,maintenance,and deterioration of LVEF at 3 months were 20.4%,52.4%,18.4%,9.2%,and at 6 months were 29.6%,45.9%,11.2%,and 13.3%;treatment 9 They were 33.3%,45.8%,12.5%,and 8.3%at months;40%,41.5%,10.8%,and 7.7%at 12 months of treatment.8.Changes in LA before and after treatment:The median LA of patients with heart failure at baseline was 45mm,and the median LA at 3,6,9,and 12 months of treatment were 42mm,41mm,42mm,and 41mm,respectively,which were all compared with baseline Significantly reduced(P<0.05).9.Changes in LVEDD before and after treatment:The median value of LVEDD in patients with heart failure at baseline was 63mm,and LVEDD was 60mm,57.5mm,58.5mm,55mm at 3,6,9,and 12 months of treatment,respectively(P<0.05),Compared with the baseline median value decreased by 3mm,5.5mm,4.5mm,8m respectively.10.NYHA classification:patients with baseline NYHA classification I-IV are 0,43.4%,41.2%,15.5%,respectively;at 3 months,7.0%,81.6%,11.8%,and 0;at 6 months,respectively 18.2,74.4%,7.4%,and 0;24.1%,65.5%,10.3%,and 0 at 9 months;32.9%,63.2%,3.9%,and 0 at 12 months.The percentages of NYHA classification improvement in the 3rd,6th,9th and 12th months were 54.6%,64.5%,58.6%and 68.4%,respectively.11.Blood pressure changes before and after treatment:After 12 months of treatment,the systolic blood pressure[(108.97115.47mmHg)vs(119.30± 18.97mmHg),P<0.001]and diastolic blood pressure[(66.05±9.90mmHg)vs(75.35)±14.54mmHg),P=0.001]were significantly lower than before treatment.12.Changes in creatinine before and after treatment:the baseline serum creatinine value of the patients with heart failure in the group was 85(69.50,98.50)umol/L,the third month of treatment[84(72.00,95.00)umol/L],6 months[83 After(70.00,98.50)umol/L],9 months[81.5(71.00,97.00)umol/L],12 months[81(74.00,105.00)umol/L],serum creatinine showed a decreasing trend compared with baseline.But there was no significant statistical difference(P>0.05).13.The baseline NT-proBNP of patients with heart failure in the group was 1509.00(437.88,3272.75)pg/ml,and the third month of treatment[367.90(149.50,829.70)pg/ml],6 months[399.90(106.93,822.13)pg/ml],9 months[459.65(178.00,742.50)pg/ml],12 months[200.05(65.21,601.95)pg/ml],NT-proBNP was significantly reduced compared with baseline,and there were significant statistics Academic difference(P<0.01).14.Safety:No serious adverse events caused by sacubitril/valsartan were observed during the visit.A total of 11 patients(4.9%)with symptomatic hypotension were observed,and 2 patients(0.9%)were intolerant of symptomatic hypotension.One patient(0.4%)had cough intolerance,and 4 patients(1.8%)had transient hyperkalemia.Five patients had a transient slight increase in creatinine.No cases of angioedema or deterioration of renal function were observed.15.Combined medication:The use rate of loop diuretics,spironolactone and digoxin showed a decreasing trend during the treatment period.The prescription rates of loop diuretics at baseline and 3,6,9,and 12 months of treatment were 58.0%,22.2%,26.1%,14.3%,and 15.1%;the prescription rates of spironolactone were 90.6%,75.2%,67.6%,and 57.1%,respectively And 60.3%.The prescription rates of digoxin were 16.7%,4.6%,4.5%,4.5%and 1.8%,respectively.16.Beta blocker usage:At the 3rd month,37.6%of patients used the target dose,40.9%of the patients used 1/2 target dose≤dosage<target dose,12.1%of patients used 1/4 target dose ≤Dosage<1/2 target dose,9.4%were treated with β-blockers lower than 1/4 target dose;at the 6th month,54.2%,28.8%,9.3%and 9.3%of the above-mentioned dose ratios were used respectively 8.5%;60.6%,26.2%,7.7%,and 6.2%at the 9th month;52.1%,28.8%,11.0%,and 12.3%at the 12th month.17.Endpoint event analysis:During the follow-up period,3 patients of the 226 enrolled patients died due to worsening heart failure,1 patient had a heart transplant,25 patients were hospitalized due to worsening heart failure,and a total of unplanned heart failure rehospitalization events occurred 32 example.Compared with the hypotension group,the incidence of the primary endpoint of the normal blood pressure group was further reduced by 65%(HR:0.346,95%CI,0.146-0.818;p=0.016);compared with the hypotension group,the primary endpoint of the hypertension group The incidence was further reduced by 84%(HR:0.158,95%CI,0.038-0.665;p=0.012).Compared with the non-ischemic cardiomyopathy group,the ischemic cardiomyopathy group had a higher incidence of primary endpoint events,but there was no statistical difference between the two groups(HR:0.649,95%CI,0.218-1.934;p=0.438).Conclusions1.As of the end of the visit,78.5%of the patients in this study received the maximum tolerated dose of sacubitril and valsartan,and 74.3%reached the target dose of treatment.Most patients with heart failure in the real world can tolerate the target dose Shacubatril and Valsartan treatment;2.After 12 months of treatment,40%of patients’ cardiac function recovered completely,and 41.5%of patients’ cardiac function partially recovered.High-dose sacubitril and valsartan treatment can significantly improve the cardiac remodeling and function of patients;3.For patients with heart failure in the real world in China,the target dose of sacubitril and valsartan is safe.;4.Heart failure and chronic disease follow-up management system helps patients titrate the dose of sacubitril and valsartan to the maximum tolerable dose or target dose. |
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