Exploratory Construction And Empirical Study Of Key Techniques For A Pragmatic Randomized Controlled Trial Of Heat-sensitive Moxibustion For Community-based Chronic Disease Management

Objective Pragmatic randomized controlled trial(pRCT)is designed to evaluate the overall effect of complex interventions in real-world medical settings.Based on the complex interventions and individualized treatment characteristics of heat-sensitive moxibustion(HSM),the pRCT,which integrates real-world study and randomization features,is more suitable for evaluating the actual treatment effects of HSM in the "heat-sensitive moxibustion town" setting.Therefore,pRCT can provide high-level evidence for the efficacy assessment of HSM in community settings,which can provide a basis for governmental health decisions and management,and help promote the high-quality construction and development of " heat-sensitive moxibustion towns".However,the successful implementation of HSM pRCT faces many methodological challenges,including rational determination of effect indicators for efficacy evaluation,and control of confounding bias during data analysis.Reasonable resolution of these key methodological difficulties is of great significance for improving the scientificity of study design and reliability of study results.Based on this,this study focuses on the key technical issues in the implementation of HSM pRCT,and conducts a methodological construction and empirical study with primary hypertension as an example,in order to provide a scientific research paradigm for the evaluation of the effectiveness of the community-based HSM intervention model,,and provide evidence-based medical evidence based on the real world for the construction of "heat-sensitive moxibustion town".Methods:1.Methodology construction(1)Construction of patient/family self-reported COSA systematic literature review was conducted to extract the outcome indicators involved in studies related to HSM /moxibustion for hypertension.Additional outcome indicators were added through physician and patient questionnaires to form a pool of indicator entries.A Delphi questionnaire was created based on the pool of indicator entries.A Delphi survey was conducted by selected multidisciplinary experts to obtain expert opinions on the applicability and importance of outcome indicators.Finally,a consensus conference was conducted to identify indicators for inclusion in the community patient/family self-reported core outcome set.(2)Screening of core confounding factorsA systematic literature review extracted confounding factors involved in clinical studies related to hypertension,and additional confounding factors were added through group discussions to form a pool of confounding factor entries.A Delphi survey questionnaire was created based on the pool of entries.A Delphi survey was conducted by selecting multidisciplinary experts to obtain expert opinions on the applicability and importance of confounding factors,and core confounding factors applicable to community-based HSM pRCT were identified based on the Delphi survey results.2.Empirical studyA multicenter,pragmatic,parallel group,patient preference randomized controlled approach was used to conduct the study.First,the seven study communities were randomized into two clusters of compulsory randomization(3)and patient preference(4).In the compulsory randomization cluster,120 hypertensive patients were completely randomized into the moxibustion group(HSM + original antihypertensive regimen)or the control group(original antihypertensive regimen only).In the patient preference cluster,200 patients were directly selected to enter the moxibustion or control group according to their preference;40 patients with no clear preference were randomized.The patient allocation ratio was 1:1 for either the randomized or the preference part.The treatment was carried out for a total of 6 months,and HSM was recommended to be applied once a day,no less than twice a week.Monthly follow-up visits were performed to evaluate blood pressure changes,and the change in systolic blood pressure(SBP)was used as the primary outcome indicator.Secondary outcome indicators included diastolic blood pressure(DBP),antihypertensive efficiency,quality of life score,TCM symptom score,new-onset cardiovascular events,compliance with thermal moxibustion treatment,and safety.Results:1.Methodology construction(1)Construction of patient/family self-reported COSAfter literature review,questionnaires,Delphi survey,and consensus meetings,a total of 29 indicators were finally included in the self-reported COS of community pRCT of HSM for hypertension,divided into two parts: HSM universal clinical study outcome indicators and disease-related indicators,which contained 5 HSM sense indicators(presence or absence of thermal sensitization,spatial location of moxibustion sensation,intensity of moxibustion sensation,frequency of moxibustion sensation,moxibustion sensation comfort),6 universal quality of life and symptom indicators(SF-36,SF-12,VAS,PHQ-9,EQ-5D,TCM symptom score),7 safety indicators(burns,foaming,dizziness,fire,constipation,skin allergy,asthma),4 study protocol compliance indicators(HSM daily treatment duration,HSM weekly frequency,HSM application points,compliance with recommended lifestyle habits),3 economic evaluation indicators(drug out-of-pocket costs,outpatient treatment costs,inpatient treatment costs),and 4 disease-related indicators(SBP,DBP,new cardiovascular events,new cerebrovascular events).(2)Screening of core confounding factorsAfter literature review,group discussion,and Delphi survey,a total of 14 confounding factors were finally included in the core set of confounding factors for the community pRCT of HSM for hypertension,including 7 baseline characteristics and lifestyle factors(age,study center,BMI,smoking,alcohol consumption,exercise,sleep duration),4 baseline blood pressure and cardiovascular disease index factors(SBP,DBP,hypertension stage,hypertension duration),1 comorbidity factors(coronary artery disease/ Charlson comorbidity index),and 2 comorbid medication factors(antihypertensive medication,antihypertensive medication dose).2.Empirical study(1)Study completion: Between March and June 2021,160 and 240 patients were recruited in the randomized and non-randomized parts,respectively,among which 140 and 210 patients in the randomized and non-randomized parts completed the last follow-up visit,with an overall follow-up rate of 87.5%.(2)The study results showed that:(1)SBP: In randomized and non-randomized parts,SBP in the HSM group from 1 to 6 months of follow-up showed a significant decreasing trend compared with baseline,and the decrease was significantly greater than that in the control group at all sites visited(Random part of the 6th month: MD=-10.57 mm Hg,95% CI(-14.98,-6.16),P < 0.001).(2)DBP: Compared with the control group,the random part of the HSM group only showed the effect of down-regulating DBP in the first 4 months of follow-up,but the advantage was not maintained to the 5th month(MD =-2.61 mm Hg,95% CI(-5.72,0.49),P > 0.05)and the 6th month(MD =-2.40 mm Hg,95% CI(-5.46,0.65),P > 0.05).However,in the non-random part,the effect of HSM on the downregulation of DBP was mainly shown in the later 4 months of follow-up(no statistical difference was found in the 4th month).(3)Antihypertensive efficiency: The antihypertensive efficiency of the random and non-random parts,the antihypertensive efficiency of the HSM group was higher than that of the control group at all points visited;In the random portion,the difference between groups was significant only at the 6th month(OR= 4.00,95% CI(1.81,8.83),P < 0.001);however,in the non-random part,the difference between groups was significant from the 2nd month,and continued to increase after each visit.(4)TCM symptom score of hypertension: The improvement range of random part of the HSM group was significantly greater than that of the control group only in the 6th month(MD=-2.50,95% CI(-4.14,-0.86),P < 0.01);However,the improvement of non-random partial HSM group was significantly greater than that of the control group in the 3rd and 6th months.(5)Quality of life: The improvement range of EQ-5D-5L index score(MD=0.034,95% CI(-0.001,0.069))and EQ-VAS score(MD =5.93,95% CI(2.26,9.59),P < 0.01)in the random part of the HSM group in the 6th month showed marginal and significant differences compared with the control group.In the non-random part,the improvement of the EQ-5D-5L index and EQ-VAS score in the 3rd and 6th months was significantly greater than that in the control group.(6)New cardiovascular and cerebrovascular events: There were 3 new cases in random part;A total of 1 new case was reported in the non-random unit.(7)Compliance of HSM: Nearly 40% to 60% of patients in random and non-random parts completed HSM treatment at least 4 times a week every month.During the experiment,the average weekly moxibustion frequency of random partial HSM group was slightly lower than that of the non-random partial HSM group.(8)Safety: A total of 29 cases of adverse events were reported in the HSM group during the trial,the incidence of adverse events was about 0.7%,all were mild and transient adverse events,and no patients withdrew due to adverse events.Conclusion:1.Methodology constructionThe methodological construction took pRCT as the starting point and constructed an efficacy evaluation method and practice system for community-based HSM pRCT by screening for core confounding factors and establishing a patient/family selfreported core outcome set.In addition,the methodological construction provided an effective solution to the key methodological difficulties of subsequent empirical studies of community-based HSM pRCT,which helped to enhance the scientificity of study design,the rigor of study implementation,and the reliability of study results.2.Empirical studyThe empirical study of community-based HSM pRCT validated the feasibility and reliability of key techniques.Meanwhile,pragmatic randomized and non-randomized evidence suggests that HSM self-administration can reduce SBP,but the effect on DBP remains uncertain.Combining the efficacy of HSM in improving hypertension TCM symptoms and quality of life,as well as the advantages of good compliance and safety,HSM can be considered for recommendation as an adjunctive treatment for hypertension management in the community.