Assessment of rehabilitation program efficacy in patients with duodenal and gastric ulcer based upon risk reduction of recurrent hospitalization

Transcription

1 2016; 5(6): ISSN: TPI 2016; 5(6): TPI Receved: Accepted: Ocheredko Oleksandr Progov Memoral Vnntsa Natonal Medcal Unversty, Ukrane. Kzlova Natala Progov Memoral Vnntsa Natonal Medcal Unversty, Ukrane. Assessment of rehabltaton program effcacy n patents wth duodenal and gastrc ulcer based upon rsk reducton of recurrent hosptalzaton Ocheredko Oleksandr and Kzlova Natala Abstract Background: Notorously known worldwde cause of morbdty and dsablty duodenal (DU) and gastrc ulcer (GU) experence ther rse n Ukrane, demonstratng formdable ncrease by 38, 4% n last decade wth the prevalence of 2299 per populaton. Every second patent s treated n-patently, every thrd experence dsablty spell annually. Reducton n related rsks confned not so much by absence of effectve therapy but rather shortcomngs n patent management and patent devoton. By WHO data 50% of patents fal to follow physcan prescrptons, 60% can t forget physcan recommendatons n frst 20 mnutes. Ubqutous belated tmng of rehabltaton ntaton n post hosptal stage appeared to be cardnal obstacle of ts effcency wth low (up to 20%) coverage, and securng clncal effect n 8% cases only. Data: Organsed by cohort desgn. Control cohort comprsed 180 patents wth frst epsode of hosptalzaton due to DU or GU n gastroenterologcal Vnntsa cty department n years. Expermental cohort conssted of 220 alke patents who enter rehabltaton program (RP). RP was admnstered randomly. Randomness was statstcally verfed on prncpal confounders. Cases were traced 4 years. Methods: We appled three modfcatons of sem-parametrc fralty model to study effect of program on the rsk of recurrent hosptalzaton. Results: All three modfcatons concded n that program secured typcally at least 39 days to recurrent hosptalzaton per patent wth drop n rsk at least at RR = 0,774. Keywords: rehabltaton, duodenal and gastrc ulcer 1. Introducton By the lterature revew and our experence tmng of rehabltaton admnstraton s the crucal to sustan ts effcency n terms of coverage, adherence, and clncal effect. Innovatve to clncal experence n Ukrane s shft n admnstraton of rehabltaton to hosptal stage. We also worked out extended program frame that combnes 10 scales, namely medcaton of ulcer, det modfcaton, overweght control, physotherapy exercses, management of контроль NSAID-nduced gastropathy, rsk factor management, blood pressure correcton, dabetes management, anxety and depresson management. To empower complance and to facltate case management we suppled patent wth dary and nculcate the sklls of recordng on drug ntakes, unusual symptoms, complants, as well as followng ndcated dates of examnatons and physcan referrals. The prme evdence of the effcacy of RP admnstraton s the 4% of dropouts only n frst 3 months. Correspondence: Ocheredko Oleksandr Progov Memoral Vnntsa Natonal Medcal Unversty, Ukrane. 2. Materals and Methods Desgn. Data organsed by cohort desgn. Control cohort comprsed 180 patents wth frst epsode of hosptalzaton wth DU or GU dagnoses n gastroenterologcal Vnntsa cty department n years. Expermental cohort conssted of 220 alke patents who enter RP. Program was admnstered randomly. Randomness was statstcally verfed on prncpal confounders. Cases were traced 4 years. RP frame. RP frame combnes 10 scales, namely medcaton of ulcer, det modfcaton, overweght control, physotherapy exercses, management of контроль NSAID-nduced gastropathy, rsk factor management, blood pressure correcton, dabetes management, anxety and depresson management. Each scale has ts content, detaled explanaton of admnstraton, check ponts, effcacy evaluaton. For nstance, we lay out medcaton scale composton. ~ 96 ~

2 Others n detales brought out elsewhere [1]. ~ 97 ~

3 Medcaton scale. Content. Assessment of patent condton, fbrogastroscopa, ntragastrc ph montorng, and H-pylor express dagnostc (De-Nol test) at hosptalzaton. Treatment of Hp-negatve ulcers by antsecretory monotherapy startng wth Group A1- IPP of 1 st generaton (omeprazole 40 mg daly) durng 4 weeks n case of duodenal ulcer and durng 8 weeks n case of gastrc ulcer. If prove to be neffectve n 10 days step to Group A2- IPP of 3 rd lne n standard dosage (rabeprazole 20 mg daly), 4 th lne n standard dosage (pantoprazole 40 mg daly), 5 th lne n standard dosage (ezomeprazole 40 mg daly) durng 4 weeks n case of duodenal ulcer and durng 8 weeks n case of gastrc ulcer. In perseverng cases double dosage of 3 rd - 5 th lnes of IPP drugs. In Hp-postve cases eradcaton of Н.pylor nfecton starts wth B1-3 rd - 5 th lnes of IPP drugs (pantoprazole 20 mg twce a day, rabeprazole 20 mg twce a day, esomeprazole 20 mg twce a day) + clarthromycn 500 mg twce a day + amoxclln 1000 mg twce a day durng 10 days and follows wth admnstraton of IPP drugs n standard dosages durng 3 weeks n case of duodenal ulcer and durng 6 weeks n case of gastrc ulcer. If neffectve n 10 days step to B2 that s 3 rd - 5 th lnes of IPP drugs n standard dosages + tetracyclne 500 mg 4 tmes a day + metrondazole 500 mg 3 tmes a day +bsmuth subctrate 120 mg 4 tmes a day durng 10 days. Check ponts. Daly: self-control by ndcaton of prescrbed drugs ntakes n dary. Weakly: assessment of clncal symptoms by general physcan. Specal ponts: evaluaton of treatment effcacy at 10 th day ntragastrc ph montorng n case of Hp-negatve ulcers; evaluaton of Н.pylor eradcaton n postve cases n two weeks upon treatment completon by fecal Н.рylor antgen test; vsts to gastroenterologst upon 1 st and 2 nd months. Effcacy evaluaton. Patent follows prescrbed therapy, admssble are 2 falures n day drug ntake a month. Patent understands regment of drug ntakes. Achevement of clncal and endoscopc certfed remsson after 4 weeks of treatment. Robust acd suppressve effect (рн>3) n 10 days from the start of treatment wth IPP. Successful Н.pylor eradcaton n postve cases. Follow up ncludes hosptal and out of the hosptal stages. To empower complance and to facltate case management we suppled patent wth dary and nculcate the sklls of recordng on drug ntakes, unusual symptoms, complants, as well as followng ndcated dates of examnatons and physcan referrals. Dary proved to be helpful especally out of the hosptal. The prme evdence of the effcacy of RP admnstraton s the 4% of dropouts only n frst 3 months. We bult effcacy estmaton on tme to next hosptalzaton that proved to be very senstve to qualty of care [2]. However, effcacy evaluaton poses statstcal challenge n part due to randomzaton bas (e.g. self-selecton bas), possble measurement error, or unavodable presence of potent unobservebles. So, treatment effect dentfcaton problem s conspcuous. We tackled t by control functon technque [3]. Model. We have chosen flexble sem-parametrc fralty model to study modfcaton effect of RP on the rsk of recurrent hosptalzaton. Fralty model ncapactates the assessment of ndvdual propensty to survve tll next hosptalzaton, ncorporatng unobserved patent s characterstc nfluenced rsk of recurrent hosptalzaton dfferently across patents. Overlookng fraltes entals based and neffcent estmaton of survval effects. Fralty model bascally ncorporates three man components: basc hazard functon, changeable n tme; functon of factors, modfyng basc hazard; fralty dstrbuton. Hazard functon defned non-parametrcally by ~ 98 ~ exponental pece-wse prors. The number of tme ntervals defned by 0, 25 quantles of observed tme spans dstrbuton that approxmately concdes wth monthly ntervals. Poolng strength and dentfcaton of basc rsks λ facltated through RW1 process, namely (Wn BUGS code): Lam []~dgamma (a0, b0[]) b0 [] <- a0/lam [-1] lam [1]~dgamma (0.1,0.1), a0~dgamma (0.1,0.1) So that poolng s defned by gamma dstrbuton wth two frst moments 0 and (λ-1) 2 /a 0. Rsk s defned as proportonal to basc, modfed by exponent of observable covarates effect β x : h t q, q x exp x 1 β x s expressed by RP effect (parameter beta), bas n randomzaton of RP admnstraton across patents (beta2), and ndvdual random effects (fraltes b ): beta* Treatment + beta2*treatment *b + b The prncpal parameter to test АТЕ (average treatment effect) s beta coeffcent, purged from possble randomzaton flaws of patent selecton to RP prescrpton by present beta2 *Treatment *b component, that s the control functon. b render ndvdual patent s effect wth expected zero value, acheved by prors generaton mechansm (rendered by b[]~dnorm (0, tau) n program scrpt). Indvdual patent s effect ncludes all possble fxed ndvdual effects both observable and unobservable. Presence of the latter s crucal for bas mnmzaton n RP effect testng. Insgnfcant beta2 bares evdence on neglgblty of bas n АТЕ estmaton due to randomzaton flaws of patent selecton to RP admnstraton. Cumulatve rsk (defned n program scrpt by Н0) was calculated as ntegraton of pont rsk h t q 1, q x on quantles bounded tme nterval q q -1 as follows: H q, q x* q q exp x q q 0 ht 1 1 * 1 Survval functons n expermental and control cohorts members (defned n program code by S [1] and S [2] ) were calculated by formulas: 40 S [1] exp H S[2] exp H 0 1 exp( beta) Implementaton and programmng. Powerful modern tool to mplement herarchcal mxt models proved to be МСМС modellng. We opted for convenent Gbbs sampler. Programmng performed n WnBUGS (Bayesan nference usng Gbbs software) envronment. Data preparaton as well as convergence dagnostcs have been performed n envronment of R v package CODA. Dsplayed graphcs were created by R package GRAPHICS. Program scrpt s gven below. It works n R envronment. Scrpt, data, ntal values are passed to and processed by WnBUGS, actvated through call «bugs» of R package R2 Wn BUGS. Sampled

4 values are returned to R as specal WnBUGS class obect (named «results» n the scrpt). pkg <- "R2WnBUGS" lbrary(pkg, character.only = TRUE) WD<-"C:/Dssertatons/Natasha/NatashaGL5" TD <- getwd() f(!s.null (WD) & WD!=TD) setwd(wd) data<-read.table ("GastroStacked.txt", header = TRUE) model.fle <- "Model/WnBugModel.txt" cat("model { for ( n 1:I){ TI[]<-Treatment []*b [Patent []] for (k n 1:K-1) {# rsk status for subect at nterval k, y[,k] <- step (Tbetw [] - a[k]) *step (a[k+1] Tbetw []) # tme spent n nterval k o[,k] <-(mn (Tbetw [], a[k+1]) - a[k])*step (Tbetw [] - a[k]) # pecewse exponental theta[,k]<-lam[k]*exp(beta*treatment[]+beta2*ti[]+ b[patent[]]) mu[,k] <- o[,k]*theta [,k]; y[,k] ~dpos (mu[,k]); # lkelhood (nu used to avod logs of zero) nu[,k] <- equals(mu[,k],0) +(1-equals(mu[,k],0))*mu[,k] LL[,k] <- y[,k]*log (nu[,k])-mu[,k]-logfact(y[,k])}} # mult-level varaton: Patent effects for ( n 1:NUM) {b[]~dnorm(0,tau); b.r[] <- b[]-mean(b[])} tau~dgamma(1, 0.01) sg <- 1/sqrt(tau) # Gamma process prors on baselne hazard for (k n 2:K-1) {lam[k]~dgamma(a0, b0[k]); b0[k] <- a0/lam[k-1]} lam[1]~dgamma(0.1,0.1) # treatment parameter beta~dnorm(0,0.001);beta2~dnorm(0,0.001); a0~dgamma(0.1,0.1) # Cum Hazard and Survvorshp H0[1] <- lam[1]*a[1]; for (k n 2:K-1) {H0[k] <- lam[k]*(a[k]- a[k-1])} for ( n 1:K-1) {S[1,] <- pow(exp(-sum(h0[1:])), exp(beta)) S[2,] <- exp(-sum(h0[1:]))} # devance Dv <- -2*sum(LL[,])}", fle=model.fle) q<-quantle(data$tbetw, probs = seq(0, 100, by=2.5)/100) q<-as.numerc(q) K<-length(q) I <- nrow(data) PatentNumber<-400 Tbetw<-data$Tbetw Treatment<-data$Treatment Patent<-data$Patent data<-lst(a=q,k=k,i=i, NUM=PatentNumber, Tbetw=Tbetw, Treatment = Treatment, Patent=Patent) nts <- functon(){ lst(b=rep(0, tmes=patentnumber), lam=rep(1, tmes=k-1), tau=1, a0=1, beta=0, beta2=0) } parameters <- c("beta", "beta2", "lam", "sg", "a0", "S", "Dv") results<-bugs(data=data,nts=nts, parameters.to.save=parameters, model="wnbugmodel.txt", debug=true, n.chans=1, n.ter=10000, bugs.seed=1966, bugs.drectory="c:/bugs/wnbugs14", workng.drectory="model", clearwd=false, DIC=FALSE, ~ 99 ~ codapkg=false) #convergency dagnostcs: Geweke's,Hedelberger and Welch s convergence dagnostc tests: codat<-read.coda(output.fle="model/coda1.txt", ndex.fle="model/codaindex.txt") geweke<-geweke.dag(codat, frac1=0.1, frac2=0.5) z<-geweke$z <-array(81:123) z<-z[] hedel<-hedel.dag(codat, eps=0.1, pvalue=0.05) raftery<-raftery.dag(codat, q=0.025, r=0.005, s=0.95, converge.eps=0.001) 3. Results and Dscusson Dstrbuton of tme spans (n days) to recurrent hosptalsaton s dsplayed n Fg.1. Dstrbuton demonstrates rght skew and conspquous devaton from normalty that n part calls for non-parametrc approach. Advantages of МСМС modellng also nclude capablty of yeldng posteror dstrbutons of parameters sampled values. We opted to dsplay 5% (0, 05) and 95% (0, 95) centles of posteror dstrbutons of sampled parameters values (Table 1) along wth convergence dagnostcs tests (Geweke s Z and Hedelberg- Welch half wdth value). Table 1: Centles values of posteror dstrbutons of sampled parameters values wth convergence dagnostcs tests Centles values Convergence tests Parameters Geweke s 0,05 Medan 0,95 Z H-W hl beta ,2363 0,4010 0,0701 1,08 0, beta2-9,397 0,8838 8,525-0,12 0, λ1 0,0009 0,0017 0,0028 0,78 0, λ2 0,0008 0,0011 0,0016-0,20 0, λ3 0,0009 0,0014 0,0021-0,25 0, λ38 0,0027 0,0039 0,0059-1,84 0, λ39 0,0036 0,0054 0,0078-1,05 0, λ40 0,0051 0,0081 0,0132-1,71 0,000251

5 The most mportant are parameter beta that actually estmates АТЕ of RP along wth beta2 that makes allowance for possble randomzaton flaws of patent selecton to RP and corrects for bas the ATE estmate due to heterogenety of control and expermental cohorts correlated wth selecton. Accordng to the results the АТЕ s proved to be sgnfcant leavng 0 beyond the lmts of 95% posteror dstrbuton nterval [-0, 4010; -0, 0701] wth medan of -0, Relatve rsk of RP admnstraton on rsk of recurrent hosptalzaton consttuted ехр (-0, 2363) = 0,790. That s, rsk of recurrent hosptalzaton reduced typcally by 21% by RP admnstraton. Values of 5% (0,05) and 95% (0,95) centles of posteror dstrbuton of sampled beta2 values negate the sgnfcance of randomzaton bas effect, for 0 lays n the mddle of 95% posteror dstrbuton nterval whch s [-9,397; 8,525]. Wde and symmetrcal around 0 posteror dstrbuton 95% nterval s conspcuous ndcaton of the absence of randomzaton nconsstences. We can suggest the absence of randomzaton nduced bas n estmaton of АТЕ that goes as corollary. Medan values of sampled values of basc rsks of recurrent hosptalzaton on 40 tme ntervals (λ1 - λ40) stpulated conspcuous pattern wth rse and levelng off from 18 to 32 months from dscharge followed by bluff declne (Fg. 2). All basc rsk estmates proved to be sgnfcant for all 95% confdence ntervals of posteror dstrbutons left zero beyond. Two survval curves tracng proportons of patents n expermental and control cohorts n wat of recurrent hosptalzaton bult by the model (Fg. 3). Dstnct patterns were observed wth decreased survval among control cohort representatves. Cumulated dfference appeared to be 49 days per patent. Ths addtonal amount of days to next hosptalzaton safeguarded by RP that consttutes the effect of RP admnstraton. We also appled 2 extended models. Second ncluded n lnear predctor mportant covarates. Only two covarates demonstrated margnally sgnfcant effect, namely GU wth 95% confdence posteror nterval of -0, 140-0, 890 and medan 0, 379, that s ncreased rsk of 1,46 aganst DU, and regular vsts to gastroenterologst wth ncreased relatve rsk RR = 1, 24. RP effect wth RR = 0,762 saved 46 addtonal days to next hosptalzaton n average per patent. Stll fraltes dstrbuton perssted to be heterogeneous that was tackled by thrd model that mplemented scale mxture prors of fraltes. Fg 3: Survval curves tracng proportons of patents n expermental and control cohorts n wat of recurrent hosptalzaton The only sgnfcant fxed covarate effect rendered by contrast GU-DU. RP effect wth RR=0,774 saved 39 addtonal days. Obtaned results and model comparson (Table 2) supported robustness of RP admnstraton effect. Table 2: Effects of RP admnstraton by 3 models Characterstcs Model #1 Model #2 Model #3 Informaton value,-2ll RR 0,790 0,762 0,774 Saved days Conclusons 1. Belated tmng of rehabltaton ntaton n post hosptal stage appeared to be cardnal obstacle of ts effcency wth low (up to 20%) coverage, and securng clncal effect n 8% cases only. 2. We shfted admnstraton of rehabltaton to hosptal stage. Program frame combnes 10 scales, namely medcaton of ulcer, det modfcaton, overweght control, physotherapy exercses, management of контроль NSAID-nduced gastropathy, rsk factor management, blood pressure correcton, dabetes management, anxety and depresson management. 3. To empower complance and to facltate case management we suppled patent wth dary and nculcate the sklls of recordng on drug ntakes, unusual symptoms, complants, as well as followng ndcated dates of examnatons and physcan referrals. The prme evdence of the effcacy of RP admnstraton s the 4% of dropouts only n frst 3 months. 4. Program effcacy estmaton reled upon tme to recurrent hosptalzaton that proved to be very senstve to qualty of care. We have chosen flexble sem-parametrc fralty models to study modfcaton effect of program on the rsk of recurrent hosptalzaton. 5. Results of three models concded n that program secured typcally at least 39 days to recurrent hosptalzaton per patent wth drop n rsk at least at RR=0, References 1. Damen Échevn. Bernard Fortn. Physcan Payment Mechansms, Hosptal Length of Stay and Rsk of Readmsson: a Natural Experment. Verson 1, Aug Wooldrdge JM. Estmatng average partal effects under condtonal moment ndependence assumptons, the Fg 2: Basc rsks of recurrent hosptalzaton by 40 month ntervals. Insttute for fscal studes, Department of economcs, ucl cemmap workng paper cwp 2004; 03/04:38. ~ 100 ~