Objective: To determine whether health services use bypatients with selected acid-related gastrointestinal disorders (pepticulcer disease, gastroesophageal reflux disease, and gastritis or dyspepsia)is lower after initial treatment with proton pump inhibitors(PPIs) than with histamine2 receptor antagonists (H2RAs).
Study Design: Retrospective, 2-year longitudinal study.
Patients and Methods: Among continuous enrollees fromDecember 1, 1996, to June 1, 2002, in a group model health maintenanceorganization, 13 971 members were electronically selectedwho began receiving antisecretory therapy during that periodand who had no previous drug therapy, endoscopy, or hospitalizationfor gastrointestinal disease. Adjusted medical costs andhealthcare use related to gastrointestinal disease (measured byoffice visits, endoscopy, or imaging and hospital admissions) andfactors associated with initial and subsequent drug therapy wereanalyzed using a 2-stage model. This method adjusted for unobservableconfounders, primarily drug selection bias, an inherentlimitation of retrospective database studies.
Results: Drug costs were more than 4-fold higher (P < .001)when PPIs rather than H2RAs were prescribed initially, but nondrugcosts and health services use showed no decrease. A historyof physicians' prescribing PPIs in the prior 12 months was associatedwith prescribing PPIs as initial therapy (odds ratio, 4.29; 95%confidence interval, 3.74-4.90) and with step-up therapy (changefrom H2RAs to PPIs). A history of physicians' prescribing H2RAs inthe prior 12 months was associated with step-down therapy(change from PPIs to H2RAs).
Conclusion: Prescribing PPI compared with H2RA therapy asinitial therapy for acid-related gastrointestinal disease produced nodecrease in nondrug costs or health services use.
(Am J Manag Care. 2004;10:433-441)
Proton pump inhibitors (PPIs) are among the mostwidely prescribed drugs. Since the 1989 introductionof omeprazole, sales of PPIs haveincreased greatly. By 2000, worldwide sales of omeprazoletotaled more than $6 billion.1 In 2001, US sales ofPPIs (more than $10 billion) were second only to salesof cholesterol-reducing agents (statins).2 Heavy use ofdirect-to-consumer advertising has made PPIs one ofthe most widely promoted drug classes.3 At the sametime, the cost of managing acid-related gastrointestinaldisorders continues to escalate, driven by the primarydirect cost of drugs, especially PPIs.4
Many studies5-11 report the superiority of PPIs overhistamine2 receptor antagonists (H2RAs) for efficacious,cost-effective treatment of acid-related gastrointestinaldisorders, especially gastroesophageal reflux disease(GERD) and peptic ulcer disease (PUD). Although thesestudies indicated that PPIs are superior to H2RAs forhealing and preventing recurrence of erosive esophagitis,the study populations lacked the variety of lesssevere and functional acid-related gastrointestinal diseasesand symptoms that primary care physicians treat.Evidence of superiority of PPIs over H2RAs is much lesscompelling in patients who have functional dyspepsia(gastroesophageal symptoms without endoscopic abnormalityor evidence of other disease known to producedyspepsia) or who have gastroesophageal symptomswithout evidence of a lesion.12-15 Therefore, although thedata suggest that PPI therapy may be more cost effectivethan H2RA therapy for selected patients who need moreintense acid suppression, these data are lacking forpatients who have the less serious gastrointestinal disorderstypically seen in primary care practice.
Treatment of acid-related gastrointestinal disease isnot limited to the initial selection of antisecretory drugs(ie, PPIs or H2RAs) but also includes their sequentialuse. Initial therapy with H2RAs may be changed to PPItherapy (step-up therapy) if needed, or initial therapywith PPIs may be changed to H2RA therapy (step-downtherapy) after symptoms are controlled. These strategieshave produced mixed results in modeling investigationsand in protocol-driven prospective trials.16,17These models are sensitive to the assumptions madeand to the drug costs used in the calculations. Moreimportant, the models do not reflect clinical practice,because the need for step-up or step-down therapy orendoscopy is predetermined. Protocol-driven prospectivestudies are further limited by the characteristicsand small size of the study populations. A recent study18showing a 58% success rate for step-down therapy after1 year included only 71 patients after rigorous exclusioncriteria were applied. Step-down therapy was studiedonly in patients who remained asymptomatic whilereceiving PPIs; this criterion excluded from analysis thesubstantial number of patients who remained symptomatic,despite PPI therapy. The study did not addressstep-up therapy.
In the present retrospective study of patients withdifferent acid-related gastrointestinal disorders (PUD,GERD, and gastritis or dyspepsia), we assessed theeffect of initial medication choice (ie, PPIs, H2RAs, orboth) and of subsequent stepwise treatment on cost anduse of healthcare in a large health maintenance organization(HMO). In particular, we examined return oninvestment by determining whether initial therapy withPPIs results in lower associated healthcare costs thaninitial therapy with H2RAs. We also assessed factorsaffecting initial and subsequent treatment strategies forthese patients.
Study Population and Design
This study was a 2-year, retrospective longitudinalanalysis of data from the administrative databases ofKaiser Permanente (KP) in northern California,19,20 agroup model HMO with about 3 million members. Thestudy population (n = 13 971) included all patients whomet the following criteria: age 18 years or older;received a new prescription for 1 or more antisecretorydrugs (PPIs or H2RAs) between December 1, 1997, andJune 1, 1998 (index period); received no prescriptionfor PPIs or H2RAs and had no hospital admission orendoscopic examination for gastrointestinal disease inthe 12 months before the index period; was diagnosedby a physician as having an acid-related gastrointestinaldisorder within 180 days of the index date; and wascontinuously enrolled at KP for 12 months before and24 months after the index date (ie, 36-month minimumenrollment). Data for each patient were collected for 24months after the index period. This study wasapproved by the KP Northern California InstitutionalReview Board.
International Classification ofDiseases, Ninth Revision, Clinical Modification (ICD-9-CM)
On the basis of 21 coded entries in the KP Outpatient SummaryClinical Records, patients were assigned to 1 of3 diagnostic groups: PUD, GERD, and dyspepsiaor gastritis (Table 1). Patient selection wasaccomplished without bias from electronicadministrative databases using an SAS (SASInstitute, Cary, NC) algorithm. Patients withdiagnoses in more than 1 category wereassigned to a single diagnostic group. Patientswhose medical record contained the diagnosticcode for PUD were assigned to this diseasegroup even if the record contained additionalcodes from different diagnostic groups; patientswere grouped in the GERD category if theirrecords contained the code for GERD and thecode for gastritis or dyspepsia but not the codefor PUD.
Data on medication use by patients and eachphysician's drug-prescribing history in the 12months preceding the index date were obtainedfrom the KP Pharmacy Information ManagementSystem; data on office visits, from theOutpatient Registration System Plus; and laboratorydata, from the Laboratory UtilizationReview System. Hospitalization data wereobtained from the Admission Discharge Transfer databaseusing selected 22 codes for diagnosis-relatedgroups 174 through 178, 182, and 183. Physicianoffice visits comprised visits to the following departmentsor divisions: medicine (including gastroenterology)and pulmonary medicine and allergy because ofpossible association of GERD with asthma), urgentcare, and emergency. Results of endoscopy and uppergastrointestinal imaging were obtained from outpatientand inpatient records using 23 codes.
Drug costs were calculated on the basis of acquisitioncost. Procedure and hospital cost data were obtainedfrom the KP Cost Management Information System.
Data on patient demographics and length of enrollmentin the health plan were obtained from the KPPatient Demographics database and from the Length ofEnrollment database. Age bands contained 10-yearranges, except for patients aged 18 through 24 years andpatients older than 74 years. Descriptive statistics wereused to describe age, sex, acid-related disorder, rate ofendoscopy, hospital admissions, and acid-suppressiontherapy continuing longer than 6 months.
Patients were categorized based on diagnoses andinitial prescription. They were followed up longitudinallyfor up to 2 years after the indexdate and identified as to whetherthey refilled their initial prescription,did not continue their initial prescription,stepped down from PPIs toH2RAs, or stepped up from H2RAs toPPIs. Figure 1 illustrates the variousprescribing pathways.
Combination therapy was definedas concurrent initial prescription ofPPIs and H2RAs or concurrent prescriptionsof PPIs and H2RAs for 100or more days or for 50% or longer ofthe study. Because few patients startedcombination therapy, thesepatients were not included in subsequentanalyses.
Predictors of PPI Initiation
Predictors of PPI initiation andsubsequent step-up or step-downtherapy were analyzed by logisticregression. Independent variablesincluded age bands, sex, diagnosticcategory (GERD, PUD, and gastritis or dyspepsia),physicians' drug-prescribing history, and current orprevious nonsteroidal anti-inflammatory drug use.
During our study, prescribing physicians at KP wereencouraged, through information in fliers or presentationsby pharmacists, to start therapy with the lessexpensive H2RAs. There were no formal clinical protocolsfor step-up or step-down implementation. However,if patients had initially received PPIs, physicians wereencouraged to step down therapy, as appropriate.
Cost and Health Services Use Analyses
When comparing direct medical costs and use forpatients initially receiving PPIs and H2RAs, a 2-stagestatistical model was used to control for drug selectionbias. This method provided an adjustment factor(inverse Mills ratio) estimated from observable variablesto adjust for unobservable confounders that may be correlatedwith treatment selection and that may affecttotal medical cost or use.24 Correlation analysis wasused to test multicolinearity between the inverse Millsratio and other variables contained in the cost or useequations.
Independent variables included in the first stage ofanalysis were the patient's age band, sex, diagnostic category,physicians' prescribing history, and presence of20 chronic diseases (based on drug prescriptions filled).Chronic diseases included human immunodeficiencyvirus infection, cardiovascular disease, hypertension,hyperlipidemia, seizure disorders, Parkinson's disease,rheumatoid arthritis, pain disorders, asthma, diabetesmellitus, thyroid disease, gout, Crohn's disease, depression,psychosis, anxiety, mania, cancer, previous organtransplantation, and renal disease. This use of population-based pharmacy data to measure chronic diseasestatus has been described as a means of predictinghealthcare use.25
Dependent variables for the second stage of analysisincluded drug costs and nondrug costs of treating acid-relatedgastrointestinal disease and frequency of physicianoffice visits, endoscopy, upper gastrointestinalimaging, or hospital admission for gastrointestinal disease.Independent or explanatory variables used in thesecond stage of analysis included the inverse Millsratio, sex, age bands, initial antisecretory drug prescription,acid-related gastrointestinal disease diagnosis,hospital admission for gastrointestinal disease,endoscopy, upper gastrointestinal imaging, current useof nonsteroidal anti-inflammatory drugs, duration ofantisecretory therapy longer than 6 months, eradication, visits to the departmentof medicine or gastroenterology, and presence ofchronic disease.
Severity of acid-related gastrointestinal disease wasmeasured by the frequency of endoscopy, upper gastrointestinalimaging, hospital admission for acid-relatedgastrointestinal disease, and proportion of patientswho required therapy for longer than 6 months duringthe 2-year follow-up. Depending on the outcome ofinterest, a variable could be dependent or independent,but never both in the same model. For example,endoscopy is an independent variable in the cost modelbut is a dependent variable when frequency ofendoscopy is the outcome of interest.
Return on investment was computed by comparingdrug and nondrug costs of treatment for acid-relatedgastrointestinal disease between patients who initiallyreceived a prescription for PPIs and patients who initiallyreceived a prescription for H2RAs. Drug costsincluded cost of antisecretory drugs (PPIs and H2RAs),prokinetic drugs (eg, cisapride and metoclopramidehydrochloride), other gastrointestinal drugs (eg, misoprostoland sucralfate), and drugs for eradication.Drugs such as bismuth subsalicylate, tetracycline,amoxicillin, metronidazole, or clarithromycin were consideredprescribed for eradication when prescribedthe same day as any of the other classes ofdrugs. Nondrug costs included costs of endoscopy, serology, upper gastrointestinal imaging, and hospitaladmissions.
Frequency of endoscopy, upper gastrointestinalimaging, physician office visits, and hospital admissionfor acid-related gastrointestinal disease was also evaluated.Because we focused on overall return on investmentand because we assumed that patients withunresolved symptoms would continue to take prescribedmedication or return for diagnostic evaluation,additional outcome data were not part of this study.
Multivariate (ordinary least squares and logistic)regression analysis was used to evaluate the relationsbetween dependent and independent variables.Ordinary least squares regression was used to analyzecontinuous variables, and logistic regression analysiswas used for dichotomous variables. Stepwise proceduresused to select independent variables having a significanteffect for the model were then repeated instandard stepwise analysis. Variables were estimated byusing maximum likelihood or analysis of variance.Statistical significance was defined at < .001. All confidenceintervals (CIs) were 95%, and all values were2-sided.
All costs were natural log transformed to reduceskewness of the data. To ensure inclusion of all subjectsin the analysis, $1 was added in the log-transformedanalysis when a cost variable was equal to zero. SAS statisticalsoftware version 8.0 was used for data analysis.
Patient demographics and characteristics are summarizedin Table 2. The 13 971 patients meeting thecriteria for newly started treatment had a female-maleratio of 59:41. The mean ± SD age of the patients was52.2 ± 15.9 years. Most patients with gastritis or dyspepsiawere younger, and more women than men had adiagnosis of GERD and gastritis or dyspepsia. Of thesewomen, 56.3% had GERD, 35.6% had gastritis or dyspepsia,and 8.0% had PUD. Patients with PUD were morelikely to have endoscopy or hospital admission for gastrointestinaldisease, and patients with gastritis or dyspepsiawere less likely to have treatment for longer than6 months. There was a concordance of 69% betweenpreendoscopic diagnoses and postendoscopic diagnoses.About 30% of all patients required treatment for longerthan 6 months.
Table 3 summarizes the disposition of patients alongtreatment pathways (initial and subsequent therapy) bydiagnoses and for the overall cohort. Step-up or step-downtherapy was used infrequently, for 12.6% ofpatients who initiallyreceived therapy with H2RAs and for 9.4% ofpatients who initially received therapy withPPIs. About one third (27.0% of patients whoinitially received PPI therapy and 35.6% ofpatients who initially received H2RA therapy)of patients discontinued therapy.
Predictors of PPI Initiation
The adjusted odds ratios (ORs) for initiationof treatment with PPIs are shown in Table4. After controlling for other variables, physicians'history of prescribing PPIs was thestrongest predictor.Physicians with a PPIprescribing ratio (PPI prescriptions/[PPI + H2RA prescriptions])greater than 50% for the past year weremore than 4 times more likely to prescribe PPIs thanH2RAs for a new patient (OR, 4.29; 95% CI, 3.74-4.90; < .001). Other factors associated with initial PPI prescriptionwere diagnosis of PUD (OR, 2.47; 95% CI, 2.05-2.96) or GERD (OR, 2.00; 95% CI, 1.79-2.20) comparedwith gastritis or dyspepsia, as well as use of medicationsfor rheumatoid arthritis (OR, 1.54; 95% CI, 1.33-1.78).Younger patients were less likely (and older patients,more likely) to receive PPIs initially. The type of PPIsprescribed was almost exclusively (approximately 95%)omeprazole; of prescriptions for H2RAs, 60% were writtenfor cimetidine, and 40% were written for ranitidinehydrochloride.
Physicians' prescribing history largely predicted useof step-up or step-down therapy (Table 4). The OR forprescribing step-up therapy was 3.47 (95% CI, 2.80-4.32)for physicians whose PPI prescribing ratio was greaterthan 50% for the past year. Use of step-up therapy wasassociated with patients' receiving or having any of thefollowing: endoscopy (OR, 3.80; 95% CI, 3.05-4.75),hospital admission related to gastrointestinal disease(OR, 3.54; 95% CI, 2.54-4.93), upper gastrointestinalimaging (OR, 2.78; 95% CI, 2.33-3.32), orlonger than 6 months of therapy (OR, 4.39;95% CI, 3.87-4.90). Gastroenterologistswere more likely to use the step-down strategythan physicians practicing other medicalspecialties (OR, 2.35; 95% CI, 1.42-3.89). Step-down therapy was morethan twice as likely (OR, 2.25; 95% CI, 1.44-3.53) to be prescribed by a physicianwhose H2RA prescribing ratio (H2RA prescriptions/[H2RA + PPI prescriptions]) was greater than 50% for the past year.
Cost and Health Services Use Analyses
No statistically significant difference infrequency of endoscopy, physician officevisits, upper gastrointestinal imaging, orhospital admission for gastrointestinal diseasewas found between patients who initiallyreceived PPI therapy and patientswho initially received H2RA therapy.During the study, 7.7% of all patients hadendoscopy, 10.4% had upper gastrointestinalimaging, and 30.5% received therapyfor longer than 6 months.
Figure 2 depicts the natural log—transformedrelative cost ratio of drug and nondrugmedical costs for patients in thisstudy. Drug costs were 4.2 times higher (< .001) for patients who initially receivedPPI therapy than for patients who initiallyreceived H2RA therapy; this cost ratioranged from 3.7 times higher for PUD to5.0 times higher for gastritis or dyspepsia.Costs of antisecretory drugs (PPIs andH2RAs) accounted for 91% of drug costs.The remaining costs were for prokineticdrugs, other gastrointestinal drugs, anddrugs for treating infection.
No statistically significant difference in nondrug costs(overall or by diagnosis) was seen between patients whoinitially received PPI therapy and patients who initiallyreceived H2RA therapy. However, nondrug costs wereslightly (but not statistically significantly) lower forpatients who had PUD (12% lower) or GERD (6% lower)and initially received PPI therapy. These nondrug costsdid not offset the much higher drug costs associatedwith initial use of PPIs. The adjusted value of 0.61for drug cost and 0.70 for nondrug cost indicated agood fit for the model. Correlation of the inverse Millsratio with other independent variables did not showmulticolinearity, particularly with the treatment variable( = −0.36); the strongest evidence of multicolinearity was with duration of treatment ( = −0.45). Thesefindings suggest that the higher drug cost for therapywith PPIs (vs H2RAs) was not offset by lower nondrugcosts.
This retrospective database study assessed the effectof initial antisecretory drug choice on cost and use ofhealth services in a managed care setting. The analysisof almost 14 000 patients using a 2-stage econometricmodel to control for relevant unobserved variables,such as drug selection bias, was based on intention totreat from the perspective of the managed care plan.
In this large managed care population, therapy initiatedwith PPIs in patients with physician diagnoses ofPUD, GERD, and gastritis or dyspepsia did not result inan observable offset in nondrug medical costs. In addition,no statistically significant difference was seen inthe frequency of endoscopy, upper gastrointestinalimaging, physician office visits (to generalists or to specialists),or hospitalization for patients who initiallyreceived a prescription for PPIs vs H2RAs. These findingsdid not support the hypothesis that initiating therapywith PPIs produces a statistically significant offsetin nondrug medical costs or medical use among patientstreated for acid-related gastrointestinal disease.
Our study further showed that, in a population ofunselected patients, most patients did not change fromthe therapy initially prescribed, whetherPPIs or H2RAs. Of patients who initiallyreceived H2RAs, 87.4% continued thistherapy, while 90.9% of patients who initiallyreceived PPI therapy continued PPItherapy. This degree of step-down therapywas lower than that achieved by treatmentprograms that systematicallyattempted to achieve high rates of step-downtherapy. Inadomi et al18 reportedthat step-down therapy was prescribedfor 58% of a selected patient populationwho had achieved full symptom reliefafter receiving PPI therapy. In our study,the major factor associated with thechoice of initial prescription was the physician'sprescribing history. This findingindicated that changing physicians' choiceof initial prescription may lead to long-termchange in patterns of medication useby patients treated for gastrointestinaldisease.
To our knowledge, this is the first publishedstudy to use actual costs in a not-for-profit managed care patient population. Regardlessof treatment strategy evaluated in modeling studies,findings related to cost-effectiveness depend on 2 factors:assumptions inherent in the model and cost ofdrugs used in treatment. A strength of our study isthat it measured real costs and was not based onassumptions that may not reflect reality. Moreover,other studies8,10,26,27 evaluated selected patients, atleast half of whom were diagnosed with more severedisease (eg, erosive esophagitis) or heartburn, conditionsthat might not be represented in a populationseen in a primary care setting. By including allpatients who received at least 1 prescription forH2RAs or PPIs, we ensured that our study populationhad a broader range of acid-related gastrointestinaldisease severity.
This retrospective database study has inherent limitations,primarily potential drug selection bias, despiteuse of the 2-stage model. We adjusted for this potentialbias by using the inverse Mills ratio. The sign for theinverse Mills ratio was negative and significant ( <.001) for drug cost and for frequency of endoscopy. Forthese 2 end points, the differences between therapy initiatedwith PPIs and therapy initiated with H2RAswould have been overestimated if the inverse Mills ratiohad not been used as an adjustment factor. Correlationof this ratio with other variables did not indicate multicolinearity.Although we cannot be sure that we adjustedfully for treatment selection bias or for unobservedvariables, we are confident that we effectively adjustedfor this variable.
Because our results are based on case mix, patientdemographics, cost of prescriptions and medical care,and physician practice patterns at KP in northernCalifornia, they might not be considered by some asapplicable to other practice settings or patient populations.By most measures, however, the membership ofour large health maintenance organization representsthe general population of California. Furthermore, ourfindings of no statistical difference between the individualcomponents of nondrug costs for each of the 2 typesof initial therapy make these results cost-independentand therefore potentially applicable to other practicesettings. The findings are based on acquisition costs atthe time of this study. Introduction of multiple genericPPIs into the market may attenuate the cost difference.The availability of over-the-counter omeprazole (eg,Prilosec) can also change the cost equation, becausesome of the cost burden could be shifted from thehealth plan to the patient.
The accuracy of diagnoses in our study populationmay also be questioned; however, a 69% concordancewas found between preendoscopy diagnoses and postendoscopydiagnoses. A small percentage (1.5%) ofpatients were included in the PUD group because ofhematemesis or blood in stools. However, this potentiallack of specificity had no material effect on our findings.An 83% overall concordance between the KP OutpatientSummary Clinical Records diagnoses of the 3 acid-relateddiseases and medical chart review was confirmedpreviously by Levin et al.19 Moreover, Allison et al20reported 17% of PUD diagnoses in another KP study asconfirmed by radiography or endoscopy. Although nodirect indicators of disease severity were used in ourretrospective study, we used surrogate measures thatmay correlate with disease severity, such as duration oftherapy, need for imaging or endoscopy, and hospitaladmissions, which at least partially adjusted for diseaseseverity.
High-dosage H2RA therapy used for patients withGERD may be equivalent to treatment with PPIs,13 andhigh-dosage PPI therapy may benefit some patients withspecific conditions of severe erosive esophagitis, such asBarrett esophagus.27,28 However, we did not adjust fordifferent dosages of PPIs or H2RAs, because we attemptedto reflect dosages used in a clinical setting. Ouranalyses assumed that all patients achieved a desiredclinical outcome regardless of type of therapy receivedinitially, although patient outcomes (eg, quality of life,quality-adjusted years of life gained, and satisfactionwith therapy) were not assessed. However, during thestudy, the healthcare industry was competitive andplaced great pressure on physicians to maintain andincrease patient satisfaction. In addition, satisfactionscores for all measures at our HMO increased duringthis period. Therefore, although we did not measure satisfactionattributable to treatment of acid-related gastrointestinalconditions, few data supported patientdissatisfaction. Moreover, lack of correlation betweeninitial drug choice and frequency of endoscopy, uppergastrointestinal imaging, or hospital admission for acid-relatedgastrointestinal disease offered no support forthe hypothesis that patients who initially received PPItherapy have better clinical outcomes than patientswho initially received H2RA therapy.
In our managed healthcare setting, prescribing PPIsas initial therapy for acid-related gastrointestinal disease(compared with H2RAs as initial therapy) yieldedno positive return on investment in nondrug costs orhealthcare services use as measured by costs and frequencyof office visits, endoscopy or imaging, and hospitaladmission. Our results did not support thehypothesis that patients who initially receive PPI therapyhave better nondrug and use outcomes than patientswho initially receive H2RA therapy.
We thank Michele M. Spence, PhD, for assistance with SAS programming,and Mirta Millares, PharmD, for review of the manuscript.The Medical Editing Department, Kaiser FoundationResearch Institute, provided editorial assistance.
From the Pharmacy Outcomes Research Group, Pharmacy Operations, KaiserPermanente Medical Care Program, Oakland (JC, RLH), and the Division ofGastroenterology, Department of Medicine, Kaiser Permanente Medical Center, Richmond(J-LS), Calif.
This research was presented at the 103rd Annual Meeting of the AmericanGastroenterological Association, Digestive Disease Week; May 19-22, 2002; San Francisco,Calif.
Address correspondence to: James Chan, PharmD, PhD, Pharmacy OutcomesResearch Group, Pharmacy Operations, Kaiser Permanente Medical Care Program, 1800Harrison, 13th Floor, Oakland, CA 94612. E-mail: firstname.lastname@example.org.
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