Does Seropositivity forHelicobacter pyloriAntibodies Increase Outpatient Costs for Gastric and Duodenal Ulcer or Inflammation?

Pharmacoeconomics 2004; 22 (15): 975-983ORIGINAL RESEARCH ARTICLE 1170-7690/04/0015-0975/$31.00/0

© 2004 Adis Data Information BV. All rights reserved.

Does Seropositivity for Helicobacterpylori Antibodies Increase OutpatientCosts for Gastric and Duodenal Ulceror Inflammation?Akira Babazono,1,2 Motonobu Miyazaki,3 Hiroshi Une,3 Eiji Yamamoto,4Toshihide Tsuda,5 Yoshio Mino6 and Alan L. Hillman7,8,9

1 Institute of Health Science, Kyushu University, Kasuga City, Fukuoka, Japan2 Graduate School of Medical Sciences, Health Care Administration and Management, Kyushu

University, Fukuoka City, Fukuoka, Japan3 Department of Hygiene and Preventive Medicine, School of Medicine, Fukuoka University,

Fukuoka City, Fukuoka, Japan4 Department of Information Science, Okayama University of Science, Okayama City,

Okayama, Japan5 Social and Environmental Life Sciences, Okayama University Graduate School of Medicine

and Dentistry, Okayama City, Okayama, Japan6 College of Social Welfare, Osaka Prefecture University, Osaka City, Osaka, Japan7 Division of General Internal Medicine, Department of Medicine, School of Medicine,

University of Pennsylvania, Philadelphia, Pennsylvania, USA8 Center for Health Policy, Leonard Davis Institute of Health Economics, University of

Pennsylvania, Philadelphia, Pennsylvania, USA9 Department of Health Care Management, The Wharton School, University of Pennsylvania,

Philadelphia, Pennsylvania, USA

Background: Helicobacter pylori is regarded as an important cause of bothAbstractpeptic ulcer and chronic gastritis. In particular, seropositivity is highest in patientswith duodenal ulcer. No studies have determined whether there are differences inthe direct medical costs associated with gastric/duodenal ulcer or inflammation,between seropositive and seronegative patients.Objective: To examine the relationship between seropositivity for H. pylori andoutpatient visits and direct medical costs for gastric/duodenal ulcer or inflamma-tion in Japan from the perspective of the payor and patients.Methods: Participants were males (n = 653) who worked for an agriculturalco-operative in Fukuoka Prefecture, attended an annual health examination(including a written lifestyle and medical survey), belonged to the same healthinsurance society consistently for 4 years from April 1996 to March 2000, andprovided a blood sample. The survey asked about lifestyle, including smoking anddrinking, and past medical history. We retrospectively analysed the annualnumber of outpatient visits per person and outpatient medical cost (Yen [¥], 2000values) per person for visits relating to gastric or duodenal ulcer or inflammation

976 Babazono et al.

using International Classification of Diseases (9th edition) – Clinical Modificationcodes. We assessed for potential confounding factors using analysis of covarianceand the chi-square test.

Results: The annual outpatient incidence of disease, the number of visits tophysicians, and the medical costs for gastric or duodenal ulcer or inflammationwere about 2-fold greater in individuals with antibodies to H. pylori comparedwith those without antibodies.

Conclusion: Population-based studies and/or randomised controlled clinical trialsthat target high-risk groups and account for the unique way in which data arecollected in Japan are needed to determine whether medical costs for gastric andduodenal ulcer might be reduced by treating asymptomatic patients who haveantibodies to H. pylori.

The spiral bacterium Helicobacter pylori was medical costs associated with gastric/duodenal ulceror inflammation, between seropositive and serone-isolated from cultures of gastric biopsy tissue ingative patients. Therefore, we compared the directpatients with chronic gastritis in 1982,[1,2] and ismedical costs associated with treating gastric/duo-regarded as an important cause of both peptic ulcerdenal ulcers or inflammation in individuals sero-and chronic gastritis.[3,4] In particular, seropositivitypositive with those who were seronegative for H.is highest in patients with duodenal ulcer.[5,6] H.pylori; from the perspective of patients and thepylori can be eradicated by bismuth compounds,payer.metronidazole, and various other antibacterials, with

a reduced rate of symptoms and recurrent ulcer aftersuccessful treatment.[7-13] The H. pylori seropositivi- Methodsty rate exceeds 50% in Japan,[14] but not all individu-als with antibodies to H. pylori develop ulcers or

Participantsinflammation of the stomach or duodenum. Like-wise, patients with gastric or duodenal ulcer or Participants included 722 males aged 40 years orinflammation do not always show seropositivity for over who worked for an agricultural co-operativeH. pylori. In addition, the prevalence of H. pylori is located in Fukuoka Prefecture (Japan) and who con-different among age groups and geographic ar- sistently belonged to the same health insurance asso-eas.[15-22] In Japan, ulcers or inflammation of the ciation between April 1996 and March 2000.stomach or duodenum are usually treated in the Among them, 714 workers took an annual healthoutpatient setting. examination, including a questionnaire in July 2000,

Computer simulations, using a decision-analytic and 675 workers consented to study enrolment. Wemodel, comparing the direct medical costs of eradi- analysed data from the 653 participants who an-cation therapy (i.e. eliminating the presence of H. swered all survey questions and provided a bloodpylori) with empiric treatment of symptoms (using sample in the examination. The survey asked aboutantacids or histamine H2 receptor antagonists) show lifestyle, including smoking and drinking, and pasteradication therapy to be the preferred strategy, de- medical history. For the purposes of the sensitivityspite the fact that the impact of H. pylori on direct analysis, history of ulcer was only considered posi-medical costs is unknown.[23,24] An economic ana- tive if a patient answered that they had been diag-lysis based on the serology of actual patients has nosed to have an ulcer at any time in the past and thenever been performed and no studies have deter- ulcer had been confirmed by upper gastrointestinalmined whether there are differences in the direct radiography or endoscopy.

© 2004 Adis Data Information BV. All rights reserved. Pharmacoeconomics 2004; 22 (15)

H. Pylori and Costs of GI Ulcer/Inflammation 977

Serology tient direct cost, including patient co-payments. Dis-counting of medical costs to account for possible

Blood samples collected from a peripheral vein alternative uses of money was not performed duringusing siliconized disposable plastic tubes were cen- the investigation period because the national lendingtrifuged within 1 hour of sampling. The resultant rate was extremely low due to an economic reces-serum was immediately stored at –40°C. IgG anti- sion in Japan. Very little profit was earned frombodies for H. pylori were measured by enzyme saving or investment during this time. We used animmunoassay (EIA) using a Pirika Plate G Helico- average exchange rate of ¥120 to $US1 from 1996 tobacter II assay kit (Biometrica). The serological test 2000. The year of costing for all monetary valueswe used is reported to have a sensitivity of about was 2000. No adjustment was performed to convert95% and a specificity of about 90% for detection of 1996–1999 values into year 2000 values.H. pylori infection.[25,26]

Statistical AnalysisMedical Service Indicators

The health-insurance database employed the In- We selected age, smoking, and alcohol use asternational Classification of Diseases (9th edition) – potential confounding factors because they contrib-Clinical Modification (ICD-9-CM) system. We ute to the occurrence of gastric or duodenal ulcer orutilised disease codes 1104 (gastric or duodenal inflammation.[27] Age was dichotomised into twoulcer) and 1105 (gastric and duodenal ulcer or in- categories: <50 or ≥50 years of age. Smokers wereflammation) to calculate the annual incidence of defined as individuals who used any kind of tobaccodisease. Outpatient visits to physicians are quite product at the time of the study or those who hadfrequent in Japan, especially when compared with abstained from such behaviour for a period of <5other ‘first world’ countries. Medical bills are issued years. Based on the questionnaire used in the exam-monthly by medical facilities and sent to the ination, those who used alcohol, in any amount, fourMedical Fee Payment Fund (a government fund) for or more times per week were regarded as drinkers.payment. All bills are initially sent to this fund for We examined the relationships between H. pyloriverification and payment. The bill is then sent to the antibody status and age, smoking, and drinking withhealth insurance society who reimburses the govern-ment. We analysed the annual number of outpatientvisits per person and the annual outpatient medicalcost per person for visits relating to gastric or duode-nal ulcer or inflammation only, using the aforemen-tioned ICD-9-CM codes.

In Japan, outpatient medical costs including phy-sician fees, examination costs and drug costs, arepaid on a fee-for-service basis, according to a feeschedule established by the government. Co-pay-ment rates were 10% until August 1997 and 20%thereafter. In addition, each insured is required tobear about 150 yen (¥) [$US1.25 in 1997] for eachdrug prescription, which, given price levels in Ja-pan, is not overly burdensome. Costs of over-the-counter medicines are not covered by health insur-ance in Japan and were not included in our analyses.

Medical costs for treating gastric/duodenal ulcersor inflammation were calculated as the total outpa-

Table I. The relationship between age, smoking, drinking and Heli-cobacter pylori antibody status

Variables H. pylori antibody Total [n (%)]status

positive negative[n (%)] [n (%)]

Age (years) 50 or over 136 97 233(58.4)* (41.6) (35.7)

under 50 208 212 420(49.5) (50.5) (64.3)

Smoking Smokers 238 197 435)(54.7) (45.3) (66.6

Non-smokers 106 112 218(48.6) (51.4) (33.4)

Drinking Drinkers 199 183 382(52.1) (47.9) (58.5)

Non-drinkers 145 126 271(53.5) (46.5) (41.5)

Total 344 309 653(52.7) (47.3) (100)

* p < 0.05 vs seronegative individuals.


978 Babazono et al.

the chi-square test. We compared annual incidence ri seropositivity rate of 53%, which was higherof disease, number of visits per person-year, and among older participants but unrelated to smokingoutpatient medical costs per person with ulcer or and drinking. These findings are consistent withinflammation of the stomach or duodenum. prior studies.[14-22,28-32] Because we specify socio-

economic status in the analyses, the impact of smok-Analysis of covariance (ANCOVA) was per-ing and drinking (which is related to H. pyloriformed using incidence, number of outpatient visits,through socio-economic status) can be ignored.and outpatient medical costs as dependent variables,

H. pylori seropositivity as the main predictive varia- Table II shows the annual incidence of inflamma-ble, and age, smoking, and drinking as covariates. tion, number of physician visits, and direct outpa-

As a sensitivity analysis, we utilised multiple tient medical costs for treating gastric/duodenal ul-logistic regression analysis to investigate the associ- cers or inflammation among patients with and with-ation between H. pylori antibody status and upper- out H. pylori antibodies. The annual mean numbergastrointestinal (GI) or endoscopy-confirmed peptic of outpatient physician visits per person was signifi-ulcer only, using age, smoking, and drinking as cantly higher among those with H. pylori antibodiescovariates. compared with those without (2.9 vs 1.4; p < 0.05)

and among those aged <50 years compared withResults those older (1.7 vs 3.2; p < 0.05).

The mean outpatient medical cost per person-Sixty four percent of study participants wereyear was ¥72 300 ($US602) among individuals withaged 40–49 years (n = 420), 35% were aged 50–59antibodies to H. pylori and ¥36 500 ($US309)years (n = 227) and 1% were aged 60–69 years (n =among those without (p = 0.02); ¥84 100 ($US701)6). Table I shows the relationship of H. pylori anti-among those aged 50 years and older versus ¥39 400body status with age, smoking, and drinking. There($US329) among those younger (p < 0.01); ¥47 800were 344 (53%) seropositive and 309 (47%) serone-($US398) among drinkers compared with ¥66 000gative individuals. In the older age group (age 50($US555) among non-drinkers (p = 0.28); andyears or over) individuals were significantly more¥65 500 ($US545) among smokers versus ¥35 200likely to be seropositive than seronegative (p <($US293) among non-smokers (p < 0.01).0.05). No relationship was observed between H.

pylori and smoking or drinking status. Table III shows the results of the ANCOVAanalysis. The annual incidence of gastric/duodenalThe average monthly salary of the individualsulcer or inflammation among patients with H. pyloriwas ¥328 000 ($US2733) in 2000. Thus, we studiedantibodies was 0.22 (95% CI 0.05, 0.39) higher thantypical white-collar workers with an overall H. pylo-

Table II. Medical service indicators according to Helicobacter pylori antibody, smoking and drinking status, and age

Variables Group Incidence Number of visits Direct medical costsa

Meanb (SD) Meanb (SD) Meanb (SD)

H. pylori Positives 0.45 (1.26) 2.94 (8.73)* 72.29 (186.59)*

Negatives 0.21 (0.89) 1.44 (7.44) 36.53 (191.53)

Age (years) 50 or over 0.46 (1.35) 3.19 (11.02)† 84.12 (276.57)†

Under 50 0.27 (0.94) 1.69 (5.99) 39.42 (113.55)

Smoking Smokers 0.39 (1.26) 2.57 (9.31) 65.50 (221.42)‡

Non-smokers 0.24 (0.73) 1.54 (5.16) 35.16 (96.88)

Drinking Drinkers 0.31 (0.99) 1.91 (6.15) 47.80 (129.56)

Non-drinkers 0.38 (1.26) 2.68 (10.37) 66.04 (250.92)

a ¥1000, 2000 values.

b Unadjusted (for other covariates) estimate.

¥ = yen; * p < 0.05 vs H. pylori negatives; † p < 0.05 vs <50 year-olds; ‡ p < 0.01 vs non-smokers.



Table III. Results of Analysis of covariance for medical service indicators

Dependent variables Parameter Estimate of SE 95% CIincreasedincidence/cost

Annual incidence of inflammation Helicobacter pylori seropositive (vs seronegative) 0.22 0.09 0.05, 0.39

≥50 year-olds (vs <50 year-olds) 0.17 0.09 –0.00, 0.35

Smokers (vs non-smokers) 0.14 0.09 –0.04, 0.32

Drinkers (vs non-drinkers) –0.07 0.09 –0.24, 0.10

Intercepta 0.11 0.10 –0.09, 0.31

Number of visits H. pylori seropositive (vs seronegative) 0.33* 0.16 0.01, 0.64

≥50 year-olds (vs <50 year-olds) 0.36* 0.17 0.03, 0.69

Smokers vs non-smokers 0.27 0.17 –0.06, 0.60

Drinkers vs non-drinkers –0.21 0.16 –0.53, 0.11

Intercepta 0.20 0.19 –0.17, 0.57

Medical costs (¥1000)b Helicobacter pylori seropositive (vs seronegative) 30.19* 14.78 1.23, 59.15

≥50 year-olds (vs <50 year-olds) 43.84** 15.39 13.68, 74.00

Smokers vs non-smokers 31.58* 15.62 0.96, 62.20

Drinkers vs non-drinkers –20.52 14.92 –49.76, 8.72

Intercepta 14.79 17.50 –19.52, 49.09

a The value of the dependent variable when all parameters are 0.

b Year 2000 values.

SE = standard error; ¥ = yen; * p < 0.05; ** p < 0.01.

among those without antibodies (p = 0.01) and smoking, and drinking as covariates. The odds ratioof peptic ulcer among those individuals with H.among patients aged 50 years or older it was 0.17pylori seropositivity compared with those without(95% CI 0.00, 0.35) higher than among youngerantibodies was 2.1 (p < 0.001); among older individ-patients (p = 0.06). We found no significant associa-uals (aged 50 years and over) relative to thosetions between incidence of gastric/duodenal diseaseyounger it was 1.5 (p < 0.05); and among smokersand smoking and drinking.compared with non-smokers it was 1.4 (p < 0.07).The number of outpatient visits per person-yearAgain, we found no significant relationship betweenamong patients with H. pylori antibodies was 0.33alcohol use and peptic ulcer.(95% CI 0.01, 0.64) higher than those without (p =

0.04); and 0.36 (95% CI 0.03, 0.69) higher amongDiscussionthe older age group (p = 0.03). We found no signif-

icant associations with smoking and drinking andDoes Positivity for Helicobacter pylorinumber of outpatient visits.Antibody Increase OutpatientOutpatient medical costs per person-year amongMedical Costs?patients with H. pylori antibodies were ¥30 200

(95% CI 1200, 59 200) [$US252] higher than those Seropositivity for H. pylori, the organism likelywithout antibodies (p = 0.04), ¥43 800 (95% CI responsible for gastric/duodenal ulcer or inflamma-13 700, 74 000) [$US365] higher in the older than in tion, is associated with more visits to physicians andthe younger age group, and ¥31 600 (95% CI 960, higher medical costs than seronegativity. The annual62 200) [$US263] higher among smokers compared incidence of disease, number of disease-related out-with non-smokers (p = 0.04). patient physician visits and medical cost per person-

Table IV shows the results of multiple logistic year were all approximately 2-fold higher in theregression analysis of the relationship between H. antibody-positive group than in those without anti-pylori antibody status and peptic ulcer using age, bodies. All three outcome indicators were signifi-


980 Babazono et al.

Table IV. Results of multiple logistic regression analysis depicting the relationship between peptic ulcer status and Helicobacter pyloriantibody, smoking and drinking status, and age

Variables Group History of peptic ulcer Ba SE Adjusted odds ratio (95% CI)

positives [n (%)] negatives [n (%)]

H. pylori Positive 117 (34.0) 227 (66.0) 0.72 0.18 2.05** (1.43, 29.81)

Negative 60 (19.4) 294 (80.6)

Age 50 or over 77 (33.0) 156 (67.0) 0.42 0.18 1.53* (1.07, 16.57)

Under 50 100 (23.8) 320 (76.2)

Smoking Smokers 128 (29.4) 307 (70.6) 0.35 0.20 1.42 (0.97, 14.38)

Non-smokers 49 (22.5) 169 (77.5)

Drinking Drinkers 105 (27.5) 277 (72.5) 0.35 0.20 1.03 (0.72, 7.48)

Non-drinkers 72 (26.6) 199 (73.4)

a Standardised regression coefficient.

SE = Standard error; * p < 0.05; ** p < 0.001.

cantly higher among smokers than among non- as we have shown, seropositivity for H. pylori issmokers, which corroborates the known association associated with higher direct medical costs thanbetween smoking and peptic ulcer.[33-38] Clearly, seronegativity. For these reasons, we are inclined tosmoking cessation decreases medical costs for gas- recommend treatment of seropositive individuals attric/duodenal ulcer or inflammation. high-risk for H. pylori infection (we define high-risk

as patients who smoke and/or those who have aIn a sensitivity analysis, we found consistenthistory of peptic ulcer disease). However, beforeresults when we evaluated only upper-GI or endos-such a policy is adopted uniformly by the federalcopy-confirmed peptic ulcers, compared with allgovernment in Japan, a natural randomised, control-ulcers reported by patients. Given the H. pyloriled clinical trial should be performed using high-riskantibody positivity rate of at least 90% in duodenalindividuals in one or more health insurance coopera-ulcer, 60–80% in gastric ulcer, and the high generaltives. Such patients could be randomised into treat-prevalence of H. pylori infection in Japan, the sig-ment, i.e. eradication of H. pylori or control groupsnificant relationship between seropositivity for H.and followed both clinically and economically for 2pylori and peptic ulcer is not surprising.[39] Annualyears. The findings of this natural experiment wouldmedical costs for patients with gastric/duodenal ul-confirm and inform policy makers about the correctcer or inflammation in the antibody-positive groupapproach to these patients. The centralised way inwere ¥30 000 ($US241) per person higher thanwhich the Japanese government collects data aboutamong similar patients without antibodies.each patient (through health insurance cooperatives)

Although we studied typical white-collar work- makes Japan a good place to conduct such experi-ers, seropositivity is related to socio-economic sta- ments.tus, which itself is associated with smoking andalcohol use. Moreover, smoking and alcohol use

Sensitivity and Specificity of Seropositivity forcontribute to gastric or duodenal ulcer and inflam-H. pylorimation. Therefore, we used smoking and alcohol use

as potential confounding factors in ANCOVA andmultiple logistic regression. Few diagnostic tests have perfect predictive

The cost of a clinical examination and the phar- value and, indeed, antibody status for H. pylori doesmaceuticals to eradicate presumptive H. pylori innot correlate perfectly with infection status. Gastric/fection is about ¥10 000–20 000 ($US83–167).[40] duodenal ulcer or inflammation is a result of infec-The cost of treating a patient with peptic ulcer is tion with H. pylori, not merely the presence of¥75 000 ($US660) [year 1996 values].[40] Moreover, antibodies to it.



The sensitivity and specificity of using seroposi- positive, while two were seronegative. We doubttivity as a marker for actual infection with H. pylori that these patients caused us to significantly under-organisms are 95% and 91%, respectively.[25] The estimate utilisation in the H. pylori seropositiveprevalence of H. pylori infection in the study popu- group. Outpatient co-payment rates increased fromlation was about 51%. Therefore, the positive and 10% to 20% in August 1997, perhaps reducing thenegative predictive values of using H. pylori sero- amount of medical services used by patients withpositivity as a marker for actual infection in this symptoms. It is difficult to predict the impact of thisstudy population were 92% and 95%, respectively. change on our results.As anticipated, in a population with a high preva- It is reported that H. pylori infection is a cause oflence of true disease, the predictive value of a mark- gastric cancer[42-46] and that eradication therapy de-er with high sensitivity and specificity is very relia- creases mortality among patients with early gastricble. cancer.[47,48] However, because of the sample size,

gastric cancer was not reported among participantsin this study. Therefore, we could not evaluate the

Limitationsrelationship between seropositivity for H. pylori andmedical costs for gastric cancer.

Diagnoses of gastric and duodenal ulcer and in- We did not consider non-medical direct costs.flammation were based on health insurance claims; Nor did we consider indirect costs because there istherefore, clinical misdiagnoses were possible. In- no consensus about how to best treat them in eco-deed, the term chronic gastritis includes disorders nomic analyses. For example, the human capitalsuch as non-ulcer dyspepsia, in which patients have approach, sometimes used in health economic anal-symptoms (e.g. upper abdominal pain, discomfort, yses, underestimates the value of the unemployedand heartburn), without organic lesions. Also, direct and those with disability, compared with workingmedical costs for concurrent conditions such as the adults. The value of a human life is probably notcommon cold could not be excluded from the data best evaluated in this way.on costs. However, these non-differential misclas-sifications are likely to have occurred randomly,

Conclusionunassociated with the positivity or negativity for H.pylori antibody, and are therefore unlikely to havebiased our results.[41] We showed that the annual outpatient incidence,

We restricted our analysis to outpatient direct the number of visits to physicians, and the medicalmedical costs, including prescription drugs, because costs per person-year for gastric or duodenal ulcer ortreatment for gastric/duodenal ulcer or inflammation inflammation were about 2-fold greater in individu-is generally undertaken in the outpatient arena in als with antibodies to H. pylori compared with thoseJapan. Inpatients with gastric/duodenal ulcer or in- without antibodies. H. pylori eradication therapy isflammation are usually patients with complications, an effective treatment for gastric and duodenal ul-i.e. bleeding. They would be rare in our sample size. cer, and it lowers rates of recurrent disease.[49] Popu-This restriction may have caused us to underesti- lation-based studies and/or randomised controlledmate the effect of seropositivity on total direct clinical trials targeting high-risk groups with anti-medical costs for gastric/duodenal ulcer or inflam- bodies but without symptoms, including smokersmation. and/or patients with a history of peptic ulcer disease

Although eradication treatment for H. pylori was but no current symptoms, should be performed innot covered by health insurance until November Japan to determine how medical costs for gastric2000, eight patients reported that they had under- and duodenal ulcer might be reduced by treatinggone eradication treatment during the period asymptomatic patients who have antibodies to H.1996–2000. Among them, six patients were sero- pylori.


982 Babazono et al.

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