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Figure 1.
Cost per 100 patients tested by strategy, broken down by cost components.

Cost per 100 patients tested by strategy, broken down by cost components.

Figure 2.
Sensitivity analysis: effect of prevalence rate of prior H pylori infection on the incremental cost of testing for active infection compared with antibody testing to avoid unnecessary treatment.

Sensitivity analysis: effect of prevalence rate of prior H pylori infection on the incremental cost of testing for active infection compared with antibody testing to avoid unnecessary treatment.

Distribution of Patients With and Without Active Helicobacter pylori Infection Treated and Untreated in the Antibody Testing and Active Testing Strategy*
Distribution of Patients With and Without Active Helicobacter pylori Infection Treated and Untreated in the Antibody Testing and Active Testing Strategy*
1.
Talley  NJSilverstein  MDAgreus  LNyren  OSonnenberg  AHoltmann  GAmerican Gastroenterological Association, AGA technical review: evaluation of dyspepsia [review]. Gastroenterology. 1998;114582- 595Article
2.
Talley  NJAxon  ABytzer  PHoltmann  GLam  SKVan Zanten  S Management of uninvestigated and functional dyspepsia: a Working Party report for the World Congress of Gastroenterology 1998. Aliment Pharmacol Ther. 1999;131135- 1148Article
3.
Chey  WDFendrick  AM Noninvasive Helicobacter pylori Diagnostic tests-recent innovations. Harrison's [online]. Available at: http://www.harrisononline.com/server-java/Arknoid/harrisons/ 1096-7133/Updates/Editorials/?Up+edl1851. Accessed May 1, 1999.
4.
Loy  CTIrwig  LMKateralis  PHTalley  NJ Do commercial serological kits for Helicobacter pylori infection differ in accuracy? a meta-analysis. Am J Gastroenterol. 1996;911138- 1144
5.
Vaira  DMalfertheiner  PMegraud  FHpSA European Study Group, Diagnosis of Helicobacter pylori infection with a new non-invasive antigen-based assay. Lancet. 1999;35430- 33Article
6.
Cutler  AFHavstad  SMa  CKBlaser  MJPerez-Perez  GISchubert  TT Accuracy of invasive and noninvasive tests to diagnose Helicobacter pylori infection. Gastroenterology. 1995;109136- 141Article
7.
Cohen  HRose  SLewin  DN  et al.  Accuracy of four commercially available serologic tests, including two office-based tests and a commercially available 13C urea breath test, for diagnosis of Helicobacter pyloriHelicobacter. 1999;449- 53Article
8.
Pounder  RENg  D The prevalence of Helicobacter pylori infection in different countries [review]. Aliment Pharmacol Ther. 1995;9 ((suppl 2)) 33- 39
9.
Allison  JHiatt  RLevin  TRLieu  TAckerson  DLibran  L H pylori status of patients on chronic suppression for peptic ulcer disease or ulcer like symptoms [abstract]. Gastroenterology. 1998;114 ((4 part 2)) A55Article
10.
Whitney  CGFarley  MMHadler  J  et al.  Increasing prevalence of multidrug-resistant Streptococcus pneumoniae in the United States. N Engl J Med. 2000;3431917- 1924Article
11.
Donskey  CJChowdhry  TKHecker  MT  et al.  Effect of antibiotic therapy on the density of vancomycin-resistant enterococci in the stool of colonized patients. N Engl J Med. 2000;3431925- 1932Article
12.
Wenzel  RPEdmond  MB Managing antibiotic resistance. N Engl J Med. 2000;3431961- 1963Article
13.
Walsh  JHPeterson  WL The treatment of Helicobacter pylori infection in the management of peptic ulcer disease [review]. N Engl J Med. 1995;333984- 991Article
Original Investigation
September 24, 2001

Noninvasive Helicobacter pylori Testing for the "Test-and-Treat" StrategyA Decision Analysis to Assess the Effect of Past Infection on Test Choice

Author Affiliations

From the Divisions of Gastroenterology (Dr Chey) and General Medicine (Dr Fendrick), and the Consortium for Health Outcomes, Innovation, and Cost-effectiveness Studies (CHOICES) (Dr Fendrick), University of Michigan Health System, Ann Arbor.

Arch Intern Med. 2001;161(17):2129-2132. doi:10.1001/archinte.161.17.2129
Abstract

Background  Clinical guidelines support a noninvasive Helicobacter pylori "test-and-treat" strategy for individuals with uncomplicated dyspepsia. However, consensus is lacking regarding the preferred noninvasive testing method.

Objective  To use decision analytic modeling to estimate the clinical and economic outcomes associated with noninvasive tests designed to detect either H pylori antibody or active H pylori infection.

Design  Decision analytic model.

Patients  A simulated patient cohort with uncomplicated dyspepsia.

Interventions  The simulated dyspepsia cohort underwent antibody testing or testing to detect active H pylori infection (active testing). Individuals testing positive received eradication therapy.

Main Outcome Measures  Appropriate and inappropriate treatment prescribed, cost per patient treated, incremental cost per unnecessary treatment avoided.

Results  Active testing led to a substantial reduction in unnecessary treatment for patients without active infection (antibody, 23.7; active, 1.4 per 100 patients) at an incremental cost of $37 per patient. The clinical advantage and cost-effectiveness of active testing was enhanced as the percentage of individuals with a positive antibody test result from past, but not current, infection increased.

Conclusions  Active testing for H pylori infection significantly decreases the inappropriate use of antimicrobial therapy when compared with antibody testing. The advantages of active testing should be enhanced as the widespread use of antimicrobial agents increases the proportion of patients with antibody to H pylori, but without active infection.

THE AMERICAN Gastroenterological Association and other professional organizations endorse a "test-and-treat" strategy for Helicobacter pylori for patients with previously unevaluated, uncomplicated dyspepsia.1,2 The driving forces behind the adoption of this strategy include the desire to decrease the use of expensive, endoscopic procedures and to use H pylori eradication therapy only in infected patients. While there is little controversy that nonendoscopic H pylori tests should be the initial test performed in this patient group, consensus is lacking regarding the preferred testing method.

Noninvasive tests for H pylori can be distinguished by their ability to detect either active infection or a systemic antibody response to the organism.3 Both office-based, qualitative antibody tests and quantitative enzyme-linked immunoabsorbent assays are available. Though antibody tests offer reasonable sensitivity to detect IgG against H pylori, a positive antibody test result cannot distinguish between individuals with active infection and those previously, but not currently, infected. Thus, positive antibody test results can occur in 3 distinct patient groups: (1) those with detectable antibody and active H pylori infection (true-positive antibody, infected); (2) those with detectable antibody, but not actively infected (true-positive antibody, not infected [TPNI]); and (3) those never infected and no antibody detectable (false-positive [FP] result). This distinction is important because the use of eradication therapy is of no clinical value in groups 2 and 3.

While clinical investigators may have included patients having TPNI results in the specificity calculation of certain antibody tests, this convention is incorrect. Technically, only individuals without detectable antibody, but with a positive antibody test result are, in fact, true-false positives in that these patients do not have the entity that the test was designed to measure.

Tests that detect active H pylori infection ("active testing") include the urea breath test (ie, urea tagged with nonradioactive carbon 13 or radioactive carbon 14) and the stool antigen test. Unlike antibody tests, active tests produce a positive result in only 2 circumstances: (1) those with active H pylori infection (true-positive result), and (2) those never infected (FP result). Individuals with TPNI are not identified because active infection with H pylori organisms is necessary to produce a positive urea breath test or stool antigen test result.

Owing largely to issues of availability, convenience, and cost, antibody tests are the most widely used noninvasive tests for H pylori. However, choosing the appropriate noninvasive H pylori test requires an explicit understanding of the tradeoffs between the lower acquisition costs of antibody testing and the superior accuracy of active testing. Accordingly, a decision analytic model was constructed to measure the clinical benefits of active testing and quantify the costs necessary to obtain them.

PATIENTS AND METHODS

A cohort of patients with uncomplicated, ulcer-like dyspepsia who had not been previously tested for H pylori was entered into the decision analytic model. Noninvasive H pylori diagnostic tests including antibody (sensitivity, 85%; specificity, 79%4) and active tests (sensitivity, 95%; specificity, 98%5) were evaluated. Principal case inputs for the antibody test were obtained from a meta-analysis that evaluated 21 studies comparing different commercially available serologic kits.4 Published studies consistently report a sensitivity and specificity exceeding 90% for the urea breath and stool antigen tests.57 Cost inputs were based on 1999 Medicare reimbursements for serologic testing ($25, Current Procedural Terminology code 86677) and the urea breath test ($100, Current Procedural Terminology codes 83013 and 83014).

In the principal analysis, active H pylori infection was estimated to be present in 30% of the individuals undergoing testing.8 Of the 70% of individuals not infected, 20% were assumed to be infected at some time in the past, yielding a TPNI rate of 14%.9 All patients who tested positive were treated with a 14-day course of a combination of lansoprazole, clarithromycin, and amoxicillin at a cost of $200. This cost input was chosen after making the assumption that most prescription medication plans acquire this therapy for less than the average wholesale price (Prevpac; TAP Pharmaceuticals Inc, Lake Forest, Ill; average wholesale price, $252).

Outcomes estimated by the model were based on the presence or absence of active H pylori infection and the appropriateness of eradication therapy given a patient's active infection status. In the antibody strategy, patients who did not benefit from prescribed therapy: those with TPNI, and those who were never infected (FP result) were included in the inappropriate treatment group. In the active testing strategy, inappropriate treatments were limited to the FP group.

Economic outcomes and incremental cost-effectiveness were also estimated by the model. The average cost per patient tested in each strategy was derived using the cost of the test (incurred by all patients) summed with the cost of H pylori eradication therapy (incurred only by patients with a positive test result). For example, in the active testing strategy, the average cost per patient tested was calculated using the following formula: Test Cost + {Cost Treatment × [(Active Hp % × Sensitivity) + (1 − Active Hp % × (1 − Specificity)]}, Where Hp % is percentage of H pylori. If a situation arose where a superior clinical outcome resulted at a higher cost, an incremental cost per appropriate treatment prescribed or incremental cost per inappropriate treatment avoided was calculated.

RESULTS
CLINICAL OUTCOMES

Using a TPNI rate of 14%, the active testing strategy led to a substantial reduction in unnecessary treatment for patients without active H pylori infection (antibody test, 23.7 per 100 patients[TPNI and FP groups]; active test, 1.4 per 100 patients [FP group]). In addition, when compared with the antibody strategy, active testing identified 3 additional patients with current infection per 100 patients tested (Table 1).

ECONOMIC OUTCOMES
Average Cost per Patient

To achieve these clinical advantages, active testing costs an additional $37 per patient tested compared with antibody testing (active test, $160 per patient; antibody test, $123 per patient). The contribution of testing and the use of appropriate and inappropriate eradication therapy to the costs for 100 patients in each strategy are shown in Figure 1. The figure demonstrates the tradeoff between testing costs ($7500 higher per 100 patients tested in the active testing strategy) and expenditures on inappropriate treatment of patients without active infection ($4460 less per 100 patients tested with active testing).

Cost-effectiveness Analysis

In the base-case analysis, an additional investment of $164 in active testing was necessary to avoid 1 unnecessary course of eradication therapy. Although an incremental $1233 must be spent on active testing to identify each additional infected individual whose condition was not diagnosed using antibody testing, at least part of this cost increase would be offset by expenditures associated with the management of patients with active infection who test false negative using the antibody test.

SENSITIVITY ANALYSIS

Sensitivity analysis was performed to evaluate the effect of altering individual input variables on the clinical and economic results. The incremental cost per unnecessary treatment avoided decreased significantly as the proportion of individuals who were TPNI increased (Figure 2). Active testing decreased the inappropriate use of eradication therapy under all circumstances evaluated, including when the prevalence of active H pylori infection in the model cohort ranged from 10% to 50%. The incremental cost per unnecessary treatment avoided did not change significantly when the sensitivity and specificity of the H pylori tests were evaluated over their published ranges. Using a TPNI rate of 14%, the cost per patient tested with the active strategy became equivalent to antibody testing ($123 per patient) when the test cost differential was reduced to $37.

The cost of therapy influenced the results of the analysis. Sensitivity analysis revealed that when the average wholesale price of $252 for the combination therapy of lansoprazole, clarithromycin, and amoxicillin (Prevpac; TAP Pharmaceuticals Inc), was used the model calculated the following results: (1) cost per patient treated using antibody testing = $149, using active testing = $175.30; (2) incremental cost per correct diagnosis = $876; and (3) incremental cost to avoid 1 unnecessary course of eradication therapy = $118.

COMMENT

A decision analytic model estimated that active testing dramatically reduced the number of patients inappropriately treated for presumed H pylori infection when compared with antibody testing. Active testing also marginally increased the number of patients correctly identified with active H pylori infection. This decrease in unnecessary therapy is important from multiple perspectives. For the patient, it makes no sense to ingest multiple medications, each with associated inconvenience, adverse effects, and out-of-pocket expense without an expectation of clinical benefit. For the payer, the cost associated with the prescribing of therapy in uninfected patients can be substantial.

From a societal perspective, targeted diagnosis is an essential weapon against the development of antimicrobial resistance—a significant and growing problem worldwide. The emergence of antimicrobial resistance is not only an issue for H pylori but also for virtually all pathogens previously considered easily treatable.1012 Recent studies by Whitney et al10 and Donskey et al11 highlight the emergence of multidrug-resistant Streptococcus pneumoniae and Enterococcus species. In an editorial accompanying those studies, Wenzel and Edmond state: "the inappropriate use of these drugs (antibiotics) threatens our ability to cope with infections."12(p1962) While the model demonstrates that the adoption of testing strategies that decrease the unnecessary use of antimicrobial agents require incremental expenditures in the short-term, it is important to consider the long-term benefits of slowing the emergence of resistant organisms. Although these future benefits are difficult to quantify, a substantial amount of resources continue to be devoted to the growing problem of antimicrobial resistance.

When interpreting the principal analysis, it is important to consider how expected changes in H pylori epidemiology will further strengthen the clinical and cost-effectiveness argument for active testing. The percentage of patients with TPNI is likely to increase as antimicrobial therapy becomes more widespread. Commonly used antimicrobial agents, such as clarithromycin or amoxicillin, can result in an H pylori cure rate of 20% to 40% when used alone.13 This "incidental" eradication, when combined with successful H pylori eradication with approved regimens, will lead to an even larger TPNI population. In addition, as the background prevalence of active H pylori infection decreases, one can expect a correlative decrease in the accuracy and cost-effectiveness of antibody testing. At the current cost differential between antibody and active tests used in the principal analysis, the incremental investment in active testing necessary to avoid 1 inappropriate course of eradication therapy fell to approximately $100 when the TPNI rate associated with antibody testing exceeded 30% (Figure 2).

Our findings suggest that active testing will markedly reduce the number of patients inappropriately treated for H pylori infection. Thus, the cost consequences of initial H pylori test choice depend not only on differences in acquisition costs but also on the treatment costs for individuals without infection. The $37-per-patient difference between the strategies demonstrates that half of the $75 difference in test cost is recovered through appropriate use of eradication therapy. Cost neutrality should not be a requirement for the adoption of active testing. The benefits for reducing unnecessary and potentially harmful therapy for patients and society must be acknowledged.

CONCLUSIONS

Active testing for H pylori achieves measurable clinical benefits over antibody testing at an incremental cost. The advantages associated with active testing should be enhanced as the widespread use of antimicrobial agents increases the proportion of individuals with TPNI. In addition, the decreasing background prevalence of H pylori should serve to strengthen the argument for active testing on clinical and economic grounds. The ability to better direct therapy to patients with active H pylori infection will also improve patient satisfaction and prove advantageous in an environment increasingly concerned with antimicrobial resistance.

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Article Information

Accepted for publication February 22, 2001.

This study was funded by an unrestricted grant from Meretek, Nashville, Tenn, to the University of Michigan.

Corresponding author: William D. Chey, MD, FACP, FACG, 3912 Taubman Center, Ann Arbor, MI 48109-0362 (e-mail: wchey@umich.edu).

References
1.
Talley  NJSilverstein  MDAgreus  LNyren  OSonnenberg  AHoltmann  GAmerican Gastroenterological Association, AGA technical review: evaluation of dyspepsia [review]. Gastroenterology. 1998;114582- 595Article
2.
Talley  NJAxon  ABytzer  PHoltmann  GLam  SKVan Zanten  S Management of uninvestigated and functional dyspepsia: a Working Party report for the World Congress of Gastroenterology 1998. Aliment Pharmacol Ther. 1999;131135- 1148Article
3.
Chey  WDFendrick  AM Noninvasive Helicobacter pylori Diagnostic tests-recent innovations. Harrison's [online]. Available at: http://www.harrisononline.com/server-java/Arknoid/harrisons/ 1096-7133/Updates/Editorials/?Up+edl1851. Accessed May 1, 1999.
4.
Loy  CTIrwig  LMKateralis  PHTalley  NJ Do commercial serological kits for Helicobacter pylori infection differ in accuracy? a meta-analysis. Am J Gastroenterol. 1996;911138- 1144
5.
Vaira  DMalfertheiner  PMegraud  FHpSA European Study Group, Diagnosis of Helicobacter pylori infection with a new non-invasive antigen-based assay. Lancet. 1999;35430- 33Article
6.
Cutler  AFHavstad  SMa  CKBlaser  MJPerez-Perez  GISchubert  TT Accuracy of invasive and noninvasive tests to diagnose Helicobacter pylori infection. Gastroenterology. 1995;109136- 141Article
7.
Cohen  HRose  SLewin  DN  et al.  Accuracy of four commercially available serologic tests, including two office-based tests and a commercially available 13C urea breath test, for diagnosis of Helicobacter pyloriHelicobacter. 1999;449- 53Article
8.
Pounder  RENg  D The prevalence of Helicobacter pylori infection in different countries [review]. Aliment Pharmacol Ther. 1995;9 ((suppl 2)) 33- 39
9.
Allison  JHiatt  RLevin  TRLieu  TAckerson  DLibran  L H pylori status of patients on chronic suppression for peptic ulcer disease or ulcer like symptoms [abstract]. Gastroenterology. 1998;114 ((4 part 2)) A55Article
10.
Whitney  CGFarley  MMHadler  J  et al.  Increasing prevalence of multidrug-resistant Streptococcus pneumoniae in the United States. N Engl J Med. 2000;3431917- 1924Article
11.
Donskey  CJChowdhry  TKHecker  MT  et al.  Effect of antibiotic therapy on the density of vancomycin-resistant enterococci in the stool of colonized patients. N Engl J Med. 2000;3431925- 1932Article
12.
Wenzel  RPEdmond  MB Managing antibiotic resistance. N Engl J Med. 2000;3431961- 1963Article
13.
Walsh  JHPeterson  WL The treatment of Helicobacter pylori infection in the management of peptic ulcer disease [review]. N Engl J Med. 1995;333984- 991Article
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