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Noninvasive Helicobacter pylori Testing for the "Test-and-Treat" Strategy
A Decision Analysis to Assess the Effect of Past Infection on Test Choice
William D. Chey, MD, FACP, FACG;
A. Mark Fendrick, MD
Arch Intern Med. 2001;161:2129-2132.
ABSTRACT
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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.
INTRODUCTION
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.5-7 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 x [(Active Hp % x Sensitivity)
+ (1 - Active Hp % x (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).
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Distribution of Patients With and Without Active Helicobacter pylori Infection Treated and Untreated in the Antibody
Testing and Active Testing Strategy*
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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).
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Figure 1. Cost per 100 patients tested by
strategy, broken down by cost components.
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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.
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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.
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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.10-12
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.
AUTHOR 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{at}umich.edu).
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.
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