Cost savings in duodenal ulcer therapy through Helicobacter pylori eradication compared with conventional therapies: results of a randomized, double-blind, multicenter trial. Gastrointestinal Utilization Trial Study Group.

BACKGROUND: We hypothesized that treatment of duodenal ulcer disease with antibiotic therapy directed toward Helicobacter pylori infection is more cost-effective than therapy with antisecretory agents. METHODS: A randomized, double-blind, multicenter clinical trial of adult patients with active duodenal ulcer and H. pylori infection was conducted. Patients were randomized to receive 500 mg of clarithromycin 3 times a day plus 40 mg of omeprazole daily for 14 days followed by 20 mg of omeprazole daily for an additional 14 days (group 1), 20 mg of omeprazole daily for 28 days (group 2), or 150 mg of ranitidine hydrochloride twice a day for 28 days (group 3). The use of ulcer-related health care resources was documented during monthly interviews for 1 year after the initial therapy. Clinical success was evaluated 4 to 6 weeks and 1 year after the end of therapy. RESULTS: Of the 819 patients enrolled, 727 completed the study. Group 1 included 243 patients; group 2, 248 patients; and group 3, 236 patients. Patients in group 1 used fewer ulcer-related health care resources during the 1 year after therapy compared with groups 2 and 3 (comparisons are given as group 1 vs group 2 and group 1 vs group 3, respectively): the number of endoscopies performed, 28 vs 76 (P<.001) and vs 71 (P<.001); patients receiving drugs to treat an ulcer, 118 vs 180 (P<.001) and vs 168 (P<.001); clinic visits, 83 vs 135 (P=.05) and vs 161 (P<.001); hospitalizations, 0 vs 5 (P=.045) and vs 6 (P=.02); and length of hospital stay, 0 vs 24 days (P=.04) and vs 37 (P=.04). When ulcer-related costs were defined as the outcome variable in a multivariate linear regression analysis, therapy was determined to have a significant influence on costs (group 1 vs group 2, P<.001; group 1 vs group 3, P=.008). Clinical success rates at the end of the study and cure of H. pylori infection were significantly greater in group 1 compared with groups 2 and 3 (P<.001). Therapy with clarithromycin plus omeprazole provided savings of $1.94 and $2.96 (compared with therapy with omeprazole and with ranitidine hydrochloride, respectively) per dollar spent within the first year after therapy. This incremental cost-benefit translates to savings of $547 or $835 per patient in group 1 (compared with patients in group 2 or group 3, respectively) during the first year after therapy. CONCLUSIONS: Combination therapy with clarithromycin and omeprazole resulted in significantly fewer uses of ulcer-related health care resources than conventional antisecretory therapy during a 1-year follow-up and significant savings in associated costs during the same period. Patients who received clarithromycin plus omeprazole also showed a significantly improved clinical outcome compared with patients who received only omeprazole or ranitidine.

Testing for Helicobacter pylori in clinical practice.

It is now accepted that cure of Helicobacter pylori infection will result in healing of chronic active gastritis and will change the natural history of gastroduodenal ulcer disease. A variety of highly sensitive and specific diagnostic methods have been developed over the past few years to establish whether a patient is infected with this organism. The two major categories of diagnostic tests for H. pylori are invasive methods, which require endoscopy, and noninvasive tests in which endoscopy is not necessary. Invasive tests include rapid urease tests, histology, and culture. Noninvasive tests include various methods of antibody detection and carbon-labeled urea breath tests. This review describes the characteristics, appropriate uses, and comparative accuracy of the available diagnostic tests for detection of H. pylori. It offers suggestions on the test of choice to establish a patient's H. pylori infection status in different clinical settings.

Helicobacter pylori and gastric cancer.

Infection with Helicobacter pylori is now recognized as the primary cause of peptic ulcers and their recurrence. Compelling evidence has also been found linking H. pylori infection to gastric cancer, the second most common cancer in the world. Given the high rate of patient morbidity and mortality associated with gastric cancer, any method by which one can reduce the occurrence of the disease or increase its early detection is desirable. The strong correlation with H. pylori infection and the current availability of easily administered tests for the detection of the pathogen argue for screening at least those individuals with a family history of gastric cancer or other risk factors. This article reviews the association between H. pylori and gastric cancer and the pathologic changes that the infection produces in the gastric mucosa, as well as the cost-effectiveness of universal testing and eradication of the infection in H. pylori-positive individuals to reduce gastric cancer.

Four-year trends in Helicobacter pylori IgG serology following successful eradication.

PURPOSE: Detection of anti-Helicobacter pylori antibodies is accurate in the diagnosis of the infection, and there is a decline in IgG titers after successful eradication. It is not known whether these titers continue to decline during the next 3 to 4 years. PATIENTS AND METHODS: Patients had been successfully treated for H pylori with triple therapy (metronidazole, tetracycline, and bismuth subsalicylate) during 1990 and 1991. Those who had frozen serum samples available from that time were contacted to have follow-up serum collected in 1994. A simultaneous [13C]urea breath test was done to confirm H pylori infection status. Serology was determined by quantitative enzyme-linked immunosorbent assay (ELISA) and qualitative immunoassay. RESULTS: All 29 patients who agreed to participate were free of H pylori infection. They had a mean decrease in H pylori IgG titers of 51% from baseline (P <0.001). Titers remained stable from 1 year to a mean of 3.5 years after therapy (range 2.8 to 4.4). Of the 29 patients, 21 (72%) remained seropositive by ELISA 3.5 years after successful H pylori treatment, and 18 (62%) remained positive by rapid serum immunoassay. CONCLUSION: IgG titers against H pylori plateau at a 50% decrease after therapy. Helicobacter pylori serology, either quantitative or qualitative, will yield false positive results in patients who have previously been treated for H pylori and should not be used to determine infection status in this population.

Evolving therapy for Helicobacter pylori infection: efficacy and economic impact in the treatment of patients with duodenal ulcer disease.

Helicobacter pylori infection is present in most patients with duodenal ulcer disease, and cure of H pylori infection has been shown to dramatically reduce ulcer recurrence. Therapeutic strategies for duodenal ulcer disease have rapidly evolved over the past several years in an effort to consistently cure H pylori infection in a safe, cost-efficient manner. This paper reviews the effectiveness of treatments for H pylori infection in patients assessed with duodenal ulcer disease. The impact of clinical success on economic effectiveness has been determined in a recent prospective outcomes trial. Treatments with clarithromycin plus omeprazole or clarithromycin plus ranitidine-bismuth-citrate (RBC) provide consistent cure of H pylori infection, with eradication rates of 70% to 80%. Recent studies suggest that higher rates of eradication are possible with triple combination therapy (e.g., clarithromycin plus a second antibiotic and a proton pump inhibitor or RBC), but the optimal triple therapy regimen (including the combination of drugs, dosage, and duration of treatment) has not yet been defined. A recent 1-year prospective outcomes trial has demonstrated that eradication therapy with clarithromycin and omeprazole, compared with standard antisecretory therapy, provides measurable savings in utilization of ulcer-related health-care resources. Combination therapy with clarithromycin plus omeprazole, clarithromycin plus RBC, or clarithromycin plus lansoprazole and amoxicillin have been approved for the treatment of H pylori infection in patients with duodenal ulcer disease. Economic analysis has confirmed that cure of H pylori infection not only contributes to the clinical resolution of duodenal ulcer disease, but also provides economic advantages by reducing costs associated with recurrence.

Diagnostic tests for Helicobacter pylori infection.

The two major catagories of diagnostic methods for Helicobacter pylori are invasive tests, or those that require endoscopy, and noninvasive, or nonendoscopic, tests. Diagnostic tests that use endoscopy include rapid urease tests, histology, and culture. Tests for which esophagogastroduodenoscopy is not necessary include various methods of antibody detection and carbon-labeled urea breath tests. Most tests are accurate, although none works perfectly and no gold standard for diagnosis exists. This article reviews the diagnostic methods available to establish H. pylori infection status and identifies some common mistakes made in testing. The costs associated with H. pylori diagnosis are evaluated and some cost-effective approaches to testing are suggested. Finally, the article offers some guidelines on choosing the appropriate diagnostic test in different clinical situations to determine the H. pylori infection status.

Accuracy and economics of Helicobacter pylori diagnosis.

Many diagnostic tests are available to establish Helicobacter pylori infection status. Most of the tests are accurate though none works perfectly, and no gold standard for diagnosis exists. Newly developed serum immunoassay kits can substitute for laboratory-based enzyme-linked immunosorbent assays, but whole blood immunoassays do not yet demonstrate adequate performance characteristics. Serologic diagnosis of H. pylori remains the most cost-effective option and should be utilized to establish initial infection in the majority of cases. If rapid urease testing is performed at endoscopy, negative results can be confirmed with a subsequent serologic test in those patients with a high probability of infection. Obtaining additional gastric tissue at endoscopy to evaluate for bacterial infection is reasonable if specimens are being taken for a mucosal defect. Confirmation of bacterial eradication cannot be justified for all post-treatment patients at present due to the expense. It is important to test for cure in those patients with complicated ulcer disease and those with recurrent symptoms after therapy.

Physician performance and patient perceptions during the rectal examination.

OBJECTIVE: To describe internal medicine residents' training and performance as well as patients' attitudes and knowledge regarding the rectal examination. DESIGN: Descriptive survey of university-trained internal medicine residents and general medicine clinic patients. SETTING: General internal medicine residents' longitudinal clinic at a university-affiliated Veterans Affairs Medical Center. PATIENTS/PARTICIPANTS: Ambulatory male veterans attending their general internal medicine clinic, all of whom were over the age of 40 years and had previously had a rectal examination (n = 100), as well as all second- and third-year University of Minnesota internal medicine residents (n = 78) were surveyed using a self-administered questionnaire. MEASUREMENTS AND MAIN RESULTS: Residents differed in their training in, practice of, and understanding of indications for the rectal examination. Little formal instruction regarding patient comfort had been provided to residents, and many residents had never received supervised instruction in the rectal examination. Patients frequently were uncertain about why the examination had been performed, lacked understanding of the results of the examination, and often had preferences for examination comfort measures that differed from those utilized by their physicians. CONCLUSIONS: Increased supervised instruction in the rectal examination in medical training programs is recommended. This should emphasize not only appropriate indications for this procedure but also attention to patient communication and comfort.

Fifteen years later: colonoscopic retroflexion revisited.

OBJECTIVE: Retroflex views of the rectal vault are included in the teaching of colonoscopic technique but are not pervasive in clinical practice. The utility of adding a retroflex maneuver at the end of colonoscopy has yet to be determined. The aim of this study was to evaluate the additional benefit of a retroflex view of the rectal vault at the completion of colonoscopic examination. METHODS: A prospective study of consecutive colonoscopies performed by a single physician was conducted. The rectal vault was first visually inspected upon withdrawal of the colonoscope. The endoscope was then readvanced into the rectum and retroflexed to view the vault. Endoscopic findings on both views were recorded along with demographic patient information. The six groups of findings sought on the two views were: retained stool, abnormal hemorrhoids, erosions/ulcerations, polyps, masses, and normal examinations. A determination on whether retroflex views influenced patient diagnosis was recorded by the endoscopist. RESULTS: There were 453 patients enrolled: 182 (40.2%) male and 271 (59.8%) female, consisting of 216 African-Americans, 232 Caucasians, and five Asians. The retroflex maneuver was performed successfully in 445 of 453 patients. In all but nine cases, the retroflex view did not produce additional information. The nine findings included three inflammatory pseudopolyps, five hyperplastic polyps, and one case of erosions/ulcerations. CONCLUSIONS: In the majority of cases, retroflexing the endoscope does not produce additional information compared with the thorough examination in straight view. The retroflex view may be of benefit if there is suspicion of pathology upon insertion or withdrawal of the colonoscope.

Long-term Helicobacter pylori recurrence after successful eradication with triple therapy.

To establish the rate of Helicobacter pylori recurrence after a standard triple-therapy regimen (bismuth subsalicylate, tetracycline, metronidazole) and determine which clinical factors affect reinfection, we prospectively followed 118 patients after successful H. pylori eradication. Elimination of H. pylori was confirmed by repeat endoscopy and urea breath test 4 wk after completion of therapy. Serial [13C]urea breath tests were performed at 3-month intervals; antral biopsies were used to verify reinfection. Recurrence of H. pylori infection occurred in 4/118 (3.4%) patients. Three of the four relapses occurred in the 1st yr after treatment. Gender, age, ethnic group, alcohol consumption, cigarette use, and gastrointestinal diagnosis do not predict H. pylori recurrence. We conclude that the rate of recurrence after successful H. pylori eradication is low, and that when reinfection takes place, it occurs most commonly within the 1st yr after treatment.

Long-term follow-up of Helicobacter pylori serology after successful eradication.

OBJECTIVE: To determine the Helicobacter pylori IgG serology pattern 12-21 months after successful organism eradication and to assess the usefulness of IgG serology in the long-term follow-up of patients. METHODS: We recruited patients from our 1990-91 study on IgG serology after H. pylori treatment. Forty-three of 45 patients (93%) agreed to participate. They had all been cured of H. pylori infection after triple antibiotic therapy and remained H. pylori negative at 1 yr posttreatment. H. pylori IgG antibody concentrations were measured in serum samples taken at 3-month intervals between 12 and 21 months posttreatment. [13C]-urea breath test was done at each blood draw to ensure continued eradication. Serology was determined by ELISA (Pylori Stat, BioWhittaker, Inc) and expressed as absorbance. RESULTS: All 43 patients (100%) continued to be free of H. pylori and demonstrated a decline in their H. pylori IgG concentration compared with baseline. The overall decline in serology among all 43 patients was approximately 50%. Forty of 43 patients (93%) had a decline of more than 20% in H. pylori IgG concentration compared with baseline. However, 28 of 43 patients (65%) remained seropositive for more than 1 yr after successful H. pylori eradication. CONCLUSION: We conclude that a 20% decline in IgG concentration has an overall sensitivity of 93% for determining H. pylori eradication 12-21 months after H. pylori treatment. Serology is an attractive alternative to endoscopy or urea breath tests in monitoring patients after H. pylori treatment, but serum IgG levels should not be expected to reach seronegative range after successful H. pylori eradication.

Patient factors affecting Helicobacter pylori eradication with triple therapy.

Duodenal ulcer recurrence and gastritis are reduced with successful Helicobacter pylori treatment. To identify the patient factor influencing H. pylori eradication, we prospectively evaluated 96 consecutive patients undergoing a single 2-wk course of bismuth, tetracycline, and metronidazole therapy. At the time of initial esophagogastroduodenoscopy with biopsies, each patient had a profile obtained which included demographic information, gastrointestinal pathology, and H. pylori status of the spouse. Elimination of H. pylori was confirmed by repeat esophagogastroduodenoscopy with biopsies 4 wk after the completion of therapy and serial urea breath tests. Eradication at 4 wk was successful in 80 of 96 (83%) patients. On multivariate analysis, H. pylori elimination was associated with advanced age (p = 0.002) and a greater amount of chronic inflammation on baseline antral biopsy (p = 0.024). Eradication was inversely associated with the presence of a gastric ulcer (p = 0.008) and lack of medication compliance (p = 0.030). Successful eradication reduced the severity of both acute and chronic antral mucosal inflammation. Household income, gender, ethnic group, smoking, alcohol intake, and H. pylori status of the spouse did not differ between the eradicated and noneradicated groups. We conclude that it will be important to control for influential patient factors in future studies of H. pylori treatment regimens.

Comparison of [13C]urea blood test to [13C]urea breath test for the diagnosis of Helicobacter pylori.

OBJECTIVE: It has been determined that the [13C]urea breath test (UBT) is a safe and effective way of detecting Helicobacter pylori (H. pylori) infection. Some individuals may have difficulty performing the exhalation component of the test, possibly due to age, or mental or physical compromise. Our aim was to determine if a commercially developed [13C]urea blood test could be utilized as a substitute for the UBT to detect H. pylori infection. METHODS: Patients who were referred by their physicians for UBT were offered study inclusion. Patients underwent baseline and 30-min UBT. A simultaneous blood sample of 3 cc was drawn into a heparinized vacutainer at the 30-min period of the UBT. [13C]urea levels in both blood and breath samples were analyzed using isotope ratio mass spectrometry. UBT > or = 6 delta per mil over baseline and urea blood tests > (-17 delta per mil) were considered positive. RESULTS: One hundred sixty-one patients (68 men/93 women) with average age of 47.0 +/- 14.2 yr were tested. Agreement between breath and blood test results occurred in 153/161 (95%) cases. Using the UBT as the diagnostic standard, the urea blood test resulted in 44 true positive, 109 true negative, four false positive, and four false negative results, giving a sensitivity of 92%, specificity of 96%, positive predictive value of 92%, and negative predictive value of 96%. CONCLUSIONS: The urea blood test was found to be comparable to the urea breath test in the detection of H. pylori infection. The urea blood test will be accurate in the diagnosis of active H. pylori infection.

Hereditary angioedema associated with pancreatitis.

A 44-year-old woman with C1q esterase inhibitor deficiency was seen in consultation for recurrent right upper quadrant abdominal discomfort, nausea, and vomiting. Each of these episodes was accompanied by concomitant peripheral edema. Initial diagnostic efforts were fruitless. In time, intermittent elevations in amylase and lipase developed, and a diagnosis of relapsing pancreatitis was made. We contend that the patient's recurrent acute pancreatitis is associated with her hereditary angioedema. Possible pathogenesis could involve intermittent intrapancreatic edema with partial ductal obstruction or loss of inhibition on the kallikrein-kinin system.

Quantitative noninvasive testing for Helicobacter pylori does not predict gastroduodenal ulcer disease.

BACKGROUND: Helicobacter pylori is strongly associated with gastric and duodenal ulcer disease. However, the diagnosis of gastroduodenal ulcers requires an endoscopic or radiographic examination. In this study, we attempted to establish a relationship between the magnitude of [13C]urea breath test results or serum H. pylori IgG levels and endoscopic findings in H. pylori-infected individuals. METHODS: Patients who had undergone endoscopy and had a positive [13C]urea breath test and/or positive H. pylori IgG serology were identified. Endoscopic diagnoses included duodenal ulcer, gastric ulcer, nonulcer dyspepsia, and others. Results of 6% or greater on the [13C]urea breath test was defined as positive for H. pylori infection. H. pylori IgG serology was determined by an enzyme linked immunosorbent assay with values of greater than or equal to 1.0 being seropositive. RESULTS: One hundred seventy-five patients were seropositive (mean = 3.01 +/- 1.58). One hundred sixty-eight patients had a positive [13C]urea breath test (mean = 25.43 +/- 16.90). One hundred fifty-five patients were common to both the groups. Statistical analysis did not reveal any relationship between quantitative [13C]urea breath test results or H. pylori IgG values and endoscopic diagnoses. CONCLUSION: The magnitude of [13C]urea breath test or H. pylori IgG serology cannot be used to predict the presence or absence of gastroduodenal ulcer disease.

Prospective evaluation of a new urea-membrane test for the detection of Helicobacter pylori in gastric antral tissue.

AIM: To determine the sensitivity, specificity, and positive and negative predictive values of a newly developed urea-membrane test for the detection of Helicobacter pylori in gastric tissue. METHODS: Patients presenting for upper endoscopy with no recent exposure to H. pylori-altering drugs were enrolled. Antral biopsy specimens were tested by the urea-membrane and urea-gel methods and submitted for histology. Patients underwent [13C]urea breath tests. Presence of H. pylori was established by histology or the combination of a positive [13C]urea breath test and a positive urea-gel test. Absence of H.pylori required both the [13C]urea breath test and the invasive tests to be negative. The urea-membrane test was reported at 1 hour. RESULTS: Ninety-nine patients (47 men and 52 women) with a mean age of 51.43 +/- 14.9 years participated. Fifty of 99 patients (prevalence, 50.5%) tested positive for H. pylori. The urea-membrane test correctly identified 49 of 50 H. pylori-positive and 46 of 49 H. pylori-negative patients, yielding sensitivity, specificity, and positive and negative predictive values of 98.0%, 93.9%, and 94.2% and 97.9%, respectively, in this population. CONCLUSIONS: Rapidly available and reliable results from the urea-membrane test can facilitate clinical decision prior to patient discharge from the endoscopy suite.

[13C]urea breath test to confirm eradication of Helicobacter pylori.

OBJECTIVE: To determine the utility of the [13C]urea breath test in confirming the eradication of Helicobacter pylori. METHODS: We reviewed our H. pylori database for patients who underwent [13C]urea breath test at baseline and 6 wk after triple therapy with tetracycline, metronidazole, and bismuth subsalicylate. Baseline infection was defined by the identification of the organism on antral biopsies or a reactive CLO test. Eradication was defined as a negative Warthin-Starry stain and a non-reactive CLO test at 24 h. All patients had a positive baseline [13C]urea breath test defined as [13C] enrichment > 6% at 60 min. RESULTS: One hundred eighteen H. pylori-infected patients (mean age 58.3 +/- 13.9 yr) met the review criteria (61 duodenal ulcers, 24 gastric ulcers, 33 non-ulcer dyspepsia). In 101/118 patients (86%), H. pylori was successfully eradicated (mean baseline breath test value 25.8 +/- 1.6). Of 101 patients, 95 had a negative 6-wk follow-up breath test (mean 2.2 +/- 0.2, p < 0.001). Of the 6/101 patients in whom treatment was successful, and who remained breath test positive at 6 wk, 4/6 were breath test negative when retested at 3 months. The remaining two patients were lost to follow-up. In 17/118 (14%) patients, H. pylori failed to be eradicated (mean baseline breath test 22.4 +/- 3.6). Fifteen of 17 patients had a positive breath test at 6 wk (mean 19.9 +/- 3.7). Two of 17 with a negative breath test at 6 wk tested positive when the breath test was repeated at 3 months. The sensitivity and specificity of [13C]urea breath test at 6 wk posttreatment are 97% and 71%, respectively. The positive and negative predictive values are 94% and 88%, respectively. CONCLUSIONS: [13C]urea breath test is a sensitive indicator of H. pylori eradication 6 wk after treatment. Antral biopsies are unnecessary to confirm eradication of H. pylori after completion of treatment.

Admixture with whole blood does not explain false-negative urease tests.

Rapid urease test sensitivity for Helicobacter pylori is reduced in the presence of active upper gastrointestinal bleeding. The aim of this study was to evaluate the in vitro effect of whole blood on rapid urease testing. Urease solution was added to normal saline, and heparinized whole blood both positive and negative for H. pylori antibody. The mixtures were then serially diluted in saline, and/or whole blood and added to three different rapid urease kits. The admixture of urease in H. pylori-seropositive whole blood diluted in either saline or whole blood enhanced performance in both kits fourfold compared with saline alone. No false-negative results were observed in either kit. Seronegative whole blood produced similar results. Undiluted saline or whole blood produced no positive rapid urease tests. Whole blood accelerates the urease reaction in vitro. Neither H. pylori antibody-positive nor -negative whole blood adversely impacted the rapid urease test. False-negative rapid urease test results in upper gastrointestinal bleeding cannot be explained by admixture with whole blood.

Value of serology as a noninvasive method for evaluating the efficacy of treatment of Helicobacter pylori infection.

The systemic humoral response to Helicobacter pylori was studied in 86 infected adult patients before antimicrobial therapy and at intervals following therapy. Endoscopy with collection of biopsy specimens was performed immediately before treatment; a 13C-labeled urea breath test was performed, and blood specimens were collected before treatment and at 1, 3, 6, 9, and 12 months after treatment. Serum samples from three patient groups (eradication success [n = 50], eradication failure [n = 16], and no treatment [n = 20]) were assayed for IgA and IgG antibodies to H. pylori by enzyme-linked immunosorbent assay. Levels of antibody to H. pylori before treatment were similar in all three groups. As expected, the no treatment and eradication failure groups had no significant changes in antibody levels during the study period. In contrast, for the eradication success group, the specific IgA and IgG antibody levels decreased progressively and significantly. We conclude that serology is a potentially useful way to monitor the success of treatment of H. pylori infection without using invasive or more expensive methods.