1SUMMARY INTRODUCTION. Aliment Pharmacol Ther 2000; 14: 389±396. Accepted for publication 6 December 1999

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1 Aliment Pharmacol Ther 2000; 14: 389±396. The omeprazole test is as sensitive as 24-h oesophageal ph monitoring in diagnosing gastro-oesophageal re ux disease in symptomatic patients with erosive oesophagitis R. FASS*, J. J. OFMANà, R.E.SAMPLINER*,L.CAMARGO*,C.WENDEL & M. B. FENNERTY *Section of Gastroenterology and Department of Medicine and Health Services Research Center, Tucson VA Medical Center and Arizona Health Sciences Center, Tucson, Arizona, USA; àdepartment of Medicine, Health Services Research, Division of Gastroenterology, Cedars-Sinai Medical Center and Zynx Health Inc., Los Angeles, CA, USA; and Department of Medicine, Division of Gastroenterology, Oregon Health Sciences University, Portland, Oregon, USA Accepted for publication 6 December SUMMARY Background: Ambulatory 24-h oesophageal ph monitoring and a short course of high dose omeprazole can be used as diagnostic modalities for GERD. However, comparative studies of the diagnostic accuracy and reliability of both strategies have not been performed. Aim: To compare the omeprazole test to ambulatory 24-h oesophageal ph monitoring in diagnosing GERD in symptomatic patients using endoscopically proven erosive oesophagitis as a gold standard. Methods: Patients with heartburn underwent an upper endoscopy. Only those with erosive oesophagitis were included in the study. Subsequently, patients underwent ambulatory 24-h oesophageal ph monitoring and an `omeprazole test.' Daily symptoms were recorded during the rst week (baseline) and repeated during the second week on therapy (omeprazole 40 mg in the morning and 20 mg in the evening). Results: Thirty- ve patients were included in the study. The omeprazole test was signi cantly more sensitive in diagnosing GERD than total acid contact time on 24-h oesophageal ph monitoring (83% vs. 60%; P < 0.03). However, the sensitivity of the ph test increased to 80% after adding patients with a positive symptom index, and patients with abnormal acid exposure in the supine or erect positions despite normal total acid contact time. Patients with a normal ph test were signi cantly younger ( years) than those with abnormal test (59 1.8; P ˆ 0.002). Conclusions: In this study an omeprazole test was at least as sensitive as ambulatory 24-h oesophageal ph monitoring in diagnosing GERD in patients with erosive oesophagitis. INTRODUCTION Heartburn and/or other symptoms suggestive of GERD, is a common complaint in primary care. 1 Current guidelines recommend empirical antisecretory therapy with diagnostic evaluation reserved for non-responders. 2 Since up to 50% of patients may not have a complete response to empirical trials with H 2 -RAs and proton Correspondence to: Dr R. Fass, Tucson VA Medical Center, 3601 S 6th Avenue, Tucson, AZ 85723, USA. Ronnie.Fass@Med.VA.gov pump inhibitors are not universally given for nonresponders, a large portion of symptomatic patients may be referred for a `diagnostic' evaluation. 3 Diagnostic tests to detect gastro-oesophageal re ux disease (GERD) which are currently available include barium oesophagram, upper endoscopy, ambulatory 24-h oesophageal ph monitoring and response to a high dose trial of a proton pump inhibitor (the omeprazole test). The sensitivity of barium oesophagram improves with increasing grade of erosive oesophagitis. 4 However, most patients with GERD lack morphological changes or Ó 2000 Blackwell Science Ltd 389

2 390 R. FASS et al. have minimal mucosal in ammation, making barium oesophagram an unreliable diagnostic tool. 5 In addition, barium re ux during an oesophagram is of questionable diagnostic signi cance and can be demonstrated in up 2to 20% of normal healthy subjects. 6, 7 The sensitivity of upper endoscopy in diagnosing GERD is also limited. Endoscopy has been the most accurate diagnostic test for detecting erosive oesophagitis and other GERD complications, such as Barrett's oesophagus. The nding of oesophagitis or Barrett's oesophagus at endoscopy is unequivocal evidence of the presence of acid re ux. However, in studies that were carried out in tertiary referral centres only 50% of the patients with GERD had evidence of oesophageal mucosal in ammation on endoscopy. 8 Furthermore, studies in community based patients, where erosive oesophagitis may be less common, have demonstrated sensitivity as low as 20%. 9 Thus, many, if not most patients with GERD will have a normal endoscopic examination, limiting the sensitivity (< 50%) of this study as a diagnostic test in patients with GERD. Ambulatory 24-h oesophageal ph monitoring has been considered by many as the gold standard diagnostic test for GERD. The reported sensitivity of ph monitoring has ranged from 79 to 96% and speci city from 85 to 100%. 10±14 The composite score and percentage total time with ph < 4 have been suggested to provide the most ef cient interpretation of the test with an accuracy of 98%. 15 However, several recent studies have demonstrated a frequent inability of ph monitoring to detect abnormal acid exposure in patients with endoscopically proven erosive oesophagitis and 16, 17 have suggested a much lower sensitivity of 65%. Due in large part to the fact that there is no perfect diagnostic test and also improved outcomes have not been demonstrated as a result of a precise diagnosis of GERD, recent guidelines also suggest that a diagnosis of GERD can be readily based on clinical symptoms. These guidelines suggest that investigation should be reserved for patients with symptoms suggestive of complications of GERD or when the response to therapy is other than expected. 18 Recently, we have shown that an omeprazole testða non-invasive test using a 7-day trial of high dose omeprazoleðis a sensitive tool for diagnosing GERD in patients with NCCP and those with symptoms suggestive of GERD (78% and 80%, respectively). 16, 19 These studies used the combination of upper endoscopy and ambulatory 24-h oesophageal ph monitoring as a gold standard for diagnosing GERD, and provided evidence that a simple, non-invasive `therapeutic test' may result in diagnostic accuracy that is equal to or greater than ph monitoring. Additionally, this `test' could serve as a diagnostic tool for primary care providers without access to invasive testing, while also serving as initial therapy. In order to test whether an omeprazole test has superior diagnostic accuracy in the identi cation of GERD, we compared its sensitivity to that of ambulatory 24-h oesophageal ph monitoring. Comparison of an omeprazole test vs. ambulatory 24-h oesophageal ph monitoring is hampered by the lack of a de nite gold standard for diagnosing GERD. However, detection of erosive oesophagitis on upper endoscopy is considered unequivocal evidence for the presence of GERD and may serve as a gold standard for this sub-population of GERD patients. Thus, the aim of this study was to compare an omeprazole test vs. ambulatory 24-h oesophageal ph monitoring in diagnosing GERD in symptomatic heartburn patients with erosive oesophagitis. MATERIALS AND METHODS Patients Patients were prospectively identi ed in primary care and gastroenterology out-patient clinics. Of the 76 patients who were screened for inclusion, 35 (46.1%) consecutive patients (33 males, 2 females; mean age years, range 26±75 years) with at least three episodes of heartburn per week for a minimum of 3 months and at least grade 2 erosive oesophagitis (Hetzel±Dent grading system) on upper endoscopy were enrolled into this study. Patients were excluded if they: had a medical contra-indication to omeprazole therapy; were unable to complete 24-h oesophageal ph monitoring; were using prescription NSAIDs; had already been empirically treated with antisecretory agents; had a duodenal and/or gastric ulcer on upper endoscopy; had a history of upper gastrointestinal surgery; were unable or unwilling to fully complete all stages of the study; were unable to or unwilling to provide an informed consent. This study was approved by the Human Subjects Committee of the University of Arizona. Study protocol (Figure 1) Patients with symptoms of GERD underwent an upper endoscopy. If erosive oesophagitis was documented (³ grade 2) patients then underwent ambulatory 24-h

3 THE OMEPRAZOLE TEST VS. PH TESTING IN DIAGNOSING GERD 391 Figure 1. Diagram of the study design. oesophageal ph monitoring. Patients without erosive oesophagitis (< grade 2) were excluded from further evaluation. Subsequently, patients underwent an omeprazole test as previously described. 16 Daily baseline symptom assessment was carried out during the rst week using a symptom recording diary. Thereafter, patients received 40 mg and 20 mg omeprazole 30 min before breakfast and dinner, respectively, over an additional period of 1 week. During the second study week patients completed a daily symptom recording diary. Both diaries were collected at the end of the baseline symptom assessment and the omeprazole test week. 16, 19 In addition, a pill count was carried out to assess compliance. Patients were noti ed about the results of the upper endoscopy and ambulatory 24-h oesophageal ph monitoring only at the completion of the study. The study coordinator was blinded to the results of 24-h oesophageal ph monitoring and the exact erosive oesophagitis grading. Upper endoscopy After informed consent was obtained, subjects underwent standard upper endoscopy. The stomach and the duodenum were inspected to exclude possible lesions. The distal portion of the oesophagus was carefully evaluated to determine the presence of mucosal injury. The extent of oesophageal mucosal damage was assessed by using the Hetzel±Dent grading system ˆ normal (no abnormalities noted). 1 ˆ erythema, hyperemia, and/or friability present (no visible macroscopic erosions). 2 ˆ super cial ulceration or erosion involving < 10% of the mucosal surface area of the last 5 cm of the oesophageal squamous mucosa. 3 ˆ super cial ulceration or erosion involving ³ 10% but 50% of the mucosal surface area of the last 5 cm of the oesophageal squamous mucosa. 4 ˆ deep ulceration anywhere in the oesophagus or con uent erosions of ³ 50% of the mucosal surface area of the last 5 cm of the oesophageal squamous mucosa. 5 ˆ stricture, which is de ned as narrowing of the oesophagus that does not allow easy passage of the endoscope without dilation. Grades 2±5 were considered diagnostic of erosive oesophagitis and GERD for the purpose of this study.

4 392 R. FASS et al. Ambulatory 24-h oesophageal ph monitoring After an overnight fast, a ph probe with a lower oesophageal sphincter identi er (Syntectics Medical, Digitrapper, MKIII) was inserted via the nose into the stomach. The ph probe was then placed 5 cm above the manometrically determined upper margin of the lower oesophageal sphincter and was connected to a digital portable recorder. A reference electrode was attached to the upper chest. Patients were instructed to keep a diary, recording meal times, position changes, and the time and type of their symptoms. Patients were encouraged to pursue their everyday activities and maintain their usual diet. At the beginning and the end of the study the electrode and the system were calibrated in standard solutions of ph 1 and ph 7. A re ux event was de ned as a fall in ph to < 4, and re ux time as the interval until ph rose above 4 again. The presence of GERD was established when the percentage total time for which ph < 4 was greater than 4.2%. 21 The percentage time ph 4 was considered abnormal in the supine and erect positions if the measured values were greater than 1.2% and 6%, respectively. Analysis of the recorded data was performed using standard, commercially available computer software (Synectics). In patients with erosive oesophagitis and negative ambulatory 24-h oesophageal ph monitoring (ph < 4 less than 4.2% of the time) a symptom index (SI) was calculated by using the patients' diary and event marker. 22, 23 A symptom index greater than 50% was considered positive. SI ˆ Symptom assessment number of symptoms with ph 4 total number of symptoms 100 Patients kept a daily record of the frequency and severity of each symptom they experienced. Symptoms such as chest pain, daytime heartburn, night-time heartburn, dif culty swallowing, and acid regurgitation were evaluated. A scale was used to determine severity of each symptom: mildðsymptom easily tolerated and did not last long, moderateðsymptom caused some discomfort but did not interfere with usual activities, severeðsymptom caused much discomfort and interfered with usual activities, disablingðsymptoms unbearable and interfered considerably with usual activities. The symptom score was calculated by summing the reported daily severity (mild ˆ 1, moderate ˆ 2, severe ˆ 3, disabling ˆ 4) multiplied by the reported daily frequency values as obtained during the week of symptom recording. The omeprazole test was considered positive if the heartburn score improved by more than 50% from the baseline score after treatment with omeprazole, i.e. if the heartburn score after treatment with omeprazole decreased by at least 50% as had been validated in prior 16, 19 studies using this criterion. STATISTICAL ANALYSIS Summaries of continuous variables were expressed as mean standard error (s.e.) and were compared using the t-test. The sensitivities of the omeprazole test and ambulatory 24-h oesophageal ph monitoring were compared using a two-sample test on the equality of 3proportions using large-sample statistics (`prtest' command in STATA STATISTICAL SOFTWARE). RESULTS Patients Thirty-six patients were enrolled into the study. One patient was thereafter excluded due to failure to complete all symptom assessment diaries. Side-effects were noted in one patient who developed diarrhoea during the omeprazole test. The patient did not require discontinuation of the drug. Patients' characteristics are summarized in Table 1. On upper endoscopy 26 patients (74.3%) had grade 2 oesophagitis, seven (20.1%) grade 3, one (2.9%) grade 4, and one (2.9%) grade 5. The latter patient also had a Table 1. Characteristics of patients Subjects (n) 35 Age (years) Range (years) 26±75 Sex (male/female) 33/2 Upper endoscopy results Grade 2 26 Grade 3 7 Grade 4 1 Grade 5 1

5 THE OMEPRAZOLE TEST VS. PH TESTING IN DIAGNOSING GERD cm length of Barrett's oesophagus con rmed by the presence of intestinal metaplasia using alcian blue staining at ph 2.5. Ambulatory 24-h oesophageal ph monitoring Ambulatory 24-h oesophageal ph monitoring was abnormal in 21 patients (60%) and within the normal range in the other 14 subjects (40%). Of the 14 patients with a normal ph test, 10 (71%) had grade 2 and four (29%) grade 3 erosive oesophagitis. The mean percentage total time for which ph < 4 in the erosive oesophagitis patients with normal ambulatory 24-h oesophageal ph monitoring was with a range of 0.5±3.9%. The mean percentage total time ph < 4 in the erosive oesophagitis group with abnormal ambulatory 24-h oesophageal ph monitoring was with a range of 4.3±32.4%. The patients with erosive oesophagitis and a normal ph test were signi cantly younger ( years) than the patients with an abnormal ph test ( years; P ˆ 0.002). There was no difference in the sensitivity or frequency of GERD symptoms between the patients with positive and negative ambulatory 24-h oesophageal ph monitoring. When the symptom index was calculated in the patients with normal ambulatory 24-h oesophageal ph monitoring, an additional three (22%) patients had values greater than or equal to 50% and were included in the calculation. Five patients had abnormal acid exposure in the supine position. Two of these patients were already included because of an abnormal symptom index. One additional patient was included because of abnormal acid exposure in the erect position despite normal percentage total time for ph < 4. Omeprazole test The omeprazole test was positive in 29 patients (83%). The remaining six patients (17%) had a negative test. Of those with a negative test, four patients had grade 2 and two grade 3 erosive oesophagitis. In the omeprazole test positive group, 19 patients (54%) had complete disappearance of symptoms and 10 (29%) had at least a 50% improvement in the symptom intensity score. Of those patients with a negative test, four (67%) had a less than 50% improvement and two (33%) had no change in the symptom intensity score (see Figure 2). No age difference was demonstrated between omeprazole test Figure 2. Changes in symptom intensity score in symptomatic patients with erosive oesophagitis during administration of the omeprazole test. Response variables include no change in symptom intensity score, less than 50%, at least 50% improvement in symptom intensity score and complete disappearance of symptoms (resolution). responders and non-responders ( vs , respectively; P ˆ 0.5). Omeprazole test versus ambulatory 24-h oesophageal ph monitoring The omeprazole test was signi cantly more sensitive than the total acid exposure score on ambulatory 24-h oesophageal ph monitoring in diagnosing GERD in patients with erosive oesophagitis (83% vs. 60%, P ˆ 0.03; 95% CI, 0.03±0.4). By adding the three patients with a positive symptom index and the four patients with abnormal acid exposure in the supine and erect positions despite normal percentage total time for ph 4, the sensitivity of the ph test increases further to 80%. Twenty-one patients (60%) had an abnormal ambulatory 24-h oesophageal ph monitoring and positive omeprazole test, eight (23%) had a positive omeprazole test but a normal ambulatory 24-h oesophageal ph monitoring, and six (17%) had both tests negative. Figure 3 demonstrates the relative diagnostic success of the different tests in various endoscopic grades of erosive oesophagitis.

6 394 R. FASS et al. Figure 3. Comparison of diagnostic accuracy of the omeprazole test and ambulatory 24-h oesophageal ph monitoring among the various grades of erosive oesophagitis. DISCUSSION The diagnosis of GERD in patients with non-erosive re ux disease is hampered by the lack of a de nitive test, making it impossible to determine the accuracy of a speci c diagnostic test or to compare two different diagnostic modalities. However, erosive oesophagitis is considered unequivocal evidence of GERD and can be used as the gold standard for comparing diagnostic strategies in this population of patients. It has been demonstrated that ambulatory 24-h oesophageal ph monitoring can be falsely negative in patients with erosive oesophagitis. Up to 23% of patients with erosive oesophagitis demonstrated 24-h oesophageal ph values within a normal range. 9, 24 Schenk et al. demonstrated an even higher false negative rate (26%) and questioned the accuracy of this test or its use as a gold standard. 17 It remains unclear why the accuracy of ambulatory 24-h oesophageal ph monitoring varies substantially. Technical issues, differences in methodology or interpretation, and the effect of the test on behaviour of the studied subjects are possible explanations. For instance, many clinicians rely exclusively on the percentage total time for ph < 4 criterion while others include patients with a normal percentage total time for ph < 4 but abnormal symptom index. Some use a composite scale such as that introduced by De Meester and Johnson. The optimal methodology and interpretation of ambulatory oesophageal ph monitoring has not been de nitively established and remains a matter of controversy which in part explains why the use of the `gold standard' test is problematic. In our study, ph testing failed to diagnose abnormal acid exposure in up to 40% of the patients with erosive oesophagitis when the percentage total time for ph < 4 was used as the only criterion. This high false-negative rate was not dependent on the grading of the erosive oesophagitis. Only when the symptom index was added did the sensitivity of the test improve from 60 to 69%. The symptom index appears to have an important role in associating atypical symptoms of GERD with events of acid re ux (ph < 4). 22 However, the usefulness of the symptom index is completely dependent on the presence of symptoms during the 24-h of ph recording and the compliance of patients with documenting the time of symptoms in a diary or by pressing the event marker immediately after experiencing symptoms. In addition, the accuracy of the symptom index in patients with erosive oesophagitis and falsely negative ph testing has not been evaluated. Furthermore, after including patients with abnormal acid exposure in the supine and erect positions despite a normal percentage total time for ph < 4 and normal symptom index, the sensitivity of the ph test improved even further (to 80% in this study). To optimize the sensitivity of 24-h oesophageal ph monitoring, all clinical parameters should be incorporated into the traditional criterion of percentage total time for ph < 4. Patients with false-negative ambulatory 24-h oesophageal ph monitoring were signi cantly younger than those with an abnormal test. However, the omeprazole test did not demonstrate this age predilection. It is unclear why the 24-h ph testing tended to be less reliable in the younger GERD patients. Decreased tolerance of the test resulting in a greater adverse impact on re ux provoking activities is a possible explanation. 25 Seventeen per cent of patients receiving an omeprazole test had false-negative results. It should be emphasized that this is a test, not an empirical therapy, and false-negatives occur as in any test. Explanations for a false-negative omeprazole test in a patient with GERD include inadequate acid suppression, insuf cient test length or use of a suboptimal symptom scale. The optimal dose and duration of therapy with an antisecretory agent(s) as a diagnostic test for GERD is not yet determined. We selected the dose used in this

7 THE OMEPRAZOLE TEST VS. PH TESTING IN DIAGNOSING GERD 395 study based on pharmacological data of the maximum dose inhibiting gastric acid. At this dose of omeprazole, most patients will achieve maximum inhibition of gastric acid secretion. The optimal dose and duration of a proton pump inhibitor to be used as a diagnostic test for GERD will require further study including studies from other centres evaluating other populations. However, in this study an omeprazole test was at least as accurate as ambulatory 24-h oesophageal ph monitoring in diagnosing GERD in patients with erosive oesophagitis, thus obviating the need for early endoscopy in the clinical setting. Comparison between other studies that assessed the omeprazole test is dif cult because of methodological differences. Shindlebeck et al. examined the sensitivity and speci city of a short course of high dose omeprazole only in patients with nonerosive re ux disease. 26 In contrast, Johnsson et al. evaluated a different dose of omeprazole (20 mg b.d. for 1 week) and found 80% sensitivity of ambulatory 24-h oesophageal ph monitoring in patients with erosive oesophagitis. 27 The sensitivity of omeprazole therapy in the patients with erosive oesophagitis was not provided in this study. Decreased sensitivity of ambulatory 24-h oesophageal ph monitoring in patients with erosive oesophagitis undergoing an omeprazole test has been reported by other investigators (50±74%). 16±19 Data about the sensitivity of the omeprazole test speci cally in patients with erosive oesophagitis are not provided in these studies and cannot be extrapolated from their results. As demonstrated in this study, the reliability of the omeprazole test in the primary care setting will require con rmation and may depend on a careful symptom assessment at baseline and during treatment. 16 Thus, a prospective evaluation of the utility of the omeprazole test in the primary care setting should be undertaken. The results of this study are limited as only patients with erosive oesophagitis from a single site were used and conclusions about the reliability of both of these tests in patients with non-erosive re ux disease cannot be assumed to be the same. Additionally, the study was carried out at a Veterans Administration Medical Center, which explains the male predominance in the study population. Furthermore, a control was not included as we were comparing one modality to another as a diagnostic testðwhether there is a `placebo' response is irrelevant in this type of study comparing two diagnostic tests. In this study an omeprazole test has been shown to be an accurate and potentially simple and clinically practical strategy that should provide a signi cant cost savings as a diagnostic test in patients with symptoms suggestive of re ux disease that have erosive oesophagitis. 16, 17, 19, 26, 27 The test is readily available and at the disposal of any primary care physician, in contrast to ambulatory 24-h oesophageal ph monitoring. Furthermore, an omeprazole test offers a decrease in 16, 19 patient discomfort in comparison to ph testing. While a positive omeprazole test con rms the diagnosis of GERD, it does not obviate the need for endoscopy to detect Barrett's oesophagus in appropriately selected patients. While 24-h oesophageal ph monitoring is a quantitative test, the omeprazole test is a qualitative test. For most primary care physicians and community based surgeons, a qualitative test is all that may be required; this is additional to the positive facts that the test is readily available, non-invasive and simple to carry out. For research purposes and limited clinical indications a quantitative test such as 24-h oesophageal ph monitoring may be more helpful. In conclusion, when compared to ambulatory 24-h oesophageal ph monitoring, an omeprazole test was at least as accurate a diagnostic strategy in this study. The use of proton pump inhibitors as a diagnostic test for GERD in other populations and the optimal proton pump inhibitor dose when used as a test will require further study. 5 ACKNOWLEDGEMENTS This study was supported in part by a research grant from Astra-Zeneca. REFERENCES 1 Locke GR, Talley NJ, Fett SL, Zinsmeister AR, Melton LJ. Prevalence and clinical spectrum of gastroesophageal re ux: a population based study in Olmsted county, Minnesota. Gastroenterology 1997; 112: 1448±56. 2 DeVault KR, Castell DO. Guidelines for the diagnosis and treatment of gastroesophageal re ux disease. Arch Intern Med 1995; 155: 2165±73. 3 Sabesin SM, Berlin RG, Humphries TJ, et al. Famotidine relieves symptoms of gastroesophageal re ux disease and heals erosions and ulcerations. Arch Intern Med 1991; 151: 2394±400.

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