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The proton pump inhibitor test for gastroesophageal reflux disease: Optimal cut-off value and duration
Digestive and Liver Disease 42 (2010) 785–790
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Alimentary Tract
The proton pump inhibitor test for gastroesophageal reflux disease: Optimal cut-off value and duration Annalisa de Leone a , Marcello Tonini b , Patrizia Dominici c , Enzo Grossi c , Fabio Pace a,∗ , on behalf of the EMERGE Study Group a
Division of Gastroenterology, Department of Clinical Sciences, “L. Sacco” University Hospital, Via G.B. Grassi, Milano, Italy Department of Physiology and Pharmacology, Section of Pharmacology and Pharmacological Biotechnologies, University of Pavia, Pavia, Italy c Medical Department – Bracco Imaging SpA, Milano, Italy b
a r t i c l e
i n f o
Article history: Received 27 October 2009 Accepted 6 April 2010 Available online 7 May 2010 Keywords: Diagnostic tests Esophagus GERD Symptom score or index
a b s t r a c t Background: There is no accepted gold standard for the diagnosis of gastroesophageal reflux disease (GERD). Aim: To assess the optimal cut-off value and duration of the proton pump inhibitor (PPI) test in GERD patients with and without oesophagitis. Methods: Prospective study of 544 patients undergoing upper GI endoscopy and treated for 2 weeks with PPIs at double dose, and for 3 additional months at standard dose. The status of the patient at end of treatment was used as an independent diagnostic standard, i.e. patients completely asymptomatic were considered as “true” GERD patients. Results: PPI test was positive in 89.7–97.8% of the patients according to the cut-off or duration of test used. Test sensitivity ranged from 95.5% to 98.8%, whereas specificity did not exceed 36.3%. Positive predictive values ranged from 87% to 80%, negative predictive values ranged from 58% to 70%, respectively. Conclusions: The PPI test is a sensitive but poorly specific test in GERD patients. Its optimal duration is 1 week, and the optimal cut-off value is a decrease of heartburn score ≥75%. The diagnostic yield is higher in erosive oesophagitis compared with non-erosive reflux disease patients, similarly to the symptomatic response to 3-month PPI therapy. © 2010 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
1. Introduction Gastro-oesophageal reflux disease (GERD) is a common condition, affecting 10–30% of the population in Western countries [1], which encompasses a broad spectrum of clinical manifestations, ranging from mild or troublesome episodes of heartburn and acid regurgitation without breaks in the oesophageal mucosa to severe oesophagitis and its complications. Although GERD has little impact on prognosis, with an annual mortality rate of approximately 1 death per 100,000 patients [2] and no effect on life expectancy even in severe cases [3], the disease causes substantial morbidity; complications develop in up to 20% of patients and quality of life can be greatly impaired [4,5]. It has suggested that, at least in the case of the typical reflux syndrome, a diagnosis can be reached on the basis of characteristic symptoms, with no need for diagnostic testing [6,7]. In fact,
∗ Corresponding author. Tel.: +39 02 39042943; fax: +39 02 39042337. E-mail addresses: [email protected] (A. de Leone), [email protected] (M. Tonini), [email protected] (P. Dominici), [email protected] (E. Grossi), [email protected] (F. Pace).
upper GI endoscopy, which is the gold standard for diagnosing oesophageal mucosal injury, actually fails to recognize as many as 50% of patients with GERD because they have no mucosal lesions [8]. On the other hand, the detection of abnormal oesophageal acid exposure by means of a 24-h pH monitoring has only a limited sensitivity for GERD diagnosis [9], which however may be slightly increased by measuring the association between symptoms and reflux episodes, using a symptom index [10]. For many years it has been suggested that a pharmacological test, i.e. the so-called PPI (proton pump inhibitor) test [11], might be useful for diagnosing GERD, particularly in the setting of primary care. The test consists of measuring the symptomatic response to a high-dose PPI treatment administered for 1–2 weeks in patients with GERD symptoms. The rationale for using short-term, highdose PPI administration as a diagnostic tool is based on the strong effect of PPIs on inhibition of gastric acid secretion, healing erosive oesophagitis [12] and improving GERD symptoms. As the test aims at establishing that the patient’s symptoms are acid-related, the dosage for the PPI test is higher than usual (in most studies, a double dose) in order to obtain a greater inhibitory effect on acid secretion [13]. No definitive consensus about the duration of the PPI test has been reached; in most studies the duration is 7–14 days
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[14]. As far as the interpretation of the test is concerned, a positive response is usually considered on the basis of main symptom (ordinarily heartburn) improvement and cut-off values between 50% and 75% of symptom improvement have been claimed to provide the best diagnostic accuracy [15]. We designed a multicenter study in patients with typical GERD symptoms with or without erosive oesophagitis, with the aim of assessing the usefulness of a short trial of high-dose PPI as a diagnostic test, and to determine (1) the optimal duration of PPI administration and (2) the best cut-off value of symptomatic response. To overcome the absence of a “hard” criterion to classify non-erosive reflux disease (NERD) as “true” GERD patients, which is needed to calculate sensitivity and specificity of the PPI test, we used the outcome after 3-months of therapy with standard PPI doses as an independent diagnostic criterion; accordingly, patients completely asymptomatic after this period of PPI therapy were classified as “true” GERD patients and vice versa. 2. Methods This study is a national multicenter collaborative investigation (the EMERGE project). The study was conducted on GERD patients with typical symptoms only, between June 2004 and June 2006 according to the rules of Good Clinical Practice. All Ethics Committees of participating centers granted authorization and written informed consent was obtained from all patients. Five hundred and forty-four adult GERD patients (265 females and 279 males, mean age 43.5 ± 12.4 years) were recruited by 59 gastroenterological Italian centres, covering the entire geographical area of Italy (see Appendix A). Inclusion/exclusion criteria are listed below. 2.1. Inclusion criteria
Table 1 Demographic and clinical features of patient population at study entry according to endoscopic results (EE, erosive esophagitis; NERD, non-erosive reflux disease).
Male, N (%) Female, N (%) Age (years) mean (±SD) Height (cm) mean (±SD) Weight (kg) mean (±SD) Smoking
EE (304/544)
NERD (240/544)
184 (60.5%) 105 (34.5%) 43.6 (±12.22) 169.86 (±8.63) 75.33 (±15.40) 164 (53.9%)
95 (39.5%) 160 (65.5%) 43.42 (±12.56) 166.84 (±8.14) 68.49 (±12.41) 115 (47.9%)
Esophagitis severity (Savary–Miller classification) Grade 1 235 (77.3%) Grade 2 52 (17.1%) Grade 3 9 (2.9%) Grade 4 8 (2.6%)
– – – –
Heartburn intensity 1 = mild 2 = moderate 3 = severe 4 = unbearable
28 (9.2%) 179 (58.8%) 88 (28.9%) 9 (2.9%)
29 (12.0%) 151 (62.9%) 53 (22.1%) 8 (3.3%)
Regurgitation
248 (81.5%)
212 (88.3%)
Patients without endoscopic oesophagitis were temporarily classified as having NERD. All patients, i.e. those with EE and those with presumptive NERD, were submitted to the PPI test and subsequently were treated with standard dose of any existing PPI for further 3 months (Fig. 1). The PPI test was conducted using omeprazole 20 mg bid for 15 days ± 1 day; only omeprazole was used since the majority of previous studies on this topic were conducted with this PPI [17–22]. During the 15 days of the PPI test the patient had to report daily in a diary the characteristics of heartburn in terms of intensity and frequency: intensity was scored in a 5-point scale, ranging from 0 = absent to 4 = unbearable and intolerable, with 1 = mild,
Patients were included provided that, before endoscopic examination, the following criteria were fulfilled: age between 18 and 65 years; presence of heartburn (±regurgitation) for at least 15 days, at least once a day, during the last 3 months; referral by the treating physician to a tertiary centre to undergo to upper GI endoscopy; ability to read and write Italian, at least 5 years of schooling; and consent to voluntary participation by signing on the Informed Consent form before study screening. 2.2. Exclusion criteria Patients who had one or more of the following at baseline were excluded from the study: treatment with PPI in the month preceding endoscopy; diagnosis of oesophagitis established during the past 12 months; pregnancy and/or lactation; concomitant cardiac, pulmonary or renal disease during the 4 weeks preceding the study, severe enough to require pharmacological treatment. 2.3. Study design After inclusion in the study, patients were submitted to upper GI endoscopy. The demographic data and clinical characteristics of the whole patient sample are shown in Table 1, according to endoscopic findings (erosive oesophagitis [EE] vs non-erosive reflux disease [NERD]). All patients underwent an upper GI endoscopy that was performed according to the standard protocol of each participating centre. A diagnosis of oesophagitis was made by identification of visible mucosal breaks graded according to the Savary–Miller classification [16].
Fig. 1. Flow of patients through the study.
A. de Leone et al. / Digestive and Liver Disease 42 (2010) 785–790
2 = moderate, 3 = severe. Daily average frequency was expressed simply by giving the number of daily heartburn attacks. This allowed a composite heartburn score to be constructed, by multiplying the daily average frequency times the intensity. Heartburn intensity and frequency were also assessed at the end of the 3month treatment period. In Appendix B the various PPIs used are shown with relative doses. Patients taking concomitant medications for medical problems other than GERD could continue this therapy, which was recorded. Patients in the study were not allowed to take any other antisecretory or prokinetic drug, while over-the-counter (OTC) antacids were allowed if needed because of insufficient symptom control. As mentioned earlier, the status of the patient after the 12 additional weeks of PPI therapy was used as an independent diagnostic criterion to classify GERD patient (who was defined as a complete responder) and non-GERD patient (a partial or no responder), for the purpose of calculating the operating characteristics of the PPI test. 2.4. Statistical analysis The sensitivity and specificity of the PPI test were calculated using a 2 × 2 contingency table. The sensitivity was defined as the fraction of all subjects with the disease (i.e., all responders to 3 and 1/2 months PPI therapy) in whom a positive result was obtained, while specificity was calculated as the fraction of those without the disease (i.e., the non-responders) who yielded a negative test result. Positive predictive values were calculated as the ratio between true positives and all positives results, and negative predictive values as the ratio between true negatives and all negative results, respectively. A receiver operating characteristic (ROC) curves analysis was performed by plotting sensitivity on the y-axis against the 1—specificity, to determine optimal diagnostic cut-off values and duration of PPI test. A chi-squared test was performed to compare proportion of patients in different groups. Statistically significant differences were judged to be present when p < 0.05. Results are presented as means with a 95% confidence intervals (CI). 3. Results Of the 544 patients recruited, 304 (55.8%) had endoscopic oesophagitis while the remaining 240 (44.2%) showed no oesophageal mucosal damage (see Table 1). The main clinical and demographic characteristics of patients are presented in Table 1. Forty-seven patients (8.7%) left the study prematurely: 7 for personal reasons unrelated to therapy, 27 for no-show or delay in presenting at follow-up visit, 13 for unspecified reasons; thus, 497 patients (91.3%) completed the entire study period, 276 with EE and 221 with NERD, respectively (Fig. 1).
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Table 2 Percentages of patients showing complete response to PPI test according to durations of the test and cut-off values for symptoms response (see Section 2).
Cut-off 50%/1 week Cut-off 50%/2 weeks Cut-off 75%/1 week Cut-off 75%/2 weeks *
GERD (%)
EE (%)
NERD (%)
p*
97.8 93.8 90.6 89.7
98.4 95.4 91.7 93.1
97.1 91.6 89.2 85.4
n.s. n.s. n.s. <0.05
Comparison of EE vs NERD patients.
Of 544 patients completing the PPI test, 488 (89.7%) had a reduction in heartburn severity >75% at the end of the 15-day period. The PPI test was positive under these assumptions in 205/240 (85.4%) of patients with NERD and in 283/304 (93.1%) of those with EE. The relative figures after 1 week only were 214/240 (89.2%) and 279/304 (91.7%). The results obtained by using a cut-off value of a reduction of heartburn score greater of 50% are presented in Table 2. The mean heartburn score at day 1 of PPI test was 7.2 ± 16.09 (SD) for the entire GERD population, while it was 5.9 ± 13.29 for EE patients and 8.8 ± 18.97 for NERD patients; at the end of the PPI test period, the relative figures were, respectively: 1.37 ± 8.64, 0.86 ± 6.50 and 1.99 ± 10.67 (p value for pre- and post-comparison within each category <0.001). Interestingly, the area under the curve of the heartburn score during the 15 test days of the NERD group differed significantly from that of the EE group, suggesting that the burden of heartburn was greater in the former: 49.51 for NERD vs. 28.47 for EE group (p = 0.011) (Fig. 2). Following this 2week period, patients were treated for 12 additional weeks with standard PPI dose; at the end of this treatment period, the percentage of completely asymptomatic patients was significantly higher in the EE (244/276, 88.4%) compared with NERD (181/221, 81.9%) patients (p = 0.02). Interestingly, the intensity of heartburn during treatment decreased differently in patients with EE and with NERD, being the reduction of intensity significantly greater in patients with EE (mean delta reduction 2.08 ± 0.77 [SD]) compared with NERD patients (mean delta reduction 1.77 ± 0.83 < 0.01) (Fig. 3). Table 3 shows sensitivity, specificity, positive and negative predictive values using two different cut-off values for the PPI test (namely, a reduction in mean heartburn score >50% and >75%) and two time intervals for PPI test (1 week and 2 weeks). The corresponding ROC curves are presented in Fig. 4. 4. Discussion The lack of a gold diagnostic standard for GERD is commonly acknowledged [23]. Among the tools available for diagnosis, endoscopy, ambulatory pH monitoring and the PPI test are those most frequently used. Upper endoscopy has shown to have rather
Fig. 2. Percentages of completely heartburn-free patients with EE and NERD after 3 months of PPI therapy. EE, erosive oesophagitis; NERD, non-erosive reflux disease.
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Table 3 Values of sensitivity, specificity and predictive values using two different cut-off values and two time intervals for PPI test.
Cut-off 50%/1 week Cut-off 50%/2 weeks Cut-off 75%/1 week Cut-off 75%/2 weeks
Sensitivity (%)
Specificity (%)
Positive predictive value (%)
Negative predictive value (%)
98.8 (95% CI: 97–99%) 96.8 (95% CI: 95–98%) 96.5 (95% CI: 94–98%) 95.5 (95% CI: 9–97%)
6.1 (95% CI: 2–10%) 19.0 (95% CI: 12–26%) 34.6 (95% CI: 25–43%) 36.3 95(% CI: 26–45%)
79.9 95 (% CI: 76–82) 83.3 95 (% CI: 80–86) 86.2 95 (% CI: 83–89) 87.1 95(% CI: 84–89)
58.3 95 (% CI: 30–85) 58.8 95 (% CI: 42–74) 70.6 95(% CI: 58–70) 64.2 95(% CI: 38–90)
Fig. 3. Decrease of heartburn intensity in EE and NERD patients from baseline to study completion (3.5 months), as assessed by a 0–4 point Likert scale. EE, erosive oesophagitis; NERD, non-erosive reflux disease.
a good specificity with value ranging from 90% to 95% [23], but the sensitivity in patients with typical GERD symptoms is only around 50%, due to the fact that a percentage from 50% to 70% of patients in fact do not show any oesophageal mucosal damage [5,24]. On the other hand, the detection of an abnormal acid exposure defined by 24-h pH monitoring does not equate to GERD [25], and even if older studies have found acceptable values for sensitivity and specificity (ranging from 79% to 96% and from 85% to 100% respectively [22,26–28]), 24-h pH monitoring has been reported to be normal in up to 25% of patients with erosive oesophagitis and in 50% of those with NERD [15,22,29]. Recently, it has been proposed that the diagnostic accuracy of pH-monitoring can be improved by extending the test over 48 h with the use of wireless techniques [30], by evaluating the symptom-reflux association [9] and by adding simultaneous impedance monitoring [9]. The above limitations of
Fig. 4. ROC curves for different thresholds and duration of PPI test. R1, cut-off value of symptoms relief ≥75% and duration of 2 weeks; R2, cut-off value of symptoms relief ≥75% and duration of 1 week; R3, cut-off value of symptoms relief ≥50% and duration of 2 weeks; R4, cut-off value of symptoms relief ≥50% and duration of 1 week.
operative diagnostic characteristics of both endoscopic examination and pH monitoring and in addition their invasiveness and costs, render the PPI test an attractive alternative for GERD diagnosis. The use of the PPI test as a diagnostic tool in GERD patients has been reported in the literature for the first time in 1995 [31]. Many subsequent studies have assessed the usefulness of this test in patients with typical symptoms, with or without erosive disease; reported sensitivity values ranged from 27% to 89% and specificity values from 35% to 73% [11,17,19,20,22,32–35]. In 2004, Numans et al. [36] performed a systematic review and a meta-analysis of the value of the PPI test in diagnosing GERD in patients with typical symptoms. From the studies analyzed, these authors reported pooled sensitivity and specificity values of 78% and 54%, respectively, when compared to 24-h pH monitoring, and 71% and 41%, respectively, when compared to upper GI endoscopy. They concluded that a successful PPI test in patients suspected of having GERD does not confidently establish the diagnosis when GERD is defined by the currently accepted reference standard. Moreover, in the studies they reviewed there was a great variability in the diagnostic comparator technique, in the duration of the test (from 4 to 8 weeks) and in dose of PPI. Recently, the same authors published a prospective open-label study [37] that evaluated the diagnostic value of the PPI test in primary care, demonstrating that in this setting the test had a very limited value in diagnosing GERD; in this study, none of the patients was investigated by upper GI endoscopy and they solely used the Symptom Association Probability (SAP) during 24-h pH monitoring as a gold standard for GERD diagnosis. Our study was specifically designed with the aim of assessing the clinical usefulness of PPI test as a confirmatory tool in a population of GERD patients with typical symptoms, and secondarily, the optimal duration of the test and the cut-off values of symptom response. The lack of an independent comparator technique such as ambulatory pH testing may represent a shortcoming of our study, since 44% of our patients had typical GERD symptoms but no sign of oesophagitis at endoscopy. At present, however, such patients are not routinely submitted to pH-monitoring to achieve an objective diagnosis, but are considered as NERD patients solely on the basis of their symptoms and empirically treated with PPIs [6,7]. We tried to reproduce as much as we could the “ordinary care” conditions, thus avoiding pH-monitoring, but used the response the PPI test using the response to 3 and 1/2 months PPI therapy as an independent diagnostic criterion, similarly to previously published data by our group [38]. One of the strengths of our study is the large population included: for the purpose of the present study, we recruited 544 patients, a number larger than any previous studies on PPI test performed so far. A possible limitation is the lack of an objective way to diagnose GERD, such as for example oesophageal pH-monitoring, in patients without endoscopic oesophagitis. However, even this technique is not considered a gold standard for GERD diagnosis [9] and moreover it is still not routinely available in clinical practice. The results of the present study suggest that around 90% of our patients have a positive PPI test, according to the various thresholds used (see Table 3). The percentages of patients with a positive response, in our population, is higher than those reported in previous studies [8,15,17,19,20,22], and appears to be greater in EE
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than in NERD subjects, with a difference which reaches the statistical significance (p < 0.05) for the cut-off of 75% and the duration of 2 weeks (Table 2). While the sensitivity of the test according to the threshold used appears to be very good, ranging from 91.7% to 98.8%, specificity appears poor, ranging from 2.9% to 36.3% (see Table 3). In our study, sensitivity values (range: 91.7–98.8%) are higher than the maximal (89%) previously reported [19], while the specificity (36.3%) is comparable with the minimum reported value (35%) [19]. Thus, based on the diagnostic operating characteristics and on the ROC analysis, the most useful cut-off value to define a positive response to PPI test is a symptom relief ≥75%, because it allows the maximal specificity value, while the optimal duration is 1 week, because sensitivity and specificity values are not different from those obtained after 2 weeks [5] (see Fig. 4). Our results showed a reduction in heartburn severity >75% after 8 days of therapy in almost all GERD patients. These results are supported by the pharmacology of PPIs which exhibits a decrease of maximal acid output by about 66% after 5 days [39] following once-daily PPI dosing and confirm the conclusion of a previous study indicating that 1 week treatment with a once-daily dosage of esomeprazole is effective as 2 weeks of treatment in establishing the presence of GERD in patients with typical symptoms [40]. A novel observation of our study is the fact that in NERD patients the reduction in heartburn severity occurs less rapidly than in EE, being maximal by the 11th day of treatment in the former and the 8th day in the latter; this result however is in keeping with other studies, showing that patients with NERD display reduced symptom relief with PPIs when compared with erosive oesophagitis patients, who exhibit a greater therapeutic gain of about 20% [41]. We further extended this observation by showing that NERD patients with typical symptoms, on average, show a smaller decrease in heartburn intensity during a subsequent 3-month course of therapy with PPI at standard dose compared to EE patients (see Fig. 4). We have no clear explanation for this finding, which may however be the consequence of NERD being a heterogeneous group, which likely include at least three categories of patients, namely: (a) “true” NERD patients, with normal endoscopy and abnormal distal oesophageal acid exposure, (b) hypersensitive oesophagus patients, with normal endoscopy, normal distal oesophageal acid exposure, and positive symptom association for reflux, and (c) functional heartburn patients, with normal endoscopy, normal distal oesophageal acid exposure, and a negative symptom association for reflux at pH-monitoring [42]. Of course, we do not know the exact distribution of these three categories in our NERD sample. In conclusion, this prospective study confirms, on a large patient sample with typical GERD symptoms, that the symptomatic response to a short period of high-dose PPI is a tool with high diagnostic sensitivity but poor specificity. Its optimal duration is 1 week and the optimal cut-off threshold is a decrease of heartburn score ≥75%. Conflict of interest None. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.dld.2010.04.002. References [1] Dent J, El-Serag HB, Wallander MA, et al. Epidemiology of gastroesophageal reflux disease: a systematic review. Gut 2005;54:710–7. [2] Savarino V, Celle G. The outcome of reflux oesophagitis: does drug-induced remission mean cure? Ital J Gastroenterol Hepatol 1998;30:475–7.
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Alimentary Tract
The proton pump inhibitor test for gastroesophageal reflux disease: Optimal cut-off value and duration Annalisa de Leone a , Marcello Tonini b , Patrizia Dominici c , Enzo Grossi c , Fabio Pace a,∗ , on behalf of the EMERGE Study Group a
Division of Gastroenterology, Department of Clinical Sciences, “L. Sacco” University Hospital, Via G.B. Grassi, Milano, Italy Department of Physiology and Pharmacology, Section of Pharmacology and Pharmacological Biotechnologies, University of Pavia, Pavia, Italy c Medical Department – Bracco Imaging SpA, Milano, Italy b
a r t i c l e
i n f o
Article history: Received 27 October 2009 Accepted 6 April 2010 Available online 7 May 2010 Keywords: Diagnostic tests Esophagus GERD Symptom score or index
a b s t r a c t Background: There is no accepted gold standard for the diagnosis of gastroesophageal reflux disease (GERD). Aim: To assess the optimal cut-off value and duration of the proton pump inhibitor (PPI) test in GERD patients with and without oesophagitis. Methods: Prospective study of 544 patients undergoing upper GI endoscopy and treated for 2 weeks with PPIs at double dose, and for 3 additional months at standard dose. The status of the patient at end of treatment was used as an independent diagnostic standard, i.e. patients completely asymptomatic were considered as “true” GERD patients. Results: PPI test was positive in 89.7–97.8% of the patients according to the cut-off or duration of test used. Test sensitivity ranged from 95.5% to 98.8%, whereas specificity did not exceed 36.3%. Positive predictive values ranged from 87% to 80%, negative predictive values ranged from 58% to 70%, respectively. Conclusions: The PPI test is a sensitive but poorly specific test in GERD patients. Its optimal duration is 1 week, and the optimal cut-off value is a decrease of heartburn score ≥75%. The diagnostic yield is higher in erosive oesophagitis compared with non-erosive reflux disease patients, similarly to the symptomatic response to 3-month PPI therapy. © 2010 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
1. Introduction Gastro-oesophageal reflux disease (GERD) is a common condition, affecting 10–30% of the population in Western countries [1], which encompasses a broad spectrum of clinical manifestations, ranging from mild or troublesome episodes of heartburn and acid regurgitation without breaks in the oesophageal mucosa to severe oesophagitis and its complications. Although GERD has little impact on prognosis, with an annual mortality rate of approximately 1 death per 100,000 patients [2] and no effect on life expectancy even in severe cases [3], the disease causes substantial morbidity; complications develop in up to 20% of patients and quality of life can be greatly impaired [4,5]. It has suggested that, at least in the case of the typical reflux syndrome, a diagnosis can be reached on the basis of characteristic symptoms, with no need for diagnostic testing [6,7]. In fact,
∗ Corresponding author. Tel.: +39 02 39042943; fax: +39 02 39042337. E-mail addresses: [email protected] (A. de Leone), [email protected] (M. Tonini), [email protected] (P. Dominici), [email protected] (E. Grossi), [email protected] (F. Pace).
upper GI endoscopy, which is the gold standard for diagnosing oesophageal mucosal injury, actually fails to recognize as many as 50% of patients with GERD because they have no mucosal lesions [8]. On the other hand, the detection of abnormal oesophageal acid exposure by means of a 24-h pH monitoring has only a limited sensitivity for GERD diagnosis [9], which however may be slightly increased by measuring the association between symptoms and reflux episodes, using a symptom index [10]. For many years it has been suggested that a pharmacological test, i.e. the so-called PPI (proton pump inhibitor) test [11], might be useful for diagnosing GERD, particularly in the setting of primary care. The test consists of measuring the symptomatic response to a high-dose PPI treatment administered for 1–2 weeks in patients with GERD symptoms. The rationale for using short-term, highdose PPI administration as a diagnostic tool is based on the strong effect of PPIs on inhibition of gastric acid secretion, healing erosive oesophagitis [12] and improving GERD symptoms. As the test aims at establishing that the patient’s symptoms are acid-related, the dosage for the PPI test is higher than usual (in most studies, a double dose) in order to obtain a greater inhibitory effect on acid secretion [13]. No definitive consensus about the duration of the PPI test has been reached; in most studies the duration is 7–14 days
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[14]. As far as the interpretation of the test is concerned, a positive response is usually considered on the basis of main symptom (ordinarily heartburn) improvement and cut-off values between 50% and 75% of symptom improvement have been claimed to provide the best diagnostic accuracy [15]. We designed a multicenter study in patients with typical GERD symptoms with or without erosive oesophagitis, with the aim of assessing the usefulness of a short trial of high-dose PPI as a diagnostic test, and to determine (1) the optimal duration of PPI administration and (2) the best cut-off value of symptomatic response. To overcome the absence of a “hard” criterion to classify non-erosive reflux disease (NERD) as “true” GERD patients, which is needed to calculate sensitivity and specificity of the PPI test, we used the outcome after 3-months of therapy with standard PPI doses as an independent diagnostic criterion; accordingly, patients completely asymptomatic after this period of PPI therapy were classified as “true” GERD patients and vice versa. 2. Methods This study is a national multicenter collaborative investigation (the EMERGE project). The study was conducted on GERD patients with typical symptoms only, between June 2004 and June 2006 according to the rules of Good Clinical Practice. All Ethics Committees of participating centers granted authorization and written informed consent was obtained from all patients. Five hundred and forty-four adult GERD patients (265 females and 279 males, mean age 43.5 ± 12.4 years) were recruited by 59 gastroenterological Italian centres, covering the entire geographical area of Italy (see Appendix A). Inclusion/exclusion criteria are listed below. 2.1. Inclusion criteria
Table 1 Demographic and clinical features of patient population at study entry according to endoscopic results (EE, erosive esophagitis; NERD, non-erosive reflux disease).
Male, N (%) Female, N (%) Age (years) mean (±SD) Height (cm) mean (±SD) Weight (kg) mean (±SD) Smoking
EE (304/544)
NERD (240/544)
184 (60.5%) 105 (34.5%) 43.6 (±12.22) 169.86 (±8.63) 75.33 (±15.40) 164 (53.9%)
95 (39.5%) 160 (65.5%) 43.42 (±12.56) 166.84 (±8.14) 68.49 (±12.41) 115 (47.9%)
Esophagitis severity (Savary–Miller classification) Grade 1 235 (77.3%) Grade 2 52 (17.1%) Grade 3 9 (2.9%) Grade 4 8 (2.6%)
– – – –
Heartburn intensity 1 = mild 2 = moderate 3 = severe 4 = unbearable
28 (9.2%) 179 (58.8%) 88 (28.9%) 9 (2.9%)
29 (12.0%) 151 (62.9%) 53 (22.1%) 8 (3.3%)
Regurgitation
248 (81.5%)
212 (88.3%)
Patients without endoscopic oesophagitis were temporarily classified as having NERD. All patients, i.e. those with EE and those with presumptive NERD, were submitted to the PPI test and subsequently were treated with standard dose of any existing PPI for further 3 months (Fig. 1). The PPI test was conducted using omeprazole 20 mg bid for 15 days ± 1 day; only omeprazole was used since the majority of previous studies on this topic were conducted with this PPI [17–22]. During the 15 days of the PPI test the patient had to report daily in a diary the characteristics of heartburn in terms of intensity and frequency: intensity was scored in a 5-point scale, ranging from 0 = absent to 4 = unbearable and intolerable, with 1 = mild,
Patients were included provided that, before endoscopic examination, the following criteria were fulfilled: age between 18 and 65 years; presence of heartburn (±regurgitation) for at least 15 days, at least once a day, during the last 3 months; referral by the treating physician to a tertiary centre to undergo to upper GI endoscopy; ability to read and write Italian, at least 5 years of schooling; and consent to voluntary participation by signing on the Informed Consent form before study screening. 2.2. Exclusion criteria Patients who had one or more of the following at baseline were excluded from the study: treatment with PPI in the month preceding endoscopy; diagnosis of oesophagitis established during the past 12 months; pregnancy and/or lactation; concomitant cardiac, pulmonary or renal disease during the 4 weeks preceding the study, severe enough to require pharmacological treatment. 2.3. Study design After inclusion in the study, patients were submitted to upper GI endoscopy. The demographic data and clinical characteristics of the whole patient sample are shown in Table 1, according to endoscopic findings (erosive oesophagitis [EE] vs non-erosive reflux disease [NERD]). All patients underwent an upper GI endoscopy that was performed according to the standard protocol of each participating centre. A diagnosis of oesophagitis was made by identification of visible mucosal breaks graded according to the Savary–Miller classification [16].
Fig. 1. Flow of patients through the study.
A. de Leone et al. / Digestive and Liver Disease 42 (2010) 785–790
2 = moderate, 3 = severe. Daily average frequency was expressed simply by giving the number of daily heartburn attacks. This allowed a composite heartburn score to be constructed, by multiplying the daily average frequency times the intensity. Heartburn intensity and frequency were also assessed at the end of the 3month treatment period. In Appendix B the various PPIs used are shown with relative doses. Patients taking concomitant medications for medical problems other than GERD could continue this therapy, which was recorded. Patients in the study were not allowed to take any other antisecretory or prokinetic drug, while over-the-counter (OTC) antacids were allowed if needed because of insufficient symptom control. As mentioned earlier, the status of the patient after the 12 additional weeks of PPI therapy was used as an independent diagnostic criterion to classify GERD patient (who was defined as a complete responder) and non-GERD patient (a partial or no responder), for the purpose of calculating the operating characteristics of the PPI test. 2.4. Statistical analysis The sensitivity and specificity of the PPI test were calculated using a 2 × 2 contingency table. The sensitivity was defined as the fraction of all subjects with the disease (i.e., all responders to 3 and 1/2 months PPI therapy) in whom a positive result was obtained, while specificity was calculated as the fraction of those without the disease (i.e., the non-responders) who yielded a negative test result. Positive predictive values were calculated as the ratio between true positives and all positives results, and negative predictive values as the ratio between true negatives and all negative results, respectively. A receiver operating characteristic (ROC) curves analysis was performed by plotting sensitivity on the y-axis against the 1—specificity, to determine optimal diagnostic cut-off values and duration of PPI test. A chi-squared test was performed to compare proportion of patients in different groups. Statistically significant differences were judged to be present when p < 0.05. Results are presented as means with a 95% confidence intervals (CI). 3. Results Of the 544 patients recruited, 304 (55.8%) had endoscopic oesophagitis while the remaining 240 (44.2%) showed no oesophageal mucosal damage (see Table 1). The main clinical and demographic characteristics of patients are presented in Table 1. Forty-seven patients (8.7%) left the study prematurely: 7 for personal reasons unrelated to therapy, 27 for no-show or delay in presenting at follow-up visit, 13 for unspecified reasons; thus, 497 patients (91.3%) completed the entire study period, 276 with EE and 221 with NERD, respectively (Fig. 1).
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Table 2 Percentages of patients showing complete response to PPI test according to durations of the test and cut-off values for symptoms response (see Section 2).
Cut-off 50%/1 week Cut-off 50%/2 weeks Cut-off 75%/1 week Cut-off 75%/2 weeks *
GERD (%)
EE (%)
NERD (%)
p*
97.8 93.8 90.6 89.7
98.4 95.4 91.7 93.1
97.1 91.6 89.2 85.4
n.s. n.s. n.s. <0.05
Comparison of EE vs NERD patients.
Of 544 patients completing the PPI test, 488 (89.7%) had a reduction in heartburn severity >75% at the end of the 15-day period. The PPI test was positive under these assumptions in 205/240 (85.4%) of patients with NERD and in 283/304 (93.1%) of those with EE. The relative figures after 1 week only were 214/240 (89.2%) and 279/304 (91.7%). The results obtained by using a cut-off value of a reduction of heartburn score greater of 50% are presented in Table 2. The mean heartburn score at day 1 of PPI test was 7.2 ± 16.09 (SD) for the entire GERD population, while it was 5.9 ± 13.29 for EE patients and 8.8 ± 18.97 for NERD patients; at the end of the PPI test period, the relative figures were, respectively: 1.37 ± 8.64, 0.86 ± 6.50 and 1.99 ± 10.67 (p value for pre- and post-comparison within each category <0.001). Interestingly, the area under the curve of the heartburn score during the 15 test days of the NERD group differed significantly from that of the EE group, suggesting that the burden of heartburn was greater in the former: 49.51 for NERD vs. 28.47 for EE group (p = 0.011) (Fig. 2). Following this 2week period, patients were treated for 12 additional weeks with standard PPI dose; at the end of this treatment period, the percentage of completely asymptomatic patients was significantly higher in the EE (244/276, 88.4%) compared with NERD (181/221, 81.9%) patients (p = 0.02). Interestingly, the intensity of heartburn during treatment decreased differently in patients with EE and with NERD, being the reduction of intensity significantly greater in patients with EE (mean delta reduction 2.08 ± 0.77 [SD]) compared with NERD patients (mean delta reduction 1.77 ± 0.83 < 0.01) (Fig. 3). Table 3 shows sensitivity, specificity, positive and negative predictive values using two different cut-off values for the PPI test (namely, a reduction in mean heartburn score >50% and >75%) and two time intervals for PPI test (1 week and 2 weeks). The corresponding ROC curves are presented in Fig. 4. 4. Discussion The lack of a gold diagnostic standard for GERD is commonly acknowledged [23]. Among the tools available for diagnosis, endoscopy, ambulatory pH monitoring and the PPI test are those most frequently used. Upper endoscopy has shown to have rather
Fig. 2. Percentages of completely heartburn-free patients with EE and NERD after 3 months of PPI therapy. EE, erosive oesophagitis; NERD, non-erosive reflux disease.
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Table 3 Values of sensitivity, specificity and predictive values using two different cut-off values and two time intervals for PPI test.
Cut-off 50%/1 week Cut-off 50%/2 weeks Cut-off 75%/1 week Cut-off 75%/2 weeks
Sensitivity (%)
Specificity (%)
Positive predictive value (%)
Negative predictive value (%)
98.8 (95% CI: 97–99%) 96.8 (95% CI: 95–98%) 96.5 (95% CI: 94–98%) 95.5 (95% CI: 9–97%)
6.1 (95% CI: 2–10%) 19.0 (95% CI: 12–26%) 34.6 (95% CI: 25–43%) 36.3 95(% CI: 26–45%)
79.9 95 (% CI: 76–82) 83.3 95 (% CI: 80–86) 86.2 95 (% CI: 83–89) 87.1 95(% CI: 84–89)
58.3 95 (% CI: 30–85) 58.8 95 (% CI: 42–74) 70.6 95(% CI: 58–70) 64.2 95(% CI: 38–90)
Fig. 3. Decrease of heartburn intensity in EE and NERD patients from baseline to study completion (3.5 months), as assessed by a 0–4 point Likert scale. EE, erosive oesophagitis; NERD, non-erosive reflux disease.
a good specificity with value ranging from 90% to 95% [23], but the sensitivity in patients with typical GERD symptoms is only around 50%, due to the fact that a percentage from 50% to 70% of patients in fact do not show any oesophageal mucosal damage [5,24]. On the other hand, the detection of an abnormal acid exposure defined by 24-h pH monitoring does not equate to GERD [25], and even if older studies have found acceptable values for sensitivity and specificity (ranging from 79% to 96% and from 85% to 100% respectively [22,26–28]), 24-h pH monitoring has been reported to be normal in up to 25% of patients with erosive oesophagitis and in 50% of those with NERD [15,22,29]. Recently, it has been proposed that the diagnostic accuracy of pH-monitoring can be improved by extending the test over 48 h with the use of wireless techniques [30], by evaluating the symptom-reflux association [9] and by adding simultaneous impedance monitoring [9]. The above limitations of
Fig. 4. ROC curves for different thresholds and duration of PPI test. R1, cut-off value of symptoms relief ≥75% and duration of 2 weeks; R2, cut-off value of symptoms relief ≥75% and duration of 1 week; R3, cut-off value of symptoms relief ≥50% and duration of 2 weeks; R4, cut-off value of symptoms relief ≥50% and duration of 1 week.
operative diagnostic characteristics of both endoscopic examination and pH monitoring and in addition their invasiveness and costs, render the PPI test an attractive alternative for GERD diagnosis. The use of the PPI test as a diagnostic tool in GERD patients has been reported in the literature for the first time in 1995 [31]. Many subsequent studies have assessed the usefulness of this test in patients with typical symptoms, with or without erosive disease; reported sensitivity values ranged from 27% to 89% and specificity values from 35% to 73% [11,17,19,20,22,32–35]. In 2004, Numans et al. [36] performed a systematic review and a meta-analysis of the value of the PPI test in diagnosing GERD in patients with typical symptoms. From the studies analyzed, these authors reported pooled sensitivity and specificity values of 78% and 54%, respectively, when compared to 24-h pH monitoring, and 71% and 41%, respectively, when compared to upper GI endoscopy. They concluded that a successful PPI test in patients suspected of having GERD does not confidently establish the diagnosis when GERD is defined by the currently accepted reference standard. Moreover, in the studies they reviewed there was a great variability in the diagnostic comparator technique, in the duration of the test (from 4 to 8 weeks) and in dose of PPI. Recently, the same authors published a prospective open-label study [37] that evaluated the diagnostic value of the PPI test in primary care, demonstrating that in this setting the test had a very limited value in diagnosing GERD; in this study, none of the patients was investigated by upper GI endoscopy and they solely used the Symptom Association Probability (SAP) during 24-h pH monitoring as a gold standard for GERD diagnosis. Our study was specifically designed with the aim of assessing the clinical usefulness of PPI test as a confirmatory tool in a population of GERD patients with typical symptoms, and secondarily, the optimal duration of the test and the cut-off values of symptom response. The lack of an independent comparator technique such as ambulatory pH testing may represent a shortcoming of our study, since 44% of our patients had typical GERD symptoms but no sign of oesophagitis at endoscopy. At present, however, such patients are not routinely submitted to pH-monitoring to achieve an objective diagnosis, but are considered as NERD patients solely on the basis of their symptoms and empirically treated with PPIs [6,7]. We tried to reproduce as much as we could the “ordinary care” conditions, thus avoiding pH-monitoring, but used the response the PPI test using the response to 3 and 1/2 months PPI therapy as an independent diagnostic criterion, similarly to previously published data by our group [38]. One of the strengths of our study is the large population included: for the purpose of the present study, we recruited 544 patients, a number larger than any previous studies on PPI test performed so far. A possible limitation is the lack of an objective way to diagnose GERD, such as for example oesophageal pH-monitoring, in patients without endoscopic oesophagitis. However, even this technique is not considered a gold standard for GERD diagnosis [9] and moreover it is still not routinely available in clinical practice. The results of the present study suggest that around 90% of our patients have a positive PPI test, according to the various thresholds used (see Table 3). The percentages of patients with a positive response, in our population, is higher than those reported in previous studies [8,15,17,19,20,22], and appears to be greater in EE
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than in NERD subjects, with a difference which reaches the statistical significance (p < 0.05) for the cut-off of 75% and the duration of 2 weeks (Table 2). While the sensitivity of the test according to the threshold used appears to be very good, ranging from 91.7% to 98.8%, specificity appears poor, ranging from 2.9% to 36.3% (see Table 3). In our study, sensitivity values (range: 91.7–98.8%) are higher than the maximal (89%) previously reported [19], while the specificity (36.3%) is comparable with the minimum reported value (35%) [19]. Thus, based on the diagnostic operating characteristics and on the ROC analysis, the most useful cut-off value to define a positive response to PPI test is a symptom relief ≥75%, because it allows the maximal specificity value, while the optimal duration is 1 week, because sensitivity and specificity values are not different from those obtained after 2 weeks [5] (see Fig. 4). Our results showed a reduction in heartburn severity >75% after 8 days of therapy in almost all GERD patients. These results are supported by the pharmacology of PPIs which exhibits a decrease of maximal acid output by about 66% after 5 days [39] following once-daily PPI dosing and confirm the conclusion of a previous study indicating that 1 week treatment with a once-daily dosage of esomeprazole is effective as 2 weeks of treatment in establishing the presence of GERD in patients with typical symptoms [40]. A novel observation of our study is the fact that in NERD patients the reduction in heartburn severity occurs less rapidly than in EE, being maximal by the 11th day of treatment in the former and the 8th day in the latter; this result however is in keeping with other studies, showing that patients with NERD display reduced symptom relief with PPIs when compared with erosive oesophagitis patients, who exhibit a greater therapeutic gain of about 20% [41]. We further extended this observation by showing that NERD patients with typical symptoms, on average, show a smaller decrease in heartburn intensity during a subsequent 3-month course of therapy with PPI at standard dose compared to EE patients (see Fig. 4). We have no clear explanation for this finding, which may however be the consequence of NERD being a heterogeneous group, which likely include at least three categories of patients, namely: (a) “true” NERD patients, with normal endoscopy and abnormal distal oesophageal acid exposure, (b) hypersensitive oesophagus patients, with normal endoscopy, normal distal oesophageal acid exposure, and positive symptom association for reflux, and (c) functional heartburn patients, with normal endoscopy, normal distal oesophageal acid exposure, and a negative symptom association for reflux at pH-monitoring [42]. Of course, we do not know the exact distribution of these three categories in our NERD sample. In conclusion, this prospective study confirms, on a large patient sample with typical GERD symptoms, that the symptomatic response to a short period of high-dose PPI is a tool with high diagnostic sensitivity but poor specificity. Its optimal duration is 1 week and the optimal cut-off threshold is a decrease of heartburn score ≥75%. Conflict of interest None. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.dld.2010.04.002. References [1] Dent J, El-Serag HB, Wallander MA, et al. Epidemiology of gastroesophageal reflux disease: a systematic review. Gut 2005;54:710–7. [2] Savarino V, Celle G. The outcome of reflux oesophagitis: does drug-induced remission mean cure? Ital J Gastroenterol Hepatol 1998;30:475–7.
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