Gyawali CP, Rogers BD, Yadlapati R, Roman S, Carlson DA, Pandolfino J. pH Impedance Monitoring on Proton Pump Inhibitor Therapy Impacts Management Decisions in Proven GERD but not in Unproven GERD. Clinical Gastroenterology and Hepatology, 2025

Авторы: Gyawali C.P. / Rogers B.D. / Yadlapati R. / Roman S. / Carlson D.A. / Pandolfino J.E.

pH Impedance Monitoring on Proton Pump Inhibitor Therapy Impacts Management Decisions in Proven GERD but not in Unproven GERD

¹ Division of Gastroenterology, Washington University School of Medicine in St. Louis, St. Louis, Missouri;
² Division of Gastroenterology, Hepatology, and Nutrition, University of Louisville School of Medicine, Louisville, Kentucky;
³ Center for Esophageal Diseases, University of California in San Diego, La Jolla, California;
⁴ Digestive Physiology, Universite de Lyon, Lyon, France;
⁵ Kenneth C. Griffin Esophageal Center, Division of Gastroenterology and Hepatology, Northwestern Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.


BACKGROUND AND AIMS: Ambulatory reflux monitoring off proton pump inhibitors (PPIs) is useful in unproven  gastroesophageal reflux disease (GERD). In this prospective clinical trial, we evaluated if on-PPI pH-impedance monitoring provides value in unproven GERD.

METHODS: Patients with typical reflux symptoms with incomplete PPI response were studied both off PPI (wireless pH monitoring) and on PPI (pH-impedance monitoring) at 2 tertiary care centers. Patients and investigators were blinded to reflux testing findings, and patients were asked to self-resume PPI for uncontrolled symptoms despite rescue antacids. Data analysis determined if on-PPI pH-impedance findings correlated with off-PPI acid exposure time (AET) or influenced PPI-related decision making.

RESULTS: Of 79 patients, all 26 (32.9%) with refractory GERD metrics on-PPI had proven GERD off-PPI. In 60 patients with proven GERD off-PPI, 56.7% had no ongoing GERD on PPI. No on-PPI pH-impedance findings predicted PPI decision making among conclusive, borderline, or no reflux (P = .872); AET (P = .107); reflux episodes numbers (P = .113); mean nocturnal baseline impedance (P = .621); and reflux-symptom association categories (P = .363). In multivariable linear and logistic regression models, off-PPI AET modestly predicted refractory GERD (odds ratio, 1.34; 95% confidence interval, 1.11-1.63; P = .003), and reflux episode numbers were borderline in predicting conclusive GERD off-PPI (odds ratio, 1.00; 95% confidence interval, 1.00-1.10; P = .04).

CONCLUSIONS: A minority of symptomatic patients will have refractory GERD evidence on pH-impedance monitoring on PPI; this strategy risks missing over half of the cohort with proven GERD if testing off PPI is unavailable. Our findings support documenting GERD off PPI first in PPI nonresponders and restricting on-PPI pH-impedance monitoring to identify refractory GERD only in patients with proven GERD with persisting symptoms.

ClinicalTrials.gov, Number: NCT03202537. https://doi.org/10.1016/}.cgh.2025.02.032.

Key words: pH-Impedance Monitoring; Wireless pH Monitoring; PPI Nonresponder; Refractory GERD.

Abbreviations used in this paper: AET, acid exposure time; BMI, body mass index; Cl, confidence interval; E-DGBI, esophageal disorder of gut-brain interaction; GERD, gastroesophageal reflux disease; IQR, interquartile range; MNBI, mean nocturnal baseline impedance; OR, odds ratio; PPI, proton pump inhibitor; RSA, reflux-symptom association.

Introduction

In the evaluation of typical esophageal symptoms suspicious for gastroesophageal reflux disease (GERD), an empiric trial of a proton pump inhibitor (PPI) is a pragmatic initial step in the absence of alarm symptoms [1]. As many as 40% do not respond to empiric PPI trials, and esophageal evaluation is often needed [2]. Because the likelihood of finding conclusive endoscopic GERD evidence is low [3], ambulatory reflux monitoring is often performed to discriminate the need for PPI therapy [4]. Reflux monitoring is performed off therapy in unproven GERD, but some have advocated for pH-impedance monitoring on therapy in patients with a high pretest likelihood of GERD, to identify patients with incomplete acid control [5]. The clinical value of this approach remains unclear.

We have previously demonstrated the value of off-PPI prolonged wireless pH monitoring in determining need for PPI continuation vs discontinuation in unproven GERD [4]. In this, the second arm of our prospective 2-center clinical trial, we determined the value of on-therapy pH-impedance monitoring in patients with unproven GERD with persisting reflux symptoms despite PPI therapy. Further, we evaluated if on-therapy pH-impedance metrics correlate with off-therapy wireless pH monitoring metrics. We hypothesized that on-therapy pH-impedance monitoring cannot identify appropriate candidates for PPI withdrawal.

Materials and Methods

This double-blind single-arm clinical trial (NCT03202537) was conducted at 2 tertiary care centers (Northwestern University and Washington University School of Medicine in St. Louis) over a 4-year period (May 2017 through May 2021).

Study Protocol

The overarching trial (National Institutes of Health RO1 DK092217-04) assessed the clinical utility of esophageal physiologic tests in symptomatic GERD patients. Inclusion criteria consisted of adults with continuing troublesome typical reflux symptoms of heartburn, regurgitation and/or esophageal chest pain at least twice a week despite optimized once daily PPI therapy for at least 8 weeks (designated incomplete PPI response). Los Angeles grades C or D esophagitis, biopsy-proven Barrett's esophagus, prior foregut surgery, findings of achalasia or esophagogastric junction outflow obstruction on high-resolution manometry, eosinophilic esophagitis (>15 eosinophils per high-power field on biopsies in the setting of endoscopic suspicion of eosinophilic esophagitis), signs and symptoms or cardiac disease, pregnancy, insufficient reflux monitoring duration (<14 h/d), and inability to provide informed consent were other exclusions. Eligible patients underwent both 96-hour wireless pH monitoring off PPI therapy for 1 week, and on-PPI pH monitoring either prior to or following off-PPI testing. Patients were instructed not to resume PPI therapy for an additional 2 weeks after off-PPI testing unless maximal over-the-counter antacids did not control symptoms. Participants and study investigators were blinded to results of off-PPI and on-PPI testing during this period. Symptoms were monitored with validated questionnaires while on and off PPI. The first arm of the study demonstrated the value of upfront off-PPI wireless pH monitoring in predicting PPI withdrawal [4]. This study evaluates the clinical value of upfront on-PPI pH-impedance monitoring in the same study population.

All patients provided written informed consent, and the study protocol was approved by the Institutional Review Board at both study sites. All authors had access to study data; all reviewed and approved the final manuscript.

pH-Impedance Monitoring

The pH-impedance catheter (Diversatek) was positioned 5 cm above the proximal extent of the lower esophageal sphincter, using high-resolution manometry localization after an overnight fast. Analysis was performed by a blinded investigator using commercially available software. Meal times were excluded, and each reflux episode was reviewed for inclusion using Wingate consensus criteria [6]. Total distal acid exposure time (AET), numbers of reflux episodes (acidic and nonacidic), and mean nocturnal baseline impedance (MNBI) were extracted and recorded. MNBI was calculated by averaging baseline impedance from three 10-minute periods between 1 AM and 3 AM from the impedance channel 5 cm above the lower esophageal sphincter. Positive reflux–symptom association (RSA) was defined by either symptom index >50% or symptom–association probability >95% (corresponding to P < .05).

Wireless pH Monitoring

The wireless pH probe (Bravo; Medtronic) was positioned 6 cm proximal to the squamocolumnar junction during sedated upper endoscopy, with a planned study duration of 96 hours. Patients were instructed to continue usual activities while remaining within 3 feet of the wireless pH receiver. Symptoms and meal-times were recorded using buttons on the receiver as well as a manual diary. The recorded pH data were reviewed and analyzed using commercially available software (Medtronic) after excluding meal times. Total distal AET was calculated for each day of the study.

Patient-Reported Symptoms

The study participants were asked to complete GERDQ at enrollment (on PPI) and again when participants presented for wireless pH monitoring (off PPI). The 6-item GERDQ is a validated questionnaire that quantifies reflux symptoms into scores ranging from 0 to 18 over a 7-day recall period, with higher scores indicating worse symptoms [7,8]. Each patient was contacted weekly by the study coordinator to monitor symptoms and to determine if PPI was resumed.

Data Capture

Demographic data, endoscopic findings, questionnaire data, and PPI use were electronically captured using REDCap (Research Electronic Data Capture) at the lead study site, and de-identified data sheets were generated for analyses. Reflux monitoring studies were interpreted in blinded fashion, and metrics from these studies were uploaded into REDCap.

GERD Definitions

Using Lyon Consensus 2.0 criteria, proven GERD off PPI on wireless pH monitoring consisted of AET >6% on ≥2 days of recording, and no GERD consisted of AET <4% on all 4 days; all other patterns were designated inconclusive [2]. On pH-impedance monitoring on PPI, conclusive GERD (synonymous with refractory GERD) required AET >4%, or total reflux episodes >80 and MNBI <1500 Ω, while no GERD evidence consisted of AET <1%, supported by total reflux episodes <40 and MNBI >2500 Ω; all other patterns were inconclusive.

Data Analysis

Data are reported as median (interquartile range [IQR]) or count and percentage for continuous and categorical variables. Categorical data were compared using the chi-square test, and continuous data were analyzed using the 2-tailed Student’s t test or analysis of variance, as appropriate. The primary analysis aimed to assess the potential utility of various pH-impedance metrics and Lyon Consensus 2.0 designations to predict PPI discontinuation [2]. Secondary outcomes consisted of predictors of PPI resumption vs discontinuation, and correlations between off-PPI and on-PPI reflux monitoring studies. Univariate logistic regression models were fit with summaries including odds ratio (OR) with its confidence interval (CI) and P value. Secondary analyses assessed relationships between pH-impedance metrics and off PPI AET from wireless pH monitoring, symptom burden measured by GERDQ at baseline and change with study intervention. In all cases, P < .05 was required for statistical significance. All statistical analyses were performed using IBM SPSS Statistics V.26.0.

Results

Overall, 79 patients (median age 48.0 years, 49.4% female, median body mass index [BMI] 26.3 kg/m²) completed both wireless pH monitoring off PPI and pH-impedance monitoring on PPI therapy (Figure 1), with a median time interval of 3.9 weeks (IQR, 1.9–6.9 weeks) between studies. The most common PPIs reported by patients consisted of omeprazole (31.6%), pantoprazole (19.0%), and esomeprazole (19.0%); other PPIs used included dexlansoprazole, lansoprazole, and rabeprazole. Reflux symptom burden was equivalent both on PPI therapy at baseline (median GERDQ 9.0 [IQR, 6.0–11.0]) and off PPI therapy (median GERDQ 10.0 [IQR, 6.0–13.0]) (P = .602). On-PPI pH-impedance studies demonstrated 26 (32.9%) with refractory GERD and 15 (19.0%) with no GERD, and 38 (48.1%) had inconclusive GERD evidence (Figure 2). Patients with refractory GERD had a higher BMI (P = .005), while patients with inconclusive GERD were younger (P = .036) than other phenotypes, but there was no gender difference between the cohorts. Overall, median AET (0.3%) and median reflux episode counts (n = 40) were low, while median MNBI was within physiologic limits (2827 Ω) (Table 1) while on PPI. Hiatus hernia was noted more often with refractory GERD. There was a gradient of AET, numbers of reflux episodes and MNBI between the 3 phenotypes, with values most abnormal in refractory GERD, and within physiologic limits with no GERD evidence (Table 1).


Figure 1. Flowsheet describing proportions of symptomatic PPI-refractory patients who were able to discontinue PPIs, with or without GERD evidence on wireless pH monitoring off-PPI and pH-impedance monitoring on optimized PPI therapy. Proven GERD off PPI requires AET >6% on ≥2 days of a 96-hour study, while refractory GERD on PPI requires AET >4% on pH-impedance monitoring. Inconclusive GERD evidence on pH-impedance monitoring on PPI could include some patients with proven GERD, while AET <4% on all days of a wireless study off PPI rules out GERD. In contrast, inconclusive or no GERD evidence on pH-impedance monitoring on PPI could represent adequate control of acid exposure on PPI or absence of GERD evidence altogether. Persisting evidence of GERD on pH-impedance monitoring on PPI is diagnostic of refractory GERD.


Figure 2. Proportions of patients with and without GERD evidence on ambulatory reflux monitoring on and off PPI therapy. The likelihood of finding conclusive GERD evidence is significantly higher when wireless pH monitoring is performed off PPI (P < .001 compared with GERD evidence on PPI therapy on pH-impedance monitoring). Inconclusive or no GERD evidence on PPI could represent GERD controlled on optimized PPI therapy.



PPI Resumption vs Discontinuation

Data on further PPI management were available in 75 patients, of which 22 (29.3%) discontinued PPI (Figure 3). There were no age, gender, or BMI differences between patients who discontinued or continued PPIs (P ≥ .107 for each comparison). Of 14 patients with AET >4% on pH-impedance on PPI, 12 (87.5%) continued PPI, numerically higher compared with patients with AET 1%–4% (n = 7 of 14 [50.0%]) or AET <1% (n = 34 of 47 [72.3%]) on PPI (P = .107). Proportions of patients with >80, 40–80, and <40 reflux episodes failed to demonstrate any significant relationship with PPI continuation (P = .113). Proportions with MNBI <1500 Ω, 1500 - 2500 Ω, and >2500 Ω also demonstrated similar PPI continuation (P = .621), as well as RSA presence or absence (P = .363). Using Lyon Consensus criteria, of 26 patients with refractory GERD, 19 (73.1%) continued PPI, compared with 23 (67.4%) of 34 with inconclusive GERD, and 11 (73.3%) of 15 with no GERD (P = .872).


Figure 3. Proportions of patients who were able to discontinue PPI therapy based on GERD evidence on and off PPI therapy. Inconclusive GERD on pH-impedance monitoring on PPI could represent controlled GERD, hence PPI discontinuation could be improper in these patients. In the presence of proven GERD (off PPI) and refractory GERD (on PPI), patients may have discontinued PPI because of their perception that the medications were ineffective or incompletely effective.

Comparisons With Wireless pH Monitoring Off PPI

All patients with refractory GERD evidence on PPI also had AET >6.0% for ≥2 days on wireless pH monitoring off PPI. In contrast, 46.7% of patients without ongoing GERD evidence, and 71.1% with inconclusive GERD on PPI had proven GERD off PPI (Figure 1).

Of 60 patients with proven GERD off PPI, 34 (56.7%) had no conclusive GERD metrics on PPI, and would not have been identified as having conclusive GERD if only on-PPI pH-impedance monitoring was performed. Among 12 patients with inconclusive GERD off-PPI, 9 (75.0%) demonstrated AET <1% (P = .041 compared with AET >6% on ≥2 days). In 7 patients with no GERD off PPI, all demonstrated AET <1% on pH-impedance testing on PPI.

In correlational analysis, AET on PPI correlated weakly with total AET off PPI across all 4 days of recording (ρ = 0.468), and highest AET on any 1 day of the wireless pH study (ρ = 0.492, P < .001 for both) (Figure 4).


Figure 4. Scatterplot demonstrating correlational analysis of AET on wireless pH monitoring off PPI and pH-impedance monitoring on PPI. (A) Very weak correlation between averaged AET across all days of recording on wireless pH monitoring off-PPI plotted against AET from on-PPI pH-impedance monitoring (r² = 0.076, P < .001). (B) Similarly weak correlation between highest day AET from off-PPI wireless pH monitoring plotted against AET from on-PPI pH-impedance monitoring (r² = 0.120, P < .001).

Multivariable Analysis

In a regression model that included age, sex, AET threshold of <1%, normal reflux episodes (<40), normal MNBI (>2500 Ω), and absence of hiatus hernia, no predictors for PPI discontinuation were found. In a separate regression model that included age, gender, presence of hiatus hernia, and pH-impedance findings of refractory GERD on PPI that consisted of abnormal AET (>4%), reflux episodes (>80), and low MNBI (<1500 Ω), no factor independently predicted PPI continuation.

In separate multivariable regression models exploring pH-impedance metrics on PPI that predict proven GERD off PPI, only reflux episodes on PPI had borderline predictability (OR, 1.05; 95% CI, 1.01–1.09; P = .014) (Table 2). In contrast, AET off PPI was a modest independent predictor of refractory GERD on PPI (OR, 1.34; P = .003) (Table 2).

Discussion

In this prospective 2-center clinical trial, we demonstrate that on-PPI pH-impedance monitoring is not able to identify incomplete PPI responders with typical GERD symptoms who can discontinue PPI therapy. Further, this approach does not identify patients with no GERD or PPI-responsive GERD but can identify refractory GERD in patients with off-PPI–proven GERD. The majority of patients with unproven GERD will not have evidence of refractory GERD on pH-impedance monitoring performed on PPI, which risks missing as many as 56.7% of patients with off-PPI GERD evidence. Conclusive GERD refractory to optimized PPI therapy was only encountered in patients with pathologic AET off PPI, indicating that the recommended paradigm of only performing on-therapy pH-impedance monitoring in patients with proven GERD has clinical value.

The fact that on-PPI pH-impedance monitoring was not of value in predicting discontinuation of PPI therapy in unselected unproven GERD is not surprising. Although the Montreal consensus suggested troublesome symptoms to be the starting point for GERD management [9], research since then has demonstrated that only a small proportion of PPI nonresponders have true GERD, and most have either no GERD or overlap between inconclusive GERD and a non-GERD process such as an esophageal disorder of gut-brain interaction (E-DGBI) [10,11]. Indeed, our findings demonstrate that of the patients with no GERD on pH-impedance monitoring performed on PPI, there is representation of patients with no GERD off therapy, proven GERD off therapy, and inconclusive GERD off therapy; therefore, no GERD evidence on PPI is not helpful in phenotyping GERD or planning management. Because all patients with refractory GERD on PPI also had proven GERD off PPI, high pretest likelihood of true GERD could be a unique situation in which off-PPI testing may not need to be considered prior to on-therapy pH-impedance monitoring [5].

When pH-impedance monitoring was first introduced, the recognition of all reflux episodes using impedance metrics was appealing [12,13]. Clinicians and investigators have favored on-PPI pH-impedance monitoring to identify patients with refractory GERD despite optimized therapy [5]. However, early studies failed to demonstrate symptom outcome prediction using on-PPI metrics. The value of reflux episode counts was not initially demonstrated, although the higher yield of RSA with pH-impedance detecting all reflux episodes [14] translated into prediction of symptom response from antireflux surgery in patients with refractory heartburn [15]. Nevertheless, abnormal AET remained the most reliable metric predicting symptom outcome from both medical and surgical antireflux therapy [16]. The suboptimal accuracy of automated pH-impedance analysis in identifying reflux episodes was quickly brought to notice [17], prompting development of the Wingate criteria for precise identification of reflux episodes [6]. Using Wingate criteria, accuracy of identification of reflux episodes improved to the extent that count >80 predicted symptom response from magnetic sphincter augmentation in regurgitation-predominant GERD, after supragastric belching and rumination syndrome were ruled out [18]. Further, baseline impedance (MNBI) renewed importance as a surrogate marker of longitudinal reflux, correlating with AET, and MNBI normalization associating with improved symptoms after therapy [19]. Subsequently, metrics were identified for on-PPI pH-impedance monitoring that predicted improved outcome from escalation of GERD management, but only in patients with previously proven GERD [20]. Our current findings support the paradigm of performing on-PPI studies in patients with proven GERD and high pretest likelihood of GERD.

Although pH-impedance monitoring on therapy does not suggest adequate predictive capacity for PPI discontinuation, definitive GERD evidence and persisting symptoms despite optimized PPI therapy is an indication for escalation of management [20]. While escalation traditionally involves mechanical antireflux options, potassium competitive acid blockers provide better healing of advanced grade esophagitis [21] as well as faster symptom response in nonerosive reflux disease [22,23], and could be an option. For the remainder, alternate esophageal or E-DGBI mechanisms for persisting symptoms need to be sought, including overlap between GERD and E-DGBI, in which both conditions need to be managed [24]. While positive RSA in the setting of normal acid burden could be an indicator of adequately treated GERD with E-DGBI driving symptoms, RSA remains the weakest link in ambulatory reflux monitoring [25], and we could not demonstrate associations between RSA and PPI discontinuation.

The strength of our study lies in the systematic evaluation of reflux metrics in a prospective clinical trial, and use of the clinically relevant outcome measure of PPI discontinuation with blinded investigators and patients in evaluating the impact of testing off and on PPI. We have previously demonstrated the value of prolonged wireless pH monitoring off therapy in predicting or refuting conclusive GERD and driving therapy in unproven GERD [26,27] The current analysis establishes the clinical value of on-therapy pH-impedance testing in proven GERD as well as patients with high pretest likelihood of GERD. Our study has a few limitations. We compared off-therapy wireless pH-monitoring with on-therapy pH-impedance monitoring, which limits our ability to evaluate the value of reflux episode counts, MNBI, and RSA on and off therapy. Our study was not designed to determine impact of escalation of GERD management on symptoms or the impact of individual symptoms on the management paradigm. Our patient cohorts presented to tertiary care centers with incomplete PPI response, and this may limit generalizability of our findings to the average primary gastroenterologist practice. Finally, we did not include patients with advanced grade esophagitis, Barrett’s esophagus or large hiatus hernias in our study—these would have been patients with endoscopic findings conclusive or suggestive of GERD, and studying these patients on PPI could have added value to our study.

In conclusion, our findings establish that in contrast to off-PPI testing, on-PPI pH-impedance monitoring is not useful as a primary test in unproven GERD because it does not discriminate presence or absence of proven GERD, or the need for discontinuation of PPI in patients not responding to therapy. However, we demonstrate that on-therapy pH-impedance monitoring can identify refractory GERD in patients with previously proven GERD.

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Correspondence

Address all correspondence to: C. Prakash Gyawali, MD, Division of Gastroenterology, 660 South Euclid Ave., Campus Box 8124, St. Louis, MO 63110. e-mail: cprakash@dom.wustl.edu.

CRediT Authorship Contributions

C. Prakash Gyawali, MD, MRCP (Conceptualization: Equal; Investigation: Equal; Supervision: Equal; Writing – original draft: Lead)
Benjamin D. Rogers (Formal analysis: Lead; Validation: Lead; Writing – review & editing: Supporting)
Rena Yadlapati (Data curation: Supporting; Investigation: Supporting; Project administration: Supporting; Writing – review & editing: Supporting)
Sabine Roman (Data curation: Supporting; Formal analysis: Supporting; Writing – review & editing: Supporting)
Dustin Carlson (Data curation: Supporting; Project administration: Supporting; Writing – review & editing: Supporting)
John Pandolfino (Conceptualization: Lead; Funding acquisition: Lead; Investigation: Equal; Methodology: Lead; Supervision: Equal; Writing – review & editing: Supporting)

Conflicts of Interest

The authors disclose the following: C. Prakash Gyawali has served as a consultant for Medtronic and Diversatek. Benjamin D. Rogers and Rena Yadlapati have no disclosures directly relevant to data presented in the article. Sabine Roman has served as a consultant for Medtronic. Dustin A. Carlson has served as a consultant for Medtronic and Diversatek, has served as a speaker for Medtronic, and has a license owned by Medtronic. John Pandolfino has served as a consultant for Medtronic and Diversatek, and has a license owned by Medtronic.

Funding

This project was supported by National Institutes of Health/National Institute on Diabetes and Digestive and Kidney Diseases R01 DK092217 (John Pandolfino) and DK125266 (Rena Yadlapati).

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