- Email: [email protected]
Most Patients With Gastroesophageal Reflux Disease Who Failed Proton Pump Inhibitor Therapy Also Have Functional Esophageal Disorders
Clinical Gastroenterology and Hepatology 2018;-:-–-
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Most Patients With Gastroesophageal Reflux Disease Who Failed Proton Pump Inhibitor Therapy Also Have Functional Esophageal Disorders Jason Abdallah,* Nina George,* Takahisa Yamasaki,* Stephen Ganocy,‡ and Ronnie Fass§ *Esophageal and Swallowing Center, Division of Gastroenterology and Hepatology, MetroHealth Medical Center, Case Western Reserve University School of Medicine, Cleveland, Ohio; ‡Department of Epidemiology and Biostatistics, Case Western Reserve University School of Medicine, Cleveland, Ohio; §Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio BACKGROUND & AIMS:
As many as 45% of patients with gastroesophageal reflux disease (GERD) still have symptoms after receiving once-daily proton pump inhibitor (PPI) therapy. We aimed to compare reflux characteristics and patterns between responders and non-responders to once-daily PPI therapy using combined impedance-pH monitoring.
METHODS:
Patients who reported heartburn and/or regurgitation at least twice per week for 3 months while receiving standard-dose PPI therapy were assigned to the PPI failure group (n [ 16). Patients who reported a complete resolution of symptoms on once-daily PPIs for at least 4 weeks were assigned to the PPI success group (n [ 13). We collected demographic data and subjects completed the short-form 36 and the GERD health-related quality of life questionnaires. Patients then underwent upper endoscopy and combined esophageal impedance-pH monitoring while on PPI therapy.
RESULTS:
Four patients in the PPI success group (31%) and 4 patients in the PPI failure group (25%) had abnormal results from the pH test (P [ 1.00). Most of the patients in the PPI failure group (75%) were found to have either functional heartburn or reflux hypersensitivity with GERD. Impedance and pH parameters did not differ significantly between the PPI failure and success group.
CONCLUSIONS:
We found no difference in reflux characteristics between patients with GERD who had successful vs failed once-daily PPI therapy. Most patients in the PPI failure group (75%) had functional esophageal disorders.
Keywords: Heartburn; Proton Pump Inhibitor; Esophagus; Impedance Test; Regurgitation; Gastroesophageal Reflux.
astroesophageal reflux disease (GERD) is a condition in which the reflux of stomach content into the esophagus causes troublesome reflux-associated symptoms.1 GERD is a chronic disorder and is highly prevalent, affecting up to 44% of the U.S. adult population at least once a month and 20% once a week.2,3 GERD is the fourth most prevalent gastrointestinal disease in the United States, with an estimated 19 million cases per year.4 The disease significantly impacts patients’ quality of life and incurs the highest cost of the alimentary tract disorders, posing a large economic burden.5,6 Proton pump inhibitors (PPIs) have revolutionized the management of patients with GERD due to their profound and prolonged acid suppression and consequently have become the mainstay of therapy.7 When compared with other acid suppressive medications, PPIs demonstrate superior mucosal healing and symptom control as well as preventing both mucosal and symptom
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relapse.8,9 In addition, PPIs are generally safe and well tolerated. Despite the success achieved with PPI therapy in the treatment of GERD patients, there remains a substantial cohort of GERD patients who demonstrate therapeutic failure. It is estimated that between 10% and 45% of patients with GERD remain symptomatic on standard-dose PPI once daily.10 Several mechanisms have been proposed to account for persistent symptoms in GERD patients who failed PPI therapy. These primarily Abbreviations used in this paper: DGER, duodenogastroesophageal reflux; GERD, gastroesophageal reflux disease; GERD-HQRL, Gastroesophageal Reflux Disease-Health Related Quality of Life; LES, lower esophageal sphincter; MNBI, mean nocturnal baseline impedance; PPI, proton pump inhibitor; SAP, symptom association probability; SF-36, 36-Item Short Form Survey; SI, symptom index. © 2018 by the AGA Institute 1542-3565/$36.00 https://doi.org/10.1016/j.cgh.2018.06.018
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include poor medication compliance and adherence, differences in PPI metabolism, residual reflux (nonacidic, bile, or acidic), concomitant functional bowel disorders, psychological comorbidity, and delayed gastric emptying.11,12 Gasiorowska et al13 showed that the degree of duodenogastroesophageal reflux (DGER) and acid did not differ significantly between responders and nonresponders to once-daily PPI, using combined pH and Bilitec tests. As a result, the authors suggested that the increase in DGER in patients taking PPI is not unique to those who failed PPI therapy and that esophageal hypersensitivity is likely contributing to symptoms in this population. None of the studies thus far that physiologically evaluated the underlying mechanisms of refractory heartburn compared impedance-pH test results between patients who failed to respond to PPI once daily with those who were successfully treated with a once-daily PPI. The aim of this study was to compare impedance-pH results in PPI responders versus failure patients to further assess the hypothesis that overlap with functional esophageal disorders and thus esophageal hypersensitivity are the basis for symptom generation in PPI failure patients.
Methods
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What You Need to Know Background Proton pump inhibitors (PPIs) are the mainstay of therapy in patients with gastroesophageal reflux disease (GERD). However, up to 45% of patients with GERD remain symptomatic on standard-dose PPI once daily. The current study compared patients who failed to respond to PPI once daily versus those who were successfully treated with a once-daily PPI, using impedance pH testing. Findings Gastroesophageal reflux characteristics were similar between patients who responded to and those who failed PPI once daily. The vast majority of GERD patients who failed PPI once a day demonstrated an overlap with functional heartburn or reflux hypersensitivity. Implications for patient care The findings support that patients with GERD who do not respond to PPI once daily may already benefit from adding a neuromodulator and possibly psychological intervention.
Study Design
Patients We conducted a prospective-based cohort study of 29 adult patients with documented baseline GERD who were on standard-dose PPI (omeprazole 20 mg daily, esomeprazole 40 mg daily, pantoprazole 40 mg daily) for at least 3 months in our Esophageal and Swallowing Center. Patients were enrolled from October 2014 to April 2017. The PPI success group included patients with a history of heartburn or regurgitation who reported a complete resolution of symptoms on once-daily PPI for at least 4 weeks. Before PPI treatment, the patients reported at least 3 episodes of GERD-related symptoms per week. The PPI failure group included patients who continued to demonstrate GERD-related symptoms on PPI once daily, at least twice per week for the last 3 months. All patients had documented baseline GERD (previous evidence of increased esophageal acid exposure using ambulatory reflux testing or erosive esophagitis, pathology-proven short-segment Barrett’s esophagus, and peptic stricture on endoscopy). We excluded patients with significant underlying comorbidities (severe heart failure, severe chronic obstructive pulmonary disease, liver cirrhosis, severe kidney failure, active malignancy, neurologic and psychiatric disorders), atypical or extraesophageal manifestations of GERD, diabetes mellitus, scleroderma, gastroparesis, active peptic ulcer disease, or known history of long-segment Barrett’s esophagus (>3 cm) on prior upper endoscopy.
This was a prospective study in which patients were enrolled and asked to provide written informed consent. Demographic data such as sex, race, age, alcohol, smoking habits, body mass index, and education level were obtained. Patients filled out the 36-Item Short Form Survey (SF-36) and the GERD-Health Related Quality of Life (GERD-HRQL) symptom severity scale. They then underwent upper endoscopy to assess for esophageal mucosal injury, as well as combined 24-hour esophageal impedance and pH monitoring while on their current PPI therapy within 2–4 weeks of enrollment.
Upper Endoscopy Esophagogastroduodenoscopy was performed using an Olympus 190 series upper endoscope (Olympus) on Q4 all enrolled subjects after an overnight fast to assess for mucosal abnormalities of the esophagus, stomach, and duodenum. The extent of esophageal mucosal inflammation was classified according to the Los Angeles Classification System.14
Ambulatory 24-Hour Esophageal Combined Impedance and pH Monitoring After an overnight fast an esophageal manometry was performed using a solid-state high-resolution catheter to identify the lower esophageal sphincter (LES). The catheter was inserted via the nostril into the stomach.
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Thereafter, the proximal margin of the LES was recorded. Subsequently the pH and Impedance catheter (Laborie Medical Technologies, Mississauga, Ontario, Canada) was placed 5 cm above the proximal margin of the LES and connected to a digital portable recorder. Reflux was defined as a pH <4 and reflux time as the interval until pH was >4 again. The test was considered positive when the percent total time the pH <4 was >4.2%. Abnormal esophageal acid exposure in the upright and supine positions was defined as a pH <4 for more than 6% and 1% of the time, respectively. In addition to acidic reflux, nonacidic reflux events that included weakly acidic (pH 4–7) and weakly alkaline (pH >7) reflux were recorded and the characteristics of the reflux, liquid, or mixed (liquid and air) were documented. The mean nocturnal baseline impedance (MNBI) was assessed using the most distal impedance channel and was then calculated using the mean of three 10-minute nighttime periods (around 1:00 a.m., 2:00 a.m., and 3:00 a.m.) for each patient. To assess the temporal relationship between reflux and symptoms, the patient’s symptom association probability (SAP) and symptom index (SI) scores were calculated. SAP is calculated using statistical analysis (cross tabulation) of a contingency table consisting of 4 possible combinations of reflux and symptoms and identifies the probability that gastroesophageal reflux episodes and symptoms are associated.15 SI is calculated as the percentage of heartburn symptoms that occurred within 2 minutes of an acid reflux event (pH <4). SI % ¼
No: of heartburn episodes at pH <4 x 100 Total no: of heartburn episodes
Significant symptom-reflux association occurred when the SAP was >95% or SI was 50%.15 Analysis of the recorded data was carried out using standard computer software.
Questionnaires Demographic questionnaire. Demographic data such as sex, race, age, and education level were obtained from all patients. Information about current alcohol and smoking habits was collected as well. Body mass index was calculated using the patient’s weight and height. 36-Item Short Form Survey. The SF-36 is a validated set of generic, coherent, and easily administered qualityof-life measures that has been shown to be useful in evaluating the clinical curative effect of GERD.16,17 This health survey contains 36 items and includes a multiitem scale that assesses 8 health domains: physical functioning, role limitations due to physical and emotional health, bodily pain, general health, vitality, social functioning, and mental health. The SF-36 scores range from 0 to 100, with higher scores indicating better functioning and well-being. GERD-HRQL Scale. The GERD-HRQL scale is a reliable, valid, responsive, and practical measure of symptom
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291 292 293 294 295 296 297 298 Statistical Analysis 299 300 Categorical data were described with number and 301 percentage, while continuous data were described using 302 mean SD and median. A chi-square test was used to 303 compare the proportion between the PPI responsive 304 groups except in instances where small numbers necessi305 tated using the Fisher’s exact test. Where data was nor306 mally distributed, groups were compared using Student’s 307 t test. With non-normally distributed data, groups were 308 compared via the nonparametric Kruskal-Wallis test. The 309 P values were adjusted using false discovery rate correc310 tion due to multiple comparisons. SAS version 9.4 (SAS 311 Institute, Cary, NC) was used for all statistical data analysis. 312 313 Results 314 315 Patient Characteristics 316 317 There were 29 patients who were enrolled and 318 completed the study. The demographic data are presented 319 in Table 1. Thirteen patients (mean age 54.5 14.5 years; 320 321 Q5 Table 1. Demographics of Study Patients 322 323 PPI Failure PPI Success 324 (n ¼ 16) (n ¼ 13) P Value 325 Age, y 46.6 13.1 54.5 14.5 .13 326 (25–69) (29–72) 327 Sex .71 328 Female 11 (68.8) 8 (61.5) 329 Male 5 (31.2) 5 (38.5) Race .36 330 White 5 (31.2) 7 (53.8) 331 Black 5 (31.2) 5 (38.5) 332 Hispanic 3 (18.8) 1 (7.7) 333 Asian 3 (18.8) 0 (0.0) 334 Education .77 High school 8 (50.0) 7 (53.8) 335 College 5 (31.2) 5 (38.5) 336 Graduate 3 (18.8) 1 (7.7) 337 Current smoker .61 338 Yes 3 (18.8) 1 (7.7) No 13 (81.2) 12 (92.3) 339 Current alcohol user .70 340 Yes 5 (31.2) 3 (23.1) 341 No 11 (68.8) 10 (76.9) 342 Hiatal hernia .41 343 Yes 3 (18.8) 5 (38.5) 344 No 13 (81.2) 8 (61.5) BMI, kg/m2 30.1 6.7 29.4 4.8 .74 345 346 347 NOTE. Values are mean SD (range) or n (%). 348 BMI, body mass index; PPI, proton pump inhibitor. severity in patients with GERD.18 It was developed to survey symptomatic outcomes and therapeutic effects in patients with GERD. The scale has 10 items that focus on heartburn symptoms, dysphagia, bloating, and medication effects on daily life. Each item is scored from 0 (no symptoms) to 5 (worse symptoms).
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Table 2. Impedance-pH and PPI Characteristics of Study Patients
No.
Sex
PPI Success 1 F 2 M 3 F 4 F 5 F 6 M 7 F 8 M 9 F 10 F 11 F 12 F 13 M PPI failure 1 F 2 M 3 M 4 F 5 F 6 F 7 M 8 F 9 F 10 M 11 F 12 M 13 F 14 F 15 F 16 F
Age (y)
PPI
Dose (mg)
Mean Time Reflux pH <4 (%)
Total Number of Reflux Events
72 43 61 42 57 67 29 47 71 66 58 32 64
Omeprazole Omeprazole Esomeprazole Omeprazole Omeprazole Omeprazole Omeprazole Omeprazole Omeprazole Esomeprazole Omeprazole Omeprazole Pantoprazole
20 20 40 20 20 20 20 20 20 40 20 20 40
0.6 12.4 3.6 2.3 0 17.9 1 19.2 0.3 1.6 1 2 1
10 16 40 51 1 32 1 26 2 14 37 6 7
13 135 79 33 27 122 42 118 61 75 21 44 57
0 4 0 5 1 10 1 8 0 0 0 0 0
6 20 41 15 8 99 17 21 24 6 21 14 19
17 135 78 74 21 65 27 131 39 90 23 36 46
67 46 25 54 59 37 39 47 41 33 69 54 33 31 57 53
Esomeprazole Omeprazole Pantoprazole Omeprazole Esomeprazole Omeprazole Omeprazole Esomeprazole Omeprazole Omeprazole Esomeprazole Omeprazole Omeprazole Omeprazole Pantoprazole Omeprazole
40 20 40 20 40 20 20 40 20 20 40 20 20 20 40 20
0.6 0 3.6 0.1 0 0.1 3.6 4.7 0.6 2 0 0.4 4 0 0.1 1.6
6 0 31 6 2 0 141 10 7 13 0 1 15 1 4 13
61 20 47 21 32 31 203 117 81 32 29 133 39 19 89 31
3 20 0 1 0 1 0 0 0 19 0 0 0 0 0 0
17 5 16 3 4 3 28 25 3 14 4 18 12 3 25 12
53 35 62 21 30 29 316 102 85 50 25 117 42 17 68 32
Acid
Weakly Acid
Weakly Alkaline
Liquid
Mix
F, female; M, male; PPI, proton pump inhibitor.
8 women and 5 men) were asymptomatic on once-daily PPI and were assigned to the PPI success group. Sixteen patients (mean age 46.6 13.1 years; 11 women and 5 men) continued to report heartburn or regurgitation despite once-daily PPI and were assigned to the PPI failure group. The majority of the patients were women (69% failure and 62% success). There were no significant differences in all demographic parameters between the 2 patient groups. There were also no significant differences in PPI dosing or distribution between the 2 patient groups (Table 2).
Questionnaires The comparison between quality-of-life scores between PPI failure and PPI success groups based on the SF-36 is depicted in Supplementary Table 1. Overall, the PPI success group had higher mean scores in all SF-36 domains. However, the scores did not reach statistical significance. Table 3 compares the GERD symptom characteristics between the PPI failure and
success groups based on the GERD-HRQL questionnaire. Heartburn or bloating experienced in the supine position as well as overall degree of heartburn were the most bothersome symptoms for PPI failure patients on a daily basis.
Endoscopy The majority of patients in both groups had normal endoscopy. In the PPI failure and success groups, 81% (13) and 69% (9), respectively, had a normal upper endoscopy. One (3%) patient, who responded to PPI therapy, had erosive esophagitis (Los Angeles grade A). Short-segment Barrett’s esophagus was seen in 2 patients (7%), both of which were in the PPI success group. Nonobstructive Schatzki rings were noted in 3 (23%) of the PPI success and 2 (13%) of the PPI failure patients. One (6%) PPI failure patient had an esophageal stricture. Hiatal hernia was noted in 5 (38%) of the PPI success and 3 (19%) of the PPI failure patients (P ¼ .41).
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Table 3. Comparison of GERD-HRQL Symptom Characteristics Between the PPI Failure and Success Groups
Table 4. Comparison of Reflux Parameters Between PPI Failure and PPI Success Patients PPI Failure
Symptom Heartburn Severity Timing Lying down Standing up After meals Diet change Sleep disturbance Dysphagia Odynophagia Bloating Medication affects
PPI Failure
PPI Success
3.13 1.09
0.54 0.52
3.19 2.63 2.88 2.88 2.88 2.50 1.56 3.00 2.06
0.98 0.89 1.02 1.36 1.26 1.37 1.03 1.32 1.48
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0.92 0.76 1.38 1.61 1.23 1.69 0.61 2.53 1.31
0.49 0.59 0.96 0.87 0.92 0.63 0.65 0.96 0.48
NOTE. Values are mean SD. GERD-HRQL, Gastroesophageal Reflux Disease-Health Related Quality of Life; PPI, proton pump inhibitor.
Ambulatory 24-Hour Combined Esophageal pH and Impedance Monitoring Abnormal pH test was present in 4 (31%) patients from the PPI success group and 4 (25%) from the PPI failure group (P ¼ 1.00). Figure 1 depicts the percentages of each type of reflux based on impedance pH testing among the PPI failure and PPI success patients. In the PPI failure group, the total number of reflux events was 1279. Of these events, the number of acidic, weakly acidic, and weakly alkaline reflux events was 250 (19.6%), 985 (77.0%), and 44 (3.4%), respectively. The number of reflux events per patient was 80. Of these
Figure 1. Comparison of the different reflux events between the proton pump inhibitor (PPI) failure and PPI success patients.
Time reflux pH <4, % Total Upright Recumbent Number of acid reflux episodes Longest acid reflux episode, min Number of reflux events Total Acid Weakly acid Weakly alkaline Liquid Mix Upright Acid Weakly acid Weakly alkaline Liquid Mix Recumbent Acid Weakly acid Weakly alkaline Liquid Mix MNBI, U
1.34 1.24 1.51 13.0
1.69 1.37 2.92 21.78
6.51 9.69
PPI Success P Value 4.84 2.15 10.3 20.8
6.87 1.76 18.3 19.6
.09 .11 .38 .15
21.4 32.9
.20
15.6 61.6 2.75 12.0 67.8
34.4 51.6 6.59 8.85 72.4
18.7 63.6 2.23 23.9 60.2
16.8 40.2 3.44 24.3 40.0
.09 .57 .22 .05 .90
13.9 52.4 2.56 8.89 61.4
33.0 48.8 6.12 7.46 70.6
14.4 57.2 2.23 18.9 54.8
14.0 39.8 3.44 19.3 38.8
.15 .36 .47 .31 .88
1.69 6.63 0.19 3.38 5.75 3334
2.80 7.05 0.75 3.84 7.03 1133
4.31 5.50 6.38 6.55 0 5.08 5.63 5.38 3.99 2710 1614
.26 .93 .37 .03 .54 .23
MNBI, mean nocturnal baseline impedance; PPI, proton pump inhibitor.
events, the number of acidic, weakly acidic, and weakly alkaline reflux events per patient was 15.7 (19.6%), 61.6 (77.0%), and 2.72 (3.4%), respectively. In the PPI success group, the total number of reflux events was 1099. Of these events, the number of acidic, weakly acidic, and weakly alkaline reflux events was 243 (22.1%), 827 (75.3%), and 29 (2.6%), respectively. The number of reflux events per patient was 84.5. Of these events, the number of acidic, weakly acidic, and weakly alkaline reflux events per patient was 18.7 (22.1%), 63.6 (75.3%), and 2.2 (2.6%), respectively. The comparison among the number of acidic, weakly acidic, and weakly alkaline reflux episodes (total, upright, recumbent) in both groups did not reach statistical significance (P ¼ .1, .6, and .2, respectively). Table 4 summarizes the comparison of acid reflux parameters between PPI failure and PPI success groups. For PPI failure patients, the mean total time pH <4 was 1.34% (range, 0%–3.6%), the mean number of acidic, weakly acidic, and weakly alkaline reflux events was 15.63, 61.56, and 2.75, respectively. For PPI success patients, the mean total time pH <4 was 4.84% (range, 0%–19.2%), the mean number of acidic, weakly acidic, and weakly alkaline reflux events was 18.69, 63.62, and 2.23, respectively. None of the comparisons reached
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Figure 2. Distribution of functional esophageal disorders, using Rome IV criteria, among gastroesophageal reflux disease (GERD) patients who failed proton pump inhibitor once daily.
statistical significance. In addition, the number of acidic, weakly acidic, and weakly alkaline reflux episodes (total, upright, recumbent) in both groups did not reach statistical significance. The mean MNBI was numerically lower in the PPI success group (2710 1614 U) as compared with the PPI failure group (3334 1133 U), but did not reach statistical significance (P ¼ .23).
PPI Failure Groups Figure 2 shows the different disorders of the PPI failure patients based on Rome IV criteria.19 Ten (62.5%) patients were found to have normal acid exposure and negative symptom reflux association (consistent with functional heartburn with GERD overlap), 2 (12.5%) patients had normal acid exposure and positive symptom reflux association (consistent with reflux hypersensitivity with GERD overlap), and 4 (25%) patients had abnormal esophageal acid exposure despite PPI therapy (consistent with persistent GERD).
Symptom Analysis Three hundred and fifteen episodes of either heartburn or regurgitation were recorded by the PPI failure group. Four patients had a positive SAP (>95%). Two patients had positive symptom correlation for acid regurgitation without evidence of acidic or weakly acidic reflux. Two other patients had positive symptom correlation for acid regurgitation with evidence of acidic and weakly acidic reflux. The mean SI and SAP for GERDrelated symptoms were 4.4% and 21.2%, respectively.
Discussion Our study demonstrated that there is no statistically significant difference in the number of reflux events, acid exposure, or nonacidic reflux parameters between GERD patients who failed versus those who were successfully treated with once-daily PPI. In addition, most GERD
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patients who failed PPI once daily appear to have an overlap with a functional esophageal disorder (either reflux hypersensitivity or functional heartburn). Thus, our results support the hypothesis that PPI failure is primarily driven by esophageal hypersensitivity. To our knowledge, this is the first study to compare impedance parameters combined with pH analysis between PPI success versus PPI failure patients. All impedance parameters, including weakly acidic and alkaline reflux, did not differ significantly between the 2 groups. This implies that the shift to nonacidic reflux is a general PPI phenomenon, as opposed to being unique to PPI failure patients. In a similar study, Gasiorowska et al13 used combined ambulatory 24-hour esophageal pH and Bilitec monitoring to demonstrate that the degree of DGER and acid exposure were not significantly different between PPI once daily responders and nonresponders. The authors also proposed based on the results of the study that the degree of DGER seen in PPI failure patients was a general PPI phenomenon and not unique to PPI failure. Furthermore, in patients who failed to respond to PPI once daily, persistent acidic reflux played an important role in symptom generation and most of the GERD-related symptoms were associated with acid reflux events, as compared with DGER. Similarly, our study showed that 25% of patients who failed PPI therapy had persistent abnormal esophageal acid exposure. These findings further support the current practice of optimizing acid suppression throughout the day by doubling or splitting the PPI dose (a.m. and p.m.) in GERD patients who failed to respond to once-daily PPI.7,12,20 It is important to note that while all of the study patients had documented GERD at baseline, the majority (62.5%) of the PPI failure patients were found to have an overlap with functional heartburn. Two patients demonstrated an overlap with reflux hypersensitivity while on PPI therapy. Because there was also no difference in impedance-pH parameters between patients who failed as compared with those who responded to PPI treatment, this further lends evidence that functional esophageal disorders and thus esophageal hypersensitivity drive most of the symptoms reported by GERD patients who failed PPI once daily. In our study, we evaluated patients with GERD symptoms who either responded or failed PPI once daily. To our knowledge, all of the studies that assessed the underlying mechanisms of refractory GERD using esophageal impedance pH included only patients who were taking PPI twice daily.21–23 As the majority of patients who report GERD-related symptoms respond to standard dose PPI once daily,10 the purpose of the study was to compare impedance-pH parameters between patients who failed versus those who responded to PPI once daily. In addition, although it is common practice to double the dose in those GERD patients who do not respond to PPI once daily, this is not an approved indication by the Food and Drug Administration.
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MNBI is a novel parameter used to calculate baseline impedance not affected by swallows and gastroesophageal reflux.24 Recently, it has been demonstrated that MNBI increases the diagnostic yield of impedance pH monitoring. In addition, nocturnal baseline impedance level has been found to be useful in distinguishing between nonerosive reflux disease patients versus those with functional heartburn.24 MNBI is significantly lower in patients with erosive reflux disease or nonerosive reflux disease than in those with functional heartburn. Our results demonstrated that even baseline impedance, as measured by MNBI, were similar between the 2 patient groups, which further supports the underlying role of esophageal hypersensitivity in patients who failed PPI therapy. There were no differences in quality-of-life symptoms between the PPI success and failure groups as measured by the SF-36 (Supplementary Table 1). We found that many patients with GERD symptoms, regardless of response to PPI, have underlying impairments of physical functioning, role limitations, and mental and general health, which are likely caused by underlying psychosocial comorbidity. In addition, the SF-36 is a general HRQL tool and not specific for GERD-related symptoms. Our study is limited by a small cohort size of 29 patients, which may have affected the results of the study. Recruitment into the study was hampered by the invasive nature of some of the procedures. In addition, it is our experience that many patients who have responded to PPI are reluctant to undergo invasive testing as part of a study protocol. Therefore, we believe that these types of prospective, invasive studies are rather difficult to perform but provide essential insight into the understanding of refractory GERD. Although our cohort size was small, our results are supported by another study13 demonstrating no difference in the degree of esophageal reflux exposure between patients who failed to respond and those who achieved symptom resolution while taking once-daily PPI. Furthermore, a study conducted by Rohof et al25 showed that partial responders to PPI are most likely explained by increased proximal reflux in a hypersensitive esophagus, as opposed to number of reflux events, increased mucosal permeability, or the position of the acid pocket. In summary, our study is the first to demonstrate that reflux characteristics, using impedance pH, were not significantly different between patients who responded to those who failed PPI once daily. The high degree of weakly acidic reflux observed in patients who do not respond to PPI treatment appears to be a general PPI phenomenon and it is not unique to PPI failure patients. In the PPI failure group, most of the patients had normal esophageal acid exposure. The vast majority of GERD patients who failed PPI once a day demonstrated an overlap with functional heartburn or reflux hypersensitivity, supporting the important role of esophageal hypersensitivity in this patient population. Thus, patients who do not respond to PPI once daily may benefit from
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adding a neuromodulator and possibly psychological intervention such as cognitive behavioral therapy, hypnotherapy, relaxation techniques, mindfulness, and biofeedback.26–28
Supplementary Material Note: To access the supplementary material accompanying this article, visit the online version of Clinical Gastroenterology and Hepatology at www.cghjournal.org, and at https://doi.org/10.1016/j.cgh.2018.06.018.
References 1. Vakil N, van Zanten SV, Kahrilas P, et al. The Montreal definition and classification of gastroesophageal reflux disease: a global evidence-based consensus. Am J Gastroenterol 2006; 101:1900–1920. 2. Dent J, El-Serag HB, Wallander MA, et al. Epidemiology of gastro-oesophageal reflux disease: a systematic review. Gut 2005;54:710–717. 3. Locke GR 3rd, Talley NJ, Fett SL, et al. Prevalence and clinical spectrum of gastroesophageal reflux: a population-based study in Olmsted County, Minnesota. Gastroenterology 1997; 112:1448–1456. 4. Sandler RS, Everhart JE, Donowitz M, et al. The burden of selected digestive diseases in the United States. Gastroenterology 2002;122:1500–1511. 5. Francis DO, Rymer JA, Slaughter JC, et al. High economic burden of caring for patients with suspected extraesophageal reflux. Am J Gastroenterol 2013;108:905–911. 6. Bytzer P, van Zanten SV, Mattsson H, et al. Partial symptomresponse to proton pump inhibitors in patients with non-erosive reflux disease or reflux oesophagitis - a post hoc analysis of 5796 patients. Aliment Pharmacol Ther 2012; 36:635–643. 7. Katz PO, Gerson LB, Vela MF. Guidelines for the diagnosis and management of gastroesophageal reflux disease. Am J Gastroenterol 2013;108:308–328. 8. Chiba N, De Gara CJ, Wilkinson JM, et al. Speed of healing and symptom relief in grade II to IV gastroesophageal reflux disease: a meta-analysis. Gastroenterology 1997;112:1798–1810. 9. Sifrim D, Castell D, Dent J, et al. Gastro-oesophageal reflux monitoring: review and consensus report on detection and definitions of acid, non-acid, and gas reflux. Gut 2004; 53:1024–1031. 10. El-Serag H, Becher A, Jones R. Systematic review: persistent reflux symptoms on proton pump inhibitor therapy in primary care and community studies. Aliment Pharmacol Ther 2010; 32:720–737. 11. Dickman R, Boaz M, Aizic S, et al. Comparison of clinical characteristics of patients with gastroesophageal reflux disease who failed proton pump inhibitor therapy versus those who fully responded. J Neurogastroenterol Motil 2011;17:387–394. 12. Hussain ZH, Henderson EE, Maradey-Romerao C, et al. The proton pump inhibitor non-responder: a clinical conundrum. Clin Transl Gastroenterol 2015;6:e115. 13. Gasiorowska A, Navarro-Rodriguez T, Wendel C, et al. Comparison of the degree of duodenogastroesophageal reflux and acid reflux between patients who failed to respond and those who were successfully treated with a proton pump inhibitor once daily. Am J Gastroenterol 2009;104:2005–2013.
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14. Armstrong D, Bennett JR, Blum AL, et al. The endoscopic assessment of esophagitis: a progress report on observer agreement. Gastroenterology 1996;111:85–92. 15. Weusten BL, Rolfs JMM, Akkermans LMA, et al. The symptom association probability: An improved method for symptom analysis of 24-hour esophageal pH data. Gastroenterology 1994;107:1741–1745. 16. Brazier JE, Harper R, Jones NM, et al. Validating the SF-36 health survey questionnaire: new outcome measure for primary care. BMJ 1992;305:160–164. 17. Jenkinson C, Coulter A, Wright L. Short form 36 (SF36) health survey questionnaire: normative data for adults of working age. BMJ 1993;306:1437–1440. 18. Velanovich V, Vallance SR, Gusz JR, et al. Quality of life scale for gastroesophageal reflux disease. J Am Coll Surg 1996; 183:217–224. 19. Aziz Q, Fass R, Gyawali CP, et al. Functional esophageal disorders. Gastroenterology 2016;150:1368–1379. 20. Fass R, Sontag SJ, Traxler B, et al. Treatment of patients with persistent heartburn symptoms: a double-blind, randomized trial. Clin Gastroenterol Hepatol 2006;4:50–56. 21. Zerbib F, Roman S, Ropert A, et al. Esophageal pH-impedance monitoring and symptom analysis in GERD: a study in patients off and on therapy. Am J Gastroenterol 2006;101:1956–1963. 22. Tutuian R, Vela MF, Hill EG, et al. Characteristics of symptomatic reflux episodes on Acid suppressive therapy. Am J Gastroenterol 2008;103:1090–1096. 23. Hemmink GJ, Bredenoord AJ, Weusten BL, et al. Esophageal pH-impedance monitoring in patients with therapy-resistant reflux symptoms: ’on’ or ’off’ proton pump inhibitor? Am J Gastroenterol 2008;103:2446–2453.
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24. Kandulski A, Weigt J, Caro C, et al. Esophageal intraluminal baseline impedance differentiates gastroesophageal reflux disease from functional heartburn. Clin Gastroenterol Hepatol 2015;13:1075–1081. 25. Rohof WO, Bennink RJ, de Jonge H, et al. Increased proximal reflux in a hypersensitive esophagus might explain symptoms resistant to proton pump inhibitors in patients with gastroesophageal reflux disease. Clin Gastroenterol Hepatol 2014; 12:1647–1655. 26. Limsrivilai J, Charatcharoenwitthaya P, Pausawasdi N, et al. Imipramine for treatment of esophageal hypersensitivity and functional heartburn: a randomized placebo-controlled trial. Am J Gastroenterol 2016;111:217–224. 27. van Peski-Oosterbaan AS, Spinhoven P, van Rood Y, van der Does JW, Bruschke AV, Rooijmans HG. Cognitive-behavioral therapy for noncardiac chest pain: a randomized trial. Am J Med 1999;106:424–429. 28. Dickman R, Schiff E, Holland A, et al. Clinical trial: acupuncture vs. doubling the proton pump inhibitor dose in refractory heartburn. Aliment Pharmacol Ther 2007;26:1333–1344.
Reprint requests Address requests for reprints to: Ronnie Fass, M.D., FACG, Case Western Reserve University, MetroHealth Medical Center, 2500 MetroHealth Drive, Cleveland, OH 44109. e-mail: [email protected]; fax: (216) 778-2074. Conflicts of interest This author discloses the following: Ronnie Fass serves as an adviser for Ironwood Pharmaceuticals, Mederi Therapeutics and Ethicon Pharmaceuticals. He is a speaker for AstraZeneca, Takeda Pharmaceuticals, and Mederi Therapeutics. He performs research for Ironwood Pharmaceuticals. The remaining authors disclose no conflicts.
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Supplementary Material Methods supplement: The study was approved by the Institutional Review Board. Other inclusion criteria were those patients who were able to read and understand English and complete study questionnaires, understand the study procedures, sign written informed consent, and comply with all study requirements. Patients on prokinetic agents, narcotics, baclofen or neuromodulators were also excluded. In addition, patients with prior biliary, gastric, or
esophageal surgery were excluded. In patients with suspected Barrett’s esophagus, four-quadrant biopsies were obtained every 2 cm. Results supplement: At least three episodes were recorded by each patient in this group. Reference supplement: Ostovaneh MR, Saeidi B, Hajifathalian K, et al. Comparing omeprazole with fluoxetine for treatment of patients with heartburn and normal endoscopy who failed once daily proton pump inhibitors: double-blind placebo-controlled trial. Neurogastroenterol Motil. 2014;26:670–678.
Supplementary Table 1. Comparison of 36-Item Short Form Survey Between PPI Failure and PPI Success Patients PPI failure SF-36 Physical Functioning Role Limit Physical Health Role Limit Emotional Health Energy/Fatigue Emotional Well Being Social Functioning Pain General Health
PPI success
P-value
678.1 284 669.2 254.6 178.1 177.9 280.8 175.0
.77 .07
206.3 134.0 230.6 111.0
.84
215 375 140.6 116.6 270.3
73.2 110.6 47.3 63.2 117.0
253.5 359.6 172.9 132.9 325
55.3 107.5 23.7 53.1 125.1
8.e1
.18 .68 .08 .52 .14
PPI, proton pump inhibitor; SF-36, Short Form 36.
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992 993 994 995 996 997 998 999 1000 1001 1002 1003 1004 1005 1006 1007 1008 1009 1010 1011 1012 1013 1014 1015 1016 1017 1018 1019 1020 1021 1022 1023 1024 1025 1026 1027 1028 1029 1030 1031 1032 1033 1034 1035 1036 1037 1038 1039 1040 1041 1042 1043 1044 1045 1046 1047 1048 1049 1050 1051 1052 1053 1054
1 2 3 4 5 6 7 8 9 10Q1 11 12Q7 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58
Most Patients With Gastroesophageal Reflux Disease Who Failed Proton Pump Inhibitor Therapy Also Have Functional Esophageal Disorders Jason Abdallah,* Nina George,* Takahisa Yamasaki,* Stephen Ganocy,‡ and Ronnie Fass§ *Esophageal and Swallowing Center, Division of Gastroenterology and Hepatology, MetroHealth Medical Center, Case Western Reserve University School of Medicine, Cleveland, Ohio; ‡Department of Epidemiology and Biostatistics, Case Western Reserve University School of Medicine, Cleveland, Ohio; §Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio BACKGROUND & AIMS:
As many as 45% of patients with gastroesophageal reflux disease (GERD) still have symptoms after receiving once-daily proton pump inhibitor (PPI) therapy. We aimed to compare reflux characteristics and patterns between responders and non-responders to once-daily PPI therapy using combined impedance-pH monitoring.
METHODS:
Patients who reported heartburn and/or regurgitation at least twice per week for 3 months while receiving standard-dose PPI therapy were assigned to the PPI failure group (n [ 16). Patients who reported a complete resolution of symptoms on once-daily PPIs for at least 4 weeks were assigned to the PPI success group (n [ 13). We collected demographic data and subjects completed the short-form 36 and the GERD health-related quality of life questionnaires. Patients then underwent upper endoscopy and combined esophageal impedance-pH monitoring while on PPI therapy.
RESULTS:
Four patients in the PPI success group (31%) and 4 patients in the PPI failure group (25%) had abnormal results from the pH test (P [ 1.00). Most of the patients in the PPI failure group (75%) were found to have either functional heartburn or reflux hypersensitivity with GERD. Impedance and pH parameters did not differ significantly between the PPI failure and success group.
CONCLUSIONS:
We found no difference in reflux characteristics between patients with GERD who had successful vs failed once-daily PPI therapy. Most patients in the PPI failure group (75%) had functional esophageal disorders.
Keywords: Heartburn; Proton Pump Inhibitor; Esophagus; Impedance Test; Regurgitation; Gastroesophageal Reflux.
astroesophageal reflux disease (GERD) is a condition in which the reflux of stomach content into the esophagus causes troublesome reflux-associated symptoms.1 GERD is a chronic disorder and is highly prevalent, affecting up to 44% of the U.S. adult population at least once a month and 20% once a week.2,3 GERD is the fourth most prevalent gastrointestinal disease in the United States, with an estimated 19 million cases per year.4 The disease significantly impacts patients’ quality of life and incurs the highest cost of the alimentary tract disorders, posing a large economic burden.5,6 Proton pump inhibitors (PPIs) have revolutionized the management of patients with GERD due to their profound and prolonged acid suppression and consequently have become the mainstay of therapy.7 When compared with other acid suppressive medications, PPIs demonstrate superior mucosal healing and symptom control as well as preventing both mucosal and symptom
G
relapse.8,9 In addition, PPIs are generally safe and well tolerated. Despite the success achieved with PPI therapy in the treatment of GERD patients, there remains a substantial cohort of GERD patients who demonstrate therapeutic failure. It is estimated that between 10% and 45% of patients with GERD remain symptomatic on standard-dose PPI once daily.10 Several mechanisms have been proposed to account for persistent symptoms in GERD patients who failed PPI therapy. These primarily Abbreviations used in this paper: DGER, duodenogastroesophageal reflux; GERD, gastroesophageal reflux disease; GERD-HQRL, Gastroesophageal Reflux Disease-Health Related Quality of Life; LES, lower esophageal sphincter; MNBI, mean nocturnal baseline impedance; PPI, proton pump inhibitor; SAP, symptom association probability; SF-36, 36-Item Short Form Survey; SI, symptom index. © 2018 by the AGA Institute 1542-3565/$36.00 https://doi.org/10.1016/j.cgh.2018.06.018
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include poor medication compliance and adherence, differences in PPI metabolism, residual reflux (nonacidic, bile, or acidic), concomitant functional bowel disorders, psychological comorbidity, and delayed gastric emptying.11,12 Gasiorowska et al13 showed that the degree of duodenogastroesophageal reflux (DGER) and acid did not differ significantly between responders and nonresponders to once-daily PPI, using combined pH and Bilitec tests. As a result, the authors suggested that the increase in DGER in patients taking PPI is not unique to those who failed PPI therapy and that esophageal hypersensitivity is likely contributing to symptoms in this population. None of the studies thus far that physiologically evaluated the underlying mechanisms of refractory heartburn compared impedance-pH test results between patients who failed to respond to PPI once daily with those who were successfully treated with a once-daily PPI. The aim of this study was to compare impedance-pH results in PPI responders versus failure patients to further assess the hypothesis that overlap with functional esophageal disorders and thus esophageal hypersensitivity are the basis for symptom generation in PPI failure patients.
Methods
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What You Need to Know Background Proton pump inhibitors (PPIs) are the mainstay of therapy in patients with gastroesophageal reflux disease (GERD). However, up to 45% of patients with GERD remain symptomatic on standard-dose PPI once daily. The current study compared patients who failed to respond to PPI once daily versus those who were successfully treated with a once-daily PPI, using impedance pH testing. Findings Gastroesophageal reflux characteristics were similar between patients who responded to and those who failed PPI once daily. The vast majority of GERD patients who failed PPI once a day demonstrated an overlap with functional heartburn or reflux hypersensitivity. Implications for patient care The findings support that patients with GERD who do not respond to PPI once daily may already benefit from adding a neuromodulator and possibly psychological intervention.
Study Design
Patients We conducted a prospective-based cohort study of 29 adult patients with documented baseline GERD who were on standard-dose PPI (omeprazole 20 mg daily, esomeprazole 40 mg daily, pantoprazole 40 mg daily) for at least 3 months in our Esophageal and Swallowing Center. Patients were enrolled from October 2014 to April 2017. The PPI success group included patients with a history of heartburn or regurgitation who reported a complete resolution of symptoms on once-daily PPI for at least 4 weeks. Before PPI treatment, the patients reported at least 3 episodes of GERD-related symptoms per week. The PPI failure group included patients who continued to demonstrate GERD-related symptoms on PPI once daily, at least twice per week for the last 3 months. All patients had documented baseline GERD (previous evidence of increased esophageal acid exposure using ambulatory reflux testing or erosive esophagitis, pathology-proven short-segment Barrett’s esophagus, and peptic stricture on endoscopy). We excluded patients with significant underlying comorbidities (severe heart failure, severe chronic obstructive pulmonary disease, liver cirrhosis, severe kidney failure, active malignancy, neurologic and psychiatric disorders), atypical or extraesophageal manifestations of GERD, diabetes mellitus, scleroderma, gastroparesis, active peptic ulcer disease, or known history of long-segment Barrett’s esophagus (>3 cm) on prior upper endoscopy.
This was a prospective study in which patients were enrolled and asked to provide written informed consent. Demographic data such as sex, race, age, alcohol, smoking habits, body mass index, and education level were obtained. Patients filled out the 36-Item Short Form Survey (SF-36) and the GERD-Health Related Quality of Life (GERD-HRQL) symptom severity scale. They then underwent upper endoscopy to assess for esophageal mucosal injury, as well as combined 24-hour esophageal impedance and pH monitoring while on their current PPI therapy within 2–4 weeks of enrollment.
Upper Endoscopy Esophagogastroduodenoscopy was performed using an Olympus 190 series upper endoscope (Olympus) on Q4 all enrolled subjects after an overnight fast to assess for mucosal abnormalities of the esophagus, stomach, and duodenum. The extent of esophageal mucosal inflammation was classified according to the Los Angeles Classification System.14
Ambulatory 24-Hour Esophageal Combined Impedance and pH Monitoring After an overnight fast an esophageal manometry was performed using a solid-state high-resolution catheter to identify the lower esophageal sphincter (LES). The catheter was inserted via the nostril into the stomach.
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Thereafter, the proximal margin of the LES was recorded. Subsequently the pH and Impedance catheter (Laborie Medical Technologies, Mississauga, Ontario, Canada) was placed 5 cm above the proximal margin of the LES and connected to a digital portable recorder. Reflux was defined as a pH <4 and reflux time as the interval until pH was >4 again. The test was considered positive when the percent total time the pH <4 was >4.2%. Abnormal esophageal acid exposure in the upright and supine positions was defined as a pH <4 for more than 6% and 1% of the time, respectively. In addition to acidic reflux, nonacidic reflux events that included weakly acidic (pH 4–7) and weakly alkaline (pH >7) reflux were recorded and the characteristics of the reflux, liquid, or mixed (liquid and air) were documented. The mean nocturnal baseline impedance (MNBI) was assessed using the most distal impedance channel and was then calculated using the mean of three 10-minute nighttime periods (around 1:00 a.m., 2:00 a.m., and 3:00 a.m.) for each patient. To assess the temporal relationship between reflux and symptoms, the patient’s symptom association probability (SAP) and symptom index (SI) scores were calculated. SAP is calculated using statistical analysis (cross tabulation) of a contingency table consisting of 4 possible combinations of reflux and symptoms and identifies the probability that gastroesophageal reflux episodes and symptoms are associated.15 SI is calculated as the percentage of heartburn symptoms that occurred within 2 minutes of an acid reflux event (pH <4). SI % ¼
No: of heartburn episodes at pH <4 x 100 Total no: of heartburn episodes
Significant symptom-reflux association occurred when the SAP was >95% or SI was 50%.15 Analysis of the recorded data was carried out using standard computer software.
Questionnaires Demographic questionnaire. Demographic data such as sex, race, age, and education level were obtained from all patients. Information about current alcohol and smoking habits was collected as well. Body mass index was calculated using the patient’s weight and height. 36-Item Short Form Survey. The SF-36 is a validated set of generic, coherent, and easily administered qualityof-life measures that has been shown to be useful in evaluating the clinical curative effect of GERD.16,17 This health survey contains 36 items and includes a multiitem scale that assesses 8 health domains: physical functioning, role limitations due to physical and emotional health, bodily pain, general health, vitality, social functioning, and mental health. The SF-36 scores range from 0 to 100, with higher scores indicating better functioning and well-being. GERD-HRQL Scale. The GERD-HRQL scale is a reliable, valid, responsive, and practical measure of symptom
3
291 292 293 294 295 296 297 298 Statistical Analysis 299 300 Categorical data were described with number and 301 percentage, while continuous data were described using 302 mean SD and median. A chi-square test was used to 303 compare the proportion between the PPI responsive 304 groups except in instances where small numbers necessi305 tated using the Fisher’s exact test. Where data was nor306 mally distributed, groups were compared using Student’s 307 t test. With non-normally distributed data, groups were 308 compared via the nonparametric Kruskal-Wallis test. The 309 P values were adjusted using false discovery rate correc310 tion due to multiple comparisons. SAS version 9.4 (SAS 311 Institute, Cary, NC) was used for all statistical data analysis. 312 313 Results 314 315 Patient Characteristics 316 317 There were 29 patients who were enrolled and 318 completed the study. The demographic data are presented 319 in Table 1. Thirteen patients (mean age 54.5 14.5 years; 320 321 Q5 Table 1. Demographics of Study Patients 322 323 PPI Failure PPI Success 324 (n ¼ 16) (n ¼ 13) P Value 325 Age, y 46.6 13.1 54.5 14.5 .13 326 (25–69) (29–72) 327 Sex .71 328 Female 11 (68.8) 8 (61.5) 329 Male 5 (31.2) 5 (38.5) Race .36 330 White 5 (31.2) 7 (53.8) 331 Black 5 (31.2) 5 (38.5) 332 Hispanic 3 (18.8) 1 (7.7) 333 Asian 3 (18.8) 0 (0.0) 334 Education .77 High school 8 (50.0) 7 (53.8) 335 College 5 (31.2) 5 (38.5) 336 Graduate 3 (18.8) 1 (7.7) 337 Current smoker .61 338 Yes 3 (18.8) 1 (7.7) No 13 (81.2) 12 (92.3) 339 Current alcohol user .70 340 Yes 5 (31.2) 3 (23.1) 341 No 11 (68.8) 10 (76.9) 342 Hiatal hernia .41 343 Yes 3 (18.8) 5 (38.5) 344 No 13 (81.2) 8 (61.5) BMI, kg/m2 30.1 6.7 29.4 4.8 .74 345 346 347 NOTE. Values are mean SD (range) or n (%). 348 BMI, body mass index; PPI, proton pump inhibitor. severity in patients with GERD.18 It was developed to survey symptomatic outcomes and therapeutic effects in patients with GERD. The scale has 10 items that focus on heartburn symptoms, dysphagia, bloating, and medication effects on daily life. Each item is scored from 0 (no symptoms) to 5 (worse symptoms).
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Table 2. Impedance-pH and PPI Characteristics of Study Patients
No.
Sex
PPI Success 1 F 2 M 3 F 4 F 5 F 6 M 7 F 8 M 9 F 10 F 11 F 12 F 13 M PPI failure 1 F 2 M 3 M 4 F 5 F 6 F 7 M 8 F 9 F 10 M 11 F 12 M 13 F 14 F 15 F 16 F
Age (y)
PPI
Dose (mg)
Mean Time Reflux pH <4 (%)
Total Number of Reflux Events
72 43 61 42 57 67 29 47 71 66 58 32 64
Omeprazole Omeprazole Esomeprazole Omeprazole Omeprazole Omeprazole Omeprazole Omeprazole Omeprazole Esomeprazole Omeprazole Omeprazole Pantoprazole
20 20 40 20 20 20 20 20 20 40 20 20 40
0.6 12.4 3.6 2.3 0 17.9 1 19.2 0.3 1.6 1 2 1
10 16 40 51 1 32 1 26 2 14 37 6 7
13 135 79 33 27 122 42 118 61 75 21 44 57
0 4 0 5 1 10 1 8 0 0 0 0 0
6 20 41 15 8 99 17 21 24 6 21 14 19
17 135 78 74 21 65 27 131 39 90 23 36 46
67 46 25 54 59 37 39 47 41 33 69 54 33 31 57 53
Esomeprazole Omeprazole Pantoprazole Omeprazole Esomeprazole Omeprazole Omeprazole Esomeprazole Omeprazole Omeprazole Esomeprazole Omeprazole Omeprazole Omeprazole Pantoprazole Omeprazole
40 20 40 20 40 20 20 40 20 20 40 20 20 20 40 20
0.6 0 3.6 0.1 0 0.1 3.6 4.7 0.6 2 0 0.4 4 0 0.1 1.6
6 0 31 6 2 0 141 10 7 13 0 1 15 1 4 13
61 20 47 21 32 31 203 117 81 32 29 133 39 19 89 31
3 20 0 1 0 1 0 0 0 19 0 0 0 0 0 0
17 5 16 3 4 3 28 25 3 14 4 18 12 3 25 12
53 35 62 21 30 29 316 102 85 50 25 117 42 17 68 32
Acid
Weakly Acid
Weakly Alkaline
Liquid
Mix
F, female; M, male; PPI, proton pump inhibitor.
8 women and 5 men) were asymptomatic on once-daily PPI and were assigned to the PPI success group. Sixteen patients (mean age 46.6 13.1 years; 11 women and 5 men) continued to report heartburn or regurgitation despite once-daily PPI and were assigned to the PPI failure group. The majority of the patients were women (69% failure and 62% success). There were no significant differences in all demographic parameters between the 2 patient groups. There were also no significant differences in PPI dosing or distribution between the 2 patient groups (Table 2).
Questionnaires The comparison between quality-of-life scores between PPI failure and PPI success groups based on the SF-36 is depicted in Supplementary Table 1. Overall, the PPI success group had higher mean scores in all SF-36 domains. However, the scores did not reach statistical significance. Table 3 compares the GERD symptom characteristics between the PPI failure and
success groups based on the GERD-HRQL questionnaire. Heartburn or bloating experienced in the supine position as well as overall degree of heartburn were the most bothersome symptoms for PPI failure patients on a daily basis.
Endoscopy The majority of patients in both groups had normal endoscopy. In the PPI failure and success groups, 81% (13) and 69% (9), respectively, had a normal upper endoscopy. One (3%) patient, who responded to PPI therapy, had erosive esophagitis (Los Angeles grade A). Short-segment Barrett’s esophagus was seen in 2 patients (7%), both of which were in the PPI success group. Nonobstructive Schatzki rings were noted in 3 (23%) of the PPI success and 2 (13%) of the PPI failure patients. One (6%) PPI failure patient had an esophageal stricture. Hiatal hernia was noted in 5 (38%) of the PPI success and 3 (19%) of the PPI failure patients (P ¼ .41).
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Table 3. Comparison of GERD-HRQL Symptom Characteristics Between the PPI Failure and Success Groups
Table 4. Comparison of Reflux Parameters Between PPI Failure and PPI Success Patients PPI Failure
Symptom Heartburn Severity Timing Lying down Standing up After meals Diet change Sleep disturbance Dysphagia Odynophagia Bloating Medication affects
PPI Failure
PPI Success
3.13 1.09
0.54 0.52
3.19 2.63 2.88 2.88 2.88 2.50 1.56 3.00 2.06
0.98 0.89 1.02 1.36 1.26 1.37 1.03 1.32 1.48
5
0.92 0.76 1.38 1.61 1.23 1.69 0.61 2.53 1.31
0.49 0.59 0.96 0.87 0.92 0.63 0.65 0.96 0.48
NOTE. Values are mean SD. GERD-HRQL, Gastroesophageal Reflux Disease-Health Related Quality of Life; PPI, proton pump inhibitor.
Ambulatory 24-Hour Combined Esophageal pH and Impedance Monitoring Abnormal pH test was present in 4 (31%) patients from the PPI success group and 4 (25%) from the PPI failure group (P ¼ 1.00). Figure 1 depicts the percentages of each type of reflux based on impedance pH testing among the PPI failure and PPI success patients. In the PPI failure group, the total number of reflux events was 1279. Of these events, the number of acidic, weakly acidic, and weakly alkaline reflux events was 250 (19.6%), 985 (77.0%), and 44 (3.4%), respectively. The number of reflux events per patient was 80. Of these
Figure 1. Comparison of the different reflux events between the proton pump inhibitor (PPI) failure and PPI success patients.
Time reflux pH <4, % Total Upright Recumbent Number of acid reflux episodes Longest acid reflux episode, min Number of reflux events Total Acid Weakly acid Weakly alkaline Liquid Mix Upright Acid Weakly acid Weakly alkaline Liquid Mix Recumbent Acid Weakly acid Weakly alkaline Liquid Mix MNBI, U
1.34 1.24 1.51 13.0
1.69 1.37 2.92 21.78
6.51 9.69
PPI Success P Value 4.84 2.15 10.3 20.8
6.87 1.76 18.3 19.6
.09 .11 .38 .15
21.4 32.9
.20
15.6 61.6 2.75 12.0 67.8
34.4 51.6 6.59 8.85 72.4
18.7 63.6 2.23 23.9 60.2
16.8 40.2 3.44 24.3 40.0
.09 .57 .22 .05 .90
13.9 52.4 2.56 8.89 61.4
33.0 48.8 6.12 7.46 70.6
14.4 57.2 2.23 18.9 54.8
14.0 39.8 3.44 19.3 38.8
.15 .36 .47 .31 .88
1.69 6.63 0.19 3.38 5.75 3334
2.80 7.05 0.75 3.84 7.03 1133
4.31 5.50 6.38 6.55 0 5.08 5.63 5.38 3.99 2710 1614
.26 .93 .37 .03 .54 .23
MNBI, mean nocturnal baseline impedance; PPI, proton pump inhibitor.
events, the number of acidic, weakly acidic, and weakly alkaline reflux events per patient was 15.7 (19.6%), 61.6 (77.0%), and 2.72 (3.4%), respectively. In the PPI success group, the total number of reflux events was 1099. Of these events, the number of acidic, weakly acidic, and weakly alkaline reflux events was 243 (22.1%), 827 (75.3%), and 29 (2.6%), respectively. The number of reflux events per patient was 84.5. Of these events, the number of acidic, weakly acidic, and weakly alkaline reflux events per patient was 18.7 (22.1%), 63.6 (75.3%), and 2.2 (2.6%), respectively. The comparison among the number of acidic, weakly acidic, and weakly alkaline reflux episodes (total, upright, recumbent) in both groups did not reach statistical significance (P ¼ .1, .6, and .2, respectively). Table 4 summarizes the comparison of acid reflux parameters between PPI failure and PPI success groups. For PPI failure patients, the mean total time pH <4 was 1.34% (range, 0%–3.6%), the mean number of acidic, weakly acidic, and weakly alkaline reflux events was 15.63, 61.56, and 2.75, respectively. For PPI success patients, the mean total time pH <4 was 4.84% (range, 0%–19.2%), the mean number of acidic, weakly acidic, and weakly alkaline reflux events was 18.69, 63.62, and 2.23, respectively. None of the comparisons reached
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Figure 2. Distribution of functional esophageal disorders, using Rome IV criteria, among gastroesophageal reflux disease (GERD) patients who failed proton pump inhibitor once daily.
statistical significance. In addition, the number of acidic, weakly acidic, and weakly alkaline reflux episodes (total, upright, recumbent) in both groups did not reach statistical significance. The mean MNBI was numerically lower in the PPI success group (2710 1614 U) as compared with the PPI failure group (3334 1133 U), but did not reach statistical significance (P ¼ .23).
PPI Failure Groups Figure 2 shows the different disorders of the PPI failure patients based on Rome IV criteria.19 Ten (62.5%) patients were found to have normal acid exposure and negative symptom reflux association (consistent with functional heartburn with GERD overlap), 2 (12.5%) patients had normal acid exposure and positive symptom reflux association (consistent with reflux hypersensitivity with GERD overlap), and 4 (25%) patients had abnormal esophageal acid exposure despite PPI therapy (consistent with persistent GERD).
Symptom Analysis Three hundred and fifteen episodes of either heartburn or regurgitation were recorded by the PPI failure group. Four patients had a positive SAP (>95%). Two patients had positive symptom correlation for acid regurgitation without evidence of acidic or weakly acidic reflux. Two other patients had positive symptom correlation for acid regurgitation with evidence of acidic and weakly acidic reflux. The mean SI and SAP for GERDrelated symptoms were 4.4% and 21.2%, respectively.
Discussion Our study demonstrated that there is no statistically significant difference in the number of reflux events, acid exposure, or nonacidic reflux parameters between GERD patients who failed versus those who were successfully treated with once-daily PPI. In addition, most GERD
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patients who failed PPI once daily appear to have an overlap with a functional esophageal disorder (either reflux hypersensitivity or functional heartburn). Thus, our results support the hypothesis that PPI failure is primarily driven by esophageal hypersensitivity. To our knowledge, this is the first study to compare impedance parameters combined with pH analysis between PPI success versus PPI failure patients. All impedance parameters, including weakly acidic and alkaline reflux, did not differ significantly between the 2 groups. This implies that the shift to nonacidic reflux is a general PPI phenomenon, as opposed to being unique to PPI failure patients. In a similar study, Gasiorowska et al13 used combined ambulatory 24-hour esophageal pH and Bilitec monitoring to demonstrate that the degree of DGER and acid exposure were not significantly different between PPI once daily responders and nonresponders. The authors also proposed based on the results of the study that the degree of DGER seen in PPI failure patients was a general PPI phenomenon and not unique to PPI failure. Furthermore, in patients who failed to respond to PPI once daily, persistent acidic reflux played an important role in symptom generation and most of the GERD-related symptoms were associated with acid reflux events, as compared with DGER. Similarly, our study showed that 25% of patients who failed PPI therapy had persistent abnormal esophageal acid exposure. These findings further support the current practice of optimizing acid suppression throughout the day by doubling or splitting the PPI dose (a.m. and p.m.) in GERD patients who failed to respond to once-daily PPI.7,12,20 It is important to note that while all of the study patients had documented GERD at baseline, the majority (62.5%) of the PPI failure patients were found to have an overlap with functional heartburn. Two patients demonstrated an overlap with reflux hypersensitivity while on PPI therapy. Because there was also no difference in impedance-pH parameters between patients who failed as compared with those who responded to PPI treatment, this further lends evidence that functional esophageal disorders and thus esophageal hypersensitivity drive most of the symptoms reported by GERD patients who failed PPI once daily. In our study, we evaluated patients with GERD symptoms who either responded or failed PPI once daily. To our knowledge, all of the studies that assessed the underlying mechanisms of refractory GERD using esophageal impedance pH included only patients who were taking PPI twice daily.21–23 As the majority of patients who report GERD-related symptoms respond to standard dose PPI once daily,10 the purpose of the study was to compare impedance-pH parameters between patients who failed versus those who responded to PPI once daily. In addition, although it is common practice to double the dose in those GERD patients who do not respond to PPI once daily, this is not an approved indication by the Food and Drug Administration.
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MNBI is a novel parameter used to calculate baseline impedance not affected by swallows and gastroesophageal reflux.24 Recently, it has been demonstrated that MNBI increases the diagnostic yield of impedance pH monitoring. In addition, nocturnal baseline impedance level has been found to be useful in distinguishing between nonerosive reflux disease patients versus those with functional heartburn.24 MNBI is significantly lower in patients with erosive reflux disease or nonerosive reflux disease than in those with functional heartburn. Our results demonstrated that even baseline impedance, as measured by MNBI, were similar between the 2 patient groups, which further supports the underlying role of esophageal hypersensitivity in patients who failed PPI therapy. There were no differences in quality-of-life symptoms between the PPI success and failure groups as measured by the SF-36 (Supplementary Table 1). We found that many patients with GERD symptoms, regardless of response to PPI, have underlying impairments of physical functioning, role limitations, and mental and general health, which are likely caused by underlying psychosocial comorbidity. In addition, the SF-36 is a general HRQL tool and not specific for GERD-related symptoms. Our study is limited by a small cohort size of 29 patients, which may have affected the results of the study. Recruitment into the study was hampered by the invasive nature of some of the procedures. In addition, it is our experience that many patients who have responded to PPI are reluctant to undergo invasive testing as part of a study protocol. Therefore, we believe that these types of prospective, invasive studies are rather difficult to perform but provide essential insight into the understanding of refractory GERD. Although our cohort size was small, our results are supported by another study13 demonstrating no difference in the degree of esophageal reflux exposure between patients who failed to respond and those who achieved symptom resolution while taking once-daily PPI. Furthermore, a study conducted by Rohof et al25 showed that partial responders to PPI are most likely explained by increased proximal reflux in a hypersensitive esophagus, as opposed to number of reflux events, increased mucosal permeability, or the position of the acid pocket. In summary, our study is the first to demonstrate that reflux characteristics, using impedance pH, were not significantly different between patients who responded to those who failed PPI once daily. The high degree of weakly acidic reflux observed in patients who do not respond to PPI treatment appears to be a general PPI phenomenon and it is not unique to PPI failure patients. In the PPI failure group, most of the patients had normal esophageal acid exposure. The vast majority of GERD patients who failed PPI once a day demonstrated an overlap with functional heartburn or reflux hypersensitivity, supporting the important role of esophageal hypersensitivity in this patient population. Thus, patients who do not respond to PPI once daily may benefit from
7
adding a neuromodulator and possibly psychological intervention such as cognitive behavioral therapy, hypnotherapy, relaxation techniques, mindfulness, and biofeedback.26–28
Supplementary Material Note: To access the supplementary material accompanying this article, visit the online version of Clinical Gastroenterology and Hepatology at www.cghjournal.org, and at https://doi.org/10.1016/j.cgh.2018.06.018.
References 1. Vakil N, van Zanten SV, Kahrilas P, et al. The Montreal definition and classification of gastroesophageal reflux disease: a global evidence-based consensus. Am J Gastroenterol 2006; 101:1900–1920. 2. Dent J, El-Serag HB, Wallander MA, et al. Epidemiology of gastro-oesophageal reflux disease: a systematic review. Gut 2005;54:710–717. 3. Locke GR 3rd, Talley NJ, Fett SL, et al. Prevalence and clinical spectrum of gastroesophageal reflux: a population-based study in Olmsted County, Minnesota. Gastroenterology 1997; 112:1448–1456. 4. Sandler RS, Everhart JE, Donowitz M, et al. The burden of selected digestive diseases in the United States. Gastroenterology 2002;122:1500–1511. 5. Francis DO, Rymer JA, Slaughter JC, et al. High economic burden of caring for patients with suspected extraesophageal reflux. Am J Gastroenterol 2013;108:905–911. 6. Bytzer P, van Zanten SV, Mattsson H, et al. Partial symptomresponse to proton pump inhibitors in patients with non-erosive reflux disease or reflux oesophagitis - a post hoc analysis of 5796 patients. Aliment Pharmacol Ther 2012; 36:635–643. 7. Katz PO, Gerson LB, Vela MF. Guidelines for the diagnosis and management of gastroesophageal reflux disease. Am J Gastroenterol 2013;108:308–328. 8. Chiba N, De Gara CJ, Wilkinson JM, et al. Speed of healing and symptom relief in grade II to IV gastroesophageal reflux disease: a meta-analysis. Gastroenterology 1997;112:1798–1810. 9. Sifrim D, Castell D, Dent J, et al. Gastro-oesophageal reflux monitoring: review and consensus report on detection and definitions of acid, non-acid, and gas reflux. Gut 2004; 53:1024–1031. 10. El-Serag H, Becher A, Jones R. Systematic review: persistent reflux symptoms on proton pump inhibitor therapy in primary care and community studies. Aliment Pharmacol Ther 2010; 32:720–737. 11. Dickman R, Boaz M, Aizic S, et al. Comparison of clinical characteristics of patients with gastroesophageal reflux disease who failed proton pump inhibitor therapy versus those who fully responded. J Neurogastroenterol Motil 2011;17:387–394. 12. Hussain ZH, Henderson EE, Maradey-Romerao C, et al. The proton pump inhibitor non-responder: a clinical conundrum. Clin Transl Gastroenterol 2015;6:e115. 13. Gasiorowska A, Navarro-Rodriguez T, Wendel C, et al. Comparison of the degree of duodenogastroesophageal reflux and acid reflux between patients who failed to respond and those who were successfully treated with a proton pump inhibitor once daily. Am J Gastroenterol 2009;104:2005–2013.
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14. Armstrong D, Bennett JR, Blum AL, et al. The endoscopic assessment of esophagitis: a progress report on observer agreement. Gastroenterology 1996;111:85–92. 15. Weusten BL, Rolfs JMM, Akkermans LMA, et al. The symptom association probability: An improved method for symptom analysis of 24-hour esophageal pH data. Gastroenterology 1994;107:1741–1745. 16. Brazier JE, Harper R, Jones NM, et al. Validating the SF-36 health survey questionnaire: new outcome measure for primary care. BMJ 1992;305:160–164. 17. Jenkinson C, Coulter A, Wright L. Short form 36 (SF36) health survey questionnaire: normative data for adults of working age. BMJ 1993;306:1437–1440. 18. Velanovich V, Vallance SR, Gusz JR, et al. Quality of life scale for gastroesophageal reflux disease. J Am Coll Surg 1996; 183:217–224. 19. Aziz Q, Fass R, Gyawali CP, et al. Functional esophageal disorders. Gastroenterology 2016;150:1368–1379. 20. Fass R, Sontag SJ, Traxler B, et al. Treatment of patients with persistent heartburn symptoms: a double-blind, randomized trial. Clin Gastroenterol Hepatol 2006;4:50–56. 21. Zerbib F, Roman S, Ropert A, et al. Esophageal pH-impedance monitoring and symptom analysis in GERD: a study in patients off and on therapy. Am J Gastroenterol 2006;101:1956–1963. 22. Tutuian R, Vela MF, Hill EG, et al. Characteristics of symptomatic reflux episodes on Acid suppressive therapy. Am J Gastroenterol 2008;103:1090–1096. 23. Hemmink GJ, Bredenoord AJ, Weusten BL, et al. Esophageal pH-impedance monitoring in patients with therapy-resistant reflux symptoms: ’on’ or ’off’ proton pump inhibitor? Am J Gastroenterol 2008;103:2446–2453.
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24. Kandulski A, Weigt J, Caro C, et al. Esophageal intraluminal baseline impedance differentiates gastroesophageal reflux disease from functional heartburn. Clin Gastroenterol Hepatol 2015;13:1075–1081. 25. Rohof WO, Bennink RJ, de Jonge H, et al. Increased proximal reflux in a hypersensitive esophagus might explain symptoms resistant to proton pump inhibitors in patients with gastroesophageal reflux disease. Clin Gastroenterol Hepatol 2014; 12:1647–1655. 26. Limsrivilai J, Charatcharoenwitthaya P, Pausawasdi N, et al. Imipramine for treatment of esophageal hypersensitivity and functional heartburn: a randomized placebo-controlled trial. Am J Gastroenterol 2016;111:217–224. 27. van Peski-Oosterbaan AS, Spinhoven P, van Rood Y, van der Does JW, Bruschke AV, Rooijmans HG. Cognitive-behavioral therapy for noncardiac chest pain: a randomized trial. Am J Med 1999;106:424–429. 28. Dickman R, Schiff E, Holland A, et al. Clinical trial: acupuncture vs. doubling the proton pump inhibitor dose in refractory heartburn. Aliment Pharmacol Ther 2007;26:1333–1344.
Reprint requests Address requests for reprints to: Ronnie Fass, M.D., FACG, Case Western Reserve University, MetroHealth Medical Center, 2500 MetroHealth Drive, Cleveland, OH 44109. e-mail: [email protected]; fax: (216) 778-2074. Conflicts of interest This author discloses the following: Ronnie Fass serves as an adviser for Ironwood Pharmaceuticals, Mederi Therapeutics and Ethicon Pharmaceuticals. He is a speaker for AstraZeneca, Takeda Pharmaceuticals, and Mederi Therapeutics. He performs research for Ironwood Pharmaceuticals. The remaining authors disclose no conflicts.
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Supplementary Material Methods supplement: The study was approved by the Institutional Review Board. Other inclusion criteria were those patients who were able to read and understand English and complete study questionnaires, understand the study procedures, sign written informed consent, and comply with all study requirements. Patients on prokinetic agents, narcotics, baclofen or neuromodulators were also excluded. In addition, patients with prior biliary, gastric, or
esophageal surgery were excluded. In patients with suspected Barrett’s esophagus, four-quadrant biopsies were obtained every 2 cm. Results supplement: At least three episodes were recorded by each patient in this group. Reference supplement: Ostovaneh MR, Saeidi B, Hajifathalian K, et al. Comparing omeprazole with fluoxetine for treatment of patients with heartburn and normal endoscopy who failed once daily proton pump inhibitors: double-blind placebo-controlled trial. Neurogastroenterol Motil. 2014;26:670–678.
Supplementary Table 1. Comparison of 36-Item Short Form Survey Between PPI Failure and PPI Success Patients PPI failure SF-36 Physical Functioning Role Limit Physical Health Role Limit Emotional Health Energy/Fatigue Emotional Well Being Social Functioning Pain General Health
PPI success
P-value
678.1 284 669.2 254.6 178.1 177.9 280.8 175.0
.77 .07
206.3 134.0 230.6 111.0
.84
215 375 140.6 116.6 270.3
73.2 110.6 47.3 63.2 117.0
253.5 359.6 172.9 132.9 325
55.3 107.5 23.7 53.1 125.1
8.e1
.18 .68 .08 .52 .14
PPI, proton pump inhibitor; SF-36, Short Form 36.
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992 993 994 995 996 997 998 999 1000 1001 1002 1003 1004 1005 1006 1007 1008 1009 1010 1011 1012 1013 1014 1015 1016 1017 1018 1019 1020 1021 1022 1023 1024 1025 1026 1027 1028 1029 1030 1031 1032 1033 1034 1035 1036 1037 1038 1039 1040 1041 1042 1043 1044 1045 1046 1047 1048 1049 1050 1051 1052 1053 1054