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Clinical Reviews

The Discrepancy Between Subjective and Objective Clinical Endpoints in Gastroesophageal Reflux Disease

Shibli, Fahmi MD; Sandhu, Dalbir S. MD; Fass, Ronnie MD, MACG

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Journal of Clinical Gastroenterology: May/June 2022 - Volume 56 - Issue 5 - p 375-383
doi: 10.1097/MCG.0000000000001687
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Abstract

Gastroesophageal reflux disease (GERD) is one of the most common disorders seen by primary care physicians and gastroenterologists, with a reported prevalence of up to 28% in individual cross-sectional surveys.1–4 Histamine-2 receptor antagonists used to be the mainstay of medical treatment for GERD until the late 1980s when proton pump inhibitors (PPIs) were approved by the Food and Drug Administration (FDA) and since then have been the principal medical therapy for the management of GERD in clinical practice.5 Other antireflux medications include Gaviscon, sucralfate, baclofen, and various prokinetics, which are used in varying degrees depending on the clinical scenario. Apart from medical therapy, surgical therapy in the form of Nissen fundoplication and its modifications and the recently introduced magnetic sphincter augmentation (LINX) procedure have added to the repertoire of GERD therapeutic modalities. In recent years, there has been a surge of various endoscopic therapies for GERD, including transoral incisionless fundoplication (TIF), Medigus ultrasonic surgical endostapler (MUSE), and the updated version of the Stretta procedure.6

Despite the multiple management options for GERD, around 40% of the patients remain symptomatic on once daily PPI, prompting an increase in dosing of the PPI, the addition of another antireflux medication, or the switching to an endoscopic or surgical intervention.7,8

Approximately 80% to 85% of erosive esophagitis (EE) patients and 50% to 60% of nonerosive reflux disease patients become asymptomatic on once-daily PPI.9–11 However, it is assumed by many that symptom resolution in GERD patients require normalization of esophageal acid exposure and complete healing of EE. As such, therapeutic trials in EE patients have focused on the complete healing of EE as a desired clinical endpoint. Similarly, therapeutic trials in NERD patients expected normalization of esophageal acid exposure for symptom resolution to occur.

In this review, we attempted to determine if the resolution of objective clinical endpoints, such as esophageal acid exposure and mucosal inflammation, is required for the resolution of subjective clinical endpoints in patients with GERD and if there is a discrepancy between the 2.

DOES SYMPTOMATIC RESPONSE TO PPI REQUIRE COMPLETE HEALING OF EE?

PPIs are the most potent antireflux medications currently available in the US market. However, studies have demonstrated a discrepancy between healing of EE and symptom resolution in patients treated with PPIs. Castell et al12 showed that the healing rates of esophageal inflammation at four weeks were 79% and 75% for esomeprazole 40 mg and lansoprazole 30 mg once daily, respectively, compared with complete symptom resolution, which was much lower at 63% and 60%, respectively. In a randomized controlled trial, 61 patients with refractory EE were assigned to receive either omeprazole 20 mg once daily or ranitidine 150 mg twice daily.13 The study showed healing rate of 50% and 79.3% at 4 and 8 weeks, respectively, whereas, symptom resolution was reported in 60% and 64%, of the patients, respectively. Similarly, Robinson et al14 compared the efficacy of omeprazole 20 mg once daily with 150 mg ranitidine twice daily for the treatment of EE. The authors demonstrated EE healing rate of 68% and 82% at 4 and 8 weeks, respectively, while complete symptom relief was noted only in 60% and 73% of the patients, respectively. Vantrappen et at15 compared higher doses of omeprazole (40 mg) with 150 mg ranitidine twice daily in 51 patients with EE at 4 and 8 weeks. The authors showed similar healing and symptom resolution rates in the omeprazole group at 4 weeks (85%), whereas, the healing rate was higher at 8 weeks as compared with the symptom resolution rate (88% and 85%, respectively). Another study, by the same author, compared lansoprazole 30 mg once daily with ranitidine 150 mg twice daily for the treatment of EE.16 The healing rate achieved at 8 weeks was higher than the symptom resolution rate at 12 weeks (96% vs. 61%, respectively). The authors also demonstrated similar discrepancy between healing rate and symptom resolution rate even when a higher dose of PPI was used (lansoprazole 60 mg), 89% and 85%, respectively.17 Moreover, Corinaldesi et al18 compared the efficacy of pantoprazole 40 mg with omeprazole 20 mg once daily in 208 patients with EE. The authors demonstrated a higher healing rate in the pantoprazole group compared with the omeprazole group at 8 weeks (94.2% vs. 91.4%, respectively). Symptom resolution rate was similar in both groups at 4 and 8 weeks (76.7% and 87.8% vs. 76.2% and 82.1%, respectively), but was lower than the healing rate (78% and 94.1% vs. 79% and 91.4%, respectively). In a similar randomized, double-blind, active-controlled trial, pantoprazole 40 mg once daily was compared with omeprazole 20 mg once daily for the treatment of EE.19 The study showed similar efficacy of both drugs in healing EE at 4 and 8 weeks (74% and 76% vs. 90% and 94%, respectively). However, symptom resolution rate was lower in the pantoprazole group at 4 and 8 weeks (67% and 85%, respectively). In a double-blind, randomized controlled trial, patients with EE were allocated to receive either pantoprazole 40 mg or nizatidine 300 mg once daily. The authors demonstrated that despite a 79% healing rate after 4 weeks of pantoprazole treatment, complete symptom relief was reported by only 63% of the patients.20 Furthermore, in a randomized placebo-controlled trial, 603 patients with mild to severe EE (Hetzel-Dent grades 2 to 4), were randomized to different doses of pantoprazole (10 mg, 20 mg, or 40 mg) or placebo.21 The healing rates for pantoprazole, with any of the studied doses, were significantly higher than placebo (59%, 78%, 88%, and 33%, respectively) after 8 weeks of treatment regardless of disease severity. However, complete symptom relief at 8 weeks was noted by 87% of those who received pantoprazole 40 mg. Interestingly, about half of those with nonhealed EE had no heartburn at the time of endoscopy on week 4 and 8.

A meta-analysis that was performed by Chiba et al22 showed that the overall pooled healing rate of PPI from 4 to 12 weeks was higher than the overall symptom resolution rate (83.6%±11.4% vs. 77.4%±10.4%, respectively). This study demonstrated that patients with EE who continued to experience GERD symptoms may or may not have healed EE.

The aforementioned studies demonstrated a symptom resolution rate that was lower than the healing rate of patients with EE treated with a PPI or histamine-2 receptor antagonists. However, there are also a series of studies demonstrating the opposite, a healing rate that was lower than the symptom resolution rate, suggesting that patients may respond symptomatically to antireflux treatment despite persistent EE. A double-blind, randomized controlled trial that included 144 patients with EE, compared omeprazole 20 mg once daily with ranitidine 150 mg twice daily at 4 and 8 weeks.23 The study showed a lower healing rate as compared with the symptom resolution rate at 4 and 8 weeks (67% and 85% vs. 72% and 86%, respectively). Furthermore, Sontag et al24 also demonstrated that the healing rate was significantly lower than symptom resolution rate in EE patients when they were evaluated at 4 and 8 weeks (39% and 73% vs. 63% and 80%, respectively) while receiving omeprazole 20 mg daily. Similarly, Bate et al25 reported lower healing rate as compared with the symptom resolution rate at 4 and 8 weeks of 20 mg omeprazole daily (52.9% and 70% vs. 72.6% and 78.2%, respectively). Another randomized, double blind, active control trial compared pantoprazole 40 mg once daily with ranitidine 150 mg twice daily in 249 patients with EE.26 Complete healing was achieved in 69% and 82% of the patients after 4 and 8 weeks, respectively, while symptom resolution was achieved in 77% and 88%, respectively. Further studies that investigated higher doses of omeprazole (40 mg once daily) have shown similar trend of discrepancy where symptom resolution rate was higher than the healing rate.24,27,28

In a post hoc analysis of 5 randomized, controlled trials that enrolled 11,945 patients, there was a poor correlation between the severity of heartburn and grading of esophageal inflammation.29 Among those with severe EE, 22% reported no or mild heartburn, and only 31% with severe heartburn also had severe EE [odds ratio (OR): 1.2; 95% confidence interval (CI): 0.8-1.7].

Thus, the aforementioned studies demonstrated that complete resolution of symptoms may not necessarily depend on complete endoscopic healing of EE. In addition, complete healing of EE may not necessarily be associated with complete resolution of symptoms. While it appears that in most EE patients, esophageal healing and symptom resolution are not mutually exclusive, in a significant number of patients symptoms resolution does not denote complete healing of EE. However, it is possible that some of the patients who demonstrated complete resolution of symptoms may show some level of improvement in their underlying EE.30Tables 1 and 2 summarize the studies that compared EE healing rates with symptom resolution rates.

TABLE 1 - Studies Demonstrating a Higher Symptom Resolution Rate as Compared With Erosive Esophagitis Healing Rate
Healing (%) Complete Symptom Relief (%) Discrepancy Rate (%)
References PPI Dose (mg) 4 Wk 8 Wk 4 Wk 8 Wk 4 Wk 8 Wk
Hetzel et al31 Ome 20 70 79 76 6
Sandmark et al23 Ome 20 67 85 72 86 5 1
Bianchi Porro et al13 Ome 20 50 79 60 64 10 15
Sontag et al24 Ome 20 39 73 63 80 24 7
Mössner et al19 Ome 20 78 94 94 16
Bate et al25 Ome 20 53 70 73 78 20 8
Corinaldesi et al18 Ome 2 79 91 82 3
Lundell et al27 Ome 40 63 86 86 90 23 4
Sontag et al24 Ome 40 45 74 71 82 26 8
Dehn et al28 Ome 40 57 71 93 92 36 21
Klinkenberg-Knol et al32 Ome 60 79 92 92 13
Koop et al26 Panto 40 69 82 77 88 8 6
Ome indicates omeprazole; Panto, pantoprazole; QD, “quaque die” (once a day).

TABLE 2 - Studies Demonstrating a Higher Erosive Esophagitis Healing Rate as Compared With Symptoms Resolution Rate
Healing (%) Complete Symptom Relief (%) Discrepancy Rate (%)
References PPI Dose (mg) 4 Wk 8 Wk 4 Wk 8 Wk 4 Wk 8 Wk
Robinson et al14 Ome 20 68 82 60 73 8 9
Hetzel et al31 Ome 40 82 85 80 2
Vantrappen et al15 Ome 40 85 96 85 88 0 8
Robinson et al16 Lanso 30 87 96 61* 35
Robinson et al16 Lanso 60 74 89 85* 4
Corinaldesi et al18 Panto 40 79 94 73 90 5 4
Mössner et al19 Panto 40 74 90 67 85 7 5
Castell et al12 Esome 40 79 63 16
Castell et al12 Lanso 30 75 61 14
Armstrong et al20 Panto 40 79 63 16
Richter et al21 Panto 40 72 88 69 87 3 1
*Twelve weeks.
Esome indicates esomeprazole; Lanso, lansoprazole; Ome, omeprazole; Panto, pantoprazole; QD, “quaque die” (once a day).

DOES SYMPTOMATIC RESPONSE TO PPI TREATMENT REQUIRE NORMALIZATION OF ESOPHAGEAL ACID EXPOSURE?

The goals of GERD treatment include symptoms improvement, EE healing, prevention of relapse of symptoms and EE, and prevention of complications. However, studies have consistently demonstrated that patients consider symptom improvement as the most important clinical outcome of GERD treatment.33–36 The treatment of GERD is predicated on the assumption that symptom improvement in a patient is associated with normalization of esophageal acid exposure or reflux burden. Thus far, very few studies have assessed the relationship between symptom resolution and normalization of esophageal acid exposure in GERD patients.

In a prospective study, 50 GERD patients who received once or twice daily PPI until complete symptom resolution was achieved underwent ambulatory 24-hour esophageal pH monitoring. The study demonstrated that despite complete resolution of symptoms, half of the patients still had abnormal esophageal acid exposure on treatment (mean DeMeester score 48.2).37 Several other studies have reported similar findings. Grigolon et al38 performed 27 ambulatory 24-hour esophageal pH monitoring tests in patients with heartburn on PPI once or twice daily. The authors demonstrated that esophageal acid exposure was abnormal in one-third of the asymptomatic patients while taking PPI. In a larger prospective study, 80 consecutive patients with heartburn and regurgitation were evaluated by a standardized symptom questionnaire and 24-hour esophageal pH monitoring, at baseline and after 4 weeks of receiving esomeprazole 40 mg once daily.39 The authors showed that 73% of all patients were asymptomatic after 4 weeks of treatment. However, 10% of those who were asymptomatic still demonstrated abnormal esophageal acid exposure. Another prospective study included 76 patients with typical GERD symptoms and abnormal 24-hour esophageal pH monitoring. The study aimed to assess the efficacy of standard dose (40 mg once daily) and double dose (40 mg twice daily) esomeprazole in patients with hiatal hernia.40 The authors demonstrated that 53.2% (7/13) of those with hiatal hernia and 90.5% (57/63) of those without hiatal hernia, normalized their esophageal acid exposure test on standard dose, while 100% of those who received double dose esomeprazole normalized their esophageal acid exposure test. Importantly, standard dose of esomeprazole resulted in symptom control in 76.3% of the 76 subjects studied. Similar study evaluated esomeprazole 40 mg, 80 mg, and esomeprazole 80 mg plus baclofen 15 mg for the treatment of GERD patients who were refractory to 40 mg esomeprazole. Of the screened patients, 67.4% had normal 24-hour esophageal pH monitoring test. After 4 weeks of treatment with high-dose esomeprazole (80 mg) 71.1% of the patients had normal 24-hour esophageal pH monitoring test and of those who received esomeprazole plus baclofen only 28.6% had normal 24-hour esophageal pH monitoring.41 Finally, a retrospective study of 172 asymptomatic GERD patients found that 54% had persistent acid reflux despite using once-daily (44%) or twice-daily PPI therapy (56%).42

Several studies assessed Barrett’s esophagus patients and demonstrated that a significant number of them continued to have abnormal esophageal acid exposure on PPI treatment despite lack of symptoms (Table 3). Katzka and colleagues studied 5 patients with Barrett’s esophagus who presented with heartburn. All patients were treated with omeprazole (20 to 60 mg once daily) until complete symptom resolution was achieved. Subsequently, an ambulatory 24-hour esophageal pH monitoring was performed, demonstrating that 80% of the patients continued to have abnormal esophageal acid exposure despite PPI therapy.43 Furthermore, a larger prospective study demonstrated that 12 (40%) Barrett’s esophagus patients who reported symptoms resolution on lansoprazole 15 to 30 mg once daily still had abnormal esophageal acid exposure on ambulatory 24-hour pH monitoring.44 When compared with those who showed normalization of esophageal acid exposure (60%), there were no differences between the groups with respect to length of Barrett’s mucosa, size of hiatal hernia, lower esophageal sphincter resting pressure, or esophageal peristaltic function. In another study, 25 patients with Barrett’s esophagus, who were considered for ablation therapy, were treated with 40 mg omeprazole twice daily. Thereafter, patients were evaluated by 24-hour esophageal pH monitoring at a mean interval of 8.6 days.45 While 80% of the patients were rendered asymptomatic on therapy, 76% demonstrated normalization of esophageal exposure. In another study, 45 patients with Barrett’s esophagus were treated with 20 mg of omeprazole twice daily and then evaluated by esophageal manometry and 24-hour esophageal pH monitoring.46 Of the 40 patients (89%) who became asymptomatic, 10 (22%) demonstrated abnormal esophageal acid exposure. There was no relationship between esophageal manometric abnormalities and persistent esophageal acid exposure. Gerson et al47 conducted a prospective study of GERD patients with (n=48) or without (n=62) Barrett’s esophagus, who were asymptomatic on PPI therapy. The authors demonstrated that 50% of the patients with Barrett’s esophagus had abnormal esophageal acid exposure. In this study, 56% of the Barrett’s esophagus patients required twice-daily PPI treatment to achieve complete symptom resolution.

TABLE 3 - The Degree of Abnormal Esophageal Acid Exposure in Asymptomatic Barrett’s Esophagus Patients on PPI Treatment
References Sample Size Population Studied Mean Age (Y) Men (%) Medication Findings
Katzka et al43 5 Barrett’s 59.4 100 Omeprazole 20-60 mg QD 80% (4/5) had abnormal acid exposure while asymptomatic
Ouatu-Lascar et al44 30 Barrett’s 66 93 Lansoprazole 15-30 mg QD 40% had abnormal acid reflux while asymptomatic
Fass et al45 25 Barrett’s 58 92 Omeprazole 40 mg BID 80% asymptomatic; 24% had persistent acid reflux
Basu et al46 45 Barrett’s 62.5 84 Omeprazole 20 mg BID 89% asymptomatic; 22% had persistent acid exposure
Gerson et al47 110 62 (GERD); 48 (Barrett’s) 58.3 (GERD); 63.6 (Barrett’s) 89 5 Different PPI’s 50% of asymptomatic Barrett’s patients had abnormal acid exposure
BID indicates “bis in die” (2 times a day); GERD, gastroesophageal reflux disease; QD, “quaque die” (once a day).

As mentioned above, studies demonstrated persistent abnormal esophageal acid exposure in GERD patients who were rendered asymptomatic on PPI treatment (Table 4). The consequences of persistent abnormal esophageal acid exposure while on PPI treatment are unclear. In addition, studies did not evaluate the long-term ramifications of having abnormal esophageal acid exposure on PPI treatment despite being asymptomatic. Several studies have attempted to identify predictive factors for abnormal esophageal acid exposure in treated asymptomatic GERD patients. The presence of a hiatal hernia was proposed by Peng and colleagues, but other investigators could not confirm their findings.37,39 Persistent gastric hyperacidity was also proposed but again this was not supported by other investigators.20,42 Reduced lower esophageal sphincter basal pressure and abnormal esophageal peristalsis were also ruled out.37

TABLE 4 - The Degree of Abnormal Esophageal Acid Exposure in Asymptomatic GERD Patients on PPI Treatment
References Sample Size Population Studied Mean Age (Y) Men (%) Medication Findings
Ours et al48 13 GERD 37 NS 4 different regimens involving omeprazole 38% had acid reflux while asymptomatic
Milkes et al37 50 GERD 58 78 5 different PPI’s 50% had abnormal reflux while asymptomatic
Jenkinson et al49 70 GERD, some underwent anti-reflux surgery 47.5 54 2 different PPI’s; varying doses 60% asymptomatic GERD patients had abnormal acid reflux
Grigolon et al38 31 GERD Range: 21-73 y 45 5 Different PPI’s 1/3 of asymptomatic patients had abnormal acid exposure
Peng et al39 80 GERD 47.6 81 Esomeprazole 40 mg QD 73% of the patients were rendered asymptomatic; 10% of these had persistent acid reflux
Lin et al42 172 GERD 56 50 6 different PPI’s; QD or BID 54% and 56% of asymptomatic patients had abnormal acid reflux while on a QD or BID PPI, respectively
BID indicates “bis in die” (2 times a day); GERD, gastroesophageal reflux disease; PPI, proton pump inhibitor; QD, “quaque die” (once a day).

In summary, it appears that a significant percentage of GERD patients who were rendered asymptomatic on PPI therapy continue to have abnormal esophageal acid exposure. The data suggest that normalization of esophageal acid exposure is not a prerequisite for resolution of symptoms. It is likely that persistent abnormal esophageal acid exposure in asymptomatic GERD patient while on PPI treatment has very limited if any clinical ramifications.

DOES SYMPTOMATIC RESPONSE TO ANTIREFLUX SURGERY REQUIRE NORMALIZATION OF ESOPHAGEAL ACID EXPOSURE AND HEALING OF EE?

Antireflux surgery is designed to restore the anatomical barrier of the esophagogastric junction (EGJ) in patients with GERD and thus prevent or reduce gastroesophageal reflux. Overall, very few studies evaluated both subjective and objective clinical endpoints postsurgical intervention.

Jenkinson et al49 evaluated 70 patients for both symptoms response and esophageal acid exposure at baseline, while on PPI therapy, and after antireflux surgery. After antireflux surgery, 27.1% (n=19) of the patients continued to be symptomatic and of those 89.5% had normal esophageal acid exposure. In contrast, 11.7% (6/51) of those who were rendered asymptomatic continued to have abnormal esophageal acid exposure. The authors concluded that symptomatic response of GERD patients to antireflux surgery is a poor indicator for esophageal acid exposure status. Lord et al50 assessed both subjective and objective clinical endpoints in 86 patients with GERD who remained symptomatic after Nissen fundoplication. Of those, 43% were back on antireflux medications. Symptoms were assessed by using structured symptom questionnaire and 24-hour esophageal pH monitoring. Overall, 77% of all symptomatic patients had normal esophageal acid exposure. The study demonstrated that the majority of patients who remained symptomatic post antireflux surgery did not have an abnormal esophageal acid exposure. Furthermore, Hamdy et al51 followed 296 GERD patients post laparoscopic Nissen fundoplication (LNF) (234 PPI responders and 62 nonresponders). At 1-year follow-up, 54% continued to be symptomatic (43% PPI nonresponders and 11% PPI responders) despite normalization of esophageal acid exposure and DeMeester score postsurgery (0.9 and 0.7 in the nonresponder group, and 5.1 and 5 in the responder group, respectively). This study demonstrated that normalization of esophageal acid exposure in patients with GERD, may not necessarily be followed by resolution of symptoms. Tosato et al52 followed 36 refractory GERD patients who underwent LNF for 12 months and reported lack of symptom improvement in 17% of them despite complete EE healing and normalization of DeMeester score.

Broerders et al53 evaluated the efficacy of LNF in 31 refractory GERD patients. Subjective and objective clinical endpoints were evaluated by the GERD-HRQL questionnaire, upper endoscopy and 24-hour esophageal pH monitoring. The authors demonstrated significant decrease in the GERD-HRQL score, and the esophageal acid exposure time as compared with baseline values (18.6 vs. 1.6 and 13.8% vs. 1.1%, respectively). However, 48.3% of the participants reported GERD symptoms that were poorly correlated with reflux events on 24-hour esophageal pH monitoring. Kellokumpu et al54 followed 139 GERD patients for 10 years after LNF. The authors reported symptom resolution in most patients. At the end of the long follow-up period, 24-hour esophageal pH monitoring was performed in 32 patients who reported complete symptom resolution. The authors demonstrated abnormal esophageal acid exposure time in 18.7% (median pH<4 25.1%) of these patients.

In the LOTUS (Long-Term Usage of Esomeprazole Versus Surgery for Treatment of Chronic GERD) trial, 514 patients were randomly assigned to 2 GERD treatment options. Subjective and objective clinical endpoints were compared at 5 years follow up.55 Of those enrolled, 248 underwent standardized laparoscopic antireflux surgery (LARS) and 266 received esomeprazole 20 or 40 mg once daily. At 5 years, regurgitation was significantly higher in the esomeprazole group than in the LARS group (13% vs. 2%, respectively; P<0.00), however, there was no significant difference in heartburn severity between the 2 groups (16% vs. 8%, respectively, P=0.16). The mean percentage time pH < 4 decreased significantly to a normal range, in the LARS group from 8.6% to 0.7% and from 8.8% to 1.9% in the esomeprazole group.

A meta-analysis identified 13 RCT’s that included 1564 GERD patients who underwent either LNF (52.05%) or laparoscopic Toupet fundoplication (LTF) (47.95%).56 Although subjectively, symptom control was similar in both groups, the study showed an overall symptoms recurrence rate of 22.72% post-LNF and 32.96% post-LTF. Objectively, esophageal acid exposure was lower after LNF as compared with LTF (standard mean difference −0.72, 95% CI: −1.47-0.03, P=0.06), however, mean Demeester scores were normal (<14.7) in both groups postoperatively.

Another systematic review and meta-analysis compared short-term and long term outcomes of laparoscopic (LARS) versus open antireflux surgery (OARS).57 In the short-term, LARS showed a higher incidence of symptoms than OARS (5.2% vs. 3.4%; respectively, OR: 1.36, 95% CI: 0.45-4.08, P=0.58). In the long term, incidence of symptoms was significantly lower in the LARS group as compared with OARS group (12.9 vs. 18.8%, respectively, OR: 0.54; 95% CI: 0.35-0.83; P=0.005). Although total acid exposure time (pH < 4) was similar in both groups, it was still abnormal postsurgery in both groups (LARS 9.3% vs. OARS 8.9%; OR: 0.87, 95% CI: 0.24-3.12, P=0.83).

The aforementioned studies demonstrate that patients post antireflux surgery may report symptom resolution despite the presence of abnormal esophageal acid exposure or remained symptomatic despite normalization of esophageal acid exposure.

DOES SYMPTOMATIC RESPONSE TO ENDOSCOPIC TREATMENT REQUIRE NORMALIZATION OF ESOPHAGEAL ACID EXPOSURE?

In the last 2 decades, various endoluminal therapies for GERD have been introduced into the market. These techniques are less invasive and safer than surgical fundoplication and decrease reliance on PPIs and other medical therapies for GERD. Presently, 3 endoluminal techniques for GERD are available in the US market, including, the Stretta procedure, TIF, and MUSE.

A recent meta-analysis that included all RCTs and observational studies of the Stretta procedure demonstrated significant improvement in the quality of life score by −14.6 (−16.48, −12.73) (P<0.001) and heartburn score by −1.53 (−1.97, −1.09) (P<0.001).58 While a significant reduction in the mean esophageal acid exposure of −3.01 (−3.72, −2.30) (P<0.001) was noted, a significant subset of patients still had an abnormal esophageal acid exposure. The meta-analysis demonstrated a dichotomy between objective and subjective clinical outcomes of the Stretta procedure. In a study by Corley et al59 patients were randomized to the Stretta procedure or sham. The authors demonstrated that only about 10% of the patients normalized their esophageal acid exposure postprocedure. In contrast, 61% demonstrated resolution of GERD symptoms and normalization of quality of life scores despite abnormal esophageal acid exposure. In another study that included 118 patients, the authors demonstrated normalization of esophageal acid exposure in only 20% of the patients who underwent the Stretta procedure. However, 70% of the patients discontinued PPI treatment, and nearly 65% and 68% had a 50% improvement in GERD-HRQOL and heartburn score, respectively.60 In a trial comparing Stretta to Nissen fundoplication, Richards et al61 demonstrated normalization of esophageal pH values in 36% of the Stretta patients, while 58% were able to discontinue PPI therapy. The latter was associated with concomitant improvement in heartburn score.

Lutfi et al62 followed 85 subjects who underwent the Stretta procedure for 3 years. Here, the authors demonstrated that 62% of the patients normalized their GERD-HRQOL scores, whereas, esophageal acid exposure normalization was noted in only 42% of them. Similarly, Tam and colleagues followed 19 GERD patients who underwent the Stretta procedure. Normalization of the GERD-HRQOL scores was reported by 85% of the patients while 65% were off PPI therapy 12 months after the procedure. Normalization of esophageal acid exposure was noted in only 45% of the patients.63 There is also a randomized controlled trial, by Aziz et al64 that demonstrated normalization of esophageal acid exposure in the Stretta arm in more than two-third of the patients. However, improvement in GERD symptoms, as assessed by GERD-HRQOL questionnaire, occurred in only 50% of the patients. Less than a handful studies of the Stretta procedure demonstrated a correlation between normalization of esophageal acid exposure and improvement in symptoms score and reduction in antireflux medications use.65,66

The TIF procedure, using the EsophyX device (Endogastric solution, Redwood City, WA), restores the angle of His by creating a valve at the esophagogastric (EGJ). This is achieved by delivering multiple full thickness, nonabsorbable fasteners at the EGJ.

In a 12-month study, Bell and Freeman67 followed 24 patients with refractory GERD post TIF. GERD-HRQOL scores improved in 50% of the patients, and 82% of them discontinued PPI therapy. However, only 61% of the patients normalized esophageal pH parameters. In another study, Wilson et al68 followed 85 patients for 12 months after the TIF procedure. Of those, 65% experienced normalization of symptom scores, and 77% were able to discontinue PPI treatment. Esophageal pH testing demonstrated normalization of esophageal acid exposure in only 43% of the patients. Similarly, in a crossover trial, 39 GERD patients were followed for 12 months post-TIF. Normalization of GERD-HRQOL was noted in 62% of the patients, and in 82% PPI therapy was discontinued. Again, normalization of esophageal pH was achieved at 12 months by only 45% of the patients.69 Finally, in a randomized controlled trial of TIF versus PPI, Witteman et al70 reported that 44% of the TIF patients normalized esophageal pH at 6-month follow-up. This esophageal pH normalization fell to 29% at 12 months. GERD-HRQOL normalized in 40% and 48% of the patients who underwent TIF at 6 and 12 months, respectively. Overall, 50% of the patients in the TIF group were dissatisfied with the procedure.

A network meta-analysis that included 10 RCTs compared the efficacy of 2 endoscopic antireflux procedures (TIF and Stretta) versus PPIs in patients with GERD. The authors demonstrated that both endoscopic procedures may have similar effectiveness in terms of improvement in HRQOL (TIF, mean difference − 9.77, 95% CI: −12.85 to 6.70; Stretta, MD − 12.22, 95% CI: −15.93 to 8.52) and heartburn scores (TIF: MD − 9.60, 95% CI: −17.79 to −1.4; Stretta: MD − 1.53, 95% CI: −2.98 to −0.08) which were superior to PPIs.71 However, Stretta was significantly better than TIF (MD − 3.25, 95% CI: −5.95 to −0.56) in improving esophageal acid exposure. PPIs were also more effective than TIF in improving esophageal acid exposure (MD 2.49, 95% CI: 0.49-4.49). The surface under the cumulative ranking curve values were, 89% for Stretta, 60.3% for PPI and 0.6% for TIF.

Another systematic review and network meta-analysis identified 7 RCTs that included 1128 patients comparing the efficacy of LNF or TIF versus sham procedure or PPI in patients with GERD.72 Surface under the cumulative ranking curve ranking indicated TIF had the highest probability of increasing patients’ health related quality of life (0.96), followed by LNF (0.66), a sham procedure (0.35), and PPIs (0.042). In contrast, LNF had the highest probability of increasing percent time at pH < 4 (0.99), followed by PPIs (0.64), TIF (0.32), and sham procedure (0.05). While this study does not provide specific health related quality of life and esophageal pH, it does suggest the presence of discrepancy between subjective and objective measurements in these cohorts of patients.

The efficacy of endoscopic anterior fundoplication using MUSE was also evaluated in 66 patients with GERD.73 At six months follow-up, 95% (48/66) of the patients improved their GERD-HRQL score by at least 50%. Cessation of PPI usage was reported in 42 (64.6%) patients, and reduction of esophageal pH < 4% was achieved in only 33% of the patients. Testoni et al74 evaluated 37 GERD patients before and 12 months after the MUSE procedure. Significant reduction by at least 50% was noted in GERD-HRQOL (70%), heartburn (65%), and regurgitation (75%), whereas no change in esophageal acid exposure parameters was noted post-MUSE as compared with baseline (DeMeester score, 21.45 and 19.46, respectively).

The aforementioned endoscopic trials also demonstrated that symptom improvement, HRQOL normalization, and cessation of PPI treatment did not require normalization of esophageal acid exposure. The latter was consistently noted in only small number of patients. Table 5. Summarizes the objective and subjective clinical parameters in GERD patients who were rendered symptom free after endoscopic intervention.

TABLE 5 - Assessment of Objective and Subjective Clinical Endpoints in GERD Patients Who Were Rendered Symptom Free After Endoscopic Intervention
Clinical Parameter Radiofrequency Ablation (Stretta) Transoral Incisionless Fundoplication (TIF) Medigus Ultrasonic Surgical Endostapler (MUSE)
Patients (N) 19-98 24-85 11-66
Duration 12-36 mo 12-36 mo 6-60 mo
Acid Exposure (% pH<4, <5% of time) 45%-83% 29%-61% 25%-54%
GERD-HRQL % normalized 50%-85% 50%-72% 73%-90%
% Off PPI’s 43%-85% 65%-82% 65%-72%
GERD-HQOL indicates gastroesophageal reflux disease-health related quality of life; PPI, proton pump inhibitor.

CONCLUSIONS

This review highlights a very important discrepancy between subjective and objective clinical endpoints in the management of GERD. A significant subset of patients with improved or resolution of symptoms and improved or normalization of HRQOL scores may continue to have abnormal esophageal acid exposure or nonhealed EE. Regardless of the therapeutic intervention, medical, surgical or endoscopic, symptom resolution may not necessarily suggest normalization of esophageal acid exposure or complete healing of EE. Furthermore, GERD patients with complete normalization of esophageal acid exposure and healing of EE may still have GERD-related symptoms. These patients may end up falling under the category of refractory GERD. In this clinical scenario the inclusion of patients with functional esophageal disorders, those with an overlap with a functional esophageal disorder or other esophageal disorders such as supragastric belching, rumination syndrome, or esophageal motor disorder may drive patients’ residual symptoms.

It also appears that complete healing of EE or normalization of esophageal acid exposure are not necessary for symptom improvement or symptom resolution. While this is confounded by placebo response, studies have demonstrated that there is no correlation between the presence or absence of EE, grading of EE, and symptom frequency, severity, or intensity.75,76

This review may also suggest that concerns which were raised about therapeutic interventions for GERD that do not normalize esophageal acid exposure maybe invalid, as long as patients demonstrate resolution or substantial improvement of their symptoms. The same can be said about complete healing of EE. However, symptom improvement in the presence of Los Angeles grades C and D EE should not be considered as a desired clinical outcome. In contrast, symptom resolution or marked symptom improvement in the presence of Los Angeles A and B EE could be considered as a satisfactory outcome.

Incorporating the new diagnostic metrics that were proposed by the Lyon Consensus meeting for both EE and NERD into clinical trials may reduce the discrepancy between objective and subjective clinical endpoints.77 Furthermore, reassessment of our aims after the introduction of Potassium Channel Blockers (PCABs) into the market will be needed.

REFERENCES

1. Olmos JA, Pogorelsky V, Tobal F, et al. Uninvestigated dyspepsia in Latin America: a population-based study. Dig Dis Sci. 2006;51:1922–1929.
2. Cho YS, Choi MG, Jeong JJ, et al. Prevalence and clinical spectrum of gastroesophageal reflux: a population-based study in Asan-si, Korea. Am J Gastroenterol. 2005;100:747–753.
3. Kennedy T, Jones R. The prevalence of gastro-oesophageal reflux symptoms in a UK population and the consultation behaviour of patients with these symptoms. Aliment Pharmacol Ther. 2000;14:1589–1594.
4. Wong WM, Lai KC, Lam KF, et al. Prevalence, clinical spectrum and health care utilization of gastro-oesophageal reflux disease in a Chinese population: a population-based study. Aliment Pharmacol Ther. 2003;18:595–604.
5. Wolfe MM, Sachs G. Acid suppression: optimizing therapy for gastroduodenal ulcer healing, gastroesophageal reflux disease, and stress-related erosive syndrome. Gastroenterology. 2000;118(suppl 1):S9–S31.
6. Shibli F, Kitayama Y, Fass R. Novel therapies for gastroesophageal reflux disease: beyond proton pump inhibitors. Curr Gastroenterol Rep. 2020;22:16.
7. Fass R. Therapeutic options for refractory gastroesophageal reflux disease. J Gastroenterol Hepatol. 2012;27(suppl 3):3–7.
8. 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.
9. Galmiche JP, Barthelemy P, Hamelin B. Treating the symptoms of gastro-oesophageal reflux disease: a double-blind comparison of omeprazole and cisapride. Aliment Pharmacol Ther. 1997;11:765–773.
10. Richter JE, Campbell DR, Kahrilas PJ, et al. Lansoprazole compared with ranitidine for the treatment of nonerosive gastroesophageal reflux disease. Arch Intern Med. 2000;160:1803–1809.
11. Richter JE, Peura D, Benjamin SB, et al. Efficacy of omeprazole for the treatment of symptomatic acid reflux disease without esophagitis. Arch Intern Med. 2000;160:1810–1816.
12. Castell DO, Kahrilas PJ, Richter JE, et al. Esomeprazole (40 mg) compared with lansoprazole (30 mg) in the treatment of erosive esophagitis. Am J Gastroenterol. 2002;97:575–583.
13. Bianchi Porro G, Pace F, Peracchia A, et al. Short-term treatment of refractory reflux esophagitis with different doses of omeprazole or ranitidine. J Clin Gastroenterol. 1992;15:192–198.
14. Robinson M, Decktor DL, Maton PN, et al. Omeprazole is superior to ranitidine plus metoclopramide in the short-term treatment of erosive oesophagitis. Aliment Pharmacol Ther. 1993;7:67–73.
15. Vantrappen G, Rutgeerts L, Schurmans P, et al. Omeprazole (40 mg) is superior to ranitidine in short-term treatment of ulcerative reflux esophagitis. Dig Dis Sci. 1988;33:523–529.
16. Robinson M, Sahba B, Avner D, et al. A comparison of lansoprazole and ranitidine in the treatment of erosive oesophagitis. Multicentre Investigational Group. Aliment Pharmacol Ther. 1995;9:25–31.
17. Robinson M, Campbell DR, Sontag S, et al. Treatment of erosive reflux esophagitis resistant to H2-receptor antagonist therapy. Lansoprazole, a new proton pump inhibitor. Dig Dis Sci. 1995;40:590–597.
18. Corinaldesi R, Valentini M, Belaïche J, et al. Pantoprazole and omeprazole in the treatment of reflux oesophagitis: a European multicentre study. Aliment Pharmacol Ther. 1995;9:667–671.
19. Mössner J, Hölscher AH, Herz R, et al. A double-blind study of pantoprazole and omeprazole in the treatment of reflux oesophagitis: a multicentre trial. Aliment Pharmacol Ther. 1995;9:321–326.
20. Armstrong D, Paré P, Pericak D, et al. Symptom relief in gastroesophageal reflux disease: a randomized, controlled comparison of pantoprazole and nizatidine in a mixed patient population with erosive esophagitis or endoscopy-negative reflux disease. Am J Gastroenterol. 2001;96:2849–2857.
21. Richter JE, Bochenek W. Oral pantoprazole for erosive esophagitis: a placebo-controlled, randomized clinical trial. Pantoprazole US GERD Study Group. Am J Gastroenterol. 2000;95:3071–3080.
22. 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.
23. Sandmark S, Carlsson R, Fausa O, et al. Omeprazole or ranitidine in the treatment of reflux esophagitis. Results of a double-blind, randomized, Scandinavian multicenter study. Scand J Gastroenterol. 1988;23:625–632.
24. Sontag SJ, Hirschowitz BI, Holt S, et al. Two doses of omeprazole versus placebo in symptomatic erosive esophagitis: the US Multicenter Study. Gastroenterology. 1992;102:109–118.
25. Bate CM, Booth SN, Crowe JP, et al. Does 40 mg omeprazole daily offer additional benefit over 20 mg daily in patients requiring more than 4 weeks of treatment for symptomatic reflux oesophagitis? Aliment Pharmacol Ther. 1993;7:501–507.
26. Koop H, Schepp W, Dammann HG, et al. Comparative trial of pantoprazole and ranitidine in the treatment of reflux esophagitis. Results of a German multicenter study. J Clin Gastroenterol. 1995;20:192–195.
27. Lundell L, Backman L, Ekström P, et al. Omeprazole or high-dose ranitidine in the treatment of patients with reflux oesophagitis not responding to “standard doses” of H2-receptor antagonists. Aliment Pharmacol Ther. 1990;4:145–155.
28. Dehn TC, Shepherd HA, Colin-Jones D, et al. Double blind comparison of omeprazole (40 mg od) versus cimetidine (400 mg qd) in the treatment of symptomatic erosive reflux oesophagitis, assessed endoscopically, histologically and by 24 h pH monitoring. Gut. 1990;31:509–513.
29. Fennerty MB, Johnson DA. Heartburn severity does not predict disease severity in patients with erosive esophagitis. MedGenMed. 2006;8:6.
30. Kahrilas PJ, Persson T, Denison H, et al. Predictors of either rapid healing or refractory reflux oesophagitis during treatment with potent acid suppression. Aliment Pharmacol Ther. 2014;40:648–656.
31. Hetzel DJ, Dent J, Reed WD, et al. Healing and relapse of severe peptic esophagitis after treatment with omeprazole. Gastroenterology. 1988;95:903–912.
32. Klinkenberg-Knol EC, Jansen JM, Festen HP, et al. Double-blind multicentre comparison of omeprazole and ranitidine in the treatment of reflux oesophagitis. Lancet. 1987;1:349–351.
33. Revicki DA, Crawley JA, Zodet MW, et al. Complete resolution of heartburn symptoms and health-related quality of life in patients with gastro-oesophageal reflux disease. Aliment Pharmacol Ther. 1999;13:1621–1630.
34. Clarrett DM, Hachem C. Gastroesophageal reflux disease (GERD). Mo Med. 2018;115:214–218.
35. Meining A, Classen M. The role of diet and lifestyle measures in the pathogenesis and treatment of gastroesophageal reflux disease. Am J Gastroenterol. 2000;95:2692–2697.
36. DeVault KR, Castell DO. Updated guidelines for the diagnosis and treatment of gastroesophageal reflux disease. Am J Gastroenterol. 2005;100:190–200.
37. Milkes D, Gerson LB, Triadafilopoulos G. Complete elimination of reflux symptoms does not guarantee normalization of intraesophageal and intragastric pH in patients with gastroesophageal reflux disease (GERD). Am J Gastroenterol. 2004;99:991–996.
38. Grigolon A, Cantù P, Savojardo D, et al. Esophageal acid exposure on proton pump inhibitors in unselected asymptomatic gastroesophageal reflux disease patients. J Clin Gastroenterol. 2008;42:969–973.
39. Peng S, Xiong LS, Xiao YL, et al. Relationship between symptom response and esophageal pH level on standard dose of esomeprazole treatment for gastroesophageal reflux disease. Chin Med J (Engl). 2010;123:2012–2017.
40. Peng S, Xiao YL, Cui Y, et al. High-dose esomeprazole is required for intraesophageal acid control in gastroesophageal reflux disease patients with hiatus hernia. J Gastroenterol Hepatol. 2012;27:893–898.
41. Bajbouj M, Becker V, Phillip V, et al. High-dose esomeprazole for treatment of symptomatic refractory gastroesophageal reflux disease—a prospective pH-metry/impedance-controlled study. Digestion. 2009;80:112–118.
42. Lin D, Triadafilopoulos G. Dual ambulatory pH monitoring in patients with gastroesophageal reflux rendered asymptomatic with proton pump inhibitor therapy. Dig Dis Sci. 2015;60:1343–1349.
43. Katzka DA, Castell DO. Successful elimination of reflux symptoms does not insure adequate control of acid reflux in patients with Barrett’s esophagus. Am J Gastroenterol. 1994;89:989–991.
44. Ouatu-Lascar R, Triadafilopoulos G. Complete elimination of reflux symptoms does not guarantee normalization of intraesophageal acid reflux in patients with Barrett’s esophagus. Am J Gastroenterol. 1998;93:711–716.
45. Fass R, Sampliner RE, Malagon IB, et al. Failure of oesophageal acid control in candidates for Barrett’s oesophagus reversal on a very high dose of proton pump inhibitor. Aliment Pharmacol Ther. 2000;14:597–602.
46. Basu KK, Bale R, West KP, et al. Persistent acid reflux and symptoms in patients with Barrett’s oesophagus on proton-pump inhibitor therapy. Eur J Gastroenterol Hepatol. 2002;14:1187–1192.
47. Gerson LB, Boparai V, Ullah N, et al. Oesophageal and gastric pH profiles in patients with gastro-oesophageal reflux disease and Barrett’s oesophagus treated with proton pump inhibitors. Aliment Pharmacol Ther. 2004;20:637–643.
48. Ours TM, Fackler WK, Richter JE, et al. Nocturnal acid breakthrough: clinical significance and correlation with esophageal acid exposure. Am J Gastroenterol. 2003;98:545–550.
49. Jenkinson AD, Kadirkamanathan SS, Scott SM, et al. Relationship between symptom response and oesophageal acid exposure after medical and surgical treatment for gastro-oesophageal reflux disease. Br J Surg. 2004;91:1460–1465.
50. Lord RV, Kaminski A, Oberg S, et al. Absence of gastroesophageal reflux disease in a majority of patients taking acid suppression medications after Nissen fundoplication. J Gastrointest Surg. 2002;6:3–9; discussion 10.
51. Hamdy E, El Nakeeb A, Hamed H, et al. Outcome of laparoscopic Nissen fundoplication for gastroesophageal reflux disease in non-responders to proton pump inhibitors. J Gastrointest Surg. 2014;18:1557–1562.
52. Tosato F, Marano S, Mattacchione S, et al. Quality of life after Nissen-Rossetti fundoplication. Surg Laparosc Endosc Percutan Tech. 2012;22:205–209.
53. Broeders JA, Bredenoord AJ, Hazebroek EJ, et al. Effects of anti-reflux surgery on weakly acidic reflux and belching. Gut. 2011;60:435–441.
54. Kellokumpu I, Voutilainen M, Haglund C, et al. Quality of life following laparoscopic Nissen fundoplication: assessing short-term and long-term outcomes. World J Gastroenterol. 2013;19:3810–3818.
55. Galmiche JP, Hatlebakk J, Attwood S, et al. Laparoscopic antireflux surgery vs esomeprazole treatment for chronic GERD: the LOTUS randomized clinical trial. JAMA. 2011;305:1969–1977.
56. Tian ZC, Wang B, Shan CX, et al. A meta-analysis of randomized controlled trials to compare long-term outcomes of nissen and toupet fundoplication for gastroesophageal reflux disease. PLoS One. 2015;10:e0127627.
57. Qu H, Liu Y, He QS. Short- and long-term results of laparoscopic versus open anti-reflux surgery: a systematic review and meta-analysis of randomized controlled trials. J Gastrointest Surg. 2014;18:1077–1086.
58. Fass R, Cahn F, Scotti DJ, et al. Systematic review and meta-analysis of controlled and prospective cohort efficacy studies of endoscopic radiofrequency for treatment of gastroesophageal reflux disease. Surg Endosc. 2017;31:4865–4882.
59. Corley DA, Katz P, Wo JM, et al. Improvement of gastroesophageal reflux symptoms after radiofrequency energy: a randomized, sham-controlled trial. Gastroenterology. 2003;125:668–676.
60. Triadafilopoulos G, DiBaise JK, Nostrant TT, et al. The Stretta procedure for the treatment of GERD: 6 and 12 month follow-up of the US open label trial. Gastrointest Endosc. 2002;55:149–156.
61. Richards WO, Houston HL, Torquati A, et al. Paradigm shift in the management of gastroesophageal reflux disease. Ann Surg. 2003;237:638–647; discussion 648–639.
62. Lutfi RE, Torquati A, Kaiser J, et al. Three year’s experience with the Stretta procedure: did it really make a difference? Surg Endosc. 2005;19:289–295.
63. Tam WC, Schoeman MN, Zhang Q, et al. Delivery of radiofrequency energy to the lower oesophageal sphincter and gastric cardia inhibits transient lower oesophageal sphincter relaxations and gastro-oesophageal reflux in patients with reflux disease. Gut. 2003;52:479–485.
64. Aziz AM, El-Khayat HR, Sadek A, et al. A prospective randomized trial of sham, single-dose Stretta, and double-dose Stretta for the treatment of gastroesophageal reflux disease. Surg Endosc. 2010;24:818–825.
65. Torquati A, Houston HL, Kaiser J, et al. Long-term follow-up study of the Stretta procedure for the treatment of gastroesophageal reflux disease. Surg Endosc. 2004;18:1475–1479.
66. Cipolletta L, Rotondano G, Dughera L, et al. Delivery of radiofrequency energy to the gastroesophageal junction (Stretta procedure) for the treatment of gastroesophageal reflux disease. Surg Endosc. 2005;19:849–853.
67. Bell RC, Freeman KD. Clinical and pH-metric outcomes of transoral esophagogastric fundoplication for the treatment of gastroesophageal reflux disease. Surg Endosc. 2011;25:1975–1984.
68. Wilson EB, Barnes WE, Mavrelis PG, et al. The effects of transoral incisionless fundoplication on chronic GERD patients: 12-month prospective multicenter experience. Surg Laparosc Endosc Percutan Tech. 2014;24:36–46.
69. Trad KS, Barnes WE, Simoni G, et al. Transoral incisionless fundoplication effective in eliminating GERD symptoms in partial responders to proton pump inhibitor therapy at 6 months: the TEMPO Randomized Clinical Trial. Surg Innov. 2015;22:26–40.
70. Witteman BP, Conchillo JM, Rinsma NF, et al. Randomized controlled trial of transoral incisionless fundoplication vs. proton pump inhibitors for treatment of gastroesophageal reflux disease. Am J Gastroenterol. 2015;110:531–542.
71. Xie P, Yan J, Ye L, et al. Efficacy of different endoscopic treatments in patients with gastroesophageal reflux disease: a systematic review and network meta-analysis. Surg Endosc. 2021;35:1500–1510.
72. Richter JE, Kumar A, Lipka S, et al. Efficacy of laparoscopic Nissen fundoplication vs transoral incisionless fundoplication or proton pump inhibitors in patients with gastroesophageal reflux disease: a systematic review and network meta-analysis. Gastroenterology. 2018;154:1298–1308.e7.
73. Zacherl J, Roy-Shapira A, Bonavina L, et al. Endoscopic anterior fundoplication with the Medigus Ultrasonic Surgical Endostapler (MUSE™) for gastroesophageal reflux disease: 6-month results from a multi-center prospective trial. Surg Endosc. 2015;29:220–229.
74. Testoni PA, Testoni S, Mazzoleni G, et al. Transoral incisionless fundoplication with an ultrasonic surgical endostapler for the treatment of gastroesophageal reflux disease: 12-month outcomes. Endoscopy. 2020;52:469–473.
75. Savarino E, Tutuian R, Zentilin P, et al. Characteristics of reflux episodes and symptom association in patients with erosive esophagitis and nonerosive reflux disease: study using combined impedance-pH off therapy. Am J Gastroenterol. 2010;105:1053–1061.
76. Patel D, Fass R, Vaezi M. Untangling nonerosive reflux disease from functional heartburn. Clin Gastroenterol Hepatol. 2021;19:1314–1326.
77. Gyawali CP, Kahrilas PJ, Savarino E, et al. Modern diagnosis of GERD: the Lyon Consensus. Gut. 2018;67:1351–1362.
Keywords:

gastroesophageal reflux disease; erosive esophagitis; heartburn; proton pump inhibitors

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