Changes in GERD symptom scores correlate with ... - Springer Link

Surg Endosc (2004) 18: 1038–1044 DOI: 10.1007/s00464-003-8243-5
Springer-Verlag New York, LLC 2004

Changes in GERD symptom scores correlate with improvement in esophageal acid exposure after the Stretta procedure G. Triadafilopoulos Gastroenterology Section, Veterans Affairs Palo Alto Health Care System, and the Division of Gastroenterology and Hepatology, Stanford University School of Medicine, 3801 Miranda Avenue, Palo Alto, Stanford, CA 94304, USA Received: 22 January 2004/Accepted: 15 February 2004/Online publication: 27 May 2004

Abstract Background: Endoscopic radiofrequency energy delivery (Stretta) is effective for managing gastroesophageal reflux disease (GERD) in selected patients. One criticism, however, is a theory that a mechanism of action is partial desensitization of the esophageal body rather than a reduction in esophageal acid exposure. To resolve this question, this study sought to determine if there is a correlation between the improvement in GERD outcomes and esophageal acid exposure after Stretta. Methods: Subgroup analyses were performed between ‘‘responder’’ and ‘‘nonresponder’’ groups from the U.S. Stretta open label trial (n = 118), on the basis of posttreatment responses for GERD health-related quality of life (HRQL) heartburn, satisfaction, and proton pump inhibitor use. Outcomes were analyzed within and between subgroups. Pearson correlation coefficient analysis was performed comparing distal esophageal acid exposure with each of the continuous outcomes (GERD-HRQL, heartburn, satisfaction). Results: Responder subgroups had significant improvements in esophageal acid exposure, whereas nonresponders had no change or less improvement in the same. Changes in GERD-HRQL and heartburn severity were correlated with changes in acid exposure (r = 0.16, p = 0.12 and r = 0.26, p = 0.01, respectively). Changes in satisfaction were negatively correlated with changes in esophageal acid exposure (r = 0.23, p = 0.02) because satisfaction, as expected, increased as acid exposure decreased. Conclusions: Responders had significant improvement in esophageal acid exposure, whereas nonresponders had less or no change. There was a positive correlation between esophageal acid exposure and both GERDHRQL and heartburn. This evidence suggests that symptomatic improvement after Stretta is attributable

Correspondence to: G. Triadafilopoulos

to a decrease in esophageal acid exposure and not to desensitization of the esophagus. Key words: Gastroesophageal reflux disease — Esophagitis — Esophageal 24-h ambulatory pH monitoring — Stretta — Esophageal sensitivity

Gastroesophageal reflux disease (GERD) is a very common esophageal condition that compromises quality of life [6, 13]. Over the past several years, endoscopically assisted interventional techniques have emerged, generating a considerable interest among physicians and patients. [4, 5, 7–9, 11, 15, 17–20, 22]. In many studies, endoscopic therapy with Stretta (delivery of temperature-controlled radiofrequency energy to the gastroesophageal junction) significantly improves or eliminates GERD symptoms, improves patient quality of life, and decreases medication use by increasing the antireflux barrier and significantly decreasing intraesophageal pH [4, 5, 15, 17–19]. The 6-mm-diameter Stretta catheter (Curon Medical, Fremont, CA, USA) contains a balloon–basket combination, which is adjustable by inflation to accommodate varying anatomy (outer diameter, 30 mm). After endoscopic positioning and inflation, the device deploys four nickel–titanium needle electrodes into the muscle of the gastroesophageal junction and cardia. The Stretta generator delivers radiofrequency energy in an automated fashion under temperature and impedance control using thermocouple monitoring while the power output is regulated by computer algorithm. Target tissue temperature is elevated and maintained at a predetermined level while mucosal temperature is maintained at body temperature to prevent ulceration. [18]. The Stretta U.S. open label trial aimed to assess, in patients with uncomplicated GERD, the long-term (12month) effect of radiofrequency energy delivery on GERD symptoms and quality of life, medication use,

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esophageal acid exposure, lower esophageal sphincter (LES) pressure and esophageal motor function, severity of esophagitis, procedure tolerability, and complications [18]. This study demonstrated that Stretta safely improves GERD symptoms and patient general quality of life, decreases esophageal acid exposure, and obviates the need for antisecretory drug therapy for the majority of treated subjects. These treatment effects were superior to that achieved by antisecretory drug regimens at baseline. The percentage of time with an esophageal pH less than 4.0 six months after Stretta, albeit significantly reduced from 10.2% to 6.4% (p £ 0.0001), did not normalize for all patients. This finding raised the possibility for some that ablation of the muscle of the gastroesophageal junction desensitizes the esophagus, thus potentially masking symptoms of GERD. Therefore, critics of the procedure proclaim that Stretta may be harmful to patients with GERD by allowing ongoing acid reflux after the procedure to damage the distal esophageal mucosa without associated symptoms, although no study has demonstrated worsened or silent esophagitis after Stretta [10]. In this post hoc study, we hypothesized that there would be a positive correlation between posttreatment GERD symptoms (GERD health-related quality of life [HRQL] and heartburn) and esophageal acid exposure, and a negative correlation between satisfaction and esophageal acid exposure. We analyzed the data from the Stretta U.S. open-label trial according to the patient’s clinical responses in terms of GERD symptoms, satisfaction, and proton pump inhibitor (PPI) use. Our findings show that Stretta relieves GERD symptoms, improves patient satisfaction, and decreases the need for PPI use through a decrease in esophageal acid exposure time, and not by desensitizing the esophageal body.

Patients and methods

24-Hour ambulatory pH monitoring The study participants underwent 24-h ambulatory esophageal pH monitoring at baseline and at 6 months (±1 month) after discontinuing H2 receptor antagonist (H2RA) therapy for 3 to 5 days and PPI therapy for 7 days. In all the participants, an ambulatory pH sensor (Digitrapper, Medtronic, Minneapolis, MN, USA) was passed transnasally and positioned with its distal sensor 5 cm above the manometrically defined upper border of the LES. After probe placement, the patients returned home with instructions to keep a diary for recording symptoms, meal intake times, and body position (upright and supine). They were encouraged to carry out normal daily activities without dietary restrictions. The percentages of time with a pH less than 4 in the proximal and distal esophagus were analyzed separately. A reflux episode was defined as a drop in pH in the proximal or distal esophagus below 4. The duration of each reflux episode was measured from the time the pH dropped below 4 to the time the pH returned to a level above 4.

Questionnaires To assess of the baseline symptoms patients while off drugs, subjects interested in enrollment who met the criteria for the study completed the validated GERD-HRQL questionnaire [21] at two separate pretreatment time points: (a) while receiving antisecretory drug therapy, and (b) after discontinuing the drug regimen (3 to 5 days for H2RAs and 7 days for PPIs). The follow-up questionnaires used in this analysis were completed by the patients while offdrugs 6 months after treatment. The GERD-HRQL assesses GERD symptoms (scale of 0 to 50, with high scores reflecting more severe symptoms), heartburn severity (scale of 0 to 5, with high scores reflecting more severe symptoms), and patient satisfaction (scale of 0 to 5, with high scores reflecting high levels of satisfaction). All questionnaire responses were processed in a blinded manner to minimize bias.

Patient outcomes For the purposes of this analysis, the participants were separated into two groups, the ‘‘responders’’ and the ‘‘nonresponders,’’ after treatment with Stretta. The responders were characterized by a posttreatment GERD-HRQL score of 10 or less (as reported by Velanovich [21]), a heartburn severity score of 1 or less, no daily PPI use, and a patient satisfaction score greater than 4. In contrast, nonresponders were those with a GERD-HRQL score greater than 10, a heartburn severity score exceeding 1, daily PPI use, and a patient satisfaction score of 4 or less.

Patients Patients were either self-referred or recruited from the principal investigators’ clinical practices. Patients were included in the study if they had chronic heartburn or regurgitation, a daily antisecretory medication requirement, and at least a partial symptom response to drugs. All the patients had a peak esophageal peristaltic amplitude greater than 30 mmHg, LES pressure greater than 5 mmHg, LES relaxation in response to swallows, and pathologic distal acid exposure at 24-h esophageal pH testing. All had normal esophageal mucosa or Hetzel grade 1 or 2 esophagitis and no hiatal hernia exceeding 2 cm at the time of enrollment. One fourth of the patients (n = 30, 25.4%) had hiatal hernias (length, £ 2 cm). Many patients had prior endoscopic evaluation or barium swallow, allowing preenrollment determination of their candidacy with respect to hiatal hernia, Barrett’s esophagus, or severe esophagitis. Additionally, all the patients had undergone an endoscopy at the time of the Stretta procedure, and the patients with endoscopic findings of hiatal hernia exceeding 2 cm, esophagitis exceeding grade 2, or mucosa suspicious for Barrett’s esophagus were excluded from the study. We also excluded patients who were pregnant or poor surgical candidates and those who had severe dysphagia, previous esophageal or gastric surgery, collagen vascular disease, or significant untreated medical conditions. The study was approved by the Institutional Research Board of Stanford University and the local committees of all the other participating institutions [18].

Statistical analysis The nonparametric Wilcoxon signed rank test was used to compare differences between baseline and posttreatment esophageal acid exposure for each responder and nonresponder subgroup (GERDHRQL, heartburn, satisfaction, and PPI use). Nonparametric Spearman correlation coefficients were calculated to measure the association between the treatment effect on pH and the treatment effect on GERDHRQL, heartburn severity, and patient satisfaction. To test the hypothesis that the correlation coefficient was significantly greater than zero (positive correlation) or less than zero (negative correlation), p values were calculated. The level of significance was set at a p value less than 0.05.

Results In this study, 72 men and 46 women with GERD who had a mean age of 47 years; (range, 22 to 75 years) and a mean body weight of 189.5 lb (range, 95 to 340 lb) were treated. The number of years they had experienced GERD symptoms was 9.5 ± 9.3 years. Most of the patients (n = 96) had dual-sensor pH monitoring 5 and

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Fig. 1. Distal esophageal acid exposure time (% time pH < 4) before and after Stretta comparing responders and nonresponders for GERD health-related qualityof-life outcome. *p < 0.05; **p < 0.001.

Fig. 2. Distal esophageal acid exposure time (% time pH < 4) before and after Stretta comparing responders and nonresponders in terms of heartburn outcome. *p < 0.05; **p < 0.001.

20 cm above the LES. The remaining 22 patients had a single-sensor pH study 5 cm above the LES. As previously reported [4], the median distal esophageal acid exposure time (for the entire cohort) improved from 10.2% to 6.4% (p < 0.001); whereas the proximal esophageal acid exposure improved from 1.9% to 0.9% (p < 0.001). The improvement in acid exposure remained statistically significant when intent-to-treat analysis was applied (p < 0.001). The GERD-HRQL responder subgroup improved in median distal esophageal acid exposure time from a baseline of 10.4% to 4.3% (p < 0.001), whereas the nonresponders exhibited no change (10.9–7.7%; p = 0.12) (Fig. 1). The heartburn responder subgroup improved in median distal esophageal acid exposure

time from a baseline of 7.8% to 4.1% (p < 0.001), whereas the nonresponders exhibited less improvement (11.2–8%; p = 0.04) (Fig. 2). The satisfaction responder subgroup improved in median distal esophageal acid exposure time from a baseline of 11% to 6.4% (p < 0.001), whereas the nonresponders exhibited no change (10.0–6.3%; p = 0.13) (Fig. 3). The PPI responder subgroup improved in median distal esophageal acid exposure time from a baseline of 10% to 6% (p < 0.001), whereas the nonresponders exhibited no change (12.1 to 12.4%; p = 0.28) (Fig. 4). The changes in GERDHRQL showed a slight positive correlation with changes in esophageal acid exposure (r = 0.16; p = 0.12) (Fig. 5). The changes in heartburn were positively correlated with changes in esophageal acid exposure

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Fig. 3. Distal esophageal acid exposure time (% time pH < 4) before and after Stretta comparing responders and nonresponders in terms of patient satisfaction outcome. *p < 0.05; **p < 0.001

Fig. 4. Distal esophageal acid exposure time (% time pH < 4) before and after Stretta comparing responders and nonresponders for proton pump inhibitor outcome. *p < 0.05; **p < 0.001

(r = 0.26; p = 0.01) (Fig. 6), whereas the changes in satisfaction were negatively correlated with changes in esophageal acid exposure (r = 0.23; p = 0.02), an expected finding given that satisfaction should increase as acid exposure decreases. Analyses also were performed for the responder and nonresponder subgroups to determine proximal esophageal acid exposure times. The GERD-HRQL responder sub-group improved in median proximal esophageal acid exposure time from a baseline of 1.8% to 0.7% (p = 0.001), whereas the nonresponders exhibited less improvement (1.9 to 1.4%; p = 0.04). The heartburn responder subgroup improved in median proximal esophageal acid exposure time from a baseline of 2% to 0.5% (p = 0.03), whereas the nonresponders

exhibited a smaller magnitude of improvement (1.8 to 1.2%; p = 0.002). The satisfaction responder subgroup improved in median distal esophageal acid exposure time from a baseline of 2.2% to 1% (p < 0.001), wheras the nonresponders exhibited no change (1.5 to 1.0%; p = 0.06). The PPI responder subgroup improved in median distal esophageal acid exposure time from a baseline of 1.9% to 1% (p < 0.001), whereas the nonresponders exhibited no change (16 to 1.1%; p = 0.31). Discussion In this study, a post hoc analysis of the 6-month data from the Stretta U.S. multicenter open-label trial was

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Fig. 5. Nonparametric Spearman correlation for GERD healthrelated quality-of-life outcome and distal esophageal acid exposure (r = 0.16; p = 0.12).

Fig. 6. Nonparametric Spearman correlation for heartburn outcome and distal esophageal acid exposure (r = 0.26; p = 0.01).

performed in an attempt to link patients’ clinical improvement in GERD parameters with proximal and distal intraesophageal pH control. We studied a group of patients with long-standing, classic GERD symptoms (heartburn and/or regurgitation) and confirmed their diagnosis with validated GERD symptom questionnaires, pH studies, and endoscopy in cases of erosive disease. Overall, symptomatic responders had either normalization or significant improvements in both proximal and distal acid exposure times, whereas nonresponders had either no improvement or less improvement. Furthermore, GERD symptom improvement, specifically heartburn, was correlated positively with improvement in acid exposure, whereas patient satisfaction was correlated negatively with improvement in acid exposure, as expected. Although the correlation coefficients for acid exposure were not particularly strong, they remained statis-

tically significant for heartburn and patient satisfaction. The degree of intraesophageal acid suppression necessary for symptom control with either medical or endoscopic therapies is not known. Normalization of esophageal acid exposure may not be feasible or necessary for up to 50% of patients who have significant symptom control after intervention. Nonetheless, our results show that the Stretta procedure reduces GERD symptoms, reduces the need for daily PPI, and improves satisfaction by significantly reducing esophageal acid exposure time, and not by desensitizing the distal esophagus to the effects of persistent acid reflux. Left untreated, GERD causes complications such as esophagitis, esophageal ulceration, stricture formation, and Barrett’s esophagus, a premalignant condition that presages esophageal adenocarcinoma [12]. Medical and surgical therapy may lead to both symptom relief and healing of esophagitis. The PPIs are the primary agents

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used for pharmacologic therapy of GERD because their efficacy ranges from 85% to 90%, as compared with the H2RAs, which carry a response rate of 50% to 60%. [3] Laparoscopic fundoplication also effectively leads to healing and symptom control in more than 90% of cases, with reduced operative morbidity, as compared with the open approach [14]. Stretta is an endoscopically assisted interventional technique that significantly improves or eliminates GERD symptoms, improves quality of life, and decreases PPI use for most patients. This study suggests that GERD improvement after Stretta is correlated with improvement in esophageal acid exposure. There are two potential mechanisms of action with Stretta. The first proposed mechanism is Mechanical. Gastric yield pressure increased by 75% and LES pressure lowered by 21% have been shown in a porcine model of reflux [20]. After Stretta, increased muscular wall thickness has been shown histopathologically in a canine model [11], and endosonographically in porcine model [2]. A modest increase in the LES pressure 6 months after Stretta also has been found in a recently reported human trial [17]. The second proposed mechanism is neurological. A tLESR frequency decreased by 54% in a canine model and by 25% to 70% in human Stretta studies incorporating 3-h postprandial esophageal manometry and pH monitoring after a standard meal (3,000 kJ; 55% fat) have been reported [5, 17]. Esophageal sensitivity and symptom induction in response to acid has received significant attention over the years. As a result of intermittent acid exposure, the esophageal mucosa undergoes histologic changes characterized by loosening of the intercellular junctions, which in turn allow hydrogen ions to permeate to the basal compartment of the mucosa and reach crucially sensitive nerve endings. In turn, restoration of mucosal integrity over time and as a result of therapy allows for less acid penetration to the deep mucosal layers, rendering the patient symptom free. A recent, as yet unpublished, report has claimed that Stretta causes distal esophageal desensitization [1]. Using a modified Bernstein test after the procedure, the authors of this report noted a delayed onset of symptoms in response to acid instillation, as compared with preprocedural values. However, it is more likely, given the data presented in this study, that these findings reflect healing of the distal esophagus attributable to a reduction in esophageal acid exposure, with associated tightening of the intercellular junctions. In conclusion, Stretta relieves GERD symptoms, improves patient satisfaction, and decreases daily PPI use through a decrease in both proximal and distal acid exposure times, and not by desensitization of the esophageal body.

Acknowledgments. The Stretta open trial investigators’ group is acknowledged for conducting this study. This group includes the gastroenterology and Otolaryngology Head and Neck Surgery Divisions, Stanford University School of Medicine (George Triadafilopoulos, MD, David S. Utley, MD, and Michael Kim, MD), Stanford, CA; the Division of Gastroenterology, Department of Medicine, University of Nebraska, Omaha, NE (John K. DiBaise, MD); the University of

Michigan Hospital, Ann Arbor, MI (Timothy T. Nostrant, MD, and John C. Rabine, MD); the University of Miami/Miami VA Medical Center, Miami, FL (Neil H. Stollman, MD); the Dallas Diagnostic Association, Dallas, TX (Paul K. Anderson, MD); the Graduate Hospital, Philadelphia, PA (Donald O. Castell, MD, and Steven A. Edmundowicz, MD), the University of California San Francisco (Douglas A. Corley, MD, and Marco G. Patti, MD), the Boston Medical Center (Michael M. Wolfe, MD), the University of Louisville (John M. Wo, MD), the Dartmouth Hitchcock Medical Center (Richard D. Rothstein, MD), and the Rochester (Louis Antignano, MD) and Rocky Mountain Gastroenterology Associates (John S. Goff, MD).

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