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A novel endoscopic full-thickness plicator for the treatment of GERD: a pilot study
NEW METHODS & MATERIALS A novel endoscopic full-thickness plicator for the treatment of GERD: a pilot study Ram Chuttani, MD, Randhir Sud, MD, Gopal Sachdev, MD, Rajesh Puri, MD, Richard Kozarek, MD, Gregory Haber, MD, Douglas Pleskow, MD, Mohammed Zaman, MD, Anthony Lembo, MD Background: The novel full-thickness plication described in this study was designed to inhibit gastroesophageal reflux by placement of a transmural plication near the gastroesophageal junction under direct endoscopic visualization. The resulting serosa-to-serosa tissue union is thought to accentuate and restore the valvular mechanism of the gastroesophageal junction. The aim of this study was to assess the safety and feasibility of endoscopic full-thickness plication for the treatment of patients with GERD symptoms. Methods: A pilot study was performed in patients with chronic heartburn and pathologic reflux requiring maintenance antisecretory therapy. A single full-thickness plication was placed in the gastric cardia within 1 to 2 cm of the gastroesophageal junction. The primary end points of the study were procedure safety and feasibility, as well as long-term durability of the full-thickness tissue fixation. Secondary end points included medication use and the GERD-Health Related Quality of Life questionnaire and Gastrointestinal Symptom Rating Scale. Results: Full-thickness plication was performed successfully in 6 of 7 patients, with one procedure aborted because of difficulty in sedating the patient. Mean procedure time was 21 minutes. Mild epigastric pain was reported by two patients and difficulty with eructation by one patient; all symptoms resolved spontaneously within 7 days of the procedure. Endoscopy at 6 Received January 9, 2003. For revision March 28, 2003. Accepted July 15, 2003. Current affiliations: Harvard Medical School, Boston, Massachusetts, University of Seattle Medical School, Seattle, Washington, Sir Ganga Ram Hospital, New Delhi, India, University of Toronto, Toronto, Canada, Maulana Azad Medical College, New Delhi, India, Divisions of Gastroenterology, Departments of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts. Presented at the annual meeting of the American Society for Gastrointestinal Endoscopy Digestive Diseases Week, May 19-23, 2002, San Francisco, California. Reprint requests: Ram Chuttani, MD, Beth Israel Deaconess Medical Center, 330 Brookline Ave., Boston, MA 02215. Copyright Ó 2003 by the American Society for Gastrointestinal Endoscopy 0016-5107/2003/$30.00 + 0 PII:S0016-5107(03)02027-3 770
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months revealed an intact plication in all patients. At 1 year after the procedure, patients reported sustained reduction in heartburn scores. One patient, who did not experience significant relief of symptoms, ultimately underwent successful laparoscopic Nissen fundoplication at 6 months after the procedure. At 1 year after the procedure, 3 of 5 patients were not taking anti-GERD medications. Conclusions: Endoscopic full-thickness plication is feasible, safe and, in this pilot study, appeared to reduce symptoms and medication use associated with GERD. (Gastrointest Endosc 2003;58:770-6.)
Heartburn and regurgitation, the most common symptoms associated with GERD, are experienced at least once per day by approximately 7% of adults in the United States. GERD is associated with a number of serious complications, including Barrett’s metaplasia and adenocarcinoma of the esophagus.1 Patients with GERD have a lower quality of life compared with patients with other chronic illnesses such as angina and heart failure.2 The most common and effective pharmacologic treatment for GERD is antisecretory medications. Because GERD is a chronic disease, many patients require life-long therapy.3-5 Because antisecretory therapy does not prevent the reflux of gastric contents into the esophagus, this treatment often relieves heartburn but not other symptoms such as regurgitation. Since the introduction of laparoscopic techniques in the early 1990s, surgical therapy has become increasingly common for the treatment of GERD. The operation most commonly performed is the Nissen fundoplication.6 An ongoing study, with 5-year follow-up comparing open Nissen fundoplication to treatment with omeprazole (20 mg/day), found surgery to be superior for the treatment of erosive esophagitis.7 However, if the dose of omeprazole was increased during periods of relapse, the two therapeutic strategies were not statistically different. The long-term durability of surgery is unknown; one study found that 63% of patients who underwent a Nissen fundoplication were taking antisecretory medications at a mean follow-up of 10.6 years.8 Nissen fundoplication is associated with significant morbidity in up to 5% of patients, including gas, bloating, and dysphagia.9 Furthermore, re-operation because of complications and/or recurrent reflux is necessary in up 13% of patients.10 Several endoscopic devices either are being used clinically or are under investigation for the treatment of GERD. The Stretta device (Curon Medical Inc., Sunnyvale, Calif.) uses radio frequency energy to create submucosal thermal lesions in the smooth muscles of the lower esophageal sphincter (LES) VOLUME 58, NO. 5, 2003
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and cardia.11,12 As the thermal lesions heal, scar tissue forms, and the resulting tissue contraction is thought to increase resistance to acid reflux. The EndoCinch (Bard Endoscopic Technologies, Billerica, Mass.) is a transoral flexible endoscopic suturing device that plicates the gastroesophageal (GE) junction.13 This device places a submucosal suture to form a ‘‘neo-esophagus’’ and thereby accentuate the valvular mechanism at the GE junction. Another endoscopic technique currently under evaluation is the injection of the biopolymer ethylene vinyl alcohol copolymer (Enteryx; Enteric Medical Technology, Palo Alto, Calif.) under fluoroscopy into the LES. Our recently published study presented data on the safety and the efficacy of the endoscopic full-thickness plication in animals.14 Based on these encouraging results, the safety, the feasibility, and the long-term durability of this procedure were evaluated in patients with symptoms caused by GERD. In addition to these primary end points, secondary end points included medication use and GERD-Health Related Quality of Life questionnaire (GERD-HRQL) and Gastrointestinal Symptom Rating Scale (GSRS) symptom scores.
PATIENTS AND METHODS Patients All patients were recruited from the gastroenterology clinic at Sir Ganga Ram Hospital, New Delhi, India. All patients had an established diagnosis of GERD. Inclusion criteria were the following: (1) heartburn or regurgitation of at least 6 months’ duration; (2) confirmation of the diagnosis of GERD by 24-hour monitoring with a pH probe (pH less than 4, greater than 4.3%; DeMeester score greater than 14.7); (3) esophagitis at endoscopy no greater than grade II (Savary-Miller); (4) heartburn and regurgitation partially, but not completely, responsive to antisecretory therapy; (5) suitability for surgery in the event of a procedure-related complication (American Society of Anesthesiologists score I or II); (6) age 18 years or greater; and (7) written patient consent. Exclusion criteria were the following: (1) prior GE surgery or surgery for GERD; (2) an esophageal motility disorder other than associated with GERD; (3) an active medical condition that would preclude completion of the protocol; (4) presence of Barrett’s epithelium; (5) hiatal hernia greater than 2 cm in length; (6) unresponsiveness of symptoms to antisecretory therapy; (7) presence of persistent dysphagia, weight loss, esophageal bleeding, vomiting (>1 per week), or gas bloat; and (8) pregnancy. The study protocol was approved by the ethics committee of the Sir Ganga Ram Hospital. All patients gave written informed consent for participation in the study. The Committee on Clinical Investigations of the Beth Israel Deaconess Medical Center approved the analysis of data. VOLUME 58, NO. 5, 2003
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Full-thickness Endoscopic Plication System The full-thickness Endoscopic Plication System (EPS) (NDO Surgical, Inc., Mansfield, Mass.) is designed to fixate stomach tissue just distal to the GE junction with serosato-serosa apposition. The device consists of a reusable instrument and a single-use, suture-based implant. In addition, a proprietary endoscopic tissue retractor and standard overtube are used to perform the full-thickness endoscopic plication procedure. Instrument. The EPS is a reusable instrument that passes two needles through tissue at the desired location to place the implant for tissue approximation, plication, and fixation. Controls on the instrument handle actuate the distal end of the device, providing for retroflexion of the distal end, opening and closing the instrument arms and deploying the implant. The instrument contains two channels, one for insertion of the tissue retractor, the other for passage of the endoscope. Endoscopic tissue retractor. The endoscopic tissue retractor is designed to engage the gastric wall up to the level of the serosa, allowing for creation of the fullthickness plication. The tissue retractor is made of stainless steel and biocompatible polymers and includes a protective outer sheath to stabilize the mucosa while engaging the gastric wall. Once inserted, the tissue is pulled into the arms of the instrument so that the implant can be deployed safely. Implant. The implant, which allows for fixation of the intramural plication, consists of pretied suture, two bolsters, and two titanium retention bridges. The suture is standard USP size 2-0 polypropylene and is pretied and prethreaded onto the retention bridges. The suture bolsters are made of soft, flexible expanded polytetrafluoroethylene (ePTFE). Endoscopic plication procedure An early generation endoscopic plication system was used for the present study. This system required the use of an overtube that has been eliminated in subsequent versions of the technology. To perform the endoscopic plication procedure, a standard upper endoscope is passed into the stomach. After inspection of the stomach, a Savary spring-tipped metal guidewire (Wilson-Cook Medical, Inc., Salem, NC) is passed through the endoscope. The endoscope is removed, and a 54F Savary dilator and specially designed overtube (60F) are passed over the guidewire. The dilator and guidewire are removed, and the EPS and endoscope assembly are passed into the stomach. The overtube is retracted so that its distal end is proximal to the GE junction, and the stomach is distended with air. The endoscope is advanced and retroflexed so that the instrument may be visualized, retroflexed, and properly positioned. The endoscopic tissue retractor then is inserted within 1 to 2 cm of the GE junction and advanced up to the level of the serosa. After this, the full thickness of the gastric wall is retracted, and the instrument arms are closed. The implant then is deployed to secure the full-thickness plication, and the tissue retractor is disengaged from the gastric wall. The arms GASTROINTESTINAL ENDOSCOPY
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are opened, and the instrument is disengaged from the implant. After closing the arms and straightening the instrument and the endoscope, both are removed, followed by the overtube. A schematic of the endoscopic plication procedure is shown in Figure 1. A serosal view of suture showing full-thickness plication and a schematic of the fullthickness plicator is shown in Figure 2. Procedures were performed by 5 of the investigators (R.C., G.S., R.P., R.K., G.H.).
Esophageal manometry Esophageal manometry was performed with an 8-channel, water-perfused catheter (MedTronics Functional Diagnostics, Shoreview, Minn.). The LES resting pressure was determined by the standard stationary pullthrough technique. Lower esophageal sphincter relaxation was measured during wet swallows (5 mL of roomtemperature water). Motility in the body of the esophagus was determined by positioning all of the catheter openings within the body of the esophagus with the most distal port 3 cm proximal to the LES. Ten wet swallows (5 mL of roomtemperature water) were administered, each separated by 30-second intervals. Pressure signals were digitized with a Polygraf (MedTronics).
24-hour pH monitoring An ambulatory 24-hour pH sensor (Digitrapper; MedTronics) was passed transnasally and positioned 5 cm proximal to the manometrically measured proximal border of the LES. Treatment with antireflux medications was discontinued before the study as follows: proton pump inhibitors (PPI), 7 days; H2 receptor antagonists (H2RA), 24 hours; and antacids, 24 hours. Manufacturer-provided MedTronics software was used to analyze the 24-hour pH data.
Study procedures Enrolled patients completed the validated GERDHRQL,15 the Medical Outcomes Study (SF-36),16 and the GSRS instruments. The GERD-HRQL assesses GERD symptoms and patient satisfaction. The SF-36 assesses quality of life, which is summarized as physical composite scores (PCS) and mental composite scores (MCS). The GSRS contains 15 items, broken down into 5 scales. The reflux scale consists of two questions regarding the severity of heartburn and regurgitation by using a 7-point Likert scale ranging from ‘‘not at all’’ to ‘‘very severe’’ discomfort. The reflux score is calculated by taking the mean of these two items—the higher the score, the greater the severity of symptoms. Questionnaires were completed after discontinuation of antireflux medications for 7 days before treatment, and then at 3, 6, and 12 months after the procedure. Patients also underwent upper endoscopy at 3 and 6 months after the procedure to assess esophagitis, as well as sustained tissue remodeling from the endoscopically placed plication. 772
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Patients experiencing a recurrence of their typical heartburn or regurgitation after discontinuation of medication were instructed to take ranitidine (150 mg twice a day). If symptoms persisted after 7 days, then treatment was initiated with omeprazole (20 mg daily) or the original PPI that the patient had been taking. Adverse events were recorded and graded as mild (transient, no intervention or medication required, not interfering with normal activities), moderate (severe enough to interfere with usual activities, no intervention other than taking acetominophen for pain), or severe (inability to perform normal activities, requiring intervention other than taking acetominophen).
RESULTS Patients The study population consisted of 7 men (mean age 31 [8] years, range 23-41 years). At baseline, all patients had an incomplete response to PPI therapy. Three patients were taking a PPI once per day; 4 required PPI twice daily to control heartburn. Baseline upper endoscopy was performed after discontinuation of PPI therapy for 1 week and within 1 month before undergoing the full-thickness plication procedure. Two patients had grade 0 esophagitis, 3 had grade 1, and 2 had grade 2 esophagitis. One patient, whose symptoms worsened after the 6-month follow-up, underwent laparoscopic Nissen fundoplication. No technical difficulties were encountered in performing the surgery. The patient continued to experience GERD symptoms even after surgery. Follow-up data at 12 months were not available for this patient. Feasibility Endoscopic full-thickness plication was completed successfully in 6 of the 7 patients. All procedures were performed in February 2001. One patient, who could not be sedated adequately with intravenously administered midazolam and meperidine, did not undergo the full-thickness endoscopic plication. Mean procedure time was 21 (8) minutes. One patient underwent a Nissen fundoplication 6 months after undergoing full-thickness plication because of persistence of symptoms. Safety After the procedure, two patients had mild mid epigastric pain, which was treated with orally administered acetominophen. One patient reported difficulty eructating after the procedure. These mild adverse events disappeared spontaneously within 7 days after the procedure. No complications requiring intervention, other than as mentioned above, occurred during the study. No late complication, such VOLUME 58, NO. 5, 2003
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Figure 1. Schematic illustration of fullthickness plication procedure. A, (step 1) Specially designed plicator enters stomach and is retroflexed and positioned within 1 to 2 cm of GE junction. B, (step 2) Plicator arms are opened and a proprietary endoscopic tissue retractor is advanced into gastric wall to the serosa. C, (step 3) Full-thickness of gastric wall is retracted and plicator arms are closed. D, (step 4) A single, pretied implant is deployed, securing serosa-to-serosa plication. E, (step 5) Resulting full-thickness plication restores normal antireflux barrier.
as stricture formation, dysphagia, or bleeding, was reported, and, likewise, at 3 and 6 months, there was no ulcer or stricture found at endoscopy in any patient. Durability The full-thickness plication appeared to be intact in all patients at endoscopy 3 and 6 months after plication. VOLUME 58, NO. 5, 2003
GERD symptoms and health-related quality of life By comparison to baseline, GERD symptoms were less in all 5 patients who completed 12-month followup. The mean reflux GSRS score decreased more than 75% at the 12-month follow-up (6.8 [1.8] to 1.8 [1.5]). Likewise, the mean GERD-HRQL scores also improved approximately 75% at the 12-month followup (18.8 [5.9] to 4.6 [5.6]) (Table 1). The mean GASTROINTESTINAL ENDOSCOPY
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Table 1. Reflux-sources before and after plication GERD-HRQL F/U mo # # # # # #
1* 2 3 4 5 6
Mean SD
B
1
16 23 11 25 14 24
5 13 0 5 1 12
18.8 5.9
3 7 3 0 3 7 4
7.5 4.7 5 2.9
GSRS: GERD score
6
12
B
5 8 3 12 2 6
NA 3 0 14 1 5
8 10 6 6 5 6
6.0 3.6
4.6 5.6
6.8 1.8
1
3
6
12
6 6 1 2 3 5
2 3 0 5 2 3
2 1 0 3 2 1
NA 0 0 4 2 1
3.8 2.2
2.6 1.6
1.6 1
1.8 1.4
F/U, Follow-up; GERD-HRQL, GERD-Health Related Quality of Life questionnaire; GSRS, Gastrointestinal Symptom Rating Scale; B, baseline; NA, not applicable; SD, standard deviation. *Patient 1 underwent Nissen fundoplication after 6-month follow-up because of an exacerbation in symptoms. 12-mo follow-up is not available for this patient.
DISCUSSION
Figure 2. Full-thickness plication in stomach of a pig. A, Serosal view of suture showing full-thickness plication. B, Schematic diagram of ePTFE bolsters and suture securing serosa-serosa plication.
GERD-HRQL and GSRS for baseline, 1, 3, 6, and 12 months after plication are shown in Figures 4 and 5, respectively. Overall quality of life, as assessed with the SF36, was improved at 12 months after the procedure. The mean PCS improved from 34.6 (7.4) at baseline to 44.8 (5.9) at 1 month after the procedure, and to 50.4 (1.3) at 12 months. The mean MCS also improved, although not much, from 48.0 (6.0) at baseline to 51.6 (2.1) at 1 month, and to 53.1 (2.1) at 12 months. At the 12-month follow-up, one patient was still taking PPIs regularly, although at a lower dose than at baseline. Another patient was taking an H2RA and the prokinetic agent mosapride intermittently. The remaining 3 patients were taking no medication for reflux symptoms. In two patients, the esophagitis score was downgraded from grade 2 to grade 1. In the remaining 3 patients, there was no change in esophagitis score (grade 1, 2 patients; grade 0, one patient). 774
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Although medical therapy is effective in most patients with GERD, many patients continue to have regurgitation despite treatment, and others are unwilling or unable to take medications on a daily basis. The need for effective non-pharmacologic therapy also is demonstrated by the rapidly increasing number of laparoscopic antireflux operations being performed since the introduction of these procedures in the early 1990s. The potential advantages of an endoscopic procedure over a surgical antireflux procedure include lower cost, shorter postoperative recovery time, reduced discomfort, and, potentially, fewer complications. An endoscopic antireflux procedure also could be an attractive alternative to long-term acid suppression. The endoscopic full-thickness plication device used in the present study is designed to inhibit reflux with a single plication near the GE junction. Fullthickness plication of the proximal stomach may improve the competency of the GE barrier by restoring the valvular mechanism of the GE junction. Other potential mechanisms include alteration of the angle of His, decreased compliance of the gastric cardia and fundus, enhancement of the LES resting pressure, and reduction in transient relaxations of the LES. The present study demonstrates that the endoscopic placement of a single, full-thickness plication in the gastric cardia technically is feasible in patients with symptoms caused by GERD. The procedures were technically simple to perform, largely because of direct endoscopic visualization throughout the entire plication procedure. It also is essential that any endoscopic intervention not preclude patients from pursuing other treatment strategies in the event that VOLUME 58, NO. 5, 2003
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Figure 3. Endoscopic views of full-thickness plication in a patient. A, Helical tissue retractor inserted approximately 1 cm from GE junction. B, Gastric wall is retracted and plication arms are opened. C, Arms of the instrument are closed and plication is deployed. D, Appearance after plication.
relief of symptoms is non-sustainable. Because endoscopic full-thickness plication is not destructive to the tissues of the GE junction, successful laparoscopic fundoplication surgery was possible in one patient in the present study. No significant complication occurred during 12 months of follow-up, suggesting that the procedure is safe. Only minor side effects were reported, all of which resolved spontaneously within 7 days. The study was not designed to demonstrate efficacy. However, all patients reported improvement in symptoms, several were able to discontinue PPI therapy, and the majority were able to avoid taking medications for GERD symptoms even after 12 months’ follow-up. Overall, the results of 24-hour pH monitoring did not improve dramatically. A significant increase in acid reflux was noted in one patient during follow-up. After the full-thickness plication, this patient experienced an initial VOLUME 58, NO. 5, 2003
improvement in symptoms, and, subsequently, his weight increased by approximately 10 kg, but this was followed by a recurrence of reflux symptoms. Based on studies in animals, the plication appears to be most effective when placed close to the GE junction (i.e., within 1-2 cm). Although placement in this location was attempted in all patients, there was significant variability, in part because of the learning curve inherent to any new procedure. In conclusion, this study demonstrates the technical feasibility of endoscopic full-thickness plication in patients with symptoms caused by GERD. In addition, the procedure appears to be safe and does not appear to interfere with subsequent laparoscopic fundoplication, if required. Based on these encouraging initial results, a multicenter study currently is in progress to further assess the effectiveness and safety of the full-thickness GASTROINTESTINAL ENDOSCOPY
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Figure 4. Results of GERD–Health Related Quality of Life. Mean GERD-HRQL scores are shown for baseline period (antisecretory medications discontinued for 1 week) and at 1, 3, 6, and 12 months. (n = 6, except for month 12, where n = 5).
Figure 5. Gastrointestinal Symptom Rating Scale reflux scores; shown are mean GSRS scores for baseline period (antisecretory medications discontinued for 1 week) and at 1, 3, 6, and 12 months (n = 6, except for month 12, where n = 5).
plication for treatment of patients with GERD symptoms. DISCLOSURE Sponsored by NDO Surgical, Inc., Mansfield, Massachusetts. Ram Chuttani, MD, has an equity position in the sponsoring company, NDO Surgical, Inc. REFERENCES 1. Lagergren J, Bergstrom R, Lindgren A, Nyren O. Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma. N Engl J Med 1999;340:825-31.
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2. Dimenas E, Glise H, Hallerback B, Hernqvist H, Svedlund J, Wiklund I. Quality of life in patients with upper gastrointestinal symptoms. An improved evaluation of treatment regimens? Scand J Gastroenterol 1993;28:681-7. 3. Dent J, Yeomans ND, Mackinnon M, Reed W, Narielvala FM, Hetzel DJ, et al. Omeprazole v ranitidine for prevention of relapse in reflux oesophagitis. A controlled double blind trial of their efficacy and safety. Gut 1994;35:590-8. 4. Lundell L. Long-term treatment of gastro-oesophageal reflux disease with omeprazole. Scand J Gastroenterol Suppl 1994; 201:74-8. 5. Hetzel DJ, Dent J, Reed WD, Narielvala FM, Mackinnon M, McCarthy JH, et al. Healing and relapse of severe peptic esophagitis after treatment with omeprazole. Gastroenterology 1988;95:903-12. 6. Jamieson GG, Watson DI, Britten-Jones R, Mitchell PC, Anvari M. Laparoscopic Nissen fundoplication. Ann Surg 1994;220:137-45. 7. Lundell L, Miettinen P, Myrvold HE, Pedersen SA, Liedman B, Hatlebakk JG, et al. Continued (5-year) follow up of a randomized clinical study comparing antireflux surgery and omeprazole in gastroesophageal reflux disease. J Am Coll Surg 2001;192:172-9; discussion 179-81. 8. Spechler SJ, Lee E, Ahnen D, Goyal RK, Hirano I, Ramirez F, et al. Long-term outcome of medical and surgical therapies for gastroesophageal reflux disease: follow-up of a randomized controlled trial. JAMA 2001;285:2331-8. 9. Hookman P, Barkin JS. Surgical complications of laparoscopic fundoplication for gastroesophageal reflux disease: call for reevaluation of surgical criteria. Am J Gastroenterol 2000;95:3305-8. 10. Lafullarde T, Watson DI, Jamieson GG, Myers JC, Game PA, Devitt PG. Laparoscopic Nissen fundoplication: five-year results and beyond. Arch Surg 2001;136:180-4. 11. Triadafilopoulos G, Dibaise JK, Nostrant TT, Stollman NH, Anderson PK, Edmundowicz SA, et al. Radiofrequency energy delivery to the gastroesophageal junction for the treatment of GERD. Gastrointest Endosc 2001;53: 407-15. 12. Utley DS, Kim M, Vierra MA, Triadafilopoulos G. Augmentation of lower esophageal sphincter pressure and gastric yield pressure after radiofrequency energy delivery to the gastroesophageal junction: a porcine model. Gastrointest Endosc 2000;52:81-6. 13. Swain CP, Brown GJ, Gong F, Mills TN. An endoscopically deliverable tissue-transfixing device for securing biosensors in the gastrointestinal tract. Gastrointest Endosc 1994;40:730-4. 14. Chuttani R, Kozarek R, Critchlow J, Lo S, Pleskow D, Brandwein S, Lembo T. A novel endoscopic full-thickness plicator for treatment of GERD: an animal model study. Gastrointest Endosc 2002;56:116-22. 15. Velanovich V. Comparison of symptomatic and quality of life outcomes of laparoscopic versus open antireflux surgery. Surgery 1999;126:782-8; discussion 788-9. 16. McHorney CA, Kosinski M, Ware JE Jr. Comparisons of the costs and quality of norms for the SF-36 health survey collected by mail versus telephone interview: results from a national survey. Med Care 1994;32:551-67.
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months revealed an intact plication in all patients. At 1 year after the procedure, patients reported sustained reduction in heartburn scores. One patient, who did not experience significant relief of symptoms, ultimately underwent successful laparoscopic Nissen fundoplication at 6 months after the procedure. At 1 year after the procedure, 3 of 5 patients were not taking anti-GERD medications. Conclusions: Endoscopic full-thickness plication is feasible, safe and, in this pilot study, appeared to reduce symptoms and medication use associated with GERD. (Gastrointest Endosc 2003;58:770-6.)
Heartburn and regurgitation, the most common symptoms associated with GERD, are experienced at least once per day by approximately 7% of adults in the United States. GERD is associated with a number of serious complications, including Barrett’s metaplasia and adenocarcinoma of the esophagus.1 Patients with GERD have a lower quality of life compared with patients with other chronic illnesses such as angina and heart failure.2 The most common and effective pharmacologic treatment for GERD is antisecretory medications. Because GERD is a chronic disease, many patients require life-long therapy.3-5 Because antisecretory therapy does not prevent the reflux of gastric contents into the esophagus, this treatment often relieves heartburn but not other symptoms such as regurgitation. Since the introduction of laparoscopic techniques in the early 1990s, surgical therapy has become increasingly common for the treatment of GERD. The operation most commonly performed is the Nissen fundoplication.6 An ongoing study, with 5-year follow-up comparing open Nissen fundoplication to treatment with omeprazole (20 mg/day), found surgery to be superior for the treatment of erosive esophagitis.7 However, if the dose of omeprazole was increased during periods of relapse, the two therapeutic strategies were not statistically different. The long-term durability of surgery is unknown; one study found that 63% of patients who underwent a Nissen fundoplication were taking antisecretory medications at a mean follow-up of 10.6 years.8 Nissen fundoplication is associated with significant morbidity in up to 5% of patients, including gas, bloating, and dysphagia.9 Furthermore, re-operation because of complications and/or recurrent reflux is necessary in up 13% of patients.10 Several endoscopic devices either are being used clinically or are under investigation for the treatment of GERD. The Stretta device (Curon Medical Inc., Sunnyvale, Calif.) uses radio frequency energy to create submucosal thermal lesions in the smooth muscles of the lower esophageal sphincter (LES) VOLUME 58, NO. 5, 2003
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and cardia.11,12 As the thermal lesions heal, scar tissue forms, and the resulting tissue contraction is thought to increase resistance to acid reflux. The EndoCinch (Bard Endoscopic Technologies, Billerica, Mass.) is a transoral flexible endoscopic suturing device that plicates the gastroesophageal (GE) junction.13 This device places a submucosal suture to form a ‘‘neo-esophagus’’ and thereby accentuate the valvular mechanism at the GE junction. Another endoscopic technique currently under evaluation is the injection of the biopolymer ethylene vinyl alcohol copolymer (Enteryx; Enteric Medical Technology, Palo Alto, Calif.) under fluoroscopy into the LES. Our recently published study presented data on the safety and the efficacy of the endoscopic full-thickness plication in animals.14 Based on these encouraging results, the safety, the feasibility, and the long-term durability of this procedure were evaluated in patients with symptoms caused by GERD. In addition to these primary end points, secondary end points included medication use and GERD-Health Related Quality of Life questionnaire (GERD-HRQL) and Gastrointestinal Symptom Rating Scale (GSRS) symptom scores.
PATIENTS AND METHODS Patients All patients were recruited from the gastroenterology clinic at Sir Ganga Ram Hospital, New Delhi, India. All patients had an established diagnosis of GERD. Inclusion criteria were the following: (1) heartburn or regurgitation of at least 6 months’ duration; (2) confirmation of the diagnosis of GERD by 24-hour monitoring with a pH probe (pH less than 4, greater than 4.3%; DeMeester score greater than 14.7); (3) esophagitis at endoscopy no greater than grade II (Savary-Miller); (4) heartburn and regurgitation partially, but not completely, responsive to antisecretory therapy; (5) suitability for surgery in the event of a procedure-related complication (American Society of Anesthesiologists score I or II); (6) age 18 years or greater; and (7) written patient consent. Exclusion criteria were the following: (1) prior GE surgery or surgery for GERD; (2) an esophageal motility disorder other than associated with GERD; (3) an active medical condition that would preclude completion of the protocol; (4) presence of Barrett’s epithelium; (5) hiatal hernia greater than 2 cm in length; (6) unresponsiveness of symptoms to antisecretory therapy; (7) presence of persistent dysphagia, weight loss, esophageal bleeding, vomiting (>1 per week), or gas bloat; and (8) pregnancy. The study protocol was approved by the ethics committee of the Sir Ganga Ram Hospital. All patients gave written informed consent for participation in the study. The Committee on Clinical Investigations of the Beth Israel Deaconess Medical Center approved the analysis of data. VOLUME 58, NO. 5, 2003
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Full-thickness Endoscopic Plication System The full-thickness Endoscopic Plication System (EPS) (NDO Surgical, Inc., Mansfield, Mass.) is designed to fixate stomach tissue just distal to the GE junction with serosato-serosa apposition. The device consists of a reusable instrument and a single-use, suture-based implant. In addition, a proprietary endoscopic tissue retractor and standard overtube are used to perform the full-thickness endoscopic plication procedure. Instrument. The EPS is a reusable instrument that passes two needles through tissue at the desired location to place the implant for tissue approximation, plication, and fixation. Controls on the instrument handle actuate the distal end of the device, providing for retroflexion of the distal end, opening and closing the instrument arms and deploying the implant. The instrument contains two channels, one for insertion of the tissue retractor, the other for passage of the endoscope. Endoscopic tissue retractor. The endoscopic tissue retractor is designed to engage the gastric wall up to the level of the serosa, allowing for creation of the fullthickness plication. The tissue retractor is made of stainless steel and biocompatible polymers and includes a protective outer sheath to stabilize the mucosa while engaging the gastric wall. Once inserted, the tissue is pulled into the arms of the instrument so that the implant can be deployed safely. Implant. The implant, which allows for fixation of the intramural plication, consists of pretied suture, two bolsters, and two titanium retention bridges. The suture is standard USP size 2-0 polypropylene and is pretied and prethreaded onto the retention bridges. The suture bolsters are made of soft, flexible expanded polytetrafluoroethylene (ePTFE). Endoscopic plication procedure An early generation endoscopic plication system was used for the present study. This system required the use of an overtube that has been eliminated in subsequent versions of the technology. To perform the endoscopic plication procedure, a standard upper endoscope is passed into the stomach. After inspection of the stomach, a Savary spring-tipped metal guidewire (Wilson-Cook Medical, Inc., Salem, NC) is passed through the endoscope. The endoscope is removed, and a 54F Savary dilator and specially designed overtube (60F) are passed over the guidewire. The dilator and guidewire are removed, and the EPS and endoscope assembly are passed into the stomach. The overtube is retracted so that its distal end is proximal to the GE junction, and the stomach is distended with air. The endoscope is advanced and retroflexed so that the instrument may be visualized, retroflexed, and properly positioned. The endoscopic tissue retractor then is inserted within 1 to 2 cm of the GE junction and advanced up to the level of the serosa. After this, the full thickness of the gastric wall is retracted, and the instrument arms are closed. The implant then is deployed to secure the full-thickness plication, and the tissue retractor is disengaged from the gastric wall. The arms GASTROINTESTINAL ENDOSCOPY
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are opened, and the instrument is disengaged from the implant. After closing the arms and straightening the instrument and the endoscope, both are removed, followed by the overtube. A schematic of the endoscopic plication procedure is shown in Figure 1. A serosal view of suture showing full-thickness plication and a schematic of the fullthickness plicator is shown in Figure 2. Procedures were performed by 5 of the investigators (R.C., G.S., R.P., R.K., G.H.).
Esophageal manometry Esophageal manometry was performed with an 8-channel, water-perfused catheter (MedTronics Functional Diagnostics, Shoreview, Minn.). The LES resting pressure was determined by the standard stationary pullthrough technique. Lower esophageal sphincter relaxation was measured during wet swallows (5 mL of roomtemperature water). Motility in the body of the esophagus was determined by positioning all of the catheter openings within the body of the esophagus with the most distal port 3 cm proximal to the LES. Ten wet swallows (5 mL of roomtemperature water) were administered, each separated by 30-second intervals. Pressure signals were digitized with a Polygraf (MedTronics).
24-hour pH monitoring An ambulatory 24-hour pH sensor (Digitrapper; MedTronics) was passed transnasally and positioned 5 cm proximal to the manometrically measured proximal border of the LES. Treatment with antireflux medications was discontinued before the study as follows: proton pump inhibitors (PPI), 7 days; H2 receptor antagonists (H2RA), 24 hours; and antacids, 24 hours. Manufacturer-provided MedTronics software was used to analyze the 24-hour pH data.
Study procedures Enrolled patients completed the validated GERDHRQL,15 the Medical Outcomes Study (SF-36),16 and the GSRS instruments. The GERD-HRQL assesses GERD symptoms and patient satisfaction. The SF-36 assesses quality of life, which is summarized as physical composite scores (PCS) and mental composite scores (MCS). The GSRS contains 15 items, broken down into 5 scales. The reflux scale consists of two questions regarding the severity of heartburn and regurgitation by using a 7-point Likert scale ranging from ‘‘not at all’’ to ‘‘very severe’’ discomfort. The reflux score is calculated by taking the mean of these two items—the higher the score, the greater the severity of symptoms. Questionnaires were completed after discontinuation of antireflux medications for 7 days before treatment, and then at 3, 6, and 12 months after the procedure. Patients also underwent upper endoscopy at 3 and 6 months after the procedure to assess esophagitis, as well as sustained tissue remodeling from the endoscopically placed plication. 772
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Patients experiencing a recurrence of their typical heartburn or regurgitation after discontinuation of medication were instructed to take ranitidine (150 mg twice a day). If symptoms persisted after 7 days, then treatment was initiated with omeprazole (20 mg daily) or the original PPI that the patient had been taking. Adverse events were recorded and graded as mild (transient, no intervention or medication required, not interfering with normal activities), moderate (severe enough to interfere with usual activities, no intervention other than taking acetominophen for pain), or severe (inability to perform normal activities, requiring intervention other than taking acetominophen).
RESULTS Patients The study population consisted of 7 men (mean age 31 [8] years, range 23-41 years). At baseline, all patients had an incomplete response to PPI therapy. Three patients were taking a PPI once per day; 4 required PPI twice daily to control heartburn. Baseline upper endoscopy was performed after discontinuation of PPI therapy for 1 week and within 1 month before undergoing the full-thickness plication procedure. Two patients had grade 0 esophagitis, 3 had grade 1, and 2 had grade 2 esophagitis. One patient, whose symptoms worsened after the 6-month follow-up, underwent laparoscopic Nissen fundoplication. No technical difficulties were encountered in performing the surgery. The patient continued to experience GERD symptoms even after surgery. Follow-up data at 12 months were not available for this patient. Feasibility Endoscopic full-thickness plication was completed successfully in 6 of the 7 patients. All procedures were performed in February 2001. One patient, who could not be sedated adequately with intravenously administered midazolam and meperidine, did not undergo the full-thickness endoscopic plication. Mean procedure time was 21 (8) minutes. One patient underwent a Nissen fundoplication 6 months after undergoing full-thickness plication because of persistence of symptoms. Safety After the procedure, two patients had mild mid epigastric pain, which was treated with orally administered acetominophen. One patient reported difficulty eructating after the procedure. These mild adverse events disappeared spontaneously within 7 days after the procedure. No complications requiring intervention, other than as mentioned above, occurred during the study. No late complication, such VOLUME 58, NO. 5, 2003
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Figure 1. Schematic illustration of fullthickness plication procedure. A, (step 1) Specially designed plicator enters stomach and is retroflexed and positioned within 1 to 2 cm of GE junction. B, (step 2) Plicator arms are opened and a proprietary endoscopic tissue retractor is advanced into gastric wall to the serosa. C, (step 3) Full-thickness of gastric wall is retracted and plicator arms are closed. D, (step 4) A single, pretied implant is deployed, securing serosa-to-serosa plication. E, (step 5) Resulting full-thickness plication restores normal antireflux barrier.
as stricture formation, dysphagia, or bleeding, was reported, and, likewise, at 3 and 6 months, there was no ulcer or stricture found at endoscopy in any patient. Durability The full-thickness plication appeared to be intact in all patients at endoscopy 3 and 6 months after plication. VOLUME 58, NO. 5, 2003
GERD symptoms and health-related quality of life By comparison to baseline, GERD symptoms were less in all 5 patients who completed 12-month followup. The mean reflux GSRS score decreased more than 75% at the 12-month follow-up (6.8 [1.8] to 1.8 [1.5]). Likewise, the mean GERD-HRQL scores also improved approximately 75% at the 12-month followup (18.8 [5.9] to 4.6 [5.6]) (Table 1). The mean GASTROINTESTINAL ENDOSCOPY
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Table 1. Reflux-sources before and after plication GERD-HRQL F/U mo # # # # # #
1* 2 3 4 5 6
Mean SD
B
1
16 23 11 25 14 24
5 13 0 5 1 12
18.8 5.9
3 7 3 0 3 7 4
7.5 4.7 5 2.9
GSRS: GERD score
6
12
B
5 8 3 12 2 6
NA 3 0 14 1 5
8 10 6 6 5 6
6.0 3.6
4.6 5.6
6.8 1.8
1
3
6
12
6 6 1 2 3 5
2 3 0 5 2 3
2 1 0 3 2 1
NA 0 0 4 2 1
3.8 2.2
2.6 1.6
1.6 1
1.8 1.4
F/U, Follow-up; GERD-HRQL, GERD-Health Related Quality of Life questionnaire; GSRS, Gastrointestinal Symptom Rating Scale; B, baseline; NA, not applicable; SD, standard deviation. *Patient 1 underwent Nissen fundoplication after 6-month follow-up because of an exacerbation in symptoms. 12-mo follow-up is not available for this patient.
DISCUSSION
Figure 2. Full-thickness plication in stomach of a pig. A, Serosal view of suture showing full-thickness plication. B, Schematic diagram of ePTFE bolsters and suture securing serosa-serosa plication.
GERD-HRQL and GSRS for baseline, 1, 3, 6, and 12 months after plication are shown in Figures 4 and 5, respectively. Overall quality of life, as assessed with the SF36, was improved at 12 months after the procedure. The mean PCS improved from 34.6 (7.4) at baseline to 44.8 (5.9) at 1 month after the procedure, and to 50.4 (1.3) at 12 months. The mean MCS also improved, although not much, from 48.0 (6.0) at baseline to 51.6 (2.1) at 1 month, and to 53.1 (2.1) at 12 months. At the 12-month follow-up, one patient was still taking PPIs regularly, although at a lower dose than at baseline. Another patient was taking an H2RA and the prokinetic agent mosapride intermittently. The remaining 3 patients were taking no medication for reflux symptoms. In two patients, the esophagitis score was downgraded from grade 2 to grade 1. In the remaining 3 patients, there was no change in esophagitis score (grade 1, 2 patients; grade 0, one patient). 774
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Although medical therapy is effective in most patients with GERD, many patients continue to have regurgitation despite treatment, and others are unwilling or unable to take medications on a daily basis. The need for effective non-pharmacologic therapy also is demonstrated by the rapidly increasing number of laparoscopic antireflux operations being performed since the introduction of these procedures in the early 1990s. The potential advantages of an endoscopic procedure over a surgical antireflux procedure include lower cost, shorter postoperative recovery time, reduced discomfort, and, potentially, fewer complications. An endoscopic antireflux procedure also could be an attractive alternative to long-term acid suppression. The endoscopic full-thickness plication device used in the present study is designed to inhibit reflux with a single plication near the GE junction. Fullthickness plication of the proximal stomach may improve the competency of the GE barrier by restoring the valvular mechanism of the GE junction. Other potential mechanisms include alteration of the angle of His, decreased compliance of the gastric cardia and fundus, enhancement of the LES resting pressure, and reduction in transient relaxations of the LES. The present study demonstrates that the endoscopic placement of a single, full-thickness plication in the gastric cardia technically is feasible in patients with symptoms caused by GERD. The procedures were technically simple to perform, largely because of direct endoscopic visualization throughout the entire plication procedure. It also is essential that any endoscopic intervention not preclude patients from pursuing other treatment strategies in the event that VOLUME 58, NO. 5, 2003
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Figure 3. Endoscopic views of full-thickness plication in a patient. A, Helical tissue retractor inserted approximately 1 cm from GE junction. B, Gastric wall is retracted and plication arms are opened. C, Arms of the instrument are closed and plication is deployed. D, Appearance after plication.
relief of symptoms is non-sustainable. Because endoscopic full-thickness plication is not destructive to the tissues of the GE junction, successful laparoscopic fundoplication surgery was possible in one patient in the present study. No significant complication occurred during 12 months of follow-up, suggesting that the procedure is safe. Only minor side effects were reported, all of which resolved spontaneously within 7 days. The study was not designed to demonstrate efficacy. However, all patients reported improvement in symptoms, several were able to discontinue PPI therapy, and the majority were able to avoid taking medications for GERD symptoms even after 12 months’ follow-up. Overall, the results of 24-hour pH monitoring did not improve dramatically. A significant increase in acid reflux was noted in one patient during follow-up. After the full-thickness plication, this patient experienced an initial VOLUME 58, NO. 5, 2003
improvement in symptoms, and, subsequently, his weight increased by approximately 10 kg, but this was followed by a recurrence of reflux symptoms. Based on studies in animals, the plication appears to be most effective when placed close to the GE junction (i.e., within 1-2 cm). Although placement in this location was attempted in all patients, there was significant variability, in part because of the learning curve inherent to any new procedure. In conclusion, this study demonstrates the technical feasibility of endoscopic full-thickness plication in patients with symptoms caused by GERD. In addition, the procedure appears to be safe and does not appear to interfere with subsequent laparoscopic fundoplication, if required. Based on these encouraging initial results, a multicenter study currently is in progress to further assess the effectiveness and safety of the full-thickness GASTROINTESTINAL ENDOSCOPY
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Figure 4. Results of GERD–Health Related Quality of Life. Mean GERD-HRQL scores are shown for baseline period (antisecretory medications discontinued for 1 week) and at 1, 3, 6, and 12 months. (n = 6, except for month 12, where n = 5).
Figure 5. Gastrointestinal Symptom Rating Scale reflux scores; shown are mean GSRS scores for baseline period (antisecretory medications discontinued for 1 week) and at 1, 3, 6, and 12 months (n = 6, except for month 12, where n = 5).
plication for treatment of patients with GERD symptoms. DISCLOSURE Sponsored by NDO Surgical, Inc., Mansfield, Massachusetts. Ram Chuttani, MD, has an equity position in the sponsoring company, NDO Surgical, Inc. REFERENCES 1. Lagergren J, Bergstrom R, Lindgren A, Nyren O. Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma. N Engl J Med 1999;340:825-31.
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2. Dimenas E, Glise H, Hallerback B, Hernqvist H, Svedlund J, Wiklund I. Quality of life in patients with upper gastrointestinal symptoms. An improved evaluation of treatment regimens? Scand J Gastroenterol 1993;28:681-7. 3. Dent J, Yeomans ND, Mackinnon M, Reed W, Narielvala FM, Hetzel DJ, et al. Omeprazole v ranitidine for prevention of relapse in reflux oesophagitis. A controlled double blind trial of their efficacy and safety. Gut 1994;35:590-8. 4. Lundell L. Long-term treatment of gastro-oesophageal reflux disease with omeprazole. Scand J Gastroenterol Suppl 1994; 201:74-8. 5. Hetzel DJ, Dent J, Reed WD, Narielvala FM, Mackinnon M, McCarthy JH, et al. Healing and relapse of severe peptic esophagitis after treatment with omeprazole. Gastroenterology 1988;95:903-12. 6. Jamieson GG, Watson DI, Britten-Jones R, Mitchell PC, Anvari M. Laparoscopic Nissen fundoplication. Ann Surg 1994;220:137-45. 7. Lundell L, Miettinen P, Myrvold HE, Pedersen SA, Liedman B, Hatlebakk JG, et al. Continued (5-year) follow up of a randomized clinical study comparing antireflux surgery and omeprazole in gastroesophageal reflux disease. J Am Coll Surg 2001;192:172-9; discussion 179-81. 8. Spechler SJ, Lee E, Ahnen D, Goyal RK, Hirano I, Ramirez F, et al. Long-term outcome of medical and surgical therapies for gastroesophageal reflux disease: follow-up of a randomized controlled trial. JAMA 2001;285:2331-8. 9. Hookman P, Barkin JS. Surgical complications of laparoscopic fundoplication for gastroesophageal reflux disease: call for reevaluation of surgical criteria. Am J Gastroenterol 2000;95:3305-8. 10. Lafullarde T, Watson DI, Jamieson GG, Myers JC, Game PA, Devitt PG. Laparoscopic Nissen fundoplication: five-year results and beyond. Arch Surg 2001;136:180-4. 11. Triadafilopoulos G, Dibaise JK, Nostrant TT, Stollman NH, Anderson PK, Edmundowicz SA, et al. Radiofrequency energy delivery to the gastroesophageal junction for the treatment of GERD. Gastrointest Endosc 2001;53: 407-15. 12. Utley DS, Kim M, Vierra MA, Triadafilopoulos G. Augmentation of lower esophageal sphincter pressure and gastric yield pressure after radiofrequency energy delivery to the gastroesophageal junction: a porcine model. Gastrointest Endosc 2000;52:81-6. 13. Swain CP, Brown GJ, Gong F, Mills TN. An endoscopically deliverable tissue-transfixing device for securing biosensors in the gastrointestinal tract. Gastrointest Endosc 1994;40:730-4. 14. Chuttani R, Kozarek R, Critchlow J, Lo S, Pleskow D, Brandwein S, Lembo T. A novel endoscopic full-thickness plicator for treatment of GERD: an animal model study. Gastrointest Endosc 2002;56:116-22. 15. Velanovich V. Comparison of symptomatic and quality of life outcomes of laparoscopic versus open antireflux surgery. Surgery 1999;126:782-8; discussion 788-9. 16. McHorney CA, Kosinski M, Ware JE Jr. Comparisons of the costs and quality of norms for the SF-36 health survey collected by mail versus telephone interview: results from a national survey. Med Care 1994;32:551-67.
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