eMedicine Feature Series

Gastroesophageal Reflux Disease Newsletter _________ Series 1, Issue 6, 2007

ENDOTHERAPY FOR GERD

Sanjeeb Shrestha, MD, FACG
Northwest Arkansas Gastroenterology Clinic

Gastroesophageal reflux disease (GERD) is a common disorder that affects almost 20% of the United States population once a week. The annual cost of GERD is estimated at more than $10 billion. GERD is a chronic condition that affects patients’ quality of life. Most patients can control their symptoms with a combination of medication and lifestyle modification. Approximately 20% of patients do not get relief from symptoms with medical treatment. Additionally, relapse is common after cessation of medication, and recent studies suggest that long-term proton pump inhibitor (PPI) use may increase the risk of hip fracture.¹ Previously, laparoscopic fundoplication was the only available option for long-term relief of GERD. Surgery was often not chosen because of the associated morbidity and mortality. Recently developed endoscopic therapies can be an attractive option because of the relative ease of the procedure and lower morbidity and mortality (as compared to surgery).

Currently, 2 endoscopic modalities are approved by the US Food and Drug Administration (FDA). These include endoscopic radiofrequency ablation (the Stretta System, Curon Medical Inc., Sunnyvale, Calif) and various suturing devices to increase the lower esophageal sphincter (LES) pressure, including endoluminal gastroplication (ELGP) and full-thickness plication (the Full-Thickness Plicator, NDO Surgical Inc., Mansfield, Mass). A third option of injectable biocompatible polymer mixed with radiopaque contrast agent (tantalum powder) dissolved in an organic carrier (Enteryx, Boston Scientific Corp., Natick, Mass) was voluntarily removed from the market in September 2005 after several deaths related to Enteryx injection were reported.

Each of these methods alters the anatomy or physiology of the gastroesophageal junction to decrease reflux symptoms. The exact mechanism of action is not yet determined, but it is related to a decreased transient lower esophageal relaxation, increased LES pressure, and alteration in visceral sensitivity. The initial enthusiasm for these endoscopic modalities has been tempered with caution because of the increased morbidity and mortality associated with the treatments. Though endoscopic therapy does have merit, it has not been accepted widely because of potential risks, low risk of mortality from the condition itself, and lack of long-term efficacy data. An ideal method should be safe, effective in the long term, and easy for the endoscopist to complete. Data are now available from several open-label and randomized sham-controlled studies on the long-term efficacy of all these endoscopic treatment modalities.

RADIOFREQUENCY ABLATION

The Stretta System delivers temperature-controlled radiofrequency (RF) energy to the distal esophagus via balloon basket assembly with 4 nickel-titanium needle electrodes coming out radially.

In 2007, 2 published studies showed the long-term efficacy of the Stretta endoscopic antireflux procedure. Though both the studies were nonrandomized, they were able to demonstrate sustained long-term improvements (up to 4 years) in symptom relief, quality of life (QOL), and decreased use of PPIs. Reymunde et al reported on their prospective single-center case series of 83 consecutive patients who underwent the Stretta procedure.² A health-related QOL assessment was performed at baseline and at 12, 36, and 48 months. The GERD QOL score was 2.4 at baseline, 4.6 at 36 months, and 4.3 at 48 months (P < .001). The mean GERD score improved from 2.7 at baseline to 0.6 at 48 months (P < .001). Daily medication use decreased from 100% at baseline to 13.6% at 48 months (P < .001).

Noar et al reported on a 4-year follow-up of their series of 109 consecutive patients who underwent the Stretta procedure.³ Heartburn score decreased from 3.6 to 1.18 (P < .001), and total heartburn score (based on GERD health-related QOL questionnaire) decreased from 27.8 to 7.1 (P < .001). Medication use decreased in 75% of the patients who were on chronic twice-daily PPI therapy.

In 2003, Corley et al reported on the only randomized, double-blind, sham-controlled trial.⁴ In this study, 64 patients were enrolled; 35 patients had RF treatment while 29 patients had a sham procedure. At 5 months, the RF-treated group had significant improvement in all primary end points of mean heartburn score, mean GERD QOL score, and mean SF-36 score (a validated 36-item instrument designed to measure health status and outcomes).

Various adverse effects have been reported as a result of the procedure, ranging in gravity from minor to death. Potential adverse effects include chest pain, fever, transient dysphagia, nausea, and vomiting; such adverse effects occur in 1.7-8% of patients. More than 6,000 patients have so far undergone the RF procedure, and, with refinement, the current complication rate is estimated to be 0.24%.

ENDOSCOPIC INJECTION

This procedure involves injection of inert material into the lower esophageal sphincter (LES), which causes augmentation of the LES and also decreases transient LES relaxation.

The available implantable device was Enteryx, which consists of tantalum dissolved in dimethyl sulfoxide and a hydrogel prosthesis (Gatekeeper, Medtronic Inc., Minneapolis, Minn).

Results of a placebo-controlled multicenter European study were published in 2005.⁵ The Enteryx injection was performed in 32 patients, and 32 patients received a placebo injection. A greater than 50% reduction in symptoms was achieved by 25 (78%) patients in the Enteryx group and 17 (53%) patients in the placebo group. Further results included 21 (65%) patients in the Enteryx group who stopped PPI therapy completely and significant improvement in GERD QOL scores in 67% of patients in the treated group.

Cohen et al reported on their open-label international clinical trial on 144 patients taking PPI therapy.⁶ The investigators followed up with the patients at 6 and 12 months. At 12 months, PPI therapy was decreased by more than 50% in 84% of the patients, and PPI was completely eliminated in 73% of the patients. The reported adverse effects included chest pain (85%) and dysphagia (24%). Out of 2,600 cases, 33 complications, including 5 deaths, were reported. One death was the result of aortoesophageal fistula. In September 2005, Boston Scientific Corporation voluntarily withdrew Enteryx from the market.

ENDOSCOPIC GASTROPLICATION

Currently, 2 commercial devices are available for endoscopic gastroplication: the EndoCinch Suturing System (Bard Endoscopic Technologies, Billerica, Mass) and the Full-Thickness Plicator (NDO Surgical Inc., Mansfield, Mass). A third device, the Endoscopic Suturing Device (Wilson-Cook Medical Inc., Winston-Salem, NC), was withdrawn from the market in 2004. These devices are designed to place sutures 1 cm below the gastroesophageal junction in the gastric cardia, thereby enhancing the competency of the gastroesophageal junction. Normally, 1-3 sutures are placed; they can be superficial (submucosal) or deep (transmural).

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Pleskow et al reported in 2005 on their open-label study of 64 patients who underwent full-thickness plication at the gastroesophageal junction with the NDO plicator.⁷ Ambulatory 24-hour pH level monitoring and esophageal manometry were done at baseline and at 3 and 6 months after plication. Out of 57 patients, 40 were no longer on PPI therapy at the end of 1 year. Scores on the GERD health-related QOL questionnaire improved compared to baseline. At 6 months, the median time of pH levels measuring less than 4 was reduced by 39% (P < .0001), and normal pH levels were seen in 30% of the patients.

Chen et al reported on their long-term multicenter US trial in 2005.⁸ They enrolled 85 patients who underwent endoluminal gastroplication with EndoCinch, and follow-up data were reported at year 1 and year 2. Out of 85 patients, 59% and 52% experienced resolution of their heartburn at 12 and 24 months, respectively (P < .0001). Resolution of regurgitation symptoms was seen in 83% and 77% of patients at 12 and 24 months, respectively. Among the 74 patients on PPI therapy at baseline, 43% at 12 months and 41% at 24 months were no longer taking PPI therapy. At 2-year follow-up, the costs of annualized medication were substantially reduced by $1382 (88%) compared to baseline (P < .0001).

Montgomery et al reported on the first randomized placebo-controlled trial to study the EndoCinch Suturing System in 2006.⁹ They randomized 46 patients to EndoCinch and placebo procedure. They found improvement in QOL assessment in both groups. The improvements were superior in the treatment group at 3 months but similar at 12 months, indicating a placebo effect. Levels of 24-hour acid exposure were not reduced. The authors postulated that this lack of efficacy could be related to loss of suture.

Pleskow et al published in January 2007 on the long-term safety and durability of effect for the NDO plicator.¹⁰ A total of 29 patients from 5 different sites underwent a single full-thickness plication at the gastric cardia. At 36-month follow-up, 57% (16/28) of patients were no longer taking daily PPI therapy. At 36 months, 55% of patients showed more than 50% improvement in GERD health-related QOL scores.

In Jan 2007, Schwartz et al reported on their randomized, double-blind, placebo-controlled trial of endoscopic gastroplication with the EndoCinch Suturing System.¹¹ In this European study, they enrolled 60 patients and randomized 20 patients each to gastroplication, a placebo procedure, or observation. Three sutures were placed with the EndoCinch plicator. Primary outcome measures were PPI use and GERD symptoms with follow-up assessments at 3, 6, and 12 months. At 3 months, a more than 50% drug reduction was seen in 65% of patients in the treatment arm as opposed to 25% in the placebo group. Heartburn frequency and QOL scores decreased in the treatment group at 3 months, with 8 patients (40%) being heartburn-free as compared to 1 patient (5%) in the placebo group. This effect lasted up to the 12-month follow-up assessment. However, reduction in esophageal acid exposure was not significantly changed in the treatment group as compared to the placebo group.

CONCLUSION

The recent nonrandomized studies demonstrate the improved safety record and sustained efficacy with the Stretta System. However, long-term efficacy data from randomized studies are not yet available. Although 12-month efficacy data for gastroplication are now available, widespread use cannot be justified until the procedure is improved such that esophageal acid exposure is diminished and the sutures are more durable. This was best summarized by Dr. Jan Tack: “For the time being, endoscopic anti-reflux procedures should be done in a controlled environment, preferably in reference centers with adequately trained and experienced staff, and within the framework of a registry or study.”¹²

REFERENCES

1. Yang YX, Lewis JD, Epstein S, Metz DC. Long-term proton pump inhibitor therapy and risk of hip fracture. JAMA. 2006;296(4):2947-53.

2. Reymunde A, Santiago N. Long term results of radiofrequency energy delivery for the treatment of GERD: sustained improvements in symptoms, quality of life, and drug use at 4-year follow-up. Gastrointest Endosc. 2007;65(3):361-6.

3. Noar MD, Lotfi-Emran S. Sustained improvement in symptoms of GERD and antisecretory drug use: 4-year follow-up of the Stretta procedure. Gastrointest Endosc. 2007;65(3):367-72.

4. Corley DA, Katz P, Wo J, et al. Improvement of gastroesophageal reflux symptoms after radiofrequency energy: a randomized, sham-controlled trial. Gastroenterology. 2003;125:668-76.

5. Deviere J, Costamagna G, Neuhaus H, et al. Non-resorbable copolymer implantation for gastroesophageal reflux disease; a randomized sham-controlled multicenter trial. Gastroenterology. 2005;128:532-40.

6. Cohen LB, Johnson DA, Ganz RA, et al. Enteryx implantation for GERD: expanded multicenter trial results and interim postapproval follow-up to 24 months. Gastrointest Endosc. 2005;61(6):650-8.

7. Pleskow D, Rothestein R, Lo S, et al. Endoscopic full-thickness placation for the treatment of GERD: 12- month follow-up for the North American open-label trial. Gastrointest Endosc. 2005;61(6):643-9.

8. Chen YK, Raijman I, Ben-Menachem T, et al. Long-term outcomes of endoluminal gastroplication: a U.S. multicenter trial. Gastrointest Endosc. 2005;61(6):659-67.

9. Montgomery M, Hakanson B, Ljungqvist O, Ahlman B, Thorell A. Twelve months’ follow-up after treatment with the EndoCinch endoscopic technique for gastro-esophageal reflux disease: a randomized, placebo-controlled study. Scand J Gastroenterol. 2006;41(12):1382-9.

10. Pleskow D, Rothstein R, Kozarek R, Haber G, Gostout C, Lembo A. Endoscopic full-thickness plication for the treatment of GERD: long-term multicenter results. Surg Endosc. 2007;21(3):439-44.

11. Schwartz MP, Wellink H, Gooszen HG, Conchillo JM, Samsom M, Smout AJ. Endoscopic gastroplication for the treatment of gastro-esophageal reflux disease: a randomized, sham-controlled trial. Gut. 2007;56:20-8.

12. Arts J, Tack J, Galmiche JP. Recent advances in clinical practice; endoscopic anti-reflux procedures. Gut. 2004;53:1207-16.

FURTHER READING

Annese V, Caletti G, Cipolleta L, et al. Endoscopic treatment of gastroesophageal reflux disease. Endoscopy. 2005;37(5):470-8.

Hogan WJ. Endoscopic therapy for gastroesophageal reflux disease. Curr Gastroenterol Rep. 2003;5:206-13.

Joish VN, Donaldson G, Stockdale W, et al. The economic impact of GERD and PUD: examination of direct and indirect costs using a large integrated employer claims database. Curr Med Res Opin. 2005;21:535-44.

AUTHOR SPOTLIGHT

Sanjeeb Shrestha, MD, FACG
Consulting Staff
Division of Gastroenterology
Northwest Arkansas Gastroenterology Clinic

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