Raising the bar in studies of endoscopic anti-reflux procedures
2005; Elsevier BV; Volume: 128; Issue: 3 Linguagem: Inglês
10.1053/j.gastro.2005.01.016
ISSN1528-0012
Autores Tópico(s)Helicobacter pylori-related gastroenterology studies
ResumoThe past few years have seen a number of endoscopic technologies introduced for the treatment of reflux. These novel approaches attempt to burn, tie, stuff, or otherwise manipulate the hiatus, with the goal of decreasing esophageal acid exposures. While interesting, these approaches have reached the consumer market largely before rigorous testing of the devices had occurred. Based on unblinded studies of relatively small numbers of patients, the devices have obtained FDA approval, and dissemination has followed. Currently, endoscopic sewing machines,1Filipi C.J. Lehman G.A. Rothstein R.I. Raijman I. Stiegmann G.V. Waring J.P. et al.Transoral, flexible endoscopic suturing for treatment of GERD a multicenter trial.Gastrointest Endosc. 2001; 53: 416-422Google Scholar, 2Tam W.C. Holloway R.H. Dent J. Rigda R. Schoeman M.N. Impact of endoscopic suturing of the gastroesophageal junction on lower esophageal sphincter function and gastroesophageal reflux in patients with reflux disease.Am J Gastroenterol. 2004; 99: 195-202Google Scholar, 3Rothstein R.I. Filipi C.J. Endoscopic suturing for gastroesophageal reflux disease clinical outcome with the Bard EndoCinch.Gastrointest Endosc Clin N Am. 2003; 13: 89-101Google Scholar a full-thickness plicator,4Chuttani R. Sud R. Sachdev G. Puri R. Kozarek R. Haber G. et al.A novel endoscopic full-thickness plicator for the treatment of GERD a pilot study.Gastrointest Endosc. 2003; 58: 770-776Google Scholar the Stretta device,5Triadafilopoulos G. DiBaise J.K. Nostrant T.T. Stollman N.H. Anderson P.K. Wolfe M.M. et al.The Stretta procedure for the treatment of GERD 6 and 12 month follow-up of the U.S. open label trial.Gastrointest Endosc. 2002; 55: 149-156Google Scholar, 6Go M.R. Dundon J.M. Karlowicz D.J. Domingo C.B. Muscarella P. Melvin W.S. Delivery of radiofrequency energy to the lower esophageal sphincter improves symptoms of gastroesophageal reflux.Surgery. 2004; 136: 786-794Google Scholar and inert injectibles7Johnson D.A. Ganz R. Aisenberg J. Cohen L.B. Deviere J. Foley T.R. et al.Endoscopic implantation of enteryx for treatment of GERD 12-month results of a prospective, multicenter trial.Am J Gastroenterol. 2003; 98: 1921-1930Google Scholar, 8Johnson D.A. Ganz R. Aisenberg J. Cohen L.B. Deviere J. Foley T.R. et al.Endoscopic, deep mural implantation of Enteryx for the treatment of GERD 6-month follow-up of a multicenter trial.Am J Gastroenterol. 2003; 98: 250-258Google Scholar are all available on the U.S. market.The “gee-whiz” momentThe early literature of the endoscopic anti-reflux devices has a “gee-whiz” aspect to it—investigators seemed more interested in proof of the principle that the procedures could be done and be done safely than in attaining high-quality evidence of efficacy in treating reflux. For that reason, early publications dwell more on methodological aspects of the performance of the procedure than on justifying the outcomes measured or the analysis performed. These studies often presented unblinded cohort data demonstrating symptom improvement, and some techniques have not had adequate proof of efficacy. As the field has matured, more interest has developed in rigorous testing of these methods in a blinded fashion. Slowly, the bar has been raised for research on endoscopic anti-reflux procedures.A sham-controlled study of EnteryxIn this setting, it is particularly refreshing to see, in this month’s edition of Gastroenterology, the report of Deviere et al9Deviere J. Costamagna G. Neuhaus H. Voderholzer W. Louis H. Tringali A. Marchese M. Fiedler T. Darb-Esfahani P. Schumacher B. Nonresorbable copolymer implantation for gastroesophageal reflux disease a randomized sham-controlled multi-center trial.Gastroenterology. 2005; 128: 532-540Abstract Full Text Full Text PDF Scopus (118) Google Scholar of a randomized, sham-controlled trial of Enteryx for the control of reflux disease. Enteryx consists of a nonresorbable copolymer that is liquid when injected, but coalesces into a rubbery substance when the carrier solution leaches out of the injectate and is absorbed into the tissues. This copolymer has been used for years in other medical areas, such as embolization of cerebral vasculature,10Hamada J. Kai Y. Morioka M. Kazekawa K. Ishimaru Y. Iwata H. et al.A mixture of ethylene vinyl alcohol copolymer and ethanol yielding a nonadhesive liquid embolic agent to treat cerebral arteriovenous malformations initial clinical experience.J Neurosurg. 2002; 97: 881-888Google Scholar, 11Jahan R. Murayama Y. Gobin Y.P. Duckwiler G.R. Vinters H.V. Vinuela F. Embolization of arteriovenous malformations with Onyx clinicopathological experience in 23 patients.Neurosurgery. 2001; 48: 984-995Google Scholar but its use as an inert bulking agent at the lower esophageal sphincter represents its first application in gastrointestinal diseases.Deviere et al9Deviere J. Costamagna G. Neuhaus H. Voderholzer W. Louis H. Tringali A. Marchese M. Fiedler T. Darb-Esfahani P. Schumacher B. Nonresorbable copolymer implantation for gastroesophageal reflux disease a randomized sham-controlled multi-center trial.Gastroenterology. 2005; 128: 532-540Abstract Full Text Full Text PDF Scopus (118) Google Scholar randomized 64 patients with GERD symptoms responsive to proton pump inhibitors to receive either Enteryx injection or a sham procedure, in which an upper endoscopy was performed, but no Enteryx was injected. Follow-up evaluation was performed at 3 and 6 months, but crossover was allowed after 3 months. The primary outcome was a greater than 50% reduction in PPI use, and the secondary outcomes were scores on a disease-specific, quality-of-life measure, the GERD-HRQL, and the need for treatment at the 3 month follow-up. Twenty-four hour pH data were also collected at baseline and at 6 months on 39 of the patients.The authors show that, at 3 months, the number of subjects achieving the primary outcome variable, a 50% reduction in proton pump inhibitor use, was significantly higher in Enteryx-treated patients than controls (81% vs. 53%, rate ratio 1.52, 95%CI 1.06–2.28). Similar improvements were noted among the Enteryx-treated patients in GERD-HRQL, as well. Six Enteryx-treated patients opted for re-treatment at 3 months, whereas 20 sham-treated patients crossed over. Six-month data are difficult to interpret given this high degree of crossover, but, of note, it does appear that the improvements in GERD-HRQL seen at 3 months persisted at 6 months. Twenty-four hour pH data, while incomplete, demonstrated no significant changes in acid exposure when comparing baseline studies to 6-month studies in those receiving Enteryx therapy. The authors conclude that Enteryx implantation is superior to a sham procedure in reducing PPI dependency and alleviating GERD symptoms.This study is important in a number of respects. The study makes Enteryx only the second endoscopic anti-reflux device to report a randomized, sham-controlled trial in a peer-reviewed manuscript. An earlier study by Corley et al, also published in Gastroenterology, used methodology similar to the present study to assess the effect of the Stretta procedure in subjects with GERD.12Corley D.A. Katz P. Wo J.M. Stefan A. Patti M. Rothstein R. et al.Improvement of gastroesophageal reflux symptoms after radiofrequency energy a randomized, sham-controlled trial.Gastroenterology. 2003; 125: 668-676Google Scholar In the Corley study, 64 subjects were randomized to receive upper endoscopy with the Stretta procedure, or upper endoscopy with insertion of the Stretta catheter, but no delivery of thermal energy. Similar to the current study, Corley et al12Corley D.A. Katz P. Wo J.M. Stefan A. Patti M. Rothstein R. et al.Improvement of gastroesophageal reflux symptoms after radiofrequency energy a randomized, sham-controlled trial.Gastroenterology. 2003; 125: 668-676Google Scholar demonstrated improvements in a standardized GERD symptom questionnaire, as well as a decreased need for medication. However, similar to the Deviere study, the Corley study was unable to demonstrate any significant effect in esophageal acid exposures on pH-metry when comparing baseline acid exposures to those after Stretta therapy. A closer look at these 2 studies helps us place these endoscopic methods in clinical context, and allows us to consider potential improvements in future studies of endoscopic anti-reflux devices.Improving study methodology in endoscopic therapyThe Corley and Deviere studies represent the best data we have available to date on endoscopic anti-reflux technologies. Both studies go to extensive effort to blind the participants in the study as to their assignment, hoping to remove the possibly significant placebo effect that accompanies these procedures. However, both of the studies have flaws. For instance, neither the Corley study12Corley D.A. Katz P. Wo J.M. Stefan A. Patti M. Rothstein R. et al.Improvement of gastroesophageal reflux symptoms after radiofrequency energy a randomized, sham-controlled trial.Gastroenterology. 2003; 125: 668-676Google Scholar nor the Deviere study asked the patients to guess which arm of the study they had been assigned. There is reason to think that some subjects in both studies might have been able to guess their assignment, thereby unblinding them as to their treatment. We know from previous studies that a significant number of subjects receiving both Stretta and Enteryx treatments have transient postprocedure chest pain as a complication of the procedure.13Deviere J. Pastorelli A. Louis H. de Maertelaer V. Lehman G. Cicala M. LeMoine O. Silverman D. Costamagna G. Endoscopic implantation of a biopolymer in the lower esophageal sphincter for gastroesophageal reflux a pilot study.Gastrointest Endosc. 2002; 55: 335-341Google Scholar, 14Triadafilopoulos G. Stretta an effective, minimally invasive treatment for gastroesophageal reflux disease.Am J Med. 2003; 115: 192S-200SGoogle Scholar Subjects undergoing diagnostic upper endoscopy rarely have significant complaints of chest pain. Therefore, subjects with chest pain following the procedure might have surmised that they were part of the intervention arm. Because all of the subjects in both studies had previously had upper endoscopy before participating in the study, they knew what a diagnostic upper endoscopy was “supposed” to feel like, making it more likely that those who received treatment sensed that something was different. In the study by Deviere et al, the vast disparity of subjects reporting chest pain in the treatment group (69%) compared with the controls (6%) substantiates this potential for bias in the study.9Deviere J. Costamagna G. Neuhaus H. Voderholzer W. Louis H. Tringali A. Marchese M. Fiedler T. Darb-Esfahani P. Schumacher B. Nonresorbable copolymer implantation for gastroesophageal reflux disease a randomized sham-controlled multi-center trial.Gastroenterology. 2005; 128: 532-540Abstract Full Text Full Text PDF Scopus (118) Google Scholar If subjects knew that they had been randomized to the intervention arm, this knowledge may have caused differential reporting of symptoms such that those receiving the intervention were less likely to report symptoms. Medication use might have been similarly affected.Additionally, subjects injected with Enteryx often report a characteristic unpleasant or “garlicky” breath odor, which is a byproduct of exhalation of the carrier solution for the copolymer, DMSO. If a subject experienced this breath odor, they might again conclude that they had gotten the intervention and not the sham. To their credit, the authors considered this issue and sought permission from their ethics committee to allow the injection of the DMSO alone, which would have addressed this problem, but were denied because of safety concerns.The issue of patient unblinding is especially important given that, in both the Corley12Corley D.A. Katz P. Wo J.M. Stefan A. Patti M. Rothstein R. et al.Improvement of gastroesophageal reflux symptoms after radiofrequency energy a randomized, sham-controlled trial.Gastroenterology. 2003; 125: 668-676Google Scholar and Deviere9Deviere J. Costamagna G. Neuhaus H. Voderholzer W. Louis H. Tringali A. Marchese M. Fiedler T. Darb-Esfahani P. Schumacher B. Nonresorbable copolymer implantation for gastroesophageal reflux disease a randomized sham-controlled multi-center trial.Gastroenterology. 2005; 128: 532-540Abstract Full Text Full Text PDF Scopus (118) Google Scholar studies, subjective measures of GERD severity, such as symptom severity scores and the amount of medication used, improved, while objective measures of GERD severity, such as 24-hour pH probe data, were unimproved. Certainly, in the case of Stretta, neurolysis leading to decreased sensation of reflux may account for the diminished symptoms and decreased medication use seen in these patients.15Kahrilas P.J. Radiofrequency energy treatment of GERD.Gastroenterology. 2003; 125: 970-973Google Scholar However, another potential explanation for these findings in both studies is that the actual procedures did little to affect the GERD, and the positive effects noted were largely from differential symptom reporting and medication use in the treated patients due to unblinding.Other issues of concern in the sham-controlled studies include the relatively short study durations, given that GERD is generally a lifelong disease. Certainly, it would be comforting to have more than 3 to 6 month randomized data prior to committing a 30-year-old individual to one of these therapies. Given some of the data on the durability (or lack thereof) of Nissen fundoplication,16Spechler S.J. Lee E. Ahnen D. Goyal R.K. 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: 2331-2338Google Scholar one might not be surprised if the competence of the endoscopic procedures also declined over time. However, in the authors’ defense, it is difficult to ask a subject with GERD to go untreated except for rescue medications for greater than a 3-month period. The studies were limited to subjects with small or no hiatal hernias and those who were PPI-responsive. Whether the findings are generalizable to those who do not fit these criteria is unclear.While these issues challenge the validity and generalizability of some of the findings of the 2 studies, there can be little argument that the information derived from these studies is superior in quality to previous data regarding these procedures. Strict entry criteria, earnest attempts at blinding, randomization, a priori fixed endpoints, and intention-to-treat analysis were all features of both the Corley12Corley D.A. Katz P. Wo J.M. Stefan A. Patti M. Rothstein R. et al.Improvement of gastroesophageal reflux symptoms after radiofrequency energy a randomized, sham-controlled trial.Gastroenterology. 2003; 125: 668-676Google Scholar and Deviere9Deviere J. Costamagna G. Neuhaus H. Voderholzer W. Louis H. Tringali A. Marchese M. Fiedler T. Darb-Esfahani P. Schumacher B. Nonresorbable copolymer implantation for gastroesophageal reflux disease a randomized sham-controlled multi-center trial.Gastroenterology. 2005; 128: 532-540Abstract Full Text Full Text PDF Scopus (118) Google Scholar studies.A separate question to be considered is whether the above studies really compare the clinically relevant treatment strategies. Sham-controlled studies have the enormous potential advantage of blinding the participants as to the performance of the procedure. However, as performed by Corley et al and Deviere et al, the studies essentially compare the endoscopic intervention to no treatment except rescue medications. This is not the choice that we as clinicians routinely face. The more usual situation is trying to decide whether to use the device or to continue/intensify medical therapy. Future studies of these devices might consider different study designs. Because these devices are being marketed as alternatives to chronic proton pump inhibition, it would be logical to compare the devices to medical management. One way to do this would be to have all subjects go through a procedure, then continue to take pills on a daily basis over the study period. One half of participants would receive the actual intervention, but placebo pills, while the other half would receive a sham procedure but actual scheduled proton pump inhibition. Data from such a study, if appropriately powered, would allow us to ascertain whether the new procedures were superior to (or at least no worse than) medical therapy.Where do endoscopic anti-reflux devices fit in our current armamentarium?So what are we to make of these devices presently? Certainly, the total number of patient-years reported in the literature for each of the procedures makes it possible that a rare but devastating complication of one of these procedures has not yet come to light. Given the lack of FDA-mandated post-marketing surveillance and complication reporting, such a complication could take years to recognize. The FDA does have a website for voluntary reporting of possible complications via the Manufacturer and User Facility Device Experience Database (MAUDE, www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfmaude/search.cfm?searchoptions=1). Review of the MAUDE database demonstrates 23 reported possible complications of the Stretta procedure, including 3 deaths, and 22 potential complications of the Enteryx procedure, including 5 deaths. Many of the reported complications are likely unrelated to the procedures. However, deaths from esophageal perforation with aspiration pneumonia are reported with Stretta, and deaths from esophago-aortic fistula are reported from Enteryx. Nonfatal complications such as inadvertent embolization of a kidney from injection into the aorta, and pericardial effusions are also reported. Some of these incidents may be due to learning curve issues. However, the responsible clinician must also ask him or herself, “What is the acceptable number of deaths and morbidity when treating proton pump inhibitor-responsive reflux with these devices?”No data substantiate that these procedures are equivalent to or better than medical therapy. Given the excellent efficacy and side effect profile of proton pump inhibitors,17Klinkenberg-Knol E.C. Nelis F. Dent J. Snel P. Mitchell B. Prichard P. et al.Long-term omeprazole treatment in resistant gastroesophageal reflux disease efficacy, safety, and influence on gastric mucosa.Gastroenterology. 2000; 18: 661-669Google Scholar until such data do exist, using endoscopic methods interchangeably with medical management in the proton pump inhibitor-responsive patient based solely on patient preference seems imprudent. To trade an effective noninvasive treatment with which we have decades of experience in millions of previous users for one which has not been shown to be better and is untested by numbers and time is illogical. Although we may justify the performance of these procedures based on the patients’ desire to “not take pills,” such a rationalization ignores our duty to provide good advice to our patients. Certainly, we see patients with diabetes who do not desire to continue taking insulin shots twice a day. We do not recommend unproven therapies to them.For these reasons, using any of these devices on an otherwise healthy patient with GERD responsive to standard medical therapy outside of clinical trials is unwise. Even among those unresponsive to medical therapy, a laparoscopic Nissen procedure is a known entity that provides good short and midterm results in experienced hands and avoids the chronic use of medication in the majority of those who undergo it.18Terry M. Smith C.D. Branum G.D. Galloway K. Waring J.P. Hunter J.G. Outcomes of laparoscopic fundoplication for gastroesophageal reflux disease and paraesophageal hernia.Surg Endosc. 2001; 15: 691-699Google Scholar, 19Hunter J.G. Trus T.L. Branum G.D. Waring J.P. Wood W.C. A physiologic approach to laparoscopic fundoplication for gastroesophageal reflux disease.Ann Surg. 1996; 223: 673-685Google Scholar, 20Bammer T. Hinder R.A. Klaus A. Klingler P.J. Five- to eight-year outcome of the first laparoscopic Nissen fundoplications.J Gastrointest Surg. 2001; 5: 42-48Google ScholarWhile we wait for higher-quality and longer-term data on these procedures, is it possible to forecast a potential role for these devices in the management of GERD? Although data are sparse, subjects who suffer symptoms or complications of volume reflux and are not surgical candidates may be reasonable candidates for these procedures. For such patients, a mechanical barrier is necessary, and medical management will not protect them from aspiration and other effects of gastric volumes in the oropharynx. The lack of another alternative for such patients, coupled with the potentially lethal effects of chronic aspiration, make consideration of an endoscopic therapy reasonable. Another group who might be reasonable candidates are those with GERD symptoms on medical therapy with very poor esophageal motility. While such patients are sometimes rejected by surgeons for fear of persistent dysphagia following the procedure, one of the procedures which is reversible by severing endoscopic sutures might be an effective and conservative measure. Again, further data will be necessary to substantiate this approach in this subgroup. Finally, elderly patients who fail medical therapy but are not surgical candidates are a reasonable group to consider. The life expectancy of these patients is such that the lack of long-term outcomes data in these procedures becomes irrelevant.This lukewarm endorsement of these procedures should not be construed as a lack of appreciation for the ingenuity of the devices or the potential for a greatly expanded role of these devices in the future. Perhaps the single most exciting and evolving area in all of endoscopy is endoscopic antireflux devices. It is more a plea for common sense and the application of the rules of evidence to our analysis of the devices. While these devices offer the promise of symptom control without the yoke of chronic medication use, we should remain patient as experience accrues in well-designed studies. It is only such data that will truly allow us to appropriately place the devices in our algorithm for the treatment of reflux disease. The past few years have seen a number of endoscopic technologies introduced for the treatment of reflux. These novel approaches attempt to burn, tie, stuff, or otherwise manipulate the hiatus, with the goal of decreasing esophageal acid exposures. While interesting, these approaches have reached the consumer market largely before rigorous testing of the devices had occurred. Based on unblinded studies of relatively small numbers of patients, the devices have obtained FDA approval, and dissemination has followed. Currently, endoscopic sewing machines,1Filipi C.J. Lehman G.A. Rothstein R.I. Raijman I. Stiegmann G.V. Waring J.P. et al.Transoral, flexible endoscopic suturing for treatment of GERD a multicenter trial.Gastrointest Endosc. 2001; 53: 416-422Google Scholar, 2Tam W.C. Holloway R.H. Dent J. Rigda R. Schoeman M.N. Impact of endoscopic suturing of the gastroesophageal junction on lower esophageal sphincter function and gastroesophageal reflux in patients with reflux disease.Am J Gastroenterol. 2004; 99: 195-202Google Scholar, 3Rothstein R.I. Filipi C.J. Endoscopic suturing for gastroesophageal reflux disease clinical outcome with the Bard EndoCinch.Gastrointest Endosc Clin N Am. 2003; 13: 89-101Google Scholar a full-thickness plicator,4Chuttani R. Sud R. Sachdev G. Puri R. Kozarek R. Haber G. et al.A novel endoscopic full-thickness plicator for the treatment of GERD a pilot study.Gastrointest Endosc. 2003; 58: 770-776Google Scholar the Stretta device,5Triadafilopoulos G. DiBaise J.K. Nostrant T.T. Stollman N.H. Anderson P.K. Wolfe M.M. et al.The Stretta procedure for the treatment of GERD 6 and 12 month follow-up of the U.S. open label trial.Gastrointest Endosc. 2002; 55: 149-156Google Scholar, 6Go M.R. Dundon J.M. Karlowicz D.J. Domingo C.B. Muscarella P. Melvin W.S. Delivery of radiofrequency energy to the lower esophageal sphincter improves symptoms of gastroesophageal reflux.Surgery. 2004; 136: 786-794Google Scholar and inert injectibles7Johnson D.A. Ganz R. Aisenberg J. Cohen L.B. Deviere J. Foley T.R. et al.Endoscopic implantation of enteryx for treatment of GERD 12-month results of a prospective, multicenter trial.Am J Gastroenterol. 2003; 98: 1921-1930Google Scholar, 8Johnson D.A. Ganz R. Aisenberg J. Cohen L.B. Deviere J. Foley T.R. et al.Endoscopic, deep mural implantation of Enteryx for the treatment of GERD 6-month follow-up of a multicenter trial.Am J Gastroenterol. 2003; 98: 250-258Google Scholar are all available on the U.S. market. The “gee-whiz” momentThe early literature of the endoscopic anti-reflux devices has a “gee-whiz” aspect to it—investigators seemed more interested in proof of the principle that the procedures could be done and be done safely than in attaining high-quality evidence of efficacy in treating reflux. For that reason, early publications dwell more on methodological aspects of the performance of the procedure than on justifying the outcomes measured or the analysis performed. These studies often presented unblinded cohort data demonstrating symptom improvement, and some techniques have not had adequate proof of efficacy. As the field has matured, more interest has developed in rigorous testing of these methods in a blinded fashion. Slowly, the bar has been raised for research on endoscopic anti-reflux procedures. The early literature of the endoscopic anti-reflux devices has a “gee-whiz” aspect to it—investigators seemed more interested in proof of the principle that the procedures could be done and be done safely than in attaining high-quality evidence of efficacy in treating reflux. For that reason, early publications dwell more on methodological aspects of the performance of the procedure than on justifying the outcomes measured or the analysis performed. These studies often presented unblinded cohort data demonstrating symptom improvement, and some techniques have not had adequate proof of efficacy. As the field has matured, more interest has developed in rigorous testing of these methods in a blinded fashion. Slowly, the bar has been raised for research on endoscopic anti-reflux procedures. A sham-controlled study of EnteryxIn this setting, it is particularly refreshing to see, in this month’s edition of Gastroenterology, the report of Deviere et al9Deviere J. Costamagna G. Neuhaus H. Voderholzer W. Louis H. Tringali A. Marchese M. Fiedler T. Darb-Esfahani P. Schumacher B. Nonresorbable copolymer implantation for gastroesophageal reflux disease a randomized sham-controlled multi-center trial.Gastroenterology. 2005; 128: 532-540Abstract Full Text Full Text PDF Scopus (118) Google Scholar of a randomized, sham-controlled trial of Enteryx for the control of reflux disease. Enteryx consists of a nonresorbable copolymer that is liquid when injected, but coalesces into a rubbery substance when the carrier solution leaches out of the injectate and is absorbed into the tissues. This copolymer has been used for years in other medical areas, such as embolization of cerebral vasculature,10Hamada J. Kai Y. Morioka M. Kazekawa K. Ishimaru Y. Iwata H. et al.A mixture of ethylene vinyl alcohol copolymer and ethanol yielding a nonadhesive liquid embolic agent to treat cerebral arteriovenous malformations initial clinical experience.J Neurosurg. 2002; 97: 881-888Google Scholar, 11Jahan R. Murayama Y. Gobin Y.P. Duckwiler G.R. Vinters H.V. Vinuela F. Embolization of arteriovenous malformations with Onyx clinicopathological experience in 23 patients.Neurosurgery. 2001; 48: 984-995Google Scholar but its use as an inert bulking agent at the lower esophageal sphincter represents its first application in gastrointestinal diseases.Deviere et al9Deviere J. Costamagna G. Neuhaus H. Voderholzer W. Louis H. Tringali A. Marchese M. Fiedler T. Darb-Esfahani P. Schumacher B. Nonresorbable copolymer implantation for gastroesophageal reflux disease a randomized sham-controlled multi-center trial.Gastroenterology. 2005; 128: 532-540Abstract Full Text Full Text PDF Scopus (118) Google Scholar randomized 64 patients with GERD symptoms responsive to proton pump inhibitors to receive either Enteryx injection or a sham procedure, in which an upper endoscopy was performed, but no Enteryx was injected. Follow-up evaluation was performed at 3 and 6 months, but crossover was allowed after 3 months. The primary outcome was a greater than 50% reduction in PPI use, and the secondary outcomes were scores on a disease-specific, quality-of-life measure, the GERD-HRQL, and the need for treatment at the 3 month follow-up. Twenty-four hour pH data were also collected at baseline and at 6 months on 39 of the patients.The authors show that, at 3 months, the number of subjects achieving the primary outcome variable, a 50% reduction in proton pump inhibitor use, was significantly higher in Enteryx-treated patients than controls (81% vs. 53%, rate ratio 1.52, 95%CI 1.06–2.28). Similar improvements were noted among the Enteryx-treated patients in GERD-HRQL, as well. Six Enteryx-treated patients opted for re-treatment at 3 months, whereas 20 sham-treated patients crossed over. Six-month data are difficult to interpret given this high degree of crossover, but, of note, it does appear that the improvements in GERD-HRQL seen at 3 months persisted at 6 months. Twenty-four hour pH data, while incomplete, demonstrated no significant changes in acid exposure when comparing baseline studies to 6-month studies in those receiving Enteryx therapy. The authors conclude that Enteryx
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