1. Minimally Invasive Management of GERD: Are We Ready For Prime Time? Presented on: September 21 st 2015 John E. Pandolfino, MD, MSCI Professor of Medicine Feinberg School of Medicine, Northwestern University Chief, Division of Gastroenterology and Hepatology Northwestern Medicine Northwestern Memorial Hospital

2. Vakil N et al. Am J Gastroenterol 2006;101:1900 GERD is a condition which develops when the reflux of stomach content causes troublesome symptoms and / or complications Esophageal Syndromes Extra-esophageal Syndromes Symptomatic Syndromes Typical reflux syndrome Reflux chest pain syndrome Syndromes with Esophageal Injury Reflux esophagitis Reflux stricture Barrett's esophagus Adenocarcinoma Established Association Reflux cough Reflux laryngitis Reflux asthma Reflux dental erosions Proposed Association Sinusitis Pulmonary fibrosis Pharyngitis Recurrent otitis media

3. Primary pathophysiology Esophagitis Severity ≈ # of reflux events X Tissue sensitivity Causticity of gastric juice X Acid clearance Determinants of Reflux Severity

4. Symptom Triggers ≈ Reflux events X Tissue sensitivity Acidity of gastric juice X Acid clearance Symptom modulators ≈ Not a primary abnormality of GERD Determinants of Reflux Severity

5. Symptom Triggers ≈ Reflux events X Tissue sensitivity Acidity of gastric juice X Acid clearance PPI therapy of GERD is compensatory, not curative Symptom modulators ≈ Targets of PPI therapy Determinants of Reflux Severity

6. PPI efficacy for potential manifestations of GERD Estimates based on available RCT data PJ Kahrilas 2011 RM #46 v4/6/11 PJK 0% 100% 25% 50% 75% Esophagitis healing Mild Severe Heartburn relief Esophagitis NERD Regurgitation relief Chest pain (50% relief) GERD (+pH) GERD (-pH) Hoarseness (improved) GERD (-) Chronic cough (improved) Placebo Therapeutic gain

7. Symptom Triggers ≈ Reflux events Tissue sensitivity X Acidity of gastric juice X Acid clearance Symptom modulators ≈ PPI Failures Abnormal in number, composition, or volume refluxed Determinants of Refractory Reflux

8. Lateral projection PA projection 6x6mm Dimensions and Asymmetry of the EGJ Pandolfino JE, et al. Gastroenterology 2003;125:1018-24 6 mmHg 4 mmHg -2 mmHg 0 mmHg 2 mmHg Distention pressure Normal GERD (-) HH GERD (+) HH -4 mmHg

9. EGJ Distensibility: Target for Therapy Kwiatek et al. J Gastrointest Surg. 2010 Feb;14(2):268-76

10. Reflux-symptom Association on PPI Therapy Mechanism of PPI failure 168 patients with symptoms Symptoms 144 (85%) No symptoms 24 (15%) Positive SI 69 (48%) Negative SI 75 (52%) +SI acid 16 (11%) +SI non-acid 53 (37%) Functional Alternative DX Acid Breakthrough Non-Acid Reflux Maine et al. Gut. 2006 Oct;55(10):1398-402 ?

11. Antireflux Surgery in GERD Indications When antireflux surgery and PPI therapy are judged to offer similar efficacy in a patient with an esophageal GERD syndrome, PPI therapy should be recommended as initial therapy because of superior safety. I.When a patient with an esophageal GERD syndrome is responsive to, but intolerant of, acid suppressive therapy, antireflux surgery should be recommended as an alternative. II.Antireflux surgery for patients with an esophageal GERD syndrome with persistent troublesome symptoms, especially troublesome regurgitation, despite PPI therapy. i.Must have proven GERD. ii.The potential benefits of antireflux surgery should be weighed against the deleterious effect of new symptoms consequent from surgery, [dysphagia, gas bloat, IBS,].

12. Endoscopic Therapies for GERD Should have similar indications: If they work When endoscopic therapies and PPI therapy are judged to offer similar efficacy in a patient with an esophageal GERD syndrome, PPI therapy should be recommended as initial therapy because of superior safety. I.When a patient with an esophageal GERD syndrome is responsive to, but intolerant of, acid suppressive therapy, endoscopic therapies could be recommended as an alternative. II.Endoscopic therapies for patients with an esophageal GERD syndrome with persistent troublesome symptoms, especially troublesome regurgitation, despite PPI therapy. i.Must have proven GERD ii.The potential benefits of endoscopic therapies should be weighed against the deleterious effect of new symptoms consequent from the procedure, [dysphagia, gas bloat, IBS,].

13. Endoscopic Therapies for GERD Guidelines/Position Statements AGA GERD Guidelines 2008: The use of currently commercially available endoluminal antireflux procedures in the management of patients with an esophageal syndrome. (Insufficient evidence to recommend) ACG Guidelines 2013: The usage of current endoscopic therapy or transoral incisionless fundoplication cannot be recommended as an alternative to medical or traditional surgical therapy. (Strong recommendation, moderate level of evidence)

14. Minimally invasive treatments for GERD A brief history Stretta2001redesigned and active EndoCinch2000moribund Enteryx 2005voluntary recall 2005 Gatekeeper2004halted 2005 NDO Plicator2005halted 2008 Esophyx (TIF)2007active development Torax (Linx)2008 active development First PublicationStatus 2015

15. Endoscopic Therapies for GERD Stretta Technique: Safe and easy to use endoscopic procedure that is performed with minimal complications {< 30 minutes}.  Transient chest pain common Balloon placement Multiple treatments Remodeling and bulking of the EGJ

16. Study Mean LESPMean %AETPPI wd StrettaShamStrettaShamStrettaSham Corley (n=64)16.2 [10.6,23]18 [14.8,22.5]9.9[4,14.7]10.7[5.9,13]58%52% Coron (n=43)*n/an.a11.4(+/-6.3)8.8 (+/-6.1)15%0% Aziz (n=36)16.2 (+/- 4.5)15.9 (+/- 3.2)6.7( +/- 2.8)8.2 (+/- 3.1)16%0% Arts (n=22)16.3 (+/- 1.9)13.3 (+/- 2.0)159n/a * This study did not include a sham arm and compared Stretta to PPI and control Endoscopic Therapies for GERD Stretta Moderate symptom improvement with ? difference in objective findings.

17. Endoscopic Therapies for GERD Stretta Conclusions: Stretta appears to be safe and is the easiest to use. Stretta should be considered in proven GERD patients with no hernia who suffer from troublesome regurgitation, belching and cough despite PPI therapy. Downside: Durability Lack of true anatomical correction

18. Endoscopic Therapies for GERD Esophyx Technique: Endoscopic procedure that is similar to fundoplication (49 minutes) Fasteners deployed Device retrieval Valve with serosa-to- serosa approximation below Z-line

19. Endoscopic Therapies for GERD Esophyx P = 0.023 RESPECT- Primary endpoint of troublesome regurgitation

20. Endoscopic Therapies for GERD Esophyx 0 5 10 15 Screening 6-month p<0.01 TIF/placebo 6-month evaluation group (n=76, PP less 4 EF & 1 lost to f/u) ULN % 0 5 10 15 Screening 6-month p=ns Sham/PPI 6-month evaluation group (n=28, PP less 9 EF & 1 lost to f/u)

21. RDQ reflux symptom scores (on medication) Screening TF/placebo 6-months TF/placebo Screening sham/PPI 6-months sham/PPI P <.001 0.6 (0, 1.3) 3.1 (2.4, 3.8) 3.3 (2.5, 4.0) 0.9 (0.1, 2.0) P <.001 TIF/placebo (n=76, PP less 4 EF & 1 lost to f/u) Sham/PPI (n=28, PP less 9 EF & 1 lost to f/u) Endoscopic Therapies for GERD Esophyx

22. Significant adverse events Adverse eventOnsetDuration Severe epigastric/abdominal painDay 12 days Severe chest painDay 52 weeks Severe musculoskeletal painDay 51 day Moderate epigastric/abdominal painDay 14 weeks Moderate dysphagiaDay 18 days Mild dysphagiaDay 11 day Mild nauseaDay 11 day TF/placebo group (n=87) Severe nauseaDay 12 days Sham/omeprazole group (n=42) Endoscopic Therapies for GERD Esophyx

23. Conclusions: TF appears to be safe, without fundoplication side effects. TF should be considered in proven GERD patients with small or absent hiatal hernia who suffer from troublesome regurgitation, despite PPI therapy. Downside: Durability Ease of use Still not helpful in patients without hernia

24. Minimally Invasive Therapy for GERD LINX Bonavina L et al. J Gastrointest Surg 2008;12:2133 In position just below Z-line

25. Lx 11 v2/16/13 PJK Ganz R, et al N Engl J Med 2013;368:719-27

26. Magnetic sphincter augmentation 3 year results of uncontrolled trial Lx 12 v1/29/14 PJK PPI useRegurgitation Esophagitis Dysphagia Ganz R, et al N Engl J Med 2013;368:719-27

27. Magnetic sphincter augmentation Primary outcome- pH-metry normalization Lx 13 v1/29/14 PJK Ganz R, et al N Engl J Med 2013;368:719-27

28. Minimally invasive Therapy for GERD LINX Conclusions: Appears to be as effective as fundoplication and is reversible. May be reserved for proven GERD patients with and without hernia who require treatment beyond PPI therapy. Downside No sham controlled data yet. Still an implant- 3% of 4000 cases have been explanted

29. EGD and possible reflux testing if EGD (-) and symptoms continue Define Phenotype-Reflux Testing Proven Refractory Reflux Hernia Proven Refractory Reflux Normal Anatomy Consider Intervention* Stretta/Esophyx/LINX? Consider Intervention* Hernia repair LINX/ Fundoplication Not Reflux Alternative Diagnosis* Neuromodulator Document Compliance Consider motility (HRIM) testing for atypical presentation Rule out eating disorder/rumination * R/O major motility disorder, belching syndrome and gastric emptying issue if not done already Lifestyle modifications Behavioral Intervention Optimize medications Lifestyle modifications Behavioral Intervention Optimize medications Northwestern Refractory GERD Approach Heartburn, Regurgitation, Chest Pain Lifestyle modifications Behavioral Intervention Stop PPI Baclofen/Neuromodulator

30. Thank You