GERD: 2014 Dilemmas and Solutions. Ronnie Fass MD, FACP Professor of Medicine Case Western Reserve University

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1 GERD: 2014 Dilemmas and Solutions Ronnie Fass MD, FACP Professor of Medicine Case Western Reserve University

2 How to Maximize Your PPI Treatment? Improve compliance and adherance Fass R. Am J Gastroenterol ;107(4):531-3.

3 GERD A Symptom Driven Disease I have heartburn I will take my medication Fass et al. Aliment Pharmacol Ther 2005;22(2):79-94.

4 Factors that may Adversely Affect Patients Compliance with PPI Therapy Knowledge about the treated disorder Desire for personal control The prescribed drug Perceived severity of symptoms Side effects Number of pills per day Additional medications Age Personality Socioeconomic status and healthcare coverage Fass et al. Aliment Pharmacol Ther 2005;22(2):79-94.

5 Time Consumption of a PPI In many Asian countries PPI s are taken after a meal Nexium 40 mg before dinner 40 mg at bedtime 24 hours Daytime Nighttime Percentage of time with intragastric ph>4 Median ph Percentage of time with intragastric ph>4 Median ph Percentage of time with intragastric ph>4 Median ph Wilder-Smith C et al. Aliment Pharmacol Ther 2010;32:1249-

6 How to Maximize Your PPI Treatment? Split the Dose! Fass R. Am J Gastroenterol ;107(4):531-3.

7 Mean Pharmacodynamic Findings of Different Esomeprazole Regimens (Per-Protocol Population, N=33) Percentage of time with intragastric ph>4 24 hour Daytime Nighttime Median ph Percentage of time with intragastric ph>4 Median ph Percentage of time with intragastric ph>4 Median ph 20 mg before breakfast mg before dinner mg twice daily mg before breakfast mg before dinner mg at bedtime mg twice daily Wilder-Smith C et al. Aliment Pharmacol Ther 2010;32:

8 Median intra-gastric ph The Effect of Different Dosing of Rabeprazole on Intra-Gastric ph MG QD 20MG BID 10MG QID Rabeprazole Dose Sugimoto et al. Aliment Pharmacol Ther Oct;36(7):

9 How to Maximize Your PPI Treatment? The more the merrier! Fass R. Am J Gastroenterol ;107(4):531-3.

$Endoscopically Confirmed Healing Rates of Refractory Reflux Esophagitis$

10 Endoscopically Confirmed Healing Rates of Refractory Reflux Esophagitis after 8 weeks of Treatment Kinoshita et al. Am J Gastroenterol 2012;107:

11 Kinoshita et al. Am J Gastroenterol 2012;107:

12 % of patients Doubling the PPI Dose Versus Adding Placebo in Patients who Failed PPI once daily Double Blind, Randomized, Placebo-Controlled, 6-Week Trial Comparison of the % of patients without any symptom during the last week of treatment P=NS Daytime heartburn Nighttime heartburn acid regurgitation Rabeprazole 20mg + placebo (N=55) Rabeprazole 20mg BID (N=59) Hershcovici T et al. DDW 2013

13 % Reduction Doubling the PPI Dose Versus Adding Placebo in Patients who Failed PPI once daily Double Blind, Randomized, Placebo-Controlled, 6-Week Trial Comparison of % reduction in symptom score, pre and post treatment, between the 2 patient groups P< Daytime heartburn Nighttime heartburn acid regurgitation Rabeprazole 20mg + placebo (N=55) Rabeprazole 20mg BID (N=59) Hershcovici T et al. DDW 2013

14 Mean number of days with <1 Doubling the PPI Dose Versus Adding Placebo in Patients who Failed PPI once daily Double Blind, Randomized, Placebo-Controlled, 6-Week Trial Comparison of the mean number of days, during the last week of treatment, with symptom intensity score <1, between the 2 patient groups Daytime heartburn Nighttime heartburn acid regurgitation Rabeprazole 20mg + placebo (N=55) Rabeprazole 20mg BID (N=59) Hershcovici T et al. DDW 2013 P=0.04

15 How to Maximize Your PPI Treatment? One PPI Does not fit all Fass R. Am J Gastroenterol ;107(4):531-3.

16 Percentage of Patients Symptomatically controlled on twice daily PPI Who were Successfully Stepped-Down to Dexlansoprazole Once Daily Fass R et al. Clin Gastroenterol Hepatol Mar;10(3): In 88% (95% CI, 82.7%-93.4%; n=125) of the patients their heartburn remained well controlled after stepping down to once daily Dexlansoprazole 30mg MR.

17 Percentage of Patients who Remained Well Controlled after Stepping Down to Dexlansoprazole MR 30 mg by Prior PPI Prior PPI % of patients who remaining well controlled, % (n/n) Esomeprazole 84.0 (21/25) Lansoprazole 85.7 (12/14) Omeprazole 88.1 (74/84) Pantoprazole (14/14) Rabeprazole 87.5 (7/8) Fass R et al. Clin Gastroenterol Hepatol Mar;10(3):247-53

18 How to Improve Nighttime GERD- Related Symptoms?

19 Breakthrough Nighttime Symptoms on PPI Once Daily Consider Giving PPI Before Dinner No breakthrough symptoms, 62% During sleep 28 Breakthrough symptoms, 38% At night 65 Mid day 45 In the morning 16 N=1064 American Gastroenterology Association. GERD Patient Study: Patients and Their Medications. Harris Interactive Inc; 2008.

20 Therapeutic options for Nighttime GERD Avoid eating at least 3 hours prior bedtime Elevate the head of the bed Avoid the R decubitus position in bed Turn off lights when enter bed and minimize disturbances to a normal sleep Treat with a PPI and if symptoms are primarily during nighttime - give before dinner Split PPI dose (am and pm before a meal) Add H2RA, carafate, gaviscon etc. before bedtime Consider non-medical treatment Fujiwara Y et al. J Gastroenterol 2012:47:760-9.

21 Ramelteon Consider for Nighttime GERD Non-Scheduled hypnotic A selective MT1 and MT2 agonist Pharmacological structure close to omeprazole ( crude omeprazole ) Reduce Acid secretion and improve sleep Lokesh Jha et al DDW 2012 Nighttime heartburn Daytime heartburn *p<0.05

22 What is the Role of the Acid Pocket?

23 The Acid Pocket The Acid Pocket

24 3D Reconstruction of MR Images Showing Gaviscon Raft Forming a Mechanical Barrier Patient in the R Lateral Position EGJ Gaviscon Fox M et al. DDW 2011

25 How to Maximize your Treatment of NERD Patients? Maximal response to treatment may require more than 4 weeks.

26 Treatment Comparison between Placebo and PPI Once Daily in NERD Patients (Pooled Difference in Proportion with Heartburn Resolution by Time) Dean et al. Clin Gastroenterol Hepatol 2004;2:

27 How to Maximize your Treatment of NERD Patients? Maximal response to treatment may require more than 4 weeks Complete resolution of symptoms an unrealistic clinical endpoint

28 Patient (%) Percentage of NERD Patients Reporting Complete Resolution of Heartburn after 4 Weeks of Treatment with Esomeprazole 40mg, Esomeprazole 20mg or Placebo * * * * Esomeprazole 40mg Esomeprazole 20mg Placebo Study 1 Study 2 * P < vs. placebo N = Katz et al. Aliment Pharmacol Ther 2003:18(9):

29 Mean Percentage of Heartburn-free Days during 4 Weeks of Treatment with Esomeprazole 40mg, Esomeprazole 20mg or Placebo in NERD Patients Days hearburn -free (%) * * Study 1 Study 2 * * 36.2 Esomeprazole 40mg Esomeprazole 20mg Placebo * P vs. placebo N = Katz et al. Aliment Pharmacol Ther 2003:18(9):

30 % patients Expectations Proportion of NERD Patients Responding to Treatment at 4 Weeks Omeprazole 20mg Omeprazole 10mg Placebo Complete absence of heartburn Resolution of heartburn Lind et al. Scand J Gastroenterol 1997 Maradey-Romero C and Fass R, J Clin Gastroenterol 2014 N = 509

31 Treatment Comparison between Placebo and PPI Once Daily in NERD Patients (Pooled Difference in Proportion with Heartburn Resolution by Time) Dean et al. Clin Gastroenterol Hepatol 2004;2: Sufficient - Complete

32 How to Maximize your Treatment of NERD Patients? Maximal response to treatment may require more than 4 weeks Completer resolution of symptoms an unrealistic clinical endpoint A growing recognition of new functional esophageal and extraesophageal disorders

33 New Functional Esophageal and Extra-Esophageal Disorders Hypersensitive esophagus Functional regurgitation Chronic Cough Throat clearing Throat Burning/Pain The burning mouth syndrome

34 What are the Non-Medical Interventions for GERD?

35 Recent Trends in Treatment Development for GERD Non-medical techniques Drug Development

36 The Rate of Antireflux Procedures Using the Nationwide Inpatient Sample Year Wang YR et al. Dis Esoph 2011;24:215-23

37 The Stretta Technique

38 The Stretta Technique

39 A Randomized, Double-blinded, Sham- Controlled Trial (STRETTA) Sham (25) Active (31) P value Heartburn GERD-HQRL SF Daily PPI -29% -46%.9 Median 24-pH < Median LESP Esophageal erosion 2% 8%.88 Corley DA et al. Gastroenterology 2003;125:

40 Noar M Surg Endosc 2014 (in press)

41 Esophyx

42 Three-year Results of a Multicenter Prospective Study of Transoral Incisionless Fundoplication N = 66 GERD-HRQL 4 25 (off PPI) 9 (on PPI) Discontinuation of Daily PPI Normalization of esophageal ph 61% (ITT) 74% (PP) 39% (ITT) 82% (PP) 18.2% underwent revisional procedures Muls V et al Surg Innov 2013;20:321-30

43 LINX Reflux Management System Reinforces the LES restoring the barrier function Expands during swallow allowing food to enter stomach Highest Magnetic Resistance Lowest Magnetic Resistance

44 The Angelchick

45 Are We Close for a Concierge Service for GERD?

46 Can we Individualize GERD Treatment at the Physiological Level? The Future! Wireless External Programmer Implantable Pulse Generator (IPG) + Bipolar Leads Investigational device, currently not FDA approved or CE Marked

47 EndoStim Implant Investigational device, currently not FDA approved or CE Marked

48 The Long-Term Effect of EndoStim on HRQL (n=24) Median composite GERD-HRQL scores Median composite GERD-HRQL scores Rodriguez L et al. endoscopy 2013;45:

49 Rodriguez L et al. endoscopy 2013;45: The Long-Term Effect of EndoStim on Intra-Esophageal Acid Exposure (n=24) Median % 24-h Distal Esophageal ph < Baseline Month 3 Month 6 Month 12 Median % 24-h Distal Esophageal ph < 4.0

50 Heart Burn The End

Unmet Needs in the Management of Gastroesophageal Reflux Disease

Unmet Needs in the Management of Gastroesophageal Reflux Disease Ronnie Fass MD Professor of Medicine Case Western Reserve University Chairman, Division of Gastroenterology and Hepatology Director, Esophageal