Refractory Heartburn: When PPI’s Fail to Sooth the Burn Ronnie Fass, MD Professor of Medicine University of Arizona Persistent Heartburn, UEGW, Barcelona Oct 2010

Definitions of Refractory Heartburn A Patient-Driven Phenomenon “Symptoms caused by the reflux of gastric contents that are not responding to a stable double dose of a PPI during a treatment period of at least 12 weeks” Versus “Patients who failed to obtain satisfactory symptomatic response after an 8 weeks course of standard-dose PPI” Fass R. Drugs 2007;67:1521-1530 Fass R et al.. Curr Gastroenterol Rep 2008;19:252-257 Fass R et al. Gut 2009;58:295-309 Hershcovici T et al. Curr Opin Gastroenterol 2010;26:367-378 Sifrim D et al. Gut 2012 (in Press) Persistent Heartburn, UEGW, Barcelona Oct 2010

Boolchand et al., Gastrointest Endosc 2006;63:228-33 Specific Indications Chosen by Primary Care Physicians to Refer GERD Patients for EGD Boolchand et al., Gastrointest Endosc 2006;63:228-33 Refractory GERD-What to Do Next, Hilo HI, August 2007

El-Serag H. et al. Aliment Pharmacol Ther 2010;32:720-37. The Epidemiology of Refractory Heartburn in Primary Care and Community Studies Non-responders 17% 32% Non-randomized trials Randomized trials Non-responders Non-responders 45% Observational trials More Common in Females El-Serag H. et al. Aliment Pharmacol Ther 2010;32:720-37. Refractory GERD Is it Real_Leon_Nov2011

The Reported Rate of Symptomatic Failure in Therapeutic Trials of GERD Patients Nonerosive reflux disease (60-70%) 40%–50% Erosive Esophagitis (20-30%) 25%–40% Barrett’s Esophagus (6-10%) 20% PPI Failure Fass R et al.. Gut 2009:58;295-309 Fass R. Drugs 2007;67:1521-1530 Fass R. Clin Gastroenterol Hepatol 2007;6:393-400 Fass R. Am J Gastroenterol 2009;104(Suppl 2):S33-S38 Hershcovici R et al. Curr Opin Gastroenterol 2010;26:367-378 Persistent Heartburn, UEGW, Barcelona Oct 2010

Erosive Oesophagitis Healing Rates are Reduced in Grades C and D Grade C & D account for only 15-30% of EE patients * * * * N=813 N=972 N=497 N=140 Week 8 P<0.01 Richter et al. Am J Gastroenterol .2001;96:656-65 Persistent Heartburn, UEGW, Barcelona Oct 2010

Dilated Intercellular Space (DIS) Diameters of Esophageal Epithelium in NERD Patients with Typical Symptoms Resistant to PPI Therapy (<50%, 4 weeks Omeprazole bid) Distal DIS (µm) (Mean CI) Proximal DIS (µm) (Mean CI) Nonresponder patients on PPI (N=10) 1.07 (1.03−1.1) 0.72 (0.64−0.79) Responders off therapy (N=33) 1.47 (1.41−1.53) 0.82 (0.79−0.84) Healthy volunteers (N=12) 0.48 (0.42−0.51) 0.42 (0.39−0.46) Ribolsi M et al. Gastroenterology 2007(132 (4 Suppl 2)#934, A-139 GERD and Minimal Changes, Acapulco, Nov 2010

Putative Underlying Mechanisms for PPI Failure Psychological comorbidity Compliance Improper dosing time Weakly acidic reflux Duodenogastro-esophageal reflux Residual acid reflux Delayed gastric emptying Concomitant functional bowel disorder Reduced PPI bioavailability Rapid PPI metabolism PPI resistance Others Functional heartburn (esophageal hypersensitivity) Eosinophilic oesophagitis Fass R et al.. Gut 2009;58:295-309 Persistent Heartburn, UEGW, Barcelona Oct 2010

Basic Rules in Refractory GERD * If GERD patients treated empirically do not respond to… *PPI once daily     NERD / Functional heartburn *PPI Twice Daily    Functional heartburn Hershcovici & Fass. J Neurogastroenterol Motil 2010;16:8-21. Refractory GERD Is it Real_Leon_Nov2011

Doubling the PPI Dose in Patients who Failed PPI Once Daily What is the evidence? None! Refractory GERD Is it Real_Leon_Nov2011

Avoid Doubling the PPI Dose if Possible Ensure compliance / adherance and lifestyle modifications before doubling the PPI dose Switch to another PPI Consider combination of PPIs with H2 blockers/prokinetics/Gaviscon/sucralfate/antacids/baclofen Fass R. Clin Gastroenterol Hepatol 2012;10:338 - 45

Prior Initiating any Work-up, Evaluate for Poor Compliance or Adherence Van Soest EM et al. Aliment Pharmacol Ther 2006;24:377-385) Persistent Heartburn, UEGW, Barcelona Oct 2010

Lifestyle Modifications Factor Trials, No. Lowered LESP Worsened pH Symptoms Tobacco 12 B Alcohol 16 No effect (B) Obesity 24 E Coffee and caffeine 14 No effect (C) Chocolate 2 Spicy foods C Citrus 3 Carbonated beverages Fatty foods 9 D Mint 1 Recumbent position RLD position Late evening meal Kaltenbach T et al. Arch Intern Med 2006;166:965-971 Refractory GERD Is it Real_Leon_Nov2011

What Is the Value of an Upper Endoscopy in Patients Who Failed PPI Once Daily? Endoscopic findings PPI failure (%) (N=105) No treatment (%) (N=91) P value Normal 58 (55.2) 37 (40.7) 0.04 Erosive esophagitis 7 (6.7) 28 (30.8) <0.05 Barrett’s esophagus 4 (3.8) 3 (3.3) 1.0 Eosinophilic esophagitis 1 (0.9) Hiatal hernia 14 (13.3) 13 (14.3) 0.85 Esophageal ring 11 (10.5) 10 (11) 0.91 Esophageal candidiasis 1 (0.95) 1(1.1) Esophageal webs Esophageal angiodysplasia Achalasia Poh CH et al. Gastrointest Endosc 2010; 71:28-34 Refractory GERD--Mechanisms & Treatment, Brazil, Nov 2010

Switching to Another PPI – Highly Successful Esomeprazole 40 mg once daily (N=138) Lansoprazole 30 mg twice daily (N=144) P value Heartburn symptom improvement, % (N) after 8 weeks 83.3 (155) 83.3 (120) 1.00 Fass R et al. Clin Gastroenterol Hepatol 2006 Refractory GERD Is it Real_Leon_Nov2011

Breakthrough Nighttime Symptoms on PPI Once Daily – Consider Giving PPI Before Dinner No breakthrough symptoms, 62% Breakthrough symptoms, 38% N=1064 American Gastroenterology Association. GERD Patient Study: Patients and Their Medications. Harris Interactive Inc; 2008. Persistent Heartburn, UEGW, Barcelona Oct 2010

Sifrim D et al. Gut 2012 (in Press) What can be Expected from Ambulatory Monitoring for Reflux “Off” Therapy? Document baseline abnormal esophageal acid exposure Classify the patient as having NERD or functional heartburn 48 – 96 hour recording with wireless pH capsule have increased diagnostic yield as compared to 24h pH test. Impedance + pH test has little value off therapy Sifrim D et al. Gut 2012 (in Press) Persistent Heartburn, UEGW, Barcelona Oct 2010

Sifrim D et al. Gut 2012 (in Press) What Can be Expected from Ambulatory Monitoring for Reflux on Therapy (PPI twice daily) Very low diagnostic yield of pH test alone as compared to impedance + pH Establish a correlation between symptoms and reflux events (SI and/or SAP) Exclude GERD as the cause of refractory heartburn (neg. SI and SAP) Still no outcome data regarding impedance + pH Sifrim D et al. Gut 2012 (in Press) Persistent Heartburn, UEGW, Barcelona Oct 2010

Clinical and not pH-Impedance profile Predict Response to PPI No reflux pattern associated with PPI failure can be demonstrated by 24 h pH-Impedance performed off therapy Body mass index (BMI) < 25 kg/m2 is an important factor of inadequate response to PPI Functional digestive disorders are independent factors of PPI failure even in patients with documented GERD Zerbib F et al. Gut 2012 (in press) Persistent Heartburn, UEGW, Barcelona Oct 2010

How Common is Residual Reflux in Patients with Heartburn Who Failed PPI bid? Symptomatic patients 172 (86%) Nonacid reflux 61 (35%) Acid reflux 13 (8%) Symptoms not associated with reflux 98 (57%) Mainie I et al. Gut, 2006; 55:1398-1402 Persistent Heartburn, UEGW, Barcelona Oct 2010

Baclofen – For Non-Acidic Reflux GABA-B agonists Reduces TLESR Mild gastrokinetic 40-50% reduction in TLESR rate Improve GERD symptoms Start with 10mg at bed time Can increase up to 20mg tid Watch for neurological side effects Lidums I et al. Gastroenterology. 2000;118:7–13. Fass R. Clin Gastroenterol Hepatol 2012;10:338 - 45 Diagnosis and Treatment of Refractory GERD, Phoenix, December 2008

Antireflux Surgery in NERD and Erosive Esophagitis Patients Refractory to Treatment Number of symptoms Before surgery 15.0 (1.7) (N=60) 12.7 (1.5) (N=81) 3 months 3.1 (0.7) (N=60) 2.1 (0.6) (N=81) 5 years 2.6 (1.0) (N=23) 0.9 (0.3) (N=21) Positive SI 47 of 57 (82%) 62 of 81 (77%) 2 of 57 (4%) 3 of 81 (4%) 3 of 24 (13%) 3 of 22 (14%) Positive SAP 42 of 51 (82%) 63 of 79 (80%) 1 of 51 (2%) 2 of 79 (3%) 2 of 18 (11%) 1 of 22 (5%) Broeders JA et al. Br J Surg 2010;97:845-852 Refractory GERD--Mechanisms & Treatment, Brazil, Nov 2010

The Prevalence of Abnormal pH Test and Bilitec Among PPI Failure and PPI Success Patients (all P>0.05) Gasiorowska A et al. Am J Gastroenterol 2009 Aug;104:2005-2013 Persistent Heartburn, UEGW, Barcelona Oct 2010

Pain Modulation in PPI Failure - TCA Antidepressants Sperber AD, Drossman DA. Aliment Pharmacol Ther 2011;33:514-524 Refractory GERD Is it Real_Leon_Nov2011

How to Use TCAs in Practice Main Principle: “Low and slow” Start 10 mg–25 mg at bedtime Increase by 10 mg–25 mg increments weekly Goal of treatment 50 mg–75 mg once daily If side effects emerge: Decrease to a lower dose Can switch to another TCA May combine with SSRIs Fass R. J Gastroenterol Hepatol 2012;27:suppl 3:3 – 7 Noncardiac Chest Pain:Advances in Diag & Treatment_Aspen_Jan2012

Nguyen TMT et al. Aliment Pharmacol Ther 2012;35:493-500 Hierarchy of Antidepressants of Choice for Esophageal Pain Reduction and Global Health Improvement Pain Reduction Global Health Improvement 1. Venlafaxine 2. Sertraline 3. Imipramine 3. Trazodone 4. Trazodone 4. Imipramine 5. Paroxetine Nguyen TMT et al. Aliment Pharmacol Ther 2012;35:493-500 Noncardiac Chest Pain:Advances in Diag & Treatment_Aspen_Jan2012

The Value of Other Therapeutic Modalities in Patients with Refractory Heartburn Endoscopic treatment – ? Complementary medicine – acupuncture Psychological treatment – Cognitive Behavioral Therapy Refractory GERD Is it Real_Leon_Nov2011

Conclusions There are various underlying mechanisms that can lead to PPI failure, and some may even overlap in the same patient. The functional heartburn group provides most of the PPI failure (twice daily) patients. Upper endoscopy has a limited role in evaluating patients who failed PPI once or twice daily. The combined Impedance + pH test provides the highest yield in evaluating refractory heartburn patients on treatment (PPI BID). Emphasizing Compliance and lifestyle modifications is our low hanging fruit. Avoid doubling the PPI dose if possible (switch PPI’s or add other anti-reflux therapies). TLESR reducers and pain modulators remain the leading therapeutic modalities for PPI failure. Persistent Heartburn, UEGW, Barcelona Oct 2010