Refractory Heartburn: When PPI’s Fail to Sooth the Burn Ronnie Fass, MD Professor of Medicine University of Arizona
Definitions of Refractory HeartburnA 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” FassR. Drugs2007;67:1521-1530 Fass R et al.. Curr Gastroenterol Rep2008;19:252-257 Fass R et al. Gut 2009;58:295-309 Hershcovici T et al. Curr Opin Gastroenterol 2010;26:367-378Sifrim D et al. Gut 2012 (in Press)
Specific Indications Chosen by Primary Care Physicians to Refer GERD Patients for EGD Boolchandet al., GastrointestEndosc2006;63:228-33
The Epidemiology of Refractory Heartburn in Primary Care and Community Studies Non-responders Non-responders Non-responders 45% Observational trials More Common in Females El-Serag H. et al. Aliment PharmacolTher2010;32:720-37. 17% 32% Non-randomized trials Randomized trials
Erosive Esophagitis(20-30%) Nonerosive reflux disease (60-70%) Barrett’s Esophagus(6-10%) 40%–50% 25%–40% 20% PPI Failure The Reported Rate of Symptomatic Failure in Therapeutic Trials of GERD Patients Fass R et al.. Gut 2009:58;295-309Fass R. Drugs 2007;67:1521-1530Fass R. Clin Gastroenterol Hepatol 2007;6:393-400Fass R. Am J Gastroenterol 2009;104(Suppl 2):S33-S38Hershcovici R et al. Curr Opin Gastroenterol 2010;26:367-378
Erosive OesophagitisHealing 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
Dilated Intercellular Space (DIS) Diameters of Esophageal Epithelium in NERD Patients with Typical Symptoms Resistant to PPI Therapy(<50%, 4 weeks Omeprazole bid) Ribolsi M et al. Gastroenterology 2007(132 (4 Suppl 2)#934, A-139
Psychological comorbidity • Compliance • Improper dosing time • Eosinophilic oesophagitis • Functional heartburn (esophageal hypersensitivity) • Weakly acidic reflux • Duodenogastro-esophageal reflux • Residual acid reflux • Reduced PPI bioavailability • Rapid PPI metabolism • PPI resistance • Others • Delayed gastric emptying • Concomitant functional bowel disorder Putative Underlying Mechanisms for PPI Failure Fass R et al.. Gut 2009;58:295-309
Basic Rules in Refractory GERD * If GERD patients treated empirically do not respond to… Hershcovici & Fass. J NeurogastroenterolMotil2010;16:8-21.
Doubling the PPI Dose in Patients who Failed PPI Once Daily What is the evidence? None!
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. ClinGastroenterolHepatol 2012;10:338 - 45
Prior Initiating any Work-up, Evaluate for Poor Compliance or Adherence Van SoestEM et al. Aliment Pharmacol Ther 2006;24:377-385)
Lifestyle Modifications Kaltenbach T et al. Arch Intern Med 2006;166:965-971
What Is the Value of an Upper Endoscopy in Patients Who Failed PPI Once Daily? Poh CH et al. Gastrointest Endosc2010; 71:28-34
Switching to Another PPI –Highly Successful Fass R et al. Clin Gastroenterol Hepatol 2006
Breakthroughsymptoms, 38% No breakthroughsymptoms, 62% Breakthrough Nighttime Symptoms on PPI Once Daily – Consider Giving PPI Before Dinner N=1064 American Gastroenterology Association. GERD Patient Study: Patients and Their Medications. Harris Interactive Inc; 2008.
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)
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)
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)
How Common is Residual Reflux in Patients with Heartburn Who Failed PPI bid? Symptomatic patients172 (86%) Nonacid reflux61 (35%) Acid reflux13 (8%) Symptoms notassociated with reflux98 (57%) MainieI et al. Gut, 2006; 55:1398-1402
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 Baclofen – For Non-Acidic Reflux Lidums I et al.Gastroenterology. 2000;118:7–13. Fass R. ClinGastroenterolHepatol 2012;10:338 - 45
Antireflux Surgery in NERD and Erosive Esophagitis Patients Refractory to Treatment Broeders JA et al. Br J Surg2010;97:845-852
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
Pain Modulation in PPI Failure - TCA Antidepressants Sperber AD, Drossman DA. Aliment PharmacolTher2011;33:514-524
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 GastroenterolHepatol 2012;27:suppl 3:3 – 7
Hierarchy of Antidepressants of Choice for Esophageal Pain Reduction and Global Health Improvement Nguyen TMT et al. Aliment PharmacolTher 2012;35:493-500
The Value of Other Therapeutic Modalities in Patients with Refractory Heartburn • Endoscopic treatment – ? • Complementary medicine – acupuncture • Psychological treatment – Cognitive Behavioral Therapy
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.