1. 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

2. 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:
Fass R et al.. Curr Gastroenterol Rep 2008;19:
Fass R et al. Gut 2009;58:
Hershcovici T et al. Curr Opin Gastroenterol 2010;26: Sifrim D et al. Gut 2012 (in Press)
Persistent Heartburn, UEGW, Barcelona Oct 2010

3. 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

4. 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:
Refractory GERD Is it Real_Leon_Nov2011

5. 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; Fass R. Drugs 2007;67: Fass R. Clin Gastroenterol Hepatol 2007;6: Fass R. Am J Gastroenterol 2009;104(Suppl 2):S33-S38 Hershcovici R et al. Curr Opin Gastroenterol 2010;26:
Persistent Heartburn, UEGW, Barcelona Oct 2010

6. 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

7. 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

8. 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:
Persistent Heartburn, UEGW, Barcelona Oct 2010

9. 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

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

11. 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:

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

13. 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:
Refractory GERD Is it Real_Leon_Nov2011

14. 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

15. Switching to Another PPI – Highly Successful
Esomeprazole 40 mg once daily (N=138)
Lansoprazole 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

16. 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

17. 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

18. 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

19. 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

20. 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:
Persistent Heartburn, UEGW, Barcelona Oct 2010

21. 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:
Diagnosis and Treatment of Refractory GERD, Phoenix, December 2008

22. 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:
Refractory GERD--Mechanisms & Treatment, Brazil, Nov 2010

23. 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:
Persistent Heartburn, UEGW, Barcelona Oct 2010

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

25. 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

26. 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:
Noncardiac Chest Pain:Advances in Diag & Treatment_Aspen_Jan2012

27. 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

28. 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