How to manage a patient with refractory heartburn

1. Persistent heartburn in a patient on PPI
Samir Haffar M.D.
Associate Professor of Gastroenterology
Al-Mouassat University Hospital – Damascus – Syria

2. Clinical History – 1
36-year-old woman with 6-year history of heartburn
Symptoms occurred from 3 times/day to 3 times/week
Symptoms occasionally awaken her from sleep during night
No dysphagia, chest pain, epigastric pain, bloating, or vomiting
Good appetite, no weight loss, denies smoking or drinking alcohol
Social worker, married, 2 toddlers at home
Considered her work & her family life to be very stressful
Unremarkable physical examination except for borderline obesity

3. Clinical History – 2
• Seen by her primary care physician: lifestyle modifications, lose
weight, less busy work schedule, & H2RA twice daily
• No improvement despite 2 months of therapy with H2RA
Unable to lose weight or change her work schedule
• Three months ago: PPI once daily half an hour before breakfast
• PPI help during first 2 weeks, symptoms recurred with less severity
She takes antacids, OTC H2RA, & another PPI before bedtime

4. Persistent heartburn in a patient on PPI
 Definition of refractory GERD
 Putative mechanisms for refractory GERD
 Diagnostic options for refractory GERD
 Therapeutic approaches of refractory GERD
 Recommendations

5.  Definition of refractory GERD

6. What constitutes refractory GERD?
• PPI one or twice daily Most investigators: bid
Some investigators: qd
• Duration 8 weeks in EE
4 weeks in NERD
Patients who failed to obtain satisfactory symptomatic
response &/or complete esophageal healing after a
full course of standard dose PPI (once a day)
EE: Ersosive esophagitis
NERD: Non Ersosive Reflux disease
Fass R et al. Aliment Pharmacol Ther 2005 ; 22 : 79 – 94.

7. Refractory GERD in each of the GERD groups
Fass R et al. Aliment Pharmacol Ther 2005 ; 22 : 79 – 94.
10 – 40% of patients fail to respond symptomatically,
either partially or completely, to a standard dose PPI

8. Symptomatic response to PPI in NERD
PPIs once daily for 4 weeks
Response correlated with extent of esophageal acid exposure
Aliment Pharmacol Ther 2000 ; 14 : 597 – 602.

9. Healing failure in patients with EE
PPI qd for 8 weeks
Richter JE et al. Am J Gastroenterol 2001 ; 96 : 3089 – 98.
Patients might continue to report GERD symptoms despite
complete healing of esophageal mucosa (up to 15%)

10.  Putative mechanisms for refractory GERD

11. Underlying mechanisms for persistent
heartburn despite treatment with PPIs
Fass R & Sifrim D. Gut 2009 ; 58 : 295 – 309.
10 – 40 % of patients

12. • Non compliance
• Improper dosing time
• Reduced PPI bioavailability
• Rapid PPI metabolism
• PPI resistance
Putative mechanisms for failure of PPI
Related to PPIs
Fass R. Clin Gastroenterol Hepatol 2008 ; 6 : 393 – 400.
Unrelated to PPIs
• Weakly acidic or alcaline reflux
• Bile reflux (DGER)
• Esophageal hypersensitivity
• Nocturnal reflux
• HP infection
• Delayed gastric emptying
• Eosinophilic esophagitis
• Psychological co-morbidity
• Others (unrelated to GERD)

13. Non compliance
Most common cause for PPI failure
• GERD is a symptom-driven disease
• By end of 6 months, 30% of patients still consume PPIs
• Factors of compliance Presence or absence of symptoms
Severity of symptoms
Personal preference
• Compliance should be assessed in all patients with
refractory GERD prior to ordering any evaluative test

14. Dosing time of PPIs
Aliment Pharmacol Ther 2000 ; 14 : 1267 – 1272.
21 volunteers taking PPI each morning
Either 15 min before breakfast or without food or drink
On day 7, intragastric pH-metry from 8:00 to 16:00 ( 8-h period)
17.2%
IQR: 4.6 – 45.5
42.0%
IQR: 31.4 – 48.8
P ˆ= 0.01

15. PPIs should be taken 30 min
prior to a meal

16. • Non compliance
• Improper dosing time
• Reduced PPI bioavailability
• Rapid PPI metabolism
• PPI resistance
Putative mechanisms for failure of PPI
Related to PPIs
Fass R. Clin Gastroenterol Hepatol 2008 ; 6 : 393 – 400.
Unrelated to PPIs
• Weakly acidic or alcaline reflux
• Bile reflux (DGER)
• Esophageal hypersensitivity
• Nocturnal reflux
• HP infection
• Delayed gastric emptying
• Eosinophilic esophagitis
• Psychological comorbidity
• Others (unrelated to GERD)

17. Esophageal pH monitoring
• Catheter esophageal pH monitoring
Wireless esophageal pH monitoring (Bravo capsule)
• Quantitative (DeMeester) & qualitative analysis (SI – SAP)
• off PPIs Test if initial diagnosis correct
on PPIs Test if symptoms due to residual acid (PPIs bid)
• Positive pH Heartburn related to acid reflux
Negative pH, positive SI Heartburn related to acid reflux
Negative pH, negative SI Heartburn not related to acid reflux

18. 24 h catheter esophageal pH monitoring
5 cm above LES

19. Normal 24 h esophageal pH monitoring
Quantitative analysis
Qualitative analysis
Bremner CG et al. Esophageal disease & testing. Taylor & Francis Group, 2005.

20. Composite scoring systems
Johnson & DeMeester is the most commonly used
Percentage of total time pH < 4
Percentage of upright time pH < 4
Percentage of supine time pH < 4
Number of reflux episodes
Number of reflux episodes >5 min
Longest reflux episode
DeMeester score
Normal ≤ 14,72

21. Mean SD Median Minimum Maximum 95th %
Total time at pH < 4 (%) 1.5 1.4 1.2 0 6.0 4.5
Upright time at pH< 4 (%) 2.2 2.3 1.6 0 9.3 8.4
Supine time at pH< 4 (%) 0.6 1.0 0.1 0 4.0 3.5
Number or reflux episodes 19.0 12.8 16.0 2.0 56.0 46.9
Number of episodes > 5 min 0.8 1.2 0 0 5.0 3.5
Longest episode (min) 6.7 7.9 4.0 0 46.0 19.8
Composite score 6.0 4.4 5.0 0.4 18.0 14.7
Normal values of DeMeester’s score
50 healthy volunteers
DeMeester TR et al. Ann Surg 1976 ; 184 : 459 – 470.

22. Qualitative analysis
Symptom–reflux correlation
• Symptom index: Positive if ≥ 50%
• Symptom sensitivity index: Positive if > 10 %
• Symptom association probability Positive if > 95%
Determine relationship between heartburn episodes & acid
reflux events, regardless if pH test is normal or abnormal

23. Percentage of total time pH < 4
Normal values
• Off therapy
5 cm above LES
20 cm above LES 1 %
Periods of meals or acidic beverages excluded
• On therapy
5 cm above LES
20 cm above LES ?
* Based on 95% CI obtained in healthy subjects treated with omeprazole 40 mg qd
Kuo B et al. Am J Gastroenterol 1996 ; 91 : 1532 – 8.
4 – 5.5 %
1.6 – 4 %*

24. Abnormal acid exposure time in heartburn
Disease Percentage of total time pH < 4
Barrett’s esophagus 93 %
* ENRD Endoscpic Negative Reflux Disease
* *NERD Non Erosive Reflux Disease
Erosive esophagitis 75 % (in one study)
ENRD*
NERD**
Functional heartburn
- SI > 50%
- SI < 50%
50 %
100 %
0 %
Hypersensitive esophagus
Non acid reflux or motor event

25. 24 hour pH monitoring is not the
gold standard for diagnosis of GERD

26. Bravo system (Medtronics)
Esophageal Probe
25 x 6 x 5.5 mm
Battery
pH
electrode
Suction
chamber
Radio
transmitter
Delivery system
Receiver
100 x 70 x 30 mm - 165 g

27. Wireless esophageal pH monitoring
Bravo capsule – 48 hours
Gastrointest Endoscopy Clin N Am 2005 ; 15 : 307 – 318.
Patients might have normal test on day 1 & abnormal test on day 2
Increase sensitivity to detect symptoms correlated with acid reflux
More studies needed in patients with refractory GERD

28. Bravo normal values
50 asymptomatic volunteers
1st 24 h 2nd 24 h
Mean
(+ SD)
95th
percentile
Mean
(+ SD)
95th
percentile
% total time at pH < 4 1.79 (2.16 5.89 1.78 (1.78) 5.64
% upright time at pH < 4 2.45 (3.14) 7.81 2.54 (2.57) 7.46
% supine time at pH < 4 0.37 (1.18) 1.58 0.34 (1.28) 1.29
Number of reflux episodes 21.2 (18.5) 55.30 22.3 (19.8) 56.15
No of reflux episodes >5 min 0.62 (1.21) 3.55 0.75 (1.15) 3.00
Longest reflux episode 3.79 (4.31) 11.23 5.95 (4.52) 17.03
DeMeester score 6.02 (4.82) 15.93 5.95 (4.52) 15.48

29. pH testing in refractory GERD
Very few studies
• Catheter pH monitoring1
PPI qd Limited value (normal test in 70%)
PPI bid Non-contributory value (normal test in 96%)
• Wireless pH monitoring
2 days: Normal test on both days in 65%
4 days3: More studies needed
High failure rate: 25%
1 Charbel S et al. . Am J Gastroenterol 2005 ; 100 : 283 – 9.
2Hirano I et al. Clin Gastroenterol Hepatol 2005 ; 3 : 1083 – 8.

30. Multichannel Intraluminal Impedance
Antegrade bolus movement during swallowing
Progression of impedance from proximal to distal
Gastrointest Endoscopy Clin N Am 2005 ; 15 : 257 – 264.

31. Multichannel Intraluminal Impedance
Retrograde bolus movement observed in reflux
Progression of impedance from distal to proximal
Gastrointest Endoscopy Clin N Am 2005 ; 15 : 257 – 264.

32. Advantages of MII
• Direction of bolus Anterograde – retrograde
• Content of refluxate Liquid – Gas – Mixed
• Height of refluxate Related to volume of refluxate
• pH characteristics Acid reflux
(combined MII-pH) Weekly acid reflux
Weekly alkaline reflux
Acid re-reflux

33. Combined MII-pH probe
• Impedance orifices
3, 5, 7, 9, 15, & 17 cm from the tip
• pH orifice
5 cm from the tip
• Ө MII-pH probe = Ө pH probe
Do not change patient comfort
Bremner CG et al. Esophageal disease & testing.
Taylor & Francis Group, NY, 1st edition, 2005.

34. “Sleuth” monitor – Sandhill
Multichannel Intraluminal Impedance with pH sensor
“Sleuth” monitor attached to the catheter
& worn around a belt during the recording period

35. • Analysis similar to esophageal pH monitoring
- Quantitative analysis
- Qualitative analysis: SI – SSI – SAP
• Healthy: Total no of reflux: 40 per 24 h
1/3 acid & 2/3 weakly acidic or alkaline
• Negative study rules out GERD as cause of symptoms
Esophageal MII-pH monitoring
Most sensitive method for reflux detection

36. GERD classification by combined MII-pH
• Acid reflux
Reflux with drop of pH from above 4.0 to below 4.0
• Superimposed acid reflux (Acid re-reflux)
Acid reflux occurs while pH < 4.0
• Weakly acidic reflux
Reflux results in esophageal pH between 4.0 & 7.0
• Weakly alkaline reflux
Reflux with nadir esophageal pH does not drop < 7.0
Sifrim D et al. Gut 2004 ; 53 ; 1024 – 1031.

37. Combined MII-pH of the esophagus
Fass R & Sifrim D. Gut 2009 ; 58 : 295 – 309.
Weakly acidic reflux
4 ≤ pH < 7
Weakly alkaline reflux
pH ≥ 7

38. MII-pH in refractory GERD
• Shift from acidic reflux to weakly acidic reflux
Regurgitation become predominant symptom
• off PPI Little value when compared with pH (10%)
on PPI Improved diagnostic yield by 20%
• Positive SI for acid reflux 10%
Positive SI for non-acid reflux 37%
Mainie I et al. Gut 2006 ; 55 : 1398 – 402.
Zerbib F et al. Am J Gastroenterol 2006 ; 101 : 1956 – 63.

39. Bilitec recorder*
Assess bile reflux by using bilirubin as surrogate marker
* Medtronic, Minneapolis, MN, USA

40. Esophageal Bilitec
Must be accompanied by 24 h esophageal pH
• Fiberoptic probe to detect bilirubin (450 nm absorption)
• Presented as per cent time bilirubin absorbance > 0.14
• Progressive increase in DGOR across spectrum of GERD
Particularly high prevalence in patients with Barrett’s
• Medtronic stops commercialization of the product

41. Esophageal pH & Bilitec study
Maximal bile reflux in the esophagus during supine period
Bremner CG et al. Esophageal disease & testing. Taylor & Francis Group, 2005.
Limited evidence of increase in DGER in refractory GERD

42. % of time with bilirubin absorbance > 0.14
Duodeno-gastro-esophageal reflux
Vaezi MF et al. Gastroenterology 1996 ; 111 : 1192 – 9.
0.4%
3.2%
14.6%
23%
46%

43. Visceral hypersensitivity
Not specifically studied in refractory GERD
• Most patients have NERD or functional heartburn
• Heartburn associated with weakly acidic reflux
• Lower perception thresholds for pain
Balloon esophageal distention
Electrical stimulation
• Dilated intercellular spaces
Promotes higher activation of sensory nerve endings

44. Dilated intercellular spaces (DIS)
• Higher activation of sensory nerve endings
• Nonspecific Asymptomatic subjects
Candida infection of esophagus
Food allergy
Eosinophilic oesophagitis
Esophageal cancer
• Disappearance of DIS & symptoms resolution after PPI
• NERD patients refractory to PPI have persistence of DIS

45. Dilated intercellular spaces
Rabbit oesophageal mucosa at electron microscopy
Farre R et al. Gut 2008 ; 57 :1366 – 74.
Acid-pepsin solution at pH 5.0
Acid-pepsin solution at pH 5.0
plus deoxycholic acid 2 mmol/l

46. Nocturnal acid breakthrough
Combined esophageal & gastric 24 h pH monitoring
Gastric pH < 4 for ≥ 60 min despite twice daily PPI
Gastrointest Endoscopy Clin N Am 2005; 15: 289 - 306.
75% of GERD patients & healthy subjects on PPI bid
No correlation between NAB & nocturnal GERD symptoms

47. Delayed gastric emptying
• Few studies evaluates frequency of gastric emptying
in refractory GERD
• Rapidly growing number of patients with DM & those
using narcotics for pain syndrome might soon make
gastroparesis one of the leading causes of PPI failure

48. Diagnosis of eosinophilic esophagitis
Relatively uncommon disorder
• Clinical symptoms of esophageal dysfunction:
Dysphagia, food impaction, refractory GERD, chest pain
• 15 eosinophils in 1 high-power field
• Lack of responsiveness to high-dose PPI
or normal pH monitoring of distal esophagus
Furuta GT et al. Gastroenterology 2007 ; 133 : 1342 – 1363.

49. Endoscopic images of eosinophilic esophagitis
Linear furrows &
adherent white exudatesConcentric rings
Small calibre esophagus
with stricture
Mucosal laceration from
Diagnostic endoscopy

50. Eosinophilic esophagitis
The ringed esophagus
Hiatus hernia
Lower esophageal ring
Adjacent ring
Zimmerman SL et al. Radiology 2005 ; 236 : 159 – 165.
Most patients have esophageal strictures
with distinctive ring-like indentations
Smooth stricture with
distinctive rings

51. Psychological comorbidity
Patients with poor symptom-reflux correlation
exhibit significant psychosocial morbidities
• High level of anxiety
• Hysteria
• Depression

52. Other diseases unrelataded to GERD
Rarely confused with GERD
• Pill-induced esophagitis
• Skin diseases with esophageal manifestations
• Zollinger-Ellison syndrome
• Achalasia

53.  Diagnostic options for refractory GERD

54. Diagnostic techniques for refractory heartburn
• UGI Endoscopy Low diagnostic yield
• pH testing PPI qd: limited value
PPI bid: non-contributory value
• MII-pH Best diagnostic tool on PPI
• Bilitec 2000 Limited evidence

55. UGI endoscopy
First test used in clinical practice for refractory GERD
• Normal endoscopy (most frequent)
• Esophageal erosions
• Pill-induced esophagitis
• Infectious esophagitis
• Zollinger-Ellison syndrome
• Eosinophilic esophagitis
Very low diagnostic yield if no alarm symptoms
ASGE guidelines. Gastrointest Endosc 2007 ; 66 : 219 – 24.

56. Erosive esophagitis in refractory GERD & untreated patients
Poh CH et al. Gastrointest Endosc 2010 ; 71 : 28 – 34.
OR of erosive esophagitis in refractory GERD: 0.11 (95% CI: 0.04-0.30)
Eosinophilic esophagitis: 0.9% of refractory GERD
Cross-sectional study
105 refractory GERD – 91 untreated patints

57.  Therapeutic approaches of refractory GERD

58. Therapeutic approaches of refractory GERD
• Compliance & dosing time
• Lifestyle modifications
• Proton-Pump Inhibitors (PPI)
• H2RA at bedtime
• Baclofen
• Promotility drugs & bile acid binders
• Pain modulators
• Endoscopic treatment for GERD
• Antireflux surgery
• Alternative medicine
First management
Standard of care

59. Compliance & proper dosing time
Evaluation of proper compliance and adequate dosing
time should be the first management when assessing
patients with heartburn who are not responding to PPIs
before instituting any other intervention

60. Lifestyle modifications
• Only weight loss and elevation of the bed head are
effective in improving GERD
• Insufficient data to support other lifestyle modifications
Kaltenbach T et al. Arch Intern Med 2006 ; 166 : 965 – 71.
Recent systematic review of all publications
It is reasonable to recommend avoidance of specific
lifestyle activities identified by patients or physicians
to trigger GERD-related symptoms

61. Proton pump inhibitors
• Switching to another PPI
• Doubling the PPI dose
½ hour before breakfast & before dinner
Increase in overall symptom relief by 25%
No evidence for further escalation of PPI dose
Two therapeutic strategies
“Standard of care”

62. H2RAs at bedtime
• Retrospective study: 56 pts – PPIs bid + H2RAs at bedtime*
72% long term improvement in overall symptoms
• Good experience accumulated so far with H2RA for GERD
Rackoff A et al. Dis Esophagus 2005 ; 18 : 370 – 3.
• H2RAs might improve GERD-related symptoms in long
term in substantial number of patients
• If clinical tolerance: H2RAs intermittently or on demand

63. TLESR
Primary mechanism of reflux in health & GERD
Three characteristics:
 Non-swallow induced
 Prolonged
 Triggered by fundic distension

64. Baclofen*
TLESR reducers
• Mechanisms Reduced reflux episodes by 40%
Increased LES basal pressure
Accelerated gastric emptying
• Doses Up to 20 mg tid
• Side effects Central nervous system side effects
Somnolence, confusion, trembling
Important limiting factor in routine usage
• Indications Weakly acidic reflux by MII-pH
Regurgitation, or sour/ bitter taste in mouth
* Gamma-aminobutyric acid B receptor agonists

65. Promotility drugs & bile acid binders
Promotility drugs
• Attractive option in delayed gastric emptying
• No available data in GERD patients who failed PPIs
Cholestyramine or sucralfate
• Unclear if any of the currently available bile acid binders
are sufficiently efficacious to improve symptoms

66. Visceral pain modulators
• No studies in GERD patients with refractory heartburn
• Attractive option Most patients from NERD group
Lack of weakly or acidic reflux
• Tricyclic antidepressants, trazodone, & SSRIs
• Used in non-mood-altering doses
• Same recommendations for non-cardiac chest pain

67. Endoscopic treatment for GERD
Interesting topic of investigation
• Requirements: efficacy, safety & durability
• Two promising techniques
Radiofrequency energy (Stretta) Refractory GERD
Endoluminal fundoplication Candidate for surgery
• Most studies open & uncontrolled with short-term results
• Few RCTs with less impressive results than open trials
Louis H et al. Best Pract Res Clin Gastroenterol 2010 ; 24 : 969 – 979.

68. Stretta procedure
• 109 patients refractory to PPI bid
• Endoscopic esophagitis or abnormal pH testing
• 4-years follow-up
• Assessment: GERD HRQL questionnaire
Heartburn
Satisfaction
Percent without PPI
• Data on long-term follow-up (4 y): sustained improvement
Noar MD et al. Gastrointest Endosc 2007 ; 65 : 367 – 72.

69. Anti-reflux surgery
• Anti-reflux surgery in refractory GERD scarcely studied
• Careful selection of patients
Positive symptom-reflux correlation in MII–pH on PPIs
Excellent results for laparoscopic Nissen fundoplication
• Postsurgical follow-up relatively short
Mainie I et a. Br J Surg 2006 ; 93 : 1483 – 7.
del Genio G et al. J Gastrointest Surg 2008 ; 12 : 1491 – 6.

70. Alternative medicine
Acupuncture
• 30 patients on PPI qd
Acupuncture biw vs doubling PPI dose/4week
Assessment: GERD symptoms diary – HRQoL by SF 36
Acupuncture more effective than doubling PPI dose
• Additional studies needed to demonstrate value of
acupuncture in this clinical situation
Dickman R et al. Aliment Pharmacol Ther 2007; 26 : 1333 – 44.

71. Traditional Chinese Medicine acupuncture
points used in the treatment protocol
.
Dickman R et al. Aliment Pharmacol Ther 2007; 26 : 1333 – 44.
Per.6 Neiguan
St.36 Zusanli
CV12 Zhangwan
CV17 Shanzhong
Liv.3 Taichong
Sp.9 Yinlingquan

72. Health-related quality of life
Assessment by Short Form 36
HRQol assessed by SF-36
SF-36 dimensions scored on a 0 (poor) to 100 (good) health scale

73.  Recommendations

74. Recommendations
Patient failed full course of PPI once a day
• Excluding poor compliance & dosage timing
• Switch to another PPI or doubling the PPI dose
2-month course of treatment
• Maintenance treatment if asymptomatic on PPI bid
Same PPI dose inducing remission – PPI qd considered
• Lack of symptom improvement → 2 strategies
Based on MII-pH on treatment
Empirical therapy

75. Management strategy based on MII-pH
Positive for acid reflux (least common scenario)
• Review compliance & dosage timing
• H2RA at bedtime
Positive for weakly acidic reflux
• Baclofen Low dose & slow increase in dose approach
• Surgery Carefully selected patient
Positive SI in esophageal MII–pH
Negative
• Pain modulators Tricyclics, trazodone, and SSRI
Same recommendations for NCCP

76. Empirical therapy for refractory GERD
MII-pH not available to many physicians
Patient’s predominant symptom might guide treatment
• Heartburn H2RA at bedtime
• Regurgitation or sour taste in mouth Baclofen
Anti-reflux surgery
• Still exhibits lack of response Pain modulators
Fass R. Clin Gastroenterol Hepatol 2008 ; 6 : 393 – 400.

77. Conclusion
• Compliance & dosing time should be evaluated first in patients
with heartburn not responsive to PPI
• In patients who failed PPI once daily, doubling PPI dose or
switching to another PPI are potential therapeutic strategies
• UGI endoscopy has very limited value if no alarm symptoms
• MII-pH monitoring on PPI provides best diagnostic tool:
Acid reflux H2RA
Weakly acidic reflux Baclofen – Anti-reflux surgery
No reflux Pain modulators

78. Thank You