Transcript What Are the Mechanisms of PPI Failure?

Refractory Heartburn: When
PPI’s Fail to Sooth the Burn
Ronnie Fass, MD
Professor of Medicine
University of Arizona
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)
Specific Indications Chosen by Primary Care
Physicians to Refer GERD Patients for EGD
Determinants for Referral for EGD
100
80
60
40
20
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Boolchand et al., Gastrointest Endosc 2006;63:228-33
The Epidemiology of Refractory Heartburn
in Primary Care and Community Studies
Non-responders
Non-responders
Non-responders
17%
45%
32%
Non-randomized
Randomized trials
trials
More Common in Females
El-Serag H. et al. Aliment Pharmacol Ther 2010;32:720-37.
Observational
trials
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%
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
Barrett’s
Esophagus
(6-10%)
20%
Erosive Oesophagitis
Healing Rates are Reduced in Grades C and D
Grade C & D account for only 15-30% of EE patients
Omeprazole
100
90.4 93.4
*
Esomeprazole
89.4 *
87.2
Patients Healed (%)
81.3
80
70.4
*
80 *
63.8
60
40
20
0
Grade A
Grade B
Grade C
Grade D
N=813
N=972
N=497
N=140
Week
P<0.01
Richter et al. Am J Gastroenterol .2001;96:656-65
8
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
Putative Underlying Mechanisms for PPI
Failure
• 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
• Delayed gastric emptying
• PPI resistance
• Others
Fass R et al.. Gut 2009;58:295-309
• Concomitant functional bowel disorder
Basic Rules in Refractory GERD
* If GERD patients treated empirically do not respond to…
*PPI once daily

*PPI Twice Daily    
NERD / Functional heartburn
Functional heartburn
Hershcovici & Fass. J Neurogastroenterol Motil 2010;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. 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)
Lifestyle Modifications
Factor
Trials,
No.
Lowered
LESP
Worsened
pH
Worsened
Symptoms
Tobacco
12
B
B
B
Alcohol
16
No effect
(B)
B
B
Obesity
24
E
E
E
Coffee and caffeine
14
E
E
No effect (C)
Chocolate
2
B
B
E
Spicy foods
2
E
E
C
Citrus
3
No effect
(B)
E
C
Carbonated beverages
2
B
E
C
Fatty foods
9
D
B
E
Mint
1
D
E
E
Recumbent position
1
E
B
B
RLD position
3
B
B
E
Late evening meal
3
E
No effect
(B)
E
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?
Endoscopic findings
PPI failure (%)
(N=105)
No treatment (%)
(N=91)
P value
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)
0
1.0
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)
1.0
Esophageal webs
1 (0.95)
0
1.0
Esophageal angiodysplasia
1 (0.95)
0
1.0
Achalasia
1 (0.95)
0
1.0
Normal
Poh CH et al. Gastrointest Endosc 2010; 71:28-34
Switching to Another PPI –
Highly Successful
Heartburn symptom
improvement, % (N)
after 8 weeks
Esomeprazole 40
mg once daily
(N=138)
Lansoprazole
30 mg twice daily
(N=144)
P value
83.3 (155)
83.3 (120)
1.00
Fass R et al. Clin Gastroenterol Hepatol 2006
Breakthrough Nighttime Symptoms
on PPI Once Daily – Consider Giving
PPI Before Dinner
During
sleep
Breakthrough
symptoms, 38%
No breakthrough
symptoms, 62%
N=1064
28
65
At night
45
Mid day
In the
morning
16
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
patients
172 (86%)
Nonacid reflux
61 (35%)
Acid reflux
13 (8%)
Mainie I et al. Gut, 2006; 55:1398-1402
Symptoms not
associated with reflux
98 (57%)
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
Inhibitory Effect of Oral Baclofen 40 mg/day
on Postprandial TLESRs
TLESRs (number/hour)
•
10
8
6
4
Placebo
Baclofen
*
2
*
*
*
61-120
121-180
1-180
0
Lidums I et al. Gastroenterology. 2000;118:7–13.
Fass R. Clin Gastroenterol Hepatol 2012;10:338 - 45
1-60
Time (min)
Antireflux Surgery in NERD and Erosive
Esophagitis Patients Refractory to Treatment
NERD
ERD
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)
47 of 57 (82%)
62 of 81 (77%)
3 months
2 of 57 (4%)
3 of 81 (4%)
5 years
3 of 24 (13%)
3 of 22 (14%)
42 of 51 (82%)
63 of 79 (80%)
3 months
1 of 51 (2%)
2 of 79 (3%)
5 years
2 of 18 (11%)
1 of 22 (5%)
Number of symptoms
Positive SI
Before surgery
Positive SAP
Before surgery
Broeders JA et al. Br J Surg 2010;97:845-852
The Prevalence of Abnormal pH Test and Bilitec Among
PPI Failure and PPI Success Patients (all P>0.05)
None
Acid reflux
DGER
Acid reflux + DGER
100%
% of patients
80%
60%
40%
20%
0%
PPI Failure (N=24)
PPI Success (N=23)
Gasiorowska A et al. Am J Gastroenterol 2009 Aug;104:2005-2013
Pain Modulation in PPI Failure TCA Antidepressants
Sperber AD, Drossman DA. Aliment Pharmacol Ther 2011;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 Gastroenterol Hepatol 2012;27:suppl 3:3 – 7
Hierarchy of Antidepressants of
Choice for Esophageal Pain Reduction
and Global Health Improvement
Pain Reduction
Global Health Improvement
1. Venlafaxine
1. Venlafaxine
2. Sertraline
2. Sertraline
3. Imipramine
3. Trazodone
4. Trazodone
4. Imipramine
5. Paroxetine
5. Paroxetine
Nguyen TMT et al. Aliment Pharmacol Ther 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.