Refractory Heartburn: When PPI’s Fail to Sooth the Burn

Ronnie Fass, MDProfessor of Medicine

University of Arizona

Definitions of Refractory HeartburnA Patient-Driven Phenomenon

“Patients who failed to obtain satisfactory symptomatic response after an 8 weeks course of standard-dose PPI”

Fass R. Drugs 2007;67:1521-1530Fass R et al.. Curr Gastroenterol Rep 2008;19:252-257Fass R et al. Gut 2009;58:295-309Hershcovici T et al. Curr Opin Gastroenterol 2010;26:367-378Sifrim D et al. Gut 2012 (in Press)

“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

Specific Indications Chosen by Primary Care Physicians to Refer GERD Patients for EGD

0

20

40

60

80

100

Determinants for Referral for EGD

Boolchand et al., Gastrointest Endosc 2006;63:228-33

The Epidemiology of Refractory Heartburn in Primary Care and Community Studies

17% 32%

Non-randomized

trials

Randomized trials

Non-responders

El-Serag H. et al. Aliment Pharmacol Ther 2010;32:720-37.

Observational trials

Non-respondersNon-responders

More Common in Females

45%

The Reported Rate of Symptomatic Failure in Therapeutic Trials of GERD Patients

PPI Failure

Nonerosive reflux disease (60-70%)

40%–50%

Erosive Esophagitis

(20-30%)

25%–40%

Barrett’s Esophagus

(6-10%)

20%

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

N=813 N=972 N=497 N=140

P<0.01Richter et al. Am J Gastroenterol .2001;96:656-65

Week 8

Grade A Grade B Grade C Grade D0

20

40

60

80

100 90.481.3

70.463.8

93.4 89.4 87.280

Omeprazole Esomeprazole

Pa

tien

ts H

ea

led

(%

)

* * **

Grade C & D account for only 15-30% of EE patients

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

• 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

Putative Underlying Mechanisms for PPI Failure

Basic Rules in Refractory GERD

*PPI once daily NERD / Functional heartburn

*PPI Twice Daily Functional heartburn

* If GERD patients treated empirically do not respond to…

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 ModificationsFactor Trials,

No.Lowered

LESPWorsened

pHWorsenedSymptoms

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

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) 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

Poh CH et al. Gastrointest Endosc 2010; 71:28-34

Switching to Another PPI –Highly Successful

Fass R et al. Clin Gastroenterol Hepatol 2006

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

Breakthrough Nighttime Symptoms on PPI Once Daily – Consider Giving

PPI Before Dinner

16

45

65

28

In themorning

Mid day

At night

Duringsleep

No breakthroughsymptoms, 62%

Breakthroughsymptoms, 38%

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?

Mainie I et al. Gut, 2006; 55:1398-1402

Symptomatic patients

172 (86%)

Nonacid reflux61 (35%)

Acid reflux13 (8%)

Symptoms notassociated 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

Lidums I et al. Gastroenterology. 2000;118:7–13.

Fass R. Clin Gastroenterol Hepatol 2012;10:338 - 45

Inhibitory Effect of Oral Baclofen 40 mg/day on Postprandial TLESRs

0

2

4

6

8

10

1-60 61-120 121-180 1-180

Time (min)

TLES

Rs (n

umbe

r/hou

r) Placebo

Baclofen*

* **

Antireflux Surgery in NERD and Erosive Esophagitis Patients Refractory to Treatment

NERD ERD

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

Before surgery 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%)

Positive SAP

Before surgery 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%)

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)

0%

20%

40%

60%

80%

100%

PPI Failure (N=24) PPI Success (N=23)

% o

f pat

ient

s

None Acid reflux DGER Acid reflux + DGER

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

• 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

Main Principle: “Low and slow”

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.