How to deal with PPIs refractory GERDthaimotility.or.th/vdo/2013/How to deal with PPI... ·...

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How to deal with PPIs – refractory GERD ?

Kitti Chunlertrith

Division of Gastroenterology, Faculty of Medicine,

Khon Kaen University

3 October 2013

• GERD : Definition, Pathophysiology, Diagnosis

• Recommendation for management of GERD

• Definition of PPIs-refractory GERD

• Mechanisms of PPIs-refractory GERD

• Common causes of PPIs-refractory GERD

• Diagnostic tools for PPIs-refractory GERD

• Therapeutic options for PPIs-refractory GERD

• Step-by-step management of PPIs-refractory GERD

Scope

GERD is a condition that develops when the reflux

of stomach contents causes troublesome

symptoms and/or complication

Am J Gastroenterol.2006;101:1900-20.

Heartburn Regurgitation

Definition of GERD

Pathophysiology of GERD

Impaired esophageal clearance

Impaired salivary function

Hiatal hernia

Impaired esophageal mucosal defence

Inappropiate TLESR

Reduced resting LES pressure

Gastric acid Pepsin

Bile

Gas

Delayed gastric emtying Pyloric imcompetence

Increased intraabdominal pressure

• Typical heartburn or regurgitation

• PPI – test

• Upper endoscopy

• Ambulatory reflux monitoring

Diagnosis of GERD

No sero-marker for diagnosis

• A presumptive diagnosis of GERD can be established in the

setting of typical symptoms of heartburn or regurgitation.

Empiric medical therapy with a proton pump inhibitor is

recommended

• Weight loss is recommended for GERD patients who are

overweight or have had recent weight gain

• Head of bed elevation and avoidance of meal 2-3 h. before bed

time should be recommended for patients with nocturnal GERD

• An 8-weeks course of PPIs is the therapy of choice for

symptom relief and healing of erosive esophagitis

• Non-responders to PPI should be referred for evaluation


Recommendations for management of GERD

• The most common GI disorder : prevalence 10 – 20%

• Proton pump inhibitors is the mainstay of treatment

• 10 – 40% of GERD fail to respond to

standard dose PPIs : PPIs-Refractory

GERD

Gastroesophageal Reflux Disease

PPI Standard dose (mg/day)

Omeprazole

Lansoprazole

Rabeprazole

Pantoprazole

Esomeprazole

20

30

20

40

40

Proton pump inhibitors

• Unresponsible to 4-8 weeks treatment with proton

pump inhibitors (1)

• Symptoms (heartburn and/or regurgitation) not

responding to double dose of a proton pump

inhibitor during a treatment period of at least 12

weeks (2)

• Bothersome symptoms that are attributable to GERD

and that persist despite treatment with a proton

pump inhibitor (3) (1) Nat Clin Pract Gastroenterol Hepatol. 2007 Dec ;4(12):658-64.

(2) Gut. 2012 Sep;61(9):1340-54.

(3) Am J Gastroenterol. 2013 Mar;108(3):308-28.

Definition of PPIs-refractory GERD

• No established consensus regarding the definition of

refractory GERD in term of symptom burden, degree of

therapeutic response and PPI dose

• Refractory GERD is a patient – driver phenomenon

• Lack of satisfactory symptomatic response to PPI once a

day is sufficient to consider patients as PPI-refactory

GERD

Definition of PPIs-refractory GERD

• 38.6% of refractory GERD had abnormal pH-testing (1)

• 31–32% and 4–16% of refractory GERD had abnormal pH-testing

during on PPI once diary and twice diary, respectively (2,3)

• 40% and 7-11% of refractory GERD , positive symptom index on

PPI one and twice daily (4, 5, 6)

• The amount of residual acid reflux was not difference in

responders to PPI and non-responders (7)

Residual acid reflux Esophageal hypersensitivity

1. Dig Dis Sci 2005;50:1909-15.

2. Am J Gastroenterol 2005;100:283-9.

3. Dig Dis Sci 2008;53:2387-93.


5. Gut 2006;55:1398-402.

6. Clin Gastroenterol Hepatol 2008;6:521-4.


pH-monitoring test during on PPI

• Profound decrease in the amount of acid reflux but with

continuing postprandial of weakly acid (1)

• Proximal extent of weekly acid reflux was the most important

determinant of symptomatic reflux event in patient who failed PPI

treatment (2, 3)

• Reflux episodes that were associated with symptoms in patients

who failed PPI, composed of both gas and liquid (2, 3)

• Heartburn patients with normal endoscopy and pH testing the risk

of reflux perception was significantly higher when gas present in

the reflux (4)

Weakly acidic reflux Non – acidic reflux

1. Gastroenterology 2001;120:1599-606.

2. Gut 2008;57:156-60


4. Gut 2008;57:443-7.

Impedance pH – monitoring study

• Persistent bile acid in the refluxate as a potential factor involved in

refractory heartburn

• Baclofen 20 mg three times daily significantly reduced the duodeno-

gastro-esophageal exposure as well as symptoms of heartburn (1)

• Only 9% of symptoms were correlated to DGOR suggesting that

DGOR play a limited role in symptom elicitation in refractory GERD (2)

• Successful symptomatic treatment of NERD with PPI is almost always

associated with dilated intercellular spaces (DIS) resolutions but

persistent of DIS and persistence of symptoms (3, 4)

1. Gut 2003;52:1397-402.




Study of refractory GERD patient

Duodeno-gastro-esophageal reflux Dilated intercellular space

• Patients who responded less well to PPI treatment were

more likely to experience psychological distress (1)

• Anxiety increased acid – induced esophageal

hyperalgesia (2)

• Acute stress is able to induce dilated intercellular space

in esophageal mucosa (3)

1. Aliment Pharmacol Ther 2008;27:473-82.

2. Psychosom Med 2010;72:802-9.

3. Gut 2007;56:1191-7.

Study of refractory GERD patient

Psychological-comorbidity

• Persistent acid reflux

• Persistent reflux of non-acid

• Persistent impairment of

esophageal mucosal integrity

• Hypersensitivity of esophagus

• Abnormal of LES

• Dysmotility of esophagus

• Esophagitis

• Functional heartburn

• Psychological co-morbidity

Reflux-related mechanism Non-reflux cause

Mechanisms of PPIs-refractory GERD

• Potassium chloride

• Ascorbic acid

• Quinidine

• Iron sulfate

• Doxycycline

• Tetracycline

• Alendronate

• Aspirin

• Naproxen

Common drug induced esophageal symptoms

• Non-compliance

• Inappropriate PPIs

administration

• Reduced PPIs

bioavailability

• Rapid PPIs metabolism

• PPIs resistance

• Non-acid reflux

• Hypersensitivity of esophagus

• Abnormal of LES

• Dysmotility of esophagus

• Esophagitis:pill,infection,

eosinophilic

• Functional heartburn

• Psychological co-morbidity

Related to PPIs Non-related to PPIs

Common causes of PPIs-refractory GERD

Poor compliance lack of response

60% adherence to PPI therapy

46% PPI taken before meal

70% primary care

20% of gastroenterologist

Advice taken at bedtime

Review PPIs used in refractory GERD

• Symptom, Medication and Lifestyle evaluation

• Upper endoscopy

• Esophageal manometry

• Ambulatory monitoring for reflux

Diagnostic tools for PPIs-refractory GERD

Lifestyle modification : weight reduction, head of bed

elevation, diet ,medication

Antisecretory drug : compliance and dosing time,

increasing dose, switching to another PPI

Add-on therapies with PPIs : alginates, H2RA at bed

time, baclofen (TLOSRs decrease)

Pain modulators : tricyclic antidepressant, trazodone,

selective serotonin reuptake inhibitors, citalopram

Endoscopic therapy : radiofrequency abration, transoral

incisionless fundoplication

Antireflux surgery : laparoscopy fundoplication

Therapeutic options for PPIs-refractory GERD

Lifestyle intervention Effect of intervention on GERD parameters

Sources of data

Recommendation

Weight loss (46,47,48) Improvement of GERD symptoms and esophageal pH

Case–Control Strong recommendation

for patients with BMI>25

or patients with recent weight gain

Head of bed elevation (50,51,52)

Improved esophageal pH and symptoms Randomized Controlled Trial

Head of bed elevation

with foam wedge or

blocks in patients with nocturnal GERD

Avoidance of late evening meals (180,181)

Improved nocturnal gastric acidity but not symptoms

Case–Control

Avoid eating meals with

high fat content within 2–3 h of reclining

Tobacco and alcohol cessation (182,183,184)

No change in symptoms or esophageal pH Case–Control

Not recommended to

improve GERD symptoms

Cessation of chocolate,

caffeine, spicy foods, citrus, carbonated beverages

No studies performed No evidence Not routinely

recommended for GERD

patients. Selective

elimination could be

considered if patients

note correlation with

GERD symptoms and

improvement with elimination

BMI, body mass index; GERD, gastroesophageal reflux disease

Am J Gastroenterol 2013; 108:308–328

Efficacy of lifestyle interventions for GERD

Gamma-aminobutyric acid B receptor agonist

Reduced TLESR rate by 40 to 60 percent

Reduced reflux episodes by 43 percent

Increased lower esophageal sphincter basal pressure

Accelerated gastric emptying

Reduced weakly acidic and bile reflux and

gastroesophageal reflux-related symptoms

Doses up to 20 mg three times daily Gastroenterology 2000;18:370

Gut 2003;52:1397

Aliment Pharmacol Ther 2012

Baclofen

Drug crosses the blood-brain barrier, a variety of

central nervous system (CNS)-related side effects

may occur

Include somnolence, confusion, dizziness,

lightheadedness, drowsiness, weakness, and

trembling.

The side effects are an important limiting factor in the

routine usage of baclofen in clinical practice.

Usually begin by giving 10 mg twice daily

Baclofen

1. Optimize PPI therapy + Lifestyle modification

Careful to interview to assess symptom, med, LSM

Good compliance and appropriate dosing

Once daily dose, before meal (15 – 30 min)

Increase PPI to twice daily (morning and evening)

Switching to another PPI

Add-on-therapy with alginates or H2-RA at bedtime

20-30% symptomatic improvement

If symptoms persist

Step-by-step management of PPIs-refractory GERD

Typical esophageal symptom

Upper endoscopy

-Erosive esophagitis

-Eosinophilic esophagitis

-Abnormal anatomy

-Specific treatment

Atypical symptoms

Refer to ENT, pulmonary or

allergy

2. Further work – up


Upper endoscopy Erosive esophagitis

CMV esophagitis

Candida esophagitis

Herpetic esophagitis

Normal If normal finding

3. Further work - up

• Reflux monitoring : 2 key issues to consider

» PPI : Stop or on PPI during reflux monitoring

» Technique : Catheter – base pH

Wireless pH

Impedance – pH

• Result from reflux monitoring may reveal

A. PPI failure with ongoing acid reflux

B. Adequate acid control but ongoing symptomatic non

acid reflux

C. No reflux

Step – by – step management of PPIs – refractory GERD

Establish diagnosis, pathophysiology or mechanism


4. Treatment : should be tailored to the specific

underlying mechanism


Functional

heartburn

Acid sensitive

esophagus

NERD

Pain modulator

SSRIs

Tricyclic

SSRIs

(Citalopram)

Surgery

TLOSR inhibitor

(Baclofen)

Surgery

Algorithm for refractory GERD management


REFRACTORY GERD

Optimize PPI therapy

Exclude other etiologies

No response

Typical symptoms Atypical symptoms

Upper Endoscopy

Normal

Specific treatment REFLUX

MONITORING

Referral to ENT, pulmonary, allergy

Abnormal (ENT, pulmonary, Or allergic disorder)

Specific treatment

High pre test probability of GERD Low pre test

probability of GERD

Test off medication with pH or impedance-pH

Test on medication with impedance-pH

Abnormal (eosinophilic

esophagitis, erosive esophagitis, other)

REFRACTORY GERD

Algorithm for refractory GERD management

Gut. 2012;61(9):1340-54.

Functional

heartburn

Acid sensitive

esophagus

NERD

Positive

Negative

Pain modulator

SSRIs

Tricyclic

SSRIs

(Citalopram)

Surgery

TLOSR inhibitor

(Baclofen)

Surgery

Pain modulator

SSRIs

Tricyclic

Test “off” PPI with pH

or impedance pH

Test “on” PPI with

impedance pH

SS

Management of PPIs-refractory GERD are

1.Careful history,optimization of PPIs therapy and

lifestyle modification.

2.If non-responder; consider investigation for others

diagnosis and mechanism of GERD by upper

endoscope and ambulatory reflux monitoring.

3.Treatment should be tailored to the specific underlying mechanism of patient PPIs failure.

Summary

Thank you

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