Refractory GERD

Abdul Aziz RaniDiv.Gastroenterology

Dept.of Internal Medicine Faculty of Medicine

University of Indonesia

Global Definition

To develop a definition for reflux disease

that is global in application and

addresses the needs of patients, physicians

(all disciplines) and regulators

Symptom Base ,Patients Centered

Montreal 2006

GERD is a condition that develops when reflux of

stomach contents causes troublesome symptoms

and/or complications

Hom C et al., Gastro Clin N Am 42 (2013); 71-91

NERDNon erosive

Reflux diseases

Troublesome symptoms are defined

by the patient

to affect their quality of life.

Mild symptoms occurring 2 or more days per week

or moderate to severe symptoms occurring more than 1 day

per week are often considered troublesome by patients.

Over-diagnosis is prevented by the concept of

troublesome

GERD can be diagnosed basedon symptoms alone

*When cardiac causes have been excluded

Heartburn

Regurgitation

Retrosternal pain* (chest pain)

Epigastric pain Extraesophageal symptoms

(chronic cough, hoarseness etc.)

Dysphagia –may indicate GERD

Troublesome symptoms

Vakil et al. Am J Gastroenterol 2006;101:1900–20

• GERD akan makin sering ditemukan, berdampak pada

kualitas hidup

• Diagnosis klinik mudah ditegakkan, berbasis simptom

• Tipikal : nyeri panas didada, regurgitasi, rasa asam

atau rasa pahit dimulut

• Sistim Skor, GERD Q versi Indonesia > 8

Simptom berdampak pada kualitas hidup yang dirasakan

pasien

• Ringan lebih dari 2 x seminggu

• Berat 1 x seminggu

Cukup akurat, dapat langsung diberikan

Terapi Empirik 8 minggu

Ringkasan diagnosis GERD berdasarkan simptom

dalam praktek sehari hari

Manfaat Tes PPI ( Proton Pump Inhibitor )

dalam praktek sehari hari

• Cukup akurat untuk menegakkan diagnosis NERD, Non

Cardiac Chest Pain (NCCP) dan Ekstra Esophageal Reflux

dalam praktek

• Dalam penelitian waktu pemberian antara 1 minggu sampai

maksimal 4 minggu

• Dalam praktek antara 1 – 2 minggu

Rabeprazol , efek cepat , cukup satu minggu,

positif ERD bila simptom berkurang 50 %

Dilanjutkan sebagai terapi Empirik sampai 8 minggu untuk

mendapatkan hasil yang optimal

PPI test , How to do in Clinical Practice

• All PPI • Omeprazol 40 mg bid• Esomeprazol 40 mg bid• Pantoprazol 40 mg bid• Lansoprazol 60 mg bid• Rabeprazol 20 mg bid

• Duration • 1- 2 weeks for atypical symptoms• 4-6 weeks for Laryngo Pharyngeal Reflux (LPR )

PPI Test in NCCP

20 patients- Rabeprazole 40mg/ 20 mg X 7 days

83 %

17%

25%

20 %

Sensitivity 83 % Specificity 75 %

GERD – positive (18 ) GERD – Negative (22) (Fass R 1998)

If the relief of symptoms with the

PPI Test is >50%,

the chance of having a GERD-

related NCCP is significantly increased

Management of uninvestigated typical reflux symptoms

• In Asia, diagnostic algorithms must consider

potentially coexistent gastric cancer & peptic ulcer

EGD – esophagogastroduodenoscopy

H. pylori - helicobacter pylori

PPI – proton pump inhibitor

Nat Clin Pract Gastroenterol Hepatol 2008; 5 (4): 187Fock KM et al. J Gastroenterol Hepatol 2008; 23: 8 - 22

PPI Initial Treatment

4-8 weeks

PPI Maintenance

PPI On demand

Uninvestigated

Mild EE or NERD

Severe EE

Frequent attacks

or Slow PPI Response

Unsatisfactory Response

The role of PPI for the treatment of GERD

PPI for the treatment of GERD

in Clinical practice

• Symptom relief is overall equivalent for all PPIs

• Switching to a different PPI for patients with incomplete

symptom relief based on the possibility of intra-subject

variability in response to different PPIs.

• Cytochrome P 450 polymorphism

• The most consistent effect Rabeprazole

• Increasing from once-daily to twice-daily dosing to improve

symptom relief

“

Statement 29: PPIs are the most effective treatmentfor patients with ERD and NERD• In a meta-analysis, after 12 weeks of treatment, healing rates were 83.6% with PPIs,

51.9% with H2RAs, 39.2% with sucralfate, and 28.2% with placebo• PPIs healing rates of esophageal inflammation and relief of heartburn symptoms two-

fold higher than H2RAs. PPIs superior in relieving heartburn symptoms in patients with NERD when compared to H2RAs

Statement 32: NERD patients will require a minimumof 4 weeks of initial continuous therapy with a PPI.Some of the NERD patients will require more than 4 weeks of treatment to achieve satisfactory symptom control.

Statement 33: ERD patients will require a minimum of 4–8 weeks of initial continuous therapy with a PPIHealing rates in those receiving PPI once daily for 8 weeks ranged from 85–96%, regardless of the PPI that was used and the underlying severity or ERDMeta-analysis of 43 therapeutic trials in ERD, 65% healing rate of esophageal mucosa after 4 weeks, 80% after 8 weeks, and 84% after 12 weeks of treatment with PPI once daily

PPI symptoms relief during the first

week

Proportion of patients with “Severe” or “Very Severe”

heartburn during the first week of treatment

0

5

10

15

20

1 2 3 4 5 6 7

Rabeprazole20mg/dayOmeprazole 40mg/day

Daytime heartburn

0

5

10

15

20

1 2 3 4 5 6 7

Nighttime heartburn

Day

Day

* *

*

* p<0.05

* p<0.05

Rabeprazole 20mg/daYy

Omeprazole 40mg/day

%of patients reporting severe or very severe

heartburn

% of patients reporting

severe or very severeheartburn

Holtmann G et al. Aliment Pharmacol Ther 2002;16: 479-485

Reduction in Heartburn Scoreafter a Single Dose in NERD

Miner P et al. Gastroenterology 2000;118:A19

Placebo Rabeprazole 20 mgRabeprazole 10 mg

Baseline

Baseline

Day 1 Day 2

Night 1 Night 2

3

2

1

0

2

1

0

Mea

n D

ayti

me

Heart

bu

rn S

co

re

Mean

Nig

htt

ime

Heart

bu

rn S

co

re

†

†

†*

* * *

*

† p<0.01, * p<0.001

NERD Patients Respond to

Rabeprazole than Esomeprazole

0.00

0.50

1.00

0 7 14 21 28 Days

Cu

mu

lati

ve

Ra

te o

f S

ym

pto

m F

ree

Pariet®

Nexium

Time to the first 24-hr heartburn free

84.4%

60.9%

No. of patients who

experienced 24-hr

symptom free

Fock KM. APDW Singapore 2003

Ringkasan terapi Obat untuk GERD dalam

praktek sehari hari

• PPI merupakan pilihan utama yang efektif dan aman untuk

penyembuhan , dan bila perlu terapi jangka panjang

• Pilihan PPI berdasarkan kecepatan penyembuhan simptom, konsisten

tidak terpengaruh oleh waktu makan, atau kemungkinan latar belakang

polimorfisme genetik pasien, interaksi obat minimum.

• H2 RA dapat digunakan untuk terapi GERD yang ringan atau sebagai

terapi maintenance

• Prokinetik dapat dikombinasikan dengan PPI dengan efek yang moderat.

Dalam praktek, pengobatan GERD tidak sulit, tapi perlu dijaga

kepatuhan pasien dan cara pemberian selama 6-8 minggu

Although PPI treatment for GERD is highly effective, about 20% will

remain to have bothersome symptoms.

• Patients failed under PPI treatment, it is very important to understand

why the medication does not work.

• Gastroscopy and pH-impedance monitoring will reveal that

a large group of patients that were referred with “PPI-refractory GORD”,

will actually do not have GORD at all but instead have functional

dyspepsia, chest pain or even achalasia.

• True PPI-refractory GORD

• persistent acid reflux often due to poor adherence to their PPI

• persistent weakly acidic reflux causing symptoms or

• hypersensitive oesophagus.

Definition of Failure of PPI Therapy:

AGA position paper

Inadequate response of heartburn to twice daily

PPI therapy

Kahrilas PJ et al Gastroenterology 2008 ; 135 : 1383- 91

PPI FAILURE, What is it, How its Clinical significance ?

Inadequate symptom relief while on PPI, Why and how to manage ?

Approximately 20–30% of patients with gastro–esophageal reflux symptoms on PPI

• failure of the antireflux barrier (transient lower esophageal sphincter relaxations)

• high proximal extent of the refluxate• esophageal hypersensitivity • impaired mucosal integrity.

Persisting acid or nonacid reflux can be demonstrated in 40–50% of cases,

room for antireflux therapy in these patients.

Gastric content refluxate

• Acidic pH < 4

• Weakly acidic pH ≥ 4 - < 7

– Pepsin

– bile

• Weakly alkaline pH > 7

• Liquid with gas

• Gas

Acid suppression is an effective therapy for symptom control in

many patients, but

20-30 % will continue to experience uncomfortable symptoms

despite acid suppression with PPIs. due to ongoing reflux of either

acid ,weakly acid,or non acid

Impedance-pH monitoring before and after 7 days of omeprazole

• PPI therapy did not achieve a significant reduction in the total number

of reflux episodes (acid and nonacid reflux combined)

• a change in the ratio of acid to nonacid reflux

• After PPI therapy the percentage of acid reflux decreased from 45% to

3%, while nonacid reflux increased from 55% to 97%.

• Heartburn was also induced by nonacid reflux

• Regurgitation was unchanged by acid suppression because it was

frequently caused by nonacid reflux in the treated state.

Systematic review on acid and nonacid reflux in GERD patients taking a PPI Weakly acidic reflux underlies most reflux episodes and is the main cause

of persistent symptoms despite PPI therapyBoeckxstaens GE, Smout A. Systematic review: role of acid, weakly acidic and

weakly alkaline reflux in gastro-oesophageal reflux disease. Aliment Pharmacol Ther 2010;32:334–43

Impedance-pH catheter with 6 impedance measuring segments (each consisting of 2 impedance electrodes spaced 2 cm apart) and1 pH electrode

Impedance-pH monitoringA acidic ,B Non acidic reflux

Impedance-pH monitoring catheter

Liquid and mixed (liquid-gas) reflux. Impedance changes in 6 measuring segmentsspanning the esophagus (Z1 to Z6),

Algorithm for testing “on” or “off” PPI therapyfor patients with persistent reflux symptoms

Effect of PPI therapy on gastroesophageal reflux episodes in 30 patients with

GERD symptoms tested “on” and “off” PPI therapy:

• Adequate PPI dosage and administration– BID instead of OD

– Higher dosage

– Before meal

• Change PPI (genetic polymorphism ) ;Rabeprazole

• Additional H2RA , night time for NAB (?)

• Confirm GERD diagnosis

– pH monitoring, intra gastric, intra esophageal Impendance monitoring for

weak or non-acidic reflux

What to do in treatment failure?

Pain modulatorsTricyclicsSSRIsTrazodone

Review againPPI dosing timeand compliance

TLESR ReductionBaclofenAntireflux surgeryEndoscopic treatment (?)

Consider addingH2RA at bedtime

Esophageal impedance + pH

Negative Positive

for acid reflux

Positive for

weakly acidic reflux

Fass & Sifrim. 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-S38

Failure of PPI Twice Daily

Potential therapeutic interventions for GERD based on their

corresponding pathophysiological mechanism

Modulating Sensation of RefluxThe final steps involves activation of esophageal mucosal

nociceptors, firing of afferent signals, and interpretation of

these signals in the brain cortex, all of which offer potential

therapeutic targets for control of esophageal symptoms

• Nociceptor blockade

• The transient receptor potential vanilloid receptor 1 (TRPV1)

• Polymodal nonselective calcium-permeable cation channel, is

activated by exposure to capsaicin , heat and acids and distension

• The TRPV antagonist AZD1386 reduced esophageal pain

thresholds in healthy volunteers

• Visceral analgesia and cortical modulation

• regulating afferent signaling and cortical interpretation of these

signals may provide relief

• Antidepressant medications may modulate esophageal sensation

peripherally at the sensory afferent level, as well as in the central

nervous system

RCT double blind

Selective serotonin reuptake inhibitor ( SSRI)

citalopram vs placebo

• patients with hypersensitive esophagus who complained

of typical symptoms

• Heartburn

• Regurgitation

• chest pain

• After 6 months of treatment, ongoing symptoms were

significantly less common with citalopram compared with

placebo (38% vs 66%)

Viazis N, Keyoglou A, Kanellopoulos AK, et al. Selective serotonin reuptakeinhibitors for the treatment of hypersensitive esophagus: a randomized,double-blind, placebo controlled study. Am J Gastroenterol 2012;107:1662–7.

Prokinetic agents

• Enhance esophageal clearance of refluxed gastric contents by

improving peristalsis. augment LES pressure, increase gastric

emptying

• Domperidone, itopride, and mosapride, may have modest benefits

for the treatment of GERD but studies are limited

Hershcovici T, Fass R Drugs 2011;71:2381–9.

Statement 31: The use of prokinetic agents either as monotherapy or adjunctive therapy to PPIs may have a role in the treatment of GERD in Asia.

• Itopride significantly reduced the extent of esophageal acid exposure and improved GERD-related symptoms as compared to baseline values

• PPI + mosapride regimen provided significantly better symptom controlin patients with ERD as compared to the PPI alone. There was nodifference between the two therapeutic arms in ERD healing ratesor symptomatic response of subjects with NERD.

Prokinetic currently available demonstrate some efficacy as sole therapy or in combination with a PPI in subsets of patients with

GERD.

Kim Y, Kim T, Choi C et al. World. J. Gastroenterol. 2005; 11: 4210–14.Madan K, Ahuja V, Kashyap P, Sharma M. Dis. Esophagus 2004; 17: 274–8.

Drug treatment for inhibition of TLESRs.

• Pharmacologic inhibition of transient lower esophageal sphincter

relaxations (TLESRs).

• g-aminobutyric acid (GABA) and glutamate may be the dominant

neurotransmitters

• Baclofen decrease the number of postprandial acid and nonacid

reflux events,nocturnal reflux activity, and duodenogastric reflux

• Baclofen at a dosage of 5 to 20 mg TID can be considered in

patients with continued symptomatic reflux despite optimal PPI

therapy, but there are no long-term data evaluating the efficacy of

baclofen in GERD

• .

• Frequent side effects, including nausea, somnolence, dizziness,

and fatigue

• Newer GABA Agonist not effective (lesogaberan, Arbaclofen

placarbil )

Cortical modulation

• Relaxation training

• Acupuncture

• Hypnotherapy

may also offer benefits to GERD patients, but trials are

limited

McDonald-Haile J et al. . Gastroenterology 1994;107:61–9.Dickman R et al. . Aliment Pharmacol Ther 2007;26:1333–44.

Jones H et al. . Gut 2006;55:1403–8.

• If persistent acid or weakly acidic reflux is measured and causing

resulting symptoms, patients are considered potential surgical

candidates.

• Oesophageal manometry is required to exclude severe

oesophageal motility abnormalities which prone to severe

dysphagia post-operatively.

• Fundoplication surgery according to Nissen or Toupet is high

effective, but dysphagia and postoperative symptoms of bloating

and dyspepsia occur frequently

• Some patients still need PPI for maintenace therapy

Surgery for GERD, indication , efficacy

• Efforts in the last decade to develop new drugs for

refractory GORD have largely failed.

• Various endoscopic alternatives for PPI treatment

and/or laparoscopic surgery did not result in the

breakthrough some expected, largely due to lack of

efficacy

Refractory GERD; Future Treatment ?

CONCLUSION

• GERD is a common problem in clinical practice with increasing prevalence

• Clinical Diagnosis base on Symptoms and patients oriented

• PPI is the main stay of effective treatment for ERD and NERD

• Newly drug development including long term PPI and , anti depressant, Baclofen, visceral analgesia and cortical modulation

Thank you