refractory gerd by prof azis rani
TRANSCRIPT
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