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NOME E NUMERO DEL PROVIDER: I&C SRL - 5387
ECM N°: 180726
TITOLO: XVII CONGRESSO NAZIONALE GISMAD
SEDE: MILANO, HOTEL NHOW
DATA: 09-10/03/2017
NEL RISPETTO DELLE NUOVE DISPOSIZIONI IN MATERIA DI ECM, A SE GUITO
DELL’ATTUAZIONE DELL’ACCORDO STATO-REGIONI DEL 5/11/09 E SUCCESSIVE
MODIFICHE, AL FINE DI GARANTIRE LA MASSIMA TRASPARENZA IN MA TERIA DI
CONFLITTO DI INTERESSI SI INFORMANO I DISCENTI CHE PRESSO IL DESK RELATORI
SONO DISPONIBILI I DOCUMENTI ATTESTANTI LE EVENTUALI COLLA BORAZIONI CHE I
DOCENTI ABBIANO AVUTO NEL CORSO DELL’ULTIMO BIENNIO CON AZI ENDE
FARMACEUTICHE E/O DIAGNOSTICHE DALLE QUALI SIA DERIVATA L’ EROGAZIONE DI
COMPENSI O FINANZIAMENTI.
Efficacia delle terapie Efficacia delle terapie di protezione della mucosadi protezione della mucosa
Prof. VINCENZO SAVARINO
Professore Ordinario di Gastroenterologia,
Università degli Studi di Genova
Direttore della Clinica Gastroenterologica
IRCCS Azienda Ospedaliera-Universitaria San
Martino-IST, Genova
TOO MUCH
ACID IN THE
Abnormaloesophageal
clearing
Insufficientantireflux
barrier
ACID IN THE
WRONG PLACE
Diet, drugsoverweight, etc
Alteredgastric
emptying Savarino V et al,
Digestion 2004
Therapy of Reflux Esophagitis Meta-Analysis (n=7635)
83.6
51.9
12w
eeks
( %
)
Placebo
Cisapride
Sucralfate
H2-blocker
PPIs
Chiba N et al, Gastroenterology 1997
39.2
37.9
28.2
20 40 60 80
Hea
ling
rate
s ≤
12w
eeks
( %
)
Placebo
Therapy of reflux esophagitis -relief of heartburn
80
60
Pat
ient
s w
ithou
t hea
rtbu
rn (
%)
(13)
(17) (12) PPI
H2RA
Chiba N et al, Gastroenterology 1997
40
20
Pat
ient
s w
ithou
t hea
rtbu
rn (
%)
(13)
(3)
(10)
(10)
1 - 2 3 - 4 6 - 8Time in weeks
Esophagitis
35%
Complicated GERD
5%
NERD
60%
Endoscopic Characterization of GERD
Martinez S et al, APT 2003
Esophagitis
21%
Barrett esophagus
1,3%
NERD
78%
Zagari RM et al, Gut 2008
MILD MODERATE SEVERE
Heartburn Grade
Heartburn Severity in Patients With EE and Patients with NERD
Venables TL et al , Scand J Gastroenterol 1997
68 %NERD*
(n=677)
32 %Erosive
Esophagitis(n=316)
GERD: Intercellular spaces
MEAN INTERCELLULAR SPACE (µM)
1.4
1.2
1.0
0.8
* *
Tobey NA et al, Gastroenterology 1996
Control Erosive Non-Erosive reflux reflux
0
0.6
0.4
0.2
Intercellular space dilations = ISD
score
0
Zentilin P et al, Am J Gastroenterol 2005
score
1score
2
Acid-Peptic Attack Weakens Cell Junctions, Leading to a Widening of Cell Gaps and Thus
Allowing Increased Acid Penetration
Acid reflux Nonacid reflux
9 cm
15 cm
17 cm
24-hour Ambulatory pH-Impedance
3 cm
5 cm
7 cm
5 cm44
Reflux
pH drop
Reflux
Zentilin P et al., Dig Liver Dis. 2004;36(9):565-9
Endoscopic + impedance-pH categorization in patients
with typical symptoms of GERD
Savarino E et al, Nat Rev Gastroenterol Hepatol 2013
The Added Value of Impedance-pH to Rome III Criteria in NERD Stratification (N=219)
% o
f pat
ient
s
25%
30%
35%
40%
45%
50%
28% 28%
39%
31%
38%
29%
3% 10%
% o
f pat
ient
s
0%
5%
10%
15%
20%
NERD pH+/SAP+ NERD pH+/SAP- HE FH
5%
2%
Rome III Criteria MII-pH/SAP Results
NARD3% 10%
Savarino E et al. Dig Liv Dis 2011; 43:542-547
60
80
100
68
54
% r
eflux e
vents
Any SxP<0.001
HeartburnP<0.001
Symptom Association With Symptom Association With Acid and Nonacid RefluxAcid and Nonacid Reflux
0
20
40
60
A NA A NA A NA A NA
36
54
1321
8
18 22% r
eflux e
vents
Vela MF et al, Gastroenterology 2001
Acid tasteP<0.003
RegurgitationP=ns
Basal cell hyperplasiaBasal cell hyperplasia
Papillary elongationPapillary elongation
Microscopic Esophagitis Distinguishes Patients with NERD from Those with Functional Heartburn
Dilated intercellular spacesDilated intercellular spaces
Savarino E et al, J Gastroenterol. 2013Zentilin P et al, Am J Gastroenterol. 2005
1
EsophagealEsophageal BaselineBaseline ImpedanceImpedance ValuesValues CorrelateCorrelate WithWith PresencePresence andand
SeveritySeverity OfOf MicroscopicMicroscopic EsophagitisEsophagitis inin GERDGERD
0,0 0,5 1,0 1,5 2,0
4000
3500
3000
2500
2000
1500
1000
500
Microscopic Esophagitis Score
Bas
eline Im
peda
nce at 3cm
abo
ve th
e LE
S( Ω )
(n)
r =-0,629; P<0,0001r =-0,629; P<0,0001
Savarino E et al. DDW 2014
SUCRALFATESUCRALFATE
Sucralfate (the aluminium salt of sucrose sulfate) iscapable of forming stable complexes with proteinmolecules of cell membranes, which favour viscousadhesiveness and the formation of a protective gelpreventing the contact with gastric juice and pepsin.
Sucralfate works in the esophagus and thestomach, by adsorbing acid, bile salts andpepsin. It has a peculiar affinity for erosions andulcers, inducing a more rapid healing of them.
Recommendations of the Romanian Society of Neurogastroenterology
concerning the use of sucralfate in GERD
Surdea-Blaga T et al, J Gastrointest Liver Dis 2016
GliGli alginatialginati sonosono prodottiprodotti costituiticostituiti dada AcidoAcidoalginico,alginico, compostocomposto chimicochimico didi origineorigine naturalenaturale chechesisi ricavaricava dada varievarie alghealghe deldel generegenere LaminariaLaminaria chechecresconocrescono nellenelle zonezone costierecostiere dell'Oceanodell'Oceano AtlanticoAtlantico..
Origine degli alginatiOrigine degli alginati
Laminaria hyperborea
Percentage of baseline transepithelial electrical
resistance (TER) of 3D human esophageal cell culture
after 30 min exposure of pH 3.0 units
Woodland P et al, Am J Physiol Gastroenterol Liver Physiol 2015
Microscopy showing fluorescein-labeled alginate on the luminal
surface of the biopsy mucosa after 1 h washing in neutral solution
Woodland P et al, Am J Physiol Gastroenterol Liver Physiol 2015
Complete heartburn relief for 7 consecutive days up to last day of medication
Heartburn-free days during the 28-day observation period
Efficacy of Adding Sodium Alginate to Efficacy of Adding Sodium Alginate to
Omeprazole in Patients with NERD Omeprazole in Patients with NERD -- A RCTA RCT
Manabe N et al., Dis Esophagus 2012; 25:373–380
PPI(n=30)
PPI + alginate(n=35)
PPI(n=30)
PPI + alginate(n=35)
Baseline and post-treatment mean HRDQ reflux
scores (ITT population) using sodium alginate
as add-on therapy
Reimer C et al, Aliment Pharmacol Ther 2016
TTHEHE IIMPORTANCEMPORTANCE OFOF MMUCOSALUCOSAL DDEFENSEEFENSE TTHERAPYHERAPY
Courtesy of Prof. C. Scarpignato
Representative examples of cross-sections of esophageal mucosa after Evans
blue (EB) perfusion. (A) No stain, undamaged mucosa+EB (B) Weak stain,
damaged mucosa(acid solution 90 min)+EB (C) Strong stain, damaged
mucosa(pepsin solution 60 min)+EB (D) No stain, damaged mucosa (acid
solution 90 min) + HA+CS +EB
Di Simone M et al, Clin Exp Gastroenterol 2012
TTHEHE IIMPORTANCEMPORTANCE OFOF BBARRIERARRIER TTHERAPYHERAPY
20 patients with
heartburn and/or acid
regurgitation for at least
3 days in the previous
week, without mucosal
breaks at endoscopy,
were randomized in a
Effect of EsoXXTM on Symptom Relief in Patients with
NERD: A Pivotal, Double Blind, Crossover Trial
Palmieri B et al. Eur Rev Med Pharmacol Sci 2013; 17:3272-3278
were randomized in a
double blind crossover
study to four daily doses
of a fixed oral
combination of HA+CS
and placebo for 14 days.
Total disappearance of
symptoms in 50% of the
patients vs. 10% during
placebo administration
Rapid Onset!
Baseline characteristics of NERD patients receiving Esoxx and placebo
Savarino V et al, Aliment Pharmacol Ther 2017
Effect of Esoxx, combined with PPI therapy, on primary and
secondary endpoints in patients with NERD : ITT analysis.
Savarino V et al, Aliment Pharmacol Ther 2017
Effect of Esoxx, combined with PPI therapy, on severity
of reflux symptoms in patients with NERD : ITT analysis.
Savarino V et al, Aliment Pharmacol Ther 2017
Effect of Esoxx, combined with PPI therapy, on frequency
of reflux symptoms in patients with NERD : ITT analysis.
Savarino V et al, Aliment Pharmacol Ther 2017
Responsiveness of high severity regurgitation and heartburn
items on the RDQ to 4 weeks of acid suppressive therapy
Kahrilas PJ et al, Clin Gastroenterol Hepatol 2012
Adverse events in NERD patients included in the ITT analysis,
receiving PPI + Esoxx or PPI + placebo
Savarino V et al, Aliment Pharmacol Ther 2017
Patients treated with Esoxx + PPI or PPI + placebo with at least
one AE classified for System Organ Class (SOC). Safety analysis
Savarino V et al, Aliment Pharmacol Ther 2017
HRQL measured in NERD patients before and after 2 week
treatment with Esoxx or placebo combined with PPIs
Savarino V et al, Aliment Pharmacol Ther 2017
Palatability assessment of Esoxx or placebo formulations used in
our study. Distribution of the 60 evalutations for each arm.
Savarino V et al, Aliment Pharmacol Ther 2017
Conclusions
- NERD represents the majority of reflux patients (up to 70%) and the
intensity of heartburn does not differ from that of ERD
- The existence of microscopic esophagitis seems to sustain the
damaging effect of acid and other substances and to induce symptoms
- The above findings support the need to improve the esophageal
mucosal defenses, mainly in combination with acid suppression
- Several compounds able to strengthen esophageal mucosa exist
- There are no controlled studies of sucralfate combined with PPIs
- Both hyaluronic acid combined with chondroitin sulphate and
alginates have demonstrated to adhere to esophageal mucosa and to
improve symptoms of GERD, particularly when associated with PPIs