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

24-hour ambulatory pH-impedance

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

DISTAL DIS AND SYMPTOMS IN HEALTHY SUBJECTS

PROXIMAL

Farrè R et al, Gut 2010

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

Diapositiva 17

1 Daniel Sifrim; 10/03/2014

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

Examples of pH pull-throughs in two GERD patients

Kwiateck et al, APT 2011

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

The End