Transcript PPIs on prescription Use in DDD/1000 inhabitants

Dyspepsi
IRF 26. januar 2010
Læge, ph.d, Christina Reimer
Behandling og behandlingsvarighed
• Ulcus
Profylakse
• Funktionel Dyspepsi
• Gastroesophageal Reflux Sygdom
A02
Midler mod syrerelaterede forstyrrelser
• Antacida
• H2-receptor antagonister
• Prostaglandiner
• Protonpumpehæmmere
• Andre midler (sucralfat, alginsyre)
Ulcus sygdom
H. pylori
ASA/NSAIDs
Ulcus ætiologi
Reimer et al, Scand J Gastroenterology 2008
Behandling og behandlingsvarighed
ved H. pylori positivt ulcus
• PPI i standarddosis x 2 dagligt
•Clarithromycin 500 mg x 2 dagligt
•Amoxicillin 1 g x 2 dagligt
Positiv H. pylori test
•Behandlingsvarighed: 7 dage
Ved større ulcera suppleres med
PPI behandling i 2-4 uger
•H.Pylori test 4-6 uger efter kur
Behandling og behandlingsvarighed
ved NSAID/ASA associeret ulcus
Seponer ASA/NSAID
PPI i standard dosis i 4-8 uger
Negativ H. pylori test
Oplysninger om forbrug af ASA/NSAID
Hvornår er vedligeholdelsesbehandling
med syrepumpehæmmer (PPI) efter
ulcusheling indiceret?
• Ved recidiverende ulcera, trods Helicobacter
pylori-negativ test (idiopatisk ulcus)
• Ved gentagne mislykkede forsøg på
Helicobacter pylori-eradikation
• Ved fortsat indikation for ASA/NSAIDbehandling.
Klinisk vejledning: Udredning og behandling af dyspepsi. DSAM 2009
Hvordan forebygges ASA/NSAIDrelaterede ulcuskomplikationer?
Genovervej indikationen for ASA/NSAID-behandling
Vurder patientens risiko for ulcus-komplikation:
•
•
•
•
•
Alder (risiko er stigende med alder, specielt > 60 år)
Tidligere ulcus
Tidligere ulcusblødning/perforation
Dyspepsi
Anden sygdom (diabetes, hjerte-kar-sygdom eller svær kronisk
leddegigt)
• Samtidig behandling med steroid, SSRI eller AK-behandling
Ofte er risikoen åbenlys
Gastroskopien var normal…….
Behandling af funktionel dyspepsi
Hva´ kommer
dyspepsi af?
Det kommer af
græsk
Medikamentel behandling af
funktionel dyspepsi
• Stort placebo respons
• H2RA og PPI hjælper kun få (10-15%)
• Ingen indikation for antacida
• Ringe symptomatisk effekt af eradikation (NNT = 15)
• Beroligelse og information om tilstandens godartede
natur hjælper
Refluks pyramiden
Adenocarcinom
Barrett og komplikationer
Svær erosiv
Mild erosiv
NERD
Forskellige former for GERD
≥60%
~35%
Non-Erosiv
Reflukssygdom
Erosiv
Oesophagitis
Barrett’s
Oesophagus
Non-progressiv
Normal endoskopi
Striktur
Ulcus
GI blødning
Adenocarcinom
i oesophagus
<5%
Virker livsstilmodifikationer ved GERD?
• Vægttab
Effektivt
•Ligge højt med hovedet
Effektivt
• Rygeophør
Ingen evidens
•Ophør med alkohol
Ingen evidens
• Kostændring
Ingen evidens
Kaltenbach et al. Arch Intern Med 166: 965-71 (2006)
Medicinsk behandling?
• Patienter med komplikationer til GERD (erosioner,
ulceration, striktur, Barretts øsofagus) og patienter
som oplever nedsat livskvalitet som følge af
symptomerne bør tilbydes medicinsk behandling
• Patienter med milde og sporadiske symptomer kan
behandles med antacida og H2-blokker
• Ved svære og hyppige symptomer behandles med
syrepumpehæmmer i standarddosis
Almost all GERD patients relapse
after treatment discontinuation
Relapsed
%
100
80
60
Severe (Grade C)
Moderate (Grade B)
Mild (Grade A)
No esophagitis
40
20
0
0
1
2
3
4
Time (months)
5
6
Lundell et al. Gut 45:172–80 (1999)
Treatment options in GERD
Continuous
maintenance
(months–years)
Intermittent
courses
(weeks)
S
S
On-demand
(days)
S
S
S
S
S
S = symptom recurrence
Endoscopy
Normal
endoscopy
NERD
Mild reflux
esophagitis
Severe reflux
esophagitis
PPI
(4)–8 weeks
Success:
continuous PPI
Bytzer P, Blum AL. Aliment Pharmacol Ther 20:389–98 (2004)
Endoscopy
Normal
endoscopy
NERD
Mild reflux
esophagitis
Severe reflux
esophagitis
PPI
(2)–4 weeks
Success:
continuous/
on-demand PPI
Bytzer & Blum, Aliment Pharmacol Ther 20:389–98 (2004)
Endoscopy
NERD
Mild reflux
esophagitis
Severe reflux
esophagitis
PPI
4 weeks
Success:
Consider on
demand or
continuous PPI
Bytzer & Blum, Aliment Pharmacol Ther 20:389–98 (2004)
Heling proportional med syrehæmning
Heling af øsofagit
(%)
100
PPI
80
H2-receptor
antagonister
60
40
placebo
20
0
0
2
4
6
Tid (uger)
8
10
12
Chiba et al 1997
Opsamling
• Behandling af ulcussygdommen er i
størstedelen af tilfældene kortvarig (4-8 uger)
• Længerevarende fast behandling med PPI er
indiceret ved erosiv reflukssygdom og som
profylakse mod ASA/NSAID-relaterede
ulcuskomplikationer
Opsamling
• Langtids-PPI-behandling af NERD kan ofte være
symptomstyret efter on-demand principperne
• Ved behandling af funktionel dyspepsi er der kun
evidens for en beskeden effekt af
syrehæmmende behandling i kortere tid
• P.g.a højt placeborespons og stort
symptomoverlap må langtids-PPI-behandling
baseret på symptomer evalueres kritisk og følges
af regelmæssige seponeringsforsøg
PPIs on prescription
Use in DDD/1000 inhabitants per day
Danish Medicines Agency. Medicinal Product Statistics 2008
Long-term use of PPIs in primary care in Denmark
• 22 GP’s with a total of 42.634 registered pts.
• Standardized search for prescription of PPIs in each
practice prescribing register
• Patients who had prescriptions of ≥120 tablets in
previous year defined as long-term users
• Indications for long-term therapy ascertained by
reviewing records for results of endoscopy, H. pylori
testing, pH-monitoring and clincal assesment by the
GP
Reasons for PPI therapy
Verified indications
Treatment based on symptoms
• Endoscopically
documented GERD
Investigated without findings
• Non-erosive reflux disease (NERD)
• Functional dyspepsia
• Unexplained or
NSAID/ASA induced
peptic ulcer or GI
bleed
Uninvestigated
• Empirical therapy of upper GI sxs
Prevalence of
long-term PPI therapy
5.3% (2.275/42.634)
had at least one PPI prescription
2.1% (901/42.634) were long-term treated
(≥120 tablets/previous year)
Verified indication
27% (247/901)
Treated based on symptoms
73% (654/901)
Reimer et al. Aliment pharm and ther. 2009
Indications and reasons
for long-term PPI therapy (N=901)
Uninvestigated symptoms 50%
Investigated symptoms 22%
Esophagitis 19%
Ulcer prophylaxis 5.7%
GI bleeding prophylaxis 2%
Barrett's esophagus 1%
Abnormal pH-monitoring 0.3%
Reimer et al. Aliment pharm and ther. 2009
Self-reported characteristics of patients longterm treated based on symptoms (n=194)
100%
80%
60%
40%
20%
0%
Daily treatment
Previous discontinuation
Previous endoscopy
Maximal acid output in 12 H.pylori-negative
subjects before, during and after 8 weeks
treatment with a PPI
45
mmol/h
40
35
30
25
20
15
10
5
0
Gillen, Gastroenterology 2004;126: 980-988
• Treatment with a PPI for at least 8 weeks induces rebound
acid hypersecretion (RAHS) after therapy has been
discontinued in H.pylori negative individuals
• It sets off 1-2 weeks after therapy is withdrawn and is a
temporary phenomenon
• Is it clinically relevant?
• Could this phenomenon provoke acid-related symptoms and
thus lead to PPI dependency?
Placebo
120 healthy volunteers
Esomeprazole 40 mg od
Week 0
4
Placebo
8
12
Week 0,1,2,3,4,5,6,7,8,9,10,11,12: GSRS (Gastrointestinal Symptom Rating Scale)
Week 0, 4, 8, 12: Gastrin, Chromogranin A (CgA)
Outcome measures
1. Have you been bothered by stomach ache or pain in the upper abdomen
during the past week?
2. Have you been bothered by heartburn during the past week?
3. Have you been bothered by acid reflux during the past week?
(1) No discomfort at all
(2) Slight discomfort
(3) Mild discomfort
(4) Moderate discomfort
(5) Moderately severe discomfort
(6) Severe discomfort
(7) Very severe discomfort
Placebo
Randomisation
Esomeprazole 40 mg x 1
0
4
placebo
8
12
Mean GSRS score for dyspepsia,
heartburn and regurgitation
p< 0.05
Reimer et al. Gastroenterology 2009
Proportion with score >2 for
dyspepsia, heartburn or regurgitation
p< 0.05
Reimer et al. Gastroenterology 2009
Conclusions
• Acid inhibition with a PPI for 8 weeks induces acid-related
symptoms in a significant proportion (44%) of previously
asymptomatic subjects when therapy is withdrawn
• The most likely underlying explanation is RAHS
• PPI dependency as one of the explanations for the prevalent
and increasing long-term use of PPIs is supported by this
study
Implications
• Rationalisation of PPI prescribing can be obtained in
subgroups of patients treated long-term based on symptoms
only
• In patients who are treated based on unspecific symptoms
that are not likely to be acid-related, a short course of
empirical therapy is important in order to avoid inducing
true acid-related symptoms caused by RAHS
• Otherwise induction of a true need for PPIs in patients with
a questionable indication for therapy in the first place is
risked