Nsaid upper gi nomber (2)
-
Upload
omar-abu-safieh -
Category
Health & Medicine
-
view
776 -
download
2
description
Transcript of Nsaid upper gi nomber (2)
NSAID Upper G/I NSAID Upper G/I Adverse Effects Adverse Effects
Minimizing Risks Minimizing Risks
The 1The 1stst Palestinian PalestinianG/I ConferenceG/I Conference
May 20-22-2010May 20-22-2010
NSAIDs NSAIDs –– a long history a long history of analgesia & toxicityof analgesia & toxicity
First recorded use of willow leaf extracts for First recorded use of willow leaf extracts for musculoskeletal conditions found on Sumerian musculoskeletal conditions found on Sumerian stone tablets.stone tablets.
Aspirin first synthesised in 1899.Aspirin first synthesised in 1899. First pathological evidence of gastric damage First pathological evidence of gastric damage
from aspirin in 1938.from aspirin in 1938. New non-aspirin, non-selective NSAIDs New non-aspirin, non-selective NSAIDs
identified in the 1950s and developed in the identified in the 1950s and developed in the 1970s.1970s.
COX-2 selective NSAIDs discovered in 1992.COX-2 selective NSAIDs discovered in 1992. First COX-2 selective NSAIDsFirst COX-2 selective NSAIDs approved in approved in
1998.1998.
Arachidonic acid
COX-1(constitutive)
COX-2(induced by inflammatory stimuli)
Non-selective NSAIDs
• Gastrointestinal cytoprotection• Platelet activity
• Inflammation• Pain• Fever
Prostaglandins Prostaglandins
COX-2 selective NSAIDs
Vane & Botting 1995
NSAIDs inhibit the COX NSAIDs inhibit the COX enzyme, which exists in two enzyme, which exists in two
formsforms
Wallace et al 2000
Gastric mucosal damage Gastric mucosal damage requires inhibition of both requires inhibition of both
COX-1 and COX-2COX-1 and COX-2Gastric damage score (%)
0
5
10
15
* p<0.05
Vehicle Celecoxib SC-560 Indo-methacin
Celecoxib+
SC-560
**
NSAID damage to the gastric mucosa.Scanning electron micrographs of normal gastric mucosa (left) andmucosal surface (right) 16 minutes after administration of aspirin.
Baskin et al 1976
Topical irritant effects Topical irritant effects from NSAIDsfrom NSAIDs
NSAID-associated gastroduodenal damage is pH-dependent
NSAID-associated gastroduodenal damage is pH-dependent
Elliott et al 1996
intraduodenal indomethacin, 40 mg/kg
intraduodenal saline
Total haemorrhagic mucosal area(%)
Gastric luminal pH
02.0 4.0 5.5 7.0
1
2
3
4
5
NSAID-associated gastroduodenal damage is pH-dependent
NSAID-associated gastroduodenal damage is pH-dependent
Elliott et al 1996
intraduodenal indomethacin, 40 mg/kg
intraduodenal saline
Total haemorrhagic mucosal area(%)
Gastric luminal pH
02.0 4.0 5.5 7.0
1
2
3
4
5
Upper GI side-Upper GI side-effectseffects
NSAID use is associated NSAID use is associated with upper GI side-effectswith upper GI side-effects NSAIDs, including COX-2 selective NSAIDs, including COX-2 selective
NSAIDs, are associated with an NSAIDs, are associated with an increased risk of upper GI symptoms.increased risk of upper GI symptoms.
NSAIDs, including COX-2 selective NSAIDs, including COX-2 selective NSAIDs, are associated with peptic NSAIDs, are associated with peptic ulceration.ulceration.
Complications of NSAID use Complications of NSAID use –– bleeding, bleeding, perforated or obstructed peptic ulcers perforated or obstructed peptic ulcers –– are a major cause of morbidity and are a major cause of morbidity and mortality.mortality.
Langman et al 1999; Silverstein et al 2000;Wolfe et al 1999
Simon et al 1999†Dyspepsia, diarrhoea, abdominal pain, nauseaand flatulence.
Incidence of upper GI symptoms in Incidence of upper GI symptoms in patients free from ulcer is similar patients free from ulcer is similar
with non-selective and COX-2 with non-selective and COX-2 selective NSAIDsselective NSAIDsPatients with upper GI symptoms†
(%)
All doses taken twice daily
0
5
10
15
20
25
30
35
Celecoxib,100 mgn=240
Celecoxib,200mgn=235
Celecoxib,400 mgn=217
Naproxen,500mgn=225
Hallas & Bytzer 1998
2.4
ACE inhibitors
NSAID ingestion is one of the NSAID ingestion is one of the few drug-related risk factors few drug-related risk factors
for dyspepsiafor dyspepsia
0.40.0 0.8 1.2 1.6 2.0
NSAIDs
Calcium blockers
Corticosteroids
Methylxanthines
Adjusted rate ratio (CI) of prescription preceeding the use of an anti-ulcer drug
Poor health-related quality of life Poor health-related quality of life among patients free from ulcer among patients free from ulcer taking NSAIDs, including COX-2 taking NSAIDs, including COX-2
selective NSAIDsselective NSAIDs
Data on file, NASA 1 & SPACE 1;Gralnek et al 2000; van der Molen et al 1997;Ware & Sherbourne 1992
US populationn=2474asthman=110diabetes mellitusn=541NSAIDs (NASA 1)n=500NSAIDs (SPACE 1)n=579
0
20
40
60
80
100Mean SF-36 score
Physic
al
func
tionin
g
Role p
hysic
al
Bodily
pain
Gener
al he
alth
Men
tal h
ealth
Role e
mot
ional
Vitality
Social
func
tionin
g
Upper GI side-effects impact Upper GI side-effects impact negatively on patientsnegatively on patients’’ lives and lives and
can lead to withdrawal from can lead to withdrawal from treatmenttreatment Productivity at work and daily activities Productivity at work and daily activities
are reduced amongst NSAID users:are reduced amongst NSAID users: 13% reduced productivity at work (n=27)13% reduced productivity at work (n=27) 26% reduced daily activities (n=61).26% reduced daily activities (n=61).
More than half of all patients who switch More than half of all patients who switch NSAIDs do so because of side-effects.NSAIDs do so because of side-effects.
44% of prescribers select the NSAID 44% of prescribers select the NSAID dose to minimise side-effects dose to minimise side-effects –– at the at the expense of pain relief.expense of pain relief.
Knott 2000; Steinfeld et al 2002; Wahlqvist et al 2003
NSAID users are at risk of NSAID users are at risk of reflux esophagitisreflux esophagitis
Reflux esophagitis LA Grades A–D.
Photos reproduced with permission from Professor G Tytgat
Avidan et al 2001
Reflux esophagitis: Reflux esophagitis: the presence of the presence of
definite mucosal definite mucosal breaks or metaplasia breaks or metaplasia
of the esophagus, of the esophagus, visible under visible under
endoscopyendoscopy..
Among patients Among patients taking non-selective taking non-selective
NSAIDs for NSAIDs for osteoarthritis, the osteoarthritis, the prevalence rate of prevalence rate of
erosive esophagitis erosive esophagitis was 21%was 21%..
A B
C D
NSAID-associated peptic NSAID-associated peptic ulcerationulceration
The majority of patients The majority of patients develop some gastric develop some gastric
erosions after each doseerosions after each doseof a non-selective NSAIDof a non-selective NSAID..
Approximately 15Approximately 15––30%30%of NSAID users develop of NSAID users develop
endoscopically evident ulcers endoscopically evident ulcers at any one time at any one time –– these will these will
be generally silentbe generally silent..
COX-2 selective NSAIDs COX-2 selective NSAIDs reduce the incidence of reduce the incidence of
peptic ulcers compared with peptic ulcers compared with non-selective NSAIDs, but non-selective NSAIDs, but
patients with risk factors or patients with risk factors or those who also use low-dose those who also use low-dose
aspirin remain at riskaspirin remain at risk..
Photo reproduced from the Interactive Atlas of Gastroenterology
Hawkey & Skelly 2002; Laine 1996; Silverstein et al 2000
Hospitalisations per1000 person/years
Femalenon-users
Male non-users
Female users
Male users
15 20 25 30 35 40 45 50 55 60 65 70 75 80 85+ yearsAge
20
15
10
5
0
25
Pérez Gutthann et al. Epidemiology 1997;8:18-24
Annual Rates of Hospitalisation for Ulcer Complications
Saskatchewan, Canada 1982-86
Hawkey et al 1997
NSAID-associated dyspepsia NSAID-associated dyspepsia may predict peptic ulcer may predict peptic ulcer
diseasedisease
ASTRONAUT
Relative risk of developing an ulcer/multiple erosions in those with moderate/severe dyspepsia
OMNIUM
0
2
4
6
8
10
Healing Maintenance
1.8
3.9
5.3
7.8
Laine et al 2004
Risk of peptic ulceration is similar Risk of peptic ulceration is similar between non-selective and COX-2 between non-selective and COX-2
selective NSAIDs with concomitant selective NSAIDs with concomitant low-dose aspirinlow-dose aspirin
placebon=410
aspirinn=406
rofecoxib + aspirinn=399
ibuprofenn=400
Cumulative incidence of ulcers (%)
*** p<0.001 versusplacebo + aspirin
0
2
4
6
8
10
12
14
16
18***
***
Upper GI Upper GI complicationscomplications
Weil et al 1995
Aspirin, alone or with another Aspirin, alone or with another NSAID, increases the risk of NSAID, increases the risk of
upper GI complicationsupper GI complicationsRelative risk
Aspirin,75 mg
once daily
Aspirin,150 mg
once daily
Aspirin,300 mg
once daily
NSAIDs Aspirin + otherNSAIDs
0
1
2
3
4
5
6
7
8
Bombardier et al 2000†Perforation, obstruction, bleedingor symptomatic peptic ulcer.
Rofecoxib carries a lower Rofecoxib carries a lower overall risk of upper GI overall risk of upper GI events thanevents than naproxennaproxen
naproxen, 500 mg twice daily
rofecoxib, 50 mgonce daily
Duration of follow-up (months)
Cumulative incidence of a confirmed upper GI event† (%)5
3
4
2
0
1
0 42 1086 12
n=8076
Hawkey & Skelly 2002
Risk of ulcer complications with Risk of ulcer complications with celecoxibcelecoxib
remains high among patients with remains high among patients with other risk factorsother risk factors
More than one risk factor
ibuprofen, 800 mg three times daily, or diclofenac, 75 mg twice daily
celecoxib, 400 mg twice daily
Patients with ulcer complications (%)
2
0
1
No risk factor
n=8059
High-risk patients with previous GI High-risk patients with previous GI disease remain at risk of upper GI disease remain at risk of upper GI
bleeding with COX-2 selective bleeding with COX-2 selective NSAIDsNSAIDs
Nørgard et al 2004
Adjusted odds ratio for upper GIbleeding
Prescription within 30 days of hospital admission
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
Celecoxib Rofecoxib Non-aspirin,non-selective
NSAIDs
n=3686
Risk FactorsRisk Factors
Patient-related factors:Patient-related factors: age >60 yearsage >60 years history of peptic ulcer disease/upper GIhistory of peptic ulcer disease/upper GI
complications.complications. Drug-related factorsDrug-related factors
use of a relatively toxic NSAIDuse of a relatively toxic NSAID use of a high dose of NSAID (or two NSAIDsuse of a high dose of NSAID (or two NSAIDs
used concurrently) used concurrently) concurrent use of an anticoagulantconcurrent use of an anticoagulant concurrent use of a corticosteroid.concurrent use of a corticosteroid. H pylori infection.H pylori infection.
Seager & Hawkey 2001
Risk factors for upper GI Risk factors for upper GI complications occurring with complications occurring with
NSAIDsNSAIDs
Weil et al 2000
Risk factors for peptic Risk factors for peptic ulcer bleedingulcer bleeding
Odds ratio
0 1 2 3 4 8
Current smoking
Diabetes
Heart failure
Dyspepsia in past year
Previous peptic ulcer
Warfarin use
Oral corticosteroid use
NSAID use
5 6 7
Risk of upper GI events Risk of upper GI events may be silentmay be silent
5050––60% of NSAID-associated 60% of NSAID-associated peptic ulcers, presentingpeptic ulcers, presenting for the for the first time as a complication,first time as a complication, have have been silent previously.been silent previously.
Most patients with endoscopic Most patients with endoscopic lesions do not develop dyspepsia: lesions do not develop dyspepsia: 9% of patients with abnormal 9% of patients with abnormal
endoscopy had dyspeptic endoscopy had dyspeptic symptoms (n=45).symptoms (n=45).
Larkai et al 1987; Singh 1998
Armstrong & Blower 1987; Singh 1998; Wolfe et al 1999
NSAIDs are associated with the NSAIDs are associated with the risk of serious upper GI risk of serious upper GI
complications, hospitalisation and complications, hospitalisation and mortalitymortality
Non-selective NSAIDs account for Non-selective NSAIDs account for approximately 20approximately 20––25% of all 25% of all reported drug adverse events.reported drug adverse events.
80% of peptic ulcer-related deaths 80% of peptic ulcer-related deaths occur in non-selective NSAID users.occur in non-selective NSAID users.
In the USA, NSAID use accounts for In the USA, NSAID use accounts for approximately 107,000 approximately 107,000 hospitalisationshospitalisations and 1 and 16,500 deaths 6,500 deaths per year.per year.
Strategies to Strategies to Prevent and Prevent and
Treat NSAID Treat NSAID
complicationscomplications
Mortality from bleeding ulcers: 5-10%
Management of NSAID-induced
peptic ulcer disease
Management of NSAID-induced
peptic ulcer diseaseDiscontinue use of NSAIDs or Discontinue use of NSAIDs or
substitute with less toxic agentssubstitute with less toxic agentsl Low-toxicity NSAIDs or COX-2 inhibitorsLow-toxicity NSAIDs or COX-2 inhibitors
Suppress acid secretionSuppress acid secretionl Normal-dose PPI therapyNormal-dose PPI therapy
l High-dose HHigh-dose H22RA therapyRA therapy
Use mucosal protectantsUse mucosal protectantsl Misoprostol (Misoprostol (substantial side-effects, )substantial side-effects, )
Seager & Hawkey, BMJ 2001; 323: 1236–9.Silverstein et al., Ann Intern Med 1995; 123: 241–9.Graham et al., Ann Intern Med 1993; 119: 257–62.Yeomans et al., N Engl J Med 1998; 338: 719–26.
32
AntacidsAntacids
l Limited efficacy, especially in preventing Limited efficacy, especially in preventing gastric ulcergastric ulcer
HH22RAsRAs
l Effective in preventing DU >GU; Effective in preventing DU >GU; some drug interactions, well toleratedsome drug interactions, well tolerated
PPIsPPIs
l More effective than HMore effective than H22RAs for healing RAs for healing
NSAID-induced ulcers, well toleratedNSAID-induced ulcers, well tolerated
Seager & Hawkey, BMJ 2001; 323: 1236–9.Goldstein et al., Gut 1999; 25(Suppl V): A101.Yeomans et al., N Engl J Med 1998; 338: 719–26.
Acid suppression in NSAID-induced peptic ulcer
Acid suppression in NSAID-induced peptic ulcer
The simplest ways to The simplest ways to avoid or reduce NSAID avoid or reduce NSAID
risksrisks ……....
DonDon’’t use an NSAID or COX-2 t use an NSAID or COX-2 inhibitor inhibitor –– use something else (e.g. use something else (e.g. paracetamol)paracetamol)
Use the lowest effective dose of the Use the lowest effective dose of the NSAID or COX-2 inhibitorNSAID or COX-2 inhibitor
But this often doesn’t work
1982 20001992
0.5
1
1.5
2
NSAID- G/I NSAID- G/I complicationcomplication
Fries etal .2004
Endoscopic Photograph Endoscopic Photograph of Gastropathyof Gastropathy
Endoscopic PhotographEndoscopic Photographof Gastric Ulcerof Gastric Ulcer
Cardiovascular Cardiovascular benefits and GI benefits and GI
risks of low-dose risks of low-dose AspirinAspirin
Low-dose Aspirin (75-Low-dose Aspirin (75-325MG) for prevention of 325MG) for prevention of
CV eventsCV events 2 prevention (established CV disease)2 prevention (established CV disease) - Decreases CV events and mortality - Decreases CV events and mortality (RCTs)(RCTs)
* RRR= 19%, ARR=1.49% per yr. * RRR= 19%, ARR=1.49% per yr. - CV benefit generally outweighs harm - CV benefit generally outweighs harm
(bleeding). (bleeding). • 1 prevention (no overt CV disease).1 prevention (no overt CV disease). - Decreases CV events, but not mortality - Decreases CV events, but not mortality (RCTs)(RCTs) * RRR= 12%, ARR= 1.49% per yr.* RRR= 12%, ARR= 1.49% per yr. - Increased bleeding may outweigh CV benefit. - Increased bleeding may outweigh CV benefit. - Use if increased risk for future cardiac events.- Use if increased risk for future cardiac events. * >10% risk of CHD in 10 yrs (AHA). * >10% risk of CHD in 10 yrs (AHA).
Potential implication of a Potential implication of a Low incidence of Aspirin-Low incidence of Aspirin-
induced ulcersinduced ulcers Anti-platelet effect may be more Anti-platelet effect may be more
important than mucosal injury as important than mucosal injury as cause of GI complications. cause of GI complications.
- Aspirin may complicate pre-existing Aspirin may complicate pre-existing GI injury.GI injury.
- Aspirin an infrequent cause of Aspirin an infrequent cause of endoscopic ulcers but higher endoscopic ulcers but higher proportion are complicated. proportion are complicated.
ACCF/ACG/AHA Consensus ACCF/ACG/AHA Consensus Document Document
management of low-dose management of low-dose Aspirin GI injuryAspirin GI injury
PPIs preferred agents for the therapy and PPIs preferred agents for the therapy and prophylaxis of aspirin-associated GI injury.prophylaxis of aspirin-associated GI injury.
Risk factors necessitating PPI therapy.Risk factors necessitating PPI therapy.- Ulcer history (complicated or uncomplicated.Ulcer history (complicated or uncomplicated.- GI bleeding. GI bleeding. - Concomitant anticoagulant or antiplatelets.Concomitant anticoagulant or antiplatelets.- Two or more of the following 3 Two or more of the following 3 ““riskrisk”” factors: factors: • Age >_ 60, steroids, dyspepsia or GERD symptoms Age >_ 60, steroids, dyspepsia or GERD symptoms
Cardiovascular Cardiovascular Benefits And GI Risks Benefits And GI Risks
Of ClopidogrelOf Clopidogrel
Aspirin + Clopidogrel vs. Aspirin + Clopidogrel vs. Aspirin Conclusions Form Aspirin Conclusions Form
Double Double –– Blind RCTS for CV Blind RCTS for CV DiseaseDisease
In patients with acute coronary In patients with acute coronary syndrome or atria fibrillation syndrome or atria fibrillation Clopidogrel plus aspirin produces Clopidogrel plus aspirin produces small but significant relative risk small but significant relative risk reductions of reductions of –– 10-20% in CV events 10-20% in CV events compared to aspirin alone. compared to aspirin alone.
ACC/AHA GUIDELINES ACC/AHA GUIDELINES Clopidogrel + AspirinClopidogrel + Aspirin
>- 1month after a bare metal stent.>- 1month after a bare metal stent. >- 1 year after a drug-eluting stent.>- 1 year after a drug-eluting stent. >- 1month and ideally one year >- 1month and ideally one year
following unstable angina or following unstable angina or NSTEMI managed without NSTEMI managed without intervention.intervention.
Long-term (e.g., 1year) following Long-term (e.g., 1year) following STEMISTEMI
ACCF/ACG/AHA Consensus ACCF/ACG/AHA Consensus DocumentDocument
Patients taking dual antiplatelet Patients taking dual antiplatelet therapy should receive a PPI.therapy should receive a PPI.
Recommendation of PPI based on:Recommendation of PPI based on:- RCTs in low-dose aspirin users. RCTs in low-dose aspirin users. - 1 case-control study of peptic ulcer 1 case-control study of peptic ulcer
bleeding among Clopidogrel or bleeding among Clopidogrel or ticlopidine users. ticlopidine users.
* RR of current PPI use=0.21(0.1-0.5). * RR of current PPI use=0.21(0.1-0.5).
PPI-Clopidogrel Interaction PPI-Clopidogrel Interaction
fact or fictionfact or fiction 3 observational studies show 3 observational studies show
associationassociation- OR/RR: 1.25-1.5.OR/RR: 1.25-1.5.• Due to confounding, when RRs < 1.5-2 canDue to confounding, when RRs < 1.5-2 can’’t t
conclude whether observed statistical association is conclude whether observed statistical association is valid.valid.
- All 5 PPIs showed positive association. All 5 PPIs showed positive association. • 5 observational studies do not show 5 observational studies do not show
significant association .significant association .• Laine 2010 Laine 2010
Potential PPL-Clopidogrel Potential PPL-Clopidogrel interctioninterction
U.S.FDA:U.S.FDA:--’’’’Concomitant use of drugs that inhibit Concomitant use of drugs that inhibit
CYP2C19(e.g.omeprazole) should be CYP2C19(e.g.omeprazole) should be discourageddiscouraged’’’’
-EMEA: -EMEA: -Discourages -Discourages ‘’‘’concomitant use of PPi concomitant use of PPi
and Clopidogrel and Clopidogrel –– containing containing medicines unless absolutely medicines unless absolutely necessarynecessary’’’’ . .
Laine 2010Laine 2010
PPL-C Clopidogrel PPL-C Clopidogrel interactioninteraction
Totality of evidence currently Totality of evidence currently insufficient to conclude whether valid insufficient to conclude whether valid statistical association or make judgment statistical association or make judgment of causality of causality
Nonetheless, healthcare providers must Nonetheless, healthcare providers must make decisions for their patients based make decisions for their patients based on the available evidence.on the available evidence.
Laine 2010Laine 2010