nsaids and gord - julie cornish
TRANSCRIPT
NSAID-associated gastric mucosal damage
NSAIDs – a long history of analgesia and toxicity
First recorded use of willow leaf extracts for musculoskeletal conditions found on Sumerian stone tablets.
Aspirin first synthesised in 1899.
First pathological evidence of gastric damage from aspirin in 1938.
New non-aspirin, non-selective NSAIDs identified in the 1950s and developed in the 1970s.
COX-2 selective NSAIDs discovered in 1992.
First COX-2 selective NSAIDs approved in 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 enzyme, which exists in two forms
Wallace et al 2000
Gastric mucosal damage requires inhibition of both COX-1 and COX-2
Gastric damage score (%)
0
5
10
15
* p<0.05
Vehicle Celecoxib SC-560 Indo-methacin
Celecoxib+
SC-560
**
Systemic effects of NSAIDs decrease the defences of the gastric mucosa
Prostaglandins regulate a variety of defence mechanisms:
– increased secretion of mucus, mucopolysaccharide and bicarbonate ions
– decreased permeability of epithelial cells
– increased restitution of the epithelial layer.
Gastric blood flow is significantly decreased by indomethacin in a rat model
Wallace et al 2000
110
Gastric blood flow (% of basal)
indomethacin,10 mg/kg
vehicle
* p<0.05
** p<0.01
10 20 30 40 50 60
90
70
50
00
Time after administration (minutes)
***
**
** **
NSAIDs increase neutrophil–endothelial adhesion
NSAIDs
Decreased prostaglandin,
increased tumour necrosis factor
Increased neutrophil–endothelial adhesion
Capillary obstruction Neutrophil release ofproteases and oxygen-
derived free radicals
Ischaemic/hypoxic cell injury
Endothelial and epithelial injury
Mucosal ulcerationWallace et al 1997
COX-2 selective NSAIDs promote leucocyte adherence to the endothelium in a rat model
Wallace et al 2000
* p<0.05 versus vehicle
celecoxib, 1.0 µmol/L
SC-560, 1.0 µmol/L
celecoxib, 3.0 µmol/L
indomethacin, 7.0 µmol/L
vehicle, 1.0 µmol/L
0 15 30 45 600
20
15
10
5
*
* *
*
*
*
Adherent leucocytes/100 µm
Time (minutes)
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 from NSAIDs
Gastric acid plays a central role inNSAID-associated gastroduodenal damage
Acidicenvironment
Bicarbonate layer
Ionic gradient
GastricacidNSAIDs Pepsin
Surfaceepithelial cells
Mucuslayer
Neutralenvironment
Mucosalblood supply
Alkaline environment
Prostaglandin production
Bicarbonate production
Mucus production
NSAIDs
NSAID-associated gastroduodenal damage is pH-dependent
Elliott et al 1996
intraduodenal indomethacin, 40 mg/kg
intraduodenal salineTotal haemorrhagic mucosal area(%)
Gastric luminal pH
02.0 4.0 5.5 7.0
1
2
3
4
5
Plachetka et al 2003
Probability of NSAID-associated gastroduodenal damage is related to gastric acidity
0
20
40
60
80
Probability of no pathology (%)100
50000 4000300020001000Integrated gastric acidity (mmol•hour/L)
Upper GI side-effects
NSAID use is associated with upper GI side-effects
NSAIDs, including COX-2 selective NSAIDs, are associated with an increased risk of upper GI symptoms.
NSAIDs, including COX-2 selective NSAIDs, are associated with peptic ulceration.
Complications of NSAID use – bleeding, perforated or obstructed peptic ulcers – are a major cause of morbidity and mortality.
Langman et al 1999; Silverstein et al 2000;Wolfe et al 1999
Cumulative incidence of upper GI symptoms is approximately 25% with both non-selective and
COX-2 selective NSAIDs
†Acid reflux, dyspepsia, epigastric discomfort, heartburn, nausea or vomiting. Langman et al 1999
non-selective NSAIDsn=1564
Cumulative incidence of upper GI symptoms† over 6 months (%)
0
10
20
30
rofecoxibn=3357
* p<0.05
*
Simon et al 1999
†Dyspepsia, diarrhoea, abdominal pain, nauseaand flatulence.
Incidence of upper GI symptoms in patients free from ulcer is similar with non-selective and COX-
2 selective 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
NSAID users have increased prevalence of heartburn, acid reflux and epigastric pain
Harvey et al 2003
n=4902
Prevalence (%)
heartburnacid refluxepigastric pain
0
10
20
30
40
50
None Aspirin NSAIDsexcluding
aspirin
Aspirin+ otherNSAIDs
Hallas & Bytzer 1998
2.4
ACE inhibitors
NSAID ingestion is one of the few drug-related risk factors for dyspepsia
0.40.0 0.8 1.2 1.6 2.0
NSAIDs
Calcium blockers
Corticosteroids
Methylxanthines
Adjusted rate ratio (CI) of prescription preceding the use of an anti-ulcer drug
Poor health-related quality of life among patients free from ulcer taking NSAIDs, including COX-2
selective 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
functi
oning
Role ph
ysica
l
Bodily
pain
Genera
l hea
lth
Mental
healt
h
Role em
otion
al
Vitality
Social
functi
oning
Upper GI side-effects impact negatively on patients’ lives and can lead to withdrawal from
treatment
Productivity at work and daily activities are reduced amongst NSAID users:
– 13% reduced productivity at work (n=27)
– 26% reduced daily activities (n=61).
More than half of all patients who switch NSAIDs do so because of side-effects.
44% of prescribers select the NSAID dose to minimise side-effects – at the expense of pain relief.
Knott 2000; Steinfeld et al 2002; Wahlqvist et al 2003
NSAID users are at risk of reflux esophagitis
Reflux esophagitis LA Grades A–D.
Photos reproduced with permission from Professor G Tytgat
Avidan et al 2001
Reflux esophagitis: the presence of definite mucosal breaks or metaplasia of the esophagus, visible under endoscopy.
Among patients taking non-selective NSAIDs for osteoarthritis, the prevalence rate of erosive esophagitis was 21%.
A B
C D
NSAID-associated peptic ulceration
The majority of patients develop some gastric erosions after each doseof a non-selective NSAID.
Approximately 15–30%of NSAID users develop endoscopically evident ulcers at any one time – these will be generally silent.
COX-2 selective NSAIDs reduce the incidence of peptic ulcers compared with non-selective NSAIDs, but patients with risk factors or those who also use low-dose aspirin remain at risk.
Photo reproduced from the Interactive Atlas of Gastroenterology
Hawkey & Skelly 2002; Laine 1996; Silverstein et al 2000
Hawkey et al 1997
NSAID-associated dyspepsia may predict peptic ulcer disease
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
Cheatum et al 1999
Prevalence of peptic ulceration is dependent on the relative NSAID toxicity
Patients with peptic ulcers (%)500 10 30 4020
FenoprofenDiclofenacNaproxenSulindac
IbuprofenIndomethacin
PiroxicamFlurbiprofen
EtodolacKetoprofen
Aspirin>1 NSAID
Other NSAIDs
Laine et al 2004
Risk of peptic ulceration is similar between non-selective and COX-2 selective NSAIDs with
concomitant low-dose aspirinplacebon=410
aspirinn=406
rofecoxib + aspirinn=399
ibuprofenn=400
Cumulative incidence of ulcers (%)
*** p<0.001 versusplacebo + aspirin
02
4
6
8
10
12
14
16
18***
***
Upper GI complications
Fourfold increased risk of serious upper GI events from non-aspirin NSAID use
Hernãndez-Díaz & Garcia Rodriguez 2000
Griffin 1991Laporte 1991Holvoet 1991Nobili 1992Keating 1992Henry 1993Kaufman 1993Savage 1993Garcia Rodriguez 1994Langman 1994Lanza 1995Traversa 1995Hallas 1995Matikainen 1996Perez Gutthann 1997MacDonald 1997Wilcox 1997Garcia Rodriguez 1998
Relative risk of upper GI bleeding or perforation
0
1
2
3
4
5
6
7
8
Study
Weil et al 1995
Aspirin, alone or with another NSAID, increases the risk of upper GI complications
Relative 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
Henry et al 1996
Risk of GI complications is dependent on the relative NSAID toxicity
Estimated relative risk of haemorrhage or perforation
Azap
ropa
zone
50.0
0.5
Piro
xicam
Keto
prof
enIn
dom
etha
cinNa
prox
enAs
pirin
Sulin
dac
Diflu
nisal
Diclo
fena
cIb
upro
fen
Bombardier et al 2000
†Perforation, obstruction, bleedingor symptomatic peptic ulcer.
Rofecoxib carries a lower overall risk of upper GI events than naproxen
naproxen, 500 mg twice dailyrofecoxib, 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
Jüni et al 2002
No long-term advantage of celecoxib overnon-selective NSAIDs in terms of ulcer
complications
diclofenac
celecoxib
ibuprofen
Duration of follow-up (months)
Cumulative proportion of ulcer complications (%)
0 3 6 9
1.0
0.8
0.6
0.4
0.2
0.012
Hawkey & Skelly 2002
Risk of ulcer complications with celecoxib remains high among patients with other 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
Hawkey & Skelly 2002
†Perforation, obstruction, bleeding or symptomatic peptic ulcer.
With rofecoxib, the risk of upper GI side-effects is higher among patients with other risk factors
3
naproxen, 500 mg twice daily
rofecoxib, 50 mg once daily
Patients with upper GI events†
(%)6
4
2
0No risk factor More than
one risk factor
5
1
High-risk patients with previous GI disease remain at risk of upper GI bleeding with COX-2
selective NSAIDs
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
Silverstein et al 2000
Annualised incidence (6-month data) (%)Upper GI ulcercomplications
Upper GI ulcer complications +
symptomatic peptic ulcers
Celecoxib + aspirin 2.01 4.7
NSAID + aspirin 2.12 6.0
Celecoxib alone 0.44
p<0.05
1.40
p<0.05
NSAID alone 1.27 2.91
Concomitant aspirin therapy increases the rate of upper GI ulcer complications with celecoxib
Risk factors
Patient-related factors:– age >60 years– history of peptic ulcer disease/upper GI
complications.
Drug-related factors– use of a relatively toxic NSAID– use of a high dose of NSAID (or two NSAIDs
used concurrently) – concurrent use of an anticoagulant– concurrent use of a corticosteroid.
Seager & Hawkey 2001
Risk factors for upper GI complications occurring with NSAIDs
Weil et al 2000
Risk factors for peptic ulcer bleeding
Odds ratio0 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
NSAID-associated dyspepsia is a risk factor for NSAID-associated ulcer complications
Risk factor Adjusted odds ratio 95% CIAge
60 years 1.0 Reference group61–75 years 5.7 (2.6–12.6)75 years 12.7 (5.5–29.4)
Male 1.0 Reference groupFemale 0.5 (0.3–1.0)Dyspepsia 2.0 (1.0–4.2)NSAID-associated dyspepsia
8.7 (4.0–18.9)
Ulcer history 2.0 (0.9–4.6)Duration of treatment
3 months 1.0 Reference group3–12 months 0.3 (0.1–0.9)1 year 0.2 (0.1–0.4)
Current smokers 1.9 (1.0–3.6)Hansen et al 1996
Risk of upper GI events may be silent
50–60% of NSAID-associated peptic ulcers, presenting for the first time as a complication, have been silent previously.
Most patients with endoscopic lesions do not develop dyspepsia:
– 9% of patients with abnormal endoscopy had dyspeptic symptoms (n=45).
Larkai et al 1987; Singh 1998
Gutthann et al 1997
female non-usersmale non-usersfemale usersmale usersHospitalisations/1000 person-years
15 20 25 30 35 40 45 50 55 60 65 70 75 80 85+
20
15
10
5
0
25
Age (years)
NSAID-associated complications are a particular problem in the elderly
Huang et al 2002
H. pylori infection and NSAID use synergistically increase the risk of peptic ulcer disease
Patients with peptic ulcer (%) NSAID users
controls100
80
40
20
0
60
H. pylori-positiven=180
H. pylori-negativen=205
H. pylori-positiven=127
H. pylori-negativen=149
Chan et al 2002
Uncertainty over the benefit of eradication ofH. pylori before initiating NSAID therapy –
eradication is beneficial
eradication6-month probability of ulcer (%)
placebo
0
10
20
30
40
Any ulcer Complicated ulcers
**
** ** p<0.01
Uncertainty over the benefit of eradication ofH. pylori before initiating NSAID therapy – PPI
therapy is as beneficial as eradication
Labenz et al 2002
* p<0.05** p<0.01
Patients with peptic ulcer (%)
triple therapy+ placebo
n=161
triple therapy+ PPIn=173
PPIsn=155
placebon=171
0
1
2
3
4
5
6
7
* *
**
Hospitalisations and mortality
Armstrong & Blower 1987; Singh 1998; Wolfe et al 1999
NSAIDs are associated with the risk of serious upper GI complications, hospitalisation and
mortality
Non-selective NSAIDs account for approximately 20–25% of all reported drug adverse events.
80% of peptic ulcer-related deaths occur in non-selective NSAID users.
In the USA, NSAID use accounts for approximately 107,000 hospitalisations and 16,500 deaths per year.
Wolfe et al 1999
†1997 US mortality data for seven selected disorders.
NSAID-associated deaths: the ‘silent epidemic’
NSAID toxicityLeukaemia AIDS
Multiple myelomaAsthma
Cervical cancer
Hodgkin’s disease0
5000
10,000
15,000
20,000
25,000
Number of deaths†
The annual costs of medical care forNSAID-associated upper GI complications are conservatively estimated to exceed US$2 billion.
Excess cost for the care of gastroduodenal disease in non-selective NSAID users increases with dose:
– <1 standard dose per day: US$56
– 1–2 standard doses per day: US$120
– >2 standard doses per day: US$157.
Singh & Triadafilopoulos 1999; Smalley et al 1996
Excess costs of treating NSAID-associated upper GI side-effects
Factor by which drug costs must be multiplied to reflect the cost of care
Country Naproxen Diclofenac PiroxicamUK 1.40–1.44 1.42–1.47 1.84–1.93France 1.36 1.65 1.67
Canada 1.31 1.22–1.67 1.95Country All NSAIDsCanada 1.66 (1.61–7.49)USA 1.45USA 2.99 (non-aspirin)
NSAID-associated upper GI side-effects substantially increase the total cost of care
Bidaut-Russell & Gabriel 2001
Management
Managing NSAID-associated upper GI side-effects
Options for therapy:– dose reduction or switch to a less toxic NSAID
– prostaglandin analogue to replace gastroprotective prostaglandins
– H2-receptor antagonist or PPI to reduce the acidity of the stomach.
Guidelines recommend that patients withat least one GI risk factor receive either a non-selective NSAID with a co-prescribed GI-supportive therapy or a COX-2 selective NSAID.
American College 2002; Dubois 2004; NICE 2001
PPIs control acid secretion by directly inhibiting the proton pump
Inhibition of acid secretion
Parietalcell
Canalicularspace
Proton pump
Inhibition of proton pump
Activation
Concentration
PPI(inactive)
Gastric glandH+
Blood
H2-receptor antagonists inhibit signal transduction to the proton pump
H+
Acid secretion
Signal transduction to activate proton pump
Parietal cell
Histamine receptorHistamine receptor antagonist
Histamine
Inhibition of histamine receptor
Gastric gland
Blood
Proton pump
PPIs, H2-receptor antagonists and prostaglandin analogues in treating NSAID-associated
heartburn
Hawkey et al 1998; Yeomans et al 1998; Wilson et al 2001
0 7 14 21 28
Patients with heartburn (%)60
40
20
0
misoprostol, 200 µg four times daily
omeprazole, 20 mg once daily
60
40
20
00 7 14 21 28
Duration of treatment (days)
Patients with heartburn (%) ranitidine, 150 mg twice daily
omeprazole, 20 mg once daily
Duration of treatment (days)
PPIs, H2-receptor antagonists and prostaglandin analogues in ulcer healing
Hawkey et al 1998; Yeomans et al 1998
–40 –30 –20 –10 0 10 20 30 40
Omeprazole, 20 mg once dailyOmeprazole, 40 mg once daily
Omeprazole, 20 mg once dailyRanitidine, 150 mg twice daily
Omeprazole, 20 mg once dailyMisoprostol, 200 µg four times daily
Therapeutic gain (%) for the first-named drug (95% CI)
PPIs and H2-receptor antagonists in ulcer prophylaxis
Yeomans et al 1998
gastric ulcer
duodenal ulcer
Omeprazole, 20 mg once daily
Ranitidine,150 mg twice daily
40
30
20
10
0
Patients developing an ulcer (%)