2. 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.
3. 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
4. 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
*
*
5. 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.
6. 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
0
0
Time after administration (minutes)
*
**
**
**
**
7. NSAIDs increase neutrophil–
endothelial adhesion
NSAIDs
Decreased
prostaglandin,
increased tumour
necrosis factor
Increased neutrophil–
endothelial adhesion
Capillary obstruction Neutrophil release of
proteases and oxygen-
derived free radicals
Ischaemic/hypoxic cell
injury
Endothelial and
epithelial injury
Mucosal ulceration
Wallace et al 1997
8. 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 60
0
20
15
10
5
*
* *
*
*
*
Adherent leucocytes/100 µm
Time (minutes)
9. NSAID damage to the gastric mucosa.
Scanning electron micrographs of normal gastric mucosa (left) and
mucosal surface (right) 16 minutes after administration of aspirin.
Baskin et al 1976
Topical irritant effects from
NSAIDs
10. Gastric acid plays a central role in
NSAID-associated gastroduodenal damage
Acidic
environment
Bicarbonate layer
Ionic gradient
Gastric
acidNSAIDs Pepsin
Surface
epithelial cells
Mucus
layer
Neutral
environment
Mucosal
blood supply
Alkaline
environment
Prostaglandin
production
Bicarbonate
production
Mucus
production
NSAIDs
11. 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
0
2.0 4.0 5.5 7.0
1
2
3
4
5
12. 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 4000300020001000
Integrated gastric acidity (mmol•hour/L)
14. 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
15. 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
NSAIDs
n=1564
Cumulative incidence of upper GI
symptoms†
over 6 months (%)
0
10
20
30
rofecoxib
n=3357
* p<0.05
*
16. Simon et al 1999
†
Dyspepsia, diarrhoea, abdominal pain, nausea
and flatulence.
Incidence of upper GI symptoms in patients free
from ulcer is similar with non-selective and COX-
2 selective NSAIDs
Patients with upper GI symptoms†
(%)
All doses
taken
twice
daily
0
5
10
15
20
25
30
35
Celecoxib,
100 mg
n=240
Celecoxib,
200mg
n=235
Celecoxib,
400 mg
n=217
Naproxen,
500mg
n=225
17. NSAID users have increased prevalence of
heartburn, acid reflux and epigastric pain
Harvey et al 2003
n=4902
Prevalence
(%)
heartburn
acid reflux
epigastric pain
0
10
20
30
40
50
None Aspirin NSAIDs
excluding
aspirin
Aspirin
+ other
NSAIDs
18. 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
19. 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 population
n=2474
asthma
n=110
diabetes mellitus
n=541
NSAIDs (NASA 1)
n=500
NSAIDs (SPACE 1)
n=579
0
20
40
60
80
100
Mean SF-36 score
Physical
functioning
R
ole
physical
Bodily
pain
G
eneralhealth
M
entalhealth
R
ole
em
otional
Vitality
Social
functioning
20. 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
21. 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
22. NSAID-associated peptic
ulceration
The majority of patients
develop some gastric
erosions after each dose
of 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
23. 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
24. Cheatum et al 1999
Prevalence of peptic ulceration is
dependent on the relative NSAID toxicity
Patients with peptic ulcers (%)
500 10 30 4020
Fenoprofen
Diclofenac
Naproxen
Sulindac
Ibuprofen
Indomethacin
Piroxicam
Flurbiprofen
Etodolac
Ketoprofen
Aspirin
>1 NSAID
Other NSAIDs
25. Laine et al 2004
Risk of peptic ulceration is similar between non-
selective and COX-2 selective NSAIDs with
concomitant low-dose aspirin
placebo
n=410
aspirin
n=406
rofecoxib + aspirin
n=399
ibuprofen
n=400
Cumulative incidence of ulcers
(%)
*** p<0.001 versus
placebo + aspirin
0
2
4
6
8
10
12
14
16
18
***
***
27. Fourfold increased risk of serious upper
GI events from non-aspirin NSAID use
Hernãndez-Díaz & Garcia Rodriguez 2000
Griffin 1991
Laporte 1991
Holvoet 1991
Nobili 1992
Keating 1992
Henry 1993
Kaufman 1993
Savage 1993
Garcia Rodriguez 1994
Langman 1994
Lanza 1995
Traversa 1995
Hallas 1995
Matikainen 1996
Perez Gutthann 1997
MacDonald 1997
Wilcox 1997
Garcia Rodriguez 1998
Relative risk of upper GI bleeding or perforation
0
1
2
3
4
5
6
7
8
Study
28. 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
+ other
NSAIDs
0
1
2
3
4
5
6
7
8
29. Henry et al 1996
Risk of GI complications is dependent
on the relative NSAID toxicity
Estimated relative risk of haemorrhage
or perforation
Azapropazone
50.0
0.5
PiroxicamKetoprofen
IndomethacinNaproxen
AspirinSulindac
DiflunisalDiclofenacIbuprofen
30. Bombardier et al 2000
†
Perforation, obstruction, bleeding
or symptomatic peptic ulcer.
Rofecoxib carries a lower overall risk
of upper GI events than naproxen
naproxen, 500 mg
twice daily
rofecoxib, 50 mg
once 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
31. Jüni et al 2002
No long-term advantage of celecoxib over
non-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
0.0
12
32. 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
33. 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
0
No risk factor More than
one risk factor
5
1
34. 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 GI
bleeding
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
35. Silverstein et al 2000
Annualised incidence (6-month data) (%)
Upper GI ulcer
complications
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
37. 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
38. Weil et al 2000
Risk factors for peptic ulcer
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
39. NSAID-associated dyspepsia is a risk factor for
NSAID-associated ulcer complications
Risk factor Adjusted odds ratio 95% CI
Age
≤60 years 1.0 Reference group
61–75 years 5.7 (2.6–12.6)
>75 years 12.7 (5.5–29.4)
Male 1.0 Reference group
Female 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 group
3–12 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
40. 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
41. Gutthann et al 1997
female non-users
male non-users
female users
male 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
42. Huang et al 2002
H. pylori infection and NSAID use synergistically
increase the risk of peptic ulcer disease
Patients with peptic ulcer (%) NSAID users
controls
100
80
40
20
0
60
H. pylori-
positive
n=180
H. pylori-
negative
n=205
H. pylori-
positive
n=127
H. pylori-
negative
n=149
43. Chan et al 2002
Uncertainty over the benefit of eradication of
H. pylori before initiating NSAID therapy –
eradication is beneficial
eradication
6-month probability of
ulcer (%)
placebo
0
10
20
30
40
Any ulcer Complicated
ulcers
**
**
** p<0.01
44. Uncertainty over the benefit of eradication of
H. 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
+ PPI
n=173
PPIs
n=155
placebo
n=171
0
1
2
3
4
5
6
7
* *
**
46. 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.
47. Wolfe et al
†
1997 US mortality data for seven selected disorders.
NSAID-associated deaths: the
‘silent epidemic’
NSAID toxicity
Leukaemia
AIDS
Multiple myeloma
Asthma
Cervical cancer
Hodgkin’s disease
0
5000
10,000
15,000
20,000
25,000
Number of deaths†
48. The annual costs of medical care for
NSAID-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
49. Factor by which drug costs must be
multiplied to reflect the cost of care
Country Naproxen Diclofenac Piroxicam
UK 1.40–1.44 1.42–1.47 1.84–1.93
France 1.36 1.65 1.67
Canada 1.31 1.22–1.67 1.95
Country All NSAIDs
Canada 1.66 (1.61–7.49)
USA 1.45
USA 2.99 (non-aspirin)
NSAID-associated upper GI side-effects
substantially increase the total cost of care
Bidaut-Russell & Gabriel 2001
51. 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 with
at 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
52. PPIs control acid secretion by
directly inhibiting the proton pump
Inhibition
of acid
secretion
Parietal
cell
Canalicular
space
Proton pump
Inhibition of
proton pump
Activation
Concentration
PPI
(inactive)
Gastric gland
H
+
Blood
53. H2-receptor antagonists inhibit signal
transduction to the proton pump
H
+
Acid secretion
Signal transduction
to activate
proton pump
Parietal cell
Histamine receptor
Histamine receptor antagonist
Histamine
Inhibition of histamine receptor
Gastric gland
Blood
Proton pump
54. 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
0
0 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)
55. 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 daily
Omeprazole, 40 mg once daily
Omeprazole, 20 mg once daily
Ranitidine, 150 mg twice daily
Omeprazole, 20 mg once daily
Misoprostol, 200 µg four times daily
Therapeutic gain (%) for the first-named drug (95% CI)
56. 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
(%)
Editor's Notes
2. NSAIDs – a long history of analgesia and toxicity
The use of willow extracts to soothe musculoskeletal complaints has a long history that stretches back to the Sumerian period. In 1828, the active ingredient, salicin, was first extracted and salicylic acid was later synthesised.1 Aspirin was developed because the use of salicylic acid in its unmodified state causes severe dyspepsia, but upper gastrointestinal (GI) side-effects continue to mar the benefits from this class of drug, despite progress in reducing toxicity through the development of non-aspirin, non-selective non-steroidal anti-inflammatory drugs (NSAIDs). The discovery of the primary mechanism behind NSAID-associated upper GI side-effects, namely the systemic inhibition of cyclooxygenase (COX)-1-mediated prostaglandin synthesis in the gastric mucosa, provided the rationale for the development of COX-2 selective NSAIDs. Although these drugs are associated with fewer side-effects than non-selective NSAIDs, the early hopes that COX-2 selective NSAIDs would be free from toxicity have not been realised. The use of NSAIDs, including COX-2 selective NSAIDs, continues to carry significant risk of injury to the gastroduodenal mucosa.2–4
3. NSAIDs inhibit the COX enzyme, which exists in two forms
NSAID-mediated inhibition of prostaglandin synthesis is the central mechanism behind both the therapeutic and toxic activity of these drugs. Prostaglandins are synthesised through the action of the COX enzyme on the cell membrane constituent, arachidonic acid.2 COX exists in two forms; the COX-1 isoform is constitutively expressed in most tissues and is believed to have a ‘housekeeping’ role, producing prostaglandins that regulate normal cell activity. The COX-2 isoform is virtually undetectable in most tissues under normal physiological conditions, but can be induced in the presence of inflammation, tissue damage or malignant transformation.2–4 Prostaglandins produced by COX-2 are thought to be mediators of pain, inflammation and fever,2–4 and the anti-inflammatory effects of NSAIDs appear to be largely attributable to inhibition of COX-2.2–4 The cardioprotective effects of NSAIDs stem from inhibiting the COX-1-mediated synthesis of thromboxanes by platelets. Aspirin has the most pronounced anti-thrombotic effect of all NSAIDs as it irreversibly inhibits COX-1 in platelets.5
4. Gastric mucosal damage requires inhibition of both COX-1 and COX-2
Although the inhibition of COX-1-mediated synthesis of prostaglandins in the gastric mucosa is the primary mechanism through which NSAIDs exert their toxicity, upper GI side-effects are unlikely to be caused solely by COX-1 inhibition. Many studies have suggested that COX-2 can contribute to gastric mucosal defence and that the inhibition of both COX isoforms is necessary for damage to the gastric mucosa. This was recently shown in a study in which the COX-1 and COX-2 isoforms in rats were selectively inhibited;6 the COX-2 selective NSAID celecoxib had no effect on gastric prostaglandin synthesis, whereas the COX-1 selective inhibitor SC-560 reduced gastric prostaglandin synthesis. However, neither of these agents caused gastric damage when given alone; significant increases in gastric damage only became apparent when both COX-1 and COX-2 were inhibited with either celecoxib plus SC-560 or with indomethacin (which inhibits COX-1 and COX-2). This evidence strongly implicates COX-2 inhibition in mucosal damage.
5. Systemic effects of NSAIDs decrease the defences of the gastric mucosa
NSAIDs influence several components of gastric mucosal defence, including decreasing the secretion of mucus and bicarbonate ions. Mucus has an important role in protecting the mucosa from bacterial colonisation and mechanical injury, and forms a microenvironment over sites of superficial injury, allowing rapid restitution to occur. By reducing the secretion of mucus and bicarbonate ions, NSAIDs diminish the mucosal defences to injury. Moreover, NSAIDs adversely affect mucosal blood flow and immunocyte function, which impairs the usually rapid rate of epithelial cell turnover and repair. This further lessens resistance to injury.
6. Gastric blood flow is significantly decreased by indomethacin in a rat model
The mucosal blood flow response is a key weapon in the gastric mucosa’s armoury against injury. A rapid increase in blood flow is able to buffer acid, remove toxic substances and promote tissue repair by trapping plasma over sites of damage. The effects of NSAIDs on the flow of blood in the microcirculation have been investigated in animal studies. In these studies, the non-selective NSAID indomethacin was shown to significantly decrease gastric blood flow,6 and this effect was prevented by the administration of prostaglandins.7 Lowered blood flow makes the stomach more susceptible to irritants – such as gastric acid in the lumen – and interferes with the healing of pre-existing lesions.7
7. NSAIDs increase neutrophil–endothelial adhesion
When a non-selective NSAID, such as indomethacin, is administered to a rat, there is a dramatic increase in the number of leucocytes adhering to the endothelial surface of blood vessels in the gastric mucosa. The accumulation of neutrophils in the blood is paralleled by rising levels of tumour necrosis factor alpha8 and this can cause obstruction leading to ischaemia and hypoxic cell injury. Neutrophils release proteases and free radicals, which can contribute directly to endothelial and epithelial damage.7
8. COX-2 selective NSAIDs promote leucocyte adherence to the endothelium in a rat model
Leucocyte adherence to the vascular endothelium within the gastric mucosa is promoted both by non-selective and COX-2 selective NSAIDs. Infusion of celecoxib into the mesenteric venules of the rat at a concentration of 1.0 μmol/L had no effect, but when infused at a concentration of 3.0 μmol/L celecoxib caused a sixfold increase in leucocyte adherence over basal levels. This effect was similar in magnitude to that achieved with 7 μmol/L indomethacin. The COX-1 selective inhibitor SC-560 did not promote adherence at concentrations of 0.3 or 1.0 μmol/L.6 These results provide further support for the role of COX-2 in defending the gastric mucosa.
9. Topical irritant effects from NSAIDs
Topical irritant properties are predominantly seen with acidic NSAIDs, of which aspirin is the best known example. Indeed, there is evidence of significant localised foci and damaged cells only 16 minutes after administration of aspirin, compared with the normal mucosa.9 The ability of NSAIDs to cause topical damage to the gastric mucosa is related, in part, to their accumulation within epithelial cells and their ability to decrease the hydrophobicity of the mucus layer in the stomach. Topical irritant effects on the epithelium are not, however, as strongly implicated in the development of gastroduodenal pathology as the systemic effects of NSAIDs. Thus, peptic ulceration and other upper GI side-effects are also observed after non-oral administration of NSAIDs.
10. Gastric acid plays a central role in NSAID-associated gastroduodenal damage
The net effect of the systemic and topical effects of NSAIDs on the GI system is to impair the mucosal barrier to gastric acid, which, together with the corrosive action of pepsin, exacerbates the initial damage, potentially resulting in deeper erosions and peptic ulceration. Moreover, gastric acid can enhance the direct absorption of some NSAIDs into the gastric mucosal cells, where they may interfere with cell metabolism, have a toxic effect on the mitochondria and cause cell disruption. Gastric acid thus plays a central role in the NSAID-associated gastroduodenal damage that can lead to upper GI symptoms and peptic ulcers, with the concomitant potential for complications such as bleeding and perforation.
11. NSAID-associated gastroduodenal damage is pH-dependent
The central role that gastric acid plays in NSAID-associated gastroduodenal injury has been highlighted in animal studies, which demonstrate that NSAID-associated damage is highly pH-dependent.10 Intraduodenal indomethacin, 40 mg/kg, caused marked macroscopic gastric mucosal damage in pylorus-ligated rats when the luminal pH was 2.0 or 4.0, but damage fell to control levels when the luminal pH was raised to 5.5 or 7.0. Elevation of the intragastric pH above 4 is, therefore, key in the management and prevention of NSAID-associated upper GI side-effects.
12. Probability of NSAID-associated gastroduodenal damage is related to gastric acidity
The pH dependence of NSAID-mediated mucosal damage has also been demonstrated in healthy individuals during a study in which naproxen was given to 37 volunteers for 6 days, either alone or in combination with a gastric antisecretory agent. The study showed that the individuals who benefited from partial inhibition of gastric acid secretion had a significantly lower incidence of gastric pathology (53%) than those whose gastric acidity had remained unchecked (89%; p=0.029).
The importance of pH in predicting the extent of damage was shown by the individuals’ integrated gastric acidity. This parameter takes into account the concentration of H+ ions (protons) over the entire 24-hour period, with a higher value equalling higher acidity. Thus, good acid control (low integrated gastric acidity) was predictive of a lower probability of NSAID-associated gastric damage; high acidity was predictive of the development of gastroduodenal pathology.11
14. NSAID use is associated with upper GI side-effects
The pain relief and control of inflammation provided by NSAIDs are an essential part of therapy for a range of conditions. However, NSAID-associated upper GI side-effects represent a major clinical problem. These side-effects range in severity from commonly occurring nuisance symptoms, such as dyspepsia and heartburn, that are not life threatening, but have a significant effect on quality of life, to peptic ulcers and, most seriously of all, to complicated peptic ulcer disease.12,13
Many patients who are at risk continue to be treated with non-selective NSAIDs and, while the COX-2 selective NSAIDs reduce the overall risk of upper GI side-effects compared with non-selective NSAIDs, they are not completely free from these effects.14,15
15. Cumulative incidence of upper GI symptoms is approximately 25% with both non-selective and COX-2 selective NSAIDs
Upper GI symptoms, such as dyspepsia, are a common, clinically significant, problem associated with the use of NSAIDs, including COX-2 selective NSAIDs. In a meta-analysis by Langman et al, the cumulative incidence of dyspeptic side-effects was approximately 25% with both non-selective and COX-2 selective NSAIDs.14 The incidence over a 6-month period was found to be 23.5% in patients taking rofecoxib compared with 25.5% in patients taking ibuprofen, diclofenac or nabumetone (p=0.02). The incidence of dyspepsia was found to be lower in the CLASS study, but the frequency between non-selective and COX-2 selective NSAIDs was again similar as in the meta-analysis described above. Thus, in the CLASS study, dyspepsia was reported by 14.4% of patients taking celecoxib for 6 months, compared with 16.1% of those taking non-selective NSAIDs (p0.05).15
16. Incidence of upper GI symptoms in patients free from ulcer is similar with non-selective and COX-2 selective NSAIDs
The incidence of the most commonly occurring upper GI symptoms associated with NSAID use was investigated in a randomised, controlled trial by Simon et al.16 Patients with rheumatoid arthritis who were free from esophageal or gastroduodenal ulceration were randomised to a non-selective or COX-2 selective NSAID for 12 weeks. The incidence of upper GI symptoms (dyspepsia, diarrhoea, abdominal pain, nausea and flatulence) was similar between the treatment groups, with 28%, 25% and 26% of patients experiencing such symptoms with celecoxib, 100, 200 and 400 mg twice daily, respectively, compared with 31% of patients taking naproxen, 500 mg twice daily. These data show that, as with non-selective NSAIDs, a significant proportion of patients are likely to experience upper GI symptoms during treatment with a COX-2 selective NSAID and may be at risk from upper GI complications.
17. NSAID users have increased prevalence of heartburn, acid reflux and epigastric pain
The characteristic symptoms of gastroesophageal reflux disease (GERD), namely heartburn, acid reflux and epigastric pain, are more prevalent amongst users of NSAIDs than non-users. This has been shown by a large community-based project in the UK, which recruited 10,537 individuals, of whom 12.9% were regularly taking a non-aspirin NSAID, 6.9% were taking aspirin and 2.4% were taking both.17 The prevalence of heartburn, gastroesophageal reflux and epigastric pain was higher in those taking aspirin or NSAIDs than in non-users, and highest in individuals who were taking both NSAIDs and aspirin.
The association between GERD and NSAID use has also been shown in a study of over 163,000 Medicaid patients in the USA, in which the relative risk of GERD for patients taking NSAIDs was 2.11.18 Furthermore, in a study in which risk factors for GERD were investigated in 1128 patients referred for endoscopy because of upper GI symptoms, GERD was present in 248 of them (22%), and the use of non-selective NSAIDs was found to be a significant independent risk factor for the development of GERD (p&lt;0.001; odds ratio 2.0; 95% CI 1.3–3.0).19
18. NSAID ingestion is one of the few drug-related risk factors for dyspepsia
NSAIDs are one of the few classes of drug that increase the risk of dyspepsia. The association between NSAIDs, other drugs, and dyspepsia was investigated in an analysis of prescription data from more than 30,000 incident users of ulcer-healing drugs in a Danish community.20 As most patients with severe dyspepsia are treated empirically with anti-ulcer drugs, prescriptions for an NSAID that were followed within 100 days by a prescription for an anti-ulcer drug were considered indicative of NSAID-associated dyspepsia. Conversely, if the anti-ulcer medication preceded the NSAID prescription, no association was assumed. This reasoning was applied to other commonly prescribed categories of drugs. Thus, among patients who had started their first recorded therapies with an ulcer drug and another non-ulcer drug within a 100-day span, NSAID ingestion emerged as one of the few definite drug-associated risk factors for dyspepsia (adjusted rate ratio 1.8, 95% CI 1.6–2.0). A recent meta-analysis of NSAIDs and dyspepsia studies has also shown an increased risk of dyspepsia with indomethacin, meclofenamate or piroxicam (odds ratio 2.8) and for high doses of other NSAIDs (odds ratio 3.1).21
19. Poor health-related quality of life among patients free from ulcer taking NSAIDs, including COX-2 selective NSAIDs
The upper GI side-effects associated with regular NSAID use can lower patients’ quality of life to a greater extent than many chronic diseases. Compared with a healthy US population, patients free from ulcer taking NSAIDs, including COX-2 selective NSAIDs, had an impaired quality of life, as measured by the Short-Form (SF)-36 Health Survey. The reduction in health-related quality of life was also apparent in comparison with reference populations of patients with chronic conditions.22–25
20. Upper GI side-effects impact negatively on patients’ lives and can lead to withdrawal from treatment
Upper GI symptoms associated with NSAID use can impact significantly upon patients’ lives and reduce both their productivity at work and routine daily activities. This was confirmed by recent results from a Swedish study, in which a questionnaire was given to patients taking NSAIDs, of whom 36% were taking COX-2 selective NSAIDs: productivity at work was reduced by 13% and daily activities were reduced by 26% because of upper GI symptoms.26 These symptoms cause many patients to switch between different types of NSAIDs in an attempt to lessen their severity and frequency. Thus, a postal survey of Norwegian NSAID users found that of the 1823 responders, 66% had switched brands or used different NSAID brands in the previous 2 years, and 52% of those switching cited side-effects as their main reason for switching brands.27 A high rate of discontinuation of NSAID treatment was also found in a US study of 1405 patients with osteoarthritis; only 15–20% of patients were still using their original NSAID after 12 months of follow-up.28
The compromise between using doses high enough to control the pain of arthritis and low enough to minimise gastric toxicity in patients receiving long-term NSAIDs has been highlighted by a survey of primary care physicians in the UK.29 Of the physicians surveyed, 44% reported their main aim when prescribing NSAIDs for osteoarthritis was not to eradicate pain completely but to minimise GI-associated side-effects by using low doses.
21. NSAID users are at risk of reflux esophagitis
Patients taking NSAIDs with symptoms of GERD may have esophagitis; however, these symptoms are a poor indicator of the presence of esophagitis. Patients with esophagitis often have a similar profile of symptoms to patients with GERD without esophagitis30 and, when esophagitis is present, the severity of heartburn is a poor indicator of the severity of esophagitis.31 Thus, patients taking NSAIDs are at risk of erosive esophagitis and the risk may be silent. Indeed, the prevalence rate of erosive esophagitis among patients taking regular therapy with a non-selective NSAID for osteoarthritis was found to be 21%.32 There are also reports implicating non-selective NSAIDs in the pathogenesis of more extensive mucosal injury such as esophageal ulceration and stricture formation.33
22. NSAID-associated peptic ulceration
Peptic ulceration is a common consequence of NSAID, including COX-2 selective NSAID, use and ranges in severity from endoscopically visible ulcers that are usually silent, to the life-threatening complication of a perforated ulcer. After a single dose of a non-selective NSAID, almost all patients develop some degree of gastric erosion and approximately 15–30% of chronic users will develop a peptic ulcer.12,34 The healing of pre-existing ulcers is delayed by the use of non-selective NSAIDs;35 COX-2 selective NSAIDs are also known to inhibit peptic ulcer healing.36
The increased risk of NSAID users developing a peptic ulcer compared with those not taking NSAIDs has been investingated in a UK population-based cohort of 458,840 individuals. The relative risk of developing a clinically symptomatic but uncomplicated peptic ulcer was estimated as 4.0 (95% CI 3.2–5.1) for users of non-aspirin NSAIDs and 2.9 (95% CI 2.3–3.6) for users of aspirin compared with those not taking aspirin. The overall population incidence of peptic ulcer was 1.03 (95% CI 0.97–1.08) cases per 1000 person-years.37
Although the incidence of gastric and duodenal ulcers is lower with COX-2 selective compared with non-selective NSAIDs, patients with risk factors, or who also use low-dose aspirin, remain at risk.15,38
23. NSAID-associated dyspepsia may predict peptic ulcer disease
The presence of peptic ulcer disease can, in some cases, be signalled by the presence of NSAID-associated dyspepsia. In the OMNIUM39 and ASTRONAUT40 studies, which compared omeprazole with misoprostol and ranitidine in the healing and maintenance of NSAID-associated lesions, patients were questioned about their overall dyspeptic symptoms at each visit prior to endoscopy, and these were related to the endoscopic findings.41 Overall, 45% of patients reported moderate-to-severe dyspeptic symptoms on entry to these studies, which diminished in most patients during treatment. Patients who experienced moderate or severe NSAID-associated dyspepsia during healing or maintenance therapy were, however, found to have a two- to eightfold increased risk of having a gastroduodenal lesion than those without dyspepsia. Although many patients with lesions did not have moderate or severe dyspepsia, the authors recommended that patients who do suffer such symptoms should be considered for endoscopy.
24. Prevalence of peptic ulceration is dependent on the relative NSAID toxicity
The likelihood of an NSAID user suffering from peptic ulceration is dependent, in part, on the relative toxicity of the NSAID taken. For example, ibuprofen is associated with a lower risk than many other NSAIDs, whereas ketoprofen and aspirin are at the more toxic end of the NSAID spectrum. Thus, among 1826 patients with osteoarthritis or rheumatoid arthritis taking non-selective NSAIDs for at least 6 months, or unable to tolerate continuous NSAID use because of upper GI symptoms, the incidence of endoscopically confirmed peptic ulcers ranged from 14.8% with fenoprofen to 43.9% with aspirin.42
25. Risk of peptic ulceration is similar between non-selective and COX-2 selective NSAIDs with concomitant low-dose aspirin
Although COX-2 selective NSAIDs are associated with a lower risk of peptic ulceration than non-selective NSAIDs, their concomitant use with low-dose aspirin increases the risk to a level similar to that seen with non-selective NSAIDs. This was demonstrated recently in a double-blind trial with 1615 patients whose osteoarthritis required NSAID therapy but who were free from ulcers at baseline.43 The cumulative incidence of ulcers in patients randomised to rofecoxib, 25 mg daily, plus low-dose enteric-coated aspirin, 81 mg daily, was significantly greater than with aspirin alone, 81 mg daily, or placebo (16.1%, 7.3% and 5.8%, respectively; p&lt;0.001 for both comparisons with rofecoxib plus aspirin), but was similar to the incidence in patients randomised to ibuprofen, 800 mg three-times daily (17.1%; p=0.62). The incidence in patients receiving both ibuprofen and aspirin was not determined, as the risks from this combination were felt to be ethically unacceptable in a study in which GI-supportive therapy was not allowed. The use of low-dose aspirin for cardioprotection is widespread and, as shown in this study, significantly increases the risk of peptic ulceration with COX-2 selective NSAIDs to the level seen with non-selective NSAIDs.
27. Fourfold increased risk of serious upper GI events from non-aspirin NSAID use
The importance of peptic ulcer disease lies in the complications of bleeding, stenosis and perforation, from which individuals taking NSAIDs are at higher risk than those not taking NSAIDs. Estimates of relative risk vary between studies; however, a systematic review of 18 case-control and cohort studies calculated a pooled relative-risk estimate of 3.8 (95% CI 3.6–4.1) for upper GI tract bleeding or perforation after exposure to non-aspirin NSAIDs.44–62 The risk of upper GI complications appears to remain constant throughout NSAID therapy, but declines rapidly once treatment is stopped.60
28. Aspirin, alone or with another NSAID, increases the risk of upper GI complications
A systematic review of epidemiological studies has shown that patients taking thromboprophylactic doses of aspirin, 75 mg daily, present a twofold increased risk of upper GI complications compared with those not taking aspirin, and the risk is further increased with the use of analgesic/anti-inflammatory doses of 150–300 mg daily.63 Adding aspirin to another non-selective NSAID results in an eightfold increase in risk compared with not adding aspirin. Furthermore, the relative risk associated with aspirin is not reduced by buffered and enteric-coated formulations. In recognition of this risk, the use of GI supportive therapy is recommended for patients with other risk factors who need to take aspirin, including those taking low-dose aspirin as a prophylactic therapy for the prevention of cardiovascular disease (see Slide 51).
29. Risk of GI complications is dependent on the relative NSAID toxicity
The likelihood of a patient suffering from upper GI complications is dependent, in part, on the relative toxicity of the NSAID taken. A meta-analysis of case control and cohort studies revealed differences between NSAIDs in the rate of hospital admission for haemorrhage or perforation, despite the wide distribution of results for each drug.64 For example, ibuprofen was associated with a lower risk than other NSAIDs, whereas azapropazone and piroxicam were generally more toxic. The authors did warn, however, that some of the differences between NSAIDs may be attributable to the dose used and that the advantage of ‘low-risk’ NSAIDs, such as ibuprofen, may be lost once the dose is increased.
30. Rofecoxib carries a lower overall risk of upper GI events than naproxen
The risk of serious upper GI events associated with NSAID use can be lessened by using a COX-2 selective NSAID instead of a non-selective NSAID. The VIGOR study investigated the incidence of gastroduodenal perforation or obstruction, upper GI bleeding and symptomatic peptic ulcers associated with the COX-2 selective NSAID rofecoxib and the non-selective NSAID naproxen.65 During a median follow-up of 9 months, there were 2.1 upper GI events per 100 patient-years with rofecoxib, and 4.5 with naproxen. The respective rates of complicated events were 0.6 and 1.4 per 100 patient-years (p=0.005). Similar benefits over non-selective NSAIDs have been demonstrated in clinical trials with other COX-2 selective NSAIDs, including the CLASS study with celecoxib, diclofenac and ibuprofen,15 and in a study with valdecoxib and diclofenac.66
COX-2 selective NSAIDs do, however, present risks of their own, and the increased incidence of cardiovascular events documented during 18 months of rofecoxib treatment has led to this product’s withdrawal from the market. Whether cardiovascular side-effects are a class effect or are specific to rofecoxib has yet to be determined.
31. No long-term advantage of celecoxib over non-selective NSAIDs in terms of ulcer complications
The COX-2 selective NSAIDs reduce the overall risk of upper GI side-effects compared with non-selective NSAIDs; however, the long-term benefit may be less certain. Despite initially lower complication rates with celecoxib over non-selective NSAIDs, a full analysis of data from the CLASS study indicates that there is no long-term difference between celecoxib and the non-selective NSAIDs in the incidence of ulcer complications.67
Although the CLASS study was reported as a three-arm trial comparing celecoxib with ibuprofen and diclofenac,15 it was actually a combined analysis of the first 6 months of two separate and longer trials. These were planned to compare celecoxib with ibuprofen, and celecoxib with diclofenac, with a follow-up of 15 and 12 months, respectively, and had protocols that differed markedly from those reported.67
Information provided to the Food and Drug Administration (FDA) shows that almost all the ulcer complications that had occurred during the second half of the trials were in patients taking celecoxib and that by 12 months there was no significant difference between the three regimens in terms of ulcer complications. Furthermore, when an alternative definition of ulcer-related complications was used (pre-specified by the FDA and including more stringent criteria to address serious upper GI bleeding), there was a non-significant trend in favour of diclofenac. These results contradict the published conclusions.67
32. Risk of ulcer complications with celecoxib remains high among patients with other risk factors
Patients taking celecoxib who also have other risk factors (such as those with a history of upper GI events, the elderly, or those taking concomitant corticosteroids or low-dose aspirin), remain at almost as high a risk of ulcer complications as those taking non-selective NSAIDs.38 This has been shown in the CLASS study in 8059 patients with osteoarthritis or rheumatoid arthritis.15
As with non-selective NSAIDs, potential risk factors should be assessed when prescribing COX-2 selective NSAIDs, and patients at high risk should be considered for prophylactic treatment (see slides 36–44).
33. With rofecoxib, the risk of upper GI side-effects is higher among patients with other risk factors
As is seen with celecoxib, patients taking rofecoxib who have background risk factors (such as those with a prior GI event, aged 65 years or over, or taking concomitant steroids) still have a large residual risk of upper GI bleeding.38 This is shown by data from the VIGOR study,65 presented at the FDA hearings (7 February 2001).
34. High-risk patients with previous GI disease remain at risk of upper GI bleeding with COX-2 selective NSAIDs
A Danish population-based case control study has confirmed that patients with increased susceptibility to upper GI complications remain at risk of upper GI bleeding with celecoxib and rofecoxib.68 Upper GI bleeding was investigated in patients who met one of four criteria: a history of non-bleeding ulcer; a history of esophagitis, gastritis, duodenitis or Mallory–Weiss lesions; use of proton pump inhibitors (PPIs) or H2-receptor antagonists within the 2 years before case status; a history of alcoholism, chronic liver disease or esophageal varices before case status. Of the 780 incident cases of upper GI bleeding that were identified, 4.5% had received prescriptions for COX-2 selective NSAIDs within the 30 days prior to the event and 12.4% had received non-aspirin, non-selective NSAIDs. The equivalent proportions for the 2906 control patients were 2.7% and 4.1%, respectively.68 Thus, the benefit of the COX-2 selective NSAIDs compared with non-selective NSAIDs may be reduced in such ‘at-risk’ patients. As with non-selective NSAIDs, potential risk factors should be assessed when prescribing COX-2 selective NSAIDs, and patients at high risk should be considered for prophylactic treatment (see slides 36–44).
35. Concomitant aspirin therapy increases the rate of upper GI complications with celecoxib
None of the COX-2 selective NSAIDs are cardioprotective, as they do not inhibit the synthesis of thromboxane in platelets; indeed, the COX-2 selective NSAID rofecoxib has been withdrawn for increasing the incidence of cardiovascular side-effects. Thus, many of the elderly patients who take these drugs must also use concomitant aspirin for cardioprotection. However, the combination of a COX-2 selective NSAID with low-dose aspirin carries a risk of upper GI complications similar to that of a non-selective NSAID given alone.
Approximately 20% of the patients in the CLASS study were taking aspirin at a dose of 325 mg/day.15 Among these patients, the annualised incidence of ulcer complications at 6 months was 2.01% in patients taking celecoxib and 2.12% for those taking non-selective NSAIDs (ibuprofen, 800 mg three times daily, or diclofenac, 75 mg twice daily; p=0.92). Thus, the combination of a COX-2 selective NSAID and low-dose aspirin carries a risk of upper GI complications similar to that of a non-selective NSAID.
37. Risk factors for upper GI complications occurring with NSAIDs
There are a number of risk factors that are associated with upper GI complications in NSAID users.69 Patients particularly at risk are those aged over 60 years, those with a history of peptic ulcer disease, taking a high-dose or relatively toxic NSAID, or concurrently using two NSAIDs, an anticoagulant or corticosteroid. Other factors such as Helicobacter pylori infection may also play a role. Dyspepsia is an additional factor in the quantification of ulcer risk. Patients taking NSAIDs who develop an ulcer complication are more likely than controls to report earlier dyspepsia and to link this to NSAID ingestion.70,71
38. Risk factors for peptic ulcer bleeding
Risk factors for peptic ulcer complications were investigated in a large case-control study of 1121 patients hospitalised for bleeding peptic ulcers.72 In addition to the risk associated with the use of non-selective NSAIDs (odds ratio 3.8), other significant accessory risk factors were warfarin treatment, previous peptic ulcer or dyspepsia, heart failure, diabetes, oral corticosteroid use and smoking. With the exception of smoking, the effect of each of these risk factors was multiplied in patients who were currently using non-selective NSAIDs compared with those who were not. Thus, the odds of upper GI complications were approximately tripled by non-selective NSAID or corticosteroid use alone, and increased 10-fold when both were taken concomitantly. As described in later slides, while the COX-2 selective NSAIDs reduce the overall risk of upper GI complications compared with non-selective NSAIDs, they are not completely free from these side-effects.
39. NSAID-associated dyspepsia is a risk factor for NSAID-associated ulcer complications
Patient-related risk factors for NSAID-associated ulcer complications were investigated in a study in Odense, Denmark.70 By comparing consecutive NSAID users admitted to hospital with an ulcer complication with a sample of NSAID users without such a complication, the risk factors for NSAID-associated ulcer complications were found to be: high age, male gender, ulcer history, smoking, dyspepsia within the past 3 months (odds ratio 2.0) and dyspepsia related to NSAID therapy (odds ratio 8.7). In another study, the adjusted odds ratio for bleeding peptic ulcer among users of NSAIDs who had suffered from dyspepsia within the last 3 months was 2.85.73
40. Risk of upper GI events may be silent
While upper GI symptoms are a risk factor for peptic ulcer disease and complications, the absence of dyspepsia does not indicate that a patient is free from the risk of ulcer complications. Risk can be silent, and patients often present with acute and serious pathology having had no significant prior symptoms. Indeed, it has been estimated that 50–60% of NSAID-associated peptic ulcers that present for the first time as a complication have previously been silent.74 Symptoms cannot therefore be considered as reliable predictors of future outcomes.75 This was illustrated when 65 patients who were regularly taking NSAIDs underwent endoscopy; of the patients shown to have mucosal lesions only 9% (4/45) had suffered from dyspepsia.76
41. NSAID-associated complications are a particular problem in the elderly
The baseline risk of NSAID-associated ulcer complications increases sharply with age. Thus, while the prevalence of upper GI complications increases with age in the general population, there is a markedly greater increase in risk in elderly patients taking NSAIDs. The incidence of hospitalisation due to upper GI complications varies from 1 to 5 per 1000 person-years in the general population but increases to 10 per 1000 person-years in non-selective NSAID users over 75 years of age, and 20 per 1000 person-years in those over 85 years.59 Indeed, nearly 75% of reports of upper GI bleeding or perforation suspected of being caused by NSAIDs are in patients aged over 60 years.77
42. H. pylori infection and NSAID use synergistically increase the risk of peptic ulcer disease
Infection with H. pylori is known to be a major cause of peptic ulcer disease.78,79 The results of a meta-analysis showed an increase in ulcer occurrence and bleeding in patients with H. pylori infection who also used NSAIDs and indicated that there is synergy between H. pylori infection and the use of NSAIDs in damaging the gastroduodenal mucosa.80
Peptic ulcer disease was significantly more common in patients taking NSAIDs than in controls, irrespective of H. pylori infection.
Peptic ulcer disease in NSAID users was found to be significantly more common among those infected with H. pylori than in those free from the infection.
In case-control studies, the risk of developing a peptic ulcer was 61 times greater among H. pylori-positive NSAID users than among H. pylori-negative individuals not taking NSAIDs.
H. pylori infection and NSAID use were found to increase the risk of ulcer bleeding 1.79-fold and 4.85-fold, respectively. When both factors were present, the risk of ulcer bleeding increased 6.13-fold.
43. Uncertainty over the benefit of eradication of H. pylori before initiating NSAID therapy – eradication is beneficial
Despite the known relationship between ulcer complications with H. pylori infection and NSAID use, uncertainty remains over the benefits of eradicating H. pylori before starting NSAID treatment.81 A recent long-term study has, however, indicated that eradication may be beneficial.82 H. pylori-positive patients with dyspepsia or a history of peptic ulcer disease who needed to start long-term NSAID therapy were randomised to receive 1-week PPI triple therapy to eradicate the bacterium, or a PPI plus placebo, followed by slow-release diclofenac, 100 mg daily, for 6 months. The 6-month probability of ulcers among patients taking NSAIDs who had previously received eradication therapy was 12.1%, compared with 34.4% in the placebo group. The corresponding 6-month probabilities of complicated ulcers (peptic ulcers with severe dyspepsia or bleeding ulcers) were 4.2% and 27.1%, respectively. Eradication treatment may, however, be insufficient alone, particularly in high-risk patients taking NSAIDs, and PPI therapy should be considered.83,84
44. Uncertainty over the benefit of eradication of H. pylori before initiating NSAID therapy – PPI therapy is as beneficial as eradication
A double-blind, four-way clinical trial has shown that therapy with a PPI may be as effective as eradication therapy in preventing ulcers in NSAID users.85 Patients receiving diclofenac who were randomised to 1-week triple therapy (omeprazole, 20 mg twice daily, clarithromycin, 500 mg twice daily, and amoxicillin 1 g twice daily) followed by placebo for 4 weeks showed the same incidence of ulcers (1.2%) as those randomised to 1 week of triple therapy followed by 4 weeks of omeprazole, 20 mg once daily. The lowest ulcer incidence was in the group randomised to omeprazole, 20 mg, for 5 weeks (0%). The low rate of ulcers in the placebo group may be a reflection of the relatively young age (mean 55 years) of patients enrolled and the short duration of treatment with an NSAID. These factors, in combination with the other known complications of H. pylori infection, have led to recommendations for H. pylori eradication in all patients.81 Furthermore, the European Helicobacter Pylori Study Group has recommended that H. pylori eradication is advisable if NSAID therapy is planned.86
46. NSAIDs are associated with the risk of serious upper GI complications, hospitalisation and mortality
The major clinical concern with NSAID use is the risk of peptic ulcer complications, such as bleeding and perforation, which is greater than with non-NSAID-associated peptic ulcers. Indeed, 80% of peptic ulcer-related deaths occur in users of non-selective NSAIDs.75 Non-selective NSAIDs account for about 20% of all reported drug adverse events in the USA and approximately 25% in the UK.75 In the USA alone, NSAID use has been estimated to account for approximately 107,000 hospitalisations and 16,500 deaths per year among patients with arthritis.13,74
47. NSAID-associated deaths: the ‘silent epidemic’
Estimates suggest that each year NSAIDs are responsible for about 16,500 deaths among patients with rheumatoid arthritis or osteoarthritis in the USA.13 This is comparable with the number of deaths from acquired immune deficiency syndrome (AIDS), and considerably greater than the number of deaths from conditions such as multiple myeloma, asthma, cervical cancer or Hodgkin’s disease. If deaths resulting from NSAID-associated upper GI complications were tabulated separately, they would represent the 15th most common cause of death in the USA.
Despite this high mortality, NSAID gastrotoxicity remains a ‘silent epidemic’; many physicians and most patients are unaware of the scale of the problem. In one survey, for example, nearly 75% of patients who used NSAIDs regularly were unaware of, or unconcerned about, possible upper GI complications.87
48. Excess costs of treating NSAID-associated upper GI side-effects
The high incidence of upper GI complications associated with NSAID use also represents a substantial demand on resources with significant medical costs incurred by treating these side-effects. It is estimated that serious upper GI complications account for about 107,000 hospitalisations each year in the USA. Conservative estimates suggest that the cost of each hospitalisation is approximately US$15,000–20,000, giving an annual cost of over US$2 billion.87
The significant additional healthcare costs associated with NSAID use were highlighted in a retrospective cohort study involving over 75,000 people in the USA aged 65 years or more. The studies calculated the annual rates of utilisation of, and payments for, medical care for NSAID-associated upper GI disorders: hospitalisation and emergency department visits for peptic ulcers, gastritis, duodenitis and upper GI bleeding; outpatient upper and lower GI radiological and endoscopic examinations; and acid-suppressive drugs. It found that the mean annual payment for the medical care of gastroduodenal disease in non-NSAID users was US$134 per patient;88 however, in users of non-selective NSAIDs this figure increased by US$57 (43%) to US$191 (p&lt;0.001). Furthermore, the excess cost associated with NSAID use increased with the dose of NSAID taken. While the excess cost was US$56 in patients taking less than one standard dose of non-selective NSAID per day, this rose to US$120 in those taking from one to two standard doses, and to US$157 in patients receiving more than two standard doses per day.88
49. NSAID-associated upper GI side-effects substantially increase the total cost of care
The cost of medical care for NSAID-associated GI side-effects adds substantially to the costs of NSAID therapy. The iatrogenic cost factors, which include the shadow costs of diagnosing, treating and preventing upper GI side-effects, have been estimated to range from 1.3 to 2.0. Thus, across different healthcare systems and with different NSAIDs, between 30% and 100% of the unit cost of the NSAID is spent again on upper GI side-effects.89
51. Managing NSAID-associated upper GI side-effects
The simplest approach to managing NSAID-associated upper GI symptoms, peptic ulcer disease and peptic ulcer complications, that of reducing the dose or switching to a less toxic NSAID, may not be achievable for all patients, if control of pain and inflammation is compromised. The concomitant use of GI-supportive therapies is often, therefore, required. Options include use of the prostaglandin analogue misoprostol to replace the missing gastroprotective prostaglandins, although this is hampered by a high incidence of side-effects. The use of an H2-receptor antagonist or a PPI to reduce the acidity of the stomach and lessen acid-related damage associated with NSAID ingestion is an alternative option.
Several guidelines have endorsed the use of gastroprotective interventions for patients taking NSAIDs, and have focused on patients with more than one risk factor for NSAID-associated ulcer complications.90 For example, the most recent American College of Rheumatology guidelines91 recommend that patients with at least one GI risk factor receive a COX-2 specific NSAID or the combination of an NSAID with a co-prescribed gastroprotective agent. The guidelines in the UK are broadly similar.92
52. PPIs control acid secretion by directly inhibiting the proton pump
The efficacy of PPIs in managing NSAID-associated upper GI side-effects is a result of their inhibitory action on the proton pump, the H+, K+-ATPase of the gastric parietal cell. The activated proton pump catalyses the final step in gastric acid secretion – the exchange of H+ ions (protons) in the cytoplasm of the parietal cell with K+ ions in the canalicular space. Inhibition of this exchange prevents the accumulation of acid, in the form of H+ ions, in the canalicular space, and thus prevents the secretion of this acid into the lumen of the stomach.
Because of the action of the proton pump under normal physiological conditions, the canalicular space of the parietal cell is extremely acidic; indeed, it is the most acidic compartment in the body. This low pH is critical in the activation of PPIs. PPIs are inactive when absorbed into the parietal cell, and undergo activation by means of a change in their chemical composition only within the uniquely acidic environment of the canalicular space. This activation process confers a high degree of specificity upon PPIs.
53. H2-receptor antagonists control acid secretion by inhibiting signal transduction to the proton pump
In contrast to PPIs, H2-receptor antagonists do not directly inhibit acid secretion, rather they modulate the activity of the proton pump by blocking one of the signal transduction pathways within the parietal cell. Thus, H2-receptor antagonists bind to the histamine receptor on the basolateral membrane of the cell and, by preventing the binding of histamine, inhibit histamine-stimulated gastric acid secretion.
There are, however, at least two other types of cell surface receptors that modulate the proton pump: the acetylcholine and gastrin receptors. In addition, several other factors, such as epidermal growth factor, somatostatin and prostaglandins, may modulate the pump via endocrine or paracrine pathways. Thus, the inhibition of acid secretion by H2-receptor antagonists is easily overcome through increased signalling via these alternative pathways. This is evident from the inability of H2-receptor antagonists to suppress meal-stimulated acid secretion, for which the gastrin pathway is dominant, and the rapid development of tolerance to these agents. Furthermore, the expression of the histamine receptor may be upregulated and its binding affinity increased in response to H2-receptor antagonist therapy; these observations may help explain the hyperacidity that occurs after therapy is stopped.
54. PPIs, H2-receptor antagonists and prostaglandin analogues in treating NSAID-associated heartburn
Studies in patients with ulcers or erosions who were receiving continuous NSAID therapy have shown that a PPI is more successful than an H2-receptor antagonists or a prostaglandin analogue in relieving NSAID-associated heartburn.
During the ASTRONAUT study,40 patients with a peptic ulcer or more than 10 erosions in the stomach or duodenum and who required continuous NSAID therapy received either omeprazole, 20 or 40 mg once daily, or ranitidine, 150 mg twice daily. Treatment with the PPI was shown to be significantly more effective in controlling heartburn than the H2-receptor antagonist.40 Similarly, in the OMNIUM study,39 patients with either a peptic ulcer or more than 10 erosions in the stomach or duodenum and requiring continuous NSAID therapy received either omeprazole, 20 mg once daily, or misoprostol, 200 μg four times daily. Omeprazole was shown to be significantly more effective than misoprostol in controlling heartburn.93
Moreover, over half of the patients in the ASTRONAUT study suffered moderate or severe dyspepsia at baseline. Omeprazole was significantly effective in controlling this symptom at both 4 and 8 weeks than ranitidine.40
55. PPIs, H2-receptor antagonists and prostaglandin analogues in ulcer healing
By effective suppression of gastric acid secretion, therapy with a PPI allows ulcer healing whilst NSAID therapy is continued. A pooled analysis of the OMNIUM and ASTRONAUT studies demonstrated that there was a significant therapeutic gain with omeprazole, 20 mg once daily, over ranitidine, 150 mg twice daily, and misoprostol, 200 µg four times daily, in the healing of NSAID-associated gastric ulcers at 8 weeks in patients who continued their normal NSAID therapy.39,40
56. PPIs and H2-receptor antagonists in ulcer prophylaxis
Following on from improved ulcer healing, the reduction in risk of ulcer recurrence with a PPI is superior to that achieved with a H2-receptor antagonist. Thus, over 6 months of prophylactic therapy in the ASTRONAUT study, the incidence of peptic ulcers among patients taking NSAIDs was reduced with omeprazole, 20 mg once daily, compared with ranitidine, 150 mg twice daily.40
