Nsaid upper gi nomber (2)

1. NSAID Upper G/I Adverse
Effects
Minimizing Risks
The 1st Palestinian
G/I Conference
May 20-22-2010

2. NSAIDs– a long history of
analgesia & 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. NSAIDs inhibit the COX enzyme,
which exists in two forms
Arachidonic acid
COX-1 COX-2
(constitutive) (induced by inflammatory stimuli)
COX-2 selective NSAIDs ×
× Non-selective NSAIDs ×
Prostaglandins Prostaglandins
• Gastrointestinal cytoprotection • Inflammation
• Platelet activity • Pain
• Fever
Vane & Botting 1995

4. Gastric mucosal damage requires
inhibition of both COX-1 and COX-2
Gastric damage score
(%)
15
*
*
10 * p<0.05
5
0
Vehicle Celecoxib SC-560 Celecoxib Indo-
+ methacin
SC-560
Wallace et al 2000

5. Topical irritant effects from
NSAIDs
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

6. NSAID-associated gastroduodenal
damage is pH-dependent
Total haemorrhagic mucosal area
(%) intraduodenal saline
5
intraduodenal
4 indomethacin, 40 mg/kg
3
2
1
0
2.0 4.0 5.5 7.0
Gastric luminal pH Elliott et al 1996

7. NSAID-associated gastroduodenal
damage is pH-dependent
Total haemorrhagic mucosal area
(%) intraduodenal saline
5
intraduodenal
4 indomethacin, 40 mg/kg
3
2
1
0
2.0 4.0 5.5 7.0
Gastric luminal pH
Elliott et al 1996

8. Upper GI side-effects

9. 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

10. Incidence of upper GI symptoms in patients
free from ulcer is similar with non-selective
andGI symptoms selective NSAIDs
Patients with upper
COX-2 †
(%)
35
30
25 All doses taken twice
daily
20
15
10
5
0
Celecoxib, Celecoxib, Celecoxib, Naproxen,
100 mg 200mg 400 mg 500mg
n=240 n=235 n=217 n=225
Simon et al 1999
†
Dyspepsia, diarrhoea, abdominal pain, nausea
and flatulence.

11. NSAID ingestion is one of the few drug-
related risk factors for dyspepsia
NSAIDs
Calcium blockers
Corticosteroids
ACE inhibitors
Methylxanthines
0.0 0.4 0.8 1.2 1.6 2.0 2.4
Adjusted rate ratio (CI) of prescription preceeding
the use of an anti-ulcer drug
Hallas & Bytzer 1998

12. Poor health-related quality of life among patients
free from ulcer taking NSAIDs, including COX-2
selective NSAIDs
US population
Mean SF-36 score
n=2474
100 asthma
n=110
80 diabetes mellitus
n=541
60 NSAIDs (NASA 1)
n=500
40 NSAIDs (SPACE 1)
n=579
20
0 y
n
n i ia l
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em lth
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Vi
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Data on file, NASA 1 & SPACE 1;
ta
er
e
Gralnek et al 2000; van der Molen et
e
fu
M
ol
R
G
R
al 1997;
Ware & Sherbourne 1992

13. 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

14. NSAID users are at risk of reflux
esophagitis
Reflux esophagitis: the 
presence of definite
mucosal breaks or
metaplasia of the
esophagus, visible under
.endoscopy
A B
Among patients taking 
non-selective NSAIDs for
osteoarthritis, the
prevalence rate of erosive
.esophagitis was 21%
C D Photos reproduced with permission
from Professor G Tytgat
Reflux esophagitis LA Grades A–D.
Avidan et al 2001

15. 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 Photo reproduced from the Interactive
.at risk Atlas of Gastroenterology
Hawkey & Skelly 2002; Laine 1996;
Silverstein et al 2000

16. Annual Rates of Hospitalisation for Ulcer
Complications
Saskatchewan, Canada 1982-86
Hospitalisations per
1000 person/years
25
Male users
20 Female users
Male
15 non-users
Female
non-users
10
5
0
15 20 25 30 35 40 45 50 55 60 65 70 75 80 85+ years
Age
Pérez Gutthann et al. Epidemiology 1997;8:18-24

17. NSAID-associated dyspepsia may
predict peptic ulcer disease
Relative risk of developing an ulcer/multiple erosions
in those with moderate/severe dyspepsia
10 OMNIUM
ASTRONAUT
8
7.8
6
5.3
4
3.9
2
1.8
0
Healing Maintenance
Hawkey et al 1997

18. Risk of peptic ulceration is similar between
non-selective and COX-2 selective NSAIDs
with concomitant low-dose aspirin
Cumulative incidence of ulcers placebo
(%) n=410
18 ***
*** aspirin
16 n=406
14 rofecoxib + aspirin
12 n=399
10 ibuprofen
8 n=400
6 *** p<0.001 versus
4 placebo + aspirin
2
0
Laine et al 2004

19. Upper GI
complications

20. Aspirin, alone or with another NSAID,
increases the risk of upper GI
Relative risk
complications
8
7
6
5
4
3
2
1
0
Aspirin, Aspirin, Aspirin, NSAIDs Aspirin
75 mg 150 mg 300 mg + other
once daily once daily once daily NSAIDs
Weil et al 1995

21. Rofecoxib carries a lower overall risk
of upper GI events than naproxen
Cumulative incidence of a naproxen, 500 mg
confirmed upper GI event† (%) twice daily
5
rofecoxib, 50 mg
once daily
4
3 n=8076
2
1
0
0 2 4 6 8 10 12
Duration of follow-up (months)
†
Perforation, obstruction, bleeding Bombardier et al 2000
or symptomatic peptic ulcer.

22. Risk of ulcer complications with celecoxib
remains high among patients with other risk
factors
Patients with ulcer complications
(%) celecoxib, 400 mg
twice daily
2 ibuprofen, 800 mg
three times daily, or
diclofenac, 75 mg
twice daily
n=8059
1
0
No risk factor More than one
risk factor
Hawkey & Skelly 2002

23. High-risk patients with previous GI disease
remain at risk of upper GI bleeding with COX-2
selective NSAIDs
Adjusted odds ratio for upper GI
bleeding
3.5
3.0
2.5 n=3686
2.0
1.5
1.0
0.5
0.0
Celecoxib Rofecoxib Non-aspirin,
non-selective
NSAIDs Nørgard et al 2004
Prescription within 30 days of hospital admission

24. Risk Factors

25. Risk factors for upper GI complications
occurring with NSAIDs
 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.
 H pylori infection.
Seager & Hawkey 2001

26. Risk factors for peptic ulcer
bleeding
NSAID use
Oral corticosteroid use
Warfarin use
Previous peptic ulcer
Dyspepsia in past year
Heart failure
Diabetes
Current smoking
0 1 2 3 4 5 6 7 8
Odds ratio
Weil et al 2000

27. 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

28. 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.
Armstrong & Blower 1987; Singh 1998; Wolfe et al 1999

29. Strategies to Prevent
and Treat NSAID
complications

30. Mortality from bleeding ulcers: 5-10%

31. Management of NSAID-induced
peptic ulcer disease
Discontinue use of NSAIDs or
substitute with less toxic agents
q Low-toxicity NSAIDs or COX-2 inhibitors
Suppress acid secretion
q Normal-dose PPI therapy
q High-dose H2RA therapy
Use mucosal protectants
q Misoprostol (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. Acid suppression in
NSAID-induced peptic ulcer
Antacids
q Limited efficacy, especially in
preventing gastric ulcer
s H2RAs
q Effective in preventing DU >GU;
some drug interactions, well tolerated
PPIs
q More effective than H2RAs for healing
NSAID-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.
32

33. The simplest ways to avoid or
..… reduce NSAID risks
 Don’t use an NSAID or COX-2 inhibitor –
use something else (e.g. paracetamol)
 Use the lowest effective dose of the NSAID
or COX-2 inhibitor
But this often doesn‘t work

34. NSAID- G/I complication
2
1.5
1
0.5
1982 1992 2000
Fries etal .2004

35. Endoscopic Photograph of
Gastropathy

36. Endoscopic Photograph
of Gastric Ulcer

37. Cardiovascular benefits
and GI risks of low-dose
Aspirin

38. Low-dose Aspirin )75-325MG( for
prevention of CV events
 2 prevention )established CV disease(
- Decreases CV events and mortality (RCTs)
* RRR= 19%, ARR=1.49% per yr.
- CV benefit generally outweighs harm (bleeding).
• 1 prevention )no overt CV disease(.
- Decreases CV events, but not mortality (RCTs)
* RRR= 12%, ARR= 1.49% per yr.
- Increased bleeding may outweigh CV benefit.
- Use if increased risk for future cardiac events.
* >10% risk of CHD in 10 yrs (AHA).

39. Potential implication of a Low
incidence of Aspirin-induced ulcers
 Anti-platelet effect may be more important than
mucosal injury as cause of GI complications.
- Aspirin may complicate pre-existing GI injury.
- Aspirin an infrequent cause of endoscopic ulcers
but higher proportion are complicated.

40. ACCF/ACG/AHA Consensus
Document
management of low-dose Aspirin GI
injury
 PPIs preferred agents for the therapy and prophylaxis
of aspirin-associated GI injury.
 Risk factors necessitating PPI therapy.
- Ulcer history (complicated or uncomplicated.
- GI bleeding.
- Concomitant anticoagulant or antiplatelets.
- Two or more of the following 3 “risk” factors:
• Age >_ 60, steroids, dyspepsia or GERD symptoms

41. Cardiovascular Benefits And
GI Risks Of Clopidogrel

42. Aspirin + Clopidogrel vs. Aspirin
Conclusions Form Double– Blind
RCTS for CV Disease
 In patients with acute coronary syndrome or
atria fibrillation Clopidogrel plus aspirin
produces small but significant relative risk
reductions of – 10-20% in CV events compared
to aspirin alone.

43. ACC/AHA GUIDELINES
Clopidogrel + Aspirin
 >- 1month after a bare metal stent.
 >- 1 year after a drug-eluting stent.
 >- 1month and ideally one year following
unstable angina or NSTEMI managed without
intervention.
 Long-term (e.g., 1year) following STEMI

44. ACCF/ACG/AHA Consensus
Document
 Patients taking dual antiplatelet therapy should
receive a PPI.
 Recommendation of PPI based on:
- RCTs in low-dose aspirin users.
- 1 case-control study of peptic ulcer bleeding
among Clopidogrel or ticlopidine users.
* RR of current PPI use=0.21(0.1-0.5).

45. PPI-Clopidogrel Interaction
fact or fiction
 3 observational studies show association
- OR/RR: 1.25-1.5.
• Due to confounding, when RRs < 1.5-2 can’t conclude
whether observed statistical association is valid.
- All 5 PPIs showed positive association.
• 5 observational studies do not show
significant association .
• Laine 2010

46. Potential PPL-Clopidogrel interction
 U.S.FDA:
-’’Concomitant use of drugs that inhibit
CYP2C19(e.g.omeprazole) should be
discouraged’’
-EMEA:
-Discourages ‘’concomitant use of PPi and
Clopidogrel – containing medicines unless
absolutely necessary’’ .
Laine 2010

47. PPL-C Clopidogrel interaction
 Totality of evidence currently insufficient to
conclude whether valid statistical association or
make judgment of causality
 Nonetheless, healthcare providers must make
decisions for their patients based on the
available evidence.
 Laine 2010