Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used but may cause gastrointestinal (GI) complications, necessitating effective management guidelines. An international panel met to develop clinical practice recommendations for NSAID-induced GI issues, particularly for healthcare providers in resource-limited settings. The consensus aims to address advances in disease management and create definitive guidelines based on existing literature and expert opinions.

1. NSAID’s , ICON G
Reidwaan Ally

2. Pharm.D.

4. Background
• Non-steroidal anti-inflammatory drugs (NSAIDs) are used by over 30 million people daily across the globe.
• The use of NSAIDs has become widespread due to the availability of these agents both as prescription
and as over-the-counter (OTC) medicines.
• The most common side effects of NSAIDs are gastrointestinal (GI) complications, which include gastritis,
ulcers, perforation, and enteropathy.

5. Need & objectives of this consensus meeting
Need:
• Several international and regional guidelines have been developed to manage NSAID-induced GI complications.
• However, none specifically focus on management of NIG highlighting the need for a comprehensive clinical guideline to
guide PCPs in the management of NIG, particularly in resource-limited regions of the world.
Objectives:
• To identify the advances in disease management and the opportunities for prevention and management of NIG in nine
nations.
• Attempt to develop definitive clinical practice guidelines for the management of patients with NIG based on the existing
literature, real-world evidence, and evidence-based practice.

6. Panel
• A modified ‘Delphi’ process was used to reach consensus and develop practice recommendations.
• gastroenterologists from countries
• All of them provided their expert inputs to formulate the
recommendations.
• These recommendations were carefully developed taking
into account existing literature, current practices, and
expert opinion of the panelists.

7. Country
International Consensus on Guiding Recommendations
for Management of Patients with Non-steroidal Anti-
inflammatory Drugs Induced Gastropathy- ICON-G
Richard Hunt, Leonid B Lazebnik, Yury C Marakhouski, Mircea Manuc, Ramesh GN, Khin S Aye, Dmitry S Bordin,
Natalia V Bakulina, Baurzhan S Iskakov, Abror A Khamraev, Yurii M Stepanov, Reidwaan Ally, Amit Garg
Euroasian J Hepatogastroenterol, 2018;8(2):148-160
Published online 2019 Feb 1. doi: 10.5005/jp-journals-10018-1281

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CYCLOOXYGENASE
Hawkey – Lancet 1999

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CYCLOOXYGENASE
53 (RCT)
15 Celecoxib – CLASS JAMA 2000; 284; 1247-55
3
14 Rofecoxib - VIGOR NEJM 2000; 343; 1520-8
9 Meloxicam – MELISSA British J Rheumatol; 1998
SELECT
META ANALYSIS Schoenfeld – Am J M 1999

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ASPIRIN
a) Cardiovascular Protection
High risk patients  Primary Protection
Secondary Protection
ISIS2; Physicians health Study; Thrombosis Prevention Trial
 Low dose Aspirin
 GIT EFFECTS

39. 39
ASPIRIN
b) Anticancer
Cox 2 expression – Tumor promoter
C Williams – J Clin Inv 2000
- Colon – Oshima – Cell 2001
- Oesophagus – Xie – Gastroenterology 2001
- Stomach – Gridley – J Nat Cancer 1993
- Lung – Schreinemachers – Epidemiology 1994

40. Anyone with a 10-year risk of a CV event ≥10%
should take aspirin for primary prevention
American Heart Association Guideline

41. Estimation of CV risk: Framingham
Calculator
http://hin.nhlbi.nih.gov/atpiii/calculator.asp?usertype=pub
55
Risk score = 15%
15 of 100 people
with this level of
risk will have a
heart attack in the
next 10 years!

42. Mr. Bosch is a 65-year-old man. He seeks your advice on
using aspirin for primary prevention of a heart attack. He
is a smoker. His BP is 135/90, total cholesterol 200 mg/dl
(5.1 mmol/l), HDL 50 mg/dl (1.3 mmol/l). He is not on
any treatment and his past medical history is
unremarkable. Would you recommend aspirin?
Yes?
No?
Case

43. 0
ASA in Primary Prevention Trials:
Vascular Events ( ) Avoided vs Major Bleeds ( )
Caused
Estimated 10-year risk of a serious CV event
0
2
4
6
8
10
12
10 20 30 40 %
( )
0
2
4
6
8
10
12
( )
UK Doc
US Phys
PPP
HOT
SAPAT
TPT
WHS
Patrono, et al. NEJM 2005
Events per 1000 patients treated per year
15
Mr Bosch’s
CV risk
AHA
Guideline

44. Vascular Events ( ) Avoided vs Major Bleeds ( )
Caused by Aspirin per 1,000 Treated per Year
0
2
4
6
8
10
12
0 10 20 30%
Do not
routinely
use aspirin Individualized
decision
Use aspirin
routinely unless
contraindicated
BENEFIT
HARM
Estimated 10-year risk of a serious vascular event
AHA
Guideline

45. Daily dose, mg Aspirin Control Reduction in CV events
1.00.50.0 1.5 2.0
Meta-analysis of ASA Trials in High-risk Patients:
What is the optimal dose of ASA in preventing vascular
events?
Antithrombotic Trialists’ Collaboration. BMJ 2002;324:71-86
500-1500 14.5% 17.2% 19%±3
160-325 11.5% 14.8% 26%±3
75-150 11.0% 15.2% 32%±6
<75 17.3% 19.4% 13%±8
Any dose 12.9% 16.1% 23%±2
(2P<0.00001)

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61. Solomon SD, et al. Circulation 2008;117:2104-2113
Pooled analysis of the CV risk of celecoxib in 6 RCTs:
Relationship between celecoxib dose, baseline CV risk, and CV outcome
CelecoxibdoseandbaselineCVrisk
Combined CV outcome = CV death, MI, stroke, heart failure, or thromboembolic event
Lower CV risk with
celecoxib 200 mg qd?

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79. use of PPI+Plavix
Juurlink DN, et al. CMAJ 2009
Does concomitant PPI increase the risk of recurrent myocardial
infarcDtion among patients taking clopidogrel?

80. 80

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83. Combined Medical & Surgical Endoscopy Unit

84. Bleeding Peptic Ulcer
• 5% of emergency
admissions
• 80% stop
spontaneously
• 10% die
• rebleeding increases
mortality 10 X
Sung S. Prevention of Rebleeding. DDW, 2001

85. 85

86. Dot
23%
Clot
13%
Bleeder
7%
NBVV
8%
Clean base
49%
Prevalence of Peptic Ulcer Bleeding Stigmata
and Risks of Re-bleeding (Hong Kong)
0
10
20
30
40
50
60
Active bleeder NBVV Clot Dot Clean base
RiskofRebleeding

87. 87

88. 88

89. Endoscopic haemostasis
 Monotherapy with either epinephrine injection or
thermal treatment (e.g. with a heater probe)
or
 A combination of epinephrine injection plus thermal
treatment and/or haemoclips
Epinephrine injection HaemoclipHeater probe

90. 90

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Efficacy of Omeprazole to prevent
peptic ulcer rebleeding following
hemostasis
Lau, et al. N Engl J Med 2000;343:310-316.
739 patients PUD bleeding
No Endoscopic Tx
N=472
Endoscopic Treatment
N=267
OR
N=5
Excluded
N=22
Enrolled
N=240

93. 93
6.7%*
5.8%*
4.2%*
22.5%
21.7%
20.0%
0%
5%
10%
15%
20%
25%
3 days 7 days 30 days
IV Omeprazole Placebo
*P <0.001
Lau JYW, et al. N Engl J Med. 2000;343:310–316.
Effect of IV Omeprazole to Prevent
Rebleeding Following Hemostasis
%PatientsWithRecurrentbleeding

94. Study flow chart: starting with
esomeprazole i.v., followed by
esomeprazole oral treatment
Sung JJ, et al. Aliment Pharmacol Ther 2008;27:666–77
oral treatment
(27 days)
i.v. treatment
(72 hours)
(0max 24 hours)
Esomeprazole i.v.,
80 mg for 30 minutes
followed by
esomeprazole i.v., 8
mg/hour for 71.5 hours
Placebo i.v. for
30 minutes followed
by placebo i.v. for
71.5 hours
Esomeprazole oral,
40 mg once daily
R
Esomeprazole oral,
40 mg once daily
Enrolment phase:
Endoscopic therapy

95. 95
Odds of endpoint summary
Meta-analysis by Khuroo. J Gastro&Hepatol 2005

96. 2
9
21
1
2
7
0
5
10
15
20
25
Rebleeding Surgery Death
Stigmata of Recent Bleed
Placebo (n=84)
Omeprazole 40 mg PO q12h
x 5 days (n=82)
Oral PPIs as an Adjunct to
Endoscopic Therapy
*P=0.02; †P=0.17; ‡P=0.98
Javid G, et al. Am J Med. 2001;111:280–284.
*
†
‡
%PatientsRebleeding
• Treatment reduced rates of rebleeding, surgery, and mortality

97. 73
11
0
19
93
56
21
12*
0
20
40
60
80
100
Spurting Visible vessel Oozing Clot
Stigmata of Recent Bleed
Placebo (n=110)
Omeprazole 40 mg PO q12h
x 5 days (n=110)
Oral PPI in Prevention of Rebleeding
Without Endoscopic Treatment
*P=0.02; †P <0.001
Khuroo M, et al. N Engl J Med. 1997;336:1054–1058.
%PatientsRebleeding
†

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100. Patients with CV disease on ASA plus ibuprofen
had increased all-cause and CV mortality
Retrospective cohort study
7107 patients received ASA after
the first admission for CV disease
All-cause mortality
R.R. 1·93, 95% CI 1·30–2·87, p=0·0011
CV mortality
R.R. 1·73, 1·05–2·84, p=0·0305
Vs. ASA alone
MacDonald & Wei. Lancet 2003
ASA + ibuprofen

101. Myocardial Infarct
Naproxen
Any non-naproxen
No. of
trials
Events/person-years
Coxib NSAID
0.6% 0.3%
0.5% 0.4%
1.2 (0.85 to 1.68)
2.04 (1.40 to 2.96)
Favours Coxib Favours NSAID
Rate ratio
Coxib:NSAID
Heterogeneity between naproxen and
non-naproxen: 2=5.3, df=1, P = 0.02
Kearney PM, et al. BMJ. 2006;332:1302-8.
Meta-analysis of published and unpublished randomised trials
42
51
Do nonselective NSAIDs have lower CV hazard than
Coxibs?

102. no
Before prescribing NSAIDs to a patient
with musculoskeletal pain….
Does the patient really require NSAIDs?
Inflammatory arthritis?
NSAIDs
yes
no
Simple analgesics
failed
Renal,git,cardiac, high BP?
yes

103. 103

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108. Estimation of CV risk: Framingham
Calculator
http://hin.nhlbi.nih.gov/atpiii/calculator.asp?usertype=pub
55
Risk score = 15%
15 of 100 people
with this level of
risk will have a
heart attack in the
next 10 years!

109. GI risk?
Naproxen is preferred
high
Any NSAIDs
low
CV risk?
Low GI
Low CV
High GI
Low CV
Low GI
High CV
High GI
High CV
Risk stratification

110. Low GI
Low CV
Low GI
High CV
High GI
Low CV
High GI
High CV
• Less ulcerogenic nsNSAIDs are preferred
• Lowest effective dose
• Shortest possible duration
Low GI + Low CV risk

111. Low GI
Low CV
Low GI
High CV
Low GI
High CV
High GI
High CV
• Naproxen is preferred
• Avoid the combination of ASA and ibuprofen
• Continue/start ASA if clinically indicated
Low GI + High CV risk
• Prophylaxis with a PPI if patient receives NSAID + aspirin
• Long-term PPI therapy and osteoporotic risk?

112. Low GI
Low CV
High GI
Low CV
High GI
Low CV
High GI
High CV
High GI / Low CV risk
1. Age>70, or
2. prior uncomplicated ulcer, or
3. concomitant steroids
NSAID + PPI
or Coxib
High GI + Low CV risk

113. 6-month double-blind trial of NSAID+PPI vs. Coxib
in patients with prior ulcer bleed
132134135135138142143
0.05
0.00
0 1 2 3 4 5 6
Celecoxib 200 mg bid
+ omeprazole placebo
Diclofenac 75 mg bid
+ omeprazole 20 mg/d
No. at risk 135135136137141142144
Recurrent ulcer bleeding at 6 months:
Celecoxib 200 mg bid: 4.9%
Diclofenac 75 mg bid + Omeprazole 20 mg od: 6.4%
0.10
Probabilityofrecurrentulcerbleeding
Months of follow-up
Chan FK, et al. N Engl J Med. 2002;347:2104-10.

114. Ulcer healed and Hp-negative before
enrolment
273 patients with NSAID-induced ulcer
bleeding
Celecoxib 200 mg bid
+ PPI bid
Celecoxib 200 mg bid
+ placebo bid
12-month double-blind RCT
Can Coxib + PPI Prevent Ulcer Bleeding
in Very High-Risk Patients?
Chan FK, et al. Lancet. 2007;369:1621-6.

115. PPI + Coxib vs Coxib alone in patients with prior
ulcer bleed:
A 12-month double-blind randomised trial
0 0
8.9
7.1
0
1
2
3
4
5
6
7
8
9
10
All patients Without ASA
Chan FK, et al. Lancet. 2007;369:1621-6.
PPI + celecoxib
200 mg bid (n = 137)
Placebo + celecoxib
200 mg bid (n = 136)
Rebleed at 12 months
Patients(%)
a P < 0.001 vs placebo
b P < 0.01 vs placebo
b
a

116. Low GI
Low CV
High GI
Low CV
High GI
Low CV
High GI
High CV
1. Prior complicated ulcer, or
2. more than two risk factors
Coxib + PPI
High GI + Low CV risk
1. Age>70, or
2. prior uncomplicated ulcer, or
3. concomitant ASA/steroids
NSAID + PPI
or Coxib
High GI / Low CV risk

117. Low GI
Low CV
High GI
Low CV
Low GI
High CV
High GI
High CV
High CV / High GI risk
Naproxen + ASA + PPI
CV risk > GI risk
e.g. recent MI + remote ulcer history
Avoid NSAIDs
GI risk > CV risk
e.g. recent GI bleed + remote MI
Low-dose coxib + ASA + PPI
failed
High GI + High CV risk
violates
current
European
guidelines?!

118. Low GI
Low CV
High GI
Low CV
Low GI
High CV
High GI
High CV
High CV / High GI risk
Naproxen + ASA + PPI
CV risk > GI risk
e.g. recent MI + remote ulcer history
Avoid NSAIDs
GI risk > CV risk
e.g. recent GI bleed + remote MI
Low-dose coxib + ASA + PPI
failed
High GI + High CV risk
CV risk = GI risk
e.g. recent MI + recent GI bleed
Alternative
analgesics

119. NSAID+PPI/coxib alone
Coxib + PPI*
Management of Patients on NSAIDs:
Balancing GI and CV risks
High CV risk
(aspirin required)
Low CV risk
Avoid NSAIDs
or coxibs†
Least ulcerogenic
NSAID
High GI riskLow GI risk
*Prior ulcer bleed, multiple GI risk factors
†Naproxen + PPI or low-dose coxib +PPI in selected cases
Naproxen + PPI

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121. THANK YOU
121