1. Prevention of NSAID-related ulcer complications
Samir Haffar M.D.
Assistant Professor of Gastroenterology

2. Non-steroidal anti-inflammatory drugs
Drug Trade name Half-Life (h) Dosing
Arylcarboxylic acids Diflunisal Dolobid® 8 – 12 250–500 mg bid
Arylalkanoic acids Diclofenac Voltaren® 2 50–75 mg bid
Ibuprofen Advil® 2 – 2.5 200–800 mg qid
Fenoprofen Nalfon® 2–3 300–600 mg qid
Naproxen Naprosyn® 12–17 250–500 bid
Indomethacin Indocin® 4.5 25–50 mg tid
Sulindac Clinoril® 16 150–200 mg bid
Enolic acids Piroxicam Feldene® 50 10–20 mg qd
Meloxicam Mobic® 15–20 7.5–15 mg qd
Non-acidic Nabumetome Relafen® 24 1000 mg qd
Coxibs Celecoxib Celebrex® 11 100–200 mg qd
Imboden JB et al Current diagnosis & treatment in rheumatology.
McGrawHill, 2nd edition, Boston, MA, USA, 2007.

3. Indications for use of NSAIDs
Analgesic - Anti-inflammatory - Antipyretic - Antithrombotic
• Rheumatic diseases (8% of people at any time)
• Prophylaxis of stroke & myocardial infarction
• Reduction of colorectal cancer
• Reduction of colorectal adenomatous polyps
• Treatment of Alzheimer’s disease

4. NSAID prescribing in Europe (1997)
Country Percentage
Belgium 5.3%
England 5.0%
Irish Republic 8.4%
Italy 11.0%
Northern Ireland 7.8%
Portugal 8.5%
Scotland 5.7%
Spain 7.0%
Overall 7.7%
Adapted from P Jepson, unpublished data, 1999.
Jones R. Am J Med 2001 ; 110 : 4S – 7S.

5. Use & cost of NSAIDs in USA in 1997
• 13 million people use NSAID regularly for various arthritides
• Hospitalizations for serious GI complications: 100 000/year
• Costs of complications > $ 2 billions/year ($ 20 000/ hosp)
• NSAID-related death: 16 500/year (15th most common cause)
• Total cost of NSAIDs use > $ 6 billions/year
Public greatly underestimate risks associated with NSAIDs use
J Rheumatol 1999 ; 26 : suppl 26 : 18 – 24.

6. US mortality from 7 selected disorders in 1997
NSAID complications represents 15th most common cause of death
Statistics don’t include deaths due to OTC NSAIDs
J Rheumatol 1999 ; 26 : suppl 26 : 18 – 24.
“Silent epidemic”

7. Sales of Bayer Aspirin
• the 1940s 100 million DM
• the mid-1990s 800 million DM annually
• 21th century Projected sales 2 billion DM per year
Jones R. Am J Med. 2001; 110: 4S – 7S.
“Aspirin” registered in 1899
Felix Hoffmann (chemist with Bayer in Germany)

8. Side effects of NSAIDs
Cardiovascular Serious CV events: MI – Stroke
Gastrointestinal GI symptoms – endoscopic lesions – GI ulcers
Renal Retention of sodium & fluid – Acute renal failure
Interstitial nephritis – nephrotic syndrome – papillary necrosis
Hepatic Modest elevation of aminotransferases (< 2-3 fold)
Acute liver injury
CNS Aseptic meningitis – Headaches – Dysphoria
Tinnitus & hearing loss Frequent in high doses of aspirin – Occurs in other NSAIDs
Neutropenia
Hypersensitivity reactions
Imboden JB et al Current diagnosis & treatment in rheumatology.
McGrawHill, Boston, MA, USA, 2nd edition, 2007.

9. Choice between various NSAIDs dominated by
“least harm principle”
balancing various potential adverse events
Key consideration when selecting NSAIDs
Cardiovascular risk
followed by risk of GI adverse events

10. NSAID-related cardiovascular morbidity
• Increased blood pressure Average of 5 mm Hg
• Congestive heart failure
• Serious CV events Myocardial infarction
Stroke
Risser A et al. Am Fam Physician 2009 ; 80 : 1371 – 1378.

11. VIGOR study
VIGOR: Vioxx Gastrointestinal Outcomes Research
Nissen SE et al. JAMA 2001; 286 : 954 – 959.
8,076 RA patients – Rofecoxib 50 mg qd vs naproxen 500 mg bid
Exclusion: Stroke, MI, CABG, aspirin, or gastroprotective agent
MI higher in rofecoxib than in naproxen group

12. Myocardial infarction of Coxibs versus placebo
Kearney PM et al. BMJ 2006 ; 332 : 1302 – 8.

13. Myocardial infarction of Coxibs versus NSAIDs
Kearney PM et al. BMJ 2006 ; 332 : 1302 – 8.
Naproxen may have some cardioprotective properties

14. GI side effects of NSAIDs
Organ Side Effects
Esophagus Esophagitis – Ulcer – Stricture
Ano-rectum Inflammation – Ulcer – Stricture
Stomach & duodenum Subepithelial hemorrhage – Erosion – Ulcer
Small Intestine Ulcers – Strictures – NSAID enteropathy
Colon No pre-existing colonic disease:
Ulcerations – Stricture – Diaphragm – Colitis
Pre-existing colonic disease:
↑ Complications of diverticular disease
Activate IBD

15. Complicated ulcers
1 – 1.5% in first year
Clinical ulcers
4 – 5%
Endoscopic ulcers
30%
Relative Severity
GI symptoms
40%
Relative Frequency
NSAID-related gastro-duodenal side effects

16. NSAIDs gastropathy
Arthritis Rheum 1995 ; 38 : 5 – 18.
Confined to mucosa
Erosion
Extend into submucosa
> 3 or 5 mm
Ulceration
No break in mucosa
Hemorrhage
Endoscopic definition more practical
Erosion: Small & superficial
Ulceration: Larger ( > 5 mm) & deeper

17. Stage Characteristics Rebleeding
I a Jet arterial bleeding 90 %
Ib Oozing 50 %
IIa Visible Vessel 25 – 30 %
IIb Adherent clot 10 – 20 %
IIc Black spot in ulcer crater 7 – 10 %
III Clean base ulcer 3 – 5 %
Forrest’s classification for PU bleeding

18. Forrest’s classification for PU bleeding
III (clean base)II-b (adherent clot)
II-a (visible vessel)I-b (oozing)
II-c (black spot)
I-a (arterial jet )

19. Peptic ulcer perforation

20. NSAIDs-induced colitis
Segmental mucosal inflammation with ulceration
Histologically nonspecific
DD: infections, IBD, ischemia, vasculitis

21. Pathogenesis of NSAID-induced GI Injury
Three main components
Best Pract Res Clin Gastroenterol 2001 ; 15 : 691 – 703.

22. GI safety of non-selective NSAIDs
RR of different NSAIDs could differ 10-fold
* Risk at higher doses (> 1.5 –2.4 g/d) comparable to others NSAIDs
Br Med J 1996 ; 312 : 1563 – 1566.
Lowest risk Ibuprofen *
Diclofenac
Moderate risk Indomethacin
Naproxen
Sulindac
Aspirin
Highest risk Azapropazone
Tolmetin
Ketoprofen
Piroxicam
Longer half-time

23. Differences between Cox-1 & Cox-2
COX-1
Housekeeping
COX-2
Inflammation
Regulation Constitutive Inducible
Range of expression 2 – 4 fold 10 – 80 fold
Tissue Expression Most tissues notably
Platelets
Endothelial cells
Kidneys
Stomach
Inflammatory sites
Synoviocytes
Fibroblasts
Monocytes

24. Clinical ulcer complications with COX-2s vs NSAIDs
Rostom A et al. Clin Gastroenterol Hepatol 2007 ; 5 : 818 – 828.
Cochrane Collaboration Systematic Review
8 studies – 73 449 patients – POB

25. RR of UGI bleeding/perforation from NSAIDs
Systematic review of observational studies since 1990
n values: number of studies
Asterix: reported in studies published after 2000
Massó González EL et al. Arthritis Rheum 2010 ; 62 : 159 2 – 1601.

26. Major GI bleeding in low dose aspirin
14 RCTs – over 57 000 patients
McQuaid KR et all. Am J Med 2006 ; 119 : 624 – 638.
Major GI bleeding: fatal – hospitalization – transfusion
Low dose asipirin: 75 – 325 mg/day
NNH during 1 year period: 833

27. Risk of UGI bleeding with aspirin
Daily aspirin dose Odds ratio (95% CI)
Any 3.2 (2.3 – 4.4)
75 mg 2.3 (1.2 – 4.4)
150 mg 3.2 (1.7 – 6.5)
300 mg 3.9 (2.5 – 6.3)
Weil J et al. BMJ 1995 ; 310 : 827 – 30.
Risk of bleeding with aspirin is dose related

28. Major GI bleeding & type of aspirin
550 incident cases & 1202 controls, 28 MA hospitals
Aspirin RR of UGI bleeding
≤ 325 mg > 325 mg/day
Plain 2.6 5.8
Enteric-coated 2.7 insufficient data
Buffered 3.1 7.0
Kelly JP et al. Lancet 1996 ; 348 : 1413 – 16.
Same risk for plain, buffered & enteric-coated aspirin

29. Risk factors for NSAID-related ulcer complications
Scheiman JM. Drugs 2006 ; 66 : 15S – 21S.

30. Helicobacter pylori eradication in prevention
of peptic ulcer in NSAID users
Vergara M et al. Aliment Pharmacol Ther 2005 ; 21 : 1411 – 1418.
Testing for HP infection & eradicating infection if positive
in patients requiring long-term NSAID therapy

31. Prevention strategies of GI risk due to NSAIDs
• Avoid use of NSAID & substitute with acetaminophen
• Use “safer” NSAID: Diclofenac, ibuprofen, coxibs
• Avoid NSAID with higher toxicity: Ketorolac, piroxicam
• Use lowest effective dose for shortest period of time
• Avoid concomitant therapy with:
Anticoagulants, corticosteroids, low-dose aspirin, APT
• Eradicate HP infection in patients with prior ulcer history
Sostres C et al. Best Pract Res Clin Gastroenterology 2010 ; 24 : 121 – 132.

32. http://hp2010.nhlbihin.net/atpiii/calculator.asp
At time of assessment
Smoking in past month
Average of 2measurements

33. Framingham Risk Score (FRS)
• Low risk < 10% 10-year risk
• Intermediate risk 10 – 20% 10-year risk
• High risk > 20% 10-year risk

34. Primary prevention of MIs by aspirin
Current situation of evidence
Men Women
Low risk No trial No benefit
Intermediate risk No benefit No benefit
High risk Reduced MI No trial
Kappagoda T et al. J Cardiopulmo Rehabil Prev 2011 ; 31 : 1 – 8.
Dose of aspirin: 500 mg/d (British Male Doctors’ Study)
100 mg on alternate days (Women’s Health Study)

35. Primary prevention of CV events & aspirin
97,387 adults aged > 40 years
CV risk % of patient taking low-dose aspirin
(ATP III)* Male Female
High risk (14%%) 59% 46%
Intermediate risk (48%) 31% 27%
Low risk (38%) 25% 18%
* According to Adult Treatment Panel III definitions (ATP III)
Kim C, et al. Am J Prev Med 2004 ; 27 : 1 – 7.

36. Factors involved in maintaining acid balance

37. Carl Schwartz: 1910

38. Strategies used during the 20th century for
counteracting action of gastric acid
Inflexion occurs during the 1980s
with introduction of drugs inhibiting gastric acid secretion
Dı az-Rubio M. Drugs 2005 ; 65 (Suppl. 1) : 1 – 6.

39. “Potent acid inhibition”
• pH > 4 1000-fold ↓ H concentration in stomach
Reduced the pepsin activity
• At least 16 h No clear evidence to 16 h as cut-off
Used in many studies
Described arbitrarily as maintaining an intragastric
pH > 4 for at least 16 h out of every 24 h

40. 0
20
40
60
80
100
Maximum pepsin activity
(%)
1 2 3 4
Gastric juice pH
pH 4 is a critical threshold for
gastric pepsin activity
Adapted from Berstad 1970

42. Patients at increased risk for NSAIDs CV toxicity
High risk Patients with risk factors for CV disease often
receive prophylactic aspirin
Arbitrarily defined as requirement for low-dose
aspirin for prevention of serious CV events
Low risk No risk factors

43. Patients at increased risk for NSAIDs GI toxicity
High risk 1. History of complicated ulcer especially recent
2. Multiple (> 2 risk factors)
HP is independent & additive risk factor & addressed separately
ACG guidelines for prevention of NSAID-related ulcer complications .
Am J Gastroenterol 2009 ; 104: 728 – 738.
Moderate risk
(1 – 2 risk factors)
1. Age > 65 years
2. High dose NSAID therapy
3. Previous history of uncomplicated ulcer
4. Concurrent use of aspirin
5. Concurrent use of corticosteroids
6. Concurrent use of anticoagulants
Low risk No risk factors

44. Prevention of NSAID-related ulcer complications
Naproxen may have some cardioprotective properties
Patients with ulcer history: search for HP & if present eradicated
ACG guidelines for prevention of NSAID-related ulcer complications.
Am J Gastroenterol 2009 ; 104: 728 – 738.
NSAID alone
(least ulcerogenic
at lowest dose)
NSAID
+
PPI/misoprostol
Alternative therapy
or
Coxibs + PPI/misoprostol
Naproxen
+
PPI/misoprostol
Naproxen
+
PPI/misoprostol
Avoid NSAIDs & coxibs
Use alternative therapy
High GI riskModerate GI riskLow GI risk
Low CV risk
High CV risk

45. SENSAR software
Appropriate use of NSAIDs in chronic rheumatic disease
• 18 experts from 10 European countries
• English-language literature from 1998 to 2008
• Three panel meeting: January, June, & November 2008
• 144 different patient profiles & 10 treatment options
• Research & Development at UCLA(RAND/UCLA)
• Statement: Appropriate – Uncertain – Inappropriate
• Coordinated by Center for Decision Analysis & Support
• Supported by Pfizer Inc
http://www.e-hims.com/Sensar/

46. European expert panel on appropriate use of NSAID
Name Speciality Country
1- Gerd R Burmester Rheumatology Germany
2-Francis Berenbaum Rheumatology France
3- Ferdinand Breedveld Rheumatology The Netherlands
4- Maxime Dougados Rheumatology France
5- Emilio Martín Mola Rheumatology Spain
6- Ignazio Olivieri Rheumatology Italy
7- Josef Smolen Rheumatology Austria
8- Stefan Lohmander Orthopaedics Sweden
9- Luigi M Biasucci Cardiology Italy
10- Matthias Hermann Cardiology Switzerland
11- Tom MacDonald Cardiology and Clinical Pharmacology UK
12- Chris Hawkey Gastroenterology UK
13- Angel Lanas Gastroenterology Spain
14- Carmelo Scarpignato Gastroenterology and Clinical Pharmacology Italy
15- Adam Bajkowski Family Medicine UK
16- Peter Dieleman Family Medicine Belgium
17- Tony Mets Geriatrics Belgium
18- Nele Van Den Noortgate Geriatrics Belgium

47. http://www.e-hims.com/Sensar/

48. SENSAR software
Appropriate use of NSAIDs in chronic rheumatic disease
• Electronic tool may offer best opportunities as quick
reference guide to panel results
• In the complex and dynamic area of NSAID use:
Such approach offer best chances of benefiting from
perspective of both science & practice
http://www.e-hims.com/Sensar/
Burmester G et al. Ann Rheum Dis 2011 ; 70 : 818 – 822.

49. Fries JF et al. Arthritis Rheum 2004; 50: 2433 – 4.
Declining risk of NSAID-induced GI complications
RA patients with serious GI events (hospitalization)
5598 patients followed over 20-year period
Dotted line: second-degree spline-fitted curve
Reduction of 67% in serious GI complications since 1992

50. Six available PPIs
Generic name Trade name Daily dose Route
Delayed release PPIs
Omeprazole Losec® 20 mg Oral
Lanzoprazole Lanzor® 30 mg Oral – IV
Pantoprazole Protonix® 40 mg Oral – IV
Rabeprazole Pariet® 20 mg Oral
Esomeprazole Nexium® 40 mg Oral – IV
Are all PPIs the same?
Immediate release PPIs
OMP Na bicarbonate Zegerid® 20 mg Oral

51. Major metabolic pathways for various PPIs
De Argila CM. Drugs 2005; 65 (Suppl. 1) : 97 – 104.
Contribution of each isoenzyme represented by thickness of arrow
Rabeprazole: Important non-enzymatic metabolism
Pantoprazole: sulfotransferase not saturable

52. Helpful facts on the use of PPIs
• Take twice daily for first 2 – 3 days of therapy
Steady state is not reached for a couple of days
• First dose should be ½ hour before breakfast
• Second dose, if used, should be ½ hour before dinner
• Not likely to be effective when used as required
Wolfe MM, Sachs G. Gastroenterology 2000; 118: S9 – S31.

53. PPI dose adjustment
• Renal failure No repercussion on PPI elimination
No need to adjust dosage
• Liver failure Half-life increases to 4 – 8 h (nl: 1 h)
Reduction of dosage
• Aged patients No dosage adjustment usually
Adjustment if hepatic or renal failure
is added to advanced age
de Argila CM. Drugs 2005; 65 (Suppl 1) : 97 – 104.

54. Which PPIs?
 Efficacy
Esomeprazole Slightly more effective
Refractory ulcer & difficult GERD
IR-omeprazole Quick onset of action – NAB*
 Interactions with other drugs
Less interaction in rabeprazole & especially pantoprazole
Dose adjustment in AVK, benzodiazepines, phenytoin
PPI & Clopidogrel: COGENT trial
 Cost considerations
* NAB: Noctural Acid Breakthrough

55. COGENT trial – Cardiovascular outcomes
4.9%
5.7%
P= 0.98
Log rang test
* DAT: Dual Antiplatelet Therapy (clpidogrel & aspirin)
Bhatt DL et al. N Engl J Med 2010 ; 363 : 1909 – 1917.
RCT – 3761 patients – Omeprazole vs placebo in DAT*
Death, nonfatal MI, revascularization, or stroke

56. COGENT trial – Gastrointestinal outcomes
1.1%
2.9%
P<0.001
Log rang test
* DAT: Dual Antiplatelet Therapy (clpidogrel & aspirin)
Bhatt DL et al. N Engl J Med 2010 ; 363 : 1909 – 1917.
RCT – 3761 patients – Omeprazole vs placebo in DAT*
Symptomatic ulcers or erosions, complicated ulcer

57. PPI & clopidogrel co-therapy
 Administer PPI in patients at high risk
Administer PPI in all patients with dyspepsia
 Prefer pantoprazole or rabeprazole
Weak inhibitors of CYP2C19
Pantoprazole considered the first choice PPI
 Separate administration by 12 – 15 hours
Half-life of PPI 1 – 2 h & clopidogrel 4 – 6 h
PPI before breakfast & clopidogrel after dinner
Lettino M. Eur J Intern Med 2010 (in press).

58. Side effects of PPI
No therapy is completely without risk
• Osteoporosis & fractures Conflicting results
• Clostridum difficile OR 2.05 (95% CI: 1.4 – 2.8)
• Pneumonia OR 1.3 (95% CI: 1.1 – 1.4)
• Acute interstitial nephritis Very rare
• Iron & vit B12 deficiencies Little evidence
Madanick RD. Clevland Clin J Med 2011 ; 78 : 39 – 49.

59. The lowest effective dose
of the cheapest drug
for the shortest possible time
Which PPIs?

60. Thank You