NSAID gastropathy

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NSAID gastropathy

• Professor Yaron Niv
• Rabin Medical Center
• Tel Aviv University

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NSAID gastropathy

• The problem
• Pathogenesis
• Role of Helicobacter pylori
• Prophylactic therapy
• Potentially safer NSAIDs

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Scope of NSAID Gastropathy(after 3 months
therapy)

• Dyspepsia 10-20
• Gastric ulcer in 15-20(x5)
• Duodenal ulcer in 5-8
• Risk of severe complication is
  2 - 4/y

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Scope of NSAID Gastropathy

• In USA NSAIDs are used regularly by 13 millions.
• 103,000 develop severe GI complication, 16,500
  deaths/y (1788).
• Mortality from GI complications in users x4.21
  controls.
• 20,000 per hospitalization, 2 b/y.

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On the Average in Quebec, for Every Dollar Spent
on NSAIDs, Another 0.73 Were Needed for GI
Problems
Gastroprotective agents, visits to
Gastroenterologists, GI diagnostic tests, GI
hospitalizations
Cost of GI-Related Events
0.94
Cost of NSAID Dispensing Fee
1.28
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NSAID - ulcer Clinical Presentation

• Among asymptomatic patients, bleeding
• or perforation is frequently the first
• manifestation of ulcer disease.
• Explanations
• 1. NSAID-induced analgesia
• 2. NSAID may exacerbate a previously existing
  silent ulcer
• 3. Anti-platelet action - bleeding

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NSAIDs Vs. H.pylori Related Ulcer

• Gastric gt Duodenal
• More often asymptomatic
• Surrounding mucosa
• normal

• Duodenal gt Gastric
• Usually pain or dyspepsia
• Surrounding mucosa
• inflamed

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NSAID gastropathy

• The problem
• Pathogenesis
• Role of Helicobacter pylori
• Prophylactic therapy
• Potentially safer NSAIDs

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NSAID - Pathogenesis

• 1. Prostaglandin (COX)
• inhibition
• 2. Impaired mucosal defense
• 3. Leukocyte margination
• 4. Topical effect

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Gastric Mucosal Barrier

• COX 1

Epithelial proliferation
H
Surface active phospholipids
H
pHlt2
HCO3-
MUCUS
HCO3-
pH7
Mucosal Cells
Circulation
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Effects of Prostaglandins Inhibition

• Cox 1 inhibition

H
pHlt2
MUCUS
HCO3-
Adhesion molecules Neutrophil adherence Stasis Mic
rovascular ischemia Free radical formation Erosion
Cellular damage
Circulation
Chronic injury
Scheiman, Clin North Am 9625279
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Mechanisms of NSAIDs Gastroduodenal Injury
NSAID
Systemic effect
Hepatic metabolism
Decrease in gastric mucosal PGs
Active NSAID metabolite
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NSAID gastropathy

• The problem
• Pathogenesis
• Role of Helicobacter pylori
• Prophylactic therapy
• Potentially safer NSAIDs

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Helicobacter pylori

• Antral gastritis - 95
• Duodenal ulcer - 90
• Gastric ulcer - 75
• Gastric adenocarcinoma
• Maltoma
• A possible synergistic relation with NSAID use?

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NSAID and Helicobacter pylori

• Before a long course of NSAID or aspirin,
  eradication (test and treat) of Helicobacter
  pylori should be considered

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????? ????????? ???? ????? ????? ? NSAIDChan,
Lancet 20023599-13

• 102 ???? ???????? ??"? ????? ????? ???????
  ?????????? ??????
• ?????????? ?????? ?????? ?"? ???? ????? (OAC) ??
  ???????? ?????? ????????????
• 6 ???? ????? ??????? 100 ??' ????
• ??????????? ???? 6 ?????

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Hp and NSAID in ulcer disease a
meta-analysisHuang, Lancet 200235914-22

• 25 acceptable studies
• Ulcer in NSAID-taker
  Hp 42, Hp- 26
• NSAID-taker Hp x 61 ulcer than non-takers Hp-
• (either factor alone x 20)
• Ulcer bleeding Hp infection x 1.79,
• NSAID x 4.85, together x 6.13

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NSAID gastropathy

• The problem
• Pathogenesis
• Role of Helicobacter pylori
• Prophylactic therapy
• Potentially safer NSAIDs

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Risk Factors for NSAID Ulcers

• Prior NSAID-induced or peptic ulcer
• Higher doses or more than one sort
• Advanced age (gt70 years)
• Anticoagulation
• Concomitant steroid use
• Major illness
• Possible H. pylori, IHD, RA, Ethanol, Smoking

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For how long?

• The greater risk is within the first 3 m of
  initiation.
• The risk of NSAID-associated GI hemorrhage
  remains constant over an extended period of
  observation.

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Options for NSAID Prophylactic Therapy (prevent
ulcer and dyspepsia)

• PPI (omeprazole 20-40mg 1x1/d) gt PGE1,
  Misoprostol (cytotec 200 ?g 1x3/d) gt H2 receptor
  antagonist (famotidine 40mg 1x2/d or ranitidine
  300 mg 1x2/d).
• Misoprostol good for prevention of gastric ulcer
  but causes diarrhea.

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Therapy of NSAID-induced dyspepsia, ulcer or
erosive gastritis

• Stop NSAID
• H. pylori status (13C-urea breath test) -
  eradication.
• PPI (if dyspepsia continuous or NSAID has to be
  continued).

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NSAIDs and time on PPI
n53,031

Hazard ratio for upper GI bleeding VA Med CTR
1.1.2000 31.12.2002 Age gt 65 (mean
74)
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NSAID gastropathy

• The problem
• Pathogenesis
• Role of Helicobacter pylori
• Prophylactic therapy
• Potentially safer NSAIDs

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COX-2 inhibitors
NSAID - needs pocket
NSAID
Arg 120
Arg 120
Iso 523
Val 523
COX-2 Pocket
75 a.a. homology
Arachidonic acid
Arachidonic acid
COX-1
COX-2
Chr 9, 71kD
Chr 1, 71kD
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GI side effects of etoricoxib vs.
diclofenacBaraf, J Rhematol 2007

• 636 centers (US and Europe), 7111 OA patients
  randomized 3593 90 mg/d etoricoxib, 3518 150
  mg/d diclofenac, follow up 12 months
• GI adverse events etoricoxib 8, diclofenac 16
  (HR 50, Plt0.001)

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Summary NSAID Gastropathy

• NSAID Gastropathy is a serious problem.
• The mechanism of NSAID ulceration is
  multifactorial.
• H. pylori may aggravate NSAID ulcers.
• PPI, Misoprostol and H2 antagonists decrease
  NSAID ulcers.
• Prophylactic therapy should be reserved for high
  risk patients.
• COX-2 inhibitor is safer.