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Nsaid upper gi nomber (2)

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Nsaid upper gi nomber (2)

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Nsaid upper gi nomber (2)

  1. 1. NSAID Upper G/I Adverse Effects Minimizing Risks The 1st Palestinian G/I Conference May 20-22-2010
  2. 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. 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. 4. Gastric mucosal damage requiresinhibition of both COX-1 and COX-2Gastric damage score(%)15 * *10 * p<0.05 5 0 Vehicle Celecoxib SC-560 Celecoxib Indo- + methacin SC-560 Wallace et al 2000
  5. 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. 6. NSAID-associated gastroduodenal damage is pH-dependentTotal haemorrhagic mucosal area(%) intraduodenal saline5 intraduodenal4 indomethacin, 40 mg/kg3210 2.0 4.0 5.5 7.0 Gastric luminal pH Elliott et al 1996
  7. 7. NSAID-associated gastroduodenal damage is pH-dependentTotal haemorrhagic mucosal area(%) intraduodenal saline5 intraduodenal4 indomethacin, 40 mg/kg3210 2.0 4.0 5.5 7.0 Gastric luminal pH Elliott et al 1996
  8. 8. Upper GI side-effects
  9. 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. 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, nauseaand flatulence.
  11. 11. NSAID ingestion is one of the few drug- related risk factors for dyspepsia NSAIDsCalcium blockers Corticosteroids ACE inhibitorsMethylxanthines 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. 12. Poor health-related quality of life among patients free from ulcer taking NSAIDs, including COX-2 selective NSAIDs US populationMean SF-36 score n=2474100 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 ol ing l em lth th l l n a na Bo ica li t ai tio sic en eal tio oc ea ta ng e n ly p io ys Vi nc y nc S ot lh h fu Ph ph di al 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. 13. Upper GI side-effects impact negatively onpatients‘ 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. 14. NSAID users are at risk of reflux esophagitis Reflux esophagitis: the  presence of definite mucosal breaks or metaplasia of the esophagus, visible under .endoscopyA 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 TytgatReflux esophagitis LA Grades A–D. Avidan et al 2001
  15. 15. NSAID-associated peptic ulcerationThe 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 whoalso 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. 16. Annual Rates of Hospitalisation for Ulcer Complications Saskatchewan, Canada 1982-86Hospitalisations per1000 person/years25 Male users20 Female users Male15 non-users Female non-users10 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. 17. NSAID-associated dyspepsia may predict peptic ulcer diseaseRelative risk of developing an ulcer/multiple erosionsin those with moderate/severe dyspepsia10 OMNIUM ASTRONAUT 8 7.8 6 5.3 4 3.9 2 1.8 0 Healing Maintenance Hawkey et al 1997
  18. 18. Risk of peptic ulceration is similar between non-selective and COX-2 selective NSAIDs with concomitant low-dose aspirinCumulative incidence of ulcers placebo(%) n=41018 *** *** aspirin16 n=40614 rofecoxib + aspirin12 n=39910 ibuprofen 8 n=400 6 *** p<0.001 versus 4 placebo + aspirin 2 0 Laine et al 2004
  19. 19. Upper GIcomplications
  20. 20. Aspirin, alone or with another NSAID, increases the risk of upper GIRelative risk complications876543210 Aspirin, Aspirin, Aspirin, NSAIDs Aspirin 75 mg 150 mg 300 mg + other once daily once daily once daily NSAIDs Weil et al 1995
  21. 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 2000or symptomatic peptic ulcer.
  22. 22. Risk of ulcer complications with celecoxib remains high among patients with other risk factorsPatients with ulcer complications(%) celecoxib, 400 mg twice daily2 ibuprofen, 800 mg three times daily, or diclofenac, 75 mg twice daily n=805910 No risk factor More than one risk factor Hawkey & Skelly 2002
  23. 23. High-risk patients with previous GI diseaseremain at risk of upper GI bleeding with COX-2 selective NSAIDsAdjusted odds ratio for upper GIbleeding3.53.02.5 n=36862.01.51.00.50.0 Celecoxib Rofecoxib Non-aspirin, non-selective NSAIDs Nørgard et al 2004 Prescription within 30 days of hospital admission
  24. 24. Risk Factors
  25. 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. 26. Risk factors for peptic ulcer bleeding NSAID useOral corticosteroid use Warfarin use Previous peptic ulcerDyspepsia in past year Heart failure Diabetes Current smoking 0 1 2 3 4 5 6 7 8 Odds ratio Weil et al 2000
  27. 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. 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. 29. Strategies to Preventand Treat NSAID complications
  30. 30. Mortality from bleeding ulcers: 5-10%
  31. 31. Management of NSAID-induced peptic ulcer diseaseDiscontinue use of NSAIDs orsubstitute with less toxic agents q Low-toxicity NSAIDs or COX-2 inhibitorsSuppress acid secretion q Normal-dose PPI therapy q High-dose H2RA therapyUse 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. 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. 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. 34. NSAID- G/I complication 21.5 10.5 1982 1992 2000 Fries etal .2004
  35. 35. Endoscopic Photograph of Gastropathy
  36. 36. Endoscopic Photograph of Gastric Ulcer
  37. 37. Cardiovascular benefitsand GI risks of low-dose Aspirin
  38. 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. 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. 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. 41. Cardiovascular Benefits And GI Risks Of Clopidogrel
  42. 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. 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. 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. 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. 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. 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

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