Peptic ulcer management in the era of nsaid


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Peptic ulcer management in the era of nsaid

  1. 1. Management NSAID induced GI complication: the role of PPI Prof Dr. Lukman Hakim Z, SpPD-KGEH
  2. 2. NSAID use is associated with upper GI side-effects <ul><li>NSAIDs, including COX-2 selective NSAIDs, are associated with an increased risk of upper GI symptoms. </li></ul><ul><li>NSAIDs, including COX-2 selective NSAIDs, are associated with peptic ulceration. </li></ul><ul><li>Complications of NSAID use – bleeding, perforated or obstructed peptic ulcers – are a major cause of morbidity and mortality. </li></ul>Langman et al 1999; Silverstein et al 2000; Wolfe et al 1999
  3. 3. NSAIDs are associated with the risk of serious upper GI complications, hospitalisation and mortality <ul><li>Non-selective NSAIDs account for approximately 20–25% of all reported drug adverse events. </li></ul><ul><li>80% of peptic ulcer-related deaths occur in non-selective NSAID users. </li></ul><ul><li>In the USA, NSAID use accounts for approximately 107,000 hospitalisations and 1 6,500 deaths per year. </li></ul>Armstrong & Blower 1987; Singh 1998; Wolfe et al 1999
  4. 4. NSAID-associated peptic ulceration <ul><li>The majority of patients develop some gastric erosions after each dose of a non-selective NSAID. </li></ul><ul><li>Approximately 15 – 30% of NSAID users develop endoscopically evident ulcers at any one time – these will be generally silent. </li></ul><ul><li>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 at risk. </li></ul>Photo reproduced from the Interactive Atlas of Gastroenterology Hawkey & Skelly 2002; Laine 1996; Silverstein 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. Prevalence of peptic ulceration is dependent on the relative NSAID toxicity Cheatum et al 1999 Patients with peptic ulcers (%) 50 0 10 30 40 20 Fenoprofen Diclofenac Naproxen Sulindac Ibuprofen Indomethacin Piroxicam Flurbiprofen Etodolac Ketoprofen Aspirin >1 NSAID Other NSAIDs
  7. 7. High-risk patients with previous GI disease remain at risk of upper GI bleeding with COX-2 selective NSAIDs N ø rgard et al 2004 n=3686 Adjusted odds ratio for upper GI bleeding Prescription within 30 days of hospital admission 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Celecoxib Rofecoxib Non-aspirin, non-selective NSAIDs
  8. 8. <ul><li>Patient-related factors: </li></ul><ul><ul><li>age >60 years </li></ul></ul><ul><ul><li>history of peptic ulcer disease/upper GI complications. </li></ul></ul><ul><li>Drug-related factors </li></ul><ul><ul><li>use of a relatively toxic NSAID(low dose aspirin or high dose NSAID therapy </li></ul></ul><ul><ul><li>use of a high dose of NSAID (or two NSAIDs used concurrently) </li></ul></ul><ul><ul><li>concurrent use of an anticoagulant </li></ul></ul><ul><ul><li>concurrent use of a corticosteroid </li></ul></ul><ul><li>Other disease </li></ul><ul><ul><li>cardiovascular disease </li></ul></ul><ul><ul><li>Helicobacter pylori infection </li></ul></ul>Risk factors for upper GI complications occurring with NSAIDs Lanza et al. Am J Gastroenterol 2009; 104:728 – 738
  9. 9. Risk of upper GI events may be silent <ul><li>50–60% of NSAID-associated peptic ulcers, presenting for the first time as a complication, have been silent previously. </li></ul><ul><li>Most patients with endoscopic lesions do not develop dyspepsia: </li></ul><ul><ul><li>9% of patients with abnormal endoscopy had dyspeptic symptoms (n=45). </li></ul></ul>Larkai et al 1987; Singh 1998
  10. 10. NSAIDs inhibit the COX enzyme, which exists in two forms Arachidonic acid COX-1 (constitutive) COX-2 (induced by inflammatory stimuli) Non-selective NSAIDs <ul><li>Gastrointestinal cytoprotection </li></ul><ul><li>Platelet activity </li></ul><ul><li>Inflammation </li></ul><ul><li>Pain </li></ul><ul><li>Fever </li></ul>Prostaglandins Prostaglandins    COX-2 selective NSAIDs Vane & Botting 1995
  11. 11. 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
  12. 12. Gastric acid plays a central role in NSAID-associated gastroduodenal damage Acidic environment Bicarbonate layer Ionic gradient Gastric acid NSAIDs Pepsin Surface epithelial cells Mucus layer Neutral environment Mucosal blood supply Alkaline environment Prostaglandin production Bicarbonate production Mucus production NSAIDs
  13. 13. NSAID-associated gastroduodenal damage is pH-dependent Elliott et al 1996 intraduodenal indomethacin, 40 mg/kg intraduodenal saline Total haemorrhagic mucosal area (%) Gastric luminal pH 0 2.0 4.0 5.5 7.0 1 2 3 4 5
  14. 14. Probability of NSAID-associated gastroduodenal damage is related to gastric acidity Plachetka et al 2003 0 20 40 60 80 Probability of no pathology (%) 100 5000 0 4000 3000 2000 1000 Integrated gastric acidity (mmol • hour/L)
  15. 15. Management
  16. 16. Algorithm for prevention of nonsteroidal antiinflammatory (NSAID)-related gastroduodenal toxicity NSAID use plus comorbid risks? NO YES <ul><li>Use lower-risk NSAIDs with minimal duration and dosage </li></ul><ul><li>Ask about surreptitious OTC NSAID and aspirin use </li></ul><ul><li>Treat known H. pylori infection, but routine testing not indicated </li></ul><ul><li>Assess cardiovascular risks </li></ul>Average Risk for Gastroduodenal Complication <ul><li>All average-risk measures plus strongly consider— </li></ul><ul><li>Assess for and treat H. pylori infection if present </li></ul><ul><li>Institute gastroprotection with misoprostol or a proton pump inhibitor </li></ul><ul><li>COX-2 selective agent if low cardiovascular risk </li></ul><ul><li>COX-2 selective agent + PPI in those with a history of GI bleeding (very high risk) </li></ul>High Risk for Gastroduodenal Complication Schlansky B and hwang JH . J Gastroenterol 2009; 44[Suppl XIX]:44–52
  17. 17. Managing NSAID-associated upper GI side-effects <ul><li>Options for therapy: </li></ul><ul><ul><li>dose reduction or switch to a less toxic NSAID </li></ul></ul><ul><ul><li>prostaglandin analogue to replace gastroprotective prostaglandins </li></ul></ul><ul><ul><li>H 2 -receptor antagonist or PPI to reduce the acidity of the stomach. </li></ul></ul><ul><li>Guidelines recommend that patients with at least one GI risk factor receive either a non-selective NSAID with a co-prescribed GI-supportive therapy or a COX-2 selective NSAID. </li></ul>American College 2002; Dubois 2004; NICE 2001
  18. 18. Methode to prevent peptic ulcer and mucosal injury in patients taking NSAID <ul><li>co-therapy with a PPI, high-dose (2 × ) H 2 RA, or the synthetic prostaglandin E1 analog, misoprostol </li></ul><ul><li>substitution of a COX-2 inhibitor for a traditional NSAID. </li></ul><ul><li>Although co-therapy with a standard-dose H 2 RA may prevent duodenal ulcers, it has not been shown to prevent NSAID-related gastric ulceration. </li></ul><ul><li>Enteric coating or buffering of NSAIDs and co-therapy with sucralfate have not been shown to be effective in preventing NSAID-related gastric or duodenal ulceration </li></ul>Lanza et al. Am J Gastroenterol 2009; 104:728 – 738
  19. 19. PPIs control acid secretion by directly inhibiting the proton pump Inhibition of acid secretion Parietal cell Canalicular space Proton pump Inhibition of proton pump Activation Concentration PPI (inactive) Gastric gland H + Blood
  20. 20. H 2 -receptor antagonists inhibit signal transduction to the proton pump H + Acid secretion Signal transduction to activate proton pump Parietal cell Histamine receptor Histamine receptor antagonist Histamine Inhibition of histamine receptor Gastric gland Blood Proton pump
  21. 21. PPIs, H 2 -receptor antagonists and prostaglandin analogues in treating NSAID-associated heartburn Hawkey et al 1998; Yeomans et al 1998; Wilson et al 2001 0 7 14 21 28 Patients with heartburn (%) 60 40 20 0 misoprostol, 200 µ g four times daily omeprazole, 20 mg once daily 60 40 20 0 0 7 14 21 28 Duration of treatment (days) Patients with heartburn (%) ranitidine, 150 mg twice daily omeprazole, 20 mg once daily Duration of treatment (days)
  22. 22. PPIs, H 2 -receptor antagonists and prostaglandin analogues in ulcer healing Hawkey et al 1998; Yeomans et al 1998 – 40 – 30 – 20 – 10 0 10 20 30 40 Omeprazole, 20 mg once daily Omeprazole, 40 mg once daily Omeprazole, 20 mg once daily Ranitidine, 150 mg twice daily Omeprazole, 20 mg once daily Misoprostol, 200 µg four times daily Therapeutic gain (%) for the first-named drug (95% CI)
  23. 23. Acid suppressor vs Cytoprotector Misoprostol is as effective as PPI
  24. 24. More adverse event shown in Misoprostol vs PPI
  25. 25. Esomeprazole treatment provides significantly greater gastric acid suppression than other PPI 0 4 8 12 16 20 24 p=0.0003 p=0.0001 Esomeprazole 40 mg Pantoprazole 40 mg Lansoprazole 30 mg Time with 24 hour intragastric pH above 4 3-way crossover study, Day 5 data, patients NSAID treatment (include COX-2 selective) hours Goldstein et al. Aliment Pharmacol Ther 2006; 23, 1189–1196 17.8 15.9 14.6 n=90
  26. 26. Esomeprazole - fast and effective healing of gastric ulcers in patients taking NSAIDs, including COX-2 selective NSAIDs * 79.0 Patients healed at 4 weeks % * p <0.05 vs ranitidine ** p<0.01 vs ranitidine Chi-squared test Ranitidine 150 mg twice daily esomeprazole 20 mg once daily 0 20 40 60 80 100 Goldstein et al. Am J Gastroenterol 2005;100:2650 - 2657 66.7
  27. 27. Esomeprazole – first PPI proven to be effective in preventing ulcers in at risk patients taking NSAIDs, including COX-2 selective NSAIDs (PLUTO study, life table analysis) COX-2 selective Patients in group Cumulative proportion of patients with gastric and/or duodenal ulcers at 6 months % Non-selective Total 35 19.1 24 0 150 10.6 168 5.9 185 12.3 192 5.2 Scheiman et al. Am J Gastroenterol 2006;101:701–710) Placebo Esomeprazole 20 mg once daily p<0.05 vs. placebo Log-rank test * * * 0 5 10 15 20
  28. 28. Summary <ul><li>Current management approach of adding PPIs to reduce NSAIDs’ ulcer risks is an effective approach </li></ul><ul><li>Esomeprazole proven to be more effective for healing and preventing gastric ulcer in patients with NSAID (incl COX-2 selective than other PPI) </li></ul>