1. Update of TARGET ( T reatment a nd R elief of G astroint e s t inal disorder) DR NORITA YASMIN MORNING READ 19/9/13 1

2. Journal of Digestive Diseases 2013; 14; 1–10 The Use Of Antiplatelet Therapy And Proton Pump Inhibitors In The Prevention Of Gastrointestinal Bleeding STATEMENTS OF THE MALAYSIAN SOCIETY OF GASTROENTEROLOGY & HEPATOLOGY (MSGH) AND THE NATIONAL HEART ASSOCIATION OF MALAYSIA (NHAM) TASK FORCE 2012 WORKING PARTY 2

3. Outline 1. Antiplatelet drugs increase the risk of GI bleeding 2. PPIs are superior to H 2 -receptor antagonists (H 2 RAs) in primary and secondary prevention of aspirin induced ulcer 3. Helicobacter pylori (H. pylori) detection and eradication is recommended for high GI risk patients before commencing long-term aspirin 4. Continuing PPIs after H. pylori eradication is superior to H. pylori eradication alone in preventing recurrent ulcer bleeding in patients on aspirin 5. In patients with previous upper GI bleeding, PPIs should be added to antiplatelet therapy to prevent recurrent ulcer bleeding 6. Patients with a high risk for GI bleeding requiring antiplatelet therapy should be on long-term PPIs Journal of Digestive Diseases 2013 ; 14; 1–10 3

4. 1. Antiplatelet drugs increase the risk of GI bleeding 4

5.  A meta-analysis of 18 trials involving 129 314 patients evaluated the bleeding risk of antiplatelet therapy.  Not surprisingly, patients on dual antiplatelet therapy were associated with an increased risk of major (RR 1.47, 95% CI 1.36–1.60) and minor bleeding (RR 1.56, 95% CI 1.47–1.66).  These patients have a 40–50% increase in risk of major and minor bleeding. Serebruary et al, 2008 5

6. Anti platelet and risk of GI bleeding Journal of Digestive Diseases 2013 ; 14; 1–10 6

7. Risks of GIT bleeding  Prior history of GI bleeding  Concomitant NSAIDs  Concomitant COX-2 inhibitors  Concomitant anticoagulants  Concomitant clopidogrel  Concomitant corticosteroids  Helicobacter pylori infection  Age >65 years  Short-term NSAIDs Journal of Digestive Diseases 2013 ; 14; 1–10 7

8. 2. PPIs are superior to H 2 -receptor antagonists (H 2 RAs) in primary and secondary prevention of aspirin induced ulcer 8

9. Primary prevention  Patients who has no previous peptic ulcer at baseline  H 2 RAs have been shown to be effective as primary prevention for aspirin-induced peptic ulcer disease in average-risk patients  PPIs have also been shown to be effective as primary prevention for aspirin-induced ulcer. Journal of Digestive Diseases 2013 ; 14; 1–10 9

10. Primary prevention of aspirin-induced ulcer TypeH2RAPPI StudyTaha et al, Lancet 2009Yeomans et al, Am J GE 2008 Duration used12 weeks26 weeks MedicationFamotidine vs placeboEsomeprazole vs placebo Gastric ulcer3.4% vs 15% 1.6% vs 5.4% Duodenal ulcer0.5% vs 8.5% Erosive esophagitis4.4% vs 19% 4.4% vs 18.3% Journal of Digestive Diseases 2013 ; 14; 1–10 10

11. Primary prevention of PUD in multiple anti platelet therapies  PPIs were found to be superior to H2RAs in the primary prevention of peptic ulcer disease, especially in those treated with multiple antiplatelet therapies  Ng et al conducted an RCT comparing the efficacy of famotidine and esomeprazole in preventing GI complications in patients with ACS or ST-elevation MI receiving aspirin, clopidogrel and enoxaparin or thrombolysis. Journal of Digestive Diseases 2013 ; 14; 1–10 11

12. Primary prevention for multiple anti platelet therapies TypeFamotidine (H2RA)Esomeprazole (PPI) UGIB6.1%0.6% Risk of UGIB (OR)0.43 (marginal)O.04 (significant) Journal of Digestive Diseases 2013 ; 14; 1–10 12 More effective

13. Secondary ulcer prevention  For secondary prevention of aspirin-induced peptic ulcer disease, PPIs again have been shown to be superior to H2RAs Journal of Digestive Diseases 2013 ; 14; 1–10 13

14. Prevention aspirin-related PUD TypeH2RAPPI Barthan et al: MedicationRanitidineLansoprazole Treatment DU for 8/52 1)Healing rate 2)Symptoms relief 89% Less rapid 98% (P <0.001) More rapid Maintenance treatment for 12/12 1) relapse150mg: 21%30mg: 5% 15mg: 12% Ng et al Medi Journal of Digestive Diseases 2013 ; 14; 1–10 14 More effective

15. Prevent recurrent aspirin- related PUD/dyspepsia TypeH2RAPPI Ng et al: MedicationsHigh dose famotidinePantoprazole PUD bleeding7.7%0% Recurrent dyspepsia12.3%0% Journal of Digestive Diseases 2013 ; 14; 1–10 15 More effective

16. 16 3. Helicobacter pylori (H. pylori) detection and eradication is recommended for high GI risk patients before commencing long-term aspirin 4. Continuing PPIs after H. pylori eradication is superior to H. pylori eradication alone in preventing recurrent ulcer bleeding in patients on aspirin

17. Risks of GIT bleeding  Prior history of GI bleeding  Concomitant NSAIDs  Concomitant COX-2 inhibitors  Concomitant anticoagulants  Concomitant clopidogrel  Concomitant corticosteroids  Helicobacter pylori infection  Age >65 years  Short-term NSAIDs Journal of Digestive Diseases 2013 ; 14; 1–10 17

18. H. Pylori eradication PPI H.Pylori eradication Aspirin/ NSAIDs Journal of Digestive Diseases 2013 ; 14; 1–10 18

19. Obviously, > risk factors a patient  higher the risk of upper GI bleeding. By identifying and eliminating the risk factors the risk of GI bleeding could be minimized. Journal of Digestive Diseases 2013 ; 14; 1–10 19

20. H. Pylori eradication TypeEradicationMaintenance therapy PPI Probability of rec bleeding in 6/12 1.9%0.9% (P > 0.05) Journal of Digestive Diseases 2013 ; 14; 1–10 20 Chan et al: effectiveness of eradication = maintenance PPI in patients with history of upper GI bleeding who were taking aspirin.

21. Meta analysis TypeEradicationShort term anti- secretory Rx (non erad) NNT Rec ulcer bleeding 4.5%23.7% (OR 0.18) 5 Journal of Digestive Diseases 2013 ; 14; 1–10 21 vs TypeEradicationMaintenance anti-secretory Rx NNT Re-bleeding1.6%5.6% (OR 0.25) 20 Anti secretory: PPI, H2RA, antacid

22. Conclusion from meta analysis  Treatment of H. pylori infection is more effective than antisecretory non-eradicating therapy (with or without long-term maintenance antisecretory therapy) in preventing recurrent bleeding from peptic ulcer.  Consequently, all patients with peptic ulcer bleeding should be tested for H. pylori infection, and eradication therapy should be prescribed to H. pylori- positive patients. Cochrane Database Syst Rev. 2004;(2):CD004062 22

23. H.Pylori eradication + maintenance PPI In patients with aspirin-induced ulcer, treatment with PPIs following successful H. pylori eradication significantly reduces the risk of recurrent ulcer complications. Journal of Digestive Diseases 2013 ; 14; 1–10 23 TypeLansoprazolePlacebo Recurrence rate @ 12/12 1.6%14%

24. Conclusion Worth detecting and eradicating H. pylori infection in patients followed by PPIs maintenance in high GI bleeding risk patients who require long-term Aspirin, although long term data is lacking Journal of Digestive Diseases 2013 ; 14; 1–10 24

25. BMJ 2013: Global eradication rates for Helicobacter pylori infection: systematic review and meta-analysis  Sequential therapy is superior to seven day triple therapy and similar to regimens of longer duration or including more than two antimicrobial agents. BMJ 2013 25

26. UKM guideline: sequential therapy for 10 days MedicationsRegime 1Regime 2 First 5 days (pack 1)Pantoprazole 40mg BD Amoxicillin 1g BD Esomeprazole 20mg BD Amoxicillin 1g BD Subsq. 5 days (pack 2)Pantoprazole 40mg BD Clarithromycin 500mg BD Metronidazole 400mg BD Esomeprazole 20mg BD Clarithromycin 500mg BD Metronidazole 400mg BD 26

27. 5. In patients with previous upper GI bleeding, PPIs should be added to antiplatelet therapy to prevent recurrent ulcer bleeding 27

28. Previous vs recent anti platelet recommendation Patients who have previous upper GI bleeding from any cause are at a higher risk of recurrence.  For patients with aspirin-induced peptic ulcer bleeding and who need to continue with antiplatelet therapy, the initial recommendation was to prescribe clopidogrel to replace aspirin for the prevention of recurrent peptic ulcer. Journal of Digestive Diseases 2013 ; 14; 1–10 28

29.  However, subsequent studies have confirmed that adding PPIs to aspirin was a better approach than replacing aspirin with clopidogrel to prevent recurrent peptic ulcer complications. multiple ulcer complications Journal of Digestive Diseases 2013 ; 14; 1–10 29 Study

30. 6. Patients with a high risk for GI bleeding requiring antiplatelet therapy should be on long-term PPIs 30

31. Risks of GIT bleeding  Prior history of GI bleeding  Concomitant NSAIDs  Concomitant COX-2 inhibitors  Concomitant anticoagulants  Concomitant clopidogrel  Concomitant corticosteroids  Helicobacter pylori infection  Age >65 years  Short-term NSAIDs Journal of Digestive Diseases 2013 ; 14; 1–10 31

32. Primary prophylaxis for average risk  Primary prophylaxis for GI bleeding is not necessary for patients with average GI bleeding risk commencing aspirin.  In average risk patients starting aspirin therapy, the risk of major upper GI bleeding is increased 1.5 to 3.2 fold and the absolute rate is increased by 0.12% per year. The number needed to harm (NNH) at one year was 833. Journal of Digestive Diseases 2013 ; 14; 1–10 32

33. Primary prevention for high risk  In patients at high risk of GI bleeding but who have not bled in the past, PPI should be added if they require antiplatelet therapy RCT on dual antiplatelet and risk of GI event Journal of Digestive Diseases 2013 ; 14; 1–10 33 TypeOmeprazolePlacebo Risk of GI event1.1%2.9% ( P< 0.001)

34. Take home message 1. Antiplatelet drugs increase the risk of GI bleeding 2. PPIs are superior to H 2 -receptor antagonists (H 2 RAs) in primary and secondary prevention of aspirin induced ulcer 3. Helicobacter pylori ( H. pylori ) detection and eradication is recommended for high GI risk patients before commencing long-term aspirin 4. Continuing PPIs after H. pylori eradication is superior to H. pylori eradication alone in preventing recurrent ulcer bleeding in patients on aspirin 5. In patients with previous upper GI bleeding, PPIs should be added to antiplatelet therapy to prevent recurrent ulcer bleeding 6. Patients with a high risk for GI bleeding requiring antiplatelet therapy should be on long-term PPIs Journal of Digestive Diseases 2013 ; 14; 1–10 34

35. Thank you for your kind attention 35