This document discusses the gastrointestinal (GI) and cardiovascular (CV) risks associated with nonsteroidal anti-inflammatory drug (NSAID) use. It outlines the mechanisms by which NSAIDs can cause GI adverse effects like gastric ulcers and bleeding. It also notes that NSAIDs are associated with increased CV risks. The document recommends prevention strategies for NSAID use based on assessing individual patient's GI and CV risk factors.

1. Practical Approach in Managing NSAID Risks: GI and CV Prof. Chutima Pramoolsinsap Division of Gastroenterology and Tropical Medicine Ramathibodi Hospital 1 st Emergency Medicine Update 2550 สมาคมเวชศาสตร์ฉุกเฉินแห่งประเทศไทย 1 September 2007

4. Major Diseases Attributable to Disability-Adjusted Life Years (DALYs) Lost of Thai People by Sex, 2002 Bureau of Policy and Strategy. Burden of Disease and Injuries in Thailand, 2002

5. Death and Injury Rates from Road Traffic Accidents, Thailand, 1984-2002 Police Information System Centre, Royal Thai Police.

7. Proportion of Thai elders with most common diseases/symptoms by age group,2002 Surveys on Elderly People in Thailand 2002, National Statistical Office. Age (yrs) 17.7 22.3 27.5 34.4 34.1 42.8 72.7 60-64 20.3 26.5 31.1 35.6 38.1 46.7 74.7 65-69 21.9 33.2 37.3 38.7 42.0 49.8 77.8 70-74 21.6 20.0 Hyper/ hypotension 45.2 29.8 Dementia 42.8 33.2 Eye diseases 41.2 36.8 Vertigo 44.9 38.7 Insomnia 54.9 47.5 Joint pain (degeneration) 77.3 75.1 Body ache, backache > 75 Total Disease/Symptom of Thai Elders

9. Willow leaf extracts for musculoskeletal conditions Aspirin first synthesised NSAIDs – a Long History of Analgesia and Toxicity 4 00 B.C. Greek physician 1899 1938 1950 1970 1982 1992 1998 Hippocrates Non-selective NSAIDs identified and developed. COX-2 selective NSAIDs discovered First COX-2 selective NSAIDs approved first endoscopic evidence that aspirin caused gastric mucosal damage. Lancet 1938;ii:1222­5 M echanism of action for aspirin

11. The 9 chemical groupings of NSAIDs http://www.fda.gov/cder/drug/infopage/COX2/NSAIDmedguide.htm

12. Range of COX-1 and COX-2 selectivity of NSAIDs COX = cyclooxy-genase; IC50 = concentration of NSAID that inhibits COX by 50%,

14. Gastrointestinal adverse effects and NSAIDs

16. 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 normal gastric mucosa 16 minutes after administration of aspirin Direct effect

17. 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 Systemic effect

18. NSAIDs increase neutrophil – endothelial adhesion NSAIDs Decreased prostaglandin, increased tumour necrosis factor Increased neutrophil– endothelial adhesion Ischaemic/hypoxic cell injury Endothelial and epithelial injury Mucosal ulceration Wallace et al 1997 Neutrophil release of proteases and oxygen-derived free radicals Capillary obstruction

20. NSAID ingestion and GI injury JIACM 2003; 4(4): 315-22

21. GI symptoms Endoscopic ulcers Clinical ulcers Serious GI events Relative severity Relative frequency NSAID-related GI Effects

23. MUCOSA CLASS VIGOR TARGET (N=4439) (N=3981) (N=4029) (N=9127) Arthritis RA OA(73%); RA OA RA (27%) NSAID (N) 10 specified Ibuprofen naproxen Ibuprofen NSAIDs diclofenac naproxen Low-dose aspirin Not stated 20% 0 24% Median follow-up 6 mo 9 mo 9 mo 12 mo Upper GI complications 1.5% 1.0% 1.4% 1.3% (annualized incidence) Upper GI clinical events 2.7% 2.8% 4.5% 2.8% (annualized incidence) Incidences of Upper GI Complications and Clinical Events (Complications plus Symptomatic Ulcers) From NSAID-only Arms of GI Outcome Studies J Cardiovasc Pharmacol 2006; 47(1):S60-6

24. Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) Trial Life-threatening or major bleeding 0 1 2 3 4 5 % of patients By aspirin dose, n=6293 <100 mg 1.9 n=990 100–150 mg 2.2 n=2857 151–300 mg 3.3 n=1385 >300 mg n=1061 3.8 Eur Heart J 2002;4:Suppl, 510

25. CURE: Aspirin plus clopidogrel All bleeding episodes 1.9 2.3 3.9 3.0 3.2 5.0 0 1 2 3 4 5  100 mg 110–162 mg  200 mg % of patients n=5259 n=3115 n=4172 Aspirin Clopidogrel + aspirin p < 0.001 Eur Heart J 2002;4:Suppl, 510

27. Risk of Hospitalization for Upper GI Bleeding with COXIBs 3.0 4.0 1.9 1 2 3 4 5 6 7 Adjusted Rate Ratio 0 Non-use celecoxib rofecoxib diclo+miso NSAIDs Mamdani et al. BMJ 2002;325(7365):624-7 1.0 1.0 >55% women Mean age >75 yrs >1% with Hx of GI bleed >16% Use of gastroprotective agent >12% Use of aspirin 100,000 (2.2)* 18,908 (3.6)* 14,583 (7.3)* 5,087 (9.6)* 5,391 (12.6)* *n (no. upper GI bleeds per 1000 person-yrs)

28. Risk Factors for NSAID-Induced Gastropathy Definite: • Age • Prior history of ulcer • Duration of NSAID therapy • Concomitant corticosteroid therapy • Concomitant warfarin therapy • Concomitant ASA / NSAID • NSAID dose • Serious systemic illness (CHF, RA, CAD, others) Possible: • Concomitant H. Pylori infection? • Smoking • Alcohol

29. Risk Factors for NSAID-Associate d GI Complications NSAIDs, nonsteroidal antiinflammatory drugs; SSRIs, selective serotonin reuptake inhibitors. Dalton SO, et al. Arch Intern Med. 2003;163:59–64. Gabriel SE, et al. Ann Intern Med. 1991;115:787–796; Garcia Rodriguez LA, et al. Lancet. 1994;343:769–772. Silverstein FE, et al. Ann Intern Med. 1995;123:241–249.

30. Distribution of Patients with GI Complications From NSAIDs by Age and Sex Am J Gastroenterol 2005;100:1685–93

31. Risk of UGI Complication for NSAID Users Impact of Ulcer History 20-60 60-69 70-79 >=80 Men complic ulcer +NSAID Men ulcer + NSAIDs Men No ulcer +NSAIDs Incidence per 1,000 person-years Based on Hemandez & Garcia-Rodriguez, BMC Medicine 2006;4:22.

32. Rates of symptomatic ulcers and ulcer complications with naproxen in patients with rheumatoid arthritis Bombadlar C et al. N Engl J Med 343;1520-8(2000): Lenas A. Gastroenterol Gastro 2007. Number events x 100 patient-years No NSAID use <65 65-74 >74 Ulcer Hx Ulcer complications >65+Hx Ulcer >65+Hx Ulcer+sterolds Age

33. Annualized Incidence % Ulcer Complications Symptomatic Ulcers and Ulcer Complications 49 / 1384 30 / 1441 11 / 1441 20 / 1384 p = 0.02 p = 0.09 All Patients 32 / 1101 16 / 1143 5 / 1143 14 / 1101 p = 0.02 p = 0.04 Patients Not Taking Aspirin 17 / 283 14/ 298 6 / 298 6 / 283 p = 0.49 p = 0.92 Patients Taking Aspirin CLASS Trial: Upper GI Complications Alone and With Symptomatic Ulcers Silverstein et al. JAMA 2000; 284:1247-1255 = celecoxib = NSAIDs (ibuprofen + diclofenac)

34. Low-dose aspirin excluded

35. Cumulative Incidence (%) *P<0.001 vs placebo and vs aspirin ROF = Rofecoxib Gastroduodenal ulcers at 12 weeks in patients with OA Aspirin Negates the GI-sparing Effect of COX-2 Inhibitors Gastroenterology 2004; 127: 395-402. * * N=381 N=387 N=377 N=374 %

36. Low-Dose Aspirin Combined with NSAID or Coxib Drug R.R 95% CI Aspirin only 3.6 2.9-4.3 NSAID only 5.0 4.3-5.9 Combined 10.2 6.2-16.7 Aspirin only 3.3 2.8-4.0 Coxib only 1.1 0.7-1.9 Combined 9.5 2.5-36.2 Lanas et al. Gut 2006

37. Risk of UGI Complication for NSAID Users Impact of ASA use 20-60 60-69 70-79 >=80 Incidence per 1,000 person-years Based on Hermandez & Garcla-Rodriguez. BMC Medicine 2006;4:22

38. Non-aspirin antiplatelet agents combined with NSAIDs Drug R.R 95% CI Aspirin only 3.6 2.9-4.3 NSAID only 5.0 4.3-5.9 Combined 10.2 6.2-16.7 Clopidogrel/Ticlid only 3.1 2.2-4.4 NSAID only 5.0 4.3-5.8 Combined 15.5 4.7-50.4 Lanas et al. Gut 2006

39. NSAID-Induced Small Bowel Lesions Endoscopic photograph of terminal ileum, demonstrating inflamed diaphragm in patient receiving long-term NSAIDs

43. Mortality Rate Attributed to NSAID/Aspirin-Associated GI Complications Am J Gastroenterol 2005;100:1685–93 Mortality rate per 1 million people Entire country population NSAID/aspirin users

44. Cardiovascular Risks Associated With COX-2–Selective Inhibitors and Nonselective NSAIDs

46. NSAID Effects on Thromboxane and Prostacylin

47. Serious Thromboembolic Cardiovascular Adverse Events in Nonaspirin Users 1. Silverstein FE, et al. JAMA. 2000;284:1247–1255. 2. Bombardier C, et al. N Engl J Med. 2000;343:1520–1528.

48. APPROVe Trial: Confirmed Thrombotic Cardiovascular Events Over Time Bresalier RS, et al. N Engl J Med. 2005; 352: 1092-1102 . September 2004 , Vioxx (rofecoxib) withdrawal from worldwide market

49. April 7, 2005 , Bextra (valdecoxib) withdrawal Parecoxib/Valdecoxib: Cardiovascular Complications After Cardiac Surgery

50. Cardiovascular Risks in NSAID Users This black box warning statement now appears in the package insert (July 2005) for celecoxib

51. Black box warning for COX-2–selective drugs. This black box warning statement now appears in the package insert (July 2005 ) for celecoxib

52. APC Trial: Concomitant Aspirin Use Does Not Decrease Cardiovascular Risk of COX-2 Selective Inhibitors

53. MEDAL Program: Confirmed Thrombotic Cardiovascular Events Over Time Cannon CP, et al; MEDAL Steering Committee. Lancet. 2006;368:1771–1781.

54. BMJ 2006;332;1302-1308 Comparison of effects of different selective COX 2 inhibitors versus myocardial infarction

55. BMJ 2006;332;1302-1308 Comparison of effects of different selective COX 2 inhibitors versus placebo on stroke

56. Comparison of effects of different selective COX2 inhibitors versus placebo on vascular death. BMJ 2006;332;1302-1308

57. Is conventional NSAIDs safe for cardiovascular events?

58. Acute Myocardial Infarction NSAID Use: Case-Control Study of MediCal* FDA Advisory Committee Meeting. Rockville, MD; February 17, 2005. Singh G, et al. Ann Rheum Dis , 2005: 64 (Suppl 3 ) : 263.

62. Black box warning for &quot;traditional&quot; NSAID group This example is from the package insert (January 2006 ) of diclofenac,

63. Comparison of effects of selective COX - 2 inhibitors versus traditional NSAIDs on myocardial infarction, BMJ 2006;332;1302-1308

64. BMJ 2006;332;1302-1308 Comparison of effects of selective COX - 2 inhibitors versus traditional NSAIDs on stroke

65. BMJ 2006;332;1302-1308 Comparison of effects of selective COX - 2 inhibitors versus traditional NSAIDs on vascular death.

67. Protective Strategies in Preventing NSAIDs-induced Ulcers and Ulcer Complications

74. Risk of adverse upper G.I. events associated with NSAIDs according to use of ulcer healing drugs. UK study: 9407 incident cases and 88,867 matched controls. BMJ 2005;331;1310-1316 Values are adjusted odds ratios* Not prescribed Prescribed Drug prescribed < 90 ulcer healing ulcer healing Interaction ratio ‡ P value for Days before index drugs in past drugs in past (95% Cl) interaction date † 90 days 90 days Celecoxib 1.44 1.06 0.73 (0.46 to 1.16) 0.18 Rofecoxib 2.33 1.06 0.45 (0.32 to 0.65) <0.001 Other selective 2.40 1.29 0.54 (0.36 to 0.81) <0.001 NSAIDs Ibuprofen 1.65 0.90 0.55 (0.43 to 0.70) <0.001 Diclofenac 2.17 1.49 0.69 (0.56 to 0.84) <0.001 Naproxen 2.73 0.83 0.31 (0.19 to 0.49) <0.001 Other non selective 2.03 1.16 0.57 (0.42 to 0.77) <0.001 NSAIDs Aspirin 1.87 0.81 0.43 (0.38 to 0.49) <0.001

76. Prevention of NSAID-induced ulcer Endoscopic remission rates for patients with endoscopically normal or hyperaemic gastric mucosa at baseline [a subset of patients with grade 0 of Lanza classification, who were treated with either pantoprazole 40 mg od or placebo for up to 12 weeks 0 4 8 12 P=0.036 92% 82% 75% 55% BIanchi Parro G, et a. Digest Liver Dis 2000 Endoscopic remission rate (%) Time (wks)

77. Efficacy of pantoprazole in the primary prevention of NSAID-induced gastroduodenal damage Patient population Treatment Treatment n Remission rate (%) duration Rheumatic 6 months Pantoprazole 20 mg od 257 89 disease; Continuous NSAID; Misoprostol 200 mg bid 258 70 high risk (p<0.001) Rheumatic 6 months Pantoprazole 20 mg od 196 90 Disease; Continuous NSAID; Pantoprazole 40 mg od 199 93 high risk Omeprazole 20 mg o.d. 200 89 (NS) SINGH, G. Int J Clin Pract 2005

84. Effect of PPIs,H2-RA and nitrates on the RR of ulcer bleeding in patients taking Low-dose ASA or Clopidogrel 0 0.5 1 2 3 4 5 6 7 8 9 10 27 Adjusted RR (95% IC) Low dose ASA 3.6 +PPI 0.32 +H2-RA 0.40 +Nitrate 0.69 Clopidogrel 3.1 +PPI 0.19 +H2-RA 0.83 +Nitrate 0.88 Lanas et al. AJG 2007

85. PPI plus COX-2 inhibitor Ulcer incidence at 6 months by NSAID type ** P <.01, *** P <.001, **** P <.0001 vs . placebo. ** *** *** **** 134 141 125 318 326 334 n= Scheiman et al. DDW 2004

86. Coxibs versus standard-NSAIDs : Effect on serious upper GI events Adjusted relative risk (95% IC) 0 0.5 1 2 3 4 5 Type of event 51% reduction Symptomatic 0.49 (0.38-0.62) Ulcers Upper GI 45% reduction Complications 0.55 (0.38-0.80) Hooper L et al. BMJ 320:948-58 (2004)

87. M anagement of UGIB from NSAID-induced Ulcers

90. High risk Low risk Pharmacologic therapy Endoscopy feasible Yes Endoscopic Hemostasis Success No Consult surgeon or refer Fail Antisecretory therapy Refer Guideline of UGIB Management Endoscopy available Yes No Others Variceal bleeding Ulcer bleeding Pharmacological therapy and monitoring Rebleed Re-endoscopy Fail

91. Endoscopic Stigmata of Ulcer Hemorrhage Active arterial bleeding Visible Vessel Adherent clot Flat spot Clean base ulcer

92. Endoscopic Stigmata of Ulcer Hemorrhage: Prevalence, Risks of R ebleeding and Reduced Risk of Rebleeding following Endoscopic Therapy Endoscopy 1997; 29 : 827-33 Not available 3 32 Clean base ulcer Not available 7 10 Flat spot Not available 10 14 Oozong without stigmata 5 33 10 Adherent clot 15-30 50 22 Visible Vessel 15-30 90 12 Active arterial bleeding Rebleed Rate with Endoscopic treatment (%) Rebleed Rate Prevalence (%) Endoscopic Appearance

93. High risk Low risk Pharmacologic therapy Endoscopy feasible Yes Endoscopic Hemostasis Success No Consult surgeon or refer Fail Antisecretory therapy Refer Guideline of UGIB Management Endoscopy available Yes No Others Variceal bleeding Ulcer bleeding Pharmacological therapy and monitoring Rebleed Re-endoscopy Fail

95. High risk Low risk Pharmacologic therapy Endoscopy feasible Yes Endoscopic Hemostasis Success No Consult surgeon or refer Fail Antisecretory therapy Refer Guideline of UGIB Management Endoscopy available Yes No Others Variceal bleeding Ulcer bleeding Pharmacological therapy and monitoring Rebleed Re-endoscopy Fail

97. Brunner, et al. Aliment Pharmacol Ther 1995 Omeprazole 80 mg loading dose+ 40 mg q. 8 hours Omeprazole 80 mg loading dose + CI 4 mg/ hour Effective PPI Dosage & Administration Intermittent Bolus V.S. Continuous Infusion

98. 0 8 6 4 2 0 8 16 24 32 40 48 Median Intragastric pH Time [h] Van Rensburg, et al. Gastroenterology 1997. (Abstract) 80 mg bolus then 8 mg/hour n = 14; median pH 6.3, 68% range IV Pantoprazole In Patients With UGI B After Endoscopic Hemostasis

100. High risk Low risk Pharmacologic therapy Endoscopy feasible Yes Endoscopic Hemostasis Success No Consult surgeon or refer Fail Antisecretory therapy Refer Guideline of UGIB Management Endoscopy available Yes No Others Variceal bleeding Ulcer bleeding Pharmacological therapy and monitoring Rebleed Re-endoscopy Fail

102. H . pylori and NSAIDs

103. H.pylori , NSAID Use and the Risk of PU Bleeding Prevalence (%) PU bleeding + - + - + - OR 1.79 95% CI; 0.97-3.32 OR 4.85 95% CI; 3.77-6.23 OR 6.13 95% CI; 3.93-9.56 Lancet 2002 HP+ NSAID uses HP+ NSAID use HP- No NSAID H pylori and NSAIDs independently and significantly increase risk of PU bleeding

106. Summary Practical Approach in Managing NSAID Risks: GI and CV

115. NSAID required? High risk Low risk - No prophylaxis -Monitor clinical signs and symptoms -Use non-NSAIDs analgesic -Use low dose, short acting NSAIDs -Limit duration of therapy -Avoid using combination of NSAIDs -Avoid to combine with corticosteriod or anticoagulant Risk assessment for NSAID-induced ulcer -Cotherapy with Gastroprotective drugs -Selective COX-2 inhibitors Yes

117. Thank you