1. RISKS of NSAIDS: Focus on GI Risks of Over-the-Counter NSAIDs Byron Cryer, M.D. University of Texas Southwestern Medical School

2. List of Available NSAIDs: Prescription & OTC * NON-SALICYLATES SALICYLATES COX-2 INHIBITORS Diclofenac (Voltaren) Aspirin a,c (Zorprin, Easprin) Celecoxib (Celebrex) Diclofenac/Misoprostol (Arthrotec)Diflunisal (Dolobid) Rofecoxib (Vioxx) Etodolac (Lodine)Salsalate (Disalcid, Salflex) Valdecoxib (Bextra) Fenoprofen (Nalfon)Choline salicylate (Trilisate) Flurbiprofen (Ansaid)Magnesium salicylate (Magan) Ibuprofen a,b,c (Motrin, Advil) Indomethacin (Indocin) Ketoprofen a,b,c (Orudis) Ketorolac (Toradol) c Meclofenamate Mefenamic acid (Ponstel) Meloxicam (Mobic) Nabumetone (Relafen) Naproxen a,b,c (Naprosyn, Anaprox) Oxaprozin (Daypro) Piroxicam (Feldene) Sulindac (Clinoril) Tolmetin (Tolectin) a Also available as OTC preparations in U.S. b OTC dose is usually half of prescribed dose C All OTC NSAIDs are non-selective COX Inhibitors * List of trade names is not exhaustive Comments on Over-the-Counter Preparations:

3. NSAIDs: What Are the Risks? Prescription & OTC GI Tract  Ulcers, perforations, bleeding, obstruction strictures, enteropathy Kidney  Sodium and fluid retention  Hyperkalemia  Acute renal failure  Hypertension Platelet  Inhibition of aggregation leading to increased potential for bleeding

4. Peptic Ulcer Hospitalization Rates Kurata JH. Semin Gastrointest Dis 1993:4 Rate per per100,000 Gastric Ulcer Duodenal Ulcer 7075808590 0 20 40 60 80 100 Uncomplicated Hemorrhage Hemorrhage Perforation 7075808590 0 20 40 Year Year 30 10 Uncomplicated Hemorrhage Hemorrhage Perforation

5. Endoscopic Photograph of Gastropathy

6. Endoscopic Photograph of Gastric Ulcer

7. Prevalence of Endoscopic NSAID-Induced Ulceration MeanRange Gastric Ulcer 15 %10 to 30% Duodenal Ulcer 5 % 4 to 10 % Clinically Significant Ulcers 2% 1 to 4% MeanRange Gastric Ulcer 15 %10 to 30% Duodenal Ulcer 5 % 4 to 10 % Clinically Significant Ulcers 2% 1 to 4%

8. Risk Factors for Serious GI Adverse Events with NSAIDs: Relative Risks Rodriguez. Lancet. 1994; Guttham. Epidemiology. 1997; Shorr. Arch Intern Med. 1993; Piper. Ann Intern Med. 1991. 051015 4.4 (2.0-9.7) 12.7 (6.3-25.7) 2.9 (2.2-3.8) 5.8 (4.0-8.6) 5.6 (4.6-6.9) 3.1 (2.5-3.7) 1.6 (1.4-2.0) 13.5 (10.3-17.7) Corticosteroid use Anticoagulant use Low dose NSAID High dose NSAID Age 70-80 Age 60-69 Age 50-59 Prior bleed Relative Risk

9. OTC NSAIDs: What Are the GI Risks? OTC NSAIDS / Low-Dose Aspirin:  Non-Aspirin NSAIDs  Low Dose Aspirin  Non-Aspirin NSAIDs in combination with Low-Dose Aspirin  NSAIDs plus ETOH  Acetaminophen and Gastrointestinal Injury  Hepatotoxicity with NSAIDs

10. Prevalence of NSAID Use in Patients Presenting with Upper GI Bleeding Prevalence of NSAID Use in Patients Presenting with Upper GI Bleeding Patient History (n = 411) Wilcox et al; Arch Int Med 1994; 154:42 0 10 20 30 40 50 Prescribed OTC Non-AspirinNSAIDsAspirin Percent using NSAIDs 14 % 7 % 9 % 35 %

11. Prevalence of OTC Analgesic Use in Patients Presenting with GI Bleeding Percent of Use * * * UGI LGI * UGI = upper gastrointestinal; LGI = lower gastrointestinal * p < 0.05 Peura DA et al. Am J Gastroenterol. 1997;92:924-928

12. NSAID Dose and Relative Risk of Upper GI Complications Cases (n) Controls (n) Adjusted RR 95% CI NSAID dose Low/medium High 92 311 290 229 2.4 4.9 1.9-3.1 4.1-5.8 Garcia Rodriguez, Hernandez-Diaz. Epidemiology. 2001;12:570-576.

13. Prescription & OTC Risks of GI Bleeding with Analgesics: Prescription & OTC Blot WJ, Mclaughlin JK. J Epidemiol Biostat. 2000;5:137-142. AnalgesicCaseControlOdds Ratio95% CI AnalgesicCaseControlOdds Ratio95% CI n=627n=590(OR) OTC use of:% Aspirin27.012.02.71.9-3.8 Ibuprofen10.15.82.41.5-3.9 Acetaminophen4.56.30.90.5-1.6 Total OTC NSAIDs36.217.53.02.2-4.1 Rx NSAIDs9.35.92.11.2-3.4 Total NSAIDS42.922.03.12.3-4.1

14. GI Bleeding According to Dose of OTC Ibuprofen Use 0 1 2 3 4 <600 mg/d 600 to 1200 mg/d >1200 mg/d Odds Ratio Blot WJ, McLaughlin J. J Epidemiol Biostat. 2000;5:137-142. DOSE

15. OTC NSAID Usage Patterns (n=535 OTC NSAID Users) Fraction of Previous Month Respondents (%) < 50 9.0 < 50 9.0 50 – 75 11.8 50 – 75 11.8 Having Used OTC NSAIDs (%) > 75 79.2 > 75 79.2 Reason for Taking OTC NSAID Respondents (%)* Prevention of Cardiac Problems 43.2 Prevention of Cardiac Problems 43.2 Other 9.0 Other 9.0 Headache 12.3 Headache 12.3 Arthritis 24.5 Arthritis 24.5 General Aches & Pain 29.9 General Aches & Pain 29.9 *Total exceeds 100 because multiple responses were allowed Bloom BS et. al Am J Gastroenterol 2001 (abstract)DURATION

16. Relative Risk of GI Problems in the Previous 30 Days with OTC NSAIDS Gastrointestinal OTC NSAID (%) Nonusers (%) Relative (95% CI) Any GI Problem 105 (19.6) 101 (9.4) 2.1 (1.61-2.67) Users (n=535) (n=1,086) Risk Constipation34 (6.3) 16 (1.5) 4.5 (2.36-7.62) Stomach Cramps/Pain18 (3.4) 12 (1.1) 3.0 (1.45-6.17) Indigestion/Heartburn11 (2.0) 10 (0.9) 2.2 (0.94-5.14) Abdominal Bloating/Gas 7 (1.3) 7 (0.6) 2.0 (0.70-5.66) Diarrhea17 (3.2) 26 (2.4) 1.3 (0.71-2.38) Nausea/Vomiting 4 (0.7) 4 (0.4) 2.0 (0.50-7.95) GI Bleeding/Ulcer 3 (0.6) 3 (0.3) 2.0 (0.40-9.86) Other Complaints27 (5.0) 33 (3.1) 1.6 (0.99-2.69) Complaint Bloom BS et. Al Am J Gastroenterol 2001 (abstract) DURATION

17. Medications Taken in the Previous 30 Days for GI Problems by OTC NSAID Users Medications Used in OTC NSAID Controls P value Previous Month OTC GI Medication 24.3 10.3 0.001 Rx GI Medication 9.5 5.2 0.001 Users (n=535)(%) Users (n=535)(%) OTC and RX GI Medication 2.1 1.3 NS Bloom BS et. al Am J Gastroenterol 2001 (abstract) (n=1,068)(%) (n=1,068)(%)

18. OTC NSAIDs: What Are the GI Risks? OTC NSAIDS / Low-Dose Aspirin:  Non-Aspirin NSAIDs  Low Dose Aspirin  Non-Aspirin NSAIDs in combination with Low-Dose Aspirin  NSAIDs plus ETOH  Acetaminophen and Gastrointestinal Injury  Hepatotoxicity with NSAIDs

19. Odds Ratio of Upper GI Bleeding In Patients Taking NSAIDS FACTOR History of gastrointestinal bleeding History of ulcer Aspirin at any dose Nitrovasodilator Antisecretory medication Patients (N=317) 37 (11.7) 69 (21.8) 73 (23.0) (3.5) 11 (3.5) 29 (9.1) Controls (N=187) 6 (3.4) 18 (9.6) (5.9) 11 (5.9) 37 (19.8) Adjusted Odds Ratio (96% CI) 3.7 (1.2-1.1) 1.8 (0.9-3.6) 3.1 (1.7-5.9) 0.3 (0.1-0.9) 0.4 (0.2-0.7) PValue 0.01 0.09 <0.001 0.04 0.001 Number (%) Lanas A.,. N Engl J Med 2000; 343:834-839 Lanas A., et al. N Engl J Med 2000; 343:834-839

20. Prior Placebo-Controlled Study of Low Dose ASA for Prevention of Cerebrovascular Events 0 10 20 30 40 13 21 38 ** * Placebo ( n = 814 ) 300 mg Q D ( n = 806 ) 1200 mg Q D ( n = 815 ) Number of Patients with G.I. Bleeding ASA Dose BMJ 1988 ;296:316

21. Risk of Acute Major UGIB According to Use of Aspirin and Ibuprofen in the Week Before Kaufman DW, Kelly JP, Wilholm BE, et al. Am J Gastroenterol. 1999;94:3189-3196.

22. Daily Aspirin Dose and Admission for Ulcer Bleeding Aspirin Dose 75 mg (n=27) 150 mg (n=22) 300 mg (n=62) Odds Ratio (95% Cl) 2.3 (1.2-4.4) 3.2 (1.7-6.5) 3.9 (2.5-6.3) Weil J et al. BMJ. 1995;310:827-830.

23. Mechanisms of NSAID/ Aspirin-induced Mucosal Injury Alterations in gastric mucosal barrier  Prostaglandin synthesis  Mucus and bicarbonate secretion  Submucosal blood flow  Mucosal ATP  Cell turnover  Platelet function (irreversible) Ivey KJ. Am J Med. 1988;84:41-48.  Prostaglandin synthesis

24. Effect of Aspirin Doses on Gastrointestinal Prostaglandins Percent of Baseline ( p < 0.05 vs. Baseline ) * StomachDuodenumRectum * * * * * * Baseline 0 20 40 60 80 100 120 10 mg ASA 81 mg ASA 325 mg ASA Cryer, et al. Gastroenterology 1999;117:17-25.

25. Risk of UGI bleeding with Different Formulations of Low-Dose Aspirin (< 325mg) 0 4 3.6 2.6 2.4 2.6 Relative Risk Gastric bleedingDuodenal bleeding 3.2 Plain ASA Coated ASA Buffered ASA 550 cases of UGIB admitted to hospital with melena or confirmed hematemesis Kelley et al, Lancet 1996; 348; 1413

26.  Lansoprazole (30 mg QD) + aspirin (100 mg daily) or Aspirin alone (100 mg daily) for 12 months. Aspirin alone (100 mg daily) for 12 months. Lai et al, N Engl J Med 2002; 346: 2033 Effect of Proton Pump Inhibitor on Upper GI Injury with Low-Dose Aspirin

27. OTC NSAIDs: What Are the GI Risks? OTC NSAIDS / Low-Dose Aspirin:  Non-Aspirin NSAIDs  Low Dose Aspirin  Low-Dose Aspirin in combination with Non-Aspirin NSAIDs  NSAIDs plus ETOH  Acetaminophen and Gastrointestinal Injury  Hepatotoxicity with NSAIDs

28. National cohort study in Denmark National cohort study in Denmark 27,694 people on aspirin 100-150 mg qd 27,694 people on aspirin 100-150 mg qd Treatment regimen Increased incidence over general population 95% CI Low-dose aspirin Low-dose aspirin + NSAIDs 2.6 5.6 2.2 - 2.9 4.4 - 7.0 Sorensen et al, Am J Gastroenterol 2000; 95; 2218 Risk of Combining Low-Dose Aspirin with NSAIDs

29. 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)

30. OTC NSAIDs: What Are the GI Risks? OTC NSAIDS / Low-Dose Aspirin:  Non-Aspirin NSAIDs  Low Dose Aspirin  Non-Aspirin NSAIDs in combination with Low-Dose Aspirin  NSAIDs plus ETOH  Acetaminophen and Gastrointestinal Injury  Hepatotoxicity with NSAIDs

31. Risk Factors for GI Bleeding Risk Factor Cases (n) Controls (n) OR (95% CI) Neither factor284411 Alcohol107752.07 (1.48-2.88) OTC ASA/NSAID160842.76 (2.03-3.74) OTC ASA/NSAID plus alcohol 71234.47 (2.73-7.32) Peura DA et al. Am J Gastroenterol. 1997;92:924-928.

32. Relative Risks of Upper Gastrointestinal Bleeding Ibuprofen (95% CI) Aspirin (95% CI) Regular Use Occasional Use Regular Use > 325 mg Regular Use   325 mg Occasional Use ETOH USER 2.7 (1.6-4.4)1.2 (0.8-1.7)7.0 (5.2-9.3)2.8 (2.0-3.8)2.4 (1.9-3.0) Never-drinker 2.2 (0.8-6.0)1.0 (0.4-2.4)5.1 (2.8-9.0)2.2 (1.2-4.1)1.4 (0.8-2.6) Kaufmann et al., Am J Gastroenterol 1999;94:3189-3196.

33. OTC NSAIDs: What Are the GI Risks? OTC NSAIDS / Low-Dose Aspirin:  Non-Aspirin NSAIDs  Low Dose Aspirin  Non-Aspirin NSAIDs in combination with Low-Dose Aspirin  NSAIDs plus ETOH  Acetaminophen and Gastrointestinal Injury  Hepatotoxicity with NSAIDs

34. Relative Risk of Upper GI Complications Cases (n) Controls (n) Adjusted RR 95% CI Acetaminophen ( mg) <1000 1001-1999 2000 2001-3999  4000 142 59 84 78 13 610 242 127 83 7 1.0 0.8 1.9 3.4 6.5 0.8-1.2 0.6-1.1 1.4-2.6 2.4-4.8 2.4-17.6 NSAID dose Low/medium High 92 311 290 229 2.4 4.9 1.9-3.1 4.1-5.8 Garcia-Rodriguez, Hernandez-Diaz. Epidemiology. 2001;12:570-576.

35. GI Bleeding Associated with Analgesics Blot WJ, Mclaughlin JK. J Epidemiol Biostat. 2000;5:137-142. AnalgesicCaseControlOdds Ratio95% CI AnalgesicCaseControlOdds Ratio95% CI n=627n=590(OR) OTC use of:% Aspirin27.012.02.71.9-3.8 Ibuprofen10.15.82.41.5-3.9 Acetaminophen4.56.30.90.5-1.6 Total OTC NSAIDs36.217.53.02.2-4.1 Rx NSAIDs9.35.92.11.2-3.4 Total NSAIDS42.922.03.12.3-4.1

36. Drug Concentration (  M) Mean Percent Inhibition of Gastric Mucosal PGE 2 00.010.1110100 0 20 40 60 80 100 Acetaminophen Rofecoxib Celecoxib Naproxen C max C C C Effects of NSAIDs and Acetaminophen on Gastric Mucosa Cryer, B and Feldman, M. (Abstract in press Am J Gastro)

37. OTC NSAIDs: What Are the GI Risks? OTC NSAIDS / Low-Dose Aspirin:  Non-Aspirin NSAIDs  Low Dose Aspirin  Non-Aspirin NSAIDs in combination with Low-Dose Aspirin  NSAIDs plus ETOH  Acetaminophen and Gastrointestinal Injury  Hepatotoxicity with NSAIDs

38. Hepatotoxicity with NSAIDs Compared with other classes of drugs, hepatotoxicity with NSAIDs is uncommon. Compared with other classes of drugs, hepatotoxicity with NSAIDs is uncommon. Mild increases in liver tests Mild increases in liver tests  1% (most NSAIDs)  15% (diclofenac) Clinically apparent hepatotoxicity is rare. Clinically apparent hepatotoxicity is rare.  Exception = Bromfenac sodium (Duract TM ) Mechanism of toxicity with NSAIDs is idiosyncratic reaction (not related to dose or duration) rather than intrinsic hepatotoxicity Mechanism of toxicity with NSAIDs is idiosyncratic reaction (not related to dose or duration) rather than intrinsic hepatotoxicity OTC NSAIDs: Ibuprofen:rare Naproxen:rare Ketoprofen:rare Aspirin:rare but some intrinsic hepatotoxicity

39. Hepatotoxicity with NSAIDs Aspirin : Some intrinsic hepatotoxicity Some intrinsic hepatotoxicity Injury related to: Injury related to: Dose: rare at 325 mg/day or less Duration: – Typically at least 6 days duration of high doses in patients with inflammatory conditions (eg., RA, SLE) Reye’s Syndrome: – Dose-related: – Median Dose = 25 mg/kg – However, risk increases 7-fold at 15 mg/kg/day (650 mg/day for 40 kg child) – Aspirin should be avoided in children with respiratory illness or varicella.

40. Summary OTC NSAIDs are associated with some GI risksOTC NSAIDs are associated with some GI risks GI Risks of OTC NSAIDs include upper and lower GI bleedingGI Risks of OTC NSAIDs include upper and lower GI bleeding Risk appears to be related to NSAID dose.Risk appears to be related to NSAID dose. Much of GI risks associated with OTC NSAIDs is related to aspirin, even at low-dose.Much of GI risks associated with OTC NSAIDs is related to aspirin, even at low-dose. Low-dose aspirin combined with NSAID increases risks 2-4 fold.Low-dose aspirin combined with NSAID increases risks 2-4 fold. Enteric-coated and buffered aspirin do not reduce risk.Enteric-coated and buffered aspirin do not reduce risk. Hepatotoxicity with OTC NSAIDs and Low-Dose Aspirin is rare.Hepatotoxicity with OTC NSAIDs and Low-Dose Aspirin is rare.