Non-steroidal anti-inflammatory drugs: Overall risks and management. Complementary roles for COX-2 inhibitors and proton pump inhibitors

Gut

Volumn 52, Issue 4, 2003, Pages 600-608

  Hawkey, C J ^a   Langman, M J S ^b  

^a QUEEN S MEDICAL CENTRE   (United Kingdom)

^b QUEEN ELIZABETH HOSPITAL   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

ACETYLSALICYLIC ACID; ANTICOAGULANT AGENT; CELECOXIB; CYCLOOXYGENASE 2 INHIBITOR; DICLOFENAC; HISTAMINE H2 RECEPTOR ANTAGONIST; IBUPROFEN; MISOPROSTOL; NAPROXEN; NONSTEROID ANTIINFLAMMATORY AGENT; PARACETAMOL; PIROXICAM; PROTON PUMP INHIBITOR; ROFECOXIB;

CARDIOVASCULAR DISEASE; CLINICAL TRIAL; COST BENEFIT ANALYSIS; DOSE RESPONSE; EDEMA; GASTROINTESTINAL DISEASE; GASTROINTESTINAL HEMORRHAGE; HUMAN; HYPERTENSION; INTESTINE PERFORATION; PEPTIC ULCER; PEPTIC ULCER BLEEDING; PRIORITY JOURNAL; PROPHYLAXIS; REVIEW; RISK BENEFIT ANALYSIS; RISK FACTOR; RISK MANAGEMENT; SIDE EFFECT; THROMBOSIS; WATER RETENTION;

ANTI-INFLAMMATORY AGENTS, NON-STEROIDAL; ANTI-ULCER AGENTS; CYCLOOXYGENASE 2; CYCLOOXYGENASE 2 INHIBITORS; CYCLOOXYGENASE INHIBITORS; DRUG INTERACTIONS; GASTROINTESTINAL DISEASES; HUMANS; ISOENZYMES; MEMBRANE PROTEINS; PEPTIC ULCER; PROSTAGLANDIN-ENDOPEROXIDE SYNTHASES; PROTON PUMPS; RISK FACTORS;

EID: 0037377905     PISSN: 00175749     EISSN: None     Source Type: Journal    
DOI: 10.1136/gut.52.4.600     Document Type: Review

References (113)

1. Rockall TA, Logan RF, Devlin HB, et al. Incidence of and mortality from acute upper gastrointestinal haemorrhage in the United Kingdom. Steering Committee and members of the National Audit of Acute Upper Gastrointestinal Haemorrhage. BMJ 1995;311:222-6.
2. Langman MJS. Ulcer complications associated with anti-inflammatory drug use. What is the extent of the disease burden? Pharmacoepidemiol Drug Safety 2001;10:13-19.
3. Hawkey CJ, Cullen DJE, Greenwood DC, et al. Prescribing of nonsteroidal anti- inflammatory drugs in general practice: Determinants and consequences. Aliment Pharmacol Ther 1997;11:293-8.
4. Mortality statistics: general. Series DH1. No. 31. Review of the Registrar General on deaths in England and Wales, 1998. National Statistics © Crown Copyright 2001.
5. Tramer MR, Moore RA, Reynolds DJM, et al. Quantitative estimation of rare adverse events which follow a biological progression: A new model applied to chronic NSAID use. Pain 2000;85:169-82.
6. Smalley WE, Ray WA, Daugherty JR, et al. Nonsteroidal anti-inflammatory drugs and the incidence of hospitalizations for peptic ulcer disease in elderly persons. Am J Epidemiol 1995;141:539-45.
7. Singh G. Recent considerations in nonsteroidal anti-inflammatory drug gastropathy. Am J Med 1998;105:31-8S.
8. Wolfe MM, Lichtenstein DR, Singh G. Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs. N Engl J Med 1999;340:1888-99.
9. Sonnenberg A. Peptic ulcer. In: Everhart JE, ed, Digestive Disease in the United States: Epidemiology and impact. Bethesda: National Institutes of Health, 1994.
10. Belton KJ, Lewis SC, Matthews JNS, et al. Systematic overview of upper gastrointestinal haemorrhage associated with non-steroidal anti-inflammatory drugs. In: Fracchia GN, ed. Prespectives in pharmacotoxicology and pharmacovigilance. Brussels: IOS Press, 1994.
11. Bombardier C, Laine L, Reicin A, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N Engl J Med 2000;343:1520-8.
12. Silverstein FE, Faich G, Goldstein JL, et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: A randomized controlled trial. Celecoxib Long-term Arthritis Safety Study. JAMA 2000;284:1247-55.
13. Berg Hrachovec J, Mora M. Reporting of 6-month vs. 12-month date in a clinical trial of celecoxib. JAMA 2002;286:2398.
14. Wright JM, Perry TP, Bassett KL, et al. Reporting of 6-month vs. 12-month date in a clinical trial of celecoxib. JAMA 2002;286:2399.
15. Silverstein F, Simon L, Faich G. Reporting of 6-month vs. 12-month date in a clinical trial of celecoxib. JAMA 2002;286:2399.
16. Langman MJ, Morgan L, Worrall A. Use of anti-inflammatory drugs by patients admitted with small or large bowel perforations and haemorrhage. BMJ 1985;290:347-9.
17. Hawkey CJ. Nonsteroidal anti-inflammatory drug gastropathy. Gastroenterology 2000;119:521-35.
18. Catella-Lawson F, McAdam B, Morrison BW, et al. Effects of specific inhibition of cyclooxygenase-2 on sodium balance, hemodynamics, and vasoactive eicosanoids. J Pharmacol Exp Ther 1999;289:735-41.
19. Rossat J, Maillard M, Nussberger J, et al. Renal effects of selective cyclooxygenase-2 inhibition in normotensive salt-depleted subjects. Clin Pharmacol Ther 1999;66:76-84.
20. Whelton A, Schulman G, Wallemark C, et al. Effects of celecoxib and naproxen on renal function in the elderly. Arch Intern Med 2000;160:1465-70.
21. Brater DC, Harris C, Redfern JS, et al. Renal effects of COX-2-selective inhibitors. Am J Nephrol 2001;21:1-15.
22. Swan SK, Rudy DW, Lasseter KC, et al. Effect of cyclooxygenase-2 inhibition on renal function in elderly persons receiving a low-salt diet. A randomized, controlled trial. Ann Intern Med 2000;133:1-9.
23. Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA 2001;286:954-9.
24. Patrono C, Patrignani P, Garcia Rodriguez LA. Cyclooxygenase-selective inhibition of prostanoid formation: transducing biochemical selectivity into clinical read-outs. J Clin Invest 2001;108:7-13.
25. Pope JE, Anderson JJ, Felson DT. A meta-analysis of the effects of nonsteroidal anti- inflammatory drugs on blood pressure. Arch Intern Med 1993;153:477-84.
26. Johnson AG, Nguyen TV, Day RO. Do nonsteroidal anti-inflammatory drugs affect blood pressure? A meta-analysis. Ann Intern Med 1994;121:289-300.
27. MacMahon S, Peto R, Cutler J, et al. Blood pressure, stroke, and coronary heart disease. Part 1, Prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias. Lancet 1990;335:765-74.
28. Page J, Henry D. Consumption of NSAIDs and the development of congestive heart failure in elderly patients: an underrecognized public health problem. Arch Intern Med 2000;160:777-84.
29. Patrono C, Coller B, Dalen JE, et al. Platelet-active drugs: The relationships among dose, effectiveness, and side effects. Chest 1998;114(suppl 5):470-88S.
30. Collaboration AT. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002;324:71-86.
31. McAdam BF, Catella-Lawson F, Mardini IA, et al. Systemic biosynthesis of prostacyclin by cyclooxygenase (COX)-2: The human pharmacology of a selective inhibitor of COX-2. Proc Natl Acad Sci U S A 1999;96:272-7.
32. Jick SS. The risk of gastrointestinal bleed, myocardial infarction, and newly diagnosed hypertension in users of meloxicam, diclofenac, naproxen, and piroxicam. Pharmacotherapy 2000;20:741-4.
33. Brochier ML. Evaluation of flurbiprofen for prevention of reinfarction and reocclusion after successful thrombolysis or angioplasty in acute myocardial infarction. Eur Heart J 1993;14:951-7.
34. Garcia Rodriguez LA, Varas C, Patrono C. Differential effects of aspirin and nonsteroidal anti-inflammatory drugs in the primary prevention of myocardial infarction in postmenopausal women. Epidemiology 2000;11:382-7.
35. Ray WA, Stein M, Hall K, et al. Non-steroidal anti-inflammatory drugs and risk of serious coronary heart disease: an observational cohort study. Lancet 2002;359:118-123.
36. Dalen JE. Selective COX-2 inhibitors, NSAIDs, aspirin, and myocardial infarction. Arch Intern Med 2002;162:1091-2.
37. Solomon DH, Glynn RJ, Levin RI, et al. Nonsteroidal anti-inflammatory drug use and acute myocardial infarction. Arch Intern Med 2002;127:1099-104.
38. Watson DJ, Rhodes T, Cai B, et al. Lower risk of thromboembolic cardiovascular events with naproxen among patients with rheumatoid arthritis. Arch Intern Med 2002;162:1105-110.
39. Rahme E Pilote L, LeLorier J. Association between naproxen use and protection against acute myocardial infarction. Arch Intern Med 2002;162:1111-15.
40. FitzGerald GA, Patrono C. The coxibs, selective inhibitors of cyclooxygenase-2. N Engl J Med 2001;345:433-42.
41. Henry D, Lim L-Y, Garcia Rodriguez LA, et al. Variability in risk of gastrointestinal complications with individual non-steroidal anti-inflammatory drugs: Results of a collaborative meta-analysis. BMJ 1996;312:1563-6.
42. Guidelines: ACoRSoO. Recommendations for the Medical Management of Osteoorthritis of the Hip and Knee. Arthritis Rheum 2000;43:1905-15.
43. Jawad AS. EULAR recommendations for the management of knee osteoarthritis. Ann Rheum Dis 2001;60:540.
44. National Institute of Clinical Excellence. Guidance on the use of cyclo-oxygenase (Cox) II selective inhibitors, celecoxib, rofecoxib, meloxicam and etodolac for osteoarthritis and rheumatoid arthritis. London: Technology Appraisal Guidance-No. 27 Government publication, 2001.
45. Laine L, Harper S, Simon T, et al. A randomized trial comparing the effect of rofecoxib, a cyclooxygenase 2-specific inhibitor, with that of ibuprofen on the gastroduodenal mucosa of patients with osteoarthritis. Gastroenterology 1999;117:776-83.
46. Hawkey C, Laine L, Simon T, et al. Comparison of the effect of rofecoxib (a cyclooxygenase 2 inhibitor), ibuprofen, and placebo on the gastroduodenal mucosa of patients with osteoarthritis: A randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2000;43:370-7.
47. Collins R, Peto R, Macmahon S, et al. Blood pressure, stroke and coronary heart disease. Part 2. Short term reductions in blood pressure: overview of randomized drug trials in their epidemiological context. Lancet 1990;335:827-38.
48. Emery P, Zeidler H, Kvien TK, et al. Celecoxib versus diclofenac in long-term management of rheumatoid arthritis: Randomised double-blind comparison. Lancet 1999;354:2106-11.
49. Simon LS, Weaver AL, Graham DY, et al. Anti-inflammatory and upper gastrointestinal effects of celecoxib in rheumatoid arthritis: A randomized controlled trial. JAMA 1999;282:1921-8.
50. Goldstein JL, Correa P, Zhao WW, et al. Reduced incidence of gastroduodenal ulcers with celecoxib, a novel cyclooxygenase-2 inhibitor, compared to naproxen in patients with arthritis. Am J Gastroenterol 2001;96:1019-27.
51. Agrawal N, Paperiello B, Zhao WW, et al. Supratherapeutic Doses of valdecoxib have a reduced incidence of gastroduodenal ulcers compared with conventional therapeutic doses of naproxen in osteoarthritis and rheumatoid arthritis patients. Arthritis Rheum 2001;44(suppl 9):A1917.
52. Goldstein JL, Fakouhi KM, Zhao WW, et al. Reduced incidence of gastroduodenal ulcers with valdecoxib compared to ibuprofen and diclofenac in patients with osteoarthritis: a multicentre trial. Gastroenterology 2001;120(suppl 5):A597.
53. Langman MJ, Jensen DM, Watson DJ, et al. Adverse upper gastrointestinal effects of rofecoxib compared with NSAIDs. JAMA 1999;282:1929-33.
54. Laine L. Stratifying the risk of clinical upper GI events in NSAID users: results from a double-blind outcomes study. Gastroenterology 2001;120:A552.
55. Schwartz JI, Malice MP, Kalyani R, et al. Comparison of rofecoxib, celecoxib, and naproxen on blood pressure in elderly volunteers. Clin Pharmacol Ther 2002;71: 7-8.
56. Whelton A, Fort JG, Puma JA, et al. Cyclooxygenase-2-specific inhibitors and cardiorenal function: a randomized, controlled trial of celecoxib and rofecoxib in older hypertensive osteoarthritis patients. (Erratum appears in Am J Ther 2001;8:220). Am J Ther 2001;8:85-95.
57. site FCw. http://www.fda.gov/cder/foi/label/1998/20998lbl.pdf, 1999.
58. FDA Rofecoxib website: http://www.fda.gov/ohrms/dockets/andcolleagues/01/slides/3677s2_01_ sponsor.pdf, 2001.
59. Konstam MA, Weir MR, Reicin A, et al. Cardiovascular thrombotic events in controlled, clinical trials of rofecoxib. Circulation 2001;104:2808-13.
60. Wight N, Gottesdiener K, Garlick NM, et al. Rofecoxib, A COX-2 inhibitor, does not inhibit human gastric mucosal prostaglandin production. Gastroenterology 2001;120:867-73.
61. Josefson D. FDA warns Merck over its promotion of rofecoxib. BMJ 2001;323:767.
62. Wallace JL, McKnight W, Reuter BK, et al. NSAID-induced gastric damage in rats: requirement for inhibition of both cyclooxygenase 1 and 2. Gastroenterology 2000;119:706-14.
63. Catella-Lawson F, Reilly MP, Kapoor SC, et al. Cyclooxygenase inhibitiors and the antiplatelet effects of aspirin. N Engl J Med 2001;345:1809-17.
64. Whittle BJ, Vane JR. A biochemical basis for the gastrointestinal toxicity of non- steroid antirheumatoid drugs. Arch Toxicol Suppl 1984;7:315-22.
65. Botting R. Paracetamol-inhibitable COX-2. J Physiol Pharmacol 2000;51:609-18.
66. Coggon D, Langman MJ, Spiegelhalter D. Aspirin, paracetamol, and haematemesis and melaena. Gut 1982;23:340-4.
67. McIntosh JH, Fung CS, Berry G, et al. Smoking, nonsteroidal anti-inflammatory drugs, and acetaminophen in gastric ulcer. A study of associations and of the effects of previous diagnosis on exposure patterns. Am J Epidemiol 1988;12B:761-70.
68. Garcia Rodriguez LA, Hernandez-Diaz S. Relative risk of upper gastrointestinal complications among users of acetaminophen and nonsteroidal anti-inflammatory drugs. Epidemiology 2001;12:570-6.
69. Lewis SC, Langman MJS, Laporte JR, et al. Dose-response relationships between individual non-aspirin non-steroidal anti-inflammatory drugs (NANSAIDs) and serious upper gastrointestinal bleeding: a meta-analysis based on individual patient data. Br J Clin Pharmacol 2002;54:320-6.
70. Day RO, Graham GG, Williams KM, et al. Clinical pharmacology of non-steroidal anti-inflammatory drugs. Pharmacol Ther 1987;33:383-433.
71. Brooks PM, Day RO. Nonsteroidal antiinflammatory drugs - differences and similarities. N Engl J Med 1991;324:1716-25.
72. Juni P, Rutjes AWS, Dieppe PA. Gastrointestinal ulcer complications: Are selective COX-2 inhibitors superior to traditional NSAIDs? BMJ 2002;324:1287-8.
73. Brater DC, McCarthy DM, Fries JF. Effects of nonsteroidal anti-inflammatory drugs on renal function: Focus on cyclooxygenase-2-selective inhibition. Am J Med 1999;107(suppl 1):65-71S.
74. Rossi AC, Hsu JP, Faich GA. Ulcerogenicity of piroxicam: an analysis of spontaneously reported data. BMJ 1987;294:147-50.
75. Langman MJ, Weil J, Wainwright P, et al. Risks of bleeding peptic ulcer associated with individual non-steroidal anti-inflammatory drugs. Lancet 1994;343:1075-8.
76. Koch M, Dezi A, Ferrario F, et al. Prevention of nonsteroidal anti-inflammatory drug- induced gastrointestinal mucosal injury: A meta-analysis of randomized controlled clinical trials. Arch Intern Med 1996;156:2321-32.
77. Silverstein FE, Graham DY, Senior JR, et al. Misoprostol reduces serious gastrointestinal complications in patients with rheumatoid arthritis receiving nonsteroidal anti-inflammatory drugs. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 1995;123:241-9.
78. Yeomans ND, Tulassay Z, Juhasz L, et al. A comparison of omeprazole with ranitidine for ulcers associated with nonsteroidal antiinflammatory drugs. Acid Suppression Trial: Ranitidine versus Omeprazole for NSAID-associated Ulcer Treatment (ASTRONAUT) Study Group. N Engl J Med 1998;338:719-26.
79. Hawkey CJ, Karrasch JA, Szczepanski L, et al. Omeprazole compared with misoprostol for ulcers associated with nonsteroidal antiinflammatory drugs. N Engl J Med 1998;338:727-34.
80. Agrawal NM, Campbell DR, Safdi MA, et al. Superiority of lansoprazole vs ranitidine in healing nonsteroidal anti-inflammatory drug-associated gastric ulcers: results of a double-blind, randomized, multicenter study. NSAID-Associated Gastric Ulcer Study Group. Arch Intern Med 2000;160:1455-61.
81. Chan FKL, Chung SCS, Suen RN, et al. Preventing recurrent upper gastrointestinal bleeding in patients with Helicobacter pylori infection who are taking low-dose aspirin or naproxen. N Engl J Med 2001;344:967-73.
82. Lai K-C, Lam S-K, Chu K-M, et al. H. pylori eradication vs. Combined proton pump inhibitor and H. pylori eradication in the prevention of recurrent peptic ulcer complications in high-risk patients receiving low-dose aspirin. Gastroenterology 2001;120(suppl 5):A550.
83. Ekstrom P, Carling L, Wetterhus S, et al. Prevention of peptic ulcer and dyspeptic symptoms with omeprazole in patients receiving continuous non-steroidal anti-inflammatory drug therapy. A nordic multicentre study. Scand J Gastroenterol 1996;31:753-8.
84. Cullen D, Bardhan KD, Eisner M, et al. Primary gastroduodenal prophylaxis with omeprazole for non-steroidal anti-inflammatory drug users. Aliment Pharmacol Ther 1998;12:135-40.
85. Taha AS, Hudson N, Hawkey CJ, et al. Famotidine for the prevention of gastric and duodenal ulcers caused by nonsteroidal antiinflammatory drugs. N Engl J Med 1996;334:1435-9.
86. Singh G, Rosen Ramey D. NSAID induced gastrointestinal complications: the ARAMIS perspective - 1997. Arthritis, Rheumatism, and Aging Medical Information System. J Rheumatol Suppl 1998;51:8-16.
87. Weil J, Langman MJ, Wainwright P, et al. Peptic ulcer bleeding: accessory risk factors and interactions with non-steroidal anti-inflammatory drugs. Gut 2000;46:27-31.
88. Langman MJS, Weil J, Wainwright P, et al. Risks of bleeding peptic ulcer associate with individual non-steroidal anti-inflammatory drugs. Lancet 1994;343:1075-8.
89. Hawkey CJ, Laine L, Harper SE, et al. Influence of risk factors on endoscopic and clinical ulcers in patients taking rofecoxib or ibuprofen in two randomized controlled trials. Aliment Pharmacol Ther 2001;15:1593-601.
90. Hawkey CJ, Tulassay Z, Szczepanski L, et al. Randomised controlled trial of Helicobacter pylori eradication in patients on non-steroidal anti-inflammatory drugs: HELP NSAIDs study. Lancet 1998;352:1016-21.
91. Hawkey CJ, Naesdal J, Wilson I, et al. Scars not bugs: Relative contribution of mucosal injury and Helicobacter pylori in the development of gastroduodenal lesions in patients taking non-steroidal anti-inflammatory drugs. Gut 2002;51:336-43.
92. Gabriel SE, Jaakkimainen L, Bombardier C. Risk for serious gastrointestinal complications related to use of nonsteroidal anti-inflammatory drugs: A meta-analysis. Ann Intern Med 1991;115:787-96.
93. Hawkey CJ, Snowden JA, Lobo A, et al. Stem cell transplantation for inflammatory bowel disease: practical and ethical issues. Gut 2000;46:869-72.
94. Garcia Rodriguez LA, Williams R, Derby LE, et al. Acute liver injury associated with nonsteroidal anti-inflammatory drugs and the role of risk factors. Arch Intern Med 1994;154:311-6.
95. FDA Celecoxib website: http://www.fda.gov/ohrms/dockets/ac/01/slides/3677s1_01_sponsor.pdf, 2001.
96. Laine L, Hawkey CJ, Bombardier C, et al. Stratifying the Risk of Clinical Upper GI Events in NSAID Users: Results froma Double-Blind Outcomes Study. Gastroenterology 2001;(suppl 5):A552.
97. Hawkey CJ, Karrasch JA, Szczepanski L, et al. Omeprazole compared with misoprostol for ulcers associated with nonsteroidal antiinflammatory drugs. Omeprazole versus Misoprostol for NSAID-induced Ulcer Management (OMNIUM) Study Group. N Engl J Med 1998;338:727-34.
98. Susser S. Causes of peptic ulcer: a selective epidemiological review. J Chronic Dis 1967;20:435-56.
99. Messer J, Reitman D, Sacks HS, et al. Association of adrenocorticosteroid therapy and peptic-ulcer disease. N Engl J Med 1983;309:21-4.
100. Piper JM, Ray WA, Daugherty JR, et al. Corticosteroid use and peptic ulcer disease: Role of nonsteroidal anti-inflammatory drugs. Ann Intern Med 1991;114:735-40.
101. Holvoet J, Terriere L, Van Hee W, et al. Relation of upper gastrointestinal bleeding to non-steroidal anti-inflammatory drugs and aspirin: A case-control study. Gut 1991;32:730-4.
102. Hochain P, Berkelmans I, Czernichow P, et al. Which patients taking non-aspirin non-steroidal anti-inflammatory drugs bleed? A case-control study. Eur J Gastroenterol Hepatol 1995;7:419-26.
103. Merck data presented to FDA F1.
104. Huang J-Q, Sridhar S, Hunt RH. Role of Helicobacter pylori infection and non- steroidal anti-inflammatory drugs in peptic ulcer disease: a meta analysis. Lancet 2002;359:14-22.
105. Hawkey CJ. Personal review: Helicobacter pylori, NSAIDs and cognitive dissonance. Aliment Pharmacol Ther 1999;13:695-702.
106. Yeomans ND, Garas G, Hawkey CJ. The nonsteroidal anti-inflammatory drugs controversy. Gastroenterol Clin North Am 2000;29:791-805.
107. Garcia Rodriguez LA, Cattaruzzi C, Troncon MG, et al. Risk of hospitalisation for upper gastrointestinal track bleeding associated with ketorolac, other nonsteroidal anti-inflammatory drugs, calcium antagonists, and other antihypertensive drugs. Arch Intern med 1998;158:33-9.
108. Lanas A, Bajador E, Serrano P, et al. Nitrovasodilators, low-dose aspirin, other nonsteroidal antiinflammatory drugs, and the risk of upper gastrointestinal bleeding. N Engl J Med 2000;343:834-9.
109. Derry S, Loke KY. Risk of gastrointestinal haemorrhage with long-term use of aspirin:a meta analysis. BMJ 2000;321:1183-7.
110. Anonymous. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee. Lancet 1996;348:1329-39.
111. van Hecken A, Depre M, Wynants K, et al. Effect of clopidogrel on naproxen- induced gastrointestinal blood loss in healthy volunteers. Drug Metab Drug Interact 1998;14:193-205.
112. Shorr RI, Ray WA, Daugherty JR, et al. Concurrent use of nonsteroidal anti- inflammatory drugs and oral anticoagulants places elderly persons at high risk for hemorrhagic peptic ulcer disease. Arch Intern Med 1993;153:1665-70.
113. Schwartz JI, De Smet M, Larson PJ, et al. Effect of rofecoxib on the pharmacokinetics of digoxin in healthy volunteers. J Clin Pharmacol 2001;41:107-12.