Consensus Development Conference on the Use of Nonsteroidal Anti-Inflammatory Agents, Including Cyclooxygenase-2 Enzyme Inhibitors and Aspirin

Abstract

See CME exam on page 1075.The American Gastroenterological Association (AGA) convened a panel of physicians in gastroenterology, rheumatology, cardiology, and internal medicine who developed this statement based on expert presentations of current scientific knowledge and through subsequent group discussion.This statement reflects the panel’s assessment of medical knowledge available when written. Thus, readers should view this statement in the context of data that invariably will accumulate after its creation.Consensus Panel StatementBackgroundNonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly used medications in the world. Well-recognized gastrointestinal (GI) complications and identification of previously unrecognized cardiac risks have amplified concerns about their use. The extent of these risks varies by patient, specific agent, dosage, and concomitant medications. To increase awareness about the benefits and the risks of gastrointestinal toxicity and myocardial infarction associated with these medications and to improve the use of NSAIDs, the American Gastroenterological Association (AGA) convened a Consensus Development Conference on the Use of NSAIDs from September 30 to October 2, 2005. The Consensus Development Panel and the speakers are listed in Appendix 1 (see supplementary material online at www.cghjournal.org). This conference examined what is known about risks of myocardial infarction and gastrointestinal toxicities of these medications, their risks in specific patients, and what interventions, if any, may diminish these risks. This conference did not address specifically the known risks of kidney disease and heart failure associated with NSAID and coxib use. These risks are well described in the medical literature. Clinicians should familiarize themselves with the existing and evolving data about these risks; in addition, more information about these issues is available at www.gastro.org.During the first day of the conference, experts presented the most recent pharmacologic, clinical, and epidemiologic research about NSAIDs and their use. These presentations, summarized in Appendix 2 (see supplementary material online at www.cghjournal.org) addressed the following key questions: 1Who is at risk and what is the risk?2Who needs these medications and what are their benefits over non-NSAIDs?3Can the risk of NSAID-induced GI toxicity be modified?4Coxib risks and benefits.5Aspirin risks and benefits.After weighing this scientific evidence, the panel developed a consensus view of the gastrointestinal and cardiovascular risks of NSAIDs, and ways in which such risks may be attenuated. Lastly, the panel identified outstanding questions that warrant further study.ConclusionsMost health professionals are aware of the increased risk of gastrointestinal toxicity associated with NSAID use. There is less familiarity, however, with the magnitude of this risk, with risks associated with specific medications, and with ways to reduce these risks.Traditional NSAIDs (or nonselective NSAIDs), coxibs (or selective NSAIDs), and aspirin (ASA) inhibit prostaglandin synthesis to varying degrees and, in turn, have anti-inflammatory, antipyretic, and analgesic effects. Nonselective NSAIDs reversibly inhibit both cyclooxygenase (COX)-1 and COX-2 activity. Coxibs reversibly inhibit COX-2 more than COX-1 because of their higher affinity for COX-2. ASA irreversibly blocks the COX enzymes. All agents discussed in this article are nonsteroidal, inhibit inflammation, and thus technically are NSAIDs. For the purposes of this article, traditional NSAIDs will be denoted as nonselective NSAIDs (nsNSAIDs), and coxibs and ASA will be denoted as such.Are nonsteroidal anti-inflammatory drugs necessary?NSAIDs, including nsNSAIDs, ASA, and coxibs are among the most widely used medications in the world. It is estimated that as many as 50 billion ASA tablets are consumed annually worldwide.1Bayer Pharmaceuticals. 2003Google Scholar In the United States, approximately 60 million prescriptions for NSAIDs are written each year, predominantly for older patients.2Phillips A.C. Polisson R.P. Simon L.S. NSAIDs and the elderly: toxicity and the economic implications.Drugs Aging. 1997; 10: 119-130Crossref PubMed Scopus (55) Google Scholar The broad use of these compounds speaks to their benefits and relative safety. These drugs are effective in acute and chronic treatment of painful and inflammatory musculoskeletal conditions, among others. Their anti-inflammatory properties appear to drive much of their benefits. Data from studies of patients with arthritis indicate that, compared with full-dose acetaminophen (1000 mg/day), NSAIDs provide superior pain control, functional outcomes, and are preferred by patients.3Pincus T. Koch G.G. Sokka T. et al.A randomized, double-blind, crossover clinical trial of diclofenac plus misoprostol versus acetaminophen in patients with osteoarthritis of the hip or knee.Arthritis Rheum. 2001; 44: 1587-1598Crossref PubMed Scopus (214) Google Scholar, 4Pincus T. Koch G. Lei H. et al.Patient preference for placebo, acetaminophen or celecoxib efficacy studies (PACES): two randomized placebo-controlled cross-over clinical trials in patients with osteoarthritis of the knee or hip.Ann Rheum Dis. 2004; 63: 931-939Crossref PubMed Scopus (152) Google Scholar, 5Case J.P. Baliunas A.J. Block J.A. Lack of efficacy of acetaminophen in treating symptomatic knee osteoarthritis: a randomized, double-blind, placebo-controlled comparison trial with diclofenac sodium.Arch Intern Med. 2003; 163: 169-178Crossref PubMed Scopus (126) Google Scholar Such data suggest that even patients with low-grade inflammation derive greater benefits with anti-inflammatory and analgesic combinations than analgesics alone. This is not to say that patients cannot benefit from simple analgesics in some cases; however, by the time such patients present to health care providers they often already have failed such approaches. It also is important to note, although beyond the scope of this article, that data suggest that the non-NSAID analgesic, acetaminophen, when used at high doses may behave pharmacologically similar to NSAIDs. Thus, it is possible that high-dose chronic acetaminophen may confer as of yet unidentified NSAID-like risks and benefits.6Catella-Lawson F. Reilly M.P. Kapoor S.C. et al.Cyclooxygenase inhibitors and the antiplatelet effects of ASA.N Engl J Med. 2001; 345: 1809-1817Crossref PubMed Scopus (869) Google ScholarWhat are the gastrointestinal consequences of nonsteroidal anti-inflammatory drug use?Gastrointestinal morbidities are the most common adverse effects associated with NSAID use, including complications in both the upper- and lower-GI tracts. Although physicians are aware of upper-GI risks attendant to NSAID use, there is less awareness of lower-GI sequelae.Gastrointestinal risks of nonselective nonsteroidal anti-inflammatory drugsSerious GI tract complications occur in 1%–4% of NSAID users annually.7Silverstein F.E. Faich G. Goldstein J.L. 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: 1247-1255Crossref PubMed Scopus (3076) Google Scholar, 8Bombardier C. Laine L. Reicin A. et al.Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis.N Engl J Med. 2000; 343: 1520-1528Crossref PubMed Scopus (3700) Google Scholar Although there is a high risk after initiation, there remains a continued risk over time such that the patient is always at risk while taking NSAIDs. Symptomatic or complicated ulcers (with bleeding, perforation, or obstruction) are the most serious GI side effects. NSAID use has surpassed Helicobacter pylori as the most commonly identified risk factor among patients with bleeding ulcers, found in 53% of patients in 1 study.9Ramosekh D. Van Leerdam M.E. Rauws E.A.J. et al.Outcome of peptic ulcer bleeding, nonsteroidal anti-inflammatory drug use and Helicobacter pylori infection.Clin Gastroenterol Hepatol. 2005; 3: 859-864Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar The average relative risk of developing a serious GI complication is 3- to 5-fold greater among NSAID users than among nonusers.10Physician’s desk reference. 59th ed. Montvale, NJ, Medical Economics Data Production Company2005Google Scholar Estimates suggest that NSAID use results in about 100,000 hospitalizations annually in the United States.11Singh G. Ramey D.R. NSAID induced gastrointestinal complications: the ARAMIS perspective.J Rheumatol. 1998; 25: 8-16Google Scholar The incidence of serious lower-GI tract complications from NSAID use is not well defined, but may account for 20% of total NSAID-associated GI morbidity.12Lanas A. Perez-Aisa M.A. Feu F. et al.A nationwide study of mortality associated with hospital admission due to severe gastrointestinal events and those associated with non-steroidal anti-inflammatory drug use.Am J Gastroenterol. 2005; 100: 1685-1693Crossref PubMed Scopus (284) Google ScholarNSAID use increases the risk for death; however, the magnitude of this increase is uncertain. A yearly mortality rate from NSAID use of 16,500 in the United States was estimated using the Arthritis, Rheumatism, and Aging Medical Information System database, a large long-term surveillance program of patients with rheumatoid arthritis.11Singh G. Ramey D.R. NSAID induced gastrointestinal complications: the ARAMIS perspective.J Rheumatol. 1998; 25: 8-16Google Scholar However, this may represent an overestimate because these data were extrapolated to a non–age-adjusted rheumatoid arthritis population, a group with higher all-cause mortality than the population in general. In a recent study using comprehensive data from the Spanish National Health system, the rate of NSAID-associated deaths was 15.3 per 100,000 users.12Lanas A. Perez-Aisa M.A. Feu F. et al.A nationwide study of mortality associated with hospital admission due to severe gastrointestinal events and those associated with non-steroidal anti-inflammatory drug use.Am J Gastroenterol. 2005; 100: 1685-1693Crossref PubMed Scopus (284) Google Scholar Still, this lower estimate is substantial given the scope of NSAID use.Notably, both NSAID-associated GI complications and deaths have been decreasing in recent years, after peaking in 1992.13Cryer B. NSAID-associated death: the rise and fall of NSAID-associated GI mortality.Am J Gastroenterol. 2005; 100: 1694-1695Crossref PubMed Scopus (81) Google Scholar This decrease has been attributed to many factors including the use of lower-dose (particularly over-the-counter) NSAIDs, the decreasing prevalence of H pylori, the increasing use of proton-pump inhibitors (PPIs), and the introduction of NSAIDs with greater GI safety, such as the coxibs.14Fries J.F. Murtagh K.N. Bennett M. et al.The rise and decline of nonsteroidal drug-associated gastropathy in rheumatoid arthritis.Arthritis Rheum. 2004; 50: 2433-2440Crossref PubMed Scopus (108) Google ScholarSome NSAID users are at greater risk for the development of GI complications. Risk factors include history of previous peptic ulcer; history of NSAID-related GI complications; advanced age; concomitant use of corticosteroids, anticoagulants, and the use of high-dose NSAIDs; or combinations of NSAIDs including ASA, coxibs, and over-the-counter products.7Silverstein F.E. Faich G. Goldstein J.L. 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: 1247-1255Crossref PubMed Scopus (3076) Google Scholar, 8Bombardier C. Laine L. Reicin A. et al.Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis.N Engl J Med. 2000; 343: 1520-1528Crossref PubMed Scopus (3700) Google Scholar, 12Lanas A. Perez-Aisa M.A. Feu F. et al.A nationwide study of mortality associated with hospital admission due to severe gastrointestinal events and those associated with non-steroidal anti-inflammatory drug use.Am J Gastroenterol. 2005; 100: 1685-1693Crossref PubMed Scopus (284) Google Scholar, 15Silverstein F.E. Graham D.Y. Senior J.R. 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: 241-249Crossref PubMed Scopus (1097) Google Scholar, 16Griffin M.R. Piper J.M. Daughtery J.R. et al.Nonsteroidal anti-inflammatory drug use and increased risk for peptic ulcer disease in elderly persons.Ann Intern Med. 1991; 114: 257-263Crossref PubMed Scopus (732) Google Scholar, 17Gabriel S.E. Jaakkimainen L. Bombardier C. Risk for serious gastrointestinal complications related to use of nonsteroidal anti-inflammatory drugs.Ann Intern Med. 1991; 115: 787-796Crossref PubMed Scopus (1226) Google Scholar Of these, the most significant is history of previous ulcer or complication, which increases the likelihood of a GI event substantially; studies cite an odds ratio as high as 13.5.7Silverstein F.E. Faich G. Goldstein J.L. 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: 1247-1255Crossref PubMed Scopus (3076) Google Scholar, 8Bombardier C. Laine L. Reicin A. et al.Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis.N Engl J Med. 2000; 343: 1520-1528Crossref PubMed Scopus (3700) Google Scholar, 12Lanas A. Perez-Aisa M.A. Feu F. et al.A nationwide study of mortality associated with hospital admission due to severe gastrointestinal events and those associated with non-steroidal anti-inflammatory drug use.Am J Gastroenterol. 2005; 100: 1685-1693Crossref PubMed Scopus (284) Google Scholar, 15Silverstein F.E. Graham D.Y. Senior J.R. 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: 241-249Crossref PubMed Scopus (1097) Google Scholar, 16Griffin M.R. Piper J.M. Daughtery J.R. et al.Nonsteroidal anti-inflammatory drug use and increased risk for peptic ulcer disease in elderly persons.Ann Intern Med. 1991; 114: 257-263Crossref PubMed Scopus (732) Google Scholar, 17Gabriel S.E. Jaakkimainen L. Bombardier C. Risk for serious gastrointestinal complications related to use of nonsteroidal anti-inflammatory drugs.Ann Intern Med. 1991; 115: 787-796Crossref PubMed Scopus (1226) Google Scholar Advancing age increases risk by about 4% per year.11Singh G. Ramey D.R. NSAID induced gastrointestinal complications: the ARAMIS perspective.J Rheumatol. 1998; 25: 8-16Google Scholar This relationship likely stems from the presence of other risk factors that are more prevalent with advancing age, such as comorbidities and concomitant use of ASA, NSAIDs, or anticoagulants, and age-related physiologic changes such as decreasing GI prostaglandin concentrations.Among nsNSAIDs, data indicate that GI safety may be superior with ibuprofen, etodolac, and nabumetone.18Garcia Rodriguez L.A. Hernandez-Diaz S. Relative risk of upper gastrointestinal complications among users of acetaminophen and nonsteroidal anti-inflammatory drugs.Epidemiology. 2001; 12: 570-576Crossref PubMed Scopus (252) Google Scholar, 19Hernandez-Diaz S. Rodriguez L.A. Association between nonsteroidal anti-inflammatory drugs and upper gastrointestinal tract bleeding/perforation: an overview of epidemiologic studies published in the 1990s.Arch Intern Med. 2000; 160: 2093-2099Crossref PubMed Scopus (655) Google Scholar, 20de Abajo F.J. Garcia Rodriguez L.A. Risk of upper gastrointestinal bleeding and perforation associated with low-dose aspirin as plain and enteric-coated formulations.BMC Clin Pharmacol. 2001; 1: 1Crossref PubMed Scopus (149) Google Scholar In contrast, NSAIDs with prominent enterohepatic circulation and significantly prolonged half-lives such as sulindac, indomethacin, piroxicam, and ketorolac have been linked to greater GI toxicity related to prolonged gastric and duodenal mucosal exposure.21Simon L.S. Mills J.A. Nonsteroidal anti-inflammatory drugs.N Engl J Med. 1980; 302 (1237–1243.): 1179-1185Crossref PubMed Scopus (170) Google Scholar As a class, coxibs are associated with less GI risk.All NSAID classes—nsNSAIDs, coxibs, and ASA—have a dose-response relationship to adverse GI events, and this relationship appears linear.11Singh G. Ramey D.R. NSAID induced gastrointestinal complications: the ARAMIS perspective.J Rheumatol. 1998; 25: 8-16Google Scholar, 15Silverstein F.E. Graham D.Y. Senior J.R. 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: 241-249Crossref PubMed Scopus (1097) Google Scholar Concurrent NSAID use, a common clinical scenario as more patients take prophylactic ASA and/or over-the-counter NSAIDs, increases risk.7Silverstein F.E. Faich G. Goldstein J.L. 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: 1247-1255Crossref PubMed Scopus (3076) Google Scholar, 12Lanas A. Perez-Aisa M.A. Feu F. et al.A nationwide study of mortality associated with hospital admission due to severe gastrointestinal events and those associated with non-steroidal anti-inflammatory drug use.Am J Gastroenterol. 2005; 100: 1685-1693Crossref PubMed Scopus (284) Google Scholar, 22Schnitzer T.J. Burmester G.R. Mysler E. et al.TARGET Study GroupComparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), reduction in ulcer complications: randomized controlled trial.Lancet. 2004; 364: 665-674Abstract Full Text Full Text PDF PubMed Scopus (629) Google Scholar, 23Laine L. Maller E.S. Yu C. et al.Ulcer formation with low-dose enteric-coated ASA and the effect of COX-2 selective inhibition: a double-blind trial.Gastroenterology. 2004; 127: 395-402Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar, 24Wilcox C.M. Shalek K.A. Costsonis G. Striking prevalence of over-the-counter nonsteroidal anti-inflammatory drug use in patients with upper gastrointestinal hemorrhage.Arch Intern Med. 1994; 154: 42-46Crossref PubMed Google Scholar When ASA is combined with NSAIDs, the relative risk of GI bleeding increases to more than 10 times that seen among those using either nsNSAIDs or ASA.12Lanas A. Perez-Aisa M.A. Feu F. et al.A nationwide study of mortality associated with hospital admission due to severe gastrointestinal events and those associated with non-steroidal anti-inflammatory drug use.Am J Gastroenterol. 2005; 100: 1685-1693Crossref PubMed Scopus (284) Google Scholar Among NSAID users, glucocorticoid use increases risk; although alone, they confer no additional risk.25Piper J.M. Ray W.A. Daughtery J.R. et al.Corticosteroid use and peptic ulcer disease: role of nonsteroidal anti-inflammatory drugs.Ann Intern Med. 1991; 114: 740Crossref Scopus (527) Google Scholar The use of alcohol and comorbidities appear to increase GI risk among NSAID users, although the strength and magnitude of such associations are less clear.15Silverstein F.E. Graham D.Y. Senior J.R. 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: 241-249Crossref PubMed Scopus (1097) Google Scholar, 25Piper J.M. Ray W.A. Daughtery J.R. et al.Corticosteroid use and peptic ulcer disease: role of nonsteroidal anti-inflammatory drugs.Ann Intern Med. 1991; 114: 740Crossref Scopus (527) Google Scholar, 26Rodriquez L.A.G. Jick H. Risk of upper gastrointestinal bleeding and perforation associated with individual non-steroidal anti-inflammatory drugs.Lancet. 1994; 343: 769-772Abstract PubMed Scopus (976) Google Scholar, 27Peura D.A. Lanza F.L. Gostout C.J. The American College of Gastroenterology Bleeding Registry: preliminary findings.Am J Gastroenterol. 1997; 92: 924-928PubMed Google ScholarGastrointestinal risks of aspirinLow-dose ASA (<325 mg/day) increases the risk for GI bleeding and hospitalization. An increasing amount of literature suggests that even cardiovascular doses of ASA increase GI risk 2–4 times.28Weil J. Colin-Jones D. Langman M. et al.Prophylactic aspirin and risk of peptic ulcer bleeding.BMJ. 1995; 310: 821-830Crossref PubMed Scopus (549) Google Scholar Among osteoarthritis patients taking enteric-coated ASA (81 mg/day), a study revealed endoscopic ulcers and erosions in 7.3% at 12 weeks.24Wilcox C.M. Shalek K.A. Costsonis G. Striking prevalence of over-the-counter nonsteroidal anti-inflammatory drug use in patients with upper gastrointestinal hemorrhage.Arch Intern Med. 1994; 154: 42-46Crossref PubMed Google Scholar In a different study of patients taking ASA for more than 3 months (at either 100 or 325 mg/day), 48% of asymptomatic patients developed endoscopic ulcers and erosions.29Niv Y. Battler A. Abuksis G. et al.Endoscopy in asymptomatic minidose ASA consumers.Dig Dis Sci. 2005; 50: 78-80Crossref PubMed Scopus (73) Google Scholar Although the relationship of endoscopic lesions to clinically relevant GI complications is controversial, clearly even lower doses of ASA result in GI toxicity. Thus, it appears that no risk-free dose of ASA exists. Further, attempts to coat or buffer ASA to mitigate GI effects have not attenuated complications.30Derry S. Loke Y.K. Risk of gastrointestinal haemorrhage with long-term use of ASA: meta-analysis.BMJ. 2000; 321: 1183-1187Crossref PubMed Google ScholarGastrointestinal risks of coxibsCoxibs were developed to decrease the GI toxicity associated with NSAIDs. These efforts stemmed from increasing understanding of specific physiologic roles that COX isoenzymes play. COX-1–mediated prostaglandin synthesis promotes the generation of the gastric mucosal protective barrier, decreases gastric acid secretion, increases production of superoxide scavenging glutathione, and promotes adequate mucosal blood flow.31Schoen R.T. Vender R.J. Mechanisms of nonsteroidal antiinflammatory drug-induced gastric damage.Am J Med. 1989; 86: 449-458Abstract Full Text PDF PubMed Scopus (340) Google Scholar, 32Scheiman J.M. NSAIDs, gastrointestinal injury and cytoprotection.Gastroenterol Clin North Am. 1996; 25: 279-298Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar, 33Laine L. Nonsteroidal antiinflammatory drug gastropathy.Gastrointest Endosc Clin N Am. 1996; 6: 489-504Abstract Full Text PDF PubMed Google Scholar, 34Hollander D. Gastrointestinal complications of nonsteroidal anti-inflammatory drugs: prophylactic and therapeutic strategies.Am J Med. 1994; 96: 274-281Abstract Full Text PDF PubMed Scopus (77) Google Scholar Thus, medications that inhibit these actions could lead to GI toxicity. COX-2, in contrast, increases local inflammation and modulates pain, and hence became a more attractive therapeutic target. Coxibs, designed to spare COX-1 and primarily inhibit COX-2 function, decrease but do not eliminate NSAID-associated GI toxicity. They are as efficacious as nsNSAIDs in relieving pain in patients with rheumatoid arthritis and osteoarthritis.7Silverstein F.E. Faich G. Goldstein J.L. 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: 1247-1255Crossref PubMed Scopus (3076) Google Scholar, 35Simon L.S. Weaver A.L. Graham D.Y. et al.The Anti-inflammatory and Upper Gastrointestinal Effects of Celecoxib In Rheumatoid Arthritis: a randomized, controlled trial.JAMA. 1999; 282: 1921-1928Crossref PubMed Scopus (817) Google Scholar, 36Emery P. Zeidler H. Kvien T.K. et al.Celecoxib versus diclofenac in long-term management of rheumatoid arthritis: randomised double-blind comparison.Lancet. 1999; 354: 2106Abstract Full Text Full Text PDF PubMed Scopus (530) Google Scholar, 37Bensen W.G. Fiechtner J.J. McMillen J.I. et al.Treatment of osteoarthritis with celecoxib, a cyclooxygenase-2 inhibitor: a randomized clinical trial.Mayo Clin Proc. 1999; 74: 1095Abstract Full Text Full Text PDF PubMed Scopus (350) Google ScholarData from large GI outcomes studies have characterized the GI effects of coxibs. The Celecoxib Long-term Arthritis Safety Study compared 3 groups of arthritis patients treated with high-dose celecoxib (400 mg twice daily), diclofenac (75 mg twice daily), and ibuprofen (800 mg, 3 times daily).7Silverstein F.E. Faich G. Goldstein J.L. 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: 1247-1255Crossref PubMed Scopus (3076) Google Scholar The primary outcome measure, gastroduodenal ulcer complications, was lower, although not statistically significantly, among those using celecoxib. Symptomatic ulcers were significantly less common among celecoxib users. Of note, 21% of patients in this study also were taking concomitant ASA. In post hoc analyses, there was no difference in ulcer complications between those taking ASA plus celecoxib compared with those taking ASA plus nsNSAIDs. Complications were significantly lower, however, between the coxib and nsNSAIDs groups among those not using ASA.The Vioxx Gastrointestinal Safety Of Rofecoxib trial evaluated the GI safety of rofecoxib among patients with rheumatoid arthritis. In this large trial, rofecoxib users had 50% fewer GI events compared with naproxen users.8Bombardier C. Laine L. Reicin A. et al.Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis.N Engl J Med. 2000; 343: 1520-1528Crossref PubMed Scopus (3700) Google Scholar Subsequent comparisons of lumericoxib with naproxen and ibuprofen showed a 75% decrease in symptomatic ulcers and their complications.22Schnitzer T.J. Burmester G.R. Mysler E. et al.TARGET Study GroupComparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), reduction in ulcer complications: randomized controlled trial.Lancet. 2004; 364: 665-674Abstract Full Text Full Text PDF PubMed Scopus (629) Google Scholar Furthermore, aggregate epidemiologic data suggest that the introduction and broader use of coxibs has led to a significant decrease in deaths owing to GI effects of NSAIDs among chronic users.14Fries J.F. Murtagh K.N. Bennett M. et al.The rise and decline of nonsteroidal drug-associated gastropathy in rheumatoid arthritis.Arthritis Rheum. 2004; 50: 2433-2440Crossref PubMed Scopus (108) Google Scholar Because these apparent GI benefits have become clearer, it has become increasingly apparent that at least some coxibs increase the risk for cardiovascular events.38Bresalier R.S. Sandler R.S. Quan H. et al.for the Adenomatous Polyp Prevention on Vioxx (APPROVe) Trial Investigators Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial.N Engl J Med. 2005; 352: 1092-1102Crossref PubMed Scopus (2280) Google ScholarWhat are the cardiovascular effects of nonsteroidal anti-inflammatory use?Cardiovascular risks of coxibsWith the increasing use of coxibs, growing data have implicated their use, particularly rofecoxib, in increasing the risk for cardiothrombotic events. In the Vioxx Gastrointestinal Safety Of Rofecoxib trial, whose participants were excluded from taking low-dose ASA, statistically more thromboembolic events occurred in those receiving rofecoxib (50 mg/day) than in those taking naproxen (500 mg twice daily) (.5% vs .1%, respectively).8Bombardier C. Laine L. Reicin A. et al.Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis.N Engl J Med. 2000; 343: 1520-1528Crossref PubMed Scopus (3700) Google Scholar In contrast, the Celecoxib Long-term Arthritis Safety Study data revealed a small, statistically insignificant difference between ibuprofen or diclofenac and celecoxib in cardiovascular or cerebrovascular events, regardless of ASA exposure.7Silverstein F.E. Faich G. Goldstein J.L. 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: 1247-1255Crossref PubMed Scopus (3076) Google Scholar, 39FDA Arthritis Advisory Committee Hearing. 2001Google Scholar Similarly, studies of lumericoxib have yielded no statistically increased risk of cardiovascular (CV) events.40Farkouh M.E. Kirshner H. Harrington R.A. et al.TARGET Study GroupComparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), cardiovascular outcomes: randomised controlled trial.Lancet. 2004; 364: 675-684Abstract Full Text Full Text PDF PubMed Scopus (485) Google ScholarSuch c