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Prospects for Changing the Burden of Nonsteroidal Anti-Inflammatory Drug Toxicity Marie R. Griffin, MD, MPH, James M. Scheiman, MD

Traditional nonsteroidal anti-inflammatory drugs (NSAIDs) increase the risk of clinically important upper gastrointestinal ulcers and bleeds about fourfold. Other risk factors for these events include advanced age, higher NSAID dose, prior ulcer or bleed, use of anticoagulants, use of corticosteroids, and poor general health. Among NSAID users with more than one risk factor, the incidence of serious ulcer complications may be as high as 4% to 8% per year. NSAIDs may also increase blood pressure and have adverse effects on renal function. NSAID-associated toxicity may be decreased by (1) trying less toxic alternative drugs; (2) using NSAIDs less frequently or at a lower dose; (3) use of cotherapy, such as misoprostol or proton pump inhibitors, to prevent complications; (4) or use of the more selective cyclooxygenase-2 inhibitors. More research is needed to determine which of these strategies or combination of strategies is optimal in terms of patient safety and cost Am J Med. 2001;110(1A):33S–37S. © 2001 by Excerpta Medica, Inc.


he relation of nonsteroidal anti-inflammatory drugs (NSAIDs) to serious upper gastrointestinal (GI) toxicity unfolded in the 1980s and 1990s1 after the marked increase in the use of these drugs.2 Methodologically strong studies in the 1990s were remarkable for their consistency in finding that NSAIDs increase the risk of serious upper GI events about fourfold.3– 8 In the United States, as many as 41,000 excess hospitalizations and 3,300 deaths occur each year among elderly NSAID users.9 A decrease in toxicity in the future is possible through several approaches: more rational use of NSAIDs; use of cotherapy to prevent NSAID-associated toxicity in selected patients; and, perhaps by preferential use of newer NSAIDs, including highly selective cyclooxygenase (COX)-2 inhibitors. NSAIDs are best known for their GI toxicity, but it is important to remember they have serious toxicity that also affects other bodily systems.

GASTROINTESTINAL TOXICITY Hospitalization for ulcer disease increases from less than 1 per 1,000 annually in most populations under age 50 to 2 to 6 per 1,000 in individuals 65 years and older.3,8,10 –14 In-hospital fatality rates associated with peptic ulcer disease are 2% to 10%.6,14 –16 Although the relative risk of

From the Department of Preventive Medicine, School of Medicine, Vanderbilt University, Nashville, Tennessee, USA (MRG); and the Department of Internal Medicine, Division of Gastroenterology, University of Michigan Medical Center, Ann Arbor, Michigan, USA (JMS). Reprints are not available. Correspondence should be addressed to Marie R. Griffin, MD, MPH, Department of Preventive Medicine, School of Medicine, Vanderbilt University, Nashville, Tennessee 37232-2637. © 2001 by Excerpta Medica, Inc. All rights reserved.

Figure 1. Gastrointestinal (GI) toxicity costs in 1989 ($110 per regular nonsteroidal anti-inflammatory drug [NSAID] user annually). Costs associated with the GI side effects of NSAIDs in the United States. (Adapted from Am J Epidemiol.3) 0002-9343/01/$20.00 33S PII S0002-9343(00)00634-3

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serious ulcer disease associated with NSAIDs differs little with age, the individual risk is much higher in older persons and others with a high baseline risk of ulcer disease. Although infrequent, hospitalization for ulcer complications contributes substantially to the estimated indirect cost of GI toxicity of $110 per NSAID user (at 1989 costs; Figure 1).3 In addition to age, factors consistently associated with an increased risk of NSAID-associated GI complications include increasing NSAID dose3,6,15,17; history of prior ulcer, GI hemorrhage, dyspepsia, and/or previous NSAID intolerance6,15,17,18; use of corticosteroids6,15,17,19; use of anticoagulants6,20; and various measures of poor health.17,18,21 Among NSAID users, about 25% of ulcer complications are the result of Helicobacter pylori colonization.22 However, such colonization, in the absence of a past history of ulcer disease, has not been convincingly shown to markedly increase the risk of serious NSAID-associated complications.23 Among NSAID users with more than one risk factor for ulcer complication, the incidence of serious complications may be as high as 4% to 8% per year.17 For elderly NSAID users, fatal complications are close to 1 per 1,000 person-years of NSAID use, and higher for those with additional risk factors, such as prior history of ulcer disease.

scriptions that covered more than 75% of the days of the year.3,9 The use of NSAIDs in the elderly is primarily for symptoms associated with osteoarthritis (OA) and other chronic musculoskeletal conditions. The high rate of adverse effects and the modest efficacy of these agents suggest that this level of use may not be appropriate. The GI toxicity of NSAIDs has been at least partially responsible for a change in the therapeutic approach to patients with both rheumatoid arthritis (RA) and OA. In RA, disease-modifying antirheumatic drugs (DMARDs) are instituted much earlier in the course of disease,46 and in OA, acetaminophen is now frequently recommended as first-line therapy.47,48 Other therapeutic options for persons with OA include a number of nondrug therapies as well as topical agents, which are associated with less toxicity. Nonmedicinal therapies, including behavior modification, should be considered primary strategies to relieve symptoms and improve function.49 Simple analgesics, such as acetaminophen, have been preferable as an initial choice of systemic medical therapy. Whether safer NSAIDs will change this preference depends on their overall safety profile, including GI toxicity, blood pressure effects, and other adverse effects.


There are clearly patients for whom NSAIDs are superior to acetaminophen for symptomatic relief. For these patients, it is important to minimize the risks of adverse effects. A meta-analysis50 of extant observational studies included NSAIDs most commonly in use in the 1980s. There were no important differences in the risk of serious upper GI disease associated with these drugs except for ibuprofen, which had a lower risk than most other NSAIDs, likely the result of the lower dosages used with this agent.50 Drugs that were not evaluated included some older NSAIDs, such as salsalate, and newer agents including nabumetone, meloxicam, and etodolac, as well as the highly selective COX-2 inhibitors. Selective COX-2 inhibitors have been in development for several years with the expectation that drugs that inhibit COX-2 and not COX-1 would have equal efficacy but lower GI toxicity than older NSAIDs. Prelicensure studies to date support that presumption; however, definitive studies with sufficient numbers of subjects that include important clinical end points are still in progress.39,40 If these drugs are significantly safer than older NSAIDs, they may become the NSAIDs of first choice for persons at risk for NSAIDasssociated toxicity. The problem of NSAID-associated toxicity has led to the development and/or use of drugs as cotherapy to prevent complications. These include misoprostol, a synthetic prostaglandin E1 analog18; proton pump inhibitors51; and high doses of histamine H2-receptor antagonists.52 These drugs approximately halve the incidence of NSAID-associated ulcers but incur additional costs and

NSAIDs have other adverse effects unrelated to the GI tract, including nephrotoxicity24 –30 and hepatotoxicity.31 Particularly worrisome is the ability of these drugs to increase blood pressure.32 In experimental studies, the acute administration of a variety of NSAIDs increases both arterial pressure and peripheral resistance.32 Several NSAIDs have been shown to interfere with the efficacy of antihypertensive drugs,29,30,33,34 increase blood pressure in hypertensive subjects,35,36 and result in the initiation of antihypertensive treatment in older persons.37,38 Unlike serious GI toxicity, which is thought to be mediated primarily through COX-1 inhibition, renal toxicity (including hypertension) with selective COX-2 inhibitors is likely to be similar to older NSAIDs.39,40 Given the prevalence of hypertension in the United States, and the high stakes associated with small increases in blood pressure, the public health implications of chronic NSAID use in elderly at-risk populations are potentially enormous.41

RATES OF USE AND ALTERNATIVES Population-based studies in the United States,21,42,43 Canada,15 England,44 and Australia16 have documented that use of nonaspirin NSAIDs in the elderly is common and that 10% to 20% have a current or recent NSAID prescription. Over a 6-month period in Alberta, Canada, 27% of elderly patients were prescribed these drugs45; among elderly Medicaid enrollees in Tennessee, 40% received at least one prescription annually and 6% had pre34S January 8, 2001 THE AMERICAN JOURNAL OF MEDICINEĺ¨


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their own adverse events. National estimates of NSAID use indicate a rapid increase in NSAID prescriptions from 1973 to 1983 and relatively stable numbers from 1984 through 1990. However, over the latter period, there was a 46-fold increase in cotherapy with gastroprotective and/or antiulcer drugs.2 Whereas H2-receptor antagonists—the most common class of drugs coprescribed— may relieve symptoms in standard doses, they have not been shown to consistently prevent NSAID-associated gastric ulcers.52–54 Only misoprostol has been demonstrated to prevent ulcer complications when used as primary prophylaxis. However, the coprescription of misoprostol with NSAIDs is controversial.55 The drug is expensive; efficacy is by no means complete, with an estimated decrease in ulcer complications of 40%; and it has relatively frequent adverse effects, predominantly diarrhea,18,56 and often does not relieve dyspeptic symptoms. Thus, the daily quality of life of patients taking misoprostol may be worse than those taking NSAIDs alone.57 Many patients will not tolerate the recommended dose of 200 ␮g four times daily.18 Limited data suggest that dosing two to three times daily may prevent ulcers and is certainly better tolerated.56 Although misoprostol is the only drug approved by the US Food and Drug Administration for prophylaxis against NSAID-related adverse GI events,18 recent research suggests that proton pump inhibitors,51,58 and high-dose H2-receptor antagonists52 may offer similar protection with fewer side effects. The level of evidence for the prophylactic use of these regimens is at least as strong as that for use of lower doses of misoprostol. COX-2 inhibitors are attractive from the standpoint of being able to use one drug rather than two; however, more studies with larger numbers of patients are needed to better define their safety profile. In addition, it may be that, similar to older NSAIDs, these drugs will be associated with a high use of H2 blockers and proton pump inhibitors to control symptoms, thus increasing costs.

SETTING A RESEARCH AGENDA Public Awareness Gastrointestinal toxicity associated with NSAIDs is responsible for significant morbidity and mortality, and constitutes a multibillion-dollar financial drain. Despite patient education efforts and public awareness campaigns, a recent survey concluded that many regular users were unaware of the potential side effects of NSAIDs. Of particular concern was the perceived safety of agents available without a prescription.59 Ongoing surveillance of NSAID-associated toxicity is needed to evaluate whether current knowledge regarding prevention of such toxicity is being put into practice.

Over-the-Counter Use In addition, evaluation of the clinical and economic impact from adverse events resulting from over-the-counter (OTC) NSAIDs is needed. Interview studies with careful history taking may be required to determine accurately the current impact of prophylactic aspirin, other lowdose (including OTC) NSAIDs, and prescription NSAIDs on the current burden of ulcer disease. Low-Dose Aspirin Because the GI toxicity of prophylactic aspirin is dose related,60 educational efforts are needed to encourage the use of the lowest effective dose (approximately 80 to 100 mg daily for most indications). In addition, an evaluation of the toxicity of these low doses of aspirin when used in conjunction with NSAIDs, including specific COX-2 inhibitors, is needed. Methodologies Large computerized databases that include prescription (and nonprescription) drug information can be used to measure the impact of NSAIDs and cotherapy on downstream costs, such as the evaluation and management of dyspepsia in addition to serious outcomes such as hospitalization and death. In the absence of clinical trials, we may need to rely on large observational studies to evaluate the relative toxicity of various treatment options, including NSAIDs plus misoprostol, NSAIDs plus proton pump inhibitors, NSAIDs plus high-dose H2-blockers, and COX-2 inhibitors. Outcomes will need to include both serious GI complications and evaluation and treatment for more minor GI symptoms. Prospective trials are needed to assess various therapeutic options (intermittent vs chronic therapy) or sequences of treatments (non-NSAID analgesic, NSAIDs, COX-2 inhibitors) on pain, disability, and quality of life for common specific diseases/syndromes (osteoarthritis of hip or knee, other chronic musculoskeletal pain). In the longer term, agents for assessment may include the potentially safer nitric oxide– donating NSAIDs or those complexed with phosphatidylcholine. Outcomes should include length of time on various treatments, need for cotherapy or evaluation for GI symptoms, and blood pressure effects. Formal economic analyses of such trials will give clinicians relevant measures of the costs and benefits of these agents/regimens. This information can then be placed in perspective with the risk of serious GI toxicity, which will be obtained through larger outcome studies. Place of Safer, More Expensive Agents The availability of safer, more expensive pharmaceutical agents that may reduce the likelihood of untoward events has raised the question of whether all chronic NSAID users should have access to them. The lack of a clear evidence-based justification for their use, coupled with an

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effort to constrain pharmaceutical expenditures, has left this question an open issue. If clinical trials with clinical disease outcomes convincingly demonstrate that a specific NSAID provides relative protection from GI adverse events in high-risk patients, the use of a safer NSAID as a first-line agent may be justified on clinical and economic grounds.61 Whether safer NSAIDs will be preferred to standard NSAIDs with cotherapy to prevent ulcers will depend on relative costs and toxicities as well as patient preferences. The development and validation of userfriendly, noninvasive instrument(s) that accurately identify NSAID users at high risk for adverse events will facilitate the appropriate use of more expensive but safer therapies. Economics Formal economic evaluations of comparative strategies should be performed to assess the clinical and economic tradeoffs accurately. A lower rate of drug-related complications may lead to higher overall expenditures; thus, both the incremental costs and benefits should be carefully measured and compared among available alternatives. On the cost side, it is critical to look beyond direct cost comparisons of drugs under investigation. We must study in detail all the health-care resources incurred over the entire episode of care, especially because a proportion of individuals prescribed one agent may eventually end up being prescribed another. Minimizing Nongastrointestinal Toxicity Knowledge of the serious GI toxicity of NSAIDs led to the development and testing of cotherapy to prevent complications as well as to NSAIDs that may have a much lower risk of serious GI complications. The development of NSAIDs that are renal sparing or that are much less likely to cause hypertension would render these drugs much more desirable. Further knowledge of the potential benefits of NSAIDs on risk of colon cancer and Alzheimer’s disease may result in extending the indications for these drugs if other toxicities can be minimized.




9. 10.










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46. Ward MM, Fries JF. Trends in antirheumatic medication use among patients with rheumatoid arthritis, 1981–1996. J Rheumatol. 1998;25:408 – 416. 47. Hochberg MC, Altman RD, Brandt KD, et al. Guidelines for the medical management of osteoarthritis. Part I: Osteoarthritis of the hip. Arthritis Rheum. 1995;38:1535–1540. 48. Hochberg MC, Altman RD, Brandt KD, et al. Guidelines for the medical management of osteoarthritis. Part II: Osteoarthritis of the knee. Arthritis Rheum. 1995;38:1541–1546. 49. Griffin MR, Brandt KD, Liang MH, et al. Practical management of osteoarthritis: integration of pharmacologic and nonpharmacologic measures. Arch Fam Med. 1995;4: 1049 –1055. 50. Henry D, Lim LL, Garcia Rodriguez LA, et al. Variability in risk of gastrointestinal complications with individual nonsteroidal anti-inflammatory drugs: results of a collaborative meta-analysis. BMJ. 1996;312:1563–1566. 51. 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;338:727–734. 52. 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: 1435–1439. 53. Koch M, Capurso L, Dezi A, et al. Prevention of NSAIDinduced gastroduodenal mucosal injury: meta-analysis of clinical trials with misoprostol and H2-receptor antagonists. Dig Dis. 1995;13(suppl 1):62–74. 54. Singh G, Ramey DR, Morfeld D, et al. Gastrointestinal tract complications of nonsteroidal anti-inflammatory drug treatment in rheumatoid arthritis. A prospective observational cohort study. Arch Intern Med. 1996;156:1530 –1536. 55. Barradell LB, Whittington R, Benfield P. Misoprostol: pharmacoeconomics of its use as prophylaxis against gastroduodenal damage induced by nonsteroidal anti-inflammatory drugs [published erratum appears in Pharmacoeconomics. 1994;6:185]. Pharmacoeconomics. 1993;3:140 –171. 56. Raskin JB, White RH, Jackson JE, et al. Misoprostol dosage in the prevention of nonsteroidal anti-inflammatory drug-induced gastric and duodenal ulcers: a comparison of three regimens. Ann Intern Med. 1995;123:344 –350. 57. Gabriel SE, Campion ME, O’Fallon M. Patient preferences for nonsteroidal antiinflammatory drug related gastrointestinal complications and their prophylaxis. J Rheumatol. 1993;20:358 –361. 58. Garcia Rodriguez LA, Ruigomez A. Secondary prevention of upper gastrointestinal bleeding associated with maintenance acid-suppressing treatment in patients with peptic ulcer bleed. Epidemiology. 1999;10:228 –232. 59. Goldstein JL, Lefkowith JB. Public misunderstanding of nonsteroidal antiinflammatory drug (NSAID)–mediated gastrointestinal (GI) toxicity: a serious potential health threat [abstract]. Gastroenterology. 1998;114:G0555. 60. Weil J, Colin-Jones C, Langman M, et al. Prophylactic aspirin and risk of peptic ulcer bleeding. BMJ. 1995;310: 827– 830. 61. Fendrick AM, Bandekar R, Chernew ME, Scheiman JM. Impact of NSAID choice and patient symptoms on the cost-effectiveness of strategies to prevent NSAID gastropathy [abstract]. Gastroenterology. 1998;114:A120.

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- Marie R. Griffin y James M. Prospects for Changing the Burden of Nonsteroidal Anti-Inflammatory Drug Toxicity.Am J Med. 2001;110(1A):33S–3...