Management of Gastroduodenopathy Associated With Use of Nonsteroidal Anti-Inflammatory Drugs
1992; Elsevier BV; Volume: 67; Issue: 4 Linguagem: Inglês
10.1016/s0025-6196(12)61552-3
ISSN1942-5546
AutoresDavid S. Loeb, David A. Ahlquist, Nicholas J. Talley,
Tópico(s)Autoimmune Bullous Skin Diseases
ResumoAdverse events associated with the use of nonsteroidal anti-inflammatory drugs (NSAIDs) are reported more frequently to the Food and Drug Administration than are those associated with any other group of drugs. The absolute risk for serious gastrointestinal events—in particular, ulcer bleeding, perforation, and death—is controversial; some investigators believe that an epidemic of NSAID-related complications is being experienced, whereas others suggest that the risks are being overemphasized. The management of patients who take NSAIDs regularly also remains controversial. Key unresolved issues include how best to identify those patients at particularly high risk for the development of ulcer complications and whether such patients should receive prophylactic therapy in an attempt to prevent such problems. In this review, we critically evaluate the currently available literature and present a management algorithm for the treatment and prevention of NSAID-associated gastroduodenopathy. Adverse events associated with the use of nonsteroidal anti-inflammatory drugs (NSAIDs) are reported more frequently to the Food and Drug Administration than are those associated with any other group of drugs. The absolute risk for serious gastrointestinal events—in particular, ulcer bleeding, perforation, and death—is controversial; some investigators believe that an epidemic of NSAID-related complications is being experienced, whereas others suggest that the risks are being overemphasized. The management of patients who take NSAIDs regularly also remains controversial. Key unresolved issues include how best to identify those patients at particularly high risk for the development of ulcer complications and whether such patients should receive prophylactic therapy in an attempt to prevent such problems. In this review, we critically evaluate the currently available literature and present a management algorithm for the treatment and prevention of NSAID-associated gastroduodenopathy. Although the frequent side effects associated with nonsteroidal anti-inflammatory drugs (NSAIDs) have been increasingly recognized, more than 30 billion NSAIDs are consumed annually in the United States alone; an estimated 1.2% of the population take NSAIDs regularly, and many more persons take them intermittently.1Baum C Kennedy DL Forbes MB Utilization of nonsteroidal antiinflammatory drugs.Arthritis Rheum. 1985; 28: 686-692Crossref PubMed Google Scholar, 2Graham DY Prevention of gastroduodenal injury induced by chronic nonsteroidal antiinflammatory drug therapy.Gastroenterology. 1989; 96: 675-681Abstract Full Text PDF PubMed Google Scholar The physician who prescribes an NSAID must balance the analgesic and antiinflammatory benefit against the potential toxic effects, particularly those that involve the gastrointestinal tract. The management of NSAID-induced gastroduodenopathy, however, remains controversial, especially in regard to long-term prophylaxis. Herein we review gastrointestinal NSAID toxicity, risk factors for development, and options for treatment and prevention. Adverse effects from NSAIDs, predominantly gastrointestinal, are reported more frequently to the Food and Drug Administration in the United States and to the Committee on Safety of Medicines in the United Kingdom than are those from any other group of drugs, even though most adverse events are unreported.3Griffin JP Survey of the spontaneous adverse drug reaction reporting schemes in fifteen countries.Br J Clin Pharmacol. 1986; 22: 83S-100SCrossref PubMed Google Scholar, 4Non-steroidal anti-inflammatory drugs and serious gastrointestinal adverse reactions—1.Br Med J. 1986; 292: 614Crossref PubMed Google Scholar, 5Langman MJS Epidemiologic evidence on the association between peptic ulceration and antiinflammatory drug use.Gastroenterology. 1989; 96: 640-646PubMed Google Scholar As many as 60% of all patients who take NSAIDs have silent gastroduodenal damage that consists of intramucosal hemorrhages or erosions.5Langman MJS Epidemiologic evidence on the association between peptic ulceration and antiinflammatory drug use.Gastroenterology. 1989; 96: 640-646PubMed Google Scholar, 6Soll AH Weinstein WM Kurata J McCarthy D Nonsteroidal anti-inflammatory drugs and peptic ulcer disease.Ann Intern Med. 1991; 114: 307-319Crossref PubMed Google Scholar, 7Graham DY Agrawal NM Roth SH Prevention of NSAID-induced gastric ulcer with misoprostol: multicentre, double-blind, placebo-controlled trial.Lancet. 1988; 2: 1277-1280Abstract PubMed Google Scholar Estimates of point prevalence for chronic peptic ulcer disease in patients receiving long-term NSAID therapy range from 10 to 30%, a 10- to 30-fold increase over that in the general population.2Graham DY Prevention of gastroduodenal injury induced by chronic nonsteroidal antiinflammatory drug therapy.Gastroenterology. 1989; 96: 675-681Abstract Full Text PDF PubMed Google Scholar, 5Langman MJS Epidemiologic evidence on the association between peptic ulceration and antiinflammatory drug use.Gastroenterology. 1989; 96: 640-646PubMed Google Scholar, 6Soll AH Weinstein WM Kurata J McCarthy D Nonsteroidal anti-inflammatory drugs and peptic ulcer disease.Ann Intern Med. 1991; 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32: 730-734Crossref PubMed Google Scholar, 13McIntosh JH Fung CS Berry G Piper DW 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; 128: 761-770PubMed Google Scholar, 14Levy M Miller DR Kaufman DW Siskind V Schwingl P Rosenberg L Strom B Shapiro S Major upper gastrointestinal tract bleeding: relation to the use of aspirin and other nonnarcotic analgesics.Arch Intern Med. 1988; 148: 281-285Crossref PubMed Google Scholar, 15Griffin MR Ray WA Schaffner W Nonsteroidal anti-inflammatory drug use and death from peptic ulcer in elderly persons.Ann Intern Med. 1988; 109: 359-363Crossref PubMed Google Scholar, 16Armstrong CP Blower AL Non-steroidal anti-inflammatory drugs and life threatening complications of peptic ulceration.Gut. 1987; 28: 527-532Crossref PubMed Google Scholar, 17Henry DA Johnston A Dobson A Duggan J Fatal peptic ulcer complications and the use of non-steroidal anti-inflammatory drugs, aspirin, and corticosteroids.Br Med J. 1987; 295: 1227-1229Crossref PubMed Google Scholar, 18Jick SS Perera DR Walker AM Jick H Non-steroidal anti-inflammatory drugs and hospital admission for perforated peptic ulcer.Lancet. 1987; 2: 380-382Abstract PubMed Google Scholar, 19Bartle WR Gupta AK Lazor J Nonsteroidal anti-inflammatory drugs and gastrointestinal bleeding: a case-control study.Arch Intern Med. 1986; 146: 2365-2367Crossref PubMed Google Scholar, 20Collier DSJ Pain JA Non-steroidal anti-inflammatory drugs and peptic ulcer perforation.Gut. 1985; 26: 359-363Crossref PubMed Google Scholar, 21Somerville K Faulkner G Langman M Non-steroidal anti-inflammatory drugs and bleeding peptic ulcer.Lancet. 1986; 1: 462-464Abstract PubMed Google Scholar and cohort studies18Jick SS Perera DR Walker AM Jick H Non-steroidal anti-inflammatory drugs and hospital admission for perforated peptic ulcer.Lancet. 1987; 2: 380-382Abstract PubMed Google Scholar22Beardon PHG Brown SV McDevitt DG Gastrointestinal events in patients prescribed non-steroidal anti-inflammatory drugs: a controlled study using record linkage in Tayside.Q J Med. 1989; 71: 497-505PubMed Google Scholar, 23Guess HA West R Strand LM Helston D Lydick EG Bergman U Wolski K Fatal upper gastrointestinal hemorrhage or perforation among users and nonusers of nonsteroidal anti-inflammatory drugs in Saskatchewan, Canada 1983.J Clin Epidemiol. 1988; 41: 35-45Abstract Full Text PDF PubMed Google Scholar, 24Bloom BS Risk and cost of gastrointestinal side effects associated with nonsteroidal anti-inflammatory drugs.Arch Intern Med. 1989; 149: 1019-1022Crossref PubMed Google Scholar, 25Carson JL Strom BL Soper KA West SL Morse ML The association of nonsteroidal anti-inflammatory drugs with upper gastrointestinal tract bleeding.Arch Intern Med. 1987; 147: 85-88Crossref PubMed Google Scholar, 26Beard K Walker AM Perera DR Jick H Nonsteroidal antiinflammatory drugs and hospitalization for gastroesophageal bleeding in the elderly.Arch Intern Med. 1987; 147: 1621-1623Crossref PubMed Google Scholar, 27Jick H Feld AD Perera DR Certain nonsteroidal antiinflammatory drugs and hospitalization for upper gastrointestinal bleeding.Pharmacotherapy. 1985; 5: 280-284PubMed Google Scholar have attempted to determine the relative risk of ulcer complications in persons who take NSAIDs; these risks have varied considerably among studies (Table 1). Unfortunately, cohort studies have generally relied on secondary analyses of health insurance registries; therefore, they may have underestimated the risks because of misclassification errors (for example, including control subjects as patients and vice versa) and availability of suboptimal data on exposure to NSAIDs.5Langman MJS Epidemiologic evidence on the association between peptic ulceration and antiinflammatory drug use.Gastroenterology. 1989; 96: 640-646PubMed Google Scholar, 29Gabriel 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: 787-796Crossref PubMed Google Scholar In contrast, some case-control studies may have overestimated the risks because determination of exposure to NSAIDs might have been more aggressively pursued in patients than in control subjects.5Langman MJS Epidemiologic evidence on the association between peptic ulceration and antiinflammatory drug use.Gastroenterology. 1989; 96: 640-646PubMed Google Scholar, 29Gabriel 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: 787-796Crossref PubMed Google Scholar On the basis of pooled estimates in a recent high-quality meta-analysis, the risk of major adverse gastrointestinal events is approximately 3 times greater in persons who take NSAIDs than in those who do not.29Gabriel 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: 787-796Crossref PubMed Google ScholarTable 1Summary of Selected Reports of the Estimates of Relative Risk of Ulcers and Ulcer Complications Associated With Nonaspirin Nonsteroidal Anti-Inflammatory Drugs*Similar relative risks have been found in studies of aspirin.28OutcomeReferenceRelative risk95% CI†CI = confidence interval.Ulcer occurrence GastricDuggan et al8Duggan JM Dobson AJ Johnson H Fahey P Peptic ulcer and non-steroidal anti-inflammatory agents.Gut. 1986; 27: 929-933Crossref PubMed Google Scholar5.01.4–26.9McIntosh et al9McIntosh JH Byth K Piper DW Environmental factors in aetiology of chronic gastric ulcer: a case control study of exposure variables before the first symptoms.Gut. 1985; 26: 789-798Crossref PubMed Google Scholar4.71.3–16.6 DuodenalDuggan et al8Duggan JM Dobson AJ Johnson H Fahey P Peptic ulcer and non-steroidal anti-inflammatory agents.Gut. 1986; 27: 929-933Crossref PubMed Google Scholar1.10.4–3.7 Type unspecifiedGriffin et al10Griffin MR Piper JM Daugherty JR Snowden M Ray WA Nonsteroidal anti-inflammatory drug use and increased risk for peptic ulcer disease in elderly persons.Ann Intern Med. 1991; 114: 257-263Crossref PubMed Google Scholar4.13.5–4.7Ulcer complication Bleeding GastricSomerville et al21Somerville K Faulkner G Langman M Non-steroidal anti-inflammatory drugs and bleeding peptic ulcer.Lancet. 1986; 1: 462-464Abstract PubMed Google Scholar2.81.5–5.4Holvoet et al12Holvoet J Terriere L Van Hee W Verbist L Fierens E Hautekeete ML Relation of upper gastrointestinal bleeding to non-steroidal anti-inflammatory drugs and aspirin: a case-control study.Gut. 1991; 32: 730-734Crossref PubMed Google Scholar9.02.5–32.5 DuodenalSomerville et al21Somerville K Faulkner G Langman M Non-steroidal anti-inflammatory drugs and bleeding peptic ulcer.Lancet. 1986; 1: 462-464Abstract PubMed Google Scholar2.71.3–5.8Holvoet et al12Holvoet J Terriere L Van Hee W Verbist L Fierens E Hautekeete ML Relation of upper gastrointestinal bleeding to non-steroidal anti-inflammatory drugs and aspirin: a case-control study.Gut. 1991; 32: 730-734Crossref PubMed Google Scholar6.52.5–16.9 Perforation (type unspecified)Collier & Pain20Collier DSJ Pain JA Non-steroidal anti-inflammatory drugs and peptic ulcer perforation.Gut. 1985; 26: 359-363Crossref PubMed Google Scholar7.34.4–11.8Jick et al18Jick SS Perera DR Walker AM Jick H Non-steroidal anti-inflammatory drugs and hospital admission for perforated peptic ulcer.Lancet. 1987; 2: 380-382Abstract PubMed Google Scholar1.60.7–3.7Ulcer deathGastricGriffin et al15Griffin MR Ray WA Schaffner W Nonsteroidal anti-inflammatory drug use and death from peptic ulcer in elderly persons.Ann Intern Med. 1988; 109: 359-363Crossref PubMed Google Scholar4.21.9–9.0 DuodenalGriffin et al15Griffin MR Ray WA Schaffner W Nonsteroidal anti-inflammatory drug use and death from peptic ulcer in elderly persons.Ann Intern Med. 1988; 109: 359-363Crossref PubMed Google Scholar7.93.7–16.8Modified from Langman and associates.28Langman MJS Brooks P Hawkey CJ Silverstein F Yeomans N Non-steroidal anti-inflammatory drug associated ulcer: epidemiology, causation and treatment.J Gastroenterol Hepatol. 1991; 6: 442-449Crossref PubMed Google Scholar By permission of Blackwell Scientific Publications.* Similar relative risks have been found in studies of aspirin.28Langman MJS Brooks P Hawkey CJ Silverstein F Yeomans N Non-steroidal anti-inflammatory drug associated ulcer: epidemiology, causation and treatment.J Gastroenterol Hepatol. 1991; 6: 442-449Crossref PubMed Google Scholar† CI = confidence interval. Open table in a new tab Modified from Langman and associates.28Langman MJS Brooks P Hawkey CJ Silverstein F Yeomans N Non-steroidal anti-inflammatory drug associated ulcer: epidemiology, causation and treatment.J Gastroenterol Hepatol. 1991; 6: 442-449Crossref PubMed Google Scholar By permission of Blackwell Scientific Publications. Bleeding is the most common serious complication of ulcers associated with long-term NSAID therapy, especially in elderly patients.5Langman MJS Epidemiologic evidence on the association between peptic ulceration and antiinflammatory drug use.Gastroenterology. 1989; 96: 640-646PubMed Google Scholar, 6Soll AH Weinstein WM Kurata J McCarthy D Nonsteroidal anti-inflammatory drugs and peptic ulcer disease.Ann Intern Med. 1991; 114: 307-319Crossref PubMed Google Scholar, 29Gabriel 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: 787-796Crossref PubMed Google Scholar For example, of all patients with bleeding peptic ulcers who were admitted to a community hospital in Nottingham, England, during a 2-year period, 35% of those 60 years of age or older had taken NSAIDs before admission in comparison with only 16% of community control subjects and 14% of hospital control subjects.21Somerville K Faulkner G Langman M Non-steroidal anti-inflammatory drugs and bleeding peptic ulcer.Lancet. 1986; 1: 462-464Abstract PubMed Google Scholar Although epidemiologic data have suggested a trend toward fewer hospitalizations and operations for peptic ulcer disease in the general population since 1950, this tendency does not pertain to gastric ulcers in elderly patients, especially in women.28Langman MJS Brooks P Hawkey CJ Silverstein F Yeomans N Non-steroidal anti-inflammatory drug associated ulcer: epidemiology, causation and treatment.J Gastroenterol Hepatol. 1991; 6: 442-449Crossref PubMed Google Scholar30Gustavsson S Kelly KA Melton III, LJ Zinsmeister AR Trends in peptic ulcer surgery: a population-based study in Rochester, Minnesota, 1956–1985.Gastroenterology. 1988; 94: 688-694PubMed Google Scholar, 31Gilinsky NH Peptic ulcer disease in the elderly.Scand J Gastroenterol Suppl. 1988; 146: 191-199Crossref PubMed Google Scholar, 32Soll AH Kurata J McGuigan JE Ulcers, nonsteroidal antiinflammatory drugs, and related matters.Gastroenterology. 1989; 96: 561-568PubMed Google Scholar, 33Kurata JH Ulcer epidemiology: an overview and proposed research framework.Gastroenterology. 1989; 96: 569-580PubMed Google Scholar Elderly patients receive NSAID therapy the most frequently; an estimated half of all NSAID prescriptions are for people older than 60 years of age.1Baum C Kennedy DL Forbes MB Utilization of nonsteroidal antiinflammatory drugs.Arthritis Rheum. 1985; 28: 686-692Crossref PubMed Google Scholar, 28Langman MJS Brooks P Hawkey CJ Silverstein F Yeomans N Non-steroidal anti-inflammatory drug associated ulcer: epidemiology, causation and treatment.J Gastroenterol Hepatol. 1991; 6: 442-449Crossref PubMed Google Scholar, 31Gilinsky NH Peptic ulcer disease in the elderly.Scand J Gastroenterol Suppl. 1988; 146: 191-199Crossref PubMed Google Scholar Patients who take NSAIDs have an increased risk of requiring emergency surgical intervention for hemorrhagic or perforated peptic ulcers, and they also have an increased mortality from peptic ulcer disease in comparison with a matched control group.15Griffin MR Ray WA Schaffner W Nonsteroidal anti-inflammatory drug use and death from peptic ulcer in elderly persons.Ann Intern Med. 1988; 109: 359-363Crossref PubMed Google Scholar, 16Armstrong CP Blower AL Non-steroidal anti-inflammatory drugs and life threatening complications of peptic ulceration.Gut. 1987; 28: 527-532Crossref PubMed Google Scholar, 17Henry DA Johnston A Dobson A Duggan J Fatal peptic ulcer complications and the use of non-steroidal anti-inflammatory drugs, aspirin, and corticosteroids.Br Med J. 1987; 295: 1227-1229Crossref PubMed Google Scholar Although NSAIDs are not significantly associated with chronic duodenal ulcers (Table 1), ulcer complications are as commonly of duodenal as of gastric origin; this finding suggests that NSAIDs cause chronic gastric ulcers (and their complications) and cause duodenal complications perhaps only in those patients with preexisting duodenal ulcer disease.12Holvoet J Terriere L Van Hee W Verbist L Fierens E Hautekeete ML Relation of upper gastrointestinal bleeding to non-steroidal anti-inflammatory drugs and aspirin: a case-control study.Gut. 1991; 32: 730-734Crossref PubMed Google Scholar, 21Somerville K Faulkner G Langman M Non-steroidal anti-inflammatory drugs and bleeding peptic ulcer.Lancet. 1986; 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(editorial).J Rheumatol. 1990; 17: 1-4PubMed Google Scholar For example, if the absolute risk of peptic ulcer complications is 1 case per 1,000 persons among those who do not take NSAIDs, then a relative risk of 3 in those who take NSAIDs translates into a complication rate of only 3 cases per 1,000 persons. The absolute risk of NSAIDs remains a contentious issue although the individual risk is probably small. Although retrospective cohort studies estimate the absolute risk of serious adverse events to be from 2 cases per 1,000 persons to 4 per 100,000,23Guess HA West R Strand LM Helston D Lydick EG Bergman U Wolski K Fatal upper gastrointestinal hemorrhage or perforation among users and nonusers of nonsteroidal anti-inflammatory drugs in Saskatchewan, Canada 1983.J Clin Epidemiol. 1988; 41: 35-45Abstract Full Text PDF PubMed Google Scholar, 26Beard K Walker AM Perera DR Jick H Nonsteroidal antiinflammatory drugs and hospitalization for gastroesophageal bleeding in the elderly.Arch Intern Med. 1987; 147: 1621-1623Crossref PubMed Google Scholar substantially higher yearly estimates of risk have been reported to the Food and Drug Administration and have been observed in a rheumatoid arthritis registry—2 to 4% and 1%, respectively.40Labeling revisions for NSAIDs.FDA Drug Bull. 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On the basis of their registry, Fries and co-workers41Fries JF Miller SR Spitz PW Williams CA Hubert HB Bloch DA Toward an epidemiology of gastropathy associated with nonsteroidal antiinflammatory drug use.Gastroenterology. 1989; 96: 647-655Abstract Full Text PDF PubMed Google Scholar estimated that, for rheumatoid arthritis alone, 20,000 hospitalizations and 2,600 deaths would be attributable to NSAIDs annually in the United States. The medical costs of gastrointestinal complications from NSAIDs have been calculated to be $3.9 billion per year.26Beard K Walker AM Perera DR Jick H Nonsteroidal antiinflammatory drugs and hospitalization for gastroesophageal bleeding in the elderly.Arch Intern Med. 1987; 147: 1621-1623Crossref PubMed Google Scholar Because of the suspected high incidence of ulceration, hemorrhage, and perforation, the Food and Drug Administration has mandated that all NSAIDs have package insert warnings.40Labeling revisions for NSAIDs.FDA Drug Bull. 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