THERAPEUTIC CONTROVERSIES Edited by Dennis F. Thompson and Marsha A. Raebel
PREVENTING UPPER GASTROINTESTINAL BLEEDING IN PATIENTS RECEIVING NONSTEROIDAL ANTIINFLAMMATORY DRUGS DavidP. Elliott
ABSTRACf: Severe upper gastrointestinal (Gl) bleeding is a serious adverse effect of nonsteroidal antiinflammatory drugs (NSAIDs) and the elderly are at increased risk of developing this complication. Bleeding episodes can be prevented. Replacing NSAIDs with acetaminophen may be appropriate when a simple analgesic is needed that eliminates the risk ofGI bleeding. Using the lowest effective NSAID dose may decrease the incidence and severity of NSAID gastropathy. Histamine Hj-receptor antagonists, sucralfate, and misoprostol have been studied for the prevention of NSAID gastropathy, but only misoprostol prevents mucosal injury in both the stomach and duodenum. Patients who have a history of peptic ulcer disease or gastric bleeding from NSAIDs are candidates for prophylactic measures. Although other patients are at risk, no one knows who should receive prophylactic therapy for NSAID gastropathy. Future studies should attempt to define patient populations that warrant prophylactic therapy.
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ASPIRIN and other nonsteroidal antiinflammatory drugs (NSAIDs) are among the most commonly used drugs in the U.S. In 1987, American pharmacies filled 74 million prescriptions for NSAIDs representing 4.5 percent of all prescriptions dispensed that year. I This figure does not include the millions of prescriptions issued for aspirin or for over-the-counter (O'TC) uses of aspirin and ibuprofen. As many as 15-25 percent of these chronic users of NSAIDs may have gastric ulcers.s-' Although only a few of these patients will develop acute bleeding, the results can be cata-
DAVID P. ELLIOTI, Pharm.D.• is an Assistant Professor and the Vice-Chair. Department of Clinical Phannacy, School of Phannacy, West Virginia University Health SCiences Center. Charleston Division, 3110 MacCorkIe Ave., SE, Charleston, WV 25304. Reprints: David P. Elliott, Pharm.D. DENNIS F. THOMPSON, Pharm.D., is the Director, Drug Information Service, and an Associate Professor of Pharmacy Practice. University of Oklahoma Health Sciences Center. Oklahoma City, OK 73190; and MARSHA A. RAEBEL, Pharm. D .• is the Coordinator of Drug Information and Clinical Pharmacy. Scott and White Memorial Hospital, and an Assistant Professor of Medicine, Texas A&M University, College of Medicine, Temple. TX 76508.
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strophic (prolonged hospitalization, surgical intervention, or death). The elderly consume half of the NSAIDs prescribed and are most likely to develop severe acute gastrointestinal (GI) bleeding. The elderly deserve special attention when considering steps to minimize GI toxicity induced by NSAIDs. 4 ,5 Throughout this article the term NSAID will refer to all nonsteroidal antiinflammatory drugs, including aspirin and other salicylates. The term NSAID gastropathy is a label for the continuum of toxicity caused by the drugs of this class, varying from small acute hemorrhages to large chronic ulcers." Acute injuries such as petechiae and erosions often heal as the GI tract adapts to the NSAID. During chronic therapy, however, ulcers develop and occasionally bleed or perforate. 7 Symptoms of gastric intolerance, such as pain and dyspepsia, do not necessarily indicate that an ulcer is present. In fact, many gastric ulcers caused by chronic NSAID use bleed without warning, especially in the elderly." NSAID gastropathy is a separate condition from peptic ulcer disease. Injury caused by these drugs more frequently occurs in the antral and prepyloric portions of the stomach instead of the duodenum. Patients at risk are older than those with classic peptic ulcer disease." Gastric injury is mediated by cyclooxygenase inhibition but other mechanisms may be involved. NSAIDs enhance basal and stimulate gastric acid secretion, which reduces bicarbonate secretion by the endothelium. Oxygen-free radical generation results in microvascular injury and decreased blood flow in the endothelium. Aspirin and phenylbutazone cause other measurable changes in the gastric mucosa such as ion trapping, acid back diffusion, and transmucosal potential differences.v" It has not been established which mechanisms cause lesions that progress to clinically significant gastric ulcers. Schoen and Vender proposed that prostaglandin inhibition aggravates injuries produced by the other mechanisms and prevents normal healing. 9
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Table I. Summary of Trials Studying NSAID Gastropathy Prevention PATIENTS CONDITION
(n)
ibuprofen, piroxicam, naproxen
OA
139 143 138
misoprostol 200 IJ.g qid 3 mo misoprostol 100 IJ.g qid placebo
17
naproxen, piroxicam, diclofenac, indomethacin
OA, RA
137 126
ranitidine ISO mg bid placebo
8 wk
23
various ibuprofen, naproxen, sulindac, indomethacin, piroxicam OA, unspecified RA, other
57 49
ranitidine ISO mg bid placebo
8 wk
62 57
ranitidine ISO mg bid placebo
8 wk
43 42 12 14
cimetidine 300 mg qid placebo cimetidine 800 mg hs placebo
8 wk
7d
REFERENCE
2
24
25
NSAID
unspecified
OA, RA
TREATMENT
DURATION
10 mo
26
aspirin 975 mg qid
OA
19 22
misoprostol 200 IJ.g qid placebo
27
aspirin 975 mg qid
healthy
28
aspirin 650 mg qid tolmetin
healthy
12 12 12 16 16 30 29 30
2d misoprostol 50 IJ.g qid misoprostol 25 IJ.g qid placebo misoprostol 25 IJ.g qid 3d placebo cimetidine 300 mg qid 6d misoprostol 200 IJ.g qid placebo
29
healthy
30
aspirin 650 mg qid
healthy
10 10 10
sucralfate I g qid 6d misoprostol 200 IJ.g qid placebo
31
aspirin 975 mg qid
healthy
32
ibuprofen 800 mg qid
healthy
30 29 30 30 30 30 30 30
misoprostol misoprostol misoprostol placebo misoprostol misoprostol misoprostol placebo
33
naproxen 500 mg bid
healthy
12 13
misoprostol 200 IJ.g bid 7d placebo
34
tolmetin 500 mg qid
healthy
30 30
misoprostol 200 IJ.g qid placebo
7d
35
aspirin 650 mg qid
healthy
24 19
ranitidine ISO mg bid placebo
4wk
200 IJ.g qid 100 IJ.g qid 50 IJ.g qid
7d
50 IJ.g qid 100 IJ.g qid 200 IJ.g qid
7d
RESULTS
Fewer gastric ulcers :::0.3 cm with misoprostol than placebo. Trend toward fewer ulcers with the higher dose as compared with low dose. Ulcer incidence: placebo 21.5%, 100 IJ.g 5.6%,200 IJ.g 1.4% Gastric ulcers present in 6% of patients in each group at end of study. No difference in gastric injury between groups. Fewer duodenal ulcers with ranitidine (1.5%) than placebo (8%). Patients on piroxicam developed ulcers more frequently than on naproxen (16 vs. 9%). Same gastric injury in both groups. Gastric ulcers developed in 10% on ranitidine and 12% on placebo. Significantly less duodenal injury with ranitidine.
Abstract. Normal endoscopy at start. No differences in gastric damage. Less duodenal injury with ranitidine at 4 and 8 wk. Duodenal ulcers developed in 4 subjects on placebo and none on ranitidine after 4 wk. Gastric injury progressed in 56% of patients on cimetidine and 52% on placebo. Only selected patients with normal or hyperemic mucosa (no erosions or ulcers) were included. Some patients received steroids. Gastric injury progressed in 42% on cimetidine and 50% on placebo. lion misoprostol vs. I on placebo had at least a 50% reduction in fecal blood loss. Aspirin was started 3 wk before misoprostol. Crossover design with I-wk washout between treatments. Bleeding and gastric secretion significantly less with misoprostol. Significantly less fecal blood loss in patients receiving misoprostol. Success (no more than 2-10 hemorrhages or erosions and no ulcers) achieved in 26.7% on placebo, 63.3% on cimetidine, and 93.1% on misoprostol in both stomach and duodenum. Differences were significant among all groups for the stomach. Misoprostol and cimetidine were not different for the duodenum. Same criteria as reference 29. Less gastric injury with misoprostol than the other two groups. Misoprostol and sucralfate were more effective than placebo in the duodenum. Higher incidence of ulcers 0.4 cm with placebo (43%) than misoprostol (0%). Significantly fewer gastric erosions and duodenal injury with misoprostol. Stomach: less damage than placebo at all doses. No differences among different doses. Duodenum: 200 and 100 IJ.g different from 50 IJ.g and placebo. Higher incidence of abdominal pain with largest misoprostol dose than other treatments. Did not evaluate the duodenum. Significantly less bleeding lesions and erosions in the antrum of the stomach. Fewer bleeding lesions in the gastric corpus and fundus. Same criteria as reference 29. Successful protection of the stomach achieved more frequently with misoprostol (90%) than placebo (24%). Less injury occurred in the duodenum, and less occurred with misoprostol, but "success" rates were similar for both groups. Fewer duodenal erosions and gastric submucosal hemorrhages with ranitidine. No difference in number of gastric erosions between groups.
NSAID = nonsteroidal antiinflammatory drug; OA = osteoarthritis; RA = rheumatoid arthritis.
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Epidemiology and Risk Factors The exact prevalence of gastric ulcers among NSAID users is unknown. Studies reporting ulcer rates among subjects taking NSAIDs had no pretreatment figures for comparison; therefore, some of the lesions seen on entry into these studies could have been due to other causes. However, McCarthy reported that the prevalence of gastric ulcers among the general population is 0.28 percent. 10 A review of NSAID gastropathy reported a point prevalence of 13 percent for gastric ulcers among NSAID users in eight studies. Graham et al. found ulcers in 25 percent of their subjects who had received NSAIDs for at least three months and were complaining of abdominal pain. 2 Larkai et al. found a 15.4 percent prevalence of gastric or duodenal ulcers among 65 patients (63 men, 2 women) who had received a NSAID daily for at least six weeks; when considering all lesions, injury was present in 68 percent of these patients. Symptoms of GI intolerance did not predict endoscopic findings because symptoms were present in 19 percent of those with normal endoscopy and 9 percent of those with abnormal findings." No one knows how often chronic ulcers fail to heal and cause acute bleeding or perforation. A multicenter study of patients with rheumatoid arthritis found that NSAID users were 6.45 times as likely to be hospitalized for GI illness than nonusers. Fries et al. estimate that NSA!D~ account for at least 2600 excess deaths due to GI bleeding among the two million patients with rheumatoid arthritis in the U.S. These authors reported that NSAID gastropathy is the most common adverse drug reaction given the frequency of NSAID use and the prevalence of NSAID gastropathy." NSAIDs increase the risk of hospitalization and mortality in elderly patients. 4 ,s.n.u Aspirin and other NSAID users aged 60 and over are two to three times more likely to be hospitalized with bleeding ulcers. n.13 People 60 years of age and older taking NSAIDs are 4.7 times more likely to die from ulcer hemorrhage or perforation than nonusers of the same age. S In contrast, a retrospective analysis of a population less than 65 years of age did not find that NSAIDs increased the risk of hospitalization from ulcers or related conditions." NSAIDs may differ in their propensity for causing acute injury.r-? Aspirin causes the greatest amount of acute damage whereas other drugs, such as sulindac and nonacetylated salicylates, spare the gastric mucosa after single doses. In contrast, no NSAIDs, including prodrugs (e.g., sulindac) and nonacetylated salicylates (e.g., salsalate, choline, magnesium salicylate), have been shown to be free of the risk of causing gastric ulcers when taken on a chronic basis. Chronic gastric injury may be dose-related as only aspirin doses above 14 to 22 tablets per week increase the risk of developing gastric ulcers. 10 Patients taking more than one NSAID at a time have an increased risk of developing gastric erosions. IS GI damage occurring with chronic use may be more common or more severe with some NSAIDs than others. An analysis of Medicaid billing data found that patients receiving sulindac had a higher prevalence of upper GI bleeding than those taking ibuprofen. Other drugs (indomethacin, naproxen sodium, phenylbutazone, and tolmetin) included in the Medicaid database were not associated with increased risk when compared with ibuprofen, The authors of the report postulated that the higher risk was
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because sulindac doses routinely prescribed were higher than the other drugs. However, uncontrolled variables may have conferred the excess risk instead of sulindac." Piroxicam, as with sulindac, may increase the risk of damage to the GI tract with chronic use when compared with other NSAIDs. A prospective trial comparing ranitidine with placebo to prevent gastroduodenal damage by NSAIDs in patients with arthritis found greater duodenal damage with piroxicam than naproxen. Greater damage occurred only in the placebo group but a higher incidence of ulcers was reported in patients receiving piroxicam. Although dosing information for each drug was not published, the selection criteria required that the patients be taking doses at least as high as naproxen 750 mg/d or piroxicam 20 rng/d." In contrast to other nonopioid analgesics, acetaminophen does not seem to cause gastric ulcers. n.u An association between acetaminophen and GI bleeding reported by older studies is probably not present; those studies did not control for acetaminophen as a substitute for NSAIDs in patients who had already developed ulcers. iz The largest number of ulcers and complications occur in elderly women. This population consumes the greatest number of NSAIDs and may receive the largest dosages when corrected for body weight." Additional factors, such as cigarette smoking, alcohol use, corticosteroid use, and previous peptic ulcers, probably also increase the risk of NSAID-induced ulcers among this group.v'"
Treatment McCarthy reported that most ulcers induced by NSAIDs heal when treated with conventional ulcer therapy even when the offending drug is continued. 10 Antacids, histamine Hrreceptor antagonists, and misoprostol heal gastric ulcers in :::;12 weeks.P-" Gastric ulcers 5 mm may need longer treatment. Sucralfate may not be effective for gastric ulcers caused by NSAIDs. Duodenal ulcers are less common, heal more easily and can be effectively treated with antacids, Hj-receptor antagonists, sucralfate, or misoprostol. iz
Prevention The greatest challenge in NSAID use is prevention of gastric ulcers that bleed or perforate. Preventive measures include: (1) minimize use of NSAIDs for all patients, particularly the elderly; (2) optimize nondrug therapy when appropriate; (3) use acetaminophen instead of NSAIDs when patients need a simple analgesic without antiinflammatory properties; and (4) minimize smoking and alcohol intake. Sulindac and piroxicam should be considered as secondline therapy because of increased risk of gastric ulcer formation compared with other drugs. 16,17 NSAID doses should be reduced to the lowest effective levels and frequencies; only one NSAID should be used at a time. Other measures (e.g., dosing with meals, early in the day, and with fluid) have been recommended" and may reduce GI symptoms," but have not been proven to reduce the risk of GI bleeding associated with chronic NSAID consumption. Likewise, enteric-coated and sustained-release aspirin products that may cause less GI discomfort than regular
1990 October, Volume 24
Preventing GI Bleeding
aspirin probably cause gastric ulcers with chronic use. Nonacetylated salicylates likewise may cause gastric ulcers with long-term therapy. to Aside from reducing NSAID exposure, difficult decisions must be made when considering specific drug therapy to prevent acute gastric events. What treatments are effective? Who should be treated? Several studies have evaluated prophylactic therapy including protocols to assess treatments in healthy subjects exposed to a single dose of aspirin.W.22 Such regimens, however, do not predict the efficacy of a drug or treatment in clinical practice since acute GI injury does not predict chronic ulcer formation. As a result, such studies are not reviewed here. Trials that have evaluated the efficacy of prophylactic therapy for periods longer than one day are summarized in Table I. All trials listed in Table I were randomized, placebocontrolled, and double-blind. Patients with arthritis were selected for some studies but others used healthy volunteers. All but three of these studies used endoscopy to evaluate the efficacy of each regimen. 26-28 Each group of investigators used somewhat different criteria to grade GI injury and define therapeutic success. Studies of patients with arthritis continued for seven days to ten months and evaluated the efficacy of misoprostol, ranitidine, and cimetidine. In a study by Graham et al., only misoprostol reduced the frequency of gastric ulcer formation. A trend toward a lower frequency with misoprostol 200 f..l.g qid than with 100 f..l.g qid did not reach statistical significance. The authors did not report data documenting protection for the duodenum." Ranitidine and cimetidine prevent erosions and ulcers in the duodenum but not the stomach. 17.23-25 Although trials using healthy subjects may not be clinically relevant, they facilitate control of variables that may confound patient trials. Because studies conducted on normal volunteers (except one report") have lasted only two to seven days, results may not apply to preventing GI injury from chronic NSAID therapy.f"?" Misoprostol, ranitidine, cimetidine, and sucralfate prevented injury in healthy subjects exposed to aspirin, ibuprofen, naproxen, and tolmetin. As reported in patients with arthritis, only misoprostol prevented gastric erosions and ulcers to a greater extent than placebo. Misoprostol in doses of 100 or 200 f..l.g qid prevented gastric and duodenal injury. A smaller dose of misoprostol (50 f..l.g qid) prevented gastric but not duodenal injury. 32 However, Berkowitz et al. reported that ranitidine protected the stomach from aspirin. Despite fewer gastric submucosal and confluent hemorrhages in the ranitidine group, there were no fewer gastric erosions when compared with placebo. None of the patients developed gastric ulcers. 35 The significance of preventing submucosal gastric hemorrhages is unknown. The lack of protection against gastric erosions found in this study is consistent with the studies using ranitidine in arthritic patients. 17•23, 24 Prospective, controlled studies agree that GI mucosal damage from NSAIDs can be prevented. Misoprostol, H r receptor antagonists, and sucralfate protect the duodenum and misoprostol protects the stomach. But which patients need the protection? Who will develop GI lesions that will perforate or bleed with long-term NSAID therapy? Can drugs prevent acute GI bleeding or perforation? No one knows for sure. Studies that address these questions have
not been published. The clinician must evaluate the individual patient who uses a NSAID. It seems appropriate that patients with histories ofGI bleeding from NSAIDs receive misoprostol. Patients with peptic ulcer disease probably should also be considered for misoprostol therapy. In addition, patients receiving other ulcerogenic drugs chronically, such as glucocorticosteroids, may be candidates for NSAID gastropathy prevention. Fries et al. recommended prophylactic therapy for patients experiencing abdominal pain on NSAID therapy." This suggestion can be debated because abdominal pain does not predict that a clinically significant lesion is present in the GI tract. Pain or discomfort should not be the sole reason to begin prophylactic treatment. 3 Elderly women have also been identified as a high-risk group. IS Although acute G I bleeding and perforations occur most frequently in people over 60, data do not support treating all members of this group. Risk factors may be additive and there may be a threshold level of combinations of these factors at which preventive treatment is indicated." The possible benefits of treatment must be balanced against potential risks. Misoprostol is the only drug that has been shown to protect both the stomach and duodenum from NSAID-induced erosions and ulcers. In a recent review in this journal, misoprostol had few reported adverse effects. 36 However, much remains unknown about its adverse effects and drug interactions that only more extensive use will reveal. Summary
Although NSAID gastropathy is a problem of enormous proportions, particularly among the elderly, it is preventable by replacing aspirin or other NSAIDs with acetaminophen whenever clinically feasible. Using the lowest effective doses of NSAIDs and avoiding sulindac and piroxicam may also prevent GI ulcers. Misoprostol should be used to prevent GI ulcers in patients with a history of GI injury from chronic NSAID use or previous peptic ulcer disease. Other patients may also benefit from prophylaxis but definitive recommendations cannot be made based on existing information. ~
References I. TOMITA DK, BAUM C, KENNEDY DL. KNAPP DE. Drug utilization in the U.S. 1987. Ninth annual review. Rockville, MD: Department of Health and Human Services, Food and Drug Administration, 1988:1-56. 2. GRAHAM DY, AGRAWAL NM, ROTH SH. Prevention of NSAID-induced gastric ulcer with misoprostol: multicentre, double-blind, placebo-controlled trial. Lancet 1988;2:1277-80. 3. LARKAI EN. SMITH JL. LIDSKY MD, GRAHAM DY. Gastroduodenal mucosal and dyspeptic symptoms in arthritis patients during chronic nonsteroidal anti-inflammatory drug use. Am J Gastroenterol1987; 82:1153-8. 4. FRIES JF, MILLER SR, SPITZ PW, WILLIAMS CA, HUBERT HB, BLOCH DA. Toward an epidemiology of gastropathy associated with nonsteroi-
dal antiinflammatory drug use. Gastroenterology 1989; 96:647-55. 5. GRIFFIN MR, RAY WA, SCHAFFNER W. Nonsteroidal antiinflammatory drug use and death from peptic ulcer in elderly persons. Ann Intern Med 1988;109:359-63. 6. SZABO S, SPILL WF, RAINSFORD KD. Non-steroidal anti-inflammatory drug-induced gastropathy: mechanisms and management. Med Toxicol Adverse Drug Exp 1989;4:77-94. 7. GRAHAM DY. Prevention of gastrointestinal injury induced by chronic nonsteroidal antiinflammatory drug therapy. Gastroenterology 1989; 96:675-81.
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8. ROTH SH, BENNETT RE. Nonsteroidal antiinflanunatory drug gastropathy. Arch Intern Med 1987;147:2093-100. 9. SCHOEN RT, VENDER RJ. Mechanisms of nonsteroidal antiinflanunatory drug-induced gastric damage. Am J Med 1989;86:449-58. 10. MCCARTIIY DM. Nonsteroidal antiinflanunatory drug-induced ulcers: management by traditional therapies. Gastroenterology 1989;96: 662-74. II. FAULKNER G, PRJCHARD P,SOMERVILL K, LANGMAN MJS. Aspirin and bleeding peptic ulcers in the elderly. Br MedJ 1988;297:1311-3. 12. MCINTOSH JH, RJNG CS, BERRY G, PIPER DW. Smoking, nonsteroidal anti-inflammatory drugs, and acetaminophen in gastric ulcer. Am J EpidemioI1988;128:761-70. 13. SOMERVILL K, FAULKNER G, LANGMAN M. Non-steroidal antiinflammatory drugs and bleeding peptic ulcer. Lancet 1986;/:462-4. 14. JICK H, FELD AD, PERERA DR. Certain nonsteroidal antiinflanunatory drugs and hospitalization for upper gastrointestinal bleeding. Pharmacotherapy 1985;5:280-4. 15. CARUSO I, PORRO BG. Gastroscopic evaluation of antiinflammatory agents. Br Med J 1980;280:75-8. 16. CARSON JL, STROM BL, MORSE ML, et al. The relative gastrointestinal toxicity of the nonsteroidal antiinflanunatory drugs. Arch Intern Med 1987;147:1054-9. 17. EHSANULLAH RSB, PAGE MC.TILDESLEY G, WOOD JR. Prevention of gastroduodenal damage induced by non-steroidal antiinflammatory drugs: controlled trial of ranitidine. Br Med J 1988;297:1017-21. 18. SOLL AH,KURATA J, MCGUIGAN JE. Ulcers, nonsteroidal antiinflanunatory drugs, and related matters. Gastroenterology 1989;96:561-8. 19. ROTH S, AGRAWAL N, MAHOWALD M, et al. Misoprostol heals gastroduodenal injury in patients with rheumatoid arthritis receiving aspirin. Arch Intern Med 1989;149:775-9. 20. STERN AJ, WARD F, HARTLEY G. Protective effect of sucralfate against aspirin-induced damage to the human gastric mucosa. Am J Med 1987; 83(suppI3B):83-5. 21. SILVERSTEIN FE, KIMMEY MB,SAUNDERS DR, SURAWICZ CM, WILLSON RA, SILVERMAN BA. Gastric protection by rnisoprostol against 1,300 mg of aspirin: an endoscopic dose-response study. Am J Med 1987;83(suppl IA):32-6. 22. SILVERSTEIN FE,KIMMEY MB,SAUNDERS DR,LEVINE DS.Gastric protection by misoprostol against 1300 mg of aspirin: an endoscopic study. Dig Dis Sci 1986;31(suppI2):137S-4IS. 23. ROBINSON MG, GRIFFIN JW, BOWERS J, et al. Effect of ranitidine gastroduodenal mucosal damage induced by nonsteroidal antiinflanunatory drugs. Dig Dis Sci 1989;34:424-8. 24. LANZA F, ROBINSON J, BOWERS J, et al. A multi-center double-blind comparison of ranitidine vs placebo in the prophylaxis of nonsteroidal antiinflammatory drug (NSAID) induced lesions in gastric and duodenal mucosae (abstract). Gastroenterology 1988;94:A250. 25. ROTH SH, BENNETT RE, MITCHELL CS, HARTMAN R1. Cimetidine therapy in nonsteroidal anti-inflanunatory drug gastropathy: doubleblind long-term evaluation. Arch Intern Med 1987;/47: 1798-801. 26. RYAN JR, VARGAS R, CLAY GA, MCMAHON FG. Role of rnisoprostol in reducing aspirin-induced gastrointestinal blood loss in arthritic patients. AmJ Med 1987;83(suppIIA):41-4. 27. HUNT IN, SMITH JL, JIANG CL, KESSLER L. Effect of synthetic prostaglandin E, analog on aspirin-induced gastric bleeding and secretion. Dig Dis Sci 1983;28:897-902. 28. COHEN MM, CLARK L, ARMSTRONG L, D'SOUZA1. Reduction of aspirin-induced fecal blood loss with low-dose rnisoprostol tablets in man. Dig Dis Sci 1985;30:605-11. 29. LANZA FL, ASPINALL RL, SWABB EA, DAVIS RE, RACK MF, RUBIN A. Double-blind, placebo-controlled endoscopic comparison of the mucosal protective effects of misoprostol versus cimetidine on tolrnetin-induced mucosal injury. Gastroenterology 1988;95:289-94. 30. LANZA F, PEACE K, GUSTITUS L, RACK MF, DICKSON B. A blinded endoscopic comparative study of misoprostol versus sucralfate and placebo in the prevention of aspirin-induced gastric and duodenal ulceration. Am J Gastroenterol 1988;83:143-6. 31. JlRANEK GC, KIMMEY MB,SAUNDERS DR,WILLSON RA,SHANAHAN W,SILVERSTEIN FE. Misoprostol reduced gastroduodenal injury from one week of aspirin: an endoscopic study. Gastroenterology 1989; 96:656-61. 32. LANZA FL, FAKOUHI D, RUBIN A, et al. A double-blind placebo-controlled comparison of the efficacy and safety of 50, 100, and 200 mcg of rnisoprostol qid in the prevention of ibuprofen-induced gastric and
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33.
34.
35.
36.
duodenal mucosal lesions and symptoms. Am J Gastroenterol1989; 84:633-6. AADLAND E, FAUSA 0, VATN M, COHEN H, QUINLAN D. Protection by rnisoprostol against naproxen-induced gastric mucosal damage. Am J Med 1987;83(suppl IA):37-40. LANZA FL. A double-blind study of the prophylactic effect of misoprostol on lesions of gastric and duodenal mucosa induced by oral administration of tolmetin in healthy subjects. Dig Dis Sci 1986; 3/(suppI2):13IS-6S. BERKOWITZ JM, ROGENES PR,SHARP IT, WARNER CWo Ranitidine protects against gastroduodenal mucosal damage associated with chronic aspirin therapy. Arch Intern Med 1987;/47:2137-9. JONES JB, BAILEY RTJr. Misoprostol: a prostaglandin E, analog with antisecretory and cytoprotective properties. DICP Ann Pharmacother 1989;23:276-82.
EXTRACTO Sangramiento gastrointestinal severo es uno de los efectos adversos de mas importancia que ocurren secundario a tratamiento con antiinflamatorios no esteroidales (NSAIDs). Algunos autores estiman que es el efecto secundario relacionado al uso de farmacos mas comun dado el uso tan frecuente de los NSAIDs y la prevalencia de esta complicaci6n. En especffico los pacientes envejecientes, quienes consumen aproximadamente la mitad de los NSAIDs recetados, tarnbien estan mas a riesgo para desarrollar gastropatia por el uso de estes. EI potencial para causar un insulto gastrointestinal varia entre los NSAIDs, sin embargo, todos pueden causar el efecto si son ingeridos cr6nicamente. Aquellos pacientes que ingieren mas de un NSAID simultaneamente aumentan aun mas su riesgo. Existen medidas que se pueden utilizar para disminuir los riesgos de sangramiento. Estas incluyen el utilizar acetaminofen cuando se desea obtener exclusivamente un efecto analgesico, y utilizar la dosis mas baja posible del NSAID que sea efectiva. EI uso de sucralfato, antagonistas de los receptores H 2 , y misoprostol son algunas de las modalidades farmacol6gicas que se han estudiado para evitar el desarrollo de gastropatia. Aquellos pacientes que tienen historial de ulceras pepticas 0 sangramiento gastrointestinal previo debido al uso de NSAIDs son candidatos para recibir medidas profilacticas. Aunque otros pacientes tarnbien estan a riesgo, no se conoce quienes son aquellos pacientes que deben recibir profilaxis para la gastropatla inducida por NSAIDs. Estudios realizados en el futuro deben estar dirigidos a definir aquellos pacientes que ameriten profilaxis. WANDA T. MALDONADO RESUME
a
Un des effets indesirables Ie plus important survenir avec les antiinflammatoires non-stercidiens (AINS) est l'hemorragie digestive haute et les personnes agees sont hauts risques de developper cette complication. Cependant, les episodes de saignements peuvent etre prevenus. Lorsqu'un simple analgesique est suffisant, Ie remplacement de I' AINS par de l'acetaminophene peut etre approprie et ainsi eliminer les risques de saignements gastrointestinaux. L'utilisation de la dose minimale efficace de I' AINS peut diminuer I'incidence et la severite des gastropathies induites par les AINS. Les antagonistes des recepteurs H 2 , Ie sucralfate et Ie misoprostol, sont des medicaments qui ont ete etudies dans la prevention des gastropathies aux AINS. Seulle misoprostol previent les traumatismes causes la muqueuse stomacale et duodenale. Les patients ayant des antecedents d'ulcere peptique ou de saignement gastrique suite la prise d'AINS sont des candidats une prophylaxie. Meme si d'autres patients sont risque, personne ne peut dire qui doit recevoir une therapie prophylactique contre les gastropathies dues aux AINS. D'autres etudes devront tenter de definir les populations de patients qui exigent une therapie prophylactique.
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PIERRE DION
PREVENTING UPPER GASTROINTESTINAL BLEEDING IN PATIENTS RECEIVING NONSTEROIDAL ANTIINFLAMMATORY DRUGS DavidP. Elliott
ABSTRACf: Severe upper gastrointestinal (Gl) bleeding is a serious adverse effect of nonsteroidal antiinflammatory drugs (NSAIDs) and the elderly are at increased risk of developing this complication. Bleeding episodes can be prevented. Replacing NSAIDs with acetaminophen may be appropriate when a simple analgesic is needed that eliminates the risk ofGI bleeding. Using the lowest effective NSAID dose may decrease the incidence and severity of NSAID gastropathy. Histamine Hj-receptor antagonists, sucralfate, and misoprostol have been studied for the prevention of NSAID gastropathy, but only misoprostol prevents mucosal injury in both the stomach and duodenum. Patients who have a history of peptic ulcer disease or gastric bleeding from NSAIDs are candidates for prophylactic measures. Although other patients are at risk, no one knows who should receive prophylactic therapy for NSAID gastropathy. Future studies should attempt to define patient populations that warrant prophylactic therapy.
Dlep Ann Pharmacother 1990;24:954-8.
ASPIRIN and other nonsteroidal antiinflammatory drugs (NSAIDs) are among the most commonly used drugs in the U.S. In 1987, American pharmacies filled 74 million prescriptions for NSAIDs representing 4.5 percent of all prescriptions dispensed that year. I This figure does not include the millions of prescriptions issued for aspirin or for over-the-counter (O'TC) uses of aspirin and ibuprofen. As many as 15-25 percent of these chronic users of NSAIDs may have gastric ulcers.s-' Although only a few of these patients will develop acute bleeding, the results can be cata-
DAVID P. ELLIOTI, Pharm.D.• is an Assistant Professor and the Vice-Chair. Department of Clinical Phannacy, School of Phannacy, West Virginia University Health SCiences Center. Charleston Division, 3110 MacCorkIe Ave., SE, Charleston, WV 25304. Reprints: David P. Elliott, Pharm.D. DENNIS F. THOMPSON, Pharm.D., is the Director, Drug Information Service, and an Associate Professor of Pharmacy Practice. University of Oklahoma Health Sciences Center. Oklahoma City, OK 73190; and MARSHA A. RAEBEL, Pharm. D .• is the Coordinator of Drug Information and Clinical Pharmacy. Scott and White Memorial Hospital, and an Assistant Professor of Medicine, Texas A&M University, College of Medicine, Temple. TX 76508.
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strophic (prolonged hospitalization, surgical intervention, or death). The elderly consume half of the NSAIDs prescribed and are most likely to develop severe acute gastrointestinal (GI) bleeding. The elderly deserve special attention when considering steps to minimize GI toxicity induced by NSAIDs. 4 ,5 Throughout this article the term NSAID will refer to all nonsteroidal antiinflammatory drugs, including aspirin and other salicylates. The term NSAID gastropathy is a label for the continuum of toxicity caused by the drugs of this class, varying from small acute hemorrhages to large chronic ulcers." Acute injuries such as petechiae and erosions often heal as the GI tract adapts to the NSAID. During chronic therapy, however, ulcers develop and occasionally bleed or perforate. 7 Symptoms of gastric intolerance, such as pain and dyspepsia, do not necessarily indicate that an ulcer is present. In fact, many gastric ulcers caused by chronic NSAID use bleed without warning, especially in the elderly." NSAID gastropathy is a separate condition from peptic ulcer disease. Injury caused by these drugs more frequently occurs in the antral and prepyloric portions of the stomach instead of the duodenum. Patients at risk are older than those with classic peptic ulcer disease." Gastric injury is mediated by cyclooxygenase inhibition but other mechanisms may be involved. NSAIDs enhance basal and stimulate gastric acid secretion, which reduces bicarbonate secretion by the endothelium. Oxygen-free radical generation results in microvascular injury and decreased blood flow in the endothelium. Aspirin and phenylbutazone cause other measurable changes in the gastric mucosa such as ion trapping, acid back diffusion, and transmucosal potential differences.v" It has not been established which mechanisms cause lesions that progress to clinically significant gastric ulcers. Schoen and Vender proposed that prostaglandin inhibition aggravates injuries produced by the other mechanisms and prevents normal healing. 9
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Table I. Summary of Trials Studying NSAID Gastropathy Prevention PATIENTS CONDITION
(n)
ibuprofen, piroxicam, naproxen
OA
139 143 138
misoprostol 200 IJ.g qid 3 mo misoprostol 100 IJ.g qid placebo
17
naproxen, piroxicam, diclofenac, indomethacin
OA, RA
137 126
ranitidine ISO mg bid placebo
8 wk
23
various ibuprofen, naproxen, sulindac, indomethacin, piroxicam OA, unspecified RA, other
57 49
ranitidine ISO mg bid placebo
8 wk
62 57
ranitidine ISO mg bid placebo
8 wk
43 42 12 14
cimetidine 300 mg qid placebo cimetidine 800 mg hs placebo
8 wk
7d
REFERENCE
2
24
25
NSAID
unspecified
OA, RA
TREATMENT
DURATION
10 mo
26
aspirin 975 mg qid
OA
19 22
misoprostol 200 IJ.g qid placebo
27
aspirin 975 mg qid
healthy
28
aspirin 650 mg qid tolmetin
healthy
12 12 12 16 16 30 29 30
2d misoprostol 50 IJ.g qid misoprostol 25 IJ.g qid placebo misoprostol 25 IJ.g qid 3d placebo cimetidine 300 mg qid 6d misoprostol 200 IJ.g qid placebo
29
healthy
30
aspirin 650 mg qid
healthy
10 10 10
sucralfate I g qid 6d misoprostol 200 IJ.g qid placebo
31
aspirin 975 mg qid
healthy
32
ibuprofen 800 mg qid
healthy
30 29 30 30 30 30 30 30
misoprostol misoprostol misoprostol placebo misoprostol misoprostol misoprostol placebo
33
naproxen 500 mg bid
healthy
12 13
misoprostol 200 IJ.g bid 7d placebo
34
tolmetin 500 mg qid
healthy
30 30
misoprostol 200 IJ.g qid placebo
7d
35
aspirin 650 mg qid
healthy
24 19
ranitidine ISO mg bid placebo
4wk
200 IJ.g qid 100 IJ.g qid 50 IJ.g qid
7d
50 IJ.g qid 100 IJ.g qid 200 IJ.g qid
7d
RESULTS
Fewer gastric ulcers :::0.3 cm with misoprostol than placebo. Trend toward fewer ulcers with the higher dose as compared with low dose. Ulcer incidence: placebo 21.5%, 100 IJ.g 5.6%,200 IJ.g 1.4% Gastric ulcers present in 6% of patients in each group at end of study. No difference in gastric injury between groups. Fewer duodenal ulcers with ranitidine (1.5%) than placebo (8%). Patients on piroxicam developed ulcers more frequently than on naproxen (16 vs. 9%). Same gastric injury in both groups. Gastric ulcers developed in 10% on ranitidine and 12% on placebo. Significantly less duodenal injury with ranitidine.
Abstract. Normal endoscopy at start. No differences in gastric damage. Less duodenal injury with ranitidine at 4 and 8 wk. Duodenal ulcers developed in 4 subjects on placebo and none on ranitidine after 4 wk. Gastric injury progressed in 56% of patients on cimetidine and 52% on placebo. Only selected patients with normal or hyperemic mucosa (no erosions or ulcers) were included. Some patients received steroids. Gastric injury progressed in 42% on cimetidine and 50% on placebo. lion misoprostol vs. I on placebo had at least a 50% reduction in fecal blood loss. Aspirin was started 3 wk before misoprostol. Crossover design with I-wk washout between treatments. Bleeding and gastric secretion significantly less with misoprostol. Significantly less fecal blood loss in patients receiving misoprostol. Success (no more than 2-10 hemorrhages or erosions and no ulcers) achieved in 26.7% on placebo, 63.3% on cimetidine, and 93.1% on misoprostol in both stomach and duodenum. Differences were significant among all groups for the stomach. Misoprostol and cimetidine were not different for the duodenum. Same criteria as reference 29. Less gastric injury with misoprostol than the other two groups. Misoprostol and sucralfate were more effective than placebo in the duodenum. Higher incidence of ulcers 0.4 cm with placebo (43%) than misoprostol (0%). Significantly fewer gastric erosions and duodenal injury with misoprostol. Stomach: less damage than placebo at all doses. No differences among different doses. Duodenum: 200 and 100 IJ.g different from 50 IJ.g and placebo. Higher incidence of abdominal pain with largest misoprostol dose than other treatments. Did not evaluate the duodenum. Significantly less bleeding lesions and erosions in the antrum of the stomach. Fewer bleeding lesions in the gastric corpus and fundus. Same criteria as reference 29. Successful protection of the stomach achieved more frequently with misoprostol (90%) than placebo (24%). Less injury occurred in the duodenum, and less occurred with misoprostol, but "success" rates were similar for both groups. Fewer duodenal erosions and gastric submucosal hemorrhages with ranitidine. No difference in number of gastric erosions between groups.
NSAID = nonsteroidal antiinflammatory drug; OA = osteoarthritis; RA = rheumatoid arthritis.
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Epidemiology and Risk Factors The exact prevalence of gastric ulcers among NSAID users is unknown. Studies reporting ulcer rates among subjects taking NSAIDs had no pretreatment figures for comparison; therefore, some of the lesions seen on entry into these studies could have been due to other causes. However, McCarthy reported that the prevalence of gastric ulcers among the general population is 0.28 percent. 10 A review of NSAID gastropathy reported a point prevalence of 13 percent for gastric ulcers among NSAID users in eight studies. Graham et al. found ulcers in 25 percent of their subjects who had received NSAIDs for at least three months and were complaining of abdominal pain. 2 Larkai et al. found a 15.4 percent prevalence of gastric or duodenal ulcers among 65 patients (63 men, 2 women) who had received a NSAID daily for at least six weeks; when considering all lesions, injury was present in 68 percent of these patients. Symptoms of GI intolerance did not predict endoscopic findings because symptoms were present in 19 percent of those with normal endoscopy and 9 percent of those with abnormal findings." No one knows how often chronic ulcers fail to heal and cause acute bleeding or perforation. A multicenter study of patients with rheumatoid arthritis found that NSAID users were 6.45 times as likely to be hospitalized for GI illness than nonusers. Fries et al. estimate that NSA!D~ account for at least 2600 excess deaths due to GI bleeding among the two million patients with rheumatoid arthritis in the U.S. These authors reported that NSAID gastropathy is the most common adverse drug reaction given the frequency of NSAID use and the prevalence of NSAID gastropathy." NSAIDs increase the risk of hospitalization and mortality in elderly patients. 4 ,s.n.u Aspirin and other NSAID users aged 60 and over are two to three times more likely to be hospitalized with bleeding ulcers. n.13 People 60 years of age and older taking NSAIDs are 4.7 times more likely to die from ulcer hemorrhage or perforation than nonusers of the same age. S In contrast, a retrospective analysis of a population less than 65 years of age did not find that NSAIDs increased the risk of hospitalization from ulcers or related conditions." NSAIDs may differ in their propensity for causing acute injury.r-? Aspirin causes the greatest amount of acute damage whereas other drugs, such as sulindac and nonacetylated salicylates, spare the gastric mucosa after single doses. In contrast, no NSAIDs, including prodrugs (e.g., sulindac) and nonacetylated salicylates (e.g., salsalate, choline, magnesium salicylate), have been shown to be free of the risk of causing gastric ulcers when taken on a chronic basis. Chronic gastric injury may be dose-related as only aspirin doses above 14 to 22 tablets per week increase the risk of developing gastric ulcers. 10 Patients taking more than one NSAID at a time have an increased risk of developing gastric erosions. IS GI damage occurring with chronic use may be more common or more severe with some NSAIDs than others. An analysis of Medicaid billing data found that patients receiving sulindac had a higher prevalence of upper GI bleeding than those taking ibuprofen. Other drugs (indomethacin, naproxen sodium, phenylbutazone, and tolmetin) included in the Medicaid database were not associated with increased risk when compared with ibuprofen, The authors of the report postulated that the higher risk was
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because sulindac doses routinely prescribed were higher than the other drugs. However, uncontrolled variables may have conferred the excess risk instead of sulindac." Piroxicam, as with sulindac, may increase the risk of damage to the GI tract with chronic use when compared with other NSAIDs. A prospective trial comparing ranitidine with placebo to prevent gastroduodenal damage by NSAIDs in patients with arthritis found greater duodenal damage with piroxicam than naproxen. Greater damage occurred only in the placebo group but a higher incidence of ulcers was reported in patients receiving piroxicam. Although dosing information for each drug was not published, the selection criteria required that the patients be taking doses at least as high as naproxen 750 mg/d or piroxicam 20 rng/d." In contrast to other nonopioid analgesics, acetaminophen does not seem to cause gastric ulcers. n.u An association between acetaminophen and GI bleeding reported by older studies is probably not present; those studies did not control for acetaminophen as a substitute for NSAIDs in patients who had already developed ulcers. iz The largest number of ulcers and complications occur in elderly women. This population consumes the greatest number of NSAIDs and may receive the largest dosages when corrected for body weight." Additional factors, such as cigarette smoking, alcohol use, corticosteroid use, and previous peptic ulcers, probably also increase the risk of NSAID-induced ulcers among this group.v'"
Treatment McCarthy reported that most ulcers induced by NSAIDs heal when treated with conventional ulcer therapy even when the offending drug is continued. 10 Antacids, histamine Hrreceptor antagonists, and misoprostol heal gastric ulcers in :::;12 weeks.P-" Gastric ulcers 5 mm may need longer treatment. Sucralfate may not be effective for gastric ulcers caused by NSAIDs. Duodenal ulcers are less common, heal more easily and can be effectively treated with antacids, Hj-receptor antagonists, sucralfate, or misoprostol. iz
Prevention The greatest challenge in NSAID use is prevention of gastric ulcers that bleed or perforate. Preventive measures include: (1) minimize use of NSAIDs for all patients, particularly the elderly; (2) optimize nondrug therapy when appropriate; (3) use acetaminophen instead of NSAIDs when patients need a simple analgesic without antiinflammatory properties; and (4) minimize smoking and alcohol intake. Sulindac and piroxicam should be considered as secondline therapy because of increased risk of gastric ulcer formation compared with other drugs. 16,17 NSAID doses should be reduced to the lowest effective levels and frequencies; only one NSAID should be used at a time. Other measures (e.g., dosing with meals, early in the day, and with fluid) have been recommended" and may reduce GI symptoms," but have not been proven to reduce the risk of GI bleeding associated with chronic NSAID consumption. Likewise, enteric-coated and sustained-release aspirin products that may cause less GI discomfort than regular
1990 October, Volume 24
Preventing GI Bleeding
aspirin probably cause gastric ulcers with chronic use. Nonacetylated salicylates likewise may cause gastric ulcers with long-term therapy. to Aside from reducing NSAID exposure, difficult decisions must be made when considering specific drug therapy to prevent acute gastric events. What treatments are effective? Who should be treated? Several studies have evaluated prophylactic therapy including protocols to assess treatments in healthy subjects exposed to a single dose of aspirin.W.22 Such regimens, however, do not predict the efficacy of a drug or treatment in clinical practice since acute GI injury does not predict chronic ulcer formation. As a result, such studies are not reviewed here. Trials that have evaluated the efficacy of prophylactic therapy for periods longer than one day are summarized in Table I. All trials listed in Table I were randomized, placebocontrolled, and double-blind. Patients with arthritis were selected for some studies but others used healthy volunteers. All but three of these studies used endoscopy to evaluate the efficacy of each regimen. 26-28 Each group of investigators used somewhat different criteria to grade GI injury and define therapeutic success. Studies of patients with arthritis continued for seven days to ten months and evaluated the efficacy of misoprostol, ranitidine, and cimetidine. In a study by Graham et al., only misoprostol reduced the frequency of gastric ulcer formation. A trend toward a lower frequency with misoprostol 200 f..l.g qid than with 100 f..l.g qid did not reach statistical significance. The authors did not report data documenting protection for the duodenum." Ranitidine and cimetidine prevent erosions and ulcers in the duodenum but not the stomach. 17.23-25 Although trials using healthy subjects may not be clinically relevant, they facilitate control of variables that may confound patient trials. Because studies conducted on normal volunteers (except one report") have lasted only two to seven days, results may not apply to preventing GI injury from chronic NSAID therapy.f"?" Misoprostol, ranitidine, cimetidine, and sucralfate prevented injury in healthy subjects exposed to aspirin, ibuprofen, naproxen, and tolmetin. As reported in patients with arthritis, only misoprostol prevented gastric erosions and ulcers to a greater extent than placebo. Misoprostol in doses of 100 or 200 f..l.g qid prevented gastric and duodenal injury. A smaller dose of misoprostol (50 f..l.g qid) prevented gastric but not duodenal injury. 32 However, Berkowitz et al. reported that ranitidine protected the stomach from aspirin. Despite fewer gastric submucosal and confluent hemorrhages in the ranitidine group, there were no fewer gastric erosions when compared with placebo. None of the patients developed gastric ulcers. 35 The significance of preventing submucosal gastric hemorrhages is unknown. The lack of protection against gastric erosions found in this study is consistent with the studies using ranitidine in arthritic patients. 17•23, 24 Prospective, controlled studies agree that GI mucosal damage from NSAIDs can be prevented. Misoprostol, H r receptor antagonists, and sucralfate protect the duodenum and misoprostol protects the stomach. But which patients need the protection? Who will develop GI lesions that will perforate or bleed with long-term NSAID therapy? Can drugs prevent acute GI bleeding or perforation? No one knows for sure. Studies that address these questions have
not been published. The clinician must evaluate the individual patient who uses a NSAID. It seems appropriate that patients with histories ofGI bleeding from NSAIDs receive misoprostol. Patients with peptic ulcer disease probably should also be considered for misoprostol therapy. In addition, patients receiving other ulcerogenic drugs chronically, such as glucocorticosteroids, may be candidates for NSAID gastropathy prevention. Fries et al. recommended prophylactic therapy for patients experiencing abdominal pain on NSAID therapy." This suggestion can be debated because abdominal pain does not predict that a clinically significant lesion is present in the GI tract. Pain or discomfort should not be the sole reason to begin prophylactic treatment. 3 Elderly women have also been identified as a high-risk group. IS Although acute G I bleeding and perforations occur most frequently in people over 60, data do not support treating all members of this group. Risk factors may be additive and there may be a threshold level of combinations of these factors at which preventive treatment is indicated." The possible benefits of treatment must be balanced against potential risks. Misoprostol is the only drug that has been shown to protect both the stomach and duodenum from NSAID-induced erosions and ulcers. In a recent review in this journal, misoprostol had few reported adverse effects. 36 However, much remains unknown about its adverse effects and drug interactions that only more extensive use will reveal. Summary
Although NSAID gastropathy is a problem of enormous proportions, particularly among the elderly, it is preventable by replacing aspirin or other NSAIDs with acetaminophen whenever clinically feasible. Using the lowest effective doses of NSAIDs and avoiding sulindac and piroxicam may also prevent GI ulcers. Misoprostol should be used to prevent GI ulcers in patients with a history of GI injury from chronic NSAID use or previous peptic ulcer disease. Other patients may also benefit from prophylaxis but definitive recommendations cannot be made based on existing information. ~
References I. TOMITA DK, BAUM C, KENNEDY DL. KNAPP DE. Drug utilization in the U.S. 1987. Ninth annual review. Rockville, MD: Department of Health and Human Services, Food and Drug Administration, 1988:1-56. 2. GRAHAM DY, AGRAWAL NM, ROTH SH. Prevention of NSAID-induced gastric ulcer with misoprostol: multicentre, double-blind, placebo-controlled trial. Lancet 1988;2:1277-80. 3. LARKAI EN. SMITH JL. LIDSKY MD, GRAHAM DY. Gastroduodenal mucosal and dyspeptic symptoms in arthritis patients during chronic nonsteroidal anti-inflammatory drug use. Am J Gastroenterol1987; 82:1153-8. 4. FRIES JF, MILLER SR, SPITZ PW, WILLIAMS CA, HUBERT HB, BLOCH DA. Toward an epidemiology of gastropathy associated with nonsteroi-
dal antiinflammatory drug use. Gastroenterology 1989; 96:647-55. 5. GRIFFIN MR, RAY WA, SCHAFFNER W. Nonsteroidal antiinflammatory drug use and death from peptic ulcer in elderly persons. Ann Intern Med 1988;109:359-63. 6. SZABO S, SPILL WF, RAINSFORD KD. Non-steroidal anti-inflammatory drug-induced gastropathy: mechanisms and management. Med Toxicol Adverse Drug Exp 1989;4:77-94. 7. GRAHAM DY. Prevention of gastrointestinal injury induced by chronic nonsteroidal antiinflammatory drug therapy. Gastroenterology 1989; 96:675-81.
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8. ROTH SH, BENNETT RE. Nonsteroidal antiinflanunatory drug gastropathy. Arch Intern Med 1987;147:2093-100. 9. SCHOEN RT, VENDER RJ. Mechanisms of nonsteroidal antiinflanunatory drug-induced gastric damage. Am J Med 1989;86:449-58. 10. MCCARTIIY DM. Nonsteroidal antiinflanunatory drug-induced ulcers: management by traditional therapies. Gastroenterology 1989;96: 662-74. II. FAULKNER G, PRJCHARD P,SOMERVILL K, LANGMAN MJS. Aspirin and bleeding peptic ulcers in the elderly. Br MedJ 1988;297:1311-3. 12. MCINTOSH JH, RJNG CS, BERRY G, PIPER DW. Smoking, nonsteroidal anti-inflammatory drugs, and acetaminophen in gastric ulcer. Am J EpidemioI1988;128:761-70. 13. SOMERVILL K, FAULKNER G, LANGMAN M. Non-steroidal antiinflammatory drugs and bleeding peptic ulcer. Lancet 1986;/:462-4. 14. JICK H, FELD AD, PERERA DR. Certain nonsteroidal antiinflanunatory drugs and hospitalization for upper gastrointestinal bleeding. Pharmacotherapy 1985;5:280-4. 15. CARUSO I, PORRO BG. Gastroscopic evaluation of antiinflammatory agents. Br Med J 1980;280:75-8. 16. CARSON JL, STROM BL, MORSE ML, et al. The relative gastrointestinal toxicity of the nonsteroidal antiinflanunatory drugs. Arch Intern Med 1987;147:1054-9. 17. EHSANULLAH RSB, PAGE MC.TILDESLEY G, WOOD JR. Prevention of gastroduodenal damage induced by non-steroidal antiinflammatory drugs: controlled trial of ranitidine. Br Med J 1988;297:1017-21. 18. SOLL AH,KURATA J, MCGUIGAN JE. Ulcers, nonsteroidal antiinflanunatory drugs, and related matters. Gastroenterology 1989;96:561-8. 19. ROTH S, AGRAWAL N, MAHOWALD M, et al. Misoprostol heals gastroduodenal injury in patients with rheumatoid arthritis receiving aspirin. Arch Intern Med 1989;149:775-9. 20. STERN AJ, WARD F, HARTLEY G. Protective effect of sucralfate against aspirin-induced damage to the human gastric mucosa. Am J Med 1987; 83(suppI3B):83-5. 21. SILVERSTEIN FE, KIMMEY MB,SAUNDERS DR, SURAWICZ CM, WILLSON RA, SILVERMAN BA. Gastric protection by rnisoprostol against 1,300 mg of aspirin: an endoscopic dose-response study. Am J Med 1987;83(suppl IA):32-6. 22. SILVERSTEIN FE,KIMMEY MB,SAUNDERS DR,LEVINE DS.Gastric protection by misoprostol against 1300 mg of aspirin: an endoscopic study. Dig Dis Sci 1986;31(suppI2):137S-4IS. 23. ROBINSON MG, GRIFFIN JW, BOWERS J, et al. Effect of ranitidine gastroduodenal mucosal damage induced by nonsteroidal antiinflanunatory drugs. Dig Dis Sci 1989;34:424-8. 24. LANZA F, ROBINSON J, BOWERS J, et al. A multi-center double-blind comparison of ranitidine vs placebo in the prophylaxis of nonsteroidal antiinflammatory drug (NSAID) induced lesions in gastric and duodenal mucosae (abstract). Gastroenterology 1988;94:A250. 25. ROTH SH, BENNETT RE, MITCHELL CS, HARTMAN R1. Cimetidine therapy in nonsteroidal anti-inflanunatory drug gastropathy: doubleblind long-term evaluation. Arch Intern Med 1987;/47: 1798-801. 26. RYAN JR, VARGAS R, CLAY GA, MCMAHON FG. Role of rnisoprostol in reducing aspirin-induced gastrointestinal blood loss in arthritic patients. AmJ Med 1987;83(suppIIA):41-4. 27. HUNT IN, SMITH JL, JIANG CL, KESSLER L. Effect of synthetic prostaglandin E, analog on aspirin-induced gastric bleeding and secretion. Dig Dis Sci 1983;28:897-902. 28. COHEN MM, CLARK L, ARMSTRONG L, D'SOUZA1. Reduction of aspirin-induced fecal blood loss with low-dose rnisoprostol tablets in man. Dig Dis Sci 1985;30:605-11. 29. LANZA FL, ASPINALL RL, SWABB EA, DAVIS RE, RACK MF, RUBIN A. Double-blind, placebo-controlled endoscopic comparison of the mucosal protective effects of misoprostol versus cimetidine on tolrnetin-induced mucosal injury. Gastroenterology 1988;95:289-94. 30. LANZA F, PEACE K, GUSTITUS L, RACK MF, DICKSON B. A blinded endoscopic comparative study of misoprostol versus sucralfate and placebo in the prevention of aspirin-induced gastric and duodenal ulceration. Am J Gastroenterol 1988;83:143-6. 31. JlRANEK GC, KIMMEY MB,SAUNDERS DR,WILLSON RA,SHANAHAN W,SILVERSTEIN FE. Misoprostol reduced gastroduodenal injury from one week of aspirin: an endoscopic study. Gastroenterology 1989; 96:656-61. 32. LANZA FL, FAKOUHI D, RUBIN A, et al. A double-blind placebo-controlled comparison of the efficacy and safety of 50, 100, and 200 mcg of rnisoprostol qid in the prevention of ibuprofen-induced gastric and
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33.
34.
35.
36.
duodenal mucosal lesions and symptoms. Am J Gastroenterol1989; 84:633-6. AADLAND E, FAUSA 0, VATN M, COHEN H, QUINLAN D. Protection by rnisoprostol against naproxen-induced gastric mucosal damage. Am J Med 1987;83(suppl IA):37-40. LANZA FL. A double-blind study of the prophylactic effect of misoprostol on lesions of gastric and duodenal mucosa induced by oral administration of tolmetin in healthy subjects. Dig Dis Sci 1986; 3/(suppI2):13IS-6S. BERKOWITZ JM, ROGENES PR,SHARP IT, WARNER CWo Ranitidine protects against gastroduodenal mucosal damage associated with chronic aspirin therapy. Arch Intern Med 1987;/47:2137-9. JONES JB, BAILEY RTJr. Misoprostol: a prostaglandin E, analog with antisecretory and cytoprotective properties. DICP Ann Pharmacother 1989;23:276-82.
EXTRACTO Sangramiento gastrointestinal severo es uno de los efectos adversos de mas importancia que ocurren secundario a tratamiento con antiinflamatorios no esteroidales (NSAIDs). Algunos autores estiman que es el efecto secundario relacionado al uso de farmacos mas comun dado el uso tan frecuente de los NSAIDs y la prevalencia de esta complicaci6n. En especffico los pacientes envejecientes, quienes consumen aproximadamente la mitad de los NSAIDs recetados, tarnbien estan mas a riesgo para desarrollar gastropatia por el uso de estes. EI potencial para causar un insulto gastrointestinal varia entre los NSAIDs, sin embargo, todos pueden causar el efecto si son ingeridos cr6nicamente. Aquellos pacientes que ingieren mas de un NSAID simultaneamente aumentan aun mas su riesgo. Existen medidas que se pueden utilizar para disminuir los riesgos de sangramiento. Estas incluyen el utilizar acetaminofen cuando se desea obtener exclusivamente un efecto analgesico, y utilizar la dosis mas baja posible del NSAID que sea efectiva. EI uso de sucralfato, antagonistas de los receptores H 2 , y misoprostol son algunas de las modalidades farmacol6gicas que se han estudiado para evitar el desarrollo de gastropatia. Aquellos pacientes que tienen historial de ulceras pepticas 0 sangramiento gastrointestinal previo debido al uso de NSAIDs son candidatos para recibir medidas profilacticas. Aunque otros pacientes tarnbien estan a riesgo, no se conoce quienes son aquellos pacientes que deben recibir profilaxis para la gastropatla inducida por NSAIDs. Estudios realizados en el futuro deben estar dirigidos a definir aquellos pacientes que ameriten profilaxis. WANDA T. MALDONADO RESUME
a
Un des effets indesirables Ie plus important survenir avec les antiinflammatoires non-stercidiens (AINS) est l'hemorragie digestive haute et les personnes agees sont hauts risques de developper cette complication. Cependant, les episodes de saignements peuvent etre prevenus. Lorsqu'un simple analgesique est suffisant, Ie remplacement de I' AINS par de l'acetaminophene peut etre approprie et ainsi eliminer les risques de saignements gastrointestinaux. L'utilisation de la dose minimale efficace de I' AINS peut diminuer I'incidence et la severite des gastropathies induites par les AINS. Les antagonistes des recepteurs H 2 , Ie sucralfate et Ie misoprostol, sont des medicaments qui ont ete etudies dans la prevention des gastropathies aux AINS. Seulle misoprostol previent les traumatismes causes la muqueuse stomacale et duodenale. Les patients ayant des antecedents d'ulcere peptique ou de saignement gastrique suite la prise d'AINS sont des candidats une prophylaxie. Meme si d'autres patients sont risque, personne ne peut dire qui doit recevoir une therapie prophylactique contre les gastropathies dues aux AINS. D'autres etudes devront tenter de definir les populations de patients qui exigent une therapie prophylactique.
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