NSAIDs (including aspirin): Primary prevention of gastroduodenal toxicity
- Mark Feldman, MD, MACP, AGAF, FACG
Mark Feldman, MD, MACP, AGAF, FACG
- Section Editor — Acid Peptic Disease
- Texas Health Presbyterian Hospital Dallas
- Clinical Professor of Internal Medicine
- University of Texas Southwestern Medical School at Dallas
- Shounak Das, MD
Shounak Das, MD
- Volunteer Clinical Faculty, University of Texas Southwestern Medical School at Dallas
- Department of Internal Medicine, Texas Health Presbyterian Hospital Dallas
Nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, cause considerable morbidity and mortality related to gastric and duodenal ulcer disease . Thus, prevention of NSAID-induced GI damage is an important clinical issue.
Misoprostol, H2 receptor antagonists, and proton pump inhibitors have been evaluated as prophylactic therapies for patients taking NSAIDs. In addition, the selective COX-2 inhibitors (coxibs) introduced a novel strategy for the reduction of NSAID-related gastroduodenal toxicity. However, the advantage of these coxibs over nonselective NSAIDs is still debatable and concerns about cardiovascular toxicity has limited the use of coxibs. (See "Overview of selective COX-2 inhibitors" and "COX-2 selective inhibitors: Adverse cardiovascular effects".)
Strategies for the primary prevention of gastroduodenal toxicity due to NSAIDs will be reviewed here. Emphasis will be placed upon studies that used clinically relevant end points (symptomatic ulcers and complicated ulcers, including bleeding, perforating, and obstructing ulcers). Studies using endoscopic detection of ulcers as the end point will be cited only when data on more meaningful clinical end points are lacking. The pathogenesis, treatment, and secondary prevention of NSAID-induced gastroduodenal injury are discussed separately. (See "NSAIDs (including aspirin): Pathogenesis of gastroduodenal toxicity" and "NSAIDs (including aspirin): Treatment of gastroduodenal toxicity" and "NSAIDs (including aspirin): Secondary prevention of gastroduodenal toxicity".)
Studies have evaluated risk factors for gastroduodenal toxicity from nonsteroidal anti-inflammatory drugs (NSAIDs) and assessment of these factors is recommended for identifying patients who should be considered for primary prophylaxis if it is felt that an NSAID must be given [2-4]. (See "NSAIDs (including aspirin): Pathogenesis of gastroduodenal toxicity".)
One prospective study of 34,701 osteoarthritis and rheumatoid arthritis patients ages 50 and above randomized to either etoricoxib or diclofenac use found the following factors to be significant predictors for gastrointestinal (GI) toxicity including bleeding, perforation, obstruction, or uncomplicated ulcer: age >64, a history of prior adverse GI events, or concurrent use of low dose aspirin .
- Wallace JL. Nonsteroidal anti-inflammatory drugs and gastroenteropathy: the second hundred years. Gastroenterology 1997; 112:1000.
- Silverstein FE, Graham DY, Senior JR, et al. Misoprostol reduces serious gastrointestinal complications in patients with rheumatoid arthritis receiving nonsteroidal anti-inflammatory drugs. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 1995; 123:241.
- Simon LS, Hatoum HT, Bittman RM, et al. Risk factors for serious nonsteroidal-induced gastrointestinal complications: regression analysis of the MUCOSA trial. Fam Med 1996; 28:204.
- Bhatt DL, Scheiman J, Abraham NS, et al. ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents. J Am Coll Cardiol 2008; 52:1502.
- Laine L, Curtis SP, Cryer B, et al. Risk factors for NSAID-associated upper GI clinical events in a long-term prospective study of 34 701 arthritis patients. Aliment Pharmacol Ther 2010; 32:1240.
- Lanza FL, Chan FK, Quigley EM, Practice Parameters Committee of the American College of Gastroenterology. Guidelines for prevention of NSAID-related ulcer complications. Am J Gastroenterol 2009; 104:728.
- Loke YK, Trivedi AN, Singh S. Meta-analysis: gastrointestinal bleeding due to interaction between selective serotonin uptake inhibitors and non-steroidal anti-inflammatory drugs. Aliment Pharmacol Ther 2008; 27:31.
- Masclee GM, Valkhoff VE, Coloma PM, et al. Risk of upper gastrointestinal bleeding from different drug combinations. Gastroenterology 2014; 147:784.
- Coxib and traditional NSAID Trialists' (CNT) Collaboration, Bhala N, Emberson J, et al. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet 2013; 382:769.
- Richy F, Bruyere O, Ethgen O, et al. Time dependent risk of gastrointestinal complications induced by non-steroidal anti-inflammatory drug use: a consensus statement using a meta-analytic approach. Ann Rheum Dis 2004; 63:759.
- Henry D, Lim LL, Garcia Rodriguez LA, et al. Variability in risk of gastrointestinal complications with individual non-steroidal anti-inflammatory drugs: results of a collaborative meta-analysis. BMJ 1996; 312:1563.
- Weideman RA, Kelly KC, Kazi S, et al. Risks of clinically significant upper gastrointestinal events with etodolac and naproxen: a historical cohort analysis. Gastroenterology 2004; 127:1322.
- Strom BL, Berlin JA, Kinman JL, et al. Parenteral ketorolac and risk of gastrointestinal and operative site bleeding. A postmarketing surveillance study. JAMA 1996; 275:376.
- García Rodríguez LA, Cattaruzzi C, Troncon MG, Agostinis L. Risk of hospitalization for upper gastrointestinal tract bleeding associated with ketorolac, other nonsteroidal anti-inflammatory drugs, calcium antagonists, and other antihypertensive drugs. Arch Intern Med 1998; 158:33.
- Reinhart DI. Minimising the adverse effects of ketorolac. Drug Saf 2000; 22:487.
- http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/019645s017lbl.pdf (Accessed on May 08, 2012).
- Silvoso GR, Ivey KJ, Butt JH, et al. Incidence of gastric lesions in patients with rheumatic disease on chronic aspirin therapy. Ann Intern Med 1979; 91:517.
- Petroski D. Endoscopic comparison of three aspirin preparations and placebo. Clin Ther 1993; 15:314.
- Hawthorne AB, Mahida YR, Cole AT, Hawkey CJ. Aspirin-induced gastric mucosal damage: prevention by enteric-coating and relation to prostaglandin synthesis. Br J Clin Pharmacol 1991; 32:77.
- Kelly JP, Kaufman DW, Jurgelon JM, et al. Risk of aspirin-associated major upper-gastrointestinal bleeding with enteric-coated or buffered product. Lancet 1996; 348:1413.
- van Oijen MG, Dieleman JP, Laheij RJ, et al. Peptic ulcerations are related to systemic rather than local effects of low-dose aspirin. Clin Gastroenterol Hepatol 2008; 6:309.
- Kiltz U, Zochling J, Schmidt WE, Braun J. Use of NSAIDs and infection with Helicobacter pylori--what does the rheumatologist need to know? Rheumatology (Oxford) 2008; 47:1342.
- Feldman M, McMahon AT. Do cyclooxygenase-2 inhibitors provide benefits similar to those of traditional nonsteroidal anti-inflammatory drugs, with less gastrointestinal toxicity? Ann Intern Med 2000; 132:134.
- Hawkey CJ. COX-2 inhibitors. Lancet 1999; 353:307.
- Silverstein FE, Faich G, Goldstein JL, et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: A randomized controlled trial. Celecoxib Long-term Arthritis Safety Study. JAMA 2000; 284:1247.
- García Rodríguez LA, Barreales Tolosa L. Risk of upper gastrointestinal complications among users of traditional NSAIDs and COXIBs in the general population. Gastroenterology 2007; 132:498.
- Battistella M, Mamdami MM, Juurlink DN, et al. Risk of upper gastrointestinal hemorrhage in warfarin users treated with nonselective NSAIDs or COX-2 inhibitors. Arch Intern Med 2005; 165:189.
- Mamdani M, Juurlink DN, Kopp A, et al. Gastrointestinal bleeding after the introduction of COX 2 inhibitors: ecological study. BMJ 2004; 328:1415.
- Dai C, Stafford RS, Alexander GC. National trends in cyclooxygenase-2 inhibitor use since market release: nonselective diffusion of a selectively cost-effective innovation. Arch Intern Med 2005; 165:171.
- Nissen SE, Yeomans ND, Solomon DH, et al. Cardiovascular Safety of Celecoxib, Naproxen, or Ibuprofen for Arthritis. N Engl J Med 2016; 375:2519.
- Koch M, Dezi A, Ferrario F, Capurso I. Prevention of nonsteroidal anti-inflammatory drug-induced gastrointestinal mucosal injury. A meta-analysis of randomized controlled clinical trials. Arch Intern Med 1996; 156:2321.
- Tamura A, Murakami K, Kadota J, OITA-GF Study Investigators. Prevalence and independent factors for gastroduodenal ulcers/erosions in asymptomatic patients taking low-dose aspirin and gastroprotective agents: the OITA-GF study. QJM 2011; 104:133.
- Graham DY, Agrawal NM, Campbell DR, et al. Ulcer prevention in long-term users of nonsteroidal anti-inflammatory drugs: results of a double-blind, randomized, multicenter, active- and placebo-controlled study of misoprostol vs lansoprazole. Arch Intern Med 2002; 162:169.
- Lai KC, Lam SK, Chu KM, et al. Lansoprazole for the prevention of recurrences of ulcer complications from long-term low-dose aspirin use. N Engl J Med 2002; 346:2033.
- Ekström P, Carling L, Wetterhus S, et al. Prevention of peptic ulcer and dyspeptic symptoms with omeprazole in patients receiving continuous non-steroidal anti-inflammatory drug therapy. A Nordic multicentre study. Scand J Gastroenterol 1996; 31:753.
- Cullen D, Bardhan KD, Eisner M, et al. Primary gastroduodenal prophylaxis with omeprazole for non-steroidal anti-inflammatory drug users. Aliment Pharmacol Ther 1998; 12:135.
- Lin KJ, Hernández-Díaz S, García Rodríguez LA. Acid suppressants reduce risk of gastrointestinal bleeding in patients on antithrombotic or anti-inflammatory therapy. Gastroenterology 2011; 141:71.
- 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.
- Hooper L, Brown TJ, Elliott R, et al. The effectiveness of five strategies for the prevention of gastrointestinal toxicity induced by non-steroidal anti-inflammatory drugs: systematic review. BMJ 2004; 329:948.
- Scheiman JM, Yeomans ND, Talley NJ, et al. Prevention of ulcers by esomeprazole in at-risk patients using non-selective NSAIDs and COX-2 inhibitors. Am J Gastroenterol 2006; 101:701.
- Goldstein JL, Cryer B, Amer F, Hunt B. Celecoxib plus aspirin versus naproxen and lansoprazole plus aspirin: a randomized, double-blind, endoscopic trial. Clin Gastroenterol Hepatol 2007; 5:1167.
- Laine L, Curtis SP, Cryer B, et al. Assessment of upper gastrointestinal safety of etoricoxib and diclofenac in patients with osteoarthritis and rheumatoid arthritis in the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) programme: a randomised comparison. Lancet 2007; 369:465.
- Chan FK, Lanas A, Scheiman J, et al. Celecoxib versus omeprazole and diclofenac in patients with osteoarthritis and rheumatoid arthritis (CONDOR): a randomised trial. Lancet 2010; 376:173.
- Targownik LE, Metge CJ, Leung S, Chateau DG. The relative efficacies of gastroprotective strategies in chronic users of nonsteroidal anti-inflammatory drugs. Gastroenterology 2008; 134:937.
- 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.
- Taha AS, McCloskey C, Prasad R, Bezlyak V. Famotidine for the prevention of peptic ulcers and oesophagitis in patients taking low-dose aspirin (FAMOUS): a phase III, randomised, double-blind, placebo-controlled trial. Lancet 2009; 374:119.
- Laine L, Kivitz AJ, Bello AE, et al. Double-blind randomized trials of single-tablet ibuprofen/high-dose famotidine vs. ibuprofen alone for reduction of gastric and duodenal ulcers. Am J Gastroenterol 2012; 107:379.
- Cryer B, Bhatt DL, Lanza FL, et al. Low-dose aspirin-induced ulceration is attenuated by aspirin-phosphatidylcholine: a randomized clinical trial. Am J Gastroenterol 2011; 106:272.
- RISK FACTORS
- NONSELECTIVE NSAIDs
- ENTERIC-COATED AND BUFFERED ASPIRIN
- Low dose aspirin for cardiovascular protection
- Dual antiplatelet therapy (eg, aspirin and clopidogrel)
- ROLE OF HELICOBACTER PYLORI
- SELECTIVE COX-2 INHIBITORS
- PREVENTION STRATEGIES
- Proton pump inhibitors
- PPI (lansoprazole) versus misoprostol
- - PPI (esomeprazole) used with either nonselective NSAIDs or COX-2 inhibitors
- - Celecoxib versus naproxen plus lansoprazole, together with low dose aspirin
- - Etoricoxib versus a nonselective diclofenac
- - Conventional NSAID with either a PPI or misoprostol versus a cox-2 inhibitor
- H2 receptor antagonists
- Aspirin-phosphatidylcholine combination
- MONITORING PATIENTS TAKING NSAIDS
- SUMMARY AND RECOMMENDATIONS