International Consensus on Guiding Recommendations for Management of Patients with Nonsteroidal Antiinflammatory Drugs Induced Gastropathy-ICON-G
Ramesh GN, Richard Hunt, Leonid B Lazebnik, Yury C Marakhouski, Mircea Manuc, Khin S Aye, Dmitry S Bordin, Natalia V Bakulina, Baurzhan S Iskakov, Abror A Khamraev, Yurii M Stepanov, Reidwaan Ally, Amit Garg
Introduction: Nonsteroidal anti-inflammatory drugs (NSAIDs), one of the most commonly used medications worldwide, are frequently associated with gastrointestinal adverse events. Primary care physicians often face the challenge of achieving adequate pain relief with NSAIDs, while keeping their adverse events to a minimum. This is especially true when long-term use of NSAIDs is required such as in patients with osteoarthritis and rheumatoid arthritis. To help primary care physicians deal with such challenges more effectively, a panel of expert gastroenterologists came together with the aim of developing practice recommendations.
Methods: A modified ‘Delphi’ process was used to reach consensus and develop practice recommendations. Twelve gastroenterologists from nine countries provided their expert inputs to formulate the recommendations. These recommendations were carefully developed taking into account existing literature, current practices, and expert opinion of the panelists.
Results: The expert panel developed a total of fifteen practice recommendations. Following are the key recommendations: NSAIDs should be prescribed only when necessary; before prescribing NSAIDs, associated modifiable and non-modifiable risk factors should be considered; H. pylori infection should be considered and treated before initiating NSAIDs; patients should be properly educated regarding NSAIDs use; patients who need to be on long-term NSAIDs should be prescribed a gastroprotective agent, preferably a proton pump inhibitor and these patients should be closely monitored for any untoward adverse events.
Conclusion/clinical significance: These practice recommendations will serve as an important tool for primary care physicians and will guide them in making appropriate therapeutic choices for their patients.
Singh G. Gastrointestinal complications of prescription and over-the-counter nonsteroidal anti-inflammatory drugs: a view from the ARAMIS database. Arthritis, Rheumatism, and Aging Medical Information System. Am J Ther 2000 Mar;7(2):115-121.
Koffeman AR, Valkhoff VE, Çelik S, W't Jong G, Sturkenboom MC, Bindels PJ, et al. High-risk use of over-the-counter nonsteroidal anti-inflammatory drugs: a population-based crosssectional study. Br J Gen Pract 2014 Apr;64(621):e191-198.
Peura DA. Gastrointestinal safety and tolerability of nonselective nonsteroidal anti-inflammatory agents and cyclooxygenase- 2-selective inhibitors. Cleve Clin J Med 2002;69(Suppl 1):SI31-139.
Harirforoosh S, Asghar W, Jamali F. Adverse effects of nonsteroidal antiinflammatory drugs: an update of gastrointestinal, cardiovascular and renal complications. J Pharm Pharm Sci 2013;16(5):821-847.
Lassen A, Hallas J, Schaffalitzky de Muckadell OB. Complicated and uncomplicated peptic ulcers in a Danish county 1993-2002: a population-based cohort study. Am J Gastroenterol 2006 May;101(5):945-953.
Chatterjee S, Dureja GP, Kadhe G, Mane A, Phansalkar AA, Sawant S, et al. Cross-Sectional Study for Prevalence of Non- Steroidal Anti-Inflammatory Drug-Induced Gastrointestinal, Cardiac and Renal Complications in India: Interim Report. Gastroenterology Res 2015 Aug;8(3-4):216-221.
Straube S, Tramèr MR, Moore RA, Derry S, McQuay HJ. Mortality with upper gastrointestinal bleeding and perforation: effects of time and NSAID use. BMC Gastroenterol 2009 Jun;9(1):41.
Yeomans ND, Lanas AI, Talley NJ, Thomson AB, Daneshjoo R, Eriksson, et al. Prevalence and incidence of gastroduodenal ulcers during treatment with vascular protective doses of aspirin. Aliment Pharmacol Ther 2005 Nov;22(9):795-801.
Takeuchi K. Pathogenesis of NSAID-induced gastric damage: Importance of cyclooxygenase inhibition and gastric hypermotility. World J Gastroenterol 2012 May;18(18):2147-2160.
Unified Clinical Protocol for Primary and Secondary Medical Care Peptic Ulcer of Stomach and Duodenum in Adults, Ukraine, 2014 Sep. Available at: http://mtd.dec.gov.ua/ images/dodatki/2014_613_PeptVyrazka_12paloi/2014_613y kpmd_PeptVyr.pdf.
Russian gastroenterological association clinical guidelines on diagnosis and treatment of NSAIDs-associated erosive and ulcerative lesions of the stomach and duodenum;2014. Available at: http://www.gastro.ru/userfiles/R_npvp_2014_6.pdf.
Abraham NS, Hlatky MA, Antman EM, Bhatt DL, Bjorkman DJ, Clark CB, Furberg CD, et al. ACCF/ACG/AHA. ACCF/ ACG/AHA 2010 Expert Consensus Document on the Concomitant Use of Proton Pump Inhibitors and Thienopyridines: A Focused Update of the 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 Expert Consensus Documents. Circulation 2010 Dec;122(24):2619-2633.
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 Mar;104(3):728-738.
NICE Guidelines: Acute upper gastrointestinal bleeding in over 16s: management. Available at: https://www.nice.org. uk/guidance/cg141.
Unified Clinical Protocol for Primary Medical Care Dyspepsia, Ukraine [August2012]. Available at: http://mtd.dec.gov.ua/ images/dodatki/2012_600/19_07_2012_ykpmd.pdf.
Rostom A, Moayyedi P, Hunt R. Canadian Association of Gastroenterology Consensus Group. Canadian consensus guidelines on long-term nonsteroidal anti-inflammatory drug therapy and the need for gastroprotection: benefits versus risks. Aliment Pharmacol Ther 2009 Mar;29(5):481-496.
Scarpignato C, Lanas A, Blandizzi C, Lems WF, Hermann M, Hunt RH, International NSAID Consensus Group. Safe prescribing of non-steroidal anti-inflammatory drugs in patients with osteoarthritis--an expert consensus addressing benefits as well as gastrointestinal and cardiovascular risks. BMC Med 2015 Mar;13:55.
Dalkey N, Helmer O. An Experimental Application of the DELPHI Method to the Use of Experts. Management Science. 1962 July;9(3):458-467
Hsu Chia-Chien, Sandford BA. The Delphi Technique: Making Sense of Consensus. Practical Assessment, Research & Evaluation. 2007 Aug;12(10):1-8.
Lanas A, Boers M, Nuevo J. Gastrointestinal events in at-risk patients starting non-steroidal anti-inflammatory drugs (NSAIDs) for rheumatic diseases: the EVIDENCE study of European routine practice. Ann Rheum Dis 2015 Apr;74(4):675-681.
Schaffer D, Florin T, Eagle C, Marschner I, Singh G, Grobler M, et al. Risk of serious NSAID-related gastrointestinal events during long-term exposure: a systematic review. Med J Aus. 2006 Nov;185(9):501-506.
Allison MC, Howatson AG, Torrance CJ, Lee FD, Russell RI. Gastrointestinal damage associated with the use of nonsteroidal anti-inflammatory drugs. N Engl J Med 1992; Sep 327(11):749-754.
García Rodríguez LA, Barreales Tolosa L. Risk of upper gastrointestinal complications among users of traditional NSAIDs and COXIBs in the general population. Gastroenterology 2007 Feb;132(2):498-506.
Hernández Díaz S, García Rodríguez LA. Association between nonsteroidal anti-inflammatory drugs and upper gastrointestinal tract bleeding/perforation. An overview of epidemiologic studies published in the 1990s. Arch Intern Med 2000 Jul;160(14):2093-2099.
García Rodríguez LA, Hernández-Díaz S. Relative risk of upper gastrointestinal complications among users of acetaminophen and nonsteroidal anti-inflammatory drugs. Epidemiology 2001 Sep;12(5):570-576.
Tarone RE, Blot WJ, McLaughlin JK. Nonselective nonaspirin nonsteroidal anti-inflammatory drugs and gastrointestinal bleeding: relative and absolute risk estimates from recent epidemiologic studies. Am J Ther 2004 Jan-Feb;11(1):17- 25.
Yeomans ND, Lanas AI, Talley NJ, Thomson AB, Daneshjoo R, Eriksson B, et al. Prevalence and incidence of gastroduodenal ulcers during treatment with vascular protective doses of aspirin. Aliment Pharmacol Ther 2005 Nov;22(9):795-801.
Derry S, Loke YK. Risk of gastrointestinal haemorrhage with long term use of aspirin: meta-analysis. BMJ 2000 Nov;321(7072):1183-1187.
Makris UE, Kohler MJ, Fraenkel L. Adverse Effects (AEs) of Topical NSAIDs in Older Adults with Osteoarthritis (OA): a Systematic Review of the Literature. J Rheumatol 2010 Jun;37(6):1236-1243.
Castellsague J, Riera-Guardia N, Calingaert B, Varas-Lorenzo C, Fourrier-Reglat A, Nicotra F, et al. Individual NSAIDs and upper gastrointestinal complications: a systematic review and meta-analysis of observational studies (the SOS project). Drug Saf 2012 Dec;35(12):1127-1146.
Huang JQ, Sridhar S, Hunt RH. Gastrointestinal safety profile of nabumetone: a meta-analysis. Am J Med 1999 Dec;107(6A):55S-61S; discussion 61S-64S.
Garg A, Shoeb A, Moodahadu LS, Sharma A, Gandhi A, Akku S. Amtolmeti: A Reappraisal of NSAID with Gastroprotection. Arthritis 2016;2016:7103705.
Fries JF, Williams CA, Bloch DA, Michel BA. Nonsteroidal anti-inflammatory drug- associated gastropathy: incidence and risk factor models. Am J Med 1991 Sep;91(3):213-222.
Koch M, Dezi A, Tarquini M, Capurso L. Prevention of nonsteroidal anti-inflammatory drug-induced gastrointestinal mucosal injury: risk factors for serious complications. Dig Liver Dis 2000 Nov;32(20):138-151.
Cardile S, Martinelli M, Barabino A, Gandullia P, Oliva S, Nardo GD, et al. Italian survey on non-steroidal anti-inflammatory drugs and gastrointestinal bleeding in children. World J Gastroenterol 2016 Feb;22(5):1877-1883.
Rafaniello C, Ferrajolo C, Sullo MG, Sessa M, Sportiello L, Balzano A, et al. Risk of gastrointestinal complications associated to NSAIDs, low-dose aspirin and their combinations: Results of a pharmacovigilance reporting system. Pharmacol Res 2016 Feb;104:108-114.
Lanas A, Benito P, Alonso J, Hernández-Cruz B, Barón-Esquivias G, Perez-Aísa Á, et al. Safe prescription recommendations for non-steroidal anti-inflammatory drugs: consensus document ellaborated by nominated experts of three scientific associations (SER-SEC-AEG). Reumatol Cli. 2014 Mar-Apr;10(2): 68-84.
Lanas A, García-Rodríguez LA, Arroyo MT, Gomollón F, Feu F, González-Pérez A, et al. Risk of upper gastrointestinal ulcer bleeding associated with selective cyclo-oxygenase-2 inhibitors, traditional non-aspirin non-steroidal anti-inflammatory drugs, aspirin and combinations. Gut 2006 Dec;55(12):1731- 1738.
Delaney JA, Opatrny L, Brophy JM, Suissa S. Drug drug interactions between antithrombotic medications and the risk of gastrointestinal bleeding. CMAJ 2007 Aug;177(4):347-351.
Nagata N, Niikura R, Aoki T, Shimbo T, Kishida Y, Sekine K, et al. Lower GI bleeding risk of nonsteroidal anti-inflammatory drugs and antiplatelet drug use alone and the effect of combined therapy. Gastrointest Endosc 2014 Dec;80(6):1124-1131.
Chang HY, Zhou M, Tang W, Alexander GC, Singh S. Risk of gastrointestinal bleeding associated with oral anticoagulants: population based retrospective cohort study. BMJ 2015 Apr;350:h1585.
Halperin D, Reber G. Influence of antidepressants on hemostasis. Dialogues Clin Neurosci 2007;9(1):47-59.
Scarpignato C, Gatta L, Zullo A, Blandizzi C; SIF-AIGOFIMMG Group; Italian Society of Pharmacology, the Italian Association of Hospital Gastroenterologists, and the Italian Federation of General Practitioners. Effective and safe proton pump inhibitor therapy in acid-related diseases - A position paper addressing benefits and potential harms of acid suppression. BMC Med 2016 Nov;14(1):179.
Mort JR, Aparasu RR, Baer RK. Interaction between selective serotonin reuptake inhibitors and nonsteroidal antiinflammatory drugs: review of the literature. Pharmacotherapy 2006 Sep;26(9):1307-1313.
Helin-Salmivaara A, Huttunen T, Grönroos JM, Klaukka T, Huupponen R. Risk of serious upper gastrointestinal events with concurrent use of NSAIDs and SSRIs: a case-control study in the general population. Eur J Clin Pharmacol 2007 Apr;63(4):403-408.
Anglin R, Yuan Y, Moayyedi P, Tse F, Armstrong D, Leontiadis GI. Risk of upper gastrointestinal bleeding with selective serotonin reuptake inhibitors with or without concurrent nonsteroidal anti-inflammatory use: a systematic review and meta-analysis. Am J Gastroenterol 2014 Jun;109(6):811- 819.
Oka Y, Okamoto K, Kawashita N, Shirakuni Y, Takagi T. Metaanalysis of the risk of upper gastrointestinal hemorrhage with combination therapy of selective serotonin reuptake inhibitors and non-steroidal anti-inflammatory drugs. Biol Pharm Bull 2014;37(6):947-953.
Sostres C, Gargallo CJ, Lanas A. Interaction between Helicobacter pylori infection, nonsteroidal anti-inflammatory drugs and/or low-dose aspirin use: old question new insights. World J Gastroenterol 2014 Jul;20(28):9439-9450.
Huang JQ, Sridhar S, Hunt RH. Role of Helicobacter pylori infection and non-steroidal anti-inflammatory drugs in pepticulcer disease: a meta-analysis. Lancet 2002 Jan;359(9300):14. 22.
Papatheodoridis GV, Sougioultzis S, Archimandritis AJ. Effects of Helicobacter pylori and nonsteroidal anti-inflammatory drugs on peptic ulcer disease: a systematic review. Clin Gastroenterol Hepatol 2006 Feb;4(2):130-142.
Vergara M, Catalan M, Gisbert JP, Calvet X. Meta-analysis: role of Helicobacter pylori eradication in the prevention of peptic ulcer in NSAID users. Aliment Pharmacol Ther 2005 Jun;21(!2):1411-1418.
Kono Y, Okada H, Takenaka R, Miura K, Kanzaki H, Hori K, et al. Does Helicobacter pylori Exacerbate Gastric Mucosal Injury in Users of Nonsteroidal Anti-Inflammatory Drugs? A Multicenter, Retrospective, Case-Control Study. Gut Liver 2016 Jan;10(1):69-75.
Pounder RE. Helicobacter pylori and NSAIDs--the end of the debate? Lancet 2002 Jan;359(9300):3-4.
Malfertheiner P, Megraud F, O'Morain CA, Gisbert JP, Kuipers EJ, Axon AT, et al. European Helicobacter and Microbiota Study Group and Consensus panel. Management of Helicobacter pylori infection-the Maastricht V/Florence Consensus Report. Gut 2017 Jan;66(1):6-30.
Fallone CA, Chiba N, van Zanten SV, Fischbach L, Gisbert JP, Hunt RH, et al. The Toronto Consensus for the Treatment of Helicobacter pylori Infection in Adults. Gastroenterology 2016 Jul;151(1):51-69.e14.
Warle-van Herwaarden MF, Koffeman AR, Valkhoff VE, 't Jong GW, Kramers C, Sturkenboom MC, et al. Time-trends in the prescribing of gastroprotective agents to primary care patients initiating low-dose aspirin or non-steroidal anti-inflammatory drugs: a population-based cohort study. Br J Clin Pharmacol 2015 Sep;80(3):589-598.
Sebaldt RJ, Petrie A, Goldsmith CH, Marentette MA. Appropriateness of NSAID and Coxib prescribing for patients with osteoarthritis by primary care physicians in Ontario: results from the CANOAR study. Am J Manag Care 2004;10(11):742- 750.
Ray WA, Stein CM, Byrd V, Shorr R, Pichert JW, Gideon P, et al. Educational program for physicians to reduce use of non-steroidal anti-inflammatory drugs among communitydwelling elderly persons: a randomized controlled trial. Med Care 2001;39(5):425-435.
Lee SH, Han CD, Yang IH, Ha CW. Prescription Pattern of NSAIDs and the Prevalence of NSAID-induced Gastrointestinal Risk Factors of Orthopaedic Patients in Clinical Practice in Korea. J Korean Med Sci 2011 Apr;26(4):561-567.
Kovac SH, Saag KG, Curtis JR, Allison J. Association of healthrelated quality of life with dual use of prescription and overthe- counter nonsteroidal antiinflammatory drugs. Arthritis Rheum 2008 Feb;59(2):227-233.
van Soest EM, Valkhoff VE, Mazzaglia G, Schade R, Molokhia M, Goldstein JL, et al. Suboptimal gastroprotective coverage of NSAID use and the risk of upper gastrointestinal bleeding and ulcers: an observational study using three European databases. Gut 2011;60:1650-1659.
Scarpignato C, Hunt RH. Nonsteroidal antiinflammatory drug-related injury to the gastrointestinal tract: clinical picture, pathogenesis, and prevention. Gastroenterol Clin North Am 2010 Sep;39(3):433-464.
Leontiadis GI, Sreedharan A, Dorward S, Barton P, Delaney B, Howden CW, et al. Systematic reviews of the clinical effectiveness and cost-effectiveness of proton pump inhibitors in acute upper gastrointestinal bleeding. Health Technol Assess 2007 Dec;11(51):iii-iv, 1-164.
Mo C, Sun G, Lu ML, Zhang L, Wang YZ, Sun X, et al. Proton pump inhibitors in prevention of low-dose aspirin-associated upper gastrointestinal injuries. World J Gastroenterol 2015 May;21(17):5382-5392.
Hawkey CJ, Karrasch JA, Szczepanski L, Walker DG, Barkun A, Swannell AJ, Yeomans ND. Omeprazole compared with misoprostol for ulcers associated with nonsteroidal antiinflammatory drugs. Omeprazole versus Misoprostol for NSAID-induced Ulcer Management (OMNIUM) Study Group. N Engl J Med 1998 Mar;338(11):727-734.
Graham DY, Agrawal NM, Campbell DR, Haber MM, Collis C, Lukasik NL, 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 Jan;162(2):169-175.
Rostom A, Dube C, Wells G, Tugwell P, Welch V, Jolicoeur E, McGowan J. Prevention of NSAID-induced gastroduodenal ulcers. Cochrane Database Syst Rev 2002;4:CD002296.
Regula J, Butruk E, Dekkers CP, de Boer SY, Raps D, Simon L, et al. Prevention of NSAID-associated gastrointestinal lesions: a comparison study pantoprazole versus omeprazole. Am J Gastroenterol 2006;101(8):1747-1755.
Vakil N, Fennerty MB. Direct comparative trials of the efficacy of proton pump inhibitors in the management of gastrooesophageal reflux disease and peptic ulcer disease. Aliment Pharmacol Ther 2003 Sep;18(6):559-568.
Castell D. Review of immediate-release omeprazole for the treatment of gastric acid-related disorders. Expert Opin Pharmacother 2005 Nov;6(14):2501-2510.
Castell D, Bagin R, Goldlust B, Major J, Hepburn B. Comparison of the effects of immediate-release omeprazole powder for oral suspension and pantoprazole delayed-release tablets on nocturnal acid breakthrough in patients with symptomatic gastro-oesophageal reflux disease. Aliment Pharmacol Ther 2005 Jun;21(12):1467-1474.
Metz DC, Vakily M, Dixit T, Mulford D. Review article: dual delayed release formulation of dexlansoprazole MR, a novel approach to overcome the limitations of conventional single release proton pump inhibitor therapy. Aliment Pharmacol- Ther 2009 May;29(9):928-937.
Yeomans N, Wilson I, Langstrom G, Hawkey C, Naesdal J, Walan A, et al. Quality of life in chronic NSAID users: a com parison of the effect of omeprazole and misoprostol. Scand J Rheumatol 2001;30(6):328-334.
Yeomans ND, Tulassay Z, Juhasz L, Rácz I, Howard JM, van Rensburg CJ, et al. A comparison of omeprazole with ranitidine for ulcers associated with nonsteroidal anti-inflammatory drugs. Acid Suppression Trial: Ranitidine vs. Omeprazole for NSAID-associated Ulcer Treatment (ASTRONAUT) Study Group. N Engl J Med 1998 Mar;338(11):719-726.
Cullen D, Bardhan KD, Eisner M, Kogut DG, Peacock RA, Thomson JM, et al. Primary gastroduodenal prophylaxis with omeprazole for non-steroidal anti-inflammatory drug users. Aliment Pharmacol Ther 1998 Feb;12(2):135-140.
Brun J, Jones R. Non-steroidal anti-inflammatory drugassociated dyspepsia: the scale of the problem. Am J Med 2001 Jan;110(1A):12S-13S.
Armstrong CP, Blower AL. Non-steroidal anti-inflammatory drugs and life threatening complications of peptic ulceration. Gut1987 May;28(5):527-532.
Schellack N. An overview of gastropathy induced by nonsteroidal anti-inflammatory drugs. S Afr Pharm J 2012;79(4): 12-18.
Sugano K, Choi MG, Lin JT, Goto S, Okada Y, Kinoshita Y, et al. LAVENDER Study Group. Multinational, doubleblind, randomised, placebo-controlled, prospective study of esomeprazole in the prevention of recurrent peptic ulcer in low-dose acetylsalicylic acid users: the LAVENDER study. Gut 2014;63(7):1061-1068.
Scheiman JM, Lanas A, Veldhuyzen van Zanten S, Baldycheva I, Svedberg LE, Nagy P. Effect of esomeprazole on gastroduodenal erosions in patients at increased gastrointestinal risk treated with low-dose acetylsalicylic acid: a post-hoc analysis of the OBERON trial. Int J Cardiol 2015 Mar;182:500- 502.
Hooper L, Brown TJ, Elliott R, Payne K, Roberts C, Symmons D.The effectiveness of five strategies for the prevention of gastrointestinal toxicity induced by non-steroidal anti-inflammatory drugs: systematic review. BMJ 2004 Oct;329(7472): 948.
Taha AS, Hudson N, Hawkey CJ, Swannell AJ, Trye PN, Cottrell J, et al. Famotidine for the prevention of gastric and duodenal ulcers caused by nonsteroidal antiinflammatory drugs. N Engl J Med 1996 May;334(22):1435-1439.
Van Groenendael JH, Markusse HM, Dijkmans BA, Breedveld FC. The effect of ranitidine on NSAID related dyspeptic symptoms with and without peptic ulcer disease of patients with rheumatoid arthritis and osteoarthritis. Clin Rheumatol 1996 Sep;15(5):450-456.
Gigante A, Tagarro I. Non-steroidal anti-inflammatory drugs and gastroprotection with proton pump inhibitors: a focus on ketoprofen/omeprazole. Clin Drug Investig 2012 Apr;32(4):221-233.
Weinblatt, Michael E, Genovese, Mark C, Kivitz, Alan J, et al. Efficacy, Safety And Tolerability Of HZT-501, Including Users Of Low-Dose Aspirin, A Single-Tablet Combination Of Ibuprofen-Famotidine: Results Of Two Phase 3 Trials. [abstract] Arthritis Rheum 2010 Oct;62(10)(Suppl 10):945.
Sostek MB, Fort JG, Estborn L, Vikman K. Long-term safety of naproxen and esomeprazole magnesium fixed-dose combination: phase III study in patients at risk for NSAID-associated gastric ulcers. Curr Med Res Opin 2011 Apr;27(4):847- 854.