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Review

Gastrointestinal and cardiovascular adverse events associated with NSAIDs

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Pages 373-384 | Received 16 Apr 2021, Accepted 05 Aug 2021, Published online: 18 Aug 2021

References

  • Montinari MR, Minelli S, De Caterina R. The first 3500 years of aspirin history from its roots - A concise summary. Vascul Pharmacol. 2019 Feb;113:1–8.
  • Bindu S, Mazumder S, Bandyopadhyay U. Non-steroidal anti-inflammatory drugs (NSAIDs) and organ damage: a current perspective. Biochem Pharmacol. 2020 Oct;180:114147.
  • Rane MA, Gitin A, Fiedler B, et al. Risks of cardiovascular disease and beyond in prescription of nonsteroidal anti-inflammatory drugs. J Cardiovasc Pharmacol Ther. 2020 Jan;25(1):3–6.
  • Zhou Y, Boudreau DM, Freedman AN. Trends in the use of aspirin and nonsteroidal anti-inflammatory drugs in the general U.S. population. Pharmacoepidemiol Drug Saf. 2014 Jan;23(1):43–50.
  • Lanas A, Perez-Aisa MA, Feu F, et al. A nationwide study of mortality associated with hospital admission due to severe gastrointestinal events and those associated with nonsteroidal antiinflammatory drug use. Am J Gastroenterol. 2005 Aug;100(8):1685–1693.
  • Lees P, Landoni MF, Giraudel J, et al. Pharmacodynamics and pharmacokinetics of nonsteroidal anti-inflammatory drugs in species of veterinary interest. J Vet Pharmacol Ther. 2004 Dec;27(6):479–490.
  • Warner TD, Vojnovic I, Giuliano F, et al. Cyclooxygenases 1, 2, and 3 and the production of prostaglandin I2: investigating the activities of acetaminophen and cyclooxygenase-2-selective inhibitors in rat tissues. J Pharmacol Exp Ther. 2004 Aug;310(2):642–647.
  • Grosser T, Fries S, FitzGerald GA. Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities. J Clin Invest. 2006 Jan;116(1):4–15.
  • Antman EM, DeMets D, Loscalzo J. Cyclooxygenase inhibition and cardiovascular risk. Circulation. 2005 Aug 2;112(5):759–770.
  • Schjerning AM, McGettigan P, Gislason G. Cardiovascular effects and safety of (non-aspirin) NSAIDs. Nat Rev Cardiol. 2020 Sep;17(9):574–584.
  • Antman EM, Bennett JS, Daugherty A, et al. Use of nonsteroidal antiinflammatory drugs: an update for clinicians: a scientific statement from the American Heart Association. Circulation. 2007 Mar 27;115(12):1634–1642.
  • McGettigan P, Henry D, Strom BL. Cardiovascular risk with non-steroidal anti-inflammatory drugs: systematic review of population-based controlled observational studies. PLoS Med. 2011 Sep;8(9):e1001098.
  • Bhala N, Emberson J, Merhi A, et al. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet. 2013 Aug 31;382(9894):769–779.
  • Schjerning Olsen AM, Fosbøl EL, Lindhardsen J, et al. Duration of treatment with nonsteroidal anti-inflammatory drugs and impact on risk of death and recurrent myocardial infarction in patients with prior myocardial infarction: a nationwide cohort study. Circulation. 2011 May 24;123(20):2226–2235.
  • Minuz P. Nonsteroidal anti-inflammatory drugs and cardiovascular risk: is prostacyclin inhibition the key event? J Am Coll Cardiol. 2008 Nov 11;52(20):1637–1639.
  • Grosser T, Yu Y, Fitzgerald GA. Emotion recollected in tranquility: lessons learned from the COX-2 saga. Annu Rev Med. 2010;61(1):17–33.
  • Nissen SE, Yeomans ND, Solomon DH, et al. Cardiovascular safety of celecoxib, naproxen, or ibuprofen for arthritis. N Engl J Med. 2016 Dec 29;375(26):2519–2529.
  • MacDonald TM, Hawkey CJ, Ford I, et al. Randomized trial of switching from prescribed non-selective non-steroidal anti-inflammatory drugs to prescribed celecoxib: the Standard care vs Celecoxib Outcome Trial (SCOT). Eur Heart J. 2017 Jun 14;38(23):1843–1850.
  • Rane MA, Foster JG, Wood SK, et al. Benefits and risks of nonsteroidal anti-inflammatory drugs: methodologic limitations lead to clinical uncertainties. Ther Innov Regul Sci. 2019 Jul;53(4):502–505.
  • Aw TJ, Haas SJ, Liew D, et al. Meta-analysis of cyclooxygenase-2 inhibitors and their effects on blood pressure. Arch Internal Med. 2005 Mar 14;165(5):490–496.
  • White WB, Kent J, Taylor A, et al. Effects of celecoxib on ambulatory blood pressure in hypertensive patients on ACE inhibitors. Hypertens. 2002 Apr;39(4):929–934.
  • Kumar B, Swee ML. Nonsteroidal anti-inflammatory drug use in a patient with hypertension: a teachable moment. JAMA Intern Med. 2015 Jun;175(6):892–893.
  • Sørensen R, Hansen ML, Abildstrom SZ, et al. Risk of bleeding in patients with acute myocardial infarction treated with different combinations of aspirin, clopidogrel, and vitamin K antagonists in Denmark: a retrospective analysis of nationwide registry data. Lancet. 2009 Dec 12;374(9706):1967–1974.
  • Scally B, Emberson JR, Spata E, et al. Effects of gastroprotectant drugs for the prevention and treatment of peptic ulcer disease and its complications: a meta-analysis of randomised trials. Lancet Gastroenterol Hepatol. 2018 Apr;3(4):231–241.
  • Bally M, Dendukuri N, Rich B, et al. Risk of acute myocardial infarction with NSAIDs in real world use: bayesian meta-analysis of individual patient data. BMJ (Clin Res Ed). 2017 May 9;357:j1909.
  • Masclee GMC, Straatman H, Arfè A, et al. Risk of acute myocardial infarction during use of individual NSAIDs: a nested case-control study from the SOS project. PloS One. 2018;13(11):e0204746.
  • Antman EM. The Aspirin-NSAID Interaction: more data, but a lack of clarity remains. J Am Coll Cardiol. 2018 Apr 24;71(16):1752–1754.
  • Breyer MD, Hao C, Qi Z. Cyclooxygenase-2 selective inhibitors and the kidney. Curr Opin Crit Care. 2001 Dec;7(6):393–400.
  • Krijthe BP, Heeringa J, Hofman A, et al. Non-steroidal anti-inflammatory drugs and the risk of atrial fibrillation: a population-based follow-up study. BMJ Open. 2014 Apr 8;4(4):e004059.
  • Zhang J, Ding EL, Song Y. Adverse effects of cyclooxygenase 2 inhibitors on renal and arrhythmia events: meta-analysis of randomized trials. Jama. 2006 Oct 4;296(13):1619–1632.
  • Schmidt M, Christiansen CF, Mehnert F, et al. Non-steroidal anti-inflammatory drug use and risk of atrial fibrillation or flutter: population based case-control study. BMJ (Clin Res Ed). 2011 Jul;4(343):d3450.
  • Liu G, Yan YP, Zheng XX, et al. Meta-analysis of nonsteroidal anti-inflammatory drug use and risk of atrial fibrillation. Am J Cardiol. 2014 Nov 15;114(10):1523–1529.
  • Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016 Jul 14;37(27):2129–2200.
  • Arfè A, Scotti L, Varas-Lorenzo C, et al. Non-steroidal anti-inflammatory drugs and risk of heart failure in four European countries: nested case-control study. BMJ (Clin Res Ed). 2016 Sep 28;354:i4857.
  • A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE steering committee. Lancet. 1996 Nov 16;348(9038):1329–1339.
  • Schjerning Olsen AM, Gislason GH, McGettigan P, et al. Association of NSAID use with risk of bleeding and cardiovascular events in patients receiving antithrombotic therapy after myocardial infarction. Jama. 2015 Feb 24;313(8):805–814.
  • Kent AP, Brueckmann M, Fraessdorf M, et al. Concomitant oral anticoagulant and nonsteroidal anti-inflammatory drug therapy in patients with atrial fibrillation. J Am Coll Cardiol. 2018 Jul 17;72(3):255–267.
  • Davidson BL, Verheijen S, Lensing AW, et al. Bleeding risk of patients with acute venous thromboembolism taking nonsteroidal anti-inflammatory drugs or aspirin. JAMA Intern Med. 2014 Jun;174(6):947–953.
  • Olsen AS, McGettigan P, Gerds TA, et al. Risk of gastrointestinal bleeding associated with oral anticoagulation and non-steroidal anti-inflammatory drugs in patients with atrial fibrillation: a nationwide study. Eur Heart J Cardiovasc Pharmacother. 2020 Sep 1;6(5):292–300.
  • Gadsbøll K, Staerk L, Fosbøl EL, et al. Increased use of oral anticoagulants in patients with atrial fibrillation: temporal trends from 2005 to 2015 in Denmark. Eur Heart J. 2017 Mar 21;38(12):899–906.
  • Meara AS, Simon LS. Advice from professional societies: appropriate use of NSAIDs. Pain Med. 2013 Dec;14(Suppl 1):S3–10.
  • Sostres C, Gargallo CJ, Lanas A. Nonsteroidal anti-inflammatory drugs and upper and lower gastrointestinal mucosal damage. Arthritis Res Ther. 2013;15(Suppl 3):S3.
  • Lanas A, Dumonceau JM, Hunt RH, et al. Non-variceal upper gastrointestinal bleeding. Nat Rev Dis Primers. 2018 Apr 19;4(1):18020.
  • Lanas A, Chan FKL. Peptic ulcer disease. Lancet. 2017 Aug 5;390(10094):613–624.
  • Lanas A. NSAIDs and aspirin. New York, NY: Springer Science+Business Media; 2016.
  • Lee HL, Chua SS, Mahadeva S. Dyspepsia in non-steroidal anti-inflammatory drug users and the effect of preventive measures. J Dig Dis. 2018 Jun;19(6):342–349.
  • Laine L, Bombardier C, Hawkey CJ, et al. Stratifying the risk of NSAID-related upper gastrointestinal clinical events: results of a double-blind outcomes study in patients with rheumatoid arthritis. Gastroenterology. 2002 Oct;123(4):1006–1012.
  • Lanas A, Benito P, Alonso J, et al. [Safe prescription recommendations for non steroidal anti-inflammatory drugs: consensus document elaborated by nominated experts of three scientific associations (SER-SEC-AEG)]. Gastroenterol Hepatol. 2014 Mar;37(3):107–127.
  • Castellsague J, Riera-Guardia N, Calingaert B, et al. Individual NSAIDs and upper gastrointestinal complications: a systematic review and meta-analysis of observational studies (the SOS project). Drug Saf. 2012 Dec 1;35(12):1127–1146.
  • Huang JQ, Sridhar S, Hunt RH. Role of Helicobacter pylori infection and non-steroidal anti-inflammatory drugs in peptic-ulcer disease: a meta-analysis. Lancet. 2002 Jan 5;359(9300):14–22.
  • Hernández-Díaz S, Rodríguez LA. Association between nonsteroidal anti-inflammatory drugs and upper gastrointestinal tract bleeding/perforation: an overview of epidemiologic studies published in the 1990s. Arch Internal Med. 2000 Jul 24;160(14):2093–2099.
  • Garcia Rodriguez LA, Jick H. Risk of upper gastrointestinal bleeding and perforation associated with individual non-steroidal anti-inflammatory drugs. Lancet. 1994 Mar 26;343(8900):769–772.
  • Massó González EL, Patrignani P, Tacconelli S, et al. Variability among nonsteroidal antiinflammatory drugs in risk of upper gastrointestinal bleeding. Arthritis Rheumatism. 2010 Jun;62(6):1592–1601.
  • Masclee GM, Valkhoff VE, Coloma PM, et al. Risk of upper gastrointestinal bleeding from different drug combinations. Gastroenterology. 2014 Oct;147(4):784–92.e9; quiz e13-4.
  • Á L, Carrera-Lasfuentes P, Arguedas Y, et al. Risk of upper and lower gastrointestinal bleeding in patients taking nonsteroidal anti-inflammatory drugs, antiplatelet agents, or anticoagulants. Clin Gastroenterol Hepatol. 2015 May;13(5):906–12.e2.
  • Reinau D, Schwenkglenks M, Früh M, et al. Glucocorticoids and the risk of peptic ulcer bleeding: case-control analysis based on Swiss claims data. Drug Saf. 2018 Jul;41(7):725–730.
  • Anglin R, Yuan Y, Moayyedi P, et al. 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.
  • Crooks CJ, West J, Card TR. Comorbidities affect risk of nonvariceal upper gastrointestinal bleeding. Gastroenterology. 2013 Jun;144(7):1384–93, 93.e1-2; quiz e18-9.
  • Watanabe T, Fujiwara Y, Chan FKL. Current knowledge on non-steroidal anti-inflammatory drug-induced small-bowel damage: a comprehensive review. J Gastroenterol. 2020 May;55(5):481–495.
  • Maiden L, Thjodleifsson B, Seigal A, et al. Long-term effects of nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 selective agents on the small bowel: a cross-sectional capsule enteroscopy study. Clin Gastroenterol Hepatol. 2007 Sep;5(9):1040–1045.
  • Kurahara K, Matsumoto T, Iida M, et al. Clinical and endoscopic features of nonsteroidal anti-inflammatory drug-induced colonic ulcerations. Am J Gastroenterol. 2001 Feb;96(2):473–480.
  • Shin SJ, Noh CK, Lim SG, et al. Non-steroidal anti-inflammatory drug-induced enteropathy. Intest Res. 2017 Oct;15(4):446–455.
  • Srinivasan A, De Cruz P. Review article: a practical approach to the clinical management of NSAID enteropathy. Scand J Gastroenterol. 2017 Sep;52(9):941–947.
  • Wang YZ, Sun G, Cai FC, et al. Clinical features, diagnosis, and treatment strategies of gastrointestinal diaphragm disease associated with nonsteroidal anti-inflammatory drugs. Gastroenterol Res Pract. 2016;2016:3679741.
  • Gerson LB, Fidler JL, Cave DR, et al. ACG clinical guideline: diagnosis and management of small bowel bleeding. Am J Gastroenterol. 2015 Sep;110(9):1265–87; quiz 88.
  • Laine L, Smith R, Min K, et al. Systematic review: the lower gastrointestinal adverse effects of non-steroidal anti-inflammatory drugs. Aliment Pharmacol Ther. 2006 Sep 1;24(5):751–767.
  • Nieuwenburg SAV, Vuik FER, Kruip M, et al. Effect of anticoagulants and NSAIDs on accuracy of faecal immunochemical tests (FITs) in colorectal cancer screening: a systematic review and meta-analysis. Gut. 2019 May;68(5):866–872.
  • Rendek Z, Falk M, Grodzinsky E, et al. Effect of oral diclofenac intake on faecal calprotectin. Scand J Gastroenterol. 2016 Jan;51(1):28–32.
  • Ishihara M, Ohmiya N, Nakamura M, et al. Risk factors of symptomatic NSAID-induced small intestinal injury and diaphragm disease. Aliment Pharmacol Ther. 2014 Sep;40(5):538–547.
  • Cho KM, Park SY, Chung JO, et al. Risk factors for small bowel bleeding in chronic nonsteroidal anti-inflammatory drug users. J Dig Dis. 2015 Sep;16(9):499–504.
  • Scarpignato C, Lanas A, Blandizzi C, et al. 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 19;13(1):55.
  • Goldstein JL, Johanson JF, Suchower LJ, et al. Healing of gastric ulcers with esomeprazole versus ranitidine in patients who continued to receive NSAID therapy: a randomized trial. Am J Gastroenterol. 2005 Dec;100(12):2650–2657.
  • Ng FH, Tunggal P, Chu WM, et al. Esomeprazole compared with famotidine in the prevention of upper gastrointestinal bleeding in patients with acute coronary syndrome or myocardial infarction. Am J Gastroenterol. 2012 Mar;107(3):389–396.
  • Rostom A, Muir K, Dube C, et al. Prevention of NSAID-related upper gastrointestinal toxicity: a meta-analysis of traditional NSAIDs with gastroprotection and COX-2 inhibitors. Drug Healthc Patient Saf. 2009;1:47–71.
  • 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 Internal Med. 2002 Jan 28;162(2):169–175.
  • Mizokami Y, Oda K, Funao N, et al. Vonoprazan prevents ulcer recurrence during long-term NSAID therapy: randomised, lansoprazole-controlled non-inferiority and single-blind extension study. Gut. 2018 Jun;67(6):1042–1051.
  • Rostom A, Muir K, Dube C, et al. Gastrointestinal safety of cyclooxygenase-2 inhibitors: a Cochrane Collaboration systematic review. Clin Gastroenterol Hepatol. 2007 Jul;5(7):818–28, 28.e1-5; quiz 768.
  • Chan FK, To KF, Wu JC, et al. Eradication of Helicobacter pylori and risk of peptic ulcers in patients starting long-term treatment with non-steroidal anti-inflammatory drugs: a randomised trial. Lancet. 2002 Jan 5;359(9300):9–13.
  • de Leest HT, Steen KS, Lems WF, et al. Eradication of Helicobacter pylori does not reduce the incidence of gastroduodenal ulcers in patients on long-term NSAID treatment: double-blind, randomized, placebo-controlled trial. Helicobacter. 2007 Oct;12(5):477–485.
  • Yuan JQ, Tsoi KK, Yang M, et al. Systematic review with network meta-analysis: comparative effectiveness and safety of strategies for preventing NSAID-associated gastrointestinal toxicity. Aliment Pharmacol Ther. 2016 Jun;43(12):1262–1275.
  • Laine L, Maller ES, Yu C, et al. Ulcer formation with low-dose enteric-coated aspirin and the effect of COX-2 selective inhibition: a double-blind trial. Gastroenterology. 2004 Aug;127(2):395–402.
  • Chan FKL, Ching JYL, Tse YK, et al. Gastrointestinal safety of celecoxib versus naproxen in patients with cardiothrombotic diseases and arthritis after upper gastrointestinal bleeding (CONCERN): an industry-independent, double-blind, double-dummy, randomised trial. Lancet. 2017 Jun 17;389(10087):2375–2382.
  • Lanas A, García-Rodríguez LA, Polo-Tomás M, et al. Time trends and impact of upper and lower gastrointestinal bleeding and perforation in clinical practice. Am J Gastroenterol. 2009 Jul;104(7):1633–1641.
  • Maseda D, Ricciotti E. NSAID-Gut microbiota interactions. Front Pharmacol. 2020;11:1153.
  • Washio E, Esaki M, Maehata Y, et al. Proton pump inhibitors increase incidence of nonsteroidal anti-inflammatory drug-induced small bowel injury: a randomized, placebo-controlled trial. Clin Gastroenterol Hepatol. 2016 Jun;14(6):809–15.e1.
  • Hawkey CJ, Ell C, Simon B, et al. Less small-bowel injury with lumiracoxib compared with naproxen plus omeprazole. Clin Gastroenterol Hepatol. 2008 May;6(5):536–544.
  • Maehata Y, Esaki M, Morishita T, et al. Small bowel injury induced by selective cyclooxygenase-2 inhibitors: a prospective, double-blind, randomized clinical trial comparing celecoxib and meloxicam. J Gastroenterol. 2012 Apr;47(4):387–393.
  • 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 Jul 17;376(9736):173–179.
  • Fujimori S, Seo T, Gudis K, et al. Prevention of nonsteroidal anti-inflammatory drug-induced small-intestinal injury by prostaglandin: a pilot randomized controlled trial evaluated by capsule endoscopy. Gastrointest Endosc. 2009 Jun;69(7):1339–1346.
  • Taha AS, McCloskey C, McSkimming P, et al. Misoprostol for small bowel ulcers in patients with obscure bleeding taking aspirin and non-steroidal anti-inflammatory drugs (MASTERS): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Gastroenterol Hepatol. 2018 Jul;3(7):469–476.
  • Scarpignato C, Dolak W, Lanas A, et al. Rifaximin reduces the number and severity of intestinal lesions associated with use of nonsteroidal anti-inflammatory drugs in humans. Gastroenterology. 2017 Apr;152(5):980–82.e3.
  • Endo H, Higurashi T, Hosono K, et al. Efficacy of Lactobacillus casei treatment on small bowel injury in chronic low-dose aspirin users: a pilot randomized controlled study. J Gastroenterol. 2011 Jul;46(7):894–905.
  • Kurokawa S, Katsuki S, Fujita T, et al. A randomized, double-blinded, placebo-controlled, multicenter trial, healing effect of rebamipide in patients with low-dose aspirin and/or non-steroidal anti-inflammatory drug induced small bowel injury. J Gastroenterol. 2014 Feb;49(2):239–244.
  • Lanas A, McCarthy D, Voelker M, et al. Short-term acetylsalicylic acid (aspirin) use for pain, fever, or colds - gastrointestinal adverse effects: a meta-analysis of randomized clinical trials. Drugs R D. 2011 Sep 1;11(3):277–288.
  • McMahon SB, Dargan P, Lanas A, et al. The burden of musculoskeletal pain and the role of topical non-steroidal anti-inflammatory drugs (NSAIDs) in its treatment. Ten underpinning statements from a global pain faculty. Curr Med Res Opin. 2021 Feb;37(2):287–292.
  • Bresalier RS, Sandler RS, Quan H, et al. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med. 2005 Mar 17;352(11):1092–1102.
  • Lanas A, García-Rodríguez LA, Arroyo MT, 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.
  • Naproxcinod: AZD 3582, HCT 3012, naproxen nitroxybutylester, nitronaproxen, NO-naproxen. Drugs R D. 2007;8(4):255–258.
  • Glowacka U, Magierowska K, Wojcik D, et al. Microbiome profile and molecular pathways alterations in gastrointestinal tract by hydrogen sulfide-releasing non-steroidal anti-inflammatory drug (ATB-352) Insight into possible safer polypharmacy. Antioxid Redox Signal. 2021 Mar 7.

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