Safety of selective non-steroidal anti-inflammatory drugs: analysis of the last years data

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most commonly used pain relievers. However, their use often threatens with serious undesirable effects, associated mainly with damage to cardiovascular system (CVS), gastrointestinal tract, kidneys and liver. Contraindications to NSAIDs prescription are clearly regulated, algorithms for their personalized appointment are determined taking into account risk factors for cardiovascular and gastrointestinal adverse events. The severity of NSAIDs side effects is mainly due to the selectivity to cyclooxygenase-2 (COX-2), as well as the physicochemical properties of various drugs. Cardiovascular adverse events differ among various NSAIDs both within commonly used drugs and among COX-2 inhibitors. It is well known that NSAIDs selective for COX-2 are safer in terms of the effect on the gastrointestinal tract than non-selective drugs. A meta-analysis showed that relatively selective COX-2 inhibitors (meloxicam, etodolac) were associated with a comparable risk of developing symptomatic ulcers and ulcers identified by endoscopy, and safety and tolerability profiles of the drugs were similar.
All NSAIDs are associated with cardiovascular toxicity, however, different drugs have significant risk differences. The mechanism of NSAIDs cardiovascular adverse effects is associated with an increase of blood pressure, sodium retention, vasoconstriction, platelet activation, and prothrombotic state. It has been shown that the risk of cardiovascular adverse events when taking COX-2 inhibitors (celecoxib, etoricoxib) significantly increases. According to a study of more than 8 million people, it was found that the risk of myocardial infarction was increased in patients taking ketorolac. Further, highest to lowest risk authors list indomethacin, etoricoxib, rofecoxib (not currently used), diclofenac, a fixed combination of diclofenac with misoprostol, piroxicam, ibuprofen, naproxen, celecoxib, meloxicam, nimesulide and ketoprofen. When taking NSAIDs, the risk of heart failure decompensation increases, and it turned out to be the greatest for ketorolac, etoricoxib, and indomethacin. Meloxicam, aceclofenac, ketoprofen almost did not increase heart failure risk. It should be noted that when using the drugs (except for indomethacin and meloxicam), there is a tendency to increase the total cardiovascular and renal risks with increasing doses. Thus, it is obvious that a very careful approach is required when choosing NSAIDs. If there is an increased risk of gastrointestinal complications associated with NSAIDs, selective NSAIDs are preferred, with both coxibs and traditional selective NSAIDs showing the best safety profile in the studies. To minimize cardiovascular side effects specialists should consider the risk level of cardiovascular complications, as well as results of large clinical studies where particular NSAIDs are compared.

non-steroidal anti-inflammatory drugs, pain, safety, side effects, gastrointestinal complications, cardiovascular complications, chronic kidney disease, hypertension, myocardial infarction, cyclooxygenase-2 inhibitors

1. Rane M.A., Gitin A., Fiedler B. et al. Risks of cardiovascular disease and beyond in prescription of nonsteroidal antiinflammatory drugs. J Cardiovasc Pharmacol Ther 2020;25(1):3–6. DOI: 10.1177/1074248419871902.

2. Karateev A.E., Nasonov E.L., Ivashkin V.T. et al. Rational use of nonsteroidal anti-inflammatory drugs. Clinical guidelines. Nauchnoprakticheskaya revmatologiya = Rheumatology Science and Practice 2018;56:1–29. (In Russ.) DOI: 10.14412/1995-4484-2018-1-29..

3. Lanas A., Garcia-Tell G., Armada B., Oteo-Alvaro A. Prescription patterns and appropriateness of NSAID therapy according to gastrointestinal risk and cardiovascular history in patients with diagnoses of osteoarthritis. BMC Med 2011;9:38. DOI: 10.1186/1741-7015-9-38.

4. Hawkey C.J. COX-1 and COX-2 inhibitors. Best Pract Res Clin Gastroenterol 2001;15(5):801–20. DOI: 10.1053/bega.2001.0236.

5. 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):821–47. DOI: 10.18433/j3vw2f.

6. Patrignani P., Tacconelli S., Bruno A. et al. Managing the adverse effects of nonsteroidal anti-inflammatory drugs. Expert Rev Clin Pharmacol 2011;4(5):605–21. DOI: 10.1586/ecp.11.36.

7. Gunter B.R., Butler K.A., Wallace R.L. et al. Non-steroidal anti-inflammatory drug-induced cardiovascular adverse events: a meta-analysis. J Clin Pharm Ther 2017;42(1):27–38. DOI: 10.1111/jcpt.12484.

8. Mason R.P., Walter M.F., McNulty H.P. et al. Rofecoxib increases susceptibility of human LDL and membrane lipids to oxidative damage: a mechanism of cardiotoxicity. J Cardiovasc Pharmacol 2006;47(Suppl. 1):7–14. DOI: 10.1097/00005344-200605001-00003.

9. Liu J.Y., Li N., Yang J. et al. Metabolic profiling of murine plasma reveals an unexpected biomarker in rofecoxibmediated cardiovascular events. Proc Natl Acad Sci USA 2010;107(390):17017–22. DOI: 10.1073/pnas.1011278107.

10. Szeto C.C., Sugano K., Wang J.G. et al. Non-steroidal anti-inflammatory drug(NSAID) therapy in patients with hypertension, cardiovascular, renal or gastrointestinal comorbidities: joint APAGE/APLAR/APSDE/APSH/APSN/PoA recommendations. Gut 2020;69(4):617–29. DOI: 10.1136/gutjnl-2019-319300.

11. Han M.H., Nam J.H., Noh E., Lee E.K. Gastrointestinal risk of non-steroidal antiinflammatory drugs and gastroprotective agents used in the treatment of osteoarthritis in elderly patients: a nationwide retrospective cohort study. Int J Clin Pharmacol Ther 2019;57(11):531–51. DOI: 10.5414/CP203377.

12. Van der Linden M.W., van der Bij S., Welsing P. et al. The balance between severe cardiovascular and gastrointestinal events among users of selective and nonselective non-steroidal anti-inflammatory drugs. Ann Rheum Dis 2009;68(5):668–73. DOI: 10.1136/ard.2007.087254.

13. Curtis E., Fuggle N., Shaw S. et al. Safety of cyclooxygenase-2 inhibitors in osteoarthritis: outcomes of a systematic review and meta-analysis. Drugs Aging 2019;36(Suppl. 1):25–44. DOI: 10.1007/s40266-019-00664-x.

14. Hawkey C., Kahan A., Steinbruck K. et al. Gastrointestinal tolerability of meloхicam compared to diclofenac in osteoarthritis patients. International MELISSA study group. Meloхicam large scale international study safety assessment. Br J Rheumatol 1988;37(9):937–45. DOI: 10.1093/rheumatology/37.9.937.

15. Laine L., White W.B., Rostom A., Hochberg M. COX-2 selective inhibitors in the treatment of osteoarthritis. Semin Arthritis Rheum 2008;38(3):165–87. DOI: 10.1016/j.semarthrit.2007.10.004.

16. Yang M., Wang H.T., Zhao M. et al. Network meta-analysis comparing relatively selective cox-2 inhibitors versus coxibs for the prevention of NSAIDinduced gastrointestinal injury. Medicine(Baltimore) 2015;94(40):1592. DOI: 10.1097/MD.0000000000001592.

17. Cooper C., Chapurlat R., Al-Daghri N. et al. Safety of oral non-selective nonsteroidal anti-inflammatory drugs in osteoarthritis: what does the literature say? Drugs Aging 2019;36(Suppl. 1):15–24. DOI: 10.1007/s40266-019-00660-1.

18. Varas-Lorenzo C., Riera-Guardia N., Calingaert B. et al. Myocardial infarction and individual nonsteroidal antiinflammatory drugs meta-analysis of observational studies. Pharmacoepidemiol Drug Saf 2013;22(6):559–70. DOI: 10.1002/pds.3437.

19. Varas-Lorenzo C., Riera-Guardia N., Calingaert B. et al. Stroke risk and NSAIDs: a systematic review of observational studies. Pharmacoepidemiol Drug Saf 2011;20(12):1225–36. DOI: 10.1002/pds.2227.

20. McGettigan P., Henry D. Cardiovascular risk with non-steroidal anti-inflammatory drugs: systematic review of populationbased controlled observational studies. PLoS Med 2011;8(9):1001098. DOI: 10.1371/journal.pmed.1001098.

21. Asghar W., Jamali F. The effect of COX-2-selective meloxicam on the myocardial, vascular and renal risks: a systematic review. Inflammopharmacology 2015;23(1):1–16. DOI: 10.1007/s10787-014-0225-9.

22. Höcherl K., Endemann D., Kammerl M.C. et al. Cyclo-oxygenase-2 inhibition increases blood pressure in rats. Br J Pharmacol 2002;136(8):1117–26. DOI: 10.1038/sj.bjp.0704821.

23. Qi Z, Hao C.M., Langenbach R.I., Breyer R.M. et al. Opposite effects of cyclooxygenase-1 and -2 activity on the pressor response to angiotensin II. J Clin Invest 2002;110(1):61–9. DOI: 10.1172/JCI14752.

24. Bulut D., Liaghat S., Hanefeld C. et al. Selective cyclo-oxygenase-2 inhibition with parecoxib acutely impairs endothelium-dependent vasodilatation in patients with essential hypertension. J Hypertens 2003;21(9):1663–7. DOI: 10.1097/00004872-20030900000015.

25. Sudano I., Flammer A.J., Roas S. et al. Nonsteroidal antiinflammatory drugs, acetaminophen, and hypertension. Curr Hypertens Rep 2012;14(4):304–9. DOI: 10.1007/s11906-012-0274-7.

26. Liew J.W., Ward M.M., Reveille J.D. et al. Nonsteroidal anti-inflammatory drug use is associated with incident hypertension in ankylosing spondylitis. Аrthritis Care Res (Hoboken) 2019. DOI: 10.1002/acr.24070.

27. Krum H., Swergold G., Gammaitoni A. et al. Blood pressure and cardiovascular outcomes in patients taking nonsteroidal antiinflammatory drugs. Cardiovasc Ther 2012;30(6):342–50. DOI: 10.1111/j.1755-5922.2011.00283.x.

28. Andersohn F., Suissa S., Garbe E. Use of first- and second-generation cyclooxygenase-2-selective nonsteroidal antiinflammatory drugs and risk of acute myocardial infarction. Circulation 2006;113(16):1950–7. DOI: 10.1161/CIRCULATIONAHA.105.602425.

29. Fosbøl E.L., Folke F., Jacobsen S. et al. Cause‐specific cardiovascular risk associated with nonsteroidal antiinflammatory drugs among healthy individuals. Circ Cardiovasc Qual Outcomes 2010;3(40):395–405. DOI: 10.1161/CIRCOUTCOMES.109.861104.

30. Masclee G.M.C., 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):0204746. DOI: 10.1371/journal.pone.0204746.

31. Bally M., Beauchamp M.E., Abrahamowicz M. et al. Risk of acute myocardial infarction with real-world NSAIDs depends on dose and timing of exposure. Pharmacoepidemiol Drug Saf 2018;27(1):69–77. DOI: 10.1002/pds.4358.

32. Ungprasert P., Srivali N., Thongprayoon C. Nonsteroidal Antiinflammatory Drugs and Risk of Incident Heart Failure: A Systematic Review and Meta-analysis of Observational Studies. Clin Cardiol 2016;39(2):111–8. DOI: 10.1002/clc.22502.

33. Ungprasert P., Kittanamongolchai W., Price C. et al. What is the “safest” non‐steroidal anti‐inflammatory drugs? Am Med J 2012;3:115–23. DOI: 10.3844/amjsp.2012.115.123.

34. White W.B. Cardiovascular risk, hypertension, and NSAIDs. Curr Rheumatol Rep 2007;9(1):36–43. DOI: 10.1007/s11926-007-0020-3.

35. Aneja A., Farkouh M.E. Adverse cardiovascular effects of NSAIDs: driven by blood pressure, or edema? Ther Adv Cardiovasc Dis 2008;2(1):53–66. DOI: 10.1177/1753944707088184.

36. Bäck M., Yin L., Ingelsson E. Cyclooxygenase-2 inhibitors and cardiovascular risk in a nation-wide cohort study after the withdrawal of rofecoxib. Eur Heart J 2012;33(150):1928–33. DOI: 10.1093/eurheartj/ehr421 pmid:22108833.

37. Arfè A., Scotti L., Varas-Lorenzo C. Non-steroidal anti-inflammatory drugs and risk of heart failure in four European countries: nested case-control study. BMJ 2016;354:4857. DOI: 10.1136/bmj.i4857.

38. Tarlovskaya E.I., Mikhailova Yu.V. Chronic heart failure and the frequency of taking nonsteroidal anti-inflammatory drugs: a register-based study on the possible risks. Rossiyskiy kardiologicheskiy zhurnal = Russian Journal of Cardiology 2020;25(1):3677. (In Russ.) DOI: 10.15829/1560-4071-2020-1-3677.

39. FDA Drug Safety Communication. FDA strengthens warning that non-aspirin nonsteroidal antiinflammatory drugs (NSAIDs) can cause heart attacks or strokes. Available on: http://www.fda.gov/Drugs/DrugSafety/ucm451800.htm.

40. Muñoz Olmo L., Juan Armas J., Gomariz García J.J. Risk of fatal/nonfatal events in patients with previous coronary heart disease/acute myocardial infarction and treatment with nonsteroidal anti-inflammatory drugs. Semergen 2018;44(5):355–63. DOI: 10.1016/j.semerg.2017.07.004.

41. Bruyère O., Cooper C., Pelletier J.P. et al. A consensus statement on the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) algorithm for the management of knee osteoarthritis – from evidence-based medicine to the real-life setting. Semin Arthritis Rheum 2016;45(Suppl 4):3–11. DOI: 10.1016/j.semarthrit.2015.11.010.

42. Barkin R.L., Beckerman M., Blum S.L. et al. Should nonsteroidal anti-inflammatory drugs (NSAIDs) be prescribed to the older adult? Drugs Aging 2010;27(10): 775–89. DOI: 10.2165/11539430000000000-00000.

43. American Geriatrics Society Panel on the Pharmacological. Management of Persistent Pain in Older Persons. Pharmacological management of persistent pain in older persons. Pain Med 2009;10(6):1062–83. DOI: 10.1111/j.1526-4637.2009.00699.x.

44. Kingsbury S.R., Hensor E.M., Walsh C.A. et al. How do people with knee osteoarthritis use osteoarthritis pain medications and does this change over time? Data from the Osteoarthritis Initiative. Arthritis Res Ther 2013;15(5):106. DOI: 10.1186/ar4286.