A Comprehensive Review of NSAID Cardiovascular Toxicity

Unfortunately, confounding by indication is a common problem across these studies. Investigators have attempted to mitigate this effect by using a cohort of osteoarthritis or other inflammatory arthritis patients. Similarly, some studies have compared cardiovascular risk of NSAIDs with non-users of NSAIDs, which can also bias the results.

Use of remote, recent and current users of NSAIDs instead of non-users could potentially reduce confounding. Finally, physician preferences of a particular NSAID, over-the-counter drug use and the effect of baby aspirin cannot be sufficiently accounted for in these studies.

Conclusions

NSAIDs are commonly used in routine clinical practice and, particularly, rheumatology practice. And perhaps for osteoarthritis, which is the most common form of arthritis, there are not many choices—clinicians are often forced to choose between NSAIDs and prescription opiates, both with their associated side effects. Also, clinicians must weigh other side effects such as GI toxicity (often much less with COX-2 inhibitors) and drug efficacy (recent meta-analysis suggests that diclofenac may be more effective) with cardiovascular toxicity.

Although the U.S. Food and Drug Administration warns for cardiovascular toxicity against all NSAIDs, naproxen’s cardiovascular safety has been demonstrated across clinical trials and observational trials. Celecoxib at lower doses has been shown to be safe from a cardiovascular standpoint, and it has a favorable GI safety prolife. Various observational studies have shown drugs that preferentially inhibit COX-2 over COX-1 (e.g., diclofenac, etodolac, meloxicam, etc.) have increased cardiovascular toxicity and should be avoided if possible. Finally, nabumetone seems to have remarkable GI safety, and initial observational studies have shown its cardiovascular safety.

In summary, current data suggest this reasonable pain treatment strategy:

1. Start with nonsystemic NSAID analgesics, topical diclofenac or acetaminophen;
2. Try naproxen next;
3. Try celecoxib next, at a low (200 mg/day) dose; and finally
4. Try other nonselective NSAIDs next, such as ibuprofen.

Deepan S. Dalal, MD, MPH, works in the Department of Medicine at Brown University Warren Alpert School of Medicine in Providence, R.I.

Maureen Dubreuil, MD, MS, works in the Department of Medicine at Boston University School of Medicine and the Division of Rheumatology in the Boston VA Healthcare system.

David T. Felson, MD, MPH, works in the Department of Medicine at Boston University School of Medicine and in the Arthritis Research UK Epidemiology Unit at the University of Manchester in Manchester, England.

References

1. Wiegand T, Vernetti C. Nonsteroidal anti-inflammatory drug (NSAID) toxicity. Medscape. 2017 Dec 20.
2. Wolfe MM, Lichtenstein DR, Singh G. Gastrointestinal toxicity of nonsteroidal anti-inflammatory drugs. N Engl J Med. 1999 Aug 12;341(7):1888–1899.
3. Singh G. Recent considerations in nonsteroidal anti-inflammatory drug gastropathy. Am J Med. 1998 Jul 27;105(1B):31S–8S.
4. Hawkey CJ. COX-2 chronology. Gut. 2005 Nov;54(11):1509–1514.
5. Halpern GM. COX-2 inhibitors: A story of greed, deception and death. Inflammopharmacology. 2005;13(4):419–425.
6. Meyer-Kirchrath J, Schror K. Cyclooxygenase-2 inhibition and side-effects of non-steroidal anti-inflammatory drugs in the gastrointestinal tract. Curr Med Chem. 2000 Nov;7(11):1121–1129.
7. Garcia Rodriguez LA, Tacconelli S, Patrignani P. Role of dose potency in the prediction of risk of myocardial infarction associated with nonsteroidal anti-inflammatory drugs in the general population. J Am Coll Cardiol. 2008 Nov 11;52(20):1628–1636.
8. Fitzgerald GA. Coxibs and cardiovascular disease. N Engl J Med. 2004 Oct 21;351(17):1709–1711.
9. Cryer B, Feldman M. Cyclooxygenase-1 and cyclooxygenase-2 selectivity of widely used nonsteroidal anti-inflammatory drugs. Am J Med. 1998 May;104(5):413–421.
10. Olsen AM, Fosbol EL, Lindhardsen J, et al. Long-term cardiovascular risk of nonsteroidal anti-inflammatory drug use according to time passed after first-time myocardial infarction: A nationwide cohort study. Circulation. 2012 Oct 16;126(16):1955–1963.
11. Padol IT, Hunt RH. Association of myocardial infarctions with COX-2 inhibition may be related to immunomodulation towards a Th1 response resulting in atheromatous plaque instability: An evidence-based interpretation. Rheumatology (Oxford). 2010 May;49(5):837–843.
12. Bombardier C, Laine L, Reicin A, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med. 2000 Nov 23;343(21):1520–1528.
13. 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.
14. Cannon CP, Curtis SP, FitzGerald GA, et al. Cardiovascular outcomes with 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. 2006 Nov 18;368(9549):1771–1781.
15. Farkouh ME, Greenberg JD, Jeger RV, et al. Cardiovascular outcomes in high risk patients with osteoarthritis treated with ibuprofen, naproxen or lumiracoxib. Ann Rheum Dis. 2007 Jun;66(6):764–770.
16. Andersohn F, Suissa S, Garbe E. Use of first- and second-generation cyclooxygenase-2-selective nonsteroidal anti-inflammatory drugs and risk of acute myocardial infarction. Circulation. 2006 Apr 25;113(16):1950–1957.
17. Antman EM, Bennett JS, Daugherty A, et al. Use of nonsteroidal anti-inflammatory drugs: An update for clinicians: A scientific statement from the American Heart Association. Circulation. 2007 Mar 27;115(12):1634–1642.
18. 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.
19. 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.
20. Felson DT. Safety of nonsteroidal anti-inflammatory drugs. N Engl J Med. 2016 Dec 29;375(26):2595–2596.
21. Garcia Rodriguez LA, Varas-Lorenzo C, Maguire A, et al. Nonsteroidal anti-inflammatory drugs and the risk of myocardial infarction in the general population. Circulation. 2004 Jun 22;109(24):3000–3006.
22. Helin-Salmivaara A, Virtanen A, Vesalainen R, et al. NSAID use and the risk of hospitalization for first myocardial infarction in the general population: A nationwide case-control study from Finland. Eur Heart J. 2006 Jul;27(14):1657–1663.
23. van Staa TP, Rietbrock S, Setakis E, et al. Does the varied use of NSAIDs explain the differences in the risk of myocardial infarction? J Intern Med. 2008 Nov;264(5):481–492.
24. Shau WY, Chen HC, Chen ST, et al. Risk of new acute myocardial infarction hospitalization associated with use of oral and parenteral non-steroidal anti-inflammation drugs (NSAIDs): A case-crossover study of Taiwan’s National Health Insurance claims database and review of current evidence. BMC Cardiovasc Disord. 2012 Feb 2;12:4.
25. Salvo F, Antoniazzi S, Duong M, et al. Cardiovascular events associated with the long-term use of NSAIDs: A review of randomized controlled trials and observational studies. Expert Opin Drug Saf. 2014 May;13(5):573–585.
26. Trelle S, Reichenbach S, Wandel S, et al. Cardiovascular safety of non-steroidal anti-inflammatory drugs: Network meta-analysis. BMJ. 2011 Jan 11;342:c7086.
27. 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.
28. 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. 2016 Sep 28;354:i4857.
29. Bleumink GS, Feenstra J, Sturkenboom MC, et al. Nonsteroidal anti-inflammatory drugs and heart failure. Drugs. 2003;63(6):525–534.
30. Varas-Lorenzo C, Riera-Guardia N, Calingaert B, et al. Stroke risk and NSAIDs: A systematic review of observational studies. Pharmacoepidemiol Drug Saf. 2011 Dec;20(12):1225–1236.
31. Ungprasert P, Srivali N, Wijarnpreecha K, et al. Non-steroidal anti-inflammatory drugs and risk of venous thromboembolism: A systematic review and meta-analysis. Rheumatology (Oxford). 2015 Apr;54(4):736–742.
32. Lee T, Lu N, Felson DT, et al. Use of non-steroidal anti-inflammatory drugs correlates with the risk of venous thromboembolism in knee osteoarthritis patients: A UK population-based case-control study. Rheumatology (Oxford). 2016 Jun;55(6):1099–1105.