Cardiovascular Risk with Non-Steroidal Anti-Inflammatory Drugs: Systematic Review of Population-Based Controlled Observational Studies – Forum

Date: 2013-03-06

Reference number: OPUSeJ 201303052316CRN

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Title: Cardiovascular Risk with Non-Steroidal Anti-Inflammatory Drugs: Systematic Review of Population-Based Controlled Observational Studies

Authors: Patricia McGettigan & David Henry

Moderator: N/A


Background: The analgesic (pain relieving), anti-pyretic (fever reducing), and anti-inflammatory (inflammation reducing) properties of the class of drug called non-steroidal anti-inflammatory drugs (NSAIDs)—so called to distinguish this class of drug from steroids, which have similar but additional effects—make NSAIDs one of the most frequently used drugs for the symptomatic treatment of many common conditions. Some preparations of NSAIDs can be bought over the counter, and all are available on prescription, but this class of drug has well documented side effects and risks: people taking NSAIDs are on average four times more likely to develop gastrointestinal complications than people not taking these drugs (that is, the relative risk of gastrointestinal complications is 4), and the relative risk for associated cardiovascular complications—cardiovascular events during treatment with NSAIDs has been one of the most studied adverse drug reactions in history—ranges from 1.0 to 2.0. Why Was This Study Done? Several large systematic reviews, including one conducted by these researchers, have previously highlighted apparent differences in cardiovascular risk between individual drugs, but these reviews have provided limited information on dose effects and relevant patient characteristics and have not directly compared the cardiovascular risks of each drug. Furthermore, most of these analyses extensively investigated only a few drugs, with little information on some widely available compounds, such as etoricoxib, etodolac, meloxicam, indomethacin, and piroxicam. Therefore, the researchers conducted this study to update cardiovascular risk estimates for all currently available NSAIDs and to compare the risks between individual drugs. In order to investigate the likely effects of over-the-counter use of NSAIDS, the researchers also wanted to include in their review an analysis of the cardiovascular risk at low doses of relevant drugs, over short time periods, and in low risk populations.

What Did the Researchers Do and Find? The researchers included only controlled observational studies in their literature search and review (conducted by searching a wide range of databases for studies published from 1985 until November 2010) because randomized controlled trials have reported only small numbers of cardiovascular events that are insufficient for the purposes of this study. The researchers assessed the methodological quality of selected studies, analyzed adjustment variables (for example, age, sex, other medications), and summarized overall results for individual drugs across studies as pooled relative risk estimates. For the subsets of studies that provided relevant data, they pooled within-study relative risk estimates with high and low doses and in people at high and low risk of cardiovascular events, and performed a series of within-study (pair-wise) comparisons and for each pair of drugs, to estimate their comparative relative risks by using a validated online tool to give a ratio of relative risks.

Using this methodology, the researchers included 30 case-control studies and 21 cohort studies: the highest overall risks were with rofecoxib and diclofenac, and the lowest risks were with ibuprofen and naproxen, The researchers found that risk was elevated with low doses of rofecoxib, celecoxib, and diclofenac, and rose with higher doses. Ibuprofen risk was only evident with higher doses. Naproxen did not cause any additional risks at any dose. Of the less studied NSAIDs, etoricoxib, etodolac, and indomethacin had the highest risks. In the pair-wise comparisons, the researchers found that etoricoxib had a higher relative risk than ibuprofen and naproxen, etodolac was not significantly different from naproxen and ibuprofen, and naproxen had a significantly lower risk than ibuprofen. Finally, the researchers showed that relative risk estimates were constant with different background risks for cardiovascular disease and increased early the course of treatment.

What Do These Findings Mean? This updated systematic review gives some new information on some familiar NSAIDs, and provides potentially important information on some little studied ones, which will help to inform clinical and regulatory decisions. The specific findings suggest that among widely used NSAIDs, naproxen and low-dose ibuprofen are least likely to increase cardiovascular risk, whereas diclofenac in doses available without prescription elevates risk. Based on sparse data, etoricoxib has a high risk of cardiovascular events and is similar to drugs that have been withdrawn because of safety concerns. Indomethacin is an older, rather toxic drug, and the new evidence on cardiovascular risk casts doubt on its continued clinical use.

Addendum: none


1. References,…5. Solomon DH, Schneeweiss S, Glynn RJ, Kiyota Y, Levin R, et al. (2004) Relationship between selective cyclooxygenase-2 inhibitors and acute myocardial infarction in older adults. Circulation 109: 2068–2073.

Bibliography: (alphabetical) N/A


1. Catella-Lawson F, McAdam B, Morrison BW, Kapoor S, Kujubu D, et al. (1999) Effects of specific inhibition of cyclooxygenase-2 on sodium balance, hemodynamics, and vasoactive eicosanoids. J Pharmacol Exp Ther 289: 735–741.

2. Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R, et al. (2000) Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med 343: 1520–1528.

3. Bertagnolli M, Eagle CJ, Zauber AG, Redston M, Solomon SD, et al. (2000) Celecoxib for the prevention of sporadic colorectal adenomas. N Engl J Med 355: 873–884.

4. Garcia Rodriguez LA, Varas-Lorenzo C, Maguire A, Gonzales-Perez A (2004) Non-steroidal anti-inflammatory drugs and the risk of myocardial infarction in the general population. Circulation 109: 3000–3006.

5. Schneeweiss S, Glynn RJ, Kiyota Y, Levin R, et al. Solomon DH (2004) Relationship between selective cyclooxygenase-2 inhibitors and acute myocardial infarction in older adults. Circulation 109: 2068–2073.

6. Henry D, Lim LL, García Rodríguez LA, Perez Gutthann S, Carson JL, et al. (1996) Variability in risk of gastrointestinal complications with individual non-steroidal anti-inflammatory drugs: results of a collaborative meta-analysis. BMJ 312: 1563–1566.

7. McGettigan P, Henry D (2006) Cardiovascular risk and inhibition of cylcooxygenase: a systematic review of the observational studies of selective and non-selective inhibitors of cyclooxygenase-2. JAMA 296: 1633–1644.

8. Fosbol EL, Folke F, Gislason GH, Jacobsen S, Rasamussen JN, et al. (2010) Cause-specific cardiovascular risk associated with non-steroidal anti-inflammatory drugs among healthy individuals. Circ Cardiovasc Qual Outcomes 3: 395–405. doi:10.1161/circoutcomes.109.861104.

9. Kearney PM, Baigent C, Godwin J, Halls H, Emberson JR, et al. (2006) Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials. BMJ 332: 1302–1308.

10. Trelle S, Reichenbach S, Wandel S, Hildebrand P, Tschannen B, et al. (2011) Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis. BMJ 342: c7086. doi:10.1136/bmj.c7086.

11. García Rodríguez LA, González-Pérez A, Bueno H, Hwa J (2011) NSAID use selectively increases the risk of non-fatal myocardial infarction: a systematic review of randomised trials and observational studies. PLoS ONE 6: e16780. doi:10.1371/journal.pone.0016780.

12. Hernández-Díaz S, Varas-Lorenzo C, García Rodríguez LA (2006) Non-steroidal antiinflammatory drugs and the risk of acute myocardial infarction. Basic Clin Pharmacol 98: 266–274.

13. Clinical Trial Service Unit and Epidemiological Studies Unit (2009) Coxib and traditional NSAID trialists’ (CNT) collaboration. Oxford: University of Oxford Clinical Trial Service Unit and Epidemiological Studies Unit.

14. Wells GA, Shea B, O’Connell D, Peterson P, Welch V, et al. (2010) The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Ottawa: Ottawa Hospital Research Institute.

15. Altman DG, Bland JM (2003) Interaction revisited: the difference between two estimates. BMJ 326: 219.

16. Hutchon DJR (2005) Calculations for comparing two estimated relative risks [computer program].

17. Anonymous (2011) Etoricoxib. Wikipedia: the free encyclopedia.

18. Barozzi N, Tett SE (2007) What happened to the prescribing of other COX-2 inhibitors, paracetamol and non-steroidal anti-inflammatory drugs when rofecoxib was withdrawn in Australia? Pharmacoepidemiol Drug Saf 16: 1184–1191.

19. Rubin BR, Burton R, Navarra S, Antigua J, Londoño J, et al. (2004) Efficacy and safety profile of treatment with etoricoxib 120 mg once daily compared with indomethacin 50 mg three times daily in acute gout: a randomized controlled trial. Arthritis Rheum 50: 598–606.

20. Schneeweiss S (2006) Sensitivity analysis and external adjustment for unmeasured confounders in epidemiologic database studies of therapeutics. Pharmacoepidemiol Drug Saf 15: 291–303.

21. Lévesque LE, Brophy JM, Zhang B (2006) Time variations in the risk of myocardial infarction among elderly users of COX-2 inhibitors. CMAJ 174: 1563–1569. doi:10.1503/cmaj.051679.

22. Helin-Salmivaara A, Virtanen A, Vesalainen R, Gronroos JM, Klaukka T, et al. (2006) 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 27: 1657–1663.

23. Solomon SD, Wittes J, Finn PV, Fowler R, Viner J, et al. (2008) Cardiovascular risk of celecoxib in 6 randomized placebo-controlled trials. Circulation 117: 2104–2113.

24. Caldwell B, Aldington S, Weatherall M, Shirtcliffe P, Beasley R (2006) Risk of cardiovascular events and celecoxib: A systematic review and meta-analysis. J R Soc Med 99: 132–140.

25. Cannon CP, Curtis SP, FitzGerald GA, Krum H, Kaur A, et al. (2006) 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 368: 1771–1781.

26. Nussmeier NA, Whelton AA, Brown MT, Langford RM, Hoeft A, et al. (2005) Implications of the COX-2 inhibitors parecoxib and valdecoxib after cardiac surgery. N Engl J Med 352: 1081–1091.

27. Lúcio M, Ferreira H, Lima JL, Reis S (2006) Interactions between oxicams and membrane bilayers: an explanation for their different COX selectivity. Med Chem 2: 447–456.

28. Anonymous (2011) Indomethacin: drug information provided by Lexi-Comp. The Merck Manual for Health Care Professionals.

29. Thompson M, Percy JS (1966) Further experience with indomethacin in the treatment of rheumatic disorders. BMJ 1: 80–83.

30. Hawkey C, Kahan A, Steinbruck K, Alegre C, Baumelou E, et al. (1998) Gastrointestinal tolerability of meloxicam compared to diclofenac in osteoarthritis patients. Br J Rheumatol 37: 937–945.

31. Olsen AMS, Fosbol EL, Lindhardsen J, Folke F, Charlot M, et al. (2011) Duration of treatment with non-steroidal anti-inflammatory drugs and impact on risk of death and recurrent myocardial infarction in patients with prior myocardial infarction: a nationwide cohort study. Circulation 123: 2226–2235.

32. Kerr DJ, Dunn JA, Langman MJ, Smith JL, Midgley RSJ, et al. (2007) Rofecoxib and cardiovascular adverse events in adjuvant treatment of colorectal cancer. N Engl J Med 357: 360–369.

33. Grosser T, Fries S, Fitzgerald GA (2006) Biological basis for the cardiovascular consequences of Cox 2 inhibition: therapeutic challenges and opportunities. J Clin Invest 116: 4–15.

34. MacDonald TM, Morant SV, Goldstein JL, Burke TA, Pettitt D (2003) Channelling bias and the incidence of gastrointestinal haemorrhage in users of meloxicam, coxibs, and older, non-specific non-steroidal anti-inflammatory drugs. Gut 52: 1265–1270.

35. Golder S, Loke YK, Bland M (2011) Meta-analyses of adverse effects data derived from randomised controlled trials as compared to observational studies: methodological overview. PLoS Med 8: e10011026. doi:10.1371/journal.pmed.1001026.

36. Catella-Lawson F, Reilly MP, Kapoor SC, Cucchiara AJ, DeMarco S, et al. (2001) Cyclo-oxygenase inhibitors and the anti-platelet effect of aspirin. New Engl J Med 345: 1809–1817.

Citation: McGettigan, Patricia and David Henry, 2011, “Cardiovascular Risk with Non-Steroidal Anti-Inflammatory Drugs: Systematic Review of Population-Based Controlled Observational Studies”, PLoS Med 8(9): e1001098. doi:10.1371/journal.pmed.1001098

Academic citations forward: Cited by 46 as of 2013-03-06:,5&hl=en

Other citations forward: none

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