Cardiovascular risk with non-steroidal anti-inflammatory drugs: systematic review of population-based controlled observational studies

Abstract

Background: Randomised trials have highlighted the cardiovascular risks of non-steroidal anti-inflammatory drugs (NSAIDs) in high doses and sometimes atypical settings. Here, we provide estimates of the comparative risks with individual NSAIDs at typical doses in community settings.

Methods and findings: We performed a systematic review of community-based controlled observational studies. We conducted comprehensive literature searches, extracted adjusted relative risk (RR) estimates, and pooled the estimates for major cardiovascular events associated with use of individual NSAIDs, in different doses, and in populations with low and high background risks of cardiovascular events. We also compared individual drugs in pair-wise (within study) analyses, generating ratios of RRs (RRRs). Thirty case-control studies included 184,946 cardiovascular events, and 21 cohort studies described outcomes in >2.7 million exposed individuals. Of the extensively studied drugs (ten or more studies), the highest overall risks were seen with rofecoxib, 1.45 (95% CI 1.33, 1.59), and diclofenac, 1.40 (1.27, 1.55), and the lowest with ibuprofen, 1.18 (1.11, 1.25), and naproxen, 1.09 (1.02, 1.16). In a sub-set of studies, risk was elevated with low doses of rofecoxib, 1.37 (1.20, 1.57), celecoxib, 1.26 (1.09, 1.47), and diclofenac, 1.22 (1.12, 1.33), and rose in each case with higher doses. Ibuprofen risk was seen only with higher doses. Naproxen was risk-neutral at all doses. Of the less studied drugs etoricoxib, 2.05 (1.45, 2.88), etodolac, 1.55 (1.28, 1.87), and indomethacin, 1.30 (1.19, 1.41), had the highest risks. In pair-wise comparisons, etoricoxib had a higher RR than ibuprofen, RRR = 1.68 (99% CI 1.14, 2.49), and naproxen, RRR = 1.75 (1.16, 2.64); etodolac was not significantly different from naproxen and ibuprofen. Naproxen had a significantly lower risk than ibuprofen, RRR = 0.92 (0.87, 0.99). RR estimates were constant with different background risks for cardiovascular disease and rose early in the course of treatment.

Conclusions: This review suggests that among widely used NSAIDs, naproxen and low-dose ibuprofen are least likely to increase cardiovascular risk. Diclofenac in doses available without prescription elevates risk. The data for etoricoxib were sparse, but in pair-wise comparisons this drug had a significantly higher RR than naproxen or ibuprofen. Indomethacin is an older, rather toxic drug, and the evidence on cardiovascular risk casts doubt on its continued clinical use. Please see later in the article for the Editors' Summary.

Figure 1. Flow diagram for derivation of studies included in the analyses.

Figure 2. Summary analyses for individual drugs.

Vertical axis indicates pooled RR.

Figure 3. Forest plot for naproxen.

Key for Figures 3-13: Abraham: 2007a, low risk myocardial infarction; 2007b, average risk myocardial infarction; 2007c, low risk stroke; 2007d, average risk stroke. Andersohn: 2006a, myocardial infarction, cardiovascular death; 2006b, non-fatal stroke. Fosbol: 2010a, myocardial infarction, cardiovascular death; 2010b, fatal, non-fatal stroke. Gislason: 2006a, recurrent myocardial infarction; 2006b, death. Gislason: 2009a, myocardial infarction; 2009b, death. Lee: 2007a, low risk cardiovascular event; 2007b, high risk cardiovascular event. Roumie: 2008/09a, low risk cardiovascular event; 2008/09b, high risk cardiovascular event.

Figure 4. Forest plot for ibuprofen.

Figure 5. Forest plot for celecoxib.

Figure 6. Forest plot for rofecoxib.

Figure 7. Forest plot for diclofenac.

Figure 8. Forest plot for indomethacin.

Figure 9. Forest plot for piroxicam.

Figure 10. Forest plot for meloxicam.

Figure 11. Forest plot for etodolac.

Figure 12. Forest plot for etoricoxib.

Figure 13. Forest plot for valdecoxib.