Fifty-one studies (of 43 unique data sets) were included in the review; 30 case-control studies (26 unique data sets; 184,946 cases and 1,18,6354 controls) and 21 cohort studies (17 unique data sets; 2,711,084 users and 2,366,480 non-users). With regard to the validity assessment, fully-reported case-control studies scores ranged from 7 to 8 out of a possible 9 points, and cohort studies scores ranged from 7 to 8 out of a possible 10 points.
A significantly greater risk of a cardiovascular event compared to control was found for naproxen (OR 1.09, 95% CI 1.02 to 1.16; Ι²=71%; 41 studies), celecoxib (OR 1.17, 95% CI 1.08 to 1.27; Ι²=84%; 35 studies), ibuprofen (OR 1.18, 95% CI 1.11 to 1.25; Ι²=83%; 38 studies), meloxicam (OR 1.20, 95% CI 1.07 to 1.33; Ι²=0%; seven studies), indomethacin (OR 1.30, 95% CI 1.19 to 1.41; Ι²=33%; 14 studies), diclofenac (OR 1.40, 95% CI 1.27 to 1.55; Ι²=87%; 29 studies), rofecoxib (OR 1.45, 95% CI 1.33 to 1.59; Ι²=84%; 34 studies), etodolac (OR 1.55, 95% CI 1.28 to 1.87; Ι²=58%; five studies) and etoricoxib (OR 2.05, 95% CI 1.45 to 2.88; Ι²=0%; four studies). No significant between group differences were found for piroxicam and valdecoxib.
Dose response relationships in the most widely used NSAIDs demonstrated no significant difference in risk of cardiovascular disease for low daily dose ibuprofen, and both low and high dose naproxen when compared with control. Risk of cardiovascular disease was significantly elevated with low doses of rofecoxib, celecoxib and diclofenac, and increased with higher daily doses. No significant difference between risk ratio estimates for risk of cardiovascular disease was found between low and high risk populations for rofecoxib, celecoxib, ibuprofen, naproxen and diclofenac.
In the most widely used NSAIDs, pair-wise comparisons demonstrated that etoricoxib had a significantly higher relative risk than ibuprofen or naproxen, etodolac was not significantly different from diclofenac, naproxen and ibuprofen. Naproxen had a small but significant advantage over ibuprofen. Diclofenac was found to have a similar risk to rofecoxib (but significantly higher risk than celecoxib, naproxen or ibuprofen), and indomethacin had a significantly higher increase (23%) in risk than naproxen.
Results on less widely used drugs were also reported, as were results from sensitivity analyses.