Thirty one randomised controlled trials evaluating seven different non-steroidal anti-inflammatory drugs were included in the analyses (table 1, fig 1). Celecoxib was investigated most (15 trials) and compared with five different interventions. Ibuprofen was evaluated least (two trials) and compared with two different interventions, whereas etoricoxib was evaluated in three trials but compared with only one intervention. Etoricoxib and diclofenac had the largest number of patient years of follow-up (26
025 and 27
819 overall, respectively), whereas ibuprofen had the lowest number of patient years of follow-up (4832 overall). In total, 116
429 patients with 117
218 patient years of follow-up were covered in the analysis of the primary outcome (table 2). The methodological quality of included trials was generally high with all but two having adequate concealment of allocation, all having adequate blinding of patients and investigators, 16 having independent event adjudication, and 13 including all randomised patients in the analysis (table 1).
Table 1 Characteristics of included trials
Fig 1Network of comparisons included in analyses. Solid lines represent direct comparisons within randomised controlled trials. Numbers denote trials comparing corresponding interventions, with overall number of patient years of follow-up in (more ...)
Table 2 Number of events by randomised intervention for each outcome
Twenty nine trials with 554 accumulated events contributed to the analysis of myocardial infarction (table 2). For three of the preparations (naproxen, diclofenac, and etoricoxib) evidence was lacking for an increased risk of myocardial infarction compared with placebo (fig 2). All other drugs seemed to be associated with an increased risk compared with placebo. Estimated rate ratios were greater than 1.3 for ibuprofen (1.61, 95% credibility interval 0.50 to 5.77), celecoxib (1.35, 0.71 to 2.72), rofecoxib (2.12, 1.26 to 3.56), and lumiracoxib (2.00, 0.71 to 6.21).
Fig 2Estimates of rate ratios for non-steroidal anti-inflammatory drugs compared with placebo. NSAID=non-steroidal anti-inflammatory drug; APTC=Antiplatelet Trialists’ Collaboration
Twenty six trials with 377 accumulated events contributed to the analysis of stroke (table 2). All drugs seemed to be associated with an increased risk compared with placebo (fig 2). Estimated rate ratios were greater than 1.3 for naproxen (1.76, 0.91 to 3.33), ibuprofen (3.36, 1.00 to 11.60), diclofenac (2.86, 1.09 to 8.36), etoricoxib (2.67, 0.82 to 8.72), and lumiracoxib (2.81, 1.05 to 7.48).
Twenty six trials with 312 accumulated events contributed to the analysis of cardiovascular death, accounting for 46% of all deaths (table 2). All drugs except naproxen showed some evidence for an increased risk of cardiovascular death compared with placebo (fig 2). The estimated rate ratios for cardiovascular death were greater than 1.3 for ibuprofen (2.39, 0.69 to 8.64), diclofenac (3.98, 1.48 to 12.70), celecoxib (2.07, 0.98 to 4.55), etoricoxib (4.07, 1.23 to 15.70), rofecoxib (1.58, 0.88 to 2.84), and lumiracoxib (1.89, 0.64 to 7.09).
Death from any cause
Twenty eight trials with 676 accumulated events contributed to the analysis on overall mortality (table 2). All the drugs seemed to be associated with increased risks of death from any cause compared with placebo (fig 2). The estimated rate ratios were greater than 1.3 for ibuprofen (1.77, 0.73 to 4.30), diclofenac (2.31, 1.00 to 4.95), celecoxib (1.50, 0.96 to 2.54), etoricoxib (2.29, 0.94 to 5.71), rofecoxib (1.56, 1.04 to 2.23), and lumiracoxib (1.75, 0.78 to 4.17).
Antiplatelet Trialists’ Collaboration composite outcome
Thirty trials with 1091 accumulated events contributed to the analysis on the Antiplatelet Trialists’ Collaboration composite outcome (table 2). All drugs seemed to be associated with increased risks of the composite of non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death compared with placebo (fig 2). The estimated rate ratios were greater than 1.3 for ibuprofen (2.26, 1.11 to 4.89), diclofenac (1.60, 0.85 to 2.99), celecoxib (1.43, 0.94 to 2.16), etoricoxib (1.53, 0.74 to 3.17), rofecoxib (1.44, 1.00 to 1.99), and lumiracoxib (2.04, 1.13 to 4.24). Figure 3 presents an overview of pairwise comparisons (rate ratios with 95% credibility intervals) of all drugs on all outcomes.
Fig 3Estimates of rate ratios for all possible comparisons of non-steroidal anti-inflammatory drugs. APTC=Antiplatelet Trialists’ Collaboration composite outcome
Figure 4 presents posterior probability curves with resulting confidence levels for the different drugs compared with placebo and different outcomes. For example, the probability that rofecoxib increases the risk of myocardial infarction by less than 30% is 3% or conversely there is 97% confidence that rofecoxib increases the risk by at least 30% (corresponding to a rate ratio of 1.3). The curves can also be used to examine the overall pattern of available evidence of a specific drug. For example, the relatively steep increases in all but one of the posterior probability curves for naproxen points to the robust evidence available for naproxen. In contrast, the relatively flat curves for etoricoxib indicate a relative lack of available evidence. However, the mostly large effects seen for etoricoxib (indicated by the right shift of the curves) nevertheless allow conclusions for clinically relevant risk increases.
Fig 4Posterior probabilities for specified rate ratios. Curves can be used to extract a probability corresponding to a specified minimally clinically relevant rate ratio or to extract a minimal rate ratio corresponding to a specified probability (more ...)
Evaluation of models, variation, and sensitivity analyses
The model fit was good for all outcomes (see web extra appendix 2). Estimates of statistical heterogeneity between direct comparisons were generally low, except for myocardial infarction (range of τ2 across outcomes: 0.03 to 0.12; see web extra appendix 2). Inconsistency between direct and indirect comparisons was low for all outcomes (range of median inconsistency factors 2% to 29%; see web extra appendix 2). However, given the relatively low number of trials and events, relevant heterogeneity or inconsistency between trials could not be ruled out. Detailed results of the sensitivity analyses are presented in web extra appendix 2: results were all compatible with main analyses. Many of the estimates were imprecise, however, and do not allow for firm conclusions to be drawn.