Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis

Abstract

Objective: To analyse the available evidence on cardiovascular safety of non-steroidal anti-inflammatory drugs.

Design: Network meta-analysis.

Data sources: Bibliographic databases, conference proceedings, study registers, the Food and Drug Administration website, reference lists of relevant articles, and reports citing relevant articles through the Science Citation Index (last update July 2009). Manufacturers of celecoxib and lumiracoxib provided additional data.

Study selection: All large scale randomised controlled trials comparing any non-steroidal anti-inflammatory drug with other non-steroidal anti-inflammatory drugs or placebo. Two investigators independently assessed eligibility.

Data extraction: The primary outcome was myocardial infarction. Secondary outcomes included stroke, death from cardiovascular disease, and death from any cause. Two investigators independently extracted data.

Data synthesis: 31 trials in 116 429 patients with more than 115 000 patient years of follow-up were included. Patients were allocated to naproxen, ibuprofen, diclofenac, celecoxib, etoricoxib, rofecoxib, lumiracoxib, or placebo. Compared with placebo, rofecoxib was associated with the highest risk of myocardial infarction (rate ratio 2.12, 95% credibility interval 1.26 to 3.56), followed by lumiracoxib (2.00, 0.71 to 6.21). Ibuprofen was associated with the highest risk of stroke (3.36, 1.00 to 11.6), followed by diclofenac (2.86, 1.09 to 8.36). Etoricoxib (4.07, 1.23 to 15.7) and diclofenac (3.98, 1.48 to 12.7) were associated with the highest risk of cardiovascular death.

Conclusions: Although uncertainty remains, little evidence exists to suggest that any of the investigated drugs are safe in cardiovascular terms. Naproxen seemed least harmful. Cardiovascular risk needs to be taken into account when prescribing any non-steroidal anti-inflammatory drug.

Conflict of interest statement

Competing interests: All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: no support from any institution for the submitted work besides the funding as described above; no financial relationships with any institutions that might have an interest in the submitted work in the previous 3 years; no other relationships or activities that could appear to have influenced the submitted work.

Figures

Fig 1 Network 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 brackets

Fig 2 Estimates of rate ratios for non-steroidal anti-inflammatory drugs compared with placebo. NSAID=non-steroidal anti-inflammatory drug; APTC=Antiplatelet Trialists’ Collaboration

Fig 3 Estimates of rate ratios for all possible comparisons of non-steroidal anti-inflammatory drugs. APTC=Antiplatelet Trialists’ Collaboration composite outcome

Fig 4 Posterior 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 or confidence level. For example, an increase in risk for myocardial infarction of at least 20% (rate ratio of at least 1.2) may be considered clinically relevant. The curve for naproxen indicates that the probability of the drug being associated with a rate ratio below this threshold is about 83%. Conversely, a probability of 90% may be considered as appropriate evidence for the outcome stroke. The curve for celecoxib indicates that someone can be 90% confident that celecoxib increases the risk for stroke by no more than 65% (rate ratio of 1.65). APTC=Antiplatelet Trialists’ Collaboration