1. Sven Trelle, senior research fellow12,
2. Stephan Reichenbach, senior research fellow14,
3. Simon Wandel, research fellow1,
4. Pius Hildebrand, clinical reviewer3,
5. Beatrice Tschannen, research fellow1,
6. Peter M Villiger, head of department and professor of rheumatology4,
7. Matthias Egger, head of department and professor of epidemiology and public health1,
8. Peter Jüni, head of division and professor of clinical epidemiology12

1. 
   
   ¹Institute of Social and Preventive Medicine, University of Bern, Switzerland
2. 
   
   ²CTU Bern, Inselspital, and University of Bern, Switzerland
3. 
   
   ³Swissmedic (Swiss Agency for Therapeutic Products), Bern
4. 
   
   ⁴Department of Rheumatology and Clinical Immunology/Allergology, Inselspital, and University of Bern

1. Correspondence to: P Jüni, Institute of Social and Preventive Medicine, University of Bern, Finkenhubelweg 11, 3012 Bern, Switzerland juni{at}ispm.unibe.ch

• Accepted 8 October 2010

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.

Footnotes

• We thank all independent trialists, Novartis, and Pfizer for providing unpublished data and Malcom Sturdy for development of the database.

• Contributors: ST and SR contributed equally to this work. ST, SR, SW, and PJ had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. PJ conceived and designed the study. ST, SR, and BT acquired the data. All authors analysed and interpreted the data. ST, SR, and PJ drafted the manuscript. SW, PH, BT, PMV, and ME critically revised the manuscript for important intellectual content. ST, SW, and PJ carried out the statistical analysis. SR, ME and PJ obtained funding. SR, PH, BT, PMV, ME, and PJ provided administrative support. PJ supervised the study.

• Funding: SR, ME, and PJ received grants (Nos 4053-40-104762/3 and 3200-066378) from the Swiss National Science Foundation’s national research programme 53 on musculoskeletal health. PJ was a programme for social medicine, preventive and epidemiological research senior research fellow funded by the Swiss National Science Foundation (grant No 3233-066377). CTU Bern is supported by the Swiss National Science Foundation. The Swiss National Science Foundation, had no role in the study design, data collection, data analysis, data interpretation, writing of the manuscript, or decision to submit the manuscript.

• 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.

• Ethical approval: Not required.

• Data sharing: No additional data available.

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: http://creativecommons.org/licenses/by-nc/2.0/ and http://creativecommons.org/licenses/by-nc/2.0/legalcode.