TY - JOUR
T1 - Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs
T2 - Meta-analyses of individual participant data from randomised trials
AU - Baigent, Colin
AU - Bhala, N.
AU - Emberson, J.
AU - Merhi, A.
AU - Abramson, S.
AU - Arber, N.
AU - Baron, J. A.
AU - Bombardier, C.
AU - Cannon, C.
AU - Farkouh, M. E.
AU - FitzGerald, G. A.
AU - Goss, P.
AU - Halls, H.
AU - Hawk, E.
AU - Hawkey, C.
AU - Hennekens, C.
AU - Hochberg, M.
AU - Holland, L. E.
AU - Kearney, P. M.
AU - Laine, L.
AU - Lanas, A.
AU - Lance, P.
AU - Laupacis, A.
AU - Oates, J.
AU - Patrono, C.
AU - Schnitzer, T. J.
AU - Solomon, S.
AU - Tugwell, P.
AU - Wilson, K.
AU - Wittes, J.
AU - Adelowo, O.
AU - Aisen, P.
AU - Al-Quorain, A.
AU - Altman, R.
AU - Bakris, G.
AU - Baumgartner, H.
AU - Bresee, C.
AU - Carducci, M.
AU - Chang, D. M.
AU - Chou, C. T.
AU - Clegg, D.
AU - Cudkowicz, M.
AU - Doody, L.
AU - Miedany, Y. El
AU - Falandry, C.
AU - Farley, J.
AU - Ford, L.
AU - Garcia-Losa, M.
AU - Gonzalez-Ortiz, M.
AU - Haghighi, M.
AU - Hala, M.
AU - Iwama, T.
AU - Jajic, Z.
AU - Kerr, D.
AU - Kim, H. S.
AU - Kohne, C.
AU - Koo, B. K.
AU - Martin, B.
AU - Meinert, C.
AU - Muller, N.
AU - Myklebust, G.
AU - Neustadt, D.
AU - Omdal, R.
AU - Ozgocmen, S.
AU - Papas, A.
AU - Patrignani, P.
AU - Pelliccia, F.
AU - Roy, V.
AU - Schlegelmilch, I.
AU - Umar, A.
AU - Wahlstrom, O.
AU - Wollheim, F.
AU - Yocum, S.
AU - Zhang, X. Y.
AU - Hall, E.
AU - McGettigan, P.
AU - Midgley, R.
AU - Moore, R. A.
AU - Philipson, R.
AU - Curtis, S.
AU - Reicin, A.
AU - Bond, J.
AU - Essex, M.
AU - Fabule, J.
AU - Morrison, B.
AU - Tive, L.
AU - Davies, K.
AU - Yau, F.
N1 - Funding Information:
The Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), where the CNT Secretariat (C Baigent, N Bhala, J Emberson, H Halls, L Holland, A Merhi, K Wilson) is located, has a policy of staff not accepting fees, honoraria, or paid consultancies. CTSU staff are, however, involved in clinical trials of lipid-modifying therapy funded by research grants from Merck to the University of Oxford, with the University the trial sponsor in all cases. In particular, C Baigent was chief investigator of the Study of Heart and Renal Protection of ezetimibe/simvastatin prior to 2011. N Arber, M Farkouh, P M Kearney, P Lance and S Solomon declare that they have no conflicts of interest. S Abramson serves as a consultant to Abbott and Pfizer. J A Baron was formerly a consultant to Merck and is currently a consultant to Bayer and to Pfizer (as a member of a safety and data monitoring committee). C Bombardier is a consultant to Abbott, AstraZeneca, Bristol-Myers Squibb (Canada and USA), and UCB, and receives research support from Abbott, Amgen, Bristol-Myers Squibb, Janssen, Hoffman La-Roche, Pfizer, and UCB Canada. C Cannon reports receiving research grants or support from Accumetrics, AstraZeneca, CSL Behring, Essentialis, GlaxoSmithKline, Merck, Regeneron, Sanofi, and Takeda. He is clinical advisor to, and holds equity in, Automedics Medical Systems. He also sits on advisory boards (but donates funds to charity) for Alnylam, Bristol-Myers Squibb, Lipimedix, and Pfizer. G FitzGerald has consulted for Boehringer Ingelheim, Lilly, Merck, BMS, Johnson and Johnson, Genentech, and Takeda. P Goss has received speaker honoraria from GlaxoSmithKline and Novartis. E Hawk reports a paid consultancy from Pozen Pharmaceuticals and is an unpaid consultant to Cancer Prevention Pharmaceuticals and PLx Pharmaceuticals. C Hawkey reports previously having received grants or honoraria from Merck, Pfizer, and AstraZeneca and at present advises Bayer, GlaxoSmithKline, and Novartis. C Hennekens reports serving on data and safety monitoring boards for Actelion, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, British Heart Foundation, Cadila, Canadian Institutes of Health Research, Lilly, Sunovion, and the Wellcome Foundation, and also serves as an advisor to legal counsel for Stryker. M Hochberg serves as a consultant or member of an advisory board for Abbott, Bioiberica SA, Boehringer Ingelheim, Bristol-Myers Squibb, Covidien, Eli Lilly, Genentech/Roche, Iroko Pharmaceuticals, Merck, Pfizer, and Regeneron. He chaired a data and safety monitoring board for Novartis and has received speaker honoraria from Bioiberica SA and IBSA. L Laine reports serving on data and safety monitoring boards for Bayer, Merck, and Eisai and has previously consulted for Pfizer, AstraZeneca, and Horizon. A Lanas is an advisor to Bayer and AstraZeneca Spain. A Laupacis reports serving on data and safety monitoring boards for Novartis and advisory boards for Pfizer and Eli Lilly, but none of these activities involve discussions about non-steroidal anti-inflammatory drugs. J Oates was a member of the scientific advisory board of Merck, concluding in 2006. C Patrono has received, during the past 2 years, consultant and speaker fees from Astra Zeneca, Bayer, Eli Lilly, Merck, NicOx, Novartis, and Servier, as well as an institutional grant from Bayer for investigator-initiated research. T Schnitzer reports paid consultancies with Merck, Janssen, Regeneron, Abbott, and McNeil, as well as research support (to Northwestern University) from Novartis, Merck, Eli Lilly, and Nuvo. P Tugwell reports paid consultancies with Bristol-Myers Squibb, Chelsea, and UCB, reports that OMERACT (Outcomes measures in Rheumatology), whose Executive he serves on in an unpaid capacity, receives support from Actellion, Alderbio, Amgen, Ardea Biosciences, Astra Zeneca, Bristol-Myers Squibb, Celgene, Centocor, Cypress/Forest, Eli Lilly, Boehringer Ingelheim, Genentech, Genzyme, Jass Pharmaceuticals, Merck, Novartis, Novo Nordisk, Pfizer, Regeneron, Savient, Takeda, UCB, and reports that the Ontario Biologics Research Initiative (OBRI) Industry Council receives support from Abbott, Roche, Schering Plough/Merck, UCB, and Bristol-Myers Squibb. J Wittes reports that Statistics Collaborative, a company in which she holds majority ownership, has consulting agreements with Merck, Bristol-Myers Squibb, AbbVie, Amgen, and Pfizer.
Funding Information:
The study was funded by core grants from the UK Medical Research Council and the British Heart Foundation. This collaboration is coordinated by the Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU) at the University of Oxford, UK. This work is supported at the CTSU by the UK Medical Research Council and the British Heart Foundation. N Bhala was funded by a MRC Health of the Public Research Fellowship. J Emberson acknowledges support from the BHF Centre of Research Excellence, Oxford, UK (RE/08/04). These organisations had no role in study design, data collection, data analysis, data interpretation or writing of the report. The authors thank the European Organization for Research and Treatment of Cancer for permission to use the data from EORTC trial 40015 for this research.
PY - 2013
Y1 - 2013
N2 - Background The vascular and gastrointestinal effects of non-steroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors (coxibs) and traditional non-steroidal anti-inflammatory drugs (tNSAIDs), are not well characterised, particularly in patients at increased risk of vascular disease. We aimed to provide such information through meta-analyses of randomised trials. Methods We undertook meta-analyses of 280 trials of NSAIDs versus placebo (124 513 participants, 68 342 personyears) and 474 trials of one NSAID versus another NSAID (229 296 participants, 165 456 person-years). The main outcomes were major vascular events (non-fatal myocardial in farction, non-fatal stroke, or vascular death); major coronary events (non-fatal myocardial infarction or coronary death); stroke; mortality; heart failure; and upper gastrointestinal complications (perforation, ob struction, or bleed). Findings Major vascular events were increased by about a third by a coxib (rate ratio [RR] 1·37, 95% CI 1·14-1·66; p=0·0009) or diclofenac (1·41, 1·12-1·78; p=0·0036), chiefl y due to an increase in major coronary events (coxibs 1·76, 1·31-2·37; p=0·0001; diclofenac 1·70, 1·19-2·41; p=0·0032). Ibuprofen also significantly increased major coronary events (2·22, 1·10-4·48; p=0·0253), but not major vascular events (1·44, 0·89-2·33). Compared with placebo, of 1000 patients allocated to a coxib or diclofenac for a year, three more had major vascular events, one of which was fatal. Naproxen did not significantly increase major vascular events (0·93, 0·69-1·27). Vascular death was increased significantly by coxibs (1·58, 99% CI 1·00-2·49; p=0·0103) and diclofenac (1·65, 0·95-2·85, p=0·0187), nonsignificantly by ibuprofen (1·90, 0·56-6·41; p=0·17), but not by naproxen (1·08, 0·48-2·47, p=0·80). The proportional eff ects on major vascular events were independent of baseline characteristics, including vascular risk. Heart failure risk was roughly doubled by all NSAIDs. All NSAID regimens increased upper gastrointestinal complications (coxibs 1·81, 1·17-2·81, p=0·0070; diclofenac 1·89, 1·16-3·09, p=0·0106; ibuprofen 3·97, 2·22-7·10, p<0·0001; and naproxen 4·22, 2·71-6·56, p<0·0001). Interpretation The vascular risks of high-dose diclofenac, and possibly ibuprofen, are comparable to coxibs, whereas high-dose naproxen is associated with less vascular risk than other NSAIDs. Although NSAIDs increase vascular and gastrointestinal risks, the size of these risks can be predicted, which could help guide clinical decision making. Funding UK Medical Research Council and British Heart Foundation.
AB - Background The vascular and gastrointestinal effects of non-steroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors (coxibs) and traditional non-steroidal anti-inflammatory drugs (tNSAIDs), are not well characterised, particularly in patients at increased risk of vascular disease. We aimed to provide such information through meta-analyses of randomised trials. Methods We undertook meta-analyses of 280 trials of NSAIDs versus placebo (124 513 participants, 68 342 personyears) and 474 trials of one NSAID versus another NSAID (229 296 participants, 165 456 person-years). The main outcomes were major vascular events (non-fatal myocardial in farction, non-fatal stroke, or vascular death); major coronary events (non-fatal myocardial infarction or coronary death); stroke; mortality; heart failure; and upper gastrointestinal complications (perforation, ob struction, or bleed). Findings Major vascular events were increased by about a third by a coxib (rate ratio [RR] 1·37, 95% CI 1·14-1·66; p=0·0009) or diclofenac (1·41, 1·12-1·78; p=0·0036), chiefl y due to an increase in major coronary events (coxibs 1·76, 1·31-2·37; p=0·0001; diclofenac 1·70, 1·19-2·41; p=0·0032). Ibuprofen also significantly increased major coronary events (2·22, 1·10-4·48; p=0·0253), but not major vascular events (1·44, 0·89-2·33). Compared with placebo, of 1000 patients allocated to a coxib or diclofenac for a year, three more had major vascular events, one of which was fatal. Naproxen did not significantly increase major vascular events (0·93, 0·69-1·27). Vascular death was increased significantly by coxibs (1·58, 99% CI 1·00-2·49; p=0·0103) and diclofenac (1·65, 0·95-2·85, p=0·0187), nonsignificantly by ibuprofen (1·90, 0·56-6·41; p=0·17), but not by naproxen (1·08, 0·48-2·47, p=0·80). The proportional eff ects on major vascular events were independent of baseline characteristics, including vascular risk. Heart failure risk was roughly doubled by all NSAIDs. All NSAID regimens increased upper gastrointestinal complications (coxibs 1·81, 1·17-2·81, p=0·0070; diclofenac 1·89, 1·16-3·09, p=0·0106; ibuprofen 3·97, 2·22-7·10, p<0·0001; and naproxen 4·22, 2·71-6·56, p<0·0001). Interpretation The vascular risks of high-dose diclofenac, and possibly ibuprofen, are comparable to coxibs, whereas high-dose naproxen is associated with less vascular risk than other NSAIDs. Although NSAIDs increase vascular and gastrointestinal risks, the size of these risks can be predicted, which could help guide clinical decision making. Funding UK Medical Research Council and British Heart Foundation.
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U2 - 10.1016/S0140-6736(13)60900-9
DO - 10.1016/S0140-6736(13)60900-9
M3 - Article
C2 - 23726390
AN - SCOPUS:84883134602
VL - 382
SP - 769
EP - 779
JO - The Lancet
JF - The Lancet
SN - 0140-6736
IS - 9894
ER -