ABSTRACT
Title
NSAIDs safety evaluation: what misses from RCTs? Methodological issues and knowledge gaps identified through the SOS project
Authors
F. Salvo (1,2), A. Fourrier-Réglat (1,2,3), F. Bazin (1,2), M. Balzarin (4), N. Riera (5), M. Haag (6), N. Moore (1,2,3), M.C. Sturkenboom (6), A. Pariente (1,2,3)
1 INSERM, U657, Bordeaux, France
2 Université Victor Segalen, Département de Pharmacologie, Bordeaux, France
3 CHU de Bordeaux, Bordeaux, France
4 Università di Padova, Dipartimento di Pediatria, Padova, Italy.
5 RTI, Health Solution, Barcelona, Spain
6 Department of Medical Informatic, Erasmus University Medical Centre, Rotterdam, The Netherlands.
1 INSERM, U657, Bordeaux, France
2 Université Victor Segalen, Département de Pharmacologie, Bordeaux, France
3 CHU de Bordeaux, Bordeaux, France
4 Università di Padova, Dipartimento di Pediatria, Padova, Italy.
5 RTI, Health Solution, Barcelona, Spain
6 Department of Medical Informatic, Erasmus University Medical Centre, Rotterdam, The Netherlands.
Abstract
Introduction
As part of the Safety Of non-Steroidal anti-inflammatory drugs (SOS) project funded by the European Commission, a systematic review of randomized clinical trials (RCTs) was performed to evaluate the gastrointestinal (GI) and cardiovascular (CV) safety of NSAIDs.
Its objective wasto identify methodological issues and knowledge gaps from RCTs with safety data on NSAIDs in adult population.
Methods
Medline, Scopus, ISI web of Science, and Cochrane database of Systematic reviews were searched for RCTs with safety data through metaanalyses on safety of NSAIDs published between 1983-2008 for the 10 most sold NSAIDs in DE, IT, NL, UK in 2007 (16 drugs), with a complementary search for RCTs published after 2005 that would not have been included in the identified metaanalyses. RCTs with no treatment arm over 100 patients were excluded. Methodological issues (power inadequacy for adverse events (AEs) detection; no defined diagnostic criteria for CV and GI AEs) and knowledge gaps were evaluated with regard to indication of use, dose and treatment duration.
Results
Among 1,159 RCTs, 195 reported the inclusion of 100 patients or more in at least one arm of NSAIDs treated patients. No adequately powered RCT for safety assessment was found for some drugs in various labeled indication (e.g. ibuprofen in ankylosing spondylitis, ketoprofen in ostoarthrosis or rheumatoid arthritis). Defined diagnostic criteria were reported in 10.8% of RCTs AEs and in 22.6%, for CV and GI AEs respectively. Follow-up length was appropriate with regard to indication for all selected drugs but celecoxib in ankylosing spondylitis (up to 3 months). Regarding RCTs that evaluated coxibs in osteoarthritis, an important imbalance was found between dosage of coxibs and dosage of traditional NSAIDs used as controls. Coxibs were mostly evaluated at low dosage (celecoxib: 200mg or less; etoricoxib: 60 mg or less) while traditional NSAIDS were mostly evaluated at high dosage (diclofenac: 150 mg/day; ibuprofen: 2400mg/day; naproxen: 1000mg/day).
Conclusion
Important methodological issues and knowledge gaps were identified in RCTs for some of the most widely used NSAIDs in 4 European countries. These issues especially concerned an inadequate definition of safety outcomes and a discrepancy in the dosages of coxibs and tNSAIDs compared in osteoarthritis RCTs.
As part of the Safety Of non-Steroidal anti-inflammatory drugs (SOS) project funded by the European Commission, a systematic review of randomized clinical trials (RCTs) was performed to evaluate the gastrointestinal (GI) and cardiovascular (CV) safety of NSAIDs.
Its objective wasto identify methodological issues and knowledge gaps from RCTs with safety data on NSAIDs in adult population.
Methods
Medline, Scopus, ISI web of Science, and Cochrane database of Systematic reviews were searched for RCTs with safety data through metaanalyses on safety of NSAIDs published between 1983-2008 for the 10 most sold NSAIDs in DE, IT, NL, UK in 2007 (16 drugs), with a complementary search for RCTs published after 2005 that would not have been included in the identified metaanalyses. RCTs with no treatment arm over 100 patients were excluded. Methodological issues (power inadequacy for adverse events (AEs) detection; no defined diagnostic criteria for CV and GI AEs) and knowledge gaps were evaluated with regard to indication of use, dose and treatment duration.
Results
Among 1,159 RCTs, 195 reported the inclusion of 100 patients or more in at least one arm of NSAIDs treated patients. No adequately powered RCT for safety assessment was found for some drugs in various labeled indication (e.g. ibuprofen in ankylosing spondylitis, ketoprofen in ostoarthrosis or rheumatoid arthritis). Defined diagnostic criteria were reported in 10.8% of RCTs AEs and in 22.6%, for CV and GI AEs respectively. Follow-up length was appropriate with regard to indication for all selected drugs but celecoxib in ankylosing spondylitis (up to 3 months). Regarding RCTs that evaluated coxibs in osteoarthritis, an important imbalance was found between dosage of coxibs and dosage of traditional NSAIDs used as controls. Coxibs were mostly evaluated at low dosage (celecoxib: 200mg or less; etoricoxib: 60 mg or less) while traditional NSAIDS were mostly evaluated at high dosage (diclofenac: 150 mg/day; ibuprofen: 2400mg/day; naproxen: 1000mg/day).
Conclusion
Important methodological issues and knowledge gaps were identified in RCTs for some of the most widely used NSAIDs in 4 European countries. These issues especially concerned an inadequate definition of safety outcomes and a discrepancy in the dosages of coxibs and tNSAIDs compared in osteoarthritis RCTs.