PMID- 31073922 OWN - NLM STAT- MEDLINE DCOM- 20190708 LR - 20210317 IS - 1179-1969 (Electronic) IS - 1170-229X (Print) IS - 1170-229X (Linking) VI - 36 IP - Suppl 1 DP - 2019 Apr TI - Safety of Cyclooxygenase-2 Inhibitors in Osteoarthritis: Outcomes of a Systematic Review and Meta-Analysis. PG - 25-44 LID - 10.1007/s40266-019-00664-x [doi] AB - OBJECTIVE: Our aim was to assess the safety of cyclooxygenase-2 (COX-2) inhibitors in the management of osteoarthritis (OA) in a systematic review and meta-analysis of randomized, placebo-controlled trials. METHODS: A comprehensive literature search was undertaken in the databases MEDLINE, Cochrane Central Register of Controlled Trials (Ovid CENTRAL) and Scopus. Randomized, double-blind, placebo-controlled, parallel-group trials that assessed adverse events (AEs) with COX-2 inhibitors in patients with OA were eligible for inclusion. Two authors appraised titles, abstracts and full-text papers for suitability and then assessed the studies for random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data and selective outcomes reporting. The primary outcomes of interest were gastrointestinal disorders, cardiac disorders, vascular disorders, nervous system disorders, skin and subcutaneous tissue disorders, hepatobiliary disorders, renal and urinary disorders, as well as overall severe and serious AEs, drug-related AEs and mortality. Secondary outcomes were withdrawals due to AEs (i.e. the number of participants who stopped the treatment due to an AE) and total number of AEs (i.e. the number of patients who experienced any AE at least once). RESULTS: Database searches identified 2149 records from which, after exclusions, 40 trials were included in the meta-analysis. The use of COX-2 inhibitors in OA was associated with a significant increased risk of drug-related AEs compared with placebo (relative risk (RR) 1.26, 95% CI 1.09-1.46; I(2) = 24%). The risk of upper gastrointestinal complications (including dyspepsia, gastritis and heartburn) was significantly increased with COX-2 inhibitors versus placebo (RR 1.19, 95% CI 1.03-1.38; I(2) = 0%), particularly for abdominal pain, which increased by 40% with COX-2 inhibitors (RR 1.40, 95% CI 1.08-1.80; I(2) = 0%). The risk of hypertension increased by 45% overall (RR 1.45, 95% CI 1.01-2.10; I(2) = 25%); however, when rofecoxib was removed from the analysis the risk of hypertension in the COX-2 inhibitor group was no longer significant (RR 1.21, 95% CI 0.80-1.83; I(2) = 20%). The overall risk of heart failure and edema was increased by nearly 70% with COX-2 inhibitors versus placebo (RR 1.68, 95% CI 1.22-2.31; 0%) and this level of risk did not change appreciably when rofecoxib was excluded (RR 1.67, 95% CI 1.21-2.29; 0%). CONCLUSIONS: In our analysis, COX-2 inhibitors were associated with an increased risk of upper gastrointestinal AEs, especially abdominal pain. We also found an increased risk of cardiovascular AEs with COX-2 inhibitors, namely hypertension, heart failure and edema. FAU - Curtis, Elizabeth AU - Curtis E AUID- ORCID: 0000-0002-5147-0550 AD - MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton General Hospital, Tremona Road, Southampton, SO16 6YD, UK. FAU - Fuggle, Nicholas AU - Fuggle N AD - MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton General Hospital, Tremona Road, Southampton, SO16 6YD, UK. FAU - Shaw, Sarah AU - Shaw S AD - MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton General Hospital, Tremona Road, Southampton, SO16 6YD, UK. FAU - Spooner, Laura AU - Spooner L AD - Portsmouth Hospitals NHS Trust, Portsmouth, UK. FAU - Ntani, Georgia AU - Ntani G AD - MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton General Hospital, Tremona Road, Southampton, SO16 6YD, UK. FAU - Parsons, Camille AU - Parsons C AD - MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton General Hospital, Tremona Road, Southampton, SO16 6YD, UK. FAU - Corp, Nadia AU - Corp N AD - Arthritis Research UK Primary Care Centre, Institute for Primary Care and Health Sciences, Keele University, Keele, UK. FAU - Honvo, Germain AU - Honvo G AD - Department of Public Health, Epidemiology and Health Economics, University of Liege, Liege, Belgium. AD - WHO Collaborating Centre for Public Heath Aspects of Musculoskeletal Health and Aging, Liege, Belgium. FAU - Baird, Janis AU - Baird J AD - MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton General Hospital, Tremona Road, Southampton, SO16 6YD, UK. FAU - Maggi, Stefania AU - Maggi S AD - Aging Program, National Research Council, Neuroscience Institute, Padua, Italy. FAU - Dennison, Elaine AU - Dennison E AD - MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton General Hospital, Tremona Road, Southampton, SO16 6YD, UK. FAU - Bruyere, Olivier AU - Bruyere O AD - Department of Public Health, Epidemiology and Health Economics, University of Liege, Liege, Belgium. AD - WHO Collaborating Centre for Public Heath Aspects of Musculoskeletal Health and Aging, Liege, Belgium. FAU - Reginster, Jean-Yves AU - Reginster JY AUID- ORCID: 0000-0001-6290-752X AD - Department of Public Health, Epidemiology and Health Economics, University of Liege, Liege, Belgium. AD - WHO Collaborating Centre for Public Heath Aspects of Musculoskeletal Health and Aging, Liege, Belgium. AD - Chair for Biomarkers of Chronic Diseases, Biochemistry Department, College of Science, King Saud University, Riyadh, Kingdom of Saudi Arabia. FAU - Cooper, Cyrus AU - Cooper C AUID- ORCID: 0000-0003-3510-0709 AD - MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton General Hospital, Tremona Road, Southampton, SO16 6YD, UK. cc@mrc.soton.ac.uk. AD - WHO Collaborating Centre for Public Heath Aspects of Musculoskeletal Health and Aging, Liege, Belgium. cc@mrc.soton.ac.uk. AD - National Institute for Health Research (NIHR) Musculoskeletal Biomedical Research Unit, University of Oxford, Oxford, UK. cc@mrc.soton.ac.uk. LA - eng GR - 21231/VAC_/Versus Arthritis/United Kingdom GR - MC_U147585819/MRC_/Medical Research Council/United Kingdom GR - MC_UP_A620_1014/MRC_/Medical Research Council/United Kingdom GR - MC_UP_A620_1017/MRC_/Medical Research Council/United Kingdom GR - 19583/VAC_/Versus Arthritis/United Kingdom GR - MC_UU_12011/4/MRC_/Medical Research Council/United Kingdom GR - G0400491/MRC_/Medical Research Council/United Kingdom GR - MC_U147585824/MRC_/Medical Research Council/United Kingdom GR - 10/33/04/DH_/Department of Health/United Kingdom GR - MC_UU_12011/1/MRC_/Medical Research Council/United Kingdom PT - Journal Article PT - Meta-Analysis PT - Research Support, Non-U.S. Gov't PT - Systematic Review PL - New Zealand TA - Drugs Aging JT - Drugs & aging JID - 9102074 RN - 0 (Cyclooxygenase 2 Inhibitors) RN - 0 (Lactones) RN - 0 (Sulfones) RN - 0QTW8Z7MCR (rofecoxib) SB - IM MH - Cyclooxygenase 2 Inhibitors/administration & dosage/*adverse effects/therapeutic use MH - Drug-Related Side Effects and Adverse Reactions/epidemiology/*etiology MH - Humans MH - Lactones/administration & dosage/*adverse effects/therapeutic use MH - Osteoarthritis/*drug therapy MH - Randomized Controlled Trials as Topic MH - Sulfones/administration & dosage/*adverse effects/therapeutic use MH - Treatment Outcome PMC - PMC6509094 COIS- O. Bruyere reports grants from Biophytis, IBSA, MEDA, Servier, SMB and Theramex outside the submitted work. C. Cooper reports personal fees from Alliance for Better Bone Health, Amgen, Eli Lilly, GlaxoSmithKline, Medtronic, Merck, Novartis, Pfizer, Roche, Servier, Takeda and UCB outside of the submitted work. J-Y. Reginster reports grants from IBSA-Genevrier, Mylan, CNIEL, Radius Health (through institution); consulting fees from IBSA-Genevrier, Mylan, CNIEL, Radius Health, Pierre Fabre; fees for participation in review activities from IBSA-Genevrier, MYLAN, CNIEL, Radius Health, Teva; payment for lectures from AgNovos, CERIN, CNIEL, Dairy Research Council (DRC), Echolight, IBSA-Genevrier, Mylan, Pfizer Consumer Health, Teva, Theramex outside of the submitted work. E. Curtis reports lecture fees and travel support from Eli Lilly, Pfizer and UCB outside of the submitted work. N. Fuggle reports travel support from Eli Lilly and Pfizer outside of the submitted work. E. Dennison reports personal fees for lectures or advisory boards from UCB and Pfizer outside of the submitted work. N. Corp reports partial funding of employment at Keele University from Versus Arthritis (registered charity), and travel support from Versus Arthritis outside of the submitted work. S. Maggi reports research grants from Takeda, MSD, Pfizer, GSK and consulting fees or honorarium from MSD and Pfizer outside of the submitted work and outside of the research topic. G. Honvo, S. Shaw, L. Spooner, G. Ntani, C. Parsons and J. Baird report nothing to disclose. EDAT- 2019/05/11 06:00 MHDA- 2019/07/10 06:00 PMCR- 2019/05/09 CRDT- 2019/05/11 06:00 PHST- 2019/05/11 06:00 [entrez] PHST- 2019/05/11 06:00 [pubmed] PHST- 2019/07/10 06:00 [medline] PHST- 2019/05/09 00:00 [pmc-release] AID - 10.1007/s40266-019-00664-x [pii] AID - 664 [pii] AID - 10.1007/s40266-019-00664-x [doi] PST - ppublish SO - Drugs Aging. 2019 Apr;36(Suppl 1):25-44. doi: 10.1007/s40266-019-00664-x.