Safety of Cyclooxygenase-2 Inhibitors in Osteoarthritis: Outcomes of a Systematic Review and Meta-Analysis

Abstract

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. ...

Endorsement by Central European experts of the revised ESCEO algorithm for the management of knee osteoarthritis

“…The absolute risk of myocardial infarction (MI) associated with NSAID use is estimated to be about 0.5-1% per year [22]; although small, the absolute risk is increased with all NSAIDs. In a recent safety meta-analysis, COX-2 inhibitors were associated with an increased risk of heart failure and edema (RR 1.68, 95% CI 1.22, 2.31) compared with placebo, which remained significant even when rofecoxib was removed from the analysis (RR 1.67, 95% CI 1.21, 2.29) [23]. While NSAIDs use overall is associated with only a small, but insignificant risk of hemorrhagic stroke, an elevated risk of hemorrhagic stroke is found with diclofenac (RR 1.27, 95% CI, 1.02, 1.59) and meloxicam (RR 1.27, 95% CI, 1.08, 1.50) [24].…”

NSAIDs in CKD: Are They Safe?

“…A recent meta-analysis of randomized placebo-controlled trials found 70% increased risk for CHF and edema with selective COX-2 inhibitor use versus placebo, even when excluding particularly high-risk agents such as rofecoxib. 49 Additionally, NSAIDs are associated with an increased dose-dependent risk for CHF hospitalization. [50][51][52] In the setting of CKD, increased ADH secretion and RAAS activation act to augment blood flow to hypoperfused nephrons though sodium and water retention.…”

Safety of Oral Non-Selective Non-Steroidal Anti-Inflammatory Drugs in Osteoarthritis: What Does the Literature Say?

“…In this narrative literature review, we have identified data on the safety of traditional nsNSAIDs (naproxen, ibuprofen, diclofenac) published since the Cochrane review of 2011 [11], to identify current understanding on the relative risk:benefit of the use of nsNSAIDs to manage pain in OA. We discuss the safety of cyclo-oxygenase (COX)-2 inhibitors as a specific class of NSAIDs (e.g., celecoxib, rofecoxib) in relation to the safety of nsNSAIDs, and in more detail as the subject of a separate systematic literature review and meta-analysis, which is presented in the subsequent article of this supplement [14].…”