Cardiovascular Risks of Diclofenac Versus Other Older COX-2 Inhibitors (Meloxicam and Etodolac) and Newer COX-2 Inhibitors (Celecoxib and Etoricoxib): A Series of Nationwide Emulated Trials

Introduction: Diclofenac has increased cardiovascular risks, but its risk profile compared with other COX-2 inhibitors remains unknown. Aims: The aim of this study was to compare the cardiovascular risks of diclofenac versus other older and newer COX-2 inhibitors (coxibs). Methods: Using Danish nationwide health registries (1999–2020), we conducted a series of emulated trials (n = 264). Eligible adults had no recent NSAID prescriptions, contraindications or conditions with low adherence. We included initiators of diclofenac (n = 1,600,202), meloxicam (n = 10,903), etodolac (n = 238,538), celecoxib (n = 77,591), and etoricoxib (n = 12,122). We computed the adjusted intention-to-treat incidence rate ratio (aIRR) with 95% confidence interval (CI) of major adverse cardiovascular events (MACE) within 30 days of initiation (5562 events). Results: MACE was 20% increased among initiators of diclofenac compared with other older COX-2 inhibitors (aIRR 1.19, 95% CI 1.10–1.28), driven by cardiac death (aIRR 1.57, 95% CI 1.21–2.03). The effect appeared strongest for women (aIRR 1.28, 95% CI 1.15–1.43), individuals with high baseline cardiovascular risk (aIRR 1.32, 95% CI 1.05–1.66), and when comparing high-dose diclofenac with low doses of the other older COX-2 inhibitors (aIRR 1.31, 95% CI 1.13–1.52). The results reflected increased rates compared with both meloxicam (aIRR 1.46, 95% CI 0.94–2.26) and etodolac (aIRR 1.18, 95% CI 1.09–1.28). Diclofenac initiators had similar increased rates of MACE compared with coxibs (aIRR 0.96, 95% CI 0.85–1.08), consistent for celecoxib (aIRR 1.02, 95% CI 0.88–1.19) and etoricoxib (aIRR 0.85, 95% CI 0.66–1.10). Conclusions: The increased cardiovascular risks associated with diclofenac initiation were higher than for other older COX-2 inhibitors (meloxicam/etodolac) and comparable to coxibs (celecoxib/etoricoxib).