Dose-dependency of diclofenac's cardiovascular risks: a series of nationwide emulated trials

Abstract Background The dose dependency of the adverse effects diclofenac remains poorly understood. Purpose To examine dose-related cardiovascular risks associated with initiation Methods We used Danish nationwide health registries (1999–2018) to conduct a series emulated trials (n=285). Eligible adults had no recent NSAID fillings, contraindications, or conditions low adherence. Individuals eligible for inclusion were ≥18 years (1) ≥90 days continuous prescription records prior (baseline); (2) prescriptions ≤90 before enrollment, and (3) exclusion criteria. Exclusion criteria reflected likelihood adherence treatment (dementia, schizophrenia, antipsychotic drug use) labeled contraindications (ulcer disease/anti-ulcer drugs, gastrointestinal bleeding, inflammatory bowel disease, thrombocytopenia, heart failure). Initiators compared healthcare-seeking non-initiators, but also head-to-head initiators high (≥75 mg pills as proxy ≥150 mg/daily) vs. (≤50 <150 mg/daily). Cox proportional-hazards regression was compute intention-to-treat hazard ratio, measure incidence rate ratio (IRR), major cardiac cerebrovascular events (MACCE) within 30 from initiation. Results Among 3,177,484 initiatiors, 31% 69% dose. Compared initiatiors 70% increased MACCE (IRR 1.70, 95% CI: 1.55–1.86), reflecting individual components an IRRs 1.66 (95% 1.54–1.79) myocardial infaction, 1.32 (1.20–1.45) ischemic stroke, 1.69 (1.54–1.86) death. effect did not differ between 1.73, 1.51–1.97) 1.68, 1.52–1.86) (Figure 1). When comparing head-to-head, we found meaningful difference in IRR (1.03, 0.89–1.19), MI (0.99, 0.87–1.11), stroke (0.95, 0.81–1.11) death (1.04, 0.90–1.21) 2). Conclusion Initiation low- high-dose consistent comparable increase risk. Funding Acknowledgement Type funding sources: Foundation. Main source(s): Novo Nordisk Foundation