High- vs. low-dose diclofenac and cardiovascular risks: a target trial emulation

Area of Science:

• Cardiovascular Pharmacology
• Drug Safety
• Epidemiology

Background:

• Non-steroidal anti-inflammatory drugs (NSAIDs) like diclofenac are widely prescribed for pain and inflammation.
• Concerns exist regarding the cardiovascular risks associated with NSAID use, particularly diclofenac.
• The dose-dependency of diclofenac's cardiovascular risk profile requires further investigation.

Purpose of the Study:

• To investigate the relationship between diclofenac dosage and the risk of major adverse cardiovascular events (MACE).
• To compare the cardiovascular risks of high-dose (≥150 mg/day) versus low-dose (<150 mg/day) diclofenac.
• To assess whether low-dose diclofenac poses a neutral cardiovascular risk.

Main Methods:

• Utilized Danish health registries and a target trial emulation design for 300 nationwide cohort studies (1996-2020).
• Included adults without prior NSAID use, contraindications, or conditions affecting adherence.
• Employed Cox regression to analyze MACE incidence rates, adjusting for multiple covariates.

Main Results:

• Diclofenac initiators (1.9 million) showed a 53% increased rate of MACE compared to non-initiators (3.8 million).
• Specific MACE risks included myocardial infarction (IRR 1.54), ischemic stroke (IRR 1.29), and cardiac death (IRR 1.92).
• Increased cardiovascular risk was comparable between high-dose (IRR 1.55) and low-dose (IRR 1.52) diclofenac initiators.

Conclusions:

• Both high- and low-dose diclofenac initiators experienced similarly elevated cardiovascular risks.
• The findings challenge the notion that low-dose diclofenac is safe concerning cardiovascular health.
• Diclofenac use should be carefully considered due to its consistent association with adverse cardiovascular outcomes.