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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

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Abstract

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).

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Authors and Affiliations

  1. Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark

    Morten Schmidt, Henrik Toft Sørensen & Lars Pedersen

  2. Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark

    Morten Schmidt

Authors
  1. Morten Schmidt
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  2. Henrik Toft Sørensen
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  3. Lars Pedersen
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Corresponding author

Correspondence to Morten Schmidt.

Ethics declarations

Funding

The study was supported by the Novo Nordisk Foundation (Grant NNF19OC0054908). The funding sources had no role in the design, conduct, analysis, or reporting of the study.

Conflicts of interest

All authors report no conflicts of interest in this work.

Ethics approval

No ethics committee approval was needed.

Consent to participate

No patient involvement.

Consent for publication

The study has been reported to the Danish Data Protection Board by Aarhus University (No. 1689).

Availability of data and material

The lead author affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned have been explained. Data sharing is not allowed.

Code availability

Not applicable.

Authors' contribution

MS conceived the study idea and designed the study with LAP. LAP collected the data and carried out the analyses. MS organized the writing and wrote the initial draft. All authors participated in the discussion and interpretation of the results and critically revised the manuscript for intellectual content and approved the final version before submission. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted. MS is the guarantor.

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Schmidt, M., Sørensen, H.T. & Pedersen, L. 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. Drug Saf 45, 983–994 (2022). https://doi.org/10.1007/s40264-022-01211-1

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