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Diclofenac use and cardiovascular risks: series of nationwide cohort studies

BMJ 2018; 362 doi: https://doi.org/10.1136/bmj.k3426 (Published 04 September 2018) Cite this as: BMJ 2018;362:k3426
  1. Morten Schmidt, registrar1 2,
  2. Henrik Toft Sørensen, professor1 3,
  3. Lars Pedersen, professor1
  1. 1Department of Clinical Epidemiology, Aarhus University Hospital, Olof Palmes Allé 43-45, 8200, Aarhus, Denmark
  2. 2Department of Cardiology, Regional Hospital West Jutland, Herning, Denmark
  3. 3Department of Health Research & Policy (Epidemiology), Stanford University, Stanford, CA, USA
  1. Correspondence to: M Schmidt morten.schmidt{at}clin.au.dk
  • Accepted 19 July 2018

Abstract

Objective To examine the cardiovascular risks of diclofenac initiation compared with initiation of other traditional non-steroidal anti-inflammatory drugs, initiation of paracetamol, and no initiation.

Design Series of 252 nationwide cohort studies, each mimicking the strict design criteria of a clinical trial (emulated trial design).

Setting Danish, nationwide, population based health registries (1996-2016).

Participants Individuals eligible for inclusion were all adults without malignancy; schizophrenia; dementia; or cardiovascular, kidney, liver, or ulcer diseases (that is, with low baseline risk). The study included 1 370 832 diclofenac initiators, 3 878 454 ibuprofen initiators, 291 490 naproxen initiators, 764 781 healthcare seeking paracetamol initiators matched by propensity score, and 1 303 209 healthcare seeking non-initiators also matched by propensity score.

Main outcome measures Cox proportional hazards regression was used to compute the intention to treat hazard ratio (as a measure of the incidence rate ratio) of major adverse cardiovascular events within 30 days of initiation.

Results The adverse event rate among diclofenac initiators increased by 50% compared with non-initiators (incidence rate ratio 1.5, 95% confidence interval 1.4 to 1.7), 20% compared with paracetamol or ibuprofen initiators (both 1.2, 1.1 to 1.3), and 30% compared with naproxen initiators (1.3, 1.1 to 1.5). The event rate for diclofenac initiators increased for each component of the combined endpoint (1.2 (1.1 to 1.4) for atrial fibrillation/flutter, 1.6 (1.3 to 2.0) for ischaemic stroke, 1.7 (1.4 to 2.0) for heart failure, 1.9 (1.6 to 2.2) for myocardial infarction, and 1.7 (1.4 to 2.1) for cardiac death) as well as for low doses of diclofenac, compared with non-initiators. Although the relative risk of major adverse cardiovascular events was highest in individuals with low or moderate baseline risk (that is, diabetes mellitus), the absolute risk was highest in individuals with high baseline risk (that is, previous myocardial infarction or heart failure). Diclofenac initiation also increased the risk of upper gastrointestinal bleeding at 30 days, by approximately 4.5-fold compared with no initiation, 2.5-fold compared with initiation of ibuprofen or paracetamol, and to a similar extent as naproxen initiation.

Conclusions Diclofenac poses a cardiovascular health risk compared with non-use, paracetamol use, and use of other traditional non-steroidal anti-inflammatory drugs.

Footnotes

  • Contributors: MS and LP conceived the study idea and designed the study. LP collected the data and carried out the analyses. MS organised the writing and wrote the initial draft. All authors participated in the discussion and interpretation of the results. All authors 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 and LP are the guarantors.

  • Funding: The study was supported by the Department of Clinical Epidemiology’s Research Foundation at Aarhus Universityand the Program for Clinical Research Infrastructure (PROCRIN) established by the Lundbeck Foundation, Novo Nordisk Foundation, and Danish Research Council (grants 11-108354 and 11-115818). The funding sources had no role in the design, conduct, analysis, or reporting of the study.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: support from the Department of Clinical Epidemiology’s Research Foundation at Aarhus University and PROCRIN for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

  • Ethical approval: Not required.

  • Data permission: The study was approved by the Danish Data Protection Agency (record No FSEID-00002467).

  • Data sharing: Not permitted.

  • 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.

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