Diclofenac use and cardiovascular risks: series of nationwide cohort studies

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.

Fig 1

Emulated trial design, to compare rates of major adverse cardiovascular events among diclofenac initiators with rates among non-initiators or initiators of active comparator drugs in Denmark. Individual level linkage of nationwide population based registries was used to emulate the eligibility criteria, washout period, treatment groups, and follow-up period of a clinical controlled trial. Eligible individuals were aged at least 18 years who had at least one year of prescription history and none of the exclusion criteria. All initiators of diclofenac and naproxen were identified during the month of January 1996. Each person was followed up to a non-fatal endpoint, death, loss to follow-up, or 30 days of follow-up. Enrolment was repeated in the months of February and March, and subsequently for every month up to December 2016. The series of 252 emulated trials were then statistically pooled into one model, generating a sample size of 1 370 832 diclofenac initiators and 291 490 naproxen initiators. A similar approach was used to identify ibuprofen initiators (n=3 878 454) and propensity score matched initiators of paracetamol (n=764 781) and NSAID non-initiators (n=1 303 209). B=baseline; MACE=major adverse cardiovascular events; D=death or emigration; F=30 days of follow-up

Fig 2

Cardiovascular risks at 30 days associated with diclofenac initiation compared with no NSAID initiation and initiation of paracetamol, ibuprofen, or naproxen. NSAID=non-steroidal anti-inflammatory drug; MACE=major adverse cardiovascular event

Fig 3

Risk of major adverse cardiovascular events after diclofenac initiation according to sex and age. NSAID=non-steroidal anti-inflammatory drug

Fig 4

Risk of major adverse cardiovascular events after diclofenac initiation according to baseline cardiovascular risk. NSAID=non-steroidal anti-inflammatory drug

Fig 5

Risk of major adverse cardiovascular events comparing initiation of low and high dose diclofenac with no NSAID initiation or initiation of paracetamol, ibuprofen, or naproxen. NSAID=non-steroidal anti-inflammatory drug