Compared with traditional nonsteroidal anti-inflammatory drugs, the use of diclofenac increases the risk for major adverse cardiovascular events (MACE), according to a new study published in the BMJ.

To investigate the cardiovascular risks associated with diclofenac, researchers conducted a series of cohort studies mimicking the design criteria of a clinical trial. They compared the rates of MACE among diclofenac initiators and non-initiators or initiators of comparator drugs (ibuprofen, naproxen, acetaminophen). This method of analysis was chosen as current risk concerns make a standard clinical trial unethical.

The Danish National Patient Registry and the Danish National Prescription Registry were used to identify the study population and to identify drug use, respectively. Individuals were eligible if they were ≥18 years, had ≥1 year of continuous prescription records, and did not redeem NSAID prescriptions in the 12 month washout period before enrollment. Patients were followed until the first occurrence of a non-fatal endpoint, death, loss at follow-up, or 30 days of follow-up, whichever occurred first; this approach was applied to every month between January 1996 and December 2016. Data from these trials (N=252) were then pooled into 1 model for analysis.

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Results showed that within 30 days, MACE occurred among 1465 (0.10%; N=1,370,832) diclofenac initiators, 2912 (0.07%; N=3,878,454) ibuprofen initiators, 205 (0.07%; N=291,490) naproxen initiators, 967 (0.13%; N=764,781) acetaminophen initiators, and 898 (0.07%; N=1,303,209) NSAID non-initiators.

Compared with NSAID non-initiators, diclofenac initiators had a 50% increased rate of MACE (incidence rate ratio [IRR] 1.5, 95% CI 1.4 to 1.7). The adverse event rate for diclofenac initiators increased for all individual outcomes compared with NSAID non-initiators: 1.2-fold for atrial fibrillation/flutter, 1.6-fold for ischemic stroke, 1.7-fold for heart failure, 1.9-fold for myocardial infarction, and 1.7-fold for cardiac death. In addition, diclofenac initiators had a 20% increased rate of MACE compared with ibuprofen and acetaminophen initiators (both IRR 1.2, 95% CI 1.1 to 1.3) and a 30% increased rate compared with naproxen initiators (IRR 1.3, 95% CI 1.1 to 1.5).

With regard to upper gastrointestinal bleeding, diclofenac initiation increased the risk at 30 days by 2.5-fold compared with ibuprofen (IRR 2.5, 2.1 to 3.1) or acetaminophen (IRR 2.4, 2.0 to 2.9) initiation and by 4.5-fold compared with no initiation (IRR 4.4, 3.5 to 5.5).

“It is time to acknowledge the potential health risk of diclofenac and to reduce its use,” write the authors in their conclusion. “Considering its cardiovascular and gastrointestinal risks, […] there is little justification to initiate diclofenac treatment before other traditional NSAIDs.”

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