Aarhus, Denmark—A large observational study suggests that diclofenac might be more likely than other nonsteroidal anti-inflammatory drugs (NSAIDs) to increase the risk of major cardiovascular events.

The report, published in BMJ, compared use of the painkiller with use of no drugs, use of acetaminophen, and use of other NSAIDs.

A study led by researchers from Aarhus University in Denmark points out that the cardiovascular risks of nonaspirin NSAIDs have been a major safety concern since the thromboembolic properties of rofecoxib, a COX 2 inhibitor, were revealed nearly 15 years ago.

“Diclofenac is a traditional non-steroidal anti-inflammatory drug (NSAID) with cyclo-oxygenase-2 (COX 2) selectivity similar to COX 2 inhibitors, but its cardiovascular risks compared with those of other traditional NSAIDs have never been examined in a randomized controlled trial,” the authors write.

They note that diclofenac is the most frequently used NSAID in low-, middle-, and high- income countries and is available OTC in most countries, including the United States, adding that, “therefore, its cardiovascular risk profile is of major clinical and public health importance.”

To assess risk of cardiovascular events, the researchers conducted a series of 252 nationwide cohort studies in line with the strict design criteria of a clinical trial, (i.e., emulated trial design). Data were from Danish national population-based health registries from 1996 to 2016.

Eligible for inclusion were all adults without malignancy; schizophrenia; dementia; or cardiovascular, kidney, liver, or ulcer diseases. The study ultimately included nearly 1.4 million diclofenac initiators, 3.9 million ibuprofen initiators, and slightly more than 290,000 naproxen initiators, as well as 764,781 healthcare-seeking paracetamol initiators matched by propensity score and about 1.3 million healthcare-seeking noninitiators also matched by propensity score.

The focus was on the risk of major adverse cardiovascular events within 30 days of initiation.

Results indicate that the adverse-event rate among diclofenac initiators increased by:
• 50% compared with noninitiators (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).

In addition, compared with noninitiators, the event rate for patients beginning diclofenac 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 ischemic stroke
• 1.7 (1.4 to 2.0) for heart failure
• 1.9 (1.6 to 2.2) for myocardial infarction
• 1.7 (1.4 to 2.1) for cardiac death

“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),” the researchers report. “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.”

Based on the results, the study team urges that diclofenac no longer be available OTC and that it have a label warning when prescribed. The authors emphasize, however, that although the relative risk was increased, the absolute risk remained low for the individual patient.

“Treatment of pain and inflammation with NSAIDs may be worthwhile for some patients to improve quality of life despite potential side effects,” they conclude. “Considering its cardiovascular and gastrointestinal risks, however, there is little justification to initiate diclofenac treatment before other traditional NSAIDs.”

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