Diclofenac is one of the most widely used non-steroidal anti-inflammatory drugs (NSAID) in the world, and is commonly available without prescription, but an analysis of data from more than 6.3 million people has now linked the drug with serious cardiovascular disorders including heart attack, stroke, and cardiac death, as well as with gastric bleeding. Results from the study, which looked at data held in Danish health and prescription registries, suggest that the cardiovascular risks associated with diclofenac use may be 20-30% higher than those of paracetamol and the NSAIDs ibuprofen and naproxen.

Reporting on their study in thebmj, the Aarhus University Hospital researchers say diclofenac shouldn’t be available over-the-counter, and should only be prescribed with boxfront warnings. “It’s time to acknowledge the potential health risk of diclofenac and to reduce its use,” write Morten Schmidt, M.D., Ph.D., registrar, Henrik Toft Sørensen, M.D., Ph.D., clinical professor and chair, and Lars Pedersen, Ph.D., professor, department of clinical epidemiology, Aarhus University. “Treatment of pain and inflammation with NSAIDs may be worthwhile for some patients to improve quality of life despite potential side effects. Considering its cardiovascular and gastrointestinal risks, however, there is little justification to initiate diclofenac treatment before other traditional NSAIDs.” The researchers’ paper is titled, “Diclofenac use and cardiovascular risks: series of nationwide cohort studies.”

The potential link between non-aspirin NSAIDs and cardiovascular has been a major concern since the thromboembolic risks associated with rofecoxib were reported back in 2005, the researchers write. Diclofenac is a traditional NSAID that has similar selectivity for cyclo-oxygenase-2 (COX 2) as COX 2 inhibitors, but the cardiovascular risks of diclofenac in comparison with other traditional NSAIDs have not been investigated through a randomized controlled trial. Current concerns about the cardiovascular safety of NSAID use mean that such a trial would now be unethical, but regulators including the European Medicines Agency are still calling for the safety of diclofenac to be assessed.

To investigate any link between diclofenac and potential cardiovascular health risks the Aarhus University Hospital researchers turned to data in the Danish National Patient Registry and the Danish National Prescription Registry to identify a study population, health outcomes, and drug use. The Danish National Prescription Registry which maintains detailed records of all prescriptions that are actually dispensed by Danish pharmacies, not just prescriptions written. Migration and mortality data were also gathered from the Danish Civil Registration System and Danish Register of Causes of Death. 

These population-based registries allowed the team to emulate the level and depth of data that would be collected through a controlled clinical trial. Eligible individuals were at least 18 years of age and had at least a year of continuous prescription records before the date of the study start in 1996. Participants were split into low, moderate, and high baseline cardiovascular risk, and data was gathered and analyzed based on whether they started using diclofenac, compared with ibuprofen, naproxen or paracetamol initiators, during the study period (1996-2016).

The overall patient population included 1,370,832 diclofenac initiators who met the inclusion criteria, 3,878,454 ibuprofen initiators, 291,490 naproxen initiators, 764,781 matched paracetamol initiators, and 1,303,209 matched non-initiators (patients who took none of the painkillers during the study period). The average age was 46-49 years among NSAID initiators, and 56 years among those who started taking paracetamol.

Results from the data analyses indicated that participants who started to take diclofenac during the trial period were at an increased risk of all major cardiovascular events, including atrial fibrillation, ischeamic stroke, heart failure, myocardial infarction, and cardiac death, irrespective of age and sex. The risks were evident whether the participants took high, or low doses of the drug.

More specifically, diclofenac initiators had a 50% increased rate of major cardiovascular events compared with participants who didn’t take NSAIDs. The rate of major adverse cardiovascular events was also 20% higher among diclofenac initiators than among those who started taking paracetamol, or ibuprofen, and 30% higher among diclofenac initiators than patients who started to take naproxen. The risk of upper gastrointestinal bleeding at 30 days of diclofenac use was similar to that associated with naproxen, but was 4.5-fold higher than it was among patients who didn't take NSAIDs and 2.5-fold higher than for paracetamol, or ibuprofen initiators. 

The results also suggested that although the absolute risks associated with diclofenac use were highest in individuals who already demonstrated high baseline cardiovascular risk, the relative risk was actually highest in people with the lowest baseline risk. And while it has previously been thought that NSAIDs are safe to use over the short term, the new study found that cardiovascular risk was elevated even within just 30 days of starting to take the drug.

The authors say their results also indicate that using diclofenac as a reference for demonstrating the safety of selective COX-2 inhibitors represents “a potential flaw in safety trials.” They are now advocating that low dose ibuprofen or naproxen should be considered as comparators. “In conclusion, our data support that initiation of diclofenac poses a cardiovascular health risk, both compared with no use, paracetamol use, and use of other traditional NSAIDs,” they state.


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