The risk of atrial fibrillation with COX-2 inhibitors may have been overlooked

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A new study in the European Heart Journal indicates that while restrictions on the use of cycloocygenase (COX)-2 inhibitors may have limited the feared cardiovascular consequences of the drugs, the risk of atrial fibrillation may have been overlooked and may warrant further consideration.

After studies showed that COX-2 inhibitors, used to treat arthritic conditions and other inflammatory disorders, were associated with an increased risk of cardiovascular events, their use was restricted or contraindicated in certain patients (ie, they could no longer be used in patients with established ischaemic heart disease or cerebrovascular disease). Additionally, the COX-2 inhibitor rofecoxib (Vioxx, MSD) was withdrawn from the market because of safety concerns. However according to Magnus Bäck (Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden) and his co-authors, the association between COX-2 inhibitors and atrial fibrillation has received “less attention” than the risk of other cardiovascular events.

They therefore investigated the risk of cardiovascular events, including atrial fibrillation, with COX-2 inhibitors after the cardiovascular side effects of the drugs had been widely accepted.

Using a Swedish database of seven million subjects (which had information on prescribing data and cause of death), the investigators assessed different cardiovascular events that occurred during the study period. They found that after the risk of cardiovascular events with COX-2 inhibitors was known, the use of COX-2 inhibitors did not significantly increase the risk of myocardial infarction, ischaemic stroke, or heart failure. The authors reported: “One possible interpretation of the present data is that the increased awareness of the serious side effects of coxibs [COX-2 inhibitors] after the withdrawal of rofecoxib and the warnings issued for NSAIDs [non-steroidal anti-inflammatory drugs] as a class of drugs have led to precautions of their use in patients with, or with risk factors for, coronary and cerebrovascular disease.”

However, according to the study findings, there was a significant association between incidence atrial fibrillation and COX-2 inhibitors after the risk of cardiovascular events had been established. This risk of atrial fibrillation was also associated with traditional non-COX-2 inhibitors, non-aspirin NSAIDs and oral steroids. A post-hoc analysis showed increased risk of atrial fibrillation and heart failure with etoricoxib (Arcoxia, MSD) but did not find any significant associations with celecoxib (Celebrex, Pfizer).

At present, the exact mechanisms behind the potential pro-arrhythmic properties of COX-2 inhibitors have not been established. An experimental study found that prostaglandin was present in the coronary sinus and pericardial fluid after myocardial ischaemia and reperfusion. Bäck et al wrote: “In the later context, prostacyclin, which represents one major COX-2 derived prostaglandin, was demonstrated to act as an endogenous antiarrhythmic through direct inhibition of epicardial sympathetic nerve activity.” Additionally, another experimental study found that deletion of cardiomyocycte COX-2 expression in mice induced interstitial and perivascular fibrosis and was associated with an enhanced susceptibility to induce arrhythmias. They added: “Nervertheless, coxibs may in addition induce direct on ion channels and intracellular signalling pathways, which are unrelated to their COX-2 inhibition.”

They concluded their paper by saying that the risk of atrial fibrillation with COX-2 inhibitors “may necessitate consideration and precautions.”

Bäck told Cardiac Rhythm News: “It is intriguing that although systemic inflammation has been associated with arrhythmias, these anti-inflammatory drugs appeared to increase the risk of atrial fibrillation. This is however an observational study and further studies are needed to establish the exact role of the COX pathway in atrial fibrillation.”