COX-2 Inhibitors Linked to Stroke Mortality

November 06, 2014

Further evidence suggesting harm of cyclooxygenase-2 (COX-2) inhibitors in patients with stroke has been reported, with this latest study showing these agents to be associated with an increased risk for stroke mortality.

The study, published online in Neurology on November 5, was conducted by a team led by Morten Schmidt, MD, from Aarhus University Hospital, Denmark.

"We found 30-day mortality from stroke increased by around 20% if patients were taking a COX-2 inhibitor before admission," coauthor Christian Christiansen, PhD, also from Aarhus University Hospital, commented to Medscape Medical News. "No such effect was seen with regular NSAIDs [nonsteroidal anti-inflammatory drugs]."

He added: "This is more evidence that COX-2 inhibitors are harmful to patients at risk of cardiovascular events and stroke. Previous studies have shown these drugs are associated with a higher risk of having a cardiovascular event or a stroke and now we have shown that they are also associated with a higher rate of mortality in stroke patients."

"Our results just emphasize the need for caution in using COX-2 inhibitors in patients with any risk factors for stroke," Dr Christiansen noted. "The latest recommendations already advise against use of these drugs and regular NSAIDs in patients with cardiovascular or stroke risk factors, with the recommended agent for pain relief being paracetamol."

Increased Risk With Etodolac

The largest risk in the study was seen with the older COX-2 inhibitors, such as etodolac and diclofenac, which were associated with a 53% and 28% increased risk for 30-day mortality after stroke, respectively. The risk associated with the newer coxibs, while still higher than in patients not taking any NSAID, was not as high as with the older COX-2 inhibitors.

Noting that rofecoxib was not found to be associated with an increased risk for stroke death, Dr Christiansen pointed out that because it was taken off the market near the start of this study, there may not have been enough patients taking this drug to show such an effect.

For the nationwide population-based cohort study, the researchers searched medical databases to identify all first-time stroke hospitalizations and subsequent mortality in Denmark between 2004 and 2012. NSAID use was tracked from prescription data.

Results showed 100,043 patients with first-time stroke: 51% ischemic stroke, 12% intracerebral hemorrhage (ICH), 5% subarachnoid hemorrhage, and 32% unspecified stroke.

Of these, 10,835 patients (10.8%) were current NSAID users. NSAIDs used were ibuprofen (51.4%), diclofenac (27.0%), etodolac (10.7%), naproxen (3.2%), celecoxib (1%), and rofecoxib (0.5%).

Dr Christiansen noted that use of diclofenac decreased over the course of the study, probably because of publicity about COX-2 inhibitors and risks for cardiovascular events.

The adjusted hazard ratio (HR) for death from ischemic stroke was 1.19 for current users of selective COX-2 inhibitors compared with nonusers. This was driven by the effect among new users (HR, 1.42).

In comparing the different COX-2 inhibitors, the risk was driven by new use of older traditional COX-2 inhibitors (HR, 1.42), with the highest risk being seen with etodolac (HR, 1.53) and diclofenac (HR, 1.28).

The propensity score–matched analysis supported the association between older COX-2 inhibitors and ischemic stroke mortality. The effect was seen only in current users of COX-2 inhibitors, which the authors say "may indicate an actual drug effect." Mortality from intracerebral hemorrhage was not associated with use of nonselective NSAIDs or COX-2 inhibitors.

On the possible mechanism behind this effect, Dr Christiansen suggested that this could involve suppression of the neuroprotective effect of prostaglandin E2. Alternatively, COX-2 inhibitors may cause larger strokes to occur or increase the risk for stroke as a complication of myocardial infarction.

Increasing Body of Evidence

The authors conclude that their study "adds to the increasing body of evidence concerning the vascular risk and prognostic impact associated with use of COX-2 inhibitors," noting that use of diclofenac has previously been reported to more than double the risk for ischemic stroke.

They add that the results give "a strong argument for increasing the efforts to ensure that patients with a high predicted risk of arterial thromboembolism (e.g., atrial fibrillation patients with high CHA2DS2-VASc score) are not prescribed COX-2 inhibitors when alternative treatment options are available."

They point out that they studied the prognostic effect of NSAID use initiated before, not after, stroke admission. "Consequently, our results do not necessarily contradict reports suggesting a role for COX-2 inhibitors in treating postischemic oxidative stress and inflammation."

The study was supported by the Department of Clinical Epidemiology's Research Foundation, Arvid Nilsson's Foundation, Aarhus University Research Foundation, and the Program for Clinical Research Infrastructure (PROCRIN) established by the Lundbeck Foundation and the Novo Nordisk Foundation.The authors have disclosed no relevant financial relationships.

Neurology. Published online November 5, 2014. Abstract

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