Combining a low-dose DOAC with an antiplatelet agent significantly reduces the risk of cardioembolic strokes and embolic stroke of undetermined source (ESUS) in patients with systemic atherosclerotic disease, a study shows.
An analysis of stroke subtypes in the COMPASS trial of low dose rivaroxaban (2.5mg twice daily) and aspirin (100mg daily) showed that the combination reduced the risk of cardioembolic stroke by 60% compared to aspirin-only treatment.
Published in JAMA Neurology, the secondary analysis was based on the double-blind, randomized, placebo-controlled study that involved 27 395 adults with stable atherosclerotic vascular disease.
The study was stopped prematurely after two years of follow up because of the 50% reduction in ischaemic stroke seen with DOAC plus aspirin treatment compared to aspirin alone.
The new analysis of stroke subtypes shows that among the 291 patients who experienced an ischaemic stroke, 20.3% were cardioembolic strokes according to TOAST criteria, 18.6% were secondary to greater than 50% stenosis of the ipsilateral internal carotid artery, 14.4% had a negative evaluation that met criteria for embolic stroke of undetermined source, and 7.2% were secondary to small vessel disease.
The restrospective analysis showed that there were significantly fewer cardioembolic strokes (hazard ratio [HR] 0.40 [95%CI, 0.20-0.78]; P = .005) and ESUS (HR 0.30 [95%CI, 0.12-0.74]; P = .006) in the combination therapy group compared with the aspirin-only group.
No significant difference was observed between the treatment groups for other stroke, though there was a non-significant trend for reduction in strokes secondary to small vessel disease (HR, 0.36 [95%CI, 0.12-1.14]; P = .07).
In another arm of the trial rivaroxaban, 5mg, twice daily showed a trend for reducing cardioembolic strokes compared with aspirin (HR, 0.57 [95%CI, 0.31-1.03]; P = .06), but was not associated with reducing other stroke subtypes, “making it a less attractive treatment option for stroke prevention,” the study authors said
The study investigators said there was a mechanistic explanation as to why a combination of DOAC and aspirin would have greater efficacy against emboli arising from nonstenotic plaques in arteries that were likely to be composed of both red and white thrombi.
“While the red thrombus is likely to respond to anticoagulation, the white thrombus component may respond better to antiplatelet agents. Factor Xa is also known to interact with protease activated receptors 1 and 2. Activation of protease-activated receptor 1 and 2 receptors in the arterial wall has the potential to increase endothelial dysfunction and inflammation.”
“Hence, inhibition of these receptors by rivaroxaban combined with the effect on thrombin generation and the anticyclooxygenase effect of aspirin may better reduce arteriogenic embolism in individuals with systemic atherosclerosis with nonstenotic plaque,” they wrote
However, the major reductions in cardioembolic strokes and ESUS seen with low dose rivaroxaban and aspirin would need to be independently confirmed before influencing clinical practice,” they wrote
“In the wake of two recent trials with neutral results assessing anticoagulant treatment for secondary stroke prevention in patients with ESUS, these findings make a compelling case for testing this combination in patients with ESUS, as well as in those with cardioembolic strokes,” they said
The trial findings also raised the possibility that that even at low doses rivaroxaban may have sufficient anticoagulant effect to prevent generation of AF-associated thrombotic stroke, they added.