Piyush Ojha, MBBS, MD, DM

Ntaios G, Swaminathan B, Berkowitz SD, Gagliardi RJ, Lang W, Siegler JE, et al. Efficacy and Safety of Rivaroxaban Versus Aspirin in Embolic Stroke of Undetermined Source and Carotid Atherosclerosis. Stroke. 2019;50:2477–2485.

Embolic stroke of undetermined source (ESUS), accounting for approximately 20% of all ischemic strokes, has been a hotly debated topic in the stroke community. The term encompasses cryptogenic strokes believed to be embolic in origin, which are not lacunar and without a cardiac or proximal large artery source. Patients qualifying as ESUS show a lot of pathophysiological heterogeneity, reflecting in the lack of sufficient evidence of trend towards a particular class of drugs and hence difficult to formulate a pharmacological plan. Multiple possible sources of emboli in these patients may explain the non-uniform response to anticoagulation over antiplatelets.

Several studies (including two major trials, NAVIGATE ESUS and RE-SPECT ESUS) have compared direct oral anticoagulants and aspirin in patients with recent ESUS for secondary stroke prevention, and failed to show any benefit of anticoagulation over antiplatelets, with associated higher risk of bleeding.

Ntaios et al. analysed one of the major ESUS subgroups, atherosclerotic internal carotid artery disease (defined as < 50% stenosis) from the NAVIGATE (New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial Versus ASA to Prevent Embolism)-ESUS trial patient data, with an aim to assess the treatment effect in these particular patients compared to the overall trial cohort along with the risk of future ischemic stroke in them.

Carotid atherosclerosis patients were divided on the basis of mild (20%–49%) stenosis or the presence of carotid plaque. Primary efficacy outcome was the recurrence of ischemic strokes, and bleeding incidents were defined as the safety outcomes.

NAVIGATE – ESUS enrolled total 7213 patients (mean age 67 years), which were followed for a median of 11 months. Approximately 11% had mild carotid stenosis, with 50% of them having an ipsilateral lesion to that of the recent stroke. Vascular risk factors such as age, hypertension, diabetes mellitus, and hyperlipidaemia were significantly associated with carotid stenosis.

Approximately 40% patients had a carotid plaque, with 65% of them having an ipsilateral lesion to the recent stroke. Besides the risk factors described for mild carotid stenosis, smoking was also associated with carotid plaques.

Among both the subgroups of patients, i.e., with mild carotid stenosis and plaques, the rate of ischemic stroke recurrence during follow-up was not statistically different between rivaroxaban- and aspirin-treated patients.

Primary and secondary efficacy outcomes were also comparable between patients with and without carotid stenosis in the overall trial population data, and with rivaroxaban and aspirin treated population. Such a finding is supported by earlier data highlighting a relatively low risk (1-2% annual) associated with mild carotid stenosis. The findings of this subgroup analysis also match with the results of earlier trials comparing anticoagulation and aspirin in patients with cerebral atherosclerosis.

There was a strong trend of higher rates of ischemic stroke recurrence in patients with carotid plaque, especially ipsilateral territory, compared with those without (5.4 versus 4.3/100 patient-years, respectively, HR, 1.23; 95% CI, 0.99–1.54). There was also a higher incidence of major bleeding in the rivaroxaban treated patients compared to those treated with aspirin in the plaque subgroup (2.0 versus 0.5/100 patient-years, HR, 3.75; 95% CI, 1.63–8.65).

The authors also observed an increased frequency of ipsilateral carotid stenosis or plaque to a qualifying ESUS stroke compared to the contralateral side, which might suggest an etiological role of the same. Similar findings have also been supported by some earlier data. Such a possibility may also be strengthened by observed lesser incidence of cardiac source of embolus (AF and PFO) in such patients in some studies.

Limitation of this study are exploratory analysis, possibility of ascertainment bias during data collection and reporting of ipsilateral carotid atherosclerosis, lack of quality control assessment for data reporting of the atherosclerosis, reliability of CTA/MRA in mild stenosis, limited information on the ulceration features and also the timing of the randomisation after the index event which limits the maximum possible benefit of antiplatelets.

The authors, hence, concluded that there is no efficacy difference between both the drugs, i.e., aspirin and rivaroxaban in patients with carotid atherosclerosis. But aspirin might be a safer option considering bleeding risk associated with rivaroxaban, a finding consistent with the overall trial population. No significant treatment interaction was observed between patients with and without carotid stenosis or plaque. Being an exploratory analysis, findings of the study should be interpreted with caution and confirmed in future studies.