Philip Chang, MD

Eikelboom JW, Connolly SJ, Bosch J, Dagenais GR, Hart RG, Shestakovska O, et al. Rivaroxaban with or without Aspirin in Stable Cardiovascular Disease. N Engl J Med. 2017

This landmark trial published in the New England Journal of Medicine found that in 27,395 patients with stable atherosclerotic cardiovascular disease (ASCVD), aspirin 100 daily plus rivaroxaban 2.5mg twice daily was superior to aspirin alone and rivaroxaban alone in preventing the primary outcome of cardiovascular death, stroke, or heart attack. In addition, secondary outcomes of all-cause death were also significantly lower in the aspirin-plus-rivaroxaban group. The effect size was large enough for the study to stop prematurely for superiority of the aspirin-plus-rivaroxaban group. From this, it is clear that treatment with rivaroxaban plus aspirin is superior to aspirin alone in a patient with coronary or peripheral vascular disease in preventing ischemic stroke (p=<0.001) without significantly increased adverse effects. However, this brings into the question – what about patients who already have a history of ischemic stroke? Ischemic stroke is an ASCVD risk equivalent, and this study brings into question – do we need to start adding apixaban for secondary ischemic stroke prevention for all-comers?

To start unpacking this question, it is important to realize the scope of the study. Only 3.8% (n=1032) study patients had stroke – which was roughly 330-350 patients in each cohort. While the study did not specifically target ischemic stroke patients, subgroup analysis of their enrolled patients with a history of stroke showed similar effects as the main group (significantly decreased CV death, stroke and all-cause mortality). It is important to note that stroke preventative data, such as blood pressure, lipid levels, and hemoglobin A1c, was not collected. In addition, a trial stopped early may overestimate the treatment effect, especially in a small subgroup analysis. Therefore, I would interpret this data with caution. However, I believe this is a very interesting field of ongoing study, especially with the stroke patient population this study selected.

The study enrollment criteria were primarily cardiac – most patients needed to have criteria for coronary heart disease, peripheral artery disease, or both. Patients younger than 65 needed to have atherosclerosis in 2 vascular beds, and 2 additional risk factors, one of which was a non-lacunar ischemic stroke. Exclusion criteria included recent stroke, as well as a history of hemorrhagic or lacunar stroke. Additional exclusion criteria included patients on any type of therapeutic anticoagulation or dual antiplatelet therapy. These criteria alone exclude a vast amount of stroke patients. Strokes from small vessel disease (up to 30% of strokes) would likely be lacunar. Stroke mechanisms that require anticoagulation or dual antiplatelet therapy (atrial fibrillation, hypercoagulability disorders, dissections, intracranial atherosclerotic disease, and in some places asymptomatic carotid stenosis with HITS). This primarily leaves then the patients with extracranial large vessel disease (carotid stenosis, aortic arch atheromas) or cryptogenic mechanism for which there is not a clear indication for dual antiplatelet therapy or anticoagulation.

As such, I have a hard time believing that symptomatic carotid stenosis would benefit much from this therapy, as most practitioners would end up referring for stenting or endarterectomy. It is the large proportion of cryptogenic stroke (up to 30% of ischemic stroke patients) for which this study is interesting. For this population, especially the young stroke or ESUS (embolic stroke of undetermined source) population, I believe that this study supports the use of aspirin plus low-dose rivaroxaban. It may be the splitting difference between empirically anticoagulating a patient for recurrent cryptogenic strokes and just maintaining them on single antiplatelet therapy. However, this may be a short-lived opinion if the RESPECT-ESUS study is positive.

In conclusion, my interpretation of the COMPASS trial is that it may be reasonable to start low-dose 2.5mg BID rivaroxaban and aspirin 100mg daily for secondary stroke prevention in patients with cryptogenic stroke, especially if it is an embolic stroke of unknown source. Further studies would be needed to solidify this.