The Year's Best in Thrombosis: ESUS – Management of Unexplained Arterial Thromboembolism

*In case of complete blood count abnormalities, consider paroxysmal nocturnal hemoglobinuria and/or myeloproliferative neoplasia testing. Note. Do not test for methylene tetrahydrofolate reductase polymorphisms, PAI-1, or tPA levels or polymorphisms; fibrinogen; or factor VIII activities.

While limited data exist on best treatment of unexplained arterial thromboembolic events in several of these anatomic territories, data have shown that in patients with ischemic stroke of uncertain cause, also termed “cryptogenic” or “noncardiogenic” stroke, anticoagulation with warfarin was not superior to antithrombotic prophylaxis with aspirin in secondary stroke prevention and led to an increased risk for bleeding.¹  Based on these findings, aspirin traditionally has been used for secondary stroke prevention in noncardiogenic stroke.^2,3 

In 2014, a new term, “Embolic Stroke of Undetermined Source” (ESUS), was coined for a subgroup within the cryptogenic stroke category.⁴  ESUS is defined by four criteria: 1) a nonlacunar brain infarct on imaging, 2) patent arteries (< 50% stenosis) proximal to the infarct, 3) absence of major-risk cardioembolic source, and 4) no other specific cause of stroke identified. Potential causes of ESUS include undetected paroxysmal atrial fibrillation or other arrhythmia, structural heart disease, arteriogenic embolism, and/or paradoxical emboli from venous circulation, all of which may not be identified with standard diagnostic assessment. The identification of ESUS as a clinical entity has possible important treatment implications. There is long-standing evidence that in ischemic stroke from a proven embolic source, secondary stroke prevention with anticoagulation is superior to antiplatelet therapy.³  Therefore, by designating a stroke as ESUS rather than cryptogenic, it suggests that the patient should be placed on anticoagulation.

In the New England Journal of Medicine in June 2018, the NAVIGATE ESUS Investigators presented results from an international, randomized, phase III trial comparing rivaroxaban 15 mg once daily with aspirin 100 mg daily for secondary stroke prevention in patients with previous ESUS as defined by Dr. Robert G. Hart and colleagues.⁵  After a second interim analysis, approximately three years after initiation of enrollment and after enrollment of 7,213 patients (3,609 in the rivaroxaban arm and 3,604 in the aspirin arm), the trial was terminated because rivaroxaban did not lead to a lower rate of thromboembolism compared with aspirin, yet increased the risk of bleeding. The primary efficacy outcome (recurrent stroke or systemic embolism) occurred at similar rates in both groups, resulting in 5.1 percent per year in the rivaroxaban group compared to 4.8 percent per year in the aspirin group (HR, 1.07; 95% CI, 0.87-1.33; p=0.52). The overwhelming majority of events were ischemic strokes (95%), with similar stroke severity in each group. Major bleeding occurred at a rate of 1.8 percent per year in the rivaroxaban group, compared with 0.7 percent per year in the aspirin group (HR, 2.72; 95% CI, 1.68-4.39; p<0.001). There was also an increased rate of life-threatening or fatal bleeding in the rivaroxaban group compared with the aspirin group (1.0% vs. 0.4% per year; HR, 2.34; 95% CI, 1.28-4.29; p=0.004); an increase of clinically relevant nonmajor bleeding (3.5% vs. 2.3 % per year; HR, 1.51; 95% CI, 1.13-2.00; p=0.004); and an increase of symptomatic intracranial hemorrhage (0.6% vs. 0.1% per year; HR, 4.02; 95% CI, 1.51-10.7; p=0.003).

A potential limitation of the study is the inclusion criteria used to designate ESUS. A commentary on the publication of Dr. Hart and colleagues highlighted that atherosclerotic plaques, even when less than 50 percent of artery diameter, can rupture with resultant arterial occlusion that is best prevented with antiplatelet therapy.⁶  Perhaps with more stringent atherosclerosis criteria, the study population would have been more heavily weighted toward embolic sources, and thus, may have shown benefit with anticoagulation. However, this theory has not yet been investigated.

Additional trials are ongoing, comparing other anticoagulants to antiplatelet therapy in similar ESUS populations (NCT02239120 for dabigatran; NCT02427126 for apixaban). For now, the results of the present rivaroxaban NAVIGATE ESUS trial indicate that antiplatelet therapy rather than anticoagulation should be the standard of care for secondary stroke prevention in patients with ESUS.

Three take-home points are worth highlighting on the topic of unexplained arterial thromboembolism: 1) a structured approach (Table) in the evaluation of a patient with “unexplained” arterial thromboembolism is a first appropriate step in the assessment process; (2) the term ESUS – by now well familiar to the neurologists – should also be familiar to the hematologist involved in these consultations; and (3) anti-platelet therapy rather than anticoagulant therapy is currently the treatment standard for patients with ESUS.