Despite improvements over the last decade, stroke remains the fifth leading cause of death and the leading cause of long-term disability in the US.1 Approximately 30% of strokes remain cryptogenic upon hospital discharge, despite extensive workup. A significant portion of people with cryptogenic strokes are eventually diagnosed with atrial fibrillation (AFib).2 Several classification systems have been developed to describe the etiology of stroke, with the Trial of Org 10172 in Acute Stroke Treatment (TOAST) being the most widely recognized and useful because it includes both cryptogenic stroke and incomplete workup. However, no scheme defines the workup required for stroke to be considered cryptogenic. Additionally, the category of embolic stroke of unknown source (ESUS) became a subcategory in 2014 but is not included in these classification schemes. Appropriate classification of stroke is essential to direct optimal secondary stroke prevention, including medication regimens.

Inpatient Stroke Workup and Cardiac Monitoring

Appropriate classification of acute stroke relies on the workup completed. The 2018 American Heart Association (AHA) guidelines recommend acute workup of ischemic stroke include head CT with head MRI considered, vascular imaging, and cardiac monitoring. Current guidelines recommend at least 24 hours of observation and cardiac monitoring during hospitalization as part of a stroke evaluation.3,4 In some strokes, prolonged cardiac rhythm evaluation is also important to determine stroke etiology, specifically for detection of underlying AFib. After inpatient cardiac evaluation, if AFib is not identified and sufficient concern remains, outpatient cardiac monitoring is available in the form of cardiac event monitor, pacemaker and implantable cardiac defibrillators, noninvasive cardiac monitoring, and implantable cardiac monitoring. Longer observation leads to increased detection of AFib, and implantable cardiac monitoring is superior to conventional follow-up for detecting AFib.5 Up to 30% of people with cryptogenic stroke are reportedly diagnosed with AFib within 3 years of implantable recording device placement.6 Increased duration and frequency of AFib episodes seem to increase infarct risk, but a threshold for causation is unknown. There is uncertainty about the importance of detecting AFib near the time of acute infarct. Some studies suggest episodes of AFib longer than 5.5 hours in the first 5 days after infarct increase recurrent embolism risk,5 but more evidence is needed to support a temporal relationship. Although longer cardiac monitoring increases AFib detection, it is unclear if everyone with cryptogenic stroke needs implantable cardiac monitoring. Studies have sought to develop a score for predicting AFib in the stroke population to help guide implantable cardiac monitoring decisions, but have reached contradictory conclusions.7-9 There is no reliable predictive mechanism to determine who should or should not have prolonged implantable cardiac monitoring for possible determination of stroke etiology. A mechanism to better stratify individuals by risk before implantable cardiac monitoring is an unmet need.

Embolic Stroke of Unknown Source

A subcategory of ischemic cryptogenic stroke, ESUS denotes specifically nonlacunar stroke in people without an immediately identifiable etiology (eg, large vessel disease, significant intracranial atherosclerosis, or major risk of cardioembolic source). A recent series reports ESUS prevalence of 16% to 32%. Stroke recurrence rates for ESUS are similar to that of cryptogenic stroke, ranging from 9.1% at 1 year to more than 30% at 10 years.5 Despite being considered embolic, the origin of the embolism is not clear after appropriate workup. Among potential sources are aortic arch atheroma, large or small vessel emboli, or cardiac emboli, such as seen in AFib. Standard treatment of people after ESUS is antiplatelet therapy10,11 and risk factor modification including treatment of hypertension and hyperlipidemia. Studies suggest that people who had ESUS have a recurrent stroke risk of 4.5% per year. It is possible, however, that up to 30% of these individuals may go on to develop AFib10 and require significantly different management. Detection of AFib after ESUS or cryptogenic stroke allows for targeted secondary prevention; however, it cannot be ensured that this was the cause of the initial infarct.

Clinical Trials for Embolic Stroke of Unknown Score

The etiology of ESUS is presumed embolic, yet by definition, the source of embolism is unknown. Guidelines recommend antithrombotic therapy for secondary prevention; however, it has been hypothesized that anticoagulation may be superior to antithrombotic therapy for secondary prevention of stroke in this population. Recently, 2 negative trialsa,b have been reported regarding treatment of the ESUS population.12,13

Rivaroxaban was not found superior to aspirin in people who had ESUS (n = 7,213) and was associated with increased risk of hemorrhage. The primary aim of this study was to determine efficacy of treatment in preventing first recurrence of stroke (ischemic or hemorrhagic) and determine the rate of major bleeding. Although the primary endpoint occurred more frequently with rivaroxaban vs aspirin (5.1% vs 4.8%), the difference was not statistically significant. The rate of stroke did not differ after treatment with rivaroxaban vs aspirin (4.7%) (Figure 1). Major bleeding, however, occurred in more people treated with rivaroxaban vs aspirin (annualized rate of 1.8% vs 0.7%), and there was significantly more symptomatic intracranial hemorrhage after treatment with rivaroxaban vs aspirin (annualized rate of 0.6% vs 0.1% ) (Figure 2).12

Figure 1. Comparison of stroke risk in NAVIGATE ESUS12 vs RE-SPECT ESUS trials.13,14 No difference between rivaroxaban and aspirin, or dabigatran and aspirin was found for either any type of stroke or systemic embolization, or in risk of ischemic stroke.

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Figure 1. Comparison of stroke risk in NAVIGATE ESUS12 vs RE-SPECT ESUS trials.13,14 No difference between rivaroxaban and aspirin, or dabigatran and aspirin was found for either any type of stroke or systemic embolization, or in risk of ischemic stroke.

Figure 2. Comparison of hemorrhage risk in NAVIGATE ESUS12 vs RE-SPECT ESUS trials.13,14 Rivaroxaban had increased risk of major bleeding (*, P < .001) and intracerebral hemorrhage (**, P < .003) compared with aspirin. No difference was seen between dabigatran and aspirin for major bleeding or intracerebral hemorrhage.

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Figure 2. Comparison of hemorrhage risk in NAVIGATE ESUS12 vs RE-SPECT ESUS trials.13,14 Rivaroxaban had increased risk of major bleeding (*, P < .001) and intracerebral hemorrhage (**, P < .003) compared with aspirin. No difference was seen between dabigatran and aspirin for major bleeding or intracerebral hemorrhage.

Dabigatran was not found superior to aspirin for prevention of secondary ischemic stroke (ischemic, hemorrhagic, or other) in both groups (n = 5,390). The annual rate of any stroke after treatment with dabigatran was 4.8 vs 4.1 after treatment with aspirin, which was not a statistically significant difference. The annual rate of ischemic stroke was 4.0% and 4.7%. respectively, again not of statistical significance (Figure 1). Major bleeding occurred in 1.7% of participants treated with dabigatran per year vs 1.4% per year after treatment with aspirin, also not significantly different statistically. Intracranial hemorrhage was not different between the 2 groups (0.7%/year) (Figure 2). Although no significant difference was found between the groups, results do suggest the risk of major bleeding increases with age, decreased renal function, and vascular disease.15

Another trial is comparing apixaban to aspirin for secondary prevention of ischemic stroke in people who had ESUS, measured with MRI 12 months after the initial event compared with baseline imaging.c Secondary endpoints include combination of recurrent ischemic or hemorrhagic stroke, or systemic embolism, major adverse cardiovascular event, and combination of major and nonmajor bleeding events. Estimated completion date for this trial is February 2021.16

There is also a multicenter studyd comparing apixaban to aspirin for prevention of recurrent stroke after a cryptogenic ischemic stroke within ESUS definitions. The primary outcome is occurrence of new stroke of any type over a period of up to 4 years. Secondary aims include determining incidence of ischemic stroke or systemic embolism, incidence of any stroke type, and death from any cause. Symptomatic intracranial hemorrhage and other major hemorrhage are the primary safety measures, and the study aims to enroll 1,100 patients. The estimated completion date is April 2022.17

Future Directions

Direct oral anticoagulants rivaroxaban (factor Xa inhibitor) and dabigatran (direct thrombin inhibitor) have been shown to have equivalent efficacy and improved safety compared with warfarin. Direct oral anticoagulants were not found superior to aspirin for secondary stroke prevention in the ESUS population without a diagnosis of AFib. Considered secondary to embolism, ESUS strokes are actually of unknown origin. If cardiac embolism is the source, it is presumed that anticoagulation offers better protection from future cardioembolic stroke compared with aspirin in people with AFib. These data also suggest that true etiology of many ESUS strokes may not be secondary to cardioembolism or that the populations in the completed trials were too diverse to see a positive impact. Redefining and narrowing the scope of the population considered to have had ESUS may improve the outcomes of focused research.14 Ongoing studies focus on ESUS subgroups and may elucidate appropriate treatment in more specific populations. In conclusion, people who had ESUS without evidence of AFib should continue to be treated with antiplatelet therapy.

a Dabigatran etexilate for secondary strokeprevention in patients with embolic stroke of undetermined source (RE-SPECT ESUS) (NCT02239120).

b Rivaroxaban versus aspirin in secondary prevention of stroke and prevention of systemic embolism in patients with recent embolic stroke of undetermined source (ESUS) (NAVIGATE ESUS) (NCT02313909)

c Apixaban for treatment of embolic stroke of undeterminedsource (ATTICUS) (NCT02427126).

d Atrial cardiopathy and antithrombotic drugs in prevention after cryptogenic stroke (ARCADIA)(NCT03192215).

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3. Powers WJ, Rabinstein AA, Ackerson T, et al. 2018 guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals From the American Heart Association/American Stroke Association. Stroke. 2018;49(3):e46-e110.

4. Kernan WN, Ovbiagele B, Black HR, et al. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2014;45(7):2160-2236.

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8. Brunner KJ, Bunch TJ, Mullin CM, et al. Clinical predictors of risk for atrial fibrillation: implications for diagnosis and monitoring. Mayo Clin Proc. 2014;89(11):1498-1505.

9. Ricci B, Chang AD, Hemendinger M, et al. A simple score that predicts paroxysmal atrial fibrillation on outpatient cardiac monitoring after embolic stroke of unknown source. J Stroke Cerebrovasc Dis. 2018;27(6):1692-1696.

10. Hart RG, Catanese L, Perera KS, Ntaios G, Connolly SJ. Embolic stroke of undetermined source: a systematic review and clinical update. Stroke. 2017;48(4):867-872.

11. Zhang C, Kasner S. Diagnosis, prognosis, and management of cryptogenic stroke. F1000Research. 2016;5: F1000 Faculty Rev-168.

12. Hart RG, Sharma M, Mundl H, et al. Rivaroxaban for stroke prevention after embolic stroke of undetermined source. N Engl J Med. 2018;378(23):2191-2201.

13. Diener HC, Donald Easton J, Granger CB, et al. Design of randomized, double-blind, evaluation in secondary stroke prevention comparing the efficacy and safety of the oral thrombin inhibitor dabigatran etexilate vs. acetylsalicylic acid in patients with embolic stroke of undetermined source (RE-SPECT ESUS). Int J Stroke. 2015;1(5):208-211.

14. Paciaroni M, Kamel H. Do the results of RE-SPECT ESUS call for a revision of the embolic stroke of undetermined source definition? Stroke. 2019;50(4):1032-1033.

15. Granger CB, Diener H-C, Sacco R, et al. Major bleeding in patients with embolic stroke of undetermined source treated with dabigatran versus acetylsalicylic acid (RE-SPECT ESUS Trial). J Am Coll Cardiol. 2019;73 (9)(S1):1757.

16. Geisler T, Poli S, Meisner C, et al. Apixaban for treatment of embolic stroke of undetermined source (ATTICUS randomized trial): rationale and study design. Int J Stroke. 2017;12(9):985-990.

17. Kamel H, Longstreth WT, Tirschwell DL, et al. The atrial cardiopathy and antithrombotic drugs in prevention after cryptogenic stroke randomized trial: rationale and methods. Int J Stroke. 2019;14(2):207-214.

KPG reports no disclosures.