Summary

1. Embolic stroke of unknown source (ESUS) and cryptogenic stroke are not the same, but both have soft definitions.
2. Most patients with ESUS or cryptogenic strokes do not have a recurrence.
3. Labelling the purported etiology of stroke based on radiographic findings or specific risk factors is not valid.
4. The presence or absence of atrial fibrillation at or around the time of stroke does not identify the cause for stroke.
5. Recurrence of large vessel stroke (diagnosed by radiographic evidence) is not improved by any specific therapy.
6. Lacunar small-vessel disease diagnosed by radiography is not improved by anticoagulation or platelet therapy.
7. Anticoagulation therapy (versus placebo) in large populations of patients with atrial fibrillation with or without prior stroke reduces the risk of recurrent stroke independent of radiographic history but does not eliminate total risk of stroke; 40% of strokes are not treated by anticoagulation and are presumably unrelated to atrial fibrillation.
8. Identifying atrial fibrillation in patients with ESUS has not been shown to reduce recurrent stroke risk.
9. Radiographic evidence of the purported cause for stroke does not improve recurrent stroke risk based on present therapy even for those with atrial fibrillation. Similar to myocardial infarction, revascularization may benefit only those who need an acute intervention to restore blood flow but not to affect risk of recurrence.
10. Treating cardiovascular risk using American Heart Association's Life's Simple 7,¹ sleep apnea,^2,3 and other predictors may be the best option to reduce risk of recurrent stroke.

Background

The etiology of the most common cause of ischemic neurological events (i.e., strokes) is hard to classify based on poorly validated angiographic findings and a broad range of risk factors (TOAST,^4,5 Causative Classification System for Ischemic Stroke,⁶ ASCOD⁷). Non-hemorrhagic strokes of undetermined etiology (cryptogenic) presumably represent ~20-40% of all strokes.⁸ When an ischemic stroke is labeled non-cryptogenic, the cause often remains obscure. Numerous risk calculators such as ABCD, ASCO, RRE, and Essen have been utilized to predict risk of a recurrent ischemic stroke.^9-12 While validated in short-term and long-term studies, these predictors did not differentiate the cause for recurrent ischemic events. A close look at these studies' methodologies reveals that individual risk factors overlap for embolic and thrombotic strokes, making a singular diagnosis problematic. In fact, a recurrent stroke may not necessarily be due to the same cause even in a given patient.

The ultimate value of predicting risk is to identify the mechanism responsible for a future event so that an effective preventative therapy can be prescribed. With overlap of risk factors for etiologies of stroke, any patient may be at risk for multiple etiologies for stroke. Previous definitions for classification of stroke etiologies have been inconsistent, and evidence to guide therapy is scarce.

Recently, ESUS-specific criteria were defined by the Cryptogenic Stroke/ESUS International Working Group to identify strokes that were considered cryptogenic but likely due to a thromboembolus.¹³ But whether it is labelled ESUS or cryptogenic, the mechanism for stroke remains uncertain. Even if a stroke is likely embolic, there are multiple potential etiologies including aortic atherosclerotic plaques, pro-thrombotic states (as may exist in patients with cancer), patent foramen ovale with paradoxical thromboemboli, atrial fibrillation with atrial appendage thromboemboli, atrial thrombi unrelated to atrial fibrillation, valvular heart thromboemboli, and left ventricular clots, among other potential causes for ESUS.⁸ Patients often have more than one potential etiology.¹⁴

In the Athens Stroke Registry, for 2,731 patients post-stroke who were followed for 31 months, initial strokes were classified using traditional definitions.^15,16 ESUS-defined patients' clinical characteristics included non-stenotic atherosclerotic plaques, moderate systolic or diastolic dysfunction, and atrial fibrillation. The ESUS patients had recurrent event rates similar to the cardio-embolic defined patients (versus much lower recurrent rates in other groups), suggesting similar etiologies. However, presence of these explanatory characteristics has not been shown to be causal. Thus, ESUS patients have multiple risks for second strokes with no clear beneficial therapy. One unfounded hypothesis is that atrial fibrillation is the leading cause of ESUS, and an opportunity to diagnose this could lead to preventative strategic anticoagulation treatment and reduce risk of further strokes.¹⁷ However, no data support this presently.

Electrocardiographic Monitoring and Cerebrovascular Accident Risk Factors

The more intense the heart rhythm monitoring in patients at risk of stroke, the more the likelihood of finding atrial fibrillation.^18-22 A Taiwan registry and a large population-based study showed the relationship of the CHADS₂ (and the CHA₂DS₂VASc) score and incidence in newly diagnosed atrial fibrillation.^23,24 To support this concept, the REVEAL AF (Incidence of AF in High Risk Patients) trial and other studies were performed.^25-30 The REVEAL AF trial, an observational study of patients without stroke or known atrial fibrillation, but with CHADS₂ scores >3, were evaluated; atrial fibrillation was observed on implantable monitors at 30 days, 6 months, 12 months, 24 months, and 30 months in 6.2 %, 20.4%, 27.1%, 33%, and 40%, respectively. In fact, the AS5F score was developed to predict atrial fibrillation after stroke.³¹ These findings lead one to the presupposition that the finding of atrial fibrillation in stroke patients equates to the causality of a cardio-embolic etiology of the stroke, ignoring the fact atrial fibrillation may be an innocent bystander or merely a marker of overall stroke risk.

The Find-AF (Finding Atrial Fibrillation in Stroke)³² and CRYSTAL-AF (Study of Continuous Cardiac Monitoring to Assess Atrial Fibrillation After Cryptogenic Stroke)²² trials evaluated the heart rhythm of patients with ESUS. In the CRYSTAL-AF trial, time to first detection of atrial fibrillation with an implantable loop recorder at 6, 12, and 36 months was 8.9%, 12.4%, and 30% versus 1.4%, 2.0%, and 3% in the control arm (with electrocardiograms and Holter and Event recorders). Of the implantable loop recorder patients, 46% had an atrial fibrillation burden of 12-24 hours as a maximum during follow-up.³³ Of patients with atrial fibrillation, 97% had an oral anticoagulant prescribed at time of atrial fibrillation diagnosis with no reported recurrent stroke difference. Presumably, the control group had the same incidence of atrial fibrillation (undetected); thus, a causal relationship between atrial fibrillation and stroke remains uncertain.

Further, lack of atrial fibrillation causality is supported by recurrent events in the TRENDS (A Prospective Study of the Clinical Significance of Atrial Arrhythmias Detected by Implanted Device Diagnostics),³⁴ ASSERT (Asymptomatic Atrial Fibrillation and Stroke Evaluation in Pacemaker Patients and the Atrial Fibrillation Reduction Atrial Pacing Trial),³⁵ and IMPACT-AF (Clinical Trial to Improve Treatment With Blood Thinners in Patients With Atrial Fibrillation)³⁶ clinical trials, where stored electrocardiogram data demonstrated no atrial fibrillation occurred within 30 days prior to an event or >30 days prior to event and, in others, atrial fibrillation only occurred after an event. Taken together, these studies more strongly support atrial fibrillation as an overall ill-defined stroke risk and explain the lack of preventive therapy based upon atrial fibrillation event-guided therapy.

To evaluate secondary treatment options in patients with noncardioembolic stroke, the WARSS (Warfarin-Aspirin Recurrent Stroke Study) was undertaken, which failed to prove efficacy in the overall study and in the cryptogenic subgroup.³⁷ Furthermore, in a specifically defined ESUS patient population, the NAVIGATE ESUS (Rivaroxaban Versus Aspirin in Secondary Prevention of Stroke and Prevention of Systemic Embolism in Patients With Recent Embolic Stroke of Undetermined Source)³⁸ and RE-SPECT ESUS (Dabigatran Etexilate for Secondary Stroke Prevention in Patients With Embolic Stroke of Undetermined Source)³⁹ trials were designed to assess oral anticoagulant efficacy versus antiplatelet therapy to reduce the risk of recurrent stroke in ESUS. In the NAVIGATE ESUS trial, efficacy of aspirin versus rivaroxaban was the same with a risk of stroke outcome of approximately 5% in 1 year, which may be no better than no therapy at all, and yet the risk of bleeding with rivaroxaban was quite a bit higher, with a hazard ratio of 2.72 (confidence intervals 1.68-4.39). With regard to the RE-SPECT ESUS trial, there was a similar recurrence rate of first stroke in both the randomized dabigatran and aspirin groups, but bleeding risks were not specifically different between the 2 groups.

Atrial fibrillation detection is possible by implantable loop recorders.⁴⁰ However, Afzal et al.⁴¹ reported that in patients who had loop recorder implantation and cryptogenic stroke, 86 out of the total 100 transmissions were false positive for atrial fibrillation and other rhythm disturbances, with only 14/100 being true positives and indicating the presence of atrial fibrillation. In addition to atrial fibrillation being misdiagnosed in this study, pauses, tachycardia, and bradycardia were also diagnosed inappropriately. Atrial fibrillation was diagnosed accurately in only ~50% of individuals.

Thus, regarding detection of atrial fibrillation after ESUS, what is the reasoning for it? Enhanced and prolonged monitoring is more likely to find atrial fibrillation. Presence of atrial fibrillation detection to date has not been associated with difference in recurrent stroke rates. Oral anticoagulant versus antiplatelet therapy has not proven beneficial in patients with ESUS.

When it comes to ESUS/cryptogenic stroke, one has to question the value of any treatment, whether it be empiric or electrocardiographically guided oral anticoagulation or antiplatelet therapy. Similar to premature ventricular contractions, atrial fibrillation in left ventricular dysfunction may indicate risk but not causality. And as in the CAST (Cardiac Arrhythmia Suppression) trial, trying to guide therapy based upon monitoring may invoke harm.⁴²

One, therefore, should consider the next step in patients with ESUS. Stop monitoring? More aggressive and accurate monitoring? Reconsideration of the risk score which we use? Considering the CHA₂DS₂VASc and CHADS₂ scores, a score of 2 is already present in those patients with an ESUS stroke. However, oral anticoagulants are ineffective. These scores may simply not apply to patients who have had a recent stroke, at least without some evidence that atrial fibrillation was the cause for the stroke. Should we use brain natriuretic peptide to differentiate cardioembolic stroke and/or d-dimer to identify hypercoagulable states and cancer? That is not clear.

A recent white paper⁴³ suggests the following approach:

1. Assess risk factors including age, sex, hypertension, obesity, and diabetes.
2. Evaluate cardiovascular dysfunction including atrial stiffness and left ventricular dysfunction.
3. Assess for rheumatic heart disease and atrial myopathy.
4. Determine if the stroke appears to be embolic.

If atrial fibrillation is suspected because of these risk factors, consider long-term monitoring with an implantable loop recorder. Otherwise, just consider short-term monitoring (≤72 hours).

It is the authors' opinion that 1) it is not clear that this approach will make a difference and 2) it is possible that detection of atrial fibrillation, accurate or not, may lead to a therapy that will create more harm than good with potential for greater expense and with need for health care intervention. Despite initial enthusiasm for intense monitoring in patients with ESUS, we have come to a point where we understand that the term ebolic stroke of unknown source is nothing but a hopeful moniker. The etiology for these neurological events remains cryptogenic. Therapeutic interventions have not been proven definitively to improve or affect risk for recurrent stroke, seriousness of stroke, disability from stroke, or any other specific outcome measure. Understanding what causes ESUS and what a cryptogenic stroke is may help better determine the need for assessing thrombogenicity. Perhaps we have been off base to put too much emphasis on atrial fibrillation. Other causes, such as cancer or other conditions that cause a thrombogenic state, are equally if not even more important.

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Clinical Topics: Anticoagulation Management, Arrhythmias and Clinical EP, Cardiac Surgery, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Anticoagulation Management and Atrial Fibrillation, Implantable Devices, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Cardiac Surgery and Arrhythmias, Cardiac Surgery and Heart Failure, Interventions and Imaging, Nuclear Imaging, Sleep Apnea

Keywords: Arrhythmias, Cardiac, Atrial Fibrillation, Risk Factors, American Heart Association, Cardiovascular Diseases, Stroke, Myocardial Infarction, Myocardial Revascularization, Sleep Apnea Syndromes, Radiography, Anticoagulants

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