Atrial Fibrillation and Cryptogenic Stroke

Clinical benefit from ISCDX

ISCDX is a blood test for the stratification of ischemic stroke and TIA patients by cause so that proper treatment and treatment regimens may be adopted to prevent subsequent and more massive, costly and debilitating recurrences. Adoption of treatment pathways during hospitalization for a known cause will result in better compliance and outcomes. Strokes and TIAs of unknown origin are at higher risk to have poor outcomes, including recurrence or death.
While the goal is for ISCDX to become the standard of care blood test for cause of stroke, ISCDX will most likely initially influence treatment decisions in the “cryptogenic” populations especially where the cause is determined to be cardioembolic and whether it is a result of AF.

 
Detecting atrial fibrillation will change outcomes
Atrial fibrillation (AF) is a cardioembolic cause of stroke and the most common type of arrhythmia. During an arrhythmia, the heart can beat too fast (300bpm), too slow, or with an irregular rhythm resulting in “blood pools” in which “blood clots” form and travel out of the heart to cause cardioembolic strokes. Both persistent and paroxysmal (intermittent) AF are predictors of first and recurrent stroke.


AF represents 50% of cardioembolic strokes and 10% of all ischemic strokes. Approximately 25% of patients with AF have “intermittent AF” that is often asymptomatic and undetected by conventional methods of brief cardiac monitoring typically used in cases of ischemic stroke. Stroke patients with AF have a 5 times greater risk of recurrence of stroke . Patients who are initially diagnosed with cryptogenic stroke can be found subsequently to have intermittent AF through longer term cardiac monitoring in many clinical studies . However, longer term cardiac monitoring, beyond 24 hours, is not standard of care in cryptogenic stroke patients, as it is considered “low yield”, not “cost effective” and poor compliance . The ability of ISCDX to identify the cryptogenic patients in the cardioembolic subset would lead to a “higher yield” and “cost effective” approach to routing these patients into appropriate care to prevent recurrence. The Figure below demonstrates the gene expression profiles that differentiate cardioembolic strokes due to atrial fibrillation compared with non atrial fibrillation causes.

Figure - Gene expression profiles for atrial fibrillation cause of stroke


RNA expression profiles

Note to Figure: (A) Hierarchical cluster analysis of the 37 genes that were significantly different in subjects with cardioembolic stroke due to atrial fibrillation compared to subjects with nonatrial fibrillation causes. Genes are shown on the y-axis and subjects are shown on the x-axis. Red indicates a high level of gene expression and blue indicates a low level of gene expression. Subjects cluster by diagnosis. One group of genes has a high level of expression in cardioembolic stroke due to atrial fibrillation and a low level of expression in nonatrial fibrillation causes. Another group of genes has a low level of expression in cardioembolic stroke due to atrial fibrillation and a high level of expression in nonatrial fibrillation causes. (B) Principal components analysis of the 37 genes found to differentiate cardioembolic stroke due to atrial fibrillation from nonatrial fibrillation causes. Each sphere represents a single subject. The ellipsoid surrounding the spheres represents two standard deviations from the group mean.


Per AHA Guidelines, the ability to identify cardioembolic patients within the cryptogenic patient populations, would lead to a change in therapeutic interventions, and outcomes:

  1. 1. Cardioembolic patients are typically treated with anticoagulation.
  2. 2. Cryptogenic strokes are treated similar to atheroembolic with antiplatelet and aspirin therapy. Guidelines specifically state not to treat cryptogenic stroke with anticoagulation.


Additionally, in strokes of cardioembolic cause (including atrial fibrillation), anticoagulants are safe and effective when properly managed, reducing stroke and systemic embolism by more than 60% when compared to antiplatelet therapy. Recently, there are new potentially safer and more effective anticoagulants and factor X medications being developed, as well as the increase in ablation procedures for managing atrial fibrillation. Without a direction as to cardioembolic cause, these highly effective treatments are unlikely to be used to prevent stroke recurrence.


Reference materials

Ovbiagele, et al. In Hospital Initiation of Secondary stroke Prevention Therapies Yields High Rates of Adherence at Follow Up. Stroke 204;35:2879-2883

http://www.medpagetoday.com/resource-center/afib/Diagnosing-PAF-Patients-Cryptogenic-Stroke/a/34328#!

The risk of stroke recurrence is four times greater among prior stroke patients with newly detected AF. (Kamel et al. J Stroke Cerebrolvasc Dis; 2009 Nov – Dec;18(6):453-7)

How to use implantable loop recorders. Jung W, et al, J Interv Card Electrophysiol. 2011 Dec;32(3):227-32. Epub 2011 Oct 13. PMID: 21993595

Atrial fibrillation detected in cryptogenic TIA or stroke. Tayal AH, et al Neurology. 2008 Nov 18;71(21):1696-701. Epub 2008 Sep 24. PMID: 18815386

Predictors of paroxysmal AF in cryptogenic strokes detected by long-term cardiac monitoring. Bhatt A, et al Stroke Res Treat. 2011 Feb 22;2011:172074.

Cronin EM, et al "Remote monitoring of cardiovascular devices - a time and activity analysis" Heart Rhythm 2012; DOI: 10.1016/j.hrthm.2012.08.002.

Jickling GC, et al: Signatures of cardioembolic and large-vessel ischemic stroke. Ann Neurol. 2010 Nov;68(5):681-92.

Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med. 2007;12:857–867

Ovbiagele, et al. In Hospital Initiation of Secondary stroke Prevention Therapies Yields High Rates of Adherence at Follow Up. Stroke 204;35:2879-2883

Important take aways…

1.

Cryptogenic stroke is a significant problem and in many cases caused by atrial fibrillation.

40% of ischemic strokes never have a cause determined leading to a 5 times greater liklelihood of recurrence.
2.

Atrial fibrillation is is difficult to detect in the hospital setting for Ischemic Stroke.

A significant portion of AF may be parosysmal or occult, and often not present during standard clinical evaluations.
3.

Using a blood test to detect AF in the acute care setting will improve outcomes and reduce costs.

Despite advance in imaging, montioring and clinical evaluations, cause is often undetermined.
4.

Ischemia Care is developing a blood test for cause of stroke, including AF.

ISCDX is developing a blood test based upon over 15 years of peer reviewed published clinical research. BASE is designed to be a final cliinical validation prior to clinical launch and adoption.