2017 Cardiovascular Symposium CRYPTOGENIC STROKE: A CARDIOVASCULAR PERSPECTIVE DR. WILLIAM DIXON AND DR. VENKATA BAVAKATI SOUTHERN MEDICAL GROUP, P.A.

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1 CRYPTOGENIC STROKE: 2017 Cardiovascular Symposium A CARDIOVASCULAR PERSPECTIVE DR. WILLIAM DIXON AND DR. VENKATA BAVAKATI SOUTHERN MEDICAL GROUP, P.A.

2 CRYPTOGENIC STROKE CRYPTOGENIC: OF OBSCURE OR UNKNOWN ORIGIN For there is nothing hidden that will not be disclosed, and nothing concealed that will not be known or brought out into the open. Luke 8:17

3 CRYPTOGENIC STROKE 1/3 of ischemic strokes classified as cryptogenic (200k annually) Cerebral infarct not clearly attributable to: -definite cardioembolism -large artery atherosclerosis (aortic arch/carotid) -small artery disease (intracerebral) Potential causes: -patent foramen ovale (PFO) -paroxysmal atrial fibrillation (PAF) -inherited thrombophilias -infections/autoimmune

4 DIAGNOSIS OF CRYPTOGENIC STROKE According to guidelines, baseline evaluations, at a minimum, should include: Noncontrast brain CT or brain MRI Blood glucose Oxygen saturation Serum electrolytes/renal function tests Complete blood count, including platelet count Markers of cardiac ischemia Prothrombin time/international Normalized Ratio (INR) Activated partial thromboplastin time Electrocardiogram Jauch et al, Stroke. 2013;44:

5 CARDIAC IMAGING-TTE VS TEE TTE as initial test -Patients 45 years with a neurologic event and no identified cerebrovascular disease -Any patient with an abrupt occlusion of a major peripheral or visceral artery -Patients with a high suspicion of left ventricular thrombus -Patients in whom TEE is contraindicated (e.g., esophageal stricture, unstable hemodynamic status) or who refuse TEE

6 CARDIAC IMAGING-TTE VS TEE TEE as initial test -Patients <45 years without known cardiovascular disease (i.e., absence of infarction or valvular disease history) -Patients with a high pretest probability of a cardiac embolic source in whom a negative TTE would be likely to be falsely negative -Patients with AF and suspected left atrial or LAA thrombus -Patients with a mechanical heart valve -Patients with suspected aortic pathology

7 TRANSCRANIAL DOPPLER (TCD) Non-invasive As sensitive or more sensitive than TEE for right-toleft shunt Patient is awake so can cooperate with valsalva Very high negative predictive value (may not need TEE)

8 TCD

9 Hold that thought.. CARDIAC MONITORING

11 PFO

12 PFO-A COMMON FINDING 25% of the general population Up to 50% in adults <55yo with cryptogenic stroke Commonly occurs in the presence of atrial septal aneurysm

13 PFO AND STROKE

14 PFO AND STROKE Venous thromboembolism PFO Acute (or chronic) elevation of right atrial > left atrial pressure Thrombus traverses PFO Thrombus goes to a bad place, i.e. cerebral vessels

right to left shunting through the PFO Septum Secundum Septum

15 PATHOPHYSIOLOGY OF PFO AND PARADOXICAL EMBOLISM Normal appearing atrial septum Agitated saline study demonstrating right to left shunting through the PFO Septum Secundum Septum Primum Blood clot passing through the PFO becoming a paradoxical embolism 4

16 PFO-HOW CONFIDENTLY CAN WE ATTRIBUTE THE STROKE TO THE PFO? An index to identify stroke-related vs incidental patent foramen ovale in cryptogenic stroke Neurology 2013;81:

17 ROPE (RISK OF PARADOXICAL EMBOLISM) SCORE: Neurology 2013;81:

18 ROPE score

19 PFO-TREATMENT OPTIONS Prevent the thrombus -Asa -warfarin -stronger antiplatelet drugs (clopidogrel, Aggrenox) -No consensus on best medical therapy Close the door -percutaneously -surgically

20 PFO-CLOSURE VS MEDICAL THERAPY Important points: Paradoxical embolism is an infrequent event Recurrence rates will be low with either management strategy in the short term

A PROSPECTIVE, MULTICENTER, RANDOMIZED CONTROLLED TRIAL TO EVALUATE THE SAFETY AND EFFICACY OF THE STARFLEX SEPTAL CLOSURE SYSTEM VERSUS BEST MEDICAL

21 A PROSPECTIVE, MULTICENTER, RANDOMIZED CONTROLLED TRIAL TO EVALUATE THE SAFETY AND EFFICACY OF THE STARFLEX SEPTAL CLOSURE SYSTEM VERSUS BEST MEDICAL THERAPY IN PATIENTS WITH A STROKE OR TRANSIENT ISCHEMIC ATTACK DUE TO PRESUMED PARADOXICAL EMBOLISM THROUGH A PATENT FORAMEN OVALE Trial Sponsor: NMT Medical Boston

22 2 YEAR PRIMARY ENDPOINT ITT STARFlex n = 447 Composite 5.9% (n=25) Stroke 3.1% (n=12) TIA 3.3% (n=13) Medical n = % (n=30) 3.4% (n=13) 4.6% (n=17) Adjusted P value* Kaplan-Meier for Primary Endpoint ITT

23 CONCLUSIONS CLOSURE I is the first completed, prospective, randomized, independently adjudicated PFO device closure study Superiority of PFO closure with STARFlex plus medical therapy over medical therapy alone was not demonstrated no significant benefit related to degree of initial shunt no significant benefit with atrial septal aneurysm insignificant trend (1.8%) favoring device driven by TIA 2 year stroke rate essentially identical in both arms (3%) Major vascular (procedural) complications in 3% of device arm Significantly higher rate of atrial fibrillation in device arm (5.7%) 60% periprocedural

24 Mass High Tech NMT Medical ends operations, starts selling assets Apr 20, 2011, 9:04am EDT

RESPECT RANDOMIZED EVALUATION OF RECURRENT STROKE COMPARING PFO CLOSURE TO ESTABLISHED CURRENT STANDARD OF CARE TREATMENT JOHN D. CARROLL, MD, JEFFREY L.

25 RESPECT RANDOMIZED EVALUATION OF RECURRENT STROKE COMPARING PFO CLOSURE TO ESTABLISHED CURRENT STANDARD OF CARE TREATMENT JOHN D. CARROLL, MD, JEFFREY L. SAVER, MD, DAVID E. THALER, MD, PHD, RICHARD W. SMALLING, MD, PHD, SCOTT BERRY, PHD, LEE A. MACDONALD, MD, DAVID S. MARKS, MD, MBA, DAVID L. TIRSCHWELL, MD FOR THE RESPECT INVESTIGATORS

26 KEY ASPECTS OF RESPECT TRIAL Device trial for secondary prevention Superiority trial: PFO closure vs. guidelinedirected medications Largest randomized PFO trial: 980 patients 499 AMPLATZER PFO Occluder; 481 MM Assumptions Paradoxical embolism was cause of initial stroke Recurrent strokes would be due to recurrent paradoxical embolism

27 RESPECT TRIAL POPULATION Included: Subjects with a PFO who have had a cryptogenic stroke within the last 270 days Excluded: Subjects aged <18 years or >60 years Subjects with identified stroke etiology Subjects who are unable to discontinue anticoagulants Carroll et al. NEJM 2012;368:

28 SUBJECT DISTRIBUTION TEE with bubble study at 6 months 1. Aspirin + clopidogrel was removed from the protocol in 2006 based on changes to the AHA/ASA treatment guidelines 13

29 PRIMARY ENDPOINT ANALYSIS ITT COHORT 50.8% RISK REDUCTION OF STROKE IN FAVOR OF DEVICE 3/9 device group patients did not have a device at time of endpoint stroke 1. Cox model used for analysis 20

30 BUT REMEMBER Recurrent events are rare in both arms And, the higher the ROPE score, the lower the recurrence rate of stroke Therefore, recurrent stroke from PFO is an infrequent event

31 RESPECT EXTENDED FOLLOW-UP RESULTS John D. Carroll, M.D. Acknowledgements Jeffrey L. Saver, M.D. David E. Thaler, M.D., Ph.D. Richard Smalling, M.D., Ph.D. Lee A. MacDonald, M.D. David S. Marks, M.D. David L. Tirschwell, M.D. for the RESPECT Investigators

32 1.00 SIGNIFICANT REDUCTION IN RECURRENT CRYPTOGENIC STROKE 54% RELATIVE RISK REDUCTION IN ITT POPULATION Event-free Probability AMPLATZER (N=499; AMPLATZER # cryptogenic PFO strokes Occluder = 10) Medical (N=499; Management # cryptogenic strokes = 10) (N=481, Medical # cryptogenic Management strokes = 19) (N=481, # cryptogenic strokes = 19) 0.85 HR: Log-rank p-value: # at Risk (KM Estimates) AMPLATZER (0%) (1.2%) (1.5%) (2.5%) (2.5%) (2.5%) MM 481 (0%) 394 (2.7%) Time 307 to Event (4.1%)(Years) 168 (4.1%) 71 (5.2%) 10 (10.8%)

33 PROCEDURE OR DEVICE RELATED SAES SAES ADJUDICATED BY DSMB No intra-procedure strokes No device embolization No device thrombosis No device erosion Very low rate of major vascular complications (0.9%) and device explants (0.4%)

34 CONCLUSIONS AMPLATZER PFO Occluder is superior to medical management in reducing recurrent cryptogenic ischemic stroke Treatment effect is fully manifest in types of strokes for which closure is intended Superiority is substantial and sustained Procedure and device are safe RESPECT reinforces need for comprehensive risk factor modification

35 MY APPROACH Was it an embolic event? Imaging evidence or strong dx by Neurology of TIA Is there evidence of right-to-left shunt (TCD)? Is the shunt intracardiac (TEE)? (pulmonary AVM) What is the ROPE score? I use arbitrary age cut-off (included in ROPE score) Frank discussion with the patient

36 2017 Cardiovascular Symposium PAROXYSMAL ATRIAL FIBRILLATION AND CRYPTOGENIC STROKE VENKATA V. BAVIKATI SOUTHERN MEDICAL GROUP, P.A.

37 DISCLOSURES No conflicts of interest

38 OBJECTIVES Understand the role of atrial fibrillation (A Fib) in patients with cryptogenic stroke Means to evaluate and diagnose A fib in this population.

39 CRYPTOGENIC STROKE One-third of ischemic strokes are classified as cryptogenic (approximately 200,000 strokes annually in the U.S.).

40 RISK OF RECURRENCE Overall, risk of recurrent stroke after cryptogenic stroke is intermediate between the high early risk after large artery atherosclerosis stroke and low risk after small artery disease stroke. Cryptogenic Stroke, Yaghi et al Circulation Research

41 RISK OF RECURRENCE 333 pts with cryptogenic stroke followed clinically and with serial imaging at 30 and 90 days Clinical recurrence at 90 days: 1.2% New MRI lesions: 14.5% Almost half in new arterial distribution Bal S et al Stroke 2012

42 ROLE OF A FIB IN CRYPTOGENIC CVA About 25% of Cryptogenic strokes have a radiographic appearance similar to that seen in stroke patients with cardioembolic source Hart etal. Embolic strokes of undetermined source: the case for a new clinical construct. Lancet Neurol. 2014;13:

43 CURRENT PARADIGM FOR SECONDARY PREVENTION Risk factor modification Statins Antiplatelets

44 WHAT ABOUT ANTICOAGULATION?

45 WARSS TRIAL Multicenter double-blind study comparing ASA to Warfarin

46 WARSS TRIAL Primary endpoint (stroke or death within 2 years) was similar between the two groups (17.8% vs. 16.0%, p = 0.25).

47 CURRENT FOLLOW-UP PARADIGM Anticoagulation Antiplatelet therapy

48 SUBCLINICAL ATRIAL FIBRILLATION Paroxysmal atrial fibrillation (PAF), as opposed to persistent AF, is transient, infrequent, and often asymptomatic. Up to 90% of PAF episodes may be asymptomatic Asymptomatic Arrhythmias in Patients With Symptomatic Paroxysmal Atrial Fibrillation and Paroxysmal Supraventricular Tachycardia. Circulation. 1994;89: Hart RG, et al. Stroke With Intermittent Atrial Fibrillation: Incidence and Predictors During Aspirin Therapy. Stroke Prevention in Atrial Fibrillation Investigators. J Am Coll Cardiol. 2000;35:

49 PERTINENT QUESTIONS How common is subclinical atrial fibrillation? Does subclinical atrial fibrillation increase risk of stroke? How common is subclinical atrial fibrillation in patients with cryptogenic stroke? What is the best modality to look for subclinical atrial fibrillation?

50 ASSERT TRIAL

51 ASSERT TRIAL Whether subclinical A Fib detected by implanted devices is associated with an increased risk of ischemic stroke in patients who did not have other evidence of A Fib 2580 patients, 65 or older, with HTN and no history of atrial fibrillation Monitored to detect subclinical A Fib ( lasting > 6 min) FU mean of 2.5 years for the primary outcome of ischemic stroke or systemic embolism

52 ASSERT TRIAL At 3 months, subclinical atrial A Fib detected by implanted devices had occurred in 261 patients (10.1%). At 2.5 year follow-up 34.7% of patients had subclinical A fib.

53 ASSERT TRIAL Subclinical A Fib Significantly increased risk of ischemic stroke or systemic embolism (hazard ratio, 2.49, P=0.007)

54 EMBRACE TRIAL

55 EMBRACE TRIAL Randomly assigned 572 patients 55 years of age or older, without known atrial fibrillation, who had had a cryptogenic ischemic stroke or TIA within the previous 6 months 30-day event-triggered recorder 24 hour conventional monitor Primary outcome: Newly detected A Fib within 90 days

56 EMBRACE TRIAL 16.1% in the Event monitor gp vs 3.2% in the holter group. p < Oral anticoagulation 18.6% vs 11.1% p= 0.01

57 EMBRACE

58 CRYSTAL- AF TRIAL

59 LOOP RECORDERS

60 MINIMALLY INVASIVE OUTPATIENT INSERTION PROCEDURE

61 LOOP RECORDER Programmable features Atrial fibrillation detection algorithm Tachycardia detection algorithm Bradycardia detection Pauses

63 LOOP RECORDER TRACING: SINUS RHYTHM

64 ILR: VENTRICULAR TACHYCARDIA

65 ILR: PAROXYSMAL COMPLETE HEART BLOCK

66 ILR: ATRIAL FIBRILLATION

67 AF MONITORING WITH RHYTHM (IR-)REGULARITY Sinus rhythm AF Normal variations Irregular irregularity

68 AT/AF SUMMARY REPORT Provides an overview of all atrial arrhythmias detected, including: Percentage of time in AT/AF Average time in AT/AF per day Number of episodes at a given duration V rate during AT/AF Average V rate Patient activity Heart rate variability Histograms Longest AF 30-day, 90-day and 14-month views

69 CRYSTAL- AF TRIAL 441 pts, > 40 yrs, with cryptogenic CVA or TIA in the last 90 days Randomized to 1:1 fashion ILR vs Usual follow-up Primary endpoint: Time to detection of first episode of A fib at 6 months Crystal AF trial NEJM 2014

70 CRYSTAL AF

71 CRYSTAL AF

72 CRYSTAL AF

73 CRYSTAL- AF 79% of first incidence of A Fib was asymptomatic Short-term monitoring not sufficient: median time to AF detection over 12 months was 84 days 97% of pts with A Fib were started on oral anticoagulation

74 GUIDELINES FOR THE PREVENTION OF STROKE IN PATIENTS WITH STROKE AND TRANSIENT ISCHEMIC ATTACK prolonged rhythm monitoring ( 30 days) for AF is reasonable within 6 months of the index event (Class IIa; Level of Evidence C). (New recommendation) Embrace and Crystal-AF trial data not included Stroke. 2014;45:00-00.

75 HEALTHCARE PROFESSIONAL GUIDE : UNDERSTANDING DIAGNOSIS AND TREATMENT OF CRYPTOGENIC STROKE These data suggest that AF is common in patients with cryptogenic stroke, and that not unexpectedly the longer a patient is monitored, the more likely AF will be detected.

76 WHAT S AT THE HEART OF MY CRYPTOGENIC STROKE? A Patient Guide to Understanding Stroke of Unknown Cause

77 Originally published February 2, 2017

78 Outpatient cardiac monitoring for occult AF is now the standard of care after a cryptogenic stroke because the detection of AF will lead to anticoagulation therapy that is superior to antiplatelet therapy

79 COST EFFECTIVENESS Insertable cardiac monitors are a cost-effective diagnostic tool for the prevention of recurrent stroke in patients with cryptogenic stroke. Cost-effectiveness of an insertable cardiac monitor to detect atrial fibrillation in patients with cryptogenic stroke. Int J Stroke 2016

80 SECULAR TRENDS IN ISCHEMIC STROKE SUBTYPES AND STROKE RISK FACTORS Population is getting older More aggressive cardiovascular risk factor Rx, Statin therapy The proportion of cardioembolic stroke increased from 26% in 2002 to 56% in 2012 (P<0.05 for trend). Stroke 2014; 45:

81 SUMMARY Atrial fibrillation is common in patients with cryptogenic stroke The longer we look, the more likely we will find it Anticoagulation is strongly recommended for secondary prevention in this high risk population

82 THANK YOU!

Application of advanced techniques in cryptogenic stroke. Oh Young Bang et al.

HOW AF IS DETECTED IN CRYPTOGENIC STROKE PATIENTS N = 1491 Incremental % AF Detection Acute stroke or TIA and no history of AF Acute Workup After CS Diagnosis ECG monitoring in Hospital 24-hour

84 HOW AF IS DETECTED IN CRYPTOGENIC STROKE PATIENTS N = 1491 Incremental % AF Detection Acute stroke or TIA and no history of AF Acute Workup After CS Diagnosis ECG monitoring in Hospital 24-hour Holter recording if normal ECG 7-day event monitor if normal Holter CRYSTAL AF 1. Jabaudon D. Et al. Usefulness of Ambulatory 7-Day ECG Monitoring for the Detection of Atrial Fibrillation and Flutter After Acute Stroke and Transient Ischemic Attack Stroke 2004;35: Cotter, P.E., et al., Incidence of atrial fibrillation detected by implantable loop recorders in unexplained stroke. Neurology, 2013 Apr 23;80(17): Ritter, M.A., et al., Occult Atrial Fibrillation in Cryptogenic Stroke: Detection by 7-Day Electrocardiogram Versus Implantable Cardiac Monitors. Stroke, 2013 May;44(5):

85 CHA2DS2-VASC SCORE

86 PAF AND CHA2DS2-VASC Observed absolute stroke rates / year in nonanticoagulated pts for single independent risk factor Prior CVA / TIA: 6 to 9 % HTN: 1.5 to 3 % DM: 2 to 3.5 % Age: 1.5 to 3 % for age > 75

Cryptogenic Stroke: What Don t We Know. Siddharth Sehgal, MD Medical Director, TMH Stroke Center Tallahassee Memorial Healthcare

Cryptogenic Stroke: What Don t We Know Siddharth Sehgal, MD Medical Director, TMH Stroke Center Tallahassee Memorial Healthcare Financial Disclosures None Objectives Principles of diagnostic evaluation