Patent Foramen Ovale and Cryptogenic Stroke: Do We Finally Have Closure? Christopher Streib, MD, MS

Patent Foramen Ovale and Cryptogenic Stroke: Do We Finally Have Closure? Christopher Streib, MD, MS 11-8-18

Outline 1. Background 2. Anatomy of patent foramen ovale (PFO) 3. Relationship between PFO and cryptogenic stroke 4. PFO closure as secondary stroke prevention 5. Patient selection 6. Summary

Incidence of PFO in cryptogenic stroke patients < 55 years old: 40 60% vs. general population: 20-25% Off-label PFO closure gained significant traction Lechat et al. NEJM 1988; Webster et al. Lancet 1988. Bridges et al. Circulation 1992;86:1902-1908

PFO Closure: 1992-2013 Is PFO closure more effective than medical management at preventing recurrent stroke? Stroke Neurologists Interventional Cardiologists Slide courtesy of Dr. Timrinder Biring

PFO Closure

Case Presentation PFO Closure

Case Presentation PFO Closure Video courtesy of Dr. Timrinder Biring

NEJM: 2012 & 2013

American Heart Association Secondary Stroke Prevention Guidelines for PFO 1. Insufficient data to establish whether anticoagulation is equivalent or superior to aspirin (Class IIb; Level of Evidence B). 2. For patients with a cryptogenic stroke or TIA and PFO without evidence of DVT, available data do not support a benefit for PFO closure (Class III; Level of Evidence A). AHA Guideline 2014. Secondary Stroke Prevention

NEJM: September 14, 2017

Cryptogenic Stroke: Case 1 39 yo female with no known medical history Small brainstem stroke resulting in subtle right-sided weakness Large PFO with atrial septal aneurysm Is PFO closure indicated?

Cryptogenic Stroke: Case 2 61 yo male with left frontal cortical infarct Only risk factors are HTN and DM Moderate-sized PFO with atrial septal aneurysm Remainder of comprehensive stroke evaluation unrevealing Is PFO closure indicated?

Cryptogenic Stroke: Case 3 48 yo male physician with a duplicated right middle cerebral artery who presented with right frontal cortical stroke four years prior Stroke work-up negative TTE did not show a PFO, but on TEE a very small PFO was seen on bubble study Is PFO closure indicated?

Cryptogenic Stroke: Case 4 45 year old male with no medical history Presents with a cortical stroke in the left hemisphere resulting in trouble speaking Large PFO with atrial septal aneurysm Remainder of comprehensive stroke evaluation unrevealing Is PFO closure indicated?

Fetal Circulation Neonatal Circulation Sadler. Fetal and Neonatal Circulation. 2009

50 45 40 35 30 25 20 15 10 5 0 PFO Prevalence (%) General Population Cryptogenic Stroke Image courtesy: http://stormanesthesia.com/anesthesia-material/miscellaneous-articles/71-pdapfo-and-fetal-circulation

Echocardiogram PFO Atrial Septal Aneurysm

TEE with bubble study - Valsalva + Valsalva TEE images courtesy of Dr. Timrinder Biring

Pulmonary Circulation

Pulmonary Circulation The pulmonary circulation effectively filters small venous emboli advanced imaging shows subsegmental PEs are not uncommon PFOs allows emboli to bypass filtration in the lungs and enter the arterial circulation 2-3mm subsegmental PE = asymptomatic 2-3mm paradoxial embolus to brain = major stroke

Middle Cerebral Artery MRI MRA

Paradoxical Embolism Upper extremity dopplers Lower extremity dopplers MR venogram pelvis https://en.wikipedia.org/wiki/vein

Paradoxical Embolism Case reports published of paradoxical embolism caught in transit In clinical practice, conclusive evidence implicating the PFO is rare Asress et al. PFO: the Current State. BMJ 2015

PFO in Cryptogenic Stroke 1. How can we determine how likely the PFO is to be related to the stroke? 2. Which patient with PFO might benefit from closure (i.e. are at highest risk of recurrent stroke without PFO closure)?

Is the PFO the Culprit? Risk of Paradoxical Embolism (RoPE) Score Model created from variables that were associated with PFO in the setting of cryptogenic stroke

Embolic Stroke of Undetermined Source (ESUS) Lacunar stroke Cortical stroke: consistent with ESUS note abrupt cut-off of otherwise normal vessel

Definition of ESUS 1. Non-lacunar strokes (distribution, size <1.5cm) 2. No cardiac arrhythmia or cardioembolic source 3. No symptomatic atherosclerosis: aortic arch, carotid arteries, intracranial No other large vessel pathology, i.e. dissection 4. Completed hypercoagulable evaluation 5. Absence of uncontrolled stroke risk factors 6. No TIAs* Hart. ESUS. Lancet Neuro 2014.

Lacunar Stroke Occlusion of small, penetrating end arteries that branch off large caliber vessels Vessel occlusion due to lipohyalinosis or in situ thrombosis secondary to microatheroma Hypertension, DM, HL, smoking lead to vessel narrowing

Lacunar Stroke Small strokes (<15-20mm) They do not produce cortical signs Lacune = lake, small CSF space on MRI or autopsy

ESUS vs. Lacunar Stroke ESUS LACUNAR Saver. RESPECT: Long-Term Outcomes. NEJM 2017

High Risk PFO In theory, a larger shunt or presence of an atrial septal aneurysm increases risk of PFO-related stroke Saver. RESPECT: Long-Term Outcomes. NEJM 2017

What Lessons Were Learned? Study Follow-up (years) N TIA ESUS PFO Size Atrial Septal Aneurysm CLOSURE 2012 2.0 909 Yes No* No No PC 2013 4.1 414 No No** No No RESPECT 2013 * 980 No Yes # No No RESPECT 2017 5.9 980 No Yes # No No + CLOSE 2017 5.3 663 No Yes modlarge No REDUCE 2017 3.2 664 No Yes modlarge Yes, or modlarge shunt *Included lacunar stroke **stroke evaluation not comprehensive # 13% had a single, deep lesion

Outcomes: REDUCE, RESPECT, CLOSE Study Number Needed to Treat to Prevent One Stroke Number Needed to Harm: Procedural Complication Number needed to Harm: Afib RESPECT 2017 42 per 5 years 42 15 CLOSE 2017 20 per 5 years * 17 27 REDUCE 2017 24 per 2 years 71 16 *compared to antiplatelet group only, not anticoagulation

Outcomes: REDUCE, RESPECT, CLOSE Study Duration (yrs) Stroke PFO Closure Stroke Medical Arm Serious Procedual Complication Afib* CLOSURE 2012 2 2.9% 3.1% 3.2% 5.7% PC 2013 4.1 0.5% 2.4% 1.5% 2.9% RESPECT (2013) RESPECT (2017) R E D U C E (2017) * 5.9 0.39 events per 100yrs 0.58 events per 100yrs 1.45 events per 100yrs 1.07 events per 100yrs 4.2% ~6.6% 4.2% 6.6% 3.2 1.4% 5.4% 1.4% * CLOSE 2017 5.3 0% 5.9% 5.9% 4.6%

Cryptogenic Stroke: Case 1 35 year old female with migraine aura No other medical problems Small brainstem stroke resulting in subtle right-sided weakness Large PFO with atrial septal aneurysm q High Risk PFO q RoPE Score q ESUS

Cryptogenic Stroke Case 2: RoPE Score 61 yo male with left frontal cortical infarct HTN and Diabetes RoPE Score = 4

Cryptogenic Stroke: Case 3 48 yo male physician with duplicated right middle cerebral artery who had a small right frontal cortical stroke four years prior Stroke work-up negative TTE did not show a PFO, but on TEE a very small PFO was seen on bubble study q ESUS q High Risk PFO q RoPE Score

Case 3: RoPE Score No stroke risk factors. RoPE Score = 8

Cryptogenic Stroke: Case 3 No stroke risk factors. RoPE Score = 8 Referred to Cardiology for evaluation of PFO PFO difficult to visualize With a duplicated MCA and very low risk PFO, we elected not to pursue closure Continued aspirin and considering anticoagulation with Apixiban. 6 years without recurrent stroke.

Cryptogenic Stroke: Case 4 45 year old male with no medical problems Presents with a cortical stroke in the left hemisphere resulting in trouble speaking Large PFO with atrial septal aneurysm Remainder of comprehensive stroke evaluation unrevealing q ESUS q High Risk PFO q RoPE Score = 8

Summary 1. PFO attributable stroke has a low risk of recurrence, even with medical therapy alone (1.0-1.5% per year) - When medical management is chosen, it is unclear if anticoagulation provides longterm benefit over antiplatelet

Summary 2. For most patients with stroke and PFO, the PFO is an incidental finding RoPE Score, radiographic findings, and clinical intuition used to assess the likelihood that the PFO is the culprit lesion

Summary 3. Determination of cryptogenic stroke requires comprehensive evaluation May include hypercoagulable testing and prolonged cardiac rhythm monitoring Specific diagnosis of ESUS is radiographic and depends upon stroke infarct pattern

Summary 4. Patients with ESUS, high risk PFO, and high RoPE score clearly benefit from PFO closure for secondary stroke prevention To realize the benefit of PFO closure, appropriate patient selection is essential and dependent upon cooperative practice between Primary Care, Cardiology, and Vascular Neurology

Thank you Chris Streib: streib@umn.edu