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Patent Foramen Ovale (PFO)To close or not to close?

Erick Tarula MD

Assistant professor of Neurology

Stroke and Neurocritical care

University of Wisconsin

2017 WI Neurological Society

October 27‐28, 2017

Disclosure Statement

I have no relevant financial relationships with the manufacturer(s) 

of any commercial product(s) and/or provider(s) of commercial 

services discussed in this CME activity.

Learning Objectives

Review evidence for the association between PFO and cryptogenic stroke

Review the data on PFO closure for secondary stroke prevention

Discuss some of the side effects of PFO closure

Discuss who and when to refer someone for PFO closure

Embryologic development and the PFO The foramen ovale is one of two fetal cardiac shunts that allow blood to enter the left atrium from the right.

PFO prevalence in adults

Autopsy studies: Prevalence of PFO in adults is about ~ 25%

Cardiac echo studies:Prevalence varies widely based on methods. Largest study had 581 patients with prevalence of 25.6%

Hagen PT, Scholz DG, Edwards WD. Incidence and size of patent foramen ovale during the first 10 decades of life: an autopsy study of 965 normal hearts. Mayo Clin Proc. 1984;59:17-20 Meissner I, et al. Mayo Clin Proc. 1999;74:862-9.

Association Between PFO and Cryptogenic Stroke

● Approximately 40% of ischemic strokes are cryptogenic, that is, of no apparent cause.

The association between PFO and cryptogenic stroke ...

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Is PFO Related Stroke Rare?

● Ischemic Strokes in the US annually: ~700,000-800,000

● ~19% are patients < 55 years: 133,000

● ~40% are “cryptogenic”: 53,200

● ~45% will have a PFO: 23,900 annually

Mechanism?

Studies referring to the PFO-Stroke association suggest different mechanisms are involved:

a) paradoxical embolism, with the passage of thrombus from the peripheral venous system to left cardiac cavities through the PFO

b) formation of thrombus in the atrium as a consequence of PFO-related arrhythmias

c) formation of thrombus in the foramen ovale canal

d) PFO-related hypercoagulability.

Association of PFO with other cardiac abnormalities

● PFO associated with Atrial septal aneurysm (ASA)

● Patients with PFO or ASA are more likely to have reduced left atrial ejection fraction

○ Few studies

● People with PFO or ASA have a higher rate of inducible atrial arrhythmia in patients with PFO undergoing EP studies

○ No good long term studies on this association

● PFO associated with Chiari network

○ embryologic remnant of the right venous sinus valve Rigatelli et al. JACC Cardiovasc Interv. 2009 Jul;2(7):655-62. Berthet, et al. Stroke. 2000;31(2):398-403. Cabanes, et al. Stroke. 2003;24:1865-1873.

Association of PFO with other cardiac abnormalities: Atrial septal Aneurysm (ASA)

● No exact definition of ASA

● Measured by length, protrusion, mobility

● Transthoracic Echocardiography (TTE) misses about ~50%

● Transesophageal Echocardiography (TEE) is the standard assessment for ASA

● 1% in autopsy studies, 2.2%-4% in transesophageal echocardiography

10-15mm

Whisnant JP, Sicks JD, et al. Frequency of atrial septal aneurysms in patients with cerebral ischemic events. Circulation. 1999;99:1942-4.. Pearson AC, Nagelhout D, Castello R, Gomez CR, Labovitz AJ. Atrial septal aneurysm and stroke: a transesophageal echocardiographic study. J Am Coll Cardiol.

1991 18 1223 9

Association of PFO with other cardiac abnormalities

● PFO associated with Atrial septal aneurysm (ASA)

● Patients with PFO or ASA are more likely to have reduced left atrial ejection fraction

○ Few studies

● People with PFO or ASA have a higher rate of inducible atrial arrhythmia in patients with PFO undergoing EP studies

○ No good long term studies on this association

● PFO associated with Chiari network

○ embryologic remnant of the right venous sinus valve Rigatelli et al. JACC Cardiovasc Interv. 2009 Jul;2(7):655-62. Berthet, et al. Stroke. 2000;31(2):398-403. Cabanes, et al. Stroke. 2003;24:1865-1873.

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PFO and Atrial Ejection Fraction (EF)

Rigatelli et. al. Left Atrial Dysfunction in Patients with Patent Foramen Ovale and Atrial Septal Aneurysm. An Alternative Concurrent Mechanism for Arterial Embolism? JACC: Cardiovascular Intervention Vol2, No.7,2009 ISSN 1936-8798/09/$36.00

Association of PFO with other cardiac abnormalities

● PFO associated with Atrial septal aneurysm (ASA)

● Patients with PFO or ASA are more likely to have reduced left atrial ejection fraction

○ Few studies

● People with PFO or ASA have a higher rate of inducible atrial arrhythmia in patients with PFO undergoing EP studies

○ No good long term studies on this association

● PFO associated with Chiari network

○ embryologic remnant of the right venous sinus valve Rigatelli et al. JACC Cardiovasc Interv. 2009 Jul;2(7):655-62. Berthet, et al. Stroke. 2000;31(2):398-403. Cabanes, et al. Stroke. 2003;24:1865-1873.

Is percutaneous PFO closure beneficial in preventing stroke in those with strokes of

cryptogenic origin?

2013 New England Journal of Medicine published 3 randomized controlled trials on PFO closure and stroke prevention.

Different devices, inclusion criteria, end points and follow up period.

Effectiveness and Safety

CLOSURE I 2013 CardioSEAL®STARFlex device

18 - 60 years of age. Ischemic stroke or TIA within the previous 6 months

909 Patients 2 years of follow-up

STARFlex CardioSEAL® Septal Occlusion System (no longer commercially available)

PC trial 2013Amplatzer PFO Occluder (St. Jude Medical)

18-60 years of age with a cryptogenic strokePFO closure VS Medical (antiplatelet and anticoagulation)

414 Patients Mean follow up 4 years

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Safety

Subgroup analysis 18-60 years of age w/ Stroke (TIA w/ MRI) 980 patients

1:1 randomization *Closure (Amplatzer PFO Occluder) VS Medical (Antiplatelet & Anticoagulant)

*Antiplatelet therapy for 6 months total then up to investigator afterward

Median follow up 2.1 years. Range 0 - 8.1 years

RESPECT Investigators 2013

No difference in intention to treat cohort

The as treated cohort→

*Pre-procedure strokes

Atrial fibrillation did not differ significantly between the two groups (3.0% and 1.5%, respectively; P=0.13)

Lessons learned 1: Overall low stroke recurrence (need large numbers!)2: Need long follow up time (>2 years)3: Probably the device type matters

RESPECT Continued… 2017Median follow up 5.9 years Intention to treat (*high medical dropout rate)

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Subgroup Analysis

18-59 yrs of age with cryptogenic embolic ischemic stroke664 patients with L→ R shunt

Randomized 2:1 PFO closure + Antiplatelet Vs AntiplateletMedian follow-up was 3.2 years Helex Septal Occluder & Cardioform Septal Occluder (GSO; W.L. Gore and Associates)

Gore REDUCE investigators 2017

6/441 (1.4%)

12/223 (5.4%)

Intention-to-treat

● 1 to 5 microbubbles as small, 6 to 25 microbubbles as moderate, and more than 25 microbubbles as large*

Subgroup Analysis

*Atrial fibrillation or flutter was classified as a serious adverse event by the local investigator.

Safety

Co-primary endpoint: MRI at 2 years with silent infarction only →

New MRI T2 hyperintensity of 3mm or greater in diameter

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1:1:1 ratio, patients 16 to 60 years of age w/ stroke attributed to PFO with an associated ASA (>10mm) or large interatrial shunt (Large shunt was defined by the appearance of

more than 30 microbubbles in the left atrium within three cardiac cycles)

1. PFO closure* plus long-term antiplatelet therapy (PFO closure group)

2. antiplatelet therapy alone (antiplatelet-only group)

3. oral anticoagulation (anticoagulation group)

● 663 patients followed for a mean (±SD) of 5.3±2.0 years.

Contraindications

PFO Closure Oral anticoagulation

0

14 Antiplatelet

*

* 1 Air embolism, 1 Fever, All others arrhythmias

You get a PFO Occluder!

You get a PFO Occluder!

Everybody gets a PFO Occluder!

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What does this new data tell us and what questions remain?

● There is probably a small cohort of people who benefit from PFO occlusion

● Particular anatomical features are important

○ PFO shunt size and presence of an ASA

● Relatively low risk from device and procedure itself

○ But no good long term data on atrial fibrillation characteristics

■ Onset, duration, long term risks?

○ There are serious adverse events. Between 2002 – 20011 the FDA received reports of >100

patients who experienced septal erosion→ emergent cardiac surgery (*Amplatzer device)

Who should we refer?

1. Those who have had an intensive evaluation of stroke mechanism→ Cryptogenic

a. Vascular imaging, Cardiac imaging (?TEE), Hypercoagulation panel, ECG (>48 hrs)

2. Age 60 or less

3. Stroke with brain imaging consistent with cardioembolic pattern

a. Cortical infarct

4. Septal abnormalities with higher risk

a. Large PFO shunt (>30 bubbles) + ASA (10mm)

5. High RoPE score >6Kent DM, Ruthazer R, Weimar C, et al. An index to identify stroke-related vs incidental patent foramen ovale in cryptogenic stroke. Neurology. 2013;81:619-625

Extra Slide depending on questions

Risk stratification

Risk of Paradoxical Embolism (RoPE) Study

Patient level meta-analysis of 12 cryptogenic stroke cohorts

Start with 10 points

Subtract 1 point for each: HTN, DM, smoker,

history of stroke, subcortical infarct and each decade from 30 up to 70

Kent et al. Neurology. 2013 81:619–625.

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How are PFOs detected

Echocardiographic techniques such as transthoracic echocardiography (TTE), transesophageal echocardiography (TEE), or transcranial echocardiography (TCE) have been used to detect PFO.

Although second harmonic imaging has increased TTE sensitivity, TEE remains the standard technique.

How are PFOs detected

Cardiac magnetic resonance (MR): Nusser et al compared 211 studies with MR and TEE and concluded that MR is inferior to TEE in the detection of right-to-left shunting and in identifying ASA

Intracardiac echography (ICE): No studied comparison but ICE enables adequate characterization of PFO, tunnel, septum and shunting

Limitations include the cost, the use of £ 9 Fr venous access, and the need for an experienced operator.

Ponnuthurai FA, van Gaal WJ, Burchell A, Mitchell AR, Wilson N, Ormerod OJ. Safety and feasibility of day case patent foramen ovale (PFO) closure facilitated by intracardiac echocardiography. Int J Cardiol 2007 Nov 23 . Nusser T, Hoher M, Merkle N, Grebe OC, Spiess J, Kestler HA, et al. Cardiac magnetic resonance imaging and transesophageal echocardiography in patients with transcatheter closure of patent foramen ovale. J Am Coll Cardiol. 2006;48:322-9.