1. Johns Hopkins University School of Medicine
PFO Device - Now Approved, How Do We Utilize It – Cardiology Perspective
Jon R. Resar
Professor of Medicine
Johns Hopkins University School of Medicine

2. Jon R. Resar, M.D. Disclosures Research/Fellowship Funding: Medtronic
Abbott Vascular
Edwards Lifesciences
CSI
 Physician Advisory Board:
Boston Scientific

3. Background
~25% of all ischemic strokes are “cryptogenic” 1or stroke of undetermined source---diagnosis of exclusion:
Not attributable to a source of definite cardioembolism, large artery atherosclerosis or small artery disease despite a standard vascular, cardiac and serologic evaluation
34-46% of ischemic strokes aged are cryptogenic2,3
PFO present in 25% of normal population and 40-50% of cryptogenic stroke patients4,5
Although per year recurrence rate is low---young and middle aged patients have cumulative life long exposure to PFO-related stroke recurrence risk
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1 Hart et al. Lancet Neurology 2014;13:
2 Putaala et al. Stroke 2009;40:
3 Wolf et al. Cerebrovascular Dis 2015;40:
4 Lechat et al. NEJM 1988;318:
5 Webster et al. Lancet 1988;332:11-12. 3

4. RESPECT Trial
Randomized, event-driven, open-label trial with blinded endpoint adjudication
Patients randomized 1:1 to AMPLATZER PFO Occluder (device) vs. guideline-directed medical management (MM)
980 subjects enrolled from 2003 to 2011
69 sites in U.S. and Canada

5. Primary Endpoint Composite of: Stroke definition:
Recurrent nonfatal ischemic stroke
Fatal ischemic stroke
Early post-randomization death (within 45 days)
Stroke definition:
Acute focal neurological deficit due to cerebral ischemia with:
Neuroanatomically relevant infarct on imaging or
Symptoms >24 hours

6. Enrollment Criteria Key Inclusion Criteria Key Exclusion Criteria
Cryptogenic stroke within last 9 months
TEE-confirmed PFO
18-60 years
Patients > 60 at higher risk of recurrent stroke from non-PFO mechanisms
Stroke due to identified cause such as:
Large vessel atherosclerosis (e.g., carotid stenosis)
Atrial fibrillation
Intrinsic small vessel disease (lacunar infarcts)
11 other specific etiologies
Inability to discontinue anticoagulation

7. Patient Flow
ICF Obtained
˅ ->Anatomy not considered suitable
Implant Attempt ˅
Transeptal puncture
˅ ->N (Reason unsuccessful) Y
˅ ˅
Device implanted Device not implanted
SADES reasons - SADES
Discontinued (withdrew consent or lost to follow up): % Device and 30.1% MM
Subject withdrawals >5-fold higher than the number of events in both data locks
42 primary endpoint events---event rate <50% of what was originally projected

8. RESPECT Final Results

9. RESPECT Final Results

10. Interpretation
These analyses support the hypothesis that PFO closure is preventing PFO-related recurrent strokes
PFO-closure cannot prevent strokes from non-PFO related causes
HR (95% CI)
Risk Reduction
P-value
Ischemic stroke
0.55 (
45%
0.046
Stroke without known mechanism
0.38 ( )
62%
0.007
Age-censored analysis (<60y)
0.42 ( )
58%
0.01

13. Adjudicated Serious Adverse Events
Event Type
AMPLATZER™ PFO Occluder
(N=499)
[3141 Pt-Yrs]
Medical
Management
(N=481)
[2669 Pt-Yrs]
P-value**
Events
Rate*
Atrial fibrillation 8
0.25 4
0.15
0.37
Major bleeding 18
0.57 15
0.56
0.96
Death from any cause 7
0.22 11
0.41
0.21
DVT/PE
0.006
Through extended follow-up, the rates of AFib, major bleeding, and death from any cause were comparable or lower in the device arm.
The one exception is that venous thromboembolic events occurred at a higher rate in the device arm, however this finding is of unclear significance.
Overall, we saw a favorable safety profile.
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* Rate expressed as number of events per 100 patient-years
**Based on the normal approximation to a difference in Poisson rates

14. FDA Voting Questions on PFO Device Based on RESPECT Trial Results
Reasonable assurance that the PFO Occluder is safe for use in patients who meet the criteria specified in the proposed indication: 15:1
Effective: 9:7
Do the benefits outweigh and risk: 11:5

15. Indications for Use Indications for Use:
The AMPLATZER PFO Occluder is intended for percutaneous, transcatheter closure of a patent foramen ovale (PFO) to prevent recurrent ischemic stroke in patients who have had a cryptogenic stroke due to a presumed paradoxical embolism.

16. PFO Studies: Meta-analysis
Patent Foramen Ovale Closure in Stroke Trials: Kaplan-Meier Curves Comparing Device Closure Versus Medical Therapy Kaplan-Meier curves comparing device closure (orange) versus medical therapy (blue). Results shown for all trials pooled (A, B) and for occluder device trials only (RESPECT [Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment (2)] and PC Trial [Percutaneous Closure of Patent Foramen Ovale in Cryptogenic Embolism (3)]) (C, D), and for both the primary composite and ischemic stroke outcomes. Secondary composite outcome (including only early death) was statistically significant for both the 3-trial (log-rank p = ) and the disc occluder-only analysis (log-rank p = ). TIA = transient ischemic attack.
David M. Kent et al. JACC 2016;67:

17. Amplatzer PFO Device Amplatzer PFO Occluder System
3 sizes RA (LA): 18 (18), 25 (18), 35 (25) mm
TorqVue Delivery System

18. So Who Do We Treat? “RESPECT Trial-Like” Patients RESPECT Trial – Key Inclusion Criteria
Age between 18 and 60 years
Stroke (not TIA)---cortical (not lacunar)
Cryptogenic---stroke of unknown cause

19. Non-Cryptogenic vs. Cryptogenic Ischemic Stroke
Non-cryptogenic stroke
Thrombo- or atheroembolism
Atrial fibrillation/atrial flutter
Intracardiac thrombus
Valvular endocarditis
Prosthetic heart valves
Thoracic aortic or carotid atherosclerosis
Venous thrombosis with right to left shunt
Intracranial arterial disease
Arterial dissection
Vasculitis
In situ thrombosis with a hypercoagulable state
Cryptogenic Stroke
Diagnosis of exclusion
Dependent on the thoroughness of the evaluation to exclude alternative known stroke etiologies

20. So Who Don’t We Treat? RESPECT Trial – Key Exclusion Criteria
Presence of embolic etiologies independent of PFO
Atrial fibrillation/flutter (chronic or paroxysmal)
Aortic arch plaques protruding >4 mm into the lumen
Atherosclerosis of intra- or extracranial vessels with >50% diameter stenosis, arterial dissection
Lacunar infarct especially in presence of hypertension, diabetes and age ≥50 years
?Hypercoagulable state
Anticardiolipin antibodies, lupus anticoagulant, B2-glycoprotein-1 antibodies or elevated plasma homocysteine despite medical therapy

21. “Brain-Stroke Team” Evaluation
Comprehensive work-up of qualifying stroke with evaluation by a neurologist---needs to be directly involved in decision making
ECG monitoring---?duration---probably 30 days
Imaging of intracranial arteries via MRA, CTA or contrast angiography
Imaging of extracranial arteries by MRA, CTA, contrast angiography or duplex ultrasound
Hypercoagulability panel
TTE/TEE

22. Risk of Paradoxical Embolism (RoPE) Score MDCalc. com (Dr
Risk of Paradoxical Embolism (RoPE) Score MDCalc.com (Dr. David Thaler)
Neurology. 81(7): , 2013

23. Utility of RoPE Score
Attempt to disaggregate from within a cryptogenic stroke population those PFOs which
are important and those which are ignorable: The higher the RoPE Score the more likely
the stroke is attributable to the PFO and the lower the recurrence rate

24. Technical Aspects: To Balloon Size or Not Balloon Size
Table 11. Device Sizing Guidelines: Shortest Distance from PFO to Aortic Root or Distance from PFO to Superior Vena Cava Orifice (mm) Suggested AMPLATZER™ PFO Occluder Size (mm)
Greater than or equal to
12.5 –
9.0 –
Less than Do not implant device
I generally balloon size---18 mm Amplatzer balloon---low pressure

25. Shunt grade ≤ %

26. Management Following Device Implantation
Aspirin 325 mg and clopidogrel prior to procedure
Same day discharge
PFO IFU: Aspirin mg for 6 months and clopidogrel for 1 month
Respect Trial---DAPT for 1 month and ASA alone through at least 6 months---90% continued ASA beyond 6 months
Personal preference: ASA and clopidogrel for 6 months
Prior DVT/PE---resumption of oral anticoagulation may be beneficial
Repeat echocardiogram with bubble study at 6 months---discontinue clopidogrel
Thereafter aspirin 81 mg daily
Conventional risk factor modification

27. Practical Considerations
Nickel-titanium alloy---nickel is released from device for at least 60 days---?nickel allergic patients---warning is in FDA IFU
MRI safe---IFU up to 3 Tesla
Document negative beta-HCG at time of procedure
Later pregnancy without concern but probably not in first 6 months after device implantation:
ASA: Risk Category C---high dose teratogenic but low dose likely okay in first two trimesters not in last trimester
Clopidogrel: Risk Category B---but experience limited
Endocarditis prophylaxis for at least 6 months

28. Conclusions
In the RESPECT Trial, PFO closure with the AMPLATZERTM PFO Occluder was more beneficial than medical management alone for patients with cryptogenic stroke and PFO to reduce the risk of recurrent stroke
Collaboration between a cardiologist and neurologist is important for proper patient selection
It is incumbent upon the implanting interventional cardiologist that appropriate (“RESPECT Trial-like”) patients are treated following a thorough evaluation
Meaningful discussion with patients is important to highlight what we know and don’t know about cryptogenic stroke in the setting of PFO
PFO closure doesn’t reduce non-PFO related stroke---continued cardiovascular disease risk factor modification is paramount