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

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

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 18-60 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 This is the Bulleted List slide. To create this particular slide, click the NEW SLIDE button on your toolbar and choose the BULLETED LIST format. (Top row, second from left) The Sub-Heading and footnote will not appear when you insert a new slide. If you need either one, copy and paste it from the sample slide. If you choose not to use a Sub-Heading, let us know when you hand in your presentation for clean-up and we’ll adjust where the bullets begin on your master page. Also, be sure to insert the presentation title onto the BULLETED LIST MASTER as follows: Choose View / Master / Slide Master from your menu. Select the text at the bottom of the slide and type in a short version of your presentation title. Click the SLIDE VIEW button in the lower left hand part of your screen to return to the slide show. (Small white rectangle) 1 Hart et al. Lancet Neurology 2014;13:429-436. 2 Putaala et al. Stroke 2009;40:1195-1203. 3 Wolf et al. Cerebrovascular Dis 2015;40:129-135. 4 Lechat et al. NEJM 1988;318:1148-1152. 5 Webster et al. Lancet 1988;332:11-12. 3

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

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

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

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): 18.2 % 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

RESPECT Final Results

RESPECT Final Results

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 (0.305-0.999 45% 0.046 Stroke without known mechanism 0.38 (0.18-0.79) 62% 0.007 Age-censored analysis (<60y) 0.42 (0.21-0.83) 58% 0.01

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. [NEXT SLIDE] * Rate expressed as number of events per 100 patient-years **Based on the normal approximation to a difference in Poisson rates

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

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.

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 = 0.0488) and the disc occluder-only analysis (log-rank p = 0.0451). TIA = transient ischemic attack. David M. Kent et al. JACC 2016;67:907-917

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

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

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

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

“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

Risk of Paradoxical Embolism (RoPE) Score MDCalc. com (Dr Risk of Paradoxical Embolism (RoPE) Score MDCalc.com (Dr. David Thaler) Neurology. 81(7):619-625, 2013

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

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 17.5 35 12.5 – 17.4 25 9.0 – 12.4 18 Less than 9.0 Do not implant device I generally balloon size---18 mm Amplatzer balloon---low pressure

Shunt grade ≤1---94.2%

Management Following Device Implantation Aspirin 325 mg and clopidogrel prior to procedure Same day discharge PFO IFU: Aspirin 81-325 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

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

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