Why Should We Treat PFO? SCAI Interventional Cardiology Fellows Course December 7, 2012 Jonathan Tobis, MD Director of Interventional Cardiology UCLA

Disclosures Jonathan Tobis, MD 1. A Principal Investigator for PREMIUM Trial using the Amplatzer PFO Occluder (St. Jude Medical) in patients with disabling migraines. 2. Investigator in the RESPECT Trial (Amplatzer device for cryptogenic stroke) Consultant to: Coherex Angel Medical W.L.Gore AGA Medical (St. Jude)

Conditions Associated with PFO (Patent Foramen Ovale) Cryptogenic Stroke < 60yo, or older Migraine Headache with aura Orthodeoxia Platypnea (O2 Sat < 92%) Acute MI with normal coronaries Decompression Illness High Altitude Pulmonary Edema Obstructive Sleep Apnea Exacerbation Raynaud’s Phenomena Dementia ? Unifying Hypothesis: some venous particle: thrombus, platelets, air bubble, low O2, or chemical, bypasses the lung and enters the arterial circulation through a PFO.

Association of Migraine and PFO 1. Migraine headache affects 12% of population (18%F - 6%M) or 27 million people in USA 2. Incidence of PFO in pts with migraine: 48% if migraine with aura 1 23% if migraine w/o aura and 20% in controls 3. Incidence of Migraine in pts with Cryptogenic Stroke and PFO: 52% had migraine with aura2 10 of 14 (71%) had suppression post closure3 4. Migraine pts have 13x incidence of MRI lesions4 Anzola, Neurology 52(8):1622-5, 1999 Sztajzel, CV Diseases 13(2):102-6, 2002 Wilmshurst, Lancet 356(9242):1648-51, 2000 Kruit, JAMA 294(4): 427-434, 2004

Scintillating Scotoma Fortification Spectra 17th century fort boundary What is a migraine? Scintillating Scotoma Fortification Spectra 17th century fort boundary

CSD: cortical spreading depolarization 3-5 mm/min Familial Migraine with Hemiplegia Human gene has been inserted to produce a mouse transgenic model CSD: cortical spreading depolarization 3-5 mm/min artery dilation then constriction Migraine: neuro-vascular dysfunction with allodynia. The question is: what triggers a migraine? This may be the connection with PFO. Courtesy of Andrew Charles, UCLA

Complex Migraine Aura vs TIA? What is a migraine? Complex Migraine Aura vs TIA?

70 y.o. woman, hx of migraines, MRI + WMLs, R hemidiaphragm paralysis, orthodeoxia: 96%  82% Lateral IVC Angio Baseline post closure 35mm cribriform Amplatzer device The hypoxemia was relieved and the migraines stopped.

% migraine improved or cured Observational Studies Effect of PFO closure on migraine Study Prevalence # migraine / # closed (%) % migraine improved or cured Length of follow up (months) Wilmshurst 2000 21/37 (57%) 86% up to 30 Morandi 2003 17/62 (27%) 88% all 6 Schwerzmann 2004 48/215 (22%) 81% all 12 Post 2004 26/66 (39%) 65% cured Reisman 2005 57/162 (35%) 70% Azarbal, Tobis 2005 37/89 (42%) 76% mean 18 Total: 206/631 (33%) 78%

230 patients with migraine ± aura assess for PFO with TCD, if +, TTE The PREMIUM Trial A Randomized Double Blind Trial of PFO Closure for Severe Migraine Headaches 230 patients with migraine ± aura assess for PFO with TCD, if +, TTE Usual HA Rx + Sham Procedure PFO Closure randomize 1o Endpoint: 50% reduction in migraine attacks 2o Endpoints: % pts with resolution of HA, # days with HA Adverse Events: due to Amplatzer device, procedure, or meds

40 y.o. man with sudden aphasia. No obvious disease or cause of stroke. TEE: Atrial Septal Aneurysm and PFO. Associations: 50% of people with cryptogenic stroke have a PFO. Presumed mechanism: paradoxical embolism

Thrombus in transit through PFO Thrombus caught in PFO has been seen by echo and at surgery, but passage of small emboli are impossible to prove. Colour Atlas of the CV System, Thomas et al.

Association of PFO and cryptogenic stroke in young adults (< 55 y.o.) Study Pts PFO (crypto) (control) P Lechat (1988) 26 54% 10% <0.01 Webster (1988) 40 50% 15% < 0.01 De Belder (1992) 39 13% 3% De Tullio (1992) 21 47% 4% Hausmann (1992) 18 11% Cabanes (1993) 64 56% 18% Total 202 46% (93/202) (29/271)

Cryptogenic Stroke - PFO Trials CLOSURE 1 RESPECT REDUCE Subjects 960 ≈ 900 (event driven endpoint) ≈ 664 Randomization 1:1 2:1 Entry Clinical Stroke or TIA Stroke on MRI Stroke or TIA on MRI Screening event 6 mos 9 mos Medical Rx Device Arm: 6mos clopidogrel & 24mos aspirin Control Arm: 24mos aspirin/warfarin or both Warfarin or aspirin ± dipyridamole Both Arms: aspirin or aspirin + dipyrid or clopidogrel Endpoint Stroke or TIA Stroke or Death Stroke/TIA on MR or death

Devices that were available in USA for PFO closure CardioSeal or StarFlex Amplatzer ASD cribriform Helex PFO Occluder

Difficulty with PFO Stroke Trials Low event rates: <2% recurrent stroke/year Availability of PFO closure off label Highest risk patients are not being randomized which lowers the event rate and makes it harder to show a difference between device and medical therapy. The RESPECT Trial closed in Jan 2012. Total of 25 events over 9 years.

CLOSURE 1 Trial using StarFlex device 909 patients PFO closure with StarFlex was “equivalent to medical Rx” Did not reach 1o endpoint of device superior to med Rx. a) warfarin  b) warfarin + aspirin or c) aspirin alone “Effective Closure Rate” only 87% End Point after 2 years Device (%) Medical Therapy (%) p Composite end point 5.9 7.7 0.30 Stroke 3.1 3.4 0.77 TIA 3.3 4.6 0.39 Major vascular complications 3.2 0.0 <0.001 Atrial fibrillation 5.7 0.7

CLOSURE 1 Trial using StarFlex device Why StarFlex event rate may not be less than medical Rx: Low complete closure rate = 87% 7% thrombus on device 6% atrial fibrillation CLOSURE: 26 pts developed Afib. 24 had the device

RESPECT Trial Results Is it a Home Run that is out of this PFO ballpark?

Device Performance Maximum Residual Shunting at Rest and Valsalva at 6 Months Grade 0: 72.7% Grade 1: 20.8% Grade 2-3: 6.5% Defined as successful delivery and release of the device for subjects in whom the delivery system was introduced into the body Defined as successful implantation with no reported in-hospital serious adverse events Defined as complete obliteration or trivial residual shunting (Grade 0 or I at rest and Valsalva) at 6 months, adjudicated by echo core lab 17

Serious Adverse Events Adjudicated as Related to Procedure, Device, or Study ✔ ✔ ✔ For all AE’s, atrial fibrillation occurred in 3.0% versus 1.5% in the device and medical groups respectively, p=0.13 Pericardial tamponade is a subset of major bleeds, and thus counted in the major bleed category as well For all SAEs, pulmonary embolism occurred in 1.2% and 0.2% in device and medical groups, respectively, p=0.124 1 case of right atrial thrombus resulted in abandonment of device implant procedure (no device received); 1 case of right atrial thrombus (located inferiorly) not attached to device detected in patient with DVT and PE 4 months after procedure 1 ischemic stroke one week post implant; 1 five months post implant with finding of severe shunting related to previously undiagnosed sinus venosus defect, requiring surgical closure For all SAEs, there were 3 device group deaths (0.6%) and 6 medical group deaths (1.2%) all of which were not study related, p= 0.334 P-values are calculated using Fisher’s Exact test 16

Primary Endpoint Analysis – ITT Cohort 50 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 20 Cox model used for analysis

Primary Endpoint Analysis – As Treated Cohort 72 Primary Endpoint Analysis – As Treated Cohort 72.7% risk reduction of stroke in favor of device ✔ ✔ The As Treated (AT) cohort demonstrates the treatment effect by classifying subjects into treatment groups according to the treatment actually received, regardless of the randomization assignment 22 Cox model used for analysis

PC Trial Results European randomized trial of Amplatzer PFO occluder vs. medical therapy. 200pts per group. Follow up mean 5 years. Recurrent stroke 1%/year, RR reduced 80% with device, but p=NS due to low event rate. Meta-analysis of RESPECT and PC Trials: pending.

So is RESPECT a Home Run? No, but given the difficulty of proving this concept, it is a “triple”. Safe Effective for preventing paradoxical embolism Better than medical therapy in pts who were actually treated From patient’s perspective: “I would rather die than be disabled from a stroke.” They will see what the effect was of actual treatment, and want their PFO closed. Neurology perspective will be crucial, and cardiologists need to form a team approach to decide which patients should get their PFO closed.

The Genie is out of the box. Thank You FDA perspective: Who here has a crystal ball or can read tea leaves? The Genie is out of the box. Thank You