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

2. 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)

3. 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.

4. 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 % 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): , 2000
Kruit, JAMA 294(4): , 2004

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

6. 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

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

8. 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.

9. % 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/ (57%)
86%
up to 30
Morandi 2003
17/ (27%)
88%
all 6
Schwerzmann 2004
48/ (22%)
81%
all 12
Post 2004
26/ (39%)
65% cured
Reisman 2005
57/ (35%)
70%
Azarbal, Tobis 2005
37/ (42%)
76%
mean 18
Total: 206/631 (33%) %

10. 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

11. 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

12. 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.

13. 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)

14. 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

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

16. 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 Total of 25 events over 9 years.

17. 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

18. 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 had the device

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

20. 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

21. 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

22. 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

23. 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

24. 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.

25. 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.

26. 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