1. Update on PFO Closures Mark Reisman, M.D., F.A.C.C.
Director, Cardiovascular Research & Education
Swedish Heart & Vascular Institute
Swedish Medical Center
Seattle, WA

2. DISCLOSURES Mark Reisman, MD Grants/Contracted Research
Coherex Medical, Inc., NMT Medical, Inc.
Ownership Interest (Stocks, Stock Options or Other Ownership Interest)
CoAptus Medical Corporation

3. Disclosure
NMT
Research grant
Coherex
Coaptus
Advisory board

4. Anatomy

5. Anatomy

6. PFO has been linked to Increased risk of:
Stroke1
Migraine headaches2
Decompression disease in divers3
Obstructive sleep apnea4
Platypnea-orthodeoxia5
“Economy-class” stroke syndrome6
Multiple infarct dementia7
Cerebral microemboli following total knee arthroplasty8
Lamy C et al. Stroke 2002;33:
Del Sette M et al. Cerebrovasc Dis 1998;8:
Wilmshurst P et al. Spums J 1997;27:82-3.
Agnoletti G et al. J Interven Cardiol 2005;18:393-5.
Kerut EK et al. J Am Coll Cardiol 2001;38:
Isayev Y et al. Neurology 2002;58:960-1.
Angeli S et al. Eur Neurol 2001;46:
Sulek CA et al. Anesthesiology 1999;91:672-6.

7. PFO Closure

8. Incidence of Recurrent Stroke (%)
“ Best available data”
Incidence of Recurrent Stroke (%)
Study Design
Medical Therapy
PFO Closure
Meta-Analysis1
3.8-12/year
0-4.9/year
Retrospective2
24.3/4-year
8.5/4-year (p=0.05)
Retrospective3
13/year ASA
5.6/year warfarin
0.6/year (p<0.001)
1 Khairy et al. Ann Intern Med 2003;139:753-60
2 Windecker et al. J Am Coll Cardiol 2004;44:750-8
3 Schuchlenz et al. Int J Cardiol 2005;101:77-82

9. “Best” Clinical evidence
Awaiting randomized data from Trials-May provide clarity not certainty
REDUCE-ongoing
Using MRI as part of trial
RESPECT-ongoing
Only stroke
Closure One-ongoing
Stroke and TIA
Final results at TCT 2010 or AHA 2010

10. Treatment options for Cryptogenic Stroke/PFO stroke
“nothing” – continue treatment with ASA and reassurance
Antiplatelet- dual therapy-no evidence
Anticoagulation-no evidence better than ASA-significant potential for complications and compliance issues
Device Closure- almost universally designed for ASD
And thus imperfect for PFO

11. Walk through decision making : For Stroke/TIA
The clinical event
Duration/type
Imaging
The patient
Age
Sex
Medications
Occupation
The anatomy
Large vs. small
Atrial septal aneurysm vs. absence
Anticipated device outcome

12. Duration- How long and when !!
Symptoms
Minutes vs. hours –how it corroborates neuro imaging
Frequency
Careful history
When the event occurred –how long ago.
The natural history of stroke in Patients with PFO is uncertain. Some authors have reported Decline and others have observed an increased
Recurrence rate

13. Type Motor tract vs. sensory Associated with headache ?
TIA vs. CVA-This is now considered an imaging diagnosis
Ischemic vs. hemorrhagic

14. NeuroImaging Location anterior vs. Posterior Posterior
Migraineurs
N=66
Non-Migraineurs
N=353
Global Middle Cerebral Artery (MCA)
3 (5)
46 (13)
Deep MCA
5 (8)*
69 (20)
Anterior Circulation
28 (42)†
219 (62)
Thalamus
9 (14)*
21 (6)
Cerebellum
4 (6)
17 (5)
Posterior Cerebral Artery
14 (21) †
27 (8)
Posterior Circulation
36 (55) †
120 (34)
NeuroImaging
Location
anterior vs. Posterior
Posterior
high frequency in
embolic stroke
Infarct
Multiple vs. single infarcts; old vs. new or both
White matter abnormalities

15. Predictors
PFO is not a significant predictor of stroke in an unselected population sample (total N=585)*
Pathology
Strokes/number of subjects
Hazard Ratio (95% CI)
P value
PFO
12/140; none had ASA
1.46 ( )
0.28
Atrial septal aneurysm (ASA)
2/11; none had PFO
3.72 ( )
0.07
Five year follow-up; 41 strokes total
Size of PFO was unrelated to risk of cerebrovascular disease
* Meissner I et al. J Am Coll Cardiol 2006;47:440-5.

16. AGE
Traditionally were predominantly interested in only Younger patients
Figure 1. Prevalences of Patent Foramen Ovale (PFO) and PFO with Concomitant Atrial Septal Aneurysm among Patients with Cryptogenic Stroke and Those with Stroke of Known Cause, According to Age Group.
Handke M et al. N Engl J Med 2007;357:

17. Gender Females Medications Birth control use with or w/o smoking
Pregnancy
Higher incidence of migraine
Atypical migraine
Migraine variant
Migraine associated with other stroke co-morbidities

18. Occupation… Recent procedures venous procedures Desk job Trauma travel
After a nice long flight and sitting “Economy Class Syndrome”
338 patients admitted to Acute stroke Unit (prospective)
42 had positive travel HX (12.4%)
Frequency of PFO in PTH group was 48%vs.
10% in the NTH
Pts were younger (56yrs of age vs. 67 yr.old) then those in the NTH
PTH had fewer stroke risks
PTH stroke patients had higher frequency of
Cardioembolic stroke and more often Ischemia in the posterior circulation (PCA) (29%vs.6.3%)
Recent procedures
venous procedures
Heckmann JG et.al Heart ;

19. …….and in general… for diagnosis
Everyone gets a hypercoagulopathy workup
Requirement for long term coumadin may impact necessity of device placement
Routine LEVD
In older patients or those with palpitations – cardionet/holter monitoring
Almost universal
Transcranial doppler for pre/post evaluation
TTE-important and effective for diagnosis
TEE

20. anatomy
PFO w/ ASA**

21. Anatomy II

22. Tunnel/SP compliance

23. All anatomy is NOT the same !!!!
Disadvantageous

24. Size of PFO does not increase risk of recurrent stroke or death (PICSS cohort)
No PFO
(N=398)
Small PFO*
(N=119)
Large PFO*
(N=84)
Event rate, %
Hazard ratio
(95% CI)
P value
15.4
1.0
18.5
1.23
( )
0.41
9.5
0.59
( )
0.16
*Large PFO: 2 mm separation of septum secundum and primum OR 10 microbubbles appearing in left atrium on TEE; all other PFOs classified as small
Homma et al. Circulation 2002;105:
….and no difference with respect to presence or absence
Of ASA

25. PFO has been linked to Increased risk of:
Stroke1
Migraine headaches2
Decompression disease in divers3
Obstructive sleep apnea4
Platypnea-orthodeoxia5
“Economy-class” stroke syndrome6
Multiple infarct dementia7
Cerebral microemboli following total knee arthroplasty8
Lamy C et al. Stroke 2002;33:
Del Sette M et al. Cerebrovasc Dis 1998;8:
Wilmshurst P et al. Spums J 1997;27:82-3.
Agnoletti G et al. J Interven Cardiol 2005;18:393-5.
Kerut EK et al. J Am Coll Cardiol 2001;38:
Isayev Y et al. Neurology 2002;58:960-1.
Angeli S et al. Eur Neurol 2001;46:
Sulek CA et al. Anesthesiology 1999;91:672-6.

26. Recent Non-Randomized Studies of PFO Closure in Migraine
Patients
Follow-up
Results
Reisman et al. JACC 2005;45:493-5
50, ± aura
37±23 weeks
56% resolution
14% ≥50% improvement
Azarbal et al.
JACC 2005;45:489-92
30, ± aura
3 months
63% resolution
80% improvement
Giardini et al.
Am Heart J 2006; 151:922-6
35, all + aura
71% F
41±11 yr
1.7±1.3 yr
91% had resolution or significant improvement

27. Frequency of Migraine Attacks at Baseline and Follow-Up
Vigna, C. et al. J Am Coll Cardiol Intv 2009;2:
Copyright ©2009 American College of Cardiology Foundation. Restrictions may apply.

28. Frequency of Disabling Attacks at Baseline and Follow-Up
Vigna, C. et al. J Am Coll Cardiol Intv 2009;2:
Copyright ©2009 American College of Cardiology Foundation. Restrictions may apply.

29. Migraine Facts Migraine effects roughly 17% of population
Migraine is associated with stroke and is considered a progressive neurological disorder
Migraine patients have both white and gray matter changes ((cognitive, exec. Function, no longer just “motor track neurology”)
Migraine is not just a headache it is a functional disorder
Migraine medications treat symptoms not pathology, especially in the episodic type.
There is no “pathologic disease signature” or biomarker, (fingerprint)

30. Some facts II
4% of migraines “transform from episodic to chronic headache
There are genetic factors,but they are predominantly in the rare types NOT the common types
Migraine suffers have a higher prevalence of thrombophilia and platelet dysfunction
Aura appears to be a major component of the PFO headache
Migraine –”PFO” –stroke complex….. predicting the patient to most benefit from closure

31. Conclusion Closure one will provide a essential information on Stroke
Migraine (secondary endpoint)
Migraine trials
Future trials will be significantly different then previous ones……..patient selection
Device iteration
Intratunnel,bioabsorbable,radiofrequency sealing,improved umbrella devices
Regulatory pathway
Will continue to be clarified as we focus in on the optimal patient to benefit.
The “large” population based studies that have been
Negative regarding PFO/stroke, PFO/migraine have HELPED define
A population that, as expected would not benefit….

32. A single story goes a long way:
My daughter had "migraines" since the onset of puberty, 10 yrs. old. She had many "migraines" that were rarely headaches, but rather the "aura" only, usually visual loss. She also had episodes of face and arm numbness and/or weakness. These episodes were never helped with standard migraine medicine. They consistently happened mid-cycle of her period, when her estrogen was the highest. She was told by her doctors that her migraines should be at her period and she shouldn't get them when she did and the medicine should work, but it didn't. When she was 16 her arm suddenly went numb and we were told it was from her neck. She gained back the feeling
about six week later. When she was 18 she suddenly lost the vision in the upper left quadrant of both eyes. She saw a pediatric neurologist who suspected a stroke, but one did not show on MRI.
Two months later she had an episode that changed her life. She was lying down on the couch
and suddenly became nauseous, could not keep her balance, falling to her left. Her heart rate
raced and her blood pressure dropped. She became weak on her entire left side. These are just a
few of the symptoms that have changed her life forever. She was taken to the hospital and given
IV's and told to go home. She lives in a college town and I presume they thought she was just
another drunk kid who couldn't stand up straight. I immediately drove to her college and knew
something was terribly wrong. I took her to the school health center and thankfully the doctor
immediately thought of a PFO that might have caused an emboli to go to her brainstem. We
immediately went to the other hospital in town and she had a Transthoracic Echocardiogram and
did have a PFO. Such a simple test that could have averted such life changing events.

33. Our search began to get help
Our search began to get help. We were told the only way to have it fixed was to be in a study
where 50% of the people got it fixed and 50% didn't. I was not willing to play Russian Roulette with my daughter's brain. Unfortunately she had another stroke or TIA and was hospitalized for four days. She now qualified for PFO closure and we found a doctor who closed it the next day after he saw her. We found this doctor through a friend who had a stroke and a heart attack at emboli passing through a PFO. Since the PFO closure she has never had a migraine or stroke or TIA since.
Sadly, she still suffers the devastating effects of the previous strokes. She has severe dysautonomia and takes 20 pills a day just to be able to stand up some of the day. She went from
being a competitive soccer player and pre-med student to not knowing what the next day will bring.
She was a lobbyist in Washington DC for the American Heart Association and raised over $1000 to
help fight heart disease and stroke by having a team in the heart walk in her town. She is truly an
amazing person.