1. PFO closures: Is there a need? Lowell Satler, MD
Washington Hospital Center

2. Lowell F. Satler, MD DISCLOSURES Grants/Contracted Research
Medtronic CardioVascular, Inc., Edwards Lifesciences LLC, Abbott Vascular
Speakers Bureau
-Daiichi-Sankyo, Inc.
-Eli Lilly and Company

3. Patent Foramen Ovale (PFO)
Persistent flap-like opening: atrial septum primum and secundum
In utero, physiologic right-to-left shunting
After birth, increased left atrial blood flow and pressure closes flap
Anatomical closure follows
A patent foramen ovale (PFO) is a persistent, usually flap-like opening between the atrial septum primum and secundum at the location of the fossa ovalis. In utero, the foramen ovale serves as a physiologic conduit for right-to-left shunting. After birth, with the establishment of pulmonary circulation, the increased left atrial blood flow and pressure results in functional closure of the foramen ovale. This functional closure is subsequently followed by anatomical closure of the septum primum and septum secundum.

4. Atrial Septal Anatomy SVC LA RV IVC Foramen Ovale Septum Primum
Superior & Inferior Limbic Ridges
Fossa Ovalis
Coronary Sinus
Eustachian Valve
IVC RV

5. Presumed mechanism of Stroke with PFO
Pressure in RA > Pressure in LA:
Early systole
Valsalva
Coughing
Pulmonary hypertension
COPD
Pregnancy
Asthmatics
Wind instruments
Decompression sickness (diving)
High altitude flying
Obstructive sleep patterns RA LA
PRA
PLA

6. Role of PFO in Clinical Disease
Cardioembolic stroke
Cryptogenic stroke • Brain abscess
Platypnea-orthodeoxia • Migraine with aura
Decompression illness • Wind instrument ischemia/stroke

7. Classification & Etiology of Strokes
Ischemic (approximately 88%)
Thrombotic
Embolic
Cryptogenic (up to 40%)
Hemorrhagic (approximately 12%)
Subarachnoid
Parenchymal
Broderick J, et al, The Greater Cincinnati/Northern Kentucky Stroke Study: preliminary first-ever and total incidence rates of stroke among blacks. Stroke, 1998 Feb; 29(2):
Rosamond W, et al, American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee, Circulation, 2008 Jan; 29;117(4): e Epub 2007 Dec 17
Meissner I, et al, Prevalence of potential risk factors for stroke assessed by transesophageal echocardiography and carotid ultrasonography: the SPARC study, Stroke Prevention: Assessment of Risk in a Community, Mayo Clin Proc Sep; 74(9):

8. Sources of Cardiogenic Emboli
Left Atrium
Atrial fibrillation
Myxoma
Atrial septal aneurysm
Paradoxical Emboli
Patent foramen ovale
Atrial septal defect
Aortic Valve
Calcific stenosis
Infective endocarditis
Prosthetic valve
Mitral Valve
Infective endocarditis
Non-bacterial endocarditis
Myxomatous valvulopathy
Prosthetic valves
Vegetations due to prothrombotic states
Left Ventricle
Ischemic dyskinesis
Cardiomyopathy
Thrombi due to prothrombotic states

9. Cryptogenic Stroke 700,000 strokes/yr in US 80-85% ischemic
30-40% of strokes remain defined as cryptogenic
40-60% frequency of PFO among cryptogenic strokes
~100,000 strokes/yr with PFO as only identified potential etiology
Kim D, Saver JL. Reviews in Neurological Diseases 2005;2(1):1-7

10. Implication of PFO in Cryptogenic Stroke
Prevalence of PFO in “Normal” Population: %
Lechat, et al - NEJM 5/88
Webster, et al - Lancet 1988
Mayo Autopsy Study
Prevalence in Stroke Population <60 y.o.: %
Ranous, Mas, et al - STROKE 1/93
Lausanne Study - Neurology 5/96

11. Multi-Center Prospective Study
PFO & ASA Study Group, Mas et al, NEJM 2001
30 centers, 581 consecutive cryptogenic stroke pts
Age 18-55
Stroke within last 3 months
All treated with aspirin 300 mg / day
Mean follow-up: 3 years, 2 months

12. Multi-Center Prospective Study
Atrial septal abnormalities on TEE
None 48%
PFO alone 37%
ASA alone 2%
PFO + ASA 9%
ASD 2%
Conclusion:
Stroke patients with both PFO & ASA - substantial risk for recurrent stroke; preventive strategies other than aspirin should be considered

13. Case 1
55 year old man
Hx: AAA, smoker, HTN, chol, achilles repair 1 week PTA
Acute left motor deficits, dysarthria over 2 hours
Outside ER: CT, labs, EKG, US, ECHO, leg doppler
Outside Diagnosis: TIA
Neurologists Work-up:
MRI: acute right parietal infarct -
New Diagnosis: STROKE
TCD Bubble: shunting to brain
TEE: moderate size PFO with
atrial septal aneurysm
Coags: negative
Homocysteine: 20 (nl <12)
Elective PFO device closure: Amplatzer

14. What is the ideal treatment?
Case 1
Work-up:
MRI: acute right parietal infarct
TCD Bubble: shunting
TEE: moderate PFO with ASA
Coags: negative
Homocysteine: 20
What is the ideal treatment?

15. Case 2 50 year old medical school professor
No PMH or vascular risk factors
Event:
During 9 hour air travel, reads book, does not get up.
After flight, enters terminal walking to customs. Has vigorous sneezing.
Within minutes becomes confused and staggers to floor, but recovers in minutes.
Hospitalized.
Neurologists Work-up:
MRI: acute right parietal infarct -
New Diagnosis: STROKE
TCD Bubble: shunting to brain
TEE: moderate size PFO with
atrial septal aneurysm
Coags: negative
Homocysteine: 20 (nl <12)
Elective PFO device closure: Amplatzer

16. Case 2 MRI: acute right MCA territory infarcts suggesting embolus
Neurologists Work-up:
MRI: acute right parietal infarct -
New Diagnosis: STROKE
TCD Bubble: shunting to brain
TEE: moderate size PFO with
atrial septal aneurysm
Coags: negative
Homocysteine: 20 (nl <12)
Elective PFO device closure: Amplatzer
TEE: Demonstrates PFO

17. What is the ideal treatment?
Case 2
Work-up:
normal CTA head and neck, routine ECHO, BP, coagulation labs, extremity dopplers
ECHO with bubble reveals large PFO with shunting at valsalva
Diagnosis:
Presumed extremity/pelvic vein clot related to stasis (prolonged sit during air travel) with paradoxical embolus after mobilizing clot (walking) and powerful valsalva (sneeze)
Neurologists Work-up:
MRI: acute right parietal infarct -
New Diagnosis: STROKE
TCD Bubble: shunting to brain
TEE: moderate size PFO with
atrial septal aneurysm
Coags: negative
Homocysteine: 20 (nl <12)
Elective PFO device closure: Amplatzer
What is the ideal treatment?

18. PFO: AAN Practice Guidelines 2004
There is insufficient evidence of superiority of aspirin or warfarin
Risks of minor bleeding appear greater with warfarin
There is insufficient evidence to evaluate efficacy of surgical or endovascular closure
Messe, et al, Neurology 2004; 62,

19. AHA-ASA 2006 Secondary Prevention Guidelines
Insufficient data exist to make a recommendation about PFO closure in patients with a first stroke and a PFO.

20. The RESPECT PFO Clinical Trial
To Close or Not to Close
The RESPECT PFO Clinical Trial
is designed to help answer this question.

21. Randomized Evaluation of Recurrent Stroke Comparing
PFO Closure to Established Current Standard of Care Treatment
IDE #G990318

22. Clinical Trial Design
The RESPECT PFO Clinical Trial is a randomized evaluation comparing device closure plus medical therapy to current medical therapy standard of care
Maximum 900 patients (450 per arm)
Maximum 75 participating institutions across the U.S.

23. Clinical Trial Design Overview
Subjects:
Recent cryptogenic stroke
18-60 years of age
Treatment:
PFO device closure versus medical therapy
Endpoints:
Stroke or Death

24. Randomization Groups
Device closure plus medical therapy will include the AMPLATZER PFO Occluder and clopidogrel for one month and aspirin for six months
Medical therapy current standard of care will include one of the four following treatments:
Aspirin alone • Warfarin alone
Clopidogrel alone • Aspirin in combination with dipyridamole

25. Study Objective Selection Criteria
To investigate whether percutaneous PFO closure is superior to current standard of care medical treatment in the prevention of recurrent embolic stroke.
Selection Criteria
Patients with PFO who have had a cryptogenic stroke due to presumed paradoxical embolism within the last 270 days.

26. Stroke - Definition
Acute focal neurological deficit presumed to be due to focal ischemia, and either:
Symptoms persisting 24 hours or greater, or
2) Symptoms persisting less than 24 hours but associated with MR or CT findings of a new, neuroanatomically relevant, cerebral infarct

27. Study Endpoints Primary Endpoint:
Recurrence of a Nonfatal Stroke, Post-randomization Death, or Fatal Ischemic Stroke

28. Study Endpoints Secondary Endpoints:
Complete closure of the defect demonstrated by TEE and bubble study at 6-month follow-up (device group)
Absence of recurrent symptomatic cryptogenic nonfatal stroke or cardiovascular death
Absence of TIA

29. Required Baseline Testing
Medical History:
Exclusion Criteria
Age <18 years or >60 years
Active endocarditis or other untreated infections
Acute or recent (within 6 months) MI or unstable angina
Organ failure (kidney, liver or lung)
Uncontrolled hypertension (>160/90mmHg)
Uncontrolled diabetes mellitus

30. Required Baseline Testing
Coagulation:
A hypercoagulation panel sent to a core lab
Exclusion Criteria
Patients who test positive for Anticardiolipin Ab of the IgG or IgM, Lupus Anticoagulant, B2-glycoprotein-1 antibodies or persistently elevated plasma Homocysteine despite medical therapy.

31. Required Baseline Testing
TEE with Bubble Study:
Exclusion Criteria
Intracardiac thrombus or tumor
Left ventricular aneurysm or akinesis
Mitral valve stenosis or severe mitral regurgitation irrespective of etiology
Aortic valve stenosis (gradient >40 mmHg) or severe aortic valve regurgitation
Mitral or aortic valve vegetation or prosthesis

32. Required Baseline Testing
TEE with Bubble Study:
Exclusion Criteria Continued
Aortic arch plaques protruding >4mm into the lumen
Left ventricular dilated cardiomyopathy with LVEF< 35%
Subjects with other source of right to left shunts identified at baseline, including an ASD and/or fenestrated septum
Anatomy in which the AMPLATZER PFO Occluder would interfere with intracardiac or intravascular structures such as valves or pulmonary veins

33. Required Baseline Testing
ECG or Holter
Exclusion Criteria:
Atrial fibrillation/atrial flutter (chronic or intermittent)
Pregnancy Test
Pregnant or desire to become pregnant within the next year

34. Device Description Self Expandable Nitinol wire 0.005 - 0.006”
Polyester Patch
Short connecting waist
Sizes: 18, 25 and 35mm

35. Endothelialization – Six Weeks Post-implant

36. Follow-up Schedule Pre-discharge (device only):
One month, six months, 12 months, 18 months, and 24 months, and annually until study end
Six-month Visit:
TEE with bubble study required for device subjects

37. To Close or Not to Close: Summary
Closure of Patent Foramen Ovale (PFO) for cryptogenic stroke is controversial
Medical therapy carries low risk of complications
Device closure may carry a low peri-procedural risk compared to surgery
No randomized data published
Clinical trials are ongoing to evaluate device based closure and gain FDA approval for this indication

38. Management of Patients with PFO After Cerebral Events
Therapy
Recommended by
PFO closure in patients with recurrent cryptogenic stroke despite medical therapy
AAN
Antiplatelet therapy
AAN, AHA/ASA, ESO, ACCP
Warfarin in the presence of deep vein thrombosis
AHA/ASA, ESO, ACCP
Warfarin in the presence of coagulation abnormalities
AHA/ASA
Warfarin rather than antiplatelet agents in the presence of ASA
ACCP= American College of Chest Physicians; AAN=American Association of Neurology; AHA/ASA=American Heart Association/American Stroke Association; and ESO, European Stroke Organization.

39. Randomized Controlled Trials on PFO Closure to Prevent Recurrent Paradoxical Ischemic Events
Device Used
Starting Year
Target Enrollment, n
Final Status
Projected Publication
PC*
Amplatzer PFO occluder
2000
450
Finished enrollment at 420
2011
Closure-I
STARFlex occluder
2003
1600
Finished enrollment
RESPECT
2004
900 (endpoint driven)
Enrolling
2013
CLOSE
Free choice
2007
900
2014
Gore REDUCE
HELEX occluder
2008
664
2016

40. Randomized Controlled Trials for PFO Closure in Migraine Headache Patients
Acronym
Place
Sham Procedure
Device
Status
MIST UK +
STARFlex
Reported
PRIMA
Global -
Amplatzer
Recruiting
PREMIUM US
MIST II
BioSTAR*
Abandoned
ESCAPE
Premere† ?
FlatStent‡
Planned

41. Top Ten Things to Know Percutaneous Device Closure of Patent Foramen Ovale for Secondary Stroke Prevention
Stroke is the third leading cause of death among adults in the United States and a major contributor to long-term functional impairment and disability.
The majority of strokes are ischemic; of these, about % do not have identifiable cause after thorough evaluation and are designated as cryptogenic (CS).
A patent foramen ovale (PFO) is a remnant of the fetal circulation and has been identified at autopsy in 27% of patients with normal hearts.

42. Top Ten Things to Know Percutaneous Device Closure of Patent Foramen Ovale for Secondary Stroke Prevention
Many observational studies suggest a strong association between PFO and CS. But a causal relationship has not been convincingly established for most affected patients.
The optimal therapy for prevention of recurrent stroke or transient ischemic attack in patients with CS and PFO has not been defined.
Estimates of annual rates of recurrent stroke among patients with PFO range from 1.5 – 12% and depend on the characteristics of the population studied, including age.

43. Top Ten Things to Know Percutaneious Device Closure of Patent Foramen Ovale for Secondary Stroke Prevention: 2010
No device for PFO closure after cryptogenic stroke has been approved by the FDA.
Randomized controlled trials offer the best means for assessing the safety and efficacy of percutaneous device closure relative to anti-thrombotic meds.
Enrollment in ongoing clinical trials has lagged considerably despite frequent calls for participation from the FDA and major professional societies.
All cardiovascular clinicians should consider referral of patients with cryptogenic stroke and PFO an ongoing studies.