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Percutaneous PFO Closure
Cath Conference – October 7th, 2010
Darryn Appleton
Case Example
• 41 yo AAF admitted to Neurology with acute stroke
• Right sided hemiparesis and aphasia, found to have left MCA
territory stroke
• Mild HTN, otherwise no risk factors, not taking contraceptives
• No prior stroke, no history of A.fib
• Brain MRI shows large superficial stroke
• MRA and carotid duplex shows no significant intra-cerebral or
extra-cranial vascular disease
• Serologies and hypercoagulability studies unremarkable
• TTE negative for LV thrombus, normal EF
Case Example
• She makes a good recovery over the first few days of hospital
stay and continues to work with PT/OT & Speech
• She has been started on Aspirin, Atorvastatin
• TEE with bubble study performed, reveals PFO with R to L
shunt on Valsalva, in addition to atrial septal aneurysm
• LE venous US negative for DVT
• Cardiology Consulted: Please evaluate for possible PFO
closure to reduce risk of recurrent stroke
Call Dr Lotun?
Outline
• Introduction
• Diagnosis
• Clinical Scenarios of Importance
• Cryptogenic Stroke
• Migraines with Aura
• Indications for Closure & Controversies
• Devices & Techniques
Introduction
• Definition
o A Patent Foramen Ovale (PFO) is a communication between the atria that
begins at the fossa ovalis in the RA and transverses to the ostium secundum
on the left atrial side
o Exists during fetal life to allow flow of oxygenated blood from the IVC to pass
from RA to LA, bypassing the lungs
o Typically closes shortly after birth as the newborn takes its first breath and LA
pressure rises and exceeds RA pressure
o Distinction between PFO and ASD is that PFO represents failure of fusion of
septum primum and septum secundum, whereas ASD represents a failure in
the formation of the interatrial septum
• Prevalence
o Autopsy studies : Around 27% of population have PFO
o More common in younger patients, prevalence declines with age
Atrial Septal Development
Atrial Septal Development
Diagnosis
• Seen on echocardiography (TTE or TEE) as a communication
between the atria allowing right to left shunting as detected
by color/spectral Doppler, or by an agitated saline contrast
injection (i.e. a bubble study)
• Shunt may not be apparent without Valsalva or cough, so
these maneuvers should be performed to rule out a PFO
• TEE w bubble study considered the reference standard with
sensitivity about 90% compared with autopsy findings
Diagnosis
Clinical Scenarios of
Importance
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Cryptogenic Stroke
Migraines (esp. w Aura)
Scuba Diving
Platypnea-Orthodeoxia Syndrome
Scuba Diving
• Presence of a PFO considered a risk factor for decompression
illness in scuba divers
o Series of 30 patients w decompression illness evaluated with 2D Echo
o Prevalence of PFO was 37% (vs 5% in their group of healthy controls)
o Prevalence was higher (61%) in those with severe signs and symptoms
• Incidence of decompression illness is however very low, and
there are currently no recommendations for divers to be
routinely screened
• For those with diagnosed PFO, it is not a contraindication to
diving and no indication for closure – simple routine
precautions advised
Lancet 1989; 1: 513-4
Platypnea-Orthodeoxia
Syndrome
• Platypnea = Dyspnea induced by assuming upright posture
and relieved with recumbency
• Orthodeoxia = Arterial desaturation in the same setting
• Causes divided into 3 main categories
o Intra-cardiac Shunting, Intrapulmonary Shunting & V/Q mismatch
• PFO with R to L shunting is associated with this condition as
an example of intra-cardiac shunt
• Important to distinguish from intra-pulmonary shunting that
may be associated with this syndrome (e.g. cirrhosis causing
hepatopulmonary syndrome)
o Bubbles crossing R to L within 4 cardiac cycles of injection favors primary intra-cardiac
lesion, whereas later than 4 cycles favors intra-pulmonary site.
Cryptogenic Stroke (CS)
• Definition
o Cerebral infarction that is not attributable to a source of definite
cardioembolism, large artery atherosclerosis, or small artery disease despite
extensive vascular, cardiac, and serologic evaluation
o Routine evaluation as below fails to identify a definite cause:
• Brain imaging with CT and/or MRI
• Neurovascular imaging with carotid duplex, transcranial Doppler, MRA,
CTA or conventional angiography
• Cardiac evaluation: TTE +/- TEE with bubble study, ECG, Holter
• Blood testing, including CBC, ESR, VDRL, RPR, lipids, homocysteine
Cryptogenic Stroke (CS)
• Clinical Importance
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780,000 Strokes per year in the US
180,000 are recurrent
Around 30-40% are designated Cryptogenic
For patients < 55 yrs, as many as 2/3 of cases are Cryptogenic
• Higher prevalence of PFO in patients with stroke,
particularly patients with Cryptogenic Stroke
o Raises two important questions:
1. Can PFO be causally implicated in a patient with CS who has a PFO?
2. If the above is true, will PFO closure reduce rate of recurrent stroke?
Proposed Mechanisms linking PFO to Stroke
1. Paradoxical Embolism
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Thromboembolic disease from the venous system (e.g. LE DVT) passing
through the PFO to the systemic circulation, resulting in embolism in the
cerebral circulation causing stroke
Thrombus in Transit
Timing is everything…
Ryder Cup, October 2010
Thrombus in Transit
Thrombus in Transit
Patient with PE
Thrombus
PFO
Other Indirect Evidence
• Brain imaging in patients with CS and PFO more frequently
demonstrate embolic phenomena
o Superficial
o Larger size
o Infarct in the territory of a large vessel
• Size of shunt important
o Steiner et al found that those with medium or large sized PFO had high frequency of
embolic brain imaging findings compared to those with no or small PFO
Stroke 1998; 29: 944-948
Other Indirect Evidence
• Increased rate of DVT in patients with CS and PFO
oLE DVT rates not especially high in patients with CS
• May be more difficult to prove paradoxical embolism without known source
• Important to consider other sites, especially pelvic veins
oPELVIS Study (Cramer et al, Stroke 2004):
• 95 patients with acute stroke, aged 18 to 60 years (mean age 46 years)
• Had MRV of pelvic veins within 72 hrs of onset of symptoms of stroke
• Again found incidence of PFO higher in CS compared with stroke of known cause
o (61% vs 9%)
• Pelvic DVT found more often in CS than in stroke of known cause
o (20% v 4%, p < 0.03)
Stroke 2004; 35: 46-50
Proposed Mechanisms linking PFO to Stroke
1. Paradoxical Embolism
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Thromboembolic disease from the venous system passing through the PFO to
the systemic circulation, resulting in embolism in the cerebral circulation
causing stroke
Other possibilities:
2. Thrombus formation on LA side, with abnormalities of
the interatrial septum acting as nidus
3. Passage of unmeasured vasoactive substances escaping
pulmonary degradation
Association of CS with PFO
• Observation studies of Stroke patients
o 1988: NEJM Case-Control study – Stroke patients aged < 55
• Overall prevalence 40% in 60 Stroke patients vs 10% in group of
100 age and gender matched controls
• Prevalence highest (54%) in patients with true CS (followed by
those with no obvious cause but at least one risk factor, followed
by identified cause)
o 1988: Lancet Case-Control study – 40 Stroke/TIA patients aged < 40
• PFO prevalence was 50% in patients with stroke/TIA vs 15% in agematched controls
Lechat et al. NEJM 1988; 318: 1148-52
Webster et al. Lancet 1988; 11-2
Association of CS with PFO
• Meta-analysis of Case-Control Studies
o Ischemic Stroke vs Controls
• PFO – OR of 1.83 (95% CI of 1.25 to 2.66) – 15 studies
• Atrial Septal Aneurysm (ASA) – OR 2.35 (1.46 to 3.77) – 9 studies
• PFO & ASA – OR 4.96 (2.37 to 10.39) – 4 studies
o Cryptogenic Stroke vs Stroke of known cause
• PFO – OR 3.16 (2.30 to 4.35) – 22 studies
• ASA – OR 3.65 (1.34 to 9.97) – 5 studies
• PFO & ASA – OR 23.36 (5.24 to 103.20)
o Association stronger for younger patients (age < 55 yrs)
Overell et al. Neurology 2000; 52: 1172-9
Association of CS with PFO
• Caveat:
o Meta-analysis has the advantage of increasing power through pooling
results of multiple smaller, usually inconclusive, prior studies
• Effectively makes N bigger
o Meta-analysis does not correct for potential sources of bias or
confounders
• Still taking about data from Case-Control studies
Association of CS with PFO
• Prospective Cohort Studies
o Meissner et al (JACC 2006) – 585 pts age > 45 years
• Randomly selected population (only 6.3% with prior stroke)
• Mean age 66.9 years
Older patients ? Attenuated contribution of PFO
• Followed for 5 years
• PFO in 24.5% (similar to background population)
• Ischemic stroke or TIA occurred in 41 patients
o PFO was not a significant independent predictor of stroke
o Di Tullio et al (JACC 2007) – 1100 pts age > 39 years
• Multi-ethnic group of patients from Northern Manhattan, no prior history of stroke
• Mean age 68.7 years
TTE used for PFO Dx ? Underestimated
• Mean follow-up about 7 years
TEE and/or Transcranial doppler may have
• PFO in about 15% of patients
Increased yield
o PFO was not a significant independent predictor of stroke
PFO and Recurrent Stroke Risk
• 4 Prospective Studies
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Mas et al (NEJM 2001)
Homma et al – PICSS – (Circulation 2002)
De Castro et al – (Stroke 2000)
Serena et al – (Stroke 2008)
o All looked at risk of recurrent stroke in patients with PFO and history of cryptogenic
stroke
o Found no increased risk of recurrent stroke with PFO compared to without
o Exception: Mas et al noted patients with both PFO and ASA had 15.2% risk of stroke at
4 years, which was significantly higher than those without ASA – HR 4.17 (1.47-11.84)
Association ≠ Causation
Criteria for Causality in Medicine
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Strength of Association
Consistency
Specificity
Temporality
Biologic Gradient
Plausibility
Coherence
Experimental Evidence
Analogy
How good is Medical Therapy?
• PICSS Study (Homma et al., Circ 2002)
o Sub-study of the WARSS study
o WARSS study: 2206 stroke patients aged 30-85 (mean age 59 years) were randomized to
receive either Warfarin or Aspirin 325mg
o Those who had TEE for clinical purposes were included in the PICSS sub-study
o 630 patients included, of whom 42% had Cryptogenic Stroke
o PFO documented in 33.8% of entire cohort, and Atrial Septal Aneurysm in 11.5%
• CS: 39.2 % had PFO, vs only 29.9% in Stroke of Known Cause
o Results:
• Primary outcome of time to recurrent stroke or death occurred in 15.9% at 2 years
o No significant difference by treatment with Aspirin vs Warfarin at 2 years
• Though a non-significant trend towards lower event rate on Wafarin in
those with CS as compared with stroke of known cause
o No significant difference by PFO vs no PFO
PICSS Study
PICSS Study
Safety of PFO closure
• Wahl et al published prospective study on PFO closure
o Indication: Secondary prevention for presumed paradoxical embolism
o Technique: No intra-procedural echo guidance (i.e. no TEE or ICE), fluoroscopically
guided only
o Devices: Amplatzer PFO Occluder (AGA)
o Baseline Characteristics:
JACC Interventions 2009; 2: 116-123
Safety of PFO closure
• Wahl et al published prospective study on PFO closure
o Results:
• N = 620 patients, 100% procedural success
• 5 procedural complications (0.8%)
o 4 AV fistulae requiring surgical correction
o 1 TIA
• Mean f/u of 3 years
o 5 ischemic strokes, 8 TIAs
• Freedom from recurrent ischemic stroke/TIA at 5 years = 97%
o However: Cohort study only, no control arm
JACC Interventions 2009; 2: 116-123
Safety of PFO closure
• Ford et al published data on Mayo Clinic experience
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Indication: Secondary prevention for patients with CS or TIA
Study design: Retrospective analysis of patients who had PFO closure for above reason
Technique: TEE/ICE was used intra-procedure
Devices: Amplatzer Septal Occluder in 99% (AGA) or CardioSEAL in 1% (NMT Medical)
Baseline Characteristics:
JACC Interventions 2009; 2: 116-123
Safety of PFO closure
• Ford et al published data on Mayo Clinic experience
o Results:
• N = 352 patients, 100% procedural success
• 12 procedural complications (3.4%)
o Atrial flutter, A. fib, vasovagal reaction
o Retroperitoneal bleed, tamponade, transient diplopia
• Mean f/u of 37 months
o Recurrence rate for combined endpoint of ischemic stroke/TIA
• 1 year – 0.9%; 4 years 2.8%
• 16 deaths during follow-up, none adjudicated as related to device or to
ischemic neurologic event
o However: Cohort study only, no control arm
JACC Interventions 2009; 2: 116-123
What about RCTs?
Closure 1
• Preliminary Results released 6/17/10 by NMT Medical:
o PFO closure with STARFlex device did not meet primary endpoint of superiority in
recurrent stroke or TIA risk reduction compared to medical therapy
o Press release quotes a small but not statistically significant reduction in outcomes with
PFO closure (though details in terms of numbers not reported)
o PFO with the STARFlex device showed a good safety profile, with complications similar to
that of standard medical therapy, and a very low rate of thrombus formation
o Full details and analysis of data is pending
PC-Trial
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Centers in Europe and Australia
Active but no longer recruiting
Enrolling patients with CS and PFO
Device = Amplatzer PFO Occluder
Goal enrollment was 500 patients
Projected completion was in 2007 but has been extended
CLOSE Trial
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Single Center in France
Enrolling patients with CS and PFO ages 16 to 60
Any PFO device can be used
Goal of 900 patients
Estimated completion 2012
Gore REDUCE Study
Summary of Guidelines
Back to our Case Example
• What is our recommendation as the consulting specialist?
o Purely evidence based answer would be that we have no definitive proof that
Percutaneous PFO closure will reduce her risk of recurrent events
o Guidelines exist, but which to follow?
• AAN: We just don’t have enough evidence, so we don’t recommend it
• ASA/AHA: She hasn’t had a recurrent event yet, so we don’t recommend it
o But: Cardiologists don’t like waiting for recurrent events!
• Europeans: May be reasonable for CS if we think she has a high risk PFO
o High risk not well defined in their guideline – co-existing ASA is likely the
strongest candidate for a variable that has been shown to increase risk
o Informed consent and discussion with patient about our state of knowledge re safety
and efficacy of closure is critical, along with discussion of alternatives – i.e. ASA or
Coumadin therapy
o Consider enrolling her in a randomized clinical study – may be the best possible answer
for an Academic Cardiologist
Migraines & PFO
• Both common problems in the general population
o Migraine prevalence = 13%
o PFO prevalence = 27%
• Migraine with Aura
o Defined as a reversible neurologic event lasting ≥ 5 minutes and ≤ 60 minutes and
usually followed by a Migraine headache within 1 hour
Migraines & PFO
• Unusually high prevalence of PFO noted in patients with
Migraine, especially Migraine with Aura (MA)
o Case-Control series point to a PFO prevalence of 48% to 67% in patients with MA
o Prospective NOMAS study (Rundek et al., Circ 2008) - same population also evaluated
for stroke/PFO association
• 1100 multiethnic subjects from Northern Manhattan, no prior strokes
• Mean age 69
• No clear association demonstrated between migraine and PFO, although:
o TTE used to diagnose PFO ? Underdiagnosed
o Older patients ? Fewer migraines
o Size of shunt also seems to be important (dose-response effect)
• Large R to L shunts more common in MA than migraine without aura
Prevalence of PFO in
Migraine sufferers
Migraines & PFO - Pathophysiology
• Proposed mechanisms linking PFO and Migraine
o Endothelial dysfunction
o Chemical Shunt hypothesis
• Substances such as serotonin, kinins, NO passing through the PFO that would
otherwise be eliminated in the pulmonary circulation thought to affect the cerebral
circulation with increased platelet activation and aggregation
o Ontogenic hypothesis
• Endocardium, vascular endothelium and platelets share a common embryologic
origin
• Possible that a single developmental defect causes both the PFO and separately an
abnormality of vascular endothelium and/or platelets that makes the patient
susceptible to migraine
o Would mean that closing the PFO may have no impact on the migraine
pathophysiology itself if this were the only mechanism
PFO Closure for Migraine
• Non-randomized observational studies
PFO Closure for Migraine
• MIST trial
o Prospective, multicenter RCT
o Double-blind sham-controlled trial: PFO closure vs Sham
o Aged 18-60 years with a history of migraine with aura starting before age 50
• ≥ 5 migraine headache days per month, but with at least 7 HA free days per month
• Failed ≥ 2 classes of preventative meds (either not tolerated or ineffective)
o Eligible patients had TTE with bubble study including provocative maneuvers
o Total of 432 patients screened for PFO
• 163 (37.7%) had moderate/large sized R to L shunt due to PFO
o Aside from main results of MIST trial confirmed the association with higher rates of
PFO in patients with MA as opposed to those with no PFO
PFO Closure for Migraine
• Results of MIST
o 147 patients ended up being randomized
• 74 patients had PFO Closure with STARFlex device (NMT Medical) plus IV Heparin
• 73 patients had groin skin incision as sham
• All were given aspirin and clopidogrel for 90 days
o Primary outcome: Migraine headache cessation during first 90 days
• No difference between the groups
o Secondary outcomes:
• Migraine incidence during healing phase
• Change in severity of migraine attacks (MIDAS and HIT scores)
• Change in frequency of migraine attacks other than elimination of attacks
• Quality of life measures
o No difference between groups for any outcome
o Exploratory analysis removing 2 patients who accounted for disproportionate
amount of symptoms  showed significant reduction in number of HA days
PFO Closure for Migraine
• MIST Trial Safety Concerns
o Serious adverse events reported in 16 patients from the implant group (6.8%) which was
higher than expected
o Events included:
• Atrial fibrillation
• Tamponade / Pericardial effusion
• Retroperitoneal bleed
• Chest pain
• Possible reasons for lack of demonstrated efficacy
o Underpowered for rigorous primary endpoint in patients at the severe end of the
migraine spectrum
o Follow-up too short?
o Incorrect hypothesis – maybe closing PFO does not alter the course?
Migraines & PFO
• Ongoing Studies:
o Prima Trial (AGA)- International
• Prospective multicenter RCT
• Patients aged 18-65 years
• Migraine with aura
• Refractory symptoms despite two or more preventative medications
• Randomized to PFO closure + Medical therapy, vs Medical therapy alone
o PREMIUM trial (AGA) is an ongoing US trial
o Two other US FDA-approved studies (MIST II and ESCAPE) had to be closed due to
difficulty recruiting
• FDA insisted on sham group receiving full RHC with angiographic confirmation of R
to L shunt
Indications for PFO Closure
• No devices are specifically and fully FDA approved for
percutaneous PFO closure for any indication
• CardioSEAL Occluder and Amplatzer PFO Occluder were
previously approved by the FDA under humanitarian device
exemption regulations for:
o Recurrent CS due to presumed paradoxical embolism through a PFO who have failed
medical therapy
• HDE withdrawn in 2006, as patient population found to be in
excess of 4000 pts per year in the US
• Access to these devices now through Investigational Device
Exemption
• All use outside this IDE considered off-label
Devices
• STARFlex (NMT Medical)
STARFlex (NMT Medical)
Devices
• CardioSEAL (NMT Medical)
Devices
• Amplatzer PFO Occluder (AGA Medical Corporation)
Newer Devices - SeptRx
Newer Devices – BioSTAR (NMT)
BioSTAR – NMT Medical
• Fully biodegradable matrix consisting of an acellular porcine
intestinal collagen layer
o Reduced thrombus formation in animal models
o Accelerated neo-endothelialization, lower immune response compared with the STARFlex device
o Remodelling of matrix already started after 30 days, fully replaced by host tissue after 2
years
• Mounted on double-umbrella framework
• Umbrellas connected by microsprings and serve as selfcentering mechanism
BioSTAR Study
• 62 patients
• Prospective cohort study
• 93.5% referred with h/o
either CS or TIA
• All implanted with either
TEE or ICE guidance
JACC Interventions 2010;3: 968-973
BioSTAR Study
BioSTAR Study
• Bottom-line:
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Appears safe compared with other devices
Low rate of recurrent embolic events
Unique properties suggest it may be more favorable than prior devices
Still lacks the support of data from:
• Large number of patients
• Randomized study with true control arm
• Longer term follow-up
Summary
• PFO has association with Cryptogenic Stroke and Migraine
with Aura, but difficult to prove causal relationship in
individual patients
• Percutaneous closure of PFO may reduce risk of recurrent
embolic events in patients with CS, but as yet unproven in
randomized trial (several trials in progress)
• PFO closure appears beneficial for MA in observational
studies but only RCT failed to show a benefit (trials in
progress)
• Percutaneous PFO closure appears generally safe and newer
devices may offer some advantages
• Essential to enroll patients in clinical trials to further evaluate
safety and efficacy