Percutaneous PFO ClosurePercutaneous PFO Closure

Cath Conference – October 7th, 2010Darryn Appleton

Case ExampleCase 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 ExampleCase 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?Call Dr Lotun?

OutlineOutline• Introduction• Diagnosis• Clinical Scenarios of Importance• Cryptogenic Stroke• Migraines with Aura

• Indications for Closure & Controversies• Devices & Techniques

IntroductionIntroduction• 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

• Prevalenceo Autopsy studies : Around 27% of population have PFOo More common in younger patients, prevalence declines with age

Atrial Septal DevelopmentAtrial Septal Development

Atrial Septal DevelopmentAtrial Septal Development

DiagnosisDiagnosis• 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

DiagnosisDiagnosis

Clinical Scenarios of Clinical Scenarios of ImportanceImportance

• Cryptogenic Stroke• Migraines (esp. w Aura)• Scuba Diving• Platypnea-Orthodeoxia Syndrome

Scuba DivingScuba Diving• Presence of a PFO considered a risk factor for decompression

illness in scuba diverso Series of 30 patients w decompression illness evaluated with 2D Echoo 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 Platypnea-Orthodeoxia SyndromeSyndrome

• 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)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)Cryptogenic Stroke (CS)• Clinical Importance

o 780,000 Strokes per year in the USo 180,000 are recurrento Around 30-40% are designated Cryptogenico 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 Strokeo 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 StrokeProposed Mechanisms linking PFO to Stroke1. Paradoxical Embolism

o 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 TransitThrombus in Transit

Timing is everything…Timing is everything…

Ryder Cup, October 2010

Thrombus in TransitThrombus in Transit

Thrombus in TransitThrombus in Transit

Patient with PEPatient with PE

PFO

Thrombus

Other Indirect EvidenceOther Indirect Evidence• Brain imaging in patients with CS and PFO more frequently

demonstrate embolic phenomenao Superficialo Larger sizeo Infarct in the territory of a large vessel

• Size of shunt importanto 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 EvidenceOther 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 StrokeProposed Mechanisms linking PFO to Stroke1. Paradoxical Embolism

o 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 PFOAssociation 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

age-matched controls

Lechat et al. NEJM 1988; 318: 1148-52Webster et al. Lancet 1988; 11-2

Association of CS with PFOAssociation 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 PFOAssociation 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 PFOAssociation 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• 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 strokeo 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• Mean follow-up about 7 years• PFO in about 15% of patients

o PFO was not a significant independent predictor of stroke

Older patients ? Attenuated contribution of PFO

TTE used for PFO Dx ? UnderestimatedTEE and/or Transcranial doppler may have Increased yield

PFO and Recurrent Stroke RiskPFO and Recurrent Stroke Risk• 4 Prospective Studies

o Mas et al (NEJM 2001)o Homma et al – PICSS – (Circulation 2002)o De Castro et al – (Stroke 2000)o 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 withouto 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 ≠ CausationAssociation ≠ Causation

Criteria for Causality in MedicineCriteria for Causality in Medicine• Strength of Association• Consistency• Specificity• Temporality• Biologic Gradient• Plausibility• Coherence• Experimental Evidence• Analogy

How good is Medical Therapy?How good is Medical Therapy?• PICSS Study (Homma et al., Circ 2002)

o Sub-study of the WARSS studyo WARSS study: 2206 stroke patients aged 30-85 (mean age 59 years) were randomized to

receive either Warfarin or Aspirin 325mgo Those who had TEE for clinical purposes were included in the PICSS sub-studyo 630 patients included, of whom 42% had Cryptogenic Strokeo 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 Causeo Results:

• Primary outcome of time to recurrent stroke or death occurred in 15.9% at 2 yearso 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 StudyPICSS Study

PICSS StudyPICSS Study

Safety of PFO closureSafety of PFO closure• Wahl et al published prospective study on PFO closure

o Indication: Secondary prevention for presumed paradoxical embolismo Technique: No intra-procedural echo guidance (i.e. no TEE or ICE), fluoroscopically

guided onlyo Devices: Amplatzer PFO Occluder (AGA)o Baseline Characteristics:

JACC Interventions 2009; 2: 116-123

Safety of PFO closureSafety 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 correctiono 1 TIA

• Mean f/u of 3 yearso 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 closureSafety of PFO closure• Ford et al published data on Mayo Clinic experience

o Indication: Secondary prevention for patients with CS or TIAo Study design: Retrospective analysis of patients who had PFO closure for above reasono Technique: TEE/ICE was used intra-procedureo Devices: Amplatzer Septal Occluder in 99% (AGA) or CardioSEAL in 1% (NMT Medical)o Baseline Characteristics:

JACC Interventions 2009; 2: 116-123

Safety of PFO closureSafety 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 reactiono Retroperitoneal bleed, tamponade, transient diplopia

• Mean f/u of 37 monthso 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 evento However: Cohort study only, no control arm

JACC Interventions 2009; 2: 116-123

What about RCTs?What about RCTs?

Closure 1 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-TrialPC-Trial• 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 TrialCLOSE Trial• 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 StudyGore REDUCE Study

Summary of GuidelinesSummary of Guidelines

Back to our Case ExampleBack 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 & PFOMigraines & PFO• Both common problems in the general population

o Migraine prevalence = 13%o PFO prevalence = 27%

• Migraine with Aurao Defined as a reversible neurologic event lasting ≥ 5 minutes and ≤ 60 minutes and

usually followed by a Migraine headache within 1 hour

Migraines & PFOMigraines & 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 MAo 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 ? Underdiagnosedo 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 Prevalence of PFO in Migraine sufferersMigraine sufferers

Migraines & PFO - PathophysiologyMigraines & PFO - Pathophysiology• Proposed mechanisms linking PFO and Migraine

o Endothelial dysfunctiono 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 migraineo Would mean that closing the PFO may have no impact on the migraine

pathophysiology itself if this were the only mechanism

PFO Closure for MigrainePFO Closure for Migraine• Non-randomized observational studies

PFO Closure for MigrainePFO Closure for Migraine• MIST trial

o Prospective, multicenter RCTo Double-blind sham-controlled trial: PFO closure vs Shamo 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 MigrainePFO 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 outcomeo Exploratory analysis removing 2 patients who accounted for disproportionate

amount of symptoms showed significant reduction in number of HA days

PFO Closure for MigrainePFO 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 efficacyo Underpowered for rigorous primary endpoint in patients at the severe end of the

migraine spectrumo Follow-up too short?o Incorrect hypothesis – maybe closing PFO does not alter the course?

Migraines & PFOMigraines & 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 trialo 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 ClosureIndications 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

DevicesDevices• STARFlex (NMT Medical)

STARFlex (NMT Medical)

DevicesDevices• CardioSEAL (NMT Medical)

DevicesDevices• Amplatzer PFO Occluder (AGA Medical Corporation)

Newer Devices - SeptRxNewer Devices - SeptRx

Newer Devices – BioSTAR (NMT)Newer Devices – BioSTAR (NMT)

BioSTAR – NMT MedicalBioSTAR – NMT Medical• Fully biodegradable matrix consisting of an acellular porcine

intestinal collagen layero Reduced thrombus formation in animal modelso Accelerated neo-endothelialization, lower immune response compared with the STAR-

Flex deviceo 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 self-

centering mechanism

BioSTAR StudyBioSTAR 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 StudyBioSTAR Study

BioSTAR StudyBioSTAR Study• Bottom-line:

o Appears safe compared with other deviceso Low rate of recurrent embolic eventso Unique properties suggest it may be more favorable than prior deviceso Still lacks the support of data from:

• Large number of patients• Randomized study with true control arm• Longer term follow-up

SummarySummary• 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