Percutaneous PFO Closure

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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?
• Introduction
• Diagnosis
• Clinical Scenarios of Importance
   • Cryptogenic Stroke
   • Migraines with Aura
• Indications for Closure & Controversies
• Devices & Techniques
• 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
• 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
          Clinical Scenarios of
•   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 = 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
   o   780,000 Strokes per year in the US
   o   180,000 are recurrent
   o   Around 30-40% are designated Cryptogenic
   o   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
  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 Transit
Timing is everything…

      Ryder Cup, October 2010
Thrombus in Transit
Thrombus in Transit
 Patient with PE


      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
  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 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: 1148-52
                   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
       • 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
   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
   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
       •   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
          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
   o   Indication: Secondary prevention for patients with CS or TIA
   o   Study design: Retrospective analysis of patients who had PFO closure for above reason
   o   Technique: TEE/ICE was used intra-procedure
   o   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 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
•   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
•   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
       • 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
• All use outside this IDE considered off-label
• STARFlex (NMT Medical)
STARFlex (NMT Medical)
• CardioSEAL (NMT Medical)
• 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 STAR-
     Flex device
   o Remodelling of matrix already started after 30 days, fully replaced by host tissue after 2

• Mounted on double-umbrella framework
• Umbrellas connected by microsprings and serve as self-
  centering 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:
   o   Appears safe compared with other devices
   o   Low rate of recurrent embolic events
   o   Unique properties suggest it may be more favorable than prior devices
   o   Still lacks the support of data from:
         • Large number of patients
         • Randomized study with true control arm
         • Longer term follow-up
• 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
• 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

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