Percutaneous PFO Closure

1. Percutaneous PFO Closure Cath Conference – October 7th, 2010 Darryn Appleton

2. 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

3. 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

4. Call Dr Lotun?

5. Outline • Introduction • Diagnosis • Clinical Scenarios of Importance • Cryptogenic Stroke • Migraines with Aura • Indications for Closure & Controversies • Devices & Techniques

6. Introduction • Definition • 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 • Exists during fetal life to allow flow of oxygenated blood from the IVC to pass from RA to LA, bypassing the lungs • Typically closes shortly after birth as the newborn takes its first breath and LA pressure rises and exceeds RA pressure • 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 • Autopsy studies : Around 27% of population have PFO • More common in younger patients, prevalence declines with age

7. Atrial Septal Development

8. Atrial Septal Development

9. 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

10. Diagnosis

11. Clinical Scenarios of Importance • Cryptogenic Stroke • Migraines (esp. w Aura) • Scuba Diving • Platypnea-Orthodeoxia Syndrome

12. Scuba Diving • Presence of a PFO considered a risk factor for decompression illness in scuba divers • Series of 30 patients w decompression illness evaluated with 2D Echo • Prevalence of PFO was 37% (vs 5% in their group of healthy controls) • 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

13. 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 • 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) • 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.

14. Cryptogenic Stroke (CS) • Definition • 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 • 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

15. Cryptogenic Stroke (CS) • Clinical Importance • 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 • Raises two important questions: • Can PFO be causally implicated in a patient with CS who has a PFO? • If the above is true, will PFO closure reduce rate of recurrent stroke?

16. Proposed Mechanisms linking PFO to Stroke • Paradoxical Embolism • 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

17. Thrombus in Transit

18. Timing is everything… Ryder Cup, October 2010

19. Thrombus in Transit

20. Thrombus in Transit

21. Patient with PE Thrombus PFO

22. Other Indirect Evidence • Brain imaging in patients with CS and PFO more frequently demonstrate embolic phenomena • Superficial • Larger size • Infarct in the territory of a large vessel • Size of shunt important • 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

23. Other Indirect Evidence • Increased rate of DVT in patients with CS and PFO • LE 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 • PELVIS 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 • (61% vs 9%) • Pelvic DVT found more often in CS than in stroke of known cause • (20% v 4%, p < 0.03) Stroke 2004; 35: 46-50

25. Proposed Mechanisms linking PFO to Stroke • Paradoxical Embolism • 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: • Thrombus formation on LA side, with abnormalities of the interatrial septum acting as nidus • Passage of unmeasured vasoactive substances escaping pulmonary degradation

26. Association of CS with PFO • Observation studies of Stroke patients • 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) • 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

27. Association of CS with PFO • Meta-analysis of Case-Control Studies • 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 • 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) • Association stronger for younger patients (age < 55 yrs) Overell et al. Neurology 2000; 52: 1172-9

28. Association of CS with PFO • Caveat: • Meta-analysis has the advantage of increasing power through pooling results of multiple smaller, usually inconclusive, prior studies • Effectively makes N bigger • Meta-analysis does not correct for potential sources of bias or confounders • Still taking about data from Case-Control studies

29. Association of CS with PFO • Prospective Cohort Studies • 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 • PFO was not a significant independent predictor of stroke • 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 • PFO was not a significant independent predictor of stroke Older patients ? Attenuated contribution of PFO TTE used for PFO Dx ? Underestimated TEE and/or Transcranial doppler may have Increased yield

30. PFO and Recurrent Stroke Risk • 4 Prospective Studies • Mas et al (NEJM 2001) • Homma et al – PICSS – (Circulation 2002) • De Castro et al – (Stroke 2000) • Serena et al – (Stroke 2008) • All looked at risk of recurrent stroke in patients with PFO and history of cryptogenic stroke • Found no increased risk of recurrent stroke with PFO compared to without • 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)

31. Association ≠ Causation

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

33. How good is Medical Therapy? • PICSS Study (Homma et al., Circ 2002) • Sub-study of the WARSS study • WARSS study: 2206 stroke patients aged 30-85 (mean age 59 years) were randomized to receive either Warfarin or Aspirin 325mg • Those who had TEE for clinical purposes were included in the PICSS sub-study • 630 patients included, of whom 42% had Cryptogenic Stroke • 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 • Results: • Primary outcome of time to recurrent stroke or death occurred in 15.9% at 2 years • 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 • No significant difference by PFO vs no PFO

34. PICSS Study

35. PICSS Study

36. Safety of PFO closure • Wahl et al published prospective study on PFO closure • Indication: Secondary prevention for presumed paradoxical embolism • Technique: No intra-procedural echo guidance (i.e. no TEE or ICE), fluoroscopically guided only • Devices: Amplatzer PFO Occluder (AGA) • Baseline Characteristics: JACC Interventions 2009; 2: 116-123

37. Safety of PFO closure • Wahl et al published prospective study on PFO closure • Results: • N = 620 patients, 100% procedural success • 5 procedural complications (0.8%) • 4 AV fistulae requiring surgical correction • 1 TIA • Mean f/u of 3 years • 5 ischemic strokes, 8 TIAs • Freedom from recurrent ischemic stroke/TIA at 5 years = 97% • However: Cohort study only, no control arm JACC Interventions 2009; 2: 116-123

38. Safety of PFO closure • Ford et al published data on Mayo Clinic experience • 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

39. Safety of PFO closure • Ford et al published data on Mayo Clinic experience • Results: • N = 352 patients, 100% procedural success • 12 procedural complications (3.4%) • Atrial flutter, A. fib, vasovagal reaction • Retroperitoneal bleed, tamponade, transient diplopia • Mean f/u of 37 months • 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 • However: Cohort study only, no control arm JACC Interventions 2009; 2: 116-123

40. What about RCTs?

41. 576 patients Goal = 900

43. Closure 1 • Preliminary Results released 6/17/10 by NMT Medical: • PFO closure with STARFlex device did not meet primary endpoint of superiority in recurrent stroke or TIA risk reduction compared to medical therapy • Press release quotes a small but not statistically significant reduction in outcomes with PFO closure (though details in terms of numbers not reported) • 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 • Full details and analysis of data is pending

44. PC-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

45. 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

46. Gore REDUCE Study Goal ~ 660 patients with CS Target completion 2014

47. Summary of Guidelines

48. Back to our Case Example • What is our recommendation as the consulting specialist? • Purely evidence based answer would be that we have no definitive proof that Percutaneous PFO closure will reduce her risk of recurrent events • 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 • But: Cardiologists don’t like waiting for recurrent events! • Europeans: May be reasonable for CS if we think she has a high risk PFO • 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 • 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 • Consider enrolling her in a randomized clinical study – may be the best possible answer for an Academic Cardiologist

49. Migraines & PFO • Both common problems in the general population • Migraine prevalence = 13% • PFO prevalence = 27% • Migraine with Aura • Defined as a reversible neurologic event lasting ≥ 5 minutes and ≤ 60 minutes and usually followed by a Migraine headache within 1 hour

50. Migraines & PFO • Unusually high prevalence of PFO noted in patients with Migraine, especially Migraine with Aura (MA) • Case-Control series point to a PFO prevalence of 48% to 67% in patients with MA • 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: • TTE used to diagnose PFO ? Underdiagnosed • Older patients ? Fewer migraines • Size of shunt also seems to be important (dose-response effect) • Large R to L shunts more common in MA than migraine without aura