1. PFO CLOSURE JOURNAL REVIEW OF EVIDENCE

2.  PFO is a remnant of fetal circulation  At autopsy-Identified in 27% of normal patients  Prevalence decline with age Hagen PT, Scholz DG, Edwards WD. Incidence and size of patent foramen ovale during the first 10 decades of life: an autopsy study of 965 normal hearts. Mayo Clin Proc. 1984;59:17–20.

3.  Contrast TTE  Detected PFO in 14.9% stroke-free subjects >39 yrs  Atrial septal aneurysm 2.5%  Most often in association with PFO Di Tullio MR, Sacco RL, Sciacca RR, et al. Patent foramen ovale and the risk of ischemic stroke in a multiethnic population. J Am Coll Cardiol.2007;49:797– 802.

4.  TEE  24.3% prevalence rate in > 45 yrs age  Atrial septal aneurysm 1.9% of subjects  4.3% associated with PFOs Meissner I, Khandheria BK, Heit JA, et al. Patent foramen ovale:innocent or guilty? Evidence from a prospective population-based study.J Am Coll Cardiol. 2006;47:440 –5.

5.  TTE and TEE with saline contrast injection  PFO is established by demonstration of an interatrial communication with right-to-left transit of contrast microbubbles within 3 to 4 cardiac cycles of right atrial opacification DIAGNOSIS

6.  Injection is performed with and without Valsalva maneuver  Coughing during injection increase sensitivity  Use of harmonic imaging increase sensitivity  Contrast material injected into lower extremities has higher sensitivity

9.  Atrial septal aneurysm is defined as a redundant and hypermobile portion of the interatrial septum that demonstrates more than 10-mm excursion from centerline during cardiac cycle

10.  No identifiable cause despite thorough evaluation  Approximately 25% to 40%  Up to 25% of patients experience recurrent stroke or TIA within 4 years of initial event despite medical therapy CRYPTOGENIC STROKE

11.  Association was first reported in 1988 by Lechat et al  Numerous observational studies suggested a strong association  More convincingly demonstrated for younger ( 55 yrs ) PFO AND CS

12. Relationship of Cryptogenic Stroke With PFO in Younger and Older Patients

13.  Lamy et al-PFO with TEE in 45.9% of 581 young CS patients

14.  Prevalence of PFO 43.9% among younger CS patients compared with 14.3% among younger patients with stroke of known cause (odds ratio 4.70, 95%,[CI] 1.89 to 11.68, P0.001)  28.3% among older CS patients compared with 11.9% among older patients with stroke of known cause (odds ratio 2.92, 95% CI 1.70 to 5.01, P0.001) Handke M, Harloff A, Olschewski M, et al. PFO and cryptogenic stroke in older patients. N Engl J Med. 2007;357:2262– 8.

15.  PFO by TEE criteria in 33.8% of patients 30 to 85 years  PFO in 39.2% of CS patients versus 29.9% of patients with a known cause of stroke (P0.02). PFO in Cryptogenic Stroke Study (PICSS) Cryptogenic (N=250) Non Non- Cryptogenic (N=351) P Value PFO Present 39.2% (98/250) 29.9% (105/351) <0.02 Homma S: Circulation, Volume 105(22).June 4, 2002.2625-2631

16.  Prospective population-based study by Meissner et al  PFO was not found to be an independent risk factor for future cerebrovascular events in the general population after correction for age and comorbidity

17.  Northern Manhattan Study (NOMAS)  PFO not associated with increased stroke risk in a multiethnic cohort of both men and women or in patients younger or older than 60 years

18.  Olmsted County SPARC study  PFO is not a significant, independent predictor of stroke among normal subjects older than 45 yrs of age

19.  Atrial Anatomy Anatomic size of PFO Magnitude of right-to-left shunt Coexistence of atrial septal aneurysm Eustachian Valve and Chiari’s Network  Hemodynamics  Venous Thrombosis and Hypercoagulable States  These associations have not been observed consistently Factors Associated With Paradoxical Embolization

20.  Estimates of annual rates of recurrent stroke among patients with PFO range from 1.5% to 12% and depend on the characteristics of the population, age  Optimal medical therapy for prevention of recurrent CS is unknown  Numerous uncontrolled studies have shown an apparent benefit of medical therapy after a CS

21. Summary Table of Medical Therapy Studies

22.  Lausanne study  Patients were treated with aspirin, anticoagulation or PFO closure-annual stroke rate was 1.9%

23.  Warfarin Aspirin Recurrent Stroke Study  First randomized controlled study to compare the effect of warfarin and aspirin after prior noncardioembolic ischemic stroke  Showed aspirin was as good as warfarin in prevention of stroke recurrence, but presence of PFO was not specifically systematically evaluated  Majority of subgroup analyses in the WARSS showed no benefit of warfarin over aspirin. WARSS

24.  Patients older than those in the Lausanne study  All subjects were treated with aspirin (325 mg daily) or warfarin(INR 1.4 to 2.8,mean 2.040.99).  2-year primary event rate for all-cause death or recurrent ischemic stroke was 15.9%.  No significant difference in primary event rates between patients with versus those without PFO PICSS

25. Percutaneous Closure of PFO  Transcatheter closure first reported in 1992 -Bridges, Lock, et al  Most commonly used devices are  Amplatzer PFO Occluder (AGAMedical)  CardioSEAL (NMT Medical) devices

26. Summary Table of Percutaneous PFO Closure Studies

27.  Systematic review of nonrandomized studies of transcatheter closure (n10) or medical therapy (n6) Khairy P, O’Donnell CP, Landzberg MJ. Transcatheter closure versus medical therapy of PFO and presumed paradoxical thromboemboli: a systematic review. Ann Intern Med. 2003;139:753– 6

28.  Wöhrle’s -recent review of nonrandomized trials  Suggested lower rate of recurrent stroke after device closure of PFO, especially among patients with coexistent atrial septal aneurysm  Mean frequency of major complications was 2.3% among patients undergoing PFO closure Wöhrle J. Closure of patent foramen ovale after cryptogenic stroke.Lancet. 2006;368:350 –2.

29.  Kutty et al.  Analyzed results of investigations performed for neurological events after PFO device closure and reported a combined recurrence rate of 3.4% for stroke/TIA and an event rate of 0.9% per year for recurrent strokes Kutty S, Brown K, Asnes JD, Rhodes JF, Latson LA. Causes of recurrent focal neurologic events after transcatheter closure of patent foramen ovale with the CardioSEAL septal occluder. Am J Cardiol 2008;101:1487–92.

30. Summary Table of Surgical PFO Closure Studies

31.  AHA/ASA guidelines for secondary stroke prevention state that “insufficient data exist to make a recommendation about PFO closure in patients with a first stroke and a PFO”  PFO closure may be considered for patients with recurrent CS despite optimal medical therapy (Class IIb, Level of Evidence: C)

32.  No device specific for PFO closure after CS has been approved by FDA  Need for completion of appropriately powered randomized, controlled clinical trials to compare medical therapy with percutaneous device closure

33. Current Ongoing Clinical Trials on PFO Closure to Prevent Recurrent Cryptogenic Stroke

34.  CLOSURE I TRIAL  Evaluation of the STARFlex Septal Closure System in Patients With a Stroke or TIA due to Presumed Paradoxical Embolism through a PFO  Prospective, multi-center, randomized, open-label, two- arm superiority trial  Patients < 60 years with CS or TIA and PFO documented by TEE, with or without atrial septal aneurysm, within 6 months of randomization

35. STARFlex®  Double umbrella comprised of MP35N framework with attached polyester fabric  23mm, 28mm, 33mm

36. Randomization 1 : 1 STARFlex® Closure (within 30 Days) 6 Months Aspirin and Clopidigrel followed by 18 Months Aspirin Best Medical Therapy 24 Months Aspirin Or Warfarin Or Combination Between June 23, 2003 and October 24, 2008, 909 patients were randomized at 87 sites in the United States and Canada. N = 909 N=447N=462

37.  Primary endpoint : 2-year incidence of stroke or TIA, all cause mortality for the first 30 days, and neurological mortality 31 days to 2 years  Followup Repeat TEE at 6 months all patients and 12/24 months if residual leak

38. 2 Year Primary Endpoint ITT STARFlex n = 447 Medical n = 462 Adjusted P value* Composite5.9% (n=25) 7.7% (n=30) 0.30 Stroke3.1% (n=12) 3.4% (n=13) 0.77 TIA3.3% (n=13) 4.6% (n=17) 0.39 *Adjusting performed using Cox Proportional Hazard Regression and adjusting for related patient characteristics including: age, atrial septal aneurysm, prior TIA/CVA, smoking, hypertension, hypercholesterolemia

39. Composite Primary Endpoint Baseline Shunt and Atrial Septal Aneurysm (TEE) STARFlex N=400 Medical N=451 P value Trace shunt7.0% (n=8/114) 8.0% (n=10/126) 0.75 Moderate shunt5.3% (n=7/132) 8.4% (n=12/143) 0.31 Substantial shunt3.6% (n=3/84) 5.3% (n=3/57) 0.62 No atrial septal aneurysm 6.4% (n=15/236) 8.5% (n=20/236) 0.38 Atrial septal aneurysm 4.9% (n=7/142) 6.5% (n=9/139) 0.58

40. Adverse Events STARFlex N=402 Medical N=458 P value Major vascular complications* 3.2% (n =13) 0.0%<0.001 Atrial fibrillation5.7% (n= 14/23 periprocedural) 0.7% (n=3) <0.001 Major bleeding2.6% (n=10) 1.1% (n=4) 0.11 Deaths (all non endpoint) 0.5% (n=2) 0.7% (n=3) ns Nervous system disorders 3.2% (n=12) 5.3% (n=20) 0.15 Any SAE16.9% (n=68) 16.6% (n=76) ns *Perforation LA (1); hematoma >5cm at access site (4); vascular surgical repair (1); peripheral nerve injury (1); procedural related transfusion (3);retroperitoneal bleed (3)

41. CONCLUSIONS  First completed, prospective, randomized PFO device closure study  Superiority of PFO closure with STARFlex® plus medical therapy over medical therapy alone was not demonstrated  No significant benefit related to degree of initial shunt  No significant benefit with atrial septal aneurysm  Insignificant trend (1.8%) favoring device driven by TIA  2 year stroke rate essentially identical in both arms (3%)

42.  Major vascular (procedural) complications in 3% of device arm  Significantly higher rate of AF in device arm (5.7%)  60% AF periprocedural  Alternative explanation unrelated to paradoxical embolism present in 80% of patients with recurrent stroke or TIA

43.  Percutaneous closure with STARFlex® plus medical therapy does not offer any significant benefit over medical therapy alone for the prevention of recurrent stroke or TIA in patients < age 60 presenting with cryptogenic stroke or TIA and a PFO

44.  Del Sette et al first reported association between migraine with aura and right-to left shunts detected with transcranial Doppler  Presumed association of PFO with migraines relates to paradoxical embolism or humoral factors that escape degradation in bypassing the pulmonary circulation Migraines

45.  A retrospective evaluation of effect of transcatheter closure of atrial shunts on migraine symptoms suggested a causal association between right-to-left shunts and migraine with aura Wilmshurst PT, Nightingale S, Walsh KP, Morrison WL. Effect on migraine of closure of cardiac right-to-left shunts to prevent recurrence of decompression illness or stroke or for haemodynamic reasons.Lancet 2000;356:1648 –51

46.  Complete resolution of migraines in 60% of patients and improvement in symptoms in 40% of patients after transcatheter closure of atrial shunts Azarbal B, Tobis J, Suh W, Chan V, Dao C, Gaster R. Association of interatrial shunts and migraine headaches: impact of transcatheter closure. J Am Coll Cardiol 2005;45:489 –92.

47.  Wahl et al.  Evaluated migraine symptoms at a mean follow-up of 5years in a retrospective cohort of patients who had transcatheter PFO closure for secondary prevention of paradoxical embolism  suggesting beneficial reduction of symptoms, especially in migraine with aura

48.  Garg P etal  Recent large case-control study  No association was found between migraines and presence of PFO Garg P, Servoss SJ, Wu JC, et al. Lack of association between migraine headache and patent foramen ovale: results of a case-control study. Circulation 2010;121:1406 –12.

49.  147 patients with a history of severe migraines and without any other indication for PFO device closure were randomized to undergo either device closure or a sham procedure  Patients were treated with aspirin and clopidogrel  No significant difference in the primary outcome of headache cessation was detected between the 2 groups 3 to 6 months after the procedure  On exploratory analysis, excluding 2 outliers, the closure group showed a greater reduction in migraine headache days compared with the sham group MIST

50.  PRIMA (PFO Repair in Migraine With Aura)  PREMIUM (Prospective Randomized Investigation to Evaluate Incidence of Headache Reduction in Subjects With Migraine and PFO Using Amplatzer PFO Occluder Compared to Medical Management) Current Ongoing Clinical Trials on PFO Closure to PreventMigra ine