1. PFO CLOSURE JOURNAL REVIEW OF EVIDENCE

2.  PFO is a remnant of fetal circulation  Identified in 27% of normal patients at autopsy  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 suggest strong association  More convincingly demonstrated for younger ( 55 yrs ) PFO AND CS Lechat P, Mas JL, Lascault G, Loron P, Theard M, Klimczac M, Drobinski G, Thomas D, Grosgogeat Y. Prevalence of patent foramen ovale in patients with stroke. N Engl J Med. 1988;318:1148 –1152.

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

13.  Prevalence of PFO among younger patients (odds ratio 4.70, 95%,[CI] 1.89 to 11.68, P0.001)  Among older patients (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. CS patientsstroke of known cause 43.9%14.3% CS patientsstroke of known cause 28.3%11.9%

14.  PFO by TEE criteria in 33.8% of patients 30 to 85 years PFO in Cryptogenic Stroke Study (PICSS) Cryptogenic (N=250) Non-CS (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

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

16.  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 Di Tullio MR, Sacco RL, Sciacca RR, Jin Z, Homma S. Patent foramen ovale and the risk of ischemic stroke in a multiethnic population. J Am Coll Cardiol. 2007;49:797– 802.

17.  Estimates of annual rates of recurrent stroke among patients with PFO range from 1.5% to 12%  Numerous uncontrolled studies have shown an apparent benefit of medical therapy after a CS

18. Summary Table of Medical Therapy Studies

19.  All subjects were treated with aspirin (325 mg daily) or warfarin(INR 1.4 to 2.8,mean 2.04)  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 and without PFO PICSS Homma S, Sacco RL, Di Tullio MR, Sciacca RR, Mohr JP. Effect of medical treatment in stroke patients with patent foramen ovale: patent foramen ovale in Cryptogenic Stroke Study. Circulation. 2002;105:2625–2631

20. Percutaneous Closure of PFO  Transcatheter closure first reported in 1992 - Bridges, Lock, et al  Most commonly used devices Bridges ND, Hellenbrand W, Latson L, Filiano J, Newburger JW,Lock JE. Transcatheter closure of patent foramen ovale after presumed paradoxical embolism. Circulation 1992;86:1902– 8.

21. Summary Table of Percutaneous PFO Closure Studies

22.  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

23.  Kutty et al  Analyzed results of investigations performed for neurological events after PFO device closure reported  Combined recurrence rate for stroke/TIA -3.4%  Event rate of recurrent strokes per year -0.9% 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.

24. Summary Table of Surgical PFO Closure Studies

25.  AHA/ASA guidelines for secondary stroke prevention  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)

26.  No device specific for PFO closure after CS approved by FDA  Need for completion of appropriately powered RCTs to compare medical therapy with percutaneous device closure

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

28.  Evaluation of STARFlex device in PFO and CS or TIA  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 CLOSURE I TRIAL

29. 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 in the United States and Canada. N = 909 N=447N=462

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

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

32. 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

33. 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

34. 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)

35. CONCLUSIONS  First completed,prospective, randomized PFO device closure study  Superiority of PFO closure with STARFlex plus medical therapy over medical therapy alone 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%)

36.  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

37.  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

38.  Randomized evaluation of recurrent stroke comparing pfo closure to established current standard of care treatment  Multicenter trial  Prospective, 1:1Randomized stratified by site and atrial septal aneurysm  Sample Size: Event driven, continued enrollment until 25 th endpoint  Patients (ages 18 to 60) with PFO who had CS within 270 days RESPECT TRIAL

39.  Device Group (Test)  Closure with the AMPLATZER PFO Occluder plus medical therapy  Medical Group (Control)  5 Medical Treatment Regimens  Aspirin  Warfarin  Clopidogrel  Aspirin with dipyridamole  Aspirin with clopidogrel

40.  Percutaneous transcatheter device  Self-expanding double-disc design  Nitinol wire mesh with polyester fabric/thread  Radiopaque marker bands  Sizes: 18, 25, 35 mm  Recapturable and repositionable AMPLATZER PFO Occluder *

41.  Primary Endpoints  Recurrence of a nonfatal ischemic stroke or  Fatal ischemic stroke or  Early post-randomization death defined as all-cause mortality  Device group – within 30 days after implant or 45 days after randomization, whichever occurs latest  Medical group – within 45 days after randomization  Secondary Endpoints  Complete closure of the defect demonstrated by TEE and bubble study at 6-month follow-up (Device Group)  Absence of recurrent symptomatic cryptogenic nonfatal stroke or cardiovascular death  Absence of TIA

42. Subject Distribution 1. Aspirin + clopidogrel was removed from the protocol in 2006 based on changes to the AHA/ASA treatment guidelines TEE with bubble study at 6 months

43. CONCLUSION  RESPECT Trial provides evidence of benefit in stroke risk reduction from closure with AMPLATZER PFO occluder over medical management alone  Primary analysis of ITT cohort was not statistically significant but trended towards superiority while secondary analyses suggested superiority  Stroke risk reduction was observed across totality of analyses with rates ranging from 46.6% - 72.7%  Very low risk of device or procedure-related complications  Follow-up of patients is ongoing

44.  Percutaneous closure of patent foramen ovale versus medical treatment in patients with cryptogenic embolism PC T RIAL

45. Inclusion Criteria  Age < 60 years  Presence of PFO (with or without ASA)  Clinically and neuro-radiologically verified ischemic stroke or TIA with documented corresponding intracranial ischemic lesion or  Clinically and radiologically verified extracranial peripheral thromboembolism

46. Primary Composite Endpoint  Composite of death from any cause, non-fatal stroke,TIA, and peripheral embolism Secondary Endpoints  Myocardial infarction and peripheral thromboembolism  New arrhythmia (atrial fibrillation)  Re-hospitalization related to PFO or its treatment  Device – related problems (dislodgement, structural failure, infection, thrombosis)

47. P ATIENT F LOW 414 P ATIENTS ELIGIBLE FOR THE S TUDY 414 P ATIENTS ELIGIBLE FOR THE S TUDY A LLOCATED TO PFO C LOSURE ( N =204) Received allocated intervention (n=191) Did not receive allocated intervention (n=13) No PFO (n=1) Withdrawn due to co-morbidity (n=3) Logistical problems (n=1) Refused PFO closure (n=3) A LLOCATED TO PFO C LOSURE ( N =204) Received allocated intervention (n=191) Did not receive allocated intervention (n=13) No PFO (n=1) Withdrawn due to co-morbidity (n=3) Logistical problems (n=1) Refused PFO closure (n=3) A LLOCATED TO MEDICAL THERAPY ( N =210) Received allocated intervention (n=200) Did not receive allocated intervention (n=10) Logistical problems (n=4) Received PFO closure (n=6) A LLOCATED TO MEDICAL THERAPY ( N =210) Received allocated intervention (n=200) Did not receive allocated intervention (n=10) Logistical problems (n=4) Received PFO closure (n=6) F OLLOW – UP COMPLETE Up to 3 years (n=23) Up to 4 years (n=21) Up to 5 years (n=127) Deceased (n=2) F OLLOW – UP INCOMPLETE Withdrew (n=7) Lost to follow-up (n=24) F OLLOW – UP COMPLETE Up to 3 years (n=23) Up to 4 years (n=21) Up to 5 years (n=127) Deceased (n=2) F OLLOW – UP INCOMPLETE Withdrew (n=7) Lost to follow-up (n=24) F OLLOW – UP COMPLETE Up to 3 years (n=27) Up to 4 years (n=24) Up to 5 years (n=117) Deceased (n=0) F OLLOW – UP INCOMPLETE Withdrew (n=11) Lost to follow-up (n=31) F OLLOW – UP COMPLETE Up to 3 years (n=27) Up to 4 years (n=24) Up to 5 years (n=117) Deceased (n=0) F OLLOW – UP INCOMPLETE Withdrew (n=11) Lost to follow-up (n=31) A NALYSIS FOR P RIMARY E NDPOINT ( N =204) Censored at time of loss to follow-up, or withdrawal (n=31) A NALYSIS FOR P RIMARY E NDPOINT ( N =204) Censored at time of loss to follow-up, or withdrawal (n=31) A NALYSIS FOR P RIMARY E NDPOINT ( N =210) Censored at time of loss to follow-up, or withdrawal (n=42) A NALYSIS FOR P RIMARY E NDPOINT ( N =210) Censored at time of loss to follow-up, or withdrawal (n=42)

48. S TRATIFIED A NALYSIS OF THE P RIMARY E NDPOINT PFO C LOSURE M EDICAL T HERAPY HR (95% CI) P- INTERACTIO N Overall 7 (3.4)11 (5.2)0.63 (0.24-1.62) Age 0.10 <45 years 1 (1.1)6 (6.2)0.16 (0.02-1.31) ≥45 years 6 (5.3)5 (4.4)1.22 (0.37-3.99) Atrial septal aneurysm 0.09 Yes 4 (8.5)2 (3.9)2.09 (0.38-11.4) No 3 (1.9)9 (6.0)0.32 (0.09-1.18) CV Index event 0.78 Stroke 5 (3.1)8 (4.9)0.58 (0.19-1.76) TIA or PE 2 (5.1)3 (6.4)0.78 (0.13-4.66) More than 1 CV event 0.22 Yes 2 (2.6)6 (7.6)0.28 (0.06-1.41) No 5 (3.9)5 (3.8)0.99 (0.29-3.45).01.03.1.25.512510

49.  Percutaneous PFO closure with Amplatzer PFO Occluder for secondary prevention of thromboembolism showed no significant reduction in ischemic and bleeding events compared with medical treatment  Observed difference in stroke (80% relative risk reduction, NNT=40) may be clinically relevant if confirmed in further studies Conclusions

50.  Del Sette et al first reported association between migraine with aura and right to left shunts detected with transcranial Doppler  Relates to paradoxical embolism or humoral factors that escape degradation in bypassing pulmonary circulation Migraine

51.  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

52.  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.

53.  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

54.  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.

55.  147 patients with history of severe migraine  No other indication for PFO device closure  Randomized to undergo either device closure or sham procedure  Patients treated with aspirin and clopidogrel  No significant difference in primary outcome of headache cessation was detected between 2 groups 3 to 6 months after procedure MIST TRIAL

56.  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

57. THANK U