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PFO CLOSURE

PFO CLOSURE. JOURNAL REVIEW OF EVIDENCE. 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. PFO is a remnant of fetal circulation

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PFO CLOSURE

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  1. PFO CLOSURE JOURNAL REVIEW OF EVIDENCE

  2. 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. PFO is a remnant of fetal circulation Identified in 27% of normal patients at autopsy Prevalence decline with age

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

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

  5. DIAGNOSIS 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

  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

  7. 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

  8. CRYPTOGENIC STROKE 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

  9. 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. Association was first reported in 1988 by Lechat et al Numerous observational studies suggest strong association More convincingly demonstrated for younger (< 55 yrs age) than older patients (>55 yrs )

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

  11. Handke M, Harloff A, Olschewski M, et al. PFO and cryptogenic stroke in older patients. N Engl J Med. 2007;357:2262– 8. 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)

  12. PFO in Cryptogenic Stroke Study (PICSS) PFO by TEE criteria in 33.8% of patients 30 to 85 years Homma S: Circulation, Volume 105(22).June 4, 2002.2625-2631

  13. Meissner I, Khandheria BK, Heit JA, et al. Patent foramen ovale:innocentor guilty? Evidence from a prospective population-based study.JAm CollCardiol. 2006;47:440 –5. 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

  14. 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 CollCardiol. 2007;49:797– 802. 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

  15. 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

  16. Summary Table of Medical Therapy Studies

  17. 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 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

  18. 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, NewburgerJW,Lock JE. Transcatheter closure of patent foramen ovale after presumed paradoxical embolism. Circulation 1992;86:1902– 8.

  19. Summary Table of Percutaneous PFO Closure Studies

  20. 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 Systematic review of nonrandomized studies of transcatheterclosure (n10) or medical therapy (n6)

  21. 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. 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%

  22. Summary Table of Surgical PFO Closure Studies

  23. 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)

  24. 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

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

  26. CLOSURE I TRIAL 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

  27. N = 909 N=447 N=462 Between June 23, 2003 and October 24, 2008 in the United States and Canada.

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

  29. 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

  30. 2 Year Primary Endpoint ITT *Adjusting performed using Cox Proportional Hazard Regression and adjusting for related patient characteristics including: age, atrial septal aneurysm, prior TIA/CVA, smoking, hypertension, hypercholesterolemia

  31. Composite Primary EndpointBaseline Shunt and Atrial Septal Aneurysm (TEE)

  32. Adverse Events *Perforation LA (1); hematoma >5cm at access site (4); vascular surgical repair (1); peripheral nerve injury (1); procedural related transfusion (3);retroperitoneal bleed (3)

  33. 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%)

  34. 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

  35. Percutaneous closure with STARFlexplus 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

  36. RESPECT TRIAL • 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 25th endpoint • Patients (ages 18 to 60) with PFO who had CS within 270 days

  37. 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

  38. AMPLATZER PFO Occluder • Percutaneoustranscatheter 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 *

  39. 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

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

  41. CONCLUSION • RESPECT Trial provides evidence of benefit in stroke risk reduction from closure with AMPLATZER PFO occluderover 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

  42. PC Trial • Percutaneous closure of patent foramen ovale versus medical treatment in patients with cryptogenic embolism

  43. 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

  44. 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)

  45. Patient Flow 414 Patients eligibleforthe Study Allocatedto PFO Closure (n=204) Receivedallocatedintervention (n=191) Did not receiveallocatedintervention (n=13) No PFO (n=1) Withdrawn due toco-morbidity (n=3) Logisticalproblems (n=1) Refused PFO closure (n=3) Allocatedtomedicaltherapy (n=210) Receivedallocatedintervention (n=200) Did not receiveallocatedintervention (n=10) Logisticalproblems (n=4) Received PFO closure (n=6) Follow – upcomplete Upto 3 years (n=23) Upto 4 years (n=21) Upto 5 years (n=127) Deceased (n=2) Follow – upincomplete Withdrew (n=7) Lost tofollow-up (n=24) Follow – upcomplete Upto 3 years (n=27) Upto 4 years (n=24) Upto 5 years (n=117) Deceased (n=0) Follow – upincomplete Withdrew (n=11) Lost tofollow-up (n=31) Analysis for Primary Endpoint (n=204) Censoredat time oflosstofollow-up, orwithdrawal (n=31) Analysis for Primary Endpoint (n=210) Censoredat time oflosstofollow-up, orwithdrawal (n=42)

  46. Stratified Analysis of the Primary Endpoint .01 .03 .1 .25 .5 1 2 5 10

  47. Conclusions • 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

  48. Migraine 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

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