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Patent foramen ovale

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Patent foramen ovale (PFO), is a type of atrial septal defect.

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Patent foramen ovale

  1. 1. Sydney Adventist Hospital Hornsby Ku-ring-gai Hospital Dr Jason Sharp MB BS FRACP FCSANZ Consultant Cardiologist
  2. 2. History  1877 – Conheim autopsy  1972 – only 128 cases of unexplained stroke had been reported in the literature  1997 – Amplatzer ASD closure device used in animals – nitinol double umbrella filled with polyester (Dacron) fabric  2012 – CLOSURE-I trial published
  3. 3. Ms EW case of a persistent neurologist  43yo female. Sensory stroke symptoms but clouded with history of possible migraine. Subtle changes on MRI + page missing but on further review it was felt there was a right thalamic stroke fitting with the symptoms. Mildly abnormal procoagulant screen. OCP (ceased).  TOE initially showed negative bubble study via antecubital vein, no PFO, mobile interatrial septum.  Referred to me for second opinion.
  4. 4. Ms EW  RepeatTOE revealed atrial septal aneurysm and PFO with positive bubble study via right femoral vein.  Admitted to hospital for PFO closure. Lesion unable to be crossed. Multiple bubble studies negative while patient ventilated.  Recommendation?
  5. 5. Ms EW continued…  Readmitted to another hospital with subsequent successful closure.
  6. 6. PFO detection  TOE  Bubble study  Femoral vs ante-cubital vein (SVC blood directed toward tricuspid valve, IVC blood directed toward PFO).  Saline vs dedicated echo contrast media  Valsalva  Degree of shunting (<5, 5-25, >25 bubbles)  Transcranial doppler
  7. 7. Methods do matter  Hamann et al: TOE/TCD detection rate was:  11.4%/4.5% via antecubital injection  18%/13.6% via antecubital injection plus the Valsalva manoeuvre  38.6%/36% via femoral injection alone  50%/50% via femoral injection plus the Valsalva manoeuvre (Neurology 1998, 50: 1423-1428)
  8. 8. What is an Atrial Septal Aneurysm?  Redundant and hypermobile portion of interatrial septum with >10mm excursion from the centreline during the cardiac cycle.  Some papers define >15mm total excursion.  2.2% ofTOE patients  4.3% of PFO patients
  9. 9. How does PFO and / or ASA cause stroke? 1. Embolisation from the venous system (e.g. DVT) to the arterial system & brain. • But there is a low rate of DVT found in these patients. • Look for history of Valsalva manoeuvre at time of stroke. 2. In situ thrombus formation 3. Atrial dysfunction
  10. 10. Is PFO a stroke risk? Overell, Bone & Lees, 2000 Neurology 55: 1172-1179. Meta-analysis of case-control studies Relative risks:  PFO 1.83 (1.25-2.66; 15 studies)  ASA 2.35 (1.46-3.77; 9 studies)  Both 4.96 (2.37-10.39; 4 studies)
  11. 11. Is PFO a stroke risk? Size of defect Migraine history More than 1 previous event Other factors (external)  Valsalva, cough, OSA  Mechanical ventilation  Surgical operations  (joint replacement, sitting posture)  Diving, aviation
  12. 12. Atrial dysfunction theory  Rigatelli et al JACC (Cardiovasc Int) July 2009  98 patients with PFO, previous stroke  50 AF controls  70 risk matched controls  Measured left atrial emptying and several other atrial function parameters.  Atrial septal aneurysm was associated with worse atrial function.  Atrial function normalised after PFO closure.
  13. 13. Age, PFO and stroke Overell et al 2000 Age range Relative Risk of Stroke <55 years RR 6 >55 years RR 2.26
  14. 14. Randomised Data?  Thanopoulos et al Catheterization & Cardiovasc Interventions Nov 2006  Non-randomised patient preference study of 92 patients with cryptogenic stroke and PFO.  2 year follow-up of antiplatelet vs closure.  0% events in closure group, 14.75% in antiplatelet group.
  15. 15. What to do about PFO? PFO in Cryptogenic Stroke Study PICSS Circulation 2002  630 strokes; 34% had PFO; half to aspirin, half to warfarin; 2 year follow-up, endpoints were death or ischaemic stroke, many older patients  No significant differences, if on treatment:  With or without PFO  Related to size of PFO  With or without atrial septal aneurysm  Between treatments  BUT!! INR target was 1.4-2.8. Only 265 had CS!!  In crypotogenic stroke with PFO 9.5% risk in warfarin group, 16.3% in aspirin group but p=0.16
  16. 16. PFO and stroke Mas et al NEJM 2001  Approximately 27% of “normal” people have a PFO.  581 patients with cryptogenic stroke treated with aspirin. 4 years follow-up. Prospective data. Recurrent stroke risk PFO and ASA 15.2% PFO alone or neither PFO nor ASA 2 to 4% • Therefore aspirin is not providing adequate protection. • SPARC data also showed ASA at high risk • Spontaneous passage of bubbles also a risk factor
  17. 17. Study Design  Prospective, multi-center, randomized, open-label, two-arm superiority trial designed to test whether PFO closure using STARFlex® plus medical therapy is superior to medical therapy alone for preventing recurrent stroke orTIA in patients with cryptogenic stroke orTIA and a PFO  Study population: Patients 60 years old or younger with a cryptogenic stroke orTIA and a PFO documented byTOE, with or without atrial septal aneurysm, within 6 months of randomization  DVT, hypercoagulopathy excluded  Primary endpoint : 2-year incidence of stroke orTIA, all cause mortality for the first 30 days, and neurological mortality 31 days to 2 years
  18. 18. Baseline Characteristics ITT STARFlex Medical P value N randomized 447 462 Mean Age 46.3 (18-61) 45.7(18-61) Male 52.1% 51.5% White 89% 90% Index cryptogenic stroke 73% 71% Mod/substantial shunt* 58% (231/400) 51% (228/451) 0.04 ASA > 10 mm* 38% (151/400) 35% (160/451) 0.49 * modified ITT
  19. 19. 2 Year Primary Endpoint ITT STARFlex n = 447 Medical n = 462 Adjusted P value* Composite 5.9% (n=25) 7.7% (n=30) 0.30 Stroke 3.1% (n=12) 3.4% (n=13) 0.77 TIA 3.3% (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
  20. 20. Adverse Events STARFlex N=402 Medical N=458 P value Major vascular complications* 3.2% (n =13) 0.0% <0.001 Atrial fibrillation 5.7% (n= 14/23 periprocedural) 0.7% (n=3) <0.001 Major bleeding 2.6% (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 SAE 16.9% (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)
  21. 21. Composite Primary Endpoint Baseline Shunt and Atrial Septal Aneurysm (TEE) STARFlex N=400 Medical N=451 P value Trace shunt 7.0% (n=8/114) 8.0% (n=10/126) 0.75 Moderate shunt 5.3% (n=7/132) 8.4% (n=12/143) 0.31 Substantial shunt 3.6% (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
  22. 22. Aspirin versus Warfarin (physician discretion) Aspirin alone (n=243) Warfarin alone (n=139) P value Composite 6.7% (n=14) 8.1% (n=9) 0.63 Stroke 3.9% (n=8) 2.7% (n=3) 0.67 TIA 2.9% (n=6) 6.3% (n=7) 0.09
  23. 23. CONCLUSIONS  CLOSURE I is the first completed, prospective, randomized, independently adjudicated 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 byTIA  2 year stroke rate essentially identical in both arms (3%)  Major vascular (procedural) complications in 3% of device arm  Significantly higher rate of atrial fibrillation in device arm (5.7%)  60% periprocedural
  24. 24. CONCLUSIONS  Alternative explanation unrelated to paradoxical embolism present in 80% of patients with recurrent stroke orTIA  cryptogenic stroke andTIA include multiple etiologies  in many patients with cryptogenic stroke orTIA a PFO may be coincidental  diagnostic criteria for paradoxical embolism are imprecise  potential efficacy of PFO device closure in better defined patient subgroups requires further study  Percutaneous closure with STARFlex® plus medical therapy does not offer any significant benefit over medical therapy alone for the prevention of recurrent stroke orTIA in patients < age 60 presenting with cryptogenic stroke orTIA and a PFO
  25. 25. CLOSURE-I trial - Issues  Procedural success 90%. “Effective closure” 86%.  So ITT closure only 77%.  BUT! “Effective closure” included trace shunting or no shunting. Pre-procedure 114 of 400 Starflex patients had trace shunting.Therefore real closure rate even lower (possibly as low as 50%).  Thrombus on device 1%.  Small absolute numbers of events.  Slow recruitment. Short follow-up.  Results incongruent with previous data
  26. 26. Incidental PFO?  Alsheikh-Ali et al, Stroke 2009  Analysis of 23 case-control studies examining presence of PFO in pts with CS (total approx 2300 pts).  In patients with CS  1/3 of PFOs are likely to be incidental in all age groups  1/5 in younger age group  1/10 if ASA + PFO
  27. 27. Starflex vs Amplatzer
  28. 28. Where to from here?  RESPECT trial  Maybe RCTs are not the answer?  Good quality registry needed.

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