2. PFO Closure: clear and borderline indications and cases where there is no evidence of benefit Michael Mullen Royal Brompton Hospital London

3. PFO Closure: clear and borderline indications and cases where there is no evidence of benefit Research GrantsNMT medical Edwards Life Science Corevalve Inc Medical Advisory BoardSutura Inc Cardio-optics ConsultancySutura Inc I have a PFO

4. Stroke Migraine DCI Cyanosis Dementia COPD OSA

5. Prevalence of PFO 020406080100 Stroke/TIA Migraine DCI OSA COPD Dementia CFS % with PFO

6. PFO Closure: clear and borderline indications and cases where there is no evidence of benefit “The only good PFO is a closed PFO” …..Dr Bernard Meier “There is no clear indication for PFO closure” …..Most neurologists

7. Stroke

8. Webster MW; Lancet 1988Webster MW; Lancet 1988 –40 stroke patients < 40 yrs old + matched controls –Contrast echo +ve 50% of patients 15% controls Lechat P; NEJM 1988Lechat P; NEJM 1988 –60 stroke patients < 55 yrs old + 100 controls Patent Foramen Ovale Cryptogenic stroke

9. 0 10 20 30 40 50 60 AllOther cause CSRF Lechat P; NEJM 1988 % with PFO

10. Patent Foramen Ovale Meta-analysis of risk of stroke 151015202530 PFO All PFO +ASA ASA PFO Age<55 ASA PFO Age>55 ASA PFO CS vs IC PFO +ASA ASA Overell Neurology 2000

11. Patent Foramen Ovale CS recurrence rate –Mas JL et al; NEJM 2001 –581 patients with CS followed for over 4 yrs –All patients received Aspirin 300mg/day –Recurrence rates PFO 2.3% (95%CI: 0.3 to 4.3)PFO 2.3% (95%CI: 0.3 to 4.3) PFO+ASA15.2% (95%CI: 1.8 to 28.6)PFO+ASA15.2% (95%CI: 1.8 to 28.6) No PFO 4.2% (95%CI: 1.8 to 6.6)No PFO 4.2% (95%CI: 1.8 to 6.6)

12. Device Closure of PFO Windecker; JACC 2004

13. Device Closure of PFO Device closure vs medical therapy Khairy; Heart 2004

14. Device Closure of PFO RCTs in Stroke RESPECT PFO (USA)RESPECT PFO (USA) –500 patients –Amplatzer PFO vs standard medical therapy –Equivalence trial –Recruitment nearing completion PC trial (Europe)PC trial (Europe) –410 patients –Amplatzer PFO device vs medical therapy –Recruitment nearing completion Closure I trial (USA)Closure I trial (USA) –Starflex vs best medical therapy in CS with PFO –800 patients powered to test superiority over medical treatment –Recruitment completed Q4 2008 –Results Q4 2009???

15. Device Closure of PFO Indications for closure ClearClear –Proven cryptogenic stroke –Pathological PFO –Young age –Multiple events or recurrence on treatment BorderlineBorderline –First stroke –TIA –Small PFO –Older age with other RFs Little evidence of benefitLittle evidence of benefit –Primary prevention of stroke –Trivial shunt –Other clear cause

16. Stroke DCI

17. Decompression illness and PFO First reported by Wilmshurst in BMJ 1986 postulated link between PFO and DCIFirst reported by Wilmshurst in BMJ 1986 postulated link between PFO and DCI Risk of DCI increased x5 in divers with PFORisk of DCI increased x5 in divers with PFO Increased incidence with size of defectIncreased incidence with size of defect Torti et al Eur H J 2004 No data on benefit of closureNo data on benefit of closure Despite this closure recommended for professional diversDespite this closure recommended for professional divers Social divers have the option of giving up, diving within safe limits or having PFO closureSocial divers have the option of giving up, diving within safe limits or having PFO closure

18. Stroke Migraine DCI

19. PFO and migraine Prevalence of migraine increased in patients with PFOPrevalence of migraine increased in patients with PFO Prevalence of PFO increased in patients with migrainePrevalence of PFO increased in patients with migraine PFO and migraine both associated with cryptogenic strokePFO and migraine both associated with cryptogenic stroke Stang Neurology 2005 Shwedt Cephalgia 2006

20. Effect of PFO Closure on Migraine Observational studies 70% 162 35% Reisman 2005 76% 89 42% Azarbal, 2005 90% 120 42% Reisman 2004 65% cured 66 39% Post 2004 81% 215 22% Schwerzmann 2004 88% 62 27% Morandi 2003 86% 3757% Wilmshurst 2000 % improved or cured (%) migraine No91% 131 27% Giardini 2006 80% 41 24% Kimmelstein 2007 70% 92 27% Luermans 2008 87% 191 24% Dubiel 2008

21. Effect of PFO Closure on Migraine prospective studies 0 1 2 3 4 5 6 7 8 SSSACtrls Pre Post Stroke 2006 N=77 All patients had migraine PFO closure SS - Previous stroke N=23 SA - No stroke N=27 DCI, TIA, migraine,MI No PFO closure Ctrls - N=27 Follow-up 1 year Composite score of migraine frequency, severity and aura

22. MIST I Study Protocol Assessment by headache specialist 3 month analysis phase by headache specialist TOE under GA and randomisation Contrast echo 3 month healing phase PFO closure with Starflex Sham procedure

23. MIST I Study 163/432 (38%) patients had right to left shunts consistent with a moderate or large PFO.163/432 (38%) patients had right to left shunts consistent with a moderate or large PFO. 147 patients were randomised.147 patients were randomised. No difference in the primary endpoint of migraine headache cessation between the implant and sham groups (3/74 versus 3/73 respectively).No difference in the primary endpoint of migraine headache cessation between the implant and sham groups (3/74 versus 3/73 respectively).

24. MIST I Study What went wrong?What went wrong? Why MIST I results so different from previous observational data?Why MIST I results so different from previous observational data?

25. MIST I Study RCTs often less positive than observational studiesRCTs often less positive than observational studies –Prospective and contemporaneous measurement of outcomes –Better recording of AEs –inclusion and exclusion criteria bias population so becomes non representative

26. MIST I Study –MIST I patients were fundamentally different to those in the observational studies Severe, migraine refractory to medical treatmentSevere, migraine refractory to medical treatment IHS guidelines lack precision and may include patients with CDH, depressionIHS guidelines lack precision and may include patients with CDH, depression Patients with other indications for PFO closure excludedPatients with other indications for PFO closure excluded

27. MIST I Study Too shortToo short Device performanceDevice performance Confounding effects of aspirin and clopidogrelConfounding effects of aspirin and clopidogrel Other shuntsOther shunts Wrong endpointWrong endpoint

28. Should PFO be closed for migraine Results of MIST study do not support routine PFO closure for migraine alone –Results of MIST study do not support routine PFO closure for migraine alone – however observational data still highly suggestive of link and in selected cases it is justifiedhowever observational data still highly suggestive of link and in selected cases it is justified

29. PFO and migraine Case History 13 yr old girl13 yr old girl Frequent incapacitating vertigoFrequent incapacitating vertigo HeadacheHeadache Occ visual auraOcc visual aura Well between attacksWell between attacks Normal neurological examinationNormal neurological examination Normal MRI and EEGNormal MRI and EEG Missing significant amount of schoolMissing significant amount of school Large resting shunt on echoLarge resting shunt on echo

30. PFO and migraine Case History Neurological opinionNeurological opinion Met with parents and patient on 2 occasionsMet with parents and patient on 2 occasions Explained potential for benefit (~50%) and potential for complication (death <1:1000, embolization 1:200, tamponade 1:500, stroke 1:500, transient AF 1:10)Explained potential for benefit (~50%) and potential for complication (death <1:1000, embolization 1:200, tamponade 1:500, stroke 1:500, transient AF 1:10) Catheterisation under GA July 2007Catheterisation under GA July 2007 Large PFO – closed with 28 mm BioSTARLarge PFO – closed with 28 mm BioSTAR No complicationsNo complications FU Jan 08FU Jan 08 Almost complete resolution of symptomsAlmost complete resolution of symptoms No loss of schoolNo loss of school

31. Stroke Migraine DCI Cyanosis

32. Stroke Migraine DCI Cyanosis Dementia COPD OSA

33. Orthodeoxyia Platypnoea Postural related hypoxia due to large PFOPostural related hypoxia due to large PFO –Post pneumonectomy –Aortic root dilatation Usually very large PFOUsually very large PFO PFO closure results in immediate improvementPFO closure results in immediate improvement Anecdotal reports and small case series onlyAnecdotal reports and small case series only

34. Hacievliyagil S et al. Respir Med 2006 PFO closure for respiratory disorders PFO closure for respiratory disorders Anecdotal reports of benefit in selected patientsAnecdotal reports of benefit in selected patients Few small trials ongoingFew small trials ongoing Should not be part of routine practiceShould not be part of routine practice

35. Indications for PFO closure Benefit Likelihood of causal relationship Size of shunt Risk Size of defect Experience of operator Technological advances

36. Superstitch

37. Conclusion Large body of evidence for pathological link between PFO and a range of clinical syndromes where right to left shunt is a plausible mechanismLarge body of evidence for pathological link between PFO and a range of clinical syndromes where right to left shunt is a plausible mechanism Increasing observational data suggests benefit in some patientsIncreasing observational data suggests benefit in some patients Results of RCTs awaitedResults of RCTs awaited In the meantime PFO closure indicated in selected patients with clinical syndrome and ‘pathological’ shunt if they understand and accept the potential for complications and potential for (or lack of) benefitIn the meantime PFO closure indicated in selected patients with clinical syndrome and ‘pathological’ shunt if they understand and accept the potential for complications and potential for (or lack of) benefit