PFO Closure: clear and borderline indications and cases where there is no evidence of benefit

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

2. PFO Closure:clear and borderline indications and cases where there is no evidence of benefit Research Grants NMT medical Edwards Life Science Corevalve Inc Medical Advisory Board Sutura Inc Cardio-optics Consultancy Sutura Inc I have a PFO

3. Stroke DCI Migraine Cyanosis OSA Dementia COPD

4. Prevalence of PFO CFS Dementia COPD OSA DCI Migraine Stroke/TIA 0 20 40 60 80 100 % with PFO

5. 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

6. Stroke

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

8. Patent Foramen OvaleCryptogenic stroke 60 50 40 % with PFO 30 20 10 0 All Other cause RF CS Lechat P; NEJM 1988

9. Patent Foramen OvaleMeta-analysis of risk of stroke PFO All ASA PFO +ASA Age<55 PFO ASA PFO +ASA Age>55 PFO ASA PFO +ASA CS vs IC PFO ASA PFO +ASA 1 5 10 15 20 25 30 Overell Neurology 2000

10. Patent Foramen OvaleCS 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+ASA 15.2% (95%CI: 1.8 to 28.6) • No PFO 4.2% (95%CI: 1.8 to 6.6)

11. Device Closure of PFO Windecker; JACC 2004

12. Device Closure of PFODevice closure vs medical therapy Khairy; Heart 2004

13. Device Closure of PFORCTs in Stroke • RESPECT PFO (USA) • 500 patients • Amplatzer PFO vs standard medical therapy • Equivalence trial • Recruitment nearing completion • PC trial (Europe) • 410 patients • Amplatzer PFO device vs medical therapy • Recruitment nearing completion • 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???

14. Device Closure of PFOIndications for closure • Clear • Proven cryptogenic stroke • Pathological PFO • Young age • Multiple events or recurrence on treatment • Borderline • First stroke • TIA • Small PFO • Older age with other RFs • Little evidence of benefit • Primary prevention of stroke • Trivial shunt • Other clear cause

15. Stroke DCI

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

17. Stroke DCI Migraine

18. PFO and migraine • Prevalence of migraine increased in patients with PFO • Prevalence of PFO increased in patients with migraine • PFO and migraine both associated with cryptogenic stroke Shwedt Cephalgia 2006 Stang Neurology 2005

19. Wilmshurst 2000 37 57% 86% Morandi 2003 62 27% 88% Schwerzmann 2004 215 22% 81% Post 2004 66 39% 65% cured Reisman 2004 120 42% 90% Azarbal, 2005 89 42% 76% Reisman 2005 162 35% 70% Kimmelstein 2007 Luermans 2008 Giardini 2006 Dubiel 2008 191 24% 92 27% 131 27% 41 24% 91% 80% 70% 87% Effect of PFO Closure on MigraineObservational studies No (%) migraine % improved or cured

20. 8 Pre 7 Post 6 5 4 3 2 1 0 SS SA Ctrls Effect of PFO Closure on Migraineprospective studies • 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 Stroke 2006

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

22. MIST I Study • 163/432 (38%) patients had right to left shunts consistent with a moderate or large PFO. • 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).

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

24. MIST I Study • RCTs 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

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

26. MIST I Study • Too short • Device performance • Confounding effects of aspirin and clopidogrel • Other shunts • Wrong endpoint

27. Should PFO be closed for migraine • 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 justified

28. PFO and migraineCase History 13 yr old girl Frequent incapacitating vertigo Headache Occ visual aura Well between attacks Normal neurological examination Normal MRI and EEG Missing significant amount of school Large resting shunt on echo

29. PFO and migraineCase History • Neurological opinion • Met 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) • Catheterisation under GA July 2007 • Large PFO – closed with 28 mm BioSTAR • No complications • FU Jan 08 • Almost complete resolution of symptoms • No loss of school

30. Stroke DCI Migraine Cyanosis

31. Stroke DCI Migraine Cyanosis OSA Dementia COPD

32. Orthodeoxyia Platypnoea • Postural related hypoxia due to large PFO • Post pneumonectomy • Aortic root dilatation • Usually very large PFO • PFO closure results in immediate improvement • Anecdotal reports and small case series only

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

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

35. Superstitch

36. Conclusion • Large 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 patients • Results 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) benefit