1. PFO Closure : a critical overview of recent data Ramesh Daggubati, MD FACC FSCAI Director of Interventional Cardiology East Carolina University Greenville, NC USA

2. Disclosure Statement of Financial Interest Consultant to St. Jude Medical

3.  PFO-related strokes, i.e. due to paradoxical embolism, have been strongly implicated as a possible cause  Patients age 20-54 are now a larger percentage of all stroke patients and among first ever strokes in the younger population there is growth in ischemic strokes 1  Cost of stroke is significant, with over $94B 2,3 spent each year in the US and EU alone – cost implications with young patients are immense, based on the loss of productivity and long-term care Background: Cryptogenic Stroke and PFO 1.Kissela, BM, Khoury, JC, Alwell, K,et al. Age at stroke Temporal trends in stroke incidence in a large, biracial population. Neurology 2012;79:1781-1787 2.Roger, V, Go, A, Lloyd-Jones, D, et. Al. Heart Disease and Stroke Statistics – 2012 Update: A Report from the American Heart Association. Circulation. 2012; 125:e2-e220 3.Allender,S, Scarborough, P, Peto, V, et al European cardiovascular disease statistics 2008 Cryptogenic stroke remains a major challenge

4. Transcatheter Closure vs Medical Therapy SECONDARY STROKE PREVENTION (recurrent event rate %) PFO ClosureMedical Therapy Khairy 2003 Meta-analysis 0-4.9%3.8-12% Windecker 2004 Retrospective 8.5% /4 ys 24.3% /4 ys Schuchlenz 2005 Retrospective 0.6% /year 13% /year Aspirin 5.6% /year Warfarin Khairy et al. Ann Intern Med 2003; 139: 753-760; Windecker et al. J Am Coll Cardiol 2004; 44: 750-758 Schuchlenz et al. J Cardiol 205; 101:77-82 - p = 0.05 p < 0.001

5. Lessons from Randomized Control Trials PFO Closure : a critical overview of recent data (1)

6. General Limitations of Randomized Control Trials (RCTs) addressing PFO Therapies Low event rates: < 2% recurrent stroke/year Difficult extrapolation of RCTs results to unselected populations in clinical practice Short follow-up duration (2-5 years) to compare long- term efficacy and safety of life-long drug treatments with interventional procedures

7. Difficult to generalize any result obtained with specific implantable device to other devices Long enrollment phase raising concerns on homogeneity of therapies Very difficult to perform RTCs when PFO closure can be obtained off-label. Selection bias with low-risk pts enrollment General Limitations of Randomized Control Trials (RCTs) addressing PFO Therapies

8. Higher risk pts get their PFO closed “off label” thus making harder to show a difference between device and medical treatment Closure I had and equal recurrence rate in the device arm because the CardioSeal/Starflex was thrombogenic and had a 14% large residual shunt. This does not mean that other trials, with better devices, have to be negative as well General Limitations of Randomized Control Trials (RCTs) addressing PFO Therapies

9. Device Principal Investigator n° pts Planned Enrolled F-up State PC-Trial (2000) Europe & Australia APOMeier B 500 4005 ycompleted RESPECT (2003) US APOSaver JL 900 9802 ycompleted CLOSURE I (2003) US & Canada STARflex Furlan A, Reisman M 1600* 9002 ycompleted REDUCE (2008) US & Denmark HelexKasner SE 664 5 yEnrolling CARDIA PFO Stroke Trial (2007) CardiaMooney MR 300 1001 yRecruiting CLOSE (2007) France Mas JL 900 3-5 yRecruiting * 2007 (april) FDA consent to reduce numbers to 900; APO= Amplatzer PFO Occluder RANDOMIZED PFO CLOSURE TRIALS

11. CLOSURE I enrolled –Wrong patients –Wrong PFOs –Wrong device RANDOMIZED PFO CLOSURE TRIALS

18. Subpopulation Differential Treatment Effect 24

19. That device closure is feasible That device closure is safe (complications 0-1.6%) That device closure is effective What does RESPECT learn us?

21. How to select patients PFO Closure : a critical overview of recent data (2)

22. The management of patients with Cryptogenic Stroke and PFO is controversial High level unbiased data do not yet exist to guide our clinical decisions with these challenging patients How to select PFO patients ?

25. Transient Ischemic Attack (TIA) / Crytogenic Stroke Migraine with Aura Orthostatic desaturation in the setting of platypnea-orthodeoxia syndrome Decompression illness and ischemic cerebral lesions in divers Paradoxical air embolism and desaturation during neurosurgical procedures (posterior fossa surgey) Obstructive sleep apnoea Peripheral and coronary embolism Refractory hypoxaemia in patients with right ventricular infarction or pulmonary hypertension PFO related conditions How to select PFO patients ?

26. SELECT APPROPRIATE PATIENTS - I Cardioembolic stroke –DWI multiple early lesions –Lesions in different territories –Posterior or cortical distribution rule out dissection There were no differences in occurrence of multiple lesion pattern in patients with cryptogenic stroke compared to patients with PFO neither for the entire group nor for a subgroup of young stroke patients less than 50 years. Patients with PFO showed a significantly higher incidence of multiple lesions in the posterior circulation

27. SELECT APPROPRIATE PATIENTS - II Collect evidence favouring paradoxical embolism as the most likely mechanism Exclude paroxysmal AF with appropriately long Holter monitoring (or, better, telemetry) –Systematic investigation of factors predisposing to DVT: Prolonged immobilization – recent prolonged travel Leg trauma Surgery – Anesthesia Coagulation disorders [Factor V Leiden - Prothrombin (G20210A)] –Search for anatomical variants and DVT in unusual locations –D-Dimer measurement –Stroke on awakening (association with OSAS) –Valsalva at onset –Exclusion of ANY other RF

28. Collect evidence favouring paradoxical embolism as the most likely mechanism Exclude paroxysmal AF with appropriately long Holter monitoring (or, better, telemetry) –Systematic investigation of factors predisposing to DVT: Prolonged immobilization – recent prolonged travel Leg trauma Surgery – Anesthesia Coagulation disorders [Factor V Leiden - Prothrombin (G20210A)] –Search for anatomical variants and DVT in unusual locations –D-Dimer measurement –Stroke on awakening (association with OSAS) –Valsalva at onset –Exclusion of ANY other RF SELECT APPROPRIATE PATIENTS - II

29. SELECT APPROPRIATE PATIENTS - III Identify “pathological” PFOs: –Association with ASA –Large (> 2mm) PFO size –Eustachian valve –>1 cm long tunnel –Large shunt on bubble test –Permanent shunt

30. SELECT APPROPRIATE PATIENTS - IV Look for systemic embolization –Occult PE

31. Look for systemic embolization –Occult PE –Silent heart lesions –Renal infarcts (?) Conclusions: Subclinical myocardial infarctions determined in CMRI were observed in 10.8% of patients with PFO after a first cryptogenic cerebral ischemic event. Our results strengthen the pathophysiologic role of a PFO with paradoxical embolism in patients with cryptogenic cerebral ischemic events. Wohrle et al.J Am Coll Cardiol Img, 2010; 3:833-839 SELECT APPROPRIATE PATIENTS - IV

32. SELECT THE APPROPRIATE DEVICE Low profile devices so as to minimize: –Anatomical distortion –Risk of local thrombosis –Risk of late erosion –Risk of inducing AF

33. SELECT THE APPROPRIATE LENGTH OF F-UP

34. Management of patients with cryptogenic stroke and patent foramen ovale  Recently, a consensus statement of recommendations was developped by approaching Italian Scientific Societies to address the urgent need of adopting a comprehensive and rationale workflow in the management of patients with Cryptogenic Stroke and PFO  The goal was to organize a common approach that may be shared by different specialists

35. Catheter Cardiovasc Interv. 2012 Aug 31. doi: 10.1002/ccd.24637 [Epub ahead of print]

36. MANAGEMENT OF PATIENTS WITH CRYPTOGENIC STROKE AND PATENT FORAMEN OVALE

37. A multidisciplinary shared approach may become a basis for a joint management of these patients, while waiting for more consistent evidences Team-based, multidisciplinary clinical judgment on an individual basis still remains the core of decision- making MANAGEMENT OF PATIENTS WITH CRYPTOGENIC STROKE AND PATENT FORAMEN OVALE

38. The future of PFO Closure PFO Closure : a critical overview of recent data (3)

39. In my view, the challenge now for the endovascular community is to refine the selection criteria The future of PFO Closure

40. “Some more indications” Decompression sickness Platypnea-orthodeoxia Syndrome Major orthopaedic surgery Posterior fossa surgery Obstructive sleep apnoea Peripheral or coronary embolism The future of PFO Closure

41. Results with newer devices may be better ! The future of PFO Closure

42. There is a trend towards: –Devices with less material –Bioresorbable devices –Non-device closure techniques Take Home Message

43. lower profile and less foreign material could reduce risk of thrombus formation softer devices and in-tunnel devices could reduce septal distortion and risk of atrial fibrillation bioresorbable devices and non device closure techniques could prevent unknown long-term device related complications The future of PFO Closure