1. P ERCUTANEOUS C LOSURE OF P ATENT F ORAMEN O VALE VERSUS M EDICAL T REATMENT IN P ATIENTS WITH C RYPTOGENIC E MBOLISM : T HE PC T RIAL NCT00166257 Bernhard Meier, Bindu Kalesan, Ahmed A. Khattab, David Hildick-Smith, Dariusz Dudek, Grethe Andersen, Reda Ibrahim, Gerhard Schuler, Antony S. Walton, Andreas Wahl, Stephan Windecker, Heinrich P. Mattle, and Peter Jüni

2. B ACKGROUND A cause-effect relationship between the presence of a PFO and risk of stroke of unknown origin is supported by  Consistency of the association  Biologic plausibility  Dose-response relationship  Proven paradoxical embolism

3. B ACKGROUND A cause-effect relationship between the presence of a PFO and risk of stroke of unknown origin is supported by  Consistency of the association  Biologic plausibility  Dose-response relationship  Proven paradoxical embolism Percutaneous PFO closure is a safe and effective minimal-invasive procedure to eliminate the atrial right-to-left shunt

4. Whether percutaneous PFO closure is superior to medical treatment among patients with stroke of unknow origin remains controversial  Observational studies suggest a lower risk of recurrence with PFO closure compared with medical treatment  CLOSURE I failed to show superiority of PFO closure over medical treatment  Outcomes may be influenced by device-type in terms of closure success and thrombus formation B ACKGROUND

5. S TUDY H YPOTHESIS Among patients with cryptogenic stroke and peripheral embolism percutaneous closure of patent foramen ovale (PFO) using the Amplatzer PFO Occluder is superior to medical treatment with antiplatelet agents or Vitamin K antagonists for secondary prevention of thromboembolism.

6. P ROCEDURES P ERCUTANEOUS PFO C LOSURE Amplatzer PFO Occluder Acetylsalicylic acid (100-325mg qd) and ticlopidine (250-500mg qd) or clopidogrel (75mg qd) for 6 months 1:1 RCT M EDICAL T REATMENT Oral anticoagulation or Antiplatelet therapy at the discretion of the neurologist

7. P ATIENT P OPULATION I NCLUSION C RITERIA Age < 60 years Presence of PFO (with or without ASA) Clinically and neuro-radiologically verified ischemic stroke or transient ischemic attack (TIA) with documented corresponding intracranial ischemic lesion or Clinically and radiologically verified extracranial peripheral thromboembolism Sufficient recovery from the thomboembolic index event to allow independent daily activities

8. P ATIENT P OPULATION E XCLUSION C RITERIA Cause for thromboembolic event other than PFO Cardiac (mural thrombus, DCM, Afib, prosthetic heart valves) Cerebral (significant intracranial disease, relevant atherosclerosis, dissection of intra- or extracranial arteries) Vascular (arteritis, vasculitis, collagen vascular disease) Hematological (hyperviscosity syndrome, hypercoagulable state) Contraindication for chronic antithrombotic Rx Clinical indication other than PFO for chronic antithrombotic Rx Previous surgical or percutaneous PFO closure Central nervous system disease seizure disorder, disability from previous stroke, etc.

9. E NDPOINTS AND S AMPLE S IZE Composite of death from any cause, non-fatal stroke, TIA, and peripheral embolism 205 patients per group provide 80% power to detect a reduction in the primary composite endpoint from 3% to 1% at a mean follow-up of 4.5 years and an α-level of 0.0492 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) P RIMARY C OMPOSITE E NDPOINT S ECONDARY E NDPOINTS

10. E NDPOINT D EFINITIONS Death  Fatal stroke  Cardiovascular death  Non-cardiovascular death Stroke  Acute focal neurological deficit lasting >24 hours with MRI or CT evidence of new intracranial lesion Peripheral embolism  End-organ ischemia other than in the brain documented by Duplex, CT, MRI, or angiography TIA  Acute neurologic deficit lasting <24 hours with complete resolution

11. S TUDY C ENTERS AND I NVESTIGATORS Australia Monash Medical Center, MelbourneS. Menahem, S. Bower, R. Harper Sir Charles Gairdner Hospital, NedlandsB.E.F. Hocking, W.Carroll Epworth Hospital, PrahranT.Walton Alfred Hospital, PrahranJ. Frayne, M. Butler, L. Iles, E. Ivens, J.Hare, E. Kotschet Austria Uni-Klinik Innere Med II, AKH ViennaP. Probst, W. Lalouschek, H. Baumgartner, R. Rosenhek Belgium A.Z. Sint-Jan AV, BruggeG. Vanhoorem, L. Muyldermans Brazil Hospital Sao Paulo, Sao PauloA.C.C. Carvalho, M.M. Fukujima C.M.C. Silva Canada Montreal Heart Institute, MontrealS. Lanthier, R. Ibrahim Queen Elizabeth II Health Sciences Centre, S. Philipps, J. Howelett Halifax Denmark Aalborg Sygehus, AalborgB. Kristensen, R. Nielsen Aarhus Universitetshospital, AarhusG. Andersen, T.S. Jensen K. Emmersten Germany Klinik d. J.W.Goethe Universität FrankfurtV. Schächinger, T. Trepels Universitätsklinikum Giessen, GiessenW. Waas, M. Jauss Herz- und Diabeteszentrum NRW, MindenW.Scholtz, D. Fassbender Johannes Wesling Klinikum Minden, MindenJ. Glahn, H. Wuttig Herzzentrum Leipzig GmbH, LeipzigG. Schuler, G. Marcus, M. Sandri Brüderkrankenhaus Trier, TrierK.E. Hauptmann, T. Gehrig Städtisches Klinikum Fulda, FuldaM. Conze, M. Emir, J.M. Klotz Klinikum d. Philipps-Universität Marburg, B. Maisch, R. Funck Marburg Germany Universitätskliniken des Saarlands,M.Böhm, B. Scheller Homburg/Saar Medizinische Universitätsklinik Würzburg, P. Schänzenbächer, WürzburgW. Müllges Leopoldina KH der Stadt Schweinfurt GmbH,J. Mühler, K. Dötter Schweinfurt Lukaskrankenhaus Neuss, NeussM. Haude, H. Degen Poland Medikal University of Gdansk, GdanskJ. Erecinski, Chojnicki, R. Sabiniewicz Card. Dept.Institute of Cardiology, KrakowD. Dudek, A. Szczudlik, P. Szermer, S. Bartus, D. Sorysz, B. Chyrchel Slovakia Slovak Institute of Cardiovascular DiseaseV. Fridrich Switzerland Bern University Hospital / InselspitalB. Meier, H. Mattle, S. Windecker, A. Wahl United Kingdom Sussex Cardiac Centre, BrightonD. Hildick-Smith, P. Kumar Western General Hospital, EdinburghB. Weller, M. Dennis, D. Northridge Royal Surrey County Hospital, GuilfordE.W. Leatham St. George´s Hosp. Med. School, LondonH. Markus, M. Punter Clarence Wing – St. Mary’s Hospital NHS Trust, I. Mallik London New Cross Hospital, WolverhamptonS.S. Khogali, L. Evans, A. Smallwood 29 Sites in Europe, Brazil, Canada and Australia

12. S TUDY O RGANISATION Grant supportSt. Jude Medical, Plymouth, Minnesota, USA Principal investigatorsBernhard Meier, Heinrich P. Mattle Study monitoringE&E CRO, Clinical Research Organization, Vienna, Austria Data managmentAcademic Research Organisation InterCorNet, Zurich Heart House, Zurich, Switzerland Statistical analysisCTU Bern (Bindu Kalesan, Peter Jüni) DSMBR. Stables, P. Sandercock, T. Gasser CECB. Martin (Chairman), R. Baumgartner, F. Eberli

13. P ATIENT F LOW 414 P ATIENTS ELIGIBLE FOR THE S TUDY A LLOCATED TO PFO C LOSURE ( N =204) Received allocated intervention (n=191) Did not receive allocated intervention (n=13) No PFO (n=1) Withdrawn due to co-morbidity (n=3) Logistical problems (n=1) Refused PFO closure (n=3) A LLOCATED TO MEDICAL THERAPY ( N =210) Received allocated intervention (n=200) Did not receive allocated intervention (n=10) Logistical problems (n=4) Received PFO closure (n=6) F OLLOW – UP COMPLETE Up to 3 years (n=23) Up to 4 years (n=21) Up to 5 years (n=127) Deceased (n=2) F OLLOW – UP INCOMPLETE Withdrew (n=7) Lost to follow-up (n=24) F OLLOW – UP COMPLETE Up to 3 years (n=27) Up to 4 years (n=24) Up to 5 years (n=117) Deceased (n=0) F OLLOW – UP INCOMPLETE Withdrew (n=11) Lost to follow-up (n=31) A NALYSIS FOR P RIMARY E NDPOINT ( N =204) Censored at time of loss to follow-up, or withdrawal (n=31) A NALYSIS FOR P RIMARY E NDPOINT ( N =210) Censored at time of loss to follow-up, or withdrawal (n=42)

14. Percutaneous PFO Closure n = 204 Medical Treatment n = 210 Age ≥ 45 years 113 (55.4)113 (53.8) Male gender 92 (45.1)114 (54.3) Family history of cerebrovascular accidents 53 (26.0)40 (19.1) Currently smoking 52 (25.5)47 (22.4) Arterial hypertension 49 (24.0)58 (27.6) Diabetes mellitus 5 (2.5)6 (2.9) Hypercholesterolemia 50 (24.5)62 (29.5) Peripheral vascular disease 3 (1.5)2 (1.0) B ASELINE C LINICAL C HARACTERISTICS

15. Percutaneous PFO Closure n = 204 Medical Treatment n = 210 Coronary artery disease 4 (2.0)4 (1.9) History of myocardial infarction 3 (1.5)1 (0.5) Migraine 47 (23.0)38 (18.1) Cerebrovascular index event Stroke165 (80.9)163 (77.6) Transient ischemic attack33 (16.2)42 (20.0) Peripheral embolism6 (2.9)5 (2.4) > 1 previous cerebrovascular event76 (37.3)79 (37.6) B ASELINE C LINICAL C HARACTERISTICS

16. A TRIAL S EPTAL A NATOMY A TRIAL S EPTAL A NEURYSM I NTER -A TRIAL R IGHT TO L EFT S HUNT %

17. P RIMARY C OMPOSITE E NDPOINT D EATH FROM ANY CAUSE, NON - FATAL S TROKE, TIA AND PERIPHERAL E MBOLISM 0 2 4 6 8 C UMULATIVE INCIDENCE (%) 204186181163142110PFO C LOSURE 21018517015913190M EDICAL THERAPY N O. AT RISK 012345 Y EARS AFTER RANDOMIZATION HR 0.63 (0.24-1.62, p=0.34) RRR 37%

18. S ECONDARY E NDPOINT S TROKE 0 2 4 6 8 C UMULATIVE INCIDENCE (%) 204188183167146112PFO C LOSURE 21018717516413492M EDICAL THERAPY N O. AT RISK 012345 Y EARS AFTER RANDOMIZATION HR 0.20 (0.02-1.72, p=0.14) RRR 80%

19. S ECONDARY E NDPOINT T RANSIENT I SCHEMIC A TTACK 0 2 4 6 8 C UMULATIVE INCIDENCE (%) 204187182163142110PFO C LOSURE 21018717416213592M EDICAL THERAPY N O. AT RISK 012345 Y EARS AFTER RANDOMIZATION HR 0.71 (0.23-2.24); p=0.56 RRR 29%

20. S ECONDARY E NDPOINTS HR 2.04 95%CI 0.19–22.5 P=0.56 HR 1.02 95%CI 0.48–2.21 P=0.95 %

21. B LEEDING AND A TRIAL F IBRILLATION HR 0.58 95%CI 0.23–1.47 p=0.25 HR 0.34 95%CI 0.04–3.30 p=0.35 HR 0.66 95%CI 0.24–1.86 p=0.43 % B LEEDING A TRIAL FIBRILLATION HR 2.60 95%CI 0.50–13.4 p=0.25 B LEEDING

22. T HROMBOEMBOLIC AND B LEEDING E VENTS HR 0.45, 95%CI 0.16 – 1.29 P=0.14 HR 0.49, 95%CI 0.19 – 1.32 P=0.16 S TROKE, TIA OR P ERIPHERAL E MBOLISM S TROKE, TIA, P ERIPHERAL E MBOLISM O R S EVERE B LEEDING %

23. S TRATIFIED A NALYSIS OF THE P RIMARY E NDPOINT PFO C LOSURE M EDICAL T HERAPY HR (95% CI) P- INTERACTION Overall 7 (3.4)11 (5.2)0.63 (0.24-1.62) Age 0.10 <45 years 1 (1.1)6 (6.2)0.16 (0.02-1.31) ≥45 years 6 (5.3)5 (4.4)1.22 (0.37-3.99) Atrial septal aneurysm 0.09 Yes 4 (8.5)2 (3.9)2.09 (0.38-11.4) No 3 (1.9)9 (6.0)0.32 (0.09-1.18) CV Index event 0.78 Stroke 5 (3.1)8 (4.9)0.58 (0.19-1.76) TIA or PE 2 (5.1)3 (6.4)0.78 (0.13-4.66) More than 1 CV event 0.22 Yes 2 (2.6)6 (7.6)0.28 (0.06-1.41) No 5 (3.9)5 (3.8)0.99 (0.29-3.45).01.03.1.25.512510

24. L IMITATIONS Study power and sample size  Observed event rate in medical Rx group (5.2%) lower than anticipated (12%) at a mean follow-up of 4 years  Power to detect hypothesized 66% relative risk reduction less than 40% Composite primary endpoint  Death – non-specific  Historical stroke definition Long recruitment duration Attrition rate

25. Percutaneous PFO closure with the Amplatzer PFO Occluder for secondary prevention of thromboembolism showed no significant reduction in ischemic and bleeding events compared with medical treatment in this trial However, the observed difference in stroke (80% relative risk reduction, NNT=40) may be clinically relevant if confirmed in further studies C ONCLUSIONS