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Percutaneous Closure of Patent Foramen Ovale versus Medical Treatment in Patients with Cryptogenic Embolism: The PC T

Percutaneous Closure of Patent Foramen Ovale versus Medical Treatment in Patients with Cryptogenic Embolism: The PC Trial NCT00166257. Bernhard Meier, Bindu Kalesan, Ahmed A. Khattab, David Hildick-Smith, Dariusz Dudek, Grethe Andersen, Reda Ibrahim, Gerhard Schuler, Antony S. Walton,

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Percutaneous Closure of Patent Foramen Ovale versus Medical Treatment in Patients with Cryptogenic Embolism: The PC T

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  1. Percutaneous Closure of Patent Foramen Ovaleversus Medical Treatment in Patients with Cryptogenic Embolism:The PC Trial 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. Background • 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. Background • 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. Background • 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

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

  6. Procedures Percutaneous PFO Closure Amplatzer PFO Occluder Acetylsalicylicacid (100-325mg qd) andticlopidine (250-500mg qd) or clopidogrel (75mg qd) for 6 months 1:1 RCT • Medical Treatment • Oral anticoagulationor • Antiplatelet therapy • atthediscretionoftheneurologist

  7. Patient Population Inclusion Criteria • 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. Patient Population Exclusion Criteria • 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. Endpoints and Sample Size Primary Composite Endpoint • 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) Secondary Endpoints

  10. EndpointDefinitions • Stroke • Acute focal neurological deficit lasting >24 hours with MRI or CT evidence of new intracranial lesion • Death • Fatal stroke • Cardiovascular death • Non-cardiovascular death • 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. Study Centers and Investigators Australia Monash Medical Center, Melbourne S. Menahem, S. Bower, R. Harper Sir Charles Gairdner Hospital, Nedlands B.E.F. Hocking, W.Carroll Epworth Hospital, PrahranT.Walton Alfred Hospital, Prahran J. Frayne, M. Butler, L. Iles, E. Ivens, J.Hare, E. Kotschet Austria Uni-KlinikInnere Med II, AKH Vienna P. Probst, W. Lalouschek, H. Baumgartner, R. Rosenhek Belgium A.Z. Sint-Jan AV, Brugge G. Vanhoorem, L. Muyldermans Brazil Hospital Sao Paulo, Sao Paulo A.C.C. Carvalho, M.M. Fukujima C.M.C. Silva Canada Montreal Heart Institute, Montreal S. Lanthier, R. Ibrahim Queen Elizabeth II Health Sciences Centre, S. Philipps, J. Howelett Halifax Denmark Aalborg Sygehus, Aalborg B. Kristensen, R. Nielsen Aarhus Universitetshospital, Aarhus G. Andersen, T.S. Jensen K. Emmersten Germany Klinik d. J.W.GoetheUniversität Frankfurt V. Schächinger, T. Trepels Universitätsklinikum Giessen, Giessen W. Waas, M. Jauss Herz- und Diabeteszentrum NRW, Minden W.Scholtz, D. Fassbender Johannes WeslingKlinikum Minden, Minden J. Glahn, H. Wuttig Herzzentrum Leipzig GmbH, Leipzig G. Schuler, G. Marcus, M. Sandri Brüderkrankenhaus Trier, Trier K.E. Hauptmann, T. Gehrig StädtischesKlinikum Fulda, Fulda M. 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 MedizinischeUniversitätsklinikWürzburg, P. Schänzenbächer, Würzburg W. Müllges Leopoldina KH derStadt Schweinfurt GmbH, J. Mühler, K. Dötter Schweinfurt Lukaskrankenhaus Neuss, Neuss M. Haude, H. Degen Poland Medikal University of Gdansk, Gdansk J. Erecinski, Chojnicki, R. Sabiniewicz Card. Dept.Institute of Cardiology, Krakow D. Dudek, A. Szczudlik, P. Szermer, S. Bartus, D. Sorysz, B. Chyrchel Slovakia Slovak Institute of Cardiovascular Disease V. Fridrich Switzerland Bern University Hospital / Inselspital B. Meier, H. Mattle, S. Windecker, A. Wahl United Kingdom Sussex Cardiac Centre, Brighton D. Hildick-Smith, P. Kumar Western General Hospital, Edinburgh B. Weller, M. Dennis, D. Northridge Royal Surrey County Hospital, Guilford E.W. Leatham St. George´s Hosp. Med. School, London H. Markus, M. Punter Clarence Wing – St. Mary’s Hospital NHS Trust, I. Mallik London New Cross Hospital, Wolverhampton S.S. Khogali, L. Evans, A. Smallwood 29 Sites in Europe, Brazil, Canada and Australia

  12. Study Organisation

  13. Patient Flow 414 Patients eligibleforthe Study Allocatedto PFO Closure (n=204) Receivedallocatedintervention (n=191) Did not receiveallocatedintervention (n=13) No PFO (n=1) Withdrawn due toco-morbidity (n=3) Logisticalproblems (n=1) Refused PFO closure (n=3) Allocatedtomedicaltherapy (n=210) Receivedallocatedintervention (n=200) Did not receiveallocatedintervention (n=10) Logisticalproblems (n=4) Received PFO closure (n=6) Follow – upcomplete Upto 3 years (n=23) Upto 4 years (n=21) Upto 5 years (n=127) Deceased (n=2) Follow – upincomplete Withdrew (n=7) Lost tofollow-up (n=24) Follow – upcomplete Upto 3 years (n=27) Upto 4 years (n=24) Upto 5 years (n=117) Deceased (n=0) Follow – upincomplete Withdrew (n=11) Lost tofollow-up (n=31) Analysis for Primary Endpoint (n=204) Censoredat time oflosstofollow-up, orwithdrawal (n=31) Analysis for Primary Endpoint (n=210) Censoredat time oflosstofollow-up, orwithdrawal (n=42)

  14. Baseline Clinical Characteristics

  15. Baseline Clinical Characteristics

  16. AtrialSeptalAnatomy Inter-Atrial Right to Left Shunt Atrial Septal Aneurysm %

  17. Primary Composite Endpoint Death fromanycause, non-fatal Stroke, TIA andperipheralEmbolism 8 HR 0.63 (0.24-1.62, p=0.34) 6 RRR 37% Cumulativeincidence (%) 4 2 0 0 1 2 3 4 5 Years after randomization No. atrisk Medical therapy 210 185 170 159 131 90 PFO Closure 204 186 181 163 142 110

  18. Secondary Endpoint Stroke 8 HR 0.20 (0.02-1.72, p=0.14) 6 Cumulativeincidence (%) 4 2 RRR 80% 0 0 1 2 3 4 5 Years after randomization No. atrisk Medical therapy 210 187 175 164 134 92 PFO Closure 204 188 183 167 146 112

  19. Secondary Endpoint Transient IschemicAttack 8 HR 0.71 (0.23-2.24); p=0.56 6 Cumulativeincidence (%) 4 RRR 29% 2 0 0 1 2 3 4 5 Years after randomization No. atrisk Medical therapy 210 187 174 162 135 92 PFO Closure 204 187 182 163 142 110

  20. Secondary Endpoints % HR 1.02 95%CI 0.48–2.21 P=0.95 HR 2.04 95%CI 0.19–22.5 P=0.56

  21. Bleedingand Atrial Fibrillation Bleeding Atrial fibrillation % HR 0.58 95%CI 0.23–1.47 p=0.25 HR 0.66 95%CI 0.24–1.86 p=0.43 HR 2.60 95%CI 0.50–13.4 p=0.25 HR 0.34 95%CI 0.04–3.30 p=0.35 Bleeding

  22. Thromboembolic and Bleeding Events % HR 0.45, 95%CI 0.16 – 1.29 P=0.14 HR 0.49, 95%CI 0.19 – 1.32 P=0.16 Stroke, TIA or Peripheral Embolism Stroke, TIA, Peripheral Embolism Or Severe Bleeding

  23. Stratified Analysis of the Primary Endpoint .01 .03 .1 .25 .5 1 2 5 10

  24. Limitations • 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. Conclusions • 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

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