ΔΙΑΔΕΡΜΙΚΕΣ ΘΕΡΑΠΕΥΤΙΚΕΣ ΠΑΡΕΜΒΑΣΕΙΣ ΣΤΟ ΑΝΟΙΚΤΟ ΩΟΕΙΔΕΣ ΤΡΗΜΑ ΚΑΙ ΣΤΟ ΜΕΣΟΚΟΛΠΙΚΟ ΕΛΛΕΙΜΜΑ

ΔΙΑΔΕΡΜΙΚΕΣ ΘΕΡΑΠΕΥΤΙΚΕΣ ΠΑΡΕΜΒΑΣΕΙΣ ΣΤΟ ΑΝΟΙΚΤΟ ΩΟΕΙΔΕΣ ΤΡΗΜΑ ΚΑΙ ΣΤΟ ΜΕΣΟΚΟΛΠΙΚΟ ΕΛΛΕΙΜΜΑ ΒΛΑΣΗΣ ΝΙΝΙΟΣ, MD, MRCP IICE 2013, ΘΕΣΣΑΛΟΝΙΚΗ

A. ASD

2

ΔΕΥΤΕΡΟΓΕΝΕΣ ΜΕΣΟΚΟΛΠΙΚΟ ΕΛΛΕΙΜΜΑ

ΔΕΥΤΕΡΟΓΕΝΕΣ ΜΕΣΟΚΟΛΠΙΚΟ ΕΛΛΕΙΜΜΑ

Contra-indications to percutaneous treatment No evidence of right heart volume overload Insignificant shunt Insufficient rim tissue Non-secundum ASD

Insufficient rim tissue

Insufficient rim tissue 3D

Contra-indications to percutaneous treatment

ΠΡΩΤΟΓΕΝΕΣ ΜΕΣΟΚΟΛΠΙΚΟ ΕΛΛΕΙΜΜΑ

ΠΡΩΤΟΓΕΝΕΣ ΜΕΣΟΚΟΛΠΙΚΟ ΕΛΛΕΙΜΜΑ

ΕΛΛΕΙΜΜΑ ΦΛΕΒΩΔΟΥΣ ΚΟΛΠΟΥ

NOVEL DATA FOR PERCUTANEOUS ASD CLOSURE Major (Rare): <1.% *Atrial-aortic wall erosion(0.1%) Embolization of the device Thromboembolism Endocarditis Death Complications Minor: 7.9% Atrial arrhythmias Transient migraine Device thrombosis Arm fractures * 2/11000-Amin et al CCI 2008

29 cases of Cardiac Perforation Device size: 12 38mm Timing: 2hrs - 3yrs 13 / 29 cases (44.8%) = Device > 25 mm Duke Heart Center J Am Coll Cardiol 2005;45:1213-

Risk factors for device erosion include: deficient aortic rim (seen in 25 of 28 cases) deficient superior rim oversized device Although death from such mechanical complications remains rare, the risk is estimated to be around 0.1%

Jan, 2012 IFU: revised contraindications Any pt with echo evidence of absent or deficient anterior-superior rim (<5mm) in multiple and sequential short axis views by TEE or ICE. Any pt in whom the device would interfere with or contact other intracardiac structures 1 0

Complete intraprocedural TEE (2D, 3D) evaluation during the placement of an ASD/PFO closure device is helpful for risk assessment regarding the potential for erosion into the atrial wall or the aortic root Careful attention should be paid to whether the device impinges on the aortic root and to whether the device contacts any portion of the atrial wall other than the interatrial sept

Proposed mechanism of erosion Disks protrude into aorta Disks moves with aorta 2 3

TEE 21 mm by 2D 23 mm by color Balloon size diameter 22 mm 24 mm Amplatzer ASD device Other factors: Unfavorable device position against aorta

/ Major AE Duke Heart Center J Am Coll Cardiol 2002;39:1836-

Mortality of Surgical ASD Closure Author Yea r Mortality (%) Dave 1973 3 Nasrallah

Mortality of Transcatheter ASD Closure Author Yea r Mortality (%) Omeish A 2001 0

Butera G et al EuroIntervention. 2011 Jul;7(3):377-85. doi: 10.4244/EIJV7I3A63. Percutaneous versus surgical closure of secundum atrial septal defects: a systematic review and meta-analysis of currently available clinical evidence. - Surgical closure: 0.08% Postprocedural complications - Surgical closure: 31% 13 original studies - Transcatheter closure: 0

Εµπειρία Αγίου Λουκά

ΑΣΘΕΝΕΙΣ ΜΕ ΔΕΥΤΕΡΟΓΕΝΕΣ ΜΕΣΟΚΟΛΠΙΚΟ ΕΛΛΕΙΜΜΑ Αριθµός Ασθενών 112/167 (67%) Ηλικία (έτη) 36,3 ± 17,1 Διάταση Δεξιών Κοιλοτήτων 68,62% RVSP>40 mmhg 30,40% Μέγιστη Διάµετρος Ελλείµµατος 24 ± 7 mm Μέγεθος Συσκευής 27.7 ± 7,5 mm Παρακολούθηση (µήνες) 34,1 ± 14,6 Διοισοφάγειο ECHO σε 6 µήνες 43/102 (42,15%)

ΑΣΘΕΝΕΙΣ ΜΕ ΑΝΟΙΚΤΟ ΩΟΕΙΔΕΣ ΤΡΗΜΑ Αριθµός Ασθενών 55/167 (33%) Ηλικία (έτη) 39,1 ± 11,5 Φύλο (24/49) (25/49) Ανεύρυσµα Μεσοκολπικού 40,81% Παροδικό Ισχαιµικό Επεισόδιο 26,50% >1 ΑΕΕ 42,86% Θροµβοφιλία 16,32% Μέγεθος Συσκευής 27.1 ± 3,8 mm Παρακολούθηση (µήνες) 36,3 ± 14,5 Διοισοφάγειο ECHO σε 6 µήνες 26,50%

AMΕΣΕΣ ΕΠΙΠΛΟΚΕΣ n µείζονες επιπλοκές κατά τη διάρκεια της επέµβασης : 0 n Ελάσσονες επιπλοκές : 5% n αιµορραγία στο σηµείο παρακέντησης n παροδική ανύψωση του ST διαστήµατος στις κατώτερες επαγωγές n παροδική εκτακτοσυστολική αρρυθµία

ΜΑΚΡΟΧΟΝΙΕΣ ΕΠΙΠΛΟΚΕΣ n καρδιακή ρήξη, εµβολή συσκευής, σχηµατισµός θρόµβου, θροµβοεµβολή ή λοιµώδης ενδοκαρδίτιδα : 0 n Περικαρδιακό υγρό : 4 (υφέθηκε εντός τριµήνου) n υποτροπή του καρδιογενούς εγκεφαλικού επεισοδίου σε χρονικό διάστηµα παρακολούθησης 24.3+14.5 µηνών : 0

BIG ASD s > 30mm Big ASDs difficult to close Always examine rims especially posterior/inferior various tips and tricks

DEFICIENT ANTERIOR RIM Deploy Amplatzer nearby LPUV D E F I C I E N T A N T E

DEFICIENT POSTERIOR RIM Deploy Amplatzer nearby RPUV

AMPLATZER 34mm

ASD CLOSURE 3D

Our experience St Lucas Hospital 24 patients (14 female) ASO: 34.7+3.5 mm Success: 24/25 F/U: 42+14 months No major immediate/long term complication

In conclusion (1) n n n ASD closure is safe, with low complication rate Adequate rims are necessary Role of 2D 3D TOE

Β. ΣΥΓΚΛΕΙΣΗ ΑΝΟΙΚΤΟΥ ΩΟΕΙΔΟΥΣ ΤΡΗΜΑΤΟΣ 2012

Causes of Stroke Ischemic Stroke (83%) Atherothromboti c Cerebrovascular Disease (15-30%) Cardioembolic (15-30%) Hemorrhagic Stroke (17%) Intracerebral Hemorrhage (70%) (15-30%)

The Problem: Not All PFO in Patients With Cryptogenic Stroke is Pathogenic; No Definitive Method to Identify Pathogenic PFO Patients without PFO Patients with PFO 60% 20% 20% Cryptogenic Stroke From Causes other than paradoxical embolus 25% will have PFO Cryptogenic Stroke from paradoxical embolus

Meta-Analysis of Transcatheter Closure vs. Medical Therapy for PFO in Prevention Presumed of Recurrent Paradoxical Neurological Embolism Events After Pooled data from 48 observational studies: 39 of closure (8,185 pts), 19 of medical therapy (2,142 pts); 10 compared both therapies. The rate of recurrent stroke or TIA after PFO closure was 0.8 vs. 5.0 events per 100 pt-yrs with medical therapy (P = 0.002) Anticoagulation appeared superior to aspirin for medical therapy medical therapy (4.1 vs. 0.4 events per 100 pt-yrs) atrial arrhythmias Implications: According to observational data, PFO closure substantially reduces the risk of recurrent stroke compared with medical therapy. Complications were more common with closure than with Agarwal S, et al. J Am Coll Cardiol Intv. 2012;5:777-789.

3 randomized trials CLOSURE (TCT 2011, Furlan et al, N Engl J Med 2012) PC (TCT 2012) RESPECT (TCT 2012)

Study Design STARFlex Closure (within 30 Days) 6 Months Aspirin and Clopidigrel followed by 18 Months Aspirin N=467 Best Medical Therapy 24 Months Aspirin Or Warfarin Or Combination N=442 5 1/3 years to enroll

CLOSURE 1 Trial using StarFlex device 909 patients End Point after 2 years Device (%) Medical Therapy (%) p 1. PFO closure with StarFlex was equivalent to medical Rx 2. Did not reach 1o endpoint of device superior to med Rx. a) warfarin b) warfarin + aspirin or c) aspirin alone

CLOSURE 1 Trial using StarFlex device Why StarFlex event rate may not be less than medical Rx: 1. Low complete closure rate = 87% 2. 7% thrombus on device

CardioSeal Arms stick up due to long tunnel and may retract with time IC E TEE at 9 yrs: LA arms still up TCD shunt inc. over time and 14% Reisman, have residual Jesurum: AJC grade 2007, 4 or 99; 5 1312- shunt

Why StarFlex recurrent stroke rate may not be less than medical Rx: 2) Thrombus on CardioSeal Implant By TEE: 7 22% at 1 mo. Risk of a PFO occluder device must be less than risk of recurrent stroke. Recurrent stroke rate 3.4% with CardioSeal Reisman, Jesurum: AJC 2007, 99; 1312-15

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, and Peter Jüni

PATIENT FLOW ALLOCATED TO PFO CLOSURE (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) Up to 3 years (n=23) Up to 5 years (n=127) Withdrew (n=7) (n=24) FOLLOW UP INCOMPLETE Logistical problems (n=1) Refused PFO closure (n=3) Up to 4 years (n=21) Deceased (n=2) Lost to follow-up ANALYSIS FOR PRIMARY ENDPOINT (N=204) Censored at time of loss to follow-up, or withdrawal (n=31) 414 PATIENTS ELIGIBLE FOR THE STUDY ALLOCATED 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) Up to 3 years (n=27) Up to 5 years (n=117) Withdrew (n=11) FOLLOW UP INCOMPLETE Up to 4 years (n=24) Deceased (n=0) Lost to follow-up (n=31) ANALYSIS FOR PRIMARY ENDPOINT (N=210) Censored at time of loss to follow-up, or withdrawal (n=42)

PROCEDURE SUCCESS AND CLOSURE RATE 100 96.9 95.9 100 91.7 80 80 % 60 60 0 PROCEDU RE SUCCE SS EFFECTIVE CLOSURE @ 6 MONTHS 0 NON E 6.2 MINIMAL MODERATE 0.7 1.4 TEE ASSESSMENT @ 6 MONTHS SEVE RE

PRIMARY COMPOSITE ENDPOINT DEATH FROM ANY CAUSE, NON-FATAL STROKE, 8TIA HR AND 0.63 PERIPHERAL (0.24-1.62, EMBOLISM C UMULATIVE INCIDENCE (%) 6 p=0.34) RRR 37% NO. AT RISK MEDICAL THERAPY PFO CLOSURE 4 0 1 2 3 4 5 YEARS AFTER RANDOMIZATION 210 204 18 5 186 170 181 15 9 163 131 142 90 110

C UMULATIVE INCIDENCE (%) 8 SECONDARY ENDPOINT STROKE HR 0.20 (0.02-1.72, p=0.14) RRR 80% NO. AT RISK MEDICAL THERAPY PFO 210 CLOSURE 0 1 3 4 5 2 YEARS AFTER RANDOMIZATION 187 175 164 134 92 204 188 183 167 146 112

BLEEDING AND ATRIAL FIBRILLATION BLEEDI NG ATRIAL FIBRILLATION % 10 8 4 HR 0.58 95%CI 0.23 1.47 p=0.25 5.7 3.4 HR 0.34 95%CI 0.04 3.30 p=0.35 HR 0.66 95%CI 0.24 1.86 p=0.43 2.9 4.3 HR 2.60 95%CI 0.50 13.4 p=0.25 2.5 1.0 0 OVERA LL BLEEDI NG SERIOUS ADVERSE EVENT MINOR ADVERSE EVENT ATRIAL FIBRILLATION

PC Trial Results European randomized trial of Amplatzer PFO occluder vs. medical therapy. 200pts per group. Follow up mean 5 years. Approx 1%/year stroke, RR reduced 80% with device, but p=ns due to low event rate.

The Final Results with Primary End Point Analyses RANDOMIZED EVALUATION OF RECURRENT STROKE COMPARING PFO CLOSURE TO ESTABLISHED CURRENT STANDARD OF CARE TREATMENT JOHN D. CARROLL, MD, JEFFREY L. SAVER, MD, DAVID E. THALER, MD, PHD, RICHARD W. SMALLING, MD, PHD, SCOTT BERRY, PHD, LEE A. MACDONALD, MD, DAVID S. MARKS, MD, MBA, DAVID L. TIRSCHWELL, MD FOR THE RESPECT INVESTIGATORS

Subject Distribution TEE with bubble study at 6 months 1. Aspirin + clopidogrel was removed from the protocol in 2006 based on changes to the AHA/ASA treatment 1 3

Serious Adverse Events Adjudicated as Related to Procedure, Device, or Study 1. 2. 3. 4. For all AE s, atrial fibrillation occurred in 3.0% versus 1.5% in the device and medical groups respectively, p=0.13 Pericardial tamponade is a subset of major bleeds, and thus counted in the major bleed category as well For all SAEs, pulmonary embolism occurred in 1.2% and 0.2% in device and medical groups, respectively, p=0.124 1 case of right atrial thrombus resulted in abandonment of device implant procedure (no device received); 1 case of right atrial thrombus (located inferiorly) not attached to device detected in patient with DVT and PE 4 months after procedure 5. 1 ischemic stroke one week post implant; 1 five months post implant with finding of severe shunting related to previously undiagnosed sinus venosus defect, requiring surgical closure 1 6

Device Performance 1. Defined as successful delivery and release of the device for subjects in whom the delivery system was introduced into the body 2. Defined as successful implantation with no reported in-hospital serious adverse events 3. Defined as complete obliteration or trivial residual shunting (Grade 0 or I at rest and Valsalva) at 6 months, adjudicated by echo core 1 8

PC Trial Major Vascular Complication Closure 1 N=909 3.2 % Atrial fibrillation 5.7 % Respect N=980 0.8 % 0.6 % PC 2.5 %

Primary End Point Analysis Intent to Treat (ITT) Raw Count Cohort 1. Relative risk is represented by the Mantel-Haenszel odds ratio 1 9

Primary Endpoint Analysis ITT Cohort 50.8% risk reduction of stroke in favor of device endpoint stroke 1. Cox model used for analysis 2 0

Primary Endpoint Analysis ITT Cohort 50.8% risk reduction of stroke in favor of device endpoint stroke 1. Cox model used for analysis 2 0

Primary Endpoint Analysis Per Protocol Cohort 63.4% risk reduction of stroke in favor of device requirements of the study protocol 2 1

Primary Endpoint Analysis As Treated Cohort 72.7% risk reduction of stroke in favor of device actually received, regardless of the randomization assignment 1. Cox model used for analysis 2 2

Primary Endpoint Analysis As Treated Cohort 72.7% risk reduction of stroke in favor of device actually received, regardless of the randomization assignment 1. Cox model used for analysis 2 2

Subpopulation Differential Treatment Effect 24

RESPECT: recurrent stroke size Device Medical

Stroke Mechanism Aspects of Endpoint Ischemic Strokes Device Arm 3 of the 9 device arm ischemic strokes occurred in patients without a device in place Of the remaining 6 device arm ischemic strokes, 3 were small, deep only infarcts 1 8

Conclusion For carefully selected patients with history of cryptogenic stroke and PFO, the RESPECT Trial provides evidence of benefit in stroke risk reduction from closure with the AMPLATZER PFO Occluder over medical management alone Stroke risk reduction was observed across the totality of analyses with rates ranging from 46.6% - 72.7% PFO closure with the AMPLATZER PFO Occluder exposes patients to a very low risk of device- or procedure-related complications 2 7

RESPECT

CASE 1 32 female 1st CVA after prolonged sitting (squating) Long tunnelled PFO

Conclusions Percutaneous closure of secundum ASD is a safe and effective option with durable results Erosion from the device is a rare possibility and requires high level of clinical suspicion and careful follow up Deficient rims and oversized devices appear to be risk factors

Conclusions PFO is involved in the pathogenesis of Cryptogenic stroke as many epidemiological studies suggest However the available randomized studies have failed to show superiority over medical treatment for two reasons Very low rate of strokes over a lifetime period (hence short follow up period) Badly functioning device (one study) A commonsense approach is required