ΣΥΓΚΛΕΙΣΗ ΑΝΟΙΚΤΟΥ ΩΟΕΙΔΟΥΣ ΤΡΗΜΑΤΟΣ ΠΕΣΡΟ. ΔΑΡΔΑ, MD, FESC 33 Ο Πανελλήνιο Καρδιολογικό Συνζδριο ΑΘΗΝΑ 2012

Transcription

1 ΣΥΓΚΛΕΙΣΗ ΑΝΟΙΚΤΟΥ ΩΟΕΙΔΟΥΣ ΤΡΗΜΑΤΟΣ 2012 ΠΕΣΡΟ. ΔΑΡΔΑ, MD, FESC 33 Ο Πανελλήνιο Καρδιολογικό Συνζδριο ΑΘΗΝΑ 2012

2 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 Alsheikh-Ali, A. A. et al. Stroke 2009;40:

3 PFO Morphology Associated with Stroke Risk American Journal of Cardiology, November 3, 2008 PFO Morphology on TEE in Pts With and Without Cryptogenic CVA Larger PFOs, longer tunnels, ASA, carry increased stroke/tia risk Symptomatic n = 58 Asymptomatic n = 58 P Value Size (mm) 3.9 ± ± Large PFO ( 4 mm) 46% 17% Presence of Atrial Septal Aneurysm 45% 21% Length of Tunnel (mm) 14 ± 6 12 ± Mild Shunting 52% 60% 0.34 Moderate Shunting 21% 21% 1.0 Severe Shunting 16% 5% 0.06

4 Stroke Prevention in PFO-Stroke Patients Surgical closure Medical therapy - Aspirin - Anticoagulation Catheter closure

5 Catheter Closure Routinely used in clinical practice since > 15 years But not proven in randomized trials till 2011

6 Meta-Analysis of Transcatheter Closure vs. Medical Therapy for PFO in Prevention of Recurrent Neurological Events After Presumed Paradoxical Embolism 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 Complications were more common with closure than with 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. Agarwal S, et al. J Am Coll Cardiol Intv. 2012;5:

7 Difficulty with randomized PFO Stroke Trials Low event rates: <2% recurrent stroke/year Availability of PFO closure off label Highest risk patients are not being randomized which lowers the event rate and makes it harder to show a difference between device and medical therapy.

8 3 randomized trials CLOSURE (TCT 2011, Furlan et al, N Engl J Med 2012) PC (TCT 2012) RESPECT (TCT 2012)

9 Study Design Randomization 1:1 N=909 STARFlex Closure (within 30 Days) 6 Months Aspirin and Clopidigrel followed by 18 Months Aspirin N=467 First Enrolled: June 2003 Best Medical Therapy 24 Months Aspirin Or Warfarin Or Combination N=442 Last Enrolled: October /3 years to enroll

10 CLOSURE 1 Trial using StarFlex device 909 patients 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 3. Effective Closure Rate only 87% End Point after 2 years Device (%) Medical Therapy (%) p Composite end point Stroke TIA Major vascular complications <0.001 Atrial fibrillation <0.001

11 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 3. 6% atrial fibrillation

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

13 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;

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15 Was the Closure I Population Representative? Patients with thrombophilia were excluded from Closure I

16 PERCUTANEOUS CLOSURE OF PATENT FORAMEN OVALE VERSUS MEDICAL TREATMENT IN PATIENTS WITH CRYPTOGENIC EMBOLISM: THE PC TRIAL NCT 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

17 PROCEDURES PERCUTANEOUS PFO CLOSURE Amplatzer PFO Occluder Acetylsalicylic acid ( mg qd) and ticlopidine ( mg qd) or clopidogrel (75mg qd) for 6 months 1:1 RCT MEDICAL TREATMENT Oral anticoagulation or Antiplatelet therapy at the discretion of the neurologist

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

19 PROCEDURE SUCCESS AND CLOSURE RATE RESIDUAL SHUNT % PROCEDURE SUCCESS EFFECTIVE 6 MONTHS NONE MINIMAL MODERATE SEVERE TEE 6 MONTHS

20 BLEEDING AND ATRIAL FIBRILLATION BLEEDING ATRIAL FIBRILLATION % 10 PFO CLOSURE MEDICAL THERAPY 8 6 HR %CI p= HR %CI p=0.43 HR %CI p= HR %CI p= OVERALL BLEEDING SERIOUS ADVERSE EVENT MINOR ADVERSE EVENT ATRIAL FIBRILLATION

21 PRIMARY COMPOSITE ENDPOINT DEATH FROM ANY CAUSE, NON-FATAL STROKE, TIA AND PERIPHERAL EMBOLISM 8 HR 0.63 ( , p=0.34) 6 RRR 37% 4 C UMULATIVE INCIDENCE (%) 2 NO. AT RISK MEDICAL THERAPY PFO CLOSURE YEARS AFTER RANDOMIZATION

22 SECONDARY ENDPOINT STROKE 8 HR 0.20 ( , p=0.14) 6 4 C UMULATIVE INCIDENCE (%) 2 RRR 80% NO. AT RISK 0 MEDICAL THERAPY 210 PFO CLOSURE YEARS AFTER RANDOMIZATION

23 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.

24 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

25 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 guidelines 13

26 Serious Adverse Events Adjudicated as Related to Procedure, Device, or Study 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 in1.2% and 0.2% indevice and medical groups, respectively, p= 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 6. For all SAEs, there were 3 device group deaths (0.6%) and 6 medical group deaths (1.2%) all of which were not study related, p= P-values are calculated using Fisher s Exact test 16

27 Device Performance Maximum Residual Shunting at Rest or Valsalva at 6 Months Grade 0: 72.7% Grade 1: 20.8% Grade 2-3: 6.5% 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 lab 18

28 PC Trial Serious Adverse Events & Device Performance Comparison of Trials Major Vascular Complication Atrial fibrillation Major bleeding Device thrombus Procedure Success Clinical 6 mos Closure 1 N=909 Respect N= % 0.8% 5.7% 2.6% 1% 89% 86% 0.6% 1.6% 0 96% 94% PC 2.5% 0.5%

29 Primary End Point Analysis Intent to Treat (ITT) Raw Count Cohort Abbreviations: D = Device group; M= Medical group The primary analysis using the raw count of the ITT cohort was deemed invalid because the exposure to the two treatment options was unequal due to a greater drop-out rate in the medical group The protocol specified that, if unequal drop-out occurred, then survival functions for the time-to-endpoint event for each treatment group would be used to provide an exposure-stratified comparison Survival analysis methods would then be used at a two-sided 0.05 level using the log-rank statistic. Hazard ratios were calculated using a Cox proportional-hazards model 1. Relative risk is represented by the Mantel-Haenszel odds ratio 2. P-value is 2-sided and calculated using Fisher s Exact test 19

30 Primary Endpoint Analysis ITT Cohort 50.8% risk reduction of stroke in favor of device 3/9 device group patients did not have a device at time of endpoint stroke 1. Cox model used for analysis 20

31 Primary Endpoint Analysis ITT Cohort 50.8% risk reduction of stroke in favor of device 3/9 device group patients did not have a device at time of endpoint stroke 1. Cox model used for analysis 20

32 Primary Endpoint Analysis Per Protocol Cohort 63.4% risk reduction of stroke in favor of device The Per Protocol (PP) cohort includes patients who adhered to the requirements of the study protocol 1. Cox model used for analysis 21

33 Primary Endpoint Analysis As Treated Cohort 72.7% risk reduction of stroke in favor of device The As Treated (AT) cohort demonstrates the treatment effect by classifying subjects into treatment groups according to the treatment actually received, regardless of the randomization assignment 1. Cox model used for analysis 22

34 Primary Endpoint Analysis As Treated Cohort 72.7% risk reduction of stroke in favor of device The As Treated (AT) cohort demonstrates the treatment effect by classifying subjects into treatment groups according to the treatment actually received, regardless of the randomization assignment 1. Cox model used for analysis 22

35 Totality of Evidence and NNT 46.6%-72.7% risk reduction of stroke in favor of device Totality of Evidence Number Needed to Treat (NNT) 1. P-values: ITT Raw Count is calculated using Fisher s Exact test; all other P-values are calculated using log-rank test 2. The NNT is the average number of subjects that need to be treated with the AMPLATZER PFO Occluder in order to prevent one stroke in the respective time intervals. The NNT is calculated as the reciprocal of the difference between the control arm and device arm event rates 3. Calculated using the Kaplan-Meier estimated event rates for each treatment group 23

36 Subpopulation Differential Treatment Effect 24

37 RESPECT: recurrent stroke size Device Medical

38 Limitations Differential drop-out rate Some medical group patients left study and underwent off-label closure ITT Results Raw count analysis invalid due to differential treatment exposure 3/9 device patients with recurrent ischemic stroke did not have device in place when stroke occurred PP and AT cohorts are relevant to assessing treatment Totality of evidence must be considered Clinically, the atrial septal aneurysm and shunt size findings are relevant and support mechanism of action Benefit became especially prominent 2-5 years after device placement 26

39 RESPECT Recurrent Cryptogenic Stroke event rate per year is low on medical Rx = 1.3%/yr. But young pts are at risk for decades. Need longer follow-up.

40 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% % PFO closure with the AMPLATZER PFO Occluder exposes patients to a effective, very low risk of device- or procedure-related complications 27

41 Dr Anthony Furlan ( PI CLOSURE) With these 3 randomized trials we can finally begin to develop a more rational approach to cryptogenic stroke and PFO Clearly this not a homogeneous population and not all patients will benefit from a device. Conversely, PC and RESPECT hint that some might benefit IAS aneurysm Big shunt

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

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47 CASE 2 29 male 1 st CVA 2 years ago nothing found not fully investigated 2 months ago complex tibial fracture operated On sc heparin post 2 weeks post operation: stopped sc heparin for 1 day Severe CVA 1 day after stopping heparin with aphasia and R hemiparesis Advised long term anticoagulation TOE: big shunt with IAS aneurysm

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51 Dr Ajay Kirtane (Columbia University, New York): cryptogenic-stroke patients are not typical stroke patients, as they are often young and healthy. With the stroke, they are now faced with a lifetime of medical therapy, with all its question marks, or undergoing an interventional procedure that allows them to stop treatment

52 PFO Stroke Trials Enrolled Population TIA Substantial Shunts Trivial or Modest Shunts STROKES Lacunes Likely Responders - substantial shunt - substantial stroke c/w embolic etiology

53 Study Design Issues with RESPECT and the PC Trial TCT 2012, Miami, Florida Sanjay Kaul, MD Cedars-Sinai Medical Center Professor, David Geffen School of Medicine at UCLA Los Angeles, California

54 PFO Closure Devices for Cryptogenic Stroke The Science of Medicine Benefit Inconclusive evidence regarding prevention of recurrent stroke Risk No increase in bleeding No Atrial fibrillation No death Slight in thromboticaes? cost Insufficient evidence to adjudicate efficacy of PFO closure for cryptogenic stroke

55 PFO Closure Devices for Cryptogenic Stroke The Art of Medicine Benefit Inconclusive (RCT) Might reduce recurrent events (observational) Risk No increase in bleeding No Atrial fibrillation No death Slight in thromboticaes? cost May consider in high-risk patients (large shunt, ASA) with recurrent strokes who don t have conventional risk factors for stroke and who cannot tolerate or are unwilling to take antithrombotic therapy (e.g., young women wanting to get pregnant)