1. TCT 2012 PFO Closure for Cryptogenic Stroke RESPECT and PC Trial Critique and Interpretation
Gregg W. Stone, MD
Columbia University Medical Center
NewYork-Presbyterian Hospital
Cardiovascular Research Foundation

2. Hemorrhagic Stroke (17%)
Causes of Stroke
Ischemic Stroke (83%)
Hemorrhagic Stroke (17%)
Atherothrombotic Cerebrovascular
Disease (15-30%)
Cardioembolic (15-30%)
Intracerebral
Hemorrhage (70%)
Cerebrovascular disease is a heterogeneous disease. A stroke occurs when a blood vessel that supplies oxygen and nutrients to the brain becomes blocked or ruptures. A portion of the brain dependent on blood flow from this vessel becomes deprived of oxygen. Within minutes, nerve cells begin to die, which results in permanent disability.1
Strokes can be categorized as either hemorrhagic or ischemic.1 Hemorrhagic strokes occur as a result of bleeding into the brain caused by an injury to the head or a ruptured aneurysm. Although less common than ischemic strokes, hemorrhagic strokes produce more fatalities. Hemorrhagic strokes are further categorized as intracerebral or subarachnoid. An intracerebral hemorrhage occurs when a defective artery in the brain ruptures and the surrounding area of the brain fills with blood. A subarachnoid hemorrhage occurs when a blood vessel on the surface of the brain ruptures and bleeds into the subarachnoid space between the skull (but not within the tissues of the brain).1
Ischemic strokes can be further divided into subcategories. A cerebral embolism is a result of a clot or embolus that forms in another portion of the body such as the heart (in the case of atrial fibrillation) and is carried through the bloodstream, becomes lodged in an artery that supplies blood to the brain, and blocks the flow of blood. Atherosclerotic cerebrovascular disease results in stroke when there is an impediment to normal blood perfusion as a result of severe arterial stenosis or occlusion due to atherosclerosis and coexisting thrombosis.2 Lacunar infarcts result from microatheroma, lipohyalinosis, and other occlusive diseases of the small penetrating arteries of the brain; these are sometimes referred to as subcortical infarcts. Cryptogenic infarcts refer to ischemic strokes in which the underlying etiology remains obscure.1,2
Other (vasculitis,
dissection, hyper-coagulable, etc (10%)
Subarachnoid
Hemorrhage (30%)
Lacunar- small vessel disease (15-30%)
Cryptogenic (10-40%) 4
References:
1. American Stroke Association. Impact of Stroke. Available at: Accessed June 21, 2002.
2. Albers GW, Easton JD, Sacco RL, Teal P. Antithrombotic and thrombolytic therapy for ischemic stroke. Chest. 1998;119(suppl):683S-698S.
Additional Reference:
Rosamond WD, Folsom AR, Chambless LE, et al. Stroke incidence and survival among middle-aged adults: 9-year follow-up at the Atherosclerosis Risk in Communities (ARIC) cohort. Stroke. 1999;30:

3. 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

4. AMPLATZER PFO Occluder
Percutaneous, transcatheter device
Self-expanding, double-disc design
Nitinol wire mesh with polyester fabric/thread
Radiopaque marker bands
Sizes: 18, 25, 35 mm
Recapturable and repositionable
AMPLATZER PFO Occluder* 7
*CAUTION: Investigational device in the United States.  Limited by Federal (or U.S.) law to investigational use.  Not available for sale in the U.S.

5. Subject Distribution TEE with bubble study at 6 months
With cryptogenic stroke within 9 months
TEE with bubble study at 6 months 13
FU until 25 events: Powered for a 75% reduction with PFO closure

6. Baseline Characteristics4.
Statistics are represented as either mean (standard deviation) or percentages
Based on a 2-sample t-test (age), Wilcoxon-Mann-Whitney test (days from stroke to date randomized), and Fisher’s Exact test (sex)
Numbers vary by site; Age N=968; Shunt N=969 14

7. 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 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
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
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= 0.334
P-values are calculated using Fisher’s Exact test 16

8. Device Performance (in 499 pts)
Maximum Residual Shunting
at Rest and Valsalva at 6 Months
Grade 0: 72.7%
Grade 1: 20.8%
Grade 2-3: 6.5%
Defined as successful delivery and release of the device for subjects in whom the delivery system was introduced into the body
Defined as successful implantation with no reported in-hospital serious adverse events
Defined as complete obliteration or trivial residual shunting (Grade 0 or I at rest and Valsalva) at 6 months, adjudicated by echo core lab 17

9. Treatment Exposure and Follow-up
Total population with greater than 2,550 years of follow-up
Device group had greater follow-up (fewer drop-outs)
48 drop-outs in the device group versus 90 in the medical group 18
P-value calculated using Wilcoxon-Mann-Whitney test

10. Primary End Point (Death within 45 days or Ischemic Stroke) – Intent to Treat (ITT) Raw Count Cohort – mean 2.6 year FU
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 19
Relative risk is represented by the Mantel-Haenszel odds ratio
P-value is 2-sided and calculated using Fisher’s Exact test

11. Primary Endpoint Analysis – ITT Cohort 50
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 20
Cox model used for analysis

12. 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
1 after randomization but prior to PFO occluder implant
1 in patient who declined procedure and crossed to medical therapy
1 in patient who required a CABG after randomization but prior to study procedure and who underwent bovine pericardium patch PFO repair during the surgery instead of device closure
Of the remaining 6 device arm ischemic strokes, 3 were small, deep only infarcts 18

13. Primary Endpoint Analysis – Per Protocol Cohort 63
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 21
Cox model used for analysis

14. Primary Endpoint Analysis – As Treated Cohort 72
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 22

15. Subpopulation Differential Treatment Effect24

16. Recurrent Cerebral Infarct Size1 Methods pre-specified; analysis post-hoc
This exploratory analysis of site-reported recurrent cerebral infarct size is provocative in suggesting that recurrent ischemic strokes in the medical versus device group are not only more frequent but also larger 25
Recurrent infarct size reported on primary endpoint population
P-value based on Fisher’s Exact test

17. Endpoint Ischemic Stroke Timing and Severity
Characteristic
Device Group
n=9
Medical Group
n=16
All Subjects
n=25
P-valuea
Months from
randomization to event 16
(22.4)
17.9
(15.5)
17.2
(17.9)
0.38
NIHSS
stroke deficit scoreb
2 (2 - 3)
2 (0 - 4)
0.70
Barthel Index
ADL scoreb
100 ( )
100 ( )
100 ( )
0.59
mRS
disability scoreb
1 (1 - 3)
1 (0 - 2)
1 (0 - 3)
0.56
P-values calculated using Mann-Whitney-Wilcoxon test
Data presented in terms of median (interquartile range) for NIHSS, Barthel and mRS. Data represented as mean (standard deviation) for months from randomization to event 13

18. 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

19. Procedures 1:1 RCT Percutaneous PFO Closure Medical Treatment
Amplatzer PFO Occluder
Acetylsalicylic acid ( mg qd)
and ticlopidine ( mg qd)
or clopidogrel (75mg qd)
for 6 months
Medical Treatment
Oral anticoagulation or
Antiplatelet therapy
at the discretion of the neurologist

20. Patient Flow 414 Patients eligible for the Study
With prior cryptogenic stroke, TIA or peripheral thromboembolism
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
Up to 3 years (n=23) Up to 4 years (n=21)
Up to 5 years (n=127) Deceased (n=2)
Follow – up incomplete
Withdrew (n=7) Lost to follow-up (n=24)
Follow – up complete
Up to 3 years (n=27) Up to 4 years (n=24)
Up to 5 years (n=117) Deceased (n=0)
Follow – up incomplete
Withdrew (n=11) 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)
Powered for a 67% reduction with PFO closure 20

21. PC Trial: Baseline Clinical Characteristics
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
Stroke
165 (80.9)
163 (77.6)
Transient ischemic attack
33 (16.2)
42 (20.0)
Peripheral embolism
6 (2.9)
5 (2.4)
> 1 previous cerebrovascular event
76 (37.3)
79 (37.6)

22. Atrial Septal Aneurysm
Atrial Septal Anatomy
Atrial Septal Aneurysm
Inter-Atrial
Right to Left Shunt %

23. Procedure Success and Closure Rate
Residual Shunt %
8 patients did not undergo PFO closure and the procedure was successful among in 96.9% of the remaining cases.
Assessment of a residual shunt at 6 months by means of transesophageal echocardiography revealed no shunt in 91.7%, a minimal shunt in 6.2%, and a severe shunt in 1.4% of patients resulting in an effective closure rate of 95.9%.
TEE 6 Months

24. PC Trial: Antiplatelet and Antithrombotic Medication%
PFO
Closure
p=ns
p<0.001
Medical
Therapy

25. Primary Composite Endpoint
Death from any cause, non-fatal Stroke,
TIA or peripheral Embolism – mean 4 year FU 8
HR 0.63 ( , p=0.34)
N=11 6
RRR 37%
Cumulative incidence (%)
N=7 4 2 1 2 3 4 5
No. at risk
Years after randomization
Medical therapy
210
185
170
159
131 90
PFO Closure
204
186
181
163
142
110

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

27. Transient Ischemic Attack
Secondary Endpoint
Transient Ischemic Attack 8
HR 0.71 ( ); p=0.56 6
Cumulative incidence (%) 4
N=7
RRR 29%
N=5 2 1 2 3 4 5
No. at risk
Years after randomization
Medical therapy
210
187
174
162
135 92
PFO Closure
204
187
182
163
142
110

28. Stratified Analysis of the Primary Endpoint
12% anticipated!→only 40% power
PFO
Closure
Medical Therapy
HR (95% CI)
P-interaction
Overall
7 (3.4)
11 (5.2)
0.63 ( )
Age
0.10
<45 years
1 (1.1)
6 (6.2)
0.16 ( )
≥45 years
6 (5.3)
5 (4.4)
1.22 ( )
Atrial septal aneurysm
0.09
Yes
4 (8.5)
2 (3.9)
2.09 ( ) No
3 (1.9)
9 (6.0)
0.32 ( )
CV Index event
0.78
Stroke
5 (3.1)
8 (4.9)
0.58 ( )
TIA or PE
2 (5.1)
3 (6.4)
0.78 ( )
More than 1 CV event
0.22
2 (2.6)
6 (7.6)
0.28 ( )
5 (3.9)
5 (3.8)
0.99 ( )
.01
.03 .1
.25 .5 1 2 5 10

29. Cross – Over to PFO Closure in Patients allocated to medical therapy16 12
Cumulative incidence (%) 8 4 1 2 3 4 5
No. at risk
Years after randomization
Medical therapy
210
178
167
155
127 88 29

30. Primary Endpoint According to Per-Protocol Analysis8
HR 0.70 ( , p=0.48) 6
N=10
RRR 30%
Cumulative incidence (%)
N=7 4 2 1 2 3 4 5
No. at risk
Years after randomization
Medical therapy
206
184
170
159
131 90
PFO Closure
196
183
178
161
140
108

31. Bleeding and 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

32. PFO – Closure vs. Medical Therapy PC Trial and Respect
Stroke HR

33. AMPLATZER PFO Occluder*
Device Design Differences:
Does Design Matter?
AMPLATZER PFO Occluder*
STARFlex®
Large septal surface contacting areas
Septal surface contact limited primarily to 8 discrete points
Nitinol wire mesh with polyester fabric/thread
Recapturable and repositionable
Sizes: 18, 25, 35 mm
Delivery: 8-9F
Double umbrella comprised of MP35N framework with attached polyester fabric
23mm, 28mm, 33mm
Delivery 10F 6
*CAUTION: Investigational device in the United States.  Limited by Federal (or U.S.) law to investigational use.  Not available for sale in the U.S.

34. RESPECT Device Group (%) N=499 Closure I Device Group (%) N=402
The AMPLATZER PFO Occluder Demonstrated Improved Implant Success and Reduced Late Complications Compared to the StarFlex Device
Event
RESPECT Device Group (%) N=499
Closure I Device Group (%) N=402
Procedural Success
96.1%
89.4%
Effective 6 Mos.
93.5%
86.4%
Thrombus on device 0%
1.0%
Atrial Fibrillation
0.6%
5.7%
Major Bleeding
1.6%
2.6%
Major Vascular Complications
0.8%
3.2%
Amplatzer Device and delivery system appeared to be associated with the following:
Lower risk of bleeding and vascular complications
Improved closure success
Less risk for clot formation and atrial fibrillation. 16

35. PFO Closure Devices for Cryptogenic Stroke Impact on Stroke in Comparative Studies (N=12)
Control
Risk ratio (95% CI)
CLOSURE 1
12/447
13/462
0.90 (0.41, 1.98)
RESPECT
9/499
16/481
0.49 (0.21, 1.11) PC
1/204
5/210
0.20 (0.02, 1.72)
Pooled RCTs
22/1150 (1.91%)
34/1153 (2.95%)
0.56 (0.28, 1.11)
Sanjay Kaul, TCT2012

36. PFO Closure Devices for Cryptogenic Stroke: The Art of Medicine
One person’s opinion
PFO Closure Devices for Cryptogenic Stroke: The Art of Medicine
Benefit
Risk
Inconclusive (RCT)
Might reduce recurrent events (observational)
No increase in bleeding
No Atrial fibrillation
No death
Slight ↑ in thrombotic AEs
? 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)
Sanjay Kaul, TCT2012

37. Questions after the RESPECT and PC trials
What are the main methodological limitations of these studies?
Despite these limitations, how do these trials inform treatment of pts with PFO and cryptogenic stroke?
What recommendation is appropriate for the guidelines? Class I, IIa, IIb or III? What level of evidence?
Which pts with PFOs should be closed vs receive medical therapy? Which medical therapy?
How and when should pts with stroke be evaluated for the presence of a PFO for possible closure?