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,
Andreas Wahl, Stephan Windecker, Heinrich P. Mattle,
and Peter Jüni
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
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
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
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
treatment with antiplatelet agents or Vitamin K
antagonists for secondary prevention of
thromboembolism.
PROCEDURES
PERCUTANEOUS PFO CLOSURE
Amplatzer PFO Occluder
Acetylsalicylic acid (100-325mg qd)
and ticlopidine (250-500mg qd)
or clopidogrel (75mg qd)
for 6 months
1:1
RCT
MEDICAL TREATMENT
Oral anticoagulation or
Antiplatelet therapy
at the discretion of the neurologist
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
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.
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
SECONDARY ENDPOINTS
•
•
•
•
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)
ENDPOINT DEFINITIONS
• 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
• Stroke

Acute focal neurological
deficit lasting >24 hours
with MRI or CT evidence of
new intracranial lesion
• TIA

Acute neurologic deficit
lasting <24 hours with
complete resolution
STUDY CENTERS AND INVESTIGATORS
Australia
Monash Medical Center, Melbourne
Sir Charles Gairdner Hospital, Nedlands
Epworth Hospital, Prahran
Alfred Hospital, Prahran
Austria
Uni-Klinik Innere Med II, AKH Vienna
Belgium
A.Z. Sint-Jan AV, Brugge
Brazil
Hospital Sao Paulo, Sao Paulo
Canada
Montreal Heart Institute, Montreal
Queen Elizabeth II Health Sciences Centre,
Halifax
Denmark
Aalborg Sygehus, Aalborg
Aarhus Universitetshospital, Aarhus
Germany
Klinik d. J.W.Goethe Universität Frankfurt
Universitätsklinikum Giessen, Giessen
Herz- und Diabeteszentrum NRW, Minden
Johannes Wesling Klinikum Minden, Minden
Herzzentrum Leipzig GmbH, Leipzig
Brüderkrankenhaus Trier, Trier
Städtisches Klinikum Fulda, Fulda
Klinikum d. Philipps-Universität Marburg,
Marburg
S. Menahem, S. Bower, R. Harper
B.E.F. Hocking, W.Carroll
T.Walton
J. Frayne, M. Butler, L. Iles, E. Ivens,
J.Hare, E. Kotschet
P. Probst, W. Lalouschek,
H. Baumgartner, R. Rosenhek
G. Vanhoorem, L. Muyldermans
A.C.C. Carvalho, M.M. Fukujima
C.M.C. Silva
S. Lanthier, R. Ibrahim
S. Philipps, J. Howelett
B. Kristensen, R. Nielsen
G. Andersen, T.S. Jensen
K. Emmersten
V. Schächinger, T. Trepels
W. Waas, M. Jauss
W.Scholtz, D. Fassbender
J. Glahn, H. Wuttig
G. Schuler, G. Marcus, M. Sandri
K.E. Hauptmann, T. Gehrig
M. Conze, M. Emir, J.M. Klotz
B. Maisch, R. Funck
Germany
Universitätskliniken des Saarlands,
Homburg/Saar
Medizinische Universitätsklinik Würzburg,
Würzburg
Leopoldina KH der Stadt Schweinfurt GmbH,
Schweinfurt
Lukaskrankenhaus Neuss, Neuss
Poland
Medikal University of Gdansk, Gdansk
Card. Dept.Institute of Cardiology, Krakow
Slovakia
Slovak Institute of Cardiovascular Disease
Switzerland
Bern University Hospital / Inselspital
United Kingdom
Sussex Cardiac Centre, Brighton
Western General Hospital, Edinburgh
Royal Surrey County Hospital, Guilford
St. George´s Hosp. Med. School, London
Clarence Wing – St. Mary’s Hospital NHS Trust,
London
New Cross Hospital, Wolverhampton
29 Sites in Europe, Brazil, Canada and Australia
M.Böhm, B. Scheller
P. Schänzenbächer,
W. Müllges
J. Mühler, K. Dötter
M. Haude, H. Degen
J. Erecinski, Chojnicki,
R. Sabiniewicz
D. Dudek, A. Szczudlik,
P. Szermer, S. Bartus,
D. Sorysz, B. Chyrchel
V. Fridrich
B. Meier, H. Mattle,
S. Windecker, A. Wahl
D. Hildick-Smith, P. Kumar
B. Weller, M. Dennis,
D. Northridge
E.W. Leatham
H. Markus, M. Punter
I. Mallik
S.S. Khogali, L. Evans,
A. Smallwood
STUDY ORGANISATION
Grant support
St. Jude Medical, Plymouth, Minnesota, USA
Principal investigators
Bernhard Meier, Heinrich P. Mattle
Study monitoring
E&E CRO, Clinical Research Organization, Vienna, Austria
Data managment
Academic Research Organisation
InterCorNet, Zurich Heart House, Zurich, Switzerland
Statistical analysis
CTU Bern (Bindu Kalesan, Peter Jüni)
DSMB
R. Stables, P. Sandercock, T. Gasser
CEC
B. Martin (Chairman), R. Baumgartner, F. Eberli
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
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 5 years (n=117)
FOLLOW – UP INCOMPLETE
Withdrew (n=11)
ANALYSIS FOR PRIMARY ENDPOINT (N=204)
ANALYSIS FOR PRIMARY ENDPOINT (N=210)
Censored at time of loss to follow-up,
or withdrawal (n=31)
Up to 4 years (n=24)
Deceased (n=0)
Lost to follow-up (n=31)
Censored at time of loss to follow-up,
or withdrawal (n=42)
BASELINE CLINICAL CHARACTERISTICS
Percutaneous
PFO Closure
Medical
Treatment
n = 204
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)
5 (2.5)
6 (2.9)
50 (24.5)
62 (29.5)
3 (1.5)
2 (1.0)
Diabetes mellitus
Hypercholesterolemia
Peripheral vascular disease
BASELINE CLINICAL CHARACTERISTICS
Percutaneous
PFO Closure
Medical
Treatment
n = 204
n = 210
Coronary artery disease
4 (2.0)
4 (1.9)
History of myocardial infarction
3 (1.5)
1 (0.5)
47 (23.0)
38 (18.1)
Stroke
165 (80.9)
163 (77.6)
Transient ischemic attack
33 (16.2)
42 (20.0)
6 (2.9)
5 (2.4)
76 (37.3)
79 (37.6)
Migraine
Cerebrovascular index event
Peripheral embolism
> 1 previous cerebrovascular event
ATRIAL SEPTAL ANATOMY
INTER-ATRIAL
RIGHT TO LEFT SHUNT
ATRIAL SEPTAL
ANEURYSM
%
50
47.0
PFO CLOSURE
40
39.1
MEDICAL THERAPY
40.8
29.7
30
23.0
24.3
23.2
20.1
20
10
0
ATRIAL SEPTAL ANEURYSM
SMALL
MODERATE
LARGE
PRIMARY COMPOSITE ENDPOINT
CUMULATIVE INCIDENCE (%)
DEATH FROM ANY CAUSE, NON-FATAL STROKE,
TIA AND PERIPHERAL EMBOLISM
8
HR 0.63 (0.24-1.62, p=0.34)
6
RRR 37%
4
2
0
0
1
NO. AT RISK
MEDICAL THERAPY
PFO CLOSURE
210
204
185
186
2
YEARS AFTER
170
181
3
4
5
131
142
90
110
RANDOMIZATION
159
163
SECONDARY ENDPOINT
CUMULATIVE INCIDENCE (%)
STROKE
8
HR 0.20 (0.02-1.72, p=0.14)
6
4
2
RRR 80%
0
NO. AT RISK
0
MEDICAL THERAPY 210
PFO CLOSURE
204
1
187
188
2
YEARS AFTER
175
183
3
4
5
164
167
134
146
92
112
RANDOMIZATION
SECONDARY ENDPOINT
CUMULATIVE INCIDENCE (%)
TRANSIENT ISCHEMIC ATTACK
8
HR 0.71 (0.23-2.24); p=0.56
6
4
RRR 29%
2
0
0
1
NO. AT RISK
MEDICAL THERAPY 210
PFO CLOSURE
204
187
187
2
YEARS AFTER
174
182
3
4
5
135
142
92
110
RANDOMIZATION
162
163
SECONDARY ENDPOINTS
%
10
HR 1.02
95%CI 0.48–2.21
P=0.95
8
6
HR 2.04
95%CI 0.19–22.5
P=0.56
6.4
6.2
PFO CLOSURE
MEDICAL THERAPY
4
2
1.0
0.5
0
MYOCARDIAL INFARCTION
PFO RELATED HOSPITALIZATIONS
BLEEDING AND ATRIAL FIBRILLATION
BLEEDING
ATRIAL FIBRILLATION
%
10
PFO CLOSURE
MEDICAL THERAPY
8
HR 0.58
95%CI 0.23–1.47
p=0.25
HR 2.60
95%CI 0.50–13.4
p=0.25
5.7
6
4
HR 0.66
95%CI 0.24–1.86
p=0.43
3.4
HR 0.34
95%CI 0.04–3.30
p=0.35
2
4.3
2.9
1.4
2.5
1.0
0.5
0
OVERALL
BLEEDING
SERIOUS ADVERSE
MINOR ADVERSE
EVENT
EVENT
ATRIAL FIBRILLATION
THROMBOEMBOLIC AND BLEEDING EVENTS
%
15
PFO CLOSURE
MEDICAL THERAPY
10
HR 0.45, 95%CI 0.16 – 1.29
P=0.14
HR 0.49, 95%CI 0.19 – 1.32
P=0.16
5.7
5.2
5
2.5
2.9
0
, TIA OR EMBOLISM
STROKE, TIASTROKE
OR PERIPHERAL
PERIPHERAL EMBOLISM
STROKE
TIA, PERIPHERAL
EMBOLISM
STROKE
, TIA,, PERIPHERAL
EMBOLISM
OR SEVERE
OR SEVERE
BLEEDING
BLEEDING
STRATIFIED ANALYSIS OF THE
PRIMARY ENDPOINT
PFO
Overall
Age
<45 years
≥45 years
CLOSURE
MEDICAL
THERAPY
HR (95% CI)
7 (3.4)
11 (5.2)
0.63 (0.24-1.62)
PINTERACTION
0.10
1 (1.1)
6 (6.2)
0.16 (0.02-1.31)
6 (5.3)
5 (4.4)
1.22 (0.37-3.99)
Atrial septal aneurysm
Yes
No
0.09
4 (8.5)
2 (3.9)
2.09 (0.38-11.4)
3 (1.9)
9 (6.0)
0.32 (0.09-1.18)
CV Index event
Stroke
TIA or PE
0.78
5 (3.1)
8 (4.9)
0.58 (0.19-1.76)
2 (5.1)
3 (6.4)
0.78 (0.13-4.66)
More than 1 CV event
Yes
No
0.22
2 (2.6)
6 (7.6)
0.28 (0.06-1.41)
5 (3.9)
5 (3.8)
0.99 (0.29-3.45)
.01 .03 .1 .25 .5 1 2 5 10
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
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