Sydney Adventist Hospital
Hornsby Ku-ring-gai Hospital
Dr Jason Sharp MB BS FRACP FCSANZ
1877 – Conheim autopsy
1972 – only 128 cases of unexplained stroke had been
reported in the literature
1997 – Amplatzer ASD closure device used in animals –
nitinol double umbrella filled with polyester (Dacron)
2012 – CLOSURE-I trial published
Ms EW case of a persistent neurologist
43yo female. Sensory stroke symptoms but
clouded with history of possible migraine.
Subtle changes on MRI + page missing but on
further review it was felt there was a right
thalamic stroke fitting with the symptoms.
Mildly abnormal procoagulant screen. OCP
TOE initially showed negative bubble study
via antecubital vein, no PFO, mobile
Referred to me for second opinion.
RepeatTOE revealed atrial septal aneurysm
and PFO with positive bubble study via right
Admitted to hospital for PFO closure. Lesion
unable to be crossed. Multiple bubble studies
negative while patient ventilated.
Ms EW continued…
Readmitted to another hospital with
subsequent successful closure.
Femoral vs ante-cubital vein (SVC blood directed
toward tricuspid valve, IVC blood directed toward
Saline vs dedicated echo contrast media
Degree of shunting (<5, 5-25, >25 bubbles)
Methods do matter
Hamann et al: TOE/TCD detection rate was:
11.4%/4.5% via antecubital injection
18%/13.6% via antecubital injection plus the Valsalva
38.6%/36% via femoral injection alone
50%/50% via femoral injection plus the Valsalva
(Neurology 1998, 50: 1423-1428)
What is an Atrial Septal
Redundant and hypermobile portion of
interatrial septum with >10mm excursion
from the centreline during the cardiac cycle.
Some papers define >15mm total excursion.
2.2% ofTOE patients
4.3% of PFO patients
How does PFO and / or ASA cause
1. Embolisation from the venous system (e.g. DVT) to the
arterial system & brain.
• But there is a low rate of DVT found in these patients.
• Look for history of Valsalva manoeuvre at time of
2. In situ thrombus formation
3. Atrial dysfunction
Is PFO a stroke risk?
Overell, Bone & Lees, 2000 Neurology 55: 1172-1179.
Meta-analysis of case-control studies
PFO 1.83 (1.25-2.66; 15 studies)
ASA 2.35 (1.46-3.77; 9 studies)
Both 4.96 (2.37-10.39; 4 studies)
Is PFO a stroke risk?
Size of defect
More than 1 previous event
Other factors (external)
Valsalva, cough, OSA
(joint replacement, sitting posture)
Atrial dysfunction theory
Rigatelli et al JACC (Cardiovasc Int) July 2009
98 patients with PFO, previous stroke
50 AF controls
70 risk matched controls
Measured left atrial emptying and several other
atrial function parameters.
Atrial septal aneurysm was associated with worse
Atrial function normalised after PFO closure.
Age, PFO and stroke
Overell et al 2000
Age range Relative Risk of Stroke
<55 years RR 6
>55 years RR 2.26
Thanopoulos et al Catheterization & Cardiovasc
Interventions Nov 2006
Non-randomised patient preference study of 92
patients with cryptogenic stroke and PFO.
2 year follow-up of antiplatelet vs closure.
0% events in closure group, 14.75% in antiplatelet
What to do about PFO?
PFO in Cryptogenic Stroke Study PICSS Circulation 2002
630 strokes; 34% had PFO; half to aspirin, half to
warfarin; 2 year follow-up, endpoints were death or
ischaemic stroke, many older patients
No significant differences, if on treatment:
With or without PFO
Related to size of PFO
With or without atrial septal aneurysm
BUT!! INR target was 1.4-2.8. Only 265 had CS!!
In crypotogenic stroke with PFO 9.5% risk in warfarin
group, 16.3% in aspirin group but p=0.16
PFO and stroke Mas et al NEJM 2001
Approximately 27% of “normal” people have a PFO.
581 patients with cryptogenic stroke treated with
aspirin. 4 years follow-up. Prospective data.
Recurrent stroke risk
PFO and ASA 15.2%
or neither PFO nor ASA
2 to 4%
• Therefore aspirin is not providing adequate protection.
• SPARC data also showed ASA at high risk
• Spontaneous passage of bubbles also a risk factor
Prospective, multi-center, randomized, open-label, two-arm
superiority trial designed to test whether PFO closure using
STARFlex® plus medical therapy is superior to medical therapy
alone for preventing recurrent stroke orTIA in patients with
cryptogenic stroke orTIA and a PFO
Study population: Patients 60 years old or younger with a
cryptogenic stroke orTIA and a PFO documented byTOE, with or
without atrial septal aneurysm, within 6 months of randomization
DVT, hypercoagulopathy excluded
Primary endpoint : 2-year incidence of stroke orTIA, all cause
mortality for the first 30 days, and neurological mortality 31 days
to 2 years
Baseline Characteristics ITT
STARFlex Medical P value
N randomized 447 462
Mean Age 46.3 (18-61) 45.7(18-61)
Male 52.1% 51.5%
White 89% 90%
ASA > 10 mm* 38%
* modified ITT
2 Year Primary Endpoint ITT
n = 447
n = 462
*Adjusting performed using Cox Proportional Hazard Regression and adjusting for related patient characteristics including:
age, atrial septal aneurysm, prior TIA/CVA, smoking, hypertension, hypercholesterolemia
Atrial fibrillation 5.7%
(n= 14/23 periprocedural)
Major bleeding 2.6%
Deaths (all non
Any SAE 16.9%
*Perforation LA (1); hematoma >5cm at access site (4); vascular surgical repair (1); peripheral nerve injury (1);
procedural related transfusion (3);retroperitoneal bleed (3)
Aspirin versus Warfarin (physician
CLOSURE I is the first completed, prospective, randomized,
independently adjudicated PFO device closure study
Superiority of PFO closure with STARFlex® plus medical therapy over
medical therapy alone was not demonstrated
no significant benefit related to degree of initial shunt
no significant benefit with atrial septal aneurysm
insignificant trend (1.8%) favoring device driven byTIA
2 year stroke rate essentially identical in both arms (3%)
Major vascular (procedural) complications in 3% of device arm
Significantly higher rate of atrial fibrillation in device arm (5.7%)
Alternative explanation unrelated to paradoxical embolism
present in 80% of patients with recurrent stroke orTIA
cryptogenic stroke andTIA include multiple etiologies
in many patients with cryptogenic stroke orTIA a PFO may be
diagnostic criteria for paradoxical embolism are imprecise
potential efficacy of PFO device closure in better defined patient
subgroups requires further study
Percutaneous closure with STARFlex® plus medical therapy does not
offer any significant benefit over medical therapy alone for the
prevention of recurrent stroke orTIA in patients < age 60 presenting
with cryptogenic stroke orTIA and a PFO
CLOSURE-I trial - Issues
Procedural success 90%. “Effective closure” 86%.
So ITT closure only 77%.
BUT! “Effective closure” included trace shunting
or no shunting. Pre-procedure 114 of 400
Starflex patients had trace shunting.Therefore
real closure rate even lower (possibly as low as
Thrombus on device 1%.
Small absolute numbers of events.
Slow recruitment. Short follow-up.
Results incongruent with previous data
Alsheikh-Ali et al, Stroke 2009
Analysis of 23 case-control studies examining
presence of PFO in pts with CS (total approx
In patients with CS
1/3 of PFOs are likely to be incidental in all age
1/5 in younger age group
1/10 if ASA + PFO