PATENT FORAMEN OVALETHE DEBATE CONTINUES…………

Sydney Adventist HospitalHornsby Ku-ring-gai Hospital

Dr Jason Sharp MB BS FRACP FCSANZ

Consultant Cardiologist

History

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) fabric

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 (ceased).

TOE initially showed negative bubble study via antecubital vein, no PFO, mobile interatrial septum.

Referred to me for second opinion.

Ms EW

Repeat TOE revealed atrial septal aneurysm and PFO with positive bubble study via right femoral vein.

Admitted to hospital for PFO closure. Lesion unable to be crossed. Multiple bubble studies negative while patient ventilated.

Recommendation?

Ms EW continued…

Readmitted to another hospital with subsequent successful closure.

PFO detection

TOE Bubble study

Femoral vs ante-cubital vein (SVC blood directed toward tricuspid valve, IVC blood directed toward PFO).

Saline vs dedicated echo contrast media Valsalva Degree of shunting (<5, 5-25, >25

bubbles) Transcranial doppler

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

manoeuvre 38.6%/36% via femoral injection alone 50%/50% via femoral injection plus the Valsalva

manoeuvre

(Neurology 1998, 50: 1423-1428)

What is an Atrial Septal Aneurysm?

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% of TOE patients 4.3% of PFO patients

How does PFO and / or ASA cause stroke?

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 stroke.

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

Relative risks: 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 defectMigraine historyMore than 1 previous event

Other factors (external) Valsalva, cough, OSA Mechanical ventilation Surgical operations

(joint replacement, sitting posture) Diving, aviation

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.

Atrial function normalised after PFO closure.

Age, PFO and strokeOverell et al 2000

Age range Relative Risk of Stroke<55 years RR 6>55 years RR 2.26

Randomised Data?

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 group.

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 Between treatments

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%PFO aloneor 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

Study Design

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 or TIA in patients with cryptogenic stroke or TIA and a PFO

Study population: Patients 60 years old or younger with a cryptogenic stroke or TIA and a PFO documented by TOE, with or without atrial septal aneurysm, within 6 months of randomization DVT, hypercoagulopathy excluded

Primary endpoint : 2-year incidence of stroke or TIA, all cause mortality for the first 30 days, and neurological mortality 31 days to 2 years

Baseline Characteristics ITT

STARFlex Medical P valueN randomized 447 462

Mean Age 46.3 (18-61) 45.7(18-61)

Male 52.1% 51.5%

White 89% 90%

Index cryptogenic stroke

73% 71%

Mod/substantial shunt*

58% (231/400)

51%(228/451)

0.04

ASA > 10 mm* 38%(151/400)

35%(160/451)

0.49

* modified ITT

2 Year Primary Endpoint ITT

STARFlexn = 447

Medicaln = 462

Adjusted P value*

Composite 5.9% (n=25)

7.7% (n=30)

0.30

Stroke 3.1% (n=12)

3.4% (n=13)

0.77

TIA 3.3% (n=13)

4.6% (n=17)

0.39

*Adjusting performed using Cox Proportional Hazard Regression and adjusting for related patient characteristics including: age, atrial septal aneurysm, prior TIA/CVA, smoking, hypertension, hypercholesterolemia

Adverse Events

STARFlexN=402

MedicalN=458

P value

Major vascular complications*

3.2%(n =13)

0.0% <0.001

Atrial fibrillation 5.7% (n= 14/23 periprocedural)

0.7% (n=3)

<0.001

Major bleeding 2.6% (n=10)

1.1% (n=4)

0.11

Deaths (all non endpoint)

0.5% (n=2)

0.7% (n=3)

ns

Nervous system disorders

3.2% (n=12)

5.3% (n=20)

0.15

Any SAE 16.9% (n=68)

16.6% (n=76)

ns

*Perforation LA (1); hematoma >5cm at access site (4); vascular surgical repair (1); peripheral nerve injury (1); procedural related transfusion (3);retroperitoneal bleed (3)

Composite Primary EndpointBaseline Shunt and Atrial Septal Aneurysm (TEE)

STARFlexN=400

MedicalN=451

P value

Trace shunt

7.0%(n=8/114)

8.0%(n=10/126)

0.75

Moderate shunt

5.3%(n=7/132)

8.4%(n=12/143)

0.31

Substantialshunt

3.6%(n=3/84)

5.3%(n=3/57)

0.62

No atrial septal aneurysm

6.4%(n=15/236)

8.5%(n=20/236)

0.38

Atrial septal aneurysm

4.9%(n=7/142)

6.5%(n=9/139)

0.58

Aspirin versus Warfarin (physician discretion)

Aspirin alone(n=243)

Warfarin alone(n=139)

P value

Composite 6.7%(n=14)

8.1%(n=9)

0.63

Stroke 3.9%(n=8)

2.7%(n=3)

0.67

TIA 2.9%(n=6)

6.3%(n=7)

0.09

CONCLUSIONS

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 by TIA 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%) 60% periprocedural

CONCLUSIONS

Alternative explanation unrelated to paradoxical embolism present in 80% of patients with recurrent stroke or TIA cryptogenic stroke and TIA include multiple etiologies in many patients with cryptogenic stroke or TIA a PFO may

be coincidental 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 or TIA in patients < age 60 presenting with cryptogenic stroke or TIA 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 50%).

Thrombus on device 1%. Small absolute numbers of events. Slow recruitment. Short follow-up. Results incongruent with previous data

Incidental PFO?

Alsheikh-Ali et al, Stroke 2009 Analysis of 23 case-control studies

examining presence of PFO in pts with CS (total approx 2300 pts).

In patients with CS 1/3 of PFOs are likely to be incidental in

all age groups 1/5 in younger age group 1/10 if ASA + PFO

Starflex vs Amplatzer

Where to from here?

RESPECT trial Maybe RCTs are not the answer? Good quality registry needed.