Andreas Wahl, Fabien Praz, Bindu Kalesan † , Marie-Luise Mono # ,

Long-Term Comparison of Medical Treatment With Percutaneous Closure of Patent Foramen Ovale for SecondaryPrevention of Paradoxical Embolism:

A Propensity-Score Matched Comparison

Andreas Wahl*, Fabien Praz*, Bindu Kalesan†, Marie-Luise Mono#,

Laura Geister#, Krassen Nedeltchev#, Lorenz Räber*,

Heinrich P. Mattle#, Peter Jüni†, Stephan Windecker*, Bernhard Meier*

Departments of Cardiology* and Neurology# and Clinical Trials Unit†

Bern University Hospital, Switzerland

Conflicts of Interest

• Research grants• Lecture and consultation fees

– AGA Medical, Plymouth, MN, USA

PFO as Predictor of Adverse Outcomein Patients With Major Pulmonary Embolism

Konstantinides S et al. Circulation 1998;97:1946

- PFO: independent predictor of mortality- Suggested mechanism: paradoxical

embolism

• 139 patients with major pulmonary embolism undergoing TEE • 35% with PFO • 59 ± 17 (17 - 89) years

• Clinical endpoints • death • cerebral embolism • arterial thrombo-embolism • major bleeding

Das RR, Stroke. 2008;39:2929-2935

Silent Cerebral Infarctions (by MR)2,040 Framingham Offsprings

(53% female; mean age, 62±9 years)

Prevalence of PFO According to Age

Age (years)

PFO in 263/965 autopsies (mean 27%)

Y=35-0.12xR2=0.6, p=0.008

Hagen PT, Mayo Clin Proc 1984; 59: 17-20

Selective mortality?

%

Percutaneous PFO Closure• Percutaneous PFO closure has been shown to be

safe and efficacious using several devices- Small procedural risk

- Minimal long-term risk

- Satisfactory closure rate

- Acceptable cost (outpatient procedure)

• Observational, non-randomized data suggest a lower risk of recurrence as compared to medical treatment alone

• No randomized trial published to date

• Limitations of ongoing randomized trials- High risk patients closed with device, not randomized

- Follow-up too short

Patient Population

Inclusion CriteriaAll patients with ischemic stroke or TIA, confirmed clinically or radiologically at the University Hospital of Bern Stroke Center between January 1994 and August 2000 were prospectively entered into the stroke/PFO registry if they had

- PFO ± atrial septal aneurysm (contrast TEE)

Exclusion CriteriaObvious other cardiac, aortic, or cerebrovascular cause

Treatment decisionBased on consensus among neurologist and patient

Patient Flow – Intention to Treat Analysis308 Patients

Jan. 1994 – Aug. 2000

Medical treatment alone158 patients

Percutaneous PFO closure150 patients

Medical treatment alone103 Patients

Percutaneous PFO closure103 Patients

Clinical Follow-upMedian 10.3 years

1,170 patient-years1,011 patient-years

After Propensity Score Matching 206 Patients

- 6 brands used- 42% Amplatzer occluders- 6% acute complications (no sequelae), no late

complications- 87% complete closure, 4% after 2nd intervention

- 50% antiplatelet therapy - 50% warfarin

- 27% PFO closure during follow-up

All neurovascular events adjudicated by neurologist

(Windecker S, JACC 44: 750-8, 2004)

PFO Closure150 Patients

Medical Treatment158 Patients

P

Age 50±12 51±13 0.55

Male , % 54 58 0.39

Diabetes mellitus, % 4 9 0.08

Hypertension, % 28 32 0.49

Hypercholesterolemia, % 45 29 0.003

Smoking, % 33 32 0.94

Cerebrovascular index event, % 0.022

- Ischemic stroke 65 77

- TIA 35 23

Mean number of CV events 1.8±1.1 1.5±1.0 0.025

More than 1 CV event, % 39 28 0.033

Patient Characteristics Before Propensity Score Matching (N=308)



P

Age 49±12 50±13 0.65

Male , % 52 55 0.68

Diabetes mellitus, % 5 3 0.47

Hypertension, % 26 30 0.54

Hypercholesterolemia, % 29 35 0.37

Smoking, % 30 31 0.88

Cerebrovascular index event, % 0.44

- Ischemic stroke 75 70

- TIA 25 30

Mean number of CV events 1.5±1.0 1.5±0.9 0.88

More than 1 CV event, % 25 28 0.64

Patient Characteristics After Propensity Score Matching (N=206)



P

Atrial septal anatomy, % 0.6

- PFO only 75 78

- PFO and atrial septal aneurysm 25 22

Interatrial shunt grade, % 0.001

- Small 3 11

- Moderate 17 28

- Large 79 61

Patient Characteristics Before Propensity Score Matching (N=308)



P

Atrial septal anatomy, % 0.41

- PFO only 74 79

- PFO and atrial septal aneurysm 26 21

Interatrial shunt grade, % 0.40

- Small 4 9

- Moderate 11 21

- Large 74 70

Patient Characteristics After Propensity Score Matching (N=206)

0

5

10

15

20

25

30

Cum

ula

tive

inci

denc

e(%

)

103 96 94 89 87 85 84 82 82 54 28Medical103 103 100 98 98 98 98 97 96 60 29PFO closure

No. at risk

0 1 2 3 4 5 6 7 8 9 10Follow-up, years

__ PFO Closure- - - Medical

p=0.033

Stroke, TIA or Peripheral Embolism

Primary Endpoint – Propensity Score Matched Cohort

Hazard Ratio = 0.43 95% CI 0.20 – 0.94

P=0.033

Stroke, TIA, or Peripheral Embolism at 10 Years

PFO Closure 10.7%

Medical Treatment 21.4%

0

5

10

15

20

25

Cum

ula

tive

inci

denc

e(%

)


No. at risk

0 1 2 3 4 5 6 7 8 9 10Follow-up, years


p=1.00

Death


PFO Closure 5.8%

Hazard Ratio = 1.00, 95% CI 0.32 – 3.10 P=1.00

Propensity Score Matched Cohort

All Cause Mortality at 10 Years

0

5

10

15

20

25

Cum

ula

tive

inci

denc

e(%

)


No. at risk

0 1 2 3 4 5 6 7 8 9 10Follow-up, years


p=0.59

Stroke


PFO Closure 5.8%

Hazard Ratio = 0.75, 95% CI 0.26 – 2.16, P=0.59

Ischemic Stroke at 10 Years


0

5

10

15

20

25

Cum

ula

tive

inci

denc

e(%

)


No. at risk

0 1 2 3 4 5 6 7 8 9 10Follow-up, years


p=0.039

TIA


PFO Closure 4.9%

Hazard Ratio = 0.3195% CI 0.10 – 0.94

P=0.039

Transient Ischemic Attack at 10 Years


.1 .15 .2 .25 .5 1 2 4 6

PFO closure better Medical tr. better

0.43 (0.20-0.94)Overall 0.033

0.42 (0.15-1.18)PFO only0.61 (0.20-1.86)PFO and ASA

0.54

0.33 (0.09-1.23)Age <55 yrs0.690.50 (0.09-2.73)Age ≥55 yrs

0.14 (0.03-0.76)Female0.071.00 (0.29-3.45)Male

0.25 (0.03-2.24)No severe shunt 0.210.70 (0.27-1.84)Severe shunt

1.00 (0.35-2.85)≤1 event0.0740.22 (0.06-0.80)>1 event

0.04 (0.00-0.63)Index event TIA0.0390.86 (0.29-2.55)Index event stroke

HR (95% CI) PStroke/TIA/Periph. Embol.Propensity-Matched Cohort

0

5

10

15

20

25

30

Cu

mul

ativ

e in

cide

nce(

%)


No. at risk

0 1 2 3 4 5 6 7 8 9 10Follow-up, years


p=0.004

Stroke, TIA or Peripheral Embolism Primary Endpoint – Intention to Treat Population

PFO Closure 9.3%

Hazard Ratio = 0.4095% CI 0.22 – 0.75

P=0.004


Ischemic Stroke, TIA, or Peripheral Embolism at 10 Years

0

5

10

15

Cu

mul

ativ

e in

cide

nce(

%)


No. at risk

0 1 2 3 4 5 6 7 8 9 10Follow-up, years


p=0.21

Death


PFO Closure 4.7%

Hazard Ratio = 0.55, 95% CI 0.22 - 1.38, P=0.21

All Cause Mortality at 10 Years

Intention to Treat Population (N=308)

0

5

10

15

Cu

mul

ativ

e in

cide

nce(

%)


No. at risk

0 1 2 3 4 5 6 7 8 9 10Follow-up, years


p=0.04

TIA


PFO Closure 4.7%

Hazard Ratio = 0.4095% CI 0.17 – 0.96

P=0.04

TIA at 10 Years

Intention to Treat Population (N=308)

Death Stroke TIA Peripheral Embolism

Stroke/TIA/PE Death/Stroke/TIA/PE

0.4 0.4 0.4

0

0.8

1.1

0.9

1.11.1

0.1

2.4

3.0

P<0.001

P<0.001

P<0.001P<0.001 P<0.001

Event Rates per Year (%)

NS

(1,796 patient-years) (1,323 patient-years)

Device No Device

Conclusions• PFO closure appears more effective

than medical treatment for secondary prevention of recurrent cerebrovascular events among patients with stroke or TIA presumably related to PFO.

• Less death, stroke, or TIA with a PFO closure device than without.

• Results require confirmation in randomized clinical trials.

Documents

Andreas Wahl*, Fabien Praz*, Bindu Kalesan † , Marie-Luise Mono # ,

Andreas Wahl, Fabien Praz, Bindu Kalesan † , Marie-Luise Mono # ,