O'Murchu - Patent Foramen Ovale - Oregon ACC Foramen Ovale: ... US for transcatheter closure of PFO after a FIRST cryptogenic stroke. ... anatomy, concurrent venous thrombosis andPublished

6/2/2014

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Patent Foramen Ovale: Much Ado About Nothing?

Brian Ó Murchú MD

Associate Professor of Medicine

Director, Structural Heart Disease Intervention

Section of Cardiology

Temple University Hospital

June 7 2014

Why a Patent Foramen Ovale is relevant

Courtesy of Chip Jungreis MD

ABCs and 1-2-3s of PFO

• A is for apple, but PE isn’t just for pulmonary embolism

• Leonardo DaVinci did more than paint ceilings

• PFO and ASD: same thing, right?

• ASA can stand for more than for acetylsalicylic acid (aspirin)

• The number of devices currently approved in the US for transcatheter closure of PFO after a FIRST cryptogenic stroke

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courtesy of Alex Davidson, MD

TEE: tubular thrombus through a patent foramen ovale

Koullias G J et al. Circulation 2004;109:3056-3057

Intraoperative demonstration of the large thrombus traversing the patent foramen ovale (arrows).


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Reconstruction of thrombus through the patent foramen ovale (arrows) and in the pulmonary artery


PE

Intermittent Right to Left shunt: Potential for Paradoxical Embolism

Res ipsa loquitur

Images courtesy of Alex Davidson MD

Septum Primum

Ostium Primum

Ostium Secundum

Right Atrium Left Atrium

Tricuspid Mitral

IVC

SVC

Endocardial cushion

Embryology: Common Atrium35 days

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Ostium Secundum


Tricuspid Mitral

IVC

SVC

Endocardial cushion

Septum Secundum

Foramen ovale

This persists from day 55 until birthDay 35-55


Tricuspid Mitral

IVC

SVC

Septum Secundum

Septum Primum

At birth…..

• The apposing portions of septum primum and septum secundumgradually fuse

• This is complete by age 2 in 75% of people

• In 25% of people, fusion fails to occur and a residual tunnel persists (patent foramen ovale)

How prevalent is a PFO? Autopsy Study

• Overall incidence 27.3% (263/965)

• No gender differences

• Far more frequent than being left-handed (7-10%)

Hagen et al Mayo Clin Proc 1984;59:17-20

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Size Distribution of PFO

Number ofPFO

Size of PFO (mm) Hagen et al Mayo Clin Proc 1984;59:17-20

Mean PFO diameter 4.9 mm range 1-19 mm1-10 mm in 98%

Incidence of PFO by Decade

Hagen et al Mayo Clin Proc 1984;59:17-20

%


Tricuspid Mitral

IVC

SVC

3 out of 4 of us in this room

Fused Septum Primumand Septum Secundum

CO(Qs)

CO(Qp) =

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Tricuspid Mitral

IVC

SVC

The 75% meet UFO

Fused Septum Primumand Septum Secundum

RV

RA

LV

LA

The “Bubble” Study


Tricuspid Mitral

IVC

SVC

UFO meets PFO

Potential for

Paradoxical Embolism

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RV

RA

LA

PFO

LV (Next Stop: The Brain)

Plane of the Atrial Septum

Intermittent Right to Left shunt: Potential for Paradoxical Embolism

Res ipsa loquitur

Images courtesy of Alex Davidson MD

ASD. PFO.

Same thing, right?

Wrong!

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ASD: Great big hole


Tricuspid Mitral

IVC

SVC

ASD:

ASD

Qp COQs

Deficient Septum Secundum

QsLifelong Volume Overload

of the Right Heart

ASD. PFO.

Same thing, right?

Wrong!

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Important Differences between ASD and PFO:

PFO

• PFO: Normal septal growth with failed fusion of the apposing walls of the foramen ovale • Right-to-left communication• Volume is NOT the concern• Concern is for paradoxical embolism of thrombus,

platelets, air bubbles, endogenous substances, desaturated blood…………….

• ASD: Deficient septal growth leaving a hole• Predominantly left-to-right shunting from the higher

pressure LA to the lower pressure RA• Volume IS the concern• Shunting of blood causes lifelong volume overload of

the right heart which results in dilation and ultimately in clinical symptoms and signs of right heart failure (not left)• Minor right-to-left component

Important Differences between ASD and PFO:

ASD

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Echocardiographic EvaluationBaseline 6 months p

Qualitative RV dimensions <0.0001

Normal 2 17

Mildy dilated 14 17

Severely dilated 21 1

Quantitative RV dimension, mm(mean±SD)

RV LAX 76 ± 9 66 ± 9 <0.0001

RV SAX 47 ± 8 37 ± 7 <0.0001

RVIT 43 ± 7 32 ± 7 <0.0001

Qualitative RV function, No. of patients

0.0003

Normal 22 34 Brochu et al Circulation 2002;106:1821-1826

1.Mugge et al. Circulation 1995;91:2785-2792. 2.Agmon et al Circulation 1999;99:1942-4. 3. Mas et al N Engl J Med 2001;345:1740-6

Atrial Septal Aneurysm (ASA):Hypermobile Redundant Septum (Primum)

•Excursion of the atrial septum from the plane of the atrial septum ≥ 10mm•Associated with PFO in 60%•TEE: 4.6% prevalence•TEE: 10.5% prevalence in young patients with stroke

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Why do we care?

Courtesy of Chip Jungreis MD

Patent Foramen Ovale: PFO Under indictment……

• Unexplained Stroke (especially in young people): due to presumed paradoxical embolism through a PFO

• Right-to-left shunting causing hypoxia (Platypnea-Orthodeoxyia)

• Decompression sickness

• Migraine

• ??High-Altitude Pulmonary Edema

Cryptogenic (unexplained) Stroke and PFO

How so?

• In patients under 55 years of age, up to 40% of strokes are cryptogenic

• Transthoracic echo and bubble study have allowed for the noninvasive, in vivo diagnosis of PFO with right to left shunting

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Diagnosis and Quantification of PFO: The “bubble study”

RV

RA

LV

LA

Autopsy: 27%Transthoracic: 5-15%Transesophageal 25%

Size: Number of bubblesWidth of the tunnel

Agmon et al Am J Cardiol 2001;88:330

Prevalence of PFO in Patients with Cryptogenic Stroke age <55

Cryptogenic Stroke

Control p

Lechat 1988 54% 10% <0.01

Webster 1988 50% 15% <0.01

Di Tullio 1992 48% 4% <0.01

Lechat et al N Engl J Med 1988;318:1148-52Webster et al Lancet 1988;2:11-12Di Tullio et al Ann Intern Med 1992;117:461-5

•Association is weaker in older patients: or maybe not..

Association of PFO and PFO with ASA with Cryptogenic Stroke:

Maybe it’s not just in the young

Handke M et al. N Engl J Med 2007;357:2262-2268

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Suspected paradoxical embolism: Is it just the PFO?

•Atrial anatomy•Size of the PFO•Atrial septal aneurysm•Fetal Remnants (Eustachian valve, Chiari network)

630 patients (ages 30-85) with PFO (TEE) and Stroke

Patent Foramen Ovale in Cryptogenic Stroke Study (PICCS)

Determined cause

n=351

Cryptogenic

n=250 p

PFO 29.9% (105/351) 39.2% (98/250) <0.02

Large PFO 9.7% (34/351) 20% (50/250) <0.001

Homma et al Circulation 2002;105:2625-2631

Atrial Septal Aneurysm and PFO:Increases the risk of Stroke Recurrence

Mas et al N Engl J Med 2001;345:1740-6

581 patients<56 yearsCryptogenic strokeAspirin

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Prevalence of PFO in Patients with Cryptogenic Stroke or with

Stroke of Known Cause

Handke M et al. N Engl J Med 2007;357:2262-2268

PFO and Stroke:Why the association with Atrial Septal

Aneurysm?

Homma et al J Am Coll Cardiol 2003;42:1066-72

PICSS Trial

Clinical Profile ComparisonPermanent and Valsalva-only Shunt

Patients

Rigatelli et al. J Am Coll Cardiol 2011;58:2257

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Paradoxical Embolism: Trifecta

• Potential transit route: PFO…….

• Venous Source

• Intermittent opening of the foramen.........

Is there a venous source of embolus when cryptogenic stroke occurs in

young patients with PFO?

• Occult Leg DVT: inconclusive results • Other venous sources: Pelvic veins?• 95 patients with Stroke • Cause determined: 49• Cryptogenic: 46• Magnetic Resonance Venography of pelvis within

72 hours of stroke

Stollberger et al Ann Intern Med 1993;119:461-465Ranoux et al Stroke 1993;24:31-34Cramer et al Stroke 2004;35:46-50

Determined (n=49)

Cryptogenic (n=46)

p

Age 49 42 0.0002

PFO (%) 19 59 0.0002

ASD (%) 0 2 1.0

High Probability for Pelvic DVT, n (%)

2/49 (4) 9/46 (20) 0.025

Acute 0/47 (0) 3/40 (7) 0.093

Chronic 2/49 (4) 6/43 (13) 0.14

Paradoxical Emboli from Large Veins in Ischemic Stroke (PELVIS)

Cramer et al Stroke 2004;35:46-50

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Atrial Hemodynamics:Might outcome of Pulmonary Embolism

be worse when a PFO is present?

• PE: well, it sure is a source of embolism

• Abrupt increase in right sided filling pressure

• 139 patients with major PE: Contrast echo for PFO detection (1988-1994)

• PFO absent 91 (65%)

• PFO present 48 (35%)

Konstantinides et al Circulation 1998;97:1946-1951

Atrial Hemodynamics:Might outcome of Pulmonary Embolism

be worse when a PFO is present?

• Mortality 29/139 (21%)

• Ischemic Stroke: 8/139 (5.8%)

• Arterial Embolism: 7/139 (5%)

• Were these events associated with PFO?


Event

PFO Present (n=48)

n, (%)

PFO Absent (n=91)

n, (%) p

Ischemic Stroke

6 (13) 2 (2.2) 0.02

Peripheral arterial embolism

7 (15) 0 <0.001

Death 16 (33) 13 (14) 0.015

Pulmonary Embolism: Is outcome worse with a PFO?


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Reconstruction of thrombus through the patent foramen ovale (arrows) and in the pulmonary artery


PE

PFO and Cryptogenic Stroke

• Association especially in younger patients

• May be influenced by specific atrial anatomy, concurrent venous thrombosis and acute changes in atrial hemodynamics

Prospective Circumspection Stroke Prevention: Assessment of Risk in a

Community (SPARC) study

Meiss ner et al J Am Coll Cardiol 2006;47:440-5

585 patients Age >45 (mean age 66)

PFO in 140 patients (24.3%) Atrial Septal Aneurysm 11 (1.9%)

PFO +ASA : 6/140 (4.3%)Fused FO +ASA: 5/437 (1.1%) p=0.0028

41 patients had a stroke PFO had no effect on strokeMean age 66………Atrial septal aneurysm was weakly associated with a higher stroke risk

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Cryptogenic Stroke and PFO: Is it Paradoxical Embolism?

A Presumptive Diagnosis of Exclusion based on

Circumstantial Evidence

Cryptogenic Stroke in patients with PFO?

• What is the best, current management of a young patient with a FIRST cryptogenic stroke when all that can be found at the crime scene is a smoking PFO…………..?

• Should treatment be with Aspirin, Warfarin, or should the defect be closed?

Cryptogenic Stroke with PFO:Treatment to prevent recurrence

• Antiplatelet therapy

• Anticoagulation

• Surgical closure

• Percutaneous closure

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Surgical Closure

• 28 patients with cryptogenic stroke and PFO• mean age 41±13, 19 months follow up• Recurrence in 4 (14.3%), all in patients over 45 years

Homma et al Stroke 1997;28:2376-81

Prevention of Recurrent Stroke:Aspirin

Mas et al N Engl J Med 2001;345:1740-6

581 patients<56 yearsCryptogenic strokeAspirin

PFO: 12% Recurrent strokeor TIA rate over 4 years

PFO with ASA:Failure

• Warfarin Aspirin Recurrent Stroke Study (WARSS): 2206 patients aged 30-85 followed for 2 years for death or recurrent stroke

• Excluded: Cardiogenic source or planned CEA for high-grade carotid stenosis

• Aspirin (325mg) vs Anticoagulation (INR 1.4-2.8)

Prevention of Recurrent Stroke:Antiplatelet and Anticoagulant Therapy

Thompson et al N Engl J Med 2001;345:1444-1451

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• PICSS (PFO in Cryptogenic Stroke Study): subgroup of the WARSS (Aspirin or Warfarin)

• Patients with cryptogenic stroke and any patient that had TEE: 630 patients aged 30-85

• Index Stroke Classification:–Determined cause 365/630 (58%)–Cryptogenic 265/630 (42%)


Prevention of Recurrent StrokeAspirin vs Warfarin

Warfarin Aspirin

Entire cohortPFO (n=203) 16.5% 13.2%

No PFO (n=398) 13.4% 17.4%

Cryptogenic cohort

PFO (n=98) 9.5% 17.9%

No PFO(n=152) 8.3% 16.3%

Primary Endpoint after 2 years:Recurrent Ischemic Stroke and

Death


All ns

Cryptogenic Stroke with PFO:Prevention of Recurrent Stroke


“……on medical therapy (with Aspirin or Warfarin), the effect of the presence of PFO does not manifest itself, at least for the 2-year duration after ischemic stroke……”

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Percutaneous PFO Closure:The Holy Grail or a device in

search of a use?

• First performed in 1974• 2 devices currently available for approved use in

the US under the following circumstances: • Criteria: “indicated for nonsurgical closure of a

patent foramen ovale (PFO) in patients with recurrent cryptogenic stroke due to presumed paradoxical embolism through a PFO and who have failed conventional drug therapy (therapeutic INR).”

Amplatzer

AGA Medical, Golden Valley MN

• Nitinol (nickel titanium alloy) mesh double-disk containing polyester fabric

• The disks are connected by a thin neck

CardioSEAL

NMT Medical, Boston MA

• Double umbrella with 4 arms• Dacron patches fixed to 2 nitinol cross bars • The wires spreading the tissue have joints made of spring coils• STARFlex: self centering, 4-6 arms

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Endothelialization

Sharafuddin et al Circulation 1997;95:2162-8

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Medical Therapy versus Percutaneous Closure

Mean

Age

Duration of Follow up

Annual Stroke Rate

Annual Death rate

Annual rate for Stroke or

Death

Medical Therapy

(n=943)

9 studies

45 33 months 1.98% 0.94% 3.12%

Percutaneous Closure

(n=1430)

12 studies

46 18 months 0.19% 0.66% 1.15%

Adapted from Homma et al Circulation 2005;112:1063-1072

Composite Outcomes in the propensity score–matched cohort

Wahl A et al. Circulation 2012;125:803-812

Randomized Trials: CLOSURE-1

• Evaluation of the STARFlex Septal Closure System in Patients with a Stroke or TIA due to the Possible Passage of Clot of Unknown Origin through a Patent Foramen Ovale

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CLOSURE-1Closure or Medical Therapy for Cryptogenic

Stroke with Patent Foramen Ovale

Furlan AJ et al. N Engl J Med 2012;366:991-999

•Prospective, multicenter, randomized, open-label, two-group superiority trial

•Inclusion Criteria:

18-60 years old

First Ischemic stroke or TIA within the previous 6 months

Presence of a PFO (contrast TEE)

•Exclusion Criteria:

Known other cause of stroke (carotid disease, atrial fibrillation,

complex aortic arch atheroma, LV dysfunction or aneurysm)

Prothrombotic disorder, APLA (pre-randomization testing)

SLE, GCA

•Randomized 1:1

Device Closure plus Medical Therapy (aspirin 81 or 325mg for 2 years,

Clopidogrel 75mg for 6 months)

OR

Medical Therapy alone: either Aspirin 325mg OR Warfarin (INR 2-3)

at the discretion of the site PI, for 2 years

CLOSURE 1: Assessment of Degree of Shunt


Defintion of shunt: appearance of bubbles in the left atrium within 5 cardiac cycles

after opacification of the right atrium, either at rest or after Valsalva maneuver

Degree of Right to Left shunt:

None: no bubbles

Trace 1-10 bubbles

Moderate 10-25 bubbles

Substantial ≥25 bubbles

PFO size was measured in the device closure arm by indentation with a soft

balloon during catheterization (mean PFO size 10.2±±±±5.1mm)

CLOSURE 1: Definition of Primary Endpoint


Primary Endpoint: Composite of

Stroke OR TIA during 2 year follow up

Death from any cause during the first 30 days

Death from Neurologic cause between day 31 and 2 years


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Primary End Point at 2 Years


Primary End Point through 2 Years of Follow-up


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CLOSURE 1: Subgroup analysis

Serious Adverse Events

Device Performance: 6 month TEE to assess Effectiveness of closure: Definition of Effective Closure: None or trace residual shunt

366 patients had TEE:Effective closure in 315 (86.1%)

Thrombus in the Left atrium: 4 of 366 (1.1%) 2/4 sustained stroke

PC TRIAL

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

Meier B et al. N Engl J Med 2013;368:1083-1091

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Study End Points: Death, non-fatal stroke, TIA or peripheral embolism

Primary End Point: Death, non-fatal stroke, TIA or peripheral embolism


Any hint as to where benefit might be lurking?


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Randomized Trials

• RESPECT: Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment

RESPECTUSA and Canada

Inclusion Criteria:

★★★★Age 18 to 60

★Cryptogenic Stroke within 270 days: acute ischemic focal neurological deficitand either symptoms persisting 1) ≥ 24 hours, or 2) < 24 hours with MR or CT onfirmed new, neuroanatomically relevant, cerebral infarct

★PFO: TEE, bubbles in the left atrium within 3 cardiac cycles of their appearance in the right atrium at rest and/or during Valsalva release

Key Exclusion Criteria:

Carotid disease, atrial fibrillation, structural heart disease, hypercoagulable states.

Any other reason to expect limited life expectancy, inability to attend follow-upvisits, or inability to provide informed consent

Carroll JD et al. N Engl J Med 2013;368:1092-1100

Grading of Right to Left Shunt


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RESPECT: Trial Endpoints

Primary Endpoints

★★★★ Recurrence of a nonfatal ischemic stroke or★★★★ Fatal ischemic stroke or★★★★ Early post-randomization death defined as all-cause mortality

Device group – within 30 days after implant or 45 days after randomization, whichever occurs latest

Medical group – within 45 days after randomization

Secondary Endpoints

★★★★ Complete closure of the defect demonstrated by TEE bubble study at 6-month follow-up (Device Group)

★★★★ Absence of recurrent cryptogenic nonfatal stroke or cardiovascular death★★★★ Absence of transient ischemic attack (TIA)


RESPECT: Power Analysis and Event Driven Design★★★★ Estimated rate of primary efficacy events at 2

years was 4.3% in the medical group and 1.05% in the device group

� An event driven trial design was employed since event rates were estimated to be low★★★★ Enrollment was stopped December 29, 2011

when the decision rule of 25 primary endpoint events was reached which led to the presentation of results


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RESPECT: Trial Enrollment and Randomization


Device Performance

Maximum Residual Shuntingat Rest and Valsalva at 6 Months

Grade 0: 72.7%Grade 1: 20.8%Grade 2-3: 6.5%


Primary End Point Analysis – Intent to Treat: Raw Count Cohort

The primary analysis using the raw count of the ITT cohort wasdeemed invalid because the exposure to the two treatment optionswas unequal due to a greater drop-out rate in the medical group


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Baseline Characteristics of Study Patients


Primary End-Point:Intention-to-Treat and As-Treated Cohorts.


Subgroup Analysis: Big shunt, ASA?


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Procedure related Adverse outcomes


Primary Endpoint Analysis – ITT Cohort50.8% risk reduction in favor of device

3/9 device group patients did not have a device at time of endpoint strokeCarroll JD et al. N Engl J Med 2013;368:1092-1100

Primary Endpoint: As Treated Cohort72.7% risk reduction in favor of device

Outcome treatment according to treatment actually received, regardless of randomization assignment


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Recurrent Stroke Size(Methods pre-specified; analysis post-hoc)

Site-reported recurrent stroke size suggests that recurrent strokes in the medical group are larger than in device-treated patients


Randomized Trials: Questions answered or not?

Detection of Atrial Fibrillation

Jabaudon D et al. Stroke 2004;35:1647-1651

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Healey JS et al. N Engl J Med 2012;366:120-129

Risk of Ischemic Stroke or Systemic Embolism over 2.5 years of follow up:

Significance of Subclinical Atrial Arrhythmias 261/2451(10.1%)

4.2%

(11/261)

1.69% per year

1.7%

(40/2319)

0.69% per year

p=0.007

Cryptogenic Stroke with PFO:Prevention of Recurrence

• Antiplatelet therapy

• Anticoagulation

• Percutaneous closure

Cryptogenic Stroke with PFO: When should percutaneous

closure be offered?

• Patient

• Defect

• Device

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Evaluation of the Young Patient with Stroke

• MRI/MRA

• Duplex of extracranial carotid arteries

• Basic: ESR, Rheumatoid factor, RPR, Antiphospholipid antibodies, UDS (cocaine)

• Hematologic abnormality: C, S, ATIII, APCR, Prothrombin mutation, Factor V Leiden

• EKG, ?Holter, event recorder in older patients

• Transthoracic echo with bubble study

• TEE

No argument

• Transcatheter Closure of PFO: •Recurrent Cryptogenic Stroke in a young

person despite therapeutic anticoagulation

• Incidental Finding: leave it alone

Nothing BUT Argument• First Cryptogenic Stroke: primary results of randomized

studies are negative, with some suggestions……..

• Accurate Stroke diagnosis (embolic): 100% Neurology

• Comprehensive evaluation including hypercoagulability

work-up: Hematology/Rheumatology

• Comprehensive cardiac evaluation: TEE, Holter or Event recording

• Younger……

• Large PFO, atrial septal aneurysm, multiple events

• Individualized management

• Informed patient: off-label use

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Procedures have Complications

• Device Erosion and embolism

• Tamponade

• Atrial Perforation

• Aorto atrial communication

Late Thrombus Complicating Percutaneous Closure: 1000 cases

Krumsdorf et al J Am Coll Cardiol 2004;43:302-9

• Specific Device affects closure rate

Successful Closure may be device specific

Rashkind Occluder

CardioSeal StarFlex Amplatzer Septal

Occluder

Amplatzer PFO

Occluder

Number of patients

7 50 20 18 72

Occlusion rate 70% 90% 90% 100% 99%

Schuchlenz et al Int J Cardiol 2005;101:77-82

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The Beatles, PFO and Migraine

Documents

O'Murchu - Patent Foramen Ovale - Oregon ACC Foramen Ovale: ... US for transcatheter closure of PFO after a FIRST cryptogenic stroke. ... anatomy, concurrent venous thrombosis andPublished