By: Vincent J.Caracciolo, MD FACC

PFO- To Close for Comfort

PFO- congenital lesion that frequently persists into adulthood ( 25-30%)- autopsy and TEE studies.

PFO – prevalence higher in cryptogenic stroke, especially < 55 years old.

Cryptogenic Stroke- occurs in absence of cardioembolic or large vessel source with a distribution not c/w small vessel distibution.

Cryptogenic stroke- 40% of all ischemic strokes in patients < 55 years old

PATENT FORAMEN OVALE

Septum primum grows to endocardial cushions

When cushions and septum primum meet- perforations form –this is foramen primum

Perforations then fuse forming Foramen secundum ( oxygenated blood to go from RA to LA)

This is effectively the Foramen ovale

At birth- Flap closure- due to O2 filling alveoli cause pulm arterioles to open and decrease PVR( this increase LA pressure and reduces RA pressure)

PFO embryology

Congenital Cardiac lesion

25-30% healthy hearts at autopsy

Most are asymptomatic

PrevalencePFO ( Patent

Foramen Ovale)Stroke patients

26% had PFO found during TEE , >45 years of age

Increased size of PFO in older patients

Interatrial septal Aneursym- ( ASA)- ( 0.2 to 2%) redundant mobile Interatrial septal tissue. Moves 1-1.5 cm during cardiac-respiratory cycle- associated with PFOs

Eustasian valve- juncture of IVC and RA

Chiaria Network– network of threads ad fibers in RA ( 2%)- strecth across RA from Eustacian valve attach to Interatrial septum

Other defects associated with PFO

Inter-atrial septal aneursym

Increased prevalence in pts with thromboembolic CVA

8-15%

28% of CVA with normal carotid arteries

Mecahnisms— possible

1.) associated with PFO

2.)Fibrin- platelet particles adhere to LA side of aneursym and dislodge during ocillations

Atrial septal aneursym ( ASA)

Eustacian Valve

Chiari Network

Absence of Cardiogenic emboli/large Vessel etiology/ distribution not c/w small vessel disease

Increased risk of CS in patients with PFO

Although PFO NOT associated with increased risk of RECURRENT stroke.

Cryptogenic Stroke ( CS)

Cryptogenic Stroke

Finding a PFO does NOT prove causal relationship

Maybe innocent bystander ( 26% of all healthy hearts)

Echo- start with transthoracic echo and then consider TEE/TCD– with contrast

TEE best- localize Flap

Sedation may preclude adequate Valsalva- identify a PFO

TCD only identify Right to left shunt shunt -not location of shunt

PFO and Stroke ( CS)

Can result in paradoxic embolus

Transient increases in RA pressure- Valsalva

Straining or Release phases-

Defacate/Lifting/pushing heavy objects/ repetitive cough

PFO and right to left shunting

Incidentally found PFO– no follow up or treatment

IF PFO is deemed causal to Cryptoigenic CVA- then medical therapy or closure of defect

Treatment of PFO

Migraine headache

Decompression sickness

Platypnea/orthodeoxia syndrome

Other clinical issues with PFO

Isolated PFO- NOT associated with recurrent stroke

Case Control Studies/meta analysis of them.

2000--- Increased risk of CVA if PFO, ASA or both in patients < 55 years old

Odds ratio 3.1, 6.1, 15.6

Retrospective data– risk of PFO and initial likelyhood of CVA

History of Straining/hypercoaguable state/ multiple CVAs, Large PFO, Large right to left shunt, Spontaneous R to L shunt, PFO Flap mobility

Another study showed no recurrent CVAs in a similar population

WHAT is the DATA

Retrospective data– PFO and initial risk of CVAHistory of Straining

hypercoaguable state/

multiple CVAs

Large PFO,

Large right to left shunt,

Spontaneous R to L shunt,

PFO Flap mobility

Prominent Eustasian valve or Chiari network

Presence of Atrial Septal Aneursym

Another study and a 2009 Meta analysis showed no recurrent CVAs in a similar population ( 33% of PFOs were incidental findings)

Restrospective data

Variable results

French PFO- ASA study- 581 pts

PICSS study- 630 pts

CODICIA study- 486 patients

NOMAS Study- 1100 pts

SPARC study

Prospective Studies

< 55 years old ( mean 42)– with Cryptogenic stroke

37% had PFO

1.7% had ASA

8.8% had both PFO and ASA

All pts got Aspirin 300 mg a day

Isolated ASA group– at 4 years no recurrence of CVA

Isolated PFO group-( regardless of size) no CVA at 4 years

Both PFO and ASA- increased risk of CVA ( 15% vs 4% in the absence of these abnormalities

French PFO- ASA Study- 581 pts ( case control)

42% were Cryptogenic CVA

TEE showed that the CS patients higher incidence of PFO- 39% vs. 29%

average age- 59 years old

Assigned to receive ASA 325 mg a day vs warfarin for INR 2-3.0

No association between PFO alone or PFO and ASA and recurrent risk of CVA or death ( different from French study)

No reduction of recurrent CVA in pts on Warfarin vs. Aspirin

PICSS sudy- 630 pts- Ischemic CVA(case control)

Transcranial Doppler quantify the magnitude of Right to left shunt- (RLSh)

2 year follow up, < 55 years old

No association between magnitude of (RLSh) and recurrent CVA whether or not a Atrial Setpum aneursym was found or not

CODICIA study- 486 pts ( prospective)

Stroke free pts, > 40 years old – Manhattan NY( mean age 69)- followed for about 6 years ( 80 months)

TTE used to detect PFO

PFO found in 14.9% patients

ASA- 2.5% of pts.

PFO alone or with ASA- statistically non-significant minor increased risk of CVA

NOMAS STUDY– 1100 patients(Prosepctive)

>45 years old, Olmstead Minnesoata- follow up- 5 years

Used TEE- found 24% had PFO, 1.9% ASA

PFO not significant risk for CVA after adjustment for comorbidities

PFO size not associated with risk of CVA

ASA– 4 fold increase increase ( statistically not significant)– only 11 pts had an ASA

SPARC study- 588 pts ( prosepctive)

True risk of primary or recurrent ischemic Stroke associated with PFO or ASA difficult to estimate

Case Control Trials-

Association between Cryptogenic stroke and PFO-

However 1/3 of all PFO found in Cryptogenic CVA are likely to be incidental findings

Prospective trials

PFO not associated with increased risk of recurrent CVA

PFO + ASA- increased risk in French PFO/ASA study but not PICSS or CODICIA studies

Conclusions

PFO +/- ASA– uncertain clinical importance in the development of first or recurrent CVA

2011 AHA/ASA guidelines

2011 AHA/ASA– antiplatelet therapy is reasonable for cryptogenic CVA where no anticoagulation is necessary ( hypercoaguable patients)

French PFO study- 216 pts with cryptogenic CVA + PFO

Risk of recurrent CVA- 2.3% on Aspirin 300 mg qd

Risk of recurrent CVA was 4.2% without PFO

PFO + ASA- recurrent CVA- 15.2%- possible Warfarin or closure

Treatment for PFO/ASD and ASA for prevention of CVA

No data on efficacy of closure on recurrent CVA

Surgical closure- recurrent risk of CVA- 7-14%

Sometimes

residual shunt persists despite closure

Lateral LA wall thrombus

Increased atrial arrythmias with closure device

PFO closure ( percutaneous vs surgical)

Closure 1 ( Starflex device)

RESPECT– 980 pts ( Amplatzer) ( CS + PFO_ = avg age- 46 years old

5 CVA vs 16 in the medical arm

No statistically significant reduction in death/CVA/TIA

When using intention to treat analyses but using raw data analysis it met statistical significance in CVA reduction alone ( p < .007%)

PC trial–( Amplatzer PFO occluder device) 414 pts (CS + PFO)-- < 60 year old

CVA relative risk reduction- 80% ( p value= .8)

PFO closure trials ( prospective/intention to treat)

Starflex device

Amplatzer Septal Occluder device

Pts <60 with PFO + CS or TIA

PFO closure (n= 447) vs med Rx (n= 462)

Staflex PFO closure devise + ASA/Plavix x 6 months then ASA alone

Med Rx- ASA or warfarin or both

Endpoint– CVA or TIA at 2 years

No differences –

Combo of CVA/TIA ( 5.5 vs 6.8%)

CVA- 2.9 vs 3.1%

TIA- 3.1 vs 4.1 %

Closure 1 Trial

Shunt size-- no differences in recurrent CVA

ASA-- no differences

Afib increased in PFO device arm– 5.7% vs. 0%

5 of 12 strokes in Device arm- device thrombosis or afib related-- ??? Another devise could do better

Critics feel study was underpowered and 2 year f/u not long enough ( i.e the CEA trials did not show benefit at 2 years)

Suspicion that highest risk pts had closure outside the study

Closure 1---subgroups

Asymptomatic PFO or ASA– NO antithrombotic therapy

Incidental PFO and surgical closure– may increase risk of post-op CVA

PFO +/- ASA with cryptogenic CVA– Aspirin

If recurrent CVA on Aspirin or PFO + DVT then warfarin x 3 months then device closure vs. Aspirin

2012 ACCP guidelines

French PFO/ASA study– 51 pts ( < 55 years old) with Cryptogenic Stroke

Recurrent CVA- 15.2% ( PFO+ ASA)– on Aspirin Rx

Suggest more aggresive therapy with Warfarin or closure

BUT no difference in outcomes in the PICCS trial

PFO with ASA ( ? Closure)