PFO CLOSUREJOURNAL REVIEW OF EVIDENCE

PFO is a remnant of fetal circulation At autopsy-Identified in 27% of normal

patients Prevalence decline with age

Hagen PT, Scholz DG, Edwards WD. Incidence and size of patent foramen ovale during the first 10 decades of life: an autopsy study of 965 normal hearts. Mayo Clin Proc. 1984;59:17–20.

Contrast TTE Detected PFO in 14.9% stroke-free subjects

>39 yrs Atrial septal aneurysm 2.5% Most often in association with PFO

Di Tullio MR, Sacco RL, Sciacca RR, et al. Patent foramen ovale and the risk of ischemic stroke in a multiethnic population. J Am Coll Cardiol.2007;49:797– 802.

TEE 24.3% prevalence rate in > 45 yrs age Atrial septal aneurysm 1.9% of subjects 4.3% associated with PFOs

Meissner I, Khandheria BK, Heit JA, et al. Patent foramen ovale:innocent or guilty? Evidence from a prospective population-based study.J Am Coll Cardiol. 2006;47:440 –5.

TTE and TEE with saline contrast injection PFO is established by demonstration of an

interatrial communication with right-to-left transit of contrast microbubbles within 3 to 4 cardiac cycles of right atrial opacification

DIAGNOSIS

Injection is performed with and without Valsalva maneuver

Coughing during injection increase sensitivity

Use of harmonic imaging increase sensitivity

Contrast material injected into lower extremities has higher sensitivity

Atrial septal aneurysm is defined as a redundant and hypermobile portion of the interatrial septum that demonstrates more than 10-mm excursion from centerline during cardiac cycle

No identifiable cause despite thorough evaluation

Approximately 25% to 40% Up to 25% of patients experience recurrent

stroke or TIA within 4 years of initial event despite medical therapy

CRYPTOGENIC STROKE

Association was first reported in 1988 by Lechat et al

Numerous observational studies suggested a strong association

More convincingly demonstrated for younger (< 55 yrs age) than older patients (>55 yrs )

PFO AND CS

Relationship of Cryptogenic Stroke With PFO in Younger and Older Patients

Lamy et al-PFO with TEE in 45.9% of 581 young CS patients

Prevalence of PFO 43.9% among younger CS patients compared with 14.3% among younger patients with stroke of known cause (odds ratio 4.70, 95% ,[CI] 1.89 to 11.68, P0.001)

28.3% among older CS patients compared with 11.9% among older patients with stroke of known cause (odds ratio 2.92, 95% CI 1.70 to 5.01, P0.001)Handke M, Harloff A, Olschewski M, et

al. PFO and cryptogenic stroke in older patients. N Engl J Med. 2007;357:2262– 8.

PFO by TEE criteria in 33.8% of patients 30 to 85 years

PFO in 39.2% of CS patients versus 29.9% of patients with a known cause of stroke (P0.02).

PFO in Cryptogenic Stroke Study (PICSS)

Cryptogenic(N=250)

Non Non-Cryptogenic(N=351)

PValue

PFOPresent

39.2%(98/250)

29.9%(105/351)

<0.02

Homma S: Circulation, Volume 105(22).June 4, 2002.2625-2631

Prospective population-based study by Meissner et al

PFO was not found to be an independent risk factor for future cerebrovascular events in the general population after correction for age and comorbidity

Northern Manhattan Study (NOMAS) PFO not associated with increased stroke risk

in a multiethnic cohort of both men and women or in patients younger or older than 60 years

Olmsted County SPARC study PFO is not a significant, independent

predictor of stroke among normal subjects older than 45 yrs of age

Atrial Anatomy Anatomic size of PFO Magnitude of right-to-left shunt Coexistence of atrial septal aneurysm Eustachian Valve and Chiari’s Network Hemodynamics Venous Thrombosis and Hypercoagulable States These associations have not been observed

consistently

Factors Associated With ParadoxicalEmbolization

Estimates of annual rates of recurrent stroke among patients with PFO range from 1.5% to 12% and depend on the characteristics of the population , age

Optimal medical therapy for prevention of recurrent CS is unknown

Numerous uncontrolled studies have shown an apparent benefit of medical therapy after a CS

Summary Table of Medical Therapy Studies

Lausanne study Patients were treated with aspirin,

anticoagulation or PFO closure-annual stroke rate was 1.9%

Warfarin Aspirin Recurrent Stroke Study First randomized controlled study to compare the

effect of warfarin and aspirin after prior noncardioembolic ischemic stroke

Showed aspirin was as good as warfarin in prevention of stroke recurrence, but presence of PFO was not specifically systematically evaluated

Majority of subgroup analyses in the WARSS showed no benefit of warfarin over aspirin.

WARSS

Patients older than those in the Lausanne study All subjects were treated with aspirin (325 mg

daily) or warfarin(INR 1.4 to 2.8,mean 2.040.99). 2-year primary event rate for all-cause death or

recurrent ischemic stroke was 15.9%. No significant difference in primary event rates

between patients with versus those without PFO

PICSS

Percutaneous Closure of PFO

Transcatheter closure first reported in 1992 -Bridges, Lock, et al

Most commonly used devices are

Amplatzer PFO Occluder (AGAMedical)

CardioSEAL (NMT Medical) devices

Summary Table of Percutaneous PFO Closure Studies

Systematic review of nonrandomized studies of transcatheter closure (n10) or medical therapy (n6)

Khairy P, O’Donnell CP, Landzberg MJ. Transcatheter closure versus medical therapy of PFO and presumed paradoxical thromboemboli: a systematic review. Ann Intern Med. 2003;139:753– 6

Wöhrle’s -recent review of nonrandomized trials

Suggested lower rate of recurrent stroke after device closure of PFO, especially among patients with coexistent atrial septal aneurysm

Mean frequency of major complications was 2.3% among patients undergoing PFO closureWöhrle J. Closure of patent foramen

ovale after cryptogenic stroke.Lancet. 2006;368:350 –2.

Kutty et al. Analyzed results of investigations performed

for neurological events after PFO device closure and reported a combined recurrence rate of 3.4% for stroke/TIA and an event rate of 0.9% per year for recurrent strokes

Kutty S, Brown K, Asnes JD, Rhodes JF, Latson LA. Causes of recurrent focal neurologic events after transcatheter closure of patent foramen ovale with the CardioSEAL septal occluder. Am J Cardiol 2008;101:1487–92.

Summary Table of Surgical PFO Closure Studies

AHA/ASA guidelines for secondary stroke prevention state that “insufficient data exist to make a recommendation about PFO closure in patients with a first stroke and a PFO”

PFO closure may be considered for patients with recurrent CS despite optimal medical therapy (Class IIb, Level of Evidence: C)

No device specific for PFO closure after CS has been approved by FDA

Need for completion of appropriately powered randomized, controlled clinical trials to compare medical therapy with percutaneous device closure

Current Ongoing Clinical Trials on

PFO Closure to Prevent

Recurrent Cryptogeni

c Stroke

CLOSURE I TRIAL Evaluation of the STARFlex Septal Closure System in

Patients With a Stroke or TIA due to Presumed Paradoxical Embolism through a PFO

Prospective, multi-center, randomized, open-label, two-arm superiority trial

Patients < 60 years with CS or TIA and PFO documented by TEE, with or without atrial septal aneurysm, within 6 months of randomization

STARFlex®

Double umbrella comprised of MP35N framework with attached polyester fabric

23mm, 28mm, 33mm

Randomization1 : 1

STARFlex®Closure (within 30 Days)

6 Months Aspirin and Clopidigrel followed by 18 Months Aspirin

Best Medical Therapy24 Months Aspirin Or Warfarin

Or Combination

Between June 23, 2003 and October 24, 2008, 909 patients were randomized at 87 sites in the United States and Canada.

N = 909

N=447 N=462

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

Followup Repeat TEE at 6 months all patients and 12/24 months if residual leak

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

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

Substantial shunt

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

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)

nsNervous 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)

CONCLUSIONS

First completed, prospective, randomized 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 AF in device arm (5.7%) 60% AF periprocedural Alternative explanation unrelated to paradoxical

embolism present in 80% of patients with recurrent stroke or TIA

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

Del Sette et al first reported association between migraine with aura and right-to left shunts detected with transcranial Doppler

Presumed association of PFO with migraines relates to paradoxical embolism or humoral factors that escape degradation in bypassing the pulmonary circulation

Migraines

A retrospective evaluation of effect of transcatheter closure of atrial shunts on migraine symptoms suggested a causal association between right-to-left shunts and migraine with aura

Wilmshurst PT, Nightingale S, Walsh KP, Morrison WL. Effect on migraine of closure of cardiac right-to-left shunts to prevent recurrence of decompression illness or stroke or for haemodynamic reasons.Lancet 2000;356:1648 –51

Complete resolution of migraines in 60% of patients and improvement in symptoms in 40% of patients after transcatheter closure of atrial shunts

Azarbal B, Tobis J, Suh W, Chan V, Dao C, Gaster R. Association ofinteratrial shunts and migraine headaches: impact of transcatheterclosure. J Am Coll Cardiol 2005;45:489 –92.

Wahl et al. Evaluated migraine symptoms at a mean

follow-up of 5years in a retrospective cohort of patients who had transcatheter PFO closure for secondary prevention of paradoxical embolism

suggesting beneficial reduction of symptoms, especially in migraine with aura

Garg P etal Recent large case-control study No association was found between migraines

and presence of PFOGarg P, Servoss SJ, Wu JC, et al. Lack of association between migraine headache and patent foramen ovale: results of a case-control study. Circulation 2010;121:1406 –12.

147 patients with a history of severe migraines and without any other indication for PFO device closure were randomized to undergo either device closure or a sham procedure

Patients were treated with aspirin and clopidogrel No significant difference in the primary outcome of

headache cessation was detected between the 2 groups 3 to 6 months after the procedure

On exploratory analysis, excluding 2 outliers, the closure group showed a greater reduction in migraine headache days compared with the sham group

MIST

PRIMA (PFO Repair in Migraine With Aura)

PREMIUM (Prospective Randomized Investigation to Evaluate Incidence of Headache Reduction in Subjects With Migraine and PFO Using Amplatzer PFO Occluder Compared to Medical Management)

Current Ongoing Clinical Trials on

PFO Closure to PreventMig

raine