PFO CLOSUREJOURNAL REVIEW OF EVIDENCE

PFO is a remnant of fetal circulation Identified in 27% of normal patients at

autopsy 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 suggest strong association

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

PFO AND CS

Lechat P, Mas JL, Lascault G, Loron P, Theard M, Klimczac M,Drobinski G, Thomas D, Grosgogeat Y. Prevalence of patent foramen ovale in patients with stroke. N Engl J Med. 1988;318:1148 –1152.

Relationship of Cryptogenic Stroke With PFO in Younger and Older Patients

Prevalence of PFO among younger patients

(odds ratio 4.70, 95% ,[CI] 1.89 to 11.68, P0.001)

Among older patients

(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.

CS patients stroke of known cause

43.9% 14.3%

CS patients stroke of known cause

28.3% 11.9%

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

PFO in Cryptogenic Stroke Study (PICSS)

Cryptogenic(N=250)

Non-CS(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 general population after correction for age and comorbidity

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.

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

Di Tullio MR, Sacco RL, Sciacca RR, Jin Z, Homma S. Patent foramenovale and the risk of ischemic stroke in a multiethnic population. J AmColl Cardiol. 2007;49:797– 802.

Estimates of annual rates of recurrent stroke among patients with PFO range from 1.5% to 12%

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

Summary Table of Medical Therapy Studies

All subjects were treated with aspirin (325 mg daily) or warfarin(INR 1.4 to 2.8,mean 2.04)

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 and without PFO

PICSS

Homma S, Sacco RL, Di Tullio MR, Sciacca RR, Mohr JP. Effect of medical treatment in stroke patients with patent foramen ovale: patent foramen ovale in Cryptogenic Stroke Study. Circulation. 2002;105:2625–2631

Percutaneous Closure of PFO

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

Most commonly used devices

Bridges ND, Hellenbrand W, Latson L, Filiano J, Newburger JW,Lock JE. Transcatheter closure of patent foramen ovale after presumed paradoxical embolism. Circulation 1992;86:1902– 8.

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

Kutty et al Analyzed results of investigations performed

for neurological events after PFO device closure reported

Combined recurrence rate for stroke/TIA -3.4%

Event rate of recurrent strokes per year -0.9%

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

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 approved by FDA

Need for completion of appropriately powered RCTs to compare medical therapy with percutaneous device closure

Current Ongoing Clinical Trials on

PFO Closure to Prevent

Recurrent Cryptogeni

c Stroke

Evaluation of STARFlex device in PFO and CS or TIA

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

CLOSURE I TRIAL

Randomization1 : 1

STARFlexClosure (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 in the United States and Canada.

N = 909

N=447 N=462

STARFlex

Double umbrella comprised of MP35N framework with attached polyester fabric

23mm, 28mm, 33mm

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

Follow up- 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 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

Randomized evaluation of recurrent stroke comparing pfo closure to established current standard of care treatment

Multicenter trial Prospective, 1:1Randomized stratified by site and atrial septal

aneurysm Sample Size: Event driven, continued enrollment until 25th endpoint Patients (ages 18 to 60) with PFO who had CS within 270 days

RESPECT TRIAL

Device Group (Test)

Closure with the AMPLATZER PFO Occluder plus medical therapy

Medical Group (Control) 5 Medical Treatment

Regimens Aspirin Warfarin Clopidogrel Aspirin with dipyridamole Aspirin with clopidogrel

Percutaneous transcatheter device

Self-expanding double-disc design

Nitinol wire mesh with polyester fabric/thread

Radiopaque marker bands Sizes: 18, 25, 35 mm Recapturable and

repositionable

AMPLATZER PFO Occluder

AMPLATZER PFO Occluder

*

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 and bubble study

at 6-month follow-up (Device Group) Absence of recurrent symptomatic cryptogenic nonfatal stroke or

cardiovascular death Absence of TIA

Subject Distribution

1. Aspirin + clopidogrel was removed from the protocol in 2006 based on changes to the AHA/ASA treatment guidelines

TEE with bubble study at 6 months

CONCLUSION

RESPECT Trial provides evidence of benefit in stroke risk reduction from closure with AMPLATZER PFO occluder over medical management alone Primary analysis of ITT cohort was not statistically significant

but trended towards superiority while secondary analyses suggested superiority

Stroke risk reduction was observed across totality of analyses with rates ranging from 46.6% - 72.7%

Very low risk of device or procedure-related complications Follow-up of patients is ongoing

Percutaneous closure of patent foramen ovale versus medical treatment in patients with cryptogenic embolism

PC TRIAL

Inclusion Criteria Age < 60 years Presence of PFO (with or without ASA) Clinically and neuro-radiologically verified ischemic stroke or

TIA with documented corresponding intracranial ischemic lesion or

Clinically and radiologically verified extracranial peripheral thromboembolism

Primary Composite Endpoint Composite of death from any cause, non-fatal stroke,TIA,

and peripheral embolismSecondary Endpoints Myocardial infarction and peripheral thromboembolism New arrhythmia (atrial fibrillation) Re-hospitalization related to PFO or its treatment Device – related problems (dislodgement, structural failure,

infection, thrombosis)

PATIENT FLOW414 PATIENTS

ELIGIBLE FOR THE STUDY

ALLOCATED TO PFO CLOSURE (N=204) Received allocated intervention (n=191) Did not receive allocated intervention (n=13)

No PFO (n=1)Withdrawn due to co-morbidity (n=3)Logistical problems (n=1)Refused PFO closure (n=3)

ALLOCATED TO MEDICAL THERAPY (N=210) Received allocated intervention (n=200) Did not receive allocated intervention (n=10)

Logistical problems (n=4)Received PFO closure (n=6)

FOLLOW – UP COMPLETE Up to 3 years (n=23) Up to 4 years (n=21) Up to 5 years (n=127) Deceased (n=2)FOLLOW – UP INCOMPLETE Withdrew (n=7) Lost to follow-up (n=24)

FOLLOW – UP COMPLETE Up to 3 years (n=27) Up to 4 years (n=24) Up to 5 years (n=117) Deceased (n=0)FOLLOW – UP INCOMPLETE Withdrew (n=11) Lost to follow-up (n=31)

ANALYSIS FOR PRIMARY ENDPOINT (N=204) Censored at time of loss to follow-up, or withdrawal (n=31)

ANALYSIS FOR PRIMARY ENDPOINT (N=210) Censored at time of loss to follow-up, or withdrawal (n=42)

STRATIFIED ANALYSIS OF THE PRIMARY ENDPOINT

PFO CLOSUR

EMEDICAL THERAPY

HR (95% CI)

P-INTERAC

TIONOverall 7 (3.4) 11 (5.2) 0.63 (0.24-

1.62)Age 0.10

<45 years 1 (1.1) 6 (6.2) 0.16 (0.02-1.31)

≥45 years 6 (5.3) 5 (4.4) 1.22 (0.37-3.99)

Atrial septal aneurysm 0.09

Yes 4 (8.5) 2 (3.9) 2.09 (0.38-11.4)

No 3 (1.9) 9 (6.0) 0.32 (0.09-1.18)

CV Index event 0.78

Stroke 5 (3.1) 8 (4.9) 0.58 (0.19-1.76)

TIA or PE 2 (5.1) 3 (6.4) 0.78 (0.13-4.66)

More than 1 CV event 0.22

Yes 2 (2.6) 6 (7.6) 0.28 (0.06-1.41)

No 5 (3.9) 5 (3.8) 0.99 (0.29-3.45)

.01 .03 .1 .25 .5 1 2 5 10

Percutaneous PFO closure with Amplatzer PFO Occluder for secondary prevention of thromboembolism showed no significant reduction in ischemic and bleeding events compared with medical treatment

Observed difference in stroke (80% relative risk reduction, NNT=40) may be clinically relevant if confirmed in further studies

Conclusions

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

Relates to paradoxical embolism or humoral factors that escape degradation in bypassing pulmonary circulation

Migraine

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 PFO

Garg 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 history of severe migraine No other indication for PFO device closure Randomized to undergo either device closure or sham

procedure Patients treated with aspirin and clopidogrel No significant difference in primary outcome of headache

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

MIST TRIAL

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

THANK U