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
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