La chiusura del forame ovale
pervio (PFO) e lo stroke
criptogenetico
:
• 1 ‐ PFO e rischio di stroke
• 2 ‐ terapia nel PFO
• 3 ‐ sviluppi futuri
Guido Gigli_Rapallo
CONCLUSIONI
In caso di ictus criptogenetico
• Si può ricercare il PFO
• Ha un significato prognostico, non è ad oggi
un provato target terapeutico
• Se c’è anche un ASA considera TAO
• Proponi al Paziente di entrare in un trial
Patent foramen ovale
Right atrial view in another heart, the oval fossa is fine and shows extensive
fenestrations
Seen from the left atrial aspect the flap valve of the oval fossa is highly fenestrated,
and the extensive tissue is prolapsing into the left atrium
A spectrum of deficiencies can affect the oval fossa flap valve, giving rise to various
degrees of fenestrations. In this case two separate holes have formed, making
interventional closure a more difficult procedure
Prevalenza del PFO
Popolazione generale all’autopsia:
27%
Adulti sani all’eco TT:
10-18%
Adulti sani all’eco TE:
26%
Windecker S, AAA Curr J Rev, 2002
Lechat et al, N Engl J Med 1988
Webster et al, Lancet 1988
•right-to-left transit of contrast microbubbles
•within 3 to 4 cardiac cycles of right atrial opacification
•spontaneously or after Valsalva or cough manouver
Echocardiography. 2006;23:616–22.
ASA: prevalenza
ASA può essere perforato:
•Al TEE:
•Controlli di popolazione:
2,2%
•Ricerca di cause diverse di
sorgenti di emboli: 4%
Tipo A: persistenza di FO
(36%)
Tipo B: associato a singolo
difetto interatriale (18%)
•Chirurgia cardiaca: 4,9%
Tipo C: associato a 2
perforazioni (20%)
•Possibile stroke embolico:
7.9-15%
Tipo D: associato a multiple
perforazioni (26%)
L’eco TT ne perde 1 su 2
ATRIAL SEPTAL ANEURYSM
Base width of 1.5 cm or greater, with at least 1.1 cm excursion
into either the left or the right atrium, or a sum of the total
excursion into the left or right atrium of 1.1 cm or greater
Mugge, A. et al. Circulation 1995;91:2785-2792
MALATTIE ASSOCIATE AL PFO
•Stroke ischemico
•Emicrania, amnesia globale transitoria
•Malattia da decompressione
•Sindrome platipnea-ortodeoxia
•Ipossiemia perioperatoria
ischemic stroke and nonstroke control subjects
<55 a
>55 a
<55 a
>55 a
.
Michael Handke, M.D., Andreas Harloff, M.D N Engl J Med 2007;357:2262-8.
Prevalenza del PFO
Popolazione generale all’autopsia:
27%
Ictus criptogenetico < 55 aa:
~ 50%
HP Adams, Stroke 1993: 24; 35-41
Cryptogenic stroke (CS) is defined
as brain infarction that is not
attributable to a source of definite
cardioembolism (CE), large artery
atherosclerosis (LAA), or small
artery disease (SAD) despite
extensive vascular, cardiac, and
serologic evaluation
Shyam Prabhakaran MD
EMBOLIA
PARADOSSA
EMBOLIA PARADOSSA
EMBOLIA PARADOSSA
The Association between the Diameter of a Patent Foramen
Ovale and the Risk of Embolic Cerebrovascular Events
Herwig W. Schuchlenz, Am J Med. 2000;109:456–462
Arguments Suggesting Paradoxical Embolism
581 young cryptogenic stroke patients.
C. Lamy, Stroke. 2002;33:706-711
Ictus in Italia
Circa 200.000 casi anno (dati 2001)
80% ischemici
31% criptogenetici
50.000 ictus/anno criptogenetici
•La frequenza del PFO è + elevata nei pz con ictus criptogenetico
•Ancora maggiore è la differenza fra la frequenza di PFO+ASA nei
pz con ictus criptogenetico rispetto a pz con ictus da causa
identificabile
•E’ dimostrata la possibilità di embolia paradossa x shunt dx>sin
Passo successivo:
Qual è il rischio di ictus in un pz con PFO o PFO+ASA?
Cosa fare? prevenzione primaria
Qual è il rischio di recidiva in pz con ictus
criptogenetico e PFO o PFO+ ASA?
Cosa fare? Prevenzione secondaria
Probability That Patients Will Remain Free from Recurrent Stroke or
Transient Ischemic Attack (TIA), According to the Presence or Absence
of Atrial Septal Abnormalities
581 CS 18-55 aa
4 anni di FU
EP: rischio di ricorrenza di stroke
Mas J et al. N Engl J Med 2001;345:1740-1746
PICSS study
630 stroke/256 CS (30-85 aa)
ASA vs TAO
FU 2 aa
EP: recurrent ischemic stroke or death
from any cause
When the event rates in patients with isolated PFO (n 159) and those with PFO
and ASA (n 44) were compared, there was no significant difference (P0.84; 2-year
event rates 14.5% versus 15.9%).
Shunichi Homma et al, Circulation. 2002;105:2625-2631
Stephan Windecker, MD; Bernhard Meier, MD Circulation. 2008;118:1989-1998
Patient Intraoperative and Postoperative Outcomes for Repaired PFO and Unrepaired PFO
Krasuski, R. A. et al. JAMA 2009;302:290-297.
Event-free survival from recurrent stroke and TIA in 2 registry
comparisons of medical treatment vs percutaneous PFO closure
Windecker S., J Am Coll Cardiol. 2004;44:750 –758
Complicanze procedurali da chiusura percutanea del PFO
Complicazioni periprocedurali: 7%
1 ematoma retroperitoneale
(chirurgia)
1 tamponamento
(pericardiocentesi)
2 versamenti pericardici
(spontanea)
2 ematomi periferici
1 sopraslievelalmento di ST
(embolia gassosa?)
2 TIA
Balbi M et al, Am Heart J 2008;156:356-60
Ma cosa dice il
neurologo?
Among patients with a cryptogenic stroke and
atrial septal abnormalities, there is insufficient
evidence to determine the superiority of aspirin
or warfarin for prevention of recurrent stroke or
death (Level U), but the risks of minor bleeding
are possibly greater with warfarin (Level C).
There is insufficient evidence regarding the
effectiveness of either surgical or
percutaneous closure of PFO (Level U).
American Academy of Neurology, 2004
103 propensity score matched pairs of patients
who underwent percutaneous PFO closure or
medical treatment.
The primary outcome was a composite of
stroke, TIA, or peripheral embolism.
Long-Term Propensity-Score Matched Comparison of Percutaneous Closure of Patent Foramen Ovale with Medical Treatment after
Paradoxical Embolism
Andreas Wahl et al,Circulation. 2012;published online before print January 11 2012
Long-Term Propensity-Score Matched Comparison of Percutaneous Closure of Patent Foramen Ovale with Medical Treatment after
Paradoxical Embolism
Andreas Wahl et al,Circulation. 2012;published online before print January 11 2012
Conclusions - In this long-term observational,
propensity score matched study, percutaneous
PFO closure was more effective than medical
treatment for secondary prevention of recurrent
cerebrovascular events among patients with PFO
related TIA or stroke…equally effective for
secondary stroke prevention and more effective
for secondary TIA.
Long-Term Propensity-Score Matched Comparison of Percutaneous Closure of Patent Foramen Ovale with Medical Treatment
after Paradoxical Embolism
Andreas Wahl et al,Circulation. 2012;published online before print January 11 2012
Osservazionali
chiusura
Osservazionali
terapia medica
“Logical assumptions and best intentions do not
amount to safety and efficacy”
•hormone replacement therapy
•bypass procedures for carotid occlusion
•coronary angioplasty for stable coronary artery
disease
all had biological plausibility and had varying
degrees of low-level evidence to support them,
until definitive randomized studies proved that
they were ineffective and/or harmful
Steven R. Messe´, MD; Scott E. Kasner, MD , Circulation November 4, 2008
CONCLUSIONI
In caso di ictus criptogenetico
• Si può ricercare il PFO
• Ha un significato prognostico, non è ad oggi
un provato target terapeutico
• Se c’è anche un ASA considera TAO
• Proponi al Paziente di entrare in un trial
.
Michael Handke, M.D., Andreas Harloff, M.D N Engl J Med 2007;357:2262-8.
Patent Foramen Ovale in Cryptogenic Stroke
Incidental or Pathogenic?
Alawi A. Alsheikh-Ali, Stroke. 2009; 40:2349-2355
J. Am. Coll. Cardiol. 2009;53;2014-2018
I dati riguardanti la relazione fra stroke criptogenetici, difetti
interatriali, forame ovale patente e aneurismi del setto interatriale sono
contrastanti.
Studi retrospettivi:
Caso-controllo: un numero di studi hanno riportato un’aumentata
prevalenza di PFO e ASA in pts con stroke criptog
Table 1
Copyright © 2009 Wolters Kluwer.
3
In comparison, the association in patients over the age of 55 was less certain (OR 1.3, 3.4, and 5.1, respectively)
(metanalisi di neurology 2000).
Avere l’associazione di ASA + PFO (o DIA) comporta n rischio maggiore di
stroke?
Dati contrastanti:
As an example, in a report of 134 patients with cerebral
embolic events, an ASA was found in 45. However, 41 of
these 45 patients had other potential sources for embolization
[29].
In patients with PFO, retrospective analyses have identified
certain risk factors that may increase the likelihood of initial
and recurrent stroke [30]
The association of ASD with cerebral embolic events has been less well studied [4,16]. In one
series of 103 patients (mean age 52 years) with a presumed paradoxical embolism and an atrial septal abnormality
undergoing percutaneous closure, a PFO alone was present in 81, an ASD alone in 12, and both a PFO and ASD in
10 [4].
— In patients with PFO, retrospective analyses have identified certain risk factors that may increase the
likelihood of initial and recurrent stroke [30]. Clinical factors include a history of Valsalva maneuver (ie, straining)
preceding the cerebral embolic event, a history of multiple strokes, and possibly a hypercoagulable state
[14,31,32].
Characteristics of the PFO identified by contrast transesophageal echocardiography (TEE) that have been
associated with increased risk of ischemic stroke include a large PFO, a large right-to-left shunt, right-to-left
shunting at rest, greater mobility of the valve of the PFO, and the presence of an atrial septal aneurysm (ASA)
[30,33-37].
Associazione fra PFO ASAS e tutti e 2 e stroke
Studi prospettici:
2 studi francesi:
Clinical and imaging findings in cryptogenic stroke patients with and without patent foramen
ovale: the PFO-ASA Study. Atrial Septal Aneurysm. (Stroke 2002) vedere lavoro e caratterizzare
gli strokes e i pazienti in quelli con stroke criptogenetico con o senza PFO, PFO+ASA, ASA
In addition to being older on average, patients in the PICSS study had higher rates of hypertension, diabetes, and
prior stroke than patients in the French PFO-ASA study, making typical stroke etiologies such as atherosclerosis and
heart disease more likely. In this setting, it would be expected that PFO or ASA would be less likely to have been
the proximate cause of stroke. The observation that patients in the PICSS study had markedly higher rates of
stroke recurrence (approximately 15 percent at two years) is compatible with this hypothesis.
Age, y 59.+-12.2
57+-13.3
59.+-11.6
Figure 8: Right atrial view showing flap valve tissue that fails to fully cover the
margins of the oval fossa
Figure 9: Right atrial view showing complete absence of the flap valve tissue
This inferiorly located atrial septal defect is near the entrance of the ICV into th
right atrium
Ostium primum
An ideal case for closure of a secundum atrial septal defect
View of the right atrium showing fenestrations within the flap valve of the oval
fossa
The defect overrides the superior rim of the oval fossa, resulting in
the SCV having direct communication to both the right and left
atriums. Note the anomalous connection of the pulmonary vein to
the SCV
Schemating drawing showing the location of different types of ASD, the
view is into an opened right atrium. HV: right ventricle; VCS: superior
caval vein; VCI: inferior caval vein; 1: upper sinus venosus defect; 2:
lower sinus venosus defect; 3: secundum defect; 4: defect involving
coronary sinus; 5; primum defect.
La Frequenza del PFO si riduce con l’età:
40% nelle prime 3 decadi
20% nell’ottava decade
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
Jochen Wöhrle, Lancet 368, 350, 2006
Michael Handke, M.D., Andreas Harloff, M.D N Engl J Med 2007;357:2262-8.
Complicanze procedurali da chiusura percutanea del PFO
Maggiori: 1,5%
tamponamento
cardiochirurgia
embolia polmonare
Minori: 7,9%
sito di puntura
aritmie
emorragie minori
BAV transitori
altro
Closure of patent foramen ovale after cryptogenic stroke
The average recurrence rate for stroke or TIA in
medically treated patients with PFO and CS is
4·0% (3·4–12·0%) for the first year and
8·6% (4·6–22·0%) within 2 years
The best medical treatment for patients with
cryptogenic stroke with patent foramen ovale and
atrial septal aneurysm seems to be anticoagulation
The annual rate for stroke or transient ischaemic
attack after closure of patent foramen ovale is
1·3% (Poisson 95% CI 1·0–1·8)
Jochen Wöhrle , The Lancet Vol 368 July 29, 2006
Kaplan-Meier Estimates of the Risk of Recurrent Cerebrovascular Events within Four Years after
the Index Stroke
Mas J et al. N Engl J Med 2001;345:1740-1746
Shunichi Homma et al, Circulation. 2002;105:2625-2631
Windecker S., J Am Coll Cardiol. 2004;44:750 –758
Adults Undergoing Percutaneous and Surgical PFO/ASD Closure, Nationwide Inpatient Sample,
1998-2004a
Opotowsky, A. R. et al. JAMA 2008;299:521-522.
However, it is possible that the combination of
PFO and atrial septal aneurysm confers an
increased risk of subsequent stroke in medically
treated patients who are less than 55 years of
age. Therefore, in younger stroke patients,
studies which can identify PFO or atrial septal
aneurysm may be considered for prognostic
purposes (Level C).
American Academy of Neurology, 2004
For patients who have had a cryptogenic stroke
and have a PFO, the evidence indicates that the
risk of subsequent stroke or death is no different
from other cryptogenic stroke patients without
PFO when treated medically with antiplatelet
agents or anticoagulants. Therefore, in persons
with a cryptogenic stroke receiving such
therapy, neurologists should communicate to
patients and their families that presence of PFO
does not confer an increased risk for
subsequent stroke compared to other
cryptogenic stroke patients without atrial
abnormalities (Level A).
American Academy of Neurology, 2004
Ictus in Italia
Circa 200.000 casi anno (dati 2001)
80% ischemici
31% criptogenetici
50.000 ictus/anno criptogenetici
Prevalenza PFO dipende dall’età: stimiamo nel
gruppo globale 35%_popolazione generale: 27%