La chiusura del forame ovale pervio (PFO) e lo strokecriptogenetico

Guido Gigli_Rapallo

:• 1 ‐ PFO e rischio di stroke• 2 ‐ terapia nel PFO• 3 ‐ sviluppi futuri

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

CONCLUSIONI

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

Windecker S, AAA Curr J Rev, 2002

Lechat et al, N Engl J Med 1988

Webster et al, Lancet 1988

Prevalenza del PFO

Popolazione generale all’autopsia: 27%

Adulti sani all’eco TT: 10-18%

Adulti sani all’eco TE: 26%

•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.

•Al TEE:

•Controlli di popolazione: 2,2%

•Ricerca di cause diverse di sorgenti di emboli: 4%

•Chirurgia cardiaca: 4,9%

•Possibile stroke embolico: 7.9-15%

ASA: prevalenza

ASA può essere perforato:

Tipo A: persistenza di FO (36%)

Tipo B: associato a singolo difetto interatriale (18%)

Tipo C: associato a 2 perforazioni (20%)

Tipo D: associato a multiple perforazioni (26%)

L’eco TT ne perde 1 su 2

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

ATRIAL SEPTAL ANEURYSM

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

<55 a

>55 a

ischemic stroke and nonstroke control subjects

<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 definedas brain infarction that is notattributable to a source of definite cardioembolism (CE), large arteryatherosclerosis (LAA), or small artery disease (SAD) despiteextensive 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

C. Lamy, Stroke. 2002;33:706-711

581 young cryptogenic stroke patients.

Circa 200.000 casi anno (dati 2001)

80% ischemici

31% criptogenetici

Ictus in Italia

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

Mas J et al. N Engl J Med 2001;345:1740-1746

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 aa4 anni di FUEP: rischio di ricorrenza di stroke

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

PICSSstudy

630 stroke/256 CS (30-85 aa)ASA vs TAOFU 2 aaEP: recurrent ischemic stroke or death from any cause

Stephan Windecker, MD; Bernhard Meier, MD Circulation. 2008;118:1989-1998

Krasuski, R. A. et al. JAMA 2009;302:290-297.

Patient Intraoperative and Postoperative Outcomes for Repaired PFO and Unrepaired PFO

Windecker S., J Am Coll Cardiol. 2004;44:750 –758

Event-free survival from recurrent stroke and TIA in 2 registry comparisons of medical treatment vs percutaneous PFO closure

Complicanze procedurali da chiusura percutanea del PFO

Complicazioni peri-procedurali: 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

Long-Term Propensity-Score Matched Comparison of Percutaneous Closure of Patent Foramen Ovale with Medical Treatment afterParadoxical Embolism

Andreas Wahl et al,Circulation. 2012;published online before print January 11 2012

103 propensity score matched pairs of patientswho 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 afterParadoxical 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, percutaneousPFO closure was more effective than medicaltreatment for secondary prevention of recurrentcerebrovascular events among patients with PFO related TIA or stroke…equally effective for secondary stroke prevention and more effectivefor secondary TIA.

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

Steven R. Messe´, MD; Scott E. Kasner, MD , Circulation November 4, 2008

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

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

CONCLUSIONI

Michael Handke, M.D., Andreas Harloff, M.D N Engl J Med 2007;357:2262-8.

.

Alawi A. Alsheikh-Ali, Stroke. 2009; 40:2349-2355

Patent Foramen Ovale in Cryptogenic Stroke

Incidental or Pathogenic?

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

Copyright © 2009 Wolters Kluwer. 3

Table 1

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 thright 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.

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

La Frequenza del PFO si riduce con l’età:

40% nelle prime 3 decadi20% nell’ottava decade

Jochen Wöhrle, Lancet 368, 350, 2006

Michael Handke, M.D., Andreas Harloff, M.D N Engl J Med 2007;357:2262-8.

Maggiori: 1,5% tamponamentocardiochirurgiaembolia polmonare

Minori: 7,9%sito di punturaaritmieemorragie minoriBAV transitorialtro

Complicanze procedurali da chiusura percutanea del PFO

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

Closure of patent foramen ovale after cryptogenic stroke

Mas J et al. N Engl J Med 2001;345:1740-1746

Kaplan-Meier Estimates of the Risk of Recurrent Cerebrovascular Events within Four Years after the Index Stroke

Shunichi Homma et al, Circulation. 2002;105:2625-2631

Windecker S., J Am Coll Cardiol. 2004;44:750 –758

Opotowsky, A. R. et al. JAMA 2008;299:521-522.

Adults Undergoing Percutaneous and Surgical PFO/ASD Closure, Nationwide Inpatient Sample, 1998-2004a

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

Circa 200.000 casi anno (dati 2001)

80% ischemici

31% criptogenetici

Ictus in Italia

50.000 ictus/anno criptogeneticiPrevalenza PFO dipende dall’età: stimiamo nel gruppo globale 35%_popolazione generale: 27%