PFO Closure: clear and borderline indications and cases where there is no evidence of benefit Michael Mullen Royal Brompton Hospital London

PFO Closure:PFO Closure:clear and borderline indications and clear and borderline indications and cases where there is no evidence of cases where there is no evidence of

benefitbenefit

Michael MullenMichael MullenRoyal Brompton HospitalRoyal Brompton Hospital

LondonLondon


benefitbenefit

Research GrantsResearch Grants NMT medicalNMT medicalEdwards Life Edwards Life

ScienceScienceCorevalve IncCorevalve Inc

Medical Advisory BoardMedical Advisory Board Sutura IncSutura IncCardio-opticsCardio-optics

ConsultancyConsultancy Sutura IncSutura Inc

I have a PFOI have a PFO

StrokeStroke

MigraineMigraine

DCIDCI

CyanosisCyanosis

DementiaDementia

COPDCOPD

OSAOSA

Prevalence of PFOPrevalence of PFO

0 20 40 60 80 100

Stroke/TIA

Migraine

DCI

OSA

COPD

Dementia

CFS

% with PFO


benefitbenefit““The only good PFO is a closed The only good PFO is a closed

PFO” …..Dr Bernard MeierPFO” …..Dr Bernard Meier

““There is no clear indication for There is no clear indication for PFO closure” …..Most PFO closure” …..Most neurologistsneurologists

StrokeStroke

• Webster MW; Lancet 1988Webster MW; Lancet 1988– 40 stroke patients < 40 yrs old + 40 stroke patients < 40 yrs old +

matched controlsmatched controls– Contrast echo +ve 50% of patients 15% Contrast echo +ve 50% of patients 15%

controlscontrols

• Lechat P; NEJM 1988Lechat P; NEJM 1988– 60 stroke patients < 55 yrs old + 100 60 stroke patients < 55 yrs old + 100

controlscontrols

Patent Foramen OvalePatent Foramen OvaleCryptogenic strokeCryptogenic stroke

Patent Foramen OvalePatent Foramen OvaleCryptogenic strokeCryptogenic stroke

0

10

20

30

40

50

60

All Othercause

CSRF

Lechat P; NEJM 1988Lechat P; NEJM 1988

% w

ith

PFO

Patent Foramen OvalePatent Foramen OvaleMeta-analysis of risk of strokeMeta-analysis of risk of stroke

11 55 1010 1515 2020 2525 3030

PFOPFOAllAll

PFO +ASAPFO +ASA

ASAASA

PFOPFOAge<55Age<55

PFO +ASAPFO +ASAASAASA

PFOPFOAge>55Age>55

PFO +ASAPFO +ASAASAASA

PFOPFOCS vs ICCS vs IC

PFO +ASAPFO +ASA

ASAASA

Overell Neurology 2000Overell Neurology 2000

Patent Foramen OvalePatent Foramen OvaleCS recurrence rateCS recurrence rate

– Mas JL et al; NEJM 2001Mas JL et al; NEJM 2001 – 581 patients with CS followed for over 4 581 patients with CS followed for over 4

yrsyrs– All patients received Aspirin 300mg/dayAll patients received Aspirin 300mg/day

– Recurrence ratesRecurrence rates•PFO PFO 2.3% 2.3% (95%CI: 0.3 to 4.3)(95%CI: 0.3 to 4.3)•PFO+ASAPFO+ASA 15.2% 15.2% (95%CI: 1.8 to 28.6)(95%CI: 1.8 to 28.6)•No PFO No PFO 4.2%4.2% (95%CI: 1.8 to 6.6)(95%CI: 1.8 to 6.6)

Device Closure of PFODevice Closure of PFO

Windecker; JACC 2004Windecker; JACC 2004

Device Closure of PFODevice Closure of PFODevice closure vs medical therapyDevice closure vs medical therapy

Khairy; Heart 2004Khairy; Heart 2004

Device Closure of PFODevice Closure of PFORCTsRCTs in Stroke in Stroke

• RESPECT PFO (USA)RESPECT PFO (USA)– 500 patients 500 patients – Amplatzer PFO vs standard medical therapyAmplatzer PFO vs standard medical therapy– Equivalence trialEquivalence trial– Recruitment nearing completionRecruitment nearing completion

• PC trial (Europe)PC trial (Europe)– 410 patients410 patients– Amplatzer PFO device vs medical therapyAmplatzer PFO device vs medical therapy– Recruitment nearing completionRecruitment nearing completion

• Closure I trial (USA) Closure I trial (USA) – Starflex vs best medical therapy in CS with PFOStarflex vs best medical therapy in CS with PFO– 800 patients powered to test superiority over medical 800 patients powered to test superiority over medical

treatmenttreatment– Recruitment completed Q4 2008Recruitment completed Q4 2008– Results Q4 2009???Results Q4 2009???

Device Closure of PFODevice Closure of PFOIndications for closureIndications for closure

• ClearClear– Proven cryptogenic strokeProven cryptogenic stroke– Pathological PFOPathological PFO– Young ageYoung age– Multiple events or recurrence Multiple events or recurrence

on treatmenton treatment• BorderlineBorderline

– First strokeFirst stroke– TIATIA– Small PFOSmall PFO– Older age with other RFsOlder age with other RFs

• Little evidence of benefitLittle evidence of benefit– Primary prevention of strokePrimary prevention of stroke– Trivial shuntTrivial shunt– Other clear causeOther clear cause

StrokeStroke

DCIDCI

Decompression illness and Decompression illness and PFOPFO

• First reported by Wilmshurst in BMJ 1986 First reported by Wilmshurst in BMJ 1986 postulated link between PFO and DCIpostulated link between PFO and DCI

• Risk of DCI increased x5 in divers with PFORisk of DCI increased x5 in divers with PFO• Increased incidence with size of defect Increased incidence with size of defect

Torti et al Eur H J 2004

• No data on benefit of closureNo data on benefit of closure

• Despite this closure recommended for Despite this closure recommended for professional diversprofessional divers

• Social divers have the option of giving up, Social divers have the option of giving up, diving within safe limits or having PFO diving within safe limits or having PFO closureclosure

StrokeStroke

MigraineMigraine

DCIDCI

PFO and migrainePFO and migraine

• Prevalence of migraine Prevalence of migraine increased in patients with PFOincreased in patients with PFO

• Prevalence of PFO increased in Prevalence of PFO increased in patients with migrainepatients with migraine

• PFO and migraine both PFO and migraine both associated with cryptogenic associated with cryptogenic strokestroke

Stang Neurology 2005

Shwedt Cephalgia 2006

Effect of PFO Closure on Effect of PFO Closure on MigraineMigraine

Observational studiesObservational studies

70%70%162 162 35%35%Reisman 2005Reisman 2005

76%76%89 89 42%42%Azarbal, 2005Azarbal, 2005

90%90%120 120 42%42%Reisman 2004Reisman 2004

65% cured65% cured66 66 39%39%Post 2004Post 2004

81%81%215 215 22%22%Schwerzmann 2004Schwerzmann 2004

88%88%62 62 27%27%Morandi 2003Morandi 2003

86%86%3737 57%57%Wilmshurst 2000Wilmshurst 2000

% improved % improved or curedor cured

(%) migraine(%) migraineNoNo

91%91%131 131 27%27%Giardini 2006Giardini 2006

80%80%41 41 24%24%Kimmelstein Kimmelstein 20072007 70%70%92 92 27%27%Luermans 2008Luermans 2008

87%87%191 191 24%24%Dubiel 2008Dubiel 2008

Effect of PFO Closure on Effect of PFO Closure on MigraineMigraine

prospective studiesprospective studies

0

1

2

3

4

5

6

7

8

SS SA Ctrls

PrePost

Stroke 2006

• N=77• All patients had migraine• PFO closure

•SS - Previous stroke N=23•SA - No stroke N=27

•DCI, TIA, migraine,MI

• No PFO closure •Ctrls - N=27

• Follow-up 1 year• Composite score of migraine

frequency, severity and aura

MIST I StudyMIST I StudyProtocolProtocol

Assessment by headache specialistAssessment by headache specialist

3 month analysis phase by headache specialist3 month analysis phase by headache specialist

TOE under GA and randomisationTOE under GA and randomisation

Contrast echoContrast echo

3 month healing phase3 month healing phase

PFO closure with StarflexPFO closure with Starflex Sham procedureSham procedure

MIST I StudyMIST I Study

• 163/432 (38%) patients had right to 163/432 (38%) patients had right to left shunts consistent with a left shunts consistent with a moderate or large PFO. moderate or large PFO.

• 147 patients were randomised.147 patients were randomised.• No difference in the primary No difference in the primary

endpoint of migraine headache endpoint of migraine headache cessation between the implant and cessation between the implant and sham groups (3/74 versus 3/73 sham groups (3/74 versus 3/73 respectively).respectively).


•What went wrong?What went wrong?

•Why MIST I results so Why MIST I results so different from previous different from previous observational data? observational data?


• RCTs often less positive than RCTs often less positive than observational studiesobservational studies– Prospective and contemporaneous Prospective and contemporaneous

measurement of outcomesmeasurement of outcomes– Better recording of AEsBetter recording of AEs– inclusion and exclusion criteria bias inclusion and exclusion criteria bias

population so becomes non population so becomes non representative representative


– MIST I patients were MIST I patients were fundamentally different to those fundamentally different to those in the observational studiesin the observational studies•Severe, migraine refractory to Severe, migraine refractory to medical treatmentmedical treatment

•IHS guidelines lack precision and IHS guidelines lack precision and may include patients with CDH, may include patients with CDH, depression depression

•Patients with other indications for Patients with other indications for PFO closure excludedPFO closure excluded


• Too shortToo short•Device performanceDevice performance•Confounding effects of Confounding effects of

aspirin and clopidogrelaspirin and clopidogrel•Other shuntsOther shunts•Wrong endpointWrong endpoint

Should PFO be closed for Should PFO be closed for migrainemigraine

• Results of MIST study do not Results of MIST study do not support routine PFO closure support routine PFO closure for migraine alone –for migraine alone –

• however observational data however observational data still highly suggestive of link still highly suggestive of link and in selected cases it is and in selected cases it is justifiedjustified

PFO and migrainePFO and migraineCase HistoryCase History

•13 yr old girl13 yr old girl•Frequent incapacitating vertigoFrequent incapacitating vertigo•HeadacheHeadache•Occ visual auraOcc visual aura

•Well between attacksWell between attacks•Normal neurological examinationNormal neurological examination•Normal MRI and EEGNormal MRI and EEG

•Missing significant amount of schoolMissing significant amount of school•Large resting shunt on echo Large resting shunt on echo

PFO and migrainePFO and migraineCase HistoryCase History

•Neurological opinionNeurological opinion•Met with parents and patient on 2 Met with parents and patient on 2

occasionsoccasions•Explained potential for benefit Explained potential for benefit

((~50%) ~50%) and potential for complication and potential for complication (death <1:1000, embolization 1:200, (death <1:1000, embolization 1:200,

tamponade 1:500, stroke 1:500, transient AF tamponade 1:500, stroke 1:500, transient AF

1:10)1:10)

•Catheterisation under GA July 2007Catheterisation under GA July 2007•Large PFO – closed with 28 mm Large PFO – closed with 28 mm

BioSTAR BioSTAR •No complicationsNo complications•FU Jan 08FU Jan 08•Almost complete resolution of Almost complete resolution of

symptomssymptoms•No loss of schoolNo loss of school

StrokeStroke

MigraineMigraine

DCIDCI

CyanosisCyanosis

StrokeStroke

MigraineMigraine

DCIDCI

CyanosisCyanosis

DementiaDementiaCOPDCOPDOSAOSA

Orthodeoxyia PlatypnoeaOrthodeoxyia Platypnoea

• Postural related Postural related hypoxia due to large hypoxia due to large PFOPFO– Post pneumonectomyPost pneumonectomy– Aortic root dilatationAortic root dilatation

• Usually very large PFOUsually very large PFO• PFO closure results in PFO closure results in

immediate improvementimmediate improvement• Anecdotal reports and Anecdotal reports and

small case series onlysmall case series only

Hacievliyagil S et al. Respir Med 2006

PFO closure for respiratory PFO closure for respiratory disordersdisorders

• Anecdotal reports of benefit in selected Anecdotal reports of benefit in selected patientspatients

• Few small trials ongoingFew small trials ongoing• Should not be part of routine practiceShould not be part of routine practice

Indications for PFO closureIndications for PFO closure

BenefitLikelihood of causal relationshipSize of shunt Risk

Size of defectExperience of operatorTechnological advances

SuperstitchSuperstitch

ConclusionConclusion• Large body of evidence for pathological link Large body of evidence for pathological link

between PFO and a range of clinical syndromes between PFO and a range of clinical syndromes where right to left shunt is a plausible where right to left shunt is a plausible mechanismmechanism

• Increasing observational data suggests benefit Increasing observational data suggests benefit in some patients in some patients

• Results of RCTs awaited Results of RCTs awaited • In the meantime PFO closure indicated in In the meantime PFO closure indicated in

selected patients with clinical syndrome and selected patients with clinical syndrome and ‘pathological’ shunt if they understand and ‘pathological’ shunt if they understand and accept the potential for complications and accept the potential for complications and potential for (or lack of) benefitpotential for (or lack of) benefit

Documents

PFO Closure: clear and borderline indications and cases where there is no evidence of benefit Michael Mullen Royal Brompton Hospital London