PFO Closure – Close Them All?

Controversies and Advances

in the Treatment of Cardiovascular Disease The Seventeenth in the Series

November 16 & 17, 2017 Montage Beverly Hills

Ted Feldman, M.D., MSCAI FACC FESC

Evanston Hospital

Disclosure Information

The following relationships exist:

Grant support: Abbott, BSC, Corvia, Edwards, WL Gore Consultant: Abbott, BSC, Edwards, WL Gore

Stock Options: Mitralign, Cardiac Dimensions

Off label use of products and investigational devices will be discussed in this presentation

Ted Feldman MD, MSCAI FACC FESC

Recurrent Stroke Risk Reduction R

EGIS

TRIE

S R

CTs

PFO in Cryptogenic Stroke

Incidental or Pathogenic?

approximately one third of PFOs are likely to be incidental and hence not benefit from closure

Stroke. 2009; 40:2349-2355

Stroke with no PFO

Stroke, incidental PFO

Pathogenic PFO

Child and adult populations

http://datacenter.kidscount.org/data/tables/99-total-population-by-child-and-adult#detailed/1/any/false/870/39,40,41/416,417

PFO Math

• 40,000 cryptogenic strokes/year

– 800,000 cryptogenic strokes/20 years

– 50% risk reduction = 400,000 strokes prevented/20 years

PFO Math

• US population age >18, 2016: 249,485,228

– 15% with PFO= 37,422,784

– Subtract 400,000 strokes prevented

– 37,022,748 cryptogenic stroke free/20 years

Concessions: 500,000 high risk PFO

• Hip replacement – In 2010, 310,800 total hip

replacements were performed among inpatients aged 45 and over. https://www.cdc.gov/nchs/products/databriefs/db186.htm

– 46,620 with PFO

• Scuba divers – 2.7 to 3.5 million active scuba

divers in the US Sports and Fitness Industry

Association

– 450,000 with PFO

more PFO math…

37,022,748 stroke free PFO patients

- 500,000 divers & hip replacement patients with PFO

= 36,522,748 low risk & 1st cryptogenic stroke free/20 years

Atrial Fibrillation

• New AF after PFO closure, persistant after 45 days = 3.8% in REDUCE

CHADS2

1.9 2.8

4 5.9

8.5

12.5

18.2

0

2

4

6

8

10

12

14

16

18

20

0 1 2 3 4 5 6

CHA2DS2VASc

0 1.3

2.2 3.2

4

6.7

9.8 9.6

6.7

15.2

0

2

4

6

8

10

12

14

16

18

20

0 1 2 3 4 5 6 7 8 9

Ad

just

ed s

tro

ke r

ate

%/y

ear

SCORE SCORE

Adjusted stroke rate % per year

Gage BF et al, JAMA 2001;285:2864–2870 Lip GY et al, Chest 2010;137(2):263-72

New AF after PFO closure persistent > 45 days = 3.8% in REDUCE

Atrial Fibrillation

• New AF after PFO closure, persistant after 45 days = 3.8% in REDUCE

• 36,522,748 have closure – 3.8% have AF= 1,387,864 with new AF

• If stroke risk is 1% per year – 13,879 new strokes/year

– x20 years = 277,573 device related strokes • If stroke risk is 1.5% = 416,359 device related strokes

– vs 400,000 strokes prevented

DVT

the rate of pulmonary embolism was 0.41 per 100 patient-years in the PFO closure group and 0.11 per 100 patient-years in the medical-therapy group (hazard ratio, 3.48; 95% CI, 0.98 to 12.34; P = 0.04 RESPECT N Engl J Med 2017;377:1022-32

• 36,522,748 have closure

– x10 years= 3,652,274.8 100s patient years

– 250,000 excess cases pulmonary embolism/10 years

PFO in Cryptogenic Stroke

Incidental or Pathogenic?

approximately one third of PFOs are likely to be incidental and hence not benefit from closure

Stroke. 2009; 40:2349-2355

Stroke with no PFO

Stroke, incidental PFO

Pathogenic PFO

RESPECT Saver JL N Engl J Med 2017;377:1022-32

When the ASCOD algorithm was applied to classify recurrent ischemic strokes, 13 of the 46 patients (28.3%) who had a recurrent ischemic stroke had a stroke that was associated with a mechanism that was determined to be unrelated to the PFO

• ASCOD coding captures presence of possible stroke etiologies, and assigns a probability of relatedness (post-hoc)

• Five phenotypes: – A = atherosclerosis

– S = small vessel disease

– C = cardiac pathology

– O = other cause

– D = dissection

• Recurrent strokes classified as either cryptogenic or of known cause

Amarenco et al. Cerebrovasc Dis 2013;36:1-5

Blinded Adjudication of Stroke Cause

ASCOD Phenotyping

Nearly 1/3 of Recurrent Strokes in Extended Follow-up Are of Known Mechanism

29

13

0

5

10

15

20

25

30

Sub

ject

s w

ith

Rec

urr

ent

Isch

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ic S

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Cryptogenic (Possibly Paradoxical Embolism)

Known Mechanisms

Atherosclerosis = 1 Small Vessel Disease = 6 Cardioembolic = 5 (AF = 4, endocarditis = 1) Other = 1 (radiation arteriopathy) Dissection = 0

RESPECT Extended Follow-up Carroll JD TCT 2015

1 out of 3 Recurrent Strokes Had Mechanism That PFO Closure Cannot Prevent

Extended Follow-up in ITT Population

0.85

0.90

0.95

1.00

0 1 2 3 4 5 6 7 8 9 10

AMPLATZER™ PFO Occluder (N=499; # strokes = 18) Event-free

Probability

Time to Event (Years)

HR: n/a (non-proportional hazards) Log-rank p-value: 0.16

Stroke of Known Mechanism

499 463 369 212 86

20

481 394 307 168

71 10

AMPLATZER

MM

# at Risk (KM Estimates)

(0%) (1.6%) (1.9%) (3.6%) (6.0%)

(6.0%)

(0%) (3.2%) (4.8%) (5.1%)

(7.0%) (12.4%)

Medical Management (N=481, # strokes = 24)

RESPECT Extended Follow-up Carroll JD TCT 2015

If we treat everyone with PFO, many will have recurrent stroke due to other cause

If Saibal treats them all…

• 36,522,748 low risk & cryptogenic stroke free/20 years

• 20 cases/day

• 6 days a week, 50 weeks= 6000/year

• Job done in 6087 years (year 8104 Anno Saibal)

The way to a man’s head is through his heart.