reducing the risk of PFO-Related recurrent ischemic stroke

Bruce Klugherz, MD

Abington Jefferson Health

October 13, 2017

Pathophysiology of PFO and Paradoxical Embolism

Normal appearing atrial septum

Septum

SecundumSeptum

Primum

Agitated saline study demonstrating

right to left shunting through the PFO

Blood clot passing through the PFO

becoming a paradoxical embolism

Embryology of PFO

Gross anatomy of PFO

RA LA

Paradoxical embolism

PFO Incidence vs Age

1–29 yrs 30%

30–79 yrs 25%

≥80 yrs 20%

Hagen PT et al. Mayo Clin Proc, 59 (1984), p 17

Comparison of Diagnostic Techniquesin Stroke patients

TTE 18%

TCD 27%

TEE 39%

Di Tullio, M. et al. Stroke, 24 (1993), pp. 1020-1024

▪ Platypnea-orthodeoxia syndrome*

▪ Decompression illness**

▪ 4.8x higher risk of major DCI

▪ Migraine with aura***

▪ 2.4x higher prevalence of PFO

▪ Cryptogenic stroke

PFO: Associated clinical syndromes

*Medina A et al. Circulation. 2001; 104: 741.

**Torti SR et al. , Eur Heart J, 25 (2004), pp. 1014-1020

***Anzola GP et al., Neurology, 52 (1999), pp. 1622-1625

supine

upright

PFO and ASA are associated with

cryptogenicstroke

Cramer SC et al. ,

Stroke, 35 (2004), pp. 46-50

PFO with ASA in cryptogenic stroke:

> 4 fold riskof recurrent

CVA/TIA

Mas JL et al.,N Engl J Med, 345 (2001) , p. 1740

PICSS trial: Medical therapy for risk reduction

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

PFO no ASA (n=159): 14.5%PFO + ASA (n=44): 15.9%

The CLOSE trial*

*Mas et al. N Engl J Med 2017; 377:1011-1021

Surgical PFO closure

Homma, S et al. Stroke. 1997;28:2376-2381

Transcatheter PFO closure

Clinical trials of PFO closure

2.“RESPECT”

3.“REDUCE”

AMPLATZER PFO Occluder

1. “CLOSURE 1”

STARFlex Occluder

Kaplan-Meier for Primary Endpoint ITT

Furlan AJ, et al. N Engl J Med 2012; 366:991-999

▪ 3/9 device group patients did not have a device at time of endpoint stroke

Primary Endpoint Analysis – ITT Cohort50.8% risk reduction of stroke in favor of device

▪ The Per Protocol (PP) cohort includes patients who adhered to the requirements of the study protocol

Primary Endpoint Analysis – Per Protocol Cohort 63.4% risk reduction of stroke in favor of device

▪ The As Treated (AT) cohort demonstrates the treatment effect by classifying subjects into treatment groups according to the treatment actually received, regardless of the randomization assignment

Primary Endpoint Analysis – As Treated Cohort 72.7% risk reduction of stroke in favor of device

Recurrent Cerebral Infarct Size

Totality of Evidence and NNT46.6%-72.7% risk reduction of stroke in favor of device

Totality of Evidence

Number Needed to Treat (NNT)

•In the RESPECT ITT population, point estimates favored closure but didn’t reach statistical significance

•RESPECT protocol required follow up until an FDA regulatory decision

•FDA Advisory Panel requested analysis of long-term outcomes using updated data (data lock, May 2016)

RESPECT Long Term follow up

Gore REDUCE Clinical StudyProtocol and primary endpoint results

Endpoints

• Two co-primary endpoints:

–Freedom from recurrent clinical ischemic stroke through at least 24 months post-randomization (unadjusted log-rank test; adjudicated by CEC)

– Incidence of new brain infarct (defined as clinical ischemic stroke or silent brain infarct*) through 24 months (binomial test of subject-based proportions)

• Subjects prospectively followed for up to 5 years

• Adjustment for testing multiplicity

* New T2 hyperintense MRI lesion with diameter ≥ 3 mm;

adjudicated by MRI core lab.

Medical management options

–Acetylsalicylic acid alone (75–325 mg once daily)

–Combination acetylsalicylic acid (50–100 mg once daily)and dipyridamole (225–400 mg once daily)

–Clopidogrel (75 mg once daily)

Adverse events

*Depression leading to suicide *Prior cardiovascular disease leading to an acute cardiovascular event

• Atrial fibrillation (AF) / flutter rate higher in the closure group– Non-serious (66 percent)– Onset in first 45 days (83 percent)– Resolved within two weeks (59 percent)– 1 / 29 with AF after closure had a stroke

Adverse events

The CLOSE trial*

*Mas et al. N Engl J Med 2017; 377:1011-1021

• Best antithrombotic therapy for secondary prevention remains uncertain

• PFO closure reduces the risk for a recurrent clinical ischemic stroke compared with medical therapy, reduces silent brain infarct (REDUCE), and may reduce infarct size (RESPECT)

• With aging there is an increased likelihood that non-PFO related risks for stroke may develop and cause a recurrent ischemic stroke independent of PFO closure.

• Afib and VTE may occur with increased frequency following PFO closure

Conclusions