reducing the risk of PFO-Related recurrent ischemic stroke · 63.4% risk reduction of stroke in...
Transcript of reducing the risk of PFO-Related recurrent ischemic stroke · 63.4% risk reduction of stroke in...
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