The document discusses whether interventional closure of a patent foramen ovale (PFO) warrants treatment for cryptogenic stroke patients compared to medical therapy alone. Initial randomized controlled trials from 2012-2013 showed no clear benefit of PFO closure, but longer term follow-up studies published in 2017-2018 demonstrated PFO closure significantly reduced the risk of recurrent stroke compared to medical therapy. While PFO closure was found to increase the risk of atrial fibrillation, it had no effect on mortality or other serious adverse events. Thus, the recent evidence supports that PFO closure is superior to medical therapy alone and is a safe and effective treatment for preventing additional ischemic strokes in cryptogenic stroke patients with a PFO.

1. Chapter 44
Does Cryptogenic Stroke
Warrant Interventional Therapy?
Sukumar Ghosh, Mukesh Palsania
Abstract
The use of patent foramen ovale (PFO) closure for cryptogenic stroke as a choice of treatment modality
for secondary prevention of ischemic stroke was controversial over more than a decade. Initial efforts
were done with different Randomized Controlled Trials (RCTs) in 2012 (CLOSURE-1) & 2013 (PC Trial,
RESPECT Trial) to show reduction in recurrence of ischemic stroke. PFO closure was not superior to
medical therapy; but long-term follow-up of RESPECT trial (RESPECT-2017) showed that PFO closure
was superior to medical therapy. With this encouraging result, further RCTs were conducted (CLOSE-
2017, REDUCE-2017, and DEFENCE-PFO-2018). The result of these trials showed that PFO closure was
superior to medical therapy (Antiplatelet or anticoagulant) in reducing ischemic stroke in PFO patients with
or without high risk PFO (Atrial septal aneurysm or PFO with large shunts) but one meta-analysis showed
that patients with large shunts (>30 bubble in LA) was associated with significant reduction in stroke but
not in small shunts. There was no effect on outcome for presence or absence of Atrial septal aneurysm.
The rise of Atrial fibrillation was associated with device closure. U.S. FDA has recently approved two
devices—Amplatzer PFO occluder and Gore cardioform septal occluder in 2016 and 2018, respectively.
Key words: Patent foramen ovale, Percutaneous closure, Amplatze Occluder, Cryptogenic stroke,
Paradoxical embolism.
INTRODUCTION
Patent foramen ovale (PFO) is found in 25% of general
population.1
Cryptogenic stroke accounts 10–40% of
ischemic stroke2,3
and paradoxical embolism from right to
left shunt, usually a PFO, is thought to be etiologic
mechanism in some patients of cryptogenic stroke,
especially in younger population with fewer traditional risk
factors. Cryptogenic stroke patient has been treated
traditionally with antiplatelet or anticoagulant agent alone or
in combination to reduce risk of recurrent stroke but still
there was 4.5% risk of recurrent stroke after 4 years in an
updated meta-analysis of randomized trial.4
So the
Chapter-44.indd 1 17-08-2019 16:30:31

2. 2 SECTION 1
search for alternative non-pharmacological therapy was
started. Several approaches for PFO closure had started
including surgical suturing and endovascular device closure.
After initial approval of two PFO closure devices by U.S.
FDA (United States Food and Drug Administration) in 2002
with humanitarian device exemption (HDE), there was rapid
growth in number of cases. HDE approval was withdrawn in
2006 because of large number of cases were performed
exceeding the limit for HDE approval by the regulatory
authority. Over the ensuing years randomized control trials
(RCTs) were initiated with several PFO closure devices in
young patients aged 18–60 years who had a cryptogenic
stroke and PFO.
STUDY RESULT OF RCTS
Three trials were published in 2012–13 (CLOSER-1, PC
trial, RESPECT trial).5-7
Result of these trials did not meet
the primary end points. It was observed that PFO closure was
not superior to medical therapy in CLOSURE-1 and PC trial.
In RESPECT trial, no significant benefit was noted from
PFO closure in intention to treat analysis patients but closure
was superior to medical therapy in treated analysis patients.
Long-term follow-up of RESPECT trial showed significant
benefit in closure group. Recently four RCTs (Respect long-
term follow-up,8
CLOSE,9
REDUCE,10
and DEFENSE
PFO11
) of PFO closure with more advanced device design
and more strong enlistment criteria have been published in
2017–18. Each of these trials have shown statistically
significant advantages of PFO device closure over medical
therapy in preventing recurrent ischemic stroke event in
young to middle aged patients with unexplained stroke and
PFO. There were no significant differences in all cause death
(RR 0.08) and cardiovascular death (RR 1.47) between
closure and medical therapy group. Closure group increased
the risk of atrial fibrillation (RR 4.25) but no significant
differences are found in major bleeding (RR 0.96) and any
serious adverse event (RR 1.03) between both groups.12
Summary of trial results are given in Table 1.
DISCUSSION
All the studies are designed to compare the role of PFO
closure and medical therapy in secondary prevention of
cryptogenic stroke. CLOSURE-1 and PC trial did not
show sufficient evidence to support use of closure device in
patients with PFO for prevention of stroke. Short-term
results of RESPECT trial did not show beneficial effect on
closure group, but long-term follow-up results have shown
that PFO closure is effective for prevention of stroke. Recent
several trials (Long-term follow-up of RESPECT trial,
CLOSE trial, REDUCE trial, DEFENSE PFO trial) have
shown benefit of closure of PFO by device to prevent
recurrent stroke as compare to medical therapy. PFO closure
results are superior to medical therapy with or without high
risk PFO (Atrial septal aneurysm, PFO with large shunt).
Procedure or device-related complications (Pericardial
effusion, Pseudoaneurysm formation) are found in closure
groups.9
To prevent adverse event we should choose a safer
device and improve the implantation procedures. These
RCTs have shown that major bleeding (Intracerebral
hemorrhage) occurred during the period of anticoagulation
therapy, so that appropriate anticoagulation or antiplatelet of
short duration will prevent major bleeding episodes. Rope
score is used as an independent predictor for recurrent
ischemic stroke and a score ≤6 identify the patients with
significant higher risk of ischemic stroke and outcome may
not be favorable with closure group. Patients with >6 rope
score have a lower rate of ischemic stroke with no mortality
in long-term follow-up13
and high rope score patients have a
chance of beneficial effect. One Indian review article shows
that PFO closure is effective and safe procedure and it is
superior to medical therapy in secondary stroke prevention in
patient of cryptogenic stroke due to PFO.14
One study which
included procedures in 75 patients with PFO and 35 patients
with ASD. PFO closures were done with amplatzer PFO
occluder under simple fluoroscopy only guidance with use of
local anesthesia exclusively with success rate of 98.7% and
only 1 (0.09%) major vascular complication. There was no
residual shunt at 6 months and no stroke recurrence at 4.3
years follow-up in PFO closure patients.15
PFO closure
significantly decreases the risk of recurrent stroke but not all
cause death and cardiovascular death. REDUCE and CLOSE
Trials had shown that risk of atrial fibrillation increased in
device closure group. Rate of atrial fibrillation was increased
during periprocedural period but not after postoperative
period and that was transient in most of cases and
successfully managed with or without pharmacologic
cardioversion.
Chapter-44.indd 2 17-08-2019 16:30:31

3. -44.317-08-
TABLE 1 Randomized trials on percutaneous closure of patent foramen ovale
Trial name Year of Numbers Mean Primary end point Result Conclusion
publication follow-up Closure Control p-value
(years)
CLOSURE-1 2012 909 2 Composite of 5.5% 6.8% HR 0.78 Closure is not superior
strokeTIA, all cause p = 0.37 to medical therapy
mortality, death from
neurologic causes
PC trial 2013 414 4.1 Composite of death, 3.4% 5.2% HR 0.63 Closure is not superior
non-fatal stroke, P = 0.34 to medical therapy
TIA, or peripheral
embolism
RESPECT trial 2013 980 2.6 Composite of Intention to treat Intention to treat HR 0.49 No significant benefit
recurrent non-fatal 0.66 events/100 pt/ 1.38 events/100 pt/ P = 0.08 for closure
ischemic stroke, fatal year as treated 0.39 year as treated 1.45 HR 0.27 Closure is superior to
ischemic stroke, or events/100 pt/year events/100 pt/year P = 0.007 medical therapy
early death after
randomization
RESPECT trial 2017 980 5.9 Composite of Intention to treat 0.58 Intention to treat 1.07 HR 0.55 Closure is superior to
(long-term recurrent non-fatal events/100 pt/year events/100 pt/year P = 0.046 medical therapy on
follow-up) ischemic stroke, fatal HR 0.38 extended follow-up
ischemic stroke, or new stroke of new stroke of P = 0.007 in intention to treat
early death after unknown mechanism unknown mechanism analysis
randomization 0.31 events/100 pt/ 0.86 events/100 pt/
year year
CLOSE trial 2017 663 5.3 Recurrent fatal or Closure v/s Closure v/s HR 0.03 Closure is superior to
non-fatal stroke antiplatelet therapy: 0 antiplatelet therapy: P<0.001 antiplatelet in pt with
4.9% 5 yrs estimate HR 0.43 ASA or PFO with large
Anticoagulant v/s P = 0.17 shunt
antiplatelet therapy Anticoagulant
1.5% v/s 3.8% 5 yrs is equivalent to
estimate antiplatelet therapy,
increase AF
REDUCE trial 2017 664 3.2 Recurrent stroke, Ischemic stroke 0.39 Ischemic stroke 1.71 HR 0.23 Closure is superior to
new brain infarct strokes/100 pt/yr strokes/100 pt /yr P = 0.002 antiplatelet therapy,
inclusive of silent New brain infarct New brain infarct HR 0.51 increased AF
brain infarct 5.7% 11.3% P = 0.04
Defense PFO 2018 120 2.8 Stroke, vascular Ischemic stroke: 0 Ischemic stroke: P = 0.023 Closure in pt with
trial death or TIMI- 2 yrs event rate: 0 10.5% Log-rank high risk PFO
defined major New ischemic lesion 2 yrs event rate: p = 0.013 characteristics
bleeding on MRI 8.8% 12.9% P = 0.24 resulted in lower rate
New ischemic lesion of ischemic stroke v/s
on MRI 18.4% medical therapy
CHAPTER44:DoesCryptogenicStrokeWarrantInterventionalTherapy?3

5. 4 SECTION 1
CONCLUSION
Recent publications of RCT provide us new evidence to
support PFO closure as a choice of treatment superior to
medical therapy to prevent ischemic strokes especially in
younger population with cryptogenic stroke. We see
comparable safety in terms of major bleeding and other
serious adverse event. PFO closure do not lower the mortality
risk but associated with increased risk of AF which is transient
and mainly periprocedural. So PFO closure in cryptogenic
stroke is a safe and effective way to prevent ischemic stroke
in selective cases after proper counseling of patients.
REFERENCES
1. 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(1):17-20.
2. O’Gara PT, Messe SR, Tuzcu EM, et al. Percutaneous device
closure of patent foramen ovale for secondary stroke prevention: a
call for completion of randomized clinical trials: a science advisory
from the American Heart Association/American Stroke Association
and the American College of Cardiology Foundation. Circulation.
2009;119(20):2743-7.
3. Sacco RL, Ellenberg JH, Mohr JP, et al. Infarcts of undetermined
cause: the NINCDS Stroke Data Bank. Ann Neurol. 989;25:382-90.
4. Mojadidi MR, Algendy AY, Elendy AL, et al. Transcatheter
patent foramen ovale closure after cryptogenic stroke: an
updated meta-analysis of randomized trials. JACC
Cardiovasc Interv. 2017;10(21);2228-30.
5. Furlan AJ, Reisman M, Massaro J, et al. Closure or medical
therapy for cryptogenic stroke with patent foramen ovale. N
Engl J Med. 2012;366(11):991-9.
6. Meier B, Kalesan B, Mattle HP, et al. Percutaneous closure
of patent foramen ovale in cryptogenic embolism.N Engl J
Med. 2013;368(12):1083-91.
7. Carroll JD, Saver JL, Thaler DE, et al. Closure of patent
foramen ovale versus medical therapy after cryptogenic
stroke. N Engl J Med. 2013;368(12):1092-100.
8. Saver JL, Carroll JD, Thaler DE, et al. Long-term outcomes
of patent foramen ovale closure or medical therapy after
stroke. N Engl J Med. 2017;377(11):1022-32.
9. Mas J, Derumeaux G, Guillon B, et al. Patent foramen
ovale closure or anticoagulation vs. antiplatelets after
stroke. N Engl J Med. 2017;377:1011-21.
10. Sondergaard L, Kasner SE, Rhodes JF, et al. Patent
foramen ovale closure or antiplatelet therapy for
cryptogenic stroke. N Engl J Med. 2017;377:1033-42.
11. Lee PH, Song JK, Kim JS, et al. Cryptogenic stroke and
high-risk patent foramen ovale: the DEFENSE-PFO trial. J
Am Coll Cardiol. 2018;71(20):2335-42.
12. Yingxu Ma, Dongping Li, Fan Bai, et al. Patent foramen
ovale closure or medical therapy for secondary prevention
of cryptogenic stroke: an update meta-analysis of
randomized controlled trials. Medicine. 2018;34:(e11965).
13. Morais LA, Sousa L, Fiarresga A, et al. RoPE score as a
predictor of recurrent ischemic events after percutaneous
patent foramen ovale closure. Int Heart J. 2018;59(6):1327-32.
14. Abhisek BS, Bhambhani A. Role of closure of patent
foramen ovale in cryptogenic stroke; current status. Natl
Med J India.2017;30(5):268-71.
15. Manolis AS, Koulouris S, Rouska E, et al. Simplified
percutaneous closure of patent foramen ovale and atrial septal
defect with use of plain fluoroscopy: single operator experience
in 110 consecutive patients. Indian Heart J. 2018;70(1);24-31.
Chapter-44.indd 4 17-08-2019 16:30:31