In the United States, approximately 600,000 strokes occur per year, and in nearly 40%, no identifiable cause can be found (cryptogenic stroke). Patent foramen ovale (PFO) has been shown to be associated with cryptogenic stroke, particularly in younger patients. Medical therapy with either aspirin or warfarin still carries a recurrent neurologic event rate of 3.4% per year, and warfarin therapy carries a small but definite risk of bleeding complications. Devices that were developed for percutaneous closure of atrial septal defects have now been adapted for the application of percutaneous PFO closure as secondary prevention in patients who have cryptogenic stroke, potentially as an alternative to long-term anticoagulation. This article reviews these new devices and some of the evidence regarding this particular application.
Samuel C. Yoon, MD
is a Clincal Assistant Professor with the Division of Cardiology at
the University of Maryland, Baltimore, MD. He received his MD from
the University of Maryland in 1995 and continued there for his
Internal Medicine residency and his Cardiology/Interventional
In the United States, approximately 600,000 strokes occur
per year, and in nearly 40%, no identifiable cause can be found
(cryptogenic stroke). Patent foramen ovale (PFO) has been shown
to be associated with cryptogenic stroke, particularly in younger
patients. Medical therapy with either aspirin or warfarin still
carries a recurrent neurologic event rate of 3.4% per year, and
warfarin therapy carries a small but definite risk of bleeding
complications. Devices that were developed for percutaneous
closure of atrial septal defects have now been adapted for the
application of percutaneous PFO closure as secondary prevention
in patients who have cryptogenic stroke, potentially as an
alternative to long-term anticoagulation. This article reviews
these new devices and some of the evidence regarding this
The first percutaneous closure of an atrial septal defect (ASD)
was performed in 1974 by placement of a Dacron (Dupont
Pharmaceuticals Corp.; Wilmington, DE) double-umbrella device.
Development of percutaneous closure devices for ASD has continued
since, primarily for closure of ASD causing hemodynamically
significant left-to-right shunts. As shown in Table 1, the success
rates for different ASD closure devices range from 35% to 90%.
Another morphologic breach of the interatrial septum, the patent
foramen ovale (PFO), has been implicated in unexplained neurologic
events. It has been estimated that 600,000 strokes occur per year
in the United States.
Up to 40% of strokes are deemed cryptogenic (stroke of undetermined
In several contrast echocardiography studies, a strong association
has been established between the diagnosis of cryptogenic stroke
and the presence of PFO in patients <55 years of age,
and PFO is an independent risk factor for cryptogenic stroke.
Pooled data suggest that PFO is present in 46% of patients with
cryptogenic stroke and in 11% of matched controls.
Based on these figures, approximately 110,000 strokes per year may
be attributable to PFO. It has also been observed that patients
with cryptogenic stroke and PFO are at risk for recurrent
neurologic events with an annual stroke rate of 1.2% to 1.9% and a
recurrent cerebrovascular accident (CVA) or transient ischemic
attack (TIA) rate of 3.4% to 3.8% per year despite medical therapy
with either aspirin or warfarin.
Additionally, patients who have cryptogenic stroke who have both
PFO and atrial septal aneurysm are four times more likely to have a
recurrent stroke compared with those without either abnormality.
These observations regarding PFO and paradoxical embolism resulting
in neurologic events have led to the investigation of expanding the
use of ASD closure devices to potentially prevent recurrent
Percutaneous closure devices
There are several devices that are available or are being
investigated for percutaneous closure of PFO (Table 2). Table 3
compares various characteristics of several of these devices.
These devices are either ASD closure devices that are applied to
PFO, modifications of prior ASD closure devices, or novel PFO
closure devices. At this time, only the Amplatzer PFO Occluder
(Figure 1) and the CardioSEAL Septal Occluder (Figure 2) have
limited U.S. Food and Drug Association approval for PFO closure in
patients who have cryptogenic stroke under Humanitarian Device
Delivery of the Amplatzer PFO Occluder and CardioSEAL Septal
Occluder are performed in a relatively similar fashion; the
following is a simplified description of the implantation of the
Amplatzer PFO Occluder.
Access is obtained through the femoral vein, and a standard right
heart catheterization is performed. The PFO Occluder device is
screwed to the tip of a delivery cable and retracted into a loader
catheter. The cable/catheter assembly is inserted through the
femoral venous sheath, advanced up the inferior vena cava, and
passed through the patent foramen ovale over a "J" guidewire into
the left atrium, with optional guidance by either transesophageal
echocardiography (TEE) or intracardiac echocardiography (ICE). The
PFO Occluder device is advanced and positioned across the PFO under
fluoroscopic guidance, and a left atrial disc is deployed beyond
the delivery sheath and pulled back firmly against the left atrial
side of the inter-atrial septum (Figure 3). A right atrial disc is
then deployed against the right atrial side of the interatrial
septum (Figure 4) by pulling the delivery sheath back over the
delivery cable. Successful occlusion is confirmed under fluoroscopy
with radiographic contrast injection (Figure 5) or by
echocardiography with bubble contrast into the right atrium. The
device is then released (Figure 6), and the delivery catheter
system is removed.
There have been several feasibility and safety studies for
percutaneous closure of PFOs, but only two studies have assessed
clinical outcomes over a long period of time. Windecker and
studied 80 patients with at least 1 paradoxical embolic event and
PFO diagnosed by contrast TEE who underwent percutaneous PFO
closure. Various occluder devices were used and not controlled for,
including the Sideris Buttoned device, PFO-STAR (now CardiaSTAR),
Amplatzer PFO Occluder, DAS Angel Wings Atrial Septal Defect
Occluder device, and the CardioSEAL Septal Occluder. Procedural
success was achieved in 78 patients (98%). All patients received
100 mg of aspirin daily for 3 to 6 months, at which time it was
discontinued unless required for another indication. During the
follow-up period (mean 1.6 ± 1.4 years), there were 8 recurrent
thromboembolic events: 6 TIAs, no CVAs, and 2 peripheral emboli.
These results suggest average annual recurrence rates of 2.5% for
TIA, 0% for CVA, 0.9% for peripheral emboli, and 3.4% for the
combined thromboembolic endpoint.
Similarly, Hung and colleagues
studied 63 patients who had one or more paradoxical systemic events
(TIA, CVA, peripheral embolus, or brain abscess in the absence of
any other identifiable etiology) with PFO diagnosed by TEE.
Patients were enrolled to undergo percutaneous PFO closure with 1
of 3 devices: the Clamshell Septal Occluder, CardioSEAL Septal
Occluder, or the Sideris Buttoned device. Effective closure was
achieved in 54 patients (86%). All patients received daily aspirin
for 6 months after device placement. During follow-up (mean 2.6 ±
2.4 years), there were 4 recurrent neurologic events (1 CVA and 3
TIAs) resulting in a calculated annualized risk of 3.2% for the
Percutaneous closure of PFO with these devices carries certain
potential periprocedural complications, including: device
embolization, air embolization, intraprocedural CVA, perforation,
or erosion resulting in cardiac tamponade or retroperitoneal
bleeding; or device complications stemming from the design (such as
device arm fracture). The rate of periprocedural complications in
these studies was 10%,
and the rate of device arm fracture was 24%.
The recurrent event rates in these studies compare favorably to
the event rates in historical controls mentioned previously,
suggesting that percutaneous closure of PFO for secondary
prevention of neurologic events may be an alternative therapy to
long-term oral anticoagulation.
The limitations of the present literature on PFO closure in
patients with cryptogenic stroke are several-fold. First, the
diagnosis of cryptogenic stroke is one of exclusion; therefore, it
is dependent on the thoroughness of the neurologic work-up. Second,
the relationship between PFO and cryptogenic stroke is not as well
established in older patients (>55 years of age), thus, the age
distribution of the cohorts studied can affect observed outcomes.
Additionally, although recurrent CVA is a relatively "hard"
endpoint, a transient recurrent event (ie, TIA) is less well
defined and may be less reliable as an endpoint on which to base
The most glaring limitation to the presently available data is
the lack of a prospective, randomized study to evaluate PFO closure
devices versus medical therapy in patients who have cryptogenic
stroke. However, the PC-Trial (Patent Foramen Ovale and Cryptogenic
Embolism Trial) is currently under way to provide just that.
Patients <60 years of age who have a documented PFO and have
suffered a cryptogenic embolic event (CVA, TIA, or peripheral
embolus) will be randomized to PFO closure with the Amplatzer PFO
Occluder or to anticoagulation therapy (aspirin or warfarin) and
will be followed up for 4.5 years. Primary endpoints will be death,
nonfatal stroke or TIA, or peripheral embolism. Secondary endpoints
will be arrhythmia, myocardial infarction, rehospitalization,
device problems, or bleeding. Target enrollment is 410
Percutaneous closure of ASD/PFO can be achieved successfully.
There are several innovative devices that are being evaluated,
particularly for the indication of PFO closure in patients with
cryptogenic stroke for secondary prevention. The question of
whether percutaneous PFO closure should be performed has yet to be
answered. While the association of PFO with cryptogenic stroke has
been established in younger patients (<55 to 60 years of age),
the implication of PFO as the cause of cryptogenic stroke has not
been established as strongly. The literature suggests that there is
potential benefit via this therapy, and perhaps the greatest
benefit is in younger patients who have cryptogenic stroke with PFO
and atrial septal aneurysm. The available long-term follow-up data
suggest that percutaneous closure of PFO has a recurrent event rate
comparable to medical therapy, and may possibly be an alternative
to long-term anticoagulation therapy. Prospective, randomized
comparison of medical therapy versus percutaneous closure of PFO in
patients with cryptogenic stroke is under way to further delineate
the role these novel devices will play.