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Stroke Prevention in the Setting of a Patent

Foramen Ovale: A Hole in the Evidence
March 9, 2011

Brandon Oberweis, MD

Faculty Peer Reviewed

Case Report:

A 48-year old gentleman with no significant past medical history presents to the emergency
department with new-onset left upper extremity hemiparesis, visual field deficits, and decreased
level of consciousness. A non-contrast CT scan was performed and revealed right-sided focal
hypoattenuation in the middle cerebral artery distribution. Following acute management of this
patient, further studies were conducted to elucidate the underlying etiology of the
cerebrovascular accident. An echocardiogram with an agitated saline contrast study (Bubble
Study) was conducted and demonstrated right-to-left passage of microbubbles via the interatrial
septum within 3-5 cardiac cycles of right atrial opacification, following Valsalva maneuver [1]
In the setting of a confirmed patent foramen ovale, should the patient receive antiplatelets,
anticoagulation, or undergo percutaneous or surgical closure of the PFO to prevent future
strokes?

Introduction:

It is well established that patent foramen ovales (PFO) exist in approximately 27% of the general
population [2]. Given this high prevalence, it is important to understand the association and
perhaps causal relationship between PFOs and cerebrovascular accidents. Although multiple
studies have demonstrated an association between PFOs and cryptogenic strokes, there is a
paucity of evidence in the literature substantiating a clear preventative management strategy [3,
4].

Cryptogenic strokes are defined as ischemic strokes that are not caused by cardioembolic
disease, large artery atherosclerosis, or small artery disease [5, 6]. It is has been shown that up to
40% of ischemic strokes are of cryptogenic origin [7]. In the absence of identifiable risk factors,
the primary mechanism by which strokes are attributed to PFOs is through paradoxical emboli.
Given the high prevalence of PFOs in the general population and the devastating consequences
of strokes, multiple studies have evaluated four primary preventative strategies: surgical closure,
percutaneous device closure, medical management with aspirin, and medical management with
warfarin.

Antiplatelets/Anticoagulation:

The first question that must be answered is whether patients with PFOs have an increased risk of
recurrent strokes compared to the general population. The Patient foramen ovale in Cryptogenic
Stroke Study (PICSS) trial was a 42-center study that evaluated transesophageal echocardiogram
(TEE) findings in 630 stroke patients, randomized to aspirin or warfarin in the Warfarin-Aspirin
Recurrent Stroke Study (WARSS). According to the PICSS trial, patients on medical therapy
with and without PFOs in the cryptogenic stroke cohort were found to have hazard ratios for
recurrent strokes and death of 0.52 and 0.50, respectively (4). These almost identical hazard
ratios emphasize the fact that with the implementation of medical therapy, patients with PFOs are
not at an increased risk of recurrent strokes compared to the general population. Although the
PICSS trial found similar hazard ratios between patients with and without PFOs who were on
medical therapy, given the large number of patients with PFOs who do not experience a
cryptogenic stroke, there are currently no recommendations for primary prevention [4, 8].

The second question to consider is whether antiplatelet therapy is sufficient or is full

anticoagulation necessary for secondary prevention of cryptogenic strokes in the setting of
PFOs. To date, the PICSS is the only prospective, randomized treatment trial that has compared
the efficacy of aspirin to warfarin in stroke prevention. Although the patients randomized to
warfarin were found to have approximately half the risk of recurrent strokes and death, it is
important to note that the differences between aspirin and warfarin were not statistically
significant. Therefore, the PICSS trial concluded that both aspirin and warfarin had similar rates
of reduction of recurrent strokes.
The PICSS trial corroborated the results of the WARSS trial, a multicenter, double blind trial
that randomized 2,206 stroke patients to aspirin or warfarin. In contrast to the PICSS trial,
patients enrolled in the WARSS trial were not selected based on the presence of PFOs. At the
end of the 24-month follow-up, there were no statistical differences between aspirin and warfarin
in any of the outcomes measured [9]. Furthermore, the WARSS trial evaluated complications
resulting from each of the medical therapies. Major hemorrhages included intracranial,
intraspinal, subarachnoid, subdural, or epidural hemorrhages or any other bleeding requiring
transfusion. Minor hemorrhages were defined as bleeding not requiring transfusion and all other
sites of hemorrhage [9]. Patients treated with warfarin were found to have a significantly
increased risk of minor hemorrhages compared to aspirin. There was however no significant
difference in major hemorrhages. Given that warfarin has a more significant risk of bleeding
than aspirin [9], and both the PICSS and WARSS trials found no significant advantage to either
medical therapy, aspirin has become the recommended modality for secondary prevention in
patients with PFOs.

PFO Closure:

Conflicting data exists on the role of surgical and percutaneous device closures in PFOs. A
recent study by Krasuski et al. sought to clarify long-term survival in patients with PFOs
undergoing surgical closure. This study sought to identify the frequency of incidentally
discovered PFO closure during cardiothoracic surgery. Of the 13,092 intraoperative
transesophageal echocardiograms, 2,277 (17%) patients were diagnosed with PFOs. Surprisingly,
patients with surgical closure of PFOs demonstrated an odds ratio of 2.47 of having a
postoperative stroke, compared to patients who did not undergo surgical PFO closure [10].
Despite the increased risk of postoperative stroke, there were no significant differences in long-
term survival between the two cohorts.

Given the increased risk of postoperative stroke with surgical closure, various studies have
evaluated the risk of stroke recurrence in patients with PFOs, treated with percutaneous device
closure compared to medical therapy. Furlan et al. conducted a prospective, multicenter,
randomized controlled trial involving 900 patients with a prior cryptogenic stroke. The
CLOSURE I trial compared optimal medical management with aspirin, warfarin, or both, with
the STARFlex PFO closure device with aspirin and clopidogrel. After two years of follow-up, no
statistically significant differences were found between the two groups in respect to stroke or
TIA (5.9% vs. 7.7%, P=0.30). PFO closure did however, lead to significantly more major
vascular complications (3.2% vs. 0.0%, P<0.001) and atrial fibrillation (5.7% vs. 0.7%,
P<0.001). The results of this trial were most recently presented at the 2010 American Heart
Association national conference [11].

Additionally, a study by Windecker et al. compared risk reduction of recurrent strokes and death
in 308 patients undergoing percutaneous device closure (150 patients), antiplatelets and
anticoagulants (158 patients), after four years of follow-up. Compared to medical therapy,
percutaneous device closure of PFOs trended toward a risk reduction of recurrent strokes and
death; however, the results were not statistically significant (8.5% vs. 24.3%, P=0.05; hazard
ratio (95% CI) 0.48 (0.23-1.01) (12). Percutaneous PFO closure was found to be superior to
medical therapy in two subgroups of patients: patients who received complete PFO occlusion
and patients who had more than one cryptogenic stroke at baseline (p-values of 0.04 and 0.01,
respectively). This study also elucidated that significant differences in the rate of recurrent
strokes and death from percutaneous and medical management only become apparent after two
years of follow-up. The authors hypothesis for these findings is that endothelialization of the
device closure may take months to years [12]. Given the finding that only a complete PFO
occlusion provides a significant reduction in adverse events, a residual shunt prior to the
completion of endothelialization of the PFO presumably will not impart a reduction in adverse
events.

Recommendations:

Patent foramen ovales are common congenital cardiac defects more prevalent in patients who
have suffered cryptogenic strokes. Regardless of a clear association between PFOs and
cryptogenic strokes, sufficient evidence of optimal management is lacking. Despite the limited
randomized controlled trials, professional societies have attempted to develop guidelines for the
management of patients with PFOs who have experienced cryptogenic strokes [6]:

American College of Chest physicians [13]:

Antiplatelets are recommended over Anticoagulation, unless patient has underlying

prothrombotic disorder or DVT

American Academy of Neurology [8]:

Following a cryptogenic stroke, presence of PFO is not a factor in risk of stroke recurrence

Insufficient evidence to determine superiority of antiplatelets, anticoagulation, PFO closure

American Heart Association/American Stroke Association [14]:

Antiplatelets are recommended instead of anticoagulation, unless anticoagulation is indicated for

other etiology

PFO closure may be considered if recurrent strokes despite medical therapy

In summary, the findings in the above research studies corroborate the professional societies
official recommendations. Given what appears to be similar efficacy of aspirin, warfarin,
surgical closure, and percutaneous device closure in the majority of patients with PFOs and
cryptogenic strokes, aspirin is the recommended management as it is associated with the least
adverse effects. However, further prospective studies are required to help close the existing
hole in the literature, to determine the optimal management of all subgroups of patients with
PFOs.

Despite the lack of evidence substantiating a definitive management strategy, logic may dictate
that a patient with a PFO who has suffered recurrent strokes despite aspirin therapy, necessitate
serious discussions regarding anticoagulation or percutaneous device closure as management
options.

Resolution of Case:

The patient in our case report was prescribed daily aspirin for secondary prevention of future
strokes. Due to the lack of evidence for the optimal management strategy, the risks and benefits
of the various management options were considered. In order to select the optimal management
strategy, it is important to note that this was the patients first episode of a cryptogenic stroke.
Given the similar efficacy of aspirin and warfarin according to the PICSS trial, as well as the
increased risk of minor hemorrhages with warfarin therapy, it was determined that daily aspirin
would be the most beneficial management strategy to prevent future strokes, likely secondary to
paradoxical emboli. The patient has done well over the past 6 months and has had no further
cryptogenic strokes or complications from antiplatelet therapy.

Dr. Oberweis is a 1st year resident at NYU Langone Medical Center

Peer reviewed by Daniel Fisher, MD, Associate Professor Medicine (Cardiology), NYU School
of Medicine

Image courtesy of Wikimedia Commons (MRI of head stroke)

References:

1. Attaran RR, Ata I, Kudithipudi V, et al. Protocol for optimal detection and exclusion of a
patent foramen ovale using transthoracic echocardiography with agitated saline microbubbles.
Echocardiography 2006;23:616-622.

2. 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. May Clin Proc. 1984;59:17-20.

3. Di Tullio M, Sacco RL, Gopal A, et al. Patent foramen ovale as a risk factor for cryptogenic
stroke. Ann Intern Med. 1992;117:461-465.

4. Homma S, Sacco RL, Di Tullio MR, Sciacca RR, Mohr JP; for the PFO in Cryptogenic Stroke
Study (PICSS) Investigators. Effect of Medical Treatment in Stroke Patients With Patent
Foramen Ovale: Patent Foramen Ovale in Cryptogenic Stroke Study. Circulation 2002;105:2625-
2631.

5. Adams HP Jr, Bendixen BH, Kappelle LJ, et al. Classification of subtype of acute ischemic
stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute
Stroke Treatment. Stroke 1993;24(1):35-41.
http://stroke.ahajournals.org/cgi/content/short/24/1/35
6. Pinto Slottow TL, Steinberg DH, Waksman R. Overview of the 2007 Food and Drug
Administration Circulatory System Devices Panel Meeting on Patent Foramen Closure Devices.
Circulation 2007;116:677-682.

7. Sacco RL, Ellenberg JH, Mohr JP, et al. Infarcts of undetermined cause: the NINCDS Stroke
Data Bank. Ann Neurol. 1989;25:382-390.
http://onlinelibrary.wiley.com/doi/10.1002/ana.410250410/pdf

8. Messe SR, Silverman IE, Kizer JR, et al. Quality Standards Subcommittee of the American
Academy of Neurology. Practice parameter: recurrent stroke with patent foramen ovale and atrial
septal aneurysm: report of the Quality Standards Subcommittee of the American Academy of
Neurology. Neurology 2004;62:1042-1050.

9. Mohr JP, Thompson JL, Lazar RM, et al. A comparison of warfarin and aspirin for the
prevention of recurrent ischemic stroke. N Engl J Med. 2001;345(20):1444-1451.
http://www.ncbi.nlm.nih.gov/pubmed/11794192

10. Krasuski RA, Haart SA, Allen D, et al. Prevalence and Repair of Intraoperatively Diagnosed
Patent Foramen Ovale and Association With Perioperative Outcomes and Long-term Survival.
JAMA 2009;302(3):290-297.

11. Furlan AJ, Reisman M, Massaro J, et al. A prospective multicenter, randomized controlled
trial to evaluate the safety and efficacy of the STARFlex septal closure system versus best
medical therapy in patients with a stroke or transient ischemic attack due to presumed
paradoxical embolism through a patent foramen ovale. Stroke 2010;41:2872-2883.
http://www.ncbi.nlm.nih.gov/pubmed/21051670

12. Windecker S, Wahl A, Nedeltchev K, et al. Comparison of Medical treatment With

Percutaneous Closure of Patent Foramen Ovale in Patients With Cryptogenic Stroke. Journal of
the American College of Cardiology 2004;44(4):750-758.
http://content.onlinejacc.org/cgi/content/short/44/4/750

13. Albers GW, Amarenco P, Easton JD, et al. Antithrombotic and thrombolytic therapy for
ischemic stroke: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.
Chest 2004;126:483S-512S.

14. Sacco RL, Adams R, Albers G, et al. American Heart Association; American Stroke
Association Council on Stroke; Council on Cardiovascular Radiology and Intervention;
American Academy of Neurology. Guidelines for prevention of stroke in patients with ischemic
stroke or transient ischemic attack: a statement for healthcare professionals from the American
Heart Association/America Stroke Association Council on Stroke: co-sponsored by the Council
on Cardiovascular Radiology and Intervention: the American Academy of neurology affirms the
value of this gui

2 Responses to Stroke Prevention in the Setting of a Patent Foramen Ovale: A

Hole in the Evidence
1. Neurological News: March 2010 on September 7, 2011 at 11:26 pm

[...] Stroke Prevention in the Setting of a Patent Foramen Ovale: A Hole in the
Evidence By Brandon Oberweis, MD. | Faculty Peer Reviewed | March 9, 2011. [...]

2. Neurological News: March 2011 on September 7, 2011 at 11:53 pm

[...] Stroke Prevention in the Setting of a Patent Foramen Ovale: A Hole in the
Evidence By Brandon Oberweis, MD. | Faculty Peer Reviewed | March 9, 2011. [...]