Management of Patients with Stroke and a Patent Foramen Ovale

Carlos J. Rodriguez, MD, MPH and Shunichi Homma, MD

AddressDepartment of Medicine, Columbia University College of Physicians & Surgeons, 630 West 168th Street, New York, NY 10032, USA.E-mail: sh23@columbia.edu

Current Cardiology Reports 2004, 6:143–146Current Science Inc. ISSN 1523–3782Copyright © 2004 by Current Science Inc.

IntroductionA patent foramen ovale (PFO) had been described as far backas 1564 by Botallo, an Italian pathologist [1]. A PFO is a per-sistent, usually flap-like opening between two overlappingembryologic structures—the atrial septum primum andsecundum. In utero, the foramen ovale serves as a physiologicconduit for right-to-left shunting in order to bypass the fetalpulmonary circulation. After birth, increased left atrial bloodflow and pressure results in functional closure of the foramenovale. This functional closure is subsequently followed byanatomic fusion of the septum primum and secundum.Fusion of the two septae fails to occur in approximately 25%to 35% of the general population [2,3], resulting in formationof a PFO. The extent of the opening ranges from minute tolarge, as the septae may partially fuse to varying degrees. Thereis no sex preference in the incidence of PFO, and a recentcohort study of a random population sample showed a stableprevalence of PFO among all age groups [4]. The mean diam-

eter of a PFO at autopsy is 4.6 mm; however, the passage ofthrombi or other embolic material as small as 1 to 2 mm cancause a clinical stroke.

Paradoxical embolism, first described in 1877 by Cohn-heim [5], occurs when venous thrombotic material crossesthrough the PFO into the arterial circulation. Reversal of thephysiologic interatrial pressure gradient, with resultant right-to-left shunting across the PFO, contributes to the passing ofembolic material through a PFO. This may also occur tran-siently in normal subjects during coughing or a Valsalvamaneuver, or with predisposing conditions such as elevatedpulmonary pressures or right ventricular failure.

Webster et al. [6] and Lechat et al. [7] found a significantlyhigher prevalence of PFO in patients younger than 55 years ofage with stroke compared with those without stroke. Di Tullioet al. [8] found that the prevalence of PFO was significantlyhigher in patients with cryptogenic stroke versus those withknown causes of stroke (42% vs 7%) in both younger andolder patients, thus concluding that PFO is associated withcryptogenic stroke regardless of age. However, the associationof PFO with paradoxical embolism among older populationsremains controversial.

Detection of a PFO requires noninvasive imagingmodalities (ie, transthoracic echocardiography [TTE] ortransesophageal echocardiography [TEE] with or withoutsaline contrast injection). Indirect proof of PFO can bederived with transcranial contrast Doppler ultrasounddemonstrating delivery of microbubbles to the cranialcirculation [9]. Multiplane TEE with saline echocontraststudy and Valsalva maneuver remains the most sensitiveand specific method for the detection of PFO [10], allow-ing for sizing of the PFO and demonstration of the degreeof right-to-left shunting. In addition, TEE allows for reli-able exclusion of other potential cardiac sources of embo-lism. The separation between the septum primum andsecundum determines the PFO size, whereas the maxi-mum number of bubbles appearing in the left atriumwithin three cardiac cycles from right atrium opacificationreflects the degree of shunt. The degree of observed shuntas well as PFO size are important morphologic and func-tional characteristics and have been shown to be highlyassociated with cryptogenic stroke [11], as well as with anincreased frequency of head computed tomography (CT)findings of cerebral embolism [12].

The four major therapeutic options in patients with a PFOand an otherwise unexplained neurologic event are 1) medi-

Observational studies have established a strong association between the presence of patent foramen ovale (PFO) and increased risk of ischemic stroke. The mechanism involved is presumed to be a paradoxical embolism from a venous thrombus that travels via the PFO to the systemic circulation. The best treatment modality to prevent recurrent stroke in patients with PFO remains undefined. There are four major choices: 1) medical therapy with anticoagulants, 2) medical therapy with antiplatelet agents, 3) surgical closure, and 4) percutaneous device closure. The Patent Foramen Ovale in Cryptogenic Stroke Study has demonstrated that antiplatelet and anticoagulant therapies are of equal benefit in preventing recurrent neurologic events in stroke patients with a PFO. Medical therapy should remain as the initial choice of secondary prophylactic therapy. PFO closure, either surgical or percutaneous, may further reduce event rates; however, this remains to be demonstrated because no randomized trial to date has compared PFO closure with medical therapy.

144 Stroke

cal therapy with anticoagulants, 2) medical therapy with anti-platelet agents, 3) surgical closure, and 4) percutaneousdevice closure. However, management of these patientsremains controversial and challenging because the naturalhistory of recurrent events in these patients is not well eluci-dated and the relative efficacy of different treatments hasrarely been compared.

Secondary Prevention DataAntiplatelet therapy and anticoagulant therapyIn terms of medical therapy, Hanna et al. [13] reported thefirst experience in secondary prevention of stroke associatedwith PFO. A total of 15 patients received nonrandomizedtherapies: surgery (n=1), percutaneous closure (n = 1), war-farin (n = 7; international normalized ratio [INR] of 1.3 to1.5), or aspirin (n = 6; 325 mg/d). No recurrent cerebralischemic events were reported after a mean of 28 months oftherapy. Hausman et al. [14] reported on 44 patients withstroke and PFO, identifying recurrent events during a mean59-month follow-up. Recurrent events (one transientischemic attack [TIA] and one stroke) occurred in two patientson antiplatelet therapy with aspirin (n = 17) and in onepatient (TIA) on warfarin (n = 24). The remaining patients (n= 3) had undergone surgical closure and had no recurrentneurologic events. Given the low number of patients under-going PFO closure in these relatively small studies, they wereessentially nonrandomized comparisons of aspirin versuswarfarin, suggesting the relative therapeutic equivalency ofthese two drugs.

In a retrospective study, Mas and Zuber [15] reported on132 nonselected stroke patients with PFO who receivedwarfarin therapy (INR of 2 to 3), antiplatelet therapy, or notherapy. Over 23 months, recurrent cerebral ischemic events(four TIAs, two strokes) occurred in six patients, all of whomreceived either antiplatelet therapy (n = 5) or no therapy (n =1), for a recurrence rate of neurologic events of 1.7% per year.In this study, the presence of interatrial septal aneurysm (ASA)with PFO multiplied the yearly stroke recurrence rate com-pared with that of PFO alone.

Bogousslavsky et al. [16] reported five deaths and 16recurrent neurologic events in 140 patients younger than 60years of age treated with aspirin, warfarin, or surgery at 36months of follow-up. In this study, nonrandomized therapyfor secondary prevention was assigned based on clinicalcharacteristics, including the presence of an ASA, a majorright-to-left shunt by saline echocontrast, a history of multi-ple prior events, or stroke precipitated by a Valsalva maneu-ver. Surgery was performed in patients with two clinical riskfactors (n = 11), warfarin was used in patients who declinedsurgery or had only one clinical risk factor (n = 37; INR of 3to 4), and all remaining patients (n = 92) received aspirin(250 mg/d). ASA and treatment type were not associatedwith stroke recurrence.

Cujec et al. [17] used the echocardiography database of auniversity neurology referral center to identify 52 patientsyounger than 60 years of age with PFO and stroke. Therapiesused in these patients were surgical closure (n = 14), warfarin(n = 38), antiplatelet therapy (n = 36), or no therapy (n = 8).Over a mean follow-up period of 46 months, 19 recurrentcerebral ischemic events occurred (12 TIAs and seven strokes;13 with antiplatelet therapy and six with anticoagulation).

More recently, Mas et al. [18], in a multicenter study,enrolled 581 stroke patients and followed them for 4 years.All patients were younger than 55 years of age; 216 had a PFO,51 had a PFO and an ASA, and 304 were without any inter-atrial septal abnormality. All patients received aspirin (300mg/d) for secondary stroke prophylaxis. The authors reporteda recurrent neurologic event (stroke or TIA) rate of 5.6% for aPFO versus 19.2% with a PFO and ASA, versus 6.2% for thosewith no septal abnormality, versus 0% for those with ASAalone, respectively. From this observational study, it wouldappear that among younger patients with a prior stroke andboth a PFO and an ASA, aspirin alone is not an effectivepreventive therapy. However, among patients taking aspirin,those with PFO alone had a neurologic event rate as low asthose without any interatrial septal abnormality.

In interpreting the results of the preceding studies, thenumber of patients was relatively small and none of thestudies randomized the therapies. The PFO in CryptogenicStroke study (PICSS) [19••] was a multicenter, double-blind, randomized trial that evaluated TEE findings in 630patients admitted with stroke from 42 centers. Enrolledpatients were randomly assigned to warfarin to achieve anINR of 2.0 or 325 mg/d of aspirin and followed for strokerecurrence or death for 24 months. All TEE studies wereanalyzed at a central location blinded to all clinical vari-ables. PFO was found in 39.2% (98 of 250) of patients withcryptogenic stroke compared with 29.9% (105 of 351) inpatients with known cause of stroke (P < 0.02). Further-more, large PFOs were found in 20% (50 of 250) of crypto-genic stroke patients compared with 9.7% (34 of 351) inthose with known cause (P < 0.001).

In PICSS, there was no significant difference in the time torecurrent stroke or death between those with and withoutPFO (P = 0.84; hazard ratio of 0.96; 95% CI, 0.62–1.48; 2-year event rates of 14.8% vs 15.4%). When the groups withand without PFO were analyzed in relation to the efficacy ofwarfarin or aspirin, no significant differences were found forthe time to primary events. Thus, for stroke patients treatedmedically with either warfarin or aspirin, the rate of recurrentstroke or death is similar between patients with and withoutPFO, at least for the 2-year duration following the initialischemic stroke event. Although large PFOs were associatedwith the initial cryptogenic stroke, this did not increase therisk for recurrent adverse events while on medical therapy.The patients with PFO and ASA, while on medical therapy,experienced recurrent event rates similar to the patients with-

Management of Patients with Stroke and a Patent Foramen Ovale • Rodriguez and Homma 145

out PFO. These results indicate that when receiving medicaltherapy, stroke patients with and without PFO have similarevent rates.

Surgical therapyThe technique of surgical PFO closure has traditionallyinvolved median sternotomy, left thoracotomy, or an infra-mammary incision performed under cardiopulmonarybypass. The PFO is usually closed by primary anastomosiswith double continuous suture, usually without the use ofpatch material. The perioperative mortality rate of the pro-cedure is reported to be less than 1.5% [20].

The data on traditional surgical PFO closure have shownmixed results in terms of secondary stroke prevention. Harveyet al. [21] reported no recurrences in four patients with a meanage of 35 years followed-up for 7 to 21 months. Zhu et al. [22]reported two patients with recurrence among six patients witha mean age of 35 years and mean follow-up of 3.9 years.Ruchat et al. [23] studied 32 patients younger than 60 years ofage followed-up for 18.8 months after surgical PFO closure.There were no recurrent neurologic events or evidence ofsilent ischemia on brain magnetic resonance imaging.Devuyst et al. [24] followed up 30 patients younger than 50years of age with stroke and surgical PFO closure without anyrecurrent ischemic events after a follow-up period of 2 years.Deriani et al. [25] reported eight TIAs in 91 patients with amean follow-up of 2 years. Homma et al. [26] followed 28cryptogenic stroke patients (17 men and 11 women with amean age of 41 ± 13 years) with a TEE-defined PFO who hadundergone surgical PFO closure with no intra- or periopera-tive complications. All patients selected for surgery had eitherrefused, could not take, or failed warfarin therapy. With amean follow-up time of 19 months, they saw four neurologicevents (14% recurrence rate; one stroke, three TIAs), all inpatients older than 45 years of age.

Traditional surgical PFO closure probably does not guar-antee freedom from recurrent neurologic events. Novel surgi-cal techniques are on the horizon, such as minimally invasivesurgical PFO closure aided by robotic cardiac surgery [27].This entails operating on the heart with robotically facilitatedsurgical instruments inserted through small chest incisions.The benefits of this approach may be decreased postoperativepain, decreased recovery times, and an improved cosmeticresult. However, there are no data on stroke recurrence usingrobotic surgical PFO closure.

Transcatheter patent foramen ovale closureNonsurgical closure of PFOs has become possible with theadvent of transcatheter closure devices, initially developed forpercutaneous closure of ASDs. In uncomplicated cases, thepatient is discharged from the hospital 24 hours after the pro-cedure and is usually instructed to follow endocarditis pro-phylaxis and to take antiplatelet therapy for at least 6 monthsfollowing implantation until the device has endothelized.

Bridges et al. [28] reported their experience in 36 patientswith a mean age of 39 years and presumed paradoxical embo-

lism. No recurrent thromboembolic events were observed atmean follow-up of 8 months. Windecker et al. [29] reportedtheir experience in 80 patients with a mean age of 52 years. Ata mean follow-up of 1.6-years, there were eight recurrentembolic events (six TIAs, two peripheral emboli), resulting inan annual recurrence of 3.4%. Hung et al. [30] reported theresults of PFO closure in 67 patients with a mean age of 46years. With follow-up of 2.6 years, they reported four recur-rent neurologic events for a 3.2% recurrence rate. Braun et al.[31] reported on 276 consecutive patients with a mean age of45 years who underwent percutaneous PFO closure. Duringmean follow-up of 15.1 months, six recurrent TIAs, nostrokes, and no peripheral embolic events occurred, for anannual recurrence rate of 1.7%. Martin et al. [32•] recentlyreported the long-term outcome in 110 patients undergoingtranscatheter PFO closure. They excluded any patient with ahypercoagulable state in addition to screening for deepvenous thrombosis. The mean age of patients was 47 years,with the oldest patient being less than 60 years of age. Theyreported only two recurrent neurologic events after a mean2.3 years of follow-up, for a 0.9% recurrence rate.

Reasons for recurrent ischemic events after either surgicalor percutaneous PFO closure remain unclear. Antiplatelet oranticoagulation therapy may need to be continued beyondthe first 6 months because recurrent embolic events can occurwithin the first 10 months after device implantation [31,32•].Thrombus formation at the site of surgical or device closurehas been reported, which could serve as a potential source ofembolism [31,33]. Also, incomplete closure of a PFO maylead to subsequent paradoxical embolization. Alternatively,the cause for the initial or subsequent stroke may not havebeen related to paradoxical embolization at all.

To date, no trial of percutaneous PFO closure hasincluded enough older patients or patients with a hypercoag-ulable state to make reasonable assessments of outcome inthese particular subgroups. Furthermore, all trials of percuta-neous or surgical closure reported only on a series of patientundergoing a respective therapy without appropriate controlgroups. There is a need for a trial to assess the efficacy of per-cutaneous closure compared with medical therapy.

ConclusionsGiven the absence of primary prevention trials, the presenceof PFO has no therapeutic consequence in otherwise healthyadults. In contrast, patients suffering a stroke or TIA in thepresence of a PFO and without another cause of ischemicstroke should receive prophylactic therapy to reduce the riskof a recurrent embolic event. There are currently no formalguidelines regarding choice of therapy because there havebeen few randomized trials. Currently, we believe it is notnecessary to close a PFO unless the patient is intolerant toaspirin or warfarin or has a recurrent event on medical ther-apy. However, the choice of therapy may further depend onseveral clinical characteristics, including the age of the patient,risk factors for hypercoagulability, multiple prior events, and a

146 Stroke

family history of stroke. In addition, patient preferencesregarding the choice of therapy are also important. The chal-lenge remains in determining which PFOs, and under whichclinical context, confer an increased risk of significant mor-bidity. To date, there is no consensus on how long medicaltreatment should be continued after the index event. Addi-tionally, the role of other antiplatelet agents remains untested.Data regarding the comparative efficacy of robotic-assistedminimally invasive surgical PFO closure, as well as the efficacyof percutaneous PFO closure versus medical therapy, is alsounknown. Trials to address these issues wait to be conducted.

References and Recommended ReadingPapers of particular interest, published recently, have been highlighted as:• Of importance•• Of major importance

1. Franson SV: The Botallo mystery. Clin Cardiol 1999, 22:434–436.2. Hagen PT, Scholz DG, Edwards WD: Incidence and size of PFO

during the first 10 decades of life: an autopsy study of 965 normal hearts. Mayo Clin Proc 1984, 59:17–20.

3. Homma S, Di Tullio MR, Sacco RL: Patent foramen ovale and ischemic stroke. In Stroke: Pathophysiology, Diagnosis, and Management. Edited by Barnett HJ, Stein BM. Boston: Churchill Livingstone; 1998:1013–1024.

4. Meissner I, Whinant JP, Khandheria BK, et al.: Prevalence of potential risk factors for stroke assessed by transesophageal echocardiography and carotid ultrasonography: the SPARC Study. Mayo Clin Proc 1999, 74:862–869.

5. Cohnheim J: Thrombose und embolie: vorslesung über allgemeine. In Pathologie. Berlin: Hirschwald; 1877:134.

6. Webster MW, Chancellor AM, Smith HJ, et al.: Patent foramen ovale in young stroke patients. Lancet 1988, 2:11–12.

7. Lechat P, Mas JL, Lescault G, et al.: Prevalence of patent foramen ovale in patients with stroke. N Engl J Med 1988, 318:1148–1152.

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

9. Massaro AR, Hoffman M, Sacco RL, et al.: Detection of paradoxical cerebral embolism using transcranial Doppler in a patient with infarct of undetermined cause. Cerebrovasc Dis 1993, 3:116–119.

10. Di Tullio MR, Sacco RL, Venketasubramanian N, et al.: Comparison of diagnostic techniques for the detection of a PFO in stroke patients. Stroke 1993, 24:1020–1024.

11. Homma S, Di Tullio MR, Sacco RL, et al.: Characteristics of patent foramen ovale associated with cryptogenic stroke, a biplane transesophageal echocardiographic study. Stroke 1994, 25:582–586.

12. Steiner MM, Di Tullio MR, Rundek T, et al.: Patent foramen ovale size and embolic brain imaging findings among patients with ischemic stroke. Stroke 1998, 29:944–948.

13. Hanna JP, Sun JP, Furlan AJ, et al.: Patent foramen ovale and brain infarct. Echocardiographic predictors, recurrence, and prevention. Stroke 1994, 25:782–786.

14. Hausman D, Mugge A, Daniel WG: Identification of patent foramen ovale permitting paradoxical embolism. J Am Coll Cardiol 1995, 26:1030–1038.

15. Mas JL, Zuber M: Recurrent cerebrovascular events in patients with patent foramen ovale, atrial septal aneurysm, or both and cryptogenic stroke or transient ischemic attack. French Study Group on Patent Foramen Ovale and Atrial Septal Aneurysm. Am Heart J 1995, 140:1083–1088.

16. Bogousslavsky J, Garazi S, Jeanrenaud X, et al.: Stroke recurrence in patients with patent foramen ovale: the Lausanne Study. Lausanne Stoke with Paradoxical Embolism Study Group. Neurology 1996, 46:1301–1305.

17. Cujec B, Mainra R, Johnson DH: Prevention of recurrent cerebral ischemic events in patients with patent foramen ovale and cryptogenic strokes or transient ischemic attacks. Can J Cardiol 1999, 15:57–64.

18. Mas JL, Arquizan C, Lamy C, et al., for the Patent Foramen Ovale and Atrial Septal Aneurysm Study Group. Recurrent cerebro-vascular events associated with patent foramen ovale, atrial septal aneurysm, or both. N Engl J Med 2001, 345:1740–1746.

19.•• Homma S, Sacco RL, Di Tullio MR, et al., for the PICSS Investigators: Effect of medical treatment in stroke patients with PFO: PFO in Cryptogenic Stroke study. Circulation 2002, 105:2625–2631.

The first randomized clinical trial comparing anticoagulant with antiplatelet therapy for secondary stroke prevention among patients with PFO.20. Pastorek JS, Allen HD, Davis JT: Current outcomes of surgical

closure of secundum atrial septal defects. Am J Cardiol 1994, 74:75–77.

21. Harvey JR, Teague SM, Anderson JL, et al.: Clinically silent atrial septal defects with evidence for cerebral embolism. Ann Intern Med 1986, 105:695–697.

22. Zhu WX, Khandheria BK, Warnes CA, et al.: Closure of patent foramen ovale for cryptogenic stroke in young patients: long-term follow-up [abstract]. Circulation 1992, 86:I–497.

23. Ruchat P, Bogousslavsky J, Hurni M, et al.: Systematic surgical closure of patent foramen ovale in selected patients with cerebrovascular events due to paradoxical embolism. Early results of a preliminary study. Eur J Cardiothorac Surg 1997, 11:824–827.

24. Devuyst G, Bogousslavsky J, Ruchat P, et al.: Prognosis after stroke followed by surgical closure of patent foramen ovale: a prospective follow-up study with brain MRI and simultaneous transesophageal and transcranial Doppler ultrasound. Neurology 1996, 47:1162–1166.

25. Deriani JA, Urgulu BS, Danielson GK, et al.: Surgical patent foramen ovale closure for prevention of the paradoxical embolism-related cerebrovascular ischemic events. Circulation 1999, 100:II171–II 175.

26. Homma S, Di Tullio MR, Sacco RL, et al.: Surgical closure of patent foramen ovale in cryptogenic stroke patients. Stroke 1997, 28:2381.

27. Argenziano M, Oz MC, DeRose JJ Jr, et al.: Totally endoscopic atrial septal defect repair with robotic assistance. Heart Surg Forum 2002, 5:294–300.

28. Bridges ND, Hellenbrand W, Latson L, et al.: Transcatheter closure of patent foramen ovale after presumed paradoxical embolism. Circulation 1992, 86:1902–1908.

29. Windecker S, Wahl A, Chatterjee T, et al.: Percutaneous closure of patent foramen ovale in patients with paradoxical embolism: long term risk of recurrent thromboembolic events. Circulation 2000, 101:893–898.

30. Hung J, Landzberg MJ, Jenkins KJ, et al.: Closure of patent foramen ovale for paradoxical emboli: intermediate-term risk of recurrent neurological events following transcatheter device placement. J Am Coll Cardiol 2000, 35:1311–1316.

31. Braun MU, Fassbender D, Schoen SP, et al.: Transcatheter closure of patent foramen ovale in patients with cerebral ischemia. J Am Coll Cardiol 2002, 39:2019–2025.

32.• Martin F, Sanchez PL, Doherty E, et al.: Percutaneous transcatheter closure of patent foramen ovale in patients with paradoxical embolism. Circulation 2002, 106:1121.

The most recent study of percutaneous PFO closure.33. Rodriguez C, Di Tullio MR, Sacco RL, Homma S: Intra-atrial

thrombus in a patient following surgical PFO closure. J Am Soc Echocardiogr 2001, 14:63–66.