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Treatment of patent foramen ovale (PFO) for secondary stroke prevention
Authors:
Steven R Messé, MD
Stephen JD Brecker, MD, FRCP, FESC, FACC
Section Editors:
Scott E Kasner, MD
Heidi M Connolly, MD, FASE
Deputy Editors:
John F Dashe, MD, PhD
Susan B Yeon, MD, JD, FACC
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Mar 2018. | This topic last updated: Jan 29, 2018.

INTRODUCTION — Options for prevention of recurrent stroke in patients with cryptogenic ischemic stroke and a patent foramen ovale (PFO) include medical therapy with antithrombotic agents and closure of the defect by percutaneous device or rarely using a surgical approach.

This topic will review the medical and interventional options for secondary stroke prevention in patients with an embolic cryptogenic stroke associated with a PFO. Cryptogenic stroke is reviewed in detail separately. (See "Cryptogenic stroke".)

The risk of stroke related to atrial septal abnormalities and indications for treating atrial septal defects in adults are discussed elsewhere. (See "Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults" and "Indications for closure and medical management of atrial septal defects in adults".)

APPROACH TO TREATMENT — Closure of a PFO may prevent paradoxical embolism and thereby reduce the risk of recurrent stroke. While some results are conflicting, evidence from randomized controlled trials on balance now suggests that PFO closure is effective in reducing the risk of recurrent stroke for select patients with cryptogenic stroke (algorithm 1). (See 'Our approach' below and 'Benefit' below.)

Our approach — Mounting evidence suggests that percutaneous PFO closure is more effective for preventing recurrent ischemic stroke than antiplatelet therapy alone for highly selected patients (age ≤60 years) who have an embolic-appearing cryptogenic ischemic stroke and a PFO [1-4]. (See 'Percutaneous closure of PFO' below.)

For patients aged ≤60 years with a cryptogenic embolic-appearing ischemic stroke who have a PFO and no other evident source of stroke despite a comprehensive evaluation, we suggest percutaneous PFO device closure in addition to antiplatelet therapy, rather than antiplatelet therapy alone (algorithm 1). The evidence suggests a greater benefit of closure in patients with a large right-to-left shunt or an associated atrial septal aneurysm (ASA). This recommendation applies to patients who place a higher value on the moderate absolute stroke risk reduction of PFO closure and a lower value on the burdens and harms associated with device placement. (See 'Percutaneous closure of PFO' below.)

For rare patients aged ≤60 years with a cryptogenic embolic-appearing ischemic stroke who have a PFO and no other evident source of stroke despite a comprehensive evaluation who have a concurrent indication for cardiac surgery (eg, indication for valve surgery), surgical closure of PFO for secondary stroke prevention after cryptogenic stroke is a reasonable alternative to percutaneous PFO closure. (See 'Surgical closure of PFO' below.)

For patients with cryptogenic stroke and PFO who are >60 years of age, we suggest antiplatelet therapy rather than percutaneous PFO device closure or anticoagulation. An exception applies to selected patients with strong clinical evidence of paradoxical embolus including patients with acute deep venous thrombosis, pulmonary embolism, or other venous thromboembolism, who are generally treated with anticoagulation for at least several months and potentially indefinitely if the deep vein thrombosis (DVT) was unprovoked or if they have a meaningful thrombophilia. (See 'Antithrombotic therapy' below and 'Benefit' below.)

National and society guidelines regarding the management of a PFO in patients with cryptogenic stroke [5-8] were published prior to the 2017 publication of three randomized trials showing reductions in risk of recurrent stroke with PFO closure compared to medical therapy [1,2,4], as reviewed below (see 'Benefit' below). Therefore, these guidelines are outdated and do not agree with our current approach to PFO closure for selected patients with cryptogenic stroke. Updated guidelines are expected.

Evaluation for cryptogenic stroke — Patients considered for PFO closure should have a comprehensive evaluation by both a stroke neurologist and a cardiologist to ensure that the diagnosis is cryptogenic ischemic stroke and that the most likely mechanism is paradoxical embolism through a PFO [9]. (See "Cryptogenic stroke", section on 'Evaluation and diagnosis'.)

By the TOAST classification (table 1), which is the most common system used in clinical practice to classify stroke subtypes, cryptogenic stroke (or stroke of undetermined origin in TOAST terminology) is defined as brain infarction that is not attributable to a source of definite cardioembolism, large artery atherosclerosis, small artery, or other determined etiology disease despite extensive vascular, cardiac, and serologic evaluation. (See "Cryptogenic stroke", section on 'Classification'.)

For the purposes of this topic review, we define cryptogenic stroke as an ischemic stroke that has been thoroughly evaluated and is characterized by the following features [10]:

No large vessel stenosis (≥50 percent) or occlusion in the territory of the infarct

No evidence of occult atrial fibrillation and no other high-risk cardioembolic source (table 2)

No radiographic acute lacunar infarction (ie, a small [≤1.5 cm] deep perforator infarct) and no clinical lacunar stroke syndrome (ie, hemiparesis/plegia, hemianesthesia without cortical signs) if imaging shows no infarct (see "Lacunar infarcts", section on 'Clinical features')

The evaluation should include neuroimaging of the brain to exclude lacunar infarction or a nonischemic brain lesion as the cause of the symptoms, and intracranial and extracranial neurovascular imaging to exclude stroke caused by large artery atherosclerosis, dissection, or other vasculopathy.

Transesophageal echocardiography is used to confirm a PFO (see 'Evaluation for PFO' below) and to exclude ascending aorta or aortic arch atheroma or a cardiac source of embolism unrelated to PFO. There should be no evidence of atrial fibrillation on a 12-lead electrocardiogram (ECG) and on 24-hour cardiac monitoring. Ambulatory cardiac monitoring for several weeks (eg, 30 days) is warranted for adult patients over age 45 with a cryptogenic ischemic stroke or cryptogenic TIA if no atrial fibrillation is detected by ECG and 24-hour monitoring.

Hematologic testing to exclude arterial hypercoagulable states (eg, antiphospholipid syndrome and hyperhomocysteinemia) is indicated for patients with cryptogenic stroke being considered for PFO closure.

Evaluation for PFO — Patients should have confirmation of PFO by echocardiography as described below. (See 'Preprocedural imaging' below.)

Is PFO the most likely stroke mechanism? — In the setting of a cryptogenic, embolic-appearing ischemic stroke in a patient ≤60 years of age who has a PFO and no other evident source of stroke despite a comprehensive evaluation, it is reasonable to conclude that paradoxical embolism through a PFO is the most likely stroke mechanism, and that PFO closure is warranted. (See 'Our approach' above.)

We suggest performing an evaluation for deep vein thrombosis (DVT) in all patients with cryptogenic stroke who have a PFO (algorithm 1) as identification of DVT can help strengthen the clinical inference of paradoxical embolism and also has important implications for therapy (including identifying an indication for anticoagulation which impacts the timing and need for PFO device closure).

Given the high prevalence of PFO in the general population and the low risk of stroke related to PFO, there is always some degree of uncertainty about the causal relationship between PFO and a cryptogenic ischemic stroke. The possibility that the PFO is an "innocent bystander" and that another mechanisms is responsible for the stroke is particularly applicable to older patients and to those with known risk factors for stroke (eg, hypertension, hypercholesterolemia, smoking) [11-13]. Causality can best be inferred in younger patients with no other apparent etiology for stroke [14], particularly if DVT is present (as a potential source for paradoxical emboli). Thrombus trapped in a PFO has rarely been reported [15-18].

We include age ≤60 as a criterion in our recommendation for PFO closure for secondary stroke prevention as the association between PFO and stroke was strongest in this subgroup and this age cut-off was used in the supporting clinical trials (see 'Benefit' below). Other criteria for identifying patients with an embolic-appearing cryptogenic stroke likely to benefit from PFO closure have not been established. Although the RoPE score (table 3) is not validated for selecting patients who might benefit from PFO closure, it may be helpful to support the decision to proceed with PFO closure in patients with very high RoPE scores, or to decline PFO closure in patients with very low RoPE scores. The RoPE score estimates the probability that a PFO is incidental or pathogenic in a patient with cryptogenic stroke [19]. The PFO-attributable fraction of stroke derived from the RoPE score (table 4) varies widely and decreases with age and the presence of vascular risk factors. High RoPE scores, as found in younger patients who lack vascular risk factors and have a cortical infarct on neuroimaging, suggest pathogenic PFOs. In contrast, low RoPE scores, as found in older patients with vascular risk factors, suggest incidental PFOs.  

Exclusions to device closure — Patients with venous thromboembolism that is provoked by a known event or an identifiable transient risk factor are generally treated with anticoagulation for 3 to 12 months. In such cases, PFO device closure, if otherwise indicated, can be postponed until anticoagulation is stopped. For patients with an embolic-appearing stroke who have an indication for chronic anticoagulation (eg, unprovoked or recurrent deep venous thrombosis), the benefit of PFO closure is uncertain. For patients with an embolic-appearing stroke who have an indication for chronic anticoagulation, we suggest an individualized multidisciplinary decision making based on the risks of thrombosis, embolism, and intervention in deciding whether to proceed with chronic anticoagulation alone or to also perform PFO closure (by percutaneous device or by surgery).

Other exclusions to percutaneous device closure include the presence of an inferior vena cava filter, elevated bleeding risk or coagulopathy, and vascular, cardiac, or PFO anatomy that is unsuitable for device placement.

Informed decision making — Consideration of PFO closure, including benefits, risks, and alternative treatment options must be discussed with the patient by the neurologist and cardiologist. The patient should understand the immediate and long-term potential benefits and risks of treatment options (including decreased risk of recurrent stroke and increased risk of atrial fibrillation with PFO percutaneous device closure) in order to make an appropriately informed decision that accounts for their own values and preferences.

PERCUTANEOUS CLOSURE OF PFO

Benefit — Mounting evidence suggests that PFO percutaneous device closure is more effective than antiplatelet therapy alone for reducing the risk of recurrent stroke in select patients aged ≤60 years with a cryptogenic nonlacunar ischemic stroke who have a PFO with a right-to-left interatrial shunt. The patients most likely to benefit may be those with a large right-to-left interatrial shunt and/or an associated atrial septal aneurysm (ASA), characteristics that suggest an increased risk for paradoxical embolism.

Randomized controlled trials of percutaneous PFO closure have all found point estimates suggesting that PFO closure is more effective than medical therapy for reducing event rates, with hazard ratios of 0.03 to 0.78. These results were not statistically significant by intention-to-treat analyses in the first three trials (CLOSURE I [20], PC [21], and RESPECT [22]), but were significant in later trials (RESPECT extended follow-up [1], REDUCE [4], and CLOSE [2]). The trials that found clear benefit for PFO device closure were likely positive because of several factors. First, these latter trials enrolled subjects when off-label PFO closure had waned to some extent, and thus it is possible that patients who were more likely to benefit were included in these studies. Furthermore, to varying degrees for the individual studies, they included a requirement for neuroimaging confirmation of stroke prior to enrollment, excluded lacunar infarcts, provided longer follow-up, and selected patients with PFO features (ie, large shunt size, or presence of an associated ASA) that may portend an increased risk of paradoxical embolism. Meta-analyses of closure trials consistently show that patients in the PFO closure groups had increased rates of newly-detected atrial fibrillation compared with the medical therapy groups [23,24]. (See 'Adverse effects' below.)

In a 2018 meta-analysis that included four trials (PC [21], RESPECT extended follow-up [1], REDUCE [4], and CLOSE [2]) with 2892 subjects and follow-up ranging from 3.2 to 5.9 years, PFO closure reduced the absolute risk of recurrent stroke by 3.2 percent (95% CI 1.4-5.0) [23]. Based on these data, the number needed to treat (NNT) with PFO device closure to prevent one recurrent stroke was approximately 31. A separate 2018 meta-analysis including the same trials found that PFO closure reduced the absolute risk of stroke or TIA by 2.9 percent (95% CI 1.2-5.4) [24]. Both meta-analyses excluded the CLOSURE I trial because it used the STARFlex PFO closure device, which was associated with higher complication and lower procedural success rates than the PFO closure devices used in the other trials, and is no longer available [23,24].

The individual trials reported the following results:

In the CLOSURE I trial, 909 adult patients ≤60 years old with a PFO and cryptogenic stroke or TIA were randomly assigned either to PFO device closure (n = 447) or to medical therapy (n = 462) [20]. Patients in the device group were treated with the STARFlex PFO closure device and received aspirin plus clopidogrel for six months followed by aspirin alone; those in the medical therapy group were treated with aspirin or warfarin or both. The primary endpoint was a composite of stroke or TIA at two years plus 30-day mortality and neurologic mortality beyond 30 days. At two years by intention-to-treat analysis, there was no significant difference between device closure and medical therapy in the rates of the primary endpoint (5.5 versus 6.8 percent, hazard ratio [HR] 0.78, 95% CI 0.45-1.35), stroke (2.9 versus 3.1 percent), or TIA (3.1 versus 4.1 percent). Major vascular complications were significantly more frequent with device closure (3.2 versus 0 percent), as was atrial fibrillation (5.7 versus 0.7 percent), most of which was periprocedural.

The PC trial randomly assigned 414 adults (<60 years of age) with PFO and ischemic stroke, TIA, or a peripheral embolic event to treatment with the Amplatzer PFO Occluder or medical therapy [21]. After a mean follow-up of four years, the composite primary endpoint of death, nonfatal stroke, TIA, or peripheral embolism for the intention-to-treat cohort occurred in 7 of 204 patients (3.4 percent) in the device closure group and 11 of 210 patients (5.2 percent) in the medical therapy group; the difference was not statistically significant (HR 0.63, 95% CI 0.24-1.62). Serious adverse events were slightly more frequent in the device closure group (21.1 percent versus 17.6 percent), including a nonsignificantly higher rate of new-onset atrial fibrillation in the device closure group (2.9 versus 1.0 percent).

In the RESPECT trial, 980 patients (age 18 to 60 years) with a PFO and cryptogenic ischemic stroke were randomly assigned to receive treatment with the Amplatzer PFO Occluder or medical therapy [22]. The primary endpoint was a composite of recurrent nonfatal ischemic stroke, fatal ischemic stroke, or early death after randomization. The trial results were analyzed after reaching the target of 25 primary endpoint events; all 25 events were nonfatal ischemic strokes. The mean follow-up was approximately 2.6 years, and the primary endpoint for the intention-to-treat cohort occurred in 9 of 499 patients (1.8 percent) in the closure group and 16 of 481 patients (3.3 percent) in the medical therapy group, a difference that was not statistically significant (0.66 versus 1.38 events per 100 patient-years, HR 0.49, 95% CI 0.22-1.11).

A later RESPECT publication reported outcomes at median follow-up of 5.9 years [1]. By intention-to-treat analysis, recurrent ischemic stroke was less frequent in the closure group compared with the medical therapy group (18 versus 28 events, 0.58 versus 1.07 events per 100 patient-years, HR 0.55, 95% CI 0.31-0.99). However, the dropout rate was higher and treatment exposure lower in the medical therapy group, leading to an unequal exposure to the risk of outcome events among the two groups.

The REDUCE trial randomly assigned 664 patients 18 to 59 years of age with cryptogenic embolic-appearing ischemic stroke and PFO with a right-to-left shunt demonstrated by means of transesophageal echocardiography [4]. Patients were randomly assigned to PFO closure combined with antiplatelet therapy or treatment with antiplatelet therapy alone in a 2:1 ratio. During a median follow-up of 3.2 years, clinical ischemic stroke by intention-to-treat analysis occurred in fewer patients in the PFO closure group compared with the antiplatelet-only group (6/441 versus 12/223 patients, 1.4 versus 5.4 percent, HR 0.23, 95% CI 0.09-0.62).

The CLOSE trial enrolled patients 16 to 60 years of age with recent cryptogenic stroke attributed to PFO who had an associated ASA or large interatrial shunt on echocardiography [2]. Patients were randomly assigned in a 1:1:1 ratio to PFO closure plus antiplatelet therapy, antiplatelet therapy alone, or oral anticoagulation, with the exception that patients with contraindications to PFO device closure or to anticoagulation were assigned to alternative non-contraindicated treatment or to antiplatelet therapy. The main arms of the trial (n = 473) compared PFO closure with antiplatelet therapy; at a mean follow-up of 5.3 years, there were no recurrent strokes among 238 patients in the PFO closure group compared with 14 strokes among 233 patients the antiplatelet-only group (HR 0.03, 95% CI 0.0-0.26).

There are important limitations of these trials that lower confidence in the results. As examples:

All of these trials utilized open label endpoint ascertainment, which increases the risk of bias.

The number of primary events was relatively low, with a total of 52 events in the CLOSURE I trial [20], 18 in the PC trial [21], 46 in the RESPECT trial [1], 18 clinical events in the REDUCE trial [4], and 14 events in the treatment groups comparing of PFO closure with antiplatelet treatment in the CLOSE trial [2].

The duration of follow-up in the CLOSURE I trial (2 years) and the primary analysis of the RESPECT trial (2.6 years) was not long enough to demonstrate benefit (eg, the trials of endarterectomy for asymptomatic carotid disease would not have demonstrated benefit at only 2 years).

There was slow enrollment in most of these trials and suspicion that patients at high risk of recurrent embolism were disproportionately treated outside of the trials with PFO closure, particularly for the earlier trials.

Adverse effects — New onset atrial fibrillation is the most common adverse effect of PFO device closure. Two meta-analyses published in 2018 found that PFO closure increased the risk of atrial fibrillation or atrial flutter [23,24], with a risk difference (ie, absolute risk increase) of 3.4 percent in one of the meta-analyses [24].

Other complications, all rare, include hematoma at the puncture site, device migration, device embolization, device erosion, and device thrombosis with possible and recurrent ischemic stroke. (See 'Recurrent ischemic stroke' below.)

Device erosion is rare (0.2 to 0.3 percent of cases) after device closure of ASDs, in most cases occurring during the first six months after implantation [25,26], and may be rarer with device closure of PFOs. Device erosion can lead to cardiac perforation with pericardial effusion, cardiac tamponade, and fistula formation or may rarely create an atrial septal defect [27,28].

Preprocedural imaging — Prior to device placement, echocardiography (transthoracic echocardiography [TTE] and/or transesophageal echocardiography [TEE]) is used to confirm the presence of a PFO by agitated saline contrast ("bubble") study at rest, with Valsalva, and with cough; the study is considered positive if one or more bubbles appear in the left heart within three cardiac cycles of bubbles filling the right atrium [29]. Multiple agitated saline contrast injections may be required to identify (or exclude) shunt via the PFO. In some cases, intermittent flow through the PFO is also visualized by color Doppler. Echocardiography (usually TEE) is often performed during the evaluation of patients with acute ischemic stroke in order to detect potential cardiogenic and aortic sources of cerebral emboli including PFO, and is an essential component of a comprehensive evaluation for cryptogenic stroke (see "Cryptogenic stroke", section on 'Cardiac and aortic evaluation'). The diagnostic evaluation of PFO is discussed in detail separately. (See "Patent foramen ovale", section on 'Diagnosis'.)

Patients who are candidates for PFO closure should undergo TEE to confirm that the intracardiac shunt is caused by a PFO, to define atrial septal anatomy (including thickness of rims around the PFO) and suitability for device closure, and to exclude other causes of embolic stroke (eg, intracardiac thrombus, mass or vegetation) or shunt [29]. The atrial septum is carefully examined to determine whether there are one or more concomitant atrial septal defects (ASDs) and/or an atrial septal aneurysm (defined a redundant mobile interatrial septal tissue in the region of the fossa ovalis with phasic excursion of at least 10 to 15 mm). The length of the PFO tunnel is also assessed. If a PFO is accompanied by one or more secundum-type ASDs, the location and size of these defects are examined to determine whether all the defects can be closed percutaneously by one or two devices, and whether a surgical approach might be preferred.

Procedure — Percutaneous PFO closure should be performed using an approved PFO closure device. Access to the right atrium is established via the right femoral vein and the PFO is crossed with a guidewire or catheter under fluoroscopic and echocardiographic guidance [25]. After the left atrium is accessed, an exchange-length stiff guidewire is advanced into a pulmonary vein. Balloon sizing may be used to determine the size of the device (typically twice the size of the balloon-stretched diameter of the defect). After the balloon is withdrawn, the delivery system is advanced into the left atrium over the guidewire. The device and the delivery system are flushed prior to insertion and the catheters aspirated to avoid air embolism. The left-sided occluder is opened in the left-atrium and retracted against the interatrial septum before the right-sided occluder is opened. After device position is confirmed by echocardiography, the closure device is released from the delivery system. Echocardiography is performed after device release to assess for residual shunting and presence of any complications.

The echocardiographic guidance is achieved by intracardiac echocardiography (ICE) or TEE. ICE, performed via a second venous access to the right atrium, is generally preferred as it avoids the general anesthesia and intubation required for TEE [30]. When TEE is not used, the percutaneous closure procedure (with ICE) is generally performed with conscious sedation.

Periprocedural antithrombotic therapy — Patients undergoing percutaneous device closure routinely receive antithrombotic therapy prior to, during, and following the procedure, though specific regimens vary. As an example, in the CLOSE trial, all patients undergoing percutaneous PFO closure received clopidogrel 300 mg, low molecular weight heparin, or continuation of their prior antiplatelet therapy before the procedure. During the procedure unfractionated heparin 100 IU/kg (up to 10,000 IU) was administered intravenously. After the procedure, patients were treated with aspirin 75 mg/day plus clopidogrel 75 mg/day for three months. From the fourth month, patients were treated with aspirin alone, clopidogrel alone, or the combination product aspirin-extended-release dipyridamole.

Following percutaneous PFO closure, we treat with aspirin 75 mg/day plus clopidogrel 75 mg/day for three months, followed by continued aspirin therapy (75 mg/day).

MEDICAL TREATMENT

General measures — Patients with PFO who have an ischemic stroke or transient ischemic attack (TIA) should be treated with all appropriate risk reduction strategies, most importantly antithrombotic therapy (see 'Antithrombotic therapy' below). Other measures include life style modification (diet and exercise), blood pressure reduction, and statins (if indicated). (See "Overview of secondary prevention of ischemic stroke" and "Antiplatelet therapy for secondary prevention of stroke".)

Antithrombotic therapy — For most patients with an embolic-appearing cryptogenic stroke and a PFO who do not have device closure, antithrombotic therapy with antiplatelet agents rather than anticoagulation is suggested. Patients with expected high risk of venous thromboembolism should be anticoagulated, as discussed below. Patients who do have device closure of a PFO should also be treated with antiplatelet agents (see 'Periprocedural antithrombotic therapy' above). Although the comparative effectiveness of different types of antithrombotic therapy for secondary stroke prevention among patients with a PFO who have had a cryptogenic ischemic stroke or TIA is uncertain (see 'Comparative studies' below), there are good data from randomized trials that aspirin is effective for ischemic stroke prevention, as discussed elsewhere. (See "Antiplatelet therapy for secondary prevention of stroke", section on 'Aspirin'.)

Anticoagulation is indicated for most patients with a cryptogenic ischemic stroke and PFO who have evidence of acute deep venous thrombosis (DVT), pulmonary embolism, other venous thromboembolism (VTE), or a hypercoagulable state. For patients in whom anticoagulation is contraindicated or in whom the long-term risk of bleeding outweighs the risk of VTE, an inferior vena cava filter should be placed promptly. (See "Overview of the treatment of lower extremity deep vein thrombosis (DVT)" and "Treatment, prognosis, and follow-up of acute pulmonary embolism in adults" and "Placement of vena cava filters and their complications".)

When used, anticoagulation is generally continued for several months specifically to treat for venous thromboembolism, and antiplatelet therapy for secondary stroke prevention is started when anticoagulation is discontinued. However, patients with an idiopathic DVT appear to be at appreciable risk for recurrence and may benefit from long-term anticoagulation. The treatment of venous thromboembolism is discussed in detail elsewhere. (See "Overview of the treatment of lower extremity deep vein thrombosis (DVT)" and "Treatment, prognosis, and follow-up of acute pulmonary embolism in adults".)

Comparative studies — The evidence comparing the benefit of antiplatelet therapy with warfarin for stroke prevention among patients with a PFO and cryptogenic ischemic stroke comes mainly from nonrandomized studies and subgroup analysis of randomized trials, as illustrated by the following observations:

In a 2015 meta-analysis of individual participant data from 12 observational studies involving 2385 medically treated patients with cryptogenic stroke and PFO, there was no significant difference between treatment with oral anticoagulation compared with antiplatelet therapy for the composite outcome of recurrent stroke, TIA, or death (9 versus 10 percent, adjusted hazard ratio [HR] 0.76, 95% CI 0.52-1.12) and no difference for the outcome of recurrent stroke alone (4 versus 5 percent, adjusted HR 0.75, 95% CI 0.44-1.27) [31].

In a subgroup analysis of the RESPECT extended follow-up trial, there was a suggestion that PFO closure did not reduce stroke risk for patients who received anticoagulant therapy (HR 1.32, 95% CI 0.43-4.03) but did reduce stroke risk for patients who received antiplatelet therapy (HR 0.38, 95% CI 0.18-0.79) [1].

In the CLOSE trial, the estimated five-year risk of stroke was 1.5 percent with anticoagulant therapy and 3.8 percent with antiplatelet therapy, but the difference was not significant (HR 0.44, 95% CI 0.11-1.48) [2].

Additional preventive measures — Certain general measures may be beneficial independent of the therapy chosen for the atrial septal abnormality. Since embolic material originates most commonly in lower extremity veins, patients at risk should avoid sitting for extended periods of time with knees flexed and legs dependent or the legs crossed, and should avoid prolonged passive standing. Risk is implicit during long airplane flights. For long-distance travelers with individual risk factors for venous thromboembolism (VTE), we suggest frequent ambulation and calf exercises, avoidance of dehydration or sedatives, and graduated compression stockings to reduce the risk of travel-associated VTE. These measures are particularly important in patients in whom deep vein thrombosis was identified at the time of the initial cerebrovascular event. Recommendations for prevention of venous thromboembolism are discussed in greater detail separately. (See "Prevention of venous thromboembolism in adult travelers".)

RECURRENT ISCHEMIC STROKE — As with any stroke, patients who have a recurrent ischemic stroke after PFO closure should have another comprehensive evaluation to determine the stroke mechanism, including assessment of the PFO closure device for defects, device thrombosis, and residual shunt. Recurrent ischemic stroke may occur in patients with a PFO, regardless of whether the PFO was closed, due to mechanisms unrelated to paradoxical embolism, such as cardiogenic embolism, large artery atherosclerosis, small artery disease, and other determined stroke etiologies. In a minority of patients with PFO closure, a residual shunt persists, allowing continued potential risk for paradoxical embolism [32-35]. Alternatively, thrombus may spontaneously form on or adjacent to the PFO device or in the left atrium due to stagnant blood flow [36], particularly given the possible increased risk of atrial arrhythmias (mainly atrial fibrillation) in patients with PFO and/or atrial septal aneurysm [37]. This risk that may be augmented after PFO closure [20,21], especially in the first few weeks after device implantation.

Recurrent stroke should be treated according to the underlying mechanism, if it can be identified:

If the recurrence occurs in a patient who has not had their PFO closed, and the PFO still appears to be the most likely cause of cryptogenic stroke, we suggest PFO closure.

For patients on antiplatelet therapy who have a recurrent cryptogenic stroke (regardless of PFO closure status) and no atrial fibrillation on re-evaluation with long-term cardiac monitoring, options include continuing the same antiplatelet agent or switching to another antiplatelet regimen. For patients with recurrent embolic stroke of undetermined source (see "Cryptogenic stroke", section on 'Embolic stroke of undetermined source'), switching to empiric anticoagulant therapy is also a reasonable option. For example, while awaiting the results of long-term cardiac monitoring, some experts would start empiric oral anticoagulation at hospital discharge for patients with acute embolic stroke that is cryptogenic after standard evaluation if there are multiple risk factors for occult atrial fibrillation. These include higher CHA2DS2-VASc score (table 5), the presence of cortical or large subcortical infarcts in multiple vascular territories, and evidence of left atrial cardiopathy (eg, left atrial dilatation, strain, reduced emptying fraction, left atrial appendage size and single lobe morphology, P wave dispersion on electrocardiogram (ECG), and frequent atrial premature beats). Further antithrombotic treatment is directed by the presence or absence of atrial fibrillation detected on 30-day cardiac monitoring, and the frequency and duration of atrial fibrillation if detected. Ongoing studies of embolic stroke from undetermined source (ESUS) may inform these decisions.

In rare cases, recurrent thrombus formation on the closure device despite anticoagulant therapy may require device removal [38].

SURGICAL CLOSURE OF PFO — For rare patients aged ≤60 years with a cryptogenic embolic-appearing ischemic stroke who have a PFO and no other evident source of stroke despite a comprehensive evaluation who have a concurrent indication for cardiac surgery (eg, indication for valve surgery, or the rare PFO that is not amenable to device closure for technical reasons), surgical closure of PFO via standard or minimally invasive (including robotic) techniques for secondary stroke prevention after cryptogenic stroke is a reasonable alternative to percutaneous PFO closure.

The reported efficacy of surgical closure of a PFO in patients with prior cerebrovascular ischemic events has been variable [11,39-41], and randomized trials comparing surgical PFO closure with percutaneous closure or with medical therapy have not been performed.

Rates of recurrent cerebrovascular events following surgical closure have ranged from 7 to 14 percent at one to two years [11,39]. Similar to findings from the randomized controlled trials for device closure of PFO, these events are likely due to mechanisms unrelated to paradoxical embolization, as illustrated by a report of 91 patients (mean age 44 years) with one or more cerebrovascular ischemic events who underwent surgical PFO closure [39]. The overall freedom from an ischemic episode at one and four years was 93 and 83 percent, respectively. The recurrent events were TIAs (there were no cerebral infarctions), one of which was attributed to giant cell arteritis. Transesophageal echocardiography showed that the closures were intact in all patients, implying that paradoxical embolization was not the cause of the ischemic events.

In patients with high cardiovascular risk and an incidentally discovered PFO, surgical closure may actually increase the risk of postoperative stroke. This conclusion comes from a retrospective study of over 13,000 adults without a prior diagnosis of PFO or atrial septal defect (ASD) who had cardiothoracic surgery [42]. A PFO was detected intraoperatively in 2277 patients, and closure was performed at the discretion of the surgeon in 28 percent. Using propensity-matched analysis, the risk of perioperative stroke was significantly higher in patients who had surgical PFO closure than in those who did not (2.8 versus 1.2 percent; odds ratio 2.47, 95% CI 1.02-6.0). There was no difference between the two groups in long-term survival. The uncontrolled retrospective design and small number of events limit the strength of this study

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults".)

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Basics topic (see "Patient education: Patent foramen ovale (The Basics)")

SUMMARY AND RECOMMENDATIONS

Mounting evidence suggests that patent foramen ovale (PFO) device closure is more effective than medical therapy alone for select patients aged ≤60 years with a cryptogenic nonlacunar ischemic stroke who have a PFO with a right-to-left interatrial shunt. The patients most likely to benefit may be those with a large right-to-left interatrial shunt and/or an associated atrial septal aneurysm (ASA), characteristics that suggest an increased risk for paradoxical embolism. (See 'Benefit' above.)

New-onset atrial fibrillation is a potential adverse effect of PFO device closure. (See 'Adverse effects' above.)

Our recommendations for PFO management in patients with cryptogenic stroke (algorithm 1) are as follows (see 'Our approach' above):

For patients age ≤60 years with an embolic-appearing cryptogenic ischemic stroke (ie, no evident source of stroke despite a comprehensive evaluation) who have a PFO with a right-to-left shunt detected by bubble study, we suggest percutaneous PFO closure in addition to antiplatelet therapy, rather than antiplatelet therapy alone (Grade 2B). (See 'Percutaneous closure of PFO' above.)

For rare patients aged ≤60 years with a cryptogenic embolic-appearing ischemic stroke who have a PFO and no other evident source of stroke despite a comprehensive evaluation and who have a concurrent indication for cardiac surgery (eg, indication for valve surgery) or a PFO that is not amenable to device closure for technical reasons, surgical closure of PFO for secondary stroke prevention after cryptogenic stroke is an alternative to percutaneous PFO closure. (See 'Surgical closure of PFO' above.)

For patients with cryptogenic stroke and PFO who are age >60 years, we suggest antiplatelet therapy rather than percutaneous PFO closure or anticoagulation (Grade 2C). An exception applies to selected patients with strong clinical evidence of paradoxical embolus, including patients with acute deep venous thrombosis, pulmonary embolism, or other venous thromboembolism, who are generally treated with anticoagulation for at least several months and potentially indefinitely if the deep vein thrombosis (DVT) was unprovoked or if they have a meaningful thrombophilia. (See 'Antithrombotic therapy' above.)

Patients considered for PFO closure should have a comprehensive evaluation by both a stroke neurologist and a cardiologist to ensure that the diagnosis is cryptogenic ischemic stroke and that the most likely mechanism is paradoxical embolism through a PFO. (See 'Evaluation for cryptogenic stroke' above and 'Evaluation for PFO' above and 'Is PFO the most likely stroke mechanism?' above.)

For patients with a previous cryptogenic stroke treated with antiplatelet therapy but not PFO closure who have a recurrent embolic-appearing cryptogenic stroke, we suggest PFO closure. Irrespective of whether the PFO was closed after the initial cryptogenic stroke, additional options for cryptogenic stroke recurrence include continuing the same antiplatelet agent or switching to another antiplatelet regimen. For patients with recurrent embolic stroke of undetermined source, switching to empiric anticoagulant therapy is also a reasonable option. (See 'Recurrent ischemic stroke' above.)

ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge Naser M Ammash, MD, and Robert S Schwartz, MD, and Joseph K Perloff, MD who contributed to earlier versions of this topic review.

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