Article

Patent Foramen Ovale Closure: State of the Art

Abstract

Patent foramen ovale (PFO) is a common abnormality affecting between 20% and 34% of the adult population. For most people, it is a benign finding; however, in some people, the PFO can open widely to enable paradoxical embolus to transit from the venous to arterial circulation, which is associated with stroke and systemic embolisation. Percutaneous closure of the PFO in patients with cryptogenic stroke has been undertaken for a number of years, and a number of purpose-specific septal occluders have been marketed. Recent randomised control trials have demonstrated that closure of PFO in patients with cryptogenic stroke is associated with reduced rates of recurrent stroke. After a brief overview of the anatomy of a PFO, this article considers the evidence for PFO closure in cryptogenic stroke. The article also addresses other potential indications for closure, including systemic arterial embolisation, decompression sickness, platypnoea–orthodeoxia syndrome and migraine with aura. The article lays out the pre-procedural investigations and preparation for the procedure. Finally, the article gives an overview of the procedure itself, including discussion of closure devices.

Received:

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Citation:Interventional Cardiology Review 2020;15:e15.

Correspondence: Patrick Calvert, Department of Cardiology, Royal Papworth Hospital NHS Foundation Trust, Papworth Road, Cambridge Biomedical Campus, Cambridge CB2 0AY, UK. E: patrick.calvert1@nhs.net

Open access:

This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Patent foramen ovale (PFO) is common and occurs in 20–34% of the population.1 In most infants, the foramen ovale closes soon after birth, with a reduction in pulmonary vascular resistance raising the left atrial pressure above that of the right atrium during the first few breaths, closing the septum. In a significant proportion of individuals, the primum and secundum atrial septa do not fuse, and the foramen ovale remains incompletely closed. There is a residual, but transitory, communication between the right and left atria, particularly likely to open during actions that cause sudden rises and falls in intrathoracic pressure, such as sneezing, coughing or straining. The pressure changes that transiently open a PFO can often be produced by asking patients with a PFO to perform and then release a Valsalva manoeuvre.

In most adults, a PFO will appear only as a chance finding during cardiac investigation, or more likely remain undetected. Some PFOs may open widely, providing a conduit for thrombus, air or vasoactive peptides to travel from the venous to arterial circulation – causing a paradoxical embolus. This transfer is associated with several clinical phenomena, including cryptogenic stroke, systemic embolus, migraine with aura and decompression sickness in divers. Percutaneous PFO closure provides a practical and elegant solution to the problem of PFO in carefully selected individuals. This review evaluates the evidence for PFO closure, discusses which patients should be considered for this treatment and reviews how the procedure should be undertaken.

The Anatomy of a Patent Foramen Ovale

As the heart develops in the foetus, the primum and secundum septa grow and overlap. At birth, the PFO should close. In patients with a PFO, the atrial septal growth is normal; however, the communication between the right and left atria (PFO) fails to close postpartum (Figure 1). This phenomenon is distinct from a hole in either septum, which would constitute an atrial septal defect (ASD) – a separate entity with different functional consequences and different indications for closure. Table 1 compares PFO and ASD.

Despite their differences, both PFOs and ASDs may permit the transit of a paradoxical embolism. The overlapping of the primum and secundum atrial septa in a PFO forms a flap valve that usually only opens when the right atrial pressure exceeds the left atrial pressure. PFOs are functionally closed most of the time, as right atrial pressure is usually less than the left atrial pressure. This pressure gradient can be reversed by manoeuvres that change the intrathoracic pressure (e.g. sneezing, coughing or straining to defecate), allowing the PFO to open, and blood, thrombus or any other substance to pass across from the right to left atrium.

Indications for Patent Foramen Ovale Closure in 2019

Cryptogenic Stroke

Often, despite extensive investigation, a clear cause cannot be found for stroke. Causes that can be identified include AF, atherosclerotic disease, carotid dissection and intracerebral pathology, such as haemorrhage or space-occupying lesions.2,3 The cause of stroke remains unknown in up to 40% of patients with a stroke diagnosis. These are designated as cryptogenic stroke. In the presence of a PFO, the presumed cause of stroke is paradoxical embolus. As the likely cause is known, the term ‘cryptogenic’ is a misclassification, but remains in use throughout the literature. An alternative term is embolic stroke of undetermined source, which was first used in 2014. This still misclassifies stroke from paradoxical embolism, where the cause is known.4–6

Echocardiographic Assessment of a Patent Foramen Ovale

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Zahn first described paradoxical embolus in 1881.7 Translocation of venous thrombus to the arterial circulation under the haemodynamic conditions in which a PFO is open leads to embolic stroke. Transit of thrombus occurs after a rapid rise and fall in right atrial pressure through the aforementioned mechanisms. The PFO channel briefly provides a communication between the atria. This mechanism is supported by case studies showing thrombus across a PFO.8–10 There is also an association between cryptogenic stroke and venous thrombosis in patients with a PFO.11

The earliest randomised trials of PFO closure (Evaluation of the STARFlex Closure System in Patients with a Stroke and/or Transient Ischemic Attack due to Presumed Paradoxical Embolism Through a Patent Foramen Ovale [CLOSURE I] and Percutaneous Closure of Patent Foramen Ovale Using the Amplatzer PFO Occluder With Medical Treatment in Patients With Cryptogenic Embolism [PC Trial]) did not demonstrate the superiority of closure compared with medical therapy.12,13 However, the studies were confounded by limited power, high crossover between groups, failure to randomise those patients whose strokes were likely to have been caused by PFO and inconsistent use of anticoagulants in the medical therapy group.14 In addition, the STARFlex occluder used in CLOSURE I has been abandoned in Europe due to concerns around residual defects and left-sided thrombus formation.15 Some have concluded that numerical equipoise in these trials were enough to recommend a one-off mechanical vaccination paradoxical embolus rather than lifelong anticoagulation.16,17 However, PFO closure was given a Class III recommendation in the 2014 American Heart Association/American Stroke Association guidelines based on the results of these trials.

Nonetheless, further randomised trials learned lessons from earlier neutral studies and have demonstrated that PFO closure is superior to medical therapy for the prevention of recurrent stroke. Early results from the Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment (RESPECT) trial were neutral for PFO closure but extended follow up of patients demonstrated a reduction in ischaemic stroke compared to medical therapy (HR 0.55; 95% CI [0.31–0.999]; p=0.046; number needed to treat [NNT] 45).18,19 The Gore Septal Occluder Device for PFO Closure in Stroke Patients (REDUCE) clinical study demonstrated that PFO closure produced significant improvement in the clinical ischaemic stroke rate (1.4 versus 5.5%; p=0.002; NNT=25) compared with antiplatelet therapy alone.20 The Device Closure Versus Medical Therapy for Cryptogenic Stroke Patients With High-Risk PFO (DEFENSE PFO) study showed that PFO closure reduced a composite endpoint of stroke, vascular death and thrombolysis in MI major bleeding at 2 years compared with medical therapy (0 versus 12.9%; p=0.013; NNT=8).21 Finally, in the PFO Closure or Anticoagulants Versus Antiplatelet Therapy to Prevent Stroke Recurrence (CLOSE) trial, no patient receiving PFO closure experienced an ischaemic stroke compared with 14 in the antiplatelet group (HR 0.03; 95% CI [0–0.26]; p<0.001; NNT=17).22

Meta-analyses of these trials confirm that PFO closure reduces the risk of ischaemic stroke in patients with a PFO and cryptogenic stroke.23-25 Absolute risk reduction is low (1.0 stroke per 100 patient-years), but this needs to be weighed against the prolonged period that younger patients are likely to be at risk. Patients with atrial septal aneurysm or large shunts may obtain greater benefit. In these trials, and in subsequent meta-analyses, AF occurred more frequently in patients who underwent PFO closure than those receiving medical therapy alone. However, this finding did not seem to counteract the overall stroke reduction in this population. Randomised trials of PFO closure for the prevention of recurrent ischaemic stroke are shown in Table 2.

Observational data suggest that post-closure AF may be transient, with a lower stroke risk than AF with other aetiology.26 No trial or observational study has demonstrated a reduction in mortality with PFO closure, and indeed meta-analysis of multiple trials has not found a significant effect either.27–29 There may be a benefit, but it will remain difficult to prove without large randomised trials with very long follow-up periods.

Patients enrolled in PFO closure trials were young, with few studies enrolling patients age >60 years. Older patients may have an increased absolute risk of paradoxical embolus, but untangling this from other causes of stroke that also increase over time is challenging. Patients needed to have symptoms consistent with stroke and confirmation of ischaemia or infarction on cross-sectional brain imaging. Transoesophageal echocardiographic confirmation of the presence of a PFO was also required. Studies excluded patients with an alternative attributable cause for their stroke, and required enrolment no longer than 6–9 months after the index stroke.

Comparison of Patent Foramen Ovale and Atrial Septal Defects

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One of the major alternative explanations for embolic stroke is AF, and this was excluded in all patients. Studies have demonstrated that over the medium to long term, PFO closure is cost-effective in both the US and UK healthcare systems.30–32 Furthermore, longer-term observational studies have shown very low stroke rates (<1%), even up to 12 years after PFO closure.33

The strict criteria of these studies are important and should be respected in clinical practice. There is little or no evidence for treatment of PFO outside these criteria, and there is no symptomatic benefit to closure in patients with cryptogenic stroke. Patients who meet trial criteria for closure should be considered for this treatment in preference to medical therapy. Patient selection is best decided in a multidisciplinary team meeting including neurology/stroke physicians, and implanting and imaging cardiologists.

Systemic Embolisation

Paradoxical emboli are likely to present with ischaemic stroke, as the brain is exquisitely sensitive to ischaemia and also receives a large proportion of cardiac output. However, systemic embolisation to the limbs, gut and down the coronary arteries have been described.10,34–36 No randomised trial evidence exists to show that closure of PFO in the case of otherwise unexplained systemic embolisation is protective. However, closure would seem to be a reasonable strategy in select cases. For example, closure of PFO would be indicated in a young patient presenting with acute MI of embolic source, with otherwise unremarkable coronary arteries and an absence of risk factors for atherosclerosis or atrial fibrillation. The indications are similar to those for cryptogenic stroke. Importantly, care must be taken to exclude alternative causes, and this may require intravascular imaging, such as optical coherence tomography, to exclude plaque rupture in the coronary artery. Cardiac MRI is also recommended to confirm a pattern consistent with MI.

Randomised Trials Comparing Patent Foramen Ovale Closure with Medical Therapy

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Decompression Illness

Divers and high-altitude pilots, who rapidly transition from high- to low-pressure environments, may suffer from decompression illness. Sudden changes in pressure causes nitrogen bubbles to form within tissues and accumulate in the venous circulation. These bubbles are filtered from the bloodstream through pulmonary capillary diffusion, but if a return to low pressure (or ascent from depth for divers) is too rapid, then this pulmonary filtration process can be overwhelmed. Gas bubbles can enter the systemic arterial circulation.37 Bubbles continue to enlarge, causing tissue trauma and even vessel occlusion. There is a wide range of symptoms, from mild muscle and joint pain, dizziness, fatigue, headache, rash and paraesthesia, to severe breathing difficulties, confusion, motor incoordination and paralysis. A right-to-left shunt, such as a PFO, allows nitrogen bubbles to bypass the pulmonary filter, increasing the risk that usually safe ascents will cause systemic embolisation.

Diving profiles are usually designed to limit the time at depth, and slowly ascend towards the surface, minimising the risk of decompression illness. Occurence of decompression illines, despite use of safe dive profiles, implies an increased risk of right-to-left shunt. Investigation for atrial septal defect or PFO should be considered.38,39 A longitudinal, non-randomised follow-up study showed that PFO closure reduced both symptomatic neurological events and total brain lesions among recreational divers with PFO and decompression illness, compared with those who continued to dive without closure.40

A recent prospective registry evaluated 489 recreational divers for PFO using transcranial Doppler. This demonstrated that large PFO was a major independent risk factor for unprovoked decompression illness (HR 92; 95% CI [12.5-689]; p<0.001).41 A recent study noted that in a cohort of 59 divers with decompression illness and PFO closure, four continued to have decompression illness over the 10-year follow-up period. This was shown to be due to residual shunting, despite reported successful closure.42 Where a professional diver wishes to continue diving, PFO closure could be recommended. Alternatively, discontinuation of diving or curtailing provocative dive profiles should be considered. If diving is recreational, then the risk–benefit analysis for continued diving with a PFO closure is less clear, and certainly procedural risk should be carefully weighed against the benefits of continuing to dive.

Platypnoea–Orthodeoxia Syndrome

Platypnoea–orthodeoxia syndrome is a rare condition characterised by dyspnoea and positional desaturation in individuals with a PFO. In certain body positions, the geometry of the atrial septum is altered, allowing a continuous stream of deoxygenated blood from the inferior vena cava to flow across the PFO. Deoxygenation is typically seen when the patient is seated, but oxygen saturations normalise when the patient lies flat.43 The distortion of the atrial septal geometry can be caused by thoracic and cardiothoracic surgery, such as pneumonectomy, aortic dilatation and aortic surgery, or may not have an identifiable cause.

Regurgitant jets from the tricuspid valve can also be directed across the PFO. Underlying cavity pressures do not affect platypnoea–orthodeoxia syndrome, and it responds well to PFO closure so long as pulmonary artery pressures are not markedly elevated. This is not usually the case. A 54-patient case series demonstrated that percutaneous closure was safe and effective for platypnoea–orthodeoxia syndrome.44

Migraine with Aura

Migraine is common in young people. It is associated with aura in approximately one-third of cases.45,46 Migraine with aura has been associated with right-to-left shunts, such as PFO.47,48 Large shunts are particularly associated with migraine with aura.49 Transfer of a vasoactive substance, usually filtered by the pulmonary circulation into the systemic circulation, is the proposed mechanism for the relationship between migraine and PFO.47

A number of non-randomised studies reported improvement in patient symptoms after closure.50 In the Migraine Intervention With STARFlex Technology (MIST) trial, patients with refractory migraine with aura were randomised to either percutaneous PFO closure or a sham procedure. There was no difference in cessation of headache or reduction in headache-free days. However, the trial population had a relatively low frequency of migraine, and a high frequency of residual shunts after closure – this trial used the same prosthesis as the negative CLOSURE 1 stroke trial with similar issues. These confounders may have negatively influenced the trial result.51

More recently, the Percutaneous Closure of PFO in Migraine with Aura (PRIMA) and Prospective Randomised Investigation to Evaluate Incidence of Headache Reduction in Subjects With Migraine and PFO Using the Amplatzer PFO Occluder Compared With Medical Management (PREMIUM) trials have reported their results.52,53 Both studies were negative for their primary endpoints, although there were some reductions in headache. These effects were small and occurred at the expense of procedural complications. The evidence for PFO closure is not strong enough to offer a routine recommendation for PFO closure in migraine with aura.

The Patent Foramen Ovale Closure Procedure

Pre-procedure Investigations

As cryptogenic stroke is the most common indication for closure, an emphasis should be placed on investigation looking for alternative causes of stroke. Cross-sectional brain imaging should be undertaken to confirm the diagnosis of an embolic stroke. Lacunar strokes are unlikely to be embolic in nature.

AF is the most common source of thrombus, with studies suggesting that 13% of patients with AF have cardiac thrombus.54 In 90% of patients with non-valvular AF, the thrombus was located in the left atrial appendage.54 The presence of AF in the context of a stroke is an indication for anticoagulation, and closure of a PFO is not indicated.

No study has shown that closure of a PFO confers additional benefit. ECG monitoring is mandatory to exclude AF, and the duration depends upon the patient’s risk factors. We recommend in young patients (<50 years) with no risk factors, using a minimum of 72-hour ambulatory surface electrocardiographic recording, and in those aged >50 years, using 6 months of implantable loop recording. Implantable loop recording has the advantage of extended rhythm surveillance; however, it is prone to false positives and false negatives.55–57 Conclusive evidence for the best strategy to diagnose AF is lacking. The high burden of supraventricular ectopics on ambulatory ECG or enlarged atrial size increases the likelihood of AF, and may indicate that an implantable loop recording is required in a younger patient.

Carotid imaging should exclude significant carotid plaque disease. Screening for thrombophilia should be considered, but its complex nature with inconsistent results means repeated investigations are often required. Thrombophilia often predisposes to venous rather than arterial thrombosis. Interpretation of complex results can be difficult, and should be undertaken in conjunction with haematologists who have a special interest in thrombosis.

The first-line investigation to exclude intracardiac thrombus is transthoracic echocardiography. A number of conditions, apart from AF, are associated with cardiac thrombus, which could embolise to cause stroke. These include MI, left ventricular aneurysm, atrial myxoma, non-compaction cardiomyopathy, left ventricular failure and mitral stenosis. Prior to closure of PFO, these should all have been excluded as the potential source of the stroke.

A key investigation while working up patients with cryptogenic stroke is bubble contrast echocardiography. A PFO needs to produce a right-to-left shunt to cause a stroke. Bubble contrast studies are initially performed with transthoracic echocardiography, with no sedation necessary. Agitated saline is injected via a peripheral venous cannula (ideally placed in the lower body, but the left antecubital fossa is usually a more realistic option), while the patient releases a Valsalva manoeuvre or sniff. In the presence of a cardiac shunt, bubbles should appear in the left side of the heart within three to four cardiac cycles of arrival in the right atrium. Later appearance of bubbles may reflect a pulmonary shunt. The study should be performed by an experienced operator. The procedure may require multiple repeats to confirm the diagnosis. Figure 1 shows a bubble study with transmission of bubbles from right-to-left. Transcranial Doppler is a non-invasive alternative to a contrast echocardiogram. It is a reliable method of assessing for the presence of a right-to-left shunt, although it does not delineate the anatomy of the PFO.58,59

A positive transthoracic bubble study or transcranial Doppler study after a cryptogenic stroke indicates the need for detailed transoesophageal echocardiography (TOE). A further bubble study can be undertaken using TOE if required. This allows the structural heart team to accurately determine the anatomy of the PFO. Assessment of a PFO is shown in Figure 1. A TOE also allows the exclusion of alternative shunts, such as ventricular septal defects, anomalous pulmonary venous drainage or sinus venosus defects. A detailed guide to TOE assessment of PFO is outside the scope of this review, and is well reviewed elsewhere.60

The Patent Foramen Ovale Closure Procedure

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Multiple specialties (including stroke physicians or neurologists, cardiac imaging specialists, radiologists and interventional cardiologists) are involved in diagnosis and treatment decisions for cryptogenic stroke with PFO. Investigation should be considered in a multidisciplinary setting, with a holistic approach to the management of the patient.

The Closure Procedure

Closure is performed as a day case procedure in many centres. The procedure can be undertaken in a standard catheter laboratory using fluoroscopic guidance and physiological monitoring. Patients undergoing this procedure will have a reduced long-term risk of stroke, but obtain no immediate symptomatic benefit from this procedure. Therefore, all possible steps to reduce complications should be taken.

In the opinion of the authors, the procedure should be, as far as possible, complication-free, because even a small complication rate is likely to neutralise the benefit over optimal medical therapy. Ultrasound-guided femoral venous access, echocardiographic guidance, adequate anticoagulation and special care to reduce the risk of air embolus are all important to ensure this goal.

Periprocedural guidance with TOE or intracardiac echocardiography is mandatory, in the opinion of the authors, to consistently achieve the best result.61,62 Furthermore, it is considered mandatory within commissioning guidelines in the UK, and recommended in the Society for Cardiovascular Angiography and Interventions 2019 consensus statement.63,64

Although the procedure can be undertaken by very experienced operators with fluoroscopy alone, echocardiographic guidance allows evaluation of interatrial septal anatomy, direct visualisation of the device position, and the relationship with aortic and mitral valves before device release. General anaesthesia is generally required to facilitate TOE, which may increase the cost and length of the procedure.

The procedure is undertaken from the femoral vein with ultrasound guidance for the puncture. Adequate anticoagulation (unfractionated heparin 80–100 IU/kg) should be administered. A 6-Fr multipurpose diagnostic catheter and a 0.035" J-tipped guidewire is used to cross the PFO and is passed into a pulmonary vein (usually the left upper pulmonary vein). This can then be exchanged for a stiff wire to assist delivery of balloons.

Devices Approved for Patent Foramen Ovale Closure

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Sizing of the PFO can be undertaken both before and after crossing with the wire, which may result in the PFO tunnel widening and shortening. Three-dimensional imaging software can be used to determine the maximum left and right atrial opening and minimum tunnel length. Balloon sizing of the PFO is usually not required, but can be performed using quantitative angiographic tools, and confirmed with TOE or intracardiac echocardiography. A left anterior oblique cranial fluoroscopic projection may assist with this, as the septum is seen in profile. Compliant balloons with marked graduations are used, but balloon sizing can still shorten and widen the PFO. Shortening may be desirable if there is a particularly long PFO tunnel, but this can increase the size of the hole, necessitating a larger device. Factors that predispose to a larger device include PFO tunnel length, the presence of atrial septal aneurysm and male sex.65 Precise sizing will depend upon the choice of device used.

Once sizing is completed, an appropriate device (with delivery sheath) can be passed into the left atrium through the PFO. The left atrial disc is deployed, followed by the right disc. Ensuring that the delivery sheath remains de-aired and flushed throughout the procedure minimises the risk of air or thrombotic embolism. After the device is deployed, confirmation of the adequate position with echocardiography and fluoroscopy should be performed prior to device release. If the device is malpositioned after release, a large gooseneck snare can be used to recover the device. The steps involved in a PFO closure procedure are shown in Figure 2.

Evidence for antiplatelet therapy after device deployment remains incomplete. Device thrombosis remains a feared complication of PFO closure. In our practice, aspirin and clopidogrel are usually given for 6 months, but evidence for this is limited and practice varied markedly between trials. Earlier discontinuation of dual antiplatelet therapy was associated with an increased frequency of minor cerebrovascular events in a study level meta-analysis of PFO closure trials.66 Long-term observation studies have suggested this is a safe practice.33

Some operators preload patients with antiplatelets, but again, the evidence for this is uncertain. Single antiplatelet therapy, usually clopidogrel 75 mg daily, is continued indefinitely, as the device may take up to 5 years to endothelialise. The European Association for Percutaneous Cardiovascular Interventions consensus statement recommends this approach at present.66

Follow-up is important, but uncertainty remains about the appropriate timeframe. As most devices endothelialise over a period of approximately 6 months, then a repeat bubble study could be considered at that stage. Timing is of particular relevance where the PFO has been closed for occupational reasons, such as professional diving.

Closure Devices

A large number of devices with varying shape and size have been marketed. Many have received CE mark status in the EU. In the US, fewer devices have been approved by the Food and Drug Administration, due to the need for randomised evidence prior to approval.

Most devices are of double-disc design, connected by a short waist. The Gore Septal Occluder (WL Gore and Associates) and the Amplatzer PFO Occluder (Abbott Vascular) are two of the more commonly used devices and are shown in Figure 3. The Gore Septal Occluder is constructed from five nitinol wires covered with expanded polytetrafluoroethylene.67 Early clinical experience has shown that it is a versatile device with easy deployment, high procedural success and low complication rates.68,69 The Amplatzer PFO Occluder is also a nitinol-based device. This device has been used most commonly in randomised clinical trials. The evidence base for its use is therefore very strong.21,22 There are numerous other commercially available devices, including the Occlutech PFO occluder (Occlutech International) and Ultrasept (Cardia), plus suture-based technologies, such as NobleStitch (HeartStitch).

Future Directions

There are a number of outstanding research questions regarding PFO closure that need to be answered. First, the optimal antiplatelet or anticoagulation regimen balancing the risk of recurrent stroke or embolism against the risk of bleeding needs to be established. Current guidance is based on consensus statements and the strategies adopted in the clinical trials mentioned earlier. Meta-analyses have not shown any clear additional benefit for anticoagulation when PFO is not closed after stroke.70 Further studies evaluating the benefit of anticoagulation and optimal duration of dual antiplatelet therapy would be welcome. Simplification of the procedure with the use of non-invasive echocardiography may be attractive, but is not recommended in consensus statements.64 A clinical trial to establish the safety and efficacy of a fluoroscopic approach with transthoracic echocardiography support is currently underway (NCT03828825).

Identification of a high risk of PFO-associated stroke prior to the first stroke remains the golden ticket. Some have published studies with scoring systems to identify high-risk PFO, but these have not identified patients prior to cryptogenic stroke, when the PFO is usually silent.71 Patients with inherited thrombophilia found to have PFO may be candidates for prophylactic PFO closure. Observational studies have suggested that those in this group who have a PFO closure have a reduced incidence of stroke or transient ischaemic attack.72 Randomised trials to assess whether this group would benefit are needed, but will be challenging to recruit, given the relatively small numbers of patients in this group.

A recent observational study of patients undergoing surgery found a significantly higher incidence of ischemic stroke over a 1-year period in those with PFO.73 This risk was mitigated for those receiving dual antiplatelet therapy or anticoagulation, or those who had undergone PFO closure. These observational data are hypothesis generating, but suggest that there may be a population that could be identified to benefit from upfront closure, but further well-designed clinical trials would be required to justify this against the procedural risk.

Furthermore, there are limited data to support differences in treatment by subgroup. A meta-analysis of trials reporting outcome by sex (RESPECT, REDUCE, CLOSURE 1) suggested that there was a significant reduction in men, and a non-significant numeral reduction in stroke for women. The majority of patients treated in these studies were men. Further work is required to identify whether there are meaningful differences in these groups. Similarly, differences between ethnic groups could also be examined.

Finally, expansion to other indications, particularly for migraine relief requires a better quality of evidence. The planned GORE CARDIOFORM Septal Occluder Migraine Clinical Study (RELIEF study) is a sham randomised controlled trial of PFO closure for migraine relief with recruitment due to start in 2020. A sham procedure is important to tease out the strong placebo effect associated with migraine studies (NCT04100135).

Conclusion

In this review, the main indications for PFO closure have been discussed (cryptogenic stroke, paradoxical systemic embolisation, platypnoea–orthodeoxia syndrome and decompression illness), together with the strengthening evidence for closure. The skills required for this procedure need to be learnt with the assistance of experienced interventional cardiologists who can proctor and advise those starting out with PFO closure. Attention to detail in the indication for the procedure, and minimising the risks to the patient during the closure are key to an effective PFO closure service.

References

  1. Calvert PA, Rana BS, Kydd AC, Shapiro LM. Patent foramen ovale: anatomy, outcomes, and closure. Nat Rev Cardiol 2011;8:148–60.
    Crossref | PubMed
  2. Handke M, Harloff A, Olschewski M, et al. Patent foramen ovale and cryptogenic stroke in older patients. N Engl J Med 2007;357:2262–8.
    Crossref | PubMed
  3. Adams HPJ, 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;24:35–41.
    Crossref | PubMed
  4. Hart RG, Diener -C, Coutts SB, et al. Embolic strokes of undetermined source: the case for a new clinical construct. Lancet Neurol 2014;13:429–38.
    Crossref | PubMed
  5. Zaman MO, Mojaddedi S, Nietlispach F, et al. PFO-mediated stroke: exposing the misnomer of “cryptogenic” stroke. Am J Cardiol 2019;123:2059–60.
    Crossref | PubMed
  6. Ntaios G. Embolic stroke of undetermined source. J Am Coll Cardiol 2020;75:333–40.
    Crossref | PubMed
  7. Zahn FW. Thrombosis of several branches of the inferior vena cava with consecutive emboli in the pulmonary, splenic, renal and right iliac arteries. Rev Méd de la Suisse Rom 1881;1:227–37 [in French].
  8. Choong CK, Calvert PA, Falter F, et al. Life-threatening impending paradoxical embolus caught “red-handed”: successful management by multidisciplinary team approach. J Thorac Cardiovasc Surg 2008;136:527–8.e8.
    Crossref | PubMed
  9. Madani H, Ransom PA. Paradoxical embolus illustrating speed of action of recombinant tissue plasminogen activator in massive pulmonary embolism. Emerg Med J 2007;24:441.
    Crossref | PubMed
  10. Kim RJ, Girardi LN. “Lots of clots”: multiple thromboemboli including a huge paradoxical embolus in a 29-year old man.
    Int J Cardiol 2008;129:e50–2.
    Crossref | PubMed
  11. Cramer SC, Rordorf G, Maki JH, et al. Increased pelvic vein thrombi in cryptogenic stroke: results of the Paradoxical Emboli from Large Veins in Ischemic Stroke (PELVIS) study. Stroke 2004;35:46–50.
    Crossref | PubMed
  12. Furlan AJ, Reisman M, Massaro J, et al. Closure or medical therapy for cryptogenic stroke with patent foramen ovale. N Engl J Med 2012;366:991–9.
    Crossref | PubMed
  13. Meier B, Kalesan B, Mattle HP, et al. Percutaneous closure of patent foramen ovale in cryptogenic embolism. N Engl J Med 2013;368:1083–91.
    Crossref | PubMed
  14. Messe SR, Kent DM. Still no closure on the question of PFO closure. N Engl J Med 2013;368:1152–3.
    Crossref | PubMed
  15. Thaler DE, Wahl A. Critique of closure or medical therapy for cryptogenic stroke with patent foramen ovale: the hole truth? Stroke 2012;43:3147-9.
    Crossref | PubMed
  16. Meier B. Closure of the patent foramen ovale with dedicated Amplatzer occluders: closing in on a mechanical vaccination. Catheter Cardiovasc Interv 2008;72:80–1.
    Crossref | PubMed
  17. Nietlispach F, Meier B. Percutaneous closure of patent foramen ovale: an underutilized prevention? Eur Heart J 2016;37:2023–8.
    Crossref | PubMed
  18. Carroll JD, Saver JL, Thaler DE, et al. Closure of patent foramen ovale versus medical therapy after cryptogenic stroke. N Engl J Med 2013;368:1092–100.
    Crossref | PubMed
  19. 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;377:1022–32.
    Crossref | PubMed
  20. 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.
    Crossref | PubMed
  21. 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;71:2335–42.
    Crossref | PubMed
  22. Mas JL, Derumeaux G, Guillon B, et al. Patent foramen ovale closure or anticoagulation vs. antiplatelets after stroke. N Engl J Med 2017;377:1011–21.
    Crossref | PubMed
  23. Turc G, Calvet D, Guerin P, et al. Closure, anticoagulation, or antiplatelet therapy for cryptogenic stroke with patent foramen ovale: systematic review of randomized trials, sequential meta-analysis, and new insights from the CLOSE study. J Am Heart Assoc 2018;7:e008356.
    Crossref | PubMed
  24. Abo-Salem E, Chaitman B, Helmy T, et al. Patent foramen ovale closure versus medical therapy in cases with cryptogenic stroke, meta-analysis of randomized controlled trials. J Neurol 2018;265:578–85.
    Crossref | PubMed
  25. Darmoch F, Al-Khadra Y, Soud M, et al. Transcatheter closure of patent foramen ovale versus medical therapy after cryptogenic stroke: a meta-analysis of randomized controlled trials. Cerebrovasc Dis 2018;45:162–9.
    Crossref | PubMed
  26. Elgendy AY, Elgendy IY, Mojadidi MK, et al. New-onset atrial fibrillation following percutaneous patent foramen ovale closure: a systematic review and meta-analysis of randomised trials. EuroIntervention 2019;14:1788–90.
    Crossref | PubMed
  27. Ha FJ, Adams H, Palmer S. Device closure for patent foramen ovale in patients with cryptogenic stroke: a paradigm in evidence. Med J Aust 2019;211:343.
    Crossref | PubMed
  28. Wahl A. Jüni P. Mono M-L. et al. Long-term propensity score-matched comparison of percutaneous closure of patent foramen ovale with medical treatment after paradoxical embolism. Circulation 2012;125:803–12.
    Crossref | PubMed
  29. Schulze V, Lin Y, Karathanos A, et al. Patent foramen ovale closure or medical therapy for cryptogenic ischemic stroke: an updated meta-analysis of randomized controlled trials. Clin Res Cardiol 2018;107:745–55.
    Crossref | PubMed
  30. Volpi JJ, Ridge JR, Nakum M, et al. Cost-effectiveness of percutaneous closure of a patent foramen ovale compared with medical management in patients with a cryptogenic stroke: from the US payer perspective. J Med Econ 2019:1–8.
    Crossref | PubMed
  31. Leppert MH, Poisson SN, Carroll JD, et al. Cost-effectiveness of patent foramen ovale closure versus medical therapy for secondary stroke prevention. Stroke 2018;49:1443–50.
    Crossref | PubMed
  32. Hildick-Smith D, Turner M, Shaw L, et al. Evaluating the cost-effectiveness of percutaneous closure of a patent foramen ovale versus medical management in patients with a cryptogenic stroke: from the UK payer perspective. J Med Econ 2019;22:131–9.
    Crossref | PubMed
  33. Wintzer-Wehekind J, Alperi A, Houde C, et al. Long-term follow-up after closure of patent foramen ovale in patients with cryptogenic embolism. J Am Coll Cardiol 2019;73:278–87.
    Crossref | PubMed
  34. Ahmed S, Sadiq A, Siddiqui AK, et al. Paradoxical arterial emboli causing acute limb ischemia in a patient with essential thrombocytosis. Am J Med Sci 2003;326:156–8.
    Crossref | PubMed
  35. Kleber FX, Hauschild T, Schulz A, et al. Epidemiology of myocardial infarction caused by presumed paradoxical embolism via a patent foramen ovale. Circ J 2017;81:1484–9.
    Crossref | PubMed
  36. Pavoni D, Zanuttini D, Spedicato L, et al. Large interatrial thrombus-in-transit resulting in acute myocardial infarction complicated by atrioventricular block and cardiogenic shock. J Am Coll Cardiol 2012;59:1329.
    Crossref | PubMed
  37. Butler BD, Hills BA. The lung as a filter for microbubbles. J Appl Physiol Respir Env Exerc Physiol 1979;47:537–43.
    Crossref | PubMed
  38. Wilmshurst PT, Byrne JC, Webb-Peploe MM. Relation between interatrial shunts and decompression sickness in divers. Lancet 1989;2:1302–6.
    Crossref | PubMed
  39. Torti SR, Billinger M, Schwerzmann M, et al. Risk of decompression illness among 230 divers in relation to the presence and size of patent foramen ovale. Eur Hear J 2004;25:1014–20.
    Crossref | PubMed
  40. Billinger M, Zbinden R, Mordasini R, et al. Patent foramen ovale closure in recreational divers: effect on decompression illness and ischaemic brain lesions during long-term follow-up. Heart 2011;97:1932–7.
    Crossref | PubMed
  41. Honeˇk J, Šrámek M, Šefc L, et al. High-grade patent foramen ovale is a risk factor of unprovoked decompression sickness in recreational divers. J Cardiol 2019;74:519–23.
    Crossref | PubMed
  42. Vanden Eede M, Van Berendoncks A, De Wolfe D, et al. Percutaneous closure of patent foramen ovale for the secondary prevention of decompression illness in sports divers: mind the gap. Undersea Hyperb Med 2019;46:625–32.
    PubMed
  43. Godart F, Rey C, Prat A, et al. Atrial right-to-left shunting causing severe hypoxaemia despite normal right-sided pressures. Report of 11 consecutive cases corrected by percutaneous closure. Eur Hear J 2000;21:483–9.
    Crossref | PubMed
  44. Shah AH, Osten M, Leventhal A, et al. Percutaneous intervention to treat platypnea-orthodeoxia syndrome: the Toronto experience. JACC Cardiovasc Interv 2016;9:1928–38.
    Crossref | PubMed
  45. Burch RC, Loder S, Loder E, et al The prevalence and burden of migraine and severe headache in the United States: updated statistics from government health surveillance studies. Headache 2015;55:21–34.
    Crossref | PubMed
  46. Lipton RB, Liberman JN, Kolodner KB, et al. Migraine headache disability and health-related quality-of-life: a population-based case-control study from England. Cephalalgia 2003;23:441–50.
    Crossref | PubMed
  47. Finocchi C, Del Sette M. Migraine with aura and patent foramen ovale: myth or reality? Neurol Sci 2015;36(Suppl 1):61–6.
    Crossref | PubMed
  48. Schwerzmann M, Nedeltchev K, Lagger F, et al. Prevalence and size of directly detected patent foramen ovale in migraine with aura. Neurology 2005;65:1415–8.
    Crossref | PubMed
  49. Anzola GP, Morandi E, Casilli F, et al. Different degrees of right-to-left shunting predict migraine and stroke: data from 420 patients. Neurology 2006;66:765–7.
    Crossref | PubMed
  50. Butera G, Biondi-Zoccai GG, Carminati M, et al. Systematic review and meta-analysis of currently available clinical evidence on migraine and patent foramen ovale percutaneous closure: much ado about nothing? Catheter Cardiovasc Interv 2010;75:494–504.
    Crossref | PubMed
  51. Dowson A., Mullen MJ., Peatfield R., et al. Migraine Intervention with STARFlex Technology (MIST) trial: a prospective, multicenter, double-blind, sham-controlled trial to evaluate the effectiveness of patent foramen ovale closure with STARFlex septal repair implant to resolve refractory migraine headache. Circulation 2008;117:1397–404.
    Crossref | PubMed
  52. Mattle HP, Evers S, Hildick-Smith D, et al. Percutaneous closure of patent foramen ovale in migraine with aura, a randomized controlled trial. Eur Hear J 2016;37:2029–36.
    Crossref | PubMed
  53. Tobis JM, Charles A, Silberstein SD, et al. Percutaneous closure of patent foramen ovale in patients with migraine: the PREMIUM trial. J Am Coll Cardiol 2017;70:2766–74.
    Crossref | PubMed
  54. Blackshear JL, Odell JA. Appendage obliteration to reduce stroke in cardiac surgical patients with atrial fibrillation. Ann Thorac Surg 1996;61:755–9.
    Crossref | PubMed
  55. Cotter PE, Martin PJ, Ring L, et al. Incidence of atrial fibrillation detected by implantable loop recorders in unexplained stroke. Neurology 2013;80:1546–50.
    Crossref | PubMed
  56. Sanna T, Diener HC, Passman RS, et al. Cryptogenic stroke and underlying atrial fibrillation. N Engl J Med 2014;370:2478–86.
    Crossref | PubMed
  57. Podd SJ, Sugihara C, Furniss SS, et al. Are implantable cardiac monitors the “gold standard” for atrial fibrillation detection? A prospective randomized trial comparing atrial fibrillation monitoring using implantable cardiac monitors and DDDRP permanent pacemakers in post atrial fibrillation ablation patients. Europace 2016;18:1000–5.
    Crossref | PubMed
  58. Nemec JJ, Marwick TH, Lorig RJ, et al. Comparison of transcranial Doppler ultrasound and transesophageal contrast echocardiography in the detection of interatrial right-to-left shunts. Am J Cardiol 1991;68:1498–502.
    Crossref | PubMed
  59. Mojadidi MK, Roberts SC, Winoker JS, et al. Accuracy of transcranial Doppler for the diagnosis of intracardiac right-to-left shunt: a bivariate meta-analysis of prospective studies. JACC Cardiovasc Imaging 2014;7:236–50.
    Crossref | PubMed
  60. Rana BS, Thomas MR, Calvert PA, et al. Echocardiographic evaluation of patent foramen ovale prior to device closure. JACC Cardiovasc Imaging 2010;3:749–60.
    Crossref | PubMed
  61. Yared K, Baggish AL, Solis J, et al. Echocardiographic assessment of percutaneous patent foramen ovale and atrial septal defect closure complications. Circ Cardiovasc Imaging 2009;2:141–9.
    Crossref | PubMed
  62. Bechis MZ, Rubenson DS, Price MJ. Imaging assessment of the interatrial septum for transcatheter atrial septal defect and patent foramen ovale closure. Interv Cardiol Clin 2017;6:505–24.
    Crossref | PubMed
  63. NHS England. Clinical Commissioning Policy: Percutaneous patent foramen ovale closure for the prevention of recurrent cerebral embolic stroke in adults (around the age 60 years and under). NHS England: 2019. https://www.england.nhs.uk/commissioning/wp-content/uploads/sites/12/201... (accessed 21 October 2020).
  64. Horlick E, Kavinsky CJ, Amin Z, et al. SCAI expert consensus statement on operator and institutional requirements for PFO closure for secondary prevention of paradoxical embolic stroke. Catheter Cardiovasc Interv 2019;93:859–74.
    Crossref | PubMed
  65. Venturini JM, Retzer EM, Estrada JR, et al. A practical scoring system to select optimally sized devices for percutaneous patent foramen ovale closure. J Struct Hear Dis 2016;2:217–23.
    Crossref | PubMed
  66. Pristipino C, Sievert H, D’Ascenzo F, et al. European position paper on the management of patients with patent foramen ovale. General approach and left circulation thromboembolism. Eur Heart J 2019;40:3182–95.
    Crossref | PubMed
  67. Sondergaard L, Loh PH, Franzen O, et al. The first clinical experience with the new GORE® septal occluder (GSO). EuroIntervention 2013;9:959–63.
    Crossref | PubMed
  68. MacDonald ST, Daniels MJ, Ormerod OJ. Initial use of the new GORE® septal occluder in patent foramen ovale closure: implantation and preliminary results. Catheter Cardiovasc Interv 2013;81:660–5.
    Crossref | PubMed
  69. Hardt SE, Eicken A, Berger F, et al. Closure of patent foramen ovale defects using GORE® CARDIOFORM septal occluder: results from a prospective European multicenter study. Catheter Cardiovasc Interv 2017;90:824–9.
    Crossref | PubMed
  70. Romoli M, Giannandrea D, Eusebi P, et al. Aspirin or anticoagulation after cryptogenic stroke with patent foramen ovale: systematic review and meta-analysis of randomized controlled trials. Neurol Sci 2020:1–6.
    Crossref | PubMed
  71. Nakayama R, Takaya Y, Akagi T, et al. Identification of high-risk patent foramen ovale associated with cryptogenic stroke: development of a scoring system. J Am Soc Echocardiogr 2019;32:811–6.
    Crossref | PubMed
  72. Buber Y, Orion D, Borik S, et al. Percutaneous closure of patent foramen ovale is associated with lower incidence cryptogenic strokes among patients with inherited thrombophialias treated with anticoagulant or antiaggregant therapy. J Am Coll Cardiol 2017;69(Suppl):962.
    PubMed
  73. Friedrich S, Ng PY, Platzbecker K, et al. Patent foramen ovale and long-term risk of ischaemic stroke after surgery. Eur Heart J 2019;40:914–24.
    Crossref | PubMed