|Year : 2015 | Volume
| Issue : 2 | Page : 46-53
How to understand patent foramen ovale clinical significance - Part II: Therapeutic strategies in cryptogenic stroke
Gabriella Falanga1, Scipione Carerj1, Giuseppe Oreto1, Bijoy Khandheria2, Concetta Zito1
1 Cardiology Unit, Department of Clinical and Experimental Medicine, University Hospital Policlinico G. Martino, Messina, USA
2 Aurora Sinai/Aurora St. Luke's Medical Centers, University of Wisconsin, School of Medicine and Public Health, Milwaukee, WI 53215, USA
|Date of Web Publication||30-Jul-2015|
Cardiology Unit, Department of Clinical and Experimental Medicine, University Hospital Policlinico G. Martino, Messina
Source of Support: None, Conflict of Interest: None
In the first part of this review, we reminded that patent foramen ovale (PFO) is a slit or tunnel-like passage in the interatrial septum occurring in approximately 25% of the population and that a number of conditions have been linked to its presence, the most important being cryptogenic stroke (CS) and migraine. We have also shown how, in the setting of neurological events, it is not often clear whether the PFO is pathogenically-related to the index event or an incidental finding, and therefore we thought to provide some useful key points for understanding PFO clinical significance in a case by case evaluation. The controversy about PFO pathogenicity has consequently prompted a paradigm shift of research interest from medical therapy with antiplatelets or anticoagulants to percutaneous transcatheter closure, in secondary prevention. Observational data and meta-analysis of observational studies previously suggested that PFO closure with a device was a safe procedure with a low recurrence rate of stroke, as compared to medical therapy. However, so far, published randomized controlled trials (CLOSURE I ® , RESPECT ® and PC Trial ® ) have not shown the superiority of PFO closure over medical therapy. Thus, the optimal strategy for secondary prevention of paradoxical embolism in patients with a PFO remains unclear. Moreover, the latest guidelines for the prevention on stroke restricted indications for PFO closure to patients with deep vein thrombosis and high-risk of its recurrence. Given these recent data, in the second part of the present review, we aim to discuss today treatment options in patients with PFO and CS, providing an updating on patients' management.
Keywords: Cryptogenic stroke, medical therapy, patent foramen ovale, percutaneous transcatheter closure
|How to cite this article:|
Falanga G, Carerj S, Oreto G, Khandheria B, Zito C. How to understand patent foramen ovale clinical significance - Part II: Therapeutic strategies in cryptogenic stroke. J Cardiovasc Echography 2015;25:46-53
|How to cite this URL:|
Falanga G, Carerj S, Oreto G, Khandheria B, Zito C. How to understand patent foramen ovale clinical significance - Part II: Therapeutic strategies in cryptogenic stroke. J Cardiovasc Echography [serial online] 2015 [cited 2021 Jan 16];25:46-53. Available from: https://www.jcecho.org/text.asp?2015/25/2/46/161779
| Introduction|| |
Stroke is among the leading causes of mortality and serious long-term disability,  with an estimated cost in terms of healthcare services, medication, and missed days of work being $38.6 billion each year in the United States alone.  Around 25% of all strokes are cryptogenic, and this reaches approximately 50% in the younger age group. 
Epidemiologic data reveal significant association between patent foramen ovale (PFO) and cryptogenic stroke (CS) both in the younger and older patient populations. , Despite medical therapy, the rate of stroke recurrence in patients with PFO is estimated to be 25% within a 4-year period. , Therefore, since the last 10 years, there has been significant interest in percutaneous closure of PFO as a potential therapeutic option. Observational data and meta-analysis of observational studies suggested that percutaneous transcatheter closure of PFO was safe and had a low recurrence rate of stroke as compared to medical therapy. ,, Thus, many physicians advised PFO closure in patients who have had CS (secondary prevention), especially in those younger. Nevertheless, recent published randomized controlled studies (RCTs) have not shown the superiority of PFO closure over medical therapy. ,, As a result, the latest guidelines for the prevention on stroke restricted indications for PFO closure to patients with deep vein thrombosis (DVT) and high-risk of its recurrence. 
| Current evidences on patent foramen ovale treatment: Who, how and when|| |
Prior to discuss for whatever strategy is better in a patient with CS and evidence of a PFO, it is very important to have some knowledge about the risk of recurrent CS, since only patients in secondary prevention could have a benefit from any therapy. The risk of recurrent CS with no form of treatment is approximately 6-8% annually (with or without a PFO). With either medical treatment or PFO closure, the annual risk decreases to approximately 2-4%. That recurrences are not completely eliminated with either approach should not be surprising since CS undoubtedly has multiple, as yet unidentified, potential etiologies and PFO may be only one of these. However, PFO is discovered in only about 50% of CS patients. Moreover, about 20% of patients who have CS from unrelated causes are expected to have a PFO based on the incidence of PFO in the general population. The real question therefore is whether medical treatment, closure of the PFO or a combination of both approaches will be superior in terms of stroke prevention, costs, and tolerance in patients with a previous CS and anatomical and clinical risk factors of recurrent CS, as previously discussed. ,
| Medical treatment|| |
Patients with PFO and CS are at risk for recurrence of cerebrovascular events, although estimates are variable. A recent meta-analysis of observational studies reported an annual incidence rate of 2.53 events (95% confidence interval [CI]: 1.91-3.35) per 100 person-years (PYs) among patients receiving medical therapy.  This overall rate was similar to the rate from the subset of studies examining outcomes in people aged <60 years (incidence rate, 2.30; 95% CI: 1.43-3.68).
In recently completed clinical trials of PFO closure compared with medical therapy, the rate of recurrent ischemic stroke among medically treated participants has ranged from 0.6% to 1.5% per year. ,,
The 2011 American Heart Association/American Stroke Association (AHA/ASA) guidelines stated that antiplatelet therapy was reasonable for patients with an ischemic stroke or transient ischemic attack (TIA) and a PFO, and that oral anticoagulation was reasonable for high-risk patients who had other risk factors, such as a hypercoagulable state.
The 2012 American College of Chest Physicians (ACCP) guidelines recommended antiplatelet therapy for patients with CS and a PFO and stated that anticoagulation was not indicated. However, for patients who experienced recurrent events despite aspirin therapy, the ACCP guidelines suggested treatment with Vitamin K antagonist (VKA) therapy and consideration of PFO closure over aspirin. Moreover, for patients with CS and PFO who had evidence of DVT, the ACCP guidelines recommended VKA therapy for 3 months and consideration of PFO closure over no VKA or aspirin therapy. 
However, the optimal medical therapy for prevention of recurrent CS is unknown, to date. The trial Warfarin-Aspirin Recurrent Stroke Study (WARSS) was the first randomized study to compare the effect of warfarin and aspirin after prior not cardioembolic ischemic stroke. This study showed that aspirin was as good as warfarin in the prevention of stroke recurrence, but the presence of PFO was not specifically and systematically evaluated.  The trial PFO in CS study (PICCS) was a 42-center study that evaluated transesophageal echocardiographic findings in patients randomly assigned to warfarin or aspirin.  In this study, 630 stroke patients were enrolled; of whom 312 (49.5%) were randomized to warfarin and 318 (50.5%) to aspirin. Of these, 265 patients experienced CS and 365 experienced known stroke subtypes. Endpoints were recurrent ischemic stroke or death. A PFO was present in 203 patients (33.8%). There was no significant difference in the time to primary end points between those with and those without PFO in the overall population (hazard ratio [HR] = 0.96; 95% CI: 0.62-1.48; 2-year event rates = 14.8% vs. 15.4%; P = 0.84) or in the CS subset (HR = 1.17; 95% CI: 0.60-2.37; 2-year event rates = 14.3% vs. 12.7%; P = 0.65). Moreover, there was no significant difference among those with no, small, or large PFO (P = 0.41 for small PFO and P = 0.16 for large PFO; 2-year event rates for no, small, and large PFO: 15.4%, 18.5%, and 9.5%, respectively). There was no significant difference between patients with isolated PFO and those with PFO associated with an atrial septal aneurysm (2-year event rates = 14.5% vs. 15.9%; P = 0.84). Finally, in patients with PFO, there was no significant difference in the time to primary end points between those treated with warfarin and those treated with aspirin (HR = 1.29; 95% CI: 0.63-2.64; 2-year event rates 16.5% vs. 13.2%; P = 0.49). In conclusion, the PICCS study demonstrated that, on medical therapy, the presence of PFO in stroke patients did not increase the chance of adverse events regardless of PFO size or the presence of atrial septal aneurysm. 
Furthermore, no RCTs have been conducted to assess the safety and efficacy of medical therapy in the secondary prevention of CS in patients with PFO, therefore no drug therapy can be considered as a "gold standard." Latest AHA/ASA guidelines  state that:
Moreover, we agree that medical therapy may be, nowadays, encouraged as preferable therapeutic option in patients with a first cryptogenic event without anatomical and/or clinical risk factors for CS recurrence. 
- There are insufficient data to establish whether anticoagulation is equivalent or superior to aspirin for secondary stroke prevention in patients with PFO, Class IIb, level of evidence B.
- For patients with an ischemic stroke or TIA and a PFO who are not undergoing anticoagulation therapy, antiplatelet therapy is recommended, Class I, level of evidence B (Class changed from II a to I).
- For patients with an ischemic stroke or TIA and both a PFO and a venous source of embolism, anticoagulation is indicated, depending on stroke characteristics, Class I, level of evidence A.
- When anticoagulation is contraindicated, an inferior vena cava filter is reasonable, Class IIa, level of evidence C (new recommendation).
| Percutaneous closure|| |
Primary surgical PFO closure has currently more or less died out with the development of devices for percutaneous closure. Patients undergoing cardiac surgery for other indications may have an incidental PFO discovered at the time of surgery, and a recent study suggests that the closure of incidental PFO in these circumstances may actually increase postoperative stroke risk. 
In 2006, the AHA/ASA and European guidelines (European stroke organization) specifically mentioned that there were insufficient data to put recommendations for PFO closure in patients with a first cerebral ischemic event, and PFO closure might be considered for patients with recurrent CS despite medical therapy (Class IIb, level of evidence C). ,
The following guidelines (AHA/ASA 2011), compared to previous, just did not define clear recommendations.  The lack of clarity regarding the role of PFO device closure for secondary prevention of CS has been the subject of debate in an advisory statement from the AHA/ASA joint with the American College of Cardiology foundation that strongly advocated referral of suitable patients for inclusion in one of several randomized trials.  On the other hand, previous nonblinded and nonrandomized interventional studies of percutaneous PFO closure were suggesting benefits of PFO closure on recurrent CS ,, and refractory migraine as well. ,,, However, following RCTs have not confirmed this positive effect.,,, Thus, a significant controversy characterized the optimal strategy for treatment of CS and coexistent PFO until a few years ago. In details, in 2012, a meta-analysis of observational studies comparing the rate of recurrent neurological events (RNE) between transcatheter closure and medical management of patients with CS/TIA and concomitant PFO showed that adjusted incidence rates of RNE were 0.8 (95% CI: 0.5-1.1) events and 5.0 (95% CI: 3.6-6.9) events/100 PYs in the transcatheter closure and medical management arm, respectively. Meta-analysis of the limited number of comparative studies and meta-regression analysis suggested that the transcatheter closure might be superior to medical therapy in the prevention of RNE after CS. Comparison of the anticoagulation and antiplatelet therapy subgroups of the medical arm yielded a significantly lower risk of RNE within patients treated with anticoagulants. Device-related complications were encountered at the rate of 4.1 (95% CI: 3.2-5.0) events/100 PYs, with atrial arrhythmias being the most frequent complication. Moreover, after transcatheter closure, RNE did not seem to be related to the pretreatment shunt size or the presence of residual shunting in the follow-up period. Significant benefit of transcatheter PFO closure was apparent in elderly patients, in patients with concomitant atrial septal aneurysm, and in those with thrombophilia.  These findings were, therefore, indicative for a benefit from PFO closure in secondary prevention and strongly pushed this treatment option over medical therapy.
Nonetheless, data from the three recently published RCTs (CLOSURE I ® , PC Trial ® and RESPECT ® ) ,, did not confirm the superiority of percutaneous intervention versus optimal medical therapy, with an additional higher incidence of recurrent atrial fibrillation (AF) and device-related thrombotic complications, therefore making this practice questionable [Table 1].
|Table 1: Clinical trials on PFO closure versus medical therapy to prevent recurrent cryptogenic stroke |
Click here to view
In the first trial, CLOSURE I ® (evaluation of the STARFlex Septal Closure System in patients with a stroke and/or TIA due to presumed paradoxical embolism through a PFO), 447 patients aged <60 years with CS or TIA and PFO (with or without atrial septal aneurysm) were randomized to PFO closure through the STARFlex device (NMT Medical Inc., Las Vegas, Nevada) and subsequent medical therapy with aspirin plus clopidogrel for 6 months, while 462 patients were randomized to medical therapy with aspirin, Warfarin or a combination of these, for 24 months. The study, designed to assess the superiority of one of the treatments, failed to show any benefit of PFO closure. There was no statistically significant difference in the primary endpoint (2 years incidence of stroke and TIA, all-cause mortality at 30 days, mortality from neurological causes to 31 days and 2 years) between the two arms of the study. Moreover, a higher incidence of AF and major vascular complications were observed for percutaneous closure compared to medical therapy.  Therefore, the results of the CLOSURE I ® apparently suggest that patients with PFO and CS/TIA should be treated medically, making clarity to the most appropriate mode of management of these patients; there are, however, several critical issues to consider in the evaluation of CLOSURE I ® findings:
The other two trials, the RESPECT ® (Randomized Evaluation of Recurrent Stroke Comparing PFO closure to established current standard of care treatment) and the PC ® (percutaneous closure of PFO using the Amplatzer PFO Occluder with medical treatment in patients with cryptogenic embolism) , trended toward a beneficial effect of device closure as compared to medical therapy, but the magnitude of effect estimate was low.
- The first doubt arises in considering the statistical power of the data: initially, the study was designed to enroll 1600 patients, and later because of slow enrollment, <1000 patients were recruited. This could reduce the statistical power of the study, to which would be more correct to conduct an evaluation of noninferiority compared to an assessment of superiority.
- The population enrolled in the CLOSURE I ® had a "low-risk" PFO: patients with DVT and coagulation abnormalities were excluded, only slightly more than half of patients (416/909) had a moderate or severe right-to-left shunt, and only one-third of patients had an atrial septal aneurysm associated with PFO (281/909).
- The device used has already been replaced with a new device, as a result of the finding of increased incidence of device's thrombosis, AF and residual shunt. 
Briefly, in the recent RCTs, although PFO closure showed a nominal 38% reduction in the hazard of recurrent stroke, this was without statistical significance compared to medical therapy. Several meta-analysis were published trying to explain these disappointing results ,,,,, and to systematically review the latest evidence on the efficacy and safety of percutaneous PFO closure. The following possible explanations were provided:
In addition, there are other reasons explaining why clinical decisions on device closure are not straightforward: A careful evaluation of possible complications needs to be considered both in pre- and intra-procedural phase. In this regards, major key points are the following:
- Firstly, a lower than initially estimated number of patients recruited, therefore the lack of sufficient statistical power (particularly for CLOSURE I ® ) needs to be considered.
- The different closure device used in the RCTs (the Amplatzer PFO Occluder in two of them, PC ® and RESPECT ® ), , and the STARFlex device in the other one, CLOSURE I ® ).  In this regards, taken altogether, a meta-analysis of the three trials does not demonstrate a statistically significant benefit of percutaneous PFO closure (stroke recurrence = 1.9% vs. 2.9% for percutaneous closure and medical treatment, respectively; P = 0.11). However, analyzing only the PC ® and RESPECT ® trials together, in which the Amplatzer PFO Occluder was used, a statistically significant benefit of percutaneous PFO closure can be observed (stroke recurrence = 1.4% vs. 3.0% for percutaneous closure and medical therapy, respectively, P = 0.04). Thus, a possible interpretation has been that the use of a dedicated, specifically designed Amplatzer PFO device could possibly reduce the risk of stroke recurrence in patients with PFO and CS.  However even this statement could be questionable.
- A large part of recurrence was not related to a PFO mediated paradoxical embolism. This raises the problem of inclusion criteria: the use of TIA as inclusion criterion (in the CLOSURE ® even patients with TIA were randomized whereas RESPECT ® and PC ® trial enrolled only patients with stroke).
- RESPECT ® and PC ® suggest a benefit of PFO closure only after 2 years. Thus, longer follow-up is probably required. Indeed, a recent long-term experience on the outcome of 800 patients undergoing PFO and followed over a 16-year period revealed a procedural success of 99% with effective closure obtained in 93% of patients. At a mean follow-up of 42.7 ± 33.4 months, 21 patients suffered a recurrent ischemic neurologic event (12 strokes, and 9 TIA) for an incidence rate of 0.79 events per 100 PYs and freedom from recurrent events of 91.6% at 10 years. There was no device-based difference in the rate of recurrent ischemic neurologic events (P = 0.82) and only Eustachian valve prominence (HR = 9.04; 95% CI: 2.07-39.44; P = 0.0034) was associated with recurrent neurologic events in this study. Thus, the long-term efficacy of PFO closure in patients with paradoxical embolism appears excellent in this observational study.
- Nonetheless, a very important issue is that carefully selected patients with features suggestive of paradoxical embolism are the most likely to benefit from PFO closure and should be the focus of the future investigation. Indeed, the greater likelihood of effective closure might simply be due to medical ability to choose the best device for a given patient's PFO anatomy, a freedom that is not available with clinical trials. 
In order to enhance the long-term benefit from PFO closure, clinical clues to paradoxical embolism have to be taken into account when linking PFO and recurrent stroke: The use of a clinical instrument to assess the probability of PFO-related CS is advised. Kent and Thaler, analyzing data from 12 studies, derived a clinical-determined score called Risk of Paradoxical Embolism (RoPE) score, aiming to provide a user-friendly and reliable instrument to assess the probability to find a PFO in a patient with CS and the probability of recurrent CS related to paradoxical embolism through the PFO.  Variables increasing the likelihood to find a PFO in CS patients included younger age, the presence of a cortical stroke on neuroimaging, and the absence of diabetes, hypertension, smoking, and prior stroke or TIA. The score consists in a 10-point system derived from these variables. In patients with a RoPE score of 0-3 have a PFO-attributable risk of 0% (95% CI: 0-4) and a 2-year stroke/TIA recurrence risk of 20%; while patients with a score of 9-10 have a PFO-attributable fraction of 88% (95% CI: 83-91) and a 2-year stroke/TIA recurrence risk of 2%. The advantage of this score is the easily application in the clinical practice; however, it is based only on clinical variables, not taking in count the importance of anatomical evaluation of the PFO and the hemodynamic features of the shunt.
- The rate of major complications of percutaneous closure is low at around 1.5-2.3% but these include death, major hemorrhage, emergency surgery, cardiac tamponade, and fatal pulmonary embolism. ,
- New onset or worsening of existing valve regurgitation has been reported after device deployment,  although a recent study using cardiac magnetic resonance quantification showed no significant effect. 
- The incidence of AF appears to be increased following device closure of PFO,  and may be associated with the use of larger devices.  This is a cause for concern as device closure may expose patients to a new and potentially more important risk factor for cerebrovascular events.
- Another important limitation is that device implantation is not necessarily the same as defect closure, and the prevalence of residual shunting depends on how vigorously it is sought.
What say the last guidelines?
The latest guidelines (AHA/ASA 2014) on stroke prevention state that: transcatheter closure "might be considered" in the setting of PFO and DVT depending on the risk of recurrent DVT (Class II b, level of evidence C), and that: For patients with a CS or TIA and a PFO without evidence for DVT, available data do not support a benefit for PFO closure (Class III, level of evidence A). 
In summary, although present evidence does not support an extensive PFO closure for the prevention of recurrent CS, a detailed analysis of recent RCTs can make us consider that the door for PFO closure might not be entirely closed, but simply restricted to selected cases. This strategy could be useful for ensuring a more tailored patients' management. Moreover, patients must be made aware of the lack of evidence from RCTs proving the efficacy of the procedure, and they must be informed about procedural risks. 
Completion of ongoing randomized studies (CLOSE ® , DEFENSE-PFO ® , GORE REDUCE ® ) [Table 2] is paramount to draw valid and solid conclusions on whether this endovascular approach offers a new glimpse of hope to patients with CS and PFO and whom medical therapy has failed or is contraindicated. ,,
With regards to migraine, in the previous review (Part I), we showed as most studies identified a possible causal relationship between PFO and migraine with aura (MA);  it is also possible to found a high prevalence of MA in people who have a large paradoxical shunt due to a PFO. The first PFO and migraine link was shown when an improvement in the prevalence and severity of symptoms was seen after PFO closure from other causes.  Similarly to what occurs in CS, hard evidence is lacking to show that the closing PFO strategy can contribute to healing migraines. Several causes make it difficult to show the efficacy of percutaneous treatment. Migraine is known for its spontaneous variability and response rate to preventive medications in about 50% of cases as well as in around 20-30% for placebo (in well conducted contemporary clinical trials). Most observations that closing PFO cures migraine were in patients after stroke, an event that may alter the course of migraine per se. Also medications used in some studies after PFO closure, e.g., aspirin , and clopidogrel, exert a little influence on migraine. Unfortunately, the only prospective and placebo-controlled trial migraine intervention with STARFlex Technology (MIST) failed to show any significant difference between the medical and the closure strategy in migraine treatment. 
Briefly, owing to the lack of evidence from prospective, long-term studies, demonstrating a clinical benefit from PFO closure, migraine does not represent per se an indication for the interventional procedure, to date.
Medical therapy and follow-up after closure
Dual antiplatelet therapy (aspirin 100 mg and clopidogrel 75 mg) is required after the procedure until the device is covered by endothelium. No data to guide the duration of antiplatelet prescription exist, but most operators recommend therapy for 3-6 months; substantial data support the efficacy of aspirin for secondary prevention of stroke, and any patients having PFO closure for this indication should, therefore, remain receiving lifelong aspirin therapy.  Patients should be submitted to a transthoracic echocardiogram with bubble contrast 6-12 months postprocedure to confirm closure of the PFO. Rigorous follow-up using transcranial Doppler at a mean of a year postprocedure reveals incomplete closure in around 20% and large residual shunts in around 14%, irrespective of the device used. Although most PFOs that close completely or near completely do so within a month, a significant minority do so between 6 and 12 months post procedure. 
| Practical clinical approach to patients with patent foramen ovale and cryptogenic stroke|| |
While considering what the 2014 AHA/ASA guidelines on stroke prevention recommend, we propose a practical flow chart for managing patients with PFO and CS:
Only after following this "roadmap" and consulting international guidelines we can:
- Consider only young people (<55 years).
- Rule out AF.
- Look at the neuroimaging lesion patterns.
- Evaluate the presence of anatomical (atrial septal aneurysm, large PFO, right-to-left shunt at rest, Eustachian valve >10 mm, chiari network and long PFO tunnel) and clinical (multiple ischemic lesions, recurrent clinical events, history of DVT or prothrombotic state, pulmonary embolism, event related to travel or prolonged immobilization) risk factors for CS recurrence.
- Use the RoPE-score.
- Recommend medical therapy in case of first cerebrovascular event without anatomical and clinical risk factors.
- Suggest percutaneous closure as an alternative to medical therapy, according to the latest guidelines in the setting of a CS with a DVT, depending on the risk of recurrent DVT.
- Consider percutaneous closure, beyond guidelines, in patients with a CS who have more than one risk factor (anatomical or clinical) for stroke recurrence, and in case of any first or recurrent cryptogenic event while receiving adequate medical therapy (antiplatelet, oral anticoagulant or both).
| Conclusions|| |
The pathophysiological link between PFO and neurological events is confused and contradictory, and should be searched with great attention. It is certainly possible that some patients might benefit from PFO closure, but there is scant evidence to justify extensive PFO closure. A careful examination of clinical and anatomical risk factors for neurological recurrence is mandatory. In the absence of a clear scientific mandate, young patients with large PFO and recurrent CS and/or at risk of DVT, who are extensively worked up by a neurologist are the group that is most likely to benefit from PFO closure.
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[Table 1], [Table 2]