Residual Shunt after Patent Foramen Ovale Closure: Preliminary Results from Italian Patent Foramen Ovale Survey

Residual Shunt after Patent Foramen Ovale Closure: Preliminary Results from Italian Patent Foramen Ovale Survey Luigi Caputi, MD,* Gianfranco Butera, MD,† Gian Paolo Anzola, MD,‡ Mario Carminati, MD,† Maria Rita Carriero, MD,* Massimo Chessa, MD,† Eustaquio Onorato, MD,x Gianluca Rigatelli, MD,k Giuseppe Sangiorgi, MD,{ Gennaro Santoro, MD,# Isabella Spadoni, MD,** Gian Paolo Ussia, MD,†† Carlo Vigna, MD,‡‡ Mario Zanchetta, MD,xx and Eugenio Parati, MD,* on behalf of Italian Patent Foramen Ovale Survey investigatorskk

Background: Percutaneous patent foramen ovale (PFO) closure is accepted as treatment for cryptogenic ischemic stroke/transient ischemic attack in young subjects. However, a thorough evaluation of residual right-to-left shunt (rRLS) after PFO closure is needed. Our aims were to analyze the characteristics related to PFO diagnosis and closure, focusing on rRLS and clinical recurrences until 24-month follow-up. Data were extrapolated from the 12-month Italian PFO Survey. Methods: In all, 1035 patients were included. PFO diagnosis and right-to-left shunt (RLS) were assessed by contrast-enhanced transesophageal and/or transthoracic echocardiography and/or transcranial Doppler. Results: PFO diagnosis with RLS data were available in 894 of 1035 (86.4%) patients. rRLS was investigated in 49.6% (6 months), 27.1% (12 months), and 3.5% (24 months), and observed in 19.5% (6 months) and 18.2% (12 months) of subjects. Large permanent rRLS was observed in less than 3% of RLSpositive patients after 1 year. Eleven of 14 and 3 of 14 neurological recurrences were observed in 10 of 444 (2.25%) and 2 of 243 (0.8%) patients within the 6- and 12-month follow-up, respectively. Among these, no large rRLS was reported. There were no neurological events at 2-year follow-up. Forty of 444 subjects had non-neurological complications, mostly cardiac arrhythmias within the sixth month. Conclusions: PFO closure is a safe procedure. rRLS is not uncommon but large rRLS is rare. Clinical complications, mostly related to cardiac arrhythmias, are not unusual. Evaluation of the data of the whole survey is underway. Key Words: Patent foramen ovale—closure—right-to-left shunt—stroke—transient ischemic attack. Ó 2013 by National Stroke Association

From the *Department of Cerebrovascular Diseases, Fondazione Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS) Neurological Institute C. Besta, Milan, Italy; †Division of Pediatric Cardiology, Policlinico San Donato, San Donato Milanese, Italy; ‡Service of Neurology, S. Orsola Hospital, Brescia, Italy; xDepartment of Cardiovascular Diseases, Humanitas Gavazzeni, Bergamo, Italy, and Clinica, Montevergine, Mercogliano, Italy; kSection of Adult Congenital and Adult Heart Disease, Rovigo General Hospital, Rovigo, Italy; {Division of Cardiology, University of Tor Vergata, Rome, Italy; #Struttura Organizzativa Dipartimentale (SOD) Diagnostica ed Interventistica Cardiovascolare, Azienda Ospedaliera Universitaria (AOU) Careggi, Florence, Italy; **Division of Pediatric Cardiology, ‘‘G: Pasquinucci’’ Hospital, Massa, Italy; ††Division of Cardiology, Ferrarotto Hospital, Catania, Italy; ‡‡Department of Cardiology, Casa Sollievo della

Sofferenza Hospital IRCCS, San Giovanni Rotondo, Italy; and xxDepartment of Cardiovascular Disease, Civil Hospital, Cittadella, Italy. Received October 31, 2012; accepted December 8, 2012. Funding sources: None. Address correspondence to Luigi Caputi, MD, Department of Cerebrovascular Diseases, Fondazione IRCCS Neurological Institute C. Besta, Via Celoria 11, 20133, Milan, Italy. E-mail: lcaputi@ istituto-besta.it. kk (see Appendix). 1052-3057/$ - see front matter Ó 2013 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2012.12.002

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Percutaneous closure of patent foramen ovale (PFO) is commonly performed to prevent recurrences of cerebrovascular ischemic events in subjects younger than 55 years of age affected by cryptogenic ischemic stroke/transient ischemic attack (TIA),1 even if there are no generally accepted criteria for PFO closure. Based on recent data,2 the question at issue is whether there is a real benefit of PFO closure when compared with the best current medical treatment. Since paradoxical embolism is the main pathogenic mechanism associated with an ischemic stroke and/or TIA related to PFO, a great effort in evaluating the persistence of right-to-left shunt (RLS) after PFO closure is desirable. Moreover, longer follow-up should be performed to observe if possible clinical recurrences are correlated with the persistence of a large RLS. Even though the efficacy of PFO closure by evaluating residual RLS (rRLS) has been described in some recent studies,3-20 their results could not be completely compared because of the different methods and criteria used. The aim of our study was, therefore, to analyze clinical practice in a large series of patients treated with percutaneous PFO closure in Italy. Through a multicentric survey, we evaluated indications, devices, and results of PFO closure up to a 36-month follow-up.

While waiting for the final results, we herein describe early results, up to the 24-month follow-up, focusing on the aspects related to rRLS after PFO closure, the diagnostic techniques utilized, and any possible link with clinical recurrences.

Methods Our entire study focused on the evaluation of indications, devices, and results of PFO closure obtained by a prospective, observational, multicentric survey (Italian PFO Survey) that used a World Wide Web–based database. The survey lasted 12 months and the patients were enrolled between November 2007 and October 2008. The follow-up continued up to 36 months. Study design and indications were previously briefly described.21 A flow chart of the entire survey is provided (Fig 1). rRLS was investigated by using contrast-enhanced transesophageal echocardiography (cTEE), contrastenhanced transthoracic echocardiography (cTTE), and/ or contrast-enhanced transcranial Doppler (cTCD), depending on the choice of each cardiology department. Follow-up was within the 6th, 12th, 24th, and 36th month.

Figure 1. Flow chart of entire Italian PFO Survey from patient screening through follow-up. Abbreviations: PFO, patent foramen ovale; RLS, right-to-left shunt.

RESIDUAL RLS AFTER PFO CLOSURE: DATA FROM ITALIAN PFO SURVEY

Since the focus of the present report was the evaluation of rRLS after PFO closure and possible correlations with clinical recurrences, we examined the description of the methods related to the diagnostic techniques and those for follow-up. As previously described,21 PFO closure was mostly performed in patients with a history of TIA/cryptogenic ischemic stroke with remaining indications consistent with other events of paradoxical embolism and migraine with aura. Fifty Italian cardiology departments agreed to participate. Forty of them enrolled at least 1 patient in the registry. In all, 1035 patients (mean age 46 years [range 5-75 years]; 619 of 1035 [60%] female) were included in the registry. PFO diagnosis and RLS were assessed by cTEE, cTTE, and/or cTCD. RLS was assessed in a visual, semiquantitative method by cTEE and cTTE: RLS was diagnosed if at least 1 microbubble (MB) appeared early in the left atrium either spontaneously or after provocative maneuvers, thus indicating no shunt if no MB was revealed up to a severe shunt if greater than 20 MB occurred. cTCD methods regarding RLS diagnosis were previously described.22 cTCD was performed according to the standardized procedure as agreed in the Consensus Conference of Venice.23 Briefly, the total MB count consisted of all MB detected during a time interval of 20 seconds or less after the appearance of the first MB. The proposed classification is as follows: small (0-10 MB), moderate (.10 MB, without shower or curtain pattern), and large (shower or curtain pattern) RLS. All our patients who exhibited RLS of 5 or more MB were considered to have a positive test result.24 Latent RLS was considered if evident only after Valsalva maneuver, permanent RLS if present even during normal breathing. Aneurysm of the interatrial septum (ASA) was diagnosed in the presence of atrial septal excursion greater than 10 mm beyond the plane of the interatrial septum in the presence of a base width greater than 15 mm. ASA was observed in 423 of 1035 (41%) patients.

Results PFO diagnoses with RLS evaluations were available in 894 of 1035 (86.4%) subjects.

Figure 2. Assessment of techniques for preprocedural patent foramen ovale diagnosis (percentage). Abbreviations: cTCD, contrast-enhanced transcranial Doppler; cTEE, contrast-enhanced transesophageal echocardiography; cTTE, contrastenhanced transthoracic echocardiography.

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Preprocedural Diagnosis cTEE, cTTE, and cTCD alone were used in 264 of 894 (29.5%), 42 of 894 (4.7%), and 173 of 894 (19.3%) patients, respectively. The combination of cTTE plus cTCD and of cTTE plus cTCD was performed in 351 of 894 (39.3%) and in 64 of 894 (7.2%) patients, respectively (Fig 2). Data concerning the techniques utilized for preprocedural diagnosis were not available in 141 of 1035 (13.6%) subjects.

Follow-up–Techniques Detailed information regarding the techniques used during follow-up, up to the 24th month, is described in Table 1 and Figure 3. Interestingly, 444 of 894 (49.6%) subjects undergoing PFO closure were evaluated by means of rRLS within the 6-month follow-up. At the 12th and 24th month, a further drop in number of evaluations was observed (243 of 894, 27.1%; 31 of 894, 3.5%, respectively). The most utilized method was cTTE alone, within the 6th (209 of 444; 47.1%) and the 12th (103 of 243; 42.4%) month and in about 75% (23 of 31) at the 24-month follow-up. Secondarily, cTCD alone and in combination with cTTE and cTEE was used in 213 of 444 (48%), 122 of 243 (50.2%), and 8 of 31 (25.8%) patients at the 6th, 12th, and 24th month, respectively (Fig 3). cTEE alone was rarely used as a technique for follow-up examinations as it was performed in about 5%-6% of patients at the 6th and 12th month. Similar results were also observed if used in combination with cTCD or cTTE (Fig 3).

Follow-up–rRLS Data regarding rRLS were available in 401 of 444 (90.3%), 198 of 243 (81.5%), and 21 of 31 (67.7%) patients evaluated at the 6th, 12th, and 24th month, respectively. rRLS was observed in about 20% of patients at the 6th (78 of 401) and 12th (36 of 198) month with a slighter increase up to less than 30% (6 of 21) at the 24th month (Table 2). Permanent RLS was detected in 25 of 78 (32%) RLS-positive patients at the 6th month, and in 11 of 36 (30.5%) and 1 of 6 (16.7%) at the 12th and 24th month, respectively (Table 2). Although there was a considerable number of permanent RLS at the 6- and 12-month follow-up, the proportion of a large permanent RLS among RLS-positive patients, at the same follow-up,

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Table 1. Diagnostic techniques utilized at 6-, 12-, and 24-month follow-up

All techniques cTEE cTTE cTCD cTEE 1 cTCD cTTE 1 cTCD cTTE 1 cTEE

6-mo Follow-up No. of patients (%)

12-mo Follow-up No. of patients (%)

24-mo Follow-up No. of patients (%)

444/894 (49.6) 21/444 (4.7) 209/444 (47.1) 74/444 (16.7) 36/444 (8.1) 103/444 (23.2) 1/444 (0.2)

243/894 (27.1) 14/243 (5.8) 103/243 (42.4) 57/243 (23.4) 6/243 (2.5) 59/243 (24.3) 4/243 (1.6)

31/894 (3.5) 0/31 (0) 23/31 (74.2) 2/31 (6.5) 1/31 (3.2) 5/31 (16.1) 0/31 (0)

Abbreviations: cTCD, contrast-enhanced transcranial Doppler; cTEE, contrast-enhanced transesophageal echocardiography; cTTE, contrastenhanced transthoracic echocardiography.

was quite low (1 of 78 [1.3%] and 1 of 36 [2.7%] patients) (Table 2). Furthermore, no large permanent RLS were observed at the 24-month follow-up. Latent RLS was observed in 53 of 78 (68%), 25 of 36 (69.45%), and 5 of 6 (83.3%) RLS-positive patients at the 6th, 12th, and 24th month, respectively. Large latent rRLS was evident in less than 5% of these subjects at the 6th (3 of 78) and 12th (1 of 36) month and no large latent RLS was found within 24 months after the procedure.

rRLS, 2 latent and 2 permanent. Five of 12 (41.6%) patients had a concomitant ASA, but it was associated with the persistence of rRLS in 2 of 12 (16.6%) patients. These 2 patients were the only ones who experienced 2 neurological recurrences. Both had a small-moderate permanent RLS, but the one who had 2 TIA within the 12th month had rRLS only at the 6th month follow-up. At the 12th month RLS was no longer detectable.

Non-neurological Complications Neurological Recurrences Fourteen neurological recurrences were observed in 12 patients up to the 12-month follow-up: 8 TIA and 2 hemorrhagic and 4 ischemic strokes. No neurological recurrences were observed at the 24-month follow-up. Ten of 444 (2.25%) patients had 11 of 14 neurological recurrences occurring within the 6-month follow-up. Two of 243 (0.8%) patients had 3 of 14 neurological recurrences occurring within the 12-month follow-up. Two of 12 patients each experienced 2 neurological recurrences. One from hemorrhagic stroke and TIA at the 6- and 12-month follow-up, respectively; the second from 2 TIA within the 12th month. Four of 12 (33.3%) patients with neurological recurrences had rRLS. It was detected in all of them within the 6th month; in 1 of them RLS was no longer detectable at the 12th month. No data regarding rRLS were available in 2 of 12 (16.6%) patients. No large rRLS was observed in those 4 patients with neurological recurrence. They had small-moderate

In all, 34 of 41 (83%) cardiac and extracardiac complications occurring in 40 of 444 (9%) subjects, and within the sixth month, were mostly related to arrhythmias. In all, 27 of 34 (79.4%) complications had specific arrhythmic patterns: atrial fibrillation (16/34), supraventricular paroxysmal tachycardia (10/34), and atrial flutter (1/34). The remaining 17% (7/41) of complications were not primarily related to arrhythmias and, as previously described,21 dealt with intracardiac conditions, pointing out the worst as device malposition, apical thrombus, myocardial ischemia, and atrial erosion. Seven of 41 (17%) complications occurred within the 12-month follow-up. No cardiacextracardiac complications were observed at the 24month follow-up.

Discussion The purpose of the present study was to analyze the characteristics related to PFO diagnosis and closure, by

Figure 3. Assessment of techniques for patent foramen ovale follow-up (percentage) at 6th, 12th, and 24th month. Abbreviations: cTCD, contrast-enhanced transcranial Doppler; cTEE, contrast-enhanced transesophageal echocardiography; cTTE, contrast-enhanced transthoracic echocardiography.

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Table 2. Estimation of residual right-to-left shunt at 6-, 12-, and 24-month follow-up

Residual RLS

6-mo Follow-up No. of patients (%)

12-mo Follow-up No. of patients (%)

24-mo Follow-up No. of patients (%)

No RLS RLS Latent Permanent s-m Latent Large latent s-m Permanent Large permanent

323/401 (80.5) 78/401 (19.5) 53/78 (68) 25/78 (32) 50/78 (64) 3/78 (3.9) 24/78 (30.8) 1/78 (1.3)

162/198 (81.8) 36/198 (18.2) 25/36 (69.4) 11/36 (30.5) 24/36 (66.7) 1/36 (2.7) 10/36 (27.7) 1/36 (2.7)

15/21 (71.4) 6/21 (28.6) 5/6 (83.3) 1/6 (16.7) 5/6 (83.3) 0 (0) 1/6 (16.7) 0 (0)

Abbreviations: RLS, right-to-left shunt; s-m, small-moderate.

examining the diagnostic techniques utilized, rRLS, and possible correlations with clinical recurrences. Our data were extrapolated from a prospective, observational, and multicentric survey (Italian PFO Survey) with a main aim of comprehensive evaluation of the clinical practice regarding PFO closure in Italy in a large series of patients. Mostly focusing on technical methods and their followup, the present data offer a more thorough and up-to-date evaluation of that previously described.21 cTEE is considered the gold standard for PFO diagnosis, but in recent years several studies have indicated cTCD as complementary to cTEE in assessing PFO and RLS.22,25-27 The data of our survey were in line with these suggestions. About 70% of subjects studied underwent cTEE alone or with cTCD within the preprocedural phase, whereas about 65% of patients underwent cTCD alone or with cTEE or cTTE. On the other hand, cTTE alone was performed in a small cohort of patients (42 of 894; 4.7%), thus indicating that it might not be considered sufficient for a correct PFO diagnosis in the majority of cardiology departments. In those centers where cTTE was the only technique used for PFO diagnosis, there could be an underestimation of PFO itself and relative RLS. Furthermore, the current amount of cTCD performed as a complementary technique to cTEE could be mainly related to the increase of a dayby-day collaboration between cardiologists and neurologists. Although there was a remarkable decrease in the number of patients at follow-up, the absolute number is still worthy of note, mostly at 6 and 12 months. Since the study was conducted by cardiologists, we can suppose the main aims were, first, to evaluate the occurrence of early complications and, secondly, to assess neurological recurrence and rRLS during a mid- to long-term followup. Furthermore, patients who felt well with no clinical events during the follow-up did not always perceive the need for further examinations. In contrast with the preprocedural diagnosis, during the entire follow-up cTTE was the most used technique,

both alone or in combination with cTCD. cTTE provides correct information regarding PFO device, but may underestimate rRLS. cTEE was rarely utilized and the combination of cTTE and cTCD was used in less than 25% of patients at the 6th and 12th month and in about 7% within the 24-month follow-up. The evaluations of rRLS were assessed non-homogeneously in several recent reports, either with cTEE or cTCD or both techniques.313,15,17 Two studies showed cTTE as the only method during the follow-up.14,16 Studies in the future should examine more carefully the best technique for RLS evaluation and thus avoid the underestimation of RLS data. rRLS was evident in about 20% of patients at the 6- and 12-month follow-up. These data are in line with those present in the literature,3-19,28-30 even if these appear highly variable, even rising to 33% of rRLS.16 It might thus depend on the entire number of population studied in those reports and the method utilized for RLS detection. On the other side, the relative and unexpected increase of rRLS at the 24th month might be explained by the low number of patients included at this time point (31 patients) and, probably, by the fact that most subjects evaluated were already known as RLS-positive. An increase of the population at this follow-up would be desirable to obtain more accurate and reliable data. Interestingly, large permanent RLS that might be considered as higher risk for neurological recurrence by paradoxical embolism31 were evident in just 1 of 78 (1.3%) and 1 of 36 (2.7%) RLS-positive subjects at the 6th and 12th month, whereas no large permanent RLS was observed at the 24th month. In comparison with the data in the literature3-19,28-30 where the range regarding the persistence of large RLS was high, from 0% to about 30%, our data would indicate the good performance of the majority of the centers included in this project. Neurological complications were observed in 2.25% and 0.8% of patients within the 6- and 12-month followup, respectively, thus indicating the need for more careful monitoring of the medical therapy in the first 6 months after the procedure. Incidence of recurrent thromboembolic

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events after PFO closure was similarly previously described (0%-4% per year).3,10,17,20,30-34 Four of 12 (33.3%) patients with neurological events had rRLS, but they showed small-moderate RLS both latent and permanent. Based on clinical experience and a recent article describing large permanent PFO as higher risk for paradoxical embolism,31 we would rule out that the neurological recurrences in the present study were strictly related to the persistence of RLS or, at least, with the presence of PFO as a sole cause. Notably, this was described in a recent article by Mono et al35 where concomitant etiologies, besides PFO, were observed in one third of their population affected by cryptogenic ischemic stroke. Furthermore, in the CLOSURE I trial, the recent completed randomized trial comparing medical treatment to PFO closure in subjects with PFO, 80% of events after PFO closure were not considered to be related to paradoxical embolism.2 Moreover, Wallenborn et al,20 in a very recent retrospective analysis, stated that atherosclerosis was considered the most common cause for recurrent events after PFO closure. Furthermore, in a recent metaanalysis of transcatheter closure versus medical therapy for PFO in recurrent neurological events, it was observed that the presence of rRLS did not predispose subjects to an increased risk of neurological recurrences in the postprocedural period.30 ASA would enhance the ischemic risk in patients with PFO.36 In our survey ASA was observed in 5 of 12 (41.6%) patients who had neurological recurrences, but just 2 of them had a residual small-moderate permanent RLS. The fact that these 2 patients each had 2 clinical events might point out a critical role of ASA plus PFO in recurrent ischemic events. We think, in any case, that the entire number of subjects with neurological recurrences and those with ASA and rRLS are not sufficient to draw noteworthy conclusions concerning PFO plus ASA and recurrent paradoxical embolism. However, it seems appropriate to pay further attention to those patients with rRLS and ASA whose ischemic risk could be enhanced compared to those without ASA. Furthermore, a considerable underestimation of rRLS among those 12 patients with neurological recurrence appears unlikely because in 8 of 12 (66.6%) combined diagnostic techniques were performed. Finally, cardiac and extracardiac complications (83%) were present in 9% of patients within the 6-month follow-up. Major complications (ie, atrial fibrillation and flutter, apical thrombus, and myocardial ischemia) were observed in 19 of 40 (47.5%) patients. Our data, similar to those previously described,2,4,9 point out the need to evaluate the possible occurrence of these critical adverse events, mainly the cardiac arrhythmias, to widen periprocedural and postprocedural safety and prevention. In conclusion, our data regard early results from the IPOS. We need to assess definite data of the follow-ups

to make a comprehensive estimation of all clinical and technical characteristics correlated with subjects who underwent percutaneous PFO closure. We can confirm that percutaneous PFO closure is a safe procedure and rRLS is not uncommon even if those at higher risk for paradoxical embolism are quite rare. The occurrence of early complications and those during follow-up are not unusual and are mostly related to cardiac arrhythmias. This information leads to a better evaluation of clinical indication for PFO closure and more accurate management of the post-procedural phase.

Study Limitations Our survey should provide a comprehensive evaluation of all data over longer periods of time. For the intrinsic and general characteristics of a survey and for our study, we cannot entirely provide strong and definite evidence of cause and effect (stroke/TIA and PFO). Data concerning complete follow-up were lacking: among the possible explanations, we think this could be mostly due to: (1) lower priority for carrying out the survey because of competing urgent tasks, (2) lack of time to carry out a survey, and (3) the fact that some patients felt well during the follow-up and did not perform further examinations. RLS estimation was assessed with different techniques, thus possibly creating a bias in a homogeneous analysis. We think, however, that this potential bias was not worthy of note because of the very common use of at least 2 techniques for every single patient. Acknowledgment: with English.

We thank Dr Andrea Smith for help

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cerebral hemodynamics–an update. Perspectives in Medicine 2012;1:236-240. Caputi L, Carriero MR, Falcone C, et al. Transcranial Doppler and transesophageal echocardiography: comparison of both techniques and prospective clinical relevance of transcranial Doppler in patent foramen ovale detection. J Stroke Cerebrovasc Dis 2009; 18:343-348. Jauss M, Zanette E. Detection of right-to-left shunt with ultrasound contrast agent and transcranial Doppler sonography. Cerebrovasc Dis 2000;10:490-496. Schwarze JJ, Sander D, Kukla C, et al. Methodological parameters influence the detection of right-to-left shunts by contrast transcranial Doppler ultrasonography. Stroke 1999;30:1234-1239. Jauss M, Kaps M, Keberle M, et al. A comparison of transesophageal echocardiography and transcranial Doppler sonography with contrast medium for detection of patent foramen ovale. Stroke 1994; 25:1265-1267. Job FP, Ringelstein EB, Grafen Y, et al. Comparison of transcranial contrast Doppler sonography and transesophageal contrast echocardiography for the detection of patent foramen ovale in young stroke patients. Am J Cardiol 1994;15:381-384. Droste DW, Kriete JU, Stypmann J, et al. Contrast transcranial Doppler ultrasound in the detection of right-toleft shunts: comparison of different procedures and different contrast agents. Stroke 1999;30:1827-1832. Scacciatella P, Butera G, Meynet I, et al. Percutaneous closure of patent foramen ovale in patients with anatomical and clinical high-risk characteristics: long-term efficacy and safety. J Interv Cardiol 2011;24:477-484. Kefer J, Sluysmans T, Hermans C, et al. Percutaneous transcatheter closure of interatrial septal defect in adults: procedural outcome and long-term results. Catheter Cardiovasc Interv 2012;79:322-330. Agarwal S, Bajaj NS, Kumbhani DJ, et al. Meta-analysis of transcatheter closure versus medical therapy for patent foramen ovale in prevention of recurrent neurological events after presumed paradoxical embolism. JACC Cardiovasc Interv 2012;5:777-789. Rigatelli G, Dell’avvocata F, Cardaioli P, et al. Permanent right-to-left shunt is the key factor in managing patent foramen ovale. J Am Coll Cardiol 2011;58:2257-2261. Bridges N, Hellenbrand W, Latson L, et al. Transcatheter closure of patent foramen ovale after presumed paradoxical embolism. Circulation 1992;86:1902-1908. Braun M, Gliech V, Boscheri A, et al. Transcatheter closure of patent foramen ovale (PFO) in patients with paradoxical embolism: periprocedural safety and mid-term follow-up results of three different device occluder systems. Eur Heart J 2004;25:424-430. Wahl A, Tai T, Praz F, et al. Late results after percutaneous closure of patent foramen ovale for secondary prevention of paradoxical embolism using the Amplatzer PFO occluder without intraprocedural echocardiography. J Am Coll Cardiol Interv 2009; 2:116-123. Mono ML, Geister L, Galimanis A, et al. Patent foramen ovale may be causal for the first stroke but unrelated to subsequent ischemic events. Stroke 2011; 42:2891-2895. Overell JR, Bone I, Lees KR. Interatrial septal abnormalities and stroke: a meta-analysis of case-control studies. Neurology 2000;55:1172-1179.

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Appendix Italian Patent Foramen Ovale Survey investigators: Luigi Caputi, Eugenio Parati, Maria Rita Carriero (Department of Cerebrovascular Diseases, Fondazione Istituto di Ricerca e Cura a carattere Scientifico, Neurological Institute C. Besta, Milan, Italy); Gianfranco Butera, Mario Carminati, Massimo Chessa (Policlinico San Donato, San Donato Milanese, Italy); Gian Paolo Anzola (Service of Neurology, Ospedale S. Orsola, Brescia, Italy); Eustaquio Onorato (Department of Cardiovascular Diseases, Humanitas Gavazzeni, Bergamo, Italy, and Clinica, Montevergine, Mercogliano, Italy); Giuseppe Sangiorgi (Division of Cardiology, Policlinico Universitario Tor Vergata, Rome, Italy); Gennaro Santoro (Struttura Organizzativa Dipartimentale Diagnostica ed Interventistica Cardiovascolare, Azienda Ospedaliera Universitaria, Careggi, Firenze, Italy); Isabella Spadoni and Sandra Giusti (Ospedale ‘‘G: Pasquinucci’’ Unita Operativa Cardiologia Pediatrica e Grown-up congenital heart, Massa, Italy); Gian Paolo Ussia (Ospedale Ferrarotto, Laboratorio di Emodinamica Divisione Clinicizzata di Cardiologia, Catania, Italy); Tommaso Langialonga (E.E. Ospedale Generale Regionale ‘‘F. Miulli,’’ Acquaviva delle Fonti, Italy); Alessandro Santo Bortone, Emanuela De Cillis (Emodinamica Interventistica–Sezione di Cardiochirurgia–DETO–Universita degli Studi di Bari– Policlinico, Bari, Italy); Francesco De Luca (Cardiologia Pediatrica Ospedale Ferrarotto, Catania, Italy); Corrado Tamburino (Divisione Clinica di Cardiologia Ospedale Ferrarotto, Catania, Italy); Mario Zanchetta (Dipartimento di Malattie Cardiovascolari, Ospedale Civile, Cittadella, Italy); Armando Liso (Villa Maria Cecilia Hospital, Cotignola, Italy); Mario De Martini (Azienda Ospedaliera Ospedale Civile di Vimercate, Desio, Italy); Felice Achilli (Dipartimento Cardiovascolare Ospedale di Lecco, Lecco, Italy); Roberto Zanini, Corrado Lettieri (Ospedale ‘‘Carlo Poma,’’ Mantova, Italy); Antonio Colombo (Ospedale San Raffaele, Milan, Italy); Francesco Bedogni (Istituto Clinico Sant’Ambrogio, Milan, Italy); Maurizio Viecca, Paolo Danna (Laboratorio di Emodinamica ‘‘Bruno Scolari’’ c/o Ospedale L. Sacco, Milan, Italy); Gabriele Vignati (Cardiologia Pediatrica Ospedale Niguarda, Milan, Italy); Alberto Margonato (Ospedale San Raffaele, Milan, Italy); Bernhard Reimers (Divisione di Cardiologia–Ospedale Civile, Mirano, Italy); Alberto Benassi, Luigi Steffanon (Hesperia Hospital Ospedale Privato, Modena, Italy); Giulietto Romeo

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Zennaro (Unit a Operativa Cardiologia/Nocsae, Modena, Italy); Raffaele Calabr o (Unit a Operativa Complessa Cardiologia, Seconda Universit a di Napoli–Azienda Ospedaliera ‘‘Monaldi’’–Azienda Ospedaliera ‘‘Monaldi–II Universit a di Napoli,’’ Naples, Italy); Diego Ardissimo, Luigi Vignali (Azienda Ospedaliero–Universitaria di Parma Unit a Operativa di Cardiologia, Parma, Italy); Claudio Cavallini (Struttura Complessa Di Cardiologia–Laboratorio di Emodinamica e Cardiologia Interventistica, Perugia, Italy); Giorgio Binetti, Egidio Mariotti (Azienda Ospedaliera Osp. S. Salvatore di Pesaro Laboratorio Emodinamica, Pesaro, Italy); Alessandro Capucci (Ospedale Polichirurgico–Unit a Operativa di Cardiologia, Piacenza, Italy); Francesco Chiarella (Struttura Semplice di Emodinamica e Interventistica Cardiovascolare, Unit a Complessa Cardiologia O. Santa Corona, Pietra Ligure, Italy); Ugo Vairo (Cardiologia Pediatrica–Azienda Ospedaliera San Carlo, Potenza, Italy); Antonino Nicosia, Giuseppe Campisi (Azienda Ospedaliera Civile–Maria Patern o Arezzo– Emodinamica, Ragusa, Italy); Paolo Pantaleo (Villa Azzurra Hospital, Rapallo, Italy); Alberto Cremonesi (Villa Maria Cecilia Hospital, Cotignola, Italy); Danilo Manari (Salus Hospital–Gruppo Villa Maria Cecilia, Reggio Emilia, Italy); Andrea Berni (Unit a Operativa Semplice di Emodinamica e Cardiologia Interventistica, Unit a Operativa Complessa di Cardiologia Ospedale Sant’Andrea, Rome, Italy); Paolo Cardaioli, Gianluca Rigatelli (Servizio di Diagnostica Cardiovascolare ed Interventistica Endoluminale, Ospedale Civile di Rovigo, Rovigo, Italy); Patrizia Presbitero, Dennis Zavalloni Parenti (Istituto Clinico Humanitas, Rozzano, Italy); Luigi Inglese (Policlinico San Donato Istituto di Ricerca e Cura a carattere Scientifico, San Donato Milanese, Italy); Carlo Vigna, Raffaele Fanelli (Ospedale Casa Sollievo della Sofferenza Istituto di Ricerca e Cura a carattere Scientifico, San Giovanni Rotondo, Italy); Carlo Pierli (Azienda Ospedaliera Universitaria Senese–Le Scotte, Siena, Italy); Sebastiano Marra (Cardiologia Ospedaliera, Azienda Ospedaliera San Giovanni Battista, Molinette di Torino, Turin, Italy); Zoran Olivari (Emodinamica– Cardiologia Ospedale Ca’ Fondello, Treviso, Italy); Jorge Salerno Uriarte (Ospedale di Circolo Fondazione Macchi– Cardiologia I, Varese, Italy); Manuela Martini (Ospedale Civile Regionale SS Giovanni e Paolo di Venezia, Venice, Italy); Leonardo Varotto, Alessandro Fontanelli (Ospedale San Bortolo di Vicenza, Unit a Operativa Complessa di Cardiologia, Vicenza, Italy).