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Is Transcatheter Closure Better than Medical Therapy for Cryptogenic Stroke with Patent Foramen Ovale? A Meta-analysis of Randomised Trials
REVIEW
Review
Is Transcatheter Closure Better than Medical Therapy for Cryptogenic Stroke with Patent Foramen Ovale? A Meta-analysis of Randomised Trials Vinayak Nagaraja, MBBS a , Jwalant Raval, MBBS b,∗ , Guy D. Eslick, MMedSc (Clin Epi), MMedStat c , David Burgess, BMed, PhD b,d and A. Robert Denniss, MD, MSc b,d a
c
Prince of Wales Hospital, Sydney, Australia b Blacktown Hospital, Sydney, Australia The Whiteley-Martin Research Centre, Discipline of Surgery, The University of Sydney, Nepean Hospital, Sydney, Australia d University of Western Sydney, Australia
Introduction: The prevalence of patent foramen ovale among patients with cryptogenic stroke is higher than that in the general population. Closure with a percutaneous device is often recommended in such patients, but it is not known whether this intervention reduces the risk of recurrent stroke. Methods: A systematic search was conducted using MEDLINE, PubMed, EMBASE, Current Contents Connect, Cochrane library, Google Scholar, Science Direct, and Web of Science. Original data were abstracted from each study and used to calculate a pooled event rate (ER), odd ratio (OR) and 95% confidence interval (95% CI). Results: Only three randomised trials comprising 2303 patients met full criteria for analysis. Procedural success (ER: 94.20%, 95% CI: 87.6–97.4%) and effective closure (ER: 92.70%, 95% CI: 85.9–96.4%) of closure therapy were good. The odds ratio for stroke (OR: 0.654, 95% CI: 0.358–1.193) and transient ischaemic attack (OR: 0.768, 95% CI: 0.413–1.429) did not confer a benefit of PFO closure over medical therapy. Age {<45 years (OR: 0.449, 95% CI: 0.117–1.722), >45 years (OR: 0.707, 95% CI: 0.27–1.856)}, gender {males (OR: 0.498, 95% CI: 0.247–1.004), females (OR: 1.16, 95% CI: 0.597–2.255)}, substantial shunt size (OR: 0.354, 95% CI: 0.089–1.406) and the presence of atrial septal aneurysm (OR: 0.7, 95% CI: 0.21–2.33) did not influence the treatment effect of PFO closure. However, the adverse events like major vascular complication (OR: 10.905, 95% CI: 1.997–59.562) and atrial fibrillation (OR: 3.297, 95% CI: 0.874–12.432) were significantly higher in the closure group. Conclusions: In patients with cryptogenic stroke or TIA who had a patent foramen ovale, closure with a device does not confer an advantage over medical therapy and is associated with adverse events like major vascular complication and atrial fibrillation. (Heart, Lung and Circulation 2013;22:903–909) © 2013 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier Inc. All rights reserved. Keywords. Patent foramen ovale; Cryptogenic stroke; Transcatheter closure; Randomised trials; Medical therapy
Introduction
E
pidemiological studies have found a prevalence of 44–66% of patent foramen ovale (PFO) in patients with cryptogenic stroke as compared with 27% in autopsy series of all-cause deaths [1]. The higher prevalence of Received 18 April 2013; received in revised form 8 July 2013; accepted 24 July 2013; available online 10 September 2013 ∗
Corresponding author at: Department of Cardiology, Blacktown Hospital, Australia. Tel.: +61 029881800. E-mail address: jwalant [email protected] (J. Raval).
PFO in patients with cryptogenic stroke suggests that at least in some patients with cryptogenic stroke, the cause of stroke might be paradoxical thromboembolism. The optimal management strategy for treating patients with cryptogenic stroke (CS) who are discovered to have a patent foramen ovale (PFO) remains to be defined. The advent of percutaneously implantable devices has offered a widely applicable closure approach not requiring open heart surgery. Catheter-based closure of patent foramen ovale was introduced in 1992 [2]. Percutaneous closure has been available for over 20 years with very little hard evidence to guide patient and device selection. Investigators
© 2013 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier Inc. All rights reserved.
1443-9506/04/$36.00 http://dx.doi.org/10.1016/j.hlc.2013.07.022
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have used their own clinical judgement to decide when and how to percutaneously close PFO. Observational long-term data suggest that closure of patent foramen ovale in patients with a history of ischaemic stroke may reduce the risk of recurrent stroke as compared with medical therapy alone [3,4]. CLOSURE 1 trial [5] failed to demonstrate any significant difference in recurrent neurological events with PFO closure compared with medical management with antiplatelet or anticoagulation therapy. Recently three randomised trials have reviewed the benefit of closure over optimal medical therapy. We synthesised the available evidence from the randomised trials on secondary stroke prevention in patients with patent foramen ovale and cryptogenic stroke and primarily focus on the comparison of the two strategies.
Methods Study Protocol We followed the Preferred Reporting Items for Systematic reviews and Meta-analyses PRISMA guidelines where possible in performing our systematic review [6]. We performed a systematic search through MEDLINE (from 1950), PubMed (from 1946), EMBASE (from 1949), Current Contents Connect (from 1998), Cochrane library, Google scholar, Science Direct, and Web of Science to May 2013. The search terms included “patent foramen ovale,” “PFO,” “atrial septal aneurysm,” “ASA transcatheter closure,” “heart septal defects (atrial),” “interatrial shunt,” “recurrent thromboembolism,” “recurrent stroke,” and “recurrent TIA.” which were searched as text word and as exploded medical subject headings where possible. No language restrictions were used in either the search or study selection. The reference lists of relevant articles were also searched for appropriate studies. A search for unpublished literature was not performed.
Study Selection We included studies that met the following inclusion criteria: • Studies identifying the population of patients with patent foramen ovale with cryptogenic stroke. • Randomised controlled trials comparing transcatheter closure and medical therapy.
Data Extraction We performed the data extraction using a standardised data extraction form, collecting information on the publication year, study design, number of cases, total sample size, population type, country, continent, mean age and clinical data. The event rate and confidence intervals were calculated.
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Potentially relevant studies identified and screened for retrieval (n=412)
Studies excluded, editorials, reviews, case reports (n=349)
Studies retrieved for more detailed evaluation (n=63) Studies excluded (n=60) 1 meta-analysis, 2 systematic reviews, 57 non randomised studies
Studies included in final analysis (n=3)
Figure 1. Flow of Included Studies.
heterogeneity using the I2 statistic, which represents the percentage of the total variability across studies which is due to heterogeneity. I2 values of 25, 50 and 75% corresponded to low, moderate and high degrees of heterogeneity respectively [8]. The quantified publication bias used the Egger’s regression model [9], with the effect of bias assessed using the fail-safe number method. The fail-safe number was the number of studies that we would need to have missed for our observed result to be nullified to statistical non-significance at the P < 0.05 level. Publication bias is generally regarded as a concern if the fail-safe number is less than 5n + 10, with n being the number of studies included in the meta-analysis [10]. All analyses were performed with Comprehensive Meta-analysis (version 2.0).
Results The original search strategy retrieved 412 studies (Fig. 1). The excluded studies included one meta-analysis [11], two systematic reviews [1,12], 57 non-randomised studies, 349 studies (editorials, reviews, case reports). The abstracts were reviewed and after applying the inclusion and exclusion criteria, articles were selected for full-text evaluation. Of the articles selected, only three studies (2303 patients) met full criteria for analysis and are summarised in Tables 1A and 1B. The years of publication ranged from 2012 to 2013 (Fig. 2).
Procedural Success and Effective Closure Procedural success (ER: 0.942, 95% CI: 0.876–0.974) and effective closure (ER: 0.927, 95% CI: 0.859–0.964) of closure therapy was good.
Odds Ratios Statistical Analysis Pooled odds ratio, event rate and 95% confidence intervals used a random effects model [7]. We tested heterogeneity with Cochran’s Q statistic, with P < 0.10 indicating heterogeneity, and quantified the degree of
The odds ratio for stroke (OR: 0.654, 95% CI: 0.358–1.193) and transient ischaemic attack (OR: 0.768, 95% CI: 0.413–1.429) do not confer an advantage of PFO closure over medical therapy. Age {<45 years (OR: 0.449, 95% CI: 0.117–1.722), >45 years (OR: 0.707, 95% CI: 0.27–1.856)},
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Table 1A. Characteristics of the Studies Included in the Meta-analysis. Author
CLOSURE I Trial (5) Closure
PC Trial (14)
Medical Therapy
Closure
RESPECT Trial (13)
Medical Therapy
Closure
Medical Therapy
Year
2012
2013
2013
Continent
North America
Europe
North America
Device
STARFlex device
Amplatzer PFO Occluder
Amplatzer PFO Occluder
Patients
447
204
499
462
210
481
Procedural success
0.89
0.96
0.96
Effective closure
0.87
0.96
0.94
Mean duration of follow-up
2 years
4.1 years
2.6 years
Death
0
0
2
0
3
6
Stroke
12
13
1
5
9
16
TIA
13
17
5
7
1
6
4
5
6
5
Age <45 years >45 years
5
11
Male
7
15
5
10
Female
15
14
4
4
No
15
20
3
9
7
7
Yes
7
9
4
2
2
9
None or trace or moderate
15
22
7
6
Substantial
3
3
2
10
Major vascular procedural complication
13
0
2
0
3
0
Atrial fibrillation
23
3
6
2
3
3
Major bleeding episode
10
4
1
3
2
0
Any serious adverse event
68
76
43
37
115
104
2
1
2
0
Atrial septal aneurysm
Shunt size
Myocardial infarction
gender {males (OR: 0.498, 95% CI: 0.247–1.004), females (OR: 1.16, 95% CI: 0.597–2.255)}, substantial shunt size (OR: 0.354, 95% CI: 0.089–1.406) and the presence of atrial septal aneurysm (OR: 0.7, 95% CI: 0.21–2.33) did not influence treatment effect of PFO closure (the P values are listed
in Table 3). However, the adverse events like major vascular complication (OR: 10.905, 95% CI: 1.997–59.562) and atrial fibrillation (OR: 3.297, 95% CI: 0.874–12.432) were significantly higher in the closure group. All the results have been tabulated in Tables 2 and 3.
Stroke Study name
Statistics for each study
Odds ratio and 95% CI
Odds Lower Upper ratio limit limit Z-Value p-Value CLOSURE I trial 0.953
0.430
2.111
-0.119
0.905
PC Trial
0.202
0.023
1.744
-1.454
0.146
RESPECT trial
0.534
0.234
1.220
-1.489
0.137
0.654
0.358
1.193
-1.385
0.166 0.01
0.1
1
10
100
Favours Closure Favours Medical Therapy
Figure 2. Stroke.
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Table 1B. Grading of Shunt Size. RESPECT Trial (13)
CLOSURE I Trial (5)
PC Trial (14)
The shunt size was graded according to the number of infused microbubbles in the left atrium within three cardiac cycles after their appearance in the right atrium at rest or during Valsalva release, as seen on a transoesophageal echocardiogram.
Classified PFO shunting based on bubbles appearing in the left atrium either spontaneously or after provocative manoeuvre within five cardiac cycles after opacification of the right atrium. None: No bubbles appearing in the left atrium on Valsalva.
All patients underwent transoesophageal echocardiography for the assessment of PFO Agitated saline solution was injected into an antecubital vein at the end of a vigorous and sustained Valsalva manoeuvre. Spontaneous or provoked right-to-left shunt was semi-quantitatively graded according to the number of bubbles detected in the left atrium after crossing the interatrial septum on a still frame:
Grade 1 indicated 1–9 bubbles; Grade 2, 10–20 bubbles; and Grade 3, more than 20 bubbles
Trace: The distinct appearance of between one and approximately 10 bubbles in the left atrium during the manoeuvre, but at no time does the appearance of the bubbles constitute a concentration that could be circumscribed as a section in the left atrial cavity. Moderate: The distinct appearance of a moderate quantity of bubbles (approximately 10–25) in the left atrium, such that a distinct circumscribable section of the left atrial cavity can be described as filled. Substantial: The distinct appearance of a significant quantity of bubbles (approximately 25 or more) in the left atrium, with some of the bubbles reaching the contralateral left atrial wall, such that complete filling of the left atrial chamber can be described.
Grade 0 = none, Grade 1 = minimal (1–5 bubbles), Grade 2 = moderate (6–20 bubbles), and Grade 3 = severe (>20 bubbles).
Heterogeneity and Publication Bias The heterogeneity of outcomes has been summarised in Tables 2 and 3. The reason for significant heterogeneity may be attributed to different population groups and variation in devices used. No publication bias was detected using the Egger’s regression model.
Discussion Our meta-analysis seeks to understand the available evidence from randomised trials for transcatheter closure in prevention of recurrent neurological events in patients with cryptogenic stroke or TIA, compared with medical management. Agarwal et al. [11] performed a meta-analysis of 48 observational studies to compare the rate of recurrent neurological events (RNE) between transcatheter closure and medical management of patients with cryptogenic stroke/transient ischaemic attack and concomitant patent foramen ovale. The adjusted incidence rates of RNE were 0.8 (95% confidence interval [CI]: 0.5–1.1) events and 5.0 (95% CI: 3.6–6.9) events/100 person-years (PY)
in the transcatheter closure and medical management arms, respectively. Meta-analysis of the limited number of comparative studies and meta-regression analysis suggested that the transcatheter closure might be superior to the medical therapy in prevention of RNE after cryptogenic stroke. 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 PY, with atrial arrhythmias being the most frequent complication. After transcatheter closure, RNE did not seem to be related to the pre-treatment shunt size or the presence of residual shunting in the follow-up period. Significant benefit of transcatheter PFO closure was apparent in elderly patients, patients with concomitant atrial septal aneurysm, and patients with thrombophilia. One of the many shortcomings of comparative observational studies examining patent foramen ovale (PFO) closure versus medical management included in metaanalysis is failure to adjust for potential confounders; therefore, the need for randomised studies would provide the best scientific evidence.
Table 2. Procedural Results. Procedural Results
Pooled Event Rate
95% CI
I2
P value
Procedural success
0.942
0.876–0.974
89.04
<0.001
Effective closure
0.927
0.859–0.964
87.76
<0.001
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Table 3. Outcomes. Primary End Point
Pooled Odds Ratio
95% CI
P value
I2
P value
Mortality
1.058
0.117–9.565
0.96
48.76
0.16
Stroke
0.654
0.358–1.193
0.17
10.31
0.33
TIA
0.768
0.413–1.429
0.41
Age < 45
0.449
0.117–1.722
0.24
22.69
0.26
Age > 45
0.707
0.27–1.856
0.48
29.91
0.23
Male
0.498
0.247–1.004
0.051
Female
1.16
0.597–2.255
Atrial septal aneurysm
0.7
0.21–2.33
Substantial shunt size
0.354
0.089–1.406
0.14
0
0.92
Subgroup analysis
0
0.97
0.66
0
0.71
0.56
54.2
0.11
34.33
0.21
Adverse events Major vascular complication
10.905
1.997–59.562
0.006
Atrial fibrillation
3.297
0.874–12.432
0.078
59.25
0.08
Major bleeding episode
1.77
0.43–7.30
0.43
34.36
0.22
Any serious adverse event
1.092
0.886–1.345
0.41
0
0.81
Myocardial infarction
2.872
0.435–18.960
0.27
0
0.67
CLOSURE 1 (evaluation of the STARFlex septal closure system in patients with a stroke and/or transient ischaemic attack due to presumed paroxysmal embolism through the patent foramen ovale) trial [5] was the first trial that reviewed the benefit of closure over optimal medical therapy. Briefly, the trial enrolled 909 patients at 87 trial sites between the ages of 18 and 60 years. The inclusion criteria included prior ischaemic stroke or transischaemic attack (TIA; radiologic evidence was not a requisite) within the previous six months and presence of a PFO on transoesophageal echocardiography. The trial randomised patients to either PFO closure or medical therapy in 1:1 fashion. The primary endpoints were a composite stroke or TIA during two years of follow-up, as well as death. An atrial septal aneurysm, defined as septal excursion of over 10 mm, was present in 35–37% of patients. Of the 447 patients assigned to the closure group, 405 underwent the actual procedure. Of those, successful closure, defined as implantation of a STARFlex device with no procedural complications, was achieved in 362 participants (89.4% success rate). At six months of follow-up, effective closure, defined as grade 0 or 1 residual shunt, was documented in 315 patients (86.1% closure rate). After two years of follow-up, a statistically non-significant difference in the incidence of the primary endpoint was found (5.5% closure group vs 6.2% medical therapy group [adjusted hazard ratio (HR), 0.78; 95% confidence interval [CI], 0.45–1.35; P = .37]). The insignificant trend towards better outcome with PFO closure was driven by less TIAs in the closure group (3.1% closure group vs 4.1%; adjusted HR, 0.75; 95% CI: 0.36–1.55; P = .44). Stroke occurrence was identical among patients undergoing PFO closure compared to medically treated patients (2.9% vs 3.1%; adjusted HR, 0.90; 95% CI: 0.41–1.98; P = .79). Further, no differences were found comparing the treatment modalities “per protocol” as compared to “intention to treat.” Unexpectedly,
0
0.65
potential alternative explanations for recurrent neurologic events (as opposed to PFO-mediated) were found in 80% of patients. Not unexpectedly, adverse events were more common in the PFO closure group. Vascular complication rate was 3.2% in the PFO closure group, with none in the medical treatment arm. Incidence of atrial fibrillation was higher in the closure group as compared to the medical treatment group (5.7 vs 0.7%; P < .001). Prespecified subgroup analysis did not demonstrate any increased benefit from closure in subgroups such as patients with atrial septal aneurysm or substantial right-to-left shunt. The RESPECT (randomised evaluation of recurrent stroke comparing PFO closure to established current standard of care) trial [13] a multicentre trial randomising PFO closure with the Amplatzer PFO occluder versus medical management, which could be either therapy with antiplatelets or anticoagulants. The trial enrolled 980 patients with prior cryptogenic stroke and a PFO between the ages of 18 and 60 years. TIAs were not included. Primary endpoints were recurrence of stroke or death. Device implantation was attempted in 464 patients. Atrial septal aneurysms were present in one-third of patients. Procedural success was 96.1% and effective closure was achieved in 93.5% of patients. One important distinction from CLOSURE 1 is the very low incidence of procedural complications, with no device-related thrombus formation or device embolisation. Major bleeding occurred in 1.6% and major vascular complications in 0.8% of cases. Median follow-up time was 2.2 years (range, 0–8.1 years). There were fewer patient dropouts in the device group (n = 48) as compared to the medical treatment group (n = 90). During follow-up, recurrent strokes occurred in nine patients in the PFO closure group compared to 16 events in the medical treatment group. Of the nine patients in the PFO closure group, three patients suffered a recurrent stroke following randomisation, but prior to PFO closure. As
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a consequence, the primary endpoint was not reached in the intention-to-treat analysis (relative risk reduction, 46.6%; P = .157), while the “as-treated analysis” (classifying patients into treatment groups according to the treatment they actually received) was statistically significant (relative risk reduction, 72.7%; P = .007). Overall, recurrent event rate was low; at five years, recurrent strokes occurred in 2.21% of patients as compared to 6.4% in the medically treated patients. Important findings of the study included two groups of patients with PFO who benefited the most from PFO closure: patients with substantial shunt size (recurrent event rate 0.8% for PFO closure vs 4.3% for medical management; HR, 0.178; 95% CI: 0.039–0.813), as well as patients with atrial septal aneurysm (recurrent event rate 1.1% for PFO closure vs 5.3% for medical management; HR, 0.187; 95% CI: 0.04–0.867). The latter group was substantiated in other non-randomised studies. Another randomised trial, the PC-Trial (percutaneous closure of PFO versus medical management in patients with cryptogenic stroke) [14], a European trial, randomised 414 patients to the two treatment strategies. Patients had to be less than 60 years of age and strokes and TIAs were allowed as index events. The primary endpoints were a composite of death, stroke, TIA, or peripheral embolism. The trial documented no statistically significant benefit of PFO closure compared to medical management (HR, 0.63; 95% CI: 0.24–1.62; P = .34). Because of a low event rate of recurrent events, the study was underpowered, questioning the validity of subgroup analyses. A little less than a quarter of patients enrolled had an atrial septal aneurysm. Presence or absence of this septal abnormality did not influence treatment effect of PFO closure.
Age and Transcatheter Closure A strong association has been demonstrated between cryptogenic stroke and PFO in patients <55 years of age [15]. Due to the greater number of stroke causes in older patients, the relationship between cryptogenic stroke and PFO is harder to establish in these patients [16]. We observed a higher rate of RNE in the older age group managed medically as compared with the younger age group [age < 45 years (OR: 0.449, 95% CI: 0.117–1.722), age > 45 years (OR: 0.707, 95% CI: 0.27–1.856)]. This result demonstrates the multifactorial aetiology of stroke in older patients and keeping in mind this statistical insignificant result PFO closure does not seem to have an obvious advantage in secondary stroke prevention over medical therapy.
Morphology of the PFO and Transcatheter Closure There have been several morphological attributes of PFO—such as tunnel length, size, presence or absence of multiple fenestrations, relative thickness of the septal components, ASA, and septal hypermobility—that have influenced the choice of devices across the published data. The prevalence of ASA in the general population has been estimated to range between 1% in autopsy studies and 2.2% in the echocardiography-based studies [17]. The presence of PFO with ASA has been shown to increase the
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risk of RNE. Our meta-analysis demonstrated PFO closure does not confer an advantage over medical therapy among individuals with PFO and ASA. Additionally, stroke patients with larger PFOs have brain imaging findings suggestive of an embolic mechanism [18], and PFO size may be an independent risk factor for recurrent cerebrovascular events [19]. PFO in Cryptogenic Stroke Study (PICSS) has shown that large PFOs were significantly more prevalent among cryptogenic stroke patients compared with those with known cause of stroke [20]. We observed that transcatheter PFO closure was not beneficial in patients with substantial shunt size.
Complications Closure of a PFO remains an invasive procedure and is not without complications. One review of 1970 patients in 11 different studies who underwent percutaneous PFO closure found cardiac tamponade in 0.3%, transient ischaemic attacks (TIAs) in 0.2%, device embolisation (and successful retrieval) in 1.1% and vascular access site problems in 1.5% [21]. There were no reported deaths, myocardial infarctions or stroke. Another review of 1349 patients found new onset of atrial fibrillation (AF) within four weeks of closure, with the arrhythmia being persistent in around half these cases [22]. In our analysis, major vascular complication (OR: 10.905, 95% CI: 1.997–59.562) and atrial fibrillation (OR: 3.297, 95% CI: 0.874–12.432) were substantially higher in the closure group. As cardiologists become more experienced with the implantation of PFO closure devices, it is likely that the rates of complications will lessen. Some preliminary conclusions can be drawn from this meta-analysis. PFO closure with contemporary devices is associated with adverse events like major vascular complication (OR: 10.905, 95% CI: 1.997–59.562) and atrial fibrillation (OR: 3.297, 95% CI: 0.874–12.432). A growing interest has been observed recently in the connection between the PFO and diving accidents [23] or migraine [24–26]. PFO closure does not confer an advantage over medical therapy on the basis of this meta-analysis. PFO closure should be recommended on a case to case basis as risks may outweigh the benefits. We must await the results of appropriately designed studies with extended followup comparing PFO closure plus long-term antiplatelet therapy with best medical therapy before we know whether PFO closure is beneficial in cryptogenic stroke in the long term.
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[17] Wahl A, Krumsdorf U, Meier B, Sievert H, Ostermayer S, Billinger K, et al. Transcatheter treatment of atrial septal aneurysm associated with patent foramen ovale for prevention of recurrent paradoxical embolism in high-risk patients. J Am Coll Cardiol 2005;45(3):377–80. [18] Steiner MM, Di Tullio MR, Rundek T, Gan R, Chen X, Liguori C, et al. Patent foramen ovale size and embolic brain imaging findings among patients with ischemic stroke. Stroke 1998;29(May (5)):944–8. [19] Schuchlenz HW, Weihs W, Horner S, Quehenberger F. The association between the diameter of a patent foramen ovale and the risk of embolic cerebrovascular events. Am J Med 2000;109(6):456–62. [20] Homma S, Sacco RL, Di Tullio MR, Sciacca RR, Mohr JP. Investigators ftPiCSS effect of medical treatment in stroke patients with patent foramen ovale: patent foramen ovale in cryptogenic stroke study. Circulation 2002;105(June (4)):2625–31. [21] Wohrle J. Closure of patent foramen ovale after cryptogenic stroke. Lancet 2006;368(9533):350–2. [22] Staubach S, Steinberg DH, Zimmermann W, Wawra N, Wilson N, Wunderlich N, et al. New onset atrial fibrillation after patent foramen ovale closure. Catheter Cardiovasc Interv 2009;74(6):889–95. [23] Schwerzmann M, Seiler C, Lipp E, Guzman R, Lovblad KO, Kraus M, et al. Relation between directly detected patent foramen ovale and ischemic brain lesions in sport divers. Ann Intern Med 2001;134(1):21–4. [24] Butera G, Biondi-Zoccai GG, Carminati M, Caputi L, Usai S, Bussone G, et al. Systematic review and metaanalysis of currently available clinical evidence on migraine and patent foramen ovale percutaneous closure: much ado about nothing? Catheter Cardiovasc Interv 2010;75(4): 494–504. [25] Wilmshurst PT, Nightingale S, Walsh KP, Morrison WL. Effect on migraine of closure of cardiac right-to-left shunts to prevent recurrence of decompression illness or stroke or for haemodynamic reasons. Lancet 2000;356(9242): 1648–51. [26] Rigatelli G, Dell’Avvocata F, Ronco F, Cardaioli P, Giordan M, Braggion G, et al. Primary transcatheter patent foramen ovale closure is effective in improving migraine in patients with high-risk anatomic and functional characteristics for paradoxical embolism. JACC Cardiovasc Interv 2010;3(3): 282–7.
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Review
Is Transcatheter Closure Better than Medical Therapy for Cryptogenic Stroke with Patent Foramen Ovale? A Meta-analysis of Randomised Trials Vinayak Nagaraja, MBBS a , Jwalant Raval, MBBS b,∗ , Guy D. Eslick, MMedSc (Clin Epi), MMedStat c , David Burgess, BMed, PhD b,d and A. Robert Denniss, MD, MSc b,d a
c
Prince of Wales Hospital, Sydney, Australia b Blacktown Hospital, Sydney, Australia The Whiteley-Martin Research Centre, Discipline of Surgery, The University of Sydney, Nepean Hospital, Sydney, Australia d University of Western Sydney, Australia
Introduction: The prevalence of patent foramen ovale among patients with cryptogenic stroke is higher than that in the general population. Closure with a percutaneous device is often recommended in such patients, but it is not known whether this intervention reduces the risk of recurrent stroke. Methods: A systematic search was conducted using MEDLINE, PubMed, EMBASE, Current Contents Connect, Cochrane library, Google Scholar, Science Direct, and Web of Science. Original data were abstracted from each study and used to calculate a pooled event rate (ER), odd ratio (OR) and 95% confidence interval (95% CI). Results: Only three randomised trials comprising 2303 patients met full criteria for analysis. Procedural success (ER: 94.20%, 95% CI: 87.6–97.4%) and effective closure (ER: 92.70%, 95% CI: 85.9–96.4%) of closure therapy were good. The odds ratio for stroke (OR: 0.654, 95% CI: 0.358–1.193) and transient ischaemic attack (OR: 0.768, 95% CI: 0.413–1.429) did not confer a benefit of PFO closure over medical therapy. Age {<45 years (OR: 0.449, 95% CI: 0.117–1.722), >45 years (OR: 0.707, 95% CI: 0.27–1.856)}, gender {males (OR: 0.498, 95% CI: 0.247–1.004), females (OR: 1.16, 95% CI: 0.597–2.255)}, substantial shunt size (OR: 0.354, 95% CI: 0.089–1.406) and the presence of atrial septal aneurysm (OR: 0.7, 95% CI: 0.21–2.33) did not influence the treatment effect of PFO closure. However, the adverse events like major vascular complication (OR: 10.905, 95% CI: 1.997–59.562) and atrial fibrillation (OR: 3.297, 95% CI: 0.874–12.432) were significantly higher in the closure group. Conclusions: In patients with cryptogenic stroke or TIA who had a patent foramen ovale, closure with a device does not confer an advantage over medical therapy and is associated with adverse events like major vascular complication and atrial fibrillation. (Heart, Lung and Circulation 2013;22:903–909) © 2013 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier Inc. All rights reserved. Keywords. Patent foramen ovale; Cryptogenic stroke; Transcatheter closure; Randomised trials; Medical therapy
Introduction
E
pidemiological studies have found a prevalence of 44–66% of patent foramen ovale (PFO) in patients with cryptogenic stroke as compared with 27% in autopsy series of all-cause deaths [1]. The higher prevalence of Received 18 April 2013; received in revised form 8 July 2013; accepted 24 July 2013; available online 10 September 2013 ∗
Corresponding author at: Department of Cardiology, Blacktown Hospital, Australia. Tel.: +61 029881800. E-mail address: jwalant [email protected] (J. Raval).
PFO in patients with cryptogenic stroke suggests that at least in some patients with cryptogenic stroke, the cause of stroke might be paradoxical thromboembolism. The optimal management strategy for treating patients with cryptogenic stroke (CS) who are discovered to have a patent foramen ovale (PFO) remains to be defined. The advent of percutaneously implantable devices has offered a widely applicable closure approach not requiring open heart surgery. Catheter-based closure of patent foramen ovale was introduced in 1992 [2]. Percutaneous closure has been available for over 20 years with very little hard evidence to guide patient and device selection. Investigators
© 2013 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier Inc. All rights reserved.
1443-9506/04/$36.00 http://dx.doi.org/10.1016/j.hlc.2013.07.022
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have used their own clinical judgement to decide when and how to percutaneously close PFO. Observational long-term data suggest that closure of patent foramen ovale in patients with a history of ischaemic stroke may reduce the risk of recurrent stroke as compared with medical therapy alone [3,4]. CLOSURE 1 trial [5] failed to demonstrate any significant difference in recurrent neurological events with PFO closure compared with medical management with antiplatelet or anticoagulation therapy. Recently three randomised trials have reviewed the benefit of closure over optimal medical therapy. We synthesised the available evidence from the randomised trials on secondary stroke prevention in patients with patent foramen ovale and cryptogenic stroke and primarily focus on the comparison of the two strategies.
Methods Study Protocol We followed the Preferred Reporting Items for Systematic reviews and Meta-analyses PRISMA guidelines where possible in performing our systematic review [6]. We performed a systematic search through MEDLINE (from 1950), PubMed (from 1946), EMBASE (from 1949), Current Contents Connect (from 1998), Cochrane library, Google scholar, Science Direct, and Web of Science to May 2013. The search terms included “patent foramen ovale,” “PFO,” “atrial septal aneurysm,” “ASA transcatheter closure,” “heart septal defects (atrial),” “interatrial shunt,” “recurrent thromboembolism,” “recurrent stroke,” and “recurrent TIA.” which were searched as text word and as exploded medical subject headings where possible. No language restrictions were used in either the search or study selection. The reference lists of relevant articles were also searched for appropriate studies. A search for unpublished literature was not performed.
Study Selection We included studies that met the following inclusion criteria: • Studies identifying the population of patients with patent foramen ovale with cryptogenic stroke. • Randomised controlled trials comparing transcatheter closure and medical therapy.
Data Extraction We performed the data extraction using a standardised data extraction form, collecting information on the publication year, study design, number of cases, total sample size, population type, country, continent, mean age and clinical data. The event rate and confidence intervals were calculated.
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Potentially relevant studies identified and screened for retrieval (n=412)
Studies excluded, editorials, reviews, case reports (n=349)
Studies retrieved for more detailed evaluation (n=63) Studies excluded (n=60) 1 meta-analysis, 2 systematic reviews, 57 non randomised studies
Studies included in final analysis (n=3)
Figure 1. Flow of Included Studies.
heterogeneity using the I2 statistic, which represents the percentage of the total variability across studies which is due to heterogeneity. I2 values of 25, 50 and 75% corresponded to low, moderate and high degrees of heterogeneity respectively [8]. The quantified publication bias used the Egger’s regression model [9], with the effect of bias assessed using the fail-safe number method. The fail-safe number was the number of studies that we would need to have missed for our observed result to be nullified to statistical non-significance at the P < 0.05 level. Publication bias is generally regarded as a concern if the fail-safe number is less than 5n + 10, with n being the number of studies included in the meta-analysis [10]. All analyses were performed with Comprehensive Meta-analysis (version 2.0).
Results The original search strategy retrieved 412 studies (Fig. 1). The excluded studies included one meta-analysis [11], two systematic reviews [1,12], 57 non-randomised studies, 349 studies (editorials, reviews, case reports). The abstracts were reviewed and after applying the inclusion and exclusion criteria, articles were selected for full-text evaluation. Of the articles selected, only three studies (2303 patients) met full criteria for analysis and are summarised in Tables 1A and 1B. The years of publication ranged from 2012 to 2013 (Fig. 2).
Procedural Success and Effective Closure Procedural success (ER: 0.942, 95% CI: 0.876–0.974) and effective closure (ER: 0.927, 95% CI: 0.859–0.964) of closure therapy was good.
Odds Ratios Statistical Analysis Pooled odds ratio, event rate and 95% confidence intervals used a random effects model [7]. We tested heterogeneity with Cochran’s Q statistic, with P < 0.10 indicating heterogeneity, and quantified the degree of
The odds ratio for stroke (OR: 0.654, 95% CI: 0.358–1.193) and transient ischaemic attack (OR: 0.768, 95% CI: 0.413–1.429) do not confer an advantage of PFO closure over medical therapy. Age {<45 years (OR: 0.449, 95% CI: 0.117–1.722), >45 years (OR: 0.707, 95% CI: 0.27–1.856)},
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Table 1A. Characteristics of the Studies Included in the Meta-analysis. Author
CLOSURE I Trial (5) Closure
PC Trial (14)
Medical Therapy
Closure
RESPECT Trial (13)
Medical Therapy
Closure
Medical Therapy
Year
2012
2013
2013
Continent
North America
Europe
North America
Device
STARFlex device
Amplatzer PFO Occluder
Amplatzer PFO Occluder
Patients
447
204
499
462
210
481
Procedural success
0.89
0.96
0.96
Effective closure
0.87
0.96
0.94
Mean duration of follow-up
2 years
4.1 years
2.6 years
Death
0
0
2
0
3
6
Stroke
12
13
1
5
9
16
TIA
13
17
5
7
1
6
4
5
6
5
Age <45 years >45 years
5
11
Male
7
15
5
10
Female
15
14
4
4
No
15
20
3
9
7
7
Yes
7
9
4
2
2
9
None or trace or moderate
15
22
7
6
Substantial
3
3
2
10
Major vascular procedural complication
13
0
2
0
3
0
Atrial fibrillation
23
3
6
2
3
3
Major bleeding episode
10
4
1
3
2
0
Any serious adverse event
68
76
43
37
115
104
2
1
2
0
Atrial septal aneurysm
Shunt size
Myocardial infarction
gender {males (OR: 0.498, 95% CI: 0.247–1.004), females (OR: 1.16, 95% CI: 0.597–2.255)}, substantial shunt size (OR: 0.354, 95% CI: 0.089–1.406) and the presence of atrial septal aneurysm (OR: 0.7, 95% CI: 0.21–2.33) did not influence treatment effect of PFO closure (the P values are listed
in Table 3). However, the adverse events like major vascular complication (OR: 10.905, 95% CI: 1.997–59.562) and atrial fibrillation (OR: 3.297, 95% CI: 0.874–12.432) were significantly higher in the closure group. All the results have been tabulated in Tables 2 and 3.
Stroke Study name
Statistics for each study
Odds ratio and 95% CI
Odds Lower Upper ratio limit limit Z-Value p-Value CLOSURE I trial 0.953
0.430
2.111
-0.119
0.905
PC Trial
0.202
0.023
1.744
-1.454
0.146
RESPECT trial
0.534
0.234
1.220
-1.489
0.137
0.654
0.358
1.193
-1.385
0.166 0.01
0.1
1
10
100
Favours Closure Favours Medical Therapy
Figure 2. Stroke.
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Table 1B. Grading of Shunt Size. RESPECT Trial (13)
CLOSURE I Trial (5)
PC Trial (14)
The shunt size was graded according to the number of infused microbubbles in the left atrium within three cardiac cycles after their appearance in the right atrium at rest or during Valsalva release, as seen on a transoesophageal echocardiogram.
Classified PFO shunting based on bubbles appearing in the left atrium either spontaneously or after provocative manoeuvre within five cardiac cycles after opacification of the right atrium. None: No bubbles appearing in the left atrium on Valsalva.
All patients underwent transoesophageal echocardiography for the assessment of PFO Agitated saline solution was injected into an antecubital vein at the end of a vigorous and sustained Valsalva manoeuvre. Spontaneous or provoked right-to-left shunt was semi-quantitatively graded according to the number of bubbles detected in the left atrium after crossing the interatrial septum on a still frame:
Grade 1 indicated 1–9 bubbles; Grade 2, 10–20 bubbles; and Grade 3, more than 20 bubbles
Trace: The distinct appearance of between one and approximately 10 bubbles in the left atrium during the manoeuvre, but at no time does the appearance of the bubbles constitute a concentration that could be circumscribed as a section in the left atrial cavity. Moderate: The distinct appearance of a moderate quantity of bubbles (approximately 10–25) in the left atrium, such that a distinct circumscribable section of the left atrial cavity can be described as filled. Substantial: The distinct appearance of a significant quantity of bubbles (approximately 25 or more) in the left atrium, with some of the bubbles reaching the contralateral left atrial wall, such that complete filling of the left atrial chamber can be described.
Grade 0 = none, Grade 1 = minimal (1–5 bubbles), Grade 2 = moderate (6–20 bubbles), and Grade 3 = severe (>20 bubbles).
Heterogeneity and Publication Bias The heterogeneity of outcomes has been summarised in Tables 2 and 3. The reason for significant heterogeneity may be attributed to different population groups and variation in devices used. No publication bias was detected using the Egger’s regression model.
Discussion Our meta-analysis seeks to understand the available evidence from randomised trials for transcatheter closure in prevention of recurrent neurological events in patients with cryptogenic stroke or TIA, compared with medical management. Agarwal et al. [11] performed a meta-analysis of 48 observational studies to compare the rate of recurrent neurological events (RNE) between transcatheter closure and medical management of patients with cryptogenic stroke/transient ischaemic attack and concomitant patent foramen ovale. The adjusted incidence rates of RNE were 0.8 (95% confidence interval [CI]: 0.5–1.1) events and 5.0 (95% CI: 3.6–6.9) events/100 person-years (PY)
in the transcatheter closure and medical management arms, respectively. Meta-analysis of the limited number of comparative studies and meta-regression analysis suggested that the transcatheter closure might be superior to the medical therapy in prevention of RNE after cryptogenic stroke. 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 PY, with atrial arrhythmias being the most frequent complication. After transcatheter closure, RNE did not seem to be related to the pre-treatment shunt size or the presence of residual shunting in the follow-up period. Significant benefit of transcatheter PFO closure was apparent in elderly patients, patients with concomitant atrial septal aneurysm, and patients with thrombophilia. One of the many shortcomings of comparative observational studies examining patent foramen ovale (PFO) closure versus medical management included in metaanalysis is failure to adjust for potential confounders; therefore, the need for randomised studies would provide the best scientific evidence.
Table 2. Procedural Results. Procedural Results
Pooled Event Rate
95% CI
I2
P value
Procedural success
0.942
0.876–0.974
89.04
<0.001
Effective closure
0.927
0.859–0.964
87.76
<0.001
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Table 3. Outcomes. Primary End Point
Pooled Odds Ratio
95% CI
P value
I2
P value
Mortality
1.058
0.117–9.565
0.96
48.76
0.16
Stroke
0.654
0.358–1.193
0.17
10.31
0.33
TIA
0.768
0.413–1.429
0.41
Age < 45
0.449
0.117–1.722
0.24
22.69
0.26
Age > 45
0.707
0.27–1.856
0.48
29.91
0.23
Male
0.498
0.247–1.004
0.051
Female
1.16
0.597–2.255
Atrial septal aneurysm
0.7
0.21–2.33
Substantial shunt size
0.354
0.089–1.406
0.14
0
0.92
Subgroup analysis
0
0.97
0.66
0
0.71
0.56
54.2
0.11
34.33
0.21
Adverse events Major vascular complication
10.905
1.997–59.562
0.006
Atrial fibrillation
3.297
0.874–12.432
0.078
59.25
0.08
Major bleeding episode
1.77
0.43–7.30
0.43
34.36
0.22
Any serious adverse event
1.092
0.886–1.345
0.41
0
0.81
Myocardial infarction
2.872
0.435–18.960
0.27
0
0.67
CLOSURE 1 (evaluation of the STARFlex septal closure system in patients with a stroke and/or transient ischaemic attack due to presumed paroxysmal embolism through the patent foramen ovale) trial [5] was the first trial that reviewed the benefit of closure over optimal medical therapy. Briefly, the trial enrolled 909 patients at 87 trial sites between the ages of 18 and 60 years. The inclusion criteria included prior ischaemic stroke or transischaemic attack (TIA; radiologic evidence was not a requisite) within the previous six months and presence of a PFO on transoesophageal echocardiography. The trial randomised patients to either PFO closure or medical therapy in 1:1 fashion. The primary endpoints were a composite stroke or TIA during two years of follow-up, as well as death. An atrial septal aneurysm, defined as septal excursion of over 10 mm, was present in 35–37% of patients. Of the 447 patients assigned to the closure group, 405 underwent the actual procedure. Of those, successful closure, defined as implantation of a STARFlex device with no procedural complications, was achieved in 362 participants (89.4% success rate). At six months of follow-up, effective closure, defined as grade 0 or 1 residual shunt, was documented in 315 patients (86.1% closure rate). After two years of follow-up, a statistically non-significant difference in the incidence of the primary endpoint was found (5.5% closure group vs 6.2% medical therapy group [adjusted hazard ratio (HR), 0.78; 95% confidence interval [CI], 0.45–1.35; P = .37]). The insignificant trend towards better outcome with PFO closure was driven by less TIAs in the closure group (3.1% closure group vs 4.1%; adjusted HR, 0.75; 95% CI: 0.36–1.55; P = .44). Stroke occurrence was identical among patients undergoing PFO closure compared to medically treated patients (2.9% vs 3.1%; adjusted HR, 0.90; 95% CI: 0.41–1.98; P = .79). Further, no differences were found comparing the treatment modalities “per protocol” as compared to “intention to treat.” Unexpectedly,
0
0.65
potential alternative explanations for recurrent neurologic events (as opposed to PFO-mediated) were found in 80% of patients. Not unexpectedly, adverse events were more common in the PFO closure group. Vascular complication rate was 3.2% in the PFO closure group, with none in the medical treatment arm. Incidence of atrial fibrillation was higher in the closure group as compared to the medical treatment group (5.7 vs 0.7%; P < .001). Prespecified subgroup analysis did not demonstrate any increased benefit from closure in subgroups such as patients with atrial septal aneurysm or substantial right-to-left shunt. The RESPECT (randomised evaluation of recurrent stroke comparing PFO closure to established current standard of care) trial [13] a multicentre trial randomising PFO closure with the Amplatzer PFO occluder versus medical management, which could be either therapy with antiplatelets or anticoagulants. The trial enrolled 980 patients with prior cryptogenic stroke and a PFO between the ages of 18 and 60 years. TIAs were not included. Primary endpoints were recurrence of stroke or death. Device implantation was attempted in 464 patients. Atrial septal aneurysms were present in one-third of patients. Procedural success was 96.1% and effective closure was achieved in 93.5% of patients. One important distinction from CLOSURE 1 is the very low incidence of procedural complications, with no device-related thrombus formation or device embolisation. Major bleeding occurred in 1.6% and major vascular complications in 0.8% of cases. Median follow-up time was 2.2 years (range, 0–8.1 years). There were fewer patient dropouts in the device group (n = 48) as compared to the medical treatment group (n = 90). During follow-up, recurrent strokes occurred in nine patients in the PFO closure group compared to 16 events in the medical treatment group. Of the nine patients in the PFO closure group, three patients suffered a recurrent stroke following randomisation, but prior to PFO closure. As
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a consequence, the primary endpoint was not reached in the intention-to-treat analysis (relative risk reduction, 46.6%; P = .157), while the “as-treated analysis” (classifying patients into treatment groups according to the treatment they actually received) was statistically significant (relative risk reduction, 72.7%; P = .007). Overall, recurrent event rate was low; at five years, recurrent strokes occurred in 2.21% of patients as compared to 6.4% in the medically treated patients. Important findings of the study included two groups of patients with PFO who benefited the most from PFO closure: patients with substantial shunt size (recurrent event rate 0.8% for PFO closure vs 4.3% for medical management; HR, 0.178; 95% CI: 0.039–0.813), as well as patients with atrial septal aneurysm (recurrent event rate 1.1% for PFO closure vs 5.3% for medical management; HR, 0.187; 95% CI: 0.04–0.867). The latter group was substantiated in other non-randomised studies. Another randomised trial, the PC-Trial (percutaneous closure of PFO versus medical management in patients with cryptogenic stroke) [14], a European trial, randomised 414 patients to the two treatment strategies. Patients had to be less than 60 years of age and strokes and TIAs were allowed as index events. The primary endpoints were a composite of death, stroke, TIA, or peripheral embolism. The trial documented no statistically significant benefit of PFO closure compared to medical management (HR, 0.63; 95% CI: 0.24–1.62; P = .34). Because of a low event rate of recurrent events, the study was underpowered, questioning the validity of subgroup analyses. A little less than a quarter of patients enrolled had an atrial septal aneurysm. Presence or absence of this septal abnormality did not influence treatment effect of PFO closure.
Age and Transcatheter Closure A strong association has been demonstrated between cryptogenic stroke and PFO in patients <55 years of age [15]. Due to the greater number of stroke causes in older patients, the relationship between cryptogenic stroke and PFO is harder to establish in these patients [16]. We observed a higher rate of RNE in the older age group managed medically as compared with the younger age group [age < 45 years (OR: 0.449, 95% CI: 0.117–1.722), age > 45 years (OR: 0.707, 95% CI: 0.27–1.856)]. This result demonstrates the multifactorial aetiology of stroke in older patients and keeping in mind this statistical insignificant result PFO closure does not seem to have an obvious advantage in secondary stroke prevention over medical therapy.
Morphology of the PFO and Transcatheter Closure There have been several morphological attributes of PFO—such as tunnel length, size, presence or absence of multiple fenestrations, relative thickness of the septal components, ASA, and septal hypermobility—that have influenced the choice of devices across the published data. The prevalence of ASA in the general population has been estimated to range between 1% in autopsy studies and 2.2% in the echocardiography-based studies [17]. The presence of PFO with ASA has been shown to increase the
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risk of RNE. Our meta-analysis demonstrated PFO closure does not confer an advantage over medical therapy among individuals with PFO and ASA. Additionally, stroke patients with larger PFOs have brain imaging findings suggestive of an embolic mechanism [18], and PFO size may be an independent risk factor for recurrent cerebrovascular events [19]. PFO in Cryptogenic Stroke Study (PICSS) has shown that large PFOs were significantly more prevalent among cryptogenic stroke patients compared with those with known cause of stroke [20]. We observed that transcatheter PFO closure was not beneficial in patients with substantial shunt size.
Complications Closure of a PFO remains an invasive procedure and is not without complications. One review of 1970 patients in 11 different studies who underwent percutaneous PFO closure found cardiac tamponade in 0.3%, transient ischaemic attacks (TIAs) in 0.2%, device embolisation (and successful retrieval) in 1.1% and vascular access site problems in 1.5% [21]. There were no reported deaths, myocardial infarctions or stroke. Another review of 1349 patients found new onset of atrial fibrillation (AF) within four weeks of closure, with the arrhythmia being persistent in around half these cases [22]. In our analysis, major vascular complication (OR: 10.905, 95% CI: 1.997–59.562) and atrial fibrillation (OR: 3.297, 95% CI: 0.874–12.432) were substantially higher in the closure group. As cardiologists become more experienced with the implantation of PFO closure devices, it is likely that the rates of complications will lessen. Some preliminary conclusions can be drawn from this meta-analysis. PFO closure with contemporary devices is associated with adverse events like major vascular complication (OR: 10.905, 95% CI: 1.997–59.562) and atrial fibrillation (OR: 3.297, 95% CI: 0.874–12.432). A growing interest has been observed recently in the connection between the PFO and diving accidents [23] or migraine [24–26]. PFO closure does not confer an advantage over medical therapy on the basis of this meta-analysis. PFO closure should be recommended on a case to case basis as risks may outweigh the benefits. We must await the results of appropriately designed studies with extended followup comparing PFO closure plus long-term antiplatelet therapy with best medical therapy before we know whether PFO closure is beneficial in cryptogenic stroke in the long term.
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