REVIEW ARTICLE
Current evidence for closure of a patent foramen ovale for cryptogenic stroke prevention E. Rhone,1 N. Chung,2 B. Clapp2
1
SUMMARY
Review criteria
A patent foramen ovale (PFO) has long been implicated as a potential mechanism for cryptogenic stroke (CS), which accounts for up to 40% of all cases of ischaemic stroke. Although there is a strong association between a PFO and CS, there is less evidence that percutaneous closure of the defect, as opposed to medical therapy with antithrombotics or anticoagulants, is the most effective form of secondary prevention. The aim of this review is to examine the evidence comparing percutaneous closure with medical therapy, with a particular focus on three recently published randomised controlled trials.
Association between PFO and cryptogenic stroke A patent foramen ovale (PFO) is a remnant of the normal fetal circulation that persists into adulthood in approximately 25% of the population (1). It has been identified as a potential route for the transfer of embolic material from the venous to the systemic arterial circulation (a process known as paradoxical embolism) and has been implicated as a possible mechanism for cryptogenic stroke (CS) which accounts for up to 40% of all cases of ischaemic strokes (2). The visualisation of an embolus trapped in a PFO is a rare, but well-documented event, with numerous case reports describing echocardiograms demonstrating a thrombus caught in transit through a PFO (3). Several cross-sectional studies have demonstrated that the presence of a PFO is a much more common finding in patients that have experienced CS compared with the general population. Lechat et al. demonstrated a prevalence for PFO of 58% in patients with CS compared to 10% in stroke-free controls (4), whereas Webster et al. found a PFO in 56% of patients with CS compared to 15% of a control group (5). A meta-analysis of case–control studies showed that patients with CS under 55 years of age were six times more likely to have a PFO than patients with other forms of stroke and that PFOmediated stroke risk was greatly potentiated by the presence of a coexisting atrial septal aneurysm (ASA) with these individuals having an odds ratios of 4.96 for ischaemic stroke and 23.26 for CS (6). ª 2013 John Wiley & Sons Ltd Int J Clin Pract, May 2014, 68, 5, 551–556. doi: 10.1111/ijcp.12312
PUBMED cited articles on cryptogenic stroke and patent foramen ovalve.
Message for the clinic In cases of cryptogenic stroke where other causes of the event have been excluded closure of a patent foramen ovale may provide effective secondary prevention.
These retrospective studies strongly suggest an association between the presence of a PFO and an increased risk of CS. Two prospective populationbased cohort studies (SPARC and NOMAS) attempted to evaluate the risk of first time ischaemic stroke associated with the presence of a PFO, an important question because of the high prevalence of PFO within the general population. Both found that the presence of a PFO was not a significant independent predictor of ischaemic stroke. However, both studies failed to separate CS from ischaemic stroke and additionally, had samples that consisted of relatively elderly populations in whom traditional risk factors are likely to play a larger role in first time stroke than the presence of a PFO (7,8).
Kings College London Medical School, London, UK 2 Department of Cardiology, St Thomas’ Hospital, London, UK Correspondence to: Brian Clapp, PhD, FRCP, Department of Cardiology, St Thomas’ Hospital, Westminster Bridge Road, London SE1 7EH, UK Tel.: + 020 71881049 Fax: + 020 71881011 Email: [email protected]
Disclosure Dr Clapp has received speaking fees and acted as a consultant for St Jude Medical. Neither Dr Chung nor Mr Rhone has any competing interests to declare.
Secondary prevention of stroke Given the high prevalence of PFOs, combined with the relatively low lifetime risk that a PFO will be symptomatic, screening is not considered justifiable and therefore primary prevention is not recommended. Instead, secondary prevention of the recurrence of neurological events in patients with PFO who have suffered a CS is the main focus (2). If the presence of a PFO is deemed to be a significant factor, there are two approaches that can be taken to prevent recurrence: closure of the PFO via surgical or percutaneous means with a view to blocking the potential pathway for paradoxical embolization, or by preventing the formation of embolic material using antithrombotic treatment (antiplatelet agents such as aspirin, clopidogrel and dipyridamole
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or anticoagulants such as warfarin) (1). Which medical therapy is more effective is still controversial. Both antiplatelet and anticoagulation therapy may be effective at preventing recurrent stroke (9,10). Therefore, antiplatelet therapy is often favoured because of a presumed higher benefit/risk ratio, because anticoagulation is associated with a higher risk of haemorrhage and requires intensive monitoring and doseadjustment (2). In 2004, the quality standards subcommittee of the American Academy of Neurology published evidence-based guidelines indicating that because ischaemic stroke patients with and without PFO have similar adverse event rates while receiving medical treatment, it is not deemed necessary to close PFOs unless there is a contraindication to medical therapy or there is recurrence of stroke whilst on medical therapy (11). Despite this guidance, biological plausibility was felt to suggest that if a PFO is associated with an increased risk of stroke, closing the hole would be of value and significant numbers of patients were treated on this basis. Extensive research has been conducted comparing the efficacy of device closure with that of medical therapy.
Is closure of a PFO superior to medical therapy? In 2003, a systematic review evaluating transcatheter closure and medical therapy in patients with a PFO and presumed paradoxical embolus found a 1-year rate of recurrent stroke/TIA to be 0–4.9% with transcatheter closure compared with 3.8–12% with medical management, suggesting that a greater number of recurrent thromboembolic events may be prevented by device closure compared with medical therapy. However, the authors warned against drawing a clear conclusion of superiority for a number of reasons. These included design issues of some of the studies such as their non-randomised nature, heterogeneity regarding the thorough assessment of the cause of the initial stroke, definitions, methods and timing of follow-up, as well as varying patient characteristics such as an older mean age and a higher prevalence of atherosclerotic risk factors in medically managed patients that may have led to an overestimation of the benefit conferred by device closure (12). A more recent non-randomised trial conducted by Windecker et al. compared the risk of recurrent stroke after an initial CS in 158 patients treated medically and 150 patients who had undergone percutaneous closure. At 4 years of follow-up, device closure resulted in a non-significant trend towards risk reduction of recurrent stroke/TIA (7.8% vs. 22.2%; p = 0.08) compared with medical treatment. Patients
who had experienced more than one cerebrovascular event at baseline and those who had no residual shunt had a lower risk for recurrent stroke or TIA after percutaneous PFO closure compared with medically treated patients (7.3% vs. 33.2%; p = 0.01; and 6.5% vs. 22.2%; p = 0.04, respectively). These results suggested that PFO closure was at least as good as medical management for the prevention of recurrent stroke and that it may be superior in those who have had more than one event and where effective closure could be achieved (13). An updated propensitymatched long-term follow-up of these patients at a median of 9 years showed a small, although significant, benefit for PFO closure; however, this was driven by a reduction in TIAs (14). The results of three large multi-centre randomised control trials comparing the effectiveness of percutaneous PFO closure with medical therapy for secondary prevention of stroke in patients with PFO have recently been published. CLOSURE I compared closure with the STARFlex device against medical therapy in preventing recurrent stroke/TIA in 909 patients (age 18–60 years) with a PFO who had experienced a previous TIA or CS. The primary end-points of the trial were stroke/ TIA during 2 years of follow-up, death from any cause during the first 30 days or death from neurological causes between 31 days and 2 years. Incidence of the primary end-point(s) was 5.5% in the closure group compared with 6.8% in the medical-therapy group (hazard ratio = 0.78; p = 0.37). The respective rates were 2.9% and 3.1% for stroke (p = 0.79) and 3.1% and 4.1% for TIA (p = 0.44). The results indicate that in patients with CS/TIA who have a PFO, closure with this device does not offer a greater benefit than medical therapy alone for the prevention of recurrent stroke/TIA (15). The PC Trial included 414 patients (under age 60) with a PFO who had suffered an ischaemic stroke, randomised to treatment with transcatheter closure using the Amplatzer PFO occluder device or medical therapy. Patients were followed up for a mean of 4.5 years. A composite primary end-point was used comprising of death from any cause, non-fatal stroke, TIA and peripheral embolism. At follow-up, the closure group had a non-significant relative risk reduction of 37% (p = 0.34) compared with the medical-therapy group as well as relative risk reductions of 80% (p = 0.14) and 29% (p = 0.58) for stroke and TIA, respectively. The investigators concluded that percutaneous PFO closure showed no significant reduction in ischaemic events compared with medical treatment in this trial, but that the observed difference in stroke may be clinically relevant (16). ª 2013 John Wiley & Sons Ltd Int J Clin Pract, May 2014, 68, 5, 551–556
Current evidence for closure of a patent foramen ovale
The final study, RESPECT, enrolled 980 participants (average age 46 years) diagnosed with both CS and a PFO and compared device closure using the Amplatzer PFO Occluder with medical therapy. The sample size and follow-up were event-driven, with enrolment and follow-up continuing until the 25th end-point was reached. The primary end-point was recurrence of a fatal or non-fatal ischaemic stroke or early postrandomisation death. All 25 primary endpoints were recurrent ischaemic strokes. Mean follow-up of patients was 2.6 years. In the Kaplan– Meier intention-to-treat analysis, there was a 50.8% relative reduction in stroke risk (nine strokes in the PFO closure arm vs. sixteen in the medical-therapy arm), but this reduction was not statistically significant (p = 0.083). However, it should be noted that three of the strokes in the closure arm occurred prior to insertion of the device. In the as-treated analyses, there was a statistically significant 72.7% relative reduction in risk (p = 0.007), with five strokes in the PFO closure arm and sixteen strokes in the medicaltherapy arm. The number of events observed was deemed too small to conduct a robust subgroup analysis based on the size of shunt or presence of ASA; however; they did observe a much greater effect of closure on the reduction in the hazard ratio in patients with a substantial right-to-left shunt on their original bubble studies (hazard ratio = 0.178, p = 0.0119) or with coexistent ASA (hazard ratio = 0.187, p = 0.0163) (17). These three RCTs have provided invaluable information in the question over whether PFO closure is superior to medical therapy alone (Tables 1 and 2). However, there are a number of issues to consider
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that may have a bearing on the interpretation of the results presented. First, the investigators in all three trials had to contend with a large degree of competition with off-label use of closure devices. This played a large part in the slow rate of recruitment across all three studies. This slow recruitment prompted the investigators of CLOSURE I to reduce the target sample size by over 600 patients, which in turn caused the trial to be underpowered. The 95% confidence interval in this trial included a reduction in the primary end-point by 55% and as such, because of the lack of power in the trial, a clinically significant treatment effect cannot be ruled out. The fact that potentially eligible patients may have undergone device closure outside the trials means that the samples may not be truly representative of the target population and may have biased the results by excluding the highest risk individuals who could have gained most from closure (18). In addition to slow recruitment, RESPECT suffered from a high attrition rate with more dropouts in the medical group (83 vs. 46), a significant number of whom (> 30) withdrew to undergo off-label percutaneous closure. This led the investigators to deem the raw count intention-to-treat analysis invalid because of the unequal drop-out rates across the two arms of the study. The high attrition rates of both RESPECT and PC (14.1% and 17.6%, respectively) compared with the number of patients who withdrew consent or who were lost to follow-up in CLOSURE (1.2%) raises questions about the true power of intention-to-treat analyses, which are favoured as they have less intrinsic bias, in these two trials.
Table 1 Inclusion criteria, primary outcome and follow-up of randomised studies
Inclusion criteria
Primary outcome
Recruitment numbers Follow-up period Number of dropouts
Effective closure (%)
Closure
Respect
PC trial
Patients (aged 18–60) with a patent foramen ovale (PFO) who had experienced a cryptogenic stroke or TIA within the 6 months prior to recruitment A composite of stroke or TIA during 2 years of follow-up, death from any cause during the first 30 days, and death from neurological causes between 31 days and 2 years 909 patients (447 in device arm, 462 in medical arm) 2 years 11–1.2% withdrew consent/lost to follow-up for intention-to-treat analysis 156 not used for per-protocol analysis 17% (69 in closure arm, 87 in medical arm) 86
Patients (aged 18–60) with a PFO who had experienced a cryptogenic stroke within 270 days of recruitment
Patients (< 60 years old) with a PFO who had experienced a cryptogenic stroke and had recovered enough to perform independent daily activities A composite of death from any cause, non-fatal stroke, TIA, and peripheral embolism
ª 2013 John Wiley & Sons Ltd Int J Clin Pract, May 2014, 68, 5, 551–556
Recurrence of non-fatal stroke, fatal ischaemic stroke or early postrandomization death defined as all-cause mortality 980 patients (499 in device arm, 481 in medical arm) Mean 2.6 years 138–14% (48 in device arm, 90 in medical arm)
93.5
414 patients (204 in device arm, 210 in medical arm) Mean 4 years 73–18% (32 in device arm, 41 in medical arm)
95.9
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Table 2 Results of randomised studies in patent foramen ovale closure
Closure
End-point
Closure arm (N = 447)
Respect Medical therapy (N = 462)
Intention-to-treat analysis N (%) Hazard ratio (95% CI) Kaplan–Meier intention-to-treat analysis N (%) 23 (5.5) 29 (6.8) Hazard ratio (95% CI) 0.78 (0.45–1.35) p = 0.37 Per-protocol analysis N (%) 22/378 (5.8) 29/375 (7.7) Hazard ratio (95% CI) 0.74 (0.42–1.29) p = 0.28 As-treated analysis N (%) Hazard ratio (95% CI) Stroke (intention-to-treat analysis) N (%) 12 (2.9) 13 (3.1) Hazard ratio (95% CI) 0.90 (0.41–1.98) p = 0.79 TIA (intention-to-treat analysis) N (%) 13 (3.1) 17 (4.1) Hazard ratio (95% CI) 0.75 (0.36–1.55) p = 0.44
Closure arm (N = 499)
PC trial Medical therapy (N = 481)
9 (1.8) 16 (3.3) 0.53 (0.23–1.22) p = 0.16
Closure arm (N = 204)
Medical therapy (N = 210)
7 (3.4) 11 (5.2) 0.63 (0.24–1.62) p = 0.34
9 (1.8) 16 (3.3) 0.49 (0.22–1.11) p = 0.08 6/471 (1.3) 14/472 (2.9) 0.37 (0.14–0.96) p = 0.03
0.70 (0.27–1.85) p = 0.48
5/472 (1.0) 16/486 (3.3) 0.27 (0.10–0.75) p = 0.01 9 (1.8) 16 (3.3) 0.53 (0.23–1.22) p = 0.16
Like CLOSURE I, the PC trial was underpowered. Although the study was designed to have a power of 80% to detect a 66% relative risk reduction, which had been arrived at from previous observational studies, the fact that the observed event rate in the medical treatment group (5.2%) was much lower than expected (12%) after 4 years meant that the power to detect this change was reduced to 40%. Additionally, it must be considered that the relative risk reduction of 66% sought by CLOSURE I and the PC trial as well as the 75% sought by RESPECT were probably overambitious targets based on observational data previously described. Observational studies have repeatedly demonstrated that PFOs tend to be more strongly associated with CS when (a) there is a larger degree of right-to-left shunt and (b) there is a coexistent ASA (with conflicting evidence regarding whether a coexisting ASA is associated with a greater risk of recurrence) (6,9,10,19–22), so that patients meeting these criteria may be considered to have a ‘high-risk’ PFO and are most likely to benefit from closure. Despite this evidence, the RCTs described above did not consider any degree of risk stratification. In CLOSURE I, only 52.9% of participants had a moderate or large degree of right-to-left shunting, and only 36.6% had a coexistent ASA, two factors that suggest a higher risk of paradoxical embolism across a PFO. The inclusion of many ‘low-risk’ patients may have masked the protective benefit conferred to those at higher risk. Indeed, among patients with shunts of
1 (0.5) 5 (2.4) 0.20 (0.02–1.72) p = 0.14
0.71 (0.23–2.24) p = 0.56
moderate or substantial size, the estimated reduction in risk of stroke was 35% (23). The PC trial had a higher proportion of patients with a moderate or large shunt (61%), but still included many individuals with small shunts. The study also had a smaller proportion of participants with an ASA (23% in closure group, and 24.3% in medical group) and the results provide no information on whether the primary outcome was worse in patients with coexistent ASA. RESPECT had a much higher proportion of patients with a moderate or large shunt (78%) and this may have played a role in the seemingly greater benefit that closure had for the patients in this study and was supported by the hypothesis-generating subgroup analysis. Some concerns have been raised regarding the effectiveness of device closure in CLOSURE I. Procedural success for device closure was relatively low with almost 14% having a significant degree of rightto-left shunting at both 6 months and 2 years. There was also a high rate of postprocedural atrial fibrillation (5.7%) and major bleeding (2.6%). These figures are far worse than those from RESPECT, which found that 6% had a significant degree of right-toleft shunt at 6 months while rates of atrial fibrillation and bleeding were 3% and 1.6%, respectively. Within the RESPECT study, the atrial fibrillation rates captured as adverse events (AE) were not statistically different between the device and medical arms (device 3%, medical 1.5%; p = 0.13). Similarly, the incidence of atrial fibrillation captured as a ‘serious ª 2013 John Wiley & Sons Ltd Int J Clin Pract, May 2014, 68, 5, 551–556
Current evidence for closure of a patent foramen ovale
adverse event’ (SAE) was low and equal in both arms (0.6%). Whether there is a different clinical impact of atrial fibrillation defined as an AE or SAE is unclear. Windecker et al. demonstrated, within a subgroup analysis, that device closure appeared to have a greater effect when there was no residual shunting (13). Although not proved, this could lead to an underestimation of any beneficial effect of device closure in studies where the rate of complete closure is suboptimal. To be confident that the correct patient group is being studied, the RESPECT study excluded TIA as some of these could be stroke mimics and may be highly subjective, with even stroke specialists having poor agreement regarding the diagnosis (24). Similarly, the RESPECT investigators reduced the likelihood of non-embolic events being included by detailed prior investigation of the patients and exclusion at the outset of subjects with small lacunar infarcts, which are thought to have a different aetiology. The recurrent events in this study were more commonly small lacunar events in the closure arm, indicating the prevention of likely embolic phenomenon. For closure of a potential pathway of cryptogenic emboli to be effective, only patients in whom this is the likely cause, as evidence by neuroimaging, need to included in studies – this sadly has not been the case to date and quite possibly would continue to be an issue with further ongoing studies. Lastly, it has been suggested that the follow-up periods of CLOSURE I and RESPECT (2 years and mean of 2.6 years, respectively) may have been inadequate to fully measure any benefit conferred from intervention. Even the PC trial with a much longer mean follow-up time of 4 years arguably has too short a follow-up period considering the fact that young patients who have experienced a CS will be at risk for many decades to come, and hence, longer follow-ups are needed (25). This is a fair assessment; however, caution is required in the interpretation of very long follow-up periods as, over time, the subjects will naturally accumulate ‘traditional’ stroke risk factors and events because of these may mask the differential effects of device closure. The results of these studies, in particular the RESPECT study, have raised debate among many physicians involved in the treatment of CS and PFO. Some feel that the negative results of the CLOSURE I and PC trials, as well as the fact that, strictly speaking, the RESPECT trial was negative (its intentionto-treat analysis trended towards superiority for device closure but was not statistically significant), suggest that it is clear that device closure is not more effective than medical therapy. However, the fact that the as-treated analysis from the RESPECT study ª 2013 John Wiley & Sons Ltd Int J Clin Pract, May 2014, 68, 5, 551–556
demonstrated statistically significant superiority for device closure in a sample of patients who were probably at higher risk than those of the other two studies has led some to argue that device closure may be more effective than medical therapy alone in a selected group of patients considered to be at a particularly high risk of recurrent stroke (particularly those with a large right-to-left shunt and those with coexistent ASA) and who are thus more likely to benefit from closure. Identifying these high-risk individuals may be aided by stratification tools such as those developed by the RoPE study investigators (26). The next step will most likely be to pool the results from these three trials in a patient-level data meta-analysis, as well as awaiting the results of the on-going REDUCE trial comparing device closure with the GORE HELEX Septal Occluder and medical therapy, although in the wake of the preceding three randomised control trials, this study may face even more difficulty regarding enrolment and withdrawal of participants.
Summary The burning question regarding secondary prevention of stroke in patients with a PFO is whether percutaneous closure is superior to medical therapy, with uncertainty still about whether this should be antiplatelets or anticoagulation. Despite observational studies suggesting that there is lower risk of recurrence with PFO closure compared with medical treatment, two recent randomised controlled trials found no significant difference between the two. The primary analysis of a third trial again showed no difference, although secondary analysis seemed to show clear superiority for percutaneous closure over medical therapy. The results of these trials are very much open to interpretation and are unlikely to change the opinion of anyone who is already convinced one way or the other regarding the utility of percutaneous closure. All of the available randomised data indicate that the recurrence rate of stroke in this otherwise healthy young population is very low irrespective of the secondary prevention used. This low event rate generates significant difficulties in the design and performance of randomised studies to detect differences between treatments. A fascinating, although very challenging, avenue for future research would be to conduct randomised controlled trials comparing device closure and medical therapy specifically targeting individuals who are likely to have a ‘high risk’ PFO and presentation (i.e. have a large degree of right-to-left shunting, a
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coexistent ASA and likely embolic neuroimaging) to see if there is a greater differential effect. It should be noted that this was the intention of the current studies and any future work would have to contend with the vagaries of human nature that can lead to differential recruitment of lower risk individuals and the failure to recruit the patients most likely to benefit as has already been seen. As for now, although no definitive answer has been provided, it has at least given clinicians useful data to consider when deciding, alongside their patients, which option may be best for them.
References 1 Hagen PT, Scholz DG, Edwards WD. Incidence and size of patent foramen ovale during the first 10 decades of life: an autopsy study of 965 normal hearts. Mayo Clin Proc 1984; 59: 17–20. 2 Kutty S, Sengupta PP, Khandheria BK. Patent foramen ovale: the known and the to be known. J Am Coll Cardiol 2012; 59: 1665–71. 3 Myers PO, Bounameaux H, Panos A et al. Impending paradoxical embolism: systematic review of prognostic factors and treatment. Chest 2010; 137: 164–70. 4 Lechat P, Mas JL, Lascault G et al. Prevalence of patent foramen ovale in patients with stroke. N Engl J Med 1988; 318: 1148–52. 5 Webster MW, Chancellor AM, Smith HJ et al. Patent foramen ovale in young stroke patients. Lancet 1988; 2: 11–2. 6 Overell JR, Bone I, Lees KR. Interatrial septal abnormalities and stroke: a meta-analysis of case-control studies. Neurology 2000; 55: 1172–9. 7 Meissner I, Khandheria BK, Heit JA et al. Patent foramen ovale: innocent or guilty? Evidence from a prospective population-based study. J Am Coll Cardiol 2006; 47: 440–5. 8 Tullio MR, Zhezhen J, Russo C et al. Patent foramen ovale, subclinical cerebrovascular disease, and ischemic stroke in a population-based cohort. J Am Coll Cardiol 2013; 62: 35–41. 9 Mas JL, Arquizan C, Lamy C et al. Patent Foramen Ovale and Atrial Septal Aneurysm Study Group. Recurrent cerebrovascular events associated with patent foramen ovale, atrial septal aneurysm, or both. N Engl J Med 2001; 345: 1740–6. 10 Homma S, Sacco RL, Di Tullio MR et al. PFO in Cryptogenic Stroke Study (PICSS) Investigators. Effect of medical treatment in stroke patients with
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Acknowledgement This work did not receive any funding. No additional data were shared in this project.
Author contribution Dr Clapp conceived the article and takes overall responsibility for it. Dr Clapp, Mr Rhone and Dr Chung were all involved in researching, writing and editing this article.
patent foramen ovale: patent foramen ovale in Cryptogenic Stroke Study. Circulation 2002; 105: 2625–31. Messe SR, Silverman IE, Kizer JR et al. Quality Standards Subcommittee of the American Academy of Neurology. Practice parameter: recurrent stroke with patent foramen ovale and atrial septal aneurysm: report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2004; 62: 1042–50. Khairy P, O’Donnell CP, Landzberg MJ. Transcatheter closure versus medical therapy of patent foramen ovale and presumed paradoxical thromboemboli: a systematic review. Ann Intern Med 2003; 139: 753–60. Windecker S, Wahl A, Nedeltchev K et al. Comparison of medical treatment with percutaneous closure of patent foramen ovale in patients with cryptogenic stroke. J Am Coll Cardiol 2004; 44: 750–8. Wahl A, J€ uni P, Mono ML et al. Long-term propensity score-matched comparison of percutaneous closure of patent foramen ovale with medical treatment after paradoxical embolism. Circulation 2012; 125: 803–12. Furlan AJ, Reisman M, Massaro J et al. CLOSURE I Investigators. Closure or medical therapy for cryptogenic stroke with patent foramen ovale. N Engl J Med 2012; 366: 991–9. Meier B, Kalesan B, Khattab AA et al. Percutaneous closure of patent foramen ovale in cryptogenic embolism. N Engl J Med 2013; 368: 1083–91. Carroll JD, Saver JL, Thaler DE et al. Closure of patent foramen ovale versus medical therapy after cryptogenic stroke. N Engl J Med 2013; 368: 1092– 100.
18 Johnston SC. Patent foramen ovale closure–closing the door except for trials. N Engl J Med 2012; 366: 1048–50. 19 Handke M, Harloff A, Olschewski M et al. Patent foramen ovale and cryptogenic stroke in older patients. N Engl J Med 2007; 357: 2262–8. 20 Homma S, Di Tullio MR, Sacco RL et al. Characteristics of patent foramen ovale associated with cryptogenic stroke. A biplane transesophageal echocardiographic study. Stroke 1994; 25: 582–6. 21 Steiner MM, Di Tullio MR, Rundek T et al. Patent foramen ovale size and embolic brain imaging findings among patients with ischemic stroke. Stroke 1998; 29: 944–8. 22 Serena J, Marti-Fabregas J, Santamarina E et al. CODICIA, Right-to-Left Shunt in Cryptogenic Stroke Study; Stroke Project of the Cerebrovascular Diseases Study Group, Spanish Society of Neurology. Recurrent stroke and massive right-to-left shunt: results from the prospective Spanish multicenter (CODICIA) study. Stroke 2008; 39: 3131–6. 23 Guijarro C. Letters to the editor re, Furlan AJ, Reisman M, Massaro J et al. CLOSURE I Investigators. Closure or medical therapy for cryptogenic stroke with patent foramen ovale. N Engl J Med 2012; 366: 991–9. 24 Castle J, Mlynash M, Lee K et al. Agreement regarding diagnosis of transient ischemic attack fairly low among stroke-trained neurologists. Stroke 2010; 41: 1367–70. 25 Thaler DE, Wahl A. Critique of closure or medical therapy for cryptogenic stroke with patent foramen ovale: the hole truth? Stroke 2012; 43: 3147–9. 26 Kent DM, Thaler DE. The risk of paradoxical embolism study. Trials 2011; 12: 185.
Paper received April 2013, accepted August 2013
ª 2013 John Wiley & Sons Ltd Int J Clin Pract, May 2014, 68, 5, 551–556
Current evidence for closure of a patent foramen ovale for cryptogenic stroke prevention E. Rhone,1 N. Chung,2 B. Clapp2
1
SUMMARY
Review criteria
A patent foramen ovale (PFO) has long been implicated as a potential mechanism for cryptogenic stroke (CS), which accounts for up to 40% of all cases of ischaemic stroke. Although there is a strong association between a PFO and CS, there is less evidence that percutaneous closure of the defect, as opposed to medical therapy with antithrombotics or anticoagulants, is the most effective form of secondary prevention. The aim of this review is to examine the evidence comparing percutaneous closure with medical therapy, with a particular focus on three recently published randomised controlled trials.
Association between PFO and cryptogenic stroke A patent foramen ovale (PFO) is a remnant of the normal fetal circulation that persists into adulthood in approximately 25% of the population (1). It has been identified as a potential route for the transfer of embolic material from the venous to the systemic arterial circulation (a process known as paradoxical embolism) and has been implicated as a possible mechanism for cryptogenic stroke (CS) which accounts for up to 40% of all cases of ischaemic strokes (2). The visualisation of an embolus trapped in a PFO is a rare, but well-documented event, with numerous case reports describing echocardiograms demonstrating a thrombus caught in transit through a PFO (3). Several cross-sectional studies have demonstrated that the presence of a PFO is a much more common finding in patients that have experienced CS compared with the general population. Lechat et al. demonstrated a prevalence for PFO of 58% in patients with CS compared to 10% in stroke-free controls (4), whereas Webster et al. found a PFO in 56% of patients with CS compared to 15% of a control group (5). A meta-analysis of case–control studies showed that patients with CS under 55 years of age were six times more likely to have a PFO than patients with other forms of stroke and that PFOmediated stroke risk was greatly potentiated by the presence of a coexisting atrial septal aneurysm (ASA) with these individuals having an odds ratios of 4.96 for ischaemic stroke and 23.26 for CS (6). ª 2013 John Wiley & Sons Ltd Int J Clin Pract, May 2014, 68, 5, 551–556. doi: 10.1111/ijcp.12312
PUBMED cited articles on cryptogenic stroke and patent foramen ovalve.
Message for the clinic In cases of cryptogenic stroke where other causes of the event have been excluded closure of a patent foramen ovale may provide effective secondary prevention.
These retrospective studies strongly suggest an association between the presence of a PFO and an increased risk of CS. Two prospective populationbased cohort studies (SPARC and NOMAS) attempted to evaluate the risk of first time ischaemic stroke associated with the presence of a PFO, an important question because of the high prevalence of PFO within the general population. Both found that the presence of a PFO was not a significant independent predictor of ischaemic stroke. However, both studies failed to separate CS from ischaemic stroke and additionally, had samples that consisted of relatively elderly populations in whom traditional risk factors are likely to play a larger role in first time stroke than the presence of a PFO (7,8).
Kings College London Medical School, London, UK 2 Department of Cardiology, St Thomas’ Hospital, London, UK Correspondence to: Brian Clapp, PhD, FRCP, Department of Cardiology, St Thomas’ Hospital, Westminster Bridge Road, London SE1 7EH, UK Tel.: + 020 71881049 Fax: + 020 71881011 Email: [email protected]
Disclosure Dr Clapp has received speaking fees and acted as a consultant for St Jude Medical. Neither Dr Chung nor Mr Rhone has any competing interests to declare.
Secondary prevention of stroke Given the high prevalence of PFOs, combined with the relatively low lifetime risk that a PFO will be symptomatic, screening is not considered justifiable and therefore primary prevention is not recommended. Instead, secondary prevention of the recurrence of neurological events in patients with PFO who have suffered a CS is the main focus (2). If the presence of a PFO is deemed to be a significant factor, there are two approaches that can be taken to prevent recurrence: closure of the PFO via surgical or percutaneous means with a view to blocking the potential pathway for paradoxical embolization, or by preventing the formation of embolic material using antithrombotic treatment (antiplatelet agents such as aspirin, clopidogrel and dipyridamole
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or anticoagulants such as warfarin) (1). Which medical therapy is more effective is still controversial. Both antiplatelet and anticoagulation therapy may be effective at preventing recurrent stroke (9,10). Therefore, antiplatelet therapy is often favoured because of a presumed higher benefit/risk ratio, because anticoagulation is associated with a higher risk of haemorrhage and requires intensive monitoring and doseadjustment (2). In 2004, the quality standards subcommittee of the American Academy of Neurology published evidence-based guidelines indicating that because ischaemic stroke patients with and without PFO have similar adverse event rates while receiving medical treatment, it is not deemed necessary to close PFOs unless there is a contraindication to medical therapy or there is recurrence of stroke whilst on medical therapy (11). Despite this guidance, biological plausibility was felt to suggest that if a PFO is associated with an increased risk of stroke, closing the hole would be of value and significant numbers of patients were treated on this basis. Extensive research has been conducted comparing the efficacy of device closure with that of medical therapy.
Is closure of a PFO superior to medical therapy? In 2003, a systematic review evaluating transcatheter closure and medical therapy in patients with a PFO and presumed paradoxical embolus found a 1-year rate of recurrent stroke/TIA to be 0–4.9% with transcatheter closure compared with 3.8–12% with medical management, suggesting that a greater number of recurrent thromboembolic events may be prevented by device closure compared with medical therapy. However, the authors warned against drawing a clear conclusion of superiority for a number of reasons. These included design issues of some of the studies such as their non-randomised nature, heterogeneity regarding the thorough assessment of the cause of the initial stroke, definitions, methods and timing of follow-up, as well as varying patient characteristics such as an older mean age and a higher prevalence of atherosclerotic risk factors in medically managed patients that may have led to an overestimation of the benefit conferred by device closure (12). A more recent non-randomised trial conducted by Windecker et al. compared the risk of recurrent stroke after an initial CS in 158 patients treated medically and 150 patients who had undergone percutaneous closure. At 4 years of follow-up, device closure resulted in a non-significant trend towards risk reduction of recurrent stroke/TIA (7.8% vs. 22.2%; p = 0.08) compared with medical treatment. Patients
who had experienced more than one cerebrovascular event at baseline and those who had no residual shunt had a lower risk for recurrent stroke or TIA after percutaneous PFO closure compared with medically treated patients (7.3% vs. 33.2%; p = 0.01; and 6.5% vs. 22.2%; p = 0.04, respectively). These results suggested that PFO closure was at least as good as medical management for the prevention of recurrent stroke and that it may be superior in those who have had more than one event and where effective closure could be achieved (13). An updated propensitymatched long-term follow-up of these patients at a median of 9 years showed a small, although significant, benefit for PFO closure; however, this was driven by a reduction in TIAs (14). The results of three large multi-centre randomised control trials comparing the effectiveness of percutaneous PFO closure with medical therapy for secondary prevention of stroke in patients with PFO have recently been published. CLOSURE I compared closure with the STARFlex device against medical therapy in preventing recurrent stroke/TIA in 909 patients (age 18–60 years) with a PFO who had experienced a previous TIA or CS. The primary end-points of the trial were stroke/ TIA during 2 years of follow-up, death from any cause during the first 30 days or death from neurological causes between 31 days and 2 years. Incidence of the primary end-point(s) was 5.5% in the closure group compared with 6.8% in the medical-therapy group (hazard ratio = 0.78; p = 0.37). The respective rates were 2.9% and 3.1% for stroke (p = 0.79) and 3.1% and 4.1% for TIA (p = 0.44). The results indicate that in patients with CS/TIA who have a PFO, closure with this device does not offer a greater benefit than medical therapy alone for the prevention of recurrent stroke/TIA (15). The PC Trial included 414 patients (under age 60) with a PFO who had suffered an ischaemic stroke, randomised to treatment with transcatheter closure using the Amplatzer PFO occluder device or medical therapy. Patients were followed up for a mean of 4.5 years. A composite primary end-point was used comprising of death from any cause, non-fatal stroke, TIA and peripheral embolism. At follow-up, the closure group had a non-significant relative risk reduction of 37% (p = 0.34) compared with the medical-therapy group as well as relative risk reductions of 80% (p = 0.14) and 29% (p = 0.58) for stroke and TIA, respectively. The investigators concluded that percutaneous PFO closure showed no significant reduction in ischaemic events compared with medical treatment in this trial, but that the observed difference in stroke may be clinically relevant (16). ª 2013 John Wiley & Sons Ltd Int J Clin Pract, May 2014, 68, 5, 551–556
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The final study, RESPECT, enrolled 980 participants (average age 46 years) diagnosed with both CS and a PFO and compared device closure using the Amplatzer PFO Occluder with medical therapy. The sample size and follow-up were event-driven, with enrolment and follow-up continuing until the 25th end-point was reached. The primary end-point was recurrence of a fatal or non-fatal ischaemic stroke or early postrandomisation death. All 25 primary endpoints were recurrent ischaemic strokes. Mean follow-up of patients was 2.6 years. In the Kaplan– Meier intention-to-treat analysis, there was a 50.8% relative reduction in stroke risk (nine strokes in the PFO closure arm vs. sixteen in the medical-therapy arm), but this reduction was not statistically significant (p = 0.083). However, it should be noted that three of the strokes in the closure arm occurred prior to insertion of the device. In the as-treated analyses, there was a statistically significant 72.7% relative reduction in risk (p = 0.007), with five strokes in the PFO closure arm and sixteen strokes in the medicaltherapy arm. The number of events observed was deemed too small to conduct a robust subgroup analysis based on the size of shunt or presence of ASA; however; they did observe a much greater effect of closure on the reduction in the hazard ratio in patients with a substantial right-to-left shunt on their original bubble studies (hazard ratio = 0.178, p = 0.0119) or with coexistent ASA (hazard ratio = 0.187, p = 0.0163) (17). These three RCTs have provided invaluable information in the question over whether PFO closure is superior to medical therapy alone (Tables 1 and 2). However, there are a number of issues to consider
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that may have a bearing on the interpretation of the results presented. First, the investigators in all three trials had to contend with a large degree of competition with off-label use of closure devices. This played a large part in the slow rate of recruitment across all three studies. This slow recruitment prompted the investigators of CLOSURE I to reduce the target sample size by over 600 patients, which in turn caused the trial to be underpowered. The 95% confidence interval in this trial included a reduction in the primary end-point by 55% and as such, because of the lack of power in the trial, a clinically significant treatment effect cannot be ruled out. The fact that potentially eligible patients may have undergone device closure outside the trials means that the samples may not be truly representative of the target population and may have biased the results by excluding the highest risk individuals who could have gained most from closure (18). In addition to slow recruitment, RESPECT suffered from a high attrition rate with more dropouts in the medical group (83 vs. 46), a significant number of whom (> 30) withdrew to undergo off-label percutaneous closure. This led the investigators to deem the raw count intention-to-treat analysis invalid because of the unequal drop-out rates across the two arms of the study. The high attrition rates of both RESPECT and PC (14.1% and 17.6%, respectively) compared with the number of patients who withdrew consent or who were lost to follow-up in CLOSURE (1.2%) raises questions about the true power of intention-to-treat analyses, which are favoured as they have less intrinsic bias, in these two trials.
Table 1 Inclusion criteria, primary outcome and follow-up of randomised studies
Inclusion criteria
Primary outcome
Recruitment numbers Follow-up period Number of dropouts
Effective closure (%)
Closure
Respect
PC trial
Patients (aged 18–60) with a patent foramen ovale (PFO) who had experienced a cryptogenic stroke or TIA within the 6 months prior to recruitment A composite of stroke or TIA during 2 years of follow-up, death from any cause during the first 30 days, and death from neurological causes between 31 days and 2 years 909 patients (447 in device arm, 462 in medical arm) 2 years 11–1.2% withdrew consent/lost to follow-up for intention-to-treat analysis 156 not used for per-protocol analysis 17% (69 in closure arm, 87 in medical arm) 86
Patients (aged 18–60) with a PFO who had experienced a cryptogenic stroke within 270 days of recruitment
Patients (< 60 years old) with a PFO who had experienced a cryptogenic stroke and had recovered enough to perform independent daily activities A composite of death from any cause, non-fatal stroke, TIA, and peripheral embolism
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Recurrence of non-fatal stroke, fatal ischaemic stroke or early postrandomization death defined as all-cause mortality 980 patients (499 in device arm, 481 in medical arm) Mean 2.6 years 138–14% (48 in device arm, 90 in medical arm)
93.5
414 patients (204 in device arm, 210 in medical arm) Mean 4 years 73–18% (32 in device arm, 41 in medical arm)
95.9
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Table 2 Results of randomised studies in patent foramen ovale closure
Closure
End-point
Closure arm (N = 447)
Respect Medical therapy (N = 462)
Intention-to-treat analysis N (%) Hazard ratio (95% CI) Kaplan–Meier intention-to-treat analysis N (%) 23 (5.5) 29 (6.8) Hazard ratio (95% CI) 0.78 (0.45–1.35) p = 0.37 Per-protocol analysis N (%) 22/378 (5.8) 29/375 (7.7) Hazard ratio (95% CI) 0.74 (0.42–1.29) p = 0.28 As-treated analysis N (%) Hazard ratio (95% CI) Stroke (intention-to-treat analysis) N (%) 12 (2.9) 13 (3.1) Hazard ratio (95% CI) 0.90 (0.41–1.98) p = 0.79 TIA (intention-to-treat analysis) N (%) 13 (3.1) 17 (4.1) Hazard ratio (95% CI) 0.75 (0.36–1.55) p = 0.44
Closure arm (N = 499)
PC trial Medical therapy (N = 481)
9 (1.8) 16 (3.3) 0.53 (0.23–1.22) p = 0.16
Closure arm (N = 204)
Medical therapy (N = 210)
7 (3.4) 11 (5.2) 0.63 (0.24–1.62) p = 0.34
9 (1.8) 16 (3.3) 0.49 (0.22–1.11) p = 0.08 6/471 (1.3) 14/472 (2.9) 0.37 (0.14–0.96) p = 0.03
0.70 (0.27–1.85) p = 0.48
5/472 (1.0) 16/486 (3.3) 0.27 (0.10–0.75) p = 0.01 9 (1.8) 16 (3.3) 0.53 (0.23–1.22) p = 0.16
Like CLOSURE I, the PC trial was underpowered. Although the study was designed to have a power of 80% to detect a 66% relative risk reduction, which had been arrived at from previous observational studies, the fact that the observed event rate in the medical treatment group (5.2%) was much lower than expected (12%) after 4 years meant that the power to detect this change was reduced to 40%. Additionally, it must be considered that the relative risk reduction of 66% sought by CLOSURE I and the PC trial as well as the 75% sought by RESPECT were probably overambitious targets based on observational data previously described. Observational studies have repeatedly demonstrated that PFOs tend to be more strongly associated with CS when (a) there is a larger degree of right-to-left shunt and (b) there is a coexistent ASA (with conflicting evidence regarding whether a coexisting ASA is associated with a greater risk of recurrence) (6,9,10,19–22), so that patients meeting these criteria may be considered to have a ‘high-risk’ PFO and are most likely to benefit from closure. Despite this evidence, the RCTs described above did not consider any degree of risk stratification. In CLOSURE I, only 52.9% of participants had a moderate or large degree of right-to-left shunting, and only 36.6% had a coexistent ASA, two factors that suggest a higher risk of paradoxical embolism across a PFO. The inclusion of many ‘low-risk’ patients may have masked the protective benefit conferred to those at higher risk. Indeed, among patients with shunts of
1 (0.5) 5 (2.4) 0.20 (0.02–1.72) p = 0.14
0.71 (0.23–2.24) p = 0.56
moderate or substantial size, the estimated reduction in risk of stroke was 35% (23). The PC trial had a higher proportion of patients with a moderate or large shunt (61%), but still included many individuals with small shunts. The study also had a smaller proportion of participants with an ASA (23% in closure group, and 24.3% in medical group) and the results provide no information on whether the primary outcome was worse in patients with coexistent ASA. RESPECT had a much higher proportion of patients with a moderate or large shunt (78%) and this may have played a role in the seemingly greater benefit that closure had for the patients in this study and was supported by the hypothesis-generating subgroup analysis. Some concerns have been raised regarding the effectiveness of device closure in CLOSURE I. Procedural success for device closure was relatively low with almost 14% having a significant degree of rightto-left shunting at both 6 months and 2 years. There was also a high rate of postprocedural atrial fibrillation (5.7%) and major bleeding (2.6%). These figures are far worse than those from RESPECT, which found that 6% had a significant degree of right-toleft shunt at 6 months while rates of atrial fibrillation and bleeding were 3% and 1.6%, respectively. Within the RESPECT study, the atrial fibrillation rates captured as adverse events (AE) were not statistically different between the device and medical arms (device 3%, medical 1.5%; p = 0.13). Similarly, the incidence of atrial fibrillation captured as a ‘serious ª 2013 John Wiley & Sons Ltd Int J Clin Pract, May 2014, 68, 5, 551–556
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adverse event’ (SAE) was low and equal in both arms (0.6%). Whether there is a different clinical impact of atrial fibrillation defined as an AE or SAE is unclear. Windecker et al. demonstrated, within a subgroup analysis, that device closure appeared to have a greater effect when there was no residual shunting (13). Although not proved, this could lead to an underestimation of any beneficial effect of device closure in studies where the rate of complete closure is suboptimal. To be confident that the correct patient group is being studied, the RESPECT study excluded TIA as some of these could be stroke mimics and may be highly subjective, with even stroke specialists having poor agreement regarding the diagnosis (24). Similarly, the RESPECT investigators reduced the likelihood of non-embolic events being included by detailed prior investigation of the patients and exclusion at the outset of subjects with small lacunar infarcts, which are thought to have a different aetiology. The recurrent events in this study were more commonly small lacunar events in the closure arm, indicating the prevention of likely embolic phenomenon. For closure of a potential pathway of cryptogenic emboli to be effective, only patients in whom this is the likely cause, as evidence by neuroimaging, need to included in studies – this sadly has not been the case to date and quite possibly would continue to be an issue with further ongoing studies. Lastly, it has been suggested that the follow-up periods of CLOSURE I and RESPECT (2 years and mean of 2.6 years, respectively) may have been inadequate to fully measure any benefit conferred from intervention. Even the PC trial with a much longer mean follow-up time of 4 years arguably has too short a follow-up period considering the fact that young patients who have experienced a CS will be at risk for many decades to come, and hence, longer follow-ups are needed (25). This is a fair assessment; however, caution is required in the interpretation of very long follow-up periods as, over time, the subjects will naturally accumulate ‘traditional’ stroke risk factors and events because of these may mask the differential effects of device closure. The results of these studies, in particular the RESPECT study, have raised debate among many physicians involved in the treatment of CS and PFO. Some feel that the negative results of the CLOSURE I and PC trials, as well as the fact that, strictly speaking, the RESPECT trial was negative (its intentionto-treat analysis trended towards superiority for device closure but was not statistically significant), suggest that it is clear that device closure is not more effective than medical therapy. However, the fact that the as-treated analysis from the RESPECT study ª 2013 John Wiley & Sons Ltd Int J Clin Pract, May 2014, 68, 5, 551–556
demonstrated statistically significant superiority for device closure in a sample of patients who were probably at higher risk than those of the other two studies has led some to argue that device closure may be more effective than medical therapy alone in a selected group of patients considered to be at a particularly high risk of recurrent stroke (particularly those with a large right-to-left shunt and those with coexistent ASA) and who are thus more likely to benefit from closure. Identifying these high-risk individuals may be aided by stratification tools such as those developed by the RoPE study investigators (26). The next step will most likely be to pool the results from these three trials in a patient-level data meta-analysis, as well as awaiting the results of the on-going REDUCE trial comparing device closure with the GORE HELEX Septal Occluder and medical therapy, although in the wake of the preceding three randomised control trials, this study may face even more difficulty regarding enrolment and withdrawal of participants.
Summary The burning question regarding secondary prevention of stroke in patients with a PFO is whether percutaneous closure is superior to medical therapy, with uncertainty still about whether this should be antiplatelets or anticoagulation. Despite observational studies suggesting that there is lower risk of recurrence with PFO closure compared with medical treatment, two recent randomised controlled trials found no significant difference between the two. The primary analysis of a third trial again showed no difference, although secondary analysis seemed to show clear superiority for percutaneous closure over medical therapy. The results of these trials are very much open to interpretation and are unlikely to change the opinion of anyone who is already convinced one way or the other regarding the utility of percutaneous closure. All of the available randomised data indicate that the recurrence rate of stroke in this otherwise healthy young population is very low irrespective of the secondary prevention used. This low event rate generates significant difficulties in the design and performance of randomised studies to detect differences between treatments. A fascinating, although very challenging, avenue for future research would be to conduct randomised controlled trials comparing device closure and medical therapy specifically targeting individuals who are likely to have a ‘high risk’ PFO and presentation (i.e. have a large degree of right-to-left shunting, a
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coexistent ASA and likely embolic neuroimaging) to see if there is a greater differential effect. It should be noted that this was the intention of the current studies and any future work would have to contend with the vagaries of human nature that can lead to differential recruitment of lower risk individuals and the failure to recruit the patients most likely to benefit as has already been seen. As for now, although no definitive answer has been provided, it has at least given clinicians useful data to consider when deciding, alongside their patients, which option may be best for them.
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Acknowledgement This work did not receive any funding. No additional data were shared in this project.
Author contribution Dr Clapp conceived the article and takes overall responsibility for it. Dr Clapp, Mr Rhone and Dr Chung were all involved in researching, writing and editing this article.
patent foramen ovale: patent foramen ovale in Cryptogenic Stroke Study. Circulation 2002; 105: 2625–31. Messe SR, Silverman IE, Kizer JR et al. Quality Standards Subcommittee of the American Academy of Neurology. Practice parameter: recurrent stroke with patent foramen ovale and atrial septal aneurysm: report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2004; 62: 1042–50. Khairy P, O’Donnell CP, Landzberg MJ. Transcatheter closure versus medical therapy of patent foramen ovale and presumed paradoxical thromboemboli: a systematic review. Ann Intern Med 2003; 139: 753–60. Windecker S, Wahl A, Nedeltchev K et al. Comparison of medical treatment with percutaneous closure of patent foramen ovale in patients with cryptogenic stroke. J Am Coll Cardiol 2004; 44: 750–8. Wahl A, J€ uni P, Mono ML et al. Long-term propensity score-matched comparison of percutaneous closure of patent foramen ovale with medical treatment after paradoxical embolism. Circulation 2012; 125: 803–12. Furlan AJ, Reisman M, Massaro J et al. CLOSURE I Investigators. Closure or medical therapy for cryptogenic stroke with patent foramen ovale. N Engl J Med 2012; 366: 991–9. Meier B, Kalesan B, Khattab AA et al. Percutaneous closure of patent foramen ovale in cryptogenic embolism. N Engl J Med 2013; 368: 1083–91. Carroll JD, Saver JL, Thaler DE et al. Closure of patent foramen ovale versus medical therapy after cryptogenic stroke. N Engl J Med 2013; 368: 1092– 100.
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Paper received April 2013, accepted August 2013
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