REVIEW URRENT C OPINION
Closure of patent foramen ovale in cryptogenic stroke: a never ending story David Calvet and Jean-Louis Mas
Purpose of review This review discusses current evidence on patent foramen ovale (PFO) closure compared with medical therapy alone in the prevention of stroke recurrence in patients with a PFO-associated cryptogenic stroke. Recent findings The Risk of Paradoxical Embolism group built a 10-point Score, based on clinical parameters, that estimates the probability of finding a PFO in a patient with cryptogenic stroke and the probability that a PFO discovered in the setting of cryptogenic stroke is related to stroke vs. incidental. Three recent randomized clinical trials failed to demonstrate the superiority of PFO closure over medical treatment alone in preventing stroke recurrence in patients aged 18–60 years who have had a cryptogenic stroke or transient ischemic attack. Summary Stronger evidence in favor of PFO closure is needed before recommending this procedure outside of a clinical trial. Results of ongoing trials are much awaited. Keywords cryptogenic stroke, medical therapy, patent foramen ovale, transcatheter closure
INTRODUCTION The patent foramen ovale (PFO) and stroke story began about 25 years ago when the first in a series of case–control studies demonstrated a strong association between PFO and cryptogenic ischemic stroke, particularly in younger patients [1,2]. This association was reported to be stronger in patients who have an atrial septal aneurysm (ASA) in addition to a PFO, and in some studies in those who have a severe right-to-left shunt or a large opening of the PFO [1]. These results suggested that paradoxical embolism through a PFO might be responsible for stroke more often than was usually suspected. As often in medicine, the ‘cart has been put before the horse’ and PFO closure has become routine in many centers. However, despite the vast literature on this subject, several important clinical questions remain largely unanswered: Is a PFO discovered in the setting of cryptogenic stroke an incidental finding or is it related to stroke? If so, what is the mechanism of stroke? What is the best therapy to prevent stroke recurrence in cryptogenic stroke with PFO?
IS PATENT FORAMEN OVALE INCIDENTAL OR STROKE-RELATED? As PFO is common in the general population [3], it may coexist by chance alone in patients with cryptogenic stroke. The probability that a PFO discovered in the setting of a cryptogenic stroke is incidental or stroke-related can be estimated using Bayes’ theorem [4]. Considering a typical population of patients with cryptogenic stroke, in which the prevalence of a PFO is about 40% and assuming that the prevalence of PFO in cryptogenic stroke unrelated to PFO is 25% (similar to that in the general population), then 50% of PFOs would be incidental [4]. The probability that a PFO is Paris Descartes University, Centre de Psychiatrie et Neurosciences INSERM UMR 894 and Department of Neurology, Centre Hospitalier Sainte-Anne, Paris, France Correspondence to Professor Jean-Louis Mas, Service de Neurologie, Hoˆpital Sainte-Anne, 1 rue Cabanis, 75674 Paris Cedex 14, France. Tel: +33 1 45 65 82 84; fax: +33 1 45 65 87 94; e-mail: [email protected] Curr Opin Neurol 2014, 27:13–19 DOI:10.1097/WCO.0000000000000052
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KEY POINTS The probability that a PFO discovered in the setting of a cryptogenic stroke is stroke-related vs. incidental depends on the patient’s age, presence of traditional risk factors, and type of cerebral infarct. The risk of stroke recurrence is low in patients with PFO-related stroke. Randomized clinical trials failed to demonstrate superiority of device closure compared with medical therapy.
stroke-related (vs. incidental) is dependent on the prevalence of PFO in the cryptogenic stroke population; the higher the prevalence of PFO, the higher the probability that PFO is stroke-related. The prevalence of PFO in a cryptogenic stroke population is itself dependent on the presence or absence of other patient characteristics. Based on a patientlevel meta-analysis of observational cohorts of cryptogenic stroke patients, the Risk of Paradoxical Embolism (RoPE) group identified several factors associated with the detection of a PFO [5 ], including younger age, the presence of a cortical stroke on neuroimaging, and the absence of diabetes, hypertension, smoking, and prior stroke or transient ischemic attack (TIA) (Table 1). These factors were incorporated into the 10-point RoPE Score that &&
estimates the probability of finding a PFO in cryptogenic stroke patients based on clinical characteristics (Table 2). The score will be 10 for a patient with all predictive factors of the presence of a PFO. Table 2 shows that the prevalence of PFO (probability of finding a PFO) increases from 23% in cryptogenic stroke patients with a score of 0 to 3 to 73% in those with 9 or 10 points, corresponding to PFO-attributable fraction estimates of approximately 0 to 90%. Interestingly, this table also shows that the patients who were the most likely to have stroke-related PFOs were also those with the lowest recurrence risk, with an estimated 2-year risk of stroke or TIA recurrence of only 2% in patients with a RoPE score of 9 or 10. However, some population-based studies have challenged the association between PFO and stroke [6,7]. Recently, a large community-based study assessed the risk of first-ever clinical stroke or subclinical cerebrovascular disease in 1100 stroke-free individuals over age 39 years in which PFO was assessed by transthoracic echocardiography [8 ]. The risk of first-ever ischemic stroke did not differ according to the presence of PFO [12.5-year cumulative risk of stroke ¼ 10.1% in patients with PFO vs. 10.4% in patients without (P ¼ 0.46)]. In addition, there was no association between PFO and silent brain infarcts on MRI (adjusted odds ratio, 1.15; 95% CI, 0.50–2.62) [8 ]. Assuming that PFO is stroke-related, the next question relates to stroke mechanism. Paradoxical &
&
Table 1. Risk of paradoxical embolism score calculator Characteristic
Points
No history of hypertension
1
No history of diabetes
1
No history of stroke or TIA
1
Nonsmoker
1
Cortical infarct on imaging
1
RoPE Score
Age (years) 18–29
5
30–39
4
40–49
3
50–59
2
60–69
1
70
0
Total score (sum of individual points) Maximum score (a patient < 30 years with no hypertension, no diabetes, no history of stroke or TIA, nonsmoker, and cortical infarct)
10
Minimum score (a patient 70 years with hypertension, diabetes, prior stroke, current smoker, and no cortical infarct)
0
&&
RoPE, Risk of Paradoxical Embolism; TIA, transient ischemic attack. Adapted with permission from [5
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Closure of patent foramen ovale and stroke Calvet and Mas Table 2. Patent foramen ovale prevalence, attributable fraction, and estimated 2-year risk of stroke/TIA by Risk of Paradoxical Embolism point score strata (using control rate of 25% in general population) Cryptogenic stroke (n ¼ 3023) RoPE Score
Number of patients
Prevalence of patients with a PFO (95% CI)
CS with PFO (n ¼ 1324) PFO-attributable fraction (95% CI)
Estimated 2-y stroke/TIA recurrence rate (95% CI)
0–3
613
23% (19–26)
4
511
35% (31–39)
38% (25–48)
0% (0–4)
20% (12–28) 12% (6–18)
5
516
34% (30–38)
34% (21–45)
7% (3–11)
6
482
47% (42–51)
62% (54–68)
8% (4–12)
7
434
54% (49–59)
72% (66–76)
6% (2–10)
8
287
67% (62–73)
84% (79–87)
6% (2–10)
9
180
73% (66–79)
88% (83–91)
2% (0–4)
CS, cryptogenic stroke; CI, confidence interval; PFO, patent foramen ovale; RoPE, Risk of Paradoxical Embolism; TIA, transient ischemic attack. Adapted with && permission from [5 ].
embolism of venous thrombi to the systemic circulation is usually thought to be the mechanism of stroke in cases of PFO. However, in the vast majority of cases, a venous source of embolism cannot be detected and paradoxical embolism remains a hypothetical diagnosis [9]. Other potential mechanisms for stroke in PFO patients include paroxysmal atrial fibrillation [10] and direct embolization of thrombi formed in the PFO tunnel or in the ASA [11,12], but documentation of these mechanisms is lacking in the vast majority of cases. Another hypothesis is that stroke would result from an occult disorder, itself associated with PFO. The mechanisms by which PFO causes stroke need to be more fully elucidated.
IS PATENT FORAMEN OVALE CLOSURE BETTER THAN MEDICAL TREATMENT TO PREVENT STROKE RECURRENCE? Therapeutic options for secondary stroke prevention in cryptogenic stroke patients with a PFO include antiplatelet therapy, oral anticoagulants, and (mainly transcatheter) PFO closure. Antiplatelet drugs are well tolerated and reduce recurrent ischemic events when used for secondary prevention in the generality of patients with ischemic stroke. Oral anticoagulation may be more appropriate than antiplatelet drugs if stasis-related thrombi originate in the cardiac chambers or the peripheral venous system. But oral anticoagulants have many drawbacks and carry a risk of major bleeding [13]. PFO closure can prevent paradoxical embolism, but this treatment will not be relevant if a PFO-unrelated mechanism of ischemic stroke is the cause. PFO closure is not without risks, including complications related to vascular access (retroperitoneal hemorrhage), cardiac perforation with and without tamponade, air
embolism, device embolization (requiring surgical revision), arrhythmias, septal erosion, and thrombus formation on the device and complications related to antithrombotic treatment, some of which may be responsible for periprocedural stroke [14–17]. In addition, device closure leaves an implant behind, with potential mid-term or longterm complications such as atrial fibrillation and septal erosions [16]. PFO closure does not guarantee shunt closure, as residual shunts are seen in 15–20% of patients at 6 months [18–20].
RESULTS OF RANDOMIZED CLINICAL TRIALS Three randomized clinical trials (RCTs) evaluated whether PFO closure is superior to antithrombotic therapy alone in preventing recurrent stroke in patients 18–60 years of age who have had a cryptogenic stroke or TIA [21 –23 ]. In the medical group, patients received aspirin or oral anticoagulants at the discretion of the investigator. Tables 3 and 4 summarize the main characteristics and results of these trials. The CLOSURE I (Evaluation of the STARFlex septal Closure System in Patients with a Stroke and/or Transient Ischemic Attack due to Presumed Paradoxical Embolism Through a Patent Forman Ovale) trial [21 ] did not detect any benefit of closure over medical treatment alone. At 2 years, the rates of the primary endpoint, as well as the rates of stroke, did not differ between groups. No difference was found according to shunt size or presence/ absence of ASA. Major vascular (procedural) complications occurred in 3.2% of patients in the device arm. Atrial fibrillation occurred more frequently in the device arm, mainly during the periprocedural period (60%).
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&&
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Cerebrovascular disease Table 3. Hypotheses, primary endpoint and details of randomized clinical trials comparing percutaneous patent foramen ovale closure with medical treatment alone for secondary stroke prevention
Hypothesis
CLOSURE Ia
PC Trialb
RESPECTc
Incidence of primary endpoint at 2 years: 6% in the medical arm and 3% in the device arm
Incidence of primary endpoint: 3%/year in the medical arm and 1%/year in the closure arm
Incidence of primary endpoint at two years: 4.3% in the medical arm and 1% in the closure arm
Sample size ¼ 1600
Mean follow up of 4.5 years
Sample size ¼ maximum of 1000
a-level of 0.05 and 80% power
Sample size ¼ 410
a-level of 0.025 and 80% power
a-level of 0.05 and 80% power Primary endpoint
Composite: stroke or TIA, death from any cause during the first 30 days, or death from neurologic causes between 31 days and 2 years
Composite: death, nonfatal stroke, TIA, peripheral embolism
Nonfatal stroke
Sites
87 sites in United States and Canada
29 sites in Europe, Brazil and Australia
69 sites in United States and Canada
Sponsor
NMT Medical
St. Jude Medical
St. Jude Medical
Closure device
STARFlex
Amplatzer
Amplatzer
a CLOSURE I: Evaluation of the STARFlex septal Closure System in Patients with a Stroke and/or Transient Ischemic Attack due to Presumed Paradoxical Embolism Through a Patent Forman Ovale. b PC Trial: Clinical Trial Comparing Percutaneous Closure of Patent Forman Ovale Using the Amplatzer PFO Occluder with Medical Treatment in Patients with Cryptogenic Embolism. c RESPECT: Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment.
The PC Trial (Clinical Trial Comparing Percutaneous Closure Of Patent Forman Ovale Using the Amplatzer PFO Occluder with Medical Treatment in Patients with Cryptogenic Embolism) [22 ] also &&
failed to show a reduction in the primary endpoint in patients treated with PFO closure vs. medical treatment alone. Procedural complications occurred in 1.5% of patients.
Table 4. Main results of randomized clinical trials assessing the effect of percutaneous patent foramen ovale closure for secondary prevention of cryptogenic stroke as compared to medical treatment alone CLOSURE Ia
PC Trialb
RESPECTc
June 2003 to October 2008
February 2000 to February 2009
August 2003 to December 2011
447/462
204/210
499/481
2.0d
4.0
2.6e
Primary endpoint (Closure group vs. Medical group)
5.5% vs. 6.8%
3.45 vs. 5.2%
1.85 vs. 3.3%
HR for Closure vs. Medical treatment (95% CI)
0.78 (0.45–1.35)
2.7% vs. 2.8%
0.63 (0.24 to 1.62)
Strokef (Closure group vs. Medical group)
0.55 vs. 2.4%
0.49 (0.22–1.11)
1.85 vs. 3.3%
Atrial fibrillation (Closure group vs. Medical group) Major bleeding (Closure group vs. Medical group)
5.75 vs. 0.7%
2.95 vs. 1.0%
3.05 vs. 1.5%
2.65 vs. 1.1%
0.55 vs. 1.5%
1.85 vs. 1.8%
Study enrollment period Number of enrolled patients (Closure group vs. Medical group) Mean follow up in years
Given percentages are for study follow-up periods. a CLOSURE I: Evaluation of the STARFlex septal Closure System in Patients with a Stroke and/or Transient Ischemic Attack due to Presumed Paradoxical Embolism Through a Patent Forman Ovale. b PC Trial: Clinical Trial Comparing Percutaneous Closure of Patent Forman Ovale Using the Amplatzer PFO Occluder with Medical Treatment in Patients with Cryptogenic Embolism. c RESPECT: Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment. d 2-year follow up in all patients at the last known follow-up visit, whichever was earlier. e 1375 patient-years in Closure group and 1184 patient-years in medical treatment group. f Three (0.7%) were periprocedural in CLOSURE I, two (0.4%) in RESPECT, and none in PC Trial according to Kaplan Meier curves of all cause mortality && (supplementary figure 4 in [22 ]). No death occurred during the periprocedural period in all the three trials.
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Closure of patent foramen ovale and stroke Calvet and Mas
Study or subgroup CLOSURE I PC Trial RESPECT
Closure Medical Therapy Risk ratio Events Total Events Total Weight M–H, Random,95% Cl 12 447 13 462 47.9% 0.95 [0.44, 2.07] 1 204 5 210 7.4% 0.21 [0.02, 0.75] 9 499 16 481 44.7% 0.54 [0.24, 1.22]
Total (95% CI) 1150 1153 100.0% Total events 22 34 Heterogeneity: Tau2 = 0.03; Chi2 = 2.20, df = 2 (P = 0.32); I2 = 11% Test for overall effect: Z = 1.37 (P = 0.17)
Risk ratio M–H, Random, 95% Cl
0.66 [0.37, 1.19] 0.01 0.1 1 10 100 Favours closure Favours control
FIGURE 1. Forest plot of risk ratios for stroke.
Finally, the RESPECT (Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment) trial [23 ] also failed to establish superiority of PFO closure over medical therapy in the intention-to-treat analysis. However, a reduction in stroke risk was found in a prespecified analysis in the per-protocol cohort (six events in the closure group vs. 14 events in the medical-therapy group) and in the as-treated cohort (five events vs. 16 events). Procedure-related or device-related serious adverse events occurred in 4.2% in the closure group. In a meta-analysis of these RCTs (using an intention-to-treat approach and a random effects model), we found no significant difference in the risk of recurrent stroke between patients treated with PFO closure and those receiving antithrombotic treatment (risk ratio for stroke after PFO closure, 0.66; 95% CI, 0.37–1.19; P ¼ 0.17) (Fig. 1). PFO closure was associated with an increased risk of atrial fibrillation (risk ratio, 3.66; 95% CI, 1.43–9.34; P ¼ 0.007). There was no difference in the risk of major bleeding between groups (risk ratio, 1.23; 95% CI, 0.45–3.37; P ¼ 0.68). These results are consistent with two recent meta-analyses [24 ,25 ]. Assuming a 50% stroke rate reduction in patients treated by PFO closure and an annual stroke risk of 1.5% in patients with cryptogenic stroke and PFO treated by medical therapy (as observed in RCTs), we estimated that 133 patients should be treated per year to avoid one stroke. In the same time, one atrial fibrillation and one major bleed would be caused every, respectively, 75 and 312 patients treated by PFO closure. &&
&
A potentially significant proportion of patients with patent foramen ovale-unrelated stroke The inclusion of patients with PFO-unrelated stroke may have reduced the ability to detect a treatment effect. Many patients included in RCTs had traditional stroke risk factors, which have been shown to be inversely associated with stroke-related PFO in the RoPE score (Tables 1 and 2) [5 ]. In addition, the definition of cryptogenic stroke varied substantially from one study to another. For example, lacunar stroke was excluded from the RESPECT trial, whereas it was apparently not an exclusion criterion in CLOSURE I and the PC Trial. Interestingly, in CLOSURE I, strokes that occurred during follow up were often attributable to another cause than the PFO. &&
A heterogeneous control group The definition of the control group of these trials is debatable. Patients were treated with aspirin or oral anticoagulants at the discretion of the investigator in charge of the patient. However, we do not know whether these treatments have similar efficacy to prevent stroke recurrence in PFO patients.
&
LIMITATIONS OF RANDOMIZED CLINICAL TRIALS Some characteristics of RCTs might partly explain why they failed to conclude on the superiority of one strategy over another.
Underpowered trials RCTs may have failed to show a difference between treatments groups because large treatment effects were assumed (66 to 75% risk reduction in the PFO closure group) and observed event rates were lower than anticipated. Indeed, the expected incidence rate in the medical group was 2–3% per year, whereas the actual rate of stroke was only 1.3% per year. Then, as discussed in the editorial accompanying the publication of the PC Trial and RESPECT [26], low statistical power can make trials more sensitive to potential bias and misclassification of even one or two events can have dramatic effects on the P values in trials with low outcome rates. The three RCTs enrolled a total number of
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2303 patients in whom only 56 strokes occurred. Using a power of 80%, we calculated that at least 60 events are needed to detect a relative effect of PFO closure of about 50%. Based on an annual risk of 1.5% in the medical group and a 2-year follow up, 1539 patients should be included in each group. The number falls to 381 patients by group in a trial with an inclusion period of 5 years and a maximum follow up of 10 years. Long-term follow up of patients included in the CLOSURE 1, RESPECT, and the PC Trial would certainly bring some useful information.
Is there a closure device effect? A single closure device was used in each trial. A recent meta-analysis suggested that the safety profile for the Amplatzer device used in the PC Trial and RESPECT might be superior to that of the STARFlex device used in CLOSURE I [24 ]. A potential device effect needs to be confirmed in further studies. &
A slow rate of enrollment Enrollment periods in RCTs were longer than expected, which could be due to widespread offlabel use of atrial septal closure devices. For example, only 5–10% of patients considered for PFO closure were enrolled in the PC Trial during the study period. Therefore, patients included in RCTs may not be representative of patients with PFO-associated cryptogenic stroke if patients treated outside RCTs were different from those enrolled in RCTs.
CONCLUSION RCTs failed to demonstrate superiority of device closure compared with medical therapy. However, there are signals pointing toward a potential small absolute benefit of PFO closure. Stronger evidence in favor of PFO closure is needed before recommending this procedure outside of a clinical trial. Wherever possible, patients with cryptogenic stroke and PFO should be enrolled in ongoing RCTs, such as Patent Foramen Ovale Closure or Anticoagulation vs. Antiplatelet Therapy to Prevent Stroke Recurrence (CLOSE, ClinicalTrials.gov number, NCT00562289), Device Closure vs. Medical Therapy for Cryptogenic Stroke Patients with High-Risk Patent Formaen Ovale (DEFENSE-PFO, NCT01550588), and Gore Helex Septal Occluder/Gore Septal Occluder for Patent Foramen Ovale (PFO) Closure in Stroke Patients (REDUCE, NCT00738894). Given the low rate of stroke recurrence, a pooled analysis of individual patient data from all RCTs will probably be necessary to conclude. 18
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Acknowledgements None. Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Overell JR, Bone I, Lees KR. Interatrial septal abnormalities and stroke: a meta-analysis of case-control studies. Neurology 2000; 55:1172– 1179. 2. Lechat P, Mas JL, Lascault G, et al. Prevalence of patent foramen ovale in patients with stroke. N Engl J Med 1988; 318:1148–1152. 3. Homma S, Sacco RL. Patent foramen ovale and stroke. Circulation 2005; 112:1063–1072. 4. Alsheikh-Ali AA, Thaler DE, Kent DM. Patent foramen ovale in cryptogenic stroke: incidental or pathogenic? Stroke 2009; 40:2349–2355. 5. Kent DM, Ruthazer R, Weimar C, et al. An index to identify stroke-related vs && incidental patent foramen ovale in cryptogenic stroke. Neurology 2013; 81:619–625. Using a patient-level meta-analysis of observational cohorts of cryptogenic stroke, the RoPE group built a score to estimate the probability of finding a PFO in cryptogenic stroke patients based on clinical characteristics and to identify strokerelated vs. incidental PFO. 6. Petty GW, Khandheria BK, Meissner I, et al. Population-based study of the relationship between patent foramen ovale and cerebrovascular ischemic events. Mayo Clin Proc 2006; 81:602–608. 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; 47:440–445. 8. Di Tullio MR, Jin Z, 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. In this large community-based study, the risk of first-ever clinical stroke did not differ according to the presence of PFO. 9. Ranoux D, Cohen A, Cabanes L, et al. Patent foramen ovale: is stroke due to paradoxical embolism? Stroke 1993; 24:31–34. 10. Berthet K, Lavergne T, Cohen A, et al. Significant association of atrial vulnerability with atrial septal abnormalities in young patients with ischemic stroke of unknown cause. Stroke 2000; 31:398–403. 11. Silver MD, Dorsey JS. Aneurysms of the septum primum in adults. Arch Pathol Lab Med 1978; 102:62–65. 12. Schneider B, Hanrath P, Vogel P, Meinertz T. Improved morphologic characterization of atrial septal aneurysm by transesophageal echocardiography: relation to cerebrovascular events. J Am Coll Cardiol 1990; 16:1000–1009. 13. Hart RG, Boop BS, Anderson DC. Oral anticoagulants and intracranial hemorrhage. Facts and hypotheses. Stroke 1995; 26:1471–1477. 14. Wohrle J. Closure of patent foramen ovale after cryptogenic stroke. Lancet 2006; 368:350–352. 15. 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; 139:753–760. 16. Verma SK, Tobis JM. Explantation of patent foramen ovale closure devices: a multicenter survey. JACC Cardiovasc Interv 2011; 4:579–585. 17. Yared K, Baggish AL, Solis J, et al. Echocardiographic assessment of percutaneous patent foramen ovale and atrial septal defect closure complications. Circ Cardiovasc Imaging 2009; 2:141–149. 18. Latson LA, Jones TK, Jacobson J, et al. Analysis of factors related to successful transcatheter closure of secundum atrial septal defects using the HELEX septal occluder. Am Heart J 2006; 151:1129–1211. 19. Thaman R, Faganello G, Gimeno JR, et al. Efficacy of percutaneous closure of patent foramen ovale: comparison among three commonly used occluders. Heart 2011; 97:394–399. 20. von Bardeleben RS, Richter C, Otto J, et al. Long term follow up after percutaneous closure of PFO in 357 patients with paradoxical embolism: difference in occlusion systems and influence of atrial septum aneurysm. Int J Cardiol 2009; 134:33–41. 21. Furlan AJ, Reisman M, Massaro J, et al. Closure or medical therapy for && cryptogenic stroke with patent foramen ovale. N Engl J Med 2012; 366:991–999. This randomized clinical trial involving 909 patients aged 18–60 years did not detect any benefit of closure PFO (using STARFlex device) over medical treatment alone.
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Closure of patent foramen ovale and stroke Calvet and Mas 22. Meier B, Kalesan B, Mattle HP, et al. Percutaneous closure of patent foramen ovale in cryptogenic embolism. N Engl J Med 2013; 368:1083– 1091. This randomized clinical trial involving 414 patients aged 18–60 years did not detect any benefit of closure of PFO (using Amplatzer device) over medical treatment alone. 23. 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– 1100. This randomized clinical trial involving 980 patients aged 18–60 failed to show a benefit of PFO closure (using Amplatzer device) but showed a reduction in stroke risk in a prespecified analysis in per-protocol and in the as-treated cohorts. &&
24. Wolfrum M, Froehlich GM, Knapp G, et al. Stroke prevention by percutaneous closure of patent foramen ovale: a systematic review and meta-analysis. Heart 2013. [Epub ahead of print]. In this meta-analysis, closure of PFO does not appear superior to medical treatment alone for secondary prevention of cryptogenic strokes. 25. Kitsios GD, Thaler DE, Kent DM. Potentially large yet uncertain benefits: a & meta-analysis of patent foramen ovale closure trials. Stroke 2013; 44:2640– 2643. This meta-analysis of PFO closure trials showed a nonsignificant 45% reduction in the risk of recurrent stroke. 26. Messe SR, Kent DM. Still no closure on the question of PFO closure. N Engl J Med 2013; 368:1152–1153. &
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Closure of patent foramen ovale in cryptogenic stroke: a never ending story David Calvet and Jean-Louis Mas
Purpose of review This review discusses current evidence on patent foramen ovale (PFO) closure compared with medical therapy alone in the prevention of stroke recurrence in patients with a PFO-associated cryptogenic stroke. Recent findings The Risk of Paradoxical Embolism group built a 10-point Score, based on clinical parameters, that estimates the probability of finding a PFO in a patient with cryptogenic stroke and the probability that a PFO discovered in the setting of cryptogenic stroke is related to stroke vs. incidental. Three recent randomized clinical trials failed to demonstrate the superiority of PFO closure over medical treatment alone in preventing stroke recurrence in patients aged 18–60 years who have had a cryptogenic stroke or transient ischemic attack. Summary Stronger evidence in favor of PFO closure is needed before recommending this procedure outside of a clinical trial. Results of ongoing trials are much awaited. Keywords cryptogenic stroke, medical therapy, patent foramen ovale, transcatheter closure
INTRODUCTION The patent foramen ovale (PFO) and stroke story began about 25 years ago when the first in a series of case–control studies demonstrated a strong association between PFO and cryptogenic ischemic stroke, particularly in younger patients [1,2]. This association was reported to be stronger in patients who have an atrial septal aneurysm (ASA) in addition to a PFO, and in some studies in those who have a severe right-to-left shunt or a large opening of the PFO [1]. These results suggested that paradoxical embolism through a PFO might be responsible for stroke more often than was usually suspected. As often in medicine, the ‘cart has been put before the horse’ and PFO closure has become routine in many centers. However, despite the vast literature on this subject, several important clinical questions remain largely unanswered: Is a PFO discovered in the setting of cryptogenic stroke an incidental finding or is it related to stroke? If so, what is the mechanism of stroke? What is the best therapy to prevent stroke recurrence in cryptogenic stroke with PFO?
IS PATENT FORAMEN OVALE INCIDENTAL OR STROKE-RELATED? As PFO is common in the general population [3], it may coexist by chance alone in patients with cryptogenic stroke. The probability that a PFO discovered in the setting of a cryptogenic stroke is incidental or stroke-related can be estimated using Bayes’ theorem [4]. Considering a typical population of patients with cryptogenic stroke, in which the prevalence of a PFO is about 40% and assuming that the prevalence of PFO in cryptogenic stroke unrelated to PFO is 25% (similar to that in the general population), then 50% of PFOs would be incidental [4]. The probability that a PFO is Paris Descartes University, Centre de Psychiatrie et Neurosciences INSERM UMR 894 and Department of Neurology, Centre Hospitalier Sainte-Anne, Paris, France Correspondence to Professor Jean-Louis Mas, Service de Neurologie, Hoˆpital Sainte-Anne, 1 rue Cabanis, 75674 Paris Cedex 14, France. Tel: +33 1 45 65 82 84; fax: +33 1 45 65 87 94; e-mail: [email protected] Curr Opin Neurol 2014, 27:13–19 DOI:10.1097/WCO.0000000000000052
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KEY POINTS The probability that a PFO discovered in the setting of a cryptogenic stroke is stroke-related vs. incidental depends on the patient’s age, presence of traditional risk factors, and type of cerebral infarct. The risk of stroke recurrence is low in patients with PFO-related stroke. Randomized clinical trials failed to demonstrate superiority of device closure compared with medical therapy.
stroke-related (vs. incidental) is dependent on the prevalence of PFO in the cryptogenic stroke population; the higher the prevalence of PFO, the higher the probability that PFO is stroke-related. The prevalence of PFO in a cryptogenic stroke population is itself dependent on the presence or absence of other patient characteristics. Based on a patientlevel meta-analysis of observational cohorts of cryptogenic stroke patients, the Risk of Paradoxical Embolism (RoPE) group identified several factors associated with the detection of a PFO [5 ], including younger age, the presence of a cortical stroke on neuroimaging, and the absence of diabetes, hypertension, smoking, and prior stroke or transient ischemic attack (TIA) (Table 1). These factors were incorporated into the 10-point RoPE Score that &&
estimates the probability of finding a PFO in cryptogenic stroke patients based on clinical characteristics (Table 2). The score will be 10 for a patient with all predictive factors of the presence of a PFO. Table 2 shows that the prevalence of PFO (probability of finding a PFO) increases from 23% in cryptogenic stroke patients with a score of 0 to 3 to 73% in those with 9 or 10 points, corresponding to PFO-attributable fraction estimates of approximately 0 to 90%. Interestingly, this table also shows that the patients who were the most likely to have stroke-related PFOs were also those with the lowest recurrence risk, with an estimated 2-year risk of stroke or TIA recurrence of only 2% in patients with a RoPE score of 9 or 10. However, some population-based studies have challenged the association between PFO and stroke [6,7]. Recently, a large community-based study assessed the risk of first-ever clinical stroke or subclinical cerebrovascular disease in 1100 stroke-free individuals over age 39 years in which PFO was assessed by transthoracic echocardiography [8 ]. The risk of first-ever ischemic stroke did not differ according to the presence of PFO [12.5-year cumulative risk of stroke ¼ 10.1% in patients with PFO vs. 10.4% in patients without (P ¼ 0.46)]. In addition, there was no association between PFO and silent brain infarcts on MRI (adjusted odds ratio, 1.15; 95% CI, 0.50–2.62) [8 ]. Assuming that PFO is stroke-related, the next question relates to stroke mechanism. Paradoxical &
&
Table 1. Risk of paradoxical embolism score calculator Characteristic
Points
No history of hypertension
1
No history of diabetes
1
No history of stroke or TIA
1
Nonsmoker
1
Cortical infarct on imaging
1
RoPE Score
Age (years) 18–29
5
30–39
4
40–49
3
50–59
2
60–69
1
70
0
Total score (sum of individual points) Maximum score (a patient < 30 years with no hypertension, no diabetes, no history of stroke or TIA, nonsmoker, and cortical infarct)
10
Minimum score (a patient 70 years with hypertension, diabetes, prior stroke, current smoker, and no cortical infarct)
0
&&
RoPE, Risk of Paradoxical Embolism; TIA, transient ischemic attack. Adapted with permission from [5
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Closure of patent foramen ovale and stroke Calvet and Mas Table 2. Patent foramen ovale prevalence, attributable fraction, and estimated 2-year risk of stroke/TIA by Risk of Paradoxical Embolism point score strata (using control rate of 25% in general population) Cryptogenic stroke (n ¼ 3023) RoPE Score
Number of patients
Prevalence of patients with a PFO (95% CI)
CS with PFO (n ¼ 1324) PFO-attributable fraction (95% CI)
Estimated 2-y stroke/TIA recurrence rate (95% CI)
0–3
613
23% (19–26)
4
511
35% (31–39)
38% (25–48)
0% (0–4)
20% (12–28) 12% (6–18)
5
516
34% (30–38)
34% (21–45)
7% (3–11)
6
482
47% (42–51)
62% (54–68)
8% (4–12)
7
434
54% (49–59)
72% (66–76)
6% (2–10)
8
287
67% (62–73)
84% (79–87)
6% (2–10)
9
180
73% (66–79)
88% (83–91)
2% (0–4)
CS, cryptogenic stroke; CI, confidence interval; PFO, patent foramen ovale; RoPE, Risk of Paradoxical Embolism; TIA, transient ischemic attack. Adapted with && permission from [5 ].
embolism of venous thrombi to the systemic circulation is usually thought to be the mechanism of stroke in cases of PFO. However, in the vast majority of cases, a venous source of embolism cannot be detected and paradoxical embolism remains a hypothetical diagnosis [9]. Other potential mechanisms for stroke in PFO patients include paroxysmal atrial fibrillation [10] and direct embolization of thrombi formed in the PFO tunnel or in the ASA [11,12], but documentation of these mechanisms is lacking in the vast majority of cases. Another hypothesis is that stroke would result from an occult disorder, itself associated with PFO. The mechanisms by which PFO causes stroke need to be more fully elucidated.
IS PATENT FORAMEN OVALE CLOSURE BETTER THAN MEDICAL TREATMENT TO PREVENT STROKE RECURRENCE? Therapeutic options for secondary stroke prevention in cryptogenic stroke patients with a PFO include antiplatelet therapy, oral anticoagulants, and (mainly transcatheter) PFO closure. Antiplatelet drugs are well tolerated and reduce recurrent ischemic events when used for secondary prevention in the generality of patients with ischemic stroke. Oral anticoagulation may be more appropriate than antiplatelet drugs if stasis-related thrombi originate in the cardiac chambers or the peripheral venous system. But oral anticoagulants have many drawbacks and carry a risk of major bleeding [13]. PFO closure can prevent paradoxical embolism, but this treatment will not be relevant if a PFO-unrelated mechanism of ischemic stroke is the cause. PFO closure is not without risks, including complications related to vascular access (retroperitoneal hemorrhage), cardiac perforation with and without tamponade, air
embolism, device embolization (requiring surgical revision), arrhythmias, septal erosion, and thrombus formation on the device and complications related to antithrombotic treatment, some of which may be responsible for periprocedural stroke [14–17]. In addition, device closure leaves an implant behind, with potential mid-term or longterm complications such as atrial fibrillation and septal erosions [16]. PFO closure does not guarantee shunt closure, as residual shunts are seen in 15–20% of patients at 6 months [18–20].
RESULTS OF RANDOMIZED CLINICAL TRIALS Three randomized clinical trials (RCTs) evaluated whether PFO closure is superior to antithrombotic therapy alone in preventing recurrent stroke in patients 18–60 years of age who have had a cryptogenic stroke or TIA [21 –23 ]. In the medical group, patients received aspirin or oral anticoagulants at the discretion of the investigator. Tables 3 and 4 summarize the main characteristics and results of these trials. The CLOSURE I (Evaluation of the STARFlex septal Closure System in Patients with a Stroke and/or Transient Ischemic Attack due to Presumed Paradoxical Embolism Through a Patent Forman Ovale) trial [21 ] did not detect any benefit of closure over medical treatment alone. At 2 years, the rates of the primary endpoint, as well as the rates of stroke, did not differ between groups. No difference was found according to shunt size or presence/ absence of ASA. Major vascular (procedural) complications occurred in 3.2% of patients in the device arm. Atrial fibrillation occurred more frequently in the device arm, mainly during the periprocedural period (60%).
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&&
&&
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Cerebrovascular disease Table 3. Hypotheses, primary endpoint and details of randomized clinical trials comparing percutaneous patent foramen ovale closure with medical treatment alone for secondary stroke prevention
Hypothesis
CLOSURE Ia
PC Trialb
RESPECTc
Incidence of primary endpoint at 2 years: 6% in the medical arm and 3% in the device arm
Incidence of primary endpoint: 3%/year in the medical arm and 1%/year in the closure arm
Incidence of primary endpoint at two years: 4.3% in the medical arm and 1% in the closure arm
Sample size ¼ 1600
Mean follow up of 4.5 years
Sample size ¼ maximum of 1000
a-level of 0.05 and 80% power
Sample size ¼ 410
a-level of 0.025 and 80% power
a-level of 0.05 and 80% power Primary endpoint
Composite: stroke or TIA, death from any cause during the first 30 days, or death from neurologic causes between 31 days and 2 years
Composite: death, nonfatal stroke, TIA, peripheral embolism
Nonfatal stroke
Sites
87 sites in United States and Canada
29 sites in Europe, Brazil and Australia
69 sites in United States and Canada
Sponsor
NMT Medical
St. Jude Medical
St. Jude Medical
Closure device
STARFlex
Amplatzer
Amplatzer
a CLOSURE I: Evaluation of the STARFlex septal Closure System in Patients with a Stroke and/or Transient Ischemic Attack due to Presumed Paradoxical Embolism Through a Patent Forman Ovale. b PC Trial: Clinical Trial Comparing Percutaneous Closure of Patent Forman Ovale Using the Amplatzer PFO Occluder with Medical Treatment in Patients with Cryptogenic Embolism. c RESPECT: Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment.
The PC Trial (Clinical Trial Comparing Percutaneous Closure Of Patent Forman Ovale Using the Amplatzer PFO Occluder with Medical Treatment in Patients with Cryptogenic Embolism) [22 ] also &&
failed to show a reduction in the primary endpoint in patients treated with PFO closure vs. medical treatment alone. Procedural complications occurred in 1.5% of patients.
Table 4. Main results of randomized clinical trials assessing the effect of percutaneous patent foramen ovale closure for secondary prevention of cryptogenic stroke as compared to medical treatment alone CLOSURE Ia
PC Trialb
RESPECTc
June 2003 to October 2008
February 2000 to February 2009
August 2003 to December 2011
447/462
204/210
499/481
2.0d
4.0
2.6e
Primary endpoint (Closure group vs. Medical group)
5.5% vs. 6.8%
3.45 vs. 5.2%
1.85 vs. 3.3%
HR for Closure vs. Medical treatment (95% CI)
0.78 (0.45–1.35)
2.7% vs. 2.8%
0.63 (0.24 to 1.62)
Strokef (Closure group vs. Medical group)
0.55 vs. 2.4%
0.49 (0.22–1.11)
1.85 vs. 3.3%
Atrial fibrillation (Closure group vs. Medical group) Major bleeding (Closure group vs. Medical group)
5.75 vs. 0.7%
2.95 vs. 1.0%
3.05 vs. 1.5%
2.65 vs. 1.1%
0.55 vs. 1.5%
1.85 vs. 1.8%
Study enrollment period Number of enrolled patients (Closure group vs. Medical group) Mean follow up in years
Given percentages are for study follow-up periods. a CLOSURE I: Evaluation of the STARFlex septal Closure System in Patients with a Stroke and/or Transient Ischemic Attack due to Presumed Paradoxical Embolism Through a Patent Forman Ovale. b PC Trial: Clinical Trial Comparing Percutaneous Closure of Patent Forman Ovale Using the Amplatzer PFO Occluder with Medical Treatment in Patients with Cryptogenic Embolism. c RESPECT: Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment. d 2-year follow up in all patients at the last known follow-up visit, whichever was earlier. e 1375 patient-years in Closure group and 1184 patient-years in medical treatment group. f Three (0.7%) were periprocedural in CLOSURE I, two (0.4%) in RESPECT, and none in PC Trial according to Kaplan Meier curves of all cause mortality && (supplementary figure 4 in [22 ]). No death occurred during the periprocedural period in all the three trials.
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Closure of patent foramen ovale and stroke Calvet and Mas
Study or subgroup CLOSURE I PC Trial RESPECT
Closure Medical Therapy Risk ratio Events Total Events Total Weight M–H, Random,95% Cl 12 447 13 462 47.9% 0.95 [0.44, 2.07] 1 204 5 210 7.4% 0.21 [0.02, 0.75] 9 499 16 481 44.7% 0.54 [0.24, 1.22]
Total (95% CI) 1150 1153 100.0% Total events 22 34 Heterogeneity: Tau2 = 0.03; Chi2 = 2.20, df = 2 (P = 0.32); I2 = 11% Test for overall effect: Z = 1.37 (P = 0.17)
Risk ratio M–H, Random, 95% Cl
0.66 [0.37, 1.19] 0.01 0.1 1 10 100 Favours closure Favours control
FIGURE 1. Forest plot of risk ratios for stroke.
Finally, the RESPECT (Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment) trial [23 ] also failed to establish superiority of PFO closure over medical therapy in the intention-to-treat analysis. However, a reduction in stroke risk was found in a prespecified analysis in the per-protocol cohort (six events in the closure group vs. 14 events in the medical-therapy group) and in the as-treated cohort (five events vs. 16 events). Procedure-related or device-related serious adverse events occurred in 4.2% in the closure group. In a meta-analysis of these RCTs (using an intention-to-treat approach and a random effects model), we found no significant difference in the risk of recurrent stroke between patients treated with PFO closure and those receiving antithrombotic treatment (risk ratio for stroke after PFO closure, 0.66; 95% CI, 0.37–1.19; P ¼ 0.17) (Fig. 1). PFO closure was associated with an increased risk of atrial fibrillation (risk ratio, 3.66; 95% CI, 1.43–9.34; P ¼ 0.007). There was no difference in the risk of major bleeding between groups (risk ratio, 1.23; 95% CI, 0.45–3.37; P ¼ 0.68). These results are consistent with two recent meta-analyses [24 ,25 ]. Assuming a 50% stroke rate reduction in patients treated by PFO closure and an annual stroke risk of 1.5% in patients with cryptogenic stroke and PFO treated by medical therapy (as observed in RCTs), we estimated that 133 patients should be treated per year to avoid one stroke. In the same time, one atrial fibrillation and one major bleed would be caused every, respectively, 75 and 312 patients treated by PFO closure. &&
&
A potentially significant proportion of patients with patent foramen ovale-unrelated stroke The inclusion of patients with PFO-unrelated stroke may have reduced the ability to detect a treatment effect. Many patients included in RCTs had traditional stroke risk factors, which have been shown to be inversely associated with stroke-related PFO in the RoPE score (Tables 1 and 2) [5 ]. In addition, the definition of cryptogenic stroke varied substantially from one study to another. For example, lacunar stroke was excluded from the RESPECT trial, whereas it was apparently not an exclusion criterion in CLOSURE I and the PC Trial. Interestingly, in CLOSURE I, strokes that occurred during follow up were often attributable to another cause than the PFO. &&
A heterogeneous control group The definition of the control group of these trials is debatable. Patients were treated with aspirin or oral anticoagulants at the discretion of the investigator in charge of the patient. However, we do not know whether these treatments have similar efficacy to prevent stroke recurrence in PFO patients.
&
LIMITATIONS OF RANDOMIZED CLINICAL TRIALS Some characteristics of RCTs might partly explain why they failed to conclude on the superiority of one strategy over another.
Underpowered trials RCTs may have failed to show a difference between treatments groups because large treatment effects were assumed (66 to 75% risk reduction in the PFO closure group) and observed event rates were lower than anticipated. Indeed, the expected incidence rate in the medical group was 2–3% per year, whereas the actual rate of stroke was only 1.3% per year. Then, as discussed in the editorial accompanying the publication of the PC Trial and RESPECT [26], low statistical power can make trials more sensitive to potential bias and misclassification of even one or two events can have dramatic effects on the P values in trials with low outcome rates. The three RCTs enrolled a total number of
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2303 patients in whom only 56 strokes occurred. Using a power of 80%, we calculated that at least 60 events are needed to detect a relative effect of PFO closure of about 50%. Based on an annual risk of 1.5% in the medical group and a 2-year follow up, 1539 patients should be included in each group. The number falls to 381 patients by group in a trial with an inclusion period of 5 years and a maximum follow up of 10 years. Long-term follow up of patients included in the CLOSURE 1, RESPECT, and the PC Trial would certainly bring some useful information.
Is there a closure device effect? A single closure device was used in each trial. A recent meta-analysis suggested that the safety profile for the Amplatzer device used in the PC Trial and RESPECT might be superior to that of the STARFlex device used in CLOSURE I [24 ]. A potential device effect needs to be confirmed in further studies. &
A slow rate of enrollment Enrollment periods in RCTs were longer than expected, which could be due to widespread offlabel use of atrial septal closure devices. For example, only 5–10% of patients considered for PFO closure were enrolled in the PC Trial during the study period. Therefore, patients included in RCTs may not be representative of patients with PFO-associated cryptogenic stroke if patients treated outside RCTs were different from those enrolled in RCTs.
CONCLUSION RCTs failed to demonstrate superiority of device closure compared with medical therapy. However, there are signals pointing toward a potential small absolute benefit of PFO closure. Stronger evidence in favor of PFO closure is needed before recommending this procedure outside of a clinical trial. Wherever possible, patients with cryptogenic stroke and PFO should be enrolled in ongoing RCTs, such as Patent Foramen Ovale Closure or Anticoagulation vs. Antiplatelet Therapy to Prevent Stroke Recurrence (CLOSE, ClinicalTrials.gov number, NCT00562289), Device Closure vs. Medical Therapy for Cryptogenic Stroke Patients with High-Risk Patent Formaen Ovale (DEFENSE-PFO, NCT01550588), and Gore Helex Septal Occluder/Gore Septal Occluder for Patent Foramen Ovale (PFO) Closure in Stroke Patients (REDUCE, NCT00738894). Given the low rate of stroke recurrence, a pooled analysis of individual patient data from all RCTs will probably be necessary to conclude. 18
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Acknowledgements None. Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Overell JR, Bone I, Lees KR. Interatrial septal abnormalities and stroke: a meta-analysis of case-control studies. Neurology 2000; 55:1172– 1179. 2. Lechat P, Mas JL, Lascault G, et al. Prevalence of patent foramen ovale in patients with stroke. N Engl J Med 1988; 318:1148–1152. 3. Homma S, Sacco RL. Patent foramen ovale and stroke. Circulation 2005; 112:1063–1072. 4. Alsheikh-Ali AA, Thaler DE, Kent DM. Patent foramen ovale in cryptogenic stroke: incidental or pathogenic? Stroke 2009; 40:2349–2355. 5. Kent DM, Ruthazer R, Weimar C, et al. An index to identify stroke-related vs && incidental patent foramen ovale in cryptogenic stroke. Neurology 2013; 81:619–625. Using a patient-level meta-analysis of observational cohorts of cryptogenic stroke, the RoPE group built a score to estimate the probability of finding a PFO in cryptogenic stroke patients based on clinical characteristics and to identify strokerelated vs. incidental PFO. 6. Petty GW, Khandheria BK, Meissner I, et al. Population-based study of the relationship between patent foramen ovale and cerebrovascular ischemic events. Mayo Clin Proc 2006; 81:602–608. 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; 47:440–445. 8. Di Tullio MR, Jin Z, 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. In this large community-based study, the risk of first-ever clinical stroke did not differ according to the presence of PFO. 9. Ranoux D, Cohen A, Cabanes L, et al. Patent foramen ovale: is stroke due to paradoxical embolism? Stroke 1993; 24:31–34. 10. Berthet K, Lavergne T, Cohen A, et al. Significant association of atrial vulnerability with atrial septal abnormalities in young patients with ischemic stroke of unknown cause. Stroke 2000; 31:398–403. 11. Silver MD, Dorsey JS. Aneurysms of the septum primum in adults. Arch Pathol Lab Med 1978; 102:62–65. 12. Schneider B, Hanrath P, Vogel P, Meinertz T. Improved morphologic characterization of atrial septal aneurysm by transesophageal echocardiography: relation to cerebrovascular events. J Am Coll Cardiol 1990; 16:1000–1009. 13. Hart RG, Boop BS, Anderson DC. Oral anticoagulants and intracranial hemorrhage. Facts and hypotheses. Stroke 1995; 26:1471–1477. 14. Wohrle J. Closure of patent foramen ovale after cryptogenic stroke. Lancet 2006; 368:350–352. 15. 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; 139:753–760. 16. Verma SK, Tobis JM. Explantation of patent foramen ovale closure devices: a multicenter survey. JACC Cardiovasc Interv 2011; 4:579–585. 17. Yared K, Baggish AL, Solis J, et al. Echocardiographic assessment of percutaneous patent foramen ovale and atrial septal defect closure complications. Circ Cardiovasc Imaging 2009; 2:141–149. 18. Latson LA, Jones TK, Jacobson J, et al. Analysis of factors related to successful transcatheter closure of secundum atrial septal defects using the HELEX septal occluder. Am Heart J 2006; 151:1129–1211. 19. Thaman R, Faganello G, Gimeno JR, et al. Efficacy of percutaneous closure of patent foramen ovale: comparison among three commonly used occluders. Heart 2011; 97:394–399. 20. von Bardeleben RS, Richter C, Otto J, et al. Long term follow up after percutaneous closure of PFO in 357 patients with paradoxical embolism: difference in occlusion systems and influence of atrial septum aneurysm. Int J Cardiol 2009; 134:33–41. 21. Furlan AJ, Reisman M, Massaro J, et al. Closure or medical therapy for && cryptogenic stroke with patent foramen ovale. N Engl J Med 2012; 366:991–999. This randomized clinical trial involving 909 patients aged 18–60 years did not detect any benefit of closure PFO (using STARFlex device) over medical treatment alone.
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Closure of patent foramen ovale and stroke Calvet and Mas 22. Meier B, Kalesan B, Mattle HP, et al. Percutaneous closure of patent foramen ovale in cryptogenic embolism. N Engl J Med 2013; 368:1083– 1091. This randomized clinical trial involving 414 patients aged 18–60 years did not detect any benefit of closure of PFO (using Amplatzer device) over medical treatment alone. 23. 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– 1100. This randomized clinical trial involving 980 patients aged 18–60 failed to show a benefit of PFO closure (using Amplatzer device) but showed a reduction in stroke risk in a prespecified analysis in per-protocol and in the as-treated cohorts. &&
24. Wolfrum M, Froehlich GM, Knapp G, et al. Stroke prevention by percutaneous closure of patent foramen ovale: a systematic review and meta-analysis. Heart 2013. [Epub ahead of print]. In this meta-analysis, closure of PFO does not appear superior to medical treatment alone for secondary prevention of cryptogenic strokes. 25. Kitsios GD, Thaler DE, Kent DM. Potentially large yet uncertain benefits: a & meta-analysis of patent foramen ovale closure trials. Stroke 2013; 44:2640– 2643. This meta-analysis of PFO closure trials showed a nonsignificant 45% reduction in the risk of recurrent stroke. 26. Messe SR, Kent DM. Still no closure on the question of PFO closure. N Engl J Med 2013; 368:1152–1153. &
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