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J Am Coll Cardiol, 2004; 44:750-758, doi:10.1016/j.jacc.2004.05.044 © 2004 by the American College of Cardiology Foundation |
* Cardiology
Neurology, University Hospital, Bern,Switzerland
Manuscript received September 7, 2003; revised manuscript received May 9, 2004, accepted May 11, 2004.
* Reprint requests and correspondence: Dr. Stephan Windecker, Director of Invasive Cardiology, Swiss Cardiovascular Center Bern, University Hospital, CH-3010 Bern, Switzerland (Email: stephan.windecker{at}insel.ch).
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Abstract |
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BACKGROUND: Patients with cryptogenic stroke and PFO are at risk for recurrent cerebrovascular events.
METHODS: We compared the risk of recurrence in 308 patients with cryptogenic stroke and PFO, who were treated either medically (158 patients) or underwent percutaneous PFO closure (150 patients) between 1994 and 2000.
RESULTS: Patients undergoing percutaneous PFO closure had a larger right-to-left shunt (p < 0.001; 95% confidence interval [CI] 1.38 to 3.07) and were more likely to have suffered more than one cerebrovascular event (p = 0.03; 95% CI 1.04 to 2.71). At four years of follow-up, percutaneous PFO closure resulted in a non-significant trend toward risk reduction of death, stroke, or transient ischemic attack (TIA) combined (8.5% vs. 24.3%; p = 0.05; 95% CI 0.23 to 1.01), and of recurrent stroke or TIA (7.8% vs. 22.2%; p = 0.08; 95% CI 0.23 to 1.11) compared with medical treatment. Patients with more than one cerebrovascular event at baseline and those with complete occlusion of PFO were at lower risk for recurrent stroke or TIA after percutaneous PFO closure compared with medically treated patients (7.3% vs. 33.2%; p = 0.01; 95% CI 0.08 to 0.81, and 6.5% vs. 22.2%; p = 0.04; 95% CI 0.14 to 0.99, respectively).
CONCLUSIONS: Percutaneous PFO closure appears at least as effective as medical treatment for prevention of recurrent cerebrovascular events in cryptogenic stroke patients with PFO. It might be more effective than medical treatment in patients with complete closure and more than one cerebrovascular event.
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Percutaneous PFO closure is a catheter-based technique using atrial septal occlusion devices. It was initially advocated for prevention of recurrent stroke in 1992 (12), and safety and feasibility have been addressed in several studies (12–19). However, the therapeutic efficacy of percutaneous PFO closure as an adjunct or alternative to medical treatment in cryptogenic stroke patients with PFO is unknown. This non-randomized study compares the risk of recurrent cerebrovascular events in patients with cryptogenic stroke and PFO who underwent percutaneous PFO closure or received medical treatment alone.
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Methods |
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Transesophageal echocardiography and diagnosis of paradoxical embolism.
The diagnosis of PFO and atrial septal aneurysm was based on contrast transesophageal echocardiography with an aerated colloid solution injected into an antecubital vein at the end of a Valsalva maneuver in all patients. Patent foramen ovale was defined as flap-like opening in the atrial septum secundum, with the septum primum serving as a one-way valve allowing for permanent or transient right-to-left shunt. Atrial septal aneurysm was diagnosed as abnormally redundant interatrial septum with an excursion of 
10 mm into the right or left atrium and a base span of at least 15 mm (20). Spontaneous or provoked right-to-left shunt was semiquantitatively graded according to the amount of bubbles detected in the left atrium after crossing the interatrial septum on a still frame: grade 0 = none, grade 1 = minimal (1 to 5 bubbles), grade 2 = moderate (6 to 20 bubbles), and grade 3 = severe (>20 bubbles) (3).
Medical treatment. Patients assigned to medical treatment were treated with a vitamin K antagonist or antiplatelet therapy at the discretion of the attending neurologist. Coumadin was adjusted to a target international normalized ratio of 2.0 to 3.0; acetylsalicylic acid was prescribed at a mean dose of 233 ± 83 mg/day, and clopidogrel at a dose of 75 mg/day.
Percutaneous PFO closure. The procedure was performed under local anesthesia and fluoroscopic guidance as described previously (15). Six different device types were utilized according to availability at different time points, including the Amplatzer PFO Occluder (n = 54), PFO STAR (n = 42), Sideris buttoned device (n = 27), Angel Wing device (n = 10), Amplatzer ASD Occluder (n = 9), and CardioSEAL (n = 8). Patients were treated with acetylsalicylic acid 100 mg once daily for six months for antithrombotic protection until full device endothelialization. A contrast transesophageal echocardiography was repeated six months after percutaneous PFO closure to assess for a residual shunt after endothelial overgrowth. Medical treatment was discontinued in 93 of 150 patients after six months. Fifty-seven patients continued medical treatment with acetylsalicylic acid 100 mg once daily owing to a residual shunt (26 patients) or presence of mild coronary artery disease as assessed by coronary angiography (31 patients).
Follow-up evaluation. All family physicians and patients were subjected to a structured interview addressing recurrence of cerebrovascular events, rehospitalizations, and device- or medication-related problems. Death, recurrent ischemic stroke, TIA, or peripheral embolism were considered adverse events. Patients with suspected recurrent cerebrovascular events were reexamined by a neurologist, and an imaging study of the brain was repeated. Follow-up information was available for all patients at some point in time, but two patients in the medical treatment group and three patients in the percutaneous PFO closure group were subsequently lost to follow-up as a result of address changes. Patients gave informed consent, and the study was approved by the local ethics committee.
Statistical analysis. Continuous variables are expressed as mean ± 1 SD and were compared by a two-sided, unpaired t test. Categorical variables are reported as counts and percentages and were compared by chi-square analysis. The Kaplan-Meier survival analysis was used to assess the risk of recurrent events. The log-rank test was used to compare the cumulative incidence curves between the treatment groups. Predictors of recurrent events according to treatment assignment were analyzed by a Cox proportional hazards model. Statistical significance was assumed with a p value <0.05. All data were analyzed with the use of SPSS software (version 10.0, SPSS Inc., Chicago, Illinois).
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Percutaneous PFO closure. Percutaneous PFO closure was successful in 148 patients (99%) and failed in 2 patients. Periprocedural complications were observed in nine patients (6%), and they included embolization of the device in four patients, air embolism in three patients, and vascular access site problems in two patients. There were no procedural deaths, no requirement for open-heart surgery, and none of the procedural complications resulted in long-term sequelae. Complete PFO closure as assessed by transesophageal echocardiographyat six months was achieved in 83% of patients, whereas a small, moderate, or large shunt persisted in 10%, 3%, or 4% of patients, respectively.
Recurrent events. Outcome events during a mean follow-up of 2.3 ± 1.7 years are summarized in Tables 3 through 5. Three deaths, 7 ischemic strokes, and 14 TIAs were observed in the medical treatment group, compared with 1 death, 2 ischemic strokes, and 7 TIAs in the percutaneous PFO closure group. In the medical treatment group, one stroke and five TIAs were encountered with oral anticoagulation, six strokes and six TIAs with antiplatelet treatment, and three TIAs in patients who had discontinued antiplatelet therapy. No peripheral embolic events were encountered during follow-up in either group.
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Discussion |
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Although several observational studies have reported the long-term outcome after medical treatment (5–8,10) and percutaneous (12–19) or surgical (34–36) PFO closure, this is the first study to compare percutaneous PFO closure with medical treatment for prevention of recurrent cerebrovascular events in patients with cryptogenic stroke and PFO. Percutaneous PFO closure was as effective as medical treatment in the overall study group. It was significantly better than medical treatment in the prevention of recurrent cerebrovascular events in two subgroups: patients with complete PFO occlusion after the intervention and patients with more than one cerebrovascular event at baseline.
The superiority of percutaneous PFO closure when compared with medical treatment in patients with complete PFO occlusion is in line with our previously reported finding that complete compared with incomplete PFO occlusion results in a significantly lower risk of recurrence in patients undergoing percutaneous PFO closure (15,16). This observation lends further support to paradoxical embolism being the prevalent mechanism for cerebrovascular events in this patient group. Furthermore, it highlights that complete PFO occlusion is desirable for therapeutic efficacy in patients undergoing percutaneous PFO closure, a goal which can be achieved in >90% of patients with the most recent devices (17,18).
The higher efficacy of percutaneous PFO closure compared with medical treatment in patients with more than one cerebrovascular event indicates that these patients represent a high-risk population. Indeed, these patients suffered recurrent cerebrovascular events despite medical treatment, suggesting inadequate protection by medical treatment alone. The fact that previous events were more frequent in patients who underwent percutaneous PFO closure enhances the results in favor of the interventional group. So does the larger PFO size in the interventional group, another established risk factor for recurrence (24–28).
Event rates between medical treatment and percutaneous PFO closure appeared to separate only after two years of follow-up. One explanation for this observation is the intention to treat analysis of our study. Thus, patients with incomplete PFO closure (17%) were included in the overall percutaneous PFO closure group. Because the device becomes fully protective only after complete endothelialization has ensued, a residual shunt during the initial months after device implantation may predispose to recurrent events despite antithrombotic therapy. This observation is validated by the early separation of cerebrovascular event rates in patients with complete PFO closure compared with the medical treatment group (Fig. 4). Another explanation for the more pronounced separation after two years of follow-up could be non-compliance with medical treatment in patients in the medical treatment group.
The benefits of percutaneous PFO closure in our study were associated with a certain risk of procedural complications, albeit without any long-term sequelae, and with the incremental cost of the procedure and the device. Ultimate proof of paradoxical embolism being the principal stroke mechanism in such patients and of the superiority of percutaneous PFO closure over medical treatment will have to await the results of prospective, randomized trials such as the Percutaneous Closure of Patent Foramen Ovale and Cryptogenic Embolism trial initiated by our group (16).
Mas et al. (10) recently reported on the clinical outcome of 581 patients (mean age 42 years) with cryptogenic stroke, who were treated with acetylsalicylic acid 300 mg/day and followed for up to 4 years. The risk of recurrent stroke or TIA at four years was 5.6% in patients with PFO alone, 19.2% in patients with both PFO and atrial septal aneurysm, 0% in patients with atrial septal aneurysm alone, and 6.2% in patients without atrial septal abnormality. The authors concluded that patients with both PFO and atrial septal aneurysm are at substantial risk for recurrence requiring additional preventive strategies beyond treatment with acetylsalicylic acid alone, whereas patients with a PFO alone are at low risk for recurrence comparable to those patients without atrial septal abnormality. It has been hypothesized, however, that a large PFO rather than the associated atrial septal aneurysm was responsible for the high recurrence rate in this study (37). We did not observe a significant difference in recurrence rates with respect to the additional presence of atrial septal aneurysm between the medical treatment and percutaneous PFO closure group in our study. However, this subgroup represented only one-fourth of the entire cohort, and a potential difference in clinical outcome might have become apparent with a larger patient group and during longer follow-up. Thus, patients with PFO and associated atrial septal aneurysm deserve further investigation with respect to the role of percutaneous PFO closure in addition to medical treatment. Despite the low recurrence rate in patients with PFO alone as reported by Mas et al. (10), it cannot be excluded that percutaneous PFO closure reduces further events even in these patients. Notably, patients without atrial septal abnormalities had significantly more competing stroke risk factors, such as arterial hypertension, smoking, or hypercholesterolemia, than PFO patients, possibly camouflaging the PFO risk.
In the prospective PICSS (5), the presence of PFO was reported not to have an adverse impact on recurrent cerebrovascular events regardless of PFO size and presence of an atrial septal aneurysm. However, only 42% of patients included in this study had suffered a cryptogenic stroke as opposed to stroke of known etiology, that is, large vessel (11%), lacunar (39%), other determined cause (4%), or conflicting mechanism (4%). Therefore, it comes as no surprise that PFO was only an innocent bystander in the majority of patients. Notwithstanding, the investigators were able to reproduce the previously documented association of PFO with cryptogenic stroke as well as a higher prevalence of large PFOs in cryptogenic stroke patients than in control subjects of known stroke cause. The recurrent stroke and death rates at two years were 9.5% and 17.9% for cryptogenic stroke patients with PFO receiving warfarin or acetylsalicylic acid, respectively (RR 0.52, 0.16 to 1.67, p = 0.3).Although not significant, this corresponds to a 48% event reduction in favor of warfarin and contrasts with the event rates of 16.5% and 13.2% for warfarin or acetylsalicylic acid treated patients, respectively, in the entire PICSS cohort of PFO patients. However, a similar 49% event reduction in favor of warfarin was observed in cryptogenic stroke patients without PFO, implying a PFO-independent but possibly anticoagulation-responsive stroke mechanism.
The recurrent event rates in our study were similar to those in the PICSS patient group (5) but higher than those reported by Mas et al. (10), suggesting important baseline differences with respect to age, cardiovascular risk factors, and number of previous cerebrovascular events. However, patients in our study were diagnosed and treated according to identical criteria established by a team of neurologists and cardiologists at a single institution, thus minimizing case-to-case variations. Because of the overall low recurrence rate of stroke, the cost and small risk of device implantation must be carefully weighed against the potential therapeutic benefit.
Study limitations. The following limitations apply to our study. The most important limitation is the non-randomized study design, which may confound the results and introduce bias. However, short of randomized trials which are not expected to be completed within the near future, these data provide important preliminary results relevant to this patient population. The diagnosis of PFO-mediated paradoxical embolism is presumptive, and therefore PFO and cryptogenic stroke may coexist without causal relationship in certain patients. Percutaneous PFO closure in such patients will not influence recurrent cerebrovascular events, a circumstance contributing to the small recurrence rate despite successful PFO closure in our and other series. Percutaneous PFO closure was performed using six different device types employed during different time periods. Current devices for percutaneous PFO closure achieve complete PFO occlusion in >95% of cases and are associated with complications in <1% of cases (18). This improvement in device performance might have a positive impact on clinical outcome in the future. Discontinuation of antithrombotic treatment in the medical treatment group could be an important confounder of the presented data. Thus, it cannot be excluded that a considerable portion of patients in the medical treatment group actually did not take antithrombotic treatment at all. However, the limitation of non-compliance with medical treatment applies to everyday clinical practice and does not affect the overall finding of our study.
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