This prospective observational study was carried out in a university hospital. Informed consent was obtained from all patients prior to enrollment in the study. Inclusion criteria were age over 18 years, history of cryptogenic stroke or TIA, and PFO documented by transesophageal echocardiography. Patients were referred from various hospitals in the Central region of Portugal (Hospitais da Universidade de Coimbra and Hospital Geral do Centro Hospitalar e Universitário in Coimbra, Centro Hospitalar do Baixo Vouga in Aveiro, Hospital Distrital da Figueira da Foz, Centro Hospitalar de Leiria/Pombal, Hospital de São Teotónio in Viseu, Centro Hospitalar da Cova da Beira in Covilhã, and Hospital Amato Lusitano in Castelo Branco).

Ischemic cerebrovascular events were defined as an acute neurological deficit persisting for over 24 hours, or less than 24 hours but associated with evidence of cerebral infarction on magnetic resonance imaging or computed tomography. Known causes of stroke including cardioembolism, carotid artery disease, lacunar cerebral infarction due to small vessel disease, and documented hypercoagulable states, such as the presence of anticardiolipin antibodies or lupus anticoagulant or hyperhomocysteinemia, were excluded.

PFO was defined by transesophageal echocardiography as evidence of passage of microbubbles from right to left atrium within three cardiac cycles following injection of agitated saline at rest and with the Valsalva maneuver. The shunt was classified as grade 1 (small: 1–20 microbubbles) or 2 (large: >20 microbubbles).6 Atrial septal aneurysm was defined as a mobile protrusion of the septum primum tissue into the atrium measuring ≥10 mm.6 The clinical characteristics of the study population included cardioembolic risk factors according to the CHA2DS2-VASc risk score,7 which was calculated without taking into account previous cerebrovascular events, since this was common to all patients.

Percutaneous PFO closure was performed using one of the following devices: Amplatzer™ PFO Occluder, Premere™ PFO Closure System, Occlutech Figulla™ occluder, Solysafe™ Septal Occluder or Gore Helex™ Septal Occluder, under fluoroscopic and intracardiac or transesophageal echocardiographic guidance.6 Procedural success was defined as successful implantation of the closure device.

Postprocedural follow-up was by transthoracic echocardiography at hospital discharge, at 1, 3, 6 and 12 months and thereafter annually. Patients were prescribed aspirin and clopidogrel for 1–3 months following the procedure, followed by single antiplatelet therapy or another antithrombotic regimen as prescribed by their attending physician, in most cases a neurologist.

Periprocedural adverse events were defined as those occurring within seven days of implantation or before hospital discharge based on the criteria of the Valve Academic Research Consortium-2 consensus document,8 including death, myocardial infarction, stroke, TIA, systemic embolization, device embolization, pericardial effusion or cardiac tamponade, or major bleeding requiring surgery or transfusion.

The primary endpoint event was defined as new stroke or TIA during follow-up, based on symptoms, neurological exams and relevant imaging studies.

In view of the absence of a control group, device effectiveness for secondary prevention of stroke or TIA was tested by comparing the rate of cerebrovascular events in the study population with the rate in a control group in the literature.5 The total number of cerebrovascular events in the study population was divided by the number of patient-years and multiplied by 100 to give the annual incidence of thromboembolism. Relative risk reduction was calculated as (expected event rate minus observed event rate) divided by expected event rate, and the number needed to treat (NNT) to prove benefit from PFO closure as the inverse of the absolute reduction in new events (1 divided by observed event rate minus expected event rate).

Secondary endpoint events were defined as all-cause death during follow-up, new stroke during follow-up, and peridevice leak in the atrial septum more than three months after the procedure. Complete PFO closure was defined as absence of interatrial and peridevice flow during follow-up. Peridevice leaks were assessed by color Doppler and classified as small (1–3 mm) or large (>3 mm).6 Transthoracic echocardiographic study to detect intracavitary thrombus, device-associated or in the atrial chamber, was performed during follow-up.

Continuous variables were presented as means ± standard deviation and categorical variables as relative frequencies. The statistical analysis was performed using SPSS version 21.0 (SPSS Inc., Chicago, IL, USA).

The sample included 193 cases of percutaneous PFO closure between January 2005 and December 2013. The baseline characteristics are summarized in Table 1. Mean age was 46.4±13.1 years, and only 13 patients (6.7%) were aged over 65; most were female (62.2%). The incidence of comorbidities was low, hypertension being the most frequent cardiovascular risk factor (n=44, 22.8%). The mean CHA2DS2-VASc score was 1.7±0.6, and 46 patients (23.8%) had a score of 0; most of the points in the score were from hypertension and female gender. On the basis of the mean CHA2DS2-VASc score, the expected annual risk for a new cerebrovascular event if undiagnosed AF had been responsible for the initial event would be 1.9%/year.

The anatomical characteristics of the PFO associated with embolic risk were documented by preprocedural transesophageal echocardiography (Table 1). In more than half of cases (n=103, 53.4%) there was a grade 2 right-to-left shunt, and the incidence of other high-risk characteristics was high, including atrial septal aneurysm (n=68, 35.2%), spontaneous right-to-left shunt (n=43, 22.3%) and a prominent Eustachian valve directing blood flow from the vena cava to the PFO (n=48, 24.9%); several patients presented more than one of these characteristics.

The devices used were the Amplatzer™ PFO Occluder (n=105, 54.4%), Premere™ PFO Closure System (n=61, 31.6%), Occlutech Figulla™ occluder (n=21, 11.0%), Solysafe™ Septal Occluder (n=5, 2.5%), and Gore Helex™ Septal Occluder(n=1, 0.5%). Mean occluder size was 24 mm (9–35).

One adverse event occurred during the procedure (0.5%), an access-related femoral pseudoaneurysm, treated by mechanical compression. There were no other periprocedural adverse events. There were also no cases of gas embolism during implantation or consequent need for treatment of neurological sequelae.

Follow-up was achieved in 190 patients (98.4%), for a mean of 4.3±2.2 years (0–9.2). Total exposure to ischemic events was 197 710 days, corresponding to 542 patient-years. Three months after the procedure, 39 patients (20.5%) were not taking antithrombotic medication, 145 (74.7%) were under single antiplatelet therapy and nine (4.7%) were under oral anticoagulation alone.

There were seven primary endpoint events (3.7% of the 190 patients who completed follow-up), all non-fatal stroke or TIA, with a time to event of 3.7±2.1 years, a rate of 1.3 events per 100 patient-years. Considering the expected rate of recurrent cryptogenic ischemic stroke or TIA in medically treated patients with PFO (4.0 events per 100 patient-years5), percutaneous PFO closure led to a relative risk reduction of 68.2% (Figure 1), with an NNT of 13.

Figure 1.

Comparison of observed vs. expected primary cerebrovascular events in a population with cryptogenic stroke or TIA.

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Table 2 shows the characteristics of patients with primary endpoint events. Nearly all were over 50 years old and with few comorbidities; CHA2DS2-VASc scores were between 1 and 2 and none was under oral anticoagulation. In most cases there was a small right-to-left shunt and only two cases presented high-risk PFO features (septal aneurysm).

Regarding secondary endpoints, there were four cases identified as new ischemic stroke on imaging studies (57.1% of cerebrovascular events during follow-up). The stroke rate was 0.7 events per 100 patient-years, corresponding to a relative risk reduction of 53.8% compared to the expected rate of isolated stroke in this clinical setting (1.6 events per 100 patient-years5) (Figure 2). There was one non-cardiovascular death, from septic shock (n=1, 0.5%). Echocardiographic follow-up studies revealed two cases (1.1%) of peridevice leak more than three months after the procedure, both small (1–3 mm). No device-related or atrial thrombi were detected.

Figure 2.

Comparison of observed vs. expected stroke in a population with cryptogenic stroke or TIA.

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The authors declare that no experiments were performed on humans or animals for this study.

The authors declare that they have followed the protocols of their work center on the publication of patient data.

The authors declare that no patient data appear in this article.