Samuel C. Yoon, MD is a Clincal Assistant Professor with the Division of Cardiology at the University of Maryland, Baltimore, MD. He received his MD from the University of Maryland in 1995 and continued there for his Internal Medicine residency and his Cardiology/Interventional Cardiology fellowships.

In the United States, approximately 600,000 strokes occur per year, and in nearly 40%, no identifiable cause can be found (cryptogenic stroke). Patent foramen ovale (PFO) has been shown to be associated with cryptogenic stroke, particularly in younger patients. Medical therapy with either aspirin or warfarin still carries a recurrent neurologic event rate of 3.4% per year, and warfarin therapy carries a small but definite risk of bleeding complications. Devices that were developed for percutaneous closure of atrial septal defects have now been adapted for the application of percutaneous PFO closure as secondary prevention in patients who have cryptogenic stroke, potentially as an alternative to long-term anticoagulation. This article reviews these new devices and some of the evidence regarding this particular application.

The first percutaneous closure of an atrial septal defect (ASD) was performed in 1974 by placement of a Dacron (Dupont Pharmaceuticals Corp.; Wilmington, DE) double-umbrella device. ¹ Development of percutaneous closure devices for ASD has continued since, primarily for closure of ASD causing hemodynamically significant left-to-right shunts. As shown in Table 1, the success rates for different ASD closure devices range from 35% to 90%. ^2-13

Another morphologic breach of the interatrial septum, the patent foramen ovale (PFO), has been implicated in unexplained neurologic events. It has been estimated that 600,000 strokes occur per year in the United States. ¹⁴ Up to 40% of strokes are deemed cryptogenic (stroke of undetermined cause). ¹⁵ In several contrast echocardiography studies, a strong association has been established between the diagnosis of cryptogenic stroke and the presence of PFO in patients <55 years of age, ^16-18 and PFO is an independent risk factor for cryptogenic stroke. ¹⁹ Pooled data suggest that PFO is present in 46% of patients with cryptogenic stroke and in 11% of matched controls. ²⁰ Based on these figures, approximately 110,000 strokes per year may be attributable to PFO. It has also been observed that patients with cryptogenic stroke and PFO are at risk for recurrent neurologic events with an annual stroke rate of 1.2% to 1.9% and a recurrent cerebrovascular accident (CVA) or transient ischemic attack (TIA) rate of 3.4% to 3.8% per year despite medical therapy with either aspirin or warfarin. ^21,22 Additionally, patients who have cryptogenic stroke who have both PFO and atrial septal aneurysm are four times more likely to have a recurrent stroke compared with those without either abnormality. ²³ These observations regarding PFO and paradoxical embolism resulting in neurologic events have led to the investigation of expanding the use of ASD closure devices to potentially prevent recurrent clinical events.

Percutaneous closure devices

There are several devices that are available or are being investigated for percutaneous closure of PFO (Table 2). Table 3 compares various characteristics of several of these devices. ²⁴ These devices are either ASD closure devices that are applied to PFO, modifications of prior ASD closure devices, or novel PFO closure devices. At this time, only the Amplatzer PFO Occluder (Figure 1) and the CardioSEAL Septal Occluder (Figure 2) have limited U.S. Food and Drug Association approval for PFO closure in patients who have cryptogenic stroke under Humanitarian Device Exemption status.

Delivery of the Amplatzer PFO Occluder and CardioSEAL Septal Occluder are performed in a relatively similar fashion; the following is a simplified description of the implantation of the Amplatzer PFO Occluder. ²⁵ Access is obtained through the femoral vein, and a standard right heart catheterization is performed. The PFO Occluder device is screwed to the tip of a delivery cable and retracted into a loader catheter. The cable/catheter assembly is inserted through the femoral venous sheath, advanced up the inferior vena cava, and passed through the patent foramen ovale over a "J" guidewire into the left atrium, with optional guidance by either transesophageal echocardiography (TEE) or intracardiac echocardiography (ICE). The PFO Occluder device is advanced and positioned across the PFO under fluoroscopic guidance, and a left atrial disc is deployed beyond the delivery sheath and pulled back firmly against the left atrial side of the inter-atrial septum (Figure 3). A right atrial disc is then deployed against the right atrial side of the interatrial septum (Figure 4) by pulling the delivery sheath back over the delivery cable. Successful occlusion is confirmed under fluoroscopy with radiographic contrast injection (Figure 5) or by echocardiography with bubble contrast into the right atrium. The device is then released (Figure 6), and the delivery catheter system is removed.

Clinical trials

There have been several feasibility and safety studies for percutaneous closure of PFOs, but only two studies have assessed clinical outcomes over a long period of time. Windecker and colleagues ²⁶ studied 80 patients with at least 1 paradoxical embolic event and PFO diagnosed by contrast TEE who underwent percutaneous PFO closure. Various occluder devices were used and not controlled for, including the Sideris Buttoned device, PFO-STAR (now CardiaSTAR), Amplatzer PFO Occluder, DAS Angel Wings Atrial Septal Defect Occluder device, and the CardioSEAL Septal Occluder. Procedural success was achieved in 78 patients (98%). All patients received 100 mg of aspirin daily for 3 to 6 months, at which time it was discontinued unless required for another indication. During the follow-up period (mean 1.6 ± 1.4 years), there were 8 recurrent thromboembolic events: 6 TIAs, no CVAs, and 2 peripheral emboli. These results suggest average annual recurrence rates of 2.5% for TIA, 0% for CVA, 0.9% for peripheral emboli, and 3.4% for the combined thromboembolic endpoint. ²⁶

Similarly, Hung and colleagues ²⁷ studied 63 patients who had one or more paradoxical systemic events (TIA, CVA, peripheral embolus, or brain abscess in the absence of any other identifiable etiology) with PFO diagnosed by TEE. Patients were enrolled to undergo percutaneous PFO closure with 1 of 3 devices: the Clamshell Septal Occluder, CardioSEAL Septal Occluder, or the Sideris Buttoned device. Effective closure was achieved in 54 patients (86%). All patients received daily aspirin for 6 months after device placement. During follow-up (mean 2.6 ± 2.4 years), there were 4 recurrent neurologic events (1 CVA and 3 TIAs) resulting in a calculated annualized risk of 3.2% for the combined endpoint.

Percutaneous closure of PFO with these devices carries certain potential periprocedural complications, including: device embolization, air embolization, intraprocedural CVA, perforation, or erosion resulting in cardiac tamponade or retroperitoneal bleeding; or device complications stemming from the design (such as device arm fracture). The rate of periprocedural complications in these studies was 10%, ²⁶ and the rate of device arm fracture was 24%. ²⁷

The recurrent event rates in these studies compare favorably to the event rates in historical controls mentioned previously, suggesting that percutaneous closure of PFO for secondary prevention of neurologic events may be an alternative therapy to long-term oral anticoagulation.

The controversy

The limitations of the present literature on PFO closure in patients with cryptogenic stroke are several-fold. First, the diagnosis of cryptogenic stroke is one of exclusion; therefore, it is dependent on the thoroughness of the neurologic work-up. Second, the relationship between PFO and cryptogenic stroke is not as well established in older patients (>55 years of age), thus, the age distribution of the cohorts studied can affect observed outcomes. Additionally, although recurrent CVA is a relatively "hard" endpoint, a transient recurrent event (ie, TIA) is less well defined and may be less reliable as an endpoint on which to base conclusions.

The most glaring limitation to the presently available data is the lack of a prospective, randomized study to evaluate PFO closure devices versus medical therapy in patients who have cryptogenic stroke. However, the PC-Trial (Patent Foramen Ovale and Cryptogenic Embolism Trial) is currently under way to provide just that. ²⁸ Patients <60 years of age who have a documented PFO and have suffered a cryptogenic embolic event (CVA, TIA, or peripheral embolus) will be randomized to PFO closure with the Amplatzer PFO Occluder or to anticoagulation therapy (aspirin or warfarin) and will be followed up for 4.5 years. Primary endpoints will be death, nonfatal stroke or TIA, or peripheral embolism. Secondary endpoints will be arrhythmia, myocardial infarction, rehospitalization, device problems, or bleeding. Target enrollment is 410 patients.

Conclusion

Percutaneous closure of ASD/PFO can be achieved successfully. There are several innovative devices that are being evaluated, particularly for the indication of PFO closure in patients with cryptogenic stroke for secondary prevention. The question of whether percutaneous PFO closure should be performed has yet to be answered. While the association of PFO with cryptogenic stroke has been established in younger patients (<55 to 60 years of age), the implication of PFO as the cause of cryptogenic stroke has not been established as strongly. The literature suggests that there is potential benefit via this therapy, and perhaps the greatest benefit is in younger patients who have cryptogenic stroke with PFO and atrial septal aneurysm. The available long-term follow-up data suggest that percutaneous closure of PFO has a recurrent event rate comparable to medical therapy, and may possibly be an alternative to long-term anticoagulation therapy. Prospective, randomized comparison of medical therapy versus percutaneous closure of PFO in patients with cryptogenic stroke is under way to further delineate the role these novel devices will play.