As an intra-cardiac right-to-left shunt, the patent foramen ovale (PFO) has gained attention over the last two decades because of its potential pathological importance in a number of disease processes including stroke, peripheral embolism, systemic oxygen desaturation (i.e. hypoxaemia) and migraine headaches. Percutaneous PFO closure, using a double-umbrella Clamshell device (Bard, USCI, Billerica, MA, US) in 36 patients after presumed paradoxical embolism, was first reported by Bridges et al., in 1992.1 Many early devices were adaptations from devices designed to close atrial septal defects (ASDs) in which the right and left anchor arms were rigidly connected to each other at a fixed distance. However, unlike an ASD, which is a hole in the interatrial septum, a PFO has a tunnel of variable length that can vary from 0 up to 20mm. Due to this anatomical variability, current devices with rigid fixed distances between the right and left disc can deform the septum and, in rare instances, can even cause the PFO to remain constantly open. Most devices commercially available today are still based on the double-disc principle. Despite the limitations, transcatheter closure of the PFO has proved to be a very safe and effective technique with high closure rates. However, results from randomised trials are still pending. The newest developments focus on bio-absorbable materials and devices with minimised foreign material mass left in the atria.
New Devices
Solysafe™ Septal Occluder
The Solysafe™ septal occluder (Swissimplant AG, Solothurn, Switzerland; see Figure 1) is a self-centring device designed for ASD and PFO closure, which is delivered over a guidewire instead of a long trans-septal sheath – a major advantage of this new system. The occluder comprises two synthetic patches that are attached to wires made of the cobalt–chromium–nickel alloy referred to as phynox. Like nitinol, phynox has properties of super-elasticity and memory retention.
The wires are fixed to a wire-holder at each end of the device. Once introduced into the defect, the two wire-holders are narrowed towards each other until the wires snap into a stable position. The snapping mechanism allows the wires to stretch the patches that are attached to them and, thus, cover the defect. Up to the point of guidewire removal the device is fully retrievable. In 2008, Ewert et al. evaluated the Solysafe occluder in 29 patients with PFO. Device implantation was successful in all cases and no major complications were reported. Complete closure in transoesophageal echocardiography was noted in all patients at six-month follow-up.2
Occlutech® PFO occluder
The Occlutech Figulla Flex® PFO occluder (Occlutech, Jena, Germany) has technical similarities to the Amplatzer® septal occluder. Unlike the Amplatzer devices, however, there is no left atrial hub. Furthermore, this newest generation of the Occlutech Figulla PFO device, which replaces the first-generation double-layered disc design, has a novel connecting mechanism. The first-generation Occlutech Figulla® single-layer PFO occluder, however, is still actively commercialised. In 2008, Krizanic et al. reported successful implantation of the Occlutech occluder (first-generation device) in 36 patients with prior cryptogenic stroke. In one additional patient, implantation was attempted but the PFO could not be crossed with a guidewire. No major in-hospital adverse events or complications occurred. One patient had transient atrial fibrillation two hours after implantation, which terminated after 12 hours as a result of medical therapy. One patient was unwilling to participate in follow-up examinations. After 60 days, transoesophageal echocardiography studies in the remaining 35 patients showed a residual shunt in three patients (8.6%). After 180 days, one patient with additional arteriosclerotic heart disease and carotid stenosis suffered a stroke without evidence of cardio-embolic origin or device-associated thrombosis.3
Atriasept II™ PFO Occluder
The Atriasept II™ occluder (see Figure 2) is the newest-generation device of the Cardia occluder family (CARDIA, Inc., Eagan, MN, US). The ‘sails’ and ‘umbrellas’ are made from polyvinyl alcohol mounted on nitinol arms. Its profile is lower and flatter than that of previous-generation Cardia occluders. The PFO occluder is available in diameter sizes of 15–35mm, and is retrievable before and after release.
In 2007, Spies et al. reported follow-up of PFO closure of the former-generation Cardia device – the Intrasept™ occluder – in 247 patients with presumed paradoxical embolism. The device was implanted successfully in all cases. Acute complications occurred in four patients (1.6%), with air embolism in two individuals, pericardial effusion in one patient and supraventricular tachycardia in one patient. Follow-up information is available for all 247 patients. Median follow-up time was 14 months (range six to 56 months). At the six-month follow-up, residual shunt was found in 13% of patients. After one year, the presence of residual shunt decreased to 10%. Following PFO closure, seven recurrent thromboembolic events (four transient ischaemic attacks [TIAs] and three strokes) were observed. No wire fractures or device-associated thrombi were seen.4
Devices Under Investigation
SeptRx™ Occluder
The SeptRx™ device (SeptRx, Inc., Freemont, US; see Figure 3) is placed directly into the PFO pocket. It is introduced into the tunnel of the PFO and stabilised by two left atrial anchors that adapt to the tunnel length without significant alteration of the configuration of the septum primum. To achieve immediate shunt closure, the device stretches the PFO pocket, causing the septum primum to approach the septum secundum. The minimal amount of material in the left and right atria is thought to reduce the risk of device-associated thrombus formation. Furthermore, the fact that this device does not significantly change the configuration of the septum primum may be a potential advantage. High radio-opacity of the device simplifies implantation guidance with fluoroscopy and transoesophageal echocardiography. The SeptRx system can be delivered over the wire and is fully repositionable. Recently, the first-in-man trial was finalised at our centre. In the 13 patients included in the trial, 11 devices were implanted successfully, with no procedural complications. Preliminary results at the six-month follow-up include a 100% closure rate verified by transcranial Doppler and transoesophageal echocardiography.5
HeartStitch™
The HeartStitch™ (Sutura Inc., Fountain Valley, CA, US) strategy is based on the SuperStitch vascular suturing system designed for vascular stitching in general surgery and the closure technique for femoral vessels and in endoscopic procedures. The device consists of polypropylene sutures and two individually deployable needles.
During the closure process, the system is introduced in the left atrium; the septum primum and septum secundum are then sutured and the system is withdrawn. With only stitches left in the heart, the risk of erosion or embolisation is not posed and the risk of thrombus formation is reduced. Early investigations in porcine models have been reported and a successful first-in-man experience has been published.6
PFx™ Closure System
The PFx™ closure system (Cierra, Redwood City, CA, US) was the very first percutaneous PFO closure system in which device implantation was not required. The system is positioned at the overlapping part of the septum primum and septum secundum via the right side of the atrial septum. Once in place, vacuum is applied through the catheter shaft to hold both septa in place while radiofrequency is administered over the electrodes of the device. This process fuses the tissue of the septum primum and secundum through denaturation of proteins by heat. Following this ‘welding’ process, the entire system is removed from the right atrium and no foreign material is left in the heart. PFO closure is achieved through inflammation and subsequent fibrosis. Results of the Paradigm I study were published in 2007 showing the feasibility of closing PFO without an implant. Although the PFx System closure rates were lower than those of implantable occluders, with a primary closing rate <80%, the study showed potential success of closing PFO without device-related complications such as atrial fibrillation, thrombus formation, TIA or device fracture.7,8 The Cierra company recently shut down its business due to financial reasons.
BioTREK™
The BioTREK™(NMT Medical, Boston, MA, US) is a fully bio-absorbable septal device, currently investigated in pre-clinical studies. The essential component of this device is a poly-4-hydroxybutyrate (Tepha, Inc., Lexington, MA, US) polymer, a novel biosynthetic polymer manufactured with recombinant DNA technology. This polymer received US Food and Drug Administration (FDA) clearance in 2007 for use in bio-absorbable sutures and absorbable surgical meshes. The main advantage of poly-4-hydroxybutyrate is that it is less inflammatory than many commonly used bio-absorbable polymers such as polylactic acid and polyglycolic acid. As BioTREK is fully absorbable and is eventually replaced with native tissue, long-term device-related complications may be avoided.
Coherex FlatStent™
The Coherex FlatStent™ PFO closure system (Coherex Medical, Inc., Salt Lake City, UT, US; see Figure 4) consists of a light-weight, self-expanding, flat nitinol lattice with integrated polyurethane foam in the intratunnel portion of the system. The integrated foam is intended to stimulate tissue growth inside the PFO tunnel. After advancing the tip of the delivery catheter over the guidewire into the left atrium, the distal anchors are unsheathed and withdrawn until they sit on the corners of the septum primum. After proper positioning is verified, the remaining part of the device is unsheathed. This ‘stent-like’ device opens within the tunnel and thus draws the septum primum and secundum into contact without significantly changing the configuration of the septum primum. Anchors on the right atrial side as well as strategically placed microtines are designed to prevent migration and embolisation of the device. The FlatStent PFO closure system can be resheathed and repositioned until detachment. At present, the device comes in two sizes, which are available within clinical trials for stretched diameters of 4–8 or 7–12mm.
Pre-clinical trials in animals have been successfully completed, and a clinical trial for CE marking is under way in Europe. Encouraging preliminary results of 49 patients were presented in July 2009, showing successful placement of the device in all patients. Immediate complete closure or trivial shunt was documented in 35 of 49 patients. To date, 32 of these patients have undergone three-month follow-up with transoesophageal echocardiography, which revealed a complete closure in 21 patients and trivial residual shunting in six patients. Six-month follow-up data of 16 patients showed complete closure in 15 patients. No recurrent thrombo-embolic events, thrombus, erosion, arrhythmia or device-induced valvular incompetence were noted during follow-up.9,10
Nit-Occlud® PFO Closure Device
The Nit-Occlud® PFO umbrella (Pfm Medical Mepro, Nonnweiler- Otzenhausen, Germany) is one of the most recent techniques for PFO closure. This double-disc nitinol device incorporates a synthetic patch on the left and right atrial side in order to achieve a high-acute closure rate. Devices are available in 20, 26 and 30mm sizes. A prospective single-centre clinical investigation has just been initiated at our centre. First patient inclusion is planned this month.
Conclusions
Although randomised trials are pending, it is common knowledge that paradoxical emboli can cause severe damage and, therefore, should be prevented. In an American Heart Association (AHA)/American Society of Anesthesiologists (ASA)/American College of Cardiology Foundation (ACCF) scientific advisory published in May 2009, which was affirmed by the American Academy of Neurology (AAN), clinicians are encouraged to enrol patients in ongoing randomised trials between medical therapy and percutaneous device closure.11 This appeal emphasises the wish of the scientific and clinical community to conclusively determine the best possible therapy for secondary stroke prevention in this patient cohort. Due to different anatomical situations in each patient, including large PFOs, PFOs with long tunnels or PFOs with atrial septum aneurysms, it is highly unlikely that a single device will emerge to be the ideal device for all patients. Several promising devices for percutaneous PFO closure are currently under investigation in pre-clinical or clinical trials. New or improved devices may further decrease the number of acute and long-term device-related complications, making the interventional procedure as safe and the device as reliable as possible. These core properties become even more important when the indication for interventional closure is discussed in ‘healthy’ patients such as migraine sufferers or divers.