Patent Foramen Ovale Closure for Stroke Prevention and Other Disorders
2018; Wiley; Volume: 7; Issue: 12 Linguagem: Inglês
10.1161/jaha.117.007146
ISSN2047-9980
AutoresF. Collado, Marie‐France Poulin, Joshua Murphy, Hani Jneid, Clifford J. Kavinsky,
Tópico(s)Aortic Disease and Treatment Approaches
ResumoHomeJournal of the American Heart AssociationVol. 7, No. 12Patent Foramen Ovale Closure for Stroke Prevention and Other Disorders Open AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citations ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toOpen AccessReview ArticlePDF/EPUBPatent Foramen Ovale Closure for Stroke Prevention and Other Disorders Fareed Moses S. Collado, MD, Marie‐France Poulin, MD, Joshua J. Murphy, MD, Hani Jneid, MD and Clifford J. Kavinsky, MD, PhD Fareed Moses S. ColladoFareed Moses S. Collado Division of Cardiology, Department of Medicine, Rush University Medical Center, Chicago, IL , Marie‐France PoulinMarie‐France Poulin Division of Cardiology, Department of Medicine, Rush University Medical Center, Chicago, IL , Joshua J. MurphyJoshua J. Murphy Division of Cardiology, Department of Medicine, Rush University Medical Center, Chicago, IL , Hani JneidHani Jneid Division of Cardiology, Department of Medicine, Baylor College of Medicine, Houston, TX and Clifford J. KavinskyClifford J. Kavinsky Division of Cardiology, Department of Medicine, Rush University Medical Center, Chicago, IL Originally published17 Jun 2018https://doi.org/10.1161/JAHA.117.007146Journal of the American Heart Association. 2018;7:e007146Stroke is the fifth‐most common cause of death and the leading cause of preventable adult disability in the United States.1 In 2013, there were 6.5 million stroke‐related deaths worldwide accounting for 11.8% of total deaths.2 Strokes cost $34 billion each year in the United States.1 This estimate includes the cost of health care, medications, and missed workdays.Cryptogenic stroke is defined as brain infarction that is not attributed to definite large‐vessel atherosclerosis, small‐artery disease, or embolism despite extensive vascular, serological, and cardiac evaluation.3 Approximately one‐third of all ischemic strokes are considered cryptogenic.4 The causal relationship between patent foramen ovale (PFO) and cryptogenic stroke has historically been controversial. Approximately 25% of the adult population has a PFO, and the condition by itself has not been shown to increase the risk of ischemic stroke.5 Yet, the prevalence of PFO is significantly higher in patients with cryptogenic stroke; up to 40% of ischemic strokes without an identifiable cause have a PFO.7 This suggests that paradoxical embolism through a PFO may be implicated in a proportion of cryptogenic strokes.The association of PFO with stroke was first described in 1877 by Julius Friedrich Cohnheim, a German pathologist and protégé of Virchow. He performed a necropsy on a 35‐year‐old woman who had a fatal stroke and found a long thrombus in the lower extremity and as well as a "very large" foramen ovale, through which he could pass 3 fingers with ease. Cohnheim then hypothesized that a torn‐off piece of thrombus arising from the lower extremity traveled to the right atrium into the left atrium and to the frontal lobe.8PFO Definition and DiagnosisThe foramen ovale is an obligatory channel during fetal life that allows placental oxygenated blood to reach the arterial circulation of the fetus. When there is incomplete postnatal fusion of the septum primum and secundum, a PFO is formed.9 The presence of a PFO with either transient or continuous right‐to‐left shunt can potentially lead to paradoxical embolism. The PFO serves as a potential conduit for venous emboli to cross into the left atrium and eventually to the arterial circulation (Figure 1). The presence of an atrial septal aneurysm (ASA) has also been associated with cryptogenic stroke.10 An ASA is described as redundant bulging atrial septal tissue that can be caused by sustained interatrial pressure difference, or can be a primary malformation involving either the fossa ovalis or the entire atrial septum. It is objectively defined on echocardiography as 15‐mm of total septal tissue excursion or a 10‐mm protrusion into either atrium from the septal midline.11 Several studies have linked the presence of ASA to stroke. In 1 study, ASA was significantly more common in patients with stroke than in those without stroke (20 of 133 [15%] versus 12 of 277 [4%]; P 10 microbubbles; and high grade shunt, "curtain effect" or numerous microbubbles recorded.14 This procedure is well tolerated by patients and can be done at bedside. Compared with TEE, advantages of TCD include increased patient comfort, a semiquantitative assessment of shunt size, and ability to detect intra‐ and extracardiac shunting.13History of PFO ClosurePercutaneous PFO closure techniques have been derived from established atrial septal defect (ASD) closure techniques. Surgical closure paved the way for minimally invasive or percutaneous closure techniques of both ASD and PFO. In 1947, Cohn reportedly closed ASDs in dogs using an atrial wall invagination technique.16 In Lyon, France, Santy performed the first successful closure of an ASD using right atrial appendage inversion in 1949. Shortly thereafter, in a series of experimental surgical closures, Hufnagel and Gillepsie used 2 nylon buttons through a right atriotomy in dogs,17 a technique that incurred a 100% mortality rate when later performed in 3 patients. The development of cardiopulmonary bypass technology opened the door for the rapid evolution of open cardiac surgical procedures. On May 6, 1953, John Gibbon successfully repaired an ASD in an 18‐year‐old woman while on cardiopulmonary bypass.18 After more than 3 decades of success with surgical closure, less‐invasive nonsurgical approaches for ASD and PFO closure were developed. In 1972, King and Mills developed an umbrella‐like device (King–Mills Cardiac Umbrella) for nonsurgical treatment of an ASD. It was composed of 6 stainless‐steel struts that contained fixation barbs and a Dacron covering for each opposing umbrella. The device was used to close 5 of 13 dogs with experimentally created ASDs.19 A 35‐mm King–Mills Cardiac Umbrella was then successfully implanted in a 17‐year‐old girl in 1975.20 Since then, there have been many versions of percutaneous ASD closure devices. The Gore Cardioform Septal Occluder (W.L. Gore and Associates, Inc,Newark, DE), and the Amplatzer PFO Occluder (Abbott Structural, Santa Clara, CA) have similar designs, with 2 opposing discs connected by a thin waist. Oppositional forces created by the 2 opposing discs seal the PFO. Both the Amplatzer PFO Occluder and the Gore Cardioform Septal Occluder are the only devices currently approved by the US Food and Drug Administration (FDA) for PFO closure in the United States; other devices are in the pipeline and awaiting future approval.FDA Approval ProcessAs shown in Figure 4, the approval process for PFO closure device has spanned 2 decades. Before 2006, the use of percutaneous PFO closure in the US was only permitted under FDA Humanitarian Device Exemption for recurrent cryptogenic stroke from a PFO after failed conventional medical therapy. In 2006, the number of eligible patients exceeded the regulatory mandated annual limit of 4000 patients, and the Humanitarian Device Exemption process was voluntarily withdrawn. Randomized clinical trials for several devices were initiated and primarily focused on 3 devices: the Amplatzer PFO Occluder, the Starflex Septal Occluder (NMT Medical Inc, Boston, MA); and the Gore Cardioform Septal Occluder. These clinical trials have now all been completed and published (see Clinical Trials section below). Based on extended follow‐up results of the RESPECT and REDUCE trials, the FDA approved the Amplatzer PFO Occluder on October 28, 2016 and the Gore Cardioform Septal Occluder on March 30, 2018 for PFO closure in the United States "to reduce the risk of recurrent ischemic stroke in patients, predominantly between the ages of 18 and 60 years, who have had a cryptogenic stroke due to a presumed paradoxical embolism, as determined by a neurologist and cardiologist following an evaluation to exclude known causes of ischemic stroke."Download figureDownload PowerPointFigure 4 Timeline showing important dates of patent foramen ovale (PFO) closure trials and US Food and Drug Administration (FDA) milestones in the United States. HDE indicates Humanitarian Device Exemption.The Amplatzer PFO OccluderAlthough there are several commercially available ASD and PFO closure devices on the market worldwide, the Amplatzer PFO Occluder was the first device to be FDA approved in the United States for PFO closure. The device has 2 self‐expanding discs composed of a nickel‐titanium (Nitinol) wire mesh with a wire diameter of 0.005 to 0.006 inches (Figure 5A). The wire mesh contains a polyester fabric that enhances the device's ability to seal the PFO and eliminate interatrial shunting. The 2 discs are connected by a short and thin waist (2 mm in diameter and 4 mm in length) that spans the PFO tunnel. Each disc is designed to conform to either side of the atrial septum and is available in 3 sizes (Figure 6). The device is most often delivered using the proprietary Amplatzer TorqVue delivery system that includes a sheath, dilator, delivery cable, and loader.Download figureDownload PowerPointFigure 5 A, The Amplatzer PFO Occluder (courtesy of Abbott. ©2018 Abbott. All rights reserved) and B, the Gore Cardioform Septal Occluder (courtesy of W.L. Gore and Associates, Inc).Download figureDownload PowerPointFigure 6 Fluoroscopic image of an Amplatzer PFO Occluder (top) and Gore Cardioform Septal Occluder (bottom) demonstrating a stable position in the atrial septum after release. The intracardiac echo (ICE) is seen in the right atrium. Red dotted lines represent the interatrial septum in this anteroposterior view.The Gore Cardioform Septal OccluderThe Gore Cardioform Septal Occluder is currently FDA approved for both ASD and PFO closure. The device is also composed of 2 discs formed by platinum‐filled Nitinol wire frames covered by a proprietary thromboresistant expanded polyetrafluoroethylene material (Figure 5B). A 0.035‐ or 0.018‐inch guidewire may be used to advance the delivery system into the left atrium. The device was designed to be soft and conformable to surrounding anatomy of the atrial septum with minimal injury (Figure 6). It is available in a variety of sizes and comes preloaded in its own delivery system.PFO Closure for Recurrent Cryptogenic Stroke PreventionRandomized Clinical Trials ResultsCLOSURE I TrialThe CLOSURE I (Evaluation of the STARFlex Closure System in Patients with a Stroke and/or Transient Ischemic Attack due to Presumed Paradoxical Embolism Through a Patent Foramen Ovale) trial was the first multicenter, open‐label, randomized trial of PFO closure for stroke prevention in the United States21 (Table 1). The trial was completed in 2008 and published in 2012. The trial randomized 909 patients in the United States and Canada to medical therapy consisting of aspirin alone or aspirin and warfarin versus closure with the STARFlex Septal Occluder and medical therapy. The primary end point was a composite of stroke or transient ischemic attack at 2 years, death from any cause within 30 days, or neurological death between 31 days and 2 years. The primary end point was observed in 5.5% in the closure group versus 6.8% in the medical therapy group (hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.45–1.35; P=0.37).21 The trial concluded that in patients with cryptogenic stroke or transient ischemic attack who had a PFO, closure with this device did not have significant benefit compared with medical therapy in preventing recurrent stroke or transient ischemic attack. A major concern in the trial was that nearly half of the strokes in the closure group occurred within the first 30 days, suggesting that these events could have been related to device placement. Although effective closure, defined as procedural success with grade 0 or 1 residual shunt, was maintained in 86.7% of patients at 2‐year follow‐up, left atrial thrombus formation was noted in 1.1% of patients. Additionally, atrial fibrillation (AF) was reported in 5.7% of patients following PFO closure, potentially mitigating the effect of device closure. Enrollment in the trial was also hindered by the preference of some physicians and patients for percutaneous closure device leading them to decline participation in the trial. Because of real and perceived flaws in the design of the STARFlex device, it is no longer manufactured.Table 1 Contemporary Randomized Trials on Percutaneous Closure of Patent Foramen OvaleTrial NameYear PublishedPFO Device UsedControl Arm(s)NMean Follow‐up (y)Primary EndpointResultsConclusionsClosure ControlP ValueCLOSURE I2012STARFlexAspirin and/or Warfarin (INR 2–3)9092Composite of stroke/TIA, all‐cause mortality, death from neurological causes5.5%6.8%HR 0.7895% CI 0.45 to 1.35P=0.37Closure is not superior to medical therapyPC Trial2013Amplatzer PFO OccluderAntiplatelet therapy or oral anticoagulation4144.1Composite of death, nonfatal stroke, TIA, or peripheral embolism3.4%5.2%HR 0.6395% CI 0.24 to 1.72P=0.34Closure is not superior to medical therapyRESPECT2013Amplatzer PFO OccluderAspirin or warfarin or Clopidogrel, or Aspirin with extended release dipyridamole9802.6Composite of recurrent nonfatal ischemic stroke, fatal ischemic stroke, or early death after randomizationIntention‐to‐treat0.66 events per 100 patients/yearAs‐treated0.39 events per 100 patients/yearIntention‐to‐treat1.38 events per 100 patients/yearAs treated1.45 events per 100 patients/yearHR 0.4995% CI 0.22 to 1.11P=0.08HR, 0.2795% CI 0.10 to 0.75P=0.007No significant benefit for closure (intention‐to treat‐analysis)Closure is superior to medical therapy (as‐treated analysis)RESPECT (Long‐term follow‐up)2017Amplatzer PFO OccluderAspirin or Warfarin or Clopidogrel, or Aspirin with extended release dipyridamole9805.9aComposite of recurrent nonfatal ischemic stroke, fatal ischemic stroke, or early death after randomizationIntention‐to‐treat0.58 events per 100 patients/yearNew stroke of unknown mechanism0.31 events per 100 patients/yearIntention‐to‐treat1.07 events per 100 patients/yearNew stroke of unknown mechanism0.86 events per 100 patients/yearHR 0.5595% CI 0.31 to 1.0 P=0.046HR 0.3895% CI 0.18 to 0.79P=0.007Closure is superior to medical therapy on extended follow‐up in intention‐to‐treat analysisCLOSE2017Any CE marked PFO device1) Antiplatelet arm: Aspirin or Clopidogrel or Aspirin with extended release dipyridamole2) Oral anticoagulant arm: Vitamin K antagonists or NOACs6635.3Recurrent fatal or nonfatal strokeClosure vs antiplatelet therapy:0Closure vs antiplatelet therapy4.9% 5‐year estimateAnticoagulant vs Antiplatelet therapy1.5% vs 3.8%, respectively, 5‐year estimateClosure vs antiplatelet therapyHR 0.0395% CI 0 to 0.26 P<0.001Anticoagulant vs Antiplatelet therapyHR 0.4395% CI 0.1 to 1.5P=0.17Closure is superior to antiplatelet in patients with ASA or PFO with large shuntAnticoagulant is equivalent to antiplatelet therapyREDUCE2017Helex Septal Occluder and Cardioform Septal OccluderAspirin or Clopidogrel or Aspirin with dipyridamole6643.2a1) Recurrent stroke2) New brain infarct inclusive of silent brain infarct (SBI)Ischemic stroke:1.4%New brain infarct:5.7%Ischemic stroke:5.4%New brain infarct:11.3%HR 0.2395% CI 0.09 to 0.62P=0.002HR 0.5195% CI 0.29 to 0.91P=0.04Closure is superior to antiplatelet therapyDEFENSE‐PFO2018Amplatzer PFO OccluderAspirin or Aspirin and Clopidogrel, or Aspirin and Cilostazol, or Warfarin1202.8aStroke, vascular death or TIMI‐defined major bleedingIschemic stroke:02 year event rate: 0New ischemic lesion on MRI:8.8%Ischemic stroke:10.5%2 year event rate:12.9%New ischemic lesion on MRI:18.4%P=0.023Log‐rank P=0.013P=0.24Closure in patients with high risk PFO characteristics resulted in lower rate of ischemic stroke versus medical therapyJohn Wiley & Sons, LtdASA indicates atrial septal aneurysm; CI, confidence interval; CLOSE, Closure of Patent Foramen Ovale or Anticoagulants Versus Antiplatelet Therapy to Prevent Stroke Recurrence; 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 Foramen Ovale; DEFENSE‐PFO, Device Closure Versus Medical Therapy for Cryptogenic Stroke Patients With High‐Risk Patent Foramen Ovale; HR, hazard ratio; INR, international normalized ratio; N, number of patients; NOACs, novel oral anticoagulants; PC, Percutaneous Closure of Patent Foramen Ovale Using the AMPLATZER PFO Occluder with Medical Treatment in Patients with Cryptogenic Embolism; PFO, patent foramen ovale; REDUCE, GORE HELEX Septal Occluder/GORE CARDIOFORM Septal Occluder and Antiplatelet Medical Management for Reduction of Recurrent Stroke or Imaging‐Confirmed TIA in Patients With Patent Foramen Ovale (PFO); RESPECT, Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment; TIA, transient ischemic attack; TIMI, thrombolysis in myocardial infarction.aMedian follow‐up reported.PC TrialThe PC (Clinical Trial Comparing Percutaneous Closure of Foramen Ovale Using the Amplatzer PFO Occluder with Medical Treatment in Patients with Cryptogenic Embolism) trial was conducted in 29 sites in Europe, Canada, Brazil, and Australia and published in 2013.22 The trial compared device closure with Amplatzer PFO Occluder versus best medical therapy in patients aged <60 years who had a PFO and an ischemic stroke, transient ischemic attack, or a peripheral thromboembolic event. The trial ultimately enrolled a total of 414 patients (Table 1). The primary end point, which was similar to the CLOSURE I trial, occurred in 7 patients in the closure group and 11 in the medical therapy group (HR, 0.63; 95% CI, 0.24–1.62: P=0.34).22 Although fewer strokes occurred in the closure group, the results, once again, did not reach statistical significance.The CLOSURE I and PC trials had similar results with a nonstatistically significant trend toward benefit for closure device as secondary prevention of stroke compared with current medical therapy. Both trials, however, did not achieve the prespecified clinical end point for efficacy. The impact of these 2 "negative" trials on PFO closure in the United States was profound, and for years the procedure was largely forgotten and not supported by stakeholder societies and third‐party payers.RESPECT TrialThe landmark study, RESPECT (Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment) trial compared medical therapy with 1 or more antiplatelet medications or warfarin alone with PFO closure using the Amplatzer PFO Occluder in 980 patients with cryptogenic stroke (Table 1).23 The primary efficacy end point was nonfatal ischemic stroke, fatal ischemic stroke, or early death after randomization. With a mean follow‐up of 2.6 years, the intention‐to‐treat cohort demonstrated a recurrence of stroke in 9 patients in the closure group and 16 in the medical therapy group (HR, 0.49; 95% CI, 0.22–1.11; P=0.08). Of note, 3 of the 9 patients in the closure group had a stroke without a device in place. One patient had a stroke after randomization before a closure device was placed, the second patient decided not to proceed after the stroke, and the third had a stroke during an unexpected coronary artery bypass graft surgery wherein the PFO was closed surgically. However, in the prespecified per‐protocol cohort, 6 patients in the closure group and 14 in the medical therapy group had a recurrent stroke (HR, 0.37; 95% CI, 0.14–0.96; P=0.03).23 Although the intention‐to‐treat cohort did not reach significance for the efficacy end point, both the prespecified per‐protocol and as‐treated analyses (5 events in the closure group versus 16 in the medical therapy group) suggested superiority of closure over medical therapy. The FDA requested supplemental long‐term analysis of the RESPECT patient cohort before considering approval of the device for PFO closure. Subsequently, in October 2015, the RESPECT investigators presented the results from their long‐term patient follow‐up (mean of 5.9 years).24 The intention‐to‐treat analysis now demonstrated a significant reduction in recurrent ischemic strokes in the PFO closure arm (HR, 0.55; 95% CI, 0.305–1.0; P=0.046).24 Reduction in new stroke of unknown mechanism was significant in the closure arm and superior to medical therapy (HR, 0.38; 95% CI, 0.18–0.79; P=0.007). Both groups reported similar rates of AF (0.25 per 100 patient‐years versus 0.15 per 100 patient‐years; P=0.37), and no device embolization or erosion were reported in the trial. The closure group did experience a higher number of deep venous thrombosis (1% versus 0.2%; P=0.218) and pulmonary embolism (2.4% versus 0.6%; P=0.034), which may be explained by a higher use of warfarin therapy in the medical group.25 Final results were published on September 14, 2017.25 Results of the long‐term follow‐up of the RESPECT trial led to FDA approval of the Amplatzer PFO Occluder device.REDUCE TrialOn August 19, 2008, The Gore‐REDUCE (Gore Helex Septal Occluder/Gore Septal Occluder for Patent Foramen Ovale Closure in Stroke Patients) clinical study began enrollment of patients aged 18 to 59 years who had a cryptogenic ischemic stroke within 180 days of randomization. A total of 664 patients were randomized either to antiplatelet therapy alone or PFO closure with the Helex Septal Occluder device or with the Cardioform Septal Occluder device, plus antiplatelet therapy. Because of design refinements, the Helex Septal Occluder device was replaced in late 2012 by the Cardioform Septal Occluder device. The co‐primary end points were freedom from recurrent ischemic stroke or new silent brain infarct on imaging. The final results demonstrated a statistically significant reduction for both primary end points. Clinical ischemic stroke occurred in 1.4% in the closure group and 5.4% in the medical therapy group (HR, 0.23; 95% CI, 0.09–0.62; P=0.04; Table 1).26 New brain infarctions were also noted to be significantly lower in the closure group (5.7%) than in the medical therapy group (11.3%; relative risk, 0.51; 95% CI, 0.29–0.91; P=0.04).26 There was a significantly higher rate of AF reported in the device closure arm, which was mostly periprocedural and transient (6.6% versus 0.4%; P≤0.001).26 The robust clinical results of the REDUCE trial led to FDA approval of the Gore Cardioform Septal Occluder for PFO closure on March 30, 2018.CLOSE TrialThe CLOSE (Closure of Patent Foramen Ovale, Oral Anticoagulants or Antiplatelet Therapy to Prevent Stroke Recurrence) trial is a multicenter, open‐label, randomized, 3‐group superiority trial conducted at 32 sites in France and 2 sites in Germany.27 Compared with other contemporary trials for PFO closure, the CLOSE trial was unique in 2 ways. First, it had 3 groups that included: (1) the device group; (2) antiplatelet or antithrombotic group; and (3) an oral anticoagulant group. Anticoagulants used in the study were comprised of vitamin K antagonists and novel oral anticoagulants. Second, the study used any PFO closure device with a CE mark and approved by the Interventional Cardiology Committee. The CLOSE trial investigated whether PFO closure in addition to antiplatelet therapy was superior to antiplatelet or anticoagulant therapy alone in preventing stroke recurrence. They included patients aged 16 to 60 years who had been diagnosed with a previous cryptogenic stroke and either an ASA or a large right‐to‐left shunt (more than 30 microbubbles in the left atrium within 3 cardiac cycles). The primary outcome was fatal or nonfatal stroke. A total of 663 patients were evaluated with a mean follow‐up of 5.3 years (Table 1).The CLOSE trial revealed that PFO closure significantly reduced the risk of recurrent stroke compared with antiplatelet therapy (HR, 0.03; 95% CI, 0–0.26; P<0.001; Table 1).27 The anticoagulant group, although showing a trend toward superiority, did not show a significant benefit over antiplatelet therapy alone (HR, 0.43; 95% CI, 0.1–1.5; P=0.17). A notable observation in the study is again the increased risk of AF with PFO closure during the periprocedural period compared with antiplatelet therapy alone (4.6% vs. 0.9%; P=0.02).27DEFENSE‐PFO TrialThe DEFENSE‐PFO (Device Closure Versus Medical Therapy for Cryptogenic Stroke Patients With High‐Risk Patent Foramen Ovale) trial was a multicenter, randomized, open‐label, superiority trial carried out in Korea that compared percutaneous PFO closure using the Amplatzer PFO Occluder to medical therapy in patients with cryptogenic stroke and high‐risk PFO.28 This trial was different from previous trials and enrolled only patients with high‐risk morphological features defined as those patients with an ASA, hypermobility of the IAS, or a large‐sized PFO (≥2 mm). Interestingly, primary endpoint events consisting of stroke, vascular death, or Thrombolysis In Myocardial Infarction–defined major bleeding occurred exclusively in the medical therapy–only group (2‐year event, 12.9% [log‐rank, P=0.013]; Table 1). Interim analysis of results led to premature cessation of the trial because of the observed differences in outcomes of the treatment arms and the overwhelmingly positive results of the other randomized clinical trials favoring device closure. Results of the study suggest that the benefits of PFO closure may be, in part, based on morphological characteristics (ie, high‐risk features) of the PFO, such as presence of ASA, hypermobility of the IAS, and large‐sized PFOs.Other Potential Indications for PFO ClosureMigraine With AuraSeveral retrospective, observational studies have noted improvement in migraine headaches in patients who have undergone PFO closure for nonmigraine indications.29 A causal relationship between right‐to‐left shunting across a PFO and migraine headache has been proposed, but remains unproven. Epidemiological studies have shown that 48% of patients who experience migraine with aura (but not migraine without aura) had a PFO.30 Several theories have been proposed to explain this association. The presence of a persistent right‐to‐left PFO‐mediated shunt allows for passage of vasoactive amines and humoral substances that are normally metabolized, activated, and inactivated by the lungs. Such substances include prostaglandin E1, E2, serotonin, bra
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