Michael J Landzberg, Paul Khairy

Congenital heart disease INDICATIONS FOR THE CLOSURE OF PATENT FORAMEN OVALE CRYPTOGENIC See end of artile for authors affiliations Correspondene to: Mihael J Landzberg, MD, Boston Adult Congenital Heart (BACH) Servie, Department of Cardiology, Children s Hospital and Brigham and Women s Hospital, 300 Longwood Avenue, Boston, MA, 02115, USA; mihael.landzberg@ ardio.hboston.org T Mihael J Landzberg, Paul Khairy Heart 2004; 90:219 224. doi: 10.1136/hrt.2003.019315 he foramen ovale, while vital to our formative development, assumes mishievous potential if it persists post-utero. Similar to other vestigial strutures, presene of a patent foramen ovale (PFO) appears to arry no physiologi or survival benefit for normal individuals. In states of abnormal right sided ardia or pulmonary vasular apaitane or resistane, PFO has been impliated in worsening hypoxaemia aused by right to left intraardia passage of deoxygenated blood (see box). More reently, a ausative role of PFO in muh more ommonly ourring syndromes, inluding emboli ishaemi stroke, migraine with aura, and erebral and utaneous deompression disease, has been suggested. Highlighting ryptogeni emboli stroke assoiated with PFO, we will systematially review the evidene for these relations, disuss therapeuti potentials, and propose guidelines for therapeuti deisions as we await the ompletion of randomised ontrolled interventional trials. STROKE AND PFO Inidene Stroke databases suggest that despite intensive evaluation, approximately 40% of all patients suffering ishaemi strokes (80% of all stroke vitims) remain without learly identifiable preipitant or ause (2002 heart and stroke statistial update, Amerian Heart Assoiation). In 1989, Webster and Lehat separately reported small ase ontrol series with inreased prevalene of PFO in patients with ryptogeni stroke (CS). 1 2 To date, these desriptive series have been followed only by additional ase ontrol studies, without prospetive olletion of primary ourrene of CS + PFO in a well defined population. While these ase ontrol series have signifiant limitations, meta-analysis by Overell and olleagues suggested a strong orrelation between PFO and primary ourrene of CS. 3 In this analysis, prevalene of CS + PFO in persons of all ages was three times greater (95% onfidene interval (CI) 2.0 to 4.3) than in non-stroke ontrols; this relation was even more ompelling in persons with CS aged, 55 years of age, where PFO prevalene was five times greater (95% CI 3.2 to 8.3) than in healthy ontrols. PFO and patient related risks Attempts to risk stratify primary CS ourrene by anatomi features of PFO have had even greater limitation, due to smaller numbers of ase ontrol studies inluding fewer patients. Most evaluation has foused on hypermobility (atrial septal aneurysm) of the septum primum. Most rigorous definition of atrial septal aneurysm requires > 10 mm tissue sway in either diretion from the septal plane (or > 15 mm total sway) with a base of moving tissue that extends > 10 mm. Anatomially, atrial septal aneurysm typially, if not invariably, is assoiated with either septal fenestrations or PFO. Case series meta-analysis points to a strong assoiation between the presene of atrial septal aneurysm + PFO and primary ourrene of CS, with all ages, and those aged, 55 years with atrial septal aneurysm + PFO having five times greater (95% CI 2.4 to 10.4) and 16 times greater (95% CI 3.0 to 86.1) assoiative risk. 3 This assoiation was onfirmed in a reent large ase ontrol analysis. 4 High risk PFO features of (1) atrial septal aneurysm, and (2) spontaneous intraardia passage of bubble ontrast without provoative manoeuvres have been applied to existing stroke databases and have been shown to arry several fold higher risk of stroke/transient ishaemi attak (TIA) reurrene when ompared to CS + PFO patients without these features. 5 Causative mehanisms of assoiation between CS + PFO remain speulative. Anedotes of thrombi viewed passing from systemi venous irulation through PFO to the systemi arterial irulation have led to the suggestion of embolisation of systemi venous thrombus via PFO as a primary mehanism of disease. Suh thrombi have generally appeared quite large, and would typially aount for large vessel erebro-olusive disease and symptomatology. However, CS patients in primary ourrene trials and CS + PFO patients in seondary prevention trials have tended to present with smaller territory, or milder, neurologi events. 6 9 This has led to speulation that smaller emboli material forms in situ within ertain PFO. The two dimensional tunnel, or 219 Heart: first published as 10.1136/hrt.2003.019315 on 16 January 2004. Downloaded from http://heart.bmj.om/ on 28 Deember 2018 by guest. Proteted by opyright. www.heartjnl.om

220 three dimensional wind sok nature of ertain PFO suggests a plausibility of a pro-oagulant milieu with stagnation as well as potential for embolisation in people harbouring suh PFO. However, diret evidene impliating suh is laking to date. TREATMENT: MEDICAL, SURGICAL AND PERCUTANEOUS Currently there are no onsensus guidelines on treating patients with CS + PFO using available treatments inluding medial therapies (antiplatelet, antioagulant), surgial PFO losure, and perutaneous losure. Medial Case series have suggested a signifiant risk of stroke/tia reurrene (4 20%/year depending upon relative high risk Typial onditions when PFO may ause or worsen hypoxaemia Table 1 Systemati review: patient harateristis transatheter losure versus medial management of PFO Charateristi Valvar pulmonary stenosis Ebstein s disease of right ventrile and triuspid valve Right ventriular infartion Orthodeoxia-platypnoea syndrome Chroni lung disease (obstrutive or restritive) Pulmonary embolism (aute or hroni) Pulmonary arteriolar hypertension (primary and seondary) Transatheter losure (n = 1107) Medial treatment (n = 895) p Value Baseline harateristis Mean (SD) age (years) 45.8 (13.4) 47.6 (12.8) 0.0024 Male sex (%) 48.3 57.0 0.0004 Atrial septal aneurysm (%) 22.4 22.1 0.8771 Thromboemboli events at presentation Stroke (%) 67.0 89.3,0.0001 TIA (%) 53.1 24.5,0.0001 Other systemi emboli event (%) 3.9 2 Multiple emboli events (%) 45.2 12.2,0.0001 Risk fators Hypertension (%) 28.3 26.3 0.3465 Diabetes (%) 4.5 25.0,0.0001 Smoking history (%) 32.6 49.5,0.0001 Hyperholesterolaemia (%) 15.5 18.4 0.2372 Means (SD) follow up (months) 18.2 (15.1) 30.2 (16.2),0.0001 TIA, transient ishaemi attak. Table 3 Systemati review: reurrent neurologi thromboemboli events with transatheter PFO losure ompared to medial treatment Reurrent events PFO losure Medial treatment RD NNT RR (95% CI) P Value Crude annualised rate Stroke 0.42% 3.09% 2.67% 37 0.144 (0.056 to 0.372),0.0001 TIA 1.43% 2.58% 1.15% 87 0.562 (0.299 to 1.058) 0.0703 Stroke or TIA 1.86% 5.80% 3.94% 25 0.327 (0.198 to 0.538),0.0001 Crude rate of stroke/tia at 1 year 2.71% 7.56% 4.85% 21 0.357 (0.234 to 0.543),0.0001 Adjusted annual rate of stroke/tia* 1.86% 5.42% 3.56% 28 0.346 (0.209 to 0.573),0.0001 Adjusted rate stroke/tia at 1 year* 2.71% 7.07% 4.36% 23 0.385 (0.252 to 0.589),0.0001 *Adjusted by indiret standardisation for imbalanes in diabetes and smoking. NNT, number needed to treat; RD, risk differene; RR, relative risk; TIA, transient ishaemi attak. features) for patients with CS + PFO using medial treatment. 5 10 13 Use of warfarin, despite inreased risk of assoiated haemorrhage, has been linially favoured over aspirin, though onfirmatory data are laking. A prospetive registry of CS patients aged 15 55 years treated with aspirin analysed reurrene over four years of stroke/tia by presene or absene of PFO with/without atrial septal aneurysm. 14 The authors suggested that there was notable attributable risk for future stroke/tia of PFO with atrial septal aneurysm, with four year stroke/tia reurrene of 15.2%/19.2% in patients with PFO + atrial septal aneurysm (hazard ratio 4.17). Of note, in this trial patients with PFO were signifiantly younger and had dereased additional stroke risks of systemi hypertension, diabetes, and higher body mass index. The WARSS trial randomised patients aged 30 85 years with reent ishaemi stroke to use of either daily aspirin (325 mg) or warfarin (target international normalised ratio (INR) 1.4 2.8), assessing reurrene of ishaemi neurologi events or death. 15 No statistial differene in ourrene of the primary end point at two years was noted between groups (16% v 17.6%, respetively). Subgroup analysis of a muh smaller number of patients with PFO and ishaemi stroke (only some with CS) found similar risk of high stroke/tia reurrene regardless of aspirin or warfarin treatment. 16 In this trial as well, patients with PFO had dereased additional stroke risks of systemi hypertension, diabetes, and sedentary life style. Heart: first published as 10.1136/hrt.2003.019315 on 16 January 2004. Downloaded from http://heart.bmj.om/ on 28 Deember 2018 by guest. Proteted by opyright. www.heartjnl.om

Surgial Surgial PFO losure appears a safe and effetive means of eradiating PFO as a potential risk for stroke/tia ourrene/ reurrene, with limited supportive data. Ishaemi neurologi event reurrene rates of 4 17%/year, seen in surgial series of PFO losure for patients with index stroke, are likely to be distorted by limited and seleted enrolment, as well as the single institutional nature of these ase series. 17 19 Perutaneous Perutaneous PFO losure, first performed in 1989, is now possible with any of 5 7 different devies depending upon availability during various phases of investigational development (fig 1). 20 In the USA, PFO may be losed perutaneously under Food and Drug Administration mandated humanitarian devie exemption (HDE) guidelines in limited speifi irumstanes, both with CardioSEAL (HDE granted 2000) and the Amplatzer PFO Oluder (HDE granted 2002). PFO losure with all other devies remains limited to investigational trials: urrently no devie has FDA pre-market approval for this indiation. Assessing effiay of perutaneous PFO losure for eah devie has been troublesome given the ase series nature of existing studies, lak of randomised ontrolled trials, as well as a lak of defined and linially meaningful end points for omparison. The oldest, ontinuous database examining perutaneous PFO losure safety and effiay outomes has suggested that, for progressive generations of double umbrella devies ulminating in CardioSEAL and its modifiations, annual reurrent ombined stroke/tia event rate Figure 1 Available perutaneous PFO olusion devies. following perutaneous losure has been onsistently less than 4%. 6 7 9 20 21 Complete PFO losure at follow up an be expeted in 90 95% of patients utilising CardioSEAL (and its urrent STARFlex self adjusting modifiation) or the 6 9 21 Amplatzer PFO Oluder. For all devies, hoie, duration, and benefit and risks of peri-implant antiplatelet or antioagulant strategies remain unlear and undefined, with urrent linial pratie mirroring post-oronary stent implantation pharmaologis (1 6 months lopidogrel, 75 mg daily, plus six months aspirin, 325 mg daily). Devie related adversity has been doumented with every oluder, with most notable ourrenes inluding devie embolisation, tissue erosion, periardial inflammation, devie related thrombosis, infetion, devie frature or dislodgement, and stroke. Important other ompliations have inluded devie related arrhythmia, transfusion requirement, and preipitation of migraine and hest pain. While exat inidenes of suh adversity are diffiult to determine from limited available published series, linially meaningful adversity most reently appears to our in less than 1 3% of all patients undergoing perutaneous PFO losure. 6 9 21 The inidene and linial relevane of devie related thrombosis and early and late post-implant atrial arrhythmias has yet to be determined and ompared to other therapeuti modalities. SYSTEMATIC REVIEW AND POOLED ANALYSIS In a reent systemati review we hose to estimate the relative benefit of perutaneous PFO losure ompared to medial therapy (tables 1 and 2, fig 2). 22 Adjusting for attributable risk due to the higher prevalene of diabetes mellitus and smoking in medially treated patients with PFO, perutaneous PFO losure was shown to have a protetive effet on stroke or TIA reurrene ompared to medial treatment (annualised inidene 1.9% v 5.4%, relative risk 0.346, 95% CI 0.209 to 0.573; p, 0.0001). At one year follow up, PFO losure was assoiated with a relative risk of 0.385 (95% CI 0.252 to 0.589) and absolute risk differene of 4.4%. Otherwise expressed, after the first year of follow up, for every 23 patients who had their PFO losed perutaneously, one stroke or TIA was prevented ompared to use of medial treatment. RANDOMISED CONTROLLED TRIALS: THE TIME HAS COME A number of attempts at randomised ontrolled trials (RCTs), inluding the perutaneous losure (PC) trial and the Paradoxial Embolism Prevention Study in Ishemi Stroke (PEPSIS) trial, ourred throughout the past deade, but failed largely due to a lak of: (1) neurologist ardiologist primary physiian teamwork and oordination of goal and effort; (2) modern preise definition of ishaemi neurologi outome; (3) data to generate realisti hypotheses and sample size requirements; (4) referring physiian and investigator motivation to enrol all andidate patients into randomised expert are; (5) industry based sponsorship of a suffiiently sized trial to adequately address power onerns; and (6) a tipping point mentality that CS + PFO is a true and highly morbid disease, requiring study and relief. This milieu has radially shifted, setting the stage for urrent RCTs of perutaneous PFO losure and other treatments for persons affeted by CS. The largest suh trial, CLOSURE-1, is a. 1600 patient trial (neurologist prinipal investigatorships), testing superiority of CardioSEAL-STARFlex versus 221 Heart: first published as 10.1136/hrt.2003.019315 on 16 January 2004. Downloaded from http://heart.bmj.om/ on 28 Deember 2018 by guest. Proteted by opyright. www.heartjnl.om

222 Figure 2 Systemati review: stroke and TIA following transatheter PFO losure ompared to medially treated patients best medial treatment in persons with imaging onfirmed index stroke, and evaluating similar hard neurologi end points as primary outome. A seond trial, RESPECT, is a 300 patient trial (primarily ardiologist prinipal investigatorship) evaluating equivaleny of Amplatzer PFO Oluder PFO olusion with liniian-determined best medial therapy in persons with linially symptomati index stroke, evaluating similar symptomatology as primary outome. Both trials are projeted to omplete enrolment within 12 18 months. In light of the above trials, we strongly advoate the following: Rapid investigation of patients with CS, inluding prompt assessment for and anatomi definition of PFO. When transthorai ehoardiography with Mueller manoeuvre (sniff foring right atrial pressure to bow the atrial septum leftward) does not suffiiently define the presene of shunting or PFO anatomy, transoesophageal ehoardiography is employed to provide greatest anatomi detail of intraardia shunting, though likely with lesser sensitivity in diagnosis. While individual institutions may offer various first line testing for presene of intravasular shunting, inluding ontrast ehoardiography 23 and transranial Doppler sonography, 24 we reommend standard transoesophageal ehoardiography 25 for all patients with CS and suspeted PFO. Reognition of high risk patient (age, 55 60 years, (+) known irulating pro-oagulant) and PFO anatomi risk ( spontaneous ehoardiographi shunting, hypermobile septum primum, tunnel-like PFO) features potentially raising risk of reurrent neurologi ishaemi events. Patient eduation regarding assoiation and partiular risk features of CS and PFO, and removal or redution of all potential prooagulant risks (trauma, obesity, inativity, oral ontraeption, igarette use, et). In patients with new onset CS, enrolment of all eligible andidates into RCTs evaluating safety and effiay of treatment arms. While we strongly favour data aquisition to answer questions regarding superiority of therapeuti hoie in trials based upon most rigorous data analysis, both CLOSURE-1 and RESPECT remain reasonable enrolment options. Choie of primary PFO losure in patients: with reurrent CS, not eligible for trial enrolment, despite ompliant medial treatment or with inability to omply safely with medial treatment; while we favour perutaneous PFO losure, surgial losure is likely a reasonable, though rarely hosen, alternative, with fewer supportive data with known irulating hyperoagulable states with reognised inreased risks of thrombosis/embolism despite reommended warfarin treatment (lupus antioagulant/antiphospholipid antibody syndrome) with persistent prooagulant risk despite best medial treatment. RIGHT SIDED CARDIAC DISEASE AND PFO Persons affeted by either ompliane or apaitane abnormalities of right sided filling may have suffiient elevation of right atrial pressure so as to promote right-to-left shunting at the level of the foramen. Understanding the aetiology of the underlying musle abnormality and targeting treatment to that, as is possible, is the mainstay of therapy for these patients. On oasion, ontrol of yanosis by means of PFO losure may be a reasonable aute and intermediate term palliation, with reognition that longer term worsening of musle funtion aused by inreased right sided volume may our. In the adult patient with suh disease, temporary PFO olusion may offer some degree of mimiry of aute haemodynami effets of losure, though there are no reognised manoeuvres that predit suessful longer term outomes with PFO losure. We advoate prolonged disussion of unknown intermediate and long term outomes with suh patients, and devie implantation for PFO losure when indiated, at entres partiipating in losure registries. DECOMPRESSIONSICKNESSINDIVERSANDPFO Deompression sikness (DCS I musuloutaneous; DCI II neurologi) arises from nitrogen and oxygen gas formation in various body tissues at inreased ambient pressure. Gas passage from the systemi venous to arterial irulation an our due to either pulmonary barotrauma or intravasular shunting. Several studies have suggested inreased inidene of PFO in divers with DCS. From initial reognition of assoiation of PFO with DCS in 1986, to urrent reports of PFO losure for divers affeted by DCS, differenes in outomes of ase series highlight the differenes in tehniques used to: (1) selet and enrol studied patients and ontrols; (2) linially diagnose DCS; (3) diagnose PFO; and (4) image neurologi events. 26 32 In light of these limitations, general reviews suggests that: (1) regardless of presene of PFO, inreasing numbers of dives may be assoiated with inreasing inidene of DCS or asymptomati neurologi events (ANEs); (2) ourrene of ANEs is likely to be ommon (25 50% of sreened patients) in high volume divers; (3) multiple reurrenes of DCS II, ANEs, and migraine headahes with aura may luster in persons with large shunt volume PFO (atrial septal aneurysm or spontaneous shunting). Standardisation of diagnosis and outome remains a major obstale for assessment of treatment for DCS prevention. Typially, more than 50% of high volume divers with ANEs remain asymptomati, and there are no reognised risks preditive of future symptomati events. In this ontext, nonetheless, previously symptomati or high volume divers with ANEs or with high risk anatomi PFO features, who wish to ontinue diving may warrant losure in entres Heart: first published as 10.1136/hrt.2003.019315 on 16 January 2004. Downloaded from http://heart.bmj.om/ on 28 Deember 2018 by guest. Proteted by opyright. www.heartjnl.om

Abbreviations ANE: asymptomati neurologi event CS: ryptogeni stroke DCS: deompression sikness HDE: humanitarian devie exemption M+A: migraine syndrome with aura PEPSIS: Paradoxial Embolism Prevention Study in Ishemi Stroke PFO: patent foramen oval RCT: randomised ontrolled trial RESPECT: Randomized Evaluation of reurrent Stroke omparing PFO losure to Established Current standard of are Treatment TIA: transient ishaemi attak WARSS: Warfarin-Aspirin Reurrent Stroke Study maintaining losure registries or partiipation in trials. Intervention for low volume sports divers with PFO without ANEs or symptoms of DCS, regardless of anatomi onerns, remains unfounded at the present. Of interest, DCS, regardless of presene of PFO, has been noted in ompressed air tunnel workers, high altitude aviators, and astronauts. Treatments offering potential for limiting the ourrene of DCS may arry partiular import for suh persons whose employment in high risk situations may plae themselves and others at partiular risk. MIGRAINE SYNDROME AND PFO The reognition of an assoiation between migraine syndrome with aura (M+A) and PFO appears to have ome full irle over the past two deades. Initial onerns from ardiologists foused on post-perutaneous PFO losure preipitation of migrainous events that mimiked original neurologi presentation. Effets from general anaesthesia, raised ambient ateholamines, and embolisation of metal or prooagulant miroaggregates were all theorised as being related to ourrene. Indiations for losure of PFO: key points A 3 to 5-fold higher prevalene of PFO is noted in patients with ryptogeni stroke Proposed high risk PFO features inlude: atrial septal aneurysm, spontaneous right-to-left shunting, and tunnellike appearane Although warfarin is often preferred over aspirin for seondary prevention of ryptogeni stroke, onfirmatory data are laking Perutaneous transatheter PFO devie losure may be performed safely with a low inidene of reurrent neurologi events Clinial trials omparing medial treatment versus transatheter losure are underway If ineligible for randomised trials, PFO losure may be onsidered in patients with reurrent events unable to safely omply with or despite medial treatment, high risk PFO feature, and/or high risk medial features (for example, hyperoagulable state, age, 55 60 years) High volume divers with deompression sikness or asymptomati neurologi events who wish to ontinue diving may warrant PFO losure in appropriate entres There is insuffiient evidene to reommend PFO losure for the indiation of migraine with aura Small epidemiologi studies have suggested a notably inreased PFO prevalene in persons suffering M+A. 33 34 The relation between this assoiation and the reognition of M+A as a risk fator for ishaemi stroke in the young is unlear, though right to left passage of irulating fators has been postulated in both syndromes. 35 Despite ase series doumenting PFO losure effets in persons with M+A, the ompeting onerns of both preipitation and redution of M+A in persons with PFO lead to our reommendation not to pursue PFO losure at the 36 37 present for persons with M+A without CS. We support improved basi aetiologi and epidemiologi study of M+A, as well as study of the effets of various antiplatelet and antioagulant agents as they are employed after perutaneous PFO losure. CONCLUSIONS Pateny of the foramen ovale, ourring in 20 30% of persons, may be a ommonly ourring intraardia anatomi variation, yet our knowledge of even basi epidemiologi priniples leading to assoiation with disease remains laking. This vestige of embryologi physiology has little if any relation to health and, on inreasingly reognised oasion, harbours potential for assoiation with atastrophi disease. Relative risks and benefits of treatments aimed at ontrolling or eliminating syndromes assoiated with PFO hinge upon study of the mehanisms of these diseases, the effets of speifi planned treatments, and randomised ontrolled omparison trials to guide individual and population treatment reommendations. Current therapeuti options for ontrol of PFO assoiated disease, inluding perutaneous PFO losure for reurrent stroke risk redution as a model, have low adverse potential. While systemati review suggests a strong favour for perutaneous PFO losure when ompared to medial treatments, these data are gleaned from ase series. RCTs, inluding a large superiority trial, CLOSURE-1, and a smaller, equivaleny trial, RESPECT, are ative and ongoing, and will likely ontribute to answering the neessary sientifi and linial questions to allow for improved patient are. We have been alled to arms to reognise patients with PFO who are at risk of assoiated devastating disease, and to forefully attak suh by enrolling suh patients, whenever possible, into RCTs testing risk limiting strategies. Until suh study is ompleted, perutaneous PFO losure remains an effetive and aeptable treatment for speifi patients with high risk features falling outside protool entry riteria.... Authors affiliations M J Landzberg, P Khairy, Boston Adult Congenital Heart (BACH) Servie, Children s Hospital and Brigham and Women s Hospital, Boston, USA REFERENCES 1 Webster MW, Chanellor AM, Smith HJ, et al. Patent foramen ovale in young stroke patients. Lanet 1988;ii:11 12. 2 Lehat P, Mas JL, Lasault G, et al. Prevalene of patent foramen ovale in patients with stroke. N Engl J Med 1988;318:1148 52. Among the first reports showing a higher prevalene of PFO in patients with strokes ompared to ontrols (40% v 10%; p, 0.001). 3 Overell JR, Bone I, Lees KR. Interatrial septal abnormalities and stroke: a metaanalysis of ase-ontrol studies. Neurology 2000;55:1172 9. 4 Agmon Y, Khandheria BK, Meissner I, et al. Frequeny of atrial septal aneurysms in patients with erebral ishemi events. Cirulation 1999;99:1942 4. 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