Case presentation: A 69-year-old

Transcription

1 CLINICIAN UPDATE Paradoxical Embolism Bradley A. Maron, MD; Prem S. Shekar, MD; Samuel Z. Goldhaber, MD Case presentation: A 69-year-old woman presented to the hospital with sudden-onset shortness of breath that occurred while standing from a sitting position. The patient was in moderate respiratory distress with a blood pressure of 109/78 mm Hg, heart rate of 109 bpm, and peripheral blood oxygen saturation level of 95% on 3Lofoxygen per nasal cannula. She had an accentuated pulmonary component of the second heart sound, sinus tachycardia on ECG, and an elevated troponin-i level. A large proximal pulmonary embolism was diagnosed by computed tomography. Transthoracic echocardiography demonstrated a right atrial (RA) mass. Transesophageal echocardiography revealed a 3.2-cm thrombus extending from the RA to the left atrium (LA) through a patent foramen ovale (PFO), consistent with impending paradoxical embolism (Figure and Figure I in the online-only Data Supplement). Overview Cerebrovascular thromboembolism is responsible annually for ischemic strokes and deaths in the United States alone, with expenditure of 36 billion dollars. 1 Ischemic stroke in the absence of conventional risk factors for cerebral vascular disease indicates that alternative mechanisms for stroke must exist. 2 Indeed, a cause is unidentified or unproven in 40% of all strokes despite comprehensive diagnostic testing. 3 These strokes are known as cryptogenic strokes. Less common causes of cryptogenic stroke include cardiac tumor, valvular strands (ie, Lambl s excrescences), aortic arch atherosclerotic plaque embolization, or intracardiac venous thromboembolism that is formed in association with structural heart disease. 2,4,5 The most common cause of cryptogenic stroke is probably paradoxical embolism due to PFO. 6,7 Paradoxical embolism, or venous thromboembolism transit from right- to left-sided cardiac chambers, may occur via interventricular, interatrial, or pulmonary arteriovenous malformations. PFO rates are higher in cryptogenic stroke patients than in the general population. In a meta-analysis of 23 case-control studies, the odds ratio for a PFO in cryptogenic stroke patients compared with those with stroke from a known cause was 2.9 (95% confidence interval, 2.1 to 4.0). 3,8 These findings are similar to those from Handke and colleagues, 9 who prospectively evaluated 503 consecutive acute stroke patients and observed that compared with stroke from a determined cause, the PFO rate in cryptogenic stroke is significantly greater. Pathophysiology of Paradoxical Embolism Normal fetal circulation is dependent on the foramen ovale, which provides a communication for oxygenated blood flow between the RA and LA during lung maturation. 10,11 At birth, decreased pulmonary vascular resistance and increased LA pressure promote closure of the foramen ovale, although a probepatent PFO is present in 27% of the general population at autopsy. 11 An atrial septal aneurysm (ASA) is a bulging of the atrial septal membrane (eg, septum primum) in the region of the fossa ovalis and is present in 1% of PFO patients. 12 The precise mechanism of stroke in PFO patients is unresolved but likely occurs due to (1) paradoxical embolism from venous thromboembolism transit through a PFO, (2) PFO- or ASA-induced thrombogenicity, or (3) LA clot formation from atrial arrhythmias that may occur in association with a PFO or ASA. From the Department of Internal Medicine, Division of Cardiovascular Medicine (B.A.M., S.Z.G.), and Department of Surgery, Division of Cardiothoracic Surgery (P.S.S.), Brigham and Women s Hospital and Harvard Medical School, Boston, Mass. The online-only Data Supplement is available with this article at Correspondence to Bradley A. Maron, MD, Division of Cardiovascular Medicine, Brigham and Women s Hospital, PBB-1, 75 Francis St, Boston, MA bmaron@partners.org (Circulation. 2010;122: ) 2010 American Heart Association, Inc. Circulation is available at DOI: /CIRCULATIONAHA

2 Maron et al Paradoxical Embolism and Patent Foramen Ovale 1969 Figure. Impending paradoxical embolism. A 64-year-old woman admitted to the hospital with shortness of breath was referred for pulmonary embolectomy to treat a saddle pulmonary embolism. On intraoperative transesophageal echocardiography, a 3.2-cm thrombus (arrowheads) traversing the interatrial septum was observed. Mechanical removal of the clot by the cardiothoracic surgeon and surgical closure of the PFO occurred uneventfully, and the patient recovered without neurological complications. TV indicates tricuspid valve. Risk Stratification of PFO Patients The annual risk of cryptogenic and recurrent stroke in PFO populations is 0.1% and 1%, respectively. 13,14 The influence of ASA on stroke risk in PFO patients remains unresolved. One analysis of patients with PFO plus ASA showed a 4-fold higher recurrent stroke rate over 4 years compared with patients with a PFO alone (19.2% versus 5.6%). 14,15 A large PFO ( 4 mm determined by balloon dilation), prominent Chiari s network (ie, sinus venosus remnant), and PFO tunnel length 14 mm appear to increase the risk of cryptogenic stroke or transient ischemic attack (TIA). 14,16 The magnitude of right-to-left shunting may positively correlate with the risk of cryptogenic stroke. 17 In the Paradoxical Embolism From Large Veins in Ischemic Stroke (PELVIS) study, cryptogenic stroke was associated with a 5-fold greater probability of pelvic deep vein thrombosis than stroke of determined origin. 18 Similarly, patients with impending paradoxical embolism often present with contemporaneous deep vein thrombosis or pulmonary embolism (Figure and Figure I in the online-only Data Supplement). 19 A genetic predisposition for cryptogenic stroke may exist. In 1 study, the factor V Leiden (G1691A) or prothrombin G20210A gene mutation conferred a 4-fold higher risk of stroke in young PFO patients compared with agematched controls. 20 However, larger epidemiological studies have not confirmed these findings. Therefore, there is insufficient evidence to implicate genetic forms of thrombophilia as independently conferring an increased risk of paradoxical embolism. Therapeutic Options to Prevent Stroke or TIA in PFO Patients Primary Prevention Prevention strategies for a first-time stroke do not differ in patients with respect to PFO status. Some have spec- Table 1. Benefits and Limitations Associated With Medical and Percutaneous Device Closure Therapies for Preventing Recurrent Cryptogenic Stroke Medical Therapy Percutaneous Device Closure Benefits Limitations Benefits Limitations Noninvasive Patient exposure to risks of minor (eg, mucosal) and major (eg, intracranial hemorrhage, blood transfusion requiring gastrointestinal hemorrhage) therapy-associated complications Minimally invasive procedure that is generally well tolerated Unpredictable postclosure delay in right-to-left shunt reduction Well-studied strategy for secondary prevention of stroke and venous thromboembolism May be discontinued if necessary Drug level monitoring required for warfarin Patient exposure to medication side effects (eg, aspirin-induced gastrointestinal intolerance, clopidogrel-induced thrombocytopenia) Potential for unfavorable drug-drug interactions and contribution to polypharmacy Potential for permanent PFO defect closure Reduction or elimination of right-to-left shunt May reduce migraine headache frequency or intensity in selected patients PFO may close incompletely Elevated rates of postprocedural atrial arrhythmias Patient exposure to risk of major procedural complications including aortic regurgitation, device embolization, cardiac tamponade, device thrombus, atrioventricular block, among others Does not eliminate need for a short term (ie, 6 mo) of dual antiplatelet therapy

3 1970 Circulation November 9, 2010 Table 2. Summary of Ongoing Randomized, Prospective Clinical Trial Comparing Medical Therapy and Percutaneous PFO Closure for the Prevention of Recurrent Cryptogenic Stroke Study Randomized evaluation of recurrent stroke comparing PFO closure to established current standard of care treatment Evaluation of the STARFlex septal closure system in patients with a stroke or TIA due to the possible passage of a clot of unknown origin through a patent foramen ovale (PFO) Patent foramen ovale and cryptogenic embolism Patent foramen ovale closure or anticoagulants vs antiplatelet therapy to prevent stroke recurrence Gore HELEX septal occluder for patent foramen ovale (PFO) closure in stroke patients ulated that PFO closure for primary prevention of stroke may be appropriate in very-high-risk patients with a large PFO, ASA, spontaneous right-toleft shunt, prominent Chiari s network, and a primary coagulopathy. 21 This hypothesis, however, requires further investigation. Secondary Prevention With Medical Therapy Antiplatelet pharmacotherapy with aspirin, aspirin plus extended-release dipyridamole, or clopidogrel is an American Heart Association/American Stroke Association class I indication for the secondary prevention of ischemic stroke. For cardioembolic stroke, warfarin is Trial Name/Goal Patient Enrollment/ Location Treatment Groups Major Inclusion Criteria RESPECT 710 US CLOSURE-I 900 US PC Trial 414 Australia, Europe CLOSE 900 Europe Gore REDUCE 664 US, Europe 1. Amplatzer PFO Occluder 2. Aspirin 3. Clopidogrel 4. Aspirin plus dipyridamole 5. Warfarin 1. Aspirin 325 mg/d and/or warfarin (INR 2.5) 2. STARFlex septal closure system 1. Investigator s choice of warfarin (INR 2 3) or aspirin mg/d or clopidogrel mg/d 2. Amplatzer PFO Occluder 1. Aspirin 2. Warfarin 3. PFO closure device of any ad hoc committee approved type 1. Antiplatelet therapy 2. Antiplatelet therapy plus device closure therapy Age y Cryptogenic stroke within 270 days of enrollment To date, 86% show PFO shunting at rest, 35% have ASA Age y Ischemic stroke within 6 mo of enrollment either right-to-left shunt or associated ASA Age 60 y Prior stroke with sufficient time to recover activities of daily living Age y either right-to-left shunt or ASA Age y Stroke or TIA within 180 d of enrollment right-to-left shunt preferred in select patients. 22 However, owing to inconsistent findings from the largest available clinical trials, optimal medical therapy for prevention of recurrent cryptogenic stroke remains unresolved. Mas and colleagues 15 observed that in 277 consecutive cryptogenic stroke patients (mean age, 40 years) treated with aspirin (300 mg/d), PFO plus ASA but not PFO alone increased the rates of stroke or TIA compared with patients without either of these defects (hazard ratio 3.91; 95% confidence interval, 1.59 to 9.59; P 0.004). Their results suggested that aspirin monotherapy is adequate in PFO patients but provides insufficient protection for those Primary 1. Recurrent nonfatal stroke 2. Postrandomization mortality 3. Fatal ischemic stroke 1. Two-year incidence of stroke or TIA 2. All-cause mortality at 30 d of follow-up 3. Neurological mortality after 31 d of follow-up 1. Time to death (fatal stroke, cardiovascular and noncardiovascular causes) 2. Time to nonfatal stroke 3. Time to peripheral embolism 1. Stroke within follow-up period (3 5 y) 1. Freedom from recurrent ischemic stroke or imaging-confirmed TIA through 24 mo after randomization INR indicates international normalized ratio; TTE, transthoracic echocardiogram; and TEE, transesophageal echocardiogram. End Point Secondary 1. Complete closure of defect at 6 mo 2. Absence of recurrent symptomatic cryptogenic nonfatal stroke or cardiovascular death 3. Incident TIA 1. Incidence of primary end point, adverse events, primary end point, and adverse events by treatment group 1. New arrhythmias 2. Myocardial infarction 3. Hospitalization related to PFO or its treatment 4. Device complications 5. Bleeding complications 1. Disabling stroke 2. Ischemic stroke 3. Intracranial hemorrhage 4. Ischemic stroke or TIA or systemic embolism 5. All-cause mortality 6. Vascular death 1. Device-associated adverse events 2. Evaluation of PFO closure by TTE/TEE with a complex interatrial defect such as ASA plus PFO. Homma and colleagues 23 prospectively compared aspirin (325 mg/d) against warfarin (international normalized ratio, 1.8 to 2.4) in 265 cryptogenic stroke patients (mean age, 59 years) enrolled in the randomized, controlled Warfarin-Aspirin Recurrent Stroke Study (WARSS). 24 Irrespective of ASA status (or PFO size), no significant difference in the 2-year rates of stroke or death among patients randomized to either treatment group was observed (aspirin, 14.3% versus warfarin, 12.7%). Rates of major bleeding from warfarin or aspirin therapy are 2% and 1%, respectively. Benefits and limita-

4 Maron et al Paradoxical Embolism and Patent Foramen Ovale 1971 tions of medical therapy are provided in Table 1. Secondary Prevention With Device Therapy The Amplatzer Septal Occluder, Sideris buttoned device, Gore Helix Septal Occluder, and CardioSEAL Septal Occlusion System are commonly used devices approved by the US Food and Drug Administration for percutaneous closure of cardiac septal defects. Successful deployment results in secure device placement, complete defect occlusion, and elimination of clinically significant hemodynamic shunting. Reports suggesting that percutaneous PFO closure reduces the risk of a future stroke or TIA are primarily from case series and observational reports. In a meta-analysis of 1430 patients undergoing PFO occlusion, the rate of recurrent stroke was 0.19% (95% confidence interval, 0.05 to 0.49), which compares favorably against large medical therapy trials that report annual recurrent event rates of 1.4%. 14 Sufficiently powered randomized trials comparing these treatment modalities have not yet been completed (Table 2), but evidence from retrospective analyses and registry data suggests that percutaneous PFO closure is a suitable option. Windecker and colleagues 25 evaluated outcomes in a large cohort of cryptogenic stroke patients undergoing either percutaneous PFO closure (n 150) or medical therapy (n 158) and observed a substantial reduction in the 4-year rates of recurrent stroke or TIA in favor of device therapy (8.5% versus 24.3%; P 0.05). Percutaneous closure also appears to be effective in patients with PFO plus ASA, particularly when associated with a substantial decrease in shunt severity. Major complication rates associated with device closure occur in 1.5% of patients, whereas the rate of minor complications such as femoral hematoma and new atrial arrhythmias is 8%. 26 Additional limitations to device therapy include incomplete device occlusion and insufficient shunt reduction. Furthermore, to prevent clot formation on the surface of the septal occluder before device endothelialization, dual antiplatelet therapy is recommended for 6 months after device implantation (Table 1). Surgical PFO closure is comparable in efficacy to percutaneous approaches, with some estimates conferring an annual recurrent stroke rate of 0.34%. 14 Surgical PFO closure as a single indication for sternotomy is uncommon but should be considered in high-risk cryptogenic stroke patients undergoing open heart surgery for other indications or in those for whom successful percutaneous closure is not possible. Summary Anticoagulation with either daily aspirin or warfarin is recommended in PFO patients to prevent recurrent stroke. Percutaneous or surgical defect closure is a reasonable treatment choice in patients with a prior cryptogenic stroke and should be considered when the PFO is associated with high-risk features (American Heart Association class IIa indication, level of evidence C). 27 Several ongoing randomized controlled clinical trials evaluating medical and percutaneous therapies for recurrent cryptogenic stroke prevention in PFO patients will provide additional data. Management of Presented Case In the case vignette, pulmonary embolectomy was recommended owing to the presence of a RA clot and the patient s high-risk clinical status. The impending paradoxical embolism discovered on intraoperative transesophageal echocardiography was excised, and the PFO was closed surgically. The patient had a full recovery without clinical evidence of stroke or TIA. She was discharged on lifelong warfarin therapy with target international normalized ratio of 2 to 3. None. Disclosures References 1. O Gara PT, Messe SR, Tuzcu EM, Catha G, Ring JC. Percutaneous device closure of patent foramen ovale for secondary stroke prevention. Circulation. 2009;119: Kizer JR, Devereux RB. Patent foramen ovale in young adults with unexplained stroke. N Engl J Med. 2005;353: Windecker S, Meier B. Is closure recommended for patent foramen ovale and cryptogenic stroke? Patent foramen ovale and cryptogenic stroke: to close or not to close? Closure: what else! Circulation. 2008;118: Maron BJ, Olivotto I, Bellone P, Conte MR, Cecchi F, Flygenring BP, Casey SA, Gohman TE, Bongioanni S, Spirito P. Clinical profile of stroke in 900 patients with hypertrophic cardiomyopathy. J Am Coll Cardiol. 2002;39: Di Tullio MR, Russo C, Jin Z, Sacco RL, Mohr JP, Homma S; Patent Foramen Ovale in Cryptogenic Stroke Study Investigators. Aortic arch plaques and risk of recurrent stroke and death. Circulation. 2009;119: Sastry S, Riding G, Morris J, Taberner D, Cherry N, Haegerty A, McCollum C. Young Adult Myocardial Infarction and Ischemic Stroke: the role of paradoxical embolism and thrombophilia (the YAMIS Study). J Am Coll Cardiol. 2006;48: Messé SR, Kasner SE. Patent foramen ovale in cryptogenic stroke: not to close. Circulation. 2008;118: Alsheikh-Ali AA, Thaler DE, Kent DM. Patent foramen ovale in cryptogenic stroke: incidental or pathogenic? Stroke. 2009;40: Handke M, Harloff A, Olschewski M, Hetzel A, Geibel A. Patent foramen ovale and cryptogenic stroke in older patients. N Engl J Med. 2007;357: Hara H, Vermani R, Ladich E, Mackey-Bojack S, Titus J, Reisman M, Gray W, Nakamura M, Mooney M, Poulose A, Schwartz RS. Patent foramen ovale: current pathology, pathophysiology, and clinical status. J Am Coll Cardiol. 2005;46: Hagen PT, Scholz DG, Edwards WD. Incidence and size of patent foramen ovale during the first 10 decades of life: an autopsy study of 965 normal hearts. Mayo Clin Proc. 1984;59: Silver MD, Dorsey JS. Aneurysms of the septum primum in adults. Arch Pathol Lab Med. 1978;102: Lock JE. Patent foramen ovale is indicated, but the case hasn t gone to trial. Circulation. 2000;101: Homma S, Sacco RL. Patent foramen ovale and stroke. Circulation. 2005;112: Mas J-L, Arquizan C, Lamy C, Zuber M, Cabanes L, Derumeaux G, Coste J. Recurrent cerebrovascular events associated with patent foramen ovale, atrial septal aneurysm, or both. N Engl J Med. 2001;345: Goel SS, Tuzcu EM, Shishehbor MH, de Oliveira EI, Borek PP, Krasuski RA,

5 1972 Circulation November 9, 2010 Rodriguez LL, Kapadia SR. Morphology of the patent foramen ovale in asymptomatic versus symptomatic (stroke or transient ischemic attack) patients. Am J Cardiol. 2009; 103: Wahl A, Krumsdorf U, Meier B, Sievert H, Ostermayer S, Billinger K, Schwerzmann M, Becker U, Seiler C, Arnold M, Mattle HP, Windecker S. Transcatheter treatment of atrial septal aneurysm associated with patent foramen ovale for prevention of recurrent paradoxical embolism in high-risk patients. J Am Coll Cardiol. 2005;45: Cramer SC, Rordorf G, Maki JH, Kramer LA, Grotta JC, Burgin S, Hinchey JA, Benesch C, Furie KL, Lutsep HL, Kelly E, Longstreth WT. Increased pelvic vein thrombi in cryptogenic stroke: results of the Paradoxical Emboli From Large Veins in Ischemic Stroke (PELVIS) Study. Stroke. 2004;35: Myers PO, Bounamequx H, Panos A, Lerch R, Kalangos A. Impending paradoxical embolism: systematic review of prognostic factors and treatment. Chest. 2010;137: Botto N, Spadoni I, Giusti S, Ait-Ali L, Sicari R, Andreassi MG. Prothrombotic mutations as risk factors for cryptogenic ischemic cerebrovascular events in young subjects with patent foramen ovale. Stroke. 2007;38: Rigatelli G, Avvocata FD, Giordan M, Braggion G, Aggio S, Chinaglia M, Roncon L, Cardaioli P, Chen JP. Embolic implications of combined risk factors in patients with patient foramen ovale (the CARPE criteria): consideration for primary prevention closure? J Interven Cardiol. 2009;22: Adams RJ, Albers G, Alberts MJ, Benavente O, Furie K, Goldstein LB, Gorelick P, Halperin J, Harbaugh R, Johnston SC, Katzan I, Kelly-Hayes M, Kenton EJ, Marks M, Sacco RL, Schwamm LH. Updated to the AHA/ASA recommendations for the prevention of stroke in patients with stroke and transient ischemic attack. Stroke. 2008; 39: Homma S, Sacco RL, Di Tullio MR, Sciacca RR, Mohr JP; PFO in Cryptogenic Stroke Study (PICSS) Investigators. Effect of medical treatment in stroke patients with patent foramen ovale: Patent Foramen Ovale in Cryptogenic Stroke Study. Circulation. 2002;105: Mohr JP, Thompson JLP, Lazar RM, Levin B, Sacco RL, Furie KL, Kistler JP, Albers GW, Pettigrew LC, Adams HP, Jackson CM, Pullicino P. A comparison of warfarin and aspirin for the prevention of recurrent ischemic stroke. N Engl J Med. 2001;345: Windecker S, Wahl A, Nedeltchev K, Arnold M, Schwerzmann M, Seiler C, Mattle HP, Meier B. Comparison of medical treatment with percutaneous closure of patent foramen ovale in patients with cryptogenic stroke. J Am Coll Cardiol. 2004;44: Bruch L, Parsi A, Grad MO, Rux S, Burmeister T, Krebs H, Kleber FX. Transcatheter closure of interatrial communications for secondary prevention of paradoxical embolism: single-center experience. Circulation. 2002; 105: Warnes CA, Williams RG, Bashore TM, Child JS, Connolly HM, Dearani JA, del Nido P, Fasules JW, Graham TP Jr, Hijazi ZM, Hunt SA, King ME, Landzberg MJ, Miner PD, Radford MJ, Walsh EP, Webb GD. ACC/AHA 2008 guidelines for the management of adults with congenital heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing committee to develop guidelines on the management of adults with congenital heart disease). Circulation. 2008;118:e714 e833.