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Yield of Transesophageal Echocardiography for Nonbacterial ThromboticEndocarditis and Other Cardiac Sources of Embolism in Cancer

Patients With Cerebral Ischemia

Tanya Dutta, MDa, Maria G. Karas, BAa, Alan Z. Segal, MDb,and Jorge R. Kizer, MD, MSca,c,*

Cerebrovascular events occur frequently in patients who succumb to cancer, andnonbacterial thrombotic endocarditis (NBTE) is a frequent postmortem finding inthese patients. Despite the excellent diagnostic accuracy of transesophageal echocar-diography (TEE) for cardiac sources of cerebral embolism, however, the prevalence ofNBTE and other cardioembolic sources in patients with cancer and cerebral ischemiahas not been investigated using this modality. This study examined the frequency ofcardioembolic findings in consecutive patients with cancer referred to our institutionfor TEE evaluation of cerebrovascular events. The study cohort comprised 51 pa-tients, of whom 18% had marantic vegetations, and 47% and 55% of whom haddefinite and definite or probable cardiac sources of embolism, respectively. Thepresent study documents, for the first time, a high frequency of marantic endocarditisand other cardioembolic sources in patients with cancer and cerebrovascular eventsselected for TEE. This finding has important implications for evaluation and man-agement in this patient population. © 2006 Elsevier Inc. All rights reserved. (Am J

Cardiol 2006;97:894–898)

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erebrovascular complications commonly occur in patientsying of cancer.1,2 The prevalence of cerebrovascular dis-ase in such patients is approximately 15%, a figure that isvenly divided between cerebral infarction and hemorrhagictroke.1 Malignancy is well recognized to lead to a hyper-oagulable state, which predisposes to venous thromboem-olism.3 The hypercoagulability of malignancy also leads tohe formation of aseptic vegetations on the cardiac valvesnonbacterial thrombotic endocarditis [NBTE]), likely inesponse to focal injury to the valvular endothelium.4 Theislodgement of these vegetations is believed to account, ateast in part, for the occurrence of arterial embolism asso-iated with neoplasia.4 Such vegetations have been found toe common in patients with cancer and stroke, with arevalence as high as 32% in postmortem series.1 However,espite NBTE’s potential role as a major source of cerebralmbolism in patients with cancer and the high resolution ofransesophageal echocardiography (TEE) for the detectionf valvular vegetations,5 the antemortem prevalence of suchegetations by TEE has not been defined in this population,or has the relative importance of paradoxic embolism inatients with cancer at high risk for venous thromboembo-ism been systematically assessed. We performed a retro-

Departments of aMedicine, bNeurology, and cPublic Health, Weilledical College of Cornell University, New York, New York. Manuscript

eceived June 28, 2005; revised manuscript received and accepted Sep-ember 22, 2005.

Dr. Kizer was supported in part by Grant HL 070854 from the Nationaleart, Lung, and Blood Institute, Bethesda, Maryland.

* Corresponding author: Tel: 212-746-2437; fax: 212-746-8561.

tE-mail address: jok2007@med.cornell.edu (J.R. Kizer).

002-9149/06/$ – see front matter © 2006 Elsevier Inc. All rights reserved.oi:10.1016/j.amjcard.2005.09.140

pective review of patients with cancer and cerebral isch-mia referred for TEE to characterize the prevalence ofBTE and other cardiac sources of embolism (CSE) in thisopulation.

• • •e queried our echocardiography laboratory’s electronic

atabase to identify patients with strokes or transient isch-mic attacks referred for TEE from January 1998 to August004 to evaluate for CSE. The medical records of the 422atients so identified were then reviewed to select thoseith evidence of active cancer within the previous 5 years,

s well as to abstract clinical, imaging, and laboratory in-ormation relating to their index cerebrovascular event.ancer comprised any malignant tumor, irrespective of site,istology, or stage, except for nonmelanoma skin cancer.atients with complex congenital heart disease, rheumaticeart disease, valvular prostheses, and suspected or provednfective endocarditis were excluded. Because aseptic andnfective vegetations cannot be reliably distinguished byorphologic echocardiographic criteria,6 clinical features

i.e., fever, bacteremia, fungemia) were used to excludenfective endocarditis.

To explore the role of bias in referral for TEE of patientsith cancer and cerebrovascular events, the records of allatients referred for transthoracic echocardiography (TTE)ith “source of embolism” indications during the last 2ears of the study period (January 2003 to August 2004)ere reviewed to select those with cerebrovascular events

nd cancer. We then compared clinical characteristics be-

ween patients who did and did not go on to have TEE.

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895Valvular Heart Disease/TEE in Cancer and Cerebral Ischemia

Hypertension was defined by history, antihypertensivereatment, or blood pressure �160/100 mm Hg during hos-italization for the index cerebrovascular event. Diabetesellitus was defined by history, oral hypoglycemic therapy

r insulin, or the detection of a fasting blood glucose �126g/dl or a random blood glucose �200 mg/dl. Hypercho-

esterolemia was defined by history, the use of cholesterol-owering medications, or fasting plasma cholesterol �240g/dl during the index hospitalization.Echocardiographic data were abstracted from electronic

eports. Patient cardioembolic findings were classified asefinite or probable CSE. Definite CSE included left atrialhrombus, valvular vegetations, proximal complex aortictheroma, and interatrial shunt (patent foramen ovale [PFO]r atrial septal defect) in the presence of venous thrombo-mbolism (lower-extremity deep vein thrombosis or pulmo-ary embolism). Probable CSE included large PFO, PFOith associated atrial septal aneurysm, and atrial septalefect of any size. Because of the focus on TEE-detectedndings, other high-risk emboligenic conditions detectablelinically (i.e., atrial fibrillation), or comparably well byTE as by TEE (i.e., severe left ventricular dysfunction orkinetic or dyskinetic segment), were not included in prob-ble CSE.

Atrial septal aneurysm was defined as displacement ofhe interatrial septum �11 mm beyond the midline.7 Prox-mal complex aortic atheroma consisted of aortic plaquerotruding �4 mm into the aortic lumen or with mobile or

able 1emographic and clinical characteristics

ariable Entire(n �

ge (yrs) 70 (3omen 19 (3ypertension 26 (5iabetes mellitus 5 (1ypercholesterolemia 14 (2urrent smoking 14 (2

llicit drug userevious myocardial infarction 3 (6revious congestive heart failure 3 (6revious stroke 4 (8revious transient ischemic attack 7 (1trial fibrillation 5 (1eripheral vascular disease 2 (4revious deep vein thrombosis or pulmonary embolism 2 (4hronic lung disease 6 (1ematologic malignancy 10 (2olid organ malignancy 41 (8Metastatic disease 9 (2oor ECOG performance status (�3) 18 (3hrombocytopenia (platelets �150,000) 9 (2reatinine �2.0 mg/dl 5 (1ntiphospholipid antibodies 1 (1rotein C, S, or antithrombin III deficiencyyperhomocysteinemia (�15 mg/dl) 2 (1

ECOG � Eastern Cooperative Oncology Group.

lcerated components,8 upstream of the left subclavian l

rtery ostium. PFO was semi-quantitated on the basis of theumber of bubbles appearing in the left atrium as small�10), medium (10 to 49), or large (�50)9 or by 2-dimen-ional separation as small (�2 mm), medium (2 to 3.9 mm),r large (�4 mm).10

Comparisons of categorical variables used the chi-squarer Fisher’s exact test, whereas those of continuous variablessed Wilcoxon’s rank-sum test (SPSS version 12, SPSS,nc., Chicago, Illinois).

Fifty-one patients with cerebral ischemia met the study’sefinition of active cancer and were eligible for inclusion.he demographic and clinical characteristics of the studyohort are listed in Table 1. Of note, 4/5 of patients hadolid organ neoplasms, 1/4 of which were metastatic. Poorerformance status (Eastern Cooperative Oncology Groupcore �3)11 was present in approximately 1/3 of patients.

NBTE was detected in 18% of the cohort. Patients withBTE tended to be younger, were more frequently smokers,

nd showed a nearly significant greater frequency of hema-ologic malignancies than their counterparts without NBTE.s listed in Table 2, patients with aseptic vegetations also

ended to have more disabling or anterior circulation strokesnd more commonly exhibited infarcts in multiple vascularerritories.

There was a high prevalence of CSE, with nearly half ofhe cohort having definite and more than half having definiter probable cardioembolic sources (Table 3). These findingsid not differ when patients with atrial fibrillation, severe

t No Vegetations(n � 42)

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p Value

71 (36–87) 56 (48–77) 0.15114 (33%) 5 (56%) 0.26620 (51%) 6 (67%) 0.4784 (10%) 1 (11%) 0.664

10 (24%) 4 (50%) 0.2028 (21%) 6 (67%) 0.012

0 0 —3 (8%) 0 0.5363 (8%) 0 0.5363 (8%) 1 (11%) 0.5776 (15%) 1 (11%) 0.6195 (13%) 0 0.3451 (3%) 1 (11%) 0.3372 (5%) 0 0.6635 (12%) 1 (11%) 0.7076 (14%) 4 (44%) 0.061

36 (865) 5 (56%) 0.0617 (19%) 2 (22%) 0.288

13 (33%) 5 (56%) 0.1806 (19%) 3 (33%) 0.3044 (12%) 1 (11%) 0.7231 (17%) 0 0.667

0 0 —1 (10%) 1 (33%) 0.423

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896 The American Journal of Cardiology (www.AJConline.org)

xcluded. Patients without NBTE tended to have a greaterrevalence of other cardioembolic sources than those withBTE.Of the entire cohort, 78% had undergone previous TTE.

atients with previous TTE tended to have a greater prev-lence of definite CSE compared with those without previ-us TTE (53% vs 33%, p � 0.181). Of the 9 patients withBTE, 7 had undergone previous TTE studies, of which 3etected valvular vegetations.

In the separate search for patients with cerebral ischemiand cancer who were referred for TTE in 2003 and 2004, 96uch patients were identified, 85 of whom did not have TEE.atients referred for TTE but not TEE were similar in agend gender to those who did go on to have TEE (data nothown). Patients who underwent TTE only tend to haveore metastatic disease (33% vs 20%, p � 0.494), poor

erformance status (41% vs 27%, p � 0.304), lacunar in-arcts (21% vs 9%, p � 0.306), and disabling strokes (58%s 27%, p � 0.056), but less ventricular dysfunction (7% vs7%, p � 0.068), compared with patients who had TTEnd TEE.

• • •n this series of patients with cancer and cerebral ischemiaeferred for TEE, this imaging modality demonstrated aigh yield of definite and probable sources of cardiogenicrain embolism. This included a marked prevalence of

able 2haracteristics of index cerebrovascular events

ariable

linical presentationAbrupt onsetLoss of consciousness or new-onset seizurePreceded by the Valsalva maneuverHeadacheAmaurosis fugaxProcedure relatedDisabling (modified Rankin �2)edications on presentation

Antiplatelet agentAnticoagulationOral contraceptiveTreatment with tissue-type plasminogen activatorrain imagingAnterior circulation strokePosterior circulation strokeCortical infarctInfarcts in multiple vascular territoriesHemorrhagic transformationLacunar infarctascular imagingCarotid stenosis (�50%)Vertebrobasilar stenosis (�50%)Middle cerebral artery stenosis (�50%)Anterior cerebral or posterior cerebral artery stenosis (�50%)Deep vein thrombosis on lower extremity Duplex study

BTE, present in �1/6 of patients, in whom previous TTE h

ad failed to detect vegetations at least as often (4 of 7imes) as it succeeded in demonstrating them. The preva-ence of interatrial shunts (PFO or atrial septal defect) wasnly marginally greater compared with population-basedgures (29% vs 26%12). There was, however, a pronounced

ncrease in PFO occurring in conjunction with atrial septalneurysm (10% vs �4.6%12), a combination that has beenocumented to quadruple recurrent stroke risk in patientsithout cancer.7

This is the largest series of its kind reported to date. Anutopsy study of patients with malignancy and cerebralnfarctions performed some 2 decades ago highlighted thearge prevalence (30%) of NBTE,1 suggesting an importantathogenetic role for these friable vegetations in cerebralmbolism in this population. That these aseptic vegetationsre common in unselected patients with cancer has beenocumented by a study using TTE.13 However, despite theotential importance of NBTE and other CSE in the contextf the hypercoagulability of malignancy, and notwithstand-ng the superior diagnostic capability of TEE for suchources,5,14 no study has previously addressed the yield ofhe latter modality in patients with cancer and cerebralschemia. This has been an especially important gap in thisrea considering that most cerebral infarctions in these pa-ients are of embolic origin.2

Our observation of a sizable prevalence of NBTE and

Cohort51)

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8%) 28 (78%) 7 (78%) 0.6550 0 —

%) 1 (3%) 1 (2%) 0.8059%) 6 (18%) 2 (22%) 0.557%) 1 (2%) 0 0.800%) 3 (8%) 1 (11%) 0.5693%) 11 (36%) 6 (67%) 0.100

0%) 7 (19%) 2 (22%) 0.572%) 4 (11%) 0 0.574

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897Valvular Heart Disease/TEE in Cancer and Cerebral Ischemia

ected patients included in this retrospective series, assumesreat clinical significance in light of the different treatmentpproaches currently advocated on the basis of specificardioembolic findings. Recent guidelines recommend un-ractionated or low-molecular-weight heparin for NBTE15

r for deep vein thrombosis16 in the setting of malignancy,hereas warfarin is currently the treatment of choice for

ntracardiac thrombus occurring with or without atrialbrillation.17 In contrast, antiplatelet therapy is currentlyavored for the treatment of complex aortic atheroma or inhe setting of stroke without a defined cardioembolicause.17

Accordingly, the findings of this study support an im-ortant role for TEE in the evaluation of appropriatelyelected patients with cancer and cerebral ischemia. Suchatients would principally include those without end-stagealignancies, with good or better performance status, andith cerebrovascular events not resulting in severe incapac-

tation, provided that esophageal pathology and bleedingiathesis are excluded or reversed. Furthermore, our find-ngs bolster the need for prospective studies that evaluatehe comparative utility of TTE and TEE in patients with

able 3ransesophageal echocardiography and lower-extremity duplex sonograph

ariable Entire C(n � 5

itral valve prolapse 11 (22itral annular calcification 11 (22ortic valve calcification 18 (36roximal complex aortic atheroma 12 (24eft atrial enlargement 9 (18eft atrial thrombus 3 (6%ubble study performed 47 (92trial septal defect 1 (2%FO 14 (28Small 8 (16Medium 3 (6%Large 3 (6%trial septal aneurysm 7 (14FO � atrial septal aneurysm 5 (10FO � deep vein thrombosis 1 (2%eft ventricular hypertrophy 3 (6%eft ventricular systolic dysfunction 8 (16Mild/moderate 6 (11Severe 2 (4%eft ventricular segmental wall motion abnormality 6 (12Akinetic segment 2 (4%eft ventricular thrombus 0itral regurgitation, moderate or greater 12 (24ortic regurgitation, moderate or greater 7 (14ortic stenosis, mild or greater 3 (6%ny definite* CSE 24 (47Excluding vegetations 16 (31ny probable† or definite* CSE 28 (55Excluding vegetations 20 (39robable† CSE only 8 (16

* Proximal complex aortic atheroma, left atrial thrombus, interatrial shu† Large PFO, PFO with coexisting atrial septal aneurysm, atrial septal d

ancer and stroke to refine the diagnostic approach in this

etting. Whether echocardiographic screening, with TEEersus TTE, could be of value in primary prevention oferebrovascular complications in especially susceptible pa-ients with cancer requires separate investigation.

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gs

No Vegetations(n � 42)

Vegetations(n � 9)

p Value

11 (26%) 0 0.09010 (24%) 1 (11%) 0.36816 (39%) 2 (22%) 0.45911 (26%) 1 (11%) 0.6668 (19%) 1 (11%) 0.4963 (7%) 0 1.00

40 (95%) 7 (78%) 0.1391 (2%) 0 1.00

13 (31%) 1 (11%) 0.4147 (17%) 1 (11%)3 (7%) 03 (7%) 06 (14%) 1 (11%) 1.004 (10%) 1 (11%) 1.001 (2%) 0 1.003 (7%) 0 0.5798 (19%) 0 0.3226 (14%) 02 (5%) 06 (14%) 0 0.5752 (5%) 0

0 0 —10 (24%) 2 (22%) 0.6466 (14%) 1 (11%) 0.6413 (7%) 0 0.579

15 (36%) 9 (100%) —15 (36%) 1 (11%) 0.24219 (45%) 9 (100%) —19 (45%) 1 (11%) 0.0727 (17%) 1 (3%) 1.00

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898 The American Journal of Cardiology (www.AJConline.org)

8. Kizer JR, Silvestry FE, Kimmel SE, Kasner SE, Wiegers SE, Erwin MB,Schwalm SA, Viswanathan MN, Pollard JR, Keane MG, et al. Racialdifferences in the prevalence of cardiac sources of embolism in subjectswith unexplained stroke or transient ischemic attack evaluated by trans-esophageal echocardiography. Am J Cardiol 2002;90:395–400.

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