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Journal of the American College of Cardiology Vol. 51, No. 9, 2008© 2008 by the American College of Cardiology Foundation ISSN 0735-1097/08/$34.00P

The Safety and Efficacy of Thrombolysisfor Strokes After Cardiac CatheterizationPooja Khatri, MD,* Robert A. Taylor, MD,† Vanessa Palumbo, MD,‡ Venkatakrishna Rajajee, MD,§Jeffrey M. Katz, MD,� Julio A. Chalela, MD,¶ Ann Geers, RN,* Joseph Haymore, MS, ACNP,#Daniel M. Kolansky, MD,** Scott E. Kasner, MD,†† for the Treatment of Acute Stroke afterCardiac Catheterization (TASCC) Study Group

Cincinnati, Ohio; Minneapolis, Minnesota; Florence, Italy; Chennai, India; Bronx, New York; Charleston,South Carolina; Washington, DC; and Philadelphia, Pennsylvania

Objectives The purpose of this study was to systematically compare clinical outcomes of patients treated with thrombolysiswith those without treatment in a multi-year, multicenter cohort of strokes after cardiac catheterization.

Background Ischemic strokes after cardiac catheterization procedures, although uncommon, lead to the morbidity and mor-tality of thousands of patients each year. Despite the availability of Food and Drug Administration–approvedthrombolytic therapy for acute ischemic stroke since 1996, thrombolysis remains unestablished in the setting ofcardiac catheterization, owing to unique concerns regarding safety and efficacy.

Methods Consecutive cases of ischemic stroke after cardiac catheterization were abstracted retrospectively and reviewedby clinicians at 7 major North American academic centers with acute stroke teams. Safety and efficacy outcomemeasures were pre-defined.

Results A total of 66 cases of ischemic strokes after cardiac catheterization were identified over 3 to 4 years; 12 (18%) weretreated with thrombolysis, consisting of 7 intravenous and 5 intra-arterial recombinant tissue plasminogen activatorcases. Improvement in stroke symptoms, as measured by the primary efficacy measure of median change in Na-tional Institutes of Health Stroke Scale score from baseline to 24 h, was greater in treated versus nontreated cases (p� 0.001). Additional secondary measures of efficacy also showed better outcomes in the treated group. There wereno significant differences in bleeding events, defined as symptomatic intracerebral hemorrhage, hemopericardium, orother systemic bleeding resulting in hemodynamic instability or blood tranfusions. Mortality rates were also similar.

Conclusions Thrombolysis might improve early outcomes after post-catheterization strokes and seems safe in this context.Emergent cerebral revascularization should be a routine consideration. (J Am Coll Cardiol 2008;51:906–11)© 2008 by the American College of Cardiology Foundation

ublished by Elsevier Inc. doi:10.1016/j.jacc.2007.09.068

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ore than 2 million cardiac catheterization procedures areerformed in the U.S. annually. Although strokes afterardiac catheterization (SCCs) are relatively rare, this high

rom the *Department of Neurology, University of Cincinnati, Cincinnati, Ohio;Department of Neurology, Neurosurgery and Radiology, University of Minnesota,inneapolis, Minnesota; ‡Department of Neurological and Psychiatric Sciences,niversity of Florence, Florence, Italy; §Critical Care and Neurology, Sundaramedical Foundation, Chennai, India; �Departments of Neurology and Radiology,orth Shore University Hospital, Bronx, New York; ¶Departments of Neurology andeurosurgery, Medical University of South Carolina, Charleston, South Carolina;

Georgetown University School of Nursing & Health Studies, Washington, DC;*Division of Cardiovascular Medicine, Hospital of the University of Pennsylvania,hiladelphia, Pennsylvania; and the ††Department of Neurology, University ofennsylvania, Philadelphia, Pennsylvania. This work was supported by the Universityf Pennsylvania Research Foundation. Dr. Kasner is supported by National Institutesf Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)23 NS02147 and the Inverso-Baglivo Foundation, and Dr. Khatra is supported byIH/NINDS P50 NS44283.

tManuscript received May 29, 2007; revised manuscript August 14, 2007, accepted

eptember 23, 2007.

olume of cardiac catheterizations in the U.S. leads tohousands of SCCs each year. Rates of SCCs, includingoth ischemic and hemorrhagic subtypes, range widely from.07% to 7.0%. Large contemporary registries of exclusivelyiagnostic and invasive coronary procedures report ratesrom 0.07% to 0.38%, and smaller studies of other invasivetudies report higher rates (1).

See page 912

The majority of SCCs are likely ischemic infarcts, forhich there is Food and Drug Administration–approved

herapy. Intravenous thrombolytic therapy with recombi-ant tissue plasminogen activator (rt-PA) within 3 h of

schemic stroke symptom onset has been shown to befficacious and cost-effective in the general stroke popula-

ion (2,3). Unfortunately, this proven therapy is provided to

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907JACC Vol. 51, No. 9, 2008 Khatri et al.March 4, 2008:906–11 Strokes After Cardiac Catheterization

nly a small fraction of all ischemic strokes, primarily owingo delayed presentation to emergency departments (4). Inddition, intra-arterial thrombolytic drugs and devicesight be effective at later time windows (5,6). The SCCs

ypically occur in hospitalized patients under close observa-ion and therefore offer the potential for early and rapidetection and treatment. However, there is debate about theafety and efficacy of thrombolysis in the peri- and post-cardiacatheterization setting (7,8).

No study has yet attempted to systematically collect datan all SCCs and characterize their treatment in either aingle or multicenter cohort. Therefore, we designed aetrospective cohort study of consecutive SCCs managed atajor academic stroke centers with organized stroke teams,

nd we compared outcomes of patients treated with throm-olysis to those without treatment. We hypothesized that1) intravenous and intra-arterial thrombolytic therapy fortrokes in the cardiac catheterization setting would beelatively safe, with complication rates comparable to SCCsot receiving thrombolytic therapy, and (2) patients treatedith thrombolytic therapy would have better outcomes than

hose not treated with thrombolysis.

ethods

e invited 15 academic centers with stroke teams toontribute, and 7 centers (National Institutes of Healthtroke Center, New York Presbyterian Hospital-Weill,niversity of Calgary, University of California Los Angeles,niversity of Cincinnati, University of Iowa, University ofennsylvania) elected to participate. A designated principal

nvestigator at each participating center identified potentialatients by reviewing all medical records or their existingtroke databases with both a stroke diagnosis (Internationallassification of Diseases of the World Health Organization-th edition [ICD-9] codes: 997.02, 436, 433.0–433.3,33.8–434.1, and 434.9) and a cardiac procedure (ICD-9odes: 36.01–337.21–37.23, 37.26, 37.27, 37.34, 88.52–8.57) during the same admission. Cardiac proceduresncluded left heart catheterization, coronary angiography,oronary angioplasty or stenting, left ventriculography, val-uloplasty, patent foramen ovale/atrial septal defect (PFO/SD) closure, and electrophysiologic diagnostic and abla-

ive studies. Seven centers collected cases from September000 to September 2003, and 1 center collected data fromeptember 2000 to September 2004. At each center, allonsecutive ischemic strokes within 36 h of cardiac cathe-erization were included, regardless of the indication forardiac catheterization, post-stroke treatment decision, orutcome. A clinician collected the following de-identifiednformation on standardized case report forms: demo-raphic information, medical history, cardiac catheteriza-ion technical details, post-stroke course, stroke localizationnd etiology, complications, and clinical outcome. Nationalnstitutes of Health Stroke Scale (NIHSS) scores were

etermined with data in the medical records, which is i

onsidered a highly reliable ap-roach (9). This protocol re-eived institutional review boardpproval at each institution un-er expedited or exemptedechanisms. Data were entered

nto spreadsheets with double-ntry.

The pre-defined primary effi-acy outcome measure was thehange in NIHSS score fromaseline to 24 h in the rt-PAroup, compared with non–t-PA group. Categorical analy-es were also performed, comparing the proportions ofatients with complete resolution (NIHSS � 0) or �5-oint improvement from baseline to 24 h in both groups.

e also planned secondary analyses excluding the mildesttroke cases (NIHSS �5), in anticipation of these patientseing excluded from thrombolytics (10). Additional pre-pecified secondary outcome measures were 7- and 30-dayIHSS scores, discharge modified Rankin Scores (mRS),

nd death during hospital stay.The pre-defined primary safety measures were the rate of

ignificant bleeding events and the rate of mortality duringhe hospital stay, comparing the rt-PA to the non–rt-PAroup. Data on all bleeding events were collected, includinguncture site hemorrhage, retroperitoneal hemorrhage, he-opericardium, and symptomatic and asymptomatic intra-

erebral hemorrhage (ICH) within 48 h of stroke. Signifi-ant bleeding events were defined as those requiring bloodransfusion or causing hemodynamic instability and thosepecifically consisting of hemopericardium or symptomaticCH. The ICHs were defined as “symptomatic” if the patientad any symptoms attributed to a new ICH by the localrincipal investigator. All transfusions given during the hospi-al stay were recorded on case report forms to ensure thatleeding events were not missed due to lack of documentation.tatistical analysis. Patient characteristics were comparedith unpaired t tests (age) and Wilcoxon rank sum test forariables that were not normally distributed (NIHSS andime factors). Chi-square or Fisher exact tests were used forategorical variables, depending on individual cell sizes.

Power calculations were difficult a priori. Assuming alpha �.05, power � 80%, and planned convenience sample ofpproximately 100 patients, we estimated an ability to detect5-point difference in NIHSS (primary efficacy outcome)

etween rt-PA cases and control subjects if only 9 casesere treated with rt-PA. A smaller total would be needed ifore patients received thrombolytics.

esults

total of 66 SCCs were identified; 12 (18%) were treatedith thrombolysis: 7 with intravenous rt-PA, and 5 with

Abbreviationsand Acronyms

CT � computedtomography

ICH � intracerebralhemorrhage

NIHSS � NationalInstitutes of Health StrokeScale

rt-PA � recombinant tissueplasminogen activator

SCC � stroke after cardiaccatheterization

ntra-arterial rt-PA. Age, medical

comorbidities, and car-

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908 Khatri et al. JACC Vol. 51, No. 9, 2008Strokes After Cardiac Catheterization March 4, 2008:906–11

iac procedure characteristics were similar between treat-ent and nontreatment groups (Table 1).Comparing the treatment and nontreatment groups,

ates of heparin use (92% vs. 69%; p � 0.31) andlycoprotein (GP) IIb/IIIa inhibitor use (25% vs. 20%; p

0.49) were similar. One case in the no rt-PA groupeceived bivalirudin during the cardiac catheterizationrocedure. In 55 patients whose activated partial throm-oplastin times (aPTTs) were recorded before the diag-osis or treatment of SCC, 19 (35%) had a prolongedPTT (�40 s), including 2 of 7 (29%) treated IV, 1 of 5

aseline Characteristics

Table 1 Baseline Characteristics

Thrombolysis(n � 12)

No Thrombolysis(n � 54) p Value

Patient characteristics

Age (yrs) 72 � 8 67 � 13 0.19

Female 6 (50%) 23 (43%) 0.50

White 8 (72%) 38 (75%) 1.00

Diabetes 3 (25%) 18 (33%) 0.74

Hypertension 9 (75%) 38 (70%) 1.00

Hyperlipidemia 8 (67%) 26 (49%) 0.35

CAD 8 (67%) 33 (61%) 1.00

CHF 1 (8%) 8 (15%) 1.00

AF 2 (17%) 14 (26%) 0.72

History of PVD 4 (33%) 8 (15%) 0.21

History of stroke 2 (17%) 5 (9%) 0.60

History of TIA 2 (17%) 5 (9%) 0.60

Procedural characteristics

Angiogram 10 (83%) 48 (86%) 1.00

Angioplasty 3 (25%) 20 (36%) 0.74

Valvuloplasty 0 (0%) 1 (2%) 1.00

EP study or ablation 2 (17%) 5 (9%) 0.60

PFO/ASD closure 0 (0%) 1 (2%) 1.00

Fluoroscopy time(median) (min)

16 24 0.20

Procedure time(median) (min)

65 75 0.73

F � atrial fibrillation; CAD � coronary artery disease; CHF � congestive heart failure; EP �

lectrophysiology; PFO/ASD � patent foramen ovale/atrial septal defect; PVD � peripheralascular disease; TIA � transient ischemic attack.

Clinical Outcomes After Thrombolysis Versus No

Table 2 Clinical Outcomes After Thrombolys

Thromb

Total cohort n �

Baseline NIHSS, median (range) 10.5

24-h NIHSS, median 4.5

Change baseline–24-h*† �6 (�

7-day NIHSS, median 3

Change baseline–7-day* �6.5 (�

Excluding baseline NIHSS �5 n �

Baseline NIHSS, median (range) 10.5

24-h NIHSS, median 4.5

Change baseline–24-h*† �6 (�

7-day NIHSS, median 3

Change baseline–7-day* �6.5 (�

*Negative numbers represent improvement; positive numbers represent worNIHSS � National Institutes of Health Stroke Scale score.

20%) treated IA, and 16 of 43 (37%) not treated withhrombolytics (p � 0.89). In 58 patients whose interna-ional normalized ratios (INRs) were recorded beforeiagnosis or treatment of SCC, 3 (5%) had an abnormalNR (�1.7), including none treated with rt-PA and 3 of6 (7%) not treated with thrombolytics (p � 1.00).ctivated clotting time data were not recorded.As expected, patients who were treated with thrombolysis

ad more severe strokes (p � 0.01). Median baselineIHSS scores were 10.5 in the rt-PA group and 6 in the

on–rt-PA group.The median time from symptom onset to treatment was

42 (range 54 to 305) min in the treated group, including 90range 75 to 168) min in the intravenous group and 240range 54 to 305) min in the intra-arterial group. Threet-PA cases received additional stroke therapies, consistingf intra-arterial clot retrieval with a microsnare device,ntra-arterial abciximab, and a possible neuroprotectivegent (in the context of a trial).

Efficacy results are summarized in Table 2. The medianhange in NIHSS score from baseline to 24 h, the primaryutcome measure of the study, was 6 in the rt-PA group andin the non–rt-PA group (p � 0.001). Either complete

esolution (NIHSS � 0) or �5-point improvement inIHSS score over the first 24 h was seen in 58% of treated

atients and 15% of untreated patients (risk ratio [RR] �.9, 95% confidence interval [CI] 1.8 to 8.8; p � 0.003).he median change in NIHSS from baseline to 7 days was.5 in the rt-PA group and 1.5 in the untreated group (p �.004).In secondary analyses excluding the mildest strokes (base-

ine NIHSS �5), a relative contraindication to rt-PA and aey determinant of clinical outcome (11), the initial differ-nce in baseline NIHSS scores was no longer significantp � 0.46) and the change in NIHSS score from baseline to4 h was still significantly greater with thrombolysis (me-ian 6 vs. 1; p � 0.008). In this subset, there was eitheromplete resolution (NIHSS � 0) or �5-point improve-ent over the first 24 h in 58% of treated patients and 21%

mbolysis

rsus No Thrombolysis

No Thrombolysis p Value

n � 54

6 (1–34) 0.01

3 (0–33) 0.69

0 (�6–7) �0.001

3 (0–33) 0.55

�1.5 (�23–7) 0.004

n � 33

8 (5–34) 0.46

6 (1–33) 0.17

�1 (�6–7) 0.008

4 (0–33) 0.41

�3 (�23–7) 0.07

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909JACC Vol. 51, No. 9, 2008 Khatri et al.March 4, 2008:906–11 Strokes After Cardiac Catheterization

f untreated patients (RR � 2.8, 95% CI 1.2 to 6.2; p �.017). The change in NIHSS score from baseline to 7 daysas marginally better with treatment (median 6.5 vs. 3; p �.07).Rates of discharge mRS 0 to 1 (30% rt-PA vs. 28%

on–rt-PA; p � 0.72) were not significantly differentetween the 2 groups. Analysis of change in NIHSS over 30ays was not performed, owing to few 30-day data points.The primary safety end points did not differ between

roups. Specifically, mortality rates were 8% in the rt-PAnd 7% in the non–rt-PA groups (p � 0.91), including 1eurologic death due to cerebral herniation in each group8% vs. 2%; p � 0.33). There were no symptomatic ICHs.here were 6 asymptomatic hemorrhages, including 3 in the

t-PA group (Table 3) and 3 in the untreated group (25% vs.%; p � 0.037). Minor puncture site bleeding rates were notignificantly different (8% rt-PA vs. 7% untreated; p �.92). There were no retroperitoneal hemorrhages, hemoperi-ardium, other sites of bleeding, or transfusions. Three patientsn the rt-PA group had an elevated aPTT after the cardiacrocedure, but none had a hemorrhagic complication.

iscussion

hrombolysis has been established as an effective treatmentor acute ischemic stroke, but its benefit and risk forschemic strokes specifically in the cardiac catheterizationetting have not previously been investigated (7). Bleeding

Cases With ICH After Thrombolysis for SCC

Table 3 Cases With ICH After Thrombolysis

Age 9 Years NIHSS at Baseline

#1 (rt-PA) 76 29

#2 (rt-PA) 72 24

#3 (rt-PA) 72 15

CT � computed tomography; ICH � intracerebral hemorrhage; NIHSS � Naplasminogen activator; SAH � subarachnoid hemorrhage; SCC � stroke afte

isks of thrombolysis might be increased after cardiacatheterization, owing to the recent invasive procedure andhe concurrent administration of antithrombotic medica-ions. Moreover, thrombi leading to SCCs arguably mighte less likely than other strokes to respond to thrombolysisn the basis of presumptions about their likely composition.or example, dislodged aortic arch plaque might be calcifiednd fibrin-dense and therefore not amenable to lysis. Alter-atively, calcific thrombi might partially lyse, leading toownstream emboli (12). In addition, air emboli and me-allic emboli might not respond to thrombolysis at all1,7,13,14).

In contrast, fresh thrombus on the tip of a guidewireight be easier to destabilize than other clot etiologies.imited evidence suggests that the broad category of car-ioembolic etiologies might be particularly amenable tohrombolysis (15). In addition, regardless of etiology, su-erimposed fresh fibrin deposition on atheroma or otheromponents might make these emboli at least partiallyesponsive to thrombolysis. Autopsy studies of coronaryrtery bypass graft patients with strokes suggest that largerlots causing territorial infarcts tend to be particularly rich inlatelets and fibrin. However, specific data on the thrombusomposition of ischemic SCCs are lacking. Thrombolysisas been shown to be equally effective across the majortroke subtypes (small-vessel, large-vessel, and cardioem-olic) (2), and therefore the pathogenesis of SCCs might berrelevant with respect to this treatment decision.

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910 Khatri et al. JACC Vol. 51, No. 9, 2008Strokes After Cardiac Catheterization March 4, 2008:906–11

Case reports and small series consisted of 39 SCCseported in the published data as of April 2007, including 1atient treated with intravenous thrombolysis alone, 2atients receiving combined intravenous/intra-arterial rt-A, and the rest treated via the intra-arterial approach

1,8,16–19). Independent function or full recovery waschieved in 23 (61%) of the 38 cases commenting onunctional outcome. These reports must be interpreted withreat caution, owing to likely publication bias towardositive clinical outcomes. We report the first systematicallyollected data on every consecutive SCC and its treatmentn either a single or multicenter cohort, thereby possibly

inimizing these biases.In our cohort, 18% were treated with thrombolytics, a far

reater proportion than in the general stroke population20). Moreover, patients were treated at a median door-to-eedle time of 90 min with intravenous rt-PA and 240 minith intra-arterial therapy, suggesting comparable or better

peed than major thrombolysis trials (5,21). Our primarynalysis showed a statistically and clinically significant earlymprovement in stroke severity in NIHSS score by 24 h.hange in NIHSS score at 24 h was 1 of the most powerfuliscriminators of the rt-PA effect in the NINDS (Nationalnstitute of Neurological Disorders and Stroke) trial (22,23)nd is likely to be a good surrogate marker for betterong-term clinical outcome (24). Similar improvementsere observed from baseline to 7 days.There were no symptomatic ICHs in our treated cases, as

ompared with 6.4% in the only randomized trial ofntravenous rt-PA (NINDS Part 1 and 2) (2) and 10% inhe only randomized trial of intra-arterial thrombolysisPROACT II) (5). A series of intra-arterial rt-PA SCCases at a single center (n � 22) reported 3 (14%) symp-omatic ICHs (19), comparable to the PROACT II rate.ur cohort had a 25% asymptomatic hemorrhage rate, also

imilar to the rates (26% to 42%) seen in major intra-arterialrials (25).

There were also no significant systemic bleeding eventsnd no increase in even minor puncture site bleeding rates,n the rt-PA group. This is consistent with the substantialublished experience with intra-arterial stroke therapiesequiring groin site arterial puncture (5,26) and case seriestudies of post-surgical thrombolysis (27,28). Our sample ofatients treated with thrombolysis is too small to estimateleeding risks with precision but, in combination with prioreports, suggests that this risk is low. We also cannotddress specific subgroups known to have higher symptom-tic ICH risk, such as elderly patients, although 2 largebservational studies of ischemic stroke patients suggest thatlderly patients benefit from thrombolysis despite increasedCH risk (1).

Antithrombotic medications administered during theardiac catheterization procedure might influence the deci-ion to treat with thrombolytics. Heparin, if associated with prolonged aPTT, is a contraindication for intravenous

t-PA in the standard protocol (2). However, heparin is

outinely administered in intra-arterial thrombolysis cases5,26). Therefore, intra-arterial rt-PA or mechanical revas-ularization might be a consideration in this situation,epending on the dose and timing of heparin received.urthermore, the risks of rt-PA for stroke in the presence ofther antithrombotic agents commonly used in cardiacnterventional procedures, such as GP IIb/IIIa inhibitors, isot known. The low intracranial and systemic hemorrhageates in our cohort suggest that periprocedural use of thesentithrombotic agents does not absolutely militate againsthrombolysis. Ongoing stroke trials using rt-PA combinedith GP IIb/IIIa inhibitors might further define these risks.Our findings suggest that thrombolysis might improve

arly outcome of SCC and seems relatively safe in thisontext. This study has the limitations inherent in itsetrospective design and modest sample size. For example,e could not control for all potential baseline differencesetween treated and untreated groups in this observationalohort. However, this systematically collected, multicenterohort of consecutive SCC patients provides compellingata to suggest that post-catheterization stroke patientsight be opportune candidates for acute intervention, and

mergent cerebral revascularization should be a routineonsideration. Future large, prospective registries to furtherharacterize this population are recommended.

cknowledgmentshe authors thank: at the University of Cincinnati, Edward. Jauch, MD (administrative, technical, or material sup-ort), Kathleen Alwell, RN (administrative, technical, oraterial support), and Julie Brock (administrative, techni-

al, or material support); at the University of Calgary,ndrew Demchuk and Michael D. Hill (administrative,

echnical, or material support); and at New York Presbyte-ian Hospital-Weill Cornell Medical Center, Alan Segaladministrative, technical, or material support) and Kevinarey (administrative, technical, or material support).

eprint requests and correspondence: Dr. Pooja Khatri, Univer-ity of Cincinnati Academic Health Center, Department ofeurology, 260 Stetson Street, Suite 2300, P.O. Box 670525,incinnati, Ohio 45267-0525. E-mail: pooja.khatri@uc.edu.

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