Role of Tissue Plasminogen Activator in Acute Ischemic Stroke

364 n The Annals of Pharmacotherapy n 2011 March, Volume 45 theannals.com

ARTICLES

Stroke is the third leading cause ofdeath in the US behind cardiovascu-

lar disease and cancer. Approximately2.7% of men and 2.5% of women olderthan 18 years have had a stroke and thereare nearly 800,000 stroke occurrenceseach year with a mortality rate approach-ing 150,000.1

Ischemic stroke commonly presentsas an acute onset of focal neurologicdeficit lasting greater than 24 hours.2 Mostpatients present with weakness on one sideof the body, visual impairment, and inabil-ity to speak. Diagnosis is confirmed withcomputed tomography (CT) scanning andmagnetic resonance imaging. Patients athighest risk of developing an ischemicstroke are those with hypertension, dia-betes, dyslipidemia, atrial fibrillation,cigarette smoking, and obesity.2,3

The immediate goal of therapy in acutestroke is to reduce neurologic injury andlong-term disability. Once the patient isthrough the hyperacute period, the goal oftherapy is to prevent recurrence and ulti-mately decrease mortality.2,3

The treatment for acute ischemicstroke has a narrow therapeutic window,making timely evaluation and diagnosis

Role of Tissue Plasminogen Activator in Acute Ischemic Stroke

Molly A Hatcher and Jessica A Starr

Cardiology

Author information provided at end of text.

OBJECTIVE: To evaluate the literature regarding the use of intravenous tissueplasminogen activator (tPA) in the treatment of acute ischemic stroke, focusingon the appropriate usage criteria and administration time window.

DATA SOURCES: A PubMed and MEDLINE search was performed (1990-November 2010) using the key words alteplase, tissue plasminogen activator,thrombolytic, ischemic stroke, and cerebrovascular accident.

STUDY SELECTION AND DATA EXTRACTION: Clinical trials published in English wereevaluated and relevant primary literature evaluating the use of tPA in acuteischemic stroke was included.

DATA SYNTHESIS: The NINDS (National Institute of Neurological Disorders andStroke) trial revealed clinical efficacy of tPA in the treatment of acute ischemic strokewhen administered within 3 hours of stroke symptom onset and served as thefoundation for the American Heart Association/American Stroke Association(AHA/ASA) acute ischemic stroke guideline recommendations. The ECASS(European Cooperative Acute Stroke Study) I, ECASS II, and ATLANTIS (AlteplaseThrombolysis for Acute Noninterventional Therapy in Ischemic Stroke), part A andB, trials each assessed the efficacy of tPA when administered beyond 3 hours ofischemic stroke onset, but the results of each trial did not support its use beyond 3hours. The ECASS III trial showed clinical efficacy of tPA when administered up to4.5 hours. The SITS-MOST (Safe Implementation of Thrombolysis in Stroke-Monitoring Study) and SITS-ISTR (Safe Implementation of Thrombolysis in StrokeInternational Stroke Thrombolysis Register) registries evaluated the safety andefficacy of tPA at both 3 and 4.5 hours and showed promising results. In 2009, theAHA/ASA stroke guidelines were updated to support the use of tPA in selectpatients up to 4.5 hours after symptom onset.

CONCLUSIONS: tPA is effective when administered up to 4.5 hours after ischemicstroke symptom onset in select patients. However, timely administration remainsparamount to achievement of optimal therapeutic outcomes.

KEY WORDS: alteplase, cerebrovascular accident, ischemic stroke, thrombolytic,tissue plasminogen activator.

Ann Pharmacother 2011;45:364-71.

Published Online, 8 Mar 2011, theannals.com, DOI 10.1345/aph.1P525

at TEXAS SOUTHERN UNIVERSITY on December 10, 2014aop.sagepub.comDownloaded from

http://aop.sagepub.com/

essential. Currently, only 2 pharmacologic agents have re-ceived a Class I, Level of Evidence A recommendationfrom the American Heart Association/American StrokeAssociation (AHA/ASA) for use in treatment of acute is-chemic stroke. These agents are intravenous tissue plas-minogen activator (tPA) and aspirin.4,5 tPA is the only fibri-nolytic agent used in the treatment of acute ischemicstroke. It is recommended due to its ability to achieve earlyreperfusion and improve neurologic outcomes; however,its use is limited by its narrow therapeutic index and strictcriteria for use.4 tPA induces its therapeutic effects by initi-ating fibrinolysis through conversion of the inactive en-zyme, plasminogen, into its active form, plasmin.6 Plasminworks by digesting the fibrin molecules that serve as thestructural framework of blood clots, thereby dissolving theoccluding thrombus responsible for an ischemic stroke.While tPA has been shown to be effective in the treatmentof ischemic stroke, it also has the potential to cause life-threatening bleeding.4-6 The risk of such adverse effects hasled to extensive research concerning the appropriate crite-ria for use of tPA in acute ischemic stroke. Currently, theAHA/ASA consensus recommendations regarding the useof tPA in acute ischemic stroke indicate that eligible pa-tients (Table 1) should receive tPA within 3 hours of is-chemic stroke symptom onset.4 This recommendationcame largely from the results of the NINDS (National In-stitute of Neurological Disorders and Stroke) trial.7 Four

other clinical studies attempted to discern the appropriateuse of tPA in acute ischemic stroke; however, none of thesetrials had results comparable to those of the NINDSstudy.8-11 The ECASS (European Cooperative Acute StrokeStudy) III trial investigated the use of tPA beyond 3 hoursafter stroke symptom onset.12 The results of this trialprompted an update in 2009 to the AHA/ASA consensusrecommendations to include the option of using tPA treat-ment up to 4.5 hours poststroke onset in patients who meeteligibility criteria (Table 2).13 In the treatment of acute is-chemic stroke, tPA is administered intravenously at a doseof 0.9 mg/kg (maximum 90 mg), with 10% of the totaldose given as a bolus over 1 minute and the remaining90% given as a continuous infusion over 1 hour.4-6

The objective of this paper is to review the literature re-garding the use of tPA in the treatment of acute ischemicstroke, focusing on the appropriate usage criteria and ad-ministration time window.

Data Sources and Selection

A search of PubMed and MEDLINE (1990-November2010) was undertaken to select literature relating to the useof tPA in acute ischemic stroke treatment. Key words in-cluded alteplase, tissue plasminogen activator, thrombolyt-ic, ischemic stroke, and cerebrovascular accident. Datasearch restrictions included articles published in English.

Establishment of the 3-Hour TreatmentWindow

The NINDS study group assessed the safetyand efficacy of tPA when administered within3 hours of symptom onset in the treatment ofacute ischemic stroke (Table 3).7 A total of 624patients were randomized to receive treatmentwith either tPA 0.9 mg/kg or placebo. Thestudy was carried out in 2 parts. The primaryendpoint of part 1 was clinical efficacy at 24hours after stroke onset. Clinical efficacy wasdefined as either complete resolution of neuro-logic deficit or improvement from baseline by4 or more points on the National Institutes ofHealth Stroke Scale (NIHSS). The primaryendpoint of part 2 was clinical benefit of tPA 3months after stroke onset. Four outcome mea-sures were used in part 2 to assess the func-tionality and recovery of patients: Barthel In-dex (BI), Modified Rankin Scale (mRS), Glas-gow Outcome Scale, and the NIHSS. Thebaseline demographics of the patients weresimilar among groups, with a median NIHSSscore of 14 in both groups in part 1 and a me-dian score of 14 in the tPA group and 15 in the

The Annals of Pharmacotherapy n 2011 March, Volume 45 n 365theannals.com

Table 1. Criteria for tPA Administration4

Diagnosis of ischemic stroke causing measurable neurologic deficit

Neurologic signs do not diminish spontaneously

Neurologic signs are not minor or isolated

Major deficits should be treated with caution

Stroke symptoms do not suggest presence of subarachnoid hemorrhage

Symptom onset no more than 3 hours prior to treatment

No head trauma, prior stroke, or myocardial infarction in the previous 3 months

No gastrointestinal or urinary tract hemorrhage in previous 21 days

No major surgery in the previous 14 days

No arterial puncture at a noncompressible site in the previous 7 days

No history of previous intracranial hemorrhage

Nonelevated blood pressure (systolic <185 mm Hg and diastolic <110 mm Hg)

No evidence of active bleeding or acute trauma upon examination

No use of oral anticoagulants, or INR ≤1.7 if anticoagulant therapy is being used

aPTT within normal range, if heparin was administered in previous 48 hours

Platelet count ≥100,000 mm3

Blood glucose concentration ≥50 mg/dL

No seizure with postictal residual neurologic impairments

Absence of multilobar infarction (hypodensity more than one third of cerebral hemisphere) upon CT examination

Potential risks and benefits of treatment are understood by patient or family members

aPTT = activated partial thromboplastin time; CT = computed tomography; INR =international normalized ratio; tPA = tissue plasminogen activator.



placebo group in part 2. Results of part 1 revealed agreater, but nonsignificant, improvement in clinical effica-cy 24 hours after stroke onset in the tPA group. Results ofpart 2 revealed significant improvements 3 months afterstroke onset in the tPA group compared to the placebogroup in all 4 outcome measures. The occurrence of in-tracranial hemorrhage was higher in the tPA group than inthe placebo group. The NINDS trial defined symptomaticintracranial hemorrhage as a hemorrhage that was not de-tected by earlier CT scans and had led to signs of hemor-rhage or a decrease in neurologic status. No significant dif-ferences were found in 90-day mortality among the tPAand placebo groups. The investigators concluded thatgreater improvements were seen in patients with ischemicstroke who were treated within 3 hours of stroke symptomonset with tPA, despite higher percentages of hemorrhagein the tPA group.

Clinical trials conducted following the publication of theNINDS trial focused on finding the appropriate time to ini-tiate treatment with tPA following stroke symptom onset.A summary of each clinical trial is presented in Table 3.

PROPOSED TREATMENT WITHIN 6 HOURS

The ECASS I, ECASS II, and ATLANTIS (AlteplaseThrombolysis for Acute Noninterventional Therapy in Is-chemic Stroke), part A trials all investigated extending theuse of tPA to within 6 hours of stroke symptom onset.8-10

The ECASS I trial assessed the safety and efficacy oftPA when administered up to 6 hours after symptom onsetin the treatment of acute ischemic stroke.8 A total of 620patients were randomized to receive treatment with eithertPA 1.1 mg/kg or placebo. The primary endpoint was pa-tient independence at 90 days determined by the BI and theabsence of symptoms at 90 days determined by the mRS.The baseline demographics were similar between thegroups, with a median NIHSS score of 12 in the tPA groupand 13 in the placebo group. No statistically significant dif-ferences were found at the end of 90 days for either of theprimary endpoints. Intracranial hemorrhagic events weresignificantly higher in the tPA group than in the placebogroup. The ECASS I trial defined an intracranial hemor-

rhagic event to be 1 of the following: a small petechiaealong the margins of the infarct, confluent petechiae withinthe infarcted area without space-occupying effect, a bloodclot not exceeding 30% of the infarcted area with mildspace-occupying effect, or a dense blood clot exceeding30% percent of the infarct volume with significant space-occupying effect. Mortality rates were higher in the tPAgroup at the end of 90 days than in the placebo group. Dueto the lack of efficacy and the higher mortality and in-tracranial hemorrhage rates found in the tPA group, theECASS I investigators concluded that tPA at a dose of 1.1mg/kg cannot be recommended for use up to 6 hours afterstroke symptom onset in patients with acute ischemicstroke.8

The ECASS II trial assessed the safety and efficacy oftPA when administered up to 6 hours after symptom onsetin the treatment of acute ischemic stroke.9 A total of 800patients were randomized to receive treatment with eithertPA 0.9 mg/kg or placebo. Less than 20% of all patientswere randomized within 3 hours of symptom onset. Theprimary endpoint was the absence of symptoms and dis-ability at 90 days determined by the mRS. The baseline de-mographics of the patients were similar between groups,with a median NIHSS score of 11 in both groups, whichwas lower than seen in the NINDS and ECASS I trials.There was a trend toward improvement in the tPA groupwith respect to the primary endpoint; however, the resultswere not significant. The overall frequency of intracranialhemorrhage was higher in the tPA group than in the place-bo group, and patients in the tPA group were 2.5 timesmore likely to develop a symptomatic intracranial hemor-rhage than were those in the placebo group. The ECASS IItrial had a broad definition of intracranial hemorrhage in-cluding hemorrhagic infarction, parenchymal infarction,and symptomatic hemorrhage. Symptomatic intracranialhemorrhage was defined as a CT scan showing blood onany site of the brain, documentation of clinical deteriora-tion, adverse events suggesting clinical worsening, or a de-crease in the NIHSS score of 4 or more points. There wereno differences in 30- or 90-day mortality between the 2treatment arms. The ECASS II trial investigators conclud-ed that the use of tPA in acute ischemic stroke did not in-crease morbidity or mortality. Further, they concluded thattPA should continue to be part of routine management inthe treatment of acute ischemic stroke within 3 hours ofsymptom onset.9

The ATLANTIS part A trial assessed the safety and effi-cacy of tPA when administered up to 6 hours after symp-tom onset in the treatment of acute ischemic stroke.10 A to-tal of 142 patients were randomized to receive either tPA0.9 mg/kg or placebo. Less than 20% of all patients wererandomized within 3 hours of symptom onset. The primaryendpoint was clinical improvement measured by a de-crease of 4 points or more on the NIHSS or complete reso-


MA Hatcher and JA Starr

Table 2. Additional tPA Eligibility Criteria for Treatment Within 4.5 Hours13

Patients must be <80 years old

Patients cannot be taking oral anticoagulants

Baseline NIHSS score must be <25

Patients cannot have a history of both stroke and diabetes

INR = international normalized ratio; NIHSS = National Institutes of HealthStroke Scale; tPA = tissue plasminogen activator.





Tabl

e3.

Sum

mar

yof

Dat

aS

ynth

esis

Trea

tmen

tan

dR

esu

lts

Stu

dya

Des

ign

Sam

ple

Pri

mar

yO

utc

om

eP

rim

ary

Ou

tco

me

Saf

ety

NIN

DS

R,D

B,

TT

T≤3

hP

art1

:dec

reas

eof

≥40-

90m

in:t

PA

51%

,pla

cebo

46%

Sym

ptom

atic

intr

acra

nial

hem

orrh

age:

tPA

6%,p

lace

bo0%

(NR

)(1

995)

7P

C,P

tPA

0.9

mg/

kg(P

art1

,po

ints

onN

IHS

Sat

24h

RR

:1.1

(95%

CI0

.8to

1.6)

n=

144;

Par

t2,n

=16

8)91

-180

min

:tP

A42

%,p

lace

bo33

%S

ympt

omat

icin

trac

rani

alhe

mor

rhag

e:tP

A7%

,pla

cebo

1%(N

R)

Pla

cebo

(Par

t1,n

=14

7;R

R:1

.3(9

5%C

I0.9

to1.

9)P

art2

,n=

165)

0-18

0m

in:t

PA

47%

,pla

cebo

39%

Dea

that

90da

ys:t

PA

17%

(p=

0.68

),pl

aceb

o21

%(N

S)

RR

:1.2

(95%

CI0

.9to

1.6)

Par

t2:c

linic

albe

nefit

atB

I:tP

A50

%,p

lace

bo38

%;O

R1.

63

mo

(95%

CI1

.1to

2.5)

;p=

0.02

6m

RS

:tP

A39

%,p

lace

bo26

%;O

R1.

7(9

5%C

I1.1

to2.

6);p

=0.

019

Gla

scow

Out

com

eS

cale

:tP

A44

%,

plac

ebo

32%

;OR

1.6

(95%

CI

1.1

to2.

5);p

=0.

025

NIH

SS

:tP

A31

%,p

lace

bo20

%;O

R1.

7(9

5%C

I1.0

to2.

9);p

=0.

033

EC

AS

SI

R,D

B,

TT

T:≤6

hIn

depe

nden

ceon

the

BIa

t90

days

OR

1.15

(95%

CI0

.98

to1.

35)

Intr

acra

nial

hem

orrh

age:

tPA

42.8

%,p

lace

bo36

.8%

(p<

0.00

1)(1

995)

8P

C,P

tPA

1.1

mg/

kg(n

=31

3)A

bsen

ceof

sym

ptom

son

the

mR

Sat

90da

ysO

R1.

47(9

5%C

I1.0

5to

2.05

)M

orta

lity:

tPA

22.4

%,p

lace

bo15

.8%

(p=

0.04

)P

lace

bo(n

=30

7)

EC

AS

SII

R,D

B,

TT

T:≤6

hm

RS

at90

days

tPA

40.3

%,p

lace

bo36

.6%

Intr

acra

nial

hem

orrh

age:

tPA

48.8

%,p

lace

bo40

.2%

(NR

)(1

998)

9P

C,P

tPA

0.9

mg/

kg(n

=40

9)O

R1.

17(9

5%C

I0.9

to1.

6)M

orta

lity:

tPA

10.5

%,p

lace

bo10

.7%

(NR

)P

lace

bo(n

=39

1)

AT

LAN

TIS

,R

,DB

,T

TT:

≤6h

Dec

reas

eof

≥4po

ints

onth

eN

IHS

Sat

24h

tPA

40%

,pla

cebo

21%

(p=

0.02

)S

ympt

omat

icin

trac

rani

alhe

mor

rhag

e:tP

A11

.3%

,pla

cebo

0%pa

rtA

PC

,PtP

A0.

9m

g/kg

(n=

71)

(p=

0.02

)(2

000)

10P

lace

bo(n

=71

)D

ecre

ase

of≥4

poin

tson

the

NIH

SS

at30

days

tPA

60%

,pla

cebo

75%

(NS

)D

eath

at30

days

:tP

A18

.3%

,pla

cebo

4.2%

(p=

0.00

8)D

eath

at90

days

:tP

A22

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,pla

cebo

7%(p

=0.

009)

AT

LAN

TIS

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TT:

with

in3-

5h

Neu

rolo

gic

reco

very

onth

eN

IHS

Sat

90da

ystP

A33

.8%

,pla

cebo

32%

(NS

)S

ympt

omat

icin

trac

rani

alhe

mor

rhag

e:tP

A7%

,pla

cebo

1.1%

part

BP

C,P

tPA

0.9

mg/

kg(n

=27

2)(p

<0.

001)

(199

9)11

Pla

cebo

(n=

275)

Asy

mpt

omat

icin

trac

rani

alhe

mor

rhag

e:tP

A11

.4%

,pla

cebo

4.7%

(p=

0.00

4)D

eath

at90

days

:tP

A11

%,p

lace

bo6.

9%(N

S)

EC

AS

SIII

R,D

B,

TT

T:w

ithin

3-4.

5h

Dis

abili

tyon

the

mR

Sat

90da

ystP

A52

.4%

,pla

cebo

45.2

%,O

R1.

34S

ympt

omat

icin

trac

rani

alhe

mor

rhag

e:tP

A2.

4%,p

lace

bo0.

2%;

(200

8)12

PC

,PtP

A0.

9m

g/kg

(n=

418)

(95%

CI1

.02

to1.

76);

p=

0.04

OR

9.85

(95%

CI1

.26

to77

.32)

;p=

0.00

8P

lace

bo(n

=40

3)D

eath

at90

days

:tP

A7.

7%,p

lace

bo8.

4%;O

R0.

90(9

5%C

I0.

54to

1.49

)

SIT

S-M

OS

TP,

OS

TT

T:≤3

hF

unct

iona

lind

epen

denc

eon

the

mR

Sat

3m

o54

.8%

(95%

CI5

3.5

to56

)S

ympt

omat

icin

trac

rani

alhe

mor

rhag

ew

ithin

24h:

1.7%

(95%

CI

(200

7)17

tPA

0.9

mg/

kg(n

=64

83)

1.4

to2.

0)M

orta

lity

at3

mo:

11.3

%(9

5%C

I10.

5to

12.1

)

SIT

S-I

ST

RP,

IBR

tPA

0.9

mg/

kgIn

depe

nden

ceon

the

mR

Sat

3m

o3-

4.5

h:58

.0%

,<3

h:56

.3%

(NS

)S

ympt

omat

icin

trac

ereb

ralh

emor

rhag

ew

ithin

24h:

3-4.

5h

(200

8)18

3-4.

5h

(n=

664)

2.2%

vs<

3h

1.6%

;OR

1.18

(95%

CI0

.89

to1.

55)

<3

h(n

=11

,865

)M

orta

lity

at3

mo:

3-4.

5h

12.7

%vs

<3

h12

.2%

;OR

1.02

(95%

CI0

.9to

1.17

)

BI=

Bar

thel

Inde

x;D

B=

doub

le-b

lind;

IBR

=In

tern

et-b

ased

regi

ster

;mR

S=

Mod

ified

Ran

kin

Sca

le;N

IHS

S=

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lIns

titut

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lthS

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cale

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c-tiv

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ndom

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tissu

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lution of symptoms at both 24 hours and 30 days. Thebaseline demographics of the patients were similar be-tween groups, with the exception of a higher percentage ofdiabetes, hypertension, and cardiac disease in the placeboarm. The median NIHSS score was 10 in the tPA groupand 11 in the placebo group. A statistically significant im-provement in neurologic deficit was noticed after 24 hoursin patients who received tPA compared to those who re-ceived placebo. Despite the positive results of tPA use at24 hours, no statistically significant differences in neuro-logic improvement were found between tPA and placebopatients at 30 days. Symptomatic intracranial hemorrhagerates at 10 days and mortality rates at both 30 and 90 dayswere higher in tPA-treated patients than in the placebo pa-tients. Symptomatic intracranial hemorrhage was not de-fined. Safety concerns were especially high for patientstreated with tPA in the 5- to 6-hour time window afterstroke onset. As a result of the safety concerns for the pa-tients who received tPA between 5 and 6 hours, the AT-LANTIS part A trial was stopped prematurely, and the in-vestigators did not support the use of tPA in patients be-yond 3 hours of stroke symptom onset. Further, theinvestigators indicated that additional investigation is nec-essary to identify patients who may benefit from treatmentwith tPA longer than 3 hours after symptom onset.10

PROPOSED TREATMENT WITHIN 5 HOURS

In response to safety concerns with ATLANTIS part A,the ATLANTIS part B trial was designed to assess thesafety and efficacy of tPA when administered between 3and 5 hours after symptom onset in acute ischemic stroke.11

A total of 613 patients were randomized to receive treat-ment with either tPA 0.9 mg/kg or placebo. Of these pa-tients, 547 received tPA between 3 and 5 hours after symp-tom onset. The primary endpoint was neurologic recoverybased on a NIHSS score of ≤1 at 90 days. The baseline de-mographics of the patients were similar between groups.The median NIHSS score was 11 in both groups. No statis-tically significant differences were found at the end of 90days for the primary endpoint. The occurrence of bothsymptomatic and asymptomatic intracranial hemorrhagewas higher in the tPA group than in the placebo group. In-tracranial hemorrhage was defined as the presence of anyblood shown on a CT scan. No significant differences werefound in 90-day mortality among the tPA and placebo pa-tient groups. The data monitoring safety board terminatedthe trial prematurely due to the small likelihood of benefitwith tPA treatment. The investigators of the ATLANTISpart B study concluded that there was no 90-day efficacybenefit in patients treated with tPA between 3 and 5 hoursafter symptom onset. Further, the investigators stated thatthey were not able to support the use of tPA beyond 3hours of symptom onset.11

PROPOSED TREATMENT WITHIN 4.5 HOURS

The ECASS III trial assessed the safety and efficacy oftPA when administered between 3 and 4.5 hours aftersymptom onset in the treatment of acute ischemic stroke.12

A total of 821 patients were randomized to receive eithertPA 0.9 mg/kg or placebo. The inclusion and exclusion cri-teria were similar to those listed in Table 1, with the excep-tion of several additional exclusion criteria: age older than80 years, any use of oral anticoagulants, baseline NIHSSscore greater than 25, and a prior history of stroke and dia-betes. The primary endpoint was disability at 90 days mea-sured by the mRS. The baseline demographics of the pa-tients were similar between groups, with the exception of ahigher percentage of patients with a previous history ofstroke in the placebo arm. The median NIHSS score was 9in the tPA group and 10 in the placebo group. Patients whoreceived tPA achieved a favorable outcome on the mRS at90 days compared to those who received placebo.12 Symp-tomatic intracerebral hemorrhage rates were significantlyhigher in the tPA group than in the placebo group. Symp-tomatic intracerebral hemorrhage was defined as “any ap-parently extravascular blood in the brain or within the cra-nium that was associated with clinical deterioration, as de-fined by an increase of 4 points or more in the score on theNIHSS, or that led to death and that was identified as thepredominant cause of the neurologic deterioration.”12 Mor-tality rates were lower in the tPA group than in the placebogroup, but this finding was not significant. The results ofthe ECASS III trial provided proof that patients who devel-op ischemic stroke can achieve benefit from tPA when ad-ministered 3-4.5 hours after symptom onset. Despite thebenefit of extending the window of opportunity to 4.5hours, the authors recommended that patients should seektreatment as soon as possible to achieve optimal clinicaloutcomes.12

The results of the ECASS III study were reinforced in apooled analysis by Lees and colleagues, who supported theuse of tPA when administered within 4.5 hours of symp-tom onset.14 Further, like ECASS III, the importance ofearly treatment was reiterated by the investigators as pa-tients treated within the first 90 minutes derived the mostbenefit. The authors stated that to achieve maximal benefit,treatment should not be delayed and that the risks of treat-ment beyond 4.5 hours might outweigh the benefit.

SAFETY AND EFFICACY EVALUATION OF tPA

Until the publication of the NINDS trial, thrombolyticswere used infrequently in acute ischemic stroke due to thesafety risks associated with thrombolysis. Early pilot stud-ies suggested that tPA had the potential to be used safelyand effectively if initiated within 3 hours of symptom on-set.15,16 The results of the NINDS trial confirmed these





findings.7 The SITS-MOST (Safe Implementation ofThrombolysis in Stroke-Monitoring Study) was a prospec-tive registry of treatment experience with tPA when admin-istered within 3 hours of acute ischemic stroke symptomonset.17 Study data were obtained from 285 medical cen-ters and were compared to the pooled results of random-ized controlled trials. A total of 6483 patients were includ-ed in the SITS-MOST cohort, and all study patients re-ceived tPA 0.9 mg/kg. The primary endpoints of theSITS-MOST registry were symptomatic hemorrhage with-in 24 hours and mortality at 3 months. Functional indepen-dence, determined by a score of 0 to 2 on the mRS at 3months, was also assessed. According to the SITS-MOSTprotocol, symptomatic intracranial hemorrhage was de-fined as a local or remote parenchymal hemorrhage seenon posttreatment scans, combined with a neurologic de-cline of 4 or more points from baseline on the NIHSS, adecline from the lowest NIHSS score between baselineand at 24 hours, or resulting in death. At 24 hours, 1.7% ofthe patients had experienced a symptomatic intracerebralhemorrhage, and the mortality rate at 3 months was 11.3%.More than half of the patients experienced functional inde-pendence. The investigators concluded that tPA, when ad-ministered within 3 hours, is safe and effective in the man-agement of acute ischemic stroke and could be consideredas part of routine care in eligible patients.17

The SITS-ISTR (Safe Implementation of Thrombolysisin Stroke International Stroke Thrombolysis Register) wasa prospective, multinational, Internet-based register that in-vestigated the safety and efficacy of tPA administration be-yond 3 hours of stroke symptom onset.18 The study com-pared the outcomes of patients treated within 3 hours to theoutcomes of patients treated between 3 and 4.5 hours. Atotal of 12,529 patients were included in the study, and allpatients received tPA 0.9 mg/kg. The primary outcomes ofthe study were symptomatic intracerebral hemorrhagewithin 24 hours, mortality at 3 months, and independenceat 3 months determined by a score of 0-2 on the mRS. Thedefinition of symptomatic intracerebral hemorrhage usedin the SITS-ISTR study was identical to that used in theSITS-MOST study. There were no significant differencesfound between treatment groups in the rate of symptomaticintracerebral hemorrhage within 24 hours or mortality at 3months. While independence rates were higher in the 3- to4.5-hour treatment group, the results were not significant.Due to the similar outcome results in both groups, the in-vestigators concluded that tPA administration remains safewhen given up to 4.5 hours after stroke onset. Support waslent in favor of extending the time-to-treatment window,but emphasis was placed on maintaining a practice of treat-ing patients as quickly as possible.18

The SITS-ISTR registry was reanalyzed in 2010. A totalof 23,942 patients were included in the analysis with 2376patients receiving tPA between 3 and 4.5 hours and 21,566

receiving tPA within 3 hours.19 Symptomatic, intracerebralhemorrhage rates were higher in patients treated between3.5 and 4 hours than in patients treated within 3 hours(2.2% vs 1.7%; p = 0.04). Mortality at 3 months was notsignificantly different between groups (12% vs 12.3%; p =0.7) Of patients treated within 3 hours, 57.5% had com-plete functional independence compared to 60.3% of thepatients treated between 3.5 and 4 hours (p = 0.02). Theauthors concluded that these results further support thesafety and efficacy of tPA between 3 and 4.5 hours in pa-tients with acute ischemic stroke; however, patients shouldbe treated as early as possible after symptom onset.19

2009 AHA/ASA GUIDELINE UPDATE RECOMMENDATIONS

The AHA/ASA consensus recommendations suggestextending the time interval of tPA administration in is-chemic stroke treatment from 3 hours to 4.5 hours in eligiblepatients. To be eligible for tPA treatment beyond the 3-hourwindow, patients must meet all of the previously establishedtPA administration criteria detailed in the 2007 AHA/ASAguidelines. If the previous criteria requirements (Table 1)have been met, patients must meet 4 additional eligibility cri-teria updated in the 2009 guidelines (Table 2).10

Summary

The recent stroke guideline update was published afteran extensive research effort made by multiple clinicalstudy investigators. The NINDS trial served as the corner-stone of clinical evidence validating the efficacy of tPA inacute ischemic stroke treatment when administered up to 3hours after symptom onset. The ECASS I, ECASS II, andATLANTIS part A trials assessed the efficacy of tPA ad-ministered up to 6 hours after ischemic stroke onset. TheECASS I and II trials failed to show efficacy of tPA whenadministered at an extended time interval from stroke onsetat doses of 1.1 and 0.9 mg/kg, respectively. Although sig-nificant improvements were seen in NIHSS scores at 24hours in the ATLANTIS part A trial, the study was stoppedprematurely due to safety concerns for patients treatedfrom 5 to 6 hours after stroke onset. The ATLANTIS partB trial attempted to shorten the administration time of tPAto within 5 hours of stroke onset in response to the safetyconcerns that were evident in the ATLANTIS part A trial.Unfortunately, the ATLANTIS part B trial was alsostopped prematurely due to the lack of efficacy resultsequal to those seen in the NINDS trial.

Successful results were seen in the ECASS III trial,which displayed the efficacy of tPA when administered upto 4.5 hours after ischemic stroke onset in select patients.Further support toward the extension of the tPA adminis-tration time window was lent after the publication of theSITS-MOST and SITS-ISTR studies. The SITS-MOST


The Annals of Pharmacotherapy n 2011 March, Volume 45 n 369theannals.com at TEXAS SOUTHERN UNIVERSITY on December 10, 2014aop.sagepub.comDownloaded from


study validated its use when given in the traditional 3-hourtime window. The SITS-ISTR study provided further evi-dence proving tPA is equally safe and effective when givenbetween 3 and 4.5 hours after stroke onset.

Although the evidence now supports the use of tPA up to4.5 hours after ischemic stroke symptom onset in specificpatient populations, urgency of treatment delivery remains atop priority. Extension of the time-to-treatment windowshould not encourage a delay in the treatment of acute is-chemic stroke. Patients should continue to be treated asquickly as possible to achieve optimal therapeutic outcomes.

Molly A Hatcher PharmD, Pharmacy Resident, Auburn University,Auburn, ALJessica A Starr PharmD BCPS, Assistant Clinical Professor, Har-rison School of Pharmacy, Auburn University, Birmingham, AL Correspondence: Dr. Starr, [email protected]/Online Access: www.theannals.com/cgi/reprint/aph.1P525

Conflict of interest: Authors reported none

References

1. Lloyd-Jones D, Adams R, Carnethon M, et al. Heart disease and strokestatistics—2009 update: a report from the American Heart AssociationStatistics Committee and Stroke Statistics Subcommittee. Circulation2009;119:e21-181.

2. Sacco RL, Adams R, Albers G, et al. Guidelines for prevention of stroke inpatients with ischemic stroke or transient ischemic attack. A statement forhealth care professionals from the American Heart Association/AmericanStroke Association Council on Stroke. Stroke 2006;37:577-617.

3. Goldstein L, Appel L, Brass L, et al. Primary prevention of ischemicstroke: a guideline from the American Heart Association/AmericanStroke Association Stroke Council. Stroke 2006;37:1583-633.

4. Adams HP, Del Zoppo G, Alberts MJ, et al. Guidelines for the earlymanagement of adults with ischemic stroke: a guideline from the Ameri-can Heart Association. Stroke 2007;38:1655-711.

5. Albers GW, Amarenco P, Easton D, et al. Antithrombotic and throm-bolytic therapy. Chest 2008;133:630S-69S.

6. Product information. Activase (alteplase). San Francisco, CA: Genen-tech, December 2005.

7. The National Institute of Neurological Disorders and Stroke rt-PA Strokestudy group (NINDS). Tissue plasminogen activator for acute ischemicstroke. N Engl J Med 1995;333:1581-7.

8. Hacke W, Kaste M, Fieschi C, et al. Intravenous thrombolysis with re-combinant tissue plasminogen activator for acute hemispheric stroke: theEuropean Cooperative Acute Stroke Study (ECASS). JAMA 1995;274:1017-25.

9. Hacke W, Kaste M, Fieschi C, et al. Randomized double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase inacute ischemic stroke (ECASS II). Lancet 1998;352:1245-51.

10. Clark WM, Albers GW, Madden KP, Hamilton S. The rtPA (alteplase) 0-to 6-hour acute stroke trial, part A (A0276g): results of a double-blind,placebo-controlled, multicenter study. Stroke 2000;31:811-6.

11. Clark WM, Wissman S, Alber GW, Jhamandas JH, Madden KP, Hamil-ton S. Recombinant tissue-type plasminogen activator (alteplase) for is-chemic stroke 3 to 5 hours after symptom onset—the ATLANTIS study:a randomized controlled trial. JAMA 1999;282:2019-26.

12. Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to4.5 hours after acute ischemic stroke. N Engl J Med 2008;359:1317-29.

13. del Zoppo GJ, Saver JL, Jauch EC, Adams HP Jr. Expansion of the timewindow for treatment of acute ischemic stroke with intravenous tissueplasminogen activator. A science advisory from the American Heart As-sociation/American Stroke Association. Stroke 2009;40:2945-8.

14. Lees KR, Bluhmki E, von Kummer R, et al. Time to treatment with intra-venous alteplase and outcome in stroke: an updated pooled analysis ofECASS, ATLANTIS, NINDS, and EPITHET trials. Lancet 2010;375:1695-703.

15. Brott TG, Haley EC Jr, Levy DE, et al. Urgent therapy for stroke. I. Pilotstudy of tissue plasminogen activator administered within 90 minutes.Stroke 1992;23:632-40.

16. Haley EC Jr, Levy DE, Brott TG, et al. Urgent therapy for stroke. II. Pilotstudy of tissue plasminogen activator administered 91-180 minutes fromonset. Stroke 1992;23:641-5.

17. Wahlgren N, Ahmed N, Davalos A, et al. Thrombolysis with alteplasefor acute ischemic stroke in the safe implementation of thrombolysis instroke-monitoring study (SITS-MOST): an observational study. Lancet2007;369:275-82.

18. Wahlgren N, Ahmed N, Davalos A, et al. Thrombolysis with alteplase 3-4.5 hours after acute ischemic stroke (SITS-ISTR): an observationalstudy. Lancet 2008;372:1303-09.

19. Ahmed N, Wahlgren N, Grond M. Implementation and outcome ofthrombolysis with alteplase 3-4.5 h after an acute stroke: an updatedanalysis from SITS-ISTR. Lancet Neurology 2010;9:866-874.

El Rol del Activador Tisular del Plasminógeno en Isquemia CerebralAguda

MA Hatcher y JA Starr

Ann Pharmacother 2011;45:364-71

EXTRACTO

OBJETIVO: Evaluar la literatura relacionada con el uso intravenoso delactivador tisular del plasminógeno (t-PA) en el tratamiento de laisquemia cerebral aguda, enfocando en los criterios de uso adecuado, yla ventana de tiempo para su administración.

FUENTES DE DATOS: Se realizó una búsqueda en la literatura utilizando lossistemas de información PubMed y MEDLINE (enero 1990 hastanoviembre 2010). Las palabras claves utilizadas fueron alteplase,activador tisular del plasminógeno, trombolítico, apoplejía isquémica oisquemia cerebral y accidente cerebrovascular.

SELECCIÓN DE ESTUDIOS Y EXTRACCIÓN DE DATOS: Se evaluaron losestudios clínicos en humanos publicados en el idioma ingles y laliteratura primaria relevante donde se evaluaba el uso de t-PA enisquemia cerebral aguda.

SÍNTESIS DE LOS DATOS: El estudio del Instituto Nacional de DesordenesNeurológicos y Apoplejía (NINDS) demostró la eficacia clínica de t-PAen el tratamiento de isquemia cerebral aguda cuando se administrabadentro de las primeras 3 horas del inicio de los síntomas de apoplejía.Este estudio fue base fundamental para las recomendaciones presentadasen las guías de manejo de apoplejía aguda publicadas por la AsociaciónAmericana del Corazón (AHA) y la Asociación Americana deApoplejías (ASA). Los estudios ECASS I y II (European CooperativeAcute Stroke Study) y el estudio ATLANTIS, parte A y B, (AlteplaseThrombolysis for Acute Noninterventional Therapy in Ischemic Stroke),evaluaron la eficacia de t-PA cuando se administra luego de las primeras3 horas del inicio de la apoplejía. Ninguno de estos estudios apoya el usode t-PA luego de 3 horas. El estudio ECASS III demostró la eficacia det-PA cuando se administra hasta 4.5 horas luego del inicio de lossíntomas. Los registros de estudios prospectivos para documentar laexperiencia de trombolisis, SITS_MOST y SITS-ISTR (SafeImplementation of Thrombolysis in Stroke-Monitoring Study y SafeImplementation of Thrombolysis in Stroke International StrokeThrombolysis Register, respectivamente), evaluaron la eficacia yseguridad del uso de t-PA a 3 y 4.5 horas luego de la apoplejía ydemostraron resultados prometedores. En el 2009, las guías de apoplejíapublicadas por las asociaciones AHA/ASA se actualizaron y apoyan eluso de t-PA en pacientes selectos hasta 4.5 horas luego del inicio de lossíntomas.







CONCLUSIONES: El activador tisular del plasminógeno es eficaz cuando seadministra hasta 4.5 horas luego del inicio de los síntomas de apoplejíaen algunos pacientes. Sin embargo, se enfatiza que es importante laadministración a tiempo para obtener resultados terapéuticos óptimos.

Traducido por Mirza Martinez

Le Rôle du Tissu Plasminogène Activé (TPA) Dans Les AccidentsCérébro-Vasculaires (ACV)

MA Hatcher et JA Starr

Ann Pharmacother 2011;45:364-71

RÉSUMÉ

OBJECTIFS: Évaluer la littérature portant sur l’utilisation du TPA par voieintraveineuse dans le traitement des ACV avec une attention sur lescritères d’utilisation et la fenêtre du temps d’administration.

SOURCES DES DONNÉES: Une recherche dans MEDLINE et PubMed a étéeffectuée entre janvier 1990 et novembre 2010 en utilisant les mots-clésalteplase, tissue plasminogen activator, thrombolytic, ischemic stroke, etcerebrovascular accident.

SÉLECTION DES DONNÉES ET EXTRACTION DES DONNÉES: Les essais cliniquesréalisés chez les humains et publiés en langue anglaise ainsi que lalittérature primaire pertinente évaluant le TPA dans le traitement desACV ont été revus.

SYNTHÈSE DES DONNÉES: L’essai NINDS a démontré l’efficacité du TPAdans le traitement des ACV lorsque administré dans les 3 heures suivantle début des symptômes et constitue la base des lignes directrices del’AHA/ASA. D’autres essais ont étudié la même question (ECASS I,ECASS II, et ATLANTIS PART A & B) et ont démontré l’inefficacitédu traitement après 3 heures. L’essai ECASS III a démontré l’efficacitédu TPA jusqu’à 4.5 heures. Les registres SITS-MOST et SITS-ISTR ontévalué l’efficacité et l’innocuité du TPA jusqu’à 3 et 4.5 heures et obtenudes résultats prometteurs. En 2009, les lignes directrices de l’AHA/ASAont été révisées pour inclure l’usage du TPA jusqu’à 4.5 heures après ledébut des symptômes.

CONCLUSION: Le TPA est efficace lorsqu’administré jusqu’à 4.5 heuresaprès le début de symptômes chez des patients sélectionnés. Cependant,une administration opportune demeure la plus importante afin d’obtenirles meilleurs résultats cliniques.

Traduit par Nicolas Paquette-Lamontagne

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Role of Tissue Plasminogen Activator in Acute Ischemic Stroke