Simultaneous Administra

tion of Recombinant TissuePlasminogen Activator and Edaravone in Acute Cerebral

Ischemic Stroke Patients

Katsunobu Takenaka, MD, PhD, Masayasu Kato, MD, PhD, Keita Yamauti, MD,

and Katsuhiko Hayashi, MD, PhD

From the Department

Cross Hospital, Takayam

Received January 31, 20

June 20, 2014.

Cooperation Promotio

FY2013 from Hida Public

Address corresponde

Department of Neurolog

3-11 Tenman-cho, Takay

E-mail: takenakaka@mbm

1052-3057/$ - see front

� 2014 by National Str

http://dx.doi.org/10.1

2748

Among the 1052 patients admitted to our hospital because of cerebral infarction

between January 1, 2007, and December 31, 2010, we report the treatment outcomes

of 48 patients (4.6% of all patients) who received recombinant tissue plasminogen

activator (rt-PA) therapy (simultaneously combinedwith edaravone) within 3 hours

after the onset of infarction. Twenty (41.7%) patients started receiving edaravone

before rt-PA administration, and 28 patients (58.3%) started receiving rt-PA and

edaravone simultaneously. The patients had an average age of 73.5 years (range,

55-93 years; male:female, 32:16). Medical histories included hypertension, diabetes

mellitus, dyslipidemia, arterial fibrillation, and a smoking history in 23 (47.8%), 7

(14.6%), 8 (16.7%), 29 (60.4%), and 8 (16.7%) of patients, respectively. Regarding

the treatment outcome of the therapy, the National Institutes of Health Stroke Scale

score, whichwas 15 points before rt-PA administration, showed a statistically signif-

icant improvement to 8 points after rt-PA administration (P , .001). The modified

Rankin Scale scores at 90 days after treatment were as follows: 0 in 12 patients

(25.0%), 1 in 11 patients (22.9%), 2 in 7 patients (14.6%), 3 in 5 patients (10.4%), 4

in 6 patients (12.5%), 5 in 5 patients (10.4%), and 6 in 2 patients (4.2%). The occluded

blood vessel reopened completely in 30 patients (62.5%) and partially in 5 patients

(10.4%). Asymptomatic hemorrhage over the entire brain developed in 2 patients

(4.2%). Thus, rt-PA therapy in combination with edaravone improved the recanali-

zation rate, reduced the incidence of intracranial hemorrhage, and improved

functional prognosis. Key Words: Edaravone—recombinant tissue plasminogen

activator—cerebral infarction—rehabilitation.

� 2014 by National Stroke Association

of Neurological Surgery, Takayama Red

a, Japan.

14; revision received June 16, 2014; accepted

n Project for Lifestyle Diseases of FY2010 to

Health Center.

nce to Katsunobu Takenaka, MD, PhD,

ical Surgery, Takayama Red Cross Hospital,

ama City, Gifu Prefecture, Japan 506-0026.

.nifty.com.

matter

oke Association

016/j.jstrokecerebrovasdis.2014.06.016

Journal of Stroke and Cerebrovascular Diseases

Introduction

Thrombolytic therapy with recombinant tissue plas-

minogen activator (rt-PA) has been well established as a

standard therapy for the treatment of acute phase cerebral

infarction since its approval in 2005 in Japan.1,2 However,

to the present date, the associated complications,

including hemorrhagic transformation and worsening of

brain edema after rt-PA administration, have not been

resolved.3,4 Thus, it is important to overcome these

challenges to improve the outcome of this therapy.

Edaravone is a therapeutic drug that has been used in

everyday clinical practice to reduce brain damage5 and

improve functional prognosis6 after acute phase cerebral

infarction. Its major pharmacologic action involves

, Vol. 23, No. 10 (November-December), 2014: pp 2748-2752

COADMINISTER RT-PA AND EDARAVONE SIMULTANEOUSLY 2749

scavenging of free radicals that develop after cerebral

infarction. We hypothesized that administration of edara-

vone before rt-PA can inhibit vascular endothelial cell

injury and neuronal cell damage that occurs after rt-PA

administration, resulting in the improvement of the treat-

ment outcome. Since 2007, we attempted to administer

edaravone in a timely manner before (or at the same

time of) rt-PA administration within 3 hours after the

onset of cerebral infarction in patients who had been

receiving rt-PA. This attempt was also conducted as

part of a case series study.

Our results showed that an improvement in the func-

tional prognosis at 90 days after treatment was achieved.

Thus, we report these findings and provide bibliograph-

ical citations.

Subjects and Methods

Among the 1052 patients with cerebral infarction who

were urgently transferred to the emergency outpatient

unit of our hospital over the 4 years between January 1,

2007, and December 31, 2010, we studied 48 patients

(4.6% patients) for whom the time of onset cerebral infarc-

tion was identified and who received intravenous rt-PA

and edaravone (Radicut Injection; Mitsubishi Tanabe

Pharma Corp, Osaka, Japan) treatments within 3 hours af-

ter the onset of symptoms. The average age of the 48 pa-

tients was 73.5 years (range, 55-93 years; male:female,

32:16). Medical histories included hypertension in 23 pa-

tients (47.8%), diabetes mellitus in 7 patients (14.6%), dys-

lipidemia in 8 patients (16.7%), arterial fibrillation in 29

patients (60.4%), and a smoking history in 8 patients

(16.7%). After the patients were urgently transferred,

they were treated according to the Japanese Guidelines

for the Management of Stroke.

All patients who were transferred to our hospital un-

derwent blood sampling, infusion for fluid replacement

(extracellular fluid solution) in the emergency depart-

ment, and a computed tomography (CT) scan in a timely

manner. After evaluation of the neurologic findings, an

examination of paralysis in the 4 extremities, an assess-

ment using the National Institutes of Health Stroke Scale

(NIHSS), and confirmation of an absence of renal

dysfunction based on blood test results, the patients

received an intravenous bolus infusion of edaravone

over approximately 30 minutes before rt-PA administra-

tion. During this procedure, magnetic resonance imaging

(MRI) and magnetic resonance angiography (MRA) tests

were added if time had permitted. After checking the vi-

tal signs and reassessing the NIHSS score, to confirm the

stability of the patient’s general condition, rt-PA was

administered and the patient was moved to an intensive

care unit (ICU). In the ICU, the patient continued to be

treated according to the vital signs and the NIHSS score.

Within 1-3 days after the start of the treatment, the patient

again underwent CT, MRI, and MRA tests to confirm the

presence/absence of hemorrhage, recanalization status of

the occluded blood vessel, and severity of brain edema.

Patients without recanalization were not excluded from

the study. The subtypes of ischemic stroke were classified

by the Trial of Org 10172 in Acute Stroke Treatment sys-

tem.7 The outcomes at 90 days after treatment were

scored using the modified Rankin Scale (mRS).

This attempt to coadminister rt-PA and edaravone to

these patients was approved by the Ethics Committee of

Takayama Red Cross Hospital. The NIHSS score data

were compared between the 2 stages (pre or postadminis-

tration). The significance of interstage differences was as-

sessed using a t test. Values of P less than .05 were

considered significant.

Results

With respect to the timing of edaravone administration

in the 48 patients who received rt-PA (combined with

edaravone), 20 patients (41.7%) started to receive edara-

vone before rt-PA administration and 28 patients

(58.3%) started to receive rt-PA and edaravone simulta-

neously. The mean time from the onset of symptoms to

intravenous edaravone infusion was 96 minutes (range,

60-170 minutes), and the mean time from the onset of

symptoms to intravenous rt-PA administration was

127 minutes (range, 73-178 minutes).

Areas of cerebral infarction included the anterior cere-

bral artery in 2 patients (left side [L]:right side [R], 2:0;

4.2%), internal carotid artery in 9 patients (L:R, 4:5;

18.8%), middle cerebral artery in 35 patients (L:R, 20:15;

72.9%), and basilar artery in 2 patients (4.2%). The types

of cerebral infarction included small artery occlusion (la-

cune) in 6 patients (12.5%), large artery atherosclerosis in

15 patients (31.2%), and cardioembolism in 27 patients

(56.2%). Although the NIHSS score before rt-PA adminis-

tration was 15 6 6.4 points, the NIHSS score after rt-PA

administration improved to 8 6 8.5 points (statistically

significant difference, P , .001; Fig 1). With respect to

the recanalization rate, complete recanalization was

observed in 30 patients (62.5%) and partial recanalization

was observed in 5 patients (10.4%). The outcomes at

90 days after treatment, as assessed using mRS scores,

were as follows: 0 in 12 patients (25.0%), 1 in 11 patients

(22.9%), 2 in 7 patients (14.6%), 3 in 5 patients (10.4%), 4

in 6 patients (12.5%), 5 in 5 patients (10.4%), and 6 in 2 pa-

tients (4.2%; Fig 2).

Seven patients (14.6%) received an additional endovas-

cular therapy because their symptoms did not improve by

rt-PA administration, and their occluded blood vessel did

not reopen. These 7 patients were classified as severe

cases because of strong disturbance of consciousness at

admission and an average NIHSS score of 20 points

before drug treatment. Nevertheless, aggressive interven-

tion using endovascular therapy induced recanalization

in 2 patients. The mRS scores of the 7 patients at

Figure 1. The National Institutes of Health Stroke Scale (NIHSS) score

data were compared between the 2 stages (pre or postadministration). NIHSS

scores in each patient on preadministration and postadministration are lined.

The thick bar was expressed as mean data. Thin bars were expressed in each

patients.

K. TAKENAKA ET AL.2750

90 days were as follows: 0 in 1 patient, 1 in 1 patient, 4 in 2

patients, 5 in 2 patient, and 6 in 1 patient. Symptomatic

hemorrhagic infarction did not develop, however, asymp-

tomatic hemorrhage over the entire brain developed in 2

patients (4.2%). Surgical treatment (drainage through

ventricular) was performed in only 1 patient (2.1%),

whose condition was complicated by hydrocephalus

caused by enlargement of brain edema after drug admin-

istration.

The timing of the initiation of rehabilitation was as fol-

lows: 13 patients (27%) started rehabilitation from the day

of hospitalization, 26 patients (54.2%) started it a few days

after hospitalization, and 3 patients (6.3%) started it

within 7 days after hospitalization. Six patients (12.5%)

did not require rehabilitation because rt-PA relieved their

paralytic symptoms completely. Thirty-five (72.9%) of the

48 patients were able to be discharged from the hospital to

their home. The mean duration of hospitalization in all

patients was 51 days.

Discussion

In the present study, we anticipated improvement of

the therapeutic effect on acute phase cerebral infarction

through the combination of 2 drugs with different mech-

Figure 2. The frequency of neurologic recovery at discharge is expressed as

a percentage.

anisms of action, namely the thrombolytic effect (effect of

dissolving a blood clot clogging a blood vessel) of rt-PA

and the scavenging effect (effect of capturing free radicals

that develop after ischemia) of edaravone, respectively.

Accordingly, we investigated the outcome of the combi-

nation therapy in consecutive patients, including 72.9%

patients with occlusion of the middle cerebral artery

and 18.8% patients with occlusion of the internal carotid

artery on MRA. There is a possibility to obtain higher

rate in recanalization during acute and late phase; howev-

er, in this study, an acute recanalization was estimated

within 3 days after this treatment. The results showed a

statistically significant improvement in the NIHSS scores

after rt-PA administration.

In the present study, it was difficult for our hospital,

which is a community medical support central hospital,

to compare the outcome of our patients with a control

group of patients that did not receive rt-PA because of

ethical factors. Thus, we compared the outcome of our pa-

tients with those of completed large clinical studies. The

results of our study were better than the previous out-

comes of the National Institute of Neurological Disorders

and Stroke rt-PA stroke study Japan Alteplase Clinical

Trial and Japan post-Marketing Alteplase Registration

Study.1,8,9 In particular, the proportion of patients with a

mRS outcome of 0-1 was 46.6%, which was comparable

to that (47.9%) reported by a study conducted in

patients with occlusion of the middle cerebral artery

territory (Japan Alteplase Clinical Trial II).2 The results

of recanalization rates recorded in the present study

were similar to those of a preliminary study that sug-

gested good recanalization rates after the coadministra-

tion of edaravone and rt-PA.10 In addition, the

usefulness of an additional endovascular therapy for pa-

tients who do not respond to rt-PA intravenous infusion

therapy was reported recently.11 Two favorable patients

scored as mRS of 0 or 1 by a rescue endovascular therapy

have succeeded in this study, which had modified the

outcome.

One of the characteristics of the present study was that

we administered edaravone to all patients who received

rt-PA. The time from the onset of symptoms to rt-PA

administration was 127 minutes, similar to the value re-

ported by the national survey. However, edaravone was

administered before rt-PA in 42% patients in the present

study. The mean time from the onset of symptoms to

edaravone administration was 96 minutes, suggesting

that edaravone was administered at least approximately

30 minutes before rt-PA administration in these patients.

We believe that we obtained good outcomes in the pre-

sent study because edaravone, which is administered in

advance, exerts protective effects on neuronal cells,5,12-15

reduces brain edema against vascular endothelial cell

injury, and inhibits blood–brain barrier disruption.16-18

This may result in the prevention of the complications

associated with rt-PA therapy, namely hemorrhagic

COADMINISTER RT-PA AND EDARAVONE SIMULTANEOUSLY 2751

infarction and brain edema due to vascular endothelial

cell injury and blood–brain barrier damage after the

recanalization of the occluded blood vessel. These find-

ings are in accordance with those of a pathologic study

on the protective effects of edaravone on changes in

vascular permeability and on the subsequent blood–brain

barrier injury after rt-PA administration in animal models

of cerebral ischemia.19 So far, there have been many

reports about the mechanism of the hemorrhagic

transformation after rt-PA therapy.20-22 As one of the

mediators, many authors have focused on matrix

metalloproteinases (MMPs), which comprise a large

family of zing endopeptidases responsible for

remodeling almost all matrix substances in brain.23,24

Expression of several MMPs is increased after ischemic

stroke in animal models.17,25,26 The MMP-9 levels are

increased after rt-PA therapy,27 and stroke patients with

elevated plasma levels of MMP-9 have greater brain

injury and poor neurologic outcome.28 Thus, simulta-

neous administration of edaravone and rt-PA may inhibit

MMP-9 activity and prevent hemorrhagic transformation,

resulted in our good outcomes, which were involved in

no symptomatic hemorrhagic infarction.

We also suggest that factors other than the drugs

contributed to the good results obtained in the present

study. In general, it is preferable for stroke patients to

receive rt-PA therapy in a hospital with experts on stroke

and a stroke care unit, where CT and MRI are available

24 hours a day. However, in our hospital, we treat and

manage all stroke patients in the ICU instead of the stroke

care unit because of existent circumstances of the hospital

and an expectation for better results. We believe that the

good results described above may be attributable to the

early administration of active rehabilitation interventions

and careful treatment/care (from the day of hospitaliza-

tion or a few days later) by introduction of bedside

rehabilitation in the ICU.

Nevertheless, the present study had a limitation; we

had to evaluate the treatment outcome of the present

study in comparison with that of a previous large study

because edaravone was concomitantly used in all the

consecutive patients included in the present study. To

overcome this, we believe that a double-blind controlled

study including the settings of administration/nonadmi-

nistration of edaravone and the timing of administration

should be conducted in the future. Fortunately, the

YAMATO (tissue type plasminogen activator [t-PA] and

Edaravon combination therapy) study and Postmarketing

Registry On Treatment with Edaravone in acute Cerebral

infarction by the Time window of 4.5 hours are ongoing,

and we wait in expectation of their results.

Conclusion

The NIHSS scores after the treatment showed a statisti-

cally significant decrease. Regarding the outcome at the

time of discharge, the proportion of patients with a mRS

of 0-1 was 47.9%. Simultaneous and concomitant use of

rt-PA and edaravone reduced the complications such as

intracranial hemorrhage and brain edema, resulting in a

functional good prognosis.

Acknowledgments: We would like to thank the Hida

Public Health Center for supporting us through its Coopera-

tion Promotion Project for Lifestyle Diseases of FY2010 to

FY2013. We also thank Mr. Paul Frederickson for his kind En-

glish education and support.

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