Michael Joseph Barbara

F. Meyerovitz, F. Polak, MD C. Donovan,

MD

#{149} Samuel

Z. Goldhaber, MD #{149} Kathleen Reagan, MD2 Kandarpa, MD, PhD #{149} Clement J. Grassi, MD #{149} Michael A. Bettmann, MD3 #{149} Donald P. Harrington, MD

#{149} Krishna

RN

Recombinant Tissue-Type Plasminogen Activator versus Urokinase in Peripheral Arterial and Graft Occlusions: A Randomized Trial’ A randomized prospective trial was undertaken to compare intraarterial administration of recombinant human tissue-type plasminogen activator (rt-PA) with urokinase (UK) in 32 patients

with

peripheral

arterial

or bypass graft occlusions. Sixteen patients were randomized to receive rt-PA and 16 to receive UK. The rtPA dose was administered as a 10mg bolus into the thrombus, followed by 5 mg/h for up to 24 hours. The UK dose was administered as a 60,000 IU bolus into the thrombus, followed by 240,000 lU/h for 2 hours, 120,000 lU/h for 2 hours, and 60,000 lU/h for up to 20 hours. Semial arteriograms were obtained at baseline and at 4, 8 or 16, and 24 hours. The endpoint was defined as 95%

or greater

clot

lysis.

The

cumu-

I

NTRAARTERIAL

ministered nase,

16 hours, and eight vs six at 24 hours. Lysis occurred more rapidly in the mt-PA group (P = .04). Major bleeding complications occurred in five rt-PA patients and two UK patients (P = .39). At 24 hours, fibninogen levels were significantly lower in the mt-PA group than in the UK group (P = .01). There was no apparent difference in 30-day clinical suc-

after

low-dose

fibnino-

arterial

relatively

umokinase

(UK)

including

changed

to UK.

sis of our

efficacy

showed

that

and

UK was

bypass

graft

mates

to

occlusions

recombinant

plasminogen an average

than

90%

with than

of their

6

pa-

controlled

mt-PA

with

AND

study population 18 years of age

to com-

angiographicabby

METHODS consisted on older

of 32 who had

documented

peripheral

the

(M.F.M,

KR.,

terms:

Arteries,

Arteries,

peripheral,

92.7214

stenosis

or obstruction,

92.7214

teries,

transluminal

angiopiasty,

92.1274.

Blood,

fibrinogen

Thrombolysis, 92.7214 92.1274

Radiology

Grafts,

#{149}

92.1274

Tissue-type #{149} Urokinase, #{149}

1990;

stenosis,

#{149} Thrombosis,

plasminogen 92.1274 175:75-78

Ar-

J.F.P.,

D.P.H.)

and Medicine

Women’s Francis

Hospital, St, Boston,

RSNA

Index

Departments

annual requested

October

23; accepted

2

Current

92.452.

Received August

address: University

25;

M.A.B.,

and

School, the 1988

July

31,

revision

November

1.

1989;

received

Supported

Inc and requests

Abbott Laboratoto M.F.M.

Department

of Radiology,

Hospital,

Washington,

occlusions,

Our

exclu-

surgery,

or

(withintraintracra-

positive

occult

blood

at stool

exami-

or bypass

graft,

patients

were

ran-

75

method of Rampling Degradation products

and Gaffney were assayed

with the method of Merskey et al (13,14) in all patients except one, in whom the Thrombo Wellcotest method (Wellcome Diagnostics, Research Triangle Park, NC) was used. All patients received concomitant intravenous hepanin (3,000-5,000-U loading dose followed by 600-1,000 U/h). An intaartenial catheter was advanced the entire

length

tenial segment, bolytic agent UK)

was

injected

of the

occluded

and a bolus (10 mg mt-PA into

the

graft

on an-

of the thromon 60,000 IU thrombus

while

D.C.

arterial,

activator,

B.C.D.,

Brigham

Harvard Medical MA 02115. From

in part by Genentech ries. Address reprint Georgetown

C.J.G.,

(S.Z.G.),

meeting.

revision

#{149}

of Radiology

K.K.,

arterial

nation; (f) severe impairment of hepatic function; (g) severe uncontrolled arterial hypertension on diabetic hemorrhagic netinopathy; and (h) pregnancy or lactation. The study was approved by our Institutional Review Board and the Food and Drug Administration, and written informed consent was obtained from all patients. After initial diagnostic arteniognaphy demonstrated the occluded peripheral an-

tion (12).

cess. From

had

domized by means of consecutively numbened sealed envelopes to receive either nt-PA (Activase; Genentech, South San Francisco, Calif) or UK (Abbokinase; Abbott Laboratories, North Chicago, Ill). Baseline blood samples were obtained to measure hematocrit, fibninogen levels, and fibnin and fibninogen degradation products. Fibminogen levels were measuned with the sodium sulfite precipita-

UK.

MATERIALS Our patients

trial

angiographic patients

or intraspinal

tery

(9-1 1). In view of these promresults, we decided to carry out

a randomized pane

tissue-type

activator (mt-PA), time to bysis of less

in more

tients ising

treated

human

native

more

streptokinase (8). More recently, Risius et al reported extremely rapid thrombolysis in peripheral arterial

and

examiocclu-

or previous Twenty-nine

nial neoplasm; (c) internal surgery on ongan biopsy within 10 days; (d) open heart surgery within 3 weeks; (e) “one plus” or

anaby-

safety

of less

nation, nations.

cranial

superior

occlusions

by exami-

had

own,

Retrospective

graft

sion criteria were (a) active internal bleeding within 3 weeks; (b) recent in 1 year) cenebrovascular accident,

(7), many

our

on bypass

than 90 days duration as assessed means of clinical history, physical

sions of bypass grafts (17 of which were saphenous vein bypass grafts), and three

streptokiand Fischhigh fre-

McNamana

of the

institutions,

hours

at

but

high-dose

vs one

vs three

of

quency of clot bysis and the bow complication mate obtained with

with

seven

with

en’s report

lative numbers of patients with successful thrombolysis (rt-PA vs UK) were four vs none at 4 hours, seven at 8 hours,

infusion

bytic agents has become an accepted approach for the treatment of mecent peripheral arterial occlusions, particularly recent occlusions of saphenous vein bypass grafts (1-6). This type of therapy was initially ad-

I

Current

University

,. RSNA, See also in

this

address: Hospital.

issue.

Department

of Radiology,

Boston.

Abbreviations:

1990

the

editorial

by Gardiner

(pp

34-36)

type

rt-PA

plasminogen

minogen

activator,

activator,

UK

recombinant t-PA

tissue=

tissue

plas-

urokinase.

75

Table

Table 1 Patient Data nt-PA (ii

UK 16)

=

2

Number of Patients Studied at Each Time Point 95% Lysis and Restitution of Antegrade Flow Lysis

57 :E 13 10

Age (y) Men(no.)

Women

93 :1: 7.3 .41 ± .06

Daysofsymptoms*

Hematocrit* Native

59 ± 17 12 4

6

(no.)

11.2

±

No.

Time (h)

.42 ± .06

Vein

graft

2

9

8

(no.)

3

2

(no.)

3

4

extravasation

2

studied 1 One

12

occurred;

ocdusions

(no.)

Dacron

graft

Gortex

*

graft

occlusions Graft location

4t 12

Suprainguinal(no.) Infrainguinal(no.)

Length

UK

16 10 1 5

16 11 4 10

Note-Percentages

occlusions

of occlusion 44±19

(cm)

42±

Mean ± standard deviation. t One patient in rt-PA group femorofemoral and femoropoplitea!

No. of Patients Restitution

with

with

95%

of Antegrade

Flow

Studied

rtPA*

4 8 16 24

1

(no.)

of Patients

and

Number

(n

rt-PA = 16)

P

UK (ii

=

Value1

16)

15.7

arterial

occlusions

Cumulative

Cumulative

16)

(n

and

One

was

not

studied

on the 4-hour

beyond

4 hours

arteniogram

(later

at 24 hours because rt-PA infusion patient was not studied beyond

patients

were

not studied

by the angiographer (one was a protocol marked clot lysis at 8 hours. but this was I Fisher exact test.

13

0(0) 1(6) 3(19) 6(38)

.10 .04 .25 .72

in parentheses.

patient

two

4(25) 7(44) 7(44) 8(50)

because

found

of termination

of rt-PA

infusion

to be a pseudoaneurysm);

was terminated 4 hours because

after bleeding of termination

three

after

patients

occurred. of UK infusion

were

after

at 24 hours because of premature termination violation at 161/2 hours; the other patient was refuted by the blinded pane! of investigators).

apparent

not

bleeding

of UK believed

infusion to have

*

had

occluded

grafts.

Table

3

Clinical

Outcome

a fter

Thrombolytic

Therapy the

catheter

was

slowly

withdrawn

proximal

end of the occlusion,

tip

catheter

of the

uous infusion through this

was

of the arterial

left.

to the

where Next,

nt-PA (n=16)

the

a contin-

thrombolytic catheter was

agent started

hours; or 240,000 lU/h of UK for 2 hours, followed by 120,000 lU/h for 2 hours, fol-

Death within 3Odays Surgery within 30days Angioplasty within 3Odays

bowed

Limb loss within

(5 mg/h

of nt-PA

to a maximum

by 60,000

lU/h

of 24

to a maximum

of 20

hours). The UK dosing regimen was a modification of the regimen reported by McNamana and Fischer (7). Angiograms were obtained at 4 hours, 8 or 16 hours (the choice for the second time point depended on the time of day), and at 24 hours, unless 95%-100% lysis with restitution of antegrade flow was demonstrated at an earlier time point, in which case the infusion was terminated.

The decision

to end therapy

because

of the protocol, routine clinical care was resumed. Patients in whom 95%-100% lyhad

not

continue

been

achieved

receiving

were

intraarterial

able

gen

levels

were

PA group

than

significantly in the UK

lower group

to

UK infu-

sion beyond 20 hours, depending on the clinical situation. Data were entered into the CLINFO system (Bolt, Beranek & Newman, Cambridge, Mass), and P values for rates of clot lysis were calculated with the Fisher exact test. The mean values of fibninogen levels for the two groups were compared with the Student t test.

RESULTS

each time numbers

clot was

point and of patients

lysis are listed a trend toward

in Table 2. There earlier thrombob-

mt-PA than with UK, and significance (P .04) was at the 8-hour time point. At

16 hours,

five

mt-PA

UK patients hours, been tients

patients

patient

were

(no

(two

lysis)

with

lysis).

16 treated

with

UK.

Major

after

onset

of treatment)

infusion penitoneal

and two episodes hematoma) and

The

patients

(two

76

Radiology

#{149}

at

bleeding

complications (defined as bleeding requiring surgery, two or more units of blood, or interruption of fibminolytic infusion that occurred within 72

hours

studied

four

By 24

95% or greaten clot lysis had achieved in only eight of 16 patreated with mt-PA and in six of

cumned episodes

of patients

studied: and

in five nt-PA requiring

episodes

patients interruption

ocof

of retmotwo UK

interrupting

and one itoneab hematoma) the episodes that

9

3

5

2

3 3

numbers

of patients.

of

infusion

episode (P required (one

in

of metnoper.39). Two of intenrupan

mt-PA

pa-

tient and one in a UK patient with retmopemitoneab hematoma) were groin hematomas. Thus, there were nine major complications among seven patients. In addition, two minor bleeding complications occurred in the mt-PA group (one case of gingival

oozing

and

one

of occult

blood

in

stool), but none occurred in the UK group. There were no intracranial hemorrhages on deaths. The clinical outcomes in the two groups of patients were similar (Table 3). Fibminogen levels at each time point are shown in the Figure. At baseline (P .79), 4 hours (P .59), 8 hours (P = .34), and 16 hours (P .95), there were no significant differ-

ences

(four

1

8

5 are

infusion

tion

ysis with statistical achieved one

0

rt-

the cumulative with 95%-100%

Sixteen patients were randomized to receive mt-PA and 16 to receive UK. The baseline characteristics of the two groups were similar (Table 1).

number

in the .01).

(P

Note-Numbers

of

95%-100% clot lysis was, of necessity, made on the spot. However, the angiographic results reported here were determined by a consensus panel blinded to treatment assignment. At the completion

sis

3odays Blood transfusion within 72 hours

#{149}rtPA Dux

Mean fibninogen levels (mg/dL) with standand deviation limits at each time point. At baseline and at 4, 8, and 16 hours, there were no statistical differences between the nt-PA and UK patients. At 24 hours, fibrino-

UK (n16)

in fibninogen

levels

between

the mt-PA and UK patients. However, at 24 hours (P .01), fibminogen 1evels were significantly lower in mt-PA patients than in UK patients. No UK April

1990

patient had a fibninogen than 100 mg/dL (1 g/L), PA

patient

had

levels

level less but one rt-

that

fell

of 3-33 hours our study, we

(4, 8 on 16, and peat arteniognams

below

100 mg/dL(lg/L). After completion of the protocol, six UK patients who did not show

by-

of

these patients. Two nt-PA patients who did not show bysis by 24 hours received UK outside of the protocol for

an

additional

DISCUSSION

by

the

strands

fibnin

noncovalent

binding

(20).

The

binds hydrophobically this fibnin-bound t-PA fibnin-bound plasminogen

has

a much

t-PA

for

fibnin-bound plasminogen than does freely circulating t-PA for circulating plasminogen. However, if large amounts of freely circulating t-PA are

present

because

administration, of plasmin

ing

of high

dosage

large

amounts

then are

formed

plasminogen,

from

circulat-

despite

the

low

af-

finity. The result is consumption of circulating fibninogen and a-2 antiplasmin, and an increase in cincubat-

ing

fibnin

and

tion

products

bytic

state

fibninogen (ie,

develops)

its relative theoretical

fibminogen

with

that

with

nt-PA

there

randomized efficacy and

that

of UK in pe-

arterial and graft from uncontrolled

suggested sis

mt-PA has strepto-

effects.

previous the

of mt-PA

mipherab results

of

knowledge,

the

rate

was

more

occlusions, studies

of thrombolyrapid

than

the mate achieved with either streptokinase or UK (9,10,23). Infusion dumations to achieve successful thrombolysis

with

hours UK

mt-PA

ranged

(mean,

3.9 hours)

necessitated

infusion

Volume

175

Number

#{149}

from

(10),

1 to 6

whereas

durations 1

lysis

than

et al (10),

in which

of mt-PA. rate of clot

8

Although

we used

sion dose is similar

a fixed

mate of 5 mg/h, to the weight-based

mt-PA this

into

the

thrombus

The our

mean

study

and

UK

indicating bus,

and

this

volumes

may

In the

present

complications in the mt-PA

study,

were group,

for

rate

dosage dosage

distinguish thrombus

ic plug

than pathologic from the

that

is perhaps

surprising,

fibninogen

levels

significantly tients than ceived UK.

lower among However,

tient

nt-PA

in the

1.

2.

group

had

(c)

to be more

clinical

gratefully

Stoll,

out-

acknowl-

MD,

Diane assisted

Dotter

CT, lysis

Anne-Marie

Wilkinson,

MD.

by

(grant

CLINFO

3.

BT,

Data 5

van

her

systemic

van Breda Urokinase thrombolysis. 111.

5.

Belkin

JJ,

after

intraarterial

dose

urokinase.

152:709-712. McNamara

TO,

era! 1986;

10.

that

were

tients graft 74(suppl

Risius MG,

Thrombolysis

graft

occlusions:

high-dose

uroki-

W,

Kandarpa

of occluded AJR

1986;

147:621-626.

RA, Geisinger human

K, et

femoropopMA,

tissue-type

for thrombolysis and

bypass

et al. plasmin-

in periph-

grafts.

Radiology

160:183-188.

Graor RA, Thrombolysis tissue-type

11.

Koltun

activator arteries

Factors

144:769-775.

B, Graor

ogen

then-

patency

JR.

and

using

1985;

grafts.

Straub

thrombolysis with J Surg 1986;

Fischer

results

Risius

6-month

arterial

GA,

CA,

Am

Thrombolysis

liteal

9.

and

high

a!.

occlu-

fibrinolytic

1986; 121 :769-773. Bomberger AB.

rates

Gardiner

strep-

complications.

B, Buckman

Surg TO,

of peripheral

8.

and

Intraarterial

initial

AJR

dose

152:35-39.

Belkin

apy. Arch McNamara

nase.

Low

of arterial

A. Katzen BT, Deutsch AS. versus streptokinase in local Radiology 1 987; 165:109-

R.

improved

Ra-

B, Young JR. et a!. Low for selective thrombol-

effects

M,

Lowe

Selective

136:1171-1178.

1984;

4.

A.

treatment

1981;

Radiology

AJ. streptokinase.

Breda

in the

affecting

It

of

111:31-37.

Graor RA, Risius dose streptokinase ysis:

6.

low-dose

1974;

Katzen

J, Seaman

Rosch with

Recombinant

a fibmin-

similar,

similar

John

was

tokinase

cannot

among mt-PA pathose who meonly one pa-

em-

(e) mt-PA decrement in fibnindid UK, and (f) nt-PA

and

sions. AJR

hemorrhagic

at 24 hours

pa-

of Mitchell I. Karmel, MD, MD, Ruth Morrison, RN, Stu-

MD,

diology

7.

however,

were

We

RN,

clot

our

(24).

for

References

in both

bleeding

those

RR 02635 from the National Institutes Health). We thank C. Quentin Brown for help in preparing the manuscript.

occlusive “good” hemostat-

prevents

than

MOl

more prevalent although the dif-

UK,

Singer,

organization

fenence did not reach statistical significance. This is probably because rtPA, although it is relatively more fi-

brin-specific

rates

a greater

Uvanovic,

of thmom-

account

lower overall success treatment groups.

lysis

edge the assistance Joseph Loscalxo,

and

groups,

large

caused

art

infu-

of occlusion 42 cm in the respectively,

44

the

complications tended prevalent with mt-PA,

(a technique

lengths were

higher

Acknowledgments:

our

that Risius et al and Gmaom et ab did not describe). More of their patients had native arterial occlusions than did those in our study, and perhaps our lower rate of clot bysis with mt-PA reflects our different patient popubation.

was

of some previous reports on either UK or mt-PA (4,7-10). The reasons this are also unclear but may partly

ogen bevel than and UK yielded comes. U

schedules of either 0.1 on 0.05 mgI kg/h used in those studies. In contrast to the protocols of those studies, all our patients received concomitant hepamin. In addition, we administered a 10-mg bolus of mt-PA over the length of the thrombus, in an attempt to increase delivery of the agent

100 mg/dL (1 g/ of major bleeding

95% or greaten lysis was not achieved by 24 hours in half or more of patients in either group, (d) bleeding

and

reasons for are unclear.

complications

hours

angio-

The lysis

than rate

pboyed in this randomized trial, (a) mt-PA tended to cause more rapid thrombolysis than UK, (b) by 24

number of (eight of 16

et al (9,11)

ogen level less L). Our overall

reflect the prospective randomized nature of this trial, with rigorous tient follow-up and documentation. In conclusion, with the doses

group and 10 of 16 in the This is in contrast to the

by Risius

mt-PA

both of the latter bein their fibmin and

to our

been no comparing

Because

rather

in a substantial in both groups

infusion lower

in

fibmino-

over

degradation

Although,

safety

(21).

clot specificity, advantages

kinase and UK, ing nonselective

have trials

degrada-

a systemic

earlier

graphic clot lysis was achieved in more than 95% of patients within 8 hours of the start of an intraarterial to

affinity

at 16 hours

Graor

to fibnin, and convents the to plas-

higher

toward

the Results

hours, introducing possible bias against UK at the 8-hour time point. Of note is that 95% or greater clot lysis by 24 hours had not been

studies

mm, which is thus formed on on within the thrombus and away from the action of its inhibitor, circulating a-2 antiplasmin (21,22). Fibnin-bound t-PA

basis for comparing of the two agents.

in the mt-PA UK group).

factured by means of recombinant DNA technology (mt-PA) (19). During thrombosis, small amounts of plasminogen are incorporated into the

(7). In points

24 hours) to obtain meand thereby have

a trend

achieved patients

Tissue-type plasminogen activator (t-PA) is a proteolytic enzyme that occurs naturally in most tissues (1518). Currently, this enzyme is manu-

18 hours) fixed time

with mt-PA, and the difference is statistically significant by the 8-hour time point. However, four UK patients and one mt-PA patient were

studied

1-36

hours.

thrombus

an objective mate of bysis

indicate

sis by 24 hours received UK for an additional 18-72 hours; successful thrombobysis was achieved in four

unsuccessfully

(mean, chose

Risius B, Lucas FV, et al. with recombinant human plasminogen

activator

with peripheral artery occlusions. Circulation

in

pa-

and bypass 1986;

1): 15-20.

B, Graor RA, Geisinger MA, Zelch Lucas FV, Young JR. Thrombolytic

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Astrup T, Stage A. Isolation of a soluble fibrinolytic activator from animal tissue. Nature 1952; 170:929-930. Rijken DC, Wijngaards G, Zaal-de Jong M, Welbergen J. Purification and partial

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April

1990