embolism. activator in patients with acute pulmonary ...

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M.D., FC.C.P;. Jeff. Weitz,. M.D.;l. Moira. Cruickshank,. M.D.;. Jean. Neemeh,. M.D.; ...... Kessler. CM,. HeitJ, Markis. J. Sharma. CV,. Dawley. D, et al. Randomized.
A randomized trial of a single bolus dosage regimen of recombinant tissue plasminogen activator in patients with acute pulmonary embolism. M Levine, J Hirsh, J Weitz, M Cruickshank, J Neemeh, A G Turpie and M Gent Chest 1990;98;1473-1479 DOI 10.1378/chest.98.6.1473 The online version of this article, along with updated information and services can be found online on the World Wide Web at: http://chestjournal.chestpubs.org/content/98/6/1473

Chest is the official journal of the American College of Chest Physicians. It has been published monthly since 1935. Copyright1990by the American College of Chest Physicians, 3300 Dundee Road, Northbrook, IL 60062. All rights reserved. No part of this article or PDF may be reproduced or distributed without the prior written permission of the copyright holder. (http://chestjournal.chestpubs.org/site/misc/reprints.xhtml) ISSN:0012-3692

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____

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preliminary report A Randomized Trial of a Single Bolus Dosage Regimen of Recombinant Tissue Plasminogen Activator in Patients with Acute Pulmonary Embolism* Mark

Levine,

Jeff Weitz, Alexander

in animals

Experiments

tissue

nant uing

thrombolysis

and

that

and

bleeding

short

after

it

disease,

is

is reduced

when

In previous

studies

rt-PA

agent

has

when

been

cleared

between

90

a short

course

by continuous

minutes

and

a double-blind

conducted

in which

acute symptomatic ing heparm were

pulmonary allocated

can

trial

embolism

who a 2-minute

to either

been

rt-PA

were receivinfusion of

rt-PA at a dose of 0.6 mg/kg (33 patients) or saline placebo (25 patients). Perfusion lung scanning was used to assess the

change

in pulmonary

T

reatment

of thrombosis

fibrinolytic

method

enzyme

for

lysis

period

have

of pulmonary

emboli

generalized

circulating a systemic

coagulation

increased

Recombinant

risk tissue

shown

when

of 12 to 24 hours,These

specific and convert mm and so produce to the

been

to induce

administered

agents

an

alternative

bolytic

therapy

new

shown

experimental specificity

early a

fibrin-

to

and

studies,

rt-PA

the

Departments

of Medicine,

and

thrombolysis

because

and although streptokinase, they

ing.4’m’3 It has rt-PA

been

in inducing

demonstrated lysis

in

of its relative

fibrin-

producing

in patients embo-

In

all

by continuous

of

these

infusion

minutes and 8 hours. with a systemic lytic

they produce less for an equivalent associated

was

fibrin,5,6

thrombolysis

thrombosis.me

of between 90 are associated

are

the and

preferentially

without

was administered

state, than

of

15

98:1473-79)

of

effective

induce

activator

and Biostatistics, McMaster Universit#{231} Hamilton, Ontario, and the tHotel Dieu Hospital, Montreal, Quebec, Canada. tScientist, Medical Research Council of Canada. §Distinguished Professor, Heart and Stroke Foundation of Ontario. #{182}Scholar, Heart and Stroke Foundation of Ontario. Supported in part by the Ontario Ministry of Health and the Heart and Stroke Foundation of Ontario. Reprint requests: Dr. L.evine, 711 Concession Street, Hamilton, Ontario, Canada L8V 1C3

which

and

a period regimens

Epidemiology

1990;

presence

animals

over These

Clinical

in

insertion

results suggest that a bolus accelerated thrombolysis and

in the

venous

nor

and convenient approach to thrumwith pulmonary embolism.

to produce

could contribute (rt-PA),

group

a generalized coagulopathy.78 rt-PA has been evaluated in clinical trials with myocardial infarction,9’2 pulmonary lism,115

no the

requirements

occurred

activator,

plasminogen

effect, 5From

in patients

plasminogen

initially

actiof pul-

of bleeding. plasminogen

provides

a

plasminogen to plaslytic state leading to a

defect which

sites. These rt-PA produces

activates

over

are not

in either

transfusion

bleeding

7,

day between

at angiogram-catheter

of

regimen

By

detected

bleeds in

Minor mainly

venipuncture

was

no major

differences

groups.

patients

(p=O.Ol7).

(Chest

obstruction.

plasminogen treatment

were any

group resolution

seven

a non-surgical

arterial

the for the

and

of the plasma

provides

pulmonary

streptokinase, approved

embolism,

at 24 hours

by activation system

relieving

Urokinase and vators presently monary

perfusion

scan

there

between

established

placebo

There

groups.

were

the in lung

in

difference

achieve

has

drug administration. Thirty-four percent rt-PA patients had a greater than 50 percent resolution in the perfusion defect at 24 hours compared to 12 percent of placebo patients (p = 0.026). At 24 hours, the mean relative improvement in the perfusion defect was 37.0 percent in ui-PA treated patients compared to 18.8

the

percent

over

To determine

objectively

with

a

thrombo-

rt-PA

of

randomized

patients

over

M.D.;t

post-study

of

thrombotic

infusion

8 hours.

regimen

days

contin-

is administered

in patients with to be an effective

FC.C.P;

M.D.; Jean Neemeh, and Michael Gent, M.Sc.

the circulation and accelerated,

from

rt-PA

shown

whether

M.D.,

recombi-

produces

increased

administered

a period thrombolysis,

(rt-PA)

both

is

Hirsh,

that

demonstrated

activator

thrombolysis

period.

lytic

have

plasminogen

Jack

M.D.4

M.D.;l Moira Cruickshank, G. Turpie, M.B., Ch.B.;

with that

fibrinogenolysis

thrombolytic excessive

the

of experimental

bleed-

effectiveness venous

of

thrombi

and pulmonary emboli in animals is increased by using high concentrations infused over a short interval. In our produced

own studies, less plasma

a 15-minute proteolysis CHEST

and

infusion regimen less experimen-

I 98 I 6 I DECEMBER,

Downloaded from chestjournal.chestpubs.org by guest on July 10, 2011 © 1990 American College of Chest Physicians

1990

1473

tal bleeding or 4 hours.

than an identical dose infused The results of these studies

us to undertake a boltis

a clinical

injection

accelerated

trial

rt-PA

of

monary

to determine

is effective

thrombolysis

in

acute

the

with

assessed

rt-PA

or

the

scan.

amid

study

matic

popimlation

pulmonary

angiograph;

embolism

or

(defined

consisted

a high

mismatch”),

plums deep ,mltrasonograph:

bleeding

acquired intracranial

process:

major

trauma,

by

Parker

had

>100

suggestive

mm

Hg);

were

Since

had the

of

efficacy

established

the

in hsmmamis,

who

were

ered

ineligihle

they

received

The

and

mm

holus

weeks’ than

regimen

hours.

was

pulmonary

all

not

was

felt

to be

by

hospitals,

and

all patients before

Recombinant

TIssue

single

the

institutional

was

informed

musing

Tennessee) prmmjectiomi

rt-PA

(Activase)

obtained

from

produced

Genentech,

by South

a San

the

was

were

it was

retroperitoneal

units

followed

of 30,000

for the

dextrose/saline dose

was

adjsmsted

to maintain

infused

the

the

to

partial

hetweemu

per the

in 500

hour). results

control

using

dose

overt,

(AVT’T)

arrangement

assigned

to

placebo.

The

diagnosis onset

according

treatment

patients

to

with were

(pulmonary of

(correspondimig actimi-FS

either

of

rt-PA

stratified

amigiographv

symptoms

a prescribed

or

pulmomlary

not)

saline

to

and

the

the

(venuent

p-value outcome.

on

in each

two

Embolism

treatment

(Levine

et at)

groups

was

ment

in

compared the

compared

chi-square at

gromups

measuures.’

The

data were

aIpha-antiplasrnin

repeated

the defect

between

repeated and

with

perfusiomi

test.

24

hiouurs

musing

ami analysis

omi daily

hemoglobin

analyzed

The

mean

and

improve-

sevemu of

days

variamice

levels,

by analysis

percent

was with

fihrinogen

of variance

with

nueasuures.

Fifty-eight patients with actite pulmonary were randomized to either rt-PA (33 placebo (25 patients). The presenting who

received

percent), dyspnea five (15 percent), In the

rt-PA

was

chest

patients) symptom

in 27 (81.8 percent), while six (18 percent)

placebo

group,

chest

pain

syncope.

patients

Twenty-two

had

angiography,

(67

the

diagnosis

six

(18

experienced

confirmed by

by a high

lung scan associated with a positive five (15 percent) by high probability ated group

with who

positive received

duplex placebo,

diagnosis confirmed (16 percent) by high a positive

with

high

and

lung

scan

duplex ultrasonography. reasonably comparable

Scan

perfusion

received rt-PA was the control patients available

by a positive

and

percent)

25

who

21.3 lung

(98 percent): received

1-Baseline

Mortality

placebo.

During

who

percent in scans were

group

(years)

Males/Females

Previous

deep

psulinonary

vein

of symptoms

Duuration

of heparin

Mean eprior

perfusion

(days)* defect

(hours)* (%)

± SEM.

to study

treatment

infusion.

58.3

and the

died

p

the

Pulmonary study

Embolism

period,

compared

one

to none

patient

of the

study

who

patients

period.

of the

rt-PA

was

reasonably

mild hypotension and a third patient

experienced

which patient

hypotension

resolved in the

shortly

after

of placebo.

There were no major group. (The 95 percent difference

bleeds in confidence

of 0 is

-

13.5

either treatment interval out the percent

to

+

percent.) Three patients in each group required fusions during the ten-day study period. None patients

had

5

8

0.2

patients unrelated

required transfusion for medical to study drug administration,

7

6

0.9

secondary

42.3±4.0

32.2±3.0

0.7

27.4±3.6

21.3±3.7

0.2

at the used four

an

overt

site

to chemotherapy.

experienced insertion

0.8

within felt hot

within 2 minutes of experienced mild

hypotension associated with urticaria within 15 minutes of injection. One group

well

hot and diaphoretic A second patient

0.6

5.6±0.8

com-

of Therapy

developed infusion,

administration

Placebo

1.0

patients,

percent

0.7

5.9±

therapy

significant

in placebo

11/14

or

was

p=O.Oi7

respectively.

One patient felt of the infusion.

placebo

embolism

Duuration Baseline

thrombosis

to 11 percent

18/15

Cancer

in the patients p = 0.07

in perfusion

improvement,

bolums infusion

(34.4

59.6±3.6

in