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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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