Download Tissue Plasminogen Activator in Acute Pulmonary

Tissue Plasminogen
Embollsm*
SamuelZ.
The
M.D.,
Goidhaber,
interest
in Acute Pulmonary
FC.C.P
of thrombolytic
use
kened
Activator
therapy
in thrombolysis
to treat
AMI
for acute
has
reawa-
trial
embo-
a concurrent
trial is comparing
rtPA
ment in right ventricular
function,
pulmonary
lism (PE).
We have investigated
human
tissue-type
plasminogen
the use of recombinant
activator
(rtPA) in patients
with
acute
study,
than
90% efficacy
FE.
In an open
more
rapid
safety
and
an FDA-approved
dose
and
label
safer.
in carefully
rate from
comparing
(UK),
used
to treat
conducted
trials,
compares
and
end
use
more
roumust
be
because
the
decade
(Fig
points
of thrombolysis
Seven
potential
of the
advantages
mortality
of thrombolysis
rate,
are:
(2) accelerated
(1) reduc-
reversal
spurred
1980s
heart failure, (3) reduced
rate of recurrent
situ the source
of the initial
PE), (4) reduced
PE
pulmonary
hypertension
thrombus
pulmonary
arteries),
(5) accelerated
(6) accelerated
clot lysis,
perfusion,
monary
capillary
tages
latter
(by
blood
are promising
3 advantages
lysing
volume.
hypotheses
have been
residual
(by lysing in
risk of chronic
in the
pulmonary
tissue
and (7) improved
The
first
4 potential
that should
demonstrated
repul-
advan-
patients
patients
(UK) or
pulmonary
reperfuslon
Improved
on lung
pulmonary
to urokinase
accelerated
scanning
capillary
and clot lysis on angiography.
blood
volume
was sustained
While
several
of the
cost.
In addition,
agents
requires
laboratory,
apparent
a small
FDA
ment
UK
NIH
and
the
more
an investment
pharmacy
disadvantages,
percentage
approved
potential
UK
frequent
Because
(and
has been
PE, even
streptokinase
has
for
Development
patency
Therefore,
Division,
Boston.
urged
Reprint requests:
Dr. Goldhaber,
Cardiovascular
and Womens Hospital,
Boston 12005
282S
safety
in the
agent,
was
causing
studies
of
efficacious
2).’
MI,
A
human
developed
animal
more
or SK (Table
early
for PE.
In lysis
rtPA
of
caused
artery
more often than SK.9”#{176}
on an open label study
of rtPA to
in the
treatment
of acute
RATES
(NHDS)
PE.
30%
20%
C.rtltlc.t.s
PE
100%)
Hospital
Discharge
Forms Citing PE
(Ooldhab.r
10%
used in only
though
the
PE
more
treat-
doses
1980,
1985
S Z: Am
Heart
1979-23.6%
1983-24.0%
1985-24.7%
widespread
Hospital,
Division,
Brigham
115:1342)
1.
of
an
and Women’s
J 1900;
Data from US National
Hospital
Discharge
Survey
provide the ratio of all deaths with any mention
of PE on the death
certificate
to the number
of discharge
forms, with PE coded
as a
primary
or secondary
diagnosis.
These ratios approximate
a case
fatality ratio but are probably
overestimates,
because
the numerator
may not be completely
included
in the denominator.
The death
rates are:
FICUIIE
immediately
for
[SK])
Brigham
UK
thrombosis
PE DEATH
Table
5From
the Cardiovascular
Harvard
Medical
School,
and
impact
AM!
(rtPA),
technology.
In
tPA appeared
of the infarct-related
we embarked
its efficacy
to treat
fibrin-specific
than
artery
However,
discernible
in thrombolysis
activator
safer
coronary
little
19791983
apparent
increased
sanctioned
moderate
12-24
h (Table
1). In
Panel
potentially
acute
D.ath
Citing
use of thrombolytic
to educate
nursing,
of these
thrombolysis
of patients
with
recurrent
of thrombolysis
immediately
risk and
of time
staff.
in 1977. The FDA
or SK administered
Consensus
advantages
proved,
there
are two
increased
hemorrhagic
therapy
plasminogen
heparin,
tissue
even 1 year after thrombolytic
therapy.
However,
radiologic
end points
such as lung scanning
and angiography
do not
guarantee
clinical
benefit,
and the clinical
significance
of
impoved
pulmonary
capillary
blood volume
is uncertain.
remain
to be
disadvantages:
and
had
interest
with
recombinant
DNA
venous
thromboembolism,
test
PE treatment.
In
(UPET),2
in which
had
of clini-
and
thromboembolism.
relatively
be tested.
The
but have not
resulted
in use of thrombolysis
for routine
the Urokinase
Pulmonary
Embolism
Trial
were
randomized
assigned
to UK
for reduction
as mortality
have
a renewed
tissue-type
right
of
heparin
such
in venous
these
recommendations
on clinical
practice.
The use of thrombolytic
second-generation,
1).1
tion
In addition,
vs heparin
for improveassessed
by echocardi-
patients.
However,
the greatest
chalis to undertake
a large-scale
trial that
thrombolysis
relevant
of UK.
regimen
PE.
life-threatening
in the past
a novel dosing
with
ography,
among
PE
lenge in FE research
cally
a comparative
only
clinical
with
appeared
(PE) or be employed
of PE?
This
issue
PE has not declined
more
rtPA
rtPA
We are now conducting
hould
thrombolysis
be
pulmonary
embolism
tinely
in the
management
death
In a trial
of urokinase
S
addressed
achieved
rtPA
of rtPA
1-FDA
Urokinase:
Streptokinase:
2,000
Approved
U/lb
250,000
bolus
Thrombolytic
for
FE
by 2,000 U/lb/h for 12-24 h
followed by 100,000
U/h for 24 h
followed
U bolus
Tissue Plasminogen
Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21594/ on 06/16/2017
Regimens
Activator
in Cardiopulmonary
Disease
Table
2-Experieswe
with
IPA in Experimental
Model
Animal
Drugs
Canine superficial
femoral venous
thrombosis
(5)
Rabbit jugular venous thrombosis
Rabbit jugular venous thrombosis
(6)
(7)
Venous
Thromboembolism5
Compared
1 mg
tPA vs 1 million
1 mg
tPA vs 500,000
Results
LU UK
more
50%
LU UK
lysis with tPA
more
49% more
lysis with
lysis with
more
lysis with
50%
0.15 mg/kg h x 4 h
tPA vs 16,000 units/kg/h
tPA
tPA
4hSK
Rabbit
embolism
pulmonary
*tpA
=
tissue-type
(8)
0.35
plasminogen
activator;
SK
=
streptokinase;
mg
UK
tPA vs 1 million
=
33%
UK
(Reprinted
urokinase.
with
permission
from J Am Coil Cardiol
tPA
1987;
10:97B.)
OPEN
In 1985-86,
trial.”’
All
We
grams.
peripheral
47
patients
patients
vein
received
over
angiogram
immediately
the
was
study
were
50
infused
rtPA
LABEL
2
additional
40 mg of rtPA
4 h (10 mg/h),
and a third
enrolled
of
h
(25
rtPA
our
initial
angiothrough
and
repeated
If this
showed
clot
If no
clot
administered
was
angiogram
lysis
a
the
lysis,
occurred,
over the
performed.
an
ensuing
Unlike
of the rtPA
heparin
evidence
rtPA
pulmonary
(Activase)
mg/h)
thereafter.
was
most
in
baseline
mg
terminated.
TRIAL
When
in
trials
in MI,
no patient
received
concomitant
and rtPA.
Of the 47 patients,
44 had
of clot lysis after
2-6 h of treatment
improvement
27%,
hemorrhagic
and
occurred,
marked
in
it was slight
Two
62%.
complication.
One
and the
coronary
other developed
artery
bypass
surgery
to control
the
bleeding;
in 11%,
patients
bled
mediastinal
surger,
angiographic
with rtPA.
from
moderate
had a major
a pelvic
tumor
tamponade
8 days after
Both
patients
required
they
subsequently
did
well
I
2. M-mode echocardiograms
using subcostal
approach
before (left) and
after
(right) thrombolytic
therapy
show
marked
decrease
in the diameter
of the
right ventricle
(RV), from 6.0 to 2.35 cm,
and an increase
in diameter
of the left
ventricle
(LV), from 3.1 to 4.2 cm. LW
wall movement,
very hypokinetic
during
FIGURE
acute
pulmonary
appreciably
after
electrocardiogram;
SEP = septum;
(Reprinted
with
Coil Cardiol 1987;
embolism,
improved
lytic therapy.
EKC
PW = posterior
wall;
TV = tricuspid
valve.
permission
from J Am
10:971-78.)
FIGuRE
3. Subcostal
two-dimensional
images at end-diastole
corresponding
to
the M-mode
tracings shown in Figure 2.
Before recombinant
tissue-type
plasminogen activator
(rtPA)
therapy
(left), the
right ventricle
(RV) is markedly
enlarged
and left ventricular
(LV) diameter
reduced.
After
infusion
of rtPA (right
panel), a remarkable
decrease
in RV size
and a corresponding
increase
in the size
of the left ventricle.
BA = right atrium;
other abbreviations
as in Figure
2. (Reprinted
with permission
from J Am Coll
Cardiol 1987; 10:971-78.)
CHEST/95/5/MAY.l9O9ISuppIement
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2838
PREMATURE
Groin
TERMINATION
OF UK (N=1O)
FIGURE
5. Time
in 2 clocks,”
each representing
12 h
of UK infusion.
The clock on the left represents
0-12
of UK; clock on the right represents
12-24
h of UK.
(9.3)
Bleed
Reasons
for discontinuing
UK were distributed
evenly
the 24-h infusion
period.
If the protocol
had required
a 12-h rather than 24-h infusion of UK, 5
(8)
Hematen
Groin
throughout
Hematuria
(6.5)
6h
additional
changes
treatment
window
from
following
symptoms
or
treatment
in the
failures
Finally,
we
protocol.
5 days
study
the
patients’8
in 1987. The principal
ment on the 2-h angiogram
and
U/lb/h
angiogram
was
was
than
twice
24 h after
The
an
U/lb
as
toward
exclusion
The
angiog-
a fixed
dose
of 100
thought
the UK
UK
by
the 2-h
infusion
reaction
h and,
(with
therefore,
fever,
had
angiographic
UK
patients
obtained
therapy.
remained
patients
2 of 23 UK
for baseline
received
patients
rigors,
back
UK
pain,
infusion
and
or
drug
treatment.
Of
investigators
the
intended
9 had
to
UK terminated
and
bleeding
and
scored
the
timing
was
sets
absent.
1 in
who
of lysis
Moderate
compared
patients
a panel
of
a particular
administered.
Of those
(p = 0.008).
by
of
of angiograms
evidence
unchanged
(Fig
tracing,
man
with
ingly,
there
mg/2
among
Panelists
as marked,
received
mod-
rtPA,
compared
with
82%
48%
or marked
lysis
with 13% who
those
angiographic
lung scans
8). An example
of
occurred
received
lung
the
h) lyses
with
greater
regimen
for
is showsi
of dyspnea
rtPA
(Fig
this
PE clot
more
UK
groups
randomized
rapidly
and
9-11).
in
PRESSURES
groups
artery
Interest-
in plasma
fibrinogen
(Fig
12).
trial
that
can
rtPA
(100
be administered
safety
than
the 24-h,
FDA-approved
UK. Of note
is that by 24 h after
PA
7). In
in a 58-year-old
(Figs
difference
and
from
rash)
terminated
UK
at 2 h, improvement
scan
history
was no significant
conclude
receiving
results
at 24 h was identical
in both
of the angiogram,
pulmonary
and
a 5-day
between
We
the
were
which
to the
levels
matched
neither
within
of rtPA
contrast
pressure
was
before
UK (p
0.002)
(Fig 6). After 2 h of therapy,
average
pulmonary artery
pressures
decreased
among
rtPA patients
but
was given without
a bolus
thromboplastin
time was
well
the
had
coded
knew
nor
slight,
perfusion
scan
2 h of
the
of intolerable
were
who
59%
drug discontinued
infusion.
22 h of therapy,
in 8 because
erate,
in
the
5).
changes
UK
angio-
by the local
investigator
to have
angiographically
clot lysis at 2 h. One of these 2 patients
experienced
allergic
an additional
angiograms
graded
full
the
of whom
each
investigators
of 45
trial
2 h (50 mg/h).
The
an IV bolus
followed
lung
22 rtPA-treated
of drug.
Only
with
prematurely,
error (Fig
period
pulmonary
investigator
clot lysis,
were
treat
of
21,
angiogram
of thrombolytic
UK patients
All
dose
100-mg
at 1.75
entered
Second,
we included
a past history
of PE.
randomized
A follow-up
initiation
and
characteristics.
entire
over
or UK, heparin
time or partial
control.
the
rtPA
judged
proved
been
3
would
have had
of the intended
completion
remaining
of our
(The
decision
about
discontinuing
spot, before
formal
analysis
of the
grams.)
After rtPA
when the thrombin
before
end points
were improve24-h lung scan. All patients
vein
for 24 h. If the
indicated
significant
discontinued.
made
on the
less
none
baseline
lung scanning
and
4). The rtPA patients
received
mg through
a peripheral
patients
received
2,000
the
to 14 days
because
had
safety.
vs UK
extended
study)
postoperative
from 7 to 10 days to enhance
We carried
out our rtPA
2,000
we
first
treatment
window.
trial patients
with
extended
underwent
raphy
(Fig
First,
(in the
of PE,
signs
in the first
the end of the 5-day
in the randomized
patients
completion
18h
(mm
dosing
initiating
Hg)
50
40
ANGIOGRAPHIC
WITHIN
2 HOURS
LYSIS
(N=45)
rt-PA
30
PA
Pressure
UK
/\13%/
IMarkedl\
/13%\
ate
\
II
(atJJ
-4
I
20
10
#{149}
rt-PA
UK
None
PRE
(zrs
\._.“cuIght
Slight
\,>‘.s1’
\\
)
FIGURE
creased
9%
after
6.
Lysis
after
2 h of therapy:
rtPA
vs UK.
7. Among
from 50/20
2 h of therapy.
pressures,
systemic arterial
artery
FIGURE
POST
TREATMENT
STATUS
rtPA patients,
pulmonary
artery
(mean
31) mm Hg to 39/15 (mean
Urokinase
patients
had no change
and neither
pressure
after
CHEST
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group had a significant
2 h of treatment.
pressures
24) mm
deHg,
in pulmonary
change
in
/ 95 / 5 / MAY, 1989 I Supplement
285S
PREMATURE
Groin
TERMINATION
OF UK (N=1O)
FIGURE
5. Time
in 2 clocks,”
each representing
12 h
of UK infusion.
The clock on the left represents
0-12
of UK; clock on the right represents
12-24
h of UK.
(9.3)
Bleed
Reasons
for discontinuing
UK were distributed
evenly
the 24-h infusion
period.
If the protocol
had required
a 12-h rather than 24-h infusion of UK, 5
(8)
Hematen
Groin
throughout
Hematuria
(6.5)
6h
additional
changes
treatment
window
from
following
symptoms
or
treatment
in the
failures
Finally,
we
protocol.
5 days
study
the
patients’8
in 1987. The principal
ment on the 2-h angiogram
and
U/lb/h
angiogram
was
was
than
twice
24 h after
The
an
U/lb
as
toward
exclusion
The
angiog-
a fixed
dose
of 100
thought
the UK
UK
by
the 2-h
infusion
reaction
h and,
(with
therefore,
fever,
had
angiographic
UK
patients
obtained
therapy.
remained
patients
2 of 23 UK
for baseline
received
patients
rigors,
back
UK
pain,
infusion
and
or
drug
treatment.
Of
investigators
the
intended
9 had
to
UK terminated
and
bleeding
and
scored
the
timing
was
sets
absent.
1 in
who
of lysis
Moderate
compared
patients
a panel
of
a particular
administered.
Of those
(p = 0.008).
by
of
of angiograms
evidence
unchanged
(Fig
tracing,
man
with
ingly,
there
mg/2
among
Panelists
as marked,
received
mod-
rtPA,
compared
with
82%
48%
or marked
lysis
with 13% who
those
angiographic
lung scans
8). An example
of
occurred
received
lung
the
h) lyses
with
greater
regimen
for
is showsi
of dyspnea
rtPA
(Fig
this
PE clot
more
UK
groups
randomized
rapidly
and
9-11).
in
PRESSURES
groups
artery
Interest-
in plasma
fibrinogen
(Fig
12).
trial
that
can
rtPA
(100
be administered
safety
than
the 24-h,
FDA-approved
UK. Of note
is that by 24 h after
PA
7). In
in a 58-year-old
(Figs
difference
and
from
rash)
terminated
UK
at 2 h, improvement
scan
history
was no significant
conclude
receiving
results
at 24 h was identical
in both
of the angiogram,
pulmonary
and
a 5-day
between
We
the
were
which
to the
levels
matched
neither
within
of rtPA
contrast
pressure
was
before
UK (p
0.002)
(Fig 6). After 2 h of therapy,
average
pulmonary artery
pressures
decreased
among
rtPA patients
but
was given without
a bolus
thromboplastin
time was
well
the
had
coded
knew
nor
slight,
perfusion
scan
2 h of
the
of intolerable
were
who
59%
drug discontinued
infusion.
22 h of therapy,
in 8 because
erate,
in
the
5).
changes
UK
angio-
by the local
investigator
to have
angiographically
clot lysis at 2 h. One of these 2 patients
experienced
allergic
an additional
angiograms
graded
full
the
of whom
each
investigators
of 45
trial
2 h (50 mg/h).
The
an IV bolus
followed
lung
22 rtPA-treated
of drug.
Only
with
prematurely,
error (Fig
period
pulmonary
investigator
clot lysis,
were
treat
of
21,
angiogram
of thrombolytic
UK patients
All
dose
100-mg
at 1.75
entered
Second,
we included
a past history
of PE.
randomized
A follow-up
initiation
and
characteristics.
entire
over
or UK, heparin
time or partial
control.
the
rtPA
judged
proved
been
3
would
have had
of the intended
completion
remaining
of our
(The
decision
about
discontinuing
spot, before
formal
analysis
of the
grams.)
After rtPA
when the thrombin
before
end points
were improve24-h lung scan. All patients
vein
for 24 h. If the
indicated
significant
discontinued.
made
on the
less
none
baseline
lung scanning
and
4). The rtPA patients
received
mg through
a peripheral
patients
received
2,000
the
to 14 days
because
had
safety.
vs UK
extended
study)
postoperative
from 7 to 10 days to enhance
We carried
out our rtPA
2,000
we
first
treatment
window.
trial patients
with
extended
underwent
raphy
(Fig
First,
(in the
of PE,
signs
in the first
the end of the 5-day
in the randomized
patients
completion
18h
(mm
dosing
initiating
Hg)
50
40
ANGIOGRAPHIC
WITHIN
2 HOURS
LYSIS
(N=45)
rt-PA
30
PA
Pressure
UK
/\13%/
IMarkedl\
/13%\
ate
\
II
(atJJ
-4
I
20
10
#{149}
rt-PA
UK
None
PRE
(zrs
\._.“cuIght
Slight
\,>‘.s1’
\\
)
FIGURE
creased
9%
after
6.
Lysis
after
2 h of therapy:
rtPA
vs UK.
7. Among
from 50/20
2 h of therapy.
pressures,
systemic arterial
artery
FIGURE
POST
TREATMENT
STATUS
rtPA patients,
pulmonary
artery
(mean
31) mm Hg to 39/15 (mean
Urokinase
patients
had no change
and neither
pressure
after
CHEST
Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21594/ on 06/16/2017
group had a significant
2 h of treatment.
pressures
24) mm
deHg,
in pulmonary
change
in
/ 95 / 5 / MAY, 1989 I Supplement
285S
PROPORTION
OF
NONPERFUSED
.50
LUNG
regimen
of
#{149}
ri-PA
DUK
similar
rtPA
and
patients
over
and
90 mm,
with the
Other
.20
UK
with
efficacy
.30
a novel
dosing
in achieving
AMI.
.10
safety,
GAUS,
in
the
with
mg/2
34
patients
8. No significant
difference
in
therapy
or after
24 h of therapy
between
segmental
scoring
method
of Parker
nonperfused
lung among
rtPA patients
and among
UK patients
decreased
from
therapy,
there
UK.
of fibrinogen
are
was
Further,
no
there
levels
now
when
engaged
difference
was
the
perfusion
lung scans before
the 2 groups.
Using
the
et al,’
the proportion
of
decreased
from 0.41 to 0.29
0.42 to 0.30.
in
no
two
in a trial
efficacy
difference
drugs
comparing
between
in the
were
rtPA
decrement
compared.
the
European
h) with
patency
and
dose
3 million
UK
same
1
massive
dosing
angiography.’
but was
heparin.
of rtPA
was
70 mg
over
90 mm
in
acute
randomized
They
found
They
of UK.
found
now
comparing
The
principal
rtPA
and
that
and heparin
posttreatment
rtPA
rtPA
end
of rtPA
trial
The most
recent
administer
a high
IV
that
vs heparin
A group
of Henry
clot
complications
is embarking
and
will
(100
points
in 13 patients
pulmonary
accelerated
with more
bleeding
of Italian
institutions
dosing
regimen
that
study plans to enroll
ment and posttreatment
PE.
vs peripheral
PE.
are
infusion
associated
A group
similar
offered
neither
improved
with the intravenous route.
investigators
compared
pretreatment
among
had
U of UK
mntrapulmonary
with
a 12-h
Ford
Hospital,
who underwent
STATUS
FIGURE
UK:
Activator
efficacy
of
are angiographic
and hemodynamic
improvement.
of American
investigators
led by Paul Stein,
M.D.,
POST
TREATMENT
artery
rtPA
although
compared
et al#{176}
compared
These
PRE
of
in the German
compared
the
coronary
In
intrapulmonary
administration
efficacy nor safety compared
0#{149}
regimen
initial
1.5 million
U given
as a bolus.
investigators
have
studied
rtPA
Verstraete
rtPA
We
with
the dose administered
Study
(GAUS),’9
which
to
Urokinase
.40
and
rtPA
million
U over 10 mm followed
by 2 million
U over 110 mm,
for a total dose of 3 million
U over
2 hs. To date,
24 patients
have been
enrolled.
This
novel
dosing
regimen
of UK is
use
lysis
than
on a
the
same
we employed
(100 mg/2 h). The Italian
60 patients
who will undergo
pretreatangiography.
trend
with thrombolytic
dose over a short
period.
therapy
is to
For example,
9. Pulmonary
angiograms
(right anterior
oblique
position).
A (left), Intraluminal
clot in right
and lower lobe arteries
(arrows) before treatment.
B (right), Evidence
of clot lysis (arrows)
2 h after
initiation
of rtPA. (Reprinted
with permission
from Lancet 1988; 2:295).
FIGURE
upper
286S
Tissue
Piasminogen
Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21594/ on 06/16/2017
Activator
in Cardiopulmonary
Disease
PA
PLASMA
PRESSURE
(mgldl)
FIBRINOGENS
#{149}
rt-PA
500
I
0 UK
400
POST
300
10. Pulmonary
artery pressure
tracings.
Pulmonary
were 118/40
(mean
PA pressure,
65) mm
Hg
and 53/19 (mean,
34) mm Hg after 2 h of rtPA.
FIGURE
pressures
treatment
Shiffinan
et al
in dogs was
mm infusion
mm
infusion.
have
been
acute
PE
in Winnipeg
Clinically,
studying
patients
bolus over
of this trial
found
more
rapid
among
of rtPA compared
the
that
those
with
the
investigators
in Hamilton,
rtPA
of rapid
randomized
to either
of PE
lysis
a 15a 90-
Ontario,
administration
rtPA
Flbrlnogen
artery
before
receiving
receiving
use
0.6
mg/kg
PRE
ofthrombolytic
therapy
on hemodynamic
or radiologic
improvement.
uncertain
whether
to dictate
practice.
the ideal management
It is well-known
that
eventually
of course,
improve
that with
will fail to have
and
one-third
scintigraphic
these
as a
TREATMENT
complete
of PE
residual
it is
can
lead
to the
pulmonary
clinical
PE will
individuals
dysfunction
residual
patients
the
PE.”
pulmonary
It is
arteries
During
the
complication
is
also
few
area
by
(TIPE)
in mortality
(Fig 2 and 3).
years,
several
had
an additional
survey.
Third,
tive
Investigation
(PIOPED)
ever
that
among
that
ventilation-perfusion
of the
scan
presence
with
These
thrombolysis
might
acute
PE.
there
is
investigators
A total
lung
for a positive
scans,
without
can,
Diagnosis
predictive
angiogram
suspicion.
Almost
with
high-probability
therefore,
undergoing
potentially
angiography
in the
Prospec-
high-probabil-
positive
pulmonary
of high clinical
PE will present
individuals
with
the
to
of 44 institutions
Embolism
patients
as
present
with
PE patients
thrombolysis
American
Pulmonary
have
First,
Pulmonary
can be
patients
with
coinvestigators,”
in PE.
among
to
trends
PE.
60 satellite
centers)
participated
results
from the unpublished
of
indicate
make
to prompt
important
for acute
thought
thrombolysis
(plus
TIPE
scans.
owing
Terrin
and Thrombolysis
in
coinvestigators,
thrombolysis
than
using
in the
patients
some
however,
is the possibility
rtPA or other
thrombolytic
of thrombolysis
some
interest
value
that
safely to half of the patients
who
Until
this extensive
survey
of 2,500
undertaken,
consider
ity
of chronic
possible
or deep leg veins may
alone
more
susceptible
be contraindicated
in almost
all
Second,
as demonstrated
by TIPE
more
R
past
in the
administered
acute
PE.
was
It
PE. Most important,
safe treatment
with
demonstrated
Embolism
R
dreaded
may lead to a reduction
of right heart failure
emerged
/
but
thrombus
in the pelvic
who
receive
heparin
agents
reversal
after
fibrinogen
levels (mgldl) were as
vs UK 394; 2 h: rtPA 225 vs UK
PE may have long-term
residual
right heart
that
is of clinical
significance.
Furthermore,
by
in the
STATUS
with
recurrent
that rapid,
4 months
rare
hypertension.
angiographic
resolution
by 1 month
patients
may
not have
complete
thrombus
plasma
follows:
pretreatment:
rtPA 409
239; 24 h: rtPA 269 vs UK 236.
be extrapolated
strategy
in routine
most patients
with
average
24 hours
focused
However,
should
12. The
FIGURE
POST
hours
2
with heparmn therapy.
We are concerned,
heparin
alone,
as many as 75% of patients
recovery
that
parameters
in PE have
POST
in
2 mm or heparmn
alone.
The principal
end point
will be scmntigraphic
improvement
on perfusion
lung scans.n
To date, studies
possible
rate
dogs
those
_____
and
is 95%
half of
lung
receive
will
thus
be spared
the delay,
discomfort,
cost,
and bleeding
risks
associated
with thrombolysis
after pulmonary
angiography.
(Of course,
based
on PIOPED,
we estimate
that about
half
of the patients
with
PE will still require
angiography
for
FIGURE
segmental
of defects
Lancet
11. Perfusion
lung scans (posterior
and lobar defects before treatment.
1988;
after
rtPA
2:295.)
therapy.
(Reprinted
view). A Multiple
B (lower), Correction
with permission
from
definitive
thrombolysis
more
with
diagnosis
have
effective
drug
the currently
of PE.)
Fourth,
resulted
in at least
regimen
(100
FDA-approved
CHEST
Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21594/ on 06/16/2017
I 95
I 5 / MAY,
new
approaches
1 potentially
safer
to
and
mg/2 h of rtPA) compared
regimens
(Table
1). We
1989 / Supplement
287S
await
with
ongoing
great
rtPA
confirm
our
ultrasound
findings.
imaging
of the
UK
of the
for
own
of
trial,
Doppler
deep
leg
group’s
which
ongoing
3 million
vs UK
a
thrombolytic
regimen
echocardiography,
and
novel
clinical
nonin-
routine
(from
these
in PE
encouraging
thrombolysis
use of thrombolytic
recurrent
PE and
tality
of venous
is obtained,
be fully
future
We
study
contraindications
PE
will
end
points
ingful
be
Until
in
which
events.
patient
entry
the
and
absence
acute
The
other
this
10 Verstraete
angiography
in the
suspicion.
Those
evolution
of us who manage
PE can learn
much
from
the
of thrombolysis
trials for acute
MI. Initially,
these
were
taken
can
to moderate
that
we learned
reduce
the
studies
and
small
angiography.
efforts
involving
no longer
the greatest
from trials
and
high
featured
clinical
mandatory
It was not until
multicentered
thousands
of patients
were
conclusively
mortality
of mortality
sized
and
were
required
rate
that
streamlined
coronary
thrombolytic
of AMI.”
and
angiography.
challenge
in PE clinical
of 25-50
patients
to trials
of the proper
role
of thrombolysis
15
larger
straighiforward
16
At present,
research
is to evolve
that recruit
hundreds
in PE treatment.
17
18
1982;
69:573-80
6 Coilen D, Stassen JM,
extrinsic
(tissue-type)
experimental
jugular
and dose of activator,
administration.
J Clin
7 Agnelli
C, Buchanan
288S
Verstraete
M. Thrombolysis
with human
plasminogen
activator
in rabbits
with
vein thrombosis:
effect of molecular
form
age of the thrombus,
and route of
Invest 1983; 71:368-76
MR, Fernandez
F, et al. A comparison
of
M, et al. Randomized
tissue-type
intravenous
streptokmnase
in acute
plasminogen
myocardial
trial of
activator
infarction.
vs.
Lancet
1:842-47
investigators.
Thrombolytic
lism:
current
status
1987;
10:968-104B
therapy
and
future
of acute
potential.
pulmonary
embo-
J Am Coil
Cardiol
19
embolism:
segmental
perfusion
plasminogen
activator
of acute
pulmonary
Neuhaus
K-L,
Niederer
W, et al. Intravenous
activator
(rt-PA)
versus
embolism.
analysis.
Tebbe
U,
and
Gottwik
urokmnase
Radiology
in the
Weber
MAJ,
recombinant
tissue
in acute
myocardial
Urokinase
Study
W,
infarction:
(GAUS).
J Am
Charbonnier
B,
M,
embolism.
H,
Feuerer
plasminogen
Lecorf
C, et al. Intravenous
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tissue-type
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Bounameaux
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Colle JP,
recombinant
massive
GAH,
M,
1988;
Verstraete
of acute
Miller
urokinase
Lancet
Results of the German
Activator
Coil Cardiol
1988; 12:581-87
20
scan
1988; 166:441-45
Come PC, Kim D, Parker
JA, Goldhaber
SZ, Braunwald
E,
Markis JE, participating
investigators.
Early reversal
of right
ventricular
dysfunction
in patients
with acute pulmonary
embolism
after treatment
with intravenous
tissue plasminogen
activator.
J Am Coil Cardiol
1987; 10:971-78
Vaughan DE, Goldhaber
SZ, Kim J, Loscalzo J, on behalf of the
participating
investigators.
Recombinant
tissue
plasminogen
activator
in patients
with pulmonary
embolism:
correlation
of
fibrinolytic
specificity
and efficacy. Circulation
1987; 75:1200-03
Cold HK, Johns JA, Leinbach
RC, et al. A randomized,
blinded,
placebo-controlled
trial of recombinant
human tissue-type
plasminogen
activator
in patients
with unstable
angina pectoris.
Circulation
1987; 75:1192-99
Goldhaber
SZ, Kessler
CM, Heit J, Markis J, Sharma
GVRK,
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D, et al. Randomised
controlled
trial of recombinant
tissue
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