Management
of
unstable
angina
has
become
more
aggressive
to
include
full
medical
therapy
with
anti-thrombotic
and
anti-ischemic
drugs
,
often
followed
by
coronary
angiography
and
revascularization
procedures
.
Much
of
the
published
data
about
the
natural
history
of
unstable
angina
corresponds
to
selected
patients
included
in
randomized
clinical
trials
.
Therefore
these
patients
may
not
represent
the
general
population
admitted
to
community
hospitals
.
Unstable
angina
is
also
quite
heterogeneous
,
with
a
wide
spectrum
of
clinical
manifestations
and
prognostic
categories
.
in
addition
,
most
of
the
data
on
the
evolution
and
prognosis
of
unstable
angina
were
obtained
before
the
development
of
new
drugs
and
interventional
procedures
for
management
of
this
disease
.
This
multicenter
study
enrolled
a
large
cohort
of
patients
admitted
with
unstable
angina
to
identify
the
clinical
and
electrocardiographic
markers
associated
with
in-hospital
death
and
myocardial
infarction
,
in
the
context
of
a
nonselected
population
admitted
consecutively
to
community
hospitals
and
treated
according
to
current
therapeutic
strategies
.
This
was
a
multicenter
prospective
study
of
consecutive
patients
admitted
to
coronary
care
units
with
unstable
angina
.
To
select
a
representative
sample
and
safeguard
against
selection
bias
,
all
consecutive
patients
admitted
to
the
coronary
care
unit
with
a
suspicion
of
an
acute
ischemic
syndrome
were
included
in
the
database
.
If
the
admission
diagnosis
turned
out
to
be
Q-wave
or
non-Q-wave
myocardial
infarction
,
or
if
a
nonischemic
cause
of
chest
pain
became
clearly
evident
,
the
process
of
data
collection
was
interrupted
and
the
patient
censored
from
subsequent
analysis
.
The
diagnosis
of
Q-wave
or
non-Q-wave
acute
myocardial
infarction
present
at
admission
was
made
on
the
basis
of
the
finding
of
an
elevated
total
creatine
phosphokinase
(
CPK
)
plasma
level
(
greater
than
2-fold
increase
above
normal
value
)
at
entry
to
the
study
or
at
any
time
up
to
12
hours
thereafter
.
for
patients
prescribed
thrombolytic
treatment
or
primary
coronary
angioplasty
at
entry
,
the
enzymatic
criteria
were
not
required
and
the
diagnosis
was
made
on
the
basis
of
the
finding
of
chest
pain
lasting
more
than
30
minutes
plus
>
=
1
mm
ST
elevation
in
at
least
3
precordial
or
2
standard
electrocardiogram
(
ECG
)
leads
.
Between
March
1991
and
May
l
992
,
1172
consecutive
patients
with
suspected
acute
ischemic
syndrome
were
prospectively
enrolled
.
This
group
represented
23
%
of
the
total
population
admitted
to
the
coronary
care
units
during
that
period
of
time
.
One
hundred
and
thirty-four
patients
(
11.4
%
)
were
excluded
:
46
patients
because
of
an
evolving
myocardial
infarction
unequivocally
present
at
hospital
admission
and
88
patients
because
of
noncardiac
chest
pain
.
The
remaining
1038
patients
with
unstable
angina
formed
the
study
population
.
Data
collected
include
demographics
and
baseline
clinical
variables
.
Electrocardiograms
were
routinely
obtained
at
admission
,
during
subsequent
episodes
of
chest
pain
,
and
at
hospital
discharge
.
Serum
total
CPK
levels
were
determined
at
admission
,
every
12
hours
during
the
first
24
hours
,
and
after
a
new
chest
pain
episode
during
hospital
stay
.
Changes
in
the
ECG
were
considered
positive
if
there
was
>
=
1
mm
of
ST-segment
elevation
or
depression
in
at
least
2
limb
leads
or
3
precordial
leads
or
symmetric
T-wave
inversion
in
at
least
3
limbs
or
precordial
leads
.
The
treatment
received
,
any
coronary
intervention
,
and
all
the
in-hospital
events
(
angina
,
acute
myocardial
infarction
,
and
death
)
were
also
recorded
.
The
investigator
who
was
responsible
for
the
patient
was
instructed
to
carry
a
daily
prospective
and
systematic
register
of
all
new
chest
pain
episodes
in
addition
to
all
the
information
related
to
the
associated
electrocardiographic
and
enzymatic
alterations
.
All
the
ECG
tracings
were
examined
by
an
ECG
core
lab
reader
who
was
blinded
to
the
patient
clinical
condition
to
validate
ST-segment
changes
>
=
1
mm
,
T-wave
changes
,
left
bundle
branch
block
,
and
left
ventricular
hypertrophy
.
Serial
electrocardiograms
were
compared
to
evaluate
if
the
changes
were
transient
or
fixed
.
The
medical
treatment
was
entirely
left
to
the
discretion
of
the
treating
physician
except
for
a
strong
recommendation
to
use
aspirin
in
all
patients
.
New
episodes
of
ischemic
chest
pain
after
admission
were
classified
as
(
1
)
recurrent
angina
,
defined
as
angina
occurring
in
the
absence
of
full
medical
therapy
or
(
2
)
refractory
angina
,
angina
occurring
while
the
patient
was
receiving
full
medical
therapy
.
Full
medical
therapy
was
defined
as
the
combination
of
aspirin
and
/
or
intravenous
heparin
,
nitrates
,
and
b-blockers
or
calcium
antagonists
at
clinically
effective
doses
.
The
adequacy
for
full
medical
therapy
was
left
to
the
decision
of
the
treating
physician
with
suggested
criteria
of
heart
rate
<
60
beats
/
min
and
systolic
blood
pressure
<
120
mm
Hg
.
Major
in-hospital
events
were
new
myocardial
infarction
and
death
from
any
cause
.
Hospital
mortality
was
defined
as
death
occurring
in
the
hospital
at
any
moment
from
arrival
through
discharge
.
The
criteria
for
new
in-hospital
acute
myocardial
infarction
included
all
of
the
following
:
(
1
)
new
prolonged
episode
of
chest
pain
after
admission
;
(
2
)
elevation
of
total
CPK
level
greater
than
twice
the
limit
of
normal
,
and
(
3
)
the
development
of
new
Q-wave
or
ST-T
changes
on
the
ECG
.
Events
that
occurred
during
or
within
24
hours
after
an
invasive
procedure
(
coronary
angiography
,
coronary
angioplasty
,
or
coronary
bypass
surgery
)
were
considered
procedure
related
.
The
remaining
events
were
prospectively
classified
as
spontaneous
.
An
ad-hoc
committee
blinded
to
the
clinical
variables
and
the
administered
treatment
examined
and
validated
all
major
events
(
acute
myocardial
infarction
or
death
during
hospitalization
)
with
a
systematic
review
of
serial
electrocardiograms
,
enzymatic
curves
,
and
clinical
charts
of
all
patients
who
had
major
events
reported
or
adjudicated
by
investigators
.
The
initially
targeted
sample
of
1000
patients
was
based
on
a
projected
24
%
rate
of
events
(
16
%
refractory
angina
,
6
%
acute
myocardial
infarction
,
and
2
%
death
)
.
An
a
level
of
significance
<
.05
was
considered
for
all
purposes
.
Unadjusted
odds
ratios
and
95
%
confidence
intervals
were
obtained
for
selected
clinical
factors
judged
to
be
associated
with
the
outcome
of
interest
.
Univariate
and
forward
stepwise
multiple
logistic
regression
models
were
used
to
evaluate
the
independent
association
of
variables
present
at
admission
to
in-hospital
acute
myocardial
infarction
or
death
.
From
28
clinical
and
electrocardiographic
variables
,
those
identified
of
potential
significance
from
the
univariate
analysis
were
chosen
for
forward
stepwise
selection
into
the
model
.
The
variables
included
in
the
model
were
age
(
with
a
cutoff
point
of
65
years
)
,
prior
myocardial
infarction
,
prior
angina
(
angina
preceding
the
48-hour
interval
before
admission
)
,
smoking
(
prior
or
current
)
,
the
number
of
angina
episodes
during
the
last
48
hours
before
admission
(
with
a
cutoff
rate
of
3
hours
)
,
the
presence
of
precipitating
factors
of
angina
(
anemia
,
tachyarrythmias
,
fever
,
hypertension
)
,
and
the
finding
of
ST-segment
depression
on
the
admission
ECG
.
Progressive
angina
was
not
included
because
of
its
significant
association
with
prior
angina
(
Pearson
's
r
=
0.70
)
.
The
model
was
validated
with
the
split-sample
technique
.
A
simple
random
sample
of
approximately
70
%
of
the
1038
cases
(
the
training
set
,
n
=
728
)
was
used
to
derive
the
predictive
model
;
the
remaining
30
%
sample
(
the
test
set
,
n
=
310
)
was
used
to
test
it
.
The
rule
obtained
from
the
training
set
was
applied
to
each
member
of
the
test
set
.
The
efficiency
of
the
model
was
assessed
by
comparison
of
the
area
under
the
receiver
operating
characteristic
(
ROC
)
curves
of
the
training
and
test
samples
.
The
model
was
also
tested
on
all
1038
cases
to
determine
its
overall
predictive
ability
(
by
use
of
the
area
under
the
ROC
curve
)
,
sensitivity
,
and
specificity
in
predicting
in-hospital
death
or
myocardial
infarction
.
The
goodness
of
fit
of
the
model
was
assessed
by
the
Hosmer-Lemeshow
test
.
Kaplan-Meier
survival
curves
were
generated
to
calculate
the
cumulative
probability
of
having
a
major
event
develop
during
hospitalization
in
the
overall
population
and
in
the
subgroups
with
and
without
refractory
angina
.
Statistical
analysis
was
performed
with
the
SPSS
system
7.5
package
(
Statistical
Package
for
the
Social
Sciences
,
1997
)
and
the
ROC
Analyzer
Program
version
6.0
.
The
patients
in
this
study
were
mostly
elderly
(
age
60.18
+-16
years
)
,
65
%
were
male
,
78
%
reported
prior
angina
(
angina
preceding
the
48
hours
interval
before
admission
)
,
and
32
%
had
experienced
a
prior
myocardial
infarction
(
Table
I
)
.
The
study
population
was
clearly
unstable
as
manifested
by
the
high
frequency
of
resting
chest
pain
(
78
%
)
,
prolonged
(
>
30
minutes
)
chest
pain
(
29
%
)
and
the
last
episode
of
pain
within
the
48
hours
preceding
admission
(
96.7
%
)
.
Angina
within
4
weeks
and
2
weeks
after
infarction
(
postinfarction
angina
)
was
observed
in
9.7
%
and
3.3
%
of
cases
,
respectively
.
Precipitating
factors
of
unstable
angina
were
not
identified
in
76
%
of
the
population
.
There
were
relatively
few
smokers
(
21.3
%
)
,
and
the
most
prevalent
risk
factors
were
hypertension
(
60.3
%
)
and
hyperlipidemia
(
43.3
%
)
.
The
presence
of
heart
failure
at
admission
was
infrequently
reported
(
1.5
%
)
.
Left
ventricular
hypertrophy
or
complete
left
bundle
branch
block
precluded
the
analysis
of
ST-T
changes
in
12.7
%
of
patients
.
ST
segment
elevation
was
frequently
observed
(
16
%
)
and
,
in
contrast
,
ST-segment
depression
was
relatively
infrequent
(
21
%
)
.
Only
16
%
of
the
patients
had
a
normal
ECG
at
entry
.
Before
hospitalization
,
treatment
consisted
of
aspirin
in
half
of
the
patients
(
50.6
%
)
,
b-blockers
in
31
%
,
nitrates
in
44
%
,
and
calcium
antagonists
in
42
%
.
Combined
treatment
with
aspirin
,
nitrates
,
and
b-blockers
or
calcium
antagonists
was
administered
to
27
%
of
the
study
population
.
Table
II
depicted
the
baseline
characteristics
of
patients
with
and
without
major
complications
during
hospitalization
.
Patients
with
complications
were
older
and
had
greater
frequency
of
prior
angina
,
ST-segment
depression
on
admission
electrocardiogram
,
and
repetitive
angina
(
>
3
episodes
)
during
the
last
48
hours
preceding
admission
.
Conversely
,
the
history
of
previous
infarction
was
less
frequent
among
patients
without
complications
during
hospitalization
.
Antithrombotic
treatment
was
administered
in
the
hospital
to
94
%
of
patients
,
with
heparin
in
57
%
(
intravenous
in
34
%
,
subcutaneous
heparin
in
23
%
)
,
aspirin
in
88
%
,
and
ticlopidine
in
5
%
of
the
patients
.
Heparin
was
used
in
34.7
%
and
63.9
%
of
patients
with
or
without
precipitating
factors
,
respectively
.
Anti-ischemic
therapy
consisted
of
the
administration
of
nitrates
in
81
%
,
b-blockers
in
71
%
,
and
calcium
antagonists
in
56
%
.
A
coronary
angiography
was
performed
in
50.2
%
of
the
population
.
The
most
relevant
angiographic
findings
were
normal
or
nonsignificant
stenosis
in
5.4
%
,
1-vessel
disease
in
32
%
,
multivessel
disease
in
61
%
,
and
left
main
involvement
in
10
%
.
A
quarter
of
the
population
was
submitted
to
revascularization
procedures
(
coronary
artery
bypass
grafting
was
performed
in
14
%
and
coronary
angioplasty
in
10.8
%
)
.
There
was
a
positive
relation
between
the
presence
and
severity
of
angina
after
admission
and
the
need
for
invasive
procedures
,
either
diagnostic
or
therapeutic
:
29.5
%
and
44.2
%
in
patients
with
recurrent
and
refractory
angina
,
respectively
,
and
11.1
%
in
the
subgroup
without
angina
after
admission
(
P
<
.
001
)
.
The
indications
for
revascularization
procedures
were
angina
after
admission
in
71
%
,
inducible
ischemia
in
6
%
,
angiographic
findings
in
21
%
,
and
preference
of
the
patient
or
his
/
her
physician
in
the
remainder
.
During
hospital
stay
,
40.8
%
of
the
patients
had
at
least
1
new
episode
of
cardiac
pain
(
Table
III
)
.
Recurrent
angina
was
diagnosed
in
200
patients
(
19.3
%
)
and
refractory
angina
in
223
(
21.5
%
)
patients
.
New
acute
myocardial
infarction
was
diagnosed
in
54
patients
(
5.2
%
)
,
and
there
were
42
in-hospital
deaths
(
4.1
%
)
.
The
combined
end
point
of
death
and
myocardial
infarction
occurred
in
83
patients
(
8.1
%
)
.
The
incidence
of
new
acute
myocardial
infarction
was
higher
during
the
first
day
and
declined
thereafter
.
On
the
other
hand
,
cases
of
death
were
evenly
distributed
during
hospitalization
.
The
Kaplan-Meier
event-free
survival
curve
for
in-hospital
infarction
or
death
is
shown
in
Fig
1
.
Fig
2
shows
the
in-hospital
survival
curve
of
patients
free
of
infarction
,
death
,
or
refractory
angina
.
The
rate
of
"
spontaneous
"
(
non-procedure-related
)
acute
myocardial
infarction
and
death
was
3.1
%
and
1.4
%
,
respectively
.
Acute
myocardial
infarction
and
death
related
to
an
interventional
procedure
rates
were
1.0
%
and
3.8
%
.
The
clinical
variables
present
at
admission
and
associated
with
an
adverse
outcome
through
the
hospitalization
period
are
summarized
in
Table
IV
.
New
acute
myocardial
infarction
or
death
was
associated
with
ST-segment
depression
(
odds
ratio
[
OR
]
2.00
,
95
%
confidence
interval
[
CI
]
1.20
to
3.40
;
P
=
.008
)
,
the
number
of
chest
pain
episodes
within
the
last
48
hours
(
OR
1.84
,
95
%
CI
1.12
to
3.07
;
P
=
.01
)
,
prior
angina
(
OR
2.70
,
95
%
CI
1.34
to
5.57
;
P
=
.001
)
,
and
age
>
65
years
(
OR
1.64
,
95
%
CI
1.00
to
2.70
;
P
=
.
01
)
.
A
negative
trend
was
noted
for
smoking
history
(
OR
0.51
,
95
%
CI
0.31
to
0.83
;
P
=
.005
)
,
and
prior
acute
myocardial
infarction
(
OR
0.58
,
95
%
CI
0.32
to
1.03
;
P
=
.
039
)
.
Age
(
OR
2.26
,
95
%
CI
1.06
to
4.69
;
P
=
.01
)
,
and
prior
angina
(
OR
4.9
,
95
%
CI
1.16
to
12.5
,
P
=
.009
)
,
were
the
only
univariate
predictors
of
in-hospital
mortality
.
The
model
was
constructed
with
all
the
variables
present
at
admission
and
found
significant
at
the
univariate
analyses
at
a
level
of
P
<
.
10
.
As
shown
in
Table
V
,
the
multivariate
analysis
retained
the
following
independent
admission
predictors
of
myocardial
infarction
or
death
:
ischemic
ST-segment
depression
in
the
ECG
upon
admission
(
OR
2.13
,
95
%
CI
1.23
to
3.68
,
P
=
.006
)
,
prior
angina
(
OR
2.23
,
95
%
CI
0.98
to
5.05
,
P
=
.05
)
,
the
number
of
angina
episodes
within
the
last
48
hours
before
admission
(
OR
1.63
,
95
%
CI
0.98
to
2.70
,
P
=
.05
)
,
and
smoking
history
(
OR
0.69
,
95
%
CI
0.56
to
0.85
,
P
=
.
004
)
.
Age
>
65
years
(
OR
1.49
,
95
%
CI
1.09
to
2.03
,
P
=
.03
)
was
significantly
related
to
in-hospital
death
.
The
overall
predictive
efficiency
was
similar
in
the
training
and
test
samples
(
ROC
curves
areas
0.57
+-0.05
and
0.53
+-0.04
respectively
,
P
=
.
29
)
.
On
all
1038
patients
,
the
area
under
the
ROC
curve
for
the
model
was
0.59
+-0.03
.
The
sensitivity
and
specificity
of
the
model
were
computed
.
To
ensure
at
least
80
%
sensitivity
,
a
predicted
probability
cutpoint
of
0.06
was
required
(
ie
,
if
the
predicted
probability
was
>
=
0.06
,
the
patient
was
classified
as
positive
)
.
This
cutpoint
resulted
in
a
sensitivity
of
80
%
and
a
specificity
of
33
%
.
The
Hosmer-Lemeshow
goodness-of-fit
statistic
was
3.51
(
degrees
of
frequency
=
7
,
P
=
.
83
)
.
The
occurrence
of
angina
after
admission
(
recurrent
or
refractory
)
showed
a
strong
univariate
relation
with
the
incidence
of
in-hospital
acute
myocardial
infarction
or
death
(
14.4
%
vs
3.2
%
,
or
5.04
,
95
%
CI
2.86
to
8.87
;
P
<
.0001
)
and
death
alone
(
6.9
%
vs
1.1
%
,
or
6.45
,
95
%
CI
2.61
to
5.9
;
P
<
.0001
)
(
Table
III
)
.
Fig
3
shows
the
Kaplan-Meier
infarction-free
survival
curves
in
patients
with
or
without
refractory
angina
.
Absence
of
refractory
angina
from
admission
to
discharge
was
associated
to
a
better
hospital
outcome
.
This
association
persisted
even
when
only
non-procedure-related
(
"
spontaneous
"
)
events
were
taken
into
consideration
10.3
%
vs
2.3
%
of
acute
myocardial
infarction
or
death
in
patients
with
or
without
refractory
angina
,
respectively
(
OR
4.40
,
95
%
CI
2.35
to
8.22
;
Table
IV
)
.
Despite
improved
treatment
of
unstable
angina
during
the
last
years
,
there
remains
a
considerable
risk
of
events
upon
admission
to
the
hospital
.
Unstable
angina
includes
a
wide
variety
of
patients
with
different
prognoses
;
accordingly
,
a
reliable
risk
stratification
for
everyday
practice
is
necessary
.
This
is
a
major
challenge
because
most
of
the
short-term
events
are
concentrated
in
an
small
number
of
patients
.
In
addition
,
to
select
appropriate
treatment
the
risk
assessment
should
be
performed
as
early
as
possible
,
ideally
during
the
first
hours
after
admission
.
This
study
indicates
that
with
current
treatment
the
clinical
variables
continue
to
be
useful
short-term
predictors
at
the
time
of
hospital
admission
.
After
performing
multivariate
logistic
regression
analysis
,
prior
angina
,
ST-segment
depression
at
the
admission
ECG
,
the
number
of
pain
episodes
in
the
last
48
hours
preceding
admission
,
smoking
history
,
and
increased
age
were
all
independently
associated
to
adverse
in-hospital
outcome
.
However
,
this
model
showed
low
specificity
(
33
%
)
.
In
this
study
it
was
also
confirmed
that
at
the
time
of
hospital
presentation
,
the
severity
of
preadmission
symptoms
is
an
important
determinant
of
in-hospital
prognosis
.
Prior
angina
and
the
number
of
episodes
of
angina
during
the
48
hours
preceding
admission
were
independent
predictors
of
an
adverse
outcome
by
multivariate
logistic
regression
analysis
.
This
finding
is
a
contribution
to
the
elucidation
of
the
controversy
regarding
the
importance
of
these
clinical
features
as
indicators
of
high
risk
.
In
the
past
,
both
a
long
history
of
ischemic
disease
and
the
lack
of
preceding
symptoms
have
been
suggested
to
identify
high-risk
subgroups
.
Our
study
confirms
that
prognosis
is
worse
in
patients
with
ST-segment
depression
on
admission
ECG
.
As
shown
in
previous
studies
,
T-wave
changes
,
although
common
,
have
no
such
prognostic
value
.
This
analysis
did
not
take
into
account
the
extension
and
severity
of
ST-segment
or
T-wave
changes
and
therefore
we
cannot
rule
out
the
possibility
of
a
worse
prognostic
significance
associated
with
more
severe
ECG
abnormalities
.
In
agreement
with
other
reports
,
patients
who
smoke
cigarettes
showed
a
better
in-hospital
course
.
In
another
study
by
Barbash
et
al
,
more
advanced
coronary
artery
disease
explained
the
worse
prognosis
of
nonsmokers
.
One
explanation
might
be
that
smokers
have
less-advanced
atherosclerotic
disease
at
the
time
of
their
first
clinical
episode
of
ischemic
disease
.
Some
common
clinical
variables
,
such
as
diabetes
and
heart
failure
,
did
not
appear
as
predictors
in
this
analysis
.
Also
,
these
variables
did
not
turn
out
to
be
independent
predictors
in
an
analysis
involving
3171
patients
with
non-ST-segment
elevation
ischemic
syndrome
in
the
ESSENCE
trial
.
We
surveyed
very
evident
heart
failure
with
overt
respiratory
distress
only
.
Thus
the
low
frequency
of
heart
failure
at
the
time
of
presentation
may
be
a
reflection
of
these
diagnostic
criteria
.
It
was
not
possible
to
assess
either
the
predictive
value
of
exertional
unstable
angina
or
that
of
subacute
angina
at
rest
(
patients
without
angina
within
the
preceding
48
hours
)
because
96.7
%
of
our
patients
belonged
to
Braunwald
's
type
III
classification
.
Recently
reported
comparisons
of
early
conservative
versus
early
invasive
therapeutic
strategy
indicates
that
there
is
no
benefit
associated
with
the
routine
use
of
any
of
these
strategies
.
Therefore
it
is
still
necessary
to
adjust
the
therapeutic
recommendation
to
the
individual
needs
of
each
patient
.
Because
of
the
lack
of
other
adequate
markers
of
instability
,
clinical
risk
stratification
performed
at
admission
and
during
hospitalization
is
still
essential
to
identify
patients
at
high
risk
in
which
an
early
interventional
strategy
may
be
recommended
.
The
findings
of
this
study
are
consistent
with
this
appreciation
:
the
appearance
of
refractory
angina
,
the
clinical
hallmark
of
instability
,
was
followed
by
a
rise
in
the
rate
of
interventions
and
of
major
events
of
44.2
%
and
22.7
%
,
respectively
,
whereas
persistent
relief
of
symptoms
after
admission
was
associated
with
a
favorable
in-hospital
outcome
and
a
lower
procedural
rate
(
11.1
%
)
.
Although
thrombotic
complications
related
to
procedures
driven
by
symptoms
can
be
considered
to
belong
to
the
unstable
state
,
interventions
can
confound
the
predictive
analyses
because
recurrence
of
angina
prompts
the
physician
to
intervene
.
The
existence
of
an
intrinsic
adverse
significance
associated
with
refractory
angina
is
supported
by
our
finding
of
a
significant
relation
between
refractory
angina
and
major
nonprocedural
(
"
spontaneous
"
)
events
.
Because
no
valid
universal
definition
of
refractory
angina
exists
,
the
criteria
used
in
this
study
may
be
different
from
those
used
by
others
.
Because
of
the
pragmatic
character
of
the
study
,
neither
the
presence
of
ECG
evidence
of
ischemia
nor
the
use
of
heparin
during
the
episodes
of
chest
pain
were
required
for
the
diagnosis
of
refractory
angina
.
In
this
study
the
use
of
intravenous
heparin
was
less
than
what
might
be
anticipated
(
57
%
)
because
in
recent
years
there
has
been
a
greater
trend
toward
increased
use
.
However
,
the
use
of
heparin
was
higher
in
patients
without
precipitating
factors
(
69.7
%
)
.
This
finding
is
not
unexpected
because
in
primary
unstable
angina
(
Braunwald
class
B
)
the
presence
of
a
thrombus
can
be
presumed
and
the
use
of
heparin
treatment
is
well
substantiated
.
The
studies
by
Theroux
and
Wallentin
showed
the
effectiveness
of
intravenous
heparin
and
low-molecular-weight
heparin
in
preventing
major
complications
during
the
acute
phase
of
unstable
angina
.
Consequently
,
in
our
study
,
a
lower
incidence
of
refractory
angina
and
a
better
outcome
could
have
been
observed
if
heparin
had
been
used
more
frequently
or
if
a
more
stringent
definition
of
refractory
angina
had
been
used
.
Nonetheless
,
mortality
rate
in
this
series
was
similar
to
that
reported
in
recent
trials
.
At
30
days
the
death
rate
was
3.6
%
and
3.9
%
in
the
heparin
arms
of
the
studies
ESSENCE
and
GUSTO
II
B
,
respectively
.
In
the
PURSUIT
trial
,
30-day
mortality
rate
was
3.7
%
in
the
control
arm
.
In
the
TIMI-IIIB
study
,
the
death
rate
of
the
early
conservative
arm
was
4.7
%
at
42
days
.
In
the
PRISM
PLUS
study
,
the
30-day
mortality
rate
was
4.0
%
in
patients
treated
with
heparin
.
The
relative
benefits
of
early
invasive
and
early
conservative
treatment
strategies
have
been
debated
for
many
years
.
Either
of
these
approaches
is
considered
clinically
appropriate
for
many
patients
.
Accordingly
,
the
identification
of
candidates
for
a
more
aggressive
strategy
has
become
of
utmost
importance
.
Because
of
its
simplicity
and
wide
availability
,
clinical
and
ECG
markers
are
widely
used
for
this
purpose
.
Unfortunately
,
the
specificity
of
the
clinical
predictors
is
insufficient
to
fulfill
the
requirements
of
risk
stratification
under
the
current
therapeutic
modalities
.
In
recent
years
,
serum
markers
such
as
troponin
T
and
C-reactive
protein
have
become
the
focus
of
interest
for
risk
stratification
of
unstable
angina
,
with
promising
results
.
It
is
very
likely
that
routine
measurements
of
these
markers
will
contribute
to
the
identification
of
those
patients
at
highest
risk
for
cardiac
events
.
A
major
question
to
be
explored
is
how
much
information
these
new
biochemical
markers
will
add
to
what
is
already
provided
by
the
classic
clinical
predictors
.
We
thank
Gianni
Tognoni
,
MD
,
for
his
assistance
in
the
design
of
the
study
;
Dr
Pierre
Theroux
for
helpful
comments
on
early
drafts
of
this
paper
;
and
Maria
Elena
Aizpurua
for
secretarial
assistance
.