Management
of
unstable angina (C0002965)
has
become
more
aggressive
to
include
full medical therapy (C0418981)
with
anti-thrombotic
and
anti-ischemic
drugs (C0013227~C0278180)
,
often
followed
by
coronary angiography (C0085532)
and revascularization procedures (C0025664~C0184661)
.
Much
of
the
published (C0034037)
data
about
the
natural history (C0175860)
of
unstable angina (C0002965)
corresponds
to
selected
patients (C0030705)
included
in
randomized clinical trials (C0206034)
.
Therefore
these
patients (C0030705)
may
not
represent
the
general
population (C0032659)
admitted
to
community hospitals (C0020003)
.
Unstable angina (C0002965)
is
also
quite
heterogeneous
,
with
a
wide (C0332464~C0426421)
spectrum
of
clinical
manifestations (C0205319)
and
prognostic categories
.
in
addition (C0332287)
,
most
of
the
data
on
the
evolution (C0015219)
and
prognosis (C0033325~C0220901)
of
unstable angina (C0002965)
were
obtained
before
the
development (C0243107)
of
new
drugs (C0013227~C0278180)
and
interventional
procedures (C0025664~C0184661)
for
management
of
this
disease (C0012634~C0028432~C0263648~C0274294)
.
This
multicenter study (C0026739~C0282439)
enrolled
a
large (C0205164~C0426415~C0443228)
cohort
of
patients (C0030705)
admitted
with
unstable angina (C0002965)
to
identify
the
This
was
a
multicenter
prospective study (C0033522)
of
consecutive
patients (C0030705)
admitted
to
coronary care units (C0010066)
with
unstable angina (C0002965)
.
To
select
a
representative
sample (C0441621)
and
safeguard
against
selection bias (C0036577)
,
all
consecutive
patients (C0030705)
admitted
to
the
coronary care unit (C0010066)
with
a
suspicion (C0242114)
of
an
acute ischemic
syndrome (C0039082)
were
included
in
the
database (C0242356)
.
If
the
admission diagnosis (C0011900~C0011901)
turned
out
to
be
Q-wave (C0429089)
or
non-Q-wave
myocardial infarction (C0027051)
,
or
if
a
nonischemic
cause (C0015127)
of
chest pain (C0008031)
became
clearly
evident
,
the
process
of
data
collection
was
interrupted
and
the
patient (C0030705)
censored
from
subsequent
analysis (C0002778)
.
The
diagnosis (C0011900~C0011901)
of
Q-wave (C0429089)
or
non-Q-wave
acute myocardial infarction (C0155626)
present
at
admission (C0457453)
was
made
on
the
basis (C0004830~C0178499)
of
the
finding (C0243095~C0263541~C0332285)
of
an
elevated total
creatine phosphokinase (C0010287)
(
CPK (C0010287)
)
plasma level (C0441889~C0456079)
(
greater
than
2-fold
increase (C0205217~C0442805~C0442808)
above
normal value (C0086715~C0220882)
)
at
entry
to
the
study
or
at
any
time (C0040223~C0183941~C0332311~C0392761~C0449243)
up
to
12
hours (C0439227)
thereafter
.
for
patients (C0030705)
prescribed
thrombolytic
treatment (C0039798~C0087111)
or
primary
coronary angioplasty (C0190211)
at
entry
,
the
enzymatic
criteria (C0243161)
were
not
required
and
the
diagnosis (C0011900~C0011901)
was
made
on
the
basis (C0004830~C0178499)
of
the
finding (C0243095~C0263541~C0332285)
of
chest pain (C0008031)
lasting
more
than
30
minutes (C0205165~C0439232)
plus
>
=
1
mm ST elevation (C0429069)
in
at
least
3
precordial
or
2
standard
electrocardiogram (C0013798)
(
ECG (C0013798)
)
leads (C0023175~C0181586~C0373667~C0475211)
.
Between
March
1991
and
May l (C0023175~C0181586~C0373667~C0475211)
992
,
1172
consecutive
patients (C0030705)
with
suspected acute ischemic
syndrome (C0039082)
were
prospectively
enrolled
.
This
group (C0439745~C0441833)
represented
23
%
of
the
total
population (C0032659)
admitted
to
the
coronary care units (C0010066)
during
that
period (C0025344~C0439531)
of
time (C0040223~C0183941~C0332311~C0392761~C0449243)
.
One
hundred
and
thirty-four
patients (C0030705)
(
11.4
%
)
were
excluded
:
46
patients (C0030705)
because
of
an
evolving
myocardial infarction (C0027051)
unequivocally
present
at
hospital admission (C0184666)
and
88
patients (C0030705)
because
of
noncardiac
chest pain (C0008031)
.
The
remaining
1038
patients (C0030705)
with
unstable angina (C0002965)
formed
the
study population (C0032659)
.
Data
collected
include
demographics (C0011298)
and
baseline (C0168634)
clinical
variables (C0439828)
.
Electrocardiograms (C0013798)
were
routinely
obtained
at
admission (C0457453)
,
during
subsequent
episodes (C0277793~C0332189)
of
chest pain (C0008031)
,
and
at
hospital discharge (C0012621~C0264273)
.
Serum (C0229671)
total
CPK levels (C0441889~C0456079)
were
determined
at
admission (C0457453)
,
every
12
hours (C0439227)
during
the
first
24
hours (C0439227)
,
and
after
a
new
chest pain (C0008031)
episode
during
hospital (C0019994)
stay
.
Changes (C0025320~C0392747~C0443172)
in
the
ECG (C0013798)
were
considered
positive
if
there
was
>
=
1
mm (C0126723~C0439200)
of
ST-segment elevation (C0520886)
or
depression (C0011570~C0460137)
in
at
least
2
limb leads (C0441100)
or
3
precordial
leads (C0023175~C0181586~C0373667~C0475211)
or
symmetric
T-wave inversion (C0520888)
in
at
least
3
limbs (C0015385~C0431777)
or
precordial
leads (C0023175~C0181586~C0373667~C0475211)
.
The
treatment (C0039798~C0087111)
received
,
any
coronary intervention
,
and
all
the
in-hospital events (C0441471)
(
angina (C0002962)
,
acute myocardial infarction (C0155626)
,
and
death (C0011065~C0220816)
)
were
also
recorded
.
The
investigator (C0035173)
who
was
responsible
for
the
patient (C0030705)
was
instructed
to
carry
a
daily (C0332173)
prospective and systematic register
of
all
new
chest pain (C0008031)
episodes
in
addition (C0332287)
to
all
the
information
related
to
the
associated (C0332281)
electrocardiographic and enzymatic alterations
.
All
the
ECG tracings (C0442822)
were
examined
by
an
ECG core lab reader (C0034754)
who
was
blinded
to
the
patient clinical
condition (C0009647~C0348080)
to
validate
ST-segment (C0429029)
changes
>
=
1
mm (C0126723~C0439200)
,
T-wave changes (C0025320~C0392747~C0443172)
,
left bundle branch block (C0023211)
,
and
left ventricular hypertrophy (C0149721)
.
Serial
electrocardiograms (C0013798)
were
compared
to
evaluate
if
the
changes (C0025320~C0392747~C0443172)
were
transient
or
fixed
.
The
medical
treatment (C0039798~C0087111)
was
entirely
left
to
the
discretion
of
the
treating
physician (C0031831)
except
for
a
strong
recommendation (C0034866)
to
use
aspirin (C0004057)
in
all
patients (C0030705)
.
New
episodes (C0277793~C0332189)
of
ischemic
chest pain (C0008031)
after
admission (C0457453)
were
classified
as
(
1
)
recurrent
angina (C0002962)
,
defined
as
angina (C0002962)
occurring
in
the
absence (C0332197~C0424530)
of
full
medical therapy (C0418981)
or
(
2
)
refractory
angina (C0002962)
,
angina (C0002962)
occurring
while
the
patient (C0030705)
was
receiving
full medical therapy (C0418981)
.
Full
medical therapy (C0418981)
was
defined
as
the
combination (C0205195~C0453882)
of
aspirin (C0004057)
and
/
or
intravenous heparin (C0354566)
,
nitrates (C0028125)
,
and
b-blockers
or
calcium antagonists (C0243076)
at
clinically effective
doses (C0018081~C0057911~C0114856~C0231807)
.
The
adequacy
for
full
medical therapy (C0418981)
was
left
to
the
decision
of
the
treating
physician (C0031831)
with
suggested
criteria (C0243161)
of
heart rate (C0018810)
<
60
beats
/
min (C0026175~C0240346~C0439232)
and
systolic blood pressure (C0428880~C0520844)
<
120
mm Hg (C0439475)
.
Major in-hospital events (C0441471)
were
new myocardial infarction (C0027051)
and
death (C0011065~C0220816)
from
any
cause (C0015127)
.
Hospital mortality (C0085556)
was
defined
as
death (C0011065~C0220816)
occurring
in
the
hospital (C0019994)
at
any
moment
from
arrival
through
discharge (C0012621~C0264273)
.
The
criteria (C0243161)
for
new
in-hospital (C0019994)
acute myocardial infarction (C0155626)
included
all
of
the
following (C0332282~C0332283)
:
(
1
)
new
prolonged
episode (C0277793~C0332189)
of
chest pain (C0008031)
after
admission (C0457453)
;
(
2
)
elevation (C0439775)
of
total CPK level (C0441889~C0456079)
greater
than
twice
the
limit (C0439801)
of
normal (C0205307~C0439166)
,
and
(
3
)
the
development (C0243107)
of
new
Q-wave (C0429089)
or ST-T changes (C0025320~C0392747~C0443172)
on
the
ECG (C0013798)
.
Events (C0441471)
that
occurred
during
or
within
24
hours (C0439227)
after
an
invasive procedure (C0038895~C0348025)
(
coronary angiography (C0085532)
,
coronary angioplasty (C0190211)
,
or
coronary bypass (C0010055)
surgery
)
were
considered
procedure (C0025664~C0184661)
related
.
The
remaining
events (C0441471)
were
prospectively
classified
as
spontaneous
.
An
ad-hoc
committee
blinded
to
the
clinical
variables (C0439828)
and
the
administered
treatment (C0039798~C0087111)
examined
and
validated
all
major
events (C0441471)
(
acute myocardial infarction (C0155626)
or
death (C0011065~C0220816)
during
hospitalization (C0019993)
)
with
a
systematic
review (C0282443)
of
serial
electrocardiograms (C0013798)
,
enzymatic
curves (C0205134)
,
and
clinical
charts (C0007963~C0178917)
of
all
patients (C0030705)
who
had
major
events (C0441471)
reported
or
adjudicated
by
investigators (C0035173)
.
The
initially
targeted
sample (C0441621)
of
1000
patients (C0030705)
was
based
on
a
projected
24
%
rate (C0034693)
of
events (C0441471)
(
16
%
refractory
angina (C0002962)
,
6
%
acute myocardial infarction (C0155626)
,
and
2
%
death (C0011065~C0220816)
)
.
An
a
level (C0441889~C0456079)
of
significance
<
.05
was
considered
for
all
purposes (C0449256)
.
Unadjusted
odds ratios (C0028873)
and
95
%
confidence intervals (C0009667)
were
obtained
for
selected
clinical (C0205210)
factors
judged
to
be
associated
with
the
outcome
of
interest (C0123730~C0205103)
.
Univariate
and
forward stepwise multiple
logistic regression (C0206031)
models
were
used
to
evaluate
the
independent
association (C0004083)
of
variables (C0439828)
present
at
admission (C0457453)
to
in-hospital (C0019994)
acute myocardial infarction (C0155626)
or
death (C0011065~C0220816)
.
From
28
clinical and electrocardiographic
variables (C0439828)
,
those
identified
of
potential (C0237399)
significance
from
the
univariate
analysis (C0002778)
were
chosen
for
forward (C0439780)
stepwise
selection (C0036576)
into
the
model (C0026336)
.
The
variables (C0439828)
included
in
the
model (C0026336)
were
age
(
with
a
cutoff point (C0324413)
of
65
years (C0439234~C0439508)
)
,
prior myocardial infarction (C0027051)
,
prior
angina (C0002962)
(
angina (C0002962)
preceding
the
48-hour (C0439586)
interval
before
admission (C0457453)
)
,
smoking
(
prior
or
current
)
,
the
number (C0237753~C0449788)
of
angina episodes (C0277793~C0332189)
during
the
last
48
hours (C0439227)
before
admission (C0457453)
(
with
a
cutoff rate (C0034693)
of
3
hours (C0439227)
)
,
the
presence (C0392148~C0392743)
of
precipitating
factors
of
angina (C0002962)
(
anemia (C0002871)
,
tachyarrythmias
,
fever (C0015967)
,
hypertension (C0020538)
)
,
and
the
finding (C0243095~C0263541~C0332285)
of
ST-segment depression (C0520887)
on
the
admission ECG (C0013798)
.
Progressive angina (C0340290)
was
not
included
because
of
its
significant
association (C0004083)
with
prior
angina (C0002962)
(
Pearson
's
r (C0035253~C0175724~C0332153~C0332575~C0439117~C0439142)
=
0.70
)
.
The
model (C0026336)
was
validated
with
the
split-sample technique (C0025664~C0449851)
.
A
simple
random sample (C0150105)
of
approximately
70
%
of
the
1038
cases
(
the
training set (C0036849~C0324444)
,
n (C0027552~C0028158~C0332125~C0347979~C0439138~C0439225~C0441922)
=
728
)
was
used
to
derive
the
predictive
model (C0026336)
;
the
remaining
30
%
sample (C0441621)
(
the
test (C0039593~C0039597~C0076174~C0154007~C0183885~C0392366~C0430738~C0496924)
set
,
n (C0027552~C0028158~C0332125~C0347979~C0439138~C0439225~C0441922)
=
310
)
was
used
to
test
it
.
The
rule (C0205159~C0522637)
obtained
from
the
training set (C0036849~C0324444)
was
applied
to
each
member
of
the
test (C0039593~C0039597~C0076174~C0154007~C0183885~C0392366~C0430738~C0496924)
set
.
The
efficiency (C0013682)
of
the
model (C0026336)
was
assessed
by
comparison
of
the
area (C0205146)
under
the
receiver
operating
characteristic
(
ROC
)
curves
of
the
training (C0040607~C0220931~C0348006~C0453962)
and test samples (C0441621)
.
The
model (C0026336)
was
also
tested
on
all
1038
cases
to
determine
its
overall predictive
ability (C0085732)
(
by
use (C0042153~C0439224~C0449865)
of
the
area (C0205146)
under
the
ROC curve (C0035787)
)
,
sensitivity (C0036667~C0312418~C0427965~C0518607)
,
and
specificity (C0037791)
in
predicting
in-hospital death (C0277608)
or
myocardial infarction (C0027051)
.
The
goodness
of
fit (C0036572~C0441548)
of
the
model (C0026336)
was
assessed
by
the
Hosmer-Lemeshow test (C0039593~C0039597~C0076174~C0154007~C0183885~C0392366~C0430738~C0496924)
.
Kaplan-Meier survival curves (C0205134)
were
generated
to
calculate
the
cumulative
probability (C0033204)
of
having
a
major
event (C0441471)
develop
during
hospitalization (C0019993)
in
the
overall
population (C0032659)
and
in
the
subgroups
with
and
without
refractory
angina (C0002962)
.
Statistical
analysis (C0002778)
was
performed
with
the
SPSS system (C0449913)
7.5
package (C0030176)
(
Statistical
Package (C0030176)
for
the
Social Sciences (C0037434)
,
1997
)
and
the
ROC Analyzer Program version (C0333052)
6.0
.
The
patients (C0030705)
in
this
study
were
mostly
elderly
(
age (C0001779~C0001792~C0001811~C0002555~C0037125~C0521993)
60.18
+-16
years (C0439234~C0439508)
)
,
65
%
were
male
,
78
%
reported
prior
angina (C0002962)
(
angina (C0002962)
preceding
the
48
hours (C0439227)
interval
before
admission (C0457453)
)
,
and
32
%
had
experienced
a
prior
myocardial infarction (C0027051)
(
Table (C0039224)
I
)
.
The
study population (C0032659)
was
clearly
unstable
as
manifested
by
the
high frequency (C0205212)
of
resting
chest pain (C0008031)
(
78
%
)
,
prolonged
(
>
30
minutes (C0205165~C0439232)
)
chest pain (C0008031)
(
29
%
)
and
the
last
episode (C0277793~C0332189)
of
pain (C0030193~C0240564)
within
the
48
hours (C0439227)
preceding
admission (C0457453)
(
96.7
%
)
.
Angina (C0002962)
within
4
weeks (C0439230~C0439506)
and
2
weeks (C0439230~C0439506)
after
infarction (C0021308)
(
postinfarction angina (C0002962)
)
was
observed
in
9.7
%
and
3.3
%
of
cases
,
respectively
.
Precipitating
factors
of
unstable angina (C0002965)
were
not
identified
in
76
%
of
the
population (C0032659)
.
There
were
relatively few
smokers (C0037366~C0037369~C0337664)
(
21.3
%
)
,
and
the
most prevalent
risk factors (C0035648)
were
hypertension
(
60.3
%
)
and
hyperlipidemia (C0020473)
(
43.3
%
)
.
The
presence (C0392148~C0392743)
of
heart failure (C0018801)
at
admission (C0457453)
was
infrequently
reported
(
1.5
%
)
.
Left ventricular hypertrophy (C0149721)
or
complete left bundle branch block (C0264915)
precluded
the
analysis (C0002778)
of
ST-T changes (C0025320~C0392747~C0443172)
in
12.7
%
of
patients (C0030705)
.
ST segment elevation (C0520886)
was
frequently
observed
(
16
%
)
and
,
in
contrast (C0110625)
,
ST-segment depression (C0520887)
was
relatively
infrequent
(
21
%
)
.
Only
16
%
of
the
patients (C0030705)
had
a
normal ECG (C0239237)
at
entry
.
Before
hospitalization (C0019993)
,
treatment (C0039798~C0087111)
consisted
of
aspirin (C0004057)
in
half
of
the
patients (C0030705)
(
50.6
%
)
,
b-blockers
in
31
%
,
nitrates (C0028125)
in
44
%
,
and
calcium antagonists (C0243076)
in
42
%
.
Combined
treatment (C0039798~C0087111)
with
aspirin (C0004057)
,
nitrates (C0028125)
,
and
b-blockers
or
calcium antagonists (C0243076)
was
administered
to
27
%
of
the
study population (C0032659)
.
Table II (C0439069~C0439453)
depicted
the
baseline (C0168634)
characteristics
of
patients (C0030705)
with
and
without
major
complications (C0009566~C0009567~C0392327)
during
hospitalization (C0019993)
.
Patients (C0030705)
with
complications (C0009566~C0009567~C0392327)
were
older
and
had
greater
frequency (C0042023~C0376249~C0439603)
of
prior
angina (C0002962)
,
ST-segment depression (C0520887)
on
admission electrocardiogram (C0013798)
,
and
repetitive
angina (C0002962)
(
>
3
episodes (C0277793~C0332189)
)
during
the
last
48
hours (C0439227)
preceding
admission (C0457453)
.
Conversely
,
the
history (C0019664~C0019665~C0262512~C0262926)
of
previous
infarction (C0021308)
was
less
frequent
among
patients (C0030705)
without
complications (C0009566~C0009567~C0392327)
during
hospitalization (C0019993)
.
Antithrombotic
treatment (C0039798~C0087111)
was
administered
in
the
hospital (C0019994)
to
94
%
of
patients (C0030705)
,
with
heparin (C0019134)
in
57
%
(
intravenous
in
34
%
,
subcutaneous heparin (C0353681)
in
23
%
)
,
aspirin (C0004057)
in
88
%
,
and
ticlopidine (C0040207)
in
5
%
of
the
patients (C0030705)
.
Heparin (C0019134)
was
used
in
34.7
%
and
63.9
%
of
patients (C0030705)
with
or
without
precipitating
factors
,
respectively
.
Anti-ischemic
therapy (C0039798~C0087111)
consisted
of
the
administration (C0001554)
of
nitrates (C0028125)
in
81
%
,
b-blockers
in
71
%
,
and
calcium antagonists (C0243076)
in
56
%
.
A
coronary angiography (C0085532)
was
performed
in
50.2
%
of
the
population (C0032659)
.
The
most relevant angiographic
findings (C0243095~C0263541~C0332285)
were
normal or nonsignificant
stenosis (C0038255)
in
5.4
%
,
1-vessel disease (C0012634~C0028432~C0263648~C0274294)
in
32
%
,
multivessel disease (C0012634~C0028432~C0263648~C0274294)
in
61
%
,
and
left main
involvement (C0205428)
in
10
%
.
A
quarter
of
the
population (C0032659)
was
submitted
to
revascularization procedures (C0025664~C0184661)
(
coronary artery bypass grafting (C0010055)
was
performed
in
14
%
and
coronary angioplasty (C0190211)
in
10.8
%
)
.
There
was
a
positive (C0205159)
relation
between
the
presence (C0392148~C0392743)
and
severity (C0237870~C0439793~C0449294)
of
angina (C0002962)
after
admission (C0457453)
and
the
need (C0027552~C0028158~C0332125~C0347979~C0439138~C0439225~C0441922)
for
invasive procedures (C0038895~C0348025)
,
either
diagnostic
or
therapeutic
:
29.5
%
and
44.2
%
in
patients (C0030705)
with
recurrent and refractory
angina (C0002962)
,
respectively
,
and
11.1
%
in
the
subgroup
without
angina (C0002962)
after
admission (C0457453)
(
P (C0016504~C0033452~C0036421~C0078414~C0439115~C0439140~C0449201~C0487890)
<
.
001
)
.
The
indications (C0237000~C0521089)
for
revascularization procedures (C0025664~C0184661)
were
angina
after
admission (C0457453)
in
71
%
,
inducible
ischemia (C0022116)
in
6
%
,
angiographic
findings (C0243095~C0263541~C0332285)
in
21
%
,
and
preference
of
the
patient
or
his
/
her
physician (C0031831)
in
the
remainder
.
During
hospital (C0019994)
stay
,
40.8
%
of
the
patients (C0030705)
had
at
least
1
new
episode (C0277793~C0332189)
of
cardiac
pain (C0030193~C0240564)
(
Table III (C0439070)
)
.
Recurrent
angina (C0002962)
was
diagnosed
in
200
patients (C0030705)
(
19.3
%
)
and
refractory
angina (C0002962)
in
223
(
21.5
%
)
patients (C0030705)
.
New
acute myocardial infarction (C0155626)
was
diagnosed
in
54
patients (C0030705)
(
5.2
%
)
,
and
there
were
42
in-hospital deaths (C0277608)
(
4.1
%
)
.
The
combined end point (C0324413)
of
death (C0011065~C0220816)
and
myocardial infarction (C0027051)
occurred
in
83
patients (C0030705)
(
8.1
%
)
.
The
incidence (C0021149~C0220856)
of
new
acute myocardial infarction (C0155626)
was
higher
during
the
first
day (C0439228~C0439229~C0439505)
and
declined
thereafter
.
On
the
other
hand (C0018563)
,
cases
of
death (C0011065~C0220816)
were
evenly
distributed
during
hospitalization (C0019993)
.
The
Kaplan-Meier
event-free survival (C0242793)
curve
for
in-hospital infarction (C0021308)
or
death (C0011065~C0220816)
is
shown
in
Fig (C0349966)
1
.
Fig (C0349966)
2
shows
the
in-hospital survival curve (C0205134)
of
patients (C0030705)
free
of
infarction (C0021308)
,
death (C0011065~C0220816)
,
or
refractory
angina (C0002962)
.
The
rate (C0034693)
of
"
spontaneous
"
(
non-procedure-related
)
acute myocardial infarction (C0155626)
and
death (C0011065~C0220816)
was
3.1
%
and
1.4
%
,
respectively
.
Acute myocardial infarction (C0155626)
and
death (C0011065~C0220816)
related
to
an
interventional procedure rates (C0034693)
were
1.0
%
and
3.8
%
.
The
clinical
variables (C0439828)
present
at
admission (C0457453)
and
associated
with
an
adverse outcome
through
the
hospitalization (C0019993)
period
are
summarized
in
Table IV (C0348016)
.
New
acute myocardial infarction (C0155626)
or
death (C0011065~C0220816)
was
associated
with
ST-segment depression (C0520887)
(
odds ratio (C0028873)
[
OR (C0134121)
]
2.00
,
95
%
confidence interval (C0009667)
[
CI (C0009968~C0056599)
]
1.20
to
3.40
;
P (C0016504~C0033452~C0036421~C0078414~C0439115~C0439140~C0449201~C0487890)
=
.008
)
,
the
number (C0237753~C0449788)
of
chest pain (C0008031)
episodes
within
the
last
48
hours (C0439227)
(
OR (C0134121)
1.84
,
95
%
CI (C0009968~C0056599)
1.12
to
3.07
;
P (C0016504~C0033452~C0036421~C0078414~C0439115~C0439140~C0449201~C0487890)
=
.01
)
,
prior
angina (C0002962)
(
OR (C0134121)
2.70
,
95
%
CI (C0009968~C0056599)
1.34
to
5.57
;
P (C0016504~C0033452~C0036421~C0078414~C0439115~C0439140~C0449201~C0487890)
=
.001
)
,
and
age (C0001779~C0001792~C0001811~C0002555~C0037125~C0521993)
>
65
years (C0439234~C0439508)
(
OR (C0134121)
1.64
,
95
%
CI (C0009968~C0056599)
1.00
to
2.70
;
P (C0016504~C0033452~C0036421~C0078414~C0439115~C0439140~C0449201~C0487890)
=
.
01
)
.
A
negative
trend (C0040833)
was
noted
for
smoking
history (C0019664~C0019665~C0262512~C0262926)
(
OR (C0134121)
0.51
,
95
%
CI (C0009968~C0056599)
0.31
to
0.83
;
P (C0016504~C0033452~C0036421~C0078414~C0439115~C0439140~C0449201~C0487890)
=
.005
)
,
and
prior acute myocardial infarction (C0155626)
(
OR (C0134121)
0.58
,
95
%
CI (C0009968~C0056599)
0.32
to
1.03
;
P (C0016504~C0033452~C0036421~C0078414~C0439115~C0439140~C0449201~C0487890)
=
.
039
)
.
Age (C0001779~C0001792~C0001811~C0002555~C0037125~C0521993)
(
OR (C0134121)
2.26
,
95
%
CI (C0009968~C0056599)
1.06
to
4.69
;
P (C0016504~C0033452~C0036421~C0078414~C0439115~C0439140~C0449201~C0487890)
=
.01
)
,
and
prior
angina (C0002962)
(
OR (C0134121)
4.9
,
95
%
CI (C0009968~C0056599)
1.16
to
12.5
,
P (C0016504~C0033452~C0036421~C0078414~C0439115~C0439140~C0449201~C0487890)
=
.009
)
,
were
the
only univariate predictors
of
in-hospital mortality (C0085556)
.
The
model (C0026336)
was
constructed
with
all
the
variables (C0439828)
present
at
admission (C0457453)
and
found
significant
at
the
univariate
analyses (C0002778)
at
a
level (C0441889~C0456079)
of
P (C0016504~C0033452~C0036421~C0078414~C0439115~C0439140~C0449201~C0487890)
<
.
10
.
As
shown
in
Table V (C0015751~C0016129~C0022084~C0042306~C0042584~C0150233~C0182934~C0220828~C0439109~C0439120~C0439132~C0439133~C0439145~C0453884)
,
the
multivariate analysis (C0026777)
retained
the
following independent
admission (C0457453)
predictors
of
myocardial infarction (C0027051)
or
death (C0011065~C0220816)
:
ischemic
ST-segment depression (C0520887)
in
the
ECG (C0013798)
upon
admission (C0457453)
(
OR (C0134121)
2.13
,
95
%
CI (C0009968~C0056599)
1.23
to
3.68
,
P (C0016504~C0033452~C0036421~C0078414~C0439115~C0439140~C0449201~C0487890)
=
.006
)
,
prior
angina (C0002962)
(
OR (C0134121)
2.23
,
95
%
CI (C0009968~C0056599)
0.98
to
5.05
,
P (C0016504~C0033452~C0036421~C0078414~C0439115~C0439140~C0449201~C0487890)
=
.05
)
,
the
number (C0237753~C0449788)
of
angina episodes (C0277793~C0332189)
within
the
last
48
hours (C0439227)
before
admission (C0457453)
(
OR (C0134121)
1.63
,
95
%
CI (C0009968~C0056599)
0.98
to
2.70
,
P (C0016504~C0033452~C0036421~C0078414~C0439115~C0439140~C0449201~C0487890)
=
.05
)
,
and
smoking
history (C0019664~C0019665~C0262512~C0262926)
(
OR (C0134121)
0.69
,
95
%
CI (C0009968~C0056599)
0.56
to
0.85
,
P (C0016504~C0033452~C0036421~C0078414~C0439115~C0439140~C0449201~C0487890)
=
.
004
)
.
Age (C0001779~C0001792~C0001811~C0002555~C0037125~C0521993)
>
65
years (C0439234~C0439508)
(
OR (C0134121)
1.49
,
95
%
CI (C0009968~C0056599)
1.09
to
2.03
,
P (C0016504~C0033452~C0036421~C0078414~C0439115~C0439140~C0449201~C0487890)
=
.03
)
was
significantly
related
to
in-hospital death (C0277608)
.
The
overall predictive
efficiency (C0013682)
was
similar
in
the
training (C0040607~C0220931~C0348006~C0453962)
and test samples (C0441621)
(
ROC
curves
areas (C0205146)
0.57
+-0.05
and
0.53
+-0.04
respectively
,
P (C0016504~C0033452~C0036421~C0078414~C0439115~C0439140~C0449201~C0487890)
=
.
29
)
.
On
all
1038
patients (C0030705)
,
the
area (C0205146)
under
the
ROC curve (C0035787)
for
the
model (C0026336)
was
0.59
+-0.03
.
The
sensitivity (C0036667~C0312418~C0427965~C0518607)
and
specificity (C0037791)
of
the
model (C0026336)
were
computed
.
To
ensure
at
least
80
%
sensitivity (C0036667~C0312418~C0427965~C0518607)
,
a
predicted
probability (C0033204)
cutpoint
of
0.06
was
required
(
ie
,
if
the
predicted
probability (C0033204)
was
>
=
0.06
,
the
patient (C0030705)
was
classified
as
positive
)
.
This
cutpoint
resulted
in
a
sensitivity (C0036667~C0312418~C0427965~C0518607)
of
80
%
and
a
specificity (C0037791)
of
33
%
.
The
Hosmer-Lemeshow
goodness-of-fit
statistic (C0038215~C0220917)
was
3.51
(
degrees (C0439489~C0449286)
of
frequency (C0042023~C0376249~C0439603)
=
7
,
P (C0016504~C0033452~C0036421~C0078414~C0439115~C0439140~C0449201~C0487890)
=
.
83
)
.
The
occurrence (C0243132)
of
angina (C0002962)
after
admission (C0457453)
(
recurrent
or
refractory
)
showed
a
strong (C0442821)
univariate relation
with
the
incidence (C0021149~C0220856)
of
in-hospital (C0019994)
acute myocardial infarction (C0155626)
or
death (C0011065~C0220816)
(
14.4
%
vs
3.2
%
,
or
5.04
,
95
%
CI (C0009968~C0056599)
2.86
to
8.87
;
P (C0016504~C0033452~C0036421~C0078414~C0439115~C0439140~C0449201~C0487890)
<
.0001
)
and
death (C0011065~C0220816)
alone
(
6.9
%
vs
1.1
%
,
or
6.45
,
95
%
CI (C0009968~C0056599)
2.61
to
5.9
;
P (C0016504~C0033452~C0036421~C0078414~C0439115~C0439140~C0449201~C0487890)
<
.0001
)
(
Table III (C0439070)
)
.
Fig (C0349966)
3
shows
the
Kaplan-Meier
infarction-free survival curves (C0205134)
in
patients (C0030705)
with
or
without
refractory
angina (C0002962)
.
Absence (C0332197~C0424530)
of
refractory
angina (C0002962)
from
admission (C0457453)
to
discharge
was
associated
to
a
better hospital (C0336603)
outcome
.
This
association (C0004083)
persisted
even
when
only
non-procedure-related
(
"
spontaneous
"
)
events (C0441471)
were
taken
into
consideration (C0518609)
10.3
%
vs
2.3
%
of
acute myocardial infarction (C0155626)
or
death (C0011065~C0220816)
in
patients (C0030705)
with
or
without
refractory
angina (C0002962)
,
respectively
(
OR (C0134121)
4.40
,
95
%
CI (C0009968~C0056599)
2.35
to
8.22
;
Table IV (C0348016)
)
.
Despite
improved
treatment (C0039798~C0087111)
of
unstable angina (C0002965)
during
the
last
years (C0439234~C0439508)
,
there
remains
a
considerable
risk (C0035647)
of
events (C0441471)
upon
admission (C0457453)
to
the
hospital (C0019994)
.
Unstable angina (C0002965)
includes
a
wide (C0332464~C0426421)
variety
of
patients (C0030705)
with
different
prognoses (C0033325~C0220901)
;
accordingly
,
a
reliable
risk (C0035647)
stratification
for
everyday practice
is
necessary
.
This
is
a
major (C0205164)
challenge
because
most
of
the
short-term events (C0441471)
are
concentrated
in
an
small
number (C0237753~C0449788)
of
patients (C0030705)
.
In
addition (C0332287)
,
to
select
appropriate
treatment (C0039798~C0087111)
the
risk assessment (C0086930)
should
be
performed
as
early
as
possible
,
ideally
during
the
first
hours (C0439227)
after
admission (C0457453)
.
This
study
indicates
that
with
current
treatment (C0039798~C0087111)
the
clinical
variables (C0439828)
continue
to
be
useful
short-term (C0443303)
predictors
at
the
time (C0040223~C0183941~C0332311~C0392761~C0449243)
of
hospital admission (C0184666)
.
After
performing
multivariate logistic
regression analysis (C0034980)
,
prior
angina (C0002962)
,
ST-segment depression (C0520887)
at
the
admission ECG (C0013798)
,
the
number (C0237753~C0449788)
of
pain episodes (C0277793~C0332189)
in
the
last
48
hours (C0439227)
preceding
admission (C0457453)
,
smoking
history (C0019664~C0019665~C0262512~C0262926)
,
and
increased
age (C0001779~C0001792~C0001811~C0002555~C0037125~C0521993)
were
all
independently
associated
to
adverse
in-hospital (C0019994)
outcome
.
However
,
this
model (C0026336)
showed
low
specificity (C0037791)
(
33
%
)
.
In
this
study
it
was
also
confirmed
that
at
the
time (C0040223~C0183941~C0332311~C0392761~C0449243)
of
hospital presentation (C0449450)
,
the
severity (C0237870~C0439793~C0449294)
of
preadmission symptoms (C0178311~C0426409)
is
an
important determinant
of
in-hospital prognosis (C0033325~C0220901)
.
Prior
angina (C0002962)
and
the
number (C0237753~C0449788)
of
episodes (C0277793~C0332189)
of
angina (C0002962)
during
the
48
hours (C0439227)
preceding
admission (C0457453)
were
independent
predictors
of
an
adverse outcome
by
multivariate logistic
regression analysis (C0034980)
.
This
finding (C0243095~C0263541~C0332285)
is
a
contribution
to
the
elucidation
of
the
controversy
regarding
the
importance
of
these
clinical (C0205210)
features
as
indicators (C0021212)
of
high risk (C0332167)
.
In
the
past
,
both
a
long
history (C0019664~C0019665~C0262512~C0262926)
of
ischemic
disease (C0012634~C0028432~C0263648~C0274294)
and
the
lack (C0332268)
of
preceding
symptoms (C0178311~C0426409)
have
been
suggested
to
identify
high-risk (C0332167)
subgroups
.
Our
study
confirms
that
prognosis (C0033325~C0220901)
is
worse
in
patients (C0030705)
with
ST-segment depression (C0520887)
on
admission ECG (C0013798)
.
As
shown
in
previous (C0205156)
studies
,
T-wave changes (C0025320~C0392747~C0443172)
,
although
common
,
have
no
such prognostic
value (C0042295~C0401806)
.
This
analysis (C0002778)
did
not
take
into
account (C0000938)
the
extension (C0231448~C0332258)
and
severity (C0237870~C0439793~C0449294)
of
ST-segment (C0429029)
or T-wave changes (C0025320~C0392747~C0443172)
and
therefore
we
cannot
rule
out
the
possibility
of
a
worse (C0105122~C0205169~C0332271)
prognostic significance
associated
with
more severe ECG abnormalities (C0000768~C0000769)
.
In
agreement
with
other
reports (C0178935~C0335038)
,
patients (C0030705)
who
smoke
cigarettes
showed
a
better
in-hospital course (C0489547)
.
In
another
study
by
Barbash
et
al
,
more advanced
coronary artery disease (C0010068)
explained
the
worse prognosis (C0278252)
of
nonsmokers
.
One
explanation
might
be
that
smokers (C0037366~C0037369~C0337664)
have
less-advanced
atherosclerotic
disease (C0012634~C0028432~C0263648~C0274294)
at
the
time (C0040223~C0183941~C0332311~C0392761~C0449243)
of
their
first clinical
episode (C0277793~C0332189)
of
ischemic
disease (C0012634~C0028432~C0263648~C0274294)
.
Some
common clinical
variables (C0439828)
,
such
as
diabetes (C0011847)
and heart failure (C0018801)
,
did
not
appear
as
predictors
in
this
analysis (C0002778)
.
Also
,
these
variables (C0439828)
did
not
turn
out
to
be
independent (C0332291)
predictors
in
an
analysis (C0002778)
involving
3171
patients (C0030705)
with
non-ST-segment elevation (C0439775)
ischemic
syndrome (C0039082)
in
the
ESSENCE (C0028910)
trial
.
We
surveyed
very evident
heart failure (C0018801)
with
overt
respiratory distress (C0476273)
only
.
Thus
the
low frequency (C0205213)
of
heart failure (C0018801)
at
the
time (C0040223~C0183941~C0332311~C0392761~C0449243)
of
presentation (C0449450)
may
be
a
reflection
of
these
diagnostic
criteria (C0243161)
.
It
was
not
possible
to
assess
either
the
predictive
value (C0042295~C0401806)
of
exertional
unstable angina (C0002965)
or
that
of
subacute
angina (C0002962)
at
rest (C0035253~C0175724~C0332153~C0332575~C0439117~C0439142)
(
patients (C0030705)
without
angina (C0002962)
within
the
preceding
48
hours (C0439227)
)
because
96.7
%
of
our
patients (C0030705)
belonged
to
Braunwald
's
type III (C0441731)
classification
.
Recently
reported
comparisons
of
early (C0205085)
conservative
versus
early invasive
therapeutic (C0039796~C0302350)
strategy
indicates
that
there
is
no
benefit
associated
with
the
routine
use (C0042153~C0439224~C0449865)
of
any
of
these
strategies
.
Therefore
it
is
still
necessary
to
adjust
the
therapeutic
recommendation (C0034866)
to
the
individual
needs (C0027552~C0028158~C0332125~C0347979~C0439138~C0439225~C0441922)
of
each
patient (C0030705)
.
Because
of
the
lack (C0332268)
of
other adequate
markers (C0181733~C0522501)
of
instability
,
clinical
risk (C0035647)
stratification
performed
at
admission (C0457453)
and
during
hospitalization (C0019993)
is
still
essential
to
identify
patients (C0030705)
at
high risk (C0332167)
in
which
an
early (C0205085)
interventional strategy
may
be
recommended
.
The
findings (C0243095~C0263541~C0332285)
of
this
study
are
consistent
with
this
appreciation
:
the
appearance (C0233426)
of
refractory
angina (C0002962)
,
the
clinical (C0205210)
hallmark
of
instability
,
was
followed
by
a
rise (C0034601~C0331968)
in
the
rate (C0034693)
of
interventions
and
of
major
events (C0441471)
of
44.2
%
and
22.7
%
,
respectively
,
whereas
persistent (C0205322)
relief
of
symptoms (C0178311~C0426409)
after
admission (C0457453)
was
associated
with
a
favorable
in-hospital (C0019994)
outcome
and
a
lower procedural
rate (C0034693)
(
11.1
%
)
.
Although
thrombotic
complications (C0009566~C0009567~C0392327)
related
to
procedures (C0025664~C0184661)
driven
by
symptoms (C0178311~C0426409)
can
be
considered
to
belong
to
the
unstable (C0443343)
state
,
interventions
can
confound
the
predictive
analyses (C0002778)
because
recurrence (C0034897)
of
angina (C0002962)
prompts
the
physician (C0031831)
to
intervene
.
The
existence
of
an
intrinsic (C0205102~C0439674)
adverse significance
associated
with
refractory
angina (C0002962)
is
supported
by
our
finding (C0243095~C0263541~C0332285)
of
a
significant relation
between
refractory
angina (C0002962)
and
major (C0205164)
nonprocedural
(
"
spontaneous
"
)
events (C0441471)
.
Because
no
valid
universal (C0175671)
definition
of
refractory
angina (C0002962)
exists
,
the
criteria (C0243161)
used
in
this
study
may
be
different
from
those
used
by
others (C0205394~C0220886~C0237094~C0237098~C0237111~C0237120~C0237127~C0237133~C0237142~C0237155~C0237161~C0237162~C0237169~C0237173~C0237178~C0237185~C0237190~C0237195~C0237206~C0237212~C0237221~C0237228~C0237237~C0237242~C0237243~C0237247~C0237255~C0237262~C0237266~C0237276~C0237283~C0237285~C0237289~C0237300~C0237305~C0237318~C0237324~C0237330~C0237338~C0237343~C0237344~C0237353~C0237357~C0237361~C0237366~C0237369~C0237373~C0237380~C0237387~C0237394~C0237395~C0449210)
.
Because
of
the
pragmatic
character (C0007952~C0486537)
of
the
study
,
neither
the
presence (C0392148~C0392743)
of
ECG evidence (C0332120)
of
ischemia (C0022116)
nor
the
use (C0042153~C0439224~C0449865)
of
heparin (C0019134)
during
the
episodes (C0277793~C0332189)
of
chest pain (C0008031)
were
required
for
the
diagnosis (C0011900~C0011901)
of
refractory
angina (C0002962)
.
In
this
study
the
use (C0042153~C0439224~C0449865)
of
intravenous heparin (C0354566)
was
less
than
what
might
be
anticipated
(
57
%
)
because
in
recent
years (C0439234~C0439508)
there
has
been
a
greater
trend (C0040833)
toward
increased
use (C0042153~C0439224~C0449865)
.
However
,
the
use (C0042153~C0439224~C0449865)
of
heparin (C0019134)
was
higher
in
patients (C0030705)
without
precipitating
factors
(
69.7
%
)
.
This
finding (C0243095~C0263541~C0332285)
is
not
unexpected
because
in
primary
unstable angina (C0002965)
(
Braunwald class B (C0004914~C0004916~C0004922~C0004923~C0005139~C0006030~C0053353~C0205170~C0332272~C0392746~C0439105~C0439127)
)
the
presence (C0392148~C0392743)
of
a
thrombus (C0087086)
can
be
presumed
and
the
use (C0042153~C0439224~C0449865)
of
heparin treatment (C0039798~C0087111)
is
well
substantiated
.
The
studies
by
Theroux
and
Wallentin
showed
the
effectiveness (C0205414)
of
intravenous heparin (C0354566)
and low-molecular-weight heparin (C0019139)
in
preventing
major
complications (C0009566~C0009567~C0392327)
during
the
acute phase (C0439557)
of
unstable angina (C0002965)
.
Consequently
,
in
our
study
,
a
lower
incidence (C0021149~C0220856)
of
refractory
angina (C0002962)
and
a
better (C0004914~C0004916~C0004922~C0004923~C0005139~C0006030~C0053353~C0205170~C0332272~C0392746~C0439105~C0439127)
outcome
could
have
been
observed
if
heparin (C0019134)
had
been
used
more
frequently
or
if
a
more (C0205172)
stringent definition
of
refractory
angina (C0002962)
had
been
used
.
Nonetheless
,
mortality rate (C0034693)
in
this
series (C0205549)
was
similar
to
that
reported
in
recent (C0332185)
trials
.
At
30
days (C0439228~C0439229~C0439505)
the
death rate (C0205848~C0220817)
was
3.6
%
and
3.9
%
in
the
heparin arms (C0003792)
of
the
studies
ESSENCE (C0028910)
and GUSTO II B (C0004914~C0004916~C0004922~C0004923~C0005139~C0006030~C0053353~C0205170~C0332272~C0392746~C0439105~C0439127)
,
respectively
.
In
the
PURSUIT trial
,
30-day mortality rate (C0034693)
was
3.7
%
in
the
control arm (C0003792)
.
In
the
TIMI-IIIB study
,
the
death rate (C0205848~C0220817)
of
the
early conservative
arm (C0003792)
was
4.7
%
at
42
days (C0439228~C0439229~C0439505)
.
In
the
PRISM PLUS (C0332287)
study
,
the
30-day mortality rate (C0034693)
was
4.0
%
in
patients (C0030705)
treated
with
heparin (C0019134)
.
The
relative (C0080103~C0205345)
benefits
of
early invasive and early conservative
treatment (C0039798~C0087111)
strategies
have
been
debated
for
many
years (C0439234~C0439508)
.
Either
of
these
approaches (C0449445)
is
considered
clinically
appropriate
for
many
patients (C0030705)
.
Accordingly
,
the
identification (C0020792)
of
candidates
for
a
more aggressive (C0001807)
strategy
has
become
of
utmost importance
.
Because
of
its
simplicity
and
wide
availability (C0470187)
,
clinical
and
ECG markers (C0181733~C0522501)
are
widely
used
for
this
purpose (C0449256)
.
Unfortunately
,
the
specificity (C0037791)
of
the
clinical (C0205210)
predictors
is
insufficient
to
fulfill
the
requirements
of
risk (C0035647)
stratification
under
the
current therapeutic
modalities (C0278616)
.
In
recent
years (C0439234~C0439508)
,
serum (C0229671)
markers (C0181733~C0522501)
such
as
troponin T (C0077404)
and
C-reactive protein (C0006560~C0201657)
have
become
the
focus (C0205234~C0344236)
of
interest (C0123730~C0205103)
for
risk (C0035647)
stratification
of
unstable angina (C0002965)
,
with
promising
results (C0332294)
.
It
is
very
likely
that
routine
measurements (C0242485)
of
these
markers (C0181733~C0522501)
will
contribute
to
the
identification (C0020792)
of
those
patients (C0030705)
at
highest risk (C0332167)
for
cardiac
events (C0441471)
.
A
major
question (C0332147)
to
be
explored
is
how much information
these
new
biochemical markers (C0206015)
will
add
to
what
is
already
provided
by
the
classic
clinical (C0205210)
predictors
.
We
thank
Gianni Tognoni
,
MD
,
for
his
assistance (C0018896)
in
the
design
of
the
study
;
Dr Pierre Theroux
for
helpful
comments (C0282411)
on
early (C0205085)
drafts
of
this
paper (C0030351~C0428642)
;
and
Maria (C0324143)
Elena Aizpurua
for
secretarial
assistance (C0018896)
.