2658
Mortality Within 24 Hours of Thrombolysis
for Myocardial Infarction
The Importance of Early Reperfusion
Neal S. Kleiman, MD; Harvey D. White, MD; E. Magnus Ohman, MD; Allan M. Ross, MD;
Lynn H. Woodlief, MS; Robert M. Califf, MD; David R. Holmes, Jr, MD; Eric Bates, MD;
Matthias Pfisterer, MD; Alec Vahanian, MD; Eric J. Topol, MD; for the GUSTO Investigators*
Downloaded from http://circ.ahajournals.org/ by guest on June 17, 2017
Background A paradoxical increased risk of death has been
reported during the first 24 hours after thrombolysis for
myocardial infarction. The mechanism of this phenomenon is
not known, nor is its relation to the success or failure of
reperfusion. The present study was a prospectively designed
analysis of deaths occurring within the first 24 hours in the
GUSTO trial.
Methods and Results There were 41 021 patients enrolled in
GUSTO, a randomized comparison of streptokinase with
intravenous or subcutaneous heparin, accelerated tissue-type
plasminogen activator (TPA), and combination of streptokinase and TPA. An angiographic mechanistic substudy examined reperfusion (using the TIMI flow grading criteria) 90
minutes after the assigned thrombolytic regimen was begun in
1567 patients. There were 1125 deaths (2.8%) within 24 hours
("early deaths") and 1726 additional deaths (4.2%) after 24
hours but within 30 days ("later deaths"). At the time of
presentation, the most potent predictors of early death were
hypotension and sinus tachycardia. In a multiple logistic
regression model, lower systolic blood pressure, shorter height,
higher heart rate, and the absence of prior smoking distinguished early death from later death. Reinfarction occurred in
26 patients (2.4%), shock in 572 patients (52%), atrioventricular block in 308 patients (28%), and tamponade in 106
patients (10%) dying early compared with 262 (15%), 788
(46%), 396 (23%), and 74 (4%) respective patients dying later.
There were no differences in early mortality among the
thrombolytic regimens for the first 6 hours after randomization. By 24 hours, however, mortality was 2.89% for streptokinase recipients, 2.84% for combination therapy recipients, and
2.36% for accelerated TPA recipients (P=.005). There was
little difference among patients with differing flow grades in
the infarct artery during the first 4 hours, although mortality
among patients with grade 2 flow was initially higher. After the
fourth hour, there were very few additional deaths during the
first day in patients with grade 3 flow. At 24 hours, mortality
was 2.35% for patients with flow grade 0 or 1, 2.92% for
patients with flow grade 2, and 0.89% for patients with flow
grade 3.
Conclusions Even with aggressive management regimens,
mortality within the first 24 hours accounted for a large
proportion of postthrombolytic deaths. Patients dying early
were more likely to present with pump failure than were those
dying later and were more likely to die of events related to left
ventricular dysfunction, although cardiac tamponade also accounted for a significant minority of these deaths. Thus, the
severity of the clinical presentation rather than the underlying
risk factors predicts early mortality. Based on the angiographic
substudy data, it appears that rather than hastening early
mortality, successful restoration of complete antegrade flow in
the infarct-related artery protects against early death.
(Circulation. 1994;90:2658-2665.)
Key Words * thrombolysis * infarction * reperfusion a
mortality * tamponade
lacebo-controlled studies of thrombolytic therapy
have demonstrated a reduction in mortality
after acute myocardial infarction.2-4 This survival benefit may be partially offset by a paradoxical
increase in the risk of death during the first 24 hours
after thrombolytic therapy is begun.5'6 Nearly half of the
deaths among patients receiving thrombolytic drugs
occur during this period.5-9 As further advances are
made in reperfusion strategies, incremental mortality
reductions will require that the mechanisms of death
during this period be elucidated. Whether these deaths
result from myocardial necrosis already present at the
time of clinical presentation, rupture, increased bleeding, reperfusion-induced injury, or failure to restore
antegrade flow in the infarct-related artery is of critical
importance in designing new therapeutic strategies.
Prior studies have been unable to address these questions due to either a lack of angiographic data or a
limited sample size. The Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded
Received May 5, 1994; revision accepted July 6, 1994.
From the Section of Cardiology (N.S.K.), Department of Medicine, Baylor College of Medicine, Houston, Tex; Cardiology
Department (H.D.W.), Green Lane Hospital, Auckland, New
Zealand; Division of Cardiology (E.M.O., L.H.W., R.M.C.), Department of Medicine, Duke University Medical Center, Durham,
NC; Division of Cardiology (A.M.R.), George Washington University Medical Center, Washington, DC; Department of Internal
Medicine (D.R.H.), Mayo Clinic, Rochester, Minn; Division of
Cardiology (E.B.), University of Michigan Medical Center, Ann
Arbor, Mich; Division of Cardiology (M.P.), University Hospital
Basel, Basel, Switzerland; Cardiology Service (A.V.), Hopital
Tenon, Paris, France; and Department of Cardiology (E.J.T.),
Cleveland Clinic Foundation, Cleveland, Ohio.
Reprint requests to Neal S. Kleiman, MD, Section of Cardiology, The Methodist Hospital, 6535 Fannin, MS F-905, Houston,
TX 77030.
Presented in part at the American Heart Association 66th
Annual Scientific Sessions, Atlanta, Ga, November 8, 1993.
*A complete listing of GUSTO Investigators can be found in
N Engl J Med. 1993;329:673-682.1
© 1994 American Heart Association, Inc.
Kleiman et al Early Mortality After Thrombolysis
Coronary Arteries (GUSTO) trial afforded a unique
opportunity to examine the relation between reperfusion and early mortality because it consisted of randomly assigned groups of patients in whom differing
rates of early reperfusion were documented and had
adequate statistical power to assess differences in early
mortality.1'10 Accordingly, the present study was prospectively designed to test the hypothesis that aggressive
thrombolysis would lower mortality at 24 hours.
Methods
Study Design and Data Collection
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The methods and results of GUSTO have been published.1
Briefly, 41 021 patients with ST-segment elevation on the
presenting ECG within 6 hours of symptom onset were randomly assigned to receive treatment with 1.5 million U streptokinase (SK) (Kabikinase) with 12 500 U heparin SC every 12
hours; 1.5 million U streptokinase with 5000-U heparin bolus
IV followed by 1000 U/h; accelerated tissue-type plasminogen
activator (TPA) (Alteplase, Genentech) 15-mg bolus then 0.75
mg/kg over 30 minutes and then 0.5 mg/kg over 60 minutes,
with the same intravenous heparin regimen; or combination
TPA plus SK consisting of 1 mg/kg TPA (maximum of 90 mg)
over 60 minutes with 10% as a bolus, 1 million U SK over 60
minutes, and 5000-U bolus heparin IV and then 1000 U/h. All
patients received 160 mg or more aspirin (Bayer) PO. Atenolol
(10 mg IV) (Tenormin, ICI Pharma) was recommended for
patients who had no contraindication to 3-blockade. The
primary end point of the study was all-cause mortality at 30
days. The study protocol specified that if there were no
difference in the primary end point between the SK arms, they
would be combined for subsequent analyses.
The time to death was defined as the interval between
randomization and death. At the time of protocol design,
mortality within 24 hours after enrollment was prespecified as
a secondary end point. Deaths occurring during this period are
referred to as early deaths. Deaths occurring after 24 hours but
within 30 days are considered later deaths. Reinfarction was
defined as the presence of at least two of the following four
criteria: recurrent ischemic symptoms lasting >15 minutes
after the resolution of the symptoms of the index infarction,
the occurrence of new ST-T-wave changes or new Q waves, a
second elevation in cardiac enzymes above the upper limit of
normal or by an additional 20% if already elevated, or
angiographic reocclusion of a previously documented patent
coronary artery. Recurrent ischemia was defined according to
the clinical judgment of the individual investigators, but guidelines given on the case report form comprised angina or its
equivalent lasting at least 15 minutes. A stroke-related death
was defined as any death in a patient who had suffered a
stroke. The GUSTO protocol called for computed tomographic scanning or magnetic resonance imaging of the brain
in all patients with suspected stroke. This was accomplished in
95% of such patients.1 Bleeding was defined as severe if it
caused hemodynamic compromise, whereas moderate bleeding was defined as that requiring transfusion but without
causing hemodynamic compromise. Baseline demographic
characteristics were collected from the enrollment form; all
data were double-entered at the data coordinating centers and
were centrally audited for inconsistencies. Source documentation was performed in approximately 12% of cases at each site.
An angiographic mechanistic substudy of 2431 patients
examined reperfusion at the randomly assigned time points of
90 minutes, 180 minutes, 24 hours, or 5 to 7 days after therapy
was begun. The randomization scheme for this substudy was
designed so that half of the patients would be assigned to
undergo angiography at the 90-minute point. To ensure that
baseline characteristics were identical to those of patients
enrolled in the main study, centers enrolling patients in this
substudy were required to include all of their GUSTO study
2659
TABLE 1. Timing of Mortality in GUSTO
No. of Cumulative Deaths (%)
Time
2h
4h
6h
12 h
24 h
30 h
Overall
Mortality
Stroke
Mortality
3 (0.01)
5 (0.01)
7 (0.02)
19 (0.05)
59 (0.14)
244 (0.60)
247 (0.7)
520 (1.3)
641 (1.6)
876 (2.1)
1125 (2.7)
2851 (7.0)
Nonstroke
Mortality
267 (0.7)
511 (1.2)
630 (1.5)
847 (2.1)
1056 (2.6)
2591 (6.4)
patients.10 Because of these entry requirements, patients in
the angiographic substudy were highly representative of patients in the main cohort. Perfusion on the 90-minute angiogram was determined by a core laboratory blinded to the
treatment assigned and was graded using the Thrombolysis in
Myocardial Ischemia Phase I (TIMI I) flow criteria."
Statistical Analysis
Descriptive statistics are provided as percentages for categorical variables and mean (25th, 50th, and 75th percentiles)
for continuous variables. For categorical variables, statistical
testing was performed using the x2 test. For continuous
variables, the Wilcoxon rank-sum test was used. Results are
also presented as odds ratios with 95% confidence intervals. A
logistic regression model was used to assess predictors of death
within 24 hours versus death after 24 hours. Candidate predictors included baseline characteristics from which a final
model was determined using a backward elimination method
(elimination criterion, P<.05).
Results
Overall Timing of Mortality
Among the 41 021 patients enrolled in GUSTO,
complete data concerning survival status at 24 hours are
available on 41 008, or 99.9%. There were 1125 early
deaths (2.8%) and 1726 additional later deaths (4.2%).
Thus, 39% of all deaths occurred within 24 hours. More
detailed timing of these deaths is shown in Table 1. Six
hundred forty-one early deaths (57%) occurred within
the first 6 hours after beginning thrombolytic therapy.
The median time from randomization to initiation of
thrombolytic therapy was 35 minutes. Of the 1125 early
deaths, 124 (11%) occurred shortly after the time of
study entry but before the assigned treatment could be
begun.
Baseline Demographic Characteristics and
Hospital Course
Important baseline characteristics of patients dying
early are compared in Table 2 with those surviving the
first 24 hours, and odds ratios for death occurring within
the early period are given in Table 3. Patients dying
early were older and more likely to be female, to have
anterior infarction, previous angina, or a history of prior
infarction than those surviving 30 days but not more so
than those dying later. The median time from the onset
of symptoms to beginning therapy was slightly (13
minutes) longer in those patients dying early than in
those surviving 30 days. Although the most potent
predictors of early death were hypotension and sinus
tachycardia, and a larger proportion of patients dying
2660
Circulation Vol 90, No 6 December 1994
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TABLE 2. Baseline Demographic Characteristics According to Time of Death
Died <24 h
Died at 24 h to 30 d
(n=1 125)
Characteristic
(n= 1726)
70.2 (64, 72, 78)
70.5 (65, 72, 78)
Age, y
647 (58)
Male, n (%)
1039 (60)
73.8 (64, 73, 82)
Weight, kg
73.9 (64, 73, 82)
168.0 (160,168,175)
168.3 (160,168,175)
Height, cm
3.31 (2.0, 3.0, 4.3)
3.43 (2.3, 3.2, 4.4)
Time to treatment, h
478 (44)
Prior angina, n (%)
769 (45)
Prior Ml, n (%)
306 (28)
478 (28)
220 (20)
416 (24)
Diabetes, n (%)
463 (29)
233 (25)
Hypercholesterolemia, n (%)
823 (48)
492 (45)
Hypertension, n (%)
944 (56)
488 (49)
History of smoking, n (%)
961 (56)
616 (55)
Anterior Ml, n (%)
648 (59)
1109 (65)
Killip class 1, n (%)
254 (23)
439 (26)
Killip class 1i, n (%)
76 (7)
100 (6)
Killip class Ill, n (%)
64 (4)
117 (10.7)
Killip class IV,n(%)
BP <100 mm Hg systolic, n (%)
360 (34)
209 (13)
HR >100 bpm, n (%)
331 (20)
237 (23)
111.4 (90,110,130)
125.9 (110,125,141)
Systolic BP, mm Hg
84.4
82 (68, 80, 95)
HR, bpm
(66, 82,100)
Mi indicates myocardial infarction; BP, blood pressure; HR, heart rate, and bpm, beats per minute.
Data for continuous variables are presented as mean (25th, 50th, and 75th percentiles).
early were in Killip class III or IV than were those
surviving, it is noteworthy that 82% were in Killip class
I or II at the time of presentation. When the baseline
characteristics of patients dying early and those dying
later are compared, they appear to be essentially simiTABLE 3. Odds Ratios for Death Within 24 Hours
Odds Ratio
of Death
95%
Confidence
<24 h
Baseline Characteristic
Limits
BP <100 mm Hg systolic
6.61
5.9, 7.4
4.5
Age >70 y
4.0, 5.0
Heart rate > 100 bpm
3.87
3.4, 4.5
Female sex
2.24
2.0, 2.5
Prior myocardial infarction
2.04
1.8, 2.3
Anterior myocardial infarction
1.94
1.7, 2.2
Diabetes
1.50
1.3,1.7
Prior angina
1.37
1.2, 1.5
Prior CABG
1.33
1.0,1.7
Hypercholesterolemia
0.62
0.53, 0.72
Family history
0.61
0.53, 0.71
Current smoker
0.47
0.41, 0.54
Killip class IV
23.9
20.3, 28.1
Treatment <2 h
0.89
0.77,1.03
BP indicates blood pressure; bpm, beats per minute; and
CABG, coronary artery bypass graft surgery.
Survived 30 d
(n=37 979)
60.2 (52, 61, 69)
28 827 (76)
79.8 (70, 79, 89)
171.4 (165,172,178)
3.07 (2.0, 2.8, 3.9)
13 730 (36)
5893 (16)
5343 (14)
12 832 (35)
14 158 (37)
26 655 (71)
14 301 (38)
32 903 (87)
4397 (12)
370 (1)
132 (0.4)
2620 (7)
3181 (9)
129.6 (113,130,144)
74.8 (62, 73, 85)
lar, except in the proportions of patients with Killip
class IV heart failure and with a history of smoking
among patients dying later. The following characteristics in the regression model predicted death within 24
hours versus death after 24 hours: decreased systolic
blood pressure, decreased height, increased heart rate,
and absence of prior smoking history.
The complications that occurred during hospitalization are reported in Table 4. Ventricular arrhythmias
occurred in 45% of patients dying early, and atrioventricular block occurred in 28%. Recurrent ischemia and
reinfarction were rarer events among patients dying
early than among those surviving. Cardiac tamponade
occurred in 10% of patients dying early, in 4% of
patients dying later, and in 0.4% of patients who
survived 30 days. Compared with the patients who died
within 24 hours but in whom tamponade was not
reported, patients with tamponade were likely to be
female (62% versus 40%, P<.0001) and to have received thrombolytic therapy within the first 2 hours of
symptoms (87% versus 77%, P=.015) but were less
likely to have had a previous infarction (8.7% versus
30%, P<.0001). Mean systolic and diastolic blood pressures were higher in the former group of patients (122
versus 110 mm Hg, P<.0001, and 75 versus 69 mm Hg,
P=.0019, respectively). There were no differences in
age, the proportion of patients with anterior infarctions,
or the proportion of patients receiving any of the four
assigned thrombolytic regimens. As depicted in Table 5,
intra-aortic balloon counterpulsation was performed in
9% of the patients who died early. Fewer than half the
Kleiman
TABLE 4. Complications and Clinical Events
Died
Died >24 h
Event, n (%)
Reinfarction
Ischemia
Shock
Anaphylaxis
Hypotension
AV block
Sustained ventricular
tachycardia
Ventricular fibrillation
Tamponade
Atrial
(n=1125)
26 (2.4)
91 (8.3)
572 (52)
5 (0.5)
724 (65)
308 (28)
and <30 d
(n=1726)
262 (15.3)
539 (32)
788 (46)
7 (0.4)
910 (53)
396 (23)
299 (26)
401 (36)
106 (10)
448 (26)
478 (28)
74 (4)
1775 (5)
1858 (5)
132 (0.4)
fibrillation/flutter
106 (10)
20 (2)
24 (2)
440 (26)
98 (6)
55 (3)
3273 (9)
452 (1)
115 (0.3)
.24 h
Complication/
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Acute MR
VSD
Bleeding
Survived
30 d
(n=37 979)
1336 (3.5)
7469 (20)
1084 (3)
199 (0.5)
3238 (9)
2672 (7)
123 (7)
Severe
25 (2)
346 (1)
Moderate
48 (4)
358 (21)
4240 (11)
AV indicates atrioventricular; MR, mitral regurgitation; and
VSD, ventricular septal defect.
patients dying early were placed on mechanical ventilators, and 256 (23%) had temporary pacemakers inserted. Cardioversion or defibrillation was performed in
485 (44%).
Coronary angiography was performed in 112 patients
(10%) dying early, and percutaneous transluminal coronary angioplasty and coronary artery bypass graft
surgery were performed considerably less frequently. In
34 patients, the angiogram was required by the angiographic substudy protocol, whereas in 78 it was performed at physician discretion. Of the 78 patients (7%)
undergoing angiograms not mandated by the angiographic substudy, data regarding patency of the infarctrelated artery were available in 58 (74%). In these 58
patients, the investigators reported that 4 (7%) had
TIMI grade 2 flow and 3 (5%) had TIMI grade 3 flow,
whereas the artery was reported to be "patent" (actual
TABLE 5. Treatments During Hospitalization
Died >24 h Survived
Died
<24 h
and <30 d
30 d
Procedure, n (%)
(n=1125) (n=1726) (n=37 979)
21 930 (58)
112 (10)
550 (32)
Coronary angiogram
191 (11)
61 (5)
PTCA
8644(23)
3375
7
137
CABG
(0.6)
(8)
(9)
97 (9)
1099 (3)
284 (17)
IABP
2272 (6)
337 (20)
Temporary pacemaker 256 (23)
3479 (9)
729 (42)
460 (41)
Mechanical ventilation
17 984 (45)
621 (36)
215 (19)
Intravenous 3-blocker
PTCA indicates percutaneous transluminal coronary angioplasty; CABG, coronary artery bypass graft surgery; and IABP,
intra-aortic balloon pump.
et
al Early Mortality After Thrombolysis
2661
flow grade unspecified) in 4 (7%). Thus, 47 patients
(81%) were reported to have a totally occluded artery.
Among the 2127 24-hour survivors in whom nonprotocol-mandated angiograms were done during the
first day, data regarding patency were available in 1527
patients (72%). TIMI grades 2 and 3 flow were reported
in 296 (19%) and 431 (28%) of these 1527 patients,
respectively, whereas the artery was reported to be
"patent" in an additional 77 patients (5%).
Early Mortality, Thrombolytic Treatment
Assignment, and Patency
Fig 1 shows the timing of mortality according to the
thrombolytic regimen assigned. There were no differences in 24-hour mortality among the SK-treated
groups (SK with intravenous heparin, 2.94%; with subcutaneous heparin, 2.85%; P=.693); therefore, they are
combined in this analysis. There was very little difference in early mortality among patients receiving the
assigned thrombolytic regimens until the sixth hour,
when the curves began to diverge. From this point on,
mortality progressed at a slower rate in the accelerated
TPA-treated patients. Odds ratios and confidence limits for mortality according to treatment are shown in Fig
2. As shown in Table 6, patients dying within the first 6
hours were more likely to have diabetes, previous
angina, or prior myocardial infarction and were more
likely at the time of clinical presentation to be either
hypotensive or in cardiogenic shock than were those
dying between hours 6 and 24. Stroke-related mortality
(Fig lb) accounted for very few early deaths in any of
the treatment groups. In Fig 3, early mortality according
to patency status is shown among patients enrolled in
the angiographic substudy and assigned to undergo a
protocol-directed angiogram 90 minutes after beginning
thrombolytic therapy. There was little difference among
patients with differing flow grades in the infarct artery
during the first 4 hours, although mortality among
patients with grade 2 flow was initially higher. However,
after the fourth hour, there were very few additional
deaths during the first day in patients with grade 3 flow.
At 24 hours, mortality in this group was approximately
one fourth of that in patients with grade 0, 1, or 2 flow.
Discussion
Even with modern aggressive reperfusion strategies,
mortality during the early hours following acute myocardial infarction accounts for more than one third of
the postinfarction deaths, but it is reduced by the
restoration of antegrade blood flow in the infarctrelated artery. Our data show that rather than being
responsible for an "early hazard," early reperfusion
appears to protect against it. This principle is consistent
with the finding that, as a rule, myocardial infarctions in
this study were more likely to be associated with pretreatment evidence of left ventricular dysfunction and
pump failure in patients who died early than in those
surviving the first 24 hours.
At least two distinct etiologies are likely to be responsible for the mechanism of these early deaths: pump
dysfunction and myocardial rupture. First, a large body
of evidence suggests that pump failure played a central
role in the early deaths in this report. Hemodynamic
evidence of left ventricular compromise was considerably more common among patients dying within the first
Circulation Vol 90, No 6 December 1994
2662
3
a
-
22.5 -
ISK
21-
t-PA + SK
-
2
p- 1.5
1
0.5
0
10
12
14
8
16
time from Randomization (hours)
18
20
22
24
b
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3
-it-PA
2.5
....SK
-
FiG 1. a, Plot of mortality according to time from randomization for
each treatment arm in GUSTO. In
this and subsequent figures, arrowheads are used on the abscissa to
represent the median time to beginning thrombolytic therapy. t-PA
indicates tissue-type plasminogen
activator (TPA); SK, streptokinase.
b, Plot of stroke-related and nonstroke-related mortality for each
treatment arm in GUSTO.
t-PA + SK
2
Non-stroke Mortality
k 1.5
U
a
1
0.5
Stroke mortality
0
0
2
4
6
8
10
12
14
16
18
20
22
24
Time from RandomizatlQn (hours)
24 hours, and in the multivariate model of mortality,
systolic blood pressure and Killip class were the strongest predictors distinguishing the deaths occurring within
the first 24 hours from those that occurred within the
remainder of the first month after infarction. We have
previously shown concordant advantages in both survival and early patency for the accelerated TPA regimen
compared with the other thrombolytic regimens tested'10 as well as improved left ventricular function and
survival at 30 days in patients with complete restoration
of antegrade flow (TIMI grade 3) in the infarct artery.'0
In the present study, a persistent survival advantage for
accelerated TPA became apparent several hours after
the initiation of therapy. In parallel, at approximately
this time, a distinct survival advantage also became
evident for patients in the angiographic study who,
regardless of thrombolytic strategy, had grade 3 flow in
the infarct-related artery on an angiogram performed
90 minutes after beginning thrombolytic therapy. Similarly, few patients in the main study who underwent
angiography and who died within the first day had
patent infarct-related arteries. In combination, these
findings indicate very strongly that failure of reperfusion is a critical factor contributing to early as well as
later mortality. On the other hand, the surprising
finding that TIMI grade 2 flow was associated with a
higher mortality during the first 4 hours than TIMI
grade 0 or 1 flow may indicate that partial reperfusion
has a detrimental effect on the myocardium. Alternately, suboptimal flow despite lysis of an occlusive
coronary thrombus may identify a group of patients in
whom myocardial necrosis has occurred rapidly with
localized edema and microvascular stasis and in whom
early mortality is likely to be high. However, the numbers of patients with grade 0 or 1 and grade 2 flow are
not adequate to allow clear distinction between these
groups.
The early survival advantage for patients with TIMI
grade 3 flow also suggests that the pump failure responsible for most of the early deaths is a consequence of
myocardial ischemia rather than preexisting necrosis.
Accordingly, the time to beginning thrombolytic therapy
was only marginally greater in patients who died early,
and the proportion with a prior infarction was also only
slightly higher. The finding that early mortality is lower
rather than higher for patients with early grade 3 flow
and for those assigned to treatment with accelerated
TPA also indicates strongly that reperfusion-induced
Kkeiman et al Early Mortality After Thrombolysis
2663
Odds
Ratio
1.5
FiG 2. Odds ratios with 95% confidence limits for death after randomization to treatment with strep.
I
tokinase (SK) (with intravenous or
subcutaneous heparin) versus accelerated tissuetype plasminogen
activator (t-PA [TPAJ).
(
0.5
0
2
4
6
a
10
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Time from
12
14
18
16
20
22
24
Randomization (hours)
necrosis is unlikely to play an important role in early
mortality. Were this true, mortality would also have
been expected to be higher rather than lower in patients
with early reperfusion.
The presence of cardiac tamponade in 10% of patients dying early suggests that in some patients, rupture
of the myocardium may have been the mechanism of
death. Given the clinical difficulty of recognizing myocardial rupture, it is possible that this figure underestimates the true frequency of rupture. That shock was
reported to develop in only 52% of patients who died
early and hypotension was reported in 65% suggests
that many of the patients who died early were unexpectedly noted either to be in extremis or to have arrested.
Previous authors have reported a biphasic frequency of
distribution of cardiorrhexis slitlike ruptures complicating small infarctions during the first day after infarction and larger ruptures occurring approximately 1 week
after the onset of large infarctions. In the first ISIS
study, the majority of early deaths in a large subgroup of
-
TABLE 6. Baseline Characteristics of Patients Dying Within 24 Hours
Characteristic
Age, y
Age >70 y, n (%)
Male, n (%)
Treated <2 h, n (%)
Anterior Mi, n (%)
Killip class, n (%)
1
11
ill
Died <6 h
(n=641)
69 (62, 71, 77)
344 (54)
239 (37)
142 (26)
341 (53)
345 (56)
144 (23)
34 (7)
90 (14)
264 (45)
Died at 6 to 24 h
(n=484)
72 (67, 72, 78)
398 (64)
236 (49)
100 (22)
275 (57)
P
<.001
<.001
<.001
.185
.182
303 (64)
110 (23)
42 (7)
27 (6)
<.001
<.001
96 (21)
.217
96 (21)
141 (24)
.003
183 (39)
295 (48)
.011
114 (24)
192 (31)
.008
78 (17)
142 (23)
.827
216 (46)
276 (45)
.262
215
273 (51)
(47)
Smoker, n (%)
.034
72 (63, 72, 80)
75 (65, 75, 83)
Weight, kg
.048
167
169
168,
175)
in
(160,
175)
170,
(160,
Height,
Mi indicates myocardial infarction; BP, blood pressure; HR, heart rate; and bpm, beats per minute.
Data for continuous varables are presented as mean (25th, 50th, and 75th percentiles).
IV
BP <100 mm Hg systolic, n (%)
HR >100 bpm, n (%)
Prior angina, n (%)
Prior Mi, n (%)
Diabetes, n (%)
Hypertension, n (%)
Circulation Vol 90, No 6 December 1994
2664
3.5
TIMI Grade 3
~
3
-
2.5
-
TIMI Grade 2
TIMIGradeOorl
---
2 1-
O_ 1.5
FIG 3. Plot of mortality according
to TIMI flow grade on the angiogram performed at 90 minutes in
the angiographic study. Data are
taken according to flow grade regardless of treatment arm.
-
7
7
7
, ,~ ~ ~ ~ ~ ~ ~ .
,,
7_
1
0.5 -
,
7
71
1-1~
'~~~~~~~~~~~.
711i
o
i.
0
_
.r
A
_d
2
4
6
12
14
8
10
16
Time from Randomization (hours)
Downloaded from http://circ.ahajournals.org/ by guest on June 17, 2017
patients undergoing autopsy were secondary to rupture
of the ventricle.12 However, in that study of early
intravenous fl-blocker therapy, it is likely that the
frequency of fatal rupture would be increased because
patients with incipient heart failure would be less likely
to be enrolled, thus decreasing the proportion of patients likely to die of early severe pump failure. In the
second phase of the TIMI II study,7 the majority of
deaths during the first 18 hours after therapy was begun
with accelerated TPA were due to pump failure,
whereas the incidence of fatal cardiac rupture during
the first 18 hours after therapy was 16%. However,
among the 50% of patients in that study who underwent
autopsy, evidence of rupture was found in 25%, whereas
it was judged to be present in 3% of patients in whom an
autopsy was not performed.8 It thus is likely that a
modest proportion of early deaths in GUSTO was
caused by myocardial rupture.
Pathological study of ventricles in which rupture has
occurred often demonstrates intramyocardial hemorrhage surrounding the rupture tract. Hemorrhage into
the myocardium has also been reported to be more
common in patients who have received thrombolytic
therapy,13 and it has been hypothesized that intramyocardial hemorrhage predisposes patients to rupture of
the heart.14 At least one report has suggested that
patients in whom rupture occurs may have a stuttering
course.15 It is possible that thrombolytic therapy hastens
this progression by dissolving the thrombus that temporarily seals the rupture site, by facilitating the dissection
by blood along necrotic tissue planes, or by allowing
recovery of myocardial contractility, thus increasing the
shear forces that lead to disruption of the myocardium.
Were rupture alone responsible for the majority of early
deaths, one would not have expected to see clear
evidence of a survival advantage for patients with
complete restoration of flow and for assignment to
treatment with accelerated TPA. It is also possible that
by limiting infarct size, reperfusion with thrombolytic
therapy decreases the substrate in which myocardial
rupture can occur. Thus, there may be a dynamic
balance between those factors favoring and those preventing rupture in patients receiving thrombolytic therapy. However, without a control group of patients who
18
20
22
24
did not receive thrombolytics, these possibilities remain
speculative.
What is more puzzling is the similarity in mortality
for the treatment regimens and for the TIMI flow
grades during the first 6 hours after treatment was
begun. The median time required for reperfusion to
occur following treatment with both SK and accelerated
TPA has previously been reported to be slightly less
than 1 hour.11,16 In addition, a small number of patients
in GUSTO died before thrombolytic therapy could be
begun. Thus, it would be unlikely for differences in
mortality to be seen during and shortly after the first
hour. The time period extending up to the sixth hour
may represent the time required for sufficient recovery
of ventricular muscle function after ischemia ("stunning")17 to prevent or reverse pump failure, or it may
represent a period during which a detrimental effect of
reperfusion is balanced by the benefit of reperfusion. As
an alternative, "reperfusion dysrhythmias"'18 during this
extremely early period may be responsible for a number
of deaths. In the TIMI II experience, the frequency of
lethal dysrhythmias did not differ between patients
dying within 4 hours and those dying between 4 and 18
hours; however, in that study, there were small numbers
of patients in each of the two groups.5 In the present
study, however, there was more evidence of both severe
pump dysfunction at the time of clinical presentation
and of preexisting cardiovascular disease (Table 6) in
those patients who died within the first 6 hours. Thus, it
appears that patients who died in this very early period
had larger, more hemodynamically significant infarctions or had more preexisting myocardial damage and
were less able to survive the initial hours until adequate
recovery of left ventricular function could occur.
The high "mortality density" within the early hours
after reperfusion therapy is in agreement with data from
other large-scale studies of patients with myocardial
infarction.2-4 The present data are unique, however, in
that they very strongly establish a link between early
restoration of antegrade coronary arterial blood flow
and a reduction of early mortality, thus suggesting that
at least a large proportion of the deaths during this
period results from a failure of reperfusion to occur. It
is also quite clear that earlier reperfusion is associated
Kleiman et al Early Mortality After Thrombolysis
with an early survival advantage, and these data strongly
suggest that future attention be directed toward more
reliable means of ensuring rapid reperfusion, even in
those patients who do not have pump dysfunction at the
time of initial presentation.
9.
Acknowledgments
10.
This study was supported by a combined grant from Bayer
(New York, NY), CIBA-Corning (Medfield, Mass), Genentech (South San Francisco, Calif), ICI Pharmaceuticals (Wilmington, Del), and Sanofi Pharmaceuticals (Paris, France).
11.
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N S Kleiman, H D White, E M Ohman, A M Ross, L H Woodlief, R M Califf, D R Holmes, Jr,
E Bates, M Pfisterer and A Vahanian
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Circulation. 1994;90:2658-2665
doi: 10.1161/01.CIR.90.6.2658
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