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170
Racial Differences in Responses to
Thrombolytic Therapy With Recombinant
Tissue-Type Plasminogen Activator
Increased Fibrin(ogen)olysis in Blacks
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David C. Sane, MD; David C. Stump, MD; Eric J. Topol, MD; Kristina N. Sigmon, MA;
Walter K. Clair, MD; Dean J. Kereiakes, MD; Barry S. George, MD;
Marcus F. Stoddard MD; Eric R. Bates, MD; Richard S. Stack, MD; Robert M. Califf, MD;
and The Thrombolysis and Angioplasty in Myocardial Infarction Study Group
To determine whether there are differences in responses to thrombolytic therapy in certain
populations, the data for the Thrombolysis and Angioplasty in Myocardial Infarction (phase 1)
study were analyzed for black and white patients. Baseline variables including risk factors and
extent of coronary artery disease were similar in the 352 white and 24 black patients. The time
from onset of chest pain to recombinant tissue-type plasminogen activator (rt-PA) therapy and
rt-PA dosing regimens were the same in the two groups. The patency rate of the infarct-related
artery at 90 minutes was 91% for blacks and was 72% for whites (p=0.051). Blacks displayed
significantly lower nadir fibrinogen levels (0.57±+0.62 versus 1.3+±0.76 g/l,p<0.0001), greater A
fibrinogen (baseline-nadir) (2.7±+1.1 versus 1.7±1.1 g/l,p<0.0001), and increased peak levels
of fibrin(ogen) degradation products (837+±865 versus 245±475 ,ug/ml, p<0.0001). rt-PA
antigen levels tended to be higher in blacks than in whites (2.8+±2.2 versus 2.2±3.2 ug/ml
[p=0.10] at the peakand 1.6±+1.3 versus 0.99±+1.4 ,g/ml [p=0.06] at the end of the maintenance
infusion). Major clinical outcomes including survival until time of hospital discharge (92% black
versus 93% white, p =0.68) were not significantly different. However, despite undergoing fewer
angioplasty procedures (25% versus 46.3%, p=O0.047), blacks received more transfusions (58.8%
versus 19.5% were administered >2 units packed erythrocytes, p=0.001). In conclusion, black
patients have an apparent enhanced sensitivity to rt-PA, which is manifested by increased
thrombolytic efficacy, a more pronounced systemic fibrinogen breakdown, and increased transfusions. (Circulation 1991;83:170-175)
C oronary artery disease is the leading cause of
death among black Americans.' Due in part
to a higher prevalence of baseline risk factors including hypertension and diabetes mellitus,2
blacks exhibit a poorer prognosis after a myocardial
infarction.2-4 It is, therefore, important to consider
the differences that may exist in the responses to
medical and surgical therapy between racial groups.
Blacks appear to have a similar reduction in mortality
to whites while receiving propranolol after a myocar-
dial infarction4 and a similar survival rate after
coronary artery bypass grafting.5 However, the
treatment of acute myocardial infarction with
thrombolytic agents has not previously been examined for race-dependent differences in response.
During the data analysis of the Thrombolysis and
Angioplasty in Myocardial Infarction (phase 1)
(TAMI-1) study, differences in certain clinical and
laboratory parameters between blacks and whites
became apparent.
From the Division of Cardiology, Department of Medicine,
Duke University, Durham, N.C. (D.C.S., K.N.S., W.K.C., R.S.S.,
R.M.C.); the Departments of Medicine and Biochemistry, University of Vermont, Burlington, Vt. (D.C.S.); the Division of Cardiology, Department of Internal Medicine, University of Michigan,
Ann Arbor, Mich. (E.J.T., E.R.B.); Christ Hospital, Cincinnati,
Ohio (D.J.K.); the Riverside Methodist Hospital, Columbus, Ohio
(B.S.G.); and the Division of Cardiology, Department of Medicine, University of Louisville, Louisville, Ky. (M.F.S.).
Presented in part at the Annual Scientific Sessions of the
American Heart Association, November 1988, Washingon, D.C.
Supported in part by research grant HL-35058 from the National
Institutes of Health and a grant from Genentech, Inc., South San
Francisco, Calif. D.C.St. was an Established Investigator of the
American Heart Association and of Genentech, Inc., during this work.
Address for reprints: David C. Sane, MD, P.O. Box 3360, Duke
University Medical Center, Durham, NC 27710.
Received March 13, 1990; revision accepted September 4, 1990.
Sane et al Racial Differences in Thrombolytic Therapy
Methods
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Patient Population
A total of 386 patients (24 black, 352 white, 10
other race), enrolled in the TAMI-1 trial from five
participating centers, were analyzed for race-specific
differences in response to thrombolytic therapy. The
patients enrolled in this study have been described in
detail in previous reports.6,7 Criteria for inclusion in
the study were acute myocardial infarction of 30
minutes to 6 hours in duration and ST-segment
elevation of at least 0.1 mV in at least two contiguous
leads of the standard 12-lead electrocardiogram.
Exclusionary criteria for entry into the protocol were
recent (<6 months) trauma, major surgery within 2
weeks, recent active internal bleeding (gastrointestinal or genitourinary), brain tumors or arteriovenous
malformations, stroke within 6 months, uncontrolled
hypertension (diastolic blood pressure > 120 mm Hg
by several measurements), prolonged cardiopulmonary resuscitation within 2 weeks, and serious
advanced illnesses such as cancer. Patients older than
75 years of age, those with previous coronary artery
bypass surgery, and those in cardiogenic shock upon
admittance to the hospital were also excluded.
rt-PA Administration
All patients were treated with an infusion of a
predominantly single-chain form of recombinant tissue-type plasminogen activator (rt-PA) (preparation
G11044), supplied by Genentech, Inc., South San
Francisco, Calif. In the first 176 patients, 60 mg was
administered intravenously during the first hour, followed by 20 mg/hr for 2 hours, then 10 mg/hr for the
next 5 hours (dose 1). A weight-adjusted dose was
used in the final 210 patients, with 1 mg/kg given
during the first hour (maximum 90 mg), followed by
the remainder of a total dose of 150 mg for the next 5
hours (dose 2). A bolus of 10% of the first-hour dose
was given throughout the study. The weight-adjusted
dose was associated with less bleeding, whereas patency rates between the two regimens were similar.8
Angiography and Angioplasty
At 90 minutes after initiation of rt-PA infusion,
coronary arteriography and left ventriculography were
performed in all patients. Patients were then assigned
to one of several treatment groups based on the
patency of the infarct-related artery as classified by the
Thrombolysis in Myocardial Infarction Trial (TIMI).9
Patients who had persistent occlusion (TIMI grade
0 or 1) were not included in the randomization. These
patients all underwent angioplasty unless the vessel
was not suitable or the area of infarction was judged to
be small. Patients with patent vessels but with more
than 50% stenosis of the left main coronary artery,
severe diffuse disease, cardiogenic shock, an unidentifiable infarct-related artery, or residual stenosis less
than 50% were also excluded. Patients with patent
infarct vessels with 50% or greater residual stenosis
and TIMI grade 2 or 3 flow were randomized to
171
receive either immediate angioplasty or delayed angioplasty 1 week later. Angioplasty was performed
sooner if clinically significant ischemia recurred. A
successful angioplasty was defined by residual stenosis
of 50% or less with TIMI grade 3 flow.
After leaving the interventional cardiac catheterization laboratory, all patients received heparin for a
minimum of 24 hours to maintain the activated
partial thromboplastin time 1.5-2.0 times the control
level. Aspirin 325 mg/day, dipyridamole 75 mg three
times each day, and diltiazem 30-90 mg four times
each day were administered throughout the hospitalization. ,-Blockers were withheld unless there was a
strong indication for their use. Lidocaine was administered intravenously for 24 hours as prophylaxis
against ventricular arrhythmias.
Recurrent ischemia was defined as more than 20
minutes of angina accompanied by ST segment elevation in the infarcted territory that was unresponsive to nitrates. Reocclusion was defined as total
occlusion of a reperfused infarct-related artery at any
time after the patient left the cardiac catheterization
laboratory. Coronary angiography with multiple
views of the infarct vessel and left ventriculography
were performed at 7-10 days in all patients who gave
informed consent.
Assessment of Bleeding Complications
The performance of coronary artery bypass grafting was the variable most strongly associated with
bleeding in the TAMI-1 study.10 To examine the
effects of thrombolytic therapy without the additional
hemostatic defects induced by cardiopulmonary bypass, only nonsurgical patients were analyzed for
hemorrhagic complications. Serial hematocrit levels
were obtained during the hospital course. Emesis and
stool were checked for occult blood. An estimate of
blood loss was calculated by adding the number of
transfused units of packed red blood cells to the
admission minus the nadir hematocrit level (A hematocrit) divided by three.10"11 The decision to transfuse was made by the attending physician.
Coagulation Parameters
rt-PA antigen, fibrinogen, fibrin(ogen) degradation
products, and fragment D-dimer were assayed at
baseline and at 3, 5, 8, and 12 hours after the
initiation of rt-PA therapy. In vitro assay artifacts
were avoided by collecting samples in 10 mM citrate
containing 1 ,uM D-Phe-Pro-Arg-chloromethyl ketone (PPACK) as previously described.12 Cell-free
plasma was prepared by centrifugation within 1 hour
of sample collection, and the plasma was stored at
-70°C until assayed. Fibrinogen levels were measured by the coagulation rate assay of Clauss13 as
modified by Vermylen et al.14 Heparin levels in the
therapeutic range do not interfere with the Clauss
method.'2 An enzyme-linked immunosorbent assay
(ELISA) based on three monoclonal antibodies was
used for calculating rt-PA antigen levels.15 Fragment
D-dimer was measured using an ELISA (American
172
Circulation Vol 83, No 1, January 1991
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TABLE 1. Clinical Characteristics of Patient Groups
Black
Characteristic
(n =24)
Age (yr)
57+10
Sex (% male)
67
Body weight (kg)
78+15
Infarct-related artery (% of patients)
Left main
0
Left anterior descending
55
Left circumflex
9
Right
36
Time from onset of chest pain to
rt-PA therapy (hr)
3.1+ 1.1
Multivessel disease (% of patients)
Two vessel
33
Three vessel
4
144±18
Systolic blood pressure (mm Hg)
Heart rate (beats/min)
83+22
51±+12
Ejection fraction (%)
History of diabetes (%)
21
71
History of smoking (%)
Dose 1 vs. dose 2 (% Dose 1)
46
White
TABLE 2. Effect of Race on Infarct Vessel Patency
Black
White
(n=352)
56+11
79
82+14
0.3
40
13
47
2.9+1.1
29
1
135-+26
79+18
52+11
13
67
46
rt-PA, recombinant tissue-type plasminogen activator.
Diagnostica) and was corrected for the generation of
D-dimerlike epitopes in rt-PA-treated normal
plasma. Fibrin(ogen) degradation products were calculated with a hemagglutination inhibition immunoassay16 performed on sera prepared by incubating
plasma with thrombin (final concentration, 65 units/
ml) and aprotinin (final concentration, 1,500 KIU/
ml) for 2 hours at 37°C. Plasminogen activator inhibitor activity was measured only on baseline samples
not containing PPACK by determining residual
rt-PA activity after adding exogenous rt-PA.17
Statistical Methods
Values are reported as mean± 1 SD. Clinical outcomes were compared by the x2 or Fisher's exact test
for discrete variables and Wilcoxon's ranked-sum test
for continuous variables. All reported probability
values are two tailed. Clinical end points were assessed with use of the intention-to-treat principle.
Caution must be used in interpretation of the probability values because of the retrospective nature of
the comparisons and the multiple statistical tests.18
Results
The baseline characteristics of the patients grouped
by race are shown in Table 1. Black and white patients
were very similar in major clinical variables including
risk factors, extent of coronary artery disease, and left
ventricular function. The time from onset of chest
pain to thrombolytic therapy and the distribution of
the two dosing regimens were also quite similar.
Clinical End Points
The infarct artery patency rate after 90 minutes of
rt-PA infusion was 91% for black patients versus 72%
Patency at 90 minutes (%)
Residual stenosis at 90
minutes (%)
Reocclusion at 7-10 days (%)
(n=24)
(n=352)
91
72
p
0.051
86+21
4.4
89+16
15
0.089
0.222
for white patients (p=0.051) (Table 2). Patients who
underwent reperfusion had similar degrees of residual stenosis and rates of reocclusion during the 7- to
10-day follow-up period.
The relation between race and other major clinical
outcomes is shown in Table 3. Survival to discharge
was the same for the two groups. Blacks and whites
were equally likely to undergo coronary artery bypass
grafting during the hospital period. However, white
patients more frequently underwent coronary angioplasty, especially during the acute period because the
90-minute patency rate was lower in whites and the
protocol mandated angioplasty of totally occluded
vessels.6
During the posthospitalization follow-up period,
survival rates at 6 and 12 months were similar, but the
number of deaths were too few to allow valid statistical comparisons (Table 3).
Coagulation Parameters
Peak rt-PA antigen levels did not differ significantly between blacks and whites (Table 4). However, there was a trend toward higher rt-PA levels in
blacks during and at the end of the rt-PA infusion.
Baseline fibrinogen levels were similar, but nadir
fibrinogen levels were markedly lower for blacks
(0.57±+0.62 g/l) than for whites (1.3+0.76 g/l). The A
fibrinogen (baseline -nadir) was also much greater
for blacks than whites.
When examined by the percentage of patients with
nadir fibrinogen levels less than 0.5 g/l and less than 1.0
g/l, a striking difference was seen. More than 50% of
blacks had nadir fibrinogen levels less than 0.5 g/l and
more than 80% had nadir levels less than 1.0 g/l.
Whites were generally resistant to severe fibrinogen
depletion, and more than 60% had nadir fibrinogen
levels greater than 1.0 g/l.
Commensurate with greater fibrinogen depletion,
the black population also had significantly greater
peak fibrin(ogen) degradation product levels. Peak
D-dimer levels were similar in blacks and whites.
Baseline plasminogen activator inhibitor levels were
also similar between the two groups.
Hemorrhagic Complications
Major overt clinical bleeding including intracranial
and gastrointestinal hemorrhage did not differ significantly between the two groups of nonsurgical patients (Table 5). Moreover, the nadir hematocrit level
and A hematocrit were similar in blacks and whites.
Transfusion of 2 units or more of packed erythrocytes
was required more frequently in blacks. Quantitative
Sane et al Racial Differences in Thrombolytic Therapy
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TABLE 3. Effect of Race on Major Clinical Outcomes
White
Black
p
(n=24)
(n=352)
Outcome
During hospitalization
92
93
0.677
Survival to discharge
6.3
8.3
Emergency CABG
0
3.7
0.444*
Urgent CABG
21
12
Elective CABG
25.0
46.3
Acute PTCA
4.2
6.8
0.047*
Emergency PTCA
13
11
Late PTCA
Postdischarget
Survival
95.5
98.8
6 Mo
98.2
12 Mo
95.5
Nonfatal MI
0
3.5
6 Mo
4.8
4.8
12 Mo
PTCA
0
5.2
6 Mo
10.0
7.3
12 Mo
CABG
0
1.6
6Mo
0
4.1
12 Mo
CABG, coronary artery bypass graft; PTCA, percutaneous
transluminal coronary angioplasty; MI, myocardial infarction.
*Test of having the procedure at any time versus having no
procedure.
tPostdischarge values are cumulative percentages of patients
who survived the initial hospitalization. Numbers in this group
were too small to assign p values.
TABLE 5. Effect of Race on Hemorrhagic Complications in
Nonsurgical Patients
White
Black
p
(n= 17)
(n=276)
Complication
Transfusion .2 units packed
19.5
0.001
RBC (%)
58.8
0.7
1.00
0.0
Intracranial bleeding (%)
(%)
9.1
1.00
Gastrointestinal bleeding
5.9
30.6+5.6 32.5±5.4 0.146
Nadir hematocrit
A Hematocrit
11.8±5.6 11.2±5.2 0.478
Units transfused +
A hematocrit/3
5.4±2.8 4.5±3.4 0.072
RBC, red blood cells.
blood loss estimated by the formula of units transfused
+ A hematocrit/311 also tended to be greater in blacks.
Discussion
Results from the TAMI-1 study were examined to
determine whether there are differences in the response to thrombolytic therapy with rt-PA between
blacks and whites. Our patient populations were quite
similar in relevant demographic and baseline characteristics. Surprising differences in therapeutic and
hematologic responses were found that may affect
both the success and the complications of fibrinolytic
therapy with rt-PA in the black population.
Increased Patency of the Infarct Vessel
A trend toward higher patency at the 90-minute
angiographic end point was observed in blacks. The
91% patency rate in blacks exceeds that in whites
(72%, p=0.051) and is greater than that observed
TABLE 4. Effect of Race on Hematologic Parameters
Black
Parameter
2.8±2.2
Peak rt-PA antigen (,g/ml)
White
2.2±3.2
(0.02/0.90/1.4/2.8/50)
p
0.101
1.6±1.3
0.99±1.4
0.058
(0.06/0.29/1.20/2.66/4.49)
(0.02/0.27/0.73/1.12/18.9)
(0.06/0.90/3.0/3.9/8.8)
End maintenance infusion
rt-PA antigen (,ug/ml)
Fibrinogen (g/l)
Baseline
Nadir
A Fibrinogen
Peak fibrin(ogen) degradation
products (1g/ml)
Peak D-dimer corrected (ng/ml)
Baseline plasminogen activator
inhibitor activity (units/ml)
173
3.31±0.90
2.99±0.92
(1.70/2.60/3.40/3.87/5.20)
(0.080/2.37/2.80/3.60/6.90)
0.57±0.62
1.3±0.76
(0.08/0.08/0.44/0.70/2.70)
(0.08/0.83/1.30/1.72/6.90)
2.7± 1.1
1.7± 1.1
(0/2.0/2.8/3.6/4.7)
(0/0.90/1.5/2.3/4.9)
0.120
<0.0001
<0.0001
837±865
245 475
<0.0001
(5/135/400/1430/2660)
0.654
(0.01/0.30/1.72/2.45/16.2)
(5/15/60/210/2660)
2.26±3.74
(0.01/0.85/1.36/2.19/40.3)
24±31
19±20
0.816
3.06±4.74
(3/7/12/19/118)
(5/5/10/26/112)
in
distributions
in
Values parentheses represent
percentiles: Oth/25th/50th/75th/100th.
rt-PA, recombinant tissue-type plasminogen activator.
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Circulation Vol 83, No 1, January 1991
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with any thrombolytic agent used alone or in combination, with the possible exception of rt-PA infused
at a rapid rate.19 Factors that may be expected to
increase the rate of reperfusion include the time
from onset of chest pain to rt-PA therapy and the
dose administered. However, these factors were essentially identical in the two groups (Table 1). After
reperfusion, the infarct-related vessel in blacks and
whites had similar degrees of residual stenosis and
reocclusion rates (Table 2).
The higher patency rates in blacks suggest altered
pharmacology of rt-PA or an increased sensitivity to
fibrinolysis at equivalent rt-PA levels. Tissue plasminogen activator antigen levels in both groups were
widely variable and not significantly different (Table
4), which is consistent with equivalent dosing regimens
and volumes of distribution. There was a trend, however, toward higher rt-PA antigen levels in black
patients at both peak and end of maintenance infusion
time points. Tissue plasminogen activator is cleared
predominantly by the liver,20,21 but hepatic blood flow
must be reduced to less than 10% of normal to affect
the pharmacodynamics of rt-PA.22 Because none of
these patients was in cardiogenic shock at hospital
admission, a reduction of blood flow to that extent
probably did not occur. Thus, intrinsic differences may
exist in the hepatic clearance of rt-PA between blacks
and whites, but more detailed pharmacological studies
will be necessary to evaluate this question. Although
population differences in the hepatic metabolism of
certain drugs have been described,23 25 we are unaware of previous reports of significant race-dependent differences in rates of clearance of human recombinant proteins such as rt-PA.
Extent of Fibrinogen Depletion
As an indication of differences in the pharmacokinetics or pharmacodynamics of rt-PA in the two
populations, blacks had significantly greater degradation of fibrinogen than did whites (Table 4). Although
baseline fibrinogen levels were equivalent, nadir fibrinogen levels were significantly lower in blacks than in
whites. Greater fibrinogen depletion in blacks was also
reflected in the greater magnitude of the A fibrinogen
(baseline - nadir). In agreement with greater fibrinogen depletion, blacks also had higher peak
fibrin(ogen) degradation product levels (Table 4).
Peak D-dimer levels were not significantly different
in the two populations despite differences in patency
rates and extent of fibrinogenolysis. Previous studies
have shown that D-dimer is a poor predictor of
reperfusion,26.27 and our results are consistent with
this observation.
Although the trend toward higher rt-PA levels in
blacks at the end of the maintenance infusion may
partially explain the increased fibrinogenolysis in this
group, other factors should be considered. Further
studies will be necessary to elucidate the exact mechanism(s) for the enhanced fibrinogenolysis during
therapy with rt-PA now observed in US blacks.
The differences observed in patency rates and fibrinogenolysis did not affect major clinical outcomes
such as survival to discharge or the necessity for
revascularization by coronary artery bypass grafting
(Table 3). Blacks did have fewer angioplasty procedures, especially acute procedures, than did whites,
reflecting the higher acute patency rates. In the 6-12month follow-up period, there was a trend for more
angioplasties in blacks than in whites, perhaps reflecting the decreased use of angioplasty in this population during the in-hospitalization period. However,
the number of patients in the postdischarge group was
too small to allow more meaningful comparisons.
Risk of Bleeding
The major complication of thrombolytic therapy is
hemorrhage. The major contributors to bleeding are
invasive procedures, especially coronary artery bypass grafting during the lytic period.10 Because cardiopulmonary bypass creates an additional set of
hemostatic defects, only nonsurgical patients were
examined for the bleeding associated with rt-PA
administration. Major overt clinical bleeding rates at
intracranial and gastrointestinal sites were similar
between blacks and whites (Table 5). However,
blacks received more transfusions than did whites,
even though the nadir hematocrit level and A hematocrit (baseline-nadir) did not differ significantly.
The difference in transfusion rates may indicate that
packed erythrocytes were administered to some
bleeding patients early in the course of the bleeding
complication, thereby avoiding an exceptionally large
drop in the hematocrit level. As a measure of bleeding, the more frequent transfusion rate in blacks
correlates with their greater extent of fibrinogen
depletion and higher fibrin(ogen) degradation product levels. Both of these factors have been significantly but weakly correlated with bleeding risk in
prior studies.102829 The excess bleeding in blacks
occurred despite fewer angioplasty procedures during the acute period, providing even stronger support
for the association of increased transfusion requirements with fibrinogen depletion.
In conclusion, this study demonstrates differences
between blacks and whites in the response to thrombolytic therapy with rt-PA. Because the black population in this study was relatively small, these findings
must be viewed as preliminary, requiring confirmation by larger studies. Further investigation will also
be necessary to determine whether the observed
differences are due chiefly to higher rt-PA levels in
blacks or to other factors. The increased 90-minute
patency rate after treatment of blacks with rt-PA, if
confirmed, may compensate for the reported worse
prognosis of myocardial infarction in this population.
However, this potential benefit should be weighed
against the increased transfusion requirement. Furthermore, these findings raise the possibility that the
rt-PA dosing regimen may need to be adjusted for
blacks and other nonwhite races to achieve a maximal
benefit to risk ratio. It is also important to recognize
Sane et al Racial Differences in Thrombolytic Therapy
that large, randomized studies may not allow for
accurate determination of race-dependent benefits
and risks of therapy if disproportionately composed
of restricted populations or if reported for the population as a whole.
Acknowledgments
We are grateful to Dagnija Thornton and Elizabeth Macy for expert technical assistance. Although
Dr. Stump had no financial interest in Genentech,
Inc., during the conduct of this study, he has since
become its employee.
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KEY WORDS
* TAMI-1
fibrinolytic therapy * hemorrhagic complications
plasminogen activator * racial stocks
Racial differences in responses to thrombolytic therapy with recombinant tissue-type
plasminogen activator. Increased fibrin(ogen)olysis in blacks. The Thrombolysis and
Angioplasty in Myocardial Infarction Study Group.
D C Sane, D C Stump, E J Topol, K N Sigmon, W K Clair, D J Kereiakes, B S George, M F
Stoddard, E R Bates and R S Stack
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Circulation. 1991;83:170-175
doi: 10.1161/01.CIR.83.1.170
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