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European Heart Journal (2002) 23, 1282–1290
doi:10.1053/euhj.2001.3083, available online at http://www.idealibrary.com on
Improved reperfusion and clinical outcome with
enoxaparin as an adjunct to streptokinase
thrombolysis in acute myocardial infarction
The AMI–SK study
M. L. Simoons1, M. Krzemiñska-Pakula2, A. Alonso3, S. G. Goodman4, A. Kali5,
U. Loos6, F. Gosset7, V. Louer7 and F. Bigonzi7 for the AMI–SK investigators*
*Thorax Centre, Erasmus University Medical Center, Rotterdam, The Netherlands; 2Wojewodski Szpital im.,
Kniaziewicza, Poland; 3Puerta de Hierro, Madrid, Spain; 4St Michael’s Hospital, Division of Cardiology,
University of Toronto, Toronto, Canada; 5National Institute of Cardiology, Budapest, Hungary;
6
Knappschafts-Krankenhaus, Recklinghausen, Germany; 7Aventis Pharma, Paris, France
Aims To establish whether the addition of enoxaparin
(a low-molecular-weight heparin) to streptokinase therapy
improves early and sustained coronary patency and clinical
outcome in patients with evolving myocardial infarction.
Methods and Results A total of 496 patients with acute
myocardial infarction treated with streptokinase were
randomized to an intravenous bolus (30 mg) and subcutaneous injections (1 mg . kg 1, twice daily) of enoxaparin (n=253), or placebo (n=243) for 3–8 days. The
median duration of treatment in both groups was 5 days.
ST-segment resolution at 90 min and 180 min measured by
electrocardiogram was improved in patients receiving
enoxaparin. Complete, partial and no ST-segment resolution at 180 min was observed in 36%, 44% and 19% in the
enoxaparin group vs 25%, 44% and 31% in the placebo
group, respectively (P=0·004). Assessment of the primary
end-point revealed improved TIMI-3 flow with enoxaparin
vs placebo (70% vs 58%, P=0·01). Combined TIMI-2 and
-3 flow was also improved (88% vs 72%, P=0·001), as was
Introduction
Reperfusion therapy is recommended in patients with
evolving myocardial infarction[1–3]. For an intravenous
regimen of reperfusion therapy three components should
be considered: a fibrinolytic drug, a platelet aggregation
Revision submitted 6 November 2001, and accepted 7 November
2001.
*See Appendix 1 for the list of Investigators.
Correspondence: Prof. dr. M. L. Simoons, Thoraxcentrum, H 560,
Erasmus University, Dr. Molewaterplein 40, 3015 GD Rotterdam,
the Netherlands.
0195-668X/02/$35.00
TIMI frame count (P=0·003). The triple clinical end-point
of death, reinfarction and recurrent angina at 30 days was
reduced with enoxaparin (13% vs 21%, P=0·03).
Conclusion Streptokinase in combination with enoxaparin is associated with better ST-segment resolution and
better angiographic patency at days 5–10, suggesting more
effective reperfusion. This was associated with a significant
reduction in clinical events, indicating less reocclusion.
(Eur Heart J, 2002; 23: 1282–1290, doi:10.1053/euhj.2001.
3083)
2002 The European Society of Cardiology. Published by
Elsevier Science Ltd. All rights reserved.
Key Words: Myocardial infarction, streptokinase,
low-molecular-weight heparin, enoxaparin.
See page 1233, doi:10.1053/euhj.2002.3246 for the Editorial
comment on this article
inhibitor, and an anticoagulant. Regimens based on
fibrin specific fibrinolytic agents (alteplase, reteplase,
tenecteplase) all include aspirin (antiplatelet) and unfractionated heparin (anticoagulant), which is supported
by three studies demonstrating improved early and
sustained coronary patency, when heparin is added to
alteplase[4–6]. However, in patients receiving streptokinase as the fibrinolytic agent heparin is not recommended, except in patients who are at risk of systemic
emboli[2,3]. In fact, the combination of streptokinase and
subcutaneous unfractionated heparin did not improve
outcome compared with streptokinase alone in the
Gruppo Italiano per lo Studio della Sopravvivenza
2002 The European Society of Cardiology. Published by Elsevier Science Ltd. All rights reserved.
The AMI–SK study
nell’Infarto miocardico (GISSI) 2 and the Third
International Study of Infarct Survival (ISIS-3)[7,8]. All
patients in these studies received aspirin. Furthermore,
intravenous heparin did not improve outcome over
subcutaneous heparin when added to streptokinase in
the first Global Utilization of Streptokinase and t-PA
for Occluded coronary arteries-study I GUSTO-I[9].
Worldwide, streptokinase is the most frequently used
fibrinolytic agent for evolving myocardial infarction.
Yet, complete early reperfusion is achieved in only about
a third of the patients[10], and reocclusion is observed in
about 10% of patients in hospital[10] and in about
one-third of patients at 3-months follow-up[11]. The
addition of a low-molecular-weight heparin, such as
enoxaparin, to streptokinase may facilitate early
reperfusion of the occluded coronary artery, as well as
prevention of thrombus extension and new thrombus
formation and thus prevention of reocclusion.
This concept is based on the properties of enoxaparin,
providing rapid reliable anticoagulation with a long
elimination half-life[12]. A recent study compared enoxaparin and unfractionated heparin in 300 patients receiving fibrinolytic therapy, mainly with streptokinase.
In that study enoxaparin reduced the risk of death,
reinfarction and readmission at 3 months by 30%[13].
The AMI–SK study was conducted to study the safety
and efficacy of enoxaparin vs placebo in patients with
evolving myocardial infarction treated with streptokinase. The primary end-point was coronary patency
(Thrombolysis In Myocardial Infarction (TIMI) grade 3
flow) assessed by angiography after approximately 8
days. In addition, early reperfusion at 90 and 180 min
was assessed by electrocardiography, and clinical outcomes (death, reinfarction, and recurrent angina) at
30 days were recorded.
Methods
Study population
Patients were recruited from June 1999 to July 2000,
in 37 hospitals in five countries: Canada, Germany,
Hungary, Poland and Spain. To be eligible, patients had
to be 18 years or older; with onset of symptoms of acute
myocardial infarction within the 12 h before randomization, and ST-segment elevation of 0·1 mV or more in
two or more limbs leads or at least 0·2 mV in two or
more precordial leads. All patients gave written
informed consent. Main exclusion criteria were: contraindications to streptokinase; cardiogenic shock; hypertension defined as a blood pressure greater than 180
(systolic) or 110 (diastolic) mmHg on repeated measurement at the time of randomization; use of glycoprotein
IIb/IIIa antagonists or oral anticoagulants within the
previous days or therapeutic dose of heparin or lowmolecular-weight heparin within the preceding hours;
need for anticoagulant therapy; any other disorder (i.e.
liver disease or renal insufficiency) that would place the
1283
patient at increased risk; and inability to follow the
protocol and to comply with the follow-up requirement
including angiography. The study complies with the
Declaration of Helsinki and the research protocol was
approved by the local ethics committees. All patients
gave informed consents.
Design and procedures
All patients were treated with streptokinase (1·5 million
units intravenously over 1 h) and received 100–325 mg
oral aspirin, once daily, for a minimum of 30 days
following randomization. Patients were randomly
assigned, through a central computerized telephone system to either enoxaparin or placebo, with enoxaparin/
placebo treatment started at the same time as, or within
1 h of, streptokinase. Enoxaparin was given as an intravenous bolus (30 mg) and then subcutaneously every
12 h (1 mg . kg 1, with a maximum of 100 mg for the
first two subcutaneous injections). Treatment was continued for a minimum of 3 days, up to angiography or
day 8, whichever was earlier. The use of antianginal
medication was at the discretion of the investigator, as
was the decision to perform revascularization. The use
of glycoprotein IIb/IIIa antagonists was not permitted
while the patient was on study medication, except when
percutaneous angioplasty was performed. All patients
were followed for 30 days.
Efficacy parameters
(1) Angiography was carried out on day 8 (range
allowed=days 5 to 10). The primary efficacy parameter
was the TIMI flow grade 3 of the infarct-related
artery[14]. Secondary efficacy angiographic parameters
were: TIMI flow grades 2 and 3 (patency) and corrected
TIMI frame count[15] on day 8 angiography;
(2) Secondary efficacy parameters were: the incidence of
successful reperfusion based on ST-segment resolution
at 90 min and 180 min[16] (ST-segment resolution was
classified as complete (d70% resolution), incomplete
(30–70% resolution) or no resolution (<30% resolution);
infarct size based on calculated myocardial enzyme
release[17]; and the incidence of clinical end-points of
death, recurrent myocardial infarction or recurrent
angina up to 30 days as single, double or triple
end-points.
Reinfarction in the first 18 h was defined as recurrent
symptoms of ischaemia at rest accompanied by new or
recurrent ST-segment elevation d0·1 mV in at least
two contiguous leads lasting d30 min. After 18 h the
definition of reinfarction was recurrent symptoms of
ischaemia at rest lasting d30 min and meeting the
ECG criteria (new or recurrent persistent ST-segment
elevation d0·1 mV or appearance of new, abnormal
Q-waves in any two contiguous leads not showing
ST-segment elevation on the qualifying ECG, or new left
Eur Heart J, Vol. 23, issue 16, August 2002
1284
M. L. Simoons et al.
bundle-branch block), or meeting enzyme criteria
(further increases in concentrations of creatinine kinase
MB, or total creatinine kinase above two times the
upper limit of normal [three times post-percutaneous
coronary intervention, five times post-coronary artery
bypass grafting (CABG)] and increased over the
previous value).
Recurrent angina was defined as one episode of
angina at rest lasting >20 min or at least two episodes of
angina at rest lasting >10 min within 24 h and associated with new ECG changes or resulting in an invasive
cardiac intervention within the same hospitalization or
rehospitalization for unstable angina.
Angiograms, electrocardiograms and cardiac enzymes
were analysed by core laboratories blinded to treatment assignment. Clinical end-points were reviewed
and adjudicated by an independent clinical review
committee, blinded to treatment assignment.
Safety parameters
The primary safety parameter was the rate of major
haemorrhage defined as haemorrhage resulting in death;
transfusion of at least two units of packed red blood
cells or whole blood; 3 g . dl 1 or greater fall in haemoglobin not associated with CABG; or any haemorrhage
that was retroperitoneal, intracranial, intraocular, or
required surgical intervention or decompression of
a closed space to stop or control the event (e.g.
cardiac tamponade). The rate of major haemorrhage
according to the TIMI definition was also recorded: a
fall in haemoglobin levels d5 g . dl 1 not associated
with CABG, intracranial haemorrhage, or cardiac
tamponade[18]. Major haemorrhages and strokes were
reviewed and adjudicated by the independent clinical
review committee.
Table 1
Patient characteristics
Number of patients randomized
Number of patients treated
Age (years)
Males
Prior MI
Prior angina
Previous aspirin user
Family history CAD
Current smoker
Hypertension
Hypercholesterolaemia
Diabetes
Enoxaparin
Placebo
253
252 (99·6)
62·811·7
183 (72·3)
24 (9·5)
67 (26·5)
40 (15·9)
64 (25·3)
102 (40·3)
101 (39·9)
83 (32·8)
43 (17·0)
243
239 (98·4)
62·911·9
193 (79·4)
33 (13·6)
74 (30·5)
49 (20·2)
51 (21·0)
99 (40·7)
106 (43·6)
76 (31·3)
36 (14·8)
All values are patient numbers (percentages); age, meanSD.
MI=myocardial infarction; CAD=coronary artery disease.
Results
Patient characteristics
In all, 496 patients were randomized, of whom 491 were
treated with streptokinase and study medication. The
baseline characteristics were similar among the two
treatment groups (Table 1). The median time from
symptom onset to streptokinase treatment was 3·3 h in
the enoxaparin group (range 0·5–11·8) and 2·8 h in the
placebo group (range 0·6–11·3), while the median time
to the first dose of study drug was 3·7 h in the enoxaparin group and 3·3 h in the placebo group. Median
duration of treatment was 5 days (range 0–15) and
patients were discharged after a median 11 days in both
groups.
Efficacy
Statistical analysis
It was estimated that 200 evaluable patients per treatment group (i.e. a total of 400 evaluable patients) would
be needed to achieve 80% power to demonstrate a
relative increase of 22% in the number of patients
reaching TIMI flow grade 3 with enoxaparin, assuming
a TIMI flow grade 3 rate of 60% at day 8 for the placebo
group and an alpha level of 5%. Chi-square tests were
used to compare the efficacy and safety of the two
treatment groups. For efficacy clinical end-points, ‘Time
to first event’ analyses were performed using the
Kaplan–Meier method and the log-rank test was used
for comparison of treatment groups.
Wilcoxon score tests were used to compare continuous variables. Patients were considered to be evaluable if
they were randomized, received streptokinase and study
medication, and had an assessable TIMI flow grade at
day 8 (range allowed=day 5 to 10). In order to achieve
400 evaluable patients it was estimated that 500 patients
should be enrolled.
Eur Heart J, Vol. 23, issue 16, August 2002
Coronary angiography was performed in 436 patients.
The infarct was related to the left anterior descending
artery in 36% to the left circumflex in 15% and to the
right coronary artery in 48%. The distribution of infarctrelated vessels was similar in the two randomized
patients groups.
Four hundred and twenty seven patients had an
assessable TIMI flow and 389 were considered evaluable
(angiography on days 5–10) and had adequate quality
for assessment of coronary perfusion. In the evaluable
population, significantly more patients receiving enoxaparin had TIMI grade 3 flow compared with those
receiving placebo (primary efficacy parameter 70·3%
vs 57·8%, P=0·01, Fig. 1). Also corrected TIMI frame
count (Fig. 2, P=0·003) and coronary patency (TIMI
flow grades 2 or 3) on days 5–10 were better
with enoxaparin 87·6% vs 71·7% for patients receiving
placebo (P<0·001). The results were similar when all 427
patients with angiography were analysed (TIMI grade 3
flow 68·2% vs 55·7%, P=0·008).
The AMI–SK study
Table 3
P = 0·001
Efficacy as reflected in clinical events at day 30
Patients (%)
88
80
Enoxaparin
P = 0·01
TIMI 3
40
70
58
Placebo
Enoxaparin
Figure 1 Patency (TIMI grade 2 or 3) at 8 days
(evaluable population, n=389). TIMI=thrombolysis in
myocardial infarction.
Table 2
Placebo
Significance (P)
TIMI 2
72
0
1285
ST-segment resolution
Enoxaparin
Placebo
At 90 min
Complete
Partial
No resolution
(n=242)
15·7
46·7
37·6
(n=233)
11·2
37·8
51·1
At 180 min
Complete
Partial
No resolution
(n=234)
36·3
44·4
19·2
(n=232)
25·4
43·5
31·0
Number of patients
randomized
Death
Reinfarction
Reangina
Death or recurrent
MI
Death, recurrent MI
or angina
Death, recurrent MI
or angina leading to
revascularization
Any revascularization
PCI
Urgent
revascularization
253
243
6·7
2·4
5·9
9·1
7·0
7·4
9·1
13·2
ns
0·01*
ns*
0·15
13·4
21·0
0·03
13·0
18·5
0·09
29·6
28·1
5·5
28·0
26·3
9·5
ns*
ns*
ns*
Significance (P)
All values given as percentages. *Unplanned analyses.
MI=myocardial infarction; PCI=percutaneous coronary intervention; ns=not significant.

 0·012


 0·014

All values given as percentages. Between brackets, number of
electrocardiograms analysed.
By electrocardiography, 15·7% of the enoxaparintreated group achieved complete resolution of the ST
segment at 90 min compared with 11·2% in the placebotreated group, while the corresponding figures at
180 min were 36·3% vs 25·4%. Differences in the STsegment resolution categories were highly significant
(P=0·012 at 90 min and P=0·004 at 180 min, respectively, Table 2), indicating improved reperfusion when
streptokinase is combined with enoxaparin. Yet, no
significant differences were achieved in infarct size, as
assessed in 479 patients: mean values 5·1 vs 5·3 geq
HBDH . l 1 in the enoxaparin and placebo group. Also
ejection fraction in 177 patients was not significantly
different: 55% vs 51% respectively.
Clinical events were less frequent in patients allocated
to enoxaparin (Table 3). Particularly the rate of the
triple end-point of death, myocardial infarction or
recurrent angina in the enoxaparin-treated group was
36% lower than in the placebo group at day 30 (13·4% vs
21·0%, P=0·03). Regarding the single end-points the
largest difference was apparent in the rate of recurrent
myocardial infarction which was statistically significant
(Table 3). The difference between the two treatments
was established early, increased during the first 2 weeks,
and was sustained up to day 30 (Fig. 3). There were no
statistically significant differences in the incidence of
revascularization at day 30, but there was a trend
toward less urgent revascularization in the enoxaparin
group (Table 3).
100
P = 0·003
Patients (%)
Enoxaparin
50
0
Placebo
20
40
60
80
100
Corrected TIMI frame count
Figure 2
Eur Heart J, Vol. 23, issue 16, August 2002
1286
M. L. Simoons et al.
30
Patients (%)
21·0%
Placebo
20
P = 0·03
13·4%
Enoxaparin
10
0
10
20
30
Days
Figure 3 Time to first event at day 30, triple end-point (all randomized),
n=496. ——=placebo; – – –=enoxaparin.
Safety
Discussion
By day 30, there were more major haemorrhages
reported in the enoxaparin group than in the placebo
group, although this difference was not statistically
significant (Table 4). All major haemorrhages occurred
within the first 8 days. No occurrences of stroke,
whether haemorrhagic or embolic, were reported in the
enoxaparin group, compared to 1·3% in the placebo
group. This difference was not statistically significant.
The serious adverse-event profile was similar in both
groups. There were 17 deaths in each group at 30 days of
follow-up, representing 6·7% in the enoxaparin patients
and 7·0% in the placebo group. The principal cause of
death was congestive heart failure, accounting for 10
patients in the enoxaparin groups and 8 in the placebo
group.
The findings in this study indicate that, in patients with
evolving myocardial infarction treated with streptokinase and aspirin, adjunctive therapy with enoxaparin
facilitates early coronary reperfusion and reduces the
risk of reocclusion, resulting in improved clinical outcome. Improved early coronary reperfusion is implied in
greater resolution of the ST segment as analysed 90 min
and 180 min after randomization. The relationship
between ST-segment resolution and early angiographic
patency has been established in several studies[16], and
among patients with normal TIMI-3 epicardial coronary
flow, those patients with complete ST-segment resolution have a significantly better outcome than patients
with incomplete or no resolution[16]. The prevention of
reocclusion by enoxaparin is apparent by the reduction in clinical events, particularly reinfarction, and
better coronary perfusion at the 5–10 day coronary
angiography, which was the primary study end-point.
Table 4
Safety as reflected in clinical events at day 30
Number of patients
treated
Enoxaparin
252
Placebo
239
Significance
(P)
Major haemorrhage
Hb decline
d3 g . dl 1
Hb decline requiring
transfusion d2 units
packed red cells
TIMI major
haemorrhage
ICH
Any stroke
4·8
4·4
2·5
2·1
0·2
0·8
1·3
1·6
0·8
0·0
0·0
0·4
1·3
0·1
All
values
given
as
percentages.
Hb=haemoglobin;
TIMI=thrombolysis in myocardial infarction; ICH=intracranial
haemorrhage.
Eur Heart J, Vol. 23, issue 16, August 2002
Reperfusion and reocclusion
This is the first study documenting improved coronary
reperfusion with anticoagulant therapy in patients
receiving streptokinase. GUSTO-I compared early intravenous administration of unfractionated heparin,
started at the same time as the fibrinolytic drugs, and
subcutaneous unfractionated heparin, started after
4 h in patients receiving streptokinase[9,10]. The latter
regimen was also studied in GISSI-2 and ISIS-3[7,8].
Angiographic findings at 90 and 180 min were similar
among patients receiving immediate intravenous and
deferred subcutaneous heparin with streptokinase at 90
and 180 min[10]. In a recent placebo-controlled trial,
dalteparin (another low molecular weight heparin) was
The AMI–SK study
investigated as an adjunct to thrombolysis with streptokinase and provided a non-significant trend toward
increased TIMI grade 3 patency at 20–28 h after
randomization, and non-invasive signs of early (90 min)
reperfusion, favouring low-molecular-weight heparin[19].
Adjunctive therapy with the glycoprotein IIb/IIIa receptor blocker eptifibatide in patients treated with streptokinase also improved early coronary perfusion, but
bleeding rates were excessive, and this combination of
therapy was not pursued[20].
With fibrin specific fibrinolytics, such as alteplase,
adjunctive unfractionated heparin has shown to improve
early and subsequent patency of the infarct-related
artery[4–6], albeit not in all studies[21]. The HeparinAspirin Reperfusion Trial (HART II) demonstrated that
enoxaparin in conjunction with recombinant tissue plasminogen activator was at least as effective as unfractionated heparin in achieving infarct-related coronary artery
patency 90 min after the onset of treatment, with a trend
toward higher rates of TIMI-3 flow (53% vs 48%)[22].
Similarly, a trend was demonstrated for lower rates of
reocclusion with enoxaparin compared with unfractionated heparin (3·1% vs 9·1%). Similar trends toward
less reocclusion were observed in patients receiving dalteparin or pentasaccharide vs unfractionated
heparin[23,24]. More recently, the Assessment of the
Safety and Efficacy of a New Thrombolytic Regimen
(ASSENT)-3 study examined the efficacy and safety of
three different thrombolytic regimens (tenecteplase plus
enoxaparin, low-dose tenecteplase plus abciximab and
unfractionated heparin, and tenecteplase plus unfractionated heparin) in 6095 patients[25]. In this study,
patients receiving enoxaparin and tenecteplase had a
significantly lower rate of clinical events (composite of
30 day mortality, in-hospital reinfarction and in-hospital
refractory ischaemia) than those receiving unfractionated heparin (11·4% vs 15·4%, P=0·0002). Bleeding
rates were higher with enoxaparin, but not significantly
so. Reduced event rates were also observed with
tenecteplase and unfractionated heparin and abciximab,
compared to tenecteplase and unfractionated heparin,
but bleeding rates were significantly higher with the
abciximab combination. The present AMI–SK study
extends these observations to patients initially treated
with streptokinase. Thus, it is implied that continuation
with an low-molecular-weight heparin, for at least a few
days after fibrinolytic therapy does reduce the risk of
thrombus extension or reocclusion and results in better
patient outcome. Other recent studies indicated that
long-term intensive anticoagulation with coumadin also
reduces the risk of reocclusion after thrombolytic
therapy[11,26] and improves outcome after myocardial
infarction in general[11].
Limitations
In the present study no significant differences were
observed in left ventricular ejection fraction or infarct
size. Nevertheless close relations between coronary
1287
reperfusion, ejection fraction and infarct size were established in other studies[10,27,28]. The absence of significant
differences in ejection fraction or infarct size in the
present study is due, most likely, to relatively low sample
size, and the missing data in part of the patients.
Outcome
Improved outcome was documented in the present study
with enoxaparin, but was not observed with unfractionated heparin, given subcutaneously or intravenously
after streptokinase in earlier megatrials[7–9]. The different findings in AMI–SK may be related to the early
initiation of antithrombotic therapy by intravenous
bolus injection, and to several pharmacological
advantages of low-molecular-weight heparin over
unfractionated heparin. First, stable high-intensity anticoagulation is achieved without the need for monitoring
coagulation parameters such as activated partial
thromboplastin time. Furthermore, low-molecularweight heparins have a greater anti-Xa activity relative
to the anti-IIa activity (about 4:1 vs 1:1 for unfractionated heparin). In patients with evolving myocardial
infarction, receiving fibrinolytic therapy, platelets are
activated, as well as factor Va, resulting in enhanced
factor Xa activity, and thrombin generation[29,30]. Prevention of such thrombin generation by low-molecularweight heparin may be more effective than thrombin
inhibition with unfractionated heparin. This is supported by studies in a canine thrombosis model, in which
enoxaparin in comparison with heparin more effectively
increased perfusion and decreased thrombus mass[31].
Low-molecular-weight heparins have been studied
extensively in acute coronary syndromes, particularly in
patients admitted with unstable angina or suspected
evolving myocardial infarction, without persistent STsegment elevation[32–40]. The results show superiority
over placebo[30] and clinical efficacy at least equal to
unfractionated heparin[33–40]. In the Efficacy and Safety
of Subcutaneous Enoxaparin in Non-Q-wave Coronary
Events (ESSENCE) and TIMI 11B studies, enoxaparin
in comparison with unfractionated heparin resulted in
a reduced rate of thrombotic complications: death,
reinfarction and recurrent angina[33,34]. The current
AMI–SK study extends these observations to patients
with ST-segment elevation myocardial infarction, receiving streptokinase. Patients treated with unfractionated
heparin may show a rebound with thrombotic events
occurring early after discontinuation of such therapy[37].
Similar observations were made with dalteparin in the
Fragmin During Instability in Coronary Artery Disease
(FRISC) study[32]. In contrast, no rebound was observed
after discontinuation of enoxaparin in the present study.
Bleeding
A combination of streptokinase and enoxaparin did
increase bleeding complications, albeit not statistically
Eur Heart J, Vol. 23, issue 16, August 2002
1288
M. L. Simoons et al.
significantly. In the current AMI–SK study, no intracranial haemorrhages occurred in patients receiving
streptokinase with enoxaparin, but more experience of
using enoxaparin with streptokinase is needed to establish the safety and the net clinical benefit of the regimen.
Conclusion
Streptokinase is the most widely used fibrinolytic agent
worldwide, in spite of studies showing superiority of
more fibrin-specific fibrinolytic agents[9]. This preference for streptokinase is based predominantly on
financial considerations, since fibrin-specific fibrinolytic
agents are considerably more expensive. If the findings
in the current study are confirmed in a larger clinical
trial, a combination of streptokinase and enoxaparin
may offer an effective thrombolytic regimen, at an
acceptable cost level. Preparations for such a large
clinical trial are ongoing.
This study was supported by a grant from Aventis Pharma.
References
[1] The Reperfusion Therapy Consensus Group. Selection of
reperfusion therapy for individual patients with evolving
myocardial infarction. Eur Heart J 1997; 18: 1371–81.
[2] The Task Force on the Management of Acute Myocardial
Infarction of the European Society of Cardiology. Acute
Myocardial Infarction: pre-hospital and in-hospital
management. Eur Heart J 1996; 17: 43–63.
[3] Ryan TJ, Antman EM, Brooks NH et al. 1999 update:
ACC/AHA guidelines for the management of patients with
acute myocardial infarction. A report of the American College
of Cardiology/American Heart Association Task Force on
Practice Guidelines (Committee on Management of Acute
Myocardial Infarction). J Am Coll Cardiol 1999; 34: 890–911.
[4] De Bono DP, Simoons ML, Tijssen J et al. Effect of early
intravenous heparin on coronary patency, infarct size, and
bleeding complications after alteplase thrombolysis: results of
a randomised double blind European Cooperative Study
Group. Br Heart J 1992; 67: 122–8.
[5] Hsia J, Hamilton WP, Kleiman N, Roberts R, Chaitman BR,
Ross AM. A comparison between heparin and lowdose aspirin as adjunctive therapy with tissue plasminogen
activator for acute myocardial infarction. Heparin-Aspirin
Reperfusion Trial (HART) Investigators. N Engl J Med 1990;
323: 1433–7.
[6] Bleich SD, Nichols T, Schumacher R et al. Effect of heparin
on coronary arterial patency after thrombolysis with tissue
plasminogen activator in acute myocardial infarction. Am J
Cardiol 1990; 66: 1412–7.
[7] Gruppo Italiano per lo Studio della Sopravvivenza
nell’Infarto miocardico. GISSI-2: a factorial randomised
trial of alteplase versus streptokinase and heparin versus
no heparin among 12,490 patients with acute myocardial
infarction. Lancet 1990; 336: 65–71.
[8] ISIS-3 (Third International Study of Infarct Survival)
Collaborative Group. ISIS-3: a randomised comparison of
streptokinase vs tissue plasminogen activator vs anistreplase
and of aspirin plus heparin vs aspirin alone among 41,299
cases of suspected acute myocardial infarction. Lancet 1992;
339 (8796): 753–70.
[9] The GUSTO Investigators. An international randomized trial
comparing four thrombolytic strategies for acute myocardial
infarction. N Engl J Med 1993; 329: 673–82.
Eur Heart J, Vol. 23, issue 16, August 2002
[10] The GUSTO Angiographic Investigators. The effects of tissue
plasminogen activator, streptokinase, or both on coronaryartery patency, ventricular function, and survival after acute
myocardial infarction. N Engl J Med 1993; 329: 1615–22.
[11] Brouwer MA, van den Bergh PJPC, Vromans RPJW et al.
Aspirin plus medium intensity coumadin versus aspirin alone
in the prevention of reocclusion after successful thrombolysis
for suspected acute myocardial infarction: preliminary results
of the Apricot-2 trial (Abstr). Circulation 2000; 102: II-600.
[12] Noble S, Spencer CM. Enoxaparin. A review of its clinical
potential in the management of coronary artery disease. Drugs
1998; 56: 259–72.
[13] Baird S, McBride S, Trouten TG. LMWH versus unfractionated heparin following thrombolysis in myocardial infarction
(Abstr). J Am Coll Cardiol 1998; 31 (Suppl a): 191a.
[14] The TIMI study group. The Thrombolysis in Myocardial
Infarction (TIMI) trial. N Engl J Med 1985; 312: 932–6.
[15] Gibson CM, Cannon CP, Daley WL et al. TIMI frame count:
a quantitative method of assessing coronary artery flow.
Circulation 1996; 93: 879–88.
[16] van ’t Hof A, Liem A, Boer MJ de, Zijlstra F on behalf of the
Zwolle Myocardial Infarction Study Group. Clinical value of
12-lead electrocardiogram after successful reperfusion therapy
for acute myocardial infarction. Lancet 1997; 350: 615–9.
[17] Hermens WT, Willems GM, Nijssen KM, Simoons ML.
Effect of thrombolytic treatment delay on myocardial infarct
size [letter]. Lancet 1992; 340 (8830): 1297.
[18] Bovill EG, Terrin ML, Stump DC et al., for the TIMI
Investigators. Hemorrhagic events during therapy with
recombinant tissue-type plasminogen activator, heparin, and
aspirin for acute myocardial infarction. Results of the
Thrombolysis in Myocardial Infraction (TIMI), Phase II
Trial. Ann Intern Med 1991; 115: 256–65.
[19] Frostfeldt G, Ahlberg G, Gustafsson G et al. Low molecular
weight heparin (dalteparin) as adjuvant treatment of
thrombolysis in acute myocardial infarction — a pilot
study: biochemical markers in acute coronary syndromes
(BIOMACS II). J Am Coll Cardiol 1999; 33: 627–33.
[20] Ronner E, Van Kesteren HA, Zijnen P et al. Safety and
efficacy of eptifibatide vs placebo in patients receiving
thrombolytic therapy with streptokinase for acute myocardial infarction. A phase II dose escalation, randomised,
double-blind study. Eur Heart J 2000; 21: 1530–6.
[21] Topol EJ, George BS, Kereiakes DJ et al. A randomized
controlled trial of intravenous tissue plasminogen activator
and early intravenous heparin in acute myocardial infarction.
Circulation 1989; 79: 281–6.
[22] Ross AM, Molhoek P, Lendergan C et al. Randomised
comparison of enoxaparin, a low-molecular-weight heparin,
with unfractionated heparin adjunctive to recombinant tissue
plasminogen activator thrombolysis and aspirin. Second Trial
of Heparin and Aspirin Reperfusion Therapy (HART II).
Circulation 2000; 104: 648–52.
[23] Dellborg M, Bergstrand L, Granger C et al. The ASSENT
PLUS investigators. LMW Heparin (Dalteparin) for improvement of patency after thrombolysis in AMI: A prospective
Randomized Multicentre Coronary Angiography Study
(Abstr). J Am Coll Cardiol 2001; 37 (2 Suppl A): 879–4.
[24] Coussement PK, Bassand JP, Convens C et al. A synthetic
factor-Xa inhibitor (ORG31540/SR9017A) as an adjunct to
fibrinolysis in acute myocardial infarction. The PENTALYSE
study. Eur Heart J 2001; 22: 1716–24.
[25] Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT-3
randomised trial in acute myocardial infarction. Lancet 2001;
358 (9282): 605–13.
[26] ASPECT-2 (Anticoagulants in the Secondary prevention of
Events in Coronary Thrombosis-2): reports on the effects
of aspirin versus aspirin plus coumadin (INR 2.0–2.5) or
coumadin (INR 3.0–4.0) on the endpoints death and death/
reMI/stroke in past MI patients. Presented at the European
Congress of Cardiology, Amsterdam 2000.
The AMI–SK study
[27] Simoons ML, Serruys PW, Brand M vd et al. Early
thrombolysis in acute myocardial infarction: limitation of
infarct size and improved survival. J Am Coll Cardiol 1986; 7:
717–28.
[28] Baardman T, Hermens, Lenderink T et al. Differential effects
of tissue plasminogen activator and streptokinase on infarct
size and on rate of enzyme release: influence of early infarct
related artery patency. The GUSTO Enzyme Substudy. Eur
Heart J 1996; 17: 237–46.
[29] Seitz R, Pelzer H, Immel A et al. Prothrombin activation by
thrombolytic agents. Fibrinolysis 1993; 7: 109–15.
[30] Rasmanis G, Versterqvist O, Green K, Edhag O, Henriksson
P. Evidence of increased platelet activation after thrombolysis
in patient with acute myocardial infarction. Br Heart J 1992;
68: 374–6.
[31] Leadley RJ Jr, Kasiewski CJ, Bostwick JS et al. Comparison
of enoxaparin, hirulog and heparin as adjunctive antithrombotic therapy during thrombolysis with rtPA in the stenosed
canine coronary artery. Thromb Haemost 1997; 78: 1278–85.
[32] Fragmin during instability in coronary artery disease (FRISC)
study group. Low molecular weight heparin during instability
in coronary artery disease. Lancet 1996; 347: 56–8.
[33] Cohen M, Demers C, Gurfinkel EP et al. For the efficacy and
safety of subcutaneous enoxaparin in non-Q-wave coronary
events study group. A comparison of low molecular weight
heparin with unfractionated heparin for unstable coronary
artery disease. N Engl J Med 1997; 337: 447–52.
[34] Antman E, McCabe CH, Gurfinkel EP et al., for the TIMI IIB
Investigators. Enoxaparin prevents death and cardiac
ischemic events in unstable angina/non-Q wave myocardial
infarction: results of the Thrombolysis in Myocardial
Infarction (TIMI IIB) trial. Circulation 1999; 100: 1593–601.
[35] Fragmin and Fast Revascularisation During Instability in
Coronary Artery Disease (FRISC II) Investigators. Longterm low-molecular-mass heparin in unstable coronary-artery
disease: FRISC II prospective randomised multicentre study.
Lancet 1999; 354: 701–4.
[36] The FRAX.I.S. Study group. Comparison of two treatment
durations (6 days and 14 days) of a low molecular weight
heparin with a 6-day treatment of unfractionated heparin in
the initial management of unstable angina or non-Q wave
myocardial infarction: FRAX.I.S. (FRAXiparine in Ischemic
Syndrome). Eur Heart J 1999; 20: 1553–62.
[37] Theroux P, Ouimet H, McCans J et al. Aspirin, heparin, or
both to treat acute unstable angina. N Engl J Med 1988; 319:
1105–11.
Appendix 1
Contributors
M. L. Simoons, F. Bigonzi, F. Gosset, V. Le Louer,
designed the study protocol, which was reviewed and
approved by the steering committee. V. Le Louer and V.
Keraudren performed the statistical analysis. F. Gosset
collected and monitored the data. F. Didier performed
the data management. M.L. Simoons wrote the manuscript. Aventis Pharma provided editorial help. All other
authors reviewed and revised the manuscript.
Steering committee
Chairman — Maarten L. Simoons (Erasmus University
Medical Center, Rotterdam, The Netherlands); Angeles
Alonso (Hospital Puerta de Hierro, Madrid, Spain);
Shaun
Goodman
(St.
Michael’s
Hospital,
1289
Toronto, Canada); Andras Kali (National Institute
of Cardiology, Budapest, Hungary); Ulrich Loos
(Knappschafts-Krankenhaus, Recklinghausen, Germany);
Maria Krzemiñska-Pakula (Wojewodski Szpital,
Kniaziewicza, Poland).
Data safety and monitoring committee
Chairman — Alain Leizorovicz (Faculte RTH Laennec,
Lyon, France); James Chesebro (Mount Sinaı̈ Medical
Center, New York, U.S.A.); Marcus D. Flather (Royal
Brompton Hospital, London, United Kingdom); Morton
J. Kern (Saint Louis University, Saint Louis, Missouri,
U.S.A.).
Clinical events committee
Chairman — William Wijns (Cardiovascular Center,
Aalst, Belgium); Franciscus W. G. Leebeek (University
Hospital Rotterdam, Rotterdam, The Netherlands);
Peter Van Der Meer (Thoraxcentrum, Rotterdam, The
Netherlands); Diederik C. A. Van Hoogenhuyze
(Cardiology
Zuiderziekenhuis,
Rotterdam,
The
Netherlands).
Investigators
Poland — Maria
Krzemiñska-Pakula
(Wojewodski
Szpital, Kniaziewicza); Edmund Nartowicz (Pañstwowy
Szpital Kliniczny AM, Marii); Jerzy Adamus (Centralny
Szpital, Warszawa); Kzrysztof Wrabec (Wojewodzki
Szpital Specjalistyczny, Wroclaw); Wlodzimierz Musial
(Pañstwowy Szpital Kliniczny AM, Bialystok); Jacek
Dubiel (Pañstwowy Szpital Kliniczny, Krakow); Andrezej
Ciesliqski (Szpital Kliniczny Nr 1, Poznañ); Teresa
Czekajska (Pañstwowy Szpital, Lublin). Spain —
Angeles Alonso (Hospital Puerta de Hierro, Madrid,
Spain); Fernando Worner (Hospital de Belvitge,
Barcelona); Juan Carlos Martin-Bentiez (Hospital
Clinico San Carlos, Madrid); Jaume Figueras (Hospital
Vall d’Hebron, Barcelona); José Maria San José (Hospital Valdecilla, Santander); Joan Bassaganyas (Hospital
Doctor Josep Trueta, Girona); José Reig-Barbe (Hospital
de Manresa, Barcelona); Antonio Lesmes (Hospital
Nuestra Sra. De Valme, Sevilla); Luis Martin Jadraque
(Hospital de la Paz, Madrid); Javier Goicolea (Hospital
do Meixoeiro, Vigo); Andres Rodriguez-Llorian (Hospital Central de Asturias, Oviedo); Francisco Fernandez
Avilés (Hospital Universitario de Valladolid, Valladolid);
Jose Guindo (Hospital Sant Pau-Barcelona, Barcelona).
Hungary — Bela Mezey (Zala County Hospital,
Zalaegerzeg); Andras Janosi (Szent Janos Hospital,
Budapest); Istvan Preda (Haynal Imre University,
Budapest); Miklos Mezofi (Kozponti Honved Korhaz,
Budapest); Andras Kali (National Institute of
Cardiology, Budapest); Emil Kalo (B A Z County
Eur Heart J, Vol. 23, issue 16, August 2002
1290
M. L. Simoons et al.
Hospital, Miskolc). Canada — James McMeekin (Royal
University Hospital, Saskatoo); Iqbal Bata (QEII Health
Sciences Center, Halifax); Louis Desjardins (CHUQ–
Pavillon CHUL, Sainte-Foy), Alexander G. G. Turpie
(Hamilton General Hospital, Hamilton). Germany —
Petra Wacker (Ev. Krankenhuis Kalk, Köln); Ulrich Loos
Eur Heart J, Vol. 23, issue 16, August 2002
(Knappschafts-Krankenhaus, Recklinghausen); Rüdiger
Wacker (Kreiskrankenhaus Gifhorn, Gifhorn); Ingeborg
Assman (Klinikum Erfurt GmbH, Erfurt); Till Höfs
(Städtisches
Klinikum
Magdeburg,
Magdeburg);
Friedhelm Saborowski (Städt. Krankenhaus Holweide,
Köln).