The Role of Thrombolytic Drugs in the Management of Acute ...

The Role of Thrombolytic Drugs in the
Management of Acute Myocardial
Infarction and Stroke
Omer IQBAL*, Mahmut TOBU*, Muzaffer DEMÝR**, Jawed FAREED*,
Salim AZIZ***, Harry MESSMORE*
* Medical Center, Loyola of University, Maywood, IL 60153 USA
** School of Medicine, Edirne, University of Trakya, TURKEY
*** Health Science Center, University of Colorado, Denver, Colorado, USA
Turk J Haematol 2002;19(2):151-177
Thrombolytic drugs play a crucial role in the ma-
With the advances in antithrombotic and antico-
nagement of patients with thrombotic and thromboem-
agulant drugs have come significant developments in
bolic complications during pre-, peri-, and postinter-
the field of thrombolytic therapy. It is now possible to
ventional cardiologic procedures and acute thrombotic
produce recombinant forms of tissue-type plasminogen
stroke, most often in combination with anticoagulants,
activator (tPA), urokinase, prourokinase, and staphylo-
antiplatelet agents or mechanical procedures, in order
kinase etc. by the use of recombinant DNA technology.
to achieve vascular reperfusion. Coronary Heart dise-
Recombinant urokinase and prourokinase are expres-
ase (CHD) is the most common cause of mortality not
sed from mouse hybridoma cell line, and the latter, a
only in the United States (accounting for 481.287 de-
precursor of urokinase, has such advantages as incre-
aths in 1995) but world-wide[1,2]. Annually an estima-
ased potency and increased effectiveness of thromboly-
ted 1.1 million Americans experience a new or recur-
tic therapy. The development of longer acting tPAs, fib-
rent acute myocardial infarction (AMI) due to CHD
rin-specific agents, and newer urokinase-type plasmi-
and in one -third of individuals the event is fatal[1]. The
nogen activators may be beneficial in new indications
age-adjusted mortality rate of CHD has declined dra-
of thrombolytic therapy such as thrombotic stroke.
matically from 2.8% per year in 1965 to 1.5% since
Hemostasis represents a physiologic homeostasis
1990[3]. The reasons for the age-adjusted decline in in-
resulting from a dynamic equilibrium between coagu-
cidence, case-fatality, and CHD mortality rate are
lation and fibrinolysis. An intact endothelium (a single
many: The advent of coronary care units with intensi-
layer of cells lining the vascular lumen, estimated to be
ve monitoring, aggressive treatment of complications,
1.000-5.000 square meters) is the largest endocrine,
and reperfusion therapies such as thrombolysis, percu-
paracrine and autocrine organ in the body and serves as
taneous transluminal coronary angioplasty (PTCA),
a unique hemostatic tool in the regulation of coagulati-
and coronary artery bypass graft (CABG) surgery[4-6].
on by synthesizing procoagulant and anticoagulant
The goal in the care of patients with AMI is to make
substances (Table 1)[7].
these effective treatments available in a timely manner.
151

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The Role of Thrombolytic Drugs in the Management of Acute
Iqbal O, Tobu M, Demir M, Fareed J, Aziz S, Messmore H.
Myocardial Infarction and Stroke
Development of antithrombin drugs, glycoprotein
ration of the direct-acting thrombin inhibitor, hirulog.
(GP) IIb/IIIa inhibitors, and low molecular weight he-
The improved antithrombotic effect and the gain in pa-
parins (LMWHs) provide favorable options for use in
tency were achieved at lower activated partial throm-
combination strategies for better long term clinical out-
boplastin time (aPTT) levels and were not associated
come. The more potent the antithrombotic drug, the
with an increased risk of bleeding[10,11].
more rapid and thorough the thrombolysis[8]. As a re-
The time from AMI to reperfusion (thrombolytic)
sult of enhanced thrombolysis, there is a reduction in
therapy is commonly divided into three periods[12].
the residual mass of mural thrombus, residual stenosis,
The first period is the time from the onset of symptoms
local shear force and increased platelet deposition and
to the patient’s action to seek treatment, such as going
reocclusion. To maximize the extent of thrombolysis,
to the hospital or calling emergency medical services
there is a necessity of the simultaneous administration
(EMS). This delay constitutes 60-70% of the total time
of antithrombotic drugs with the lytic agent because of
to starting reperfusion (thrombolytic) therapy. This de-
an increase in thrombin generation[8,9]. In a recent
lay may be shortened by primary prevention through
study [Hirulog Early Reperfusion/Occlusion (HERO)
the education of patients and their families about heart
trial] of a randomized double-blind comparison of hi-
disease and the importance of early response to symp-
rulog versus heparin in patients receiving streptokinase
toms. Delay results in cardiac muscle loss. The second
and aspirin for AMI, White et al and Chesesbro have
component of delay is the time to EMS response and
shown that hirulog is more effective at achieving early
transit time to an emergency care facility (3-8% of the
thrombolysis in myocardial infarction (TIMI) 3 flow
total delay). The third delay is the time from arrival at
than heparin does as an adjunct to streptokinase and as-
the hospital to definitive treatment (25-33% of the total
pirin in AMI, and that the effect of hirulog may be do-
delay). Factors contributing to effective, timely reperfu-
se-dependent[10,11]. The early patency achieved with
sion therapy are patient education, EMS availability and
streptokinase can be improved by adjunctive adminst-
proficiency, and reduced delay in the hospital[1,2,13,14].
Table 1. Substances secreted by the endothelium
Prothrombotic
Antithrombotic
Stimulation of platelet aggregation and adhesion:
Inhibition of platelet aggregation:
von Willebrand factor
Prostacyclin
Platelet activating factor
Nitric oxide
Procoagulant factors:
ADPase
Tissue factor
Anticoagulant binding and inhibition of thrombin
Binding factors IXa and Xa
and tissue factor:
Factor V
Antithrombin
Acceleration by heparin like molecules
Thrombomodulin activation of protein C and S
a-2 macroglobulin
Tissue factor pathway inhibitor (TFPI)
Inhibition of fibrinolysis:
Fibrinolysis:
tPA inhibitor
tPA
Cytokines:
Interleukin-1
Tumor necrosis factor (TNF)
Turk J Haematol 2002;19(2):151-177
152

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The Role of Thrombolytic Drugs in the Management of Acute
Myocardial Infarction and Stroke
Iqbal O, Tobu M, Demir M, Fareed J, Aziz S, Messmore H.
Trials of prehospital thrombolytic therapy have resulted
Patients who are candidates for thrombolytic the-
in reduced time to treatment and improvement in mor-
rapy must be identified as soon as possible after pre-
tality rates[3,15-19].
sentation, using the National Heart Attack Alert Prog-
ram Coordinating Committee eligibility criteria[20].
Table 1 lists the substances secreted by the vascu-
About 20% of the patients with AMI receive throm-
lar endothelium. Selection criteria are listed in Table 2.
bolytic therapy. An additional 15% are eligible but ne-
Table 3 lists the thrombolytic drugs currently in use
ver receive the therapy[21].
and under development. Distinctive features of the ava-
ilable thrombolytic agents are shown in Tables 4, 5,
Relative contraindication are not included in the
and 6. Selection of the specific drug for a particular pa-
table below because the survival benefit for thromboly-
tient must include prior use because antibody-mediated
tic therapy should justify the risks associated with rela-
resistance may have developed (see Table 4, 5 and 6 for
tive contraindications[22].
immunogenicity of each drug). Cost factors also are
More than 90% of patients who present with ST
important, as shown in the above table 4 and 5.
segment elevation have coronary thrombotic occlusion
SELECTION CRITERIA for LYTIC
and early thrombolytic intervention reduced the morta-
THERAPY
lity by approximately 30% as per the placebo-control-
Table 2. Selection criteria for thrombolytic therapy
Indications:
Chest pain for > 30 minutes and < 12 hours
No congestive heart failure or hypotension
ST elevation (0.1 mm) in two contiguous leads or new bundle branch block
Absolute contraindications:
Acute: Active internal bleeding
Blood pressure > 200/120 mmHg
Suspected aortic dissection
Subacute or chronic
Arteriovenous malformations
Tumor involving spinal cord or cranial structures
Hemorrhagic retinopathy
Pregnancy
Active peptic ulcer
Warfarin use
Bleeding diathesis
In the past 2 months
Trauma or surgery in the past 2 weeks with a risk of bleeding into closed space
Spinal or intracranial procedure in the past 8 weeks
Recent head trauma
Prolonged or traumatic cardiopulmonary resuscitation
Prior hemorrhagic stroke or any stroke within the prior year.
* Advanced age is not a contraindication. Elderly parents have increased complications (especially intracranial hemorrhage) but al-
so the highest absolute mortality reduction.
Turk J Haematol 2002;19(2):151-177
153

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The Role of Thrombolytic Drugs in the Management of Acute
Iqbal O, Tobu M, Demir M, Fareed J, Aziz S, Messmore H.
Myocardial Infarction and Stroke
Table 3. Three generations of thrombolytic agents
First generation
Streptokinase
Urokinase
Second generation
Recombinant tissue plasminogen activator (rtPA, alteplase, Duteplase)
Anisoylated plasminogen streptokinase activator complex (APSAC, Anistreplase).
Single-Chain urokinase type plasminogen activator (scu-PA, prourokinase)
Third generation
Vampire bat salivary plasminogen activator
Reteplase (rPA)
TNK-tPA
Lanoteplase (n-PA)
Staphylokinase
Recombinant glycosylated plasminogen activator
Thrombolytic drugs under development
Antibody-targeting thrombolytic agents
Polyethylene glycol-coupled thrombolytic agents
Mutants and variants of plasminogen activator
Recombinant chimeric plasminogen activator (fibrolase)
Table 4. Characteristics of first generation thrombolytics
Characteristics
Streptokinase
Urokinase
Source
Gr C Streptococci
Recombinant, human fetal kidney
Molecular weight (Kd)
47
35-55
Immunogenecity
Yes
No
Mode of action
Forms an activator complex
Direct
Plasma half-life (min)
18-23
14-20
Metabolism
Hepatic
Hepatic
Dose
1.5 million units
3 million units
Cost per dose
$300
$2000
led randomized trials of the 1980s[23-28].
lex (APSAC), or indirect activators, such as streptoki-
nase. Average doses are shown in the tables 4-6. AP-
PHARMACOLOGY and CLINICAL USE
SAC and tPA are “fibrin-specific” in that they bind to
The characteristics and functional properties of
fibrin and activate plasminogen at the site, whereas
thrombolytic agents commonly in current use and sum-
streptokinase and urokinase are not fibrin-specific,
marized in Tables 3-6. These drugs are either direct ac-
lysing both fibrinogen and fibrin. Streptokinase and
tivators of plasminogen, such as tPA, urokinase, and
APSAC (which contains streptokinase) cannot be re-
anisoylated plasminogen-streptokinase activator comp-
used because they are antigenic and give rise to circu-
Turk J Haematol 2002;19(2):151-177
154

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The Role of Thrombolytic Drugs in the Management of Acute
Myocardial Infarction and Stroke
Iqbal O, Tobu M, Demir M, Fareed J, Aziz S, Messmore H.
Table 5. Characteristics of second generation thrombolytics
Character
APSAC
rtPA
Scu-PA (saruplase)
Source
Gr C Streptococci
Recombinant
Prodrug from a naturally
plasminogen anisoylated
human
occuring physiologic
protease
Molecular weight (Kd)
131
63-70
49
Immunogenecity
Yes
No
No
Mode of action
Direct
Direct
Direct
Fibrin specificity
+
++
+
Plasma half-life (min)
70-120
4-6
9
Metabolism
Hepatic
Hepatic
Hepatic
Dose
30 units IV over 2-5
15 mg bolus + 90 min
20 mg bolus + 60 mg
minutes
infusion
infusion for 1 hour.
Cost per dose
$2400
$2200
$2100
Table 6. Characteristics of third generation drugs
Character
r-PA
n-PA
TNK-tPA
Vam. bat PA
Staphylokinase
Source
Recombinant,
Chinese
Variant of
Saliva of
PA of bacterial
human hamster tPA-rearranging
desmodus
origin-strains
mutant
ovary cells
gene sequence
rotundus
of Staphylococ-
type PA
cus aureus
MW (Kd)
39
39
39
52
15.5
Immunogenecity
No
?
No
Yes
Yes
Mode of action
Direct
Direct
Direct
Indirect
Indirect
Fibrin specificity
Yes
+
+++
+++
+++
Plasma half-life (min)
14
37
20
170
6
Metabolism
Renal
Hepatic
Hepatic
Hepatic
Hepatic
Dose
20 million
120.000 U/kg
0.5 mg single
0.5 mg single
1.5 mg + 15 mg
units
single bolus
bolus
bolus
double bolus
over 30 minutes
lating antibodies. Because urokinase and tPA are of hu-
therapy[29]. All thrombolytic drugs have the potential
man origin, they do not induce antibodies. As a practi-
to cause more bleeding in elderly than in younger pati-
cal matter, urokinase is rarely used for AMI because of
ents, and most manufacturers’ warnings advise cauti-
the necessity for intracoronary administration. The two
on. This risk must be weighed against anticipated be-
commercially available recombinant forms of tPA, re-
nefit. A synopsis of thrombolytic therapy in AMI trials
teplase and alteplase, are given intravenously, as are
is given in the Table 7.
streptokinase and APSAC. APSAC has not been studi-
FIRST GENERATION THROMBOLYTIC
ed in patients over 75 years of age and may be unsafe
AGENTS
in this age group. Theoretically, the longer half-life of
a single bolus of APSAC makes it ideal for prehospital
Streptokinase
Turk J Haematol 2002;19(2):151-177
155

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The Role of Thrombolytic Drugs in the Management of Acute
Iqbal O, Tobu M, Demir M, Fareed J, Aziz S, Messmore H.
Myocardial Infarction and Stroke
Streptokinase is the most extensively studied agent
ment was 101 vs 240 minutes, respectively. Patients
todate. It is not an enzyme and activates the fibrinoly-
treated in their home had fewer Q-wave myocardial in-
tic system by forming a 1:1 stoichiometric complex
farctions and improved left ventricular function com-
with plasminogen that in turn converts plasminogen to
pared with the group treated in the hospital[29]. The
plasmin. Streptokinase causes systemic conversion of
Myocardial Infarction Triage and Intervention (MITI)
plasminogen to plasmin and depletion of circulating
trial was the largest randomized trial of pre-hospital
fibrinogen, plasminogen and F V and F VIII. With the
thrombolysis in the US. The trial evaluated 360 pati-
usual dose of 1.5 million units streptokinase, the fibri-
ents who were initially screened by paramedics using a
nogen level drops to 20% of the pretreatment level with
checklist and electrocardiograms. Because the trial inc-
corresponding higher levels of fibrinogen degradation
luded only patients with a short delay to treatment in
products that may result in a modest increase in ble-
both prehospital and hospital settings (92 minutes in
eding complications.
prehospital-treated vs 120 minutes in hospital-treated
patients), prehospital treatment provided only a modest
CHOICE of AGENT
time saving of 33 minutes.
The type of thrombolytic drug is not as critical and
Modulation of Endogenous Fibrinolytic
important as the delay to adminstration (Table 8). The
Activity
GUSTO-I trial showed that accelerated tPA was better
than streptokinase for most patients with AMI[69]. The
TAFI is a latent carboxypeptidase B like enzyme
GUSTO-III trial showed no mortality benefit of retep-
that is activated by thrombin-thrombomodulin comp-
lase over alteplase. Both lanoteplase and TNK-tPA (Te-
lex and attenuates fibrinolysis by cleaving carboxyter-
necteplase) can be adminstered as a single bolus. TNK-
minal lysine residues from fibrin[75,76]. The fibrinoly-
tPA was recently approved by the Food and Drug Ad-
tic process is retarded by removal of these lysine resi-
ministration[70].
dues which decreases the plasminogen or plasmin bin-
PREHOSPITAL THROMBOLYSIS
ding to thrombin. It has been shown in dogs and rabbits
that a potato-derived carboxypeptidase B inhibitor inc-
Several prehospital thrombolytic therapy trials we-
reases tPA-induced thrombolysis[77,78].
re designed to evaluate time-saving, left ventricular
function, infarct size, and differences in mortality ra-
Factor XIIIa Inhibitors
tes[16-19,29,71-74]. The largest trial, the European Myo-
The Laki-Lorand F XIIIa, a thrombin-activated
cardial Infarction Project (EMIP) was carried in 15 Eu-
transglutaminase, crosslinks the a and g-chains of fib-
ropean countries and Canada. Administration of anist-
rinogen to form a-polymers and g-dimers, respectively.
replase as a bolus in the prehospital setting in 2750 pa-
As the fibrin polymer is stabilised due to crosslinking,
tients was compared with hospital treatment in 2719
it is rendered more refractory to degradation by plas-
patients. The 30-day mortality rate was 9.7% vs 11.1%
min[79]. It is therefore thought that inhibition of F XI-
in the prehospital and hospital groups, respectively
IIa makes the thrombus susceptible to lysis. Tridegin, a
(risk reduction= 13%, 95% CI-1-26%, p= 0.08). The
peptide isolated from the giant Amazon leech, Ha-
cardiac mortality rate was 8.3% vs 9.8%, respectively
ementeria ghiliani, is a specific F XIIIa inhibitor and
(risk reduction= 16%, 95% CI= 0-29%, p= 0.049).
has been shown to enhance fibrinolysis in vitro when
There was no obvious correlation between the reducti-
added prior to clotting of fibrinogen[80,81]. Destabilase,
on in mortality at 30 days and the interval between the
a leech enzyme that hydrolyses g-g crosslinks also in-
onset of symptoms and the first injection. There were
hibits F XIII action[82,83].
no differences between the groups in the incidence of
bleeding, overall incidence of stroke, ventricular fibril-
PAI-1
1 Inhibitors
lation, or shock during the hospital period. The Gram-
Inhibition of PAI-1, which is a major physiologic
pian Region Early Anistreplase Trial (GREAT) compa-
inhibitor of tPA and uPA, esults in increased endogeno-
red prehospital thrombolytic therapy given by the prac-
us fibrinolytic activity. PAI-1 synthesis is decreased in
titioner in patients’ homes with treatment after hospital
vitro by lipid lowering drugs, such as niacin and fibra-
arrival in 311 patients[29]. The average time to treat-
tes[84,85]. Similarly, peptides that block PAI-1 activity
Turk J Haematol 2002;19(2):151-177
156

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The Role of Thrombolytic Drugs in the Management of Acute
Myocardial Infarction and Stroke
Iqbal O, Tobu M, Demir M, Fareed J, Aziz S, Messmore H.
Table 7. Synopsis of thrombolytic therapy in AMI trials
Trial name
Population,
Drug
Major
(Ref. #)
Design
n, age
procedure
endpoints
Results
GISSI-1[30] R, OL, PC,
11, 712; no
IV SK vs no
Mortality
Reduction in
MCS
age limit
lytic therapy
benefits at 21
mortality of 10.7%
days and 1
at 21 days and of
year
17.2% at 1 year
GISSI-2[31] MCS, R, OL,
12, 381; no
IV SK
Mortality rate,
SK and tPA were
2 X 2 factorial
age limit
vs tPA
rate of reinfarction,
equally effective
stroke rate,
within 6 hours of
incidence of post
the onset of
infarction angina
symptoms
ISIS-2[32]
MCS, PC,
17, 187; no
IV SK + aspirin
Mortality and
SK & aspirin
R, DB, 2 X 2
age limit
vs placebo
stroke risk
independently
factorial
reduced mortality
in patients with
AMI. The
combination of two
drugs had a
synergistic effect on
mortality without
increase in rates of
stroke.
ISAM[33]
P, R, DB, PC,
1.741;
SK vs
21-day
Nonsignificant
MCS
< 75 years
placebo
mortality rate
reduction in 21-day
mortality rate;
significantly higher
LVEF
White HD
R, DB
219; no
SK vs
LVEF;
Increased LVEF and
et al[34]
age limit
placebo
mortality rate
significantly lower
mortality rate in
SK group
TIMI-1[35]
R, DB, MCS
290;
IV SK or
Coronary angiography
Higher reperfusion
< 75 years
placebo
to assess reperfusion
rate with rtPA; no
vs IV rtPA or
at 90 min
difference in
placebo
mortality rate,
bleeding
complications
or LVF
ASSET[36]
R, MCS,
5013;
TPA vs
Mortality
TPA treatment
DB, PC
18-75 years
placebo
rate
within 5 hr of onset
of symptoms
reduced mortality
sustained to 1 year
but not rates of
recurrent infarction
or development of
heart failure
compared with
placebo
Turk J Haematol 2002;19(2):151-177
157

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The Role of Thrombolytic Drugs in the Management of Acute
Iqbal O, Tobu M, Demir M, Fareed J, Aziz S, Messmore H.
Myocardial Infarction and Stroke
Table 7. Synopsis of thrombolytic therapy in AMI trials (continuation)
Trial name
Population,
Drug/
Major
(Ref. #)
Design
n, age
procedure
endpoints
Results
TAMI-6[37]
P, R, DB,
197; < 75
TPA vs
Vessel patency
Better early patency
PC, MCS
years
placebo
at 6-24 hrs.
with tPA but similar
rate for late
patency, inhospital
mortality rate, LVEF
LATE[38]
R, MCS,
5711; > 18
RtPA vs placebo; Mortality
Reduces 35-day
DB, PC
years
6-24 hr from
rate
mortality rate even
onset of
if given up to 12 hr
symptoms
after onset of
symptoms
GREAT[29]
P, R, DB,
311; no
Anistreplase
Mortality
52% lower 1-year
PG, MCS
age limit
at home vs in
rate
mortality rate in
hospital
home-treated group
TEAM-2[39] R, DB,
370; < 76
Anistreplase
Early patency and
Both agents were
MCS
years
(APSAC) or SK
reocclusion rates
equally effective
and safe
AIMS[40]
R, MCS,
1004; < 70
APSAC or
Mortality
IV APSAC within
DB, PC
years
placebo
6 hr of onset of
symptoms reduced
mortality in AMI
Meinertz T
R
313; no
APSAC vs
28-day
Less cardiogenic
et al[41]
age limit
heparin
mortality rate
shock and 56%
lower 28-day
mortality rate in
APSAC Group
ISIS-3[42]
MCS, PC, R,
41,299; no
IV SK,
Mortality and
No difference in
DB, OL,
age limit
APSAC,
reinfarction rate at
35-day mortality
3X2 factorial
rtPA
35 days and 6 months
rates
TIMI-4[43]
R, DB,
382; < 80
Front-loaded
Coronary angiographic
TIMI grade 3 flow
MCS
years
r-PA or APSAC estimation of
at 90 min’rtPA
or combination
infarct-related artery
60.2%, APSAC
of r-tPA and
patency and TIMI
42.9%,
APSAC
grade 3 flow at 90 min
combination 44.8%
GUSTO-1
R, OL,
41,021; no
IV SK + SC
Mortality,
Reduced mortality
[44]
MCS
age limit
heparin,
hemorrhagic
rate in tPA + IV
IV SK + IV
stroke
heparin group
heparin,
accelerated
tPA + IV heparin,
SK + tPA + IV
heparin
GUSTO-III R, MCS,
15,059; no
Alteplase vs
Mortality and
Both agents were
[45]
OL
age limit
reteplase
stroke risk
identical
INJECT[46] R, DB,
6010; >18
Reteplase
Mortality at 35
Reteplase is safe
MCS
years
vs SK
days and 6 months
and effective
thrombolytic agent
Turk J Haematol 2002;19(2):151-177
158

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The Role of Thrombolytic Drugs in the Management of Acute
Myocardial Infarction and Stroke
Iqbal O, Tobu M, Demir M, Fareed J, Aziz S, Messmore H.
Table 7. Synopsis of thrombolytic therapy in AMI trials (continuation)
Trial name
Population,
Drug/
Major
(Ref. #)
Design
n, age
procedure
endpoints
Results
RAPID
R, MCS,
606; 18-75
r-PA (reteplase
Artery
r-PA given as
[47]
OL
years
bolus vs infu-
patency and LVF
double bolus of 10
sion of standard
MU + 10 MU 30
-dose alteplase
min apart resulted
in more rapid and
complete
reperfusion than
standard dose tPA
and was associated
with improved
global and regional
LV function at
discharge
RAPID-II
R, MCS,
324; >18
Double bolus
Artery
Double bolus dose
[48]
PG, OL
years
reteplase or
patency and
of reteplase was
ront-loaded
TIMI grade 3 flow
associated with
accelerated
at 90 min
higher rates of
alteplase
reperfusion at 60
and 90 min after
initiation of therapy
than front-loaded
alteplase infusion,
without increase in
risk of complication
COBALT
R, MCS,
7169; no
Accelerated
Mortality and
Accelerated
[49]
OL
age limit
infusion of
stroke risk
infusion alteplase
alteplase or
remains preferred
double bolus
regimen
of alteplase
TAMI-7
R, MCS
219;
5 different
Patency rate,
Accelerated tPA
[50]
18-76 years
regimens of
reocclusion rate,
adminstration
tPA
LVEF, death,
according to
bleeding
protocol 3 is
relatively safe,
achieving high
90-min patency
rate and low rates
of reocclusion and
complications
Carney RJ
R, OL
281; no
Standard vs
TIMI grade 3 flow
Better patency at 60
et al[51]
age limit
accelerated
at 60 min and
min but not at 90
tPA regimen
90 min
min. Similar rates of
recurrent ischemia,
reinfarction, stroke
and bleeding
Turk J Haematol 2002;19(2):151-177
159

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The Role of Thrombolytic Drugs in the Management of Acute
Iqbal O, Tobu M, Demir M, Fareed J, Aziz S, Messmore H.
Myocardial Infarction and Stroke
Table 7. Synopsis of thrombolytic therapy in AMI trials (continuation)
Trial name
Population,
Drug/
Major
(Ref. #)
Design
n, age
procedure
endpoints
Results
COMPASS
R, MCS
3089; >
Saruplase
Efficacy, safety
Similar mortality
[52]
DB
20 years
vs SK
and mortality
rate, but more
hemorrhageic
stroke in Saruplase
group
PERM[53]
Retrospective
481; no
SK vs tPA
TIMI grade 3 flow
SK, but not tPA, was
age limit
at 90 min
found to be less
effective when
administered after
3 hr, regardless of
whether TIMI flow
grades 2 and 3
were poled or
grade 3 flow was
considered alone
In TIME[54] R, MCS,
602
Lanoteplase
TIMI grade 3 at
Increased coronary
DB, DP
or alteplase
60 and 90 min
patency in
lanoteplase group
PACT[55]
R
606; no
Precatheterization
Predischarge
No significant
age limit
tPA or placebo
EF
difference between
two groups in
predischarge EF
GUSTO
P, R, MCS,
2.431; no
IV SK + SC
TIMI grade 3
Highest patency at
Angiograp
OL
age limit
heparin, IV
flow at 90 min
90 min with tPA
hic Investi
SK + IV heparin,
and IV heparin:
gators [56]
accelerated
81% vs 54% with
tPA + IV heparin,
SK and SC heparin;
SK + tPA + IV heparin
73% combination
In TIME-II
R, MCS,
17.078;
Lanoteplase
30-day
Similar 30-day
[57]
DB
no age limit
vs tPA
mortality rate
mortality rate;
higher incidence of
intracranial
hemorrhage in tPA
group
TIMI-10A
Phase I,
113; no
Dose ranging
Coronary
TIMI grade 3 flow
[58]
dose-ranging
age limit
of TNK-tPA
angiography at
at 90 min in 64% of
pilot trial
90 min and
patients; major
hemorrhage
hemorrhage 6.2%
TIMI-10B
R, MCS
886; no
Single bolus
Coronary angiography
TIMI grade 3 flow
[59]
age limit
of TNK-tPA
at 90 min and
is similar
vs front-loaded
hemorrhage
tPA
ASSENT-2
P, R, DB,
16.949;
TNK-tPA
All cause mortality
Nearly identical all
[60]
OL, MCS
no age limit
(tenecteplase)
at 30 days
cause mortality rate
vs front-loaded
at 30 days and
alteplase
similar intracranial
hemorrhage rate
Turk J Haematol 2002;19(2):151-177
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