Clinical Trials Report
Monthly Focus: Cardiovascular & Renal
1. Introduction
2. Overview of pharmacology
3. Myocardial infarction
4. Trials of dosing in acute MI
5. Thrombolysis versus primary
angioplasty/stenting in MI
6. Thrombolysis and angioplasty
in MI
7. Stroke
8. Acute coronary syndromes
9. Pulmonary thromboembolism
10. Deep vein thrombosis
11. Peripheral vascular disease
12. Thrombosed central venous
catheters
13. Expert opinion
Ashley Publications
www.ashley-pub.com
Alteplase: descendancy in
myocardial infarction, ascendancy
in stroke
Sheila A Doggrell
Doggrell Biomedical Communications, 47 Caronia Crescent, Lynfield, Auckland, New Zealand
Tissue type plasminogen activator is available, through recombinant technol-
ogy, for thrombolytic use as alteplase. Alteplase is relatively clot specific and
should cause less bleeding side effects than the non-specific agents such as
streptokinase. Alteplase has been used successfully in evolving myocardial
infarction (MI) to reopen occluded coronary arteries. It is probably equally
effective or superior to streptokinase in opening arteries and reducing mor-
tality in MI. Alteplase is most effective when given early in MI and is probably
ineffective when given 12 h after the onset of symptoms. The effectiveness of
alteplase in MI can be increased by front loading with a bolus of 15 mg, fol-
lowed by an infusion of 50 mg over 30 min and 35 mg over 60 min. Percuta-
neous transluminal coronary angioplasty or stenting is associated with a
greater patency and lower rates of serious bleeding, recurrent ischaemia and
death than alteplase in MI and is likely to take over from alteplase as the
standard MI treatment. A reduced dose of alteplase to increase coronary
artery patency prior to angioplasty may be useful in MI. An exciting new indi-
cation for the use of alteplase is in stroke, where it has become the first ben-
eficial intervention. Alteplase is used to reopen occluded cerebral vessels but
is associated with an increased risk of intracerebral haemorrhage. Alteplase is
beneficial if given within 3 h of the onset of stroke but not after this time
period. Therefore, the next challenge is to increase the percentage of people
being diagnosed and treated within this period. Clinical trials have not estab-
lished a role for alteplase in the treatment of acute coronary syndromes or
deep vein thrombosis. However, alteplase is useful in treating pulmonary
thromboembolism and peripheral vascular disease.
Keywords: alteplase, myocardial infarction, peripheral vascular disease, stroke, thromboembolism
Expert Opin. Investig. Drugs (2001) 10(11):2013-2029
1. Introduction
The GISSI trial, using iv. streptokinase, was the landmark study establishing
that a thrombolytic agent could reduce early mortality in MI [1]. It has subse-
quently been shown that this benefit is still present after 10 years [2].
Tissue type plasminogen activator is a human thrombolytic protein with a cir-
culation half-life of several minutes. It is available, through recombinant technol-
ogy, for pharmacological use as alteplase. The first part of this review describes the
use of alteplase in acute MI. This use is now decreasing due to safer treatments
such as angioplasty and stenting. The second part of this review considers the
increasing use of alteplase as a treatment for stroke. The final part of this review
considers the use of alteplase in other conditions associated with excessive throm-
bosis; acute coronary syndromes, pulmonary embolism, deep vein thrombosis and
peripheral vascular disease.
2001 © Ashley Publications Ltd ISSN 1354-3784 2013
Alteplase: descendancy in myocardial infarction, ascendancy in stroke
2. Overview of pharmacology
Tissue plasminogen activator is a circulating serine protease
that contains 527 amino acid residues. It is a poor plas-
minogen activator in the absence of fibrin. Tissue plas-
minogen activator binds to fibrin via lysine binding sites at
its amino terminus. Subsequently, endogenous tissue plas-
minogen activator converts plasminogen to the active
enzyme plasmin. Plasmin disrupts the fibrin meshwork of
fresh thrombi by cleaving arginine-lysine bonds. Since cir-
culating plasmin inhibitors inactivate free plasmin, tissue
plasminogen has relatively clot-specific effects. Its half-life
in the circulation is approximately 5 min due to hepatic
metabolism, however activity in the thrombus is longer.
Tissue plasminogen activator has been synthesised in single
(alteplase) or dual (duteplase) chain forms, which have dif-
ferent activities. This review discusses alteplase only.
Streptokinase and, to a lesser extent, anistreplase, are not
clot specific and cause a generalised coagulation defect. They
also cause transient hypotension and are antigenic. Alteplase
has less effect on circulation clotting factors and therefore is
theoretically less likely to cause bleeding.
3. Myocardial infarction
There is complete coronary occlusion in approximately 80%
of patients with prolonged chest pain and ST segment eleva-
tion. The rationale for giving thrombolytic agents in patients
with evolving MI is to reopen an occluded coronary artery in
order to minimise MI injury, by salvaging myocytes to pre-
serve cardiac function, ultimately improving overall survival.
Clinical trials have established alteplase as an effective throm-
bolytic agent in MI.
3.1 Thrombolysis in Myocardial Infarction (TIMI)
In the Thrombolysis in Myocardial Infarction trial, per-
fusion was graded and this grading system has been com-
monly used in studies of thrombolysis ever since. TIMI
grade 0 represents no reperfusion, grade I represents pene-
tration without perfusion, grade II represents partial per-
fusion and grade III represents complete perfusion [3].
In the TIMI I trial, alteplase proved superior to strep-
tokinase in eliciting reperfusion in patients with evolving
MI [3]. The 290 patients entered the trial within 7 h of the
onset of symptoms and received either alteplase (40, 20
and 20 mg in successive hours) or 1.5 million units of
streptokinase over 1 h [3]. Ninety minutes after the start of
therapy, occluded infarct related arteries had opened in
62% of patients in the alteplase and 31% of the streptoki-
nase group [3]. The occurrence of bleeding events, adminis-
tration of blood transfusions and re-occlusion of the
infarct-related artery was comparable in the two groups [3].
However, this TIMI trial was too small to obtain reliable
mortality information.
2014 Expert Opin. Investig. Drugs (2001) 10(11)
3.2 Anglo-Scandinavian Study of Early Thrombolysis
(ASSET)
The ASSET trial was larger than TIMI and was able to dem-
onstrate that alteplase, given within 5 h of acute MI, increased
survival. Only 38% of 13,318 acute MI patients were
included in the ASSET trial comparing alteplase (100 mg)
and placebo [4]. The others were excluded for having symp-
toms which lasted longer than 5 h. At 1 month the fatality
rates were 7.2% for alteplase and 9.8% for placebo [4]. More
alteplase patients had bleeding complications (6.3% minor,
1.4% major) than placebo patients (0.8%, 0.4%) [4]. How-
ever, the incidence of stroke was similar in both groups (1.1%
alteplase, 1.0% placebo) [4].
At the 6-month follow-up to ASSET, the survival benefit
with alteplase was maintained. The 6-month mortality rates
were 10.4% with alteplase and 13.1% with placebo [5]. This
benefit was even greater when only patients with a proven MI
were included (alteplase, 12.6%; placebo, 17.1%) [5]. The
benefit was observed both in patients with anterior (alteplase,
15.6%; placebo, 21.2%) and inferior MI (alteplase, 7.7%;
placebo, 12.8%) [5]. However, treatment with alteplase had no
effect on subsequent cardiac events after 1 month (re-admis-
sions, re-infarctions and death) nor to treatment for angina or
heart failure [5].
3.3 Guppo Italiano per lo Studio della Sopravvivenza
nell’Infarto Miocardico (GISSI-2)
The GISSI-2 trial compared streptokinase and alteplase in
patients with acute MI admitted to a coronary care unit within
6 h of onset of symptoms and demonstrated that both were
equally effective and safe [6]. The 12,490 patients received strep-
tokinase (1.5 MU iv. over 30 - 60 min) or alteplase (100 mg iv.
over 3 h), with and without heparin and, if not contraindicated,
atenolol and aspirin [6]. Similar percentages of patients in the
alteplase and streptokinase groups had the end point of death
plus severe left ventricular damage [6]. The incidence of major
in-hospital cardiac complications (re-infarction and post-infarc-
tion angina) was similar in the alteplase and streptokinase
groups [6]. The International Study Group added 8401 patients
to those in GISSI-2 [7]. In this combined group, more haemor-
rhagic strokes were reported with alteplase (1.3%) than with
streptokinase (0.9%) but more major bleeds were observed with
streptokinase than alteplase [7].
3.4 Late Assessment of Thrombolytic Efficacy (LATE)
Since up to 30% of patients with acute MI arrive in hospital
6 - 24 h after symptom onset, it is of the utmost importance
to establish the risks and benefits of late thrombolysis.
Thrombolytic therapy reduces mortality after acute MI,
even when treatment is initiated relatively late after the onset
of symptoms. In the LATE study, 5711 patients with symp-
toms and ECG criteria consistent with acute MI were ran-
domised to iv. alteplase (100 mg over 3 h) or placebo within
6 - 24 h of symptom onset [8]. Patients also received aspirin

and heparin [8]. Mortality after 35 days was lower, but not
significantly so, with alteplase (8.86%) than with placebo
(10.31%) [8]. However, when limited to patients treated
within 12 h, mortality was significantly less with alteplase
(8.90%) than placebo (11.97%) [8]. Treatment with alteplase
increased the risk of haemorrhagic stroke [8]. The authors
concluded that the time window for thrombolysis with
alteplase could be extended to 12 h from symptom onset [8].
The mechanisms behind the benefit of alteplase in LATE
may include stabilisation of the ECG. In an ancillary study to
LATE, signal-averaged ECGs were recorded before hospital
discharge in 150 patients who had received alteplase and 160
placebo patients [9]. There was a trend towards alteplase
reducing ECG abnormalities and QRS duration [9]. When the
patients were divided into those that had elevated ST eleva-
tion and those that did not, it was shown that alteplase only
reduced ECG abnormalities and QRS duration in those with
ST elevation [9].
In LATE, alteplase had no overall benefit on the 1-year
mortality of the 2973 patients with ST segment elevation
[10]. However, those patients with ST segment elevation who
were treated with alteplase within 3 h of hospital admission
did have a lower mortality (15.8 vs. 19.6%) [10]. Patients
with ST depression > 2 mm also had lower mortality after
1 year when treated with alteplase (20.1%) rather than pla-
cebo (31.9%) [10].
Cardiac rupture is a catastrophic complication of acute MI
responsible for 5 - 20% of all in-hospital deaths. It can take
several forms, including free wall rupture, ventricular pseu-
doaneurysm formation, ventricular septal rupture, papillary
muscle rupture and, less frequently, atrial rupture. Many cli-
nicians were concerned that late treatment with alteplase
may cause an excessive occurrence of death from cardiac rup-
ture, as seems to be the case with streptokinase. However this
is not the case with alteplase in LATE. After 35 days, 52
patients had died of cardiac rupture, 42 of electromechanical
dissociation, 82 of asystole and 370 of other causes [11].
Alteplase had no significant effect on the incidence of cardiac
rupture in patients treated within or after 12 h [11]. However,
alteplase did shorten the time of onset of cardiac rupture,
when it occurred [11].
3.5 Global Utilisation of Streptokinase and Tissue
Plasminogen Activator for Occluded Coronary
Arteries (GUSTO)
In GUSTO, four treatment strategies for reperfusion were
compared in 41,021 patients with an ST-segment eleva-
tion within 6 h of onset of symptoms. The treatments
were streptokinase with sc. heparin; streptokinase and
intravenous heparin; accelerated-dose alteplase (15 mg
bolus, 0.75 mg/kg over 30 min and 0.5 mg/kg over
60 min) with iv. heparin; or a combination of both activa-
tors with iv. heparin [12]. Unlike previous studies, GUSTO
showed alteplase to be superior to streptokinase in reduc-
ing mortality. This difference is probably due to acceler-
Expert Opin. Investig. Drugs (2001) 10(11)
Doggrell
ated dose alteplase being used in GUSTO and not in
previous studies (see Section 4).
In GUSTO, there was no difference in mortality between
groups at 6 h, but at 24 h the mortality was lower with alteplase
(2.36%) than with streptokinase (2.89%) [13]. Accelerated
alteplase also lowered 30-day mortality (6.3%), compared with
the other regimens (7.0 - 7.4%) and this was maintained after
1 year (alteplase 9.1%, streptokinase 10.1%) [14].
In GUSTO, early thrombolysis was associated with a lower
overall 30-day mortality rate (< 2 h, 5.5%; > 4 h, 9.0%), how-
ever, it made no difference whether the thrombolysis occured
with alteplase or streptokinase [15].
Angiography was performed in 2431 patients in GUSTO
[12]. The rate of patency of the infarct-related artery at
90 min was highest in the group given accelerated-dose
alteplase and heparin (81%). Other combinations gave the
following rates of patency; streptokinase and sc. heparin
(54%), streptokinase and iv. heparin (60%), combination
therapy and iv. heparin (73%) [12]. Flow through the infarct-
related artery at 90 min was normal in 54% of the alteplase
and heparin group but < 40% in the other groups [12]. By
180 min, the patency rates were the same in all four groups
[12]. Re-occlusion was infrequent and similar in all four
groups (4.9 - 6.4%) [12]. A subsequent study showed that
there was a good correlation between 30-day mortality and
90 min patency rates [16]. This supports the theory that an
improved survival with thrombolytic therapy is an achieve-
ment of early, complete perfusion [16].
Alteplase was also more effective than streptokinase in
reducing the infarct size. In this subset of the GUSTO angi-
ographic study, 90 min coronary patency rates were higher
in the alteplase (87 - 90%) than the streptokinase
groups (46 - 53%) [17]. Infarct size was defined as cumulative
alpha-hydroxybutyrate dehydrogenase (HBDH) release/l
plasma, within 72 h of the first symptoms [17]. The HBDH
test measures the myocardial isoforms of lactate dehydroge-
nase. There was a small reduction in the infarct size and
accelerated release of HBDH in the alteplase groups com-
pared to the streptokinase groups [17].
3.6 Time to treatment
Previous studies have demonstrated that the best results with
alteplase are achieved with early treatment, although LATE indi-
cates that there is some benefit with treatment for 6 - 12 h after
the onset of acute MI symptoms. The National Registry of
Myocardial Infarction (NRMI) is a cross-sectional database of
patients hospitalised with acute MI. Analysis of this database
confirmed that patients with acute MI treated early with
alteplase are more likely to survive the acute hospitalisation than
patients treated later. Of 71,253 patients in NMRI-2, 39% of
patients presented to participating hospitals within 2 h of acute
symptom onset and received alteplase, 36% were treated within
2.1 - 4 h, 12% between 4.1 - 6 h and the remaining 13% there-
after [18]. In-hospital death rates increased progressively with
increasing delays in times of administration of alteplase [18].
2015
Alteplase: descendancy in myocardial infarction, ascendancy in stroke
4. Trials of dosing in acute MI
There have been a number of trials investigating the appropri-
ate dosing regimen to use when administering alteplase and
these have led to increased benefit being observed with
alteplase. In 1988, the angiographic effects of 70 mg of
alteplase with an initial bolus of 10 mg given over 90 min,
was studied in patients with acute MI of < 6 h duration [19].
This was the first report of using front-loaded or accelerated
alteplase. At the end of the infusion, patency of the infarct-
related artery (TIMI grade II or III) was restored in 69.4% of
alteplase-treated patients [19].
The patency rates with alteplase were further improved by
increasing the front loading and the dose. This front-loading/
accelerated regimen consisted of 100 mg of alteplase with an
initial bolus dose of 15 mg followed by an infusion of 50 mg
over 30 min and 35 mg over 60 min [20]. Coronary angiogra-
phy 90 min after the start of treatment showed a patent inf-
arct-related artery (TIMI grade II or III) in 84.4% of 199
patients given this regimen of alteplase [20].
TIMI 4 compared front-loaded alteplase, anistreplase (a
streptokinase-plasminogen complex) and the two in com-
bination. The trial demonstrated higher rates of reper-
fusion and trends towards overall clinical benefit and
survival with front-loading. This has consequently become
the standard way of delivering alteplase. The 382 patients
with acute MI were treated with alteplase (15 mg bolus, a
0.75 mg/kg infusion over 30 min to a maximum of 50 mg,
followed by 0.50 mg/kg over 60 min up to a maximum of
35 mg), anistreplase or the two in combination [21]. Pat-
ency (TIMI grade II or III flow) at 60 min was higher in
front-loaded alteplase (78%) than anistreplase (60%) or
combination treated patients (59%) [21]. Most importantly,
the mortality rate at 6 weeks was lower in the alteplase
(2.2%) than anistreplase (8.8%) or combination treated
(7.2%) [21]. Thus, more rapid reperfusion of the infarct-
related artery is associated with improved clinical outcome.
The benefits of this regiment of front-loading were con-
firmed in GUSTO [13].
A pilot study has investigated the effects of a higher initial
bolus and a shorter infusion of alteplase and shown similar
patency rates as with the lower front-loading dose of
alteplase. The regimen was 20 mg alteplase bolus followed
by 80 mg iv. infusion over 60 min. This was compared to
streptokinase and 70 or 100 mg alteplase over 90 min [22]. In
the pilot study, TIMI grade 3 was achieved in 85% of
patients in 90 min with the new regimen of alteplase, which
compares favourably to the other treatments; 50% streptoki-
nase, 60% 70 mg alteplase and 70% 100 mg alteplase [22].
There was no excessive bleeding with this new regimen [22].
The authors suggested that this new regimen should be
tested in a large trial.
Accelerated infusion of alteplase over 90 min induces
more rapid lysis of coronary artery thrombi than a 3 h
infusion. The Continuous Infusion versus Double-Bolus
2016 Expert Opin. Investig. Drugs (2001) 10(11)
Administration of Alteplase (COBALT) investigated
whether further shortening of the administration of
alteplase was beneficial and showed that this was not the
case. COBALT enrolled 7169 patients with acute MI to
weight-adjusted, accelerated infusion of 100 mg alteplase
or to a bolus of 50 mg of alteplase over 1 - 3 min, followed
30 min later by a second bolus of 50 mg (or 40 mg for
patients who weighed < 60 kg) [23]. The trial was ended
prematurely due to concern about the safety of the double-
bolus injection [23]. Thus, the 30-day mortality was higher
in the double-bolus group (7.98%) when compared with
7.53% in the accelerated-infusion group [23]. The rates of
any stroke (1.92%), in particular haemorrhagic stroke
(1.12%), were higher, but not significantly so, in the dou-
ble-bolus when compared with the accelerated-infusion
group (1.52% any stroke, 0.81% haemorrhagic stroke) [23].
In the Double-Bolus Lysis Efficacy trial, front-loading and
double-bolus alteplase were compared and shown to cause
comparable reperfusion, but mortality was greater with dou-
ble-bolus alteplase [24]. The 461 patients with acute MI
received 100 mg alteplase either as front-loading (15 mg bolus
followed by 50 mg over a 30 min period, followed by 35 mg
over a 60 min period) or double-bolus (two 50 mg bolus
injections 30 min apart) [24]. The patency was similar with
both regimens at 90 min and 24 h [24]. The in-hospital mor-
tality was 1.3% with front-loading and 4.5% with double-
bolus alteplase [24]. Similar rates were observed for 30-day
mortality, but were not significant [24].
Some studies have indicated that alteplase is equivalent to
streptokinase (GISSI-2 and the International Study Group),
whereas GUSTO demonstrated that alteplase was superior.
The reason for this difference is probably due to the dosing.
In the studies where alteplase was shown to be equivalent to
streptokinase, a 3 h infusion was used, whereas in GUSTO
accelerated alteplase was used.
5.Thrombolysis versus primary angioplasty/
stenting in MI
After the completion of large, randomised placebo-control-
led trials of thrombolytic therapy (including alteplase),
reperfusion therapy for acute MI became the norm. How-
ever, this treatment has drawbacks, including failure to
achieve arterial patency in about 20% of patients, serious
bleeding complications and an increased incidence of recur-
rent ischaemia. Percutaneous transluminal coronary angi-
oplasty or stenting is associated with 90% patency and low
rates of serious bleeding, recurrent ischaemia and death.
Thus, angioplasty or stenting may be equivalent or better
treatments for acute MI than thrombolysis. This has been
tested in several trials.
5.1 Primary Angioplasty in Myocardial Infarction
(PAMI)
The PAMI trial compared treatment of acute MI with either

alteplase or primary percutaneous transluminal coronary angi-
oplasty and indicated that better outcomes were achieved with
angioplasty. The 395 enrolled patients presented within 12 h of
the onset of MI were treated with heparin and aspirin before
being randomly assigned to percutaneous transluminal coro-
nary angioplasty or alteplase, 100 mg over 3 h [25]. The in-hos-
pital mortality rates were lower (p = 0.06) with angioplasty
(2.6%) than alteplase (6.5%) [25]. Re-infarction or death in the
hospital was also lower with angioplasty (5.1%) than alteplase
(12%) [25]. There was no intracranial bleeding with angioplasty
but this occurred with 2% of alteplase patients [25]. Left ven-
tricular ejection fractions at rest and during exercise were simi-
lar after angioplasty and alteplase [25]. After 6 months, re-
infarction or death had occurred in fewer patients treated with
angioplasty (8.5%) than alteplase (16.8%) [25].
Recurrent ischaemia occurred in 28% of patients after treat-
ment with alteplase but only in 10.3% of angioplasty patients
[26]. The incidence of recurrent ischaemia was similar within the
first 2 days of admission (14.5% alteplase, 9.2% angioplasty),
however, after 2 days hospital treatment ischaemia was greater
in alteplase (13.5%) than angioplasty patients (1.1%). [26]. This
recurrent ischaemia translated into higher rates of death or re-
infarction (7.5% alteplase, 3.1% angioplasty), catheterisation
and revascularisation procedures and prolonged hospital stay
after alteplase [26]. The development of recurrent ischaemia
after reperfusion of the infarct-related vessel in acute MI con-
tributes to increased patient morbidity, resource utilisation,
length of hospital stay and costs. The lower incidence of recur-
rent ischaemia after 2 days in patients with angiography when
compared to alteplase should facilitate early discharge without
expensive pre-discharge angiography or exercise testing.
The 395 patients were subsequently divided into those
with anterior wall (138) and non-anterior wall acute MI
(257) and angioplasty was shown to have benefits over
alteplase in both [27]. Thus, in patients with anterior wall
MI, in-hospital mortality was lower with angioplasty (1.4%)
than alteplase (11.9%) [27]. Also, in anterior wall MI, angi-
oplasty reduced rates of death or re-infarction (1.4% angi-
oplasty, 18.0% alteplase), recurrent myocardial ischaemia
(11.3% angioplasty, 28.4% alteplase) and stroke (0.0%
angioplasty, 6.0% alteplase) [27]. In patients with non-ante-
rior wall MI, the in-hospital mortality rates were similar
with alteplase and angioplasty [27]. However, the angioplasty
non-anterior wall MI patients had lower rates of recurrent
myocardial ischaemia (9.7% angioplasty, 27.8% alteplase),
fewer unscheduled catherisation and revascularisation proce-
dures and a shorter hospital stay [27].
The PAMI trial also suggested that patients with conditions
formerly contraindicating thrombolytic therapy might benefit
from preferential treatment with angioplasty without anteced-
ent thrombolysis [28]. In PAMI, conditions were present in
151 patients, which formerly would have contraindicated
thrombolytic therapy (age > 70 years, symptom duration
> 4 h, or prior bypass surgery) [28]. The in-hospital mortality
was similar in lytic eligible patients with alteplase and angi-
Expert Opin. Investig. Drugs (2001) 10(11)
Doggrell
oplasty [28]. In contrast, in patients with former thrombolytic
contraindications, angioplasty was superior to alteplase in
both in-hospital mortality (2.9% angioplasty, 13.2%
alteplase) and 6-month mortality (2.9% angioplasty, 15.7%
alteplase) [28]. These beneficial effects of angioplasty over
alteplase were maintained at 2 years [29]. Thus, the combined
end point of death or re-infarction was 14.9% for angioplasty
and 23.0% for alteplase [29]. Angioplasty treated patients also
suffered less recurrent ischaemia (36.4%; 48.0%, alteplase),
lower re-intervention rates (27.2%; 46.5%, alteplase) and
reduced hospital re-admission rates (58.5%; 69.0%, alteplase)
[29].
Although PAMI provides convincing evidence that angi-
oplasty is more effective than alteplase for the treatment of
acute MI, this result is only proven for the dose of alteplase
tested, which was 100 mg over 3 h.
5.2 Global Use of Strategies to Open Occluded
Coronary Arteries in Acute Coronary Syndromes
(GUSTO IIB)
The PAMI study demonstrated that angioplasty is superior to
alteplase (100 mg over 3 h) in the treatment of acute MI, and
front-loaded/accelerated alteplase is superior to other alteplase
regimens in thrombolysis. However, studies in acute MI have
shown that front-loaded/accelerated alteplase is superior to
other alteplase regimens in thrombolysis. Therefore, front-
loaded alteplase may reduce the difference in outcomes
between lysis and angioplasty. GUSTO IIB, which used front-
loading, showed only short-term benefit of angioplasty over
alteplase. The 1138 patients who presented within 12 h of
acute MI (with ST-segment elevation) were randomised to
angioplasty or accelerated thrombolytic therapy with alteplase
[30]. The accelerated dose was the standard 15 mg bolus, fol-
lowed by 0.75 mg/kg up to 50 mg over 30 min and 0.50 mg/
kg up to 35 mg over 60 min, with a maximum total dose of
100 mg [30]. The primary composite end point of death, non
fatal re-infarction and non-fatal disabling stroke at 30 days
was lower with angioplasty (9.6%) than with alteplase
(13.7%) [30]. However, at 6 months, there was no difference
in this primary outcome between angioplasty (13.3%) and
alteplase (15.7%) [30]. Angioplasty was associated with more
(40.3%) bleeding events than alteplase (34.2%), with the
exception of stroke (angioplasty, 1.1%; alteplase, 1.9%) [30].
Advancing age is a risk factor for adverse outcome in acute
MI patients. In GUSTO IIB, for every 10 year patient group,
outcome was improved to a greater extent with angioplasty
than with alteplase [31].
5.3 High risk inferior acute MI
Angioplasty is greatly superior to alteplase in the treatment of
high risk MI. High risk inferior acute MI was defined as hav-
ing ST-segment elevation in the inferior leads and ST-segment
depression in the precordial leads. In high risk MI, primary
angioplasty proved a superior treatment to alteplase. The 110
patients were randomly assigned, within 6 h of symptoms, to
2017
Alteplase: descendancy in myocardial infarction, ascendancy in stroke
accelerated-dose alteplase or angiography [32]. With these
small patient numbers, the lower rate of in-hospital mortality
and re-infarction of 3.6% with angioplasty was not signifi-
cantly different than the 9.1% with alteplase [32]. However,
the angina recurrence rate was lower with angioplasty (1.8%)
than alteplase (20%), as was the rate of repeat target vessel
revascularisation (3.6%, angioplasty; 29.1%, alteplase) [32].
Left ventricular ejection fraction was higher at discharge with
angioplasty (55.2%) than alteplase (48.2%) [32]. There were
no haemorrhagic strokes, no emergency coronary artery
bypass graft and identical need for blood transfusions in both
groups [32]. After one year, the incidence of death, re-infarc-
tion and revascularisation was lower in the angioplasty (11%)
than alteplase group (53%) [32].
5.4 Anterior MI
The size of the areas at risk of an occluded coronary artery is
an important determinant of outcome in patients with acute
MI. Patients with anterior acute MI have worse immediate
and long-term prognosis than patients with non-anterior
acute MI, who normally have smaller areas at risk. Patients
with large areas at risk benefit more from reperfusion of the
infarct-related artery, whereas the benefit of thrombolysis in
patients with small areas at risk is usually modest. If primary
angioplasty yields a more complete restoration of blood flow
through the infarct-related artery than does systemic throm-
bolysis, the benefit from angioplasty should be more striking
in patients with anterior acute MI.
Primary angioplasty was found to be superior to alteplase
in anterior MI. Patients (n = 220) with anterior acute MI
were randomised to angioplasty or alteplase (15 mg bolus,
0.75 mg/kg over 30 min to maximum of 50 mg and
0.50 mg/kg over 60 min to a maximum of 60 mg) within 5 h
of symptoms [33]. This study confirmed there was lower in-
hospital mortality with angioplasty (2.8%) than alteplase
(10.8%) [33]. During hospitalisation, the frequency of post-
infarction angina or a positive stress test was less with angi-
oplasty (11.9%) than alteplase (25.2%), as was the frequency
of revascularisation (22.0%, angioplasty; 47.7%, alteplase)
[33]. At 6 months these benefits of angioplasty over alteplase
remained for death (4.6%, angioplasty; 11.7%, alteplase) and
revascularisation (31.2%, angioplasty; 55.9%, alteplase) [33].
5.5 Stenting versus thrombolysis for occluded
coronary arteries in patients with acute MI
Coronary stenting is becoming increasingly important in
the treatment of patients with acute MI. Stenting with a
GP IIb/IIIa antagonist (abciximab) is superior to front-
loaded alteplase in acute MI. In the 71 patients who
received stenting with abciximab, the size of the final inf-
arct (14.3% of left ventricle) was smaller than in the 69
who received alteplase (19.4%) [34]. The incidence of the
composite of death, re-infarction or stroke at 6 months was
also lower in the stenting with abciximab (8.5%) than
alteplase patients (23.2%) [34].
2018 Expert Opin. Investig. Drugs (2001) 10(11)
5.6 Stenting versus Thrombolysis in Acute Myocardial
Infarction Trial (STAT)
When compared to alteplase, primary stenting reduces death,
re-infarction, stroke and revascularisation. In this trial, 123
acute MI patients were assigned to stenting or alteplase [35].
The primary end point composite of death, re-infarction,
stroke or repeat target vessel revascularisation for ischaemia at
6 months was lower with stenting (24.2%) than alteplase
(55.7%) [35]. The occurrence of death and stroke were not dif-
ferent, however, re-infarction was lower (but not significantly)
with stenting (6.5%) than alteplase (16.4%) [35]. The main
differences observed with stenting were reductions in recur-
rent stable ischaemia (9.7%, stenting; 26.2%, alteplase) and
repeat revascularisation (14.5%, stenting; 49.2%, alteplase)
[35]. The mean length of initial hospitalisation was 4 days with
stenting and 7 days with alteplase [35].
5.7 Infarctartery occlusion
Re-occlusion of the infarct artery during treatment of MI is
an unwanted effect that occurs more often with thrombolysis
than with angiography or stenting. Thus, meta-analysis shows
that following thrombolysis, re-occlusion occurs in about
16% of the initially occluded arteries [36], whereas the inci-
dence of re-occlusion in studies with angioplasty ranges from
5 - 17% and with stenting from 0 - 6% [37].
6. Thrombolysis and angioplasty in MI
6.1 Thrombolysis in Myocardial Infarction (TIMI)
Phase II
In alteplase-treated acute MI patients, the outcome is similar
regardless of whether patients are invasively managed with
angioplasty or a conservative strategy is taken using angi-
oplasty only when spontaneously or exercise-induced ischae-
mia is present. In TIMI II, 3262 patients were treated with
alteplase within 4 h of the onset of chest pain considered to
be acute MI [40]. In the first 520 patients, the dose of
alteplase was 150 mg administered over 6 h (90 mg in the
first hour, including a 9 mg bolus, 20 mg in second hour and
10 mg in each of the next 4 h) [38]. Due to an unacceptably
high rate of intracranial haemorrhage, the dose was reduced
to 100 mg in the next 2742 patients (6 mg bolus, plus 54 mg
in the first hour, 20 mg in the second hour and 5 mg in each
of the next 4 h) [38]. Subsequently, 1636 patients underwent
coronary arteriography 18 - 48 h later, with angioplasty if
suitable [38]. Other patients underwent a more conservative
strategy in which arteriography and angioplasty were per-
formed only in patients with spontaneous or exercise-
induced ischaemia [38]. Angioplasty was performed in 56.7%
of the 1636 patients and 13.3% of the conservatively man-
aged patients [38]. The primary end points of re-infarction or
death occurred in similar percentages of patients in both
groups [38]. Intracranial haemorrhage was observed in 0.5%
of patients who received 100 mg alteplase and 1.3% of
patients who received 150 mg alteplase [38].

6.2 Plasminogen-activator Angioplasty Compatibility
Trial (PACT)
The use of a reduced dose of alteplase to increase coronary
artery patency prior to angioplasty facilitates preservation of
greater left ventricle function. Following aspirin and heparin,
606 patients were randomised to a 50 mg bolus of alteplase or
placebo, followed by immediate angiography with angioplasty
if needed [39]. Patency on catheterisation laboratory arrival
was 61% with alteplase and 34% with placebo [39]. No differ-
ences were observed in stroke or major bleeding [39]. Conva-
lescent left ventricle ejection fraction was highest with a
patent infarct-related artery on catheterisation laboratory
arrival (TIMI-III) or when produced by angioplasty within
1 h of bolus [39]. Thus, alteplase and angioplasty can be used
together, this may be appropriate when angioplasty or stent-
ing is planned but cannot occur rapidly.
7. Stroke
Ischaemic stroke affects 750,000 people annually in the USA.
It is the third most common cause of death and hospitalisa-
tion. Cerebral angiography has demonstrated arterial occlu-
sion in 80% of acute infarctions. The rationale for using
thrombolysis in stroke is similar to that in MI, in that restor-
ing blood flow should reduce the ischaemia and limit the tis-
sue damage which, in the case of stroke, is neurologic
disability. Since intracerebral haemorrhage was a major com-
plication reported in early trials of thrombolytic therapy in
stroke, the use of alteplase required careful evaluation of both
risks and benefits.
7.1 Intravenous alteplase
7.1.1 Pilot studies
Pilot studies indicated that although systemic alteplase was not
without risk in stroke, it does have potential for benefit. Follow-
ing neurological evaluation and computed tomography (CT),
74 patients with acute ischaemic stroke were treated with
alteplase (0.35 - 1.08 mg/kg) in an open-label, dose-escalation
design within 90 min of onset of symptoms [40]. Intracranial
haematoma occurred in three patients and was related to the
increasing dose of alteplase [40]. Intracranial haematoma did not
occur in any of the 58 patients treated with ≤ 0.85 mg/kg [40].
Major neurological improvement (defined as an improvement
of ≥ 4 points on the National Institute of Health Stroke Scale,
NIHSS) occurred in 30% of patients at 2 h after alteplase initi-
ation and 46% of patients at 24 h [40]. Neurological improve-
ment was not related to increasing the dose of alteplase or to
stroke type [40].
A second open-label pilot investigated whether the entry
window might be safely lengthened to include 91 - 180 min
and tested three doses (0.6 - 0.95 mg/kg) of alteplase in 20
patients [41]. Two patients with doses of 0.85 and 0.95 mg/kg
alteplase died of intracerebral haemorrhage [41]. Minor extrac-
ranial bleeding (e.g., from the gums) was observed in one-
third of patients and occurred even with the lowest dose of
Expert Opin. Investig. Drugs (2001) 10(11)
Doggrell
alteplase [41]. Three patients improved by ≥ 4 points on the
NIHSS scale within 24 h [41].
The TPA Bridging Study Group was a pilot study for
NINDS (discussed in section 7.3) and demonstrated that it
was possible to use alteplase early in stroke, with potential
improvement. This double-blind study enrolled 27 patients
within 180 min of stroke onset to 0.85 mg/kg alteplase or
placebo over 1 h [42]. Out of 10 patients, the 6 treated with
alteplase within 90 min improved by 4 or more points on
the NIHSS scale within 24 h, compared to 1 of 10 patients
in the placebo group [42]. Two of 4 patients treated with
alteplase after 90 - 180 min showed improvement, as did 2
of 3 placebo from this group [42]. However, in this small
group, the benefits of alteplase were no longer clinically
apparent after 7 - 10 days [42]. One fatal intracerebral haem-
orrhage occurred in the placebo group [42].
7.2 Large intravenous trials
7.2.1 European Co-operative Acute Stroke Study
(ECASS) I and II
Intravenous alteplase may be beneficial to stroke patients with
moderate - to - severe neurologic deficit and without extended
infarcts. In ECASS, 620 stroke patients were randomised to
alteplase (1.1 mg/kg) or placebo [43]. The patients enrolled
had stable moderate - to - severe hemispheric stroke syn-
drome, defined as moderate to high grade hemiparesis (mus-
cle paralysis on one side), sensory disturbance, dysarthia
(imperfect speech articulation) or non-fluent aphasia
(impaired language expression) and occasional hemianopia
(defective vision in half of the visual field) [43]. Patients also
had no major or minor early infarct signs on the initial CT
scan and could be treated within 6 h [43]. Patients with the
most severe hemispheric stroke syndrome were excluded [43].
Of the 620 patients, 109 patients were included despite major
protocol violations (mainly extended early infarct signs) and
these patients were excluded from the target population analy-
sis [43]. Intention-to-treat analysis showed that alteplase did
not alter the primary end point of the Barthel Index and mod-
ified Rankin Scale after 90 days [43]. However, in the target
population, alteplase improved the Rankin Scale [43]. In both
analyses, alteplase improved the secondary end point, which
was a combination of Barthel Index, Rankin Scale, Scandina-
vian Stroke Scale at 90 days and 30-day mortality [43].
Alteplase also improved the NIHSS at 24 h and 90 days.
Alteplase improved neurologic recovery at 90 days in the tar-
get population and shortened in-hospital stay [43]. At 90 days,
mortality was greater with alteplase (22.4%) than placebo
(15.8%) [43]. However, in the target population, the 90-day
mortality was not significantly different between alteplase
(19.4%) and placebo (14.8%) [43]. Alteplase did not increase
the total number of intracerebral haemorrhages significantly,
but did increase the frequency of the serious type of haemor-
rhage that caused mass effect (parenchymal haemorrhage) [43].
Thus, in order to get a beneficial effect with alteplase in stroke
there may have to be a careful selection of patients.
2019
Alteplase: descendancy in myocardial infarction, ascendancy in stroke
In ECASS, 450 patients had a CT scan on day 1 and
day 7. These showed that the lesion volumes were greater at
day 7 than at day 1 and that alteplase did not alter the
lesion volumes [44].
The hyperdense middle cerebral artery sign (HMCAS),
seen on CT scans, is a marker of thrombus in the middle cere-
bral artery. HMCAS is a common finding when a CT scan is
performed within a few hours of the onset of stroke symp-
toms. HMCAS has been associated with severe neurological
deficit, extensive brain damage and poor clinical outcome.
This marker was present in 107 of the ECASS patients. In
these patients the initial deficit was more severe and the risk of
poor functional outcome was greater than in patients without
the HMCAS marker [45]. Patients with the marker who were
given alteplase had better neurological recovery than patients
receiving placebo [45].
A secondary analysis of ECASS included 87 patients ran-
domised to treatment within 3 h of the onset of symptoms,
which was the therapeutic window under the NINDS protocol
(trial discussed below). As the sample size was small, most of
the differences between alteplase and placebo were not signifi-
cant. However, there was a tendency for alteplase to improve
the primary end points of the modified Rankin Scale and the
Barthel Index and the secondary end points of combined Bar-
thel/Rankin, long-term Scandinavian Stroke Scale and the
NIHSS [46]. Mortality at 90 days was higher and parenchymal
haemorrhage occurred more often with alteplase [46].
Following the NINDS trial, which gave more positive
results for alteplase in stroke, ECASS was retrospectively ana-
lysed using the NINDS trial statistical methodology (global
end point analysis). Using this analysis, there was a favourable
outcome of 8% in the modified Rankin scale, 14% for the
NIHSS and a non-significant 6% for the Barthel index [47].
Alteplase also improved the global end point [47].
ECASS II enrolled 800 patients to a slightly lower dose of
alteplase (0.9 mg/kg) or placebo, within 6 h of symptom
onset. Very little benefit was observed with this lower dose
[48]. A CT scan was used to exclude patients with signs of
major infarction [48]. Favourable modified Rankin scale out-
comes at 90 days were observed in similar percentages of
alteplase (40.3%) and placebo (36.6%) patients [48]. When
modified Rankin scores were dichotomised for death or
dependency, more alteplase (54.3%) than placebo (46.0%)
patients had favourable outcomes [48]. The results were similar
whether treatment was 0 - 3 or 3 - 6 h [52]. Similar percentages
of alteplase and placebo patients died [48]. Symptomatic
intracranial haemorrhage occurred in more alteplase (8.8%)
than placebo patients (3.4%) [48].
7.2.3 The National Institute of Neurological Disorders
and Stroke (NINDS) and follow-up trials
NINDS demonstrated that alteplase, given early after the
onset of symptoms, was beneficial in ischaemic stroke but did
increase the incidence of symptomatic intracerebral haemor-
rhage. To be eligible, patients had to have suffered an ischae-
2020 Expert Opin. Investig. Drugs (2001) 10(11)
mic stroke with a clearly defined time of onset, a deficit
measurable on the NIHSS and baseline CT scan of the brain
that showed no evidence of intracranial haemorrhage [49]. Part
1 of the study (291 patients) tested the clinical activity of
alteplase (0.9 mg/kg to a maximum of 90 mg with 10% given
as a bolus and 90% as a constant infusion over 60 min)
administered within 3 h of the onset of stroke [49]. This test-
ing used as its end point an improvement of 4 points on the
NIHSS scale or the resolution of the neurologic deficit within
24 h of the onset of stroke [49]. Alteplase had no effect within
24 h but at 3 months had improved all four outcome scales,
compared to placebo [49]. In part 2 of the study (333 patients),
a global test statistic was used to assess clinical outcome at
3 months [49]. This global test was scored on the Barthel
index, modified Rankin scale, Glasgow outcome scale and
NIHSS [49]. Patients treated with alteplase were at least 30%
more likely to have minimal or no disability at 3 months on
the assessments scales, compared to placebo [49]. Symptomatic
intracerebral haemorrhage within 36 h after the onset of
stroke occurred in 6.4% of patients given alteplase but only
0.6% of placebo patients [49]. Mortality at 3 months was 17%
in the alteplase and 21% in the placebo group [49]. Following
the NINDS trial, the FDA approved alteplase treatment for
acute ischaemic stroke within 3 h.
In NINDS, all stroke subgroups showed a similar favoura-
ble response to alteplase and therefore this sub-selection of
patients is not required. Post-hoc analysis of NINDS showed
that although outcome was related to age-by-deficit severity
interaction, diabetes, age-by-blood pressure interaction and
early CT finding, this did not alter the likelihood of a favour-
able response to alteplase [50].
Some of the patients in NINDS underwent single-photon
emission computed tomography (SPECT), which indicated
that a substantial defect exists in stroke patients with larger
hemispheric infarcts who meet NINDS criteria [51]. At 24 h,
reperfusion was greater in alteplase patients than the placebo
group, with relative improvement in the region-of-interest
scores of 87% with alteplase and 28% with placebo [51].
The follow-up of the NINDS trial showed that at
12 months, alteplase treated patients were still 30% more
likely to have minimal or no disability than placebo
patients [52]. Mortality rates were similar in the alteplase
(24%) and placebo (28%) patients as were the rates of
recurrent stroke [52].
Further analysis of the NINDS trial has been undertaken
to identify if there is any difference between the patients
who had alteplase treatment 0 - 90 min and 91 - 180 min
after onset of symptoms. The results demonstrate that earlier
treatment is better. Thus, patients treated 0 - 90 min from
stroke onset with alteplase have increased odds of improve-
ment at 24 h and favourable 3-month outcome, compared
to patients treated later than 90 min [53]. There was no effect
of onset-to-treatment time on intracranial haemorrhage,
possibly due to the small number of intracerebral haemor-
rhage occurring in NINDS [53].

Following the favourable outcome of the NINDS trial,
the next challenge was to implement the protocol, particu-
larly the time constraint and then to assess the outcome
widely. In Cologne, 453 consecutive patients with a pre-
sumed diagnosis of acute stroke were referred to the Uni-
versity Hospital and 100 patients were treated with
alteplase [54]. Only 26 patients were treated within 90 min
of the onset of stroke symptoms [54]. After 3 months, 53
patients recovered to fully independent function [54]. The
rates of total, symptomatic and fatal intracerebral haemor-
rhage were 11%, 5% and 1%, respectively [54], this was
comparable to NINDS. An extension of this study showed
that after one year, 41% of the Cologne patients showed
minimal or no disability, which was the same percentage as
in the NINDS trial [55].
Implementation in US hospitals, with experienced acute
stroke treatment systems, highlighted the importance of
adhering to the NINDS protocol. In one study, deviations
from the NINDS protocol guidelines were identified in 56
of 189 patients (30%), although only 8% were beyond the
3 h window [56]. The incidence of symptomatic intracere-
bral haemorrhage was 11% among patients with protocols,
compared with 4% in patients who were treated according
to the guidelines [56].
The STARS (Standard Treatment with Alteplase to
Reverse Stroke) trial was set up according to the NINDS
protocol after the FDA approved alteplase for the treatment
of stroke. The STARS trial demonstrated that a favourable
outcome and low rates of intracerebral haemorrhage could
be achieved at multiple centres across the USA. The study
monitored consecutive patients enrolled at 24 academic and
33 community medical centres, without a control group
[57]. The median time from stroke onset to alteplase treat-
ment was 2 h 44 min for the 389 patients [57]. The 30-day
mortality rate was 13% [61]. Thirty days after treatment,
35% of patients had very favourable outcomes (modified
Rankin score, 0 - 1) and 43% were functionally independ-
ent (modified Rankin score, 0 - 2) [57]. Thirteen patients
(3.3%) experienced symptomatic intracerebral haemor-
rhage after 3 days and seven died [57]. This is an important
finding, as it is lower than the 6.4% occurrence in NINDS.
A further 28 patients suffered asymptomatic intracerebral
haemorrhage within 3 days of alteplase treatment [57]. Pro-
tocol violations were reported for 127 (33%) patients,
including treatment with alteplase more than 3 h after
symptom onset and treatment with anti-coagulants within
24 h of alteplase [57].
The implementation of the NINDS protocol has been
less successful in Cleveland [58]. Only 70 (1.8%) of 3948
patients admitted to hospital with ischaemic stroke from
July 1997 through June 1998 received iv. alteplase [58]. Of
these, 11 patients had a symptomatic intracerebral haemor-
rhage, with 6 being fatal [58]. Half of the patients treated
had deviations from the NINDS protocol [58].
Expert Opin. Investig. Drugs (2001) 10(11)
Doggrell
7.2.4 Alteplase Thrombolysis for Acute Non-
interventional Therapy in Ischaemic Stroke
(ATLANTIS)
The 3 h limit after the onset of symptoms greatly restricts the
use of alteplase in stroke. Most stroke patients present more
than 3 h after symptoms. At the time of the ATLANTIS trial,
this was reflected in the finding that, since approval, < 5% of
US stroke patients receive alteplase. When alteplase was
administered within 3 - 5 h of acute ischaemic stroke, there
was no benefit, however there was an increased risk of serious
bleeding. The 547 patients received either alteplase (0.9 mg/
kg) or placebo iv. over 1 h [59]. Excellent neurologic recovery
at day 90, measured on the NIHSS, was similar in the
alteplase (34%) and placebo group (32%) [59]. There were no
differences between alteplase and placebo, at days 30 and 90,
on the Barthel index, modified Rankin scale and Glasgow
Outcome [59]. In the first 10 days, the rate of symptomatic
intracerebral haemorrhage was greater with alteplase (7.0%)
than placebo (1.1%), as was the rate of asymptomatic intrac-
erebral haemorrhage (alteplase, 11.4%; placebo, 4.7%) and
fatal intracerebral haemorrhage (alteplase 3.0%; placebo,
0.3%) [59]. Mortality at 90 days was higher but not signifi-
cantly, with alteplase (11.0%) when compared to placebo
(6.9%). Further studies may be required to determine
whether there are any subgroups that may benefit for alteplase
after 3 h.
The ATLANTIS study was part B of a study that was origi-
nally designed to test the safety and efficacy of alteplase
between 0 - 6 h. The original trial, which became part A, was
halted by the Safety Committee, who had concerns about
treating patients with alteplase after 5 - 6 h, however. this has
recently been reported [60]. Excluding time-to-treatment,
enrolment criteria was similar to the NINDS alteplase stroke
trial [60]. The 142 patients enrolled in this study showed no
improvement with alteplase. This largely represents no
improvement after 3 - 6 h as this is when the majority of the
patients were enrolled [60]. There did seem to be an initial
improvement, at 24 h more alteplase patients (40%) than pla-
cebo patients (21%) had a 4-point improvement on the
NIHSS [60]. However, after 30 days more placebo (75%) than
alteplase (60%) patients showed the 4-point improvement [60].
Treatment with alteplase also increased the rate of intracerebral
haemorrhage within 10 days (11% alteplase, 0% placebo) and
mortality at 90 days (23% alteplase, 7% placebo) [60].
7.3 Pilot studies with local alteplase
In a pilot study with local alteplase, the 10 patients enrolled,
who had no apparent hypodensity areas on a CT scan, could
be treated within 6 h and the occluded arteries were verified
by cerebral angiography [61]. Local administration of alteplase
(maximum dose 32 mg) re-canalised the carotid arteries of all
10 patients with blocked arteries and this was associated with
improvement in the NIHSS in some patients [61]. However,
haemorrhage transformation (defined as haemorrhage lesion
2021
Alteplase: descendancy in myocardial infarction, ascendancy in stroke
with or without extensive brain oedema) occurred in three of
the patients [61], indicating that this is a risky procedure.
More recently, intra-arterial (ia.) alteplase tested in stroke
patients who were considered to be poor candidates for iv.
therapy has been shown to be safe. The eight patients were
considered to be poor candidates for iv. alteplase, due to the
severity of their stroke (NIHSS > 18) and/or because they
presented at the emergency room more than 3 h after the
onset of stroke symptoms [62]. A maximum total dose of
40 mg of alteplase was given intra-arterially via superselec-
tive catheterisation [62]. Neurological improvement (a
decrease in the NIHSS score ≥ 2) occurred in four patients
[62]. There was a dose-related improvement in perfusion
grade and decrease in thrombus grade with alteplase [62].
Asymptomatic intraparenchymal haemorrhage was observed
on CT scans in two patients at 24 h [62]. Intra-arterial
alteplase should now be tested further in patients who are
poor candidates for iv. alteplase.
7.4 Combination intra-arterial and intravenous
alteplase
Intra-arterial administration offers the advantage of direct
drug delivery to the occlusion site with possible higher reca-
nalisation rates. However, the disadvantages of ia. are that it
requires interventional techniques, is time-consuming and
restricted to a few centers. Intravenous administration leads to
drug dilution and may require higher dosages, thereby
increasing the risk of systemic adverse effects but allowing for
more widespread and rapid use.
7.4.1 Emergency Management of Stroke (EMS)
Bridging Trial
This pilot study enrolled 35 patients within 3 h of the onset
of stroke, who were randomised to iv. alteplase or placebo, fol-
lowed by local ia. alteplase [63]. The iv. dose of alteplase was
0.6 mg/kg to a maximum of 60 mg with 10% as a bolus over
1 min followed by a controlled 30 min infusion of the
remaining dose [63]. For ia., 1 mg of alteplase was infected
beyond the thrombus, 1 mg into the thrombus, followed by
an infusion of 10 mg/h to a maximum of 20 mg [63]. Repeat
arteriography was performed at 15 min intervals and if the
vessel was not patent, infusion was continued [63]. There were
two deaths with the combined but none with the local ia.
alteplase [63]. Clots were found in 22 of 34 patients and reca-
nalisation was better in the combined (6 of 11) than placebo/
local ia. alteplase treatment (1 of 10) [63]. Life-threatening
bleeding occurred in two of the combination patients and
moderate - to - severe bleeding occurred in two combination
and one placebo/local ia. alteplase treated patient [63].
7.4.2 A retrospective analysis
A further combination study demonstrated considerable
benefit and risk in patients with severe acute ischaemic
stroke. Inclusion criteria was acute ischaemic stroke in the
carotid artery distribution with a minimum NIHSS of 10
2022 Expert Opin. Investig. Drugs (2001) 10(11)
(median was 21) and planned initiation of alteplase within
3 h [64]. In this study, 20 patients were treated with iv.
alteplase (0.6 mg/kg to a maximum of 60 mg, with 15% as
bolus followed by a continuous infusion over 30 min) [64].
Sixteen of the 20 patients were also treated with ia. alteplase
(up to 0.3 mg/kg or 24 mg, whichever was less) [64]. The
median time from stroke onset to iv. alteplase was 2 h 2 min
and to ia. alteplase was 3 h 30 min. Half of the patients
recovered to a modified Rankin Scale of 0 or 1, three
patients to a score of 2 and five patients to 4 or 5 [64]. Unfor-
tunately, one patient developed a symptomatic intracerebral
haemorrhage and died and another patient died of a compli-
cation of the stroke [64]. The authors suggested that the
greater than expected proportion of favourable outcomes in
severe ischaemic stroke reflected the short time to initiation
of thrombolysis [64].
7.5 Alteplase in cerebral venous thrombosis
Cerebral venous thrombosis is an uncommon condition char-
acterised by headache, focal deficits, seizures, disorders of con-
sciousness and papilledema, which can present in isolation or
in association. A pilot study of 12 patients has suggested that
alteplase may be of use in this condition. Magnetic resonance
venography and contrast venography were used to identify the
thrombi in the superior sagittal sinus and transverse/sigmoid
sinus [65]. A micro-catheter was used to administer the
alteplase. A loading dose of alteplase was instilled throughout
the clot at 1 mg/cm, followed by continuous intra-thrombus
infusion at 1 - 2 mg/h, heparin was also given [65]. Flow was
restored completely in six patients and partially in three, with
a mean alteplase dose of 46 mg in 29 h [65]. Symptoms
improved in these nine patients concomitantly with flow res-
toration [65]. Two of the three patients in whom flow was not
restored showed haemorrhage worsening [65].
8. Acute coronary syndromes
As coronary thrombosis plays a critical role in the pathogene-
sis of acute coronary syndromes (unstable angina and non-Q
wave MI), the role of thrombolytic therapy has been investi-
gated. An early study showed some promise but subsequent
studies have failed to establish a role for alteplase in the treat-
ment of acute coronary syndromes.
8.1 Pilot
Thrombolysis improves pacing thresholds in patients with rest
angina, provided there is an intracoronary thrombus. Forty
patients with rest angina, angiographically documented coro-
nary artery disease and pacing-induced ischaemia were
assigned to alteplase (150 mg/8 h) or placebo [66]. Patients
were also receiving nitrates, a beta-adrenoceptor blocker, a cal-
cium channel blocker, aspirin and heparin [66]. The ischaemic
pacing threshold, which was unaltered by placebo, was
increased from 112 to 127 beats/min in alteplase treated
patients [66]. Intracoronary thrombi were identified in seven of

the alteplase treated patients and these patients also showed
improvement in their ischaemic pacing threshold [66].
8.2 Thrombolysis in Myocardial Ischaemia (TIMI) IIIA
trial
In patients presenting with unstable angina or non-Q wave
MI, alteplase improves culprit lesions but may be harmful.
In the TIMI IIIA trial, 306 patients with unstable angina or
non-Q wave MI received a 90 min front-loaded infusion of
alteplase (0.8 mg/kg iv.; maximum, 80 mg with 1/3 of total
dose as initial bolus) or placebo plus conventional anginal
therapy (nitrates, calcium channel blockers and beta-block-
ers) and heparinisation [67]. Substantial improvement (by ≥
20% reduction of stenosis or two TIMI grades) was seen
with alteplase in 15% of all culprit lesions compared to 5%
of lesions with placebo [67]. Greater improvement with
alteplase was observed in lesions containing apparent throm-
bus (36% alteplase, 15% placebo) and in patients evolving a
non-Q wave MI [67].
The TIMI IIIB trial extended the same dose treatment of
alteplase and placebo to 1473 patients within 24 h of ischae-
mic chest discomfort at rest, considered to represent unstable
angina or non-Q wave MI [68]. All patients were treated with
bed rest, anti-ischaemic medications, aspirin and heparin [68].
Alteplase had no effect on the primary end point of death, MI
or failure of initial therapy at 6 weeks [68]. However, fatal and
non-fatal MI (re-infarction in non-Q wave MI patients)
occurred more frequently in altplase-treated (7.4%) than pla-
cebo patients (4.9%) [68]. Also, there were four intracranial
haemorrhages (0.55%) in the alteplase compared to none in
the placebo group [68]. After 1 year there was no difference in
the incidence of fatal and non-fatal MI between the alteplase
(12.4%) and placebo groups (10.6%) [69]. There are many
possible reasons for the lack of benefit of thrombolytic ther-
apy in acute coronary syndromes in this trial. The dose of
alteplase (average 63 mg) may have been too low. However, it
is difficult to consider using a higher dose as the incidence of
intracranial haemorrhage was 0.55%. The thrombi in patients
with unstable angina are predominantly of platelets rather
than erythrocytes. Erythrocytes are more resistant than plate-
lets to lysis with alteplase. The conclusion of this study was
that alteplase should not be used routinely in patients with
unstable angina or non-Q wave MI.
8.3 Low dose alteplase
As intracoronary thrombosis is often the cause of instability in
unstable angina, protracted, low dose alteplase may be benefi-
cial in such patients. Sixty-seven patients with the same entry
criteria as the TIMI III trial (unstable angina refractory to the
standard anti-anginal therapy) were enrolled [70]. Patients with
acute MI were excluded by serial enzymatic and ECG tests
[70]. Those enrolled received either alteplase (0.03 mg/kg/h for
3 days) plus heparin to achieve an activated clotting time of
250 - 400 s, or placebo and the same dose of heparin [70]. No
major bleeding was observed in either group [70]. One
Expert Opin. Investig. Drugs (2001) 10(11)
Doggrell
alteplase and four placebo patients developed acute MI during
the hospital period [70]. Alteplase reduced the occurrence of
chest pain by seven episodes in 3 days (two episodes in pla-
cebo group) and total ischaemic burden to 46 min/day (114
min/day, placebo) [70]. After a follow-up of 14 months,
alteplase patients were more frequently angina-free and had a
lower incidence of re-admission to hospital than placebo
patients [70]. Despite the beneficial effects of thrombolysis, the
authors commented that thrombolytic therapy should not be
considered a definite solution for patients affected by unstable
angina [70]. Rather the lysis should be considered a useful tem-
porary integration of standard anti-anginal therapy and a
bridge toward the next step in the diagnosis and therapy of
these patients [70]. Indeed > 75% of the patients in the study
underwent coronary artery surgery or angioplasty during
one year of follow-up [70].
9. Pulmonary thromboembolism
Open studies have shown that alteplase can be used to cause
lysis in pulmonary embolism. This lysis is associated with
improved right ventricle wall motion and a decrease in size of
perfusion defects.
In pulmonary embolism, alteplase acts more rapidly and is
safer than urokinase in the treatment of acute pulmonary
embolism. The 45 patients enrolled had angiographically doc-
umented pulmonary embolism in a segmental or more proxi-
mal pulmonary artery [71]. Patients also had symptoms for 14
days before the onset of the trial [71]. After 2 h, 82% of patients
treated with alteplase (100 mg alteplase over 2 h, 50 mg/h)
showed clot lysis, compared with 48% of urokinase-treated
patients [71]. Improvement in lung scan reperfusion and reduc-
tion in fibrinogen was similar in both groups [71]. Major bleed-
ing was observed in eight of the urokinase but none of the
alteplase patients [71]. Another study has confirmed that
alteplase (10 mg as bolus, then 90 mg over 2 h) acted faster
than urokinase in massive pulmonary embolism [72].
A small study demonstrated that alteplase gives greater
improvement in pulmonary embolism than heparin alone but
also causes more bleeding. The 36 patients either received a
2 h infusion of alteplase (10 mg bolus, then 90 mg over 2 h)
followed by heparin or heparin alone [73]. The vascular
obstruction, assessed by the Miller index at pulmonary angi-
ography, decreased in the alteplase group from 28.3 to 24.8,
2 h after the start of the infusion but was not altered by
heparin [73]. Mean pulmonary artery pressure decreased from
30.2 to 21.2 mmHg in the alteplase group while increasing
slightly with heparin [73]. Bleeding occurred in 14 of 20
alteplase treated patients and 6 of 16 in the heparin group [73].
There were three major bleeding episodes in the alteplase
group and two in the heparin group [73]. Two patients died
after alteplase administration and one after heparin adminis-
tration [73]. Because of the high frequency of bleeding with
alteplase, patients should be carefully selected before alteplase
is given. The less critically ill patients should receive the
2023
Alteplase: descendancy in myocardial infarction, ascendancy in stroke
standard heparin therapy until newer, safer dosage regimens of
alteplase are established.
A further study comparing alteplase to heparin alone,
indicated that alteplase rapidly improves right ventricle
function and pulmonary perfusion and may lead to a lower
rate of adverse clinical outcomes. Alteplase (100 mg over
2 h) was given to 46 of the 101 patients [74]. Right ventricu-
lar wall motion at 24 h showed improvement in 39% of
alteplase and 17% of heparin alone patients and worsening
in 2% of alteplase and 17% of heparin patients [74]. Pulmo-
nary perfusion was improved 14.6% by alteplase and 1.5%
by heparin alone [74].
Studies in experimental venous thromboembolism indicate
that rapid iv. low dose alteplase causes more rapid clot lysis
and fewer bleeding complications than more prolonged infu-
sions. Bolus or 2 h infusions of alteplase gave similar results in
acute massive pulmonary embolism. The 53 patients with
acute massive pulmonary embolism (baseline Miller index ≥
17/34 and mean pulmonary pressure ≥ 20 mmHg) were given
either 0.6 mg/kg bolus injection of alteplase over 15 min with
a maximum dose of 50 mg or 100 mg alteplase over 2 h [75].
Continuous monitoring of total pulmonary resistance over 12
h demonstrated that both regimens had similar effects [75]. At
20 - 28 h, the absolute improvement was modest and similar;
14% in bolus and 13% in 2 h group [75]. Major bleeding but
no death or intracranial bleeding, occurred in one patient in
the 2 h group and three patients in the bolus group [75]. A fur-
ther comparison of the same alteplase regimens in 90 haemo-
dynamically stable patients with pulmonary embolism gave
similar results [76].
Alteplase and streptokinase have similar efficacy in massive
pulmonary embolism. Fifty patients received either alteplase
(100 mg 2 h infusion) or streptokinase, followed by heparin
[77]. Thrombolysis occurred more rapidly with alteplase than
streptokinase [77]. There was no difference with alteplase and
streptokinase in the right heart haemodynamics at 12 h or in
improvement of pulmonary vascular obstruction at 24 - 48 h
or at 10 days [77]. Additionally, there was no difference in
bleeding complications and no patients suffered intracranial
haemorrhage [77]. Alteplase still worked faster than streptoki-
nase, and the outcomes remained similar, when the infusion
of streptokinase was shortened to 2 h [78]
10. Deep vein thrombosis
Deep vein thrombosis of the lower extremity is a common
condition. It causes pain in the acute setting and may lead to
life-threatening pulmonary embolism. In rare cases it can lead
to limb-threatening ischaemia. The classical treatment of
acute deep vein thrombosis is heparin followed by oral antico-
agulants. Theoretically, thrombolysis could dissolve the clot,
however, it may also release the clots to travel to the lungs
causing pulmonary embolism. However, small trials have
shown that lysis is often incomplete with alteplase and bleed-
ing is excessive.
2024 Expert Opin. Investig. Drugs (2001) 10(11)
Of 12 patients with acute proximal deep vein thrombosis,
who received 0.5 mg/kg alteplase for 4 h, only seven showed
> 50% lysis [79]. Increasing the infusion to 8 h, did not
increase the lysis [79]. One year follow-up indicated that lysis
of > 50% was associated with a favourable outcome. Thus,
at follow-up, only 25% of patients with > 50% lysis suffered
post-phlebitic syndrome, defined as persistent (> 1 month
duration) pain, swelling of the legs and evidence of reflux on
Doppler ultrasonography [79]. In contrast, 56% of patients
with < 50% lysis had the syndrome [79]. This study did,
however, suggest that lysis with alteplase may be beneficial
and led to further trials.
In venographically-documented proximal deep vein throm-
bosis, a 0.05 mg/kg/h dose of alteplase for 24 h into a periph-
eral vein, with a maximum of 150 mg, only caused complete
or more than 50% lysis in 10 of 36 patients [80]. One of the
alteplase treated patients suffered a non-fatal intracranial
haemorrhage [80]. From this study, the authors concluded that
alternative dosing regimens and modes of administration of
alteplase should be investigated to improve efficacy and safety.
A higher dose of alteplase (0.25 and 0.5 mg/kg/24 h during
3 - 7 days) caused lysis in 32 patients with deep vein throm-
bosis but also caused excessive bleeding [80]. Both doses of
alteplase caused similar reductions in quantitative venography
of the venous thrombosis, Marder’s score (18 - 13 with the
0.25; and 17.5 - 15.5 with the 0.5 mg alteplase) [81]. Alteplase
caused some recanalisation of the initially obstructed veins
[81]. Major bleeding was observed in 7 patients with 0.25 mg
and 5 patients with 0.5 mg alteplase [81].
Local or systemic application of low dose alteplase is not
very effective in deep vein thrombosis. The 137 patients
with acute deep vein thrombosis above the calf region were
treated with 20 mg of alteplase for 4 h for 4 - 7 days [82].
The alteplase was applied either locally via a dorsal pedal
vein or systemically using a cubital (elbow) vein [82]. Heparin
was also given continuously to give an activated partial
thromboplastin time that was 1.5 - 2 times the normal value
[82]. Lysis of more than 50% of the original thrombus and
complete recanalisation of all affected veins were reached in
only one-third of all patients and were independent of site of
alteplase administration [82]. Bleeding complications
occurred in 27% of patients [82]. In the local group treat-
ment had to be discontinued 10 times and in eight cases this
was due to major haemorrhage [82]. In the systematic group,
four cases of macrohematuria led to the premature termina-
tion of treatment [82]. Unfortunately, this study does not
have a placebo. Nonetheless, it is clear cut that alteplase is
not very effective and causes unacceptable bleeding [82].
A recent review suggested that there have only been five
good trials of alteplase in deep vein thrombosis (and this
included the trials discussed above) and these do not support
routine use of alteplase for deep vein thrombosis [83]. Thus,
although alteplase was more likely than placebo to cause
> 50% lysis, it was also more likely to cause complications [83].
However, there is insufficient evidence to discard this poten-

tially effective treatment in all patients [83]. Trials are needed
to test whether patients with limb-threatening thrombosis or
a high risk of severe post-phleibitic syndrome can benefit
without excessive bleeding [83].
11. Peripheral vascular disease
Intermittent claudication, the main symptom of peripheral
arterial disease, is common in the elderly; the prevalence is
approximately 6% in 50 - 60 year old patients and 10 - 20% in
those over the age of 70. Symptoms progress in 10 - 20% of
patients, leading to amputation in 7% within five years. Moreo-
ver, intermittent claudication is often associated with general-
ised atherosclerosis (e.g., coronary and cerebral vessels), which is
responsible for a 2-fold increase in death rate, largely from MI
and stroke when compared to individuals without intermittent
claudication. Functional independence is threatened in those
with claudication due to limits on mobility. Chronic peripheral
arterial disease can lead to gangrene and limb loss, hospitalisa-
tion and surgical revascularisation.
11.1 Surgery versus Thrombolysis for Ischaemia of the
Lower Extremity (STILE)
Catheter directed thrombolysis is based on the principle that
activation of fibrin-bound plasminogen to the active enzyme
plasmin is the most effective means of lysing pathologic
thrombi. Direct delivery of a thrombolytic agent produces
increased plasmin activity at the desired location, protects
intrathombus plasmin and circulating antiplasmins and per-
mits effective thrombolysis at a reduced dose. Thrombolysis
benefits patients with acute but not chronic, limb ischaemia.
The 393 patients with worsening lower limb ischaemia
within the last 6 months, due to native arterial or bypass
graft occlusion, were treated with either surgery or catheter-
directed thrombolysis with alteplase (0.05 mg/kg/h for up to
12 h, with the dose not exceeding 100 mg) or urokinase [84].
The primary end point was a composite of death, ongoing/
recurrent ischaemia, major amputation and major morbidity
after 30 days [84]. The trial ended prematurely as surgery
was shown to have benefit over thrombolysis at this primary
end point, primarily by reducing ongoing/recurrent ischae-
mia [84]. However, patients with acute ischaemia (deteriora-
tion of 0 - 14 days) had lower amputation rates and shorter
hospital stays with thrombolysis than surgery [84]. Con-
versely, patients with chronic ischaemia (> 14 days) had less
ongoing/recurrent ischaemia and a trend towards lower
morbidity with surgery than thrombolysis [84]. Thus, the
authors suggest a combination of catheter directed throm-
bolysis for acute limb ischaemia and surgical revascularisa-
tion for chronic limb ischaemia as the best approach.
Subsequently, the results from the 273 patients with native
artery occlusions in STILE were separated and showed that
surgical revascularisation was more effective and durable
than thrombolysis [85]. Therefore, after one year the inci-
dence of recurrent ischaemia was lower with surgery (64%)
Expert Opin. Investig. Drugs (2001) 10(11)
Doggrell
than lysis (35%), as was the incidence of major amputation
(0% surgery, 10% lysis) [85].
11.2 Further studies with catheters
A further study has confirmed that catheter-delivered alteplase
is effective in clot lysis in peripheral vascular disease but may
cause bleeding. The 20 patients had suffered occlusion for 27
days and received alteplase 2 mg/kg to a maximum of 40 mg
and iv. heparin [86]. Clot lysis was achieved in 18 of 21 infu-
sions but three infusions resulted in major bleeding complica-
tions and one death [86]. As this is an unacceptably high level
of complications, a lower dose of alteplase should be tested.
Indeed, a lower dose of alteplase has proven effective in
peripheral arterial occlusions. A pilot study demonstrated sys-
temic bleeding with 10 mg but not 2.5 mg/h [87]. In this open
study of 288 patients, the mean dose of alteplase was 2.97 mg
and the time for lysis was 78 min [87]. After 2 years, there was
95% patency of embolic occlusions and 72% patency of
thrombotic occlusions [87].
Catheter delivered thrombolysis may also benefit patients
with occluded lower extremity bypass grafts. The 124 patients
in STILE with lower limb bypass graft occlusion were ran-
domised to surgery or ia. catheter-directed thrombolysis with
alteplase (0.05 mg/kg/h up to 12 h) or urokinase [88]. There
was a high rate of failed catheter placement (39%) that led to
surgical revascularisation [88]. Overall, there was an improved
composite clinical outcome (death, amputation, ongoing/
recurrent ischaemia and major morbidity) after 30 days and
after one year with surgery than with lysis, probably due to
the failed catheterisation [88]. Thus, following successful cath-
eter placement, patency was restored by lysis in 84% and 42%
of patients had a major reduction in their planned operation
[88]. Acutely ischaemic patients (0 - 14 days) randomised to
lysis demonstrated a trend toward a lower major amputation
rate at 30 days that was significant at 1 year, compared to sur-
gical patients [88]. However, in patients with > 14 days of
ischaemia, there was no difference in limb salvage between
lysis and surgery but higher ongoing/recurrent ischaemia in
lysis patients [88].
11.3 Angioplasty and alteplase
A pilot trial has suggested that a combination of angioplasty and
alteplase may be beneficial in the treatment of peripheral vascu-
lar disease. Sixteen of the enrolled patients had claudication due
to iliac or femoropopliteal artery occlusions and were given
alteplase followed by angioplasty or to angioplasty alone [89].
Primary patency rates were improved with alteplase/angioplasty
(86% at 6 months, 51% at 1 year) than with angioplasty alone
(11% at 6 months and 1 year) [89]. Obviously, a much larger
trial of this alteplase/angioplasty combination is needed.
11.4 Thrombolysis study group
Accelerated thrombolysis with high-dose bolus alteplase
may enable patients with more acute leg ischaemia to be
treated without recourse to surgery. The 93 patients with
2025
Alteplase: descendancy in myocardial infarction, ascendancy in stroke

acute leg ischaemia of < 30-day duration received either
high-dose bolus alteplase hand injected into the thrombus
(3 doses of 5 mg over 30 min, then 3.5 mg/h for up to 4 h,
then 0.5 - 1 mg/h) or conventional low dose alteplase (0.5 -
1 mg/h) [90]. The median duration of infusion was 4 h for
high-dose and 20 h for low-dose alteplase [90]. Thromboly-
sis was achieved in 45 of 49 high-dose and 39 of 44 low-
dose infusions [90]. More adjunctive procedures were
required following high-dose (26) than low-dose (16)
alteplase [90]. Thirty days after treatment commenced, limb
salvage was achieved in 39 of 49 high-dose and 37 of 44
low-dose alteplase patients [90]. Four patients in the high-
dose group and five in the low-dose group died [90]. Three
patients in each group suffered a major haemorrhage and
one in the low-dose group suffered a stroke [90].
12. Thrombosed central venous catheters
Central venous catheters have become a cornerstone of
antineoplastic therapy. Obstruction, with resulting loss of
ability to withdraw and/or infuse material, occurs in up to
25% of catheters. In 50 dysfunctional central venous
catheters, 2 mg of alteplase restored function more relia-
bly and dissolved thrombi faster than 10,000 units of
urokinase [91]. Thus, after 2 h, 13 of 22 urokinase cathe-
ters and 25 of 28 alteplase catheters had full function and
7 urokinase and 17 alteplase catheters had complete reso-
lution of thrombi [91].
13. Expert opinion
13.1 Descendancy in MI
Large well-conducted clinical trials established the benefit of
alteplase in the treatment of MI. Although, at present alteplase
remains the standard treatment for MI, it is likely to be super-
seded by angioplasty and/or stenting which have greater bene-
fits in centers that have invasive catheterisation capability.
13.2 Ascendancy in stroke
The use of alteplase in clinical trials is increasing and evolving.
The previous lack of effective treatments for stroke is likely to
make alteplase a major advance in this condition. Alteplase is
only effective if given within 3 h of the onset of stroke symp-
toms. The new challenge is to translate these trials into clini-
cal use in stroke by increasing the percentage of people being
diagnosed and treated with alteplase within 3 h.
13.3 Use in other conditions
Clinical trials have not established a role for alteplase in the
treatment of acute coronary syndromes or deep vein throm-
bosis. However, alteplase is useful in treating pulmonary
thromboembolism and peripheral vascular disease.

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Affiliation
Sheila A Doggrell
Department of Physiology and Pharmacology, The
University of Queensland, Brisbane, 4072
Queensland, Australia
E-mail: s_doggrell@yahoo.com
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