From the Coronary Care and Cardiovascular Research Units, Green Lane
Hospital, Auckland, New Zealand, and the Department of Cardiology, University
Hospital Gasthuisberg, Leuven, Belgium.
Correspondence to Professor Harvey White, Cardiology Department, Green Lane Hospital, Private Bag 92 189, Auckland 1030, New Zealand () or Professor Frans Van de Werf, Department of Cardiology, University Hospital Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium () e-mail frans.vandewerf{at}vz.kuleuven.ac.be
Abstract
Abstract—Thrombolytic
therapy has been a major advance in the management of acute myocardial
infarction. Unfortunately, it continues to be underused or is
administered later than is optimal. Thrombolytic therapy
works by lysing infarct artery thrombi and achieving reperfusion,
thereby reducing infarct size, preserving left ventricular
function, and improving survival. The most effective
thrombolytic regimens achieve angiographic epicardial
infarct-artery patency in only
A
short distance from its origin the left coronary artery was
completely obliterated by a red thrombus that had formed at a point of
great narrowing. . .
Thus did James Herrick describe the autopsy
of his first patient in his seminal paper in
1912,1 attributing myocardial infarction to
coronary artery thrombus. He went on to state, "The hope for
the damaged myocardium lies in the direction of securing a
supply of blood." Over the next 68 years, controversy raged as to
whether coronary artery thrombus was a cause of myocardial
infarction or whether the clot formed after death and was merely a
postmortem finding. In 1980, DeWood and
colleagues2 reported finding thrombus in the
infarct-related arteries of
The most important therapeutic goal in the management of acute
myocardial infarction is early restoration of complete infarct artery
perfusion after the occurrence of an acute coronary occlusion.
More than 200 000 patients have been randomized in clinical trials of
thrombolytic therapy, and in no other area of medicine
has a therapy been so extensively investigated. Each year between 1.5
and 2 million patients worldwide are admitted to hospital with acute
myocardial infarction. Unfortunately, many of these patients do not
receive thrombolytic therapy, and countless lives are
lost despite the best scientific evidence of its safety and efficacy.
Underusage and delay in administering thrombolytic
therapy are the two greatest challenges facing physicians caring for
patients with acute myocardial infarction.
The first use of thrombolytic therapy in patients
with acute myocardial infarction was reported by Fletcher and
colleagues in 1958.3 In the early 1960s and
1970s, 24 trials were performed evaluating the efficacy of
intravenous streptokinase.4 By modern
standards, these trials had major design flaws. For instance, patients
were randomized up to 72 hours after the onset of myocardial
infarction, and low doses of streptokinase (50 000 to 150 000 IU)
were used. The theoretical basis for the administration of
thrombolytic therapy was also not yet established, and
this, together with lack of evidence of efficacy in a single trial, led
to the abandonment of further investigation into this mode of
treatment.
In 1969, Chazov administered intracoronary streptokinase
in Russia,5 and it is now nearly 20 years since
Rentrop et al6 reported its use, thereby
rejuvenating interest in reperfusion as a treatment modality for the
management of acute myocardial infarction. Since then, several new
thrombolytic agents, including tissue
plasminogen activator (alteplase or reteplase),
and adjunctive antiplatelet and antithrombotic regimens have been
developed. In this article, we highlight some of these important
developments and their clinical implications.
Importance of Infarct Artery Patency
The primary goal of thrombolytic therapy is rapid,
complete, and sustained restoration of infarct artery blood flow. The
GUSTO-I angiographic substudy strongly correlated 90-minute patency of
the infarct-related artery with the mortality reduction achieved with
accelerated alteplase.7 Regardless of the
thrombolytic agent used, an occluded infarct-related
artery (ie, TIMI grade 0 or 1 flow)8 at 90
minutes was associated with an 8.9% 30-day mortality rate, and
"normal" perfusion (TIMI grade 3 flow) with a 4.0% mortality rate.
Patients with "partial" perfusion (TIMI grade 2 flow, ie,
infarct-related artery fills to full length but more slowly than
adjacent normal vessels) had an intermediate mortality rate of 7.4%.
In addition, at 5 to 7 days, left ventricular ejection
fractions were higher, end-systolic volumes were smaller, and
regional wall motion in the infarct zone was less depressed in patients
with TIMI grade 3 flow than in those with lesser TIMI flow
grades,9 confirming the hypothesis that early
perfusion at 90 minutes results in preservation of left
ventricular function and reduced mortality.
The benefits of early reperfusion may, however, be reduced by
subsequent reocclusion of the infarct-related artery. Early reocclusion
causes loss of ventricular function and doubles the
mortality rate.10 The incidence of reocclusion
varies from 4.9% to 25%, depending on the
thrombolytic and adjunctive therapies
used.9 11 Late reocclusion (occurring up to 1
year after reperfusion) may occur in 25% to 30% of patent
infarct-related arteries.12 13 Because long-term
patency of the infarct-related artery has been shown to be an
independent prognostic factor,14 15 even silent
late reocclusion may be associated with a poor outcome.
Eligibility
The proportion of patients presenting with myocardial
infarction who are eligible for thrombolytic therapy
has varied in reports because of differing eligibility criteria, and
depends partly on whether "eligibility" is based on the admission
ECG and time window criteria (Table 1
In a recent prospective study, 53% of patients presenting to four
coronary care units in Auckland were eligible for reperfusion therapy
on the basis of ECG criteria (ST-segment elevation or new left
bundle-branch block) and a 12-hour time window.32
Thirty-three percent of the patients had ST-segment depression, paced
rhythms, or T-wave inversion, and 14% presented after 12
hours.
The goal should be to treat all eligible patients with reperfusion
therapy as soon as possible. Contraindications against
thrombolytic therapy exist in 7% to 10% of
patients.32 33 Ineligibility for
thrombolysis does not mean that the patient is
ineligible for reperfusion, and percutaneous
revascularization should be considered in such
cases.
Time
Early Treatment
Boersma and colleagues39 recently
analyzed 22 trials that had compared fibrinolytic therapy with
placebo or control treatment in at least 100 patients (n=50 246). They
came to a different conclusion, namely, that the relation between
treatment delay and mortality reduction was expressed significantly
better by a nonlinear than a linear regression equation
(P=.03) (Fig 1
These analyses are from nonrandomized comparisons of patients
treated earlier versus those treated later and need to be interpreted
cautiously. Patients who present earlier may have larger infarcts,
and those presenting later are more often elderly, female,
diabetic, or hypertensive or have had previous infarctions or bypass
surgery.40
The greatest delay between symptom onset and
thrombolytic therapy is due to late
presentation by patients, and this accounted for 55% of
the total treatment delay in GUSTO-I.40
Unfortunately, public education programs aiming to reduce these delays
have had variable results.41
In GUSTO-I, the delay between hospital admission and treatment—the
"door-to-needle" time—was 64 minutes. Patients in the United
States faced slightly longer delays (median, 66 minutes) than those
outside the United States (median, 60 minutes).40
It is disappointing to note that in the GUSTO-III trial, which
commenced randomization 5 years after GUSTO-I, the median delay was 54
minutes. Whichever thrombolytic regimen is used, it is
important that treatment delays be reduced for the benefit of all
eligible patients.
Age
The GUSTO-I trial had no upper age limit for randomization, and the
oldest patient enrolled was 110 years of age.48
Multivariate analysis confirmed that older age
was the most important adverse prognostic factor, with a 30-day
mortality rate of 1.1% in patients <45 years and 20.5% in those >75
years old.47 All but the oldest patients (those
>85 years of age) had a lower mortality rate, and the net clinical
benefit (death plus nonfatal disabling stroke) was greater in patients
randomized to receive accelerated
alteplase.49
Thrombolytic therapy remains underused in the elderly.
Patients >75 years of age are six times less likely to receive
thrombolytic therapy than younger
patients.50 In a North American registry of the
GUSTO-I trial, 30.1% of patients presenting with acute myocardial
infarction were >75 years old, but only 17.8% were randomized in the
study.51 There are several possible reasons why
elderly patients are less likely to receive
thrombolytic therapy, including the higher frequency of
anginal equivalents, more nondiagnostic ECGs, later
presentation, a higher incidence of comorbid disease, and
relative contraindications against the use of
thrombolytic therapy. With regard to
cost-effectiveness, the elderly are likely to obtain greater benefit
from thrombolytic therapy because the average number of
life-years added by treatment with accelerated alteplase is greater
than in younger patients (Table 2
It might be expected that a more aggressive
thrombolytic regimen, such as accelerated alteplase,
would cause more intracerebral hemorrhage in
elderly patients and that the net clinical benefit (death plus nonfatal
disabling stroke) would be lessened. However, because mortality from
intracerebral hemorrhage increases dramatically
with age, intracerebral hemorrhage contributes
more to the mortality component of the net clinical benefit, and few
patients survive with disabling strokes (Fig 2
Infarct Site
Forty percent of thrombolytic-eligible patients have
inferior ST-segment elevation on the presenting
ECG.38 In the FTT overview, patients with
inferior ST-segment elevation who were randomized within 12
hours of symptom onset had a mortality reduction of 13% (95% CI,
-24% to 0%).
Patients with inferior infarcts are a
heterogeneous group, and adverse prognostic factors may not
be apparent on admission when the decision as to whether or not to give
thrombolytic therapy must be made. Before the
thrombolytic era, the incidence of second- or
third-degree heart block complicating inferior infarction
was
Patients with lateral or circumflex artery infarcts not involving the
inferior surface of the heart have usually been excluded
from randomized trials because of the requirement for 2 mm of
ST-segment elevation in leads V4 to
V6 (Table 1
If patients have a good history of prolonged ischemic chest
pain and a normal ECG, they should have another ECG 30 minutes later,
because it may take time for significant ST-segment abnormalities to
manifest.
Contraindications
As thrombolytic therapy has become more widely
used and the results of the megatrials have confirmed its efficacy and
safety, the contraindications have widened in some instances and
narrowed in others. In many circumstances, however, no data are
available and recommendations must be based on reasonable judgments.
Depending on patient demographics and the regimen used,
thrombolysis is associated with an increase in the
stroke rate of
Oral Anticoagulants and Known Bleeding Disorders
Little information is available about the safety of
thrombolytic therapy in patients with common
abnormalities such as von Willebrand's disease, which affects
0.1% of the population. The clinical manifestations of this disorder
are variable. If patients have had only mild bleeding associated
with trauma, it may be reasonable to administer
thrombolysis, whereas if transfusion has been required,
thrombolysis would be contraindicated.
Other Contraindications
There are no data on fetal safety when thrombolytic
therapy is administered during pregnancy, and there is also a risk of
maternal bleeding in the first week postpartum.
Recent bleeding from peptic ulceration in the previous 6 weeks is
considered a contraindication against the use of
thrombolytic therapy, but "vague" indigestion
should not prevent patients from receiving thrombolytic
therapy.
In a case-control study from GUSTO-I,60 the risk of
intracerebral hemorrhage in patients who had
previously suffered transient ischemic attacks was 2.8 times
that of control cases.60 Patients with a history
of dementia had 3.4 times the risk of intracerebral
hemorrhage. This may relate to the known increased bleeding
risk associated with cerebral amyloid angiopathy.
Mycotic aneurysms associated with infective endocarditis may
bleed, and because of this possibility, endocarditis is considered a
contraindication against the use of thrombolytic
therapy.
Catastrophic hemoptysis may occur with cavitating pulmonary
tuberculosis, and thrombolytic therapy is therefore
contraindicated.
Because the liver produces coagulant factors and there is a possibility
of portal hypertension and esophageal varices with the propensity for
uncontrollable hematemesis, thrombolytic therapy is
contraindicated in cases of advanced liver disease.
Percutaneous revascularization is
preferable to thrombolytic therapy if there is a strong
possibility of systemic embolism from a fresh left atrial thrombus or a
protuberant left ventricular thrombus.
Patients with acute myocardial infarction and a history of hypertension
or elevated blood pressure on admission have a greater risk of
intracranial hemorrhage after
thrombolysis.46 In general,
patients with a previous history of hypertension represent a
higher-risk group (older age, more women, higher incidence of diabetes,
and Killip class >I). They therefore have a worse clinical outcome,
including both a higher cardiac death rate and higher total and
hemorrhage stroke rates.61 In GUSTO-I,
the risk of death in patients with a high systolic blood
pressure at entry was similar to that in normotensive patients
(excluding patients with a systolic pressure of <120
mm Hg, in whom the risk of death was higher).62
The risk of intracranial hemorrhage, however, increased with
systolic blood pressure, especially at systolic
pressures of >170 mm Hg, although there was no clear threshold
for this effect.62 The rate of intracranial
hemorrhage was doubled if the systolic pressure was
Sufficient anti-streptokinase antibodies develop to neutralize a
standard dose of streptokinase within 3 to 4 days after initial
administration. At 4 years, 50%63 of patients
still have elevated levels of antibodies. Because of concerns mainly
about efficacy but also about allergy,64 65
streptokinase should not be readministered except in the first 24 to 48
hours.
Factors That Should Not Be Considered Contraindications
Menstruation
Nontraumatic Cardiopulmonary Resuscitation
Diabetes
With regard to efficacy, the GUSTO-I angiography substudy showed that
thrombolytic therapy is equally efficacious in
restoring early coronary artery patency in patients with and
without diabetes.61 In the FTT analysis,
diabetics had a 21% reduction in 35-day mortality with
thrombolytic therapy compared with control therapy,
which corresponds to 37 lives saved per 1000 patients treated versus 15
lives in nondiabetic patients. Thus, diabetic patients with acute
myocardial infarction are just as eligible for
thrombolytic therapy as nondiabetics, but their early
mortality rates remain high even after adjustment for both clinical and
angiographic variables.61 A higher
reocclusion rate and reduced compensatory hyperkinesis of the
noninfarct zones have been proposed as explanations for this excess in
early mortality.61
Subgroups
Although thrombolysis has become the mainstay of
acute treatment in the majority of patients with suspected acute
myocardial infarction, uncertainties still remain with regard to the
clinical benefit of this therapy in certain subgroups of patients.
ST-Segment Depression
Patients with ischemic chest pain and ST-segment depression are
a heterogeneous group. Some patients with ST-segment
depression in the anterior leads may actually be developing a true
transmural posterior infarction. Others may develop non–Q-wave
infarction or may have unstable angina without myocardial necrosis. In
general, the deeper the ST-segment depression and the greater the
number of leads involved, the greater the likelihood of myocardial
necrosis and thus non–Q-wave infarction.77 In
the LATE study,78 mortality rates in 528 patients
with confirmed non–Q-wave infarction and ST-segment depression of
Cardiogenic Shock
Prior Coronary Artery Bypass Graft Surgery
The poor outcome in these patients may be explained by a higher
prevalence of multivessel disease and impaired left
ventricular function and a lower 90-minute coronary
artery patency rate after
thrombolysis,47 81 most likely
because of the presence of large thrombi when a vein graft is the
infarct-related vessel. This probably also explains the greater benefit
observed in these patients when they are given a more potent lytic
agent such as alteplase.82 Indeed, although the
difference was not significant, this group had one of the largest
treatment differences in GUSTO-I: the 30-day mortality rate was 11% in
patients who received streptokinase and 8.3% in those randomized to
receive alteplase.
Prehospital Treatment
Eight trials have randomized patients to receive prehospital or
in-hospital thrombolytic therapy. When combined, these
trials show a significant 17% reduction in early mortality with
prehospital treatment (21 lives saved per 1000 patients treated;
P=.02) (Fig 3
Late Treatment
A 12-hour time window for administration of
thrombolytic therapy is now widely
accepted.93 The FTT overview showed that
thrombolytic therapy reduced mortality by 14% (SD,
5%) in patients randomized between 7 and 12 hours after symptom onset
(P=.005),38 and there was a
nonsignificant 5% reduction in mortality among the 9000 patients who
presented after 12 hours. Because patients from the LATE and
ASSET studies were not subdivided by ECG criteria in this
analysis, the benefit in patients presenting between 13 and
18 hours with ST-segment elevation or bundle-branch block could be of
the order of 10 lives saved per 1000 patients
treated.38
Patients who present late may have stuttering infarcts, or the
infarct-related artery may have been patent at some stage after the
initial occlusion,34 enabling salvage of
myocardium beyond 6 hours. The major benefit of late
treatment, however, is probably not due to myocardial salvage but
rather to other mechanisms (Table 5
Choice of Agent
Three megatrials randomizing a total of 103 069 patients have
compared the effects on mortality of various
thrombolytic agents. In the GISSI-2/International
Study,33 79 20 891 patients were randomized to
receive either streptokinase or alteplase infused over a period of 3
hours in a factorial design, followed by randomization at 12 hours to
either no heparin or subcutaneous heparin (12 500 IU) given twice
daily. Mortalities at 30 days were similar (8.9% with streptokinase
versus 8.5% with alteplase).
The ISIS-3 trial randomized 41 299 patients to receive either
streptokinase, anistreplase, or duteplase (a form of tissue
plasminogen activator not commercially
available) infused over a period of 4 hours. As in GISSI-2, there was a
factorial design with subcutaneous heparin or control therapy beginning
4 hours after initiation of thrombolytic therapy.
Mortality was similar with all three thrombolytic
regimens: 10.5% with streptokinase, 10.3% with duteplase, and 10.6%
with anistreplase.27
The GUSTO-I trial randomized 41 021 patients to receive one of four
thrombolytic regimens.29 The
lowest mortality rate at 30 days (6.3%) was achieved with accelerated
alteplase infused over a period of 90 minutes with immediate
administration of intravenous heparin, compared with 7.2%
for streptokinase plus subcutaneous heparin (as administered in
ISIS-4,31 although 36% of patients in GUSTO-I
also received intravenous heparin), 7.4% for streptokinase
plus immediate intravenous heparin, and 7.0% for
combination therapy with streptokinase plus alteplase plus
intravenous heparin. At 30 days, the reduction in mortality
was 14% in the accelerated alteplase group compared with the combined
streptokinase groups, equating to an extra 10 lives saved per 1000
patients treated. For the combined end point of death plus nonfatal
disabling stroke, there were 11 fewer events per 1000 patients treated.
The benefit was consistent across most subgroups, including
patients with anterior or inferior infarcts and those
presenting earlier or later. The greatest benefit was seen in
patients with higher-risk baseline
characteristics.94 A nomogram has been developed
that incorporates age, Killip class, heart rate, systolic blood
pressure, history of infarction, and infarct location into a model for
nonquantitative guidance in selecting alteplase over
streptokinase.94
Why did ISIS-3 and GISSI-2 fail to demonstrate any mortality
differences between streptokinase and tissue plasminogen
activator, as the GUSTO-I trial did? First, the failure to
use intravenous heparin in the former trials may have
disadvantaged duteplase in GISSI-2 and alteplase in
ISIS-3.95 Second, a 3-hour infusion of alteplase
has been shown to produce less 90-minute patency than an accelerated
alteplase regimen, which delivers substantially more of the drug to an
average-weight patient in the first 60 minutes, as in GUSTO-I, and the
absolute improvement in TIMI grade 3 flow with an accelerated alteplase
regimen is of the order of 13%.96
Cost-effectiveness
Several studies have used retrospective data and varying
assumptions to show that thrombolytic therapy is very
cost-effective compared with other accepted medical
therapies.97 An international issue is the
appropriate allocation of scarce healthcare resources, and many
hospitals worldwide use streptokinase because it is 7 to 8 times
cheaper than alteplase. The GUSTO-I study prospectively gathered
details of hospital and medical charges in a subgroup of US
patients.98 Compared with streptokinase therapy,
the additional cost of accelerated alteplase per extra life-year saved
was US $27 382 (in 1992 dollars). The cost-effectiveness of
preferentially using alteplase varied according to the age of the
patients and the site of infarction (Table 2
Long-term Follow-up
Early and sustained coronary artery patency after
thrombolysis has many beneficial effects. Some of these
are very much time-dependent (eg, salvage of ischemic
myocardium with preservation of left
ventricular function), whereas other are less affected by
the time of recanalization (eg, attenuation of
infarct expansion, left ventricular remodeling, enhanced
electrical stability, and provision of collateral
flow).14 56 99 100 One would expect that these
favorable effects would result in survival benefits not only during the
hospital stay but also afterward. Surprisingly, no extra survival
benefit after hospital discharge has been observed in patients given
intravenous thrombolytic therapy. A
meta-analysis performed by the FTT Collaborative Group of more
than 40 000 patients participating in placebo-controlled trials of
intravenous thrombolysis indicated that the
risk of death after 1 month was equal in survivors of acute myocardial
infarction whether or not intravenous
thrombolytic therapy was given on admission and
irrespective of the time this treatment was
started.101
There are many explanations for the absence of any extra long-term
benefit. Only a minority of patients are treated within a time window
that allows substantial salvage of ischemic myocardial tissue.
The incidence of optimal reperfusion with the present fibrinolytic
agents is only
New Agents
New fibrinolytic agents are being developed to improve the
efficacy of clot lysis and/or ease of administration. Novel
plasminogen activators have been designed or
purified from natural sources with one or more of the following
properties: a prolonged half-life (allowing bolus administration),
enhanced fibrin specificity, or resistance to natural
inhibitors such as plasminogen
activator inhibitor-1. The following novel
plasminogen activators are in different stages
of clinical development or marketing or will enter clinical testing
very soon: mutants of native tissue plasminogen
activator (reteplase, lanoteplase, TNK-tPA);
Desmodus salivary plasminogen
activator-
Reteplase
Why did the enhanced patency rates with reteplase at 60 and 90
minutes not translate into lower mortality? This might have been due to
chance, because the observed patency difference at 90 minutes would
have been expected to produce a mortality difference of
<15%.7 Alternatively, it may be that patency
rates with each agent fluctuate at different time points. In a small
group (96 patients) in the RAPID-2 angiographic study, alteplase
produced higher patency rates at 30 minutes than reteplase (39.0%
versus 27.3%; P=NS), and this very early advantage might
have offset the later patency advantage of reteplase. Another possible
explanation is that reocclusion rates might have been higher with
reteplase.
TNK-tPA
Lanoteplase
Saruplase
Staphylokinase
As a bacterial protein, staphylokinase induces antibody formation and
resistance to repeated administration. However, preliminary studies
suggest that the immunogenicity of staphylokinase can be reduced by
site-directed mutagenesis. Large comparative trials are needed to
determine the safety and full clinical potential of this agent.
The Future
A number of new therapeutic strategies may achieve greater
early and, consequently, greater long-term benefits in patients with an
acute myocardial infarction. Greater reductions of infarct size are
possible by earlier administration of more effective
thrombolytic regimens, eg, prehospital bolus
administration of new fibrinolytic agents with equal or higher potency
for clot lysis, such as TNK-tPA, lanoteplase, or staphylokinase, and
better conjunctive antithrombotic therapies (eg, direct antithrombins
or glycoprotein IIb/IIIa receptor antagonists).
Reocclusion and reinfarction in the days or weeks after the acute event
may be better prevented by new antiplatelet agents (eg, oral
glycoprotein IIb/IIIa receptor antagonists),
prolonged subcutaneous antithrombin therapy (eg, low-molecular-weight
heparin or direct antithrombins), better selection of patients for
additional revascularization, lipid-modifying
agents (eg, statins), and plaque-stabilizing agents. Reperfusion damage
may also be diminished by earlier treatment and by therapies that
improve the microcirculation (eg, inhibition of neutrophil chemotaxis
or adhesion or enhancement of endogenous adenosine
activity). Greater attenuation of left ventricular
remodeling (eg, using ACE inhibitors) and better
antiarrhythmic treatment may also increase the long-term clinical
benefit of successful thrombolysis.
The risk of bleeding complications, particularly hemorrhagic stroke,
must also be decreased. There is a need for more careful selection of
patients for thrombolysis, and it may be just as
effective and safer to administer a reduced dose of a fibrinolytic
agent in conjunction with a more potent antithrombotic agent (eg,
abciximab or other glycoprotein IIb/IIIa receptor
antagonists).
Each of the strategies mentioned above needs to be tested in large
clinical trials. Because it is unethical to conduct these trials with a
placebo control, it is likely that in the future, investigators will
increasingly seek to demonstrate equivalence of
treatments.126 Equivalence of new
thrombolytic regimens should be established first in
terms of mortality, the primary efficacy outcome.
Secondary aspects of innovative treatments, such as side effects, ease
of use, and cost, also need to be evaluated. It is generally accepted
that in the field of thrombolysis, a 1% absolute
difference in mortality, if still demonstrable at long-term follow-up,
is clinically important. As shown in the GUSTO-I
trial,29 this 1% difference (or a relative 14%
difference) may prevent 1 of every 7 deaths. For a disease with a high
prevalence and mortality rate, this reduction is relevant at the
population level. If a 1% absolute difference is chosen as the limit
of a range of equivalence, it is important that the population of
randomized patients includes those at high risk, for example, elderly
patients, as in the GUSTO-I trial. Otherwise, if a low-risk population
with, say, a baseline mortality of 5% is studied or if patients less
likely to benefit, such as those treated late, are included, the chance
of showing "equivalence" is much higher. An alternative approach
would be to use an odds reduction as the prespecified limit of the
range of equivalence,127 because the mortality
rates in the standard treatment arm may vary depending on the selection
criteria. Either a 1% absolute difference or a 14% relative
difference (whichever is the smallest), as shown between streptokinase
and alteplase in the GUSTO-I trial,29 could be
regarded as appropriate boundaries for equivalence. This flexible
definition of equivalence has the advantage of keeping the boundaries
for equivalence narrow, as illustrated in the following example. If
30-day mortality in the standard treatment group is 5%, the upper
boundary for equivalence should be 5.7% (5% plus 14% of 5%) and not
6% (1% absolute difference). On the other hand, if 30-day mortality
in the control group is 10%, the upper boundary for equivalence should
be 11% (1% absolute difference) and not 11.4% (10% plus 14% of
10%). This dual definition is being used in the ongoing ASSENT-2 trial
comparing the new thrombolytic, TNK-tPA, with an
accelerated infusion of alteplase, whereas an odds reduction definition
for equivalence has been used in the COMPASS trial comparing
streptokinase with saruplase.122 127
It should be stressed that, although the statistics involved are
rather complex, it remains the responsibility of clinical investigators
to define the equivalence (interchangeability) of two alternative
treatments. It is possible that in the future, other definitions of
equivalence of reperfusion strategies will emerge if, for example,
newer and more reliable surrogate end points for efficacy, such as
infarct size, become better validated.
In conclusion, many improvements in pharmacological reperfusion
seem possible. Not only can higher initial patency rates be achieved
and maintained, but the net clinical benefit resulting from successful
reperfusion can probably also be increased. The "ideal"
thrombolytic agent has not yet been developed (Table 7
Selected Abbreviations and Acronyms
References
© 1998 American Heart Association, Inc.
Clinical Cardiology: New Frontiers
Thrombolysis for Acute Myocardial Infarction
50% of patients within 90 minutes.
Bleeding requiring transfusion occurs in 5% of patients and stroke
in 1.8% with these regimens, which include adjunctive aspirin and
intravenous heparin. There are several ways in which
reperfusion rates and thus patient outcomes might be improved, such as
different dosing regimens of established agents; combinations of
different agents; improved adjunctive therapy such as direct
antithrombin agents, low-molecular-weight heparin, or
glycoprotein IIb/IIIa receptor antagonists; or
the development of novel thrombolytic agents with
enhanced fibrin specificity, resistance to native
inhibitors, or prolonged half-lives allowing bolus
administration. All of these strategies are being tested in clinical
trials. The best approach currently is to administer
thrombolytic therapy as soon as possible to all
patients without contraindications who present within 12 hours of
symptom onset and have ST-segment elevation on the ECG or new-onset
left bundle-branch block, unless an alternative reperfusion strategy
is planned.
Key Words: myocardial infarction • plasminogen activators • streptokinase • thrombolysis90% of patients undergoing acute
coronary artery surgery in the first few hours after the onset
of acute myocardial infarction. Although Herrick was referring to
collateral blood flow when he wrote of "securing a supply of
blood," his original insight forms the basis for the use of
thrombolytic therapy. 
) or
on a discharge diagnosis of myocardial infarction. In ISIS-4, 70% of
patients who presented with suspected acute myocardial
infarction received thrombolytic
therapy.31 This figure, however, may
represent only a subset of patients presenting with
myocardial infarction, because only a few patients per month were
randomized in the trial in each hospital.
View this table:
[in a new window]
Table 1. Eligibility Criteria for Thrombolytic Therapy in
Clinical Trials
The timing of the onset of ischemic symptoms is only a
crude measure for determining when the infarct-related artery occluded
and myocyte necrosis began. This is because occlusion may occur
intermittently,34 myocardial demands may vary,
and the presence and function of collateral circulation may play an
important role. In animals, myocardial necrosis begins within 15
minutes of the onset of a coronary artery occlusion, with a
"wave front" of myocyte necrosis proceeding from the endocardium to
the epicardium.35 After 40 minutes of occlusion,
necrosis is 38% complete; at 3 hours it is 57% complete; at 6 hours
71% complete; and at 24 hours 85% complete. Depletion of ATP occurs
over a similar time frame.36 In humans, the time
window is likely to be longer because of the factors mentioned above,
and ischemic preconditioning may also extend the time during
which myocardial salvage may occur.37
Streptokinase therapy was associated with a 51% reduction in
mortality (SD, 12%) at 21 days in a retrospective subgroup
analysis of patients randomized to streptokinase or control
treatment within 1 hour of symptom onset in the GISSI-1 trial. This
observation was considered "hypothesis-generating" by the FTT
Collaborative Group,38 who analyzed nine
trials of fibrinolytic therapy that had randomized more than 1000
patients each (n=58 600). They concluded that there was no marked
discontinuity at 0 to 1 hours and only a gradual diminution of benefit
with delay (30% reduction at 0 to 1 hours [SD, 9%]; 25% reduction
at 2 to 3 hours [SD, 5%]; and 18% reduction at 4 to 6 hours [SD,
5%]). For each hour of delay in administering
thrombolytic therapy, 1.6 additional lives were lost
for every 1000 patients treated. ). Their
analysis excluded 4250 patients from the
USIM26 and ISIS-327 trials,
both of which were included in the FTT analysis. USIM included
patients with unstable angina (32%), and ISIS-3 included patients
without or with only minor ST-segment elevation. The proportional
mortality reduction was 48% in patients treated within 1 hour (95%
CI, 31% to 61%), and patients treated within 2 hours had a
significantly greater mortality reduction (44%; CI, 32% to 53%) than
those treated later (20%; CI, 15% to 25%). These benefits exceed the
FTT linear finding of 1.6 lives saved per 1000 patients for each hour
of earlier treatment. The implied benefit from treatment 1 hour earlier
in GUSTO-I, five lives saved per 1000 patients treated, was also
greater than the FTT finding.
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Figure 1. Mortality among fibrinolytic-treated and control
patients according to treatment delay. Reproduced with permission from
Reference 39.
Older age is associated with increasing rates of mortality and
intracerebral hemorrhage after
thrombolytic therapy, regardless of the
thrombolytic agent used. Concerns about increasing
hemorrhagic risk caused a number of the early
thrombolytic trials to impose an upper age limit for
randomization,21 22 42 43 and physicians became
reluctant to use thrombolytic therapy in patients >75
years of age. Indeed, the 1990 American College of
Cardiology/American Heart Association guidelines for
the early management of patients with acute myocardial infarction
stated that physicians should be judicious in the selection of older
patients for thrombolysis and suggested that treatment
of patients >75 years old was not well established by the available
evidence.44 The elderly have potentially the most
to gain from reperfusion strategies because of their high absolute
mortality rate. Almost half of all deaths after acute myocardial
infarction occur in patients >75 years old,45
and older age is the most important prognostic factor after myocardial
infarction.46 47 No randomized,
placebo-controlled thrombolytic trial has been designed
specifically to assess benefits and risks in the elderly. However, the
FTT overview showed that mortality was significantly lower in patients
65 to 74 years old who had received thrombolytic
therapy than in control patients (16.1% versus 13.5%;
P<.00001), and there was a nonsignificant trend toward a
reduction in mortality in patients 
75 years old (25.3% versus
24.3%).38 ).52 For example,
among patients <65 years of age, there were 5 fewer deaths or
disabling strokes per 1000 patients treated with accelerated alteplase
than in those given streptokinase. In patients between the ages of 75
and 85 years, there were 17 fewer deaths or disabling strokes with
accelerated alteplase.
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Table 2. Cost Per Additional Year of Life for Accelerated
Alteplase Versus Streptokinase After Myocardial Infarction in Selected
Patient Subgroups ). The greater cardiac benefit of
alteplase in the elderly maintains the advantage of this therapy up to
the age of 85 years. For patients >85 years old, the best regimen in
GUSTO-I appeared to be streptokinase plus subcutaneous
heparin.49
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Figure 2. Incidence of mortality, stroke, and nonfatal
disabling stroke with increasing age.
Patients with anterior or inferior infarcts should
receive thrombolytic therapy. Although
inferior infarcts are usually smaller, the GISSI-1 trial
showed that the benefit of thrombolytic therapy was
related to the amount of ST-segment elevation rather than the site of
the infarct.53 19%,54 but nowadays the incidence is
11.8% with thrombolytic therapy, and the need for
temporary pacemakers is uncommon.29 Right
ventricular infarction occurs in 30% of patients with
inferior infarcts, and those with ECG evidence of right
ventricular infarction have a mortality rate of
30%.55 In the FTT overview, patients with acute
inferior infarction and a previous infarction had a
mortality rate of 13%. Patients with inferior infarction
and anterior ST-segment depression are also at high risk. All of these
patient groups are at high absolute risk and are likely to benefit
substantially from thrombolysis, which reduces
mortality and preserves left ventricular
function.24 A patent infarct-related artery has
the potential to provide collaterals to another infarct zone in the
event of subsequent coronary occlusion and can decrease
arrhythmogenesis and remodeling of the left
ventricle.56 Treatment of elderly patients with
inferior infarcts has been shown to be particularly
cost-effective compared with other widely used treatments (Table 2
).52 ), even though these leads are not
usually affected by repolarization abnormalities. It would seem logical
that patients with occlusive thrombus in a circumflex artery would
benefit from thrombolytic therapy, and these patients
could be identified by 1 mm of ST-segment elevation in the lateral
precordium or lead aVL or by an echocardiogram showing a lateral
wall motion abnormality. True posterior infarcts should also be
treated. The FTT overview showed that patients with bundle-branch block
patterns also benefit from thrombolytic therapy. The
trials that included such patients did not specify that the
bundle-branch block must be new. ST-segment elevation is easily
recognized in the presence of right bundle-branch block, and new
infarction can also be detected in the presence of left bundle-branch
block.57 If the diagnosis is uncertain and an old
ECG is not readily available, echocardiography may
help to determine whether there is a regional wall motion abnormality.
Although sequential examinations may be required to determine whether
this was due to acute ischemia, stunning, previous
long-standing necrosis, or myocardial disease, the absence of
myocardial thinning and the presence of contralateral wall hyperkinesis
would be supportive evidence for an acute ischemic event.
Bedside measurement of cardiac proteins such as myoglobin or troponin T
may also aid management. 0.4% to 0.8%,29 38 58 and
there is bleeding requiring transfusion in 5% of cases, depending
on the number of invasive procedures performed.29
Table 3 lists major contraindications and
Table 4 relative contraindications
against the use of thrombolytic therapy. For the
individual patient, the size of the infarct, the
hemodynamic status, any history of previous infarction,
the time elapsed since symptom onset, and the patient's age, etc, must
be weighed against the risk of bleeding to determine the likelihood of
benefit or harm. If percutaneous
revascularization procedures are available, the
threshold for administering thrombolytic therapy in the
presence of contraindications should be higher. However, if
thrombolytic therapy is the only option available, then
contraindications in very sick patients may outweigh the possibility of
benefit.
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Table 3. Major Contraindications Against the Use of
Thrombolytic
Therapy
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Table 4. Relative Contraindications Against the Use of
Thrombolytic Therapy
Some authorities and most recent trials have considered oral
anticoagulants to be an absolute contraindication against the use of
thrombolytic therapy. In a multivariate
logistic regression analysis of 2469 patients with acute
myocardial infarction, those on oral anticoagulants before admission
had a significantly higher risk of intracranial hemorrhage
after thrombolysis.59
Theoretically, these patients would be at increased risk of bleeding
because of depletion of the vitamin K–dependent clotting factors
(factors II, VII, IX, and X). However, if the international normalized
ratio is subtherapeutic, it may be reasonable to administer
thrombolytic therapy as indicated and to delay or
reduce the first dose of heparin. If the international normalized ratio
is in the therapeutic range, one approach would be to administer
thrombolytic therapy simultaneously with
fresh frozen plasma to replenish the clotting factors. It should be
acknowledged, however, that these approaches have not been formally
evaluated.
Hemorrhagic pancreatitis could be aggravated by
thrombolytic therapy and is therefore considered a
relative contraindication against the use of
thrombolytic therapy. 175 mm Hg at study entry. The effect of elevated
diastolic blood pressure at entry on clinical outcomes is
less striking. In GUSTO-I, there was a slight increase in the rates of
intracranial hemorrhage with increasing diastolic
blood pressure, but no significant increase in mortality was observed
in patients with high diastolic blood pressures on
admission (100 mm Hg). It is unknown whether acute treatment of
high blood pressure on admission reduces the risk of intracranial
hemorrhage after thrombolysis. However, in
patients for whom coronary angioplasty is inappropriate or
unavailable, it would seem reasonable to lower the blood pressure
immediately and then administer thrombolytic
therapy.46 In some patients with a very high
blood pressure on admission and a low risk of dying of cardiac
causes,62 the risk of hemorrhagic stroke may
outweigh the potential reduction in mortality and morbidity.
Active bleeding at the time of presentation with acute
myocardial infarction is usually considered a contraindication against
the use of thrombolytic therapy. However, menstrual
bleeding is not due to hematological abnormalities but rather to high
local concentrations of native plasminogen activator and decreased
procoagulants in the endometrial fluid, together with active sloughing
of the endometrium induced by prostaglandin-mediated
arteriolar spasm. Although menstrual bleeding could theoretically be
increased during the first 12 to 18 hours of menstruation, this has not
been observed in the few women who have received
thrombolytic therapy on day 1 of their menstrual cycle.
There have been reports of 24 women who have safely received
thrombolytic therapy during menstruation, although
moderate bleeding may be increased, requiring
transfusion.66 Thus, the risk of bleeding is not
a sufficient reason to deny women the benefits of
thrombolytic therapy.
Small series of patients have reported no significant
complications from resuscitation lasting <10
minutes.67 68 69 No significant bleeding has been
reported even when resuscitation was continued for 2 hours or when
patients with rib fractures were given thrombolytic
therapy.70 Nontraumatic cardiopulmonary
resuscitation should therefore not be considered a contraindication
against the use of thrombolytic therapy.
Diabetic patients have been less frequently treated with
thrombolytic agents because of concerns about the
increased risk of bleeding complications. The 1990 American College of
Cardiology/American Heart Association guidelines for
the management of acute myocardial infarction classified diabetic
hemorrhagic retinopathy as an absolute contraindication
against the use of thrombolytic
therapy.71 In the FTT analysis, however,
the incidence of stroke and major bleeding complications after
thrombolytic therapy was only slightly higher in
diabetic patients (stroke, 1.9% versus 1.0%; major bleeding, 1.3%
versus 1.0%),38 and in the GISSI-2/International
Study Group trial, the incidence of these complications was similar
among diabetic and nondiabetic patients.72
Intraocular hemorrhage and, more specifically, retinal bleeding
are extremely uncommon complications of thrombolytic
therapy. In the GUSTO-I study, 300 of the 6011 diabetic patients were
estimated to have proliferative retinopathy, but none had intraocular
hemorrhages, and the calculated upper 95% confidence limit of the
possible occurrence of intraocular hemorrhage was only
0.05%.73 It is unlikely that
thrombolytic therapy would increase vitreous
hemorrhage, which is due to vitreous detachment, in patients
with diabetic retinopathy. Also, the few nondiabetic
patients reported have shown no limitation of visual acuity at
follow-up.74 75 Thus, the concerns many
clinicians have about bleeding complications after
thrombolysis in diabetic patients are not supported by
the results of large-scale clinical trials.
Patients without ST-segment elevation are currently not given
thrombolytic therapy. In the FTT
analysis,38 mortality at 35 days in such
patients was nonsignificantly higher after thrombolysis
(15.2%) than after control treatment (13.8%). A possible explanation
for this negative outcome is the procoagulant effect of fibrinolytic
agents, which may cause progression of a nonobstructive mural thrombus
to complete occlusion. Theoretically, thrombolytic
therapy could worsen a coronary artery stenosis by
causing intraplaque hemorrhage, and lysis of a subocclusive
thrombus could also cause distal embolism and
infarction.76 2 mm were significantly lower in those who received alteplase
(8.6% versus 16.6% at 35 days [P<.006] and 20.1%
versus 31.9% at 1 year [P<.006]). This post hoc
analysis of patients treated late suggests that
thrombolytic therapy may be beneficial in selected
patients with typical symptoms and deep ST-segment depression (2
mm), because these patients are most likely developing a true posterior
wall infarction or non–Q-wave infarction. The overall outcomes in
patients with ST-segment depression observed in the FTT study may
represent a net benefit in patients with posterior wall
infarction or non–Q-wave infarction and harm in those patients with
unstable angina. New prospective trials in patients with
ischemic chest pain and deep ST-segment depression are
needed.
Thrombolytic therapy may be less effective in patients
with cardiogenic shock. In the GISSI-1 trial,18
hospital mortality rates in Killip class IV patients were high, with no
difference between control patients and those treated with
streptokinase (69.9% versus 70.1%, respectively). Also, in the FTT
overview,38 patients with both a systolic
blood pressure of <100 mm Hg and a heart rate of >100 bpm had
high mortality rates at 35 days, with a statistically nonsignificant
difference in favor of thrombolysis (53.8% versus
61.1%). In view of these observations, cardiogenic shock is considered
an indication for primary angioplasty, although there are also no
randomized data showing benefit. If primary angioplasty is unavailable,
thrombolytic therapy, preferably using a
non–fibrin-specific agent such as streptokinase, should be given.
Lower mortality rates were observed in Killip class IV patients given
streptokinase than in those given alteplase in both the
GISSI-2/International Study Group trial (64.9% with streptokinase
versus 78.1% with alteplase;
P<.05)33 79 and the GUSTO-I trial
(55.6% with streptokinase versus 62% with alteplase;
P=.06).29 A possible explanation for
these observations is that a sufficiently high coronary
perfusion pressure is needed for local fibrin-specific clot
lysis,80 whereas the induction of a general lytic
state with subsequent local clot lysis can occur at low
arterial blood pressures with a non–fibrin-specific agent.
Although hypotension may occur during administration of streptokinase,
this is unrelated to the initial blood pressure and is usually rapidly
reversible with administration of fluids and cessation of the
streptokinase infusion. It is important that a full dose of a
thrombolytic agent is given when the patient is
hemodynamically stable, either by recommencement of
streptokinase at a lower infusion rate or by administration of
alteplase or reteplase; otherwise, angioplasty should be
considered.
In GUSTO-I, prior bypass surgery was an independent predictor of a
higher 30-day mortality rate.47 ).83 84 85 86 87 88 89 90
Complication rates are similar in both community-initiated and
hospital-initiated thrombolysis, although
ventricular fibrillation may occur more frequently in the
community with prehospital administration,89
necessitating well-trained staff and the availability of
defibrillators. These benefits arise from earlier treatment, and
similar benefits would be expected if patients were able to be
evaluated expeditiously and treated quickly in hospital. Prehospital
administration of thrombolytic therapy has been shown
to be of the greatest value in sparsely populated communities with
transport delays to hospital of >1 hour. However, several
studies91 92 have shown that 20 patients with
chest pain require evaluation for every patient found to be eligible
for thrombolytic therapy. Each community needs to
define the best approach for expeditious delivery of reperfusion
therapy on the basis of local transportation times, resources, and
available expertise.
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Figure 3. Results of trials comparing prehospital with
in-hospital administration of thrombolytic therapy.
Relative risk of early death (in hospital or within 30 days, except for
the Barbash trial,85 which used a 60-day end point) and
95% CIs are shown. Redn indicates reduction. ).56
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Table 5. Potential Benefits of Late
Reperfusion ). 50%,9 and even in patients who
receive treatment early and have TIMI grade 3 flow, adequate tissue
reperfusion is often not achieved ("no reflow" or "impaired
reflow").102 103 Furthermore, reocclusion and
reinfarction are frequently observed after hospital
discharge,12 13 104 105 106 107 and late mortality rates
are high in patients with very poor residual left
ventricular function who survive the hospital phase because
of successful
thrombolysis.108 109
Thrombolytic therapy may have other important benefits
besides mortality reduction, such as preservation of left
ventricular function, which can improve exercise tolerance
and quality of life. There have been surprisingly few studies
evaluating these potential benefits.110 
1, derived from the
saliva of the vampire bat, Desmodus rotundus; saruplase
(recombinant single-chain urokinase plasminogen
activator); and staphylokinase, produced by
Staphylococcus aureus. Combinations of different
fibrinolytic agents (chimeric plasminogen
activators consisting of various portions of tissue
plasminogen activator and urokinase) have also
been investigated, without any clear evidence that their
benefit-to-risk ratio will outperform the single-agent
regimens.111 Murine monoclonal anti-human fibrin
antibodies conjugated with fibrinolytic agents have not been tested in
patients, although there is evidence of increased
thrombolytic potency in
animals.112 Table 6
compares the properties of five new fibrinolytic agents that have been
or will be approved for clinical use over the next few years with those
of alteplase and streptokinase. Each of these new agents will be
briefly discussed.
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Table 6. New Versus Established Fibrinolytic Agents in Acute
Myocardial Infarction
Reteplase (Boehringer Mannheim) is a deletion mutant
of alteplase (Fig 4) and
represents the first of the third-generation fibrinolytics to
become commercially available. The kringle-2 and protease domains of
native tissue plasminogen activator have been
maintained, but the kringle-1, finger, and epidermal growth factor
domains have been deleted, as have the carbohydrate side chains.
Elimination of the kringle-1 and epidermal growth factor domains
reduces hepatic receptor binding, which, along with the lack of
carbohydrate groups, prolongs plasma clearance. Reteplase has a
half-life approximately twice that of alteplase (Table 6) but less
fibrin specificity because of the deletion of the finger domain. In two
angiographic trials, reteplase (given as two 10-IU boluses 30 minutes
apart) yielded more TIMI grade 3 flow at 90 minutes than a 3-hour
(62.7% versus 49.0%; P<.05)113 or
90-minute (59.9% versus 45.2%; P=.01) infusion of
alteplase.114 However, the same dose of reteplase
showed only a small (and not statistically significant) benefit over
streptokinase in the INJECT trial115 and no
benefit over alteplase in the GUSTO-III trial.58
In the latter trial, the absolute difference in 30-day mortality
between reteplase and alteplase was 0.23% in favor of alteplase, with
a 95% CI of -1.11% to 0.66%. These results do not support the
equivalence of reteplase and accelerated alteplase if a 1% absolute
difference in mortality is considered an appropriate boundary of
equivalence. On the other hand, for the secondary end point of death or
disabling stroke, the 95% CIs were <1%, suggesting that the two
treatments were interchangeable. Stroke occurred in 1.64% of patients
treated with reteplase and 1.79% of those treated with alteplase
(P=.5). These results clearly indicate the importance of
defining boundaries for equivalence in any future clinical evaluation
of new plasminogen activators.
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Figure 4. Molecular structure of alteplase, reteplase,
lanoteplase, and TNK-tPA.
TNK-tPA is a genetically engineered triple-combination
mutant of native tissue plasminogen activator
with amino acid substitutions at the following sites: a threonine (T)
is replaced by an asparagine, which adds a glycosylation site to
position 103; an asparagine (N) is replaced by a glutamine, thereby
removing a glycosylation site from site 117; and four amino acids,
lysine (K), histidene (H), and arginine (R), are replaced by four
alanines (A) at sites 296–299. (Fig 4). These substitutions result in
reduced plasma clearance, increased fibrin specificity, and resistance
to plasminogen activator
inhibitor-1.116 In the TIMI-10B
study, a large, phase II efficacy trial in 886 patients, a single 40-mg
bolus of TNK-tPA produced TIMI grade 3 flow rates at 90 minutes that
were identical to those seen with accelerated alteplase (63% in both
groups).117 Furthermore, TIMI frame counting in
TIMI-10B suggested faster and more complete reperfusion with 40 mg of
TNK-tPA than with accelerated alteplase. The best angiographic results
were obtained with a dose/weight ratio of ±0.5 mg/kg. In the ASSENT-1
trial in 3325 patients, an intracranial hemorrhage rate of
0.76% was observed with the 40-mg dose of TNK-tPA. This incidence was
considered acceptable, because 14.6% of the patients in ASSENT-1 were
>75 years old. On the basis of the results of TIMI-10B and ASSENT-1,
16 500 patients with acute myocardial infarction are being randomized
in a double-blind manner to receive weight-adjusted TNK-tPA or
alteplase in the ASSENT-2 phase III mortality trial. The results are
expected in early 1999.
Like reteplase, lanoteplase, or n-PA, is a deletion mutant of
alteplase in which one amino acid is substituted in position 117 (Fig 4).118 In the InTIME-1 trial, a single 120-IU/kg
bolus of lanoteplase produced TIMI grade 3 flow in 57.1% of patients
compared with 46.4% in patients treated with alteplase. There were
also fewer adverse events with lanoteplase. At 30 days, the combined
incidence of death, reinfarction, heart failure, and major bleeding
(including one intracranial hemorrhage in a patient treated with
alteplase) was 11% with lanoteplase and 24% with alteplase.
Lanoteplase will be compared with alteplase in a large mortality trial
(InTIME-2), and the results should be available in early 1999.
Saruplase, or prourokinase, is a naturally occurring
glycoprotein that is rapidly converted into urokinase by
plasmin but appears to have some intrinsic plasminogen
activating potential.119 In a comparative trial
with streptokinase, recombinant saruplase was associated with earlier
reperfusion, higher patency rates, and slightly less fibrinogen
breakdown.120 In the SESAM study, similar TIMI
grade 2 and 3 flows were observed with saruplase and a 3-hour infusion
of alteplase.121 In the COMPASS equivalence trial
(n=3089 patients), 30-day mortality rates were lower with saruplase (80
mg/h) than with streptokinase (5.7% versus 6.7%), but there was also
an increased rate of intracranial hemorrhage (0.7% versus
0.3%).122 Single-bolus administration (80 mg) of
saruplase is being explored as well. This agent is expected to be
approved for use in Europe this year.
Staphylokinase, a 136-amino-acid protein produced by certain
strains of Staphylococcus aureus, has a unique mechanism of
fibrin selectivity.123 In two angiographic
studies, recombinant staphylokinase (in doses between 20 and 30 mg) was
at least as potent as alteplase and significantly more
fibrin-specific.124 125 ). Further refinements of molecules,
with carefully performed dose-ranging studies to choose the best dose
for achievement of TIMI grade 3 flow (or corrected TIMI frame counts)
with an acceptable safety profile, are needed to improve on the results
achieved with tissue plasminogen activator,
together with large clinical trials to assess clinical end points and
safety. Adjunctive therapies with glycoprotein IIb/IIIa
receptor antagonists, direct thrombin
inhibitors, and low-molecular-weight heparins also need to
be tested. Data on cost-effectiveness compared with current therapies
will also be required.
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Table 7. Characteristics of an "Ideal" Thrombolytic
Agent
ASSENT
=
Assessment of the Safety and Efficacy of a New Thrombolytic
Agent
ASSET
=
Anglo-Scandinavian Study of Early Thrombolysis
COMPASS
=
Comparison of Saruplase and Streptokinase in Acute Myocardial
Infarction
FTT
=
Fibrinolytic Therapy Trialists
GISSI-1
=
Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto
Miocardico
GISSI-2
=
Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto
Miocardico
GUSTO-I
=
Global Utilization of Streptokinase and Tissue Plasminogen
Activator for Occluded Coronary Arteries
GUSTO-III
=
Global Use of Strategies to Open Occluded Coronary Arteries
INJECT
=
International Joint Efficacy Comparison of Thrombolytics
InTIME
=
Intravenous n-PA for Treating Infarcting
Myocardium Early
ISIS-3
=
Third International Study of Infarct Survival
ISIS-4
=
Fourth International Study of Infarct Survival
LATE
=
Late Assessment of Thrombolytic Efficacy
n-PA
=
novel plasminogen activator; lanoteplase
RAPID-2
=
Reteplase Versus Alteplase Patency Investigation During Acute
Myocardial Infarction
SESAM
=
Study in Europe with Saruplase and Alteplase in Myocardial Infarction
TIMI
=
Thrombolysis in Myocardial Infarction
TNK-tPA
=
TNK-tissue plasminogen activator
USIM
=
Urochinasi per via Sistemica nell'Infarto Miocardico