Thrombolysis For Acute Myocardial Infarction: Clinical Cardiology: New Frontiers

Clinical Cardiology: New Frontiers
Thrombolysis for Acute Myocardial Infarction

Harvey D. White, DSc; Frans JJ. Van de Werf, MD
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 «=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 Ilb/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. (Circulation. 1998;97:1632-1646.)
Key Words: myocardial infarction • plasminogen activators • streptokinase • thrombolysis
A short distance from its origin the left coronary artery acute myocardial infarction. Unfortunately, many of these
was completely obliterated by a red thrombus that had patients do not receive thrombolytic therapy, and countless
formed at a point of great narrowing. . . lives are lost despite the best scientific evidence of its
safety and efficacy. Underusage and delay in administering
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T hus did James Herrick describe the autopsy of his first

patient in his seminal paper in 1912,' attributing myo-
cardial infarction to coronary artery thrombus. He went on to
thrombolytic therapy are the two greatest challenges facing
physicians caring for patients with acute myocardial
infarction.
state, "The hope for the damaged myocardium lies in the The first use of thrombolytic therapy in patients with
direction of securing a supply of blood." Over the next 68 acute myocardial infarction was reported by Fletcher and
years, controversy raged as to whether coronary artery throm- colleagues in 1958.3 In the early 1960s and 1970s, 24 trials
bus was a cause of myocardial infarction or whether the clot were performed evaluating the efficacy of intravenous
formed after death and was merely a postmortem finding. In streptokinase.4 By modern standards, these trials had major
1980, DeWood and colleagues2 reported finding thrombus in design flaws. For instance, patients were randomized up to
the infarct-related arteries of ^90% of patients undergoing 72 hours after the onset of myocardial infarction, and low
acute coronary artery surgery in the first few hours after the doses of streptokinase (50 000 to 150 000 IU) were used.
onset of acute myocardial infarction. Although Herrick was The theoretical basis for the administration of thrombolytic
referring to collateral blood flow when he wrote of "securing therapy was also not yet established, and this, together
a supply of blood," his original insight forms the basis for the with lack of evidence of efficacy in a single trial, led to the
use of thrombolytic therapy. abandonment of further investigation into this mode of
The most important therapeutic goal in the management treatment.
of acute myocardial infarction is early restoration of In 1969, Chazov administered intracoronary streptokinase in
complete infarct artery perfusion after the occurrence of an Russia,5 and it is now nearly 20 years since Rentrop et al6
acute coronary occlusion. More than 200 000 patients have reported its use, thereby rejuvenating interest in reperfusion as a
been randomized in clinical trials of thrombolytic therapy, treatment modality for the management of acute myocardial
and in no other area of medicine has a therapy been so infarction. Since then, several new thrombolytic agents, includ-
extensively investigated. Each year between 1.5 and 2 ing tissue plasminogen activator (alteplase or reteplase), and
million patients worldwide are admitted to hospital with adjunctive antiplatelet and antithrombotic regimens have been
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 (e-mail
harveyw@ahsl.co.nz) or Professor Frans Van de Werf, Department of Cardiology, University Hospital Gasthuisberg, Herestraat 49, B-3000 Leuven,
Belgium (e-mail frans.vandewerf@vz.kuleuven.ac.be).
© 1998 American Heart Association, Inc.
1632
White and Van de Werf April 28, 1998 1633
to 1 year after reperfusion) may occur in 25% to 30% of

Selected Abbreviations and Acronyms patent infarct-related arteries.12-13 Because long-term patency
ASSENT = Assessment of the Safety and Efficacy of a New of the infarct-related artery has been shown to be an inde-
Thrombolytic Agent
pendent prognostic factor,14'15 even silent late reocclusion
ASSET = Anglo-Scandinavian Study of Early Thrombolysis
COMPASS = Comparison of Saruplase and Streptokinase in Acute
may be associated with a poor outcome.
Myocardial Infarction
FIT = Fibrinolytic Therapy Trialists Eligibility
GISSI-1 = Gruppo Italiano per lo Studio della Streptochinasi The proportion of patients presenting with myocardial infarc-
nell'Infarto Miocardico tion who are eligible for thrombolytic therapy has varied in
GISSI-2 = Gruppo Italiano per lo Studio della Sopravvivenza reports because of differing eligibility criteria, and depends
nell'Infarto Miocardico
partly on whether "eligibility" is based on the admission ECG
GUSTO-I = Global Utilization of Streptokinase and Tissue
Plasminogen Activator for Occluded Coronary and time window criteria (Table 1) or on a discharge
Arteries diagnosis of myocardial infarction. In ISIS-4, 70% of patients
GUSTO-III = Global Use of Strategies to Open Occluded who presented with suspected acute myocardial infarction
Coronary Arteries received thrombolytic therapy.31 This figure, however, may
INJECT = International Joint Efficacy Comparison of represent only a subset of patients presenting with myocardial
Thrombolytics
infarction, because only a few patients per month were
InTIME = Intravenous n-PA for Treating Infarcting
Myocardium Early randomized in the trial in each hospital.
ISIS-3 = Third International Study of Infarct Survival In a recent prospective study, 53% of patients presenting to
ISIS-4 = Fourth International Study of Infarct Survival four coronary care units in Auckland were eligible for
LATE = Late Assessment of Thrombolytic Efficacy reperfusion therapy on the basis of ECG criteria (ST-segment
n-PA = novel plasminogen activator; lanoteplase elevation or new left bundle-branch block) and a 12-hour
RAPID-2 = Reteplase Versus Alteplase Patency Investigation
time window.32 Thirty-three percent of the patients had
During Acute Myocardial Infarction
SESAM = Study in Europe with Saruplase and Alteplase in
ST-segment depression, paced rhythms, or T-wave inversion,
Myocardial Infarction and 14% presented after 12 hours.
TIMI = Thrombolysis in Myocardial Infarction The goal should be to treat all eligible patients with
TNK-tPA = TNK-tissue plasminogen activator reperfusion therapy as soon as possible. Contraindications
USIM = Urochinasi per via Sistemica nell'Infarto Miocardico against thrombolytic therapy exist in 7% to 10% of pa-
tients.32'33 Ineligibility for thrombolysis does not mean that the
patient is ineligible for reperfusion, and percutaneous revas-

developed. In this article, we highlight some of these important cularization should be considered in such cases.
developments and their clinical implications.
Time
Importance of Infarct Artery Patency The timing of the onset of ischemic symptoms is only a crude
The primary goal of thrombolytic therapy is rapid, complete, measure for determining when the infarct-related artery
and sustained restoration of infarct artery blood flow. The occluded and myocyte necrosis began. This is because
GUSTO-I angiographic substudy strongly correlated 90- occlusion may occur intermittently,34 myocardial demands
minute patency of the infarct-related artery with the mortality may vary, and the presence and function of collateral circu-
reduction achieved with accelerated alteplase.7 Regardless of lation may play an important role. In animals, myocardial
the thrombolytic agent used, an occluded infarct-related necrosis begins within 15 minutes of the onset of a coronary
artery (ie, TIMI grade 0 or 1 flow)8 at 90 minutes was artery occlusion, with a "wave front" of myocyte necrosis
associated with an 8.9% 30-day mortality rate, and "normal" proceeding from the endocardium to the epicardium.35 After
perfusion (TIMI grade 3 flow) with a 4.0% mortality rate. 40 minutes of occlusion, necrosis is 38% complete; at 3 hours
Patients with "partial" perfusion (TIMI grade 2 flow, ie, it is 57% complete; at 6 hours 71% complete; and at 24 hours
infarct-related artery fills to full length but more slowly than 85% complete. Depletion of ATP occurs over a similar time
adjacent normal vessels) had an intermediate mortality rate of frame.36 In humans, the time window is likely to be longer
7.4%. In addition, at 5 to 7 days, left ventricular ejection because of the factors mentioned above, and ischemic pre-
fractions were higher, end-systolic volumes were smaller, and conditioning may also extend the time during which myocar-
regional wall motion in the infarct zone was less depressed in dial salvage may occur.37
patients with TIMI grade 3 flow than in those with lesser
TIMI flow grades,9 confirming the hypothesis that early Early Treatment
perfusion at 90 minutes results in preservation of left ventric- Streptokinase therapy was associated with a 51 % reduction in
ular function and reduced mortality. mortality (SD, 12%) at 21 days in a retrospective subgroup
The benefits of early reperfusion may, however, be re- analysis of patients randomized to Streptokinase or control
duced by subsequent reocclusion of the infarct-related artery. treatment within 1 hour of symptom onset in the GISSI-1
Early reocclusion causes loss of ventricular function and trial. This observation was considered "hypothesis-generat-
doubles the mortality rate.10 The incidence of reocclusion ing" by the FTT Collaborative Group,38 who analyzed nine
varies from 4.9% to 25%, depending on the thrombolytic and trials of fibrinolytic therapy that had randomized more than
adjunctive therapies used.9'11 Late reocclusion (occurring up 1000 patients each (n=58 600). They concluded that there
1634 Thrombolysis for Acute MI
TABLE 1. Eligibility Criteria for Thrombolytic Therapy in Clinical Trials

ST-Segment Elevation
Time From
Symptom Limb Leads Leads V, to V3 Leads V4 to V6 ST-Segment
Trial Onset, h (n) (n) (n) Depression Other Criteria
16
Western Washington >1 mm (2) >1.5mm(2) >1 mm (2) Not eligible One lead with ST elevation if no Q
waves or hyperacute T waves
Interuniversity17 <4 s1 mm (1) >2mm(1) >2mm(1) Not eligible
18
GISSI-1 <12 >1 mm (1) >2mm(1) >2 mm (1) As for ST elevation
ISAM19 <6 >1 mm (1) >2mm(1) >2mm(1) Not eligible
ECSG20 <5 >2 mm (2) >3 mm (2) >2 mm (2) Yes if other criteria Patients with ST depression of >2
mm in precordial leads eligible if
associated with ST elevation of 1
mm in 2 limb leads or V4 to V6
AIMS21 <6 >1 mm (2) >2 mm (2) >2 mm (2) Not eligible
ASSET22 <5 Acute infarction clinically suspected
ISIS-223 <24 Acute infarction clinically suspected
White et al24'25 <6 >1 mm (2) >2 mm (2) >1 mm (2) Not eligible
USIM26 <4 a! mm (1) >2mm(1) >2mm(1) As for ST elevation
27
ISIS-3 <24 Acute infarction clinically suspected
28
EMERAS 6-24 Acute infarction clinically suspected
GUSTO-129 <6 si mm (2) >2 mm (2) >2 mm (2) Not eligible
LATE30 6-24 >1 mm (2) >2 mm (2) >2 mm (2) >2 mm in 2 leads Abnormal Q or T waves in 2 leads
AIMS indicates Anistreplase in Acute Myocardial Infarction; ECSG, European Cooperative Study Group; EMERAS, Estudio Multicentrico Estreptoquinasa Republicas
de America del Sur; and ISAM, Intravenous Streptokinase in Acute Myocardial Infarction. Modified with permission from Reference 32.
was no marked discontinuity at 0 to 1 hours and only a with unstable angina (32%), and ISIS-3 included patients
gradual diminution of benefit with delay (30% reduction at 0 without or with only minor ST-segment elevation. The
to 1 hours [SD, 9%]; 25% reduction at 2 to 3 hours [SD, 5%]; proportional mortality reduction was 48% in patients treated
and 18% reduction at 4 to 6 hours [SD, 5%]). For each hour within 1 hour (95% CI, 31% to 61%), and patients treated
of delay in administering thrombolytic therapy, 1.6 additional within 2 hours had a significantly greater mortality reduction
lives were lost for every 1000 patients treated. (44%; CI, 32% to 53%) than those treated later (20%; CI,
Boersma and colleagues39 recently analyzed 22 trials that 15% to 25%). These benefits exceed the FTT linearfindingof
had compared fibrinolytic therapy with placebo or control 1.6 lives saved per 1000 patients for each hour of earlier
treatment in at least 100 patients (n=50 246), They came to treatment. The implied benefit from treatment 1 hour earlier
in GUSTO-I, five lives saved per 1000 patients treated, was
a different conclusion, namely, that the relation between
treatment delay and mortality reduction was expressed sig- also greater than the FTT finding.
These analyses are from nonrandomized comparisons of
nificantly better by a nonlinear than a linear regression
patients treated earlier versus those treated later and need to
equation (F=.03) (Fig 1). Their analysis excluded 4250
be interpreted cautiously. Patients who present earlier may
patients from the USIM26 and ISIS-327 trials, both of which have larger infarcts, and those presenting later are more often
were included in the FTT analysis. USIM included patients elderly, female, diabetic, or hypertensive or have had previ-
ous 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 aim-
ing 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. Pa-
tients in the United States faced slightly longer delays
o (median, 66 minutes) than those outside the United States
Time to 0-1
treatment (h) (median, 60 minutes).40 It is disappointing to note that in the
Average 0.75
delay (h) GUSTO-III trial, which commenced randomization 5 years
Figure 1. Mortality among fibrinolytic-treated and control after GUSTO-I, the median delay was 54 minutes. Whichever
patients according to treatment delay. Reproduced with permis- thrombolytic regimen is used, it is important that treatment
sion from Reference 39. delays be reduced for the benefit of all eligible patients.
Age TABLE 2. Cost Per Additional Year of Life for Accelerated

Older age is associated with increasing rates of mortality and Alteplase Versus Streptokinase After Myocardial Infarction in
intracerebral hemorrhage after thrombolytic therapy, regard- Selected Patient Subgroups
less of the thrombolytic agent used. Concerns about increas- Cost Per Additional Life-Year
ing hemorrhagic risk caused a number of the early (in 1993 US dollars)
thrombolytic trials to impose an upper age limit for random-
Age of Patient, y Anterior Infarction Inferior Infarction
ization,21'22'42"43 and physicians became reluctant to use
thrombolytic therapy in patients >75 years of age. Indeed, <40 123609 203 071
the 1990 American College of Cardiology/American Heart 41-60 49877 74896
Association guidelines for the early management of patients 61-75 20601 27873
with acute myocardial infarction stated that physicians should >75 13410 16246
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 benefit (death plus nonfatal disabling stroke) would be lessened.
have potentially the most to gain from reperfusion strategies However, because mortality from intracerebral hemorrhage in-
because of their high absolute mortality rate. Almost half of creases dramatically with age, intracerebral hemorrhage contrib-
all deaths after acute myocardial infarction occur in patients utes more to the mortality component of the net clinical benefit,
>75 years old,45 and older age is the most important prog- and few patients survive with disabling strokes (Fig 2). The
nostic factor after myocardial infarction.46'47 No randomized, greater cardiac benefit of alteplase in the elderly maintains the
placebo-controlled thrombolytic trial has been designed spe- advantage of this therapy up to the age of 85 years. For patients
cifically to assess benefits and risks in the elderly. However, >85 years old, the best regimen in GUSTO-I appeared to be
the FTT overview showed that mortality was significantly streptokinase plus subcutaneous heparin.49
lower in patients 65 to 74 years old who had received
thrombolytic therapy than in control patients (16.1% versus Infarct Site
13.5%; P<.00001), and there was a nonsignificant trend Patients with anterior or inferior infarcts should receive
toward a reduction in mortality in patients >75 years old thrombolytic therapy. Although inferior infarcts are usually
(25.3% versus 24.3%).38 smaller, the GISSI-1 trial showed that the benefit of
The GUSTO-I trial had no upper age limit for randomiza- thrombolytic therapy was related to the amount of ST-
tion, and the oldest patient enrolled was 110 years of age.48 segment elevation rather than the site of the infarct.53
Forty percent of thrombolytic-eligible patients have inferi-
Multivariate analysis confirmed that older age was the most

important adverse prognostic factor, with a 30-day mortality or ST-segment elevation on the presenting ECG.38 In the FTT
rate of 1.1% in patients <45 years and 20.5% in those >75 overview, patients with inferior ST-segment elevation who
years old.47 All but the oldest patients (those >85 years of were randomized within 12 hours of symptom onset had a
age) had a lower mortality rate, and the net clinical benefit mortality reduction of 13% (95% CI, -24% to 0%).
(death plus nonfatal disabling stroke) was greater in patients Patients with inferior infarcts are a heterogeneous group,
randomized to receive accelerated alteplase.49 and adverse prognostic factors may not be apparent on
Thrombolytic therapy remains underused in the elderly. admission when the decision as to whether or not to give
Patients >75 years of age are six times less likely to receive thrombolytic therapy must be made. Before the thrombolytic I
thrombolytic therapy than younger patients.50 In a North era, the incidence of second- or third-degree heart block
American registry of the GUSTO-I trial, 30.1% of patients complicating inferior infarction was =19%,54 but nowadays
presenting with acute myocardial infarction were >75 years the incidence is ^11.8% with thrombolytic therapy, and the
old, but only 17.8% were randomized in the study.5' There are need for temporary pacemakers is uncommon.29 Right ven-
several possible reasons why elderly patients are less likely to tricular infarction occurs in <==30% of patients with inferior
receive thrombolytic therapy, including the higher frequency infarcts, and those with ECG evidence of right ventricular
of anginal equivalents, more nondiagnostic ECGs, later pre- infarction have a mortality rate of 30%.55 In the FTT
sentation, a higher incidence of comorbid disease, and rela- overview, patients with acute inferior infarction and a previ-
tive contraindications against the use of thrombolytic therapy. ous infarction had a mortality rate of 13%. Patients with
With regard to cost-effectiveness, the elderly are likely to inferior infarction and anterior ST-segment depression are
obtain greater benefit from thrombolytic therapy because the
average number of life-years added by treatment with accel- - Mortality
erated alteplase is greater than in younger patients (Table 2).52 - Stroke

- Non-fatal disabling stroke
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. <45 45-49 50-54 55-58 59-61 62-64 65-68 69-71 72-76 >76
It might be expected that a more aggressive thrombolytic Age (years in deciles)
regimen, such as accelerated alteplase, would cause more intra- Figure 2. Incidence of mortality, stroke, and nonfatal disabling
cerebral hemorrhage in elderly patients and that the net clinical stroke with increasing age.
also at high risk. All of these patient groups are at high TABLE 3. Major Contraindications Against the Use of
absolute risk and are likely to benefit substantially from Thrombolytic Therapy
thrombolysis, which reduces mortality and preserves left Any previous history of hemorrhagic stroke
ventricular function.24 A patent infarct-related artery has the History of stroke, dementia, or central nervous system damage
potential to provide collaterals to another infarct zone in the within 1 year
event of subsequent coronary occlusion and can decrease Head trauma or brain surgery within 6 months
arrhythmogenesis and remodeling of the left ventricle.56
Known intracranial neoplasm
Treatment of elderly patients with inferior infarcts has been
Suspected aortic dissection
shown to be particularly cost-effective compared with other
widely used treatments (Table 2).52 Internal bleeding within 6 weeks
Patients with lateral or circumflex artery infarcts not Active bleeding or known bleeding disorder
involving the inferior surface of the heart have usually been Major surgery, trauma, or bleeding within 6 weeks
excluded from randomized trials because of the requirement Traumatic cardiopulmonary resuscitation within 3 weeks
for 2 mm of ST-segment elevation in leads V4 to V6 (Table 1),
even though these leads are not usually affected by repolar-
weighed against the risk of bleeding to determine the likeli-
ization abnormalities. It would seem logical that patients with
hood of benefit or harm. If percutaneous revascularization
occlusive thrombus in a circumflex artery would benefit from
procedures are available, the threshold for administering
thrombolytic therapy, and these patients could be identified
thrombolytic therapy in the presence of contraindications
by 1 mm of ST-segment elevation in the lateral precordium or
should be higher. However, if thrombolytic therapy is the
lead aVL or by an echocardiogram showing a lateral wall
only option available, then contraindications in very sick
motion abnormality. True posterior infarcts should also be
treated. The FTT overview showed that patients with bundle- patients may outweigh the possibility of benefit.
branch block patterns also benefit from thrombolytic therapy.
The trials that included such patients did not specify that the Oral Anticoagulants and Known
bundle-branch block must be new. ST-segment elevation is Bleeding Disorders
Some authorities and most recent trials have considered oral
easily recognized in the presence of right bundle-branch
anticoagulants to be an absolute contraindication against the
block, and new infarction can also be detected in the presence
use of thrombolytic therapy. In a multivariate logistic regres-
of left bundle-branch block.57 If the diagnosis is uncertain and
sion analysis of 2469 patients with acute myocardial infarc-
an old ECG is not readily available, echocardiography may
tion, those on oral anticoagulants before admission had a
help to determine whether there is a regional wall motion

abnormality. Although sequential examinations may be re- significantly higher risk of intracranial hemorrhage after
quired to determine whether this was due to acute ischemia, thrombolysis.59 Theoretically, these patients would be at
stunning, previous long-standing necrosis, or myocardial increased risk of bleeding because of depletion of the vitamin
disease, the absence of myocardial thinning and the presence K-dependent clotting factors (factors II, VII, IX, and X).
of contralateral wall hyperkinesis would be supportive evi- However, if the international normalized ratio is subtherapeu-
dence for an acute ischemic event. Bedside measurement of tic, it may be reasonable to administer thrombolytic therapy
cardiac proteins such as myoglobin or troponin T may also as indicated and to delay or reduce the first dose of heparin.
aid management. If the international normalized ratio is in the therapeutic
If patients have a good history of prolonged ischemic chest range, one approach would be to administer thrombolytic
pain and a normal ECG, they should have another ECG 30 therapy simultaneously with fresh frozen plasma to replenish
minutes later, because it may take time for significant
ST-segment abnormalities to manifest. TABLE 4. Relative Contraindications Against the Use of
Thrombolytic Therapy
Contraindications Oral anticoagulant therapy
As thrombolytic therapy has become more widely used and Acute pancreatitis
the results of the megatrials have confirmed its efficacy and
Pregnancy or within 1 week postpartum
safety, the contraindications have widened in some instances
Active peptic ulceration
and narrowed in others. In many circumstances, however, no
data are available and recommendations must be based on Transient ischemic attack within 6 months
reasonable judgments. Depending on patient demographics Dementia
and the regimen used, thrombolysis is associated with an Infective endocarditis
increase in the stroke rate of *»0.4% to 0.8%,2938'58 and there Active cavitating pulmonary tuberculosis
is bleeding requiring transfusion in ««5% of cases, depending Advanced liver disease
on the number of invasive procedures performed.29 Table 3 Intracardiac thrombi
lists major contraindications and Table 4 relative contraindi-
Uncontrolled hypertension (systolic blood pressure >180 mmHg,
cations against the use of thrombolytic therapy. For the diastolic blood pressure >110 mm Hg)
individual patient, the size of the infarct, the hemodynamic
Puncture of noncompressible blood vessel within 2 weeks
status, any history of previous infarction, the time elapsed
Previous streptokinase therapy
since symptom onset, and the patient's age, etc, must be
White and Van de Werf April 28,1998 1637
the clotting factors. It should be acknowledged, however, that threshold for this effect.62 The rate of intracranial hemorrhage
these approaches have not been formally evaluated. was doubled if the systolic pressure was >175 mmHg at
Little information is available about the safety of study entry. The effect of elevated diastolic blood pressure at
thrombolytic therapy in patients with common abnormalities entry on clinical outcomes is less striking. In GUSTO-I, there
such as von Willebrand's disease, which affects 0.1% of the was a slight increase in the rates of intracranial hemorrhage
population. The clinical manifestations of this disorder are with increasing diastolic blood pressure, but no significant
variable. If patients have had only mild bleeding associated increase in mortality was observed in patients with high
with trauma, it may be reasonable to administer thrombolysis, diastolic blood pressures on admission (^100 mm Hg). It is
whereas if transfusion has been required, thrombolysis would unknown whether acute treatment of high blood pressure on
be contraindicated. admission reduces the risk of intracranial hemorrhage after
thrombolysis. However, in patients for whom coronary an-
Other Contraindications gioplasty is inappropriate or unavailable, it would seem
Hemorrhagic pancreatitis could be aggravated by reasonable to lower the blood pressure immediately and then
thrombolytic therapy and is therefore considered a relative administer thrombolytic therapy.46 In some patients with a
contraindication against the use of thrombolytic therapy. very high blood pressure on admission and a low risk of dying
There are no data on fetal safety when thrombolytic of cardiac causes,62 the risk of hemorrhagic stroke may
therapy is administered during pregnancy, and there is also a outweigh the potential reduction in mortality and morbidity.
risk of maternal bleeding in the first week postpartum. Sufficient anti-streptokinase antibodies develop to neutral-
Recent bleeding from peptic ulceration in the previous 6 ize a standard dose of streptokinase within 3 to 4 days after
weeks is considered a contraindication against the use of initial administration. At 4 years, 50%63 of patients still have
thrombolytic therapy, but "vague" indigestion should not elevated levels of antibodies. Because of concerns mainly
prevent patients from receiving thrombolytic therapy. about efficacy but also about allergy,64'65 streptokinase should
In a case-control study from GUSTO-I,60 the risk of not be readministered except in the first 24 to 48 hours.
intracerebral hemorrhage in patients who had previously
suffered transient ischemic attacks was 2.8 times that of Factors That Should Not Be
control cases.60 Patients with a history of dementia had 3.4 Considered Contraindications
times the risk of intracerebral hemorrhage. This may relate to Menstruation
the known increased bleeding risk associated with cerebral Active bleeding at the time of presentation with acute
amyloid angiopathy. myocardial infarction is usually considered a contraindication
Mycotic aneurysms associated with infective endocarditis against the use of thrombolytic therapy. However, menstrual
may bleed, and because of this possibility, endocarditis is bleeding is not due to hematological abnormalities but rather
considered a contraindication against the use of thrombolytic to high local concentrations of native plasminogen activator
therapy. and decreased procoagulants in the endometrial fluid, to-
Catastrophic hemoptysis may occur with cavitating pulmo- gether with active sloughing of the endometrium induced by
nary tuberculosis, and thrombolytic therapy is therefore prostaglandin-mediated arteriolar spasm. Although menstrual
contraindicated. bleeding could theoretically be increased during the first 12 to
Because the liver produces coagulant factors and there is a 18 hours of menstruation, this has not been observed in the
possibility of portal hypertension and esophageal varices with few women who have received thrombolytic therapy on day
the propensity for uncontrollable hematemesis, thrombolytic 1 of their menstrual cycle. There have been reports of 24
therapy is contraindicated in cases of advanced liver disease. women who have safely received thrombolytic therapy dur-
Percutaneous revascularization is preferable to ing menstruation, although moderate bleeding may be in-
thrombolytic therapy if there is a strong possibility of creased, requiring transfusion.66 Thus, the risk of bleeding is
systemic embolism from a fresh left atrial thrombus or a not a sufficient reason to deny women the benefits of
protuberant left ventricular thrombus. thrombolytic therapy.
Patients with acute myocardial infarction and a history of
hypertension or elevated blood pressure on admission have a Nontraumatic Cardiopulmonary Resuscitation
greater risk of intracranial hemorrhage after thrombolysis.46 Small series of patients have reported no significant compli-
In general, patients with a previous history of hypertension cations from resuscitation lasting <10 minutes.67'69 No sig-
represent a higher-risk group (older age, more women, higher nificant bleeding has been reported even when resuscitation
incidence of diabetes, and Killip class >I). They therefore was continued for 2 hours or when patients with rib fractures
have a worse clinical outcome, including both a higher were given thrombolytic therapy.70 Nontraumatic cardiopul-
cardiac death rate and higher total and hemorrhage stroke monary resuscitation should therefore not be considered a
rates.61 In GUSTO-I, the risk of death in patients with a high contraindication against the use of thrombolytic therapy.
systolic blood pressure at entry was similar to that in
normotensive patients (excluding patients with a systolic Diabetes
pressure of <120 mmHg, in whom the risk of death was Diabetic patients have been less frequently treated with
higher).62 The risk of intracranial hemorrhage, however, thrombolytic agents because of concerns about the increased
increased with systolic blood pressure, especially at systolic risk of bleeding complications. The 1990 American College
pressures of >170 mmHg, although there was no clear of Cardiology/American Heart Association guidelines for the
management of acute myocardial infarction classified dia- segment depression in the anterior leads may actually be
betic hemorrhagic retinopathy as an absolute contraindication developing a true transmural posterior infarction. Others may
against the use of thrombolytic therapy.71 In the FIT analysis, develop non-Q-wave infarction or may have unstable angina
however, the incidence of stroke and major bleeding compli- without myocardial necrosis. In general, the deeper the
cations after thrombolytic therapy was only slightly higher in ST-segment depression and the greater the number of leads
diabetic patients (stroke, 1.9% versus 1.0%; major bleeding, involved, the greater the likelihood of myocardial necrosis
1.3% versus 1.0%),38 and in the GISSI-2/International Study and thus non-Q-wave infarction.77 In the LATE study,78
Group trial, the incidence of these complications was similar mortality rates in 528 patients with confirmed non-Q-wave
among diabetic and nondiabetic patients.72 Intraocular hem- infarction and ST-segment depression of ^2 mm were
orrhage and, more specifically, retinal bleeding are extremely significantly lower in those who received alteplase (8.6%
uncommon complications of thrombolytic therapy. In the versus 16.6% at 35 days [P<.006] and 20.1% versus 31.9%
GUSTO-I study, 300 of the 6011 diabetic patients were at 1 year [P<.006]). This post hoc analysis of patients treated
estimated to have proliferative retinopathy, but none had late suggests that thrombolytic therapy may be beneficial in
intraocular hemorrhages, and the calculated upper 95% con- selected patients with typical symptoms and deep ST-seg-
fidence limit of the possible occurrence of intraocular hem- ment depression (>2 mm), because these patients are most
orrhage was only 0.05%.73 It is unlikely that thrombolytic likely developing a true posterior wall infarction or non-Q-
therapy would increase vitreous hemorrhage, which is due to wave infarction. The overall outcomes in patients with
vitreous detachment, in patients with diabetic retinopathy. ST-segment depression observed in the FTT study may
Also, the few nondiabetic patients reported have shown no represent a net benefit in patients with posterior wall infarc-
limitation of visual acuity at follow-up.74'75 Thus, the concerns tion or non-Q-wave infarction and harm in those patients
many clinicians have about bleeding complications after with unstable angina. New prospective trials in patients with
thrombolysis in diabetic patients are not supported by the ischemic chest pain and deep ST-segment depression are
results of large-scale clinical trials. needed.
With regard to efficacy, the GUSTO-I angiography sub-
study showed that thrombolytic therapy is equally efficacious Cardiogenic Shock
in restoring early coronary artery patency in patients with and Thrombolytic therapy may be less effective in patients with
without diabetes.61 In the FTT analysis, diabetics had a 21% cardiogenic shock. In the GISSI-1 trial,18 hospital mortality
reduction in 35-day mortality with thrombolytic therapy rates in Killip class IV patients were high, with no difference
compared with control therapy, which corresponds to 37 lives between control patients and those treated with streptokinase
saved per 1000 patients treated versus 15 lives in nondiabetic (69.9% versus 70.1%, respectively). Also, in the FTT over-
patients. Thus, diabetic patients with acute myocardial infarc- view,38 patients with both a systolic blood pressure of
tion are just as eligible for thrombolytic therapy as nondia-
<100 mmHg and a heart rate of >100 bpm had high
betics, but their early mortality rates remain high even after
mortality rates at 35 days, with a statistically nonsignificant
adjustment for both clinical and angiographic variables.61 A
difference in favor of thrombolysis (53.8% versus 61.1%). In
higher reocclusion rate and reduced compensatory hyperki-
view of these observations, cardiogenic shock is considered
nesis of the noninfarct zones have been proposed as expla-
an indication for primary angioplasty, although there are also
nations for this excess in early mortality.61
no randomized data showing benefit. If primary angioplasty
is unavailable, thrombolytic therapy, preferably using a non-
Subgroups
Although thrombolysis has become the mainstay of acute fibrin-specific agent such as streptokinase, should be given.
treatment in the majority of patients with suspected acute Lower mortality rates were observed in Killip class IV
myocardial infarction, uncertainties still remain with regard patients given streptokinase than in those given alteplase in
to the clinical benefit of this therapy in certain subgroups of both the GISSI-2/International Study Group trial (64.9% with
patients. streptokinase versus 78.1% with alteplase; P<.05)33'79 and the
GUSTO-I trial (55.6% with streptokinase versus 62% with
ST-Segment Depression alteplase; P=.06).29 A possible explanation for these obser-
Patients without ST-segment elevation are currently not given vations is that a sufficiently high coronary perfusion pressure
thrombolytic therapy. In the FTT analysis,38 mortality at 35 is needed for local fibrin-specific clot lysis,80 whereas the
days in such patients was nonsignificantly higher after induction of a general lytic state with subsequent local clot
thrombolysis (15.2%) than after control treatment (13.8%). A lysis can occur at low arterial blood pressures with a
possible explanation for this negative outcome is the proco- non-fibrin-specific agent. Although hypotension may occur
agulant effect of fibrinolytic agents, which may cause pro- during administration of streptokinase, this is unrelated to the
gression of a nonobstructive mural thrombus to complete initial blood pressure and is usually rapidly reversible with
occlusion. Theoretically, thrombolytic therapy could worsen administration of fluids and cessation of the streptokinase
a coronary artery stenosis by causing intraplaque hemorrhage, infusion. It is important that a full dose of a thrombolytic
and lysis of a subocclusive thrombus could also cause distal agent is given when the patient is hemodynamically stable,
embolism and infarction.76 either by recommencement of streptokinase at a lower infu-
Patients with ischemic chest pain and ST-segment depression rate or by administration of alteplase or reteplase;
sion are a heterogeneous group. Some patients with ST- otherwise, angioplasty should be considered.
Study N Treatment Mortally Bedn±»d Odds RMto and CL

_ Jm> Pre-hospital Hospital
DHtofonco Group Group
(mm)
• «l itn. t-
Barbash (r*f83) 87 AKeplase (120mg over 6 hours) 36 0.0% 6.8% 87 ± 50
GREAT (ntSSI 311 Anistreplase (30u, IV bolus) 130 6.7% 11.5% 44 ± 30 • •
11.6%
EMIP (nf87) 5649 Anistreplase (30u, IV bolus) 55 9.7% 11.1% 15 ±8
MITI (rtfSS) 360 Alteptase (lOOmg over 3 hours) 33 57% 8.1% 31 ± 35
*
Crude Subtotal 6607 9.1% 10.7% 17 ±8 <?>
Crude Total 6607 9.1% 10.7% 17 ± 8 4

0.0 0.5 1.0 1.5 2.0
Test tor homogeneity: CM square - 4.69

Treatment effect 2P - 0.023
Figure 3. Results of trials comparing prehospital with in-hospital administration of thrombolytic therapy. Relative risk of early death (in hospi-
tal 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.
Prior Coronary Artery Bypass Graft Surgery that thrombolytic therapy reduced mortality by 14% (SD, 5%)
In GUSTO-I, prior bypass surgery was an independent in patients randomized between 7 and 12 hours after symp-
predictor of a higher 30-day mortality rate.47 tom onset (/J=.005),38 and there was a nonsignificant 5%
The poor outcome in these patients may be explained by a reduction in mortality among the 9000 patients who presented
higher prevalence of multivessel disease and impaired left after 12 hours. Because patients from the LATE and ASSET
ventricular function and a lower 90-minute coronary artery studies were not subdivided by ECG criteria in this analysis,
patency rate after thrombolysis,47'81 most likely because of the the benefit in patients presenting between 13 and 18 hours
presence of large thrombi when a vein graft is the infarct- with ST-segment elevation or bundle-branch block could be
related vessel. This probably also explains the greater benefit of the order of 10 lives saved per 1000 patients treated.38
observed in these patients when they are given a more potent Patients who present late may have stuttering infarcts, or
lytic agent such as alteplase.82 Indeed, although the difference the infarct-related artery may have been patent at some stage
was not significant, this group had one of the largest treat- after the initial occlusion,34 enabling salvage of myocardium
ment differences in GUSTO-I: the 30-day mortality rate was beyond 6 hours. The major benefit of late treatment, however,
11% in patients who received streptokinase and 8.3% in those is probably not due to myocardial salvage but rather to other
randomized to receive alteplase. mechanisms (Table 5).56
Prehospital Treatment Choice of Agent

Eight trials have randomized patients to receive prehospital or Three megatrials randomizing a total of 103 069 patients have
in-hospital thrombolytic therapy. When combined, these tri- compared the effects on mortality of various thrombolytic
als show a significant 17% reduction in early mortality with agents. In the GISSI-2/International Study,33'79 20 891 pa-
prehospital treatment (21 lives saved per 1000 patients tients were randomized to receive either streptokinase or
treated; P=.02) (Fig 3).83'90 Complication rates are similar in alteplase infused over a period of 3 hours in a factorial design,
both community-initiated and hospital-initiated thrombolysis, followed by randomization at 12 hours to either no heparin or
although ventricular fibrillation may occur more frequently in subcutaneous heparin (12 500 IU) given twice daily. Mortal-
the community with prehospital administration,89 necessitat- ities at 30 days were similar (8.9% with streptokinase versus
ing well-trained staff and the availability of defibrillators. 8.5% with alteplase).
These benefits arise from earlier treatment, and similar The ISIS-3 trial randomized 41 299 patients to receive either
benefits would be expected if patients were able to be streptokinase, anistreplase, or duteplase (a form of tissue plas-
evaluated expeditiously and treated quickly in hospital. Pre- minogen activator not commercially available) infused over a
hospital administration of thrombolytic therapy has been period of 4 hours. As in GISSI-2, there was a factorial design
shown to be of the greatest value in sparsely populated
communities with transport delays to hospital of >1 hour. TABLE 5. Potential Benefits of Late Reperfusion
However, several studies91'92 have shown that «=20 patients
with chest pain require evaluation for every patient found to Reduction in infarct size
be eligible for thrombolytic therapy. Each community needs Improved scar formation and healing
to define the best approach for expeditious delivery of Decreased infarct expansion
reperfusion therapy on the basis of local transportation times, Decreased non-infarct zone remodeling
resources, and available expertise. Decreased left ventricular volumes
Reduced mural thrombus formation
Late Treatment Lower incidence of arrhythmias
A 12-hour time window for administration of thrombolytic
therapy is now widely accepted.93 The FTT overview showed Provision of collateral blood flow to another infarct zone
with subcutaneous heparin or control therapy beginning 4 hours other are less affected by the time of recanalization (eg,
after initiation of thrombolytic therapy. Mortality was similar attenuation of infarct expansion, left ventricular remodeling,
with all three thrombolytic regimens: 10.5% with streptokinase, enhanced electrical stability, and provision of collateral
10.3% with duteplase, and 10.6% with anistreplase.27 flow).'456-99-100 One would expect that these favorable effects
The GUSTO-I trial randomized 41 021 patients to receive would result in survival benefits not only during the hospital
one of four thrombolytic regimens.29 The lowest mortality stay but also afterward. Surprisingly, no extra survival benefit
rate at 30 days (6.3%) was achieved with accelerated alte- after hospital discharge has been observed in patients given
plase infused over a period of 90 minutes with immediate intravenous thrombolytic therapy. A meta-analysis performed
administration of intravenous heparin, compared with 7.2% by the FTT Collaborative Group of more than 40 000 patients
for streptokinase plus subcutaneous heparin (as administered participating in placebo-controlled trials of intravenous
in ISIS-4,31 although 36% of patients in GUSTO-I also thrombolysis indicated that the risk of death after 1 month
received intravenous heparin), 7.4% for streptokinase plus was equal in survivors of acute myocardial infarction whether
immediate intravenous heparin, and 7.0% for combination or not intravenous thrombolytic therapy was given on admis-
therapy with streptokinase plus alteplase plus intravenous sion and irrespective of the time this treatment was started.101
heparin. At 30 days, the reduction in mortality was 14% in the There are many explanations for the absence of any extra
accelerated alteplase group compared with the combined long-term benefit. Only a minority of patients are treated
streptokinase groups, equating to an extra 10 lives saved per within a time window that allows substantial salvage of
1000 patients treated. For the combined end point of death ischemic myocardial tissue. The incidence of optimal reper-
plus nonfatal disabling stroke, there were 11 fewer events per fusion with the present fibrinolytic agents is only ~50%,9and
1000 patients treated. The benefit was consistent across most even in patients who receive treatment early and have TM
subgroups, including patients with anterior or inferior infarcts grade 3 flow, adequate tissue reperfusion is often not
and those presenting earlier or later. The greatest benefit was achieved ("no reflow" or "impaired reflow").102'10 Further-
seen in patients with higher-risk baseline characteristics.94 A more, reocclusion and reinfarction are frequently observed
nomogram has been developed that incorporates age, Killip after hospital discharge,12-13'104-'07 and late mortality rates are
class, heart rate, systolic blood pressure, history of infarction, high in patients with very poor residual left ventricular
and infarct location into a model for nonquantitative guidance function who survive the hospital phase because of successful
in selecting alteplase over streptokinase.94 thrombolysis.108-109 Thrombolytic therapy may have other
Why did ISIS-3 and GISSI-2 fail to demonstrate any mortality important benefits besides mortality reduction, such as pres-
differences between streptokinase and tissue plasminogen acti- ervation of left ventricular function, which can improve
exercise tolerance and quality of life. There have been
vator, as the GUSTO-I trial did? First, the failure to use

intravenous heparin in the former trials may have disadvantaged surprisingly few studies evaluating these potential benefits.
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 New Agents
patency than an accelerated alteplase regimen, which delivers New fibrinolytic agents are being developed to improve the
substantially more of the drug to an average-weight patient in the efficacy of clot lysis and/or ease of administration. Novel
first 60 minutes, as in GUSTO-I, and the absolute improvement plasminogen activators have been designed or purified from
in TEVII grade 3 flow with an accelerated alteplase regimen is of natural sources with one or more of the following properties: a
the order of 13%.96 prolonged half-life (allowing bolus administration), enhanced
fibrin specificity, or resistance to natural inhibitors such as
Cost-effectiveness plasminogen activator inhibitor-1. The following novel plasmin-
Several studies have used retrospective data and varying ogen activators are in different stages of clinical development or
assumptions to show that thrombolytic therapy is very cost- marketing or will enter clinical testing very soon: mutants of
effective compared with other accepted medical therapies.97 native tissue plasminogen activator (reteplase, lanoteplase,
An international issue is the appropriate allocation of scarce TNK-tPA); Desmodus salivary plasminogen activator-ab de-
healthcare resources, and many hospitals worldwide use rived from the saliva of the vampire bat, Desmodus mtundus;
streptokinase because it is 7 to 8 times cheaper than alteplase. saruplase (recombinant single-chain urokinase plasminogen ac-
The GUSTO-I study prospectively gathered details of hospi- tivator); and staphylokinase, produced by Staphylococcus au-
tal and medical charges in a subgroup of US patients.98 reus. Combinations of different fibrinolytic agents (chimeric
Compared with streptokinase therapy, the additional cost of plasminogen activators consisting of various portions of tissue
accelerated alteplase per extra life-year saved was US plasminogen activator and urokinase) have also been investi-
$27 382 (in 1992 dollars). The cost-effectiveness of prefer- gated, without any clear evidence that their benefit-to-risk ratio
entially using alteplase varied according to the age of the will outperform the single-agent regimens."1 Murine monoclo-
patients and the site of infarction (Table 2). nal anti-human fibrin antibodies conjugated with fibrinolytic
agents have not been tested in patients, although there is
Long-term Follow-up evidence of increased thrombolytic potency in animals." Table
Early and sustained coronary artery patency after 6 compares the properties of five new fibrinolytic agents that
thrombolysis has many beneficial effects. Some of these are have been or will be approved for clinical use over the next few
very much time-dependent (eg, salvage of ischemic myocar- years with those of alteplase and streptokinase. Each of these
dium with preservation of left ventricular function), whereas new agents will be briefly discussed.
TABLE 6. New Versus Established Fibrinolytic Agents in Acute Myocardial Infarction

Streptokinase Alteplase Staphylokinase TNK-tPA Reteplase Lanoteplase Saruplase
Molecular weight, D 47000 70000 16500 70000 39000 53500 46500
Plasma half-life, min 23-29 4-8 6 20 15 23 9
Fibrin specificity - ++ +++ + +++ + + ±
Plasminogen activation Indirect Direct Indirect Direct Direct Direct Direct
Dose* 1.5 MIU/60 min 100 mg/90 min 20-30 mg/30 min 0.5 mg/kg bolus 2x10 IU boluses 1 20 lU/kg bolus 80 mg/60 min
30 min apart
Antigenicity + + - - - -
Hypotension + - - - - -
Patency at 90 minutes + + ++ + + +(+?) + + +(+?) + ++ + + ++ + +++
Hemorrhagic stroke + ++ ? + or + + ++ ? ++
Mortality reduction + ++ ? 9 ++ 9
+ (+)
Cost + + ++ ++(?) + + +(?) ++ + + + +(?) + +(?)
Concomitant heparinf 9
+ + + + + +
MIU indicates million units.
*Most frequently used/tested.
fWith the exception of Streptokinase, and to some extent alteplase, the need for concomitant heparin has not been formally tested.
Reteplase reteplase showed only a small (and not statistically significant)

Reteplase (Boehringer Mannheim) is a deletion mutant of benefit over Streptokinase in the INJECT trial"5 and no benefit
alteplase (Fig 4) and represents the first of the third-generation over alteplase in the GUSTO-HI trial.58 In the latter trial, the
fibrinolytics to become commercially available. The kringle-2 absolute difference in 30-day mortality between reteplase and
and protease domains of native tissue plasminogen activator alteplase was 0.23% in favor of alteplase, with a 95% CI of
have been maintained, but the kringle-1, ringer, and epidermal —1.11% to 0.66%. These results do not support the equivalence
growth factor domains have been deleted, as have the carbohy- of reteplase and accelerated alteplase if a 1% absolute difference
drate side chains. Elimination of the kringle-1 and epidermal in mortality is considered an appropriate boundary of equiva-
growth factor domains reduces hepatic receptor binding, which, lence. On the other hand, for the secondary end point of death or
along with the lack of carbohydrate groups, prolongs plasma disabling stroke, the 95% CIs were <1%, suggesting that the
clearance. Reteplase has a half-life approximately twice that of two treatments were interchangeable. Stroke occurred in 1.64%
alteplase (Table 6) but less fibrin specificity because of the of patients treated with reteplase and 1.79% of those treated with
deletion of the finger domain. In two angiographic trials, alteplase (P=.5). These results clearly indicate the importance of
reteplase (given as two 10-IU boluses 30 minutes apart) yielded defining boundaries for equivalence in any future clinical eval-
more TEVII grade 3 flow at 90 minutes than a 3-hour (62.7% uation of new plasminogen activators.
versus 49.0%; P<.05)113 or 90-minute (59.9% versus 45.2%; Why did the enhanced patency rates with reteplase at 60 and
f=.01) infusion of alteplase.114 However, the same dose of 90 minutes not translate into lower mortality? This might have
kringle-1 kringle-2
epidermal
growth factor
signal
lanoteplase Figure 4. Molecular structure of alteplase, rete-

plase, lanoteplase, and TNK-tPA.
TNK-tPA reteplase
been due to chance, because the observed patency difference at patency rates, and slightly less fibrinogen breakdown.120 In
90 minutes would have been expected to produce a mortality the SESAM study, similar TIMI grade 2 and 3 flows were
difference of <15%.7 Alternatively, it may be that patency rates observed with saruplase and a 3-hour infusion of alteplase.121
with each agent fluctuate at different time points. In a small In the COMPASS equivalence trial (n=3089 patients), 30-
group (96 patients) in the RAPED-2 angiographic study, alte- day mortality rates were lower with saruplase (80 mg/h) than
plase produced higher patency rates at 30 minutes than reteplase with streptokinase (5.7% versus 6.7%), but there was also an
(39.0% versus 27.3%; />=NS), and this very early advantage increased rate of intracranial hemorrhage (0.7% versus
might have offset the later patency advantage of reteplase. 0.3%).122 Single-bolus administration (80 mg) of saruplase is
Another possible explanation is that reocclusion rates might being explored as well. This agent is expected to be approved
have been higher with reteplase. for use in Europe this year.
TNK-tPA Staphylokinase
TNK-tPA is a genetically engineered triple-combination mutant Staphylokinase, a 136-amino-acid protein produced by cer-
of native tissue plasminogen activator with amino acid substitu- tain strains of Staphylococcus aureus, has a unique mecha-
tions at the following sites: a threonine (T) is replaced by an nism of fibrin selectivity.123 In two angiographic studies,
asparagine, which adds a glycosylation site to position 103; an recombinant Staphylokinase (in doses between 20 and 30 mg)
asparagine (N) is replaced by a glutamine, thereby removing a was at least as potent as alteplase and significantly more
glycosylation site from site 117; and four amino acids, lysine fibrin-specific.124'125
(K), histidene (H), and arginine (R), are replaced by four As a bacterial protein, Staphylokinase induces antibody
alanines (A) at sites 296-299. (Fig 4). These substitutions result formation and resistance to repeated administration. How-
in reduced plasma clearance, increased fibrin specificity, and ever, preliminary studies suggest that the immunogenicity of
resistance to plasminogen activator inhibitor-1.116 In the TIMI- Staphylokinase can be reduced by site-directed mutagenesis.
10B study, a large, phase n efficacy trial in 886 patients, a single Large comparative trials are needed to determine the safety
40-mg bolus of TNK-tPA produced TIMI grade 3 flow rates at and full clinical potential of this agent.
90 minutes that were identical to those seen with accelerated
alteplase (63% in both groups).117 Furthermore, TIMI frame The Future
counting in TIMI-1 OB suggested faster and more complete A number of new therapeutic strategies may achieve greater
reperfusion with 40 mg of TNK-tPA than with accelerated early and, consequently, greater long-term benefits in patients
alteplase. The best angiographic results were obtained with a with an acute myocardial infarction. Greater reductions of infarct
size are possible by earlier administration of more effective
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 thrombolytic regimens, eg, prehospital bolus administration of
with the 40-mg dose of TNK-tPA. This incidence was consid- new fibrinolytic agents with equal or higher potency for clot
ered acceptable, because 14.6% of the patients in ASSENT-1 lysis, such as TNK-tPA, lanoteplase, or Staphylokinase, and
were >75 years old. On the basis of the results of TIMI-10B and better conjunctive antithrombotic therapies (eg, direct antithrom-
ASSENT-1,16 500 patients with acute myocardial infarction are bins or glycoprotein Eb/OIa receptor antagonists). Reocclusion
being randomized in a double-blind manner to receive weight- and reinfarction in the days or weeks after the acute event may
adjusted TNK-tPA or alteplase in the ASSENT-2 phase m be better prevented by new antiplatelet agents (eg, oral glyco-
mortality trial. The results are expected in early 1999. protein nb/ma receptor antagonists), prolonged subcutaneous
antithrombin therapy (eg, low-molecular-weight heparin or di-
Lanoteplase rect antithrombins), better selection of patients for additional
Like reteplase, lanoteplase, or n-PA, is a deletion mutant of revascularization, lipid-modifying agents (eg, statins), and
alteplase in which one amino acid is substituted in position plaque-stabilizing agents. Reperfusion damage may also be
117 (Fig 4).118 In the InTIME-1 trial, a single 120-IU/kg bolus diminished by earlier treatment and by therapies that improve
of lanoteplase produced TIMI grade 3 flow in 57.1% of the microcirculation (eg, inhibition of neutrophil chemotaxis or
patients compared with 46.4% in patients treated with alte- adhesion or enhancement of endogenous adenosine activity).
plase. There were also fewer adverse events with lanoteplase. Greater attenuation of left ventricular remodeling (eg, using
At 30 days, the combined incidence of death, reinfarction, ACE inhibitors) and better antiarrhythmic treatment may also
heart failure, and major bleeding (including one intracranial increase the long-term clinical benefit of successful
hemorrhage in a patient treated with alteplase) was 11% with thrombolysis.
lanoteplase and 24% with alteplase. Lanoteplase will be The risk of bleeding complications, particularly hemor-
compared with alteplase in a large mortality trial (InTIME-2), rhagic stroke, must also be decreased. There is a need for
and the results should be available in early 1999. more careful selection of patients for thrombolysis, and it
may be just as effective and safer to administer a reduced
Saruplase dose of a fibrinolytic agent in conjunction with a more potent
Saruplase, or prourokinase, is a naturally occurring glycopro- antithrombotic agent (eg, abciximab or other glycoprotein
tein that is rapidly converted into urokinase by plasmin but Ilb/IIIa receptor antagonists).
appears to have some intrinsic plasminogen activating poten- Each of tV\e strategies mentioned above needs to be tested
tial.119 In a comparative trial with streptokinase, recombinant in large clinical trials. Because it is unethical to conduct these
saruplase was associated with earlier reperfusion, higher trials with a placebo control, it is likely that in the future,
investigators will increasingly seek to demonstrate equiva- TABLE 7. Characteristics of an "Ideal" Thrombolytic Agent
lence of treatments.126 Equivalence of new thrombolytic
Rapid reperfusion (15-30 min)
regimens should be established first in terms of mortality, the
Close to 100% efficacy for reperfusion
primary efficacy outcome.
Secondary aspects of innovative treatments, such as side Can be given as a rapid intravenous bolus
effects, ease of use, and cost, also need to be evaluated. It is Low rate of intracranial hemorrhage
generally accepted that in the field of thrombolysis, a 1% Low rate of systemic bleeding
absolute difference in mortality, if still demonstrable at Specific for recent thrombi
long-term follow-up, is clinically important. As shown in the Low rate of early reocclusion
GUSTO-I trial,29 this 1% difference (or a relative 14% Sustained patency long-term
difference) may prevent 1 of every 7 deaths. For a disease
No effect on blood pressure
with a high prevalence and mortality rate, this reduction is
No antigenicity
relevant at the population level. If a 1% absolute difference is
chosen as the limit of a range of equivalence, it is important No negative interactions with adjunctive treatment
that the population of randomized patients includes those at No other significant side effects
high risk, for example, elderly patients, as in the GUSTO-I Acceptable cost
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 therapies with glycoprotein nb/ffla receptor antagonists, direct
"equivalence" is much higher. An alternative approach would thrombin inhibitors, and low-molecular-weight heparins also
be to use an odds reduction as the prespecified limit of the need to be tested. Data on cost-effectiveness compared with
range of equivalence,127 because the mortality rates in the current therapies will also be required.
standard treatment arm may vary depending on the selection
criteria. Either a 1% absolute difference or a 14% relative References
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Thrombolysis For Acute Myocardial Infarction: Clinical Cardiology: New Frontiers

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Thrombolysis For Acute Myocardial Infarction: Clinical Cardiology: New Frontiers

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Clinical Cardiology: New Frontiers

Thrombolysis for Acute Myocardial Infarction

T hus did James Herrick describe the autopsy of his first

to 1 year after reperfusion) may occur in 25% to 30% of

patient is ineligible for reperfusion, and percutaneous revas-

TABLE 1. Eligibility Criteria for Thrombolytic Therapy in Clinical Trials

Age TABLE 2. Cost Per Additional Year of Life for Accelerated

Multivariate analysis confirmed that older age was the most

erated alteplase is greater than in younger patients (Table 2).52 - Stroke

help to determine whether there is a regional wall motion

Study N Treatment Mortally Bedn±»d Odds RMto and CL

Barbash (r*f83) 87 AKeplase (120mg over 6 hours) 36 0.0% 6.8% 87 ± 50

GREAT (ntSSI 311 Anistreplase (30u, IV bolus) 130 6.7% 11.5% 44 ± 30 • •

Crude Total 6607 9.1% 10.7% 17 ± 8 4

Test tor homogeneity: CM square - 4.69

Prehospital Treatment Choice of Agent

vator, as the GUSTO-I trial did? First, the failure to use

TABLE 6. New Versus Established Fibrinolytic Agents in Acute Myocardial Infarction

Reteplase reteplase showed only a small (and not statistically significant)

lanoteplase Figure 4. Molecular structure of alteplase, rete-

dose/weight ratio of ±0.5 mg/kg. In the ASSENT-1 trial in 3325

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