Download Critical Analysis of Various Drugs Used for Thrombolytic Therapy in

Chapter
24
Critical Analysis of Various Drugs
Used for Thrombolytic Therapy in
Acute Myocardial Infarction
Gurpreet Singh Wander, Shibba Takkar Chhabra
INTRODUCTION
Thrombolytics recanalize thrombotic occlusion associated with STsegment elevation myocardial infarction (STEMI) and restoration of
coronary flow reduces infarct size and improves myocardial function
and survival over the short-term and long-term. Thrombolytic
therapy for acute myocardial infarction (AMI) was incorporated
into the armamentarium of clinicians over 2 decades ago, and has
evolved from first generation thrombolytic—streptokinase (SK) to
newer thrombolytics such as alteplase (t-PA), reteplase (rPA) and
tenecteplase (TNK). This article provides an overview of the various
thrombolytic agents utilized in the management of patients with
AMI.
HISTORY OF THROMBOLYTIC AGENTS
In 1933, Dr William Tillett discovered SK through sheer chance when
he observed that streptococci agglutinated plasma but not serum.
He concluded that any plasma containing streptococci would not
clot and this laid the foundation for thrombolysis in various settings.
Christensen and MacLeod coined the term “streptokinase” in 1945.1
Streptokinase was originally utilized in the treatment of patients
with tuberculous hemorrhagic pleural effusions and tuberculous
meningitis. In 1958, Fletcher first reported the use of thrombolytic
therapy for the management of AMI.2 The breakthrough discovery of
SK in the treatment of patients with AMI was followed by a search for
ideal thrombolytic agent, which led to the emergence of second and
third generation thrombolytics.
(PAI-1). The generational classification of the thrombolytic agents
are presented in Table 1 and properties of an ideal thrombolytic
agent are presented in Table 2.
Streptokinase
Streptokinase is a nonfibrinogen-specific fibrinolytic agent,
produced by hemolytic streptococci that activates plasminogen
independent of its association with fibrin. It is not an enzyme and
therefore does not exhibit plasmin activity by proteolytic cleavage of
plasminogen. Instead, it binds noncovalently to plasminogen in a 1:1
equimolar fashion and thereby confers plasmin activity (Figure 2).
The Gruppo Italiano per lo Studio della Streptochinasi nell’Infarto
Miocardico (GISSI) and the International Study of Infarct Survival
(ISIS) trials3-5 firmly established the efficacy of intravenous SK in
the management of patients with AMI. In the GISSI trial, at 21 days
there was 18% reduction in overall hospital mortality following the
administration of SK compared with the control group. The extent of
the beneficial effect appeared to be related to the time of onset of
THROMBOLYTIC AGENTS IN ACUTE MYOCARDIAL
INFARCTION: CLASSIFICATION AND MECHANISM
OF ACTION
Thrombolytic agents act by converting the proenzyme, plasminogen
to plasmin, the active enzyme. Plasminogen activators that
preferentially activate fibrin-bound plasminogen are fibrin-specific.
In contrast, nonspecific plasminogen activators do not discriminate
between fibrin-bound and circulating plasminogen. Activation of
circulating plasminogen results in the generation of unopposed
plasmin that can trigger the systemic lytic state (Figure 1).
Thrombolytic agents can be categorized in several ways.
Classification schemes can be devised on the basis of the source
of the agent, the propensity for enhanced enzymatic activity on
fibrin or cell surface or the mechanism of action (enzymatic versus
nonenzymatic) or different generation wise. Newer thrombolytic
agents have been developed in order to provide longer half-life to
enable bolus administration, fibrin specificity and to be resistant
to natural inhibitors such as plasminogen activator inhibitor-1
Figure 1: Consequences of activation of fibrin-bound or circulating
plasminogen. Plasminogen activators with little or no affinity for fibrin do not
distinguish between fibrin-bound and circulating plasminogen. Activation of
circulating plasminogen results in systemic plasminemia and subsequent
degradation of fibrinogen and other clotting factors
Cardiology
Section 4
TABLE 1 │ Generational classification of the thrombolytic
agents
Generation of
thrombolytic
drug
Fibrin specific
Nonfibrin specific
First
—
—
Recombinant tissue
plasminogen activator*
(t-PA)
Alteplase
Tenecteplase* (TNK-tPA)
Reteplase*
Monteplase
Lanoteplase
Pamiteplase
Staphylokinase
Desmoteplase
(Bat-PA)
Chimeric thrombolytics
Streptokinase*
Urokinase *
Prourokinase
(scu-PA)
Second
Third
APSAC
—
—
—
—
—
—
—
* Approved for clinical use
TABLE 2 │ Desirable features of ideal thrombolytic drug
• Fibrin specificity
• Longer half life ( bolus administration)
• Good patency
• Low or no reocclusion rate and systemic bleeding
• Resistant to plasminogen activator inhibitor-1(PAI-1)
• Nonantigenic and cost effective
chest pain to SK infusion [risk ratio (RR) 0.74, 0.80, 0.87 and 1.19 for
the 0–3, 3–6, 6–9 and 9–12 hours subgroups].3 Likewise in the ISIS2 trial, patients with AMI randomized to SK and aspirin compared
with neither treatment resulted in significant reduction not only
in death (8% versus 13.2%), but also stroke (0.6% versus 1.1%) and
reinfarction (1.8% versus 2.9%).4 The early survival benefit obtained
with SK and aspirin persisted up to 10 years during follow-up.5
Allergic reaction manifesting as rash, fever, chills, rigors and
rarely, anaphylaxis occurs in about 5% of patients treated with SK.
Transient hypotension is common with SK and reflects plasminmediated release of bradykinin. Patients given SK invariably develop
antistreptococcal antibodies, precluding readministration.
Tissue Plasminogen Activator (Alteplase)
110
The tissue plasminogen activator (t-PA) molecule contains the
following five domains: (1) finger, (2) epidermal growth factor, (3)
Kringle 1 and (4) Kringle 2 and (5) serine protease (Figure 3).6 In
the absence of fibrin, t-PA is a weak plasminogen activator. Plasma
clearance of t-PA is mediated to a varying degree by residues in
each of the domains except the serine protease domain, which is
responsible for the enzymatic activity of t-PA. Alteplase is a t-PA
produced by recombinant deoxyribonucleic acid (DNA) technology.
The accelerated dose regimen of t-PA over 90 minutes produces
more rapid thrombolysis than the standard 3 hours infusion of t-PA.
The recommended dosage regimen for t-PA is a 15 mg intravenous
bolus followed by an infusion of 0.75 mg/kg (maximum 50 mg) over
30 minutes, followed by an infusion of 0.5 mg/kg (maximum 35 mg)
over 60 minutes.
The Global Use of Strategies to Open Occluded Coronary Arteries
(GUSTO), GISSI-27 and ISIS-38 investigators compared intravenous
SK and t-PA in the treatment of AMI. Although no significant
difference was observed between SK and t-PA in GISSI-2 and ISIS-3,
the GUSTO trial demonstrated that an accelerated regimen of t-PA
resulted in significant reductions in death and disabling strokes
among patients with AMI. Accelerated t-PA group resulted in 14%
Figure 2: Mechanism of action of streptokinase. Streptokinase binds to
plasminogen and induces a conformational change in plasminogen that
exposes its active site. The Streptokinase-plasminogen complex then
serves as the activator of additional plasminogen molecules
reduction in mortality at 30 days compared with the SK strategies.
There was slight excess of hemorrhagic stroke for accelerated t-PA
when compared with the SK strategies. However, the combined
endpoint of death or disabling stroke was significantly lower in
the accelerated t-PA group than in the SK only groups (6.9% versus
7.8%, P = 0.006).9 The Phase-I Thrombolysis in Myocardial Infarction
(TIMI) trial demonstrated that the administration of alteplase in
patients with AMI resulted in reperfusion in twice as many occluded
infarct-related arteries compared with SK during the first 90 minutes
of initiation of treatment.10
Reteplase
Reteplase is a recombinant deletion mutant form of t-PA, and has a
longer half-life of 13–16 minutes. It binds fibrin, and has the ability to
penetrate into thrombi. Reteplase when compared with accelerated
alteplase infusion regimen was demonstrated to offer no significant
benefit in terms of reduction in 30 days mortality among patients with
AMI.11 Likewise, rPA in combination with abciximab did not provide
significant benefit in terms of 30 days survival.12 However a doubledose rPA (10 + 10 MU) utilized in the Revitalising Areas by Planning,
Investment and Development (RAPID) trial resulted in complete,
rapid and sustained thrombolysis of infarct-related arteries (IRAs) at
90 minutes and 5–14 days (63% versus 49%, P = 0.019; and 88% versus
71%, P < 0.001) compared with alteplase and improved regional
and global left ventricular function at discharge. The RAPID II trial
further confirmed the advantage of rPA over accelerated alteplase
in achieving higher rates of early reperfusion in the IRA and fewer
acute coronary interventions. This, however, did not translate into
improved clinical outcomes in the International Joint Efficacy
Comparison of Thrombolytics (INJECT) trial, which demonstrated
no significant difference between rPA and SK in reducing 35-day
mortality.13
Tenecteplase
Tenecteplase is a mutant form of t-PA with specific amino acid
substitutions in the Kringle 1 domain and protease domain.
A single bolus TNK was demonstrated to be associated with
increased IRA patency rates (64% TIMI 3 flow with 50 mg bolus
Section 4
Chapter 24 Critical Analysis of Various Drugs Used for Thrombolytic Therapy...
Figure 3: Molecular structure of alteplase (t-PA), reteplase (rPA), and tenecteplase (TNK). Streptokinase (SK) is the least fibrin-specific thrombolytic
agent in clinical use; the progressive increase in relative fibrin specificity for the various thrombolytics is shown at the bottom
dose) in the TIMI 10A trial.14 In the TIMI 10B trial, TNK (40
mg) and alteplase produced similar rates of TIMI grade 3 flow
at 90 minutes (62.8% versus 62.7%, respectively, P = NS).15
Subsequently the Assessment of the Safety and Efficacy of
a New Thrombolytic (ASSENT-1) Trial demonstrated that the
safety profile of TNK was comparable to alteplase.16 ASSENT-217
compared single-bolus TNK with accelerated dose t-PA and the
30-days mortality rate with TNK was 6.179% and with t-PA 6.151%.
The rate of intracranial hemorrhage (ICH) was 0.93% with TNK and
0.94% with t-PA. Major bleeding occurred in 4.66% of TNK-treated
patients compared with 5.94% of t-PA-treated patients (P = 0.0002).
There was no specific subgroup of patients for whom TNK or t-PA
was significantly better, with the exception of patients treated after 4
hours from the onset of symptoms, among whom the mortality rate
was 7.0% with TNK and 9.2% with t-PA. Furthermore, the ASSENT-3
Trial demonstrated that the addition of enoxaparin or abciximab to
TNK reduced ischemic complications.18
Despite the differences observed between the thrombolytic
agents in individual studies, a subsequent meta-analysis, however,
did not demonstrate significant differences between the various
thrombolytic agents (alteplase, SK, rPA and TNK) in reducing
mortality (Figure 4)19 though total stroke and hemorrhagic stroke
rates were lower in SK group.
A comparison of approved fibrinolytic agents is shown in Table 3.17
Other Fibrinolytic Agents
Derived from cultured fetal kidney cells, urokinase is a two-chain
serine protease, which directly converts plasminogen to plasmin. It
was used on rare occasions as an intracoronary (IC) infusion [6,000
international unit (IU)/minutes] to an average cumulative dose of
5,000,000 IU to lyse IC thrombi that were believed to be responsible for
an evolving STEMI.20 Saruplase or prourokinase (scuPA), a naturally
occurring glycoprotein, is converted by plasmin into urokinase, and
seems to have intrinsic plasminogen activating potential. Saruplase
was compared with SK in the Prourokinase in Myocardial Infarction
(PRIMI) and Comparative Trial of Saruplase versus Streptokinase
(COMPASS) and with alteplase in Study in Europe with Saruplase
and Alteplase in Myocardial Infarction (SESAM) Trial. Although the
mortality rates were comparable between scuPA and other agents,
111
Cardiology
Section 4
Figure 4: Meta-analyses: No difference in mortality when all alteplase (including accelerated and nonaccelerated
alteplase regimens) compared with streptokinase. t-PA, alteplase; SK, streptokinase
TABLE 3 │ Comparison of approved fibrinolytic agents17
Streptokinase
(SK)
Parameter
Alteplase
(t-PA)
Reteplase
(rPA)
TNK t-PA
Dose
1.5 MU in 30–60 min
Up to 100 mg in 90 min
(based on weight)
10 U X 2 (30 min apart)
each over 2 min
30–50 mg based on
weight
Bolus administration
No
No
Yes
Yes
Allergic reactions (hypotension most
common)
Yes
No
No
No
Systemic fibrinogen depletion
Marked
Mild
Moderate
Minimal
90-min patency rates (%)
≈50
≈75
≈75
≈75
TIMI grade 3 flow (%)
32
54
60
63
Cost per dose (US $)
568
2,750
2,750
2,750 for 50 mg
Antigenic
Abbreviations: TNK t-PA, Tenecteplase tissue plasminogen activatot; TIMI, Thrombolysis in myocardial infarction; US, United States
scuPA was overcome by other adverse events such as increased
reinfarction rates and hemorrhagic stokes.1
Anistreplase or anisoylated plasminogen-SK activator complex
(APSAC) is another form of SK, an equimolar acylated complex of
human lys-plasminogen and SK. This complex acts on plasminogen
upon deacylation spontaneously in plasma. Usually administered
in a dose of 30 mg over 2 to 5 minutes intravenously, it has a side
112
effect profile similar to that of SK, a patency profile similar to that of
conventional dose t-PA and a mortality benefit similar to that of SK or
t-PA (ISIS-3).8
Staphylokinase, a highly fibrin-specific plasminogen acti­
vator requires priming on the surface of a clot. Recombinant
staphylokinase in STAR Trial achieved TIMI flow grade 3 (TFG3)
at 90 minutes in 62% of STAR patients versus 58% of t-PA patients.
Section 4
Chapter 24 Critical Analysis of Various Drugs Used for Thrombolytic Therapy...
Study of Tamoxifen and Raloxifene therapy was not associated
with increased mortality, hemorrhagic or allergic complications.
However, there was an occurrence of antibody-mediated STARneutralizing activity from the 2nd week following treatment.21 The
pegulated-staphylokinase (PEG-Sak) evaluated in the Collaborative
Angiographic Patency Trial of Recombinant Staphylokinase
(CAPTORS) II Trial demonstrated comparable TFG3 rates to that with
t-PA.22
Lanoteplase (nPA), a variant of t-PA with greater fibrinolytic
activity and slower clearance from the plasma, resulted in equivalent
thrombolytic efficacy to alteplase (InTIME).23 However, nPA was
associated with an increased risk of hemorrhagic strokes.
LIMITATIONS OF THROMBOLYSIS
Contraindications to Thrombolysis
Although the use of fibrinolytic therapy was associated with
significant reduction in mortality, it was soon demonstrated to be
overcome by a number of limitations. An analysis from the TIMI-9
registry demonstrated that 10.3% of patients have contraindications
to thrombolysis, which consisted of prior stroke or transient ischemic
attack, recent cardiopulmonary resuscitation (CPR), trauma, surgery,
recent bleeding and persistent hypertension (Table 4).24
Timing of Thrombolytic Treatment
The benefit of fibrinolytic therapy decreases as time progresses
following the onset of symptoms (Figure 5). Prehospital
administration of thrombolysis was beneficial if administered within
70 minutes in terms of reduction in the composite score of death,
stroke, serious bleed and infarct size (P = 0.009).25 A meta-analysis
by Morrison demonstrated that prehospital thrombolysis resulted in
significant decrease in time to thrombolysis and all-cause mortality.26
The Comparison of Primary Angioplasty and Prehospital Fibrinolysis
in Acute Myocardial Infarction (CAPTIM) Trial reported a trend
toward a lower rate of mortality among STEMI patients receiving
prehospital fibrinolysis as compared with primary percutaneous
TABLE 4 │Contraindications and cautions for fibrinolytic use in ST-segment elevation myocardial infarction (STEMI)17*
Absolute Contraindications
• Any prior intracranial hemorrhage
• Known structural cerebral vascular lesion (e.g. arteriovenous malformation)
• Known malignant intracranial neoplasm (primary or metastatic)
• Ischemic stroke within 3 months except acute ischemic stroke within 3 hours
• Suspected aortic dissection
• Active bleeding or bleeding diathesis (excluding menses)
• Significant closed head or facial trauma within 3 months
Relative Contraindications
• History of chronic severe poorly controlled hypertension
• Severe uncontrolled hypertension on presentation (SBP >180 mm Hg or DBP >110 mm Hg)†
• History of prior ischemic stroke > 3 months, dementia, or known intracranial pathology not covered in contraindications
• Traumatic or prolonged (>10 min) CPR or major surgery (<3 wk)
• Recent (within 2-4 wk) internal bleeding
• Noncompressible vascular punctures
• For streptokinase, anistreplase: Prior exposure (>5 days ago) or prior allergic reaction to these agents
• Pregnancy
• Active peptic ulcer
• Current use of anticoagulants: The higher the INR, the higher the risk of bleeding
Abbreviations: SBP, Systolic blood pressure; DBP, Diastolic blood pressure; CPR, Cardiopulmonary resuscitation; INR, International normalized ratio
*
†
Viewed as advisory for clinical decision-making, and may not be all-inclusive or definitive.
Could be an absolute contraindication in low-risk patients with myocardial infarction (MI).
Figure 5: Importance of time to reperfusion in patients undergoing fibrinolysis
For every 30-minute delay, there is a progressive increase in the in-hospital mortality rate
113
Cardiology
Section 4
coronary intervention (PCI), especially if patients were treated
within 2 hours of the onset of symptoms.17 Boersma evaluated the
relation between treatment delay and short-term mortality (up to 35
days) and greater benefit was observed among patients who received
fibrinolytic therapy at 0–1 hours’ time-interval from symptom onset
(65, 37, 26 and 29 lives saved/1,000 treated patients in the 0–1, 1–2,
2–3 and 3–6 hours intervals, respectively).27 In the GUSTO-1 trial,
females, elderly, diabetics and patients with previous infarction
or bypass surgery were associated with longer presentation and
treatment delays.
Cerebrovascular Events
The Fibrinolysis Therapy Trialists (FTT) collaborators analysis
demonstrated that thrombolysis was associated with an increase
in stroke rate compared to control patients (1.2% versus 0.8%, P
< 0.00001).28 An analysis from the GUSTO-1 Study demonstrated
that the overall incidence of stroke following fibrinolytic therapy
was 1.4% (95% of stroke occurred within 5 days). Combination
treatment with SK and t-PA was associated with significantly more
stroke than SK alone (1.64% versus 1.19%, P < 0.007). Of these, among
41% of the cases, the stroke was fatal. Intracranial hemorrhage
occurred in 0.46% of cases who received SK and 0.88% of cases
who received combination therapy (P < 0.001).29 Another analysis
demonstrated a slight increase in ICH among patients receiving t-PA
(0.95%).30 Intracranial hemorrhage is the most serious complication
of fibrinolytic therapy; its frequency varies with the clinical
characteristics of the patient (low bodyweight, increased age and
hypertension at presentation associated with increased risk) and the
fibrinolytic agent prescribed (Figure 6).
Patency of Infarct Arteries
Early patency of the IRAs is not demonstrated in all patients treated
with fibrinolytic therapy. Angiography following fibrinolytic therapy
demonstrates that TFG3 is achieved in only approximately 40–60%
of cases. In an analysis from the GUSTO Trial, the patency of infarct
artery (TFG 2/3) at 90 minutes was achieved in 81% of cases in the
accelerated t-PA group compared to only 54% in the SK group (P <
0.001). Normal flow (TFG3) was achieved in 54% of patients who
received t-PA compared to 40% among those who received the other
treatments (SK + subcutaneous heparin, SK + intravenous heparin,
combination of SK, t-PA and heparin).9 The mortality at 30 days was
significantly increased among those who had reduced flow compared
to those who had normal flow (8.9% versus 4.4%, P = 0.009).
Even patients with TFG3 may not achieve adequate myocardial
perfusion, especially if there is a great delay between the onset of
symptoms and restoration of epicardial flow. Myocardial no-reflow
may occur due to microvascular damage and reperfusion injury.
Fibrinolysis may actually exacerbate microembolization of platelet
aggregates because of the exposure of clot-bound thrombin, an
extremely potent platelet agonist.
Reinfarction and Recurrent Ischemia
Thrombolysis is also overcome by frequent occurrence of recurrent
ischemia, reocclusion of the infarct artery (reocclusion within
5–7 days occurred in 4.9–6.4% cases in the GUSTO analysis) and
reinfarction. Reinfarction occurred in 4.3% of cases following
thrombolysis at a median of 3.8 days after thrombolysis. The 30 days
and mortality from 30 days to 1 year was significantly increased
among those who had reinfarction (11.3% versus 3.5% and 4.7%
versus 3.2%, respectively, P < 0.001).31
Age
114
Several studies have demonstrated that short-term and long-term
mortality increases with age. In the GUSTO-1 subanalysis, there was
Figure 6: Estimation of risk of intracranial hemorrhage (ICH) with
fibrinolysis. The number of risk factors is the sum of the points based on
criteria established in the studies shown.
*Although the exact risk factors varied among the studies, common risk
factors across all the studies included increased age, low body weight, and
hypertension on admission.
**If the overall incidence of ICH is assumed to be 0.75%, patients without risk
factors who receive streptokinase have a 0.26% probability of ICH. The risk
is 0.96%, 1.32%, and 2.17% in patients with one, two, or three risk factors,
respectively.
not only an increase in 30-day mortality with age [3.0% (< 65 years),
9.5% (65–74 years), 19.6% (75–85 years), and 30.3% (> 85 years)],
there was also an increase in stroke, cardiogenic shock, bleeding and
reinfarction. Accelerated t-PA was associated with fewer combined
death or disabling stroke in all but the oldest patients, who showed
a weak trend toward a lower incidence with SK plus subcutaneous
Section 4
Chapter 24 Critical Analysis of Various Drugs Used for Thrombolytic Therapy...
heparin. Likewise, accelerated t-PA treatment resulted in lower 1
year mortality in all but the oldest patients (47% t-PA versus 40.3%
SK).32 Weaver and colleagues demonstrated that 28% of patients
hospitalized for AMI were greater than or equal to 75 years of age
and only 5% of patients were administered a systemic thrombolytic
agent. Though, there was an increase in mortality with increasing age,
the relative and absolute risk reductions associated with fibrinolytic
administration were quite favorable.33
Infarct Size and Site
The extent of myocardial injury appears to be more relevant than the
site in determining in-hospital mortality and efficacy of thrombolytic
therapy. In the GISSI Trial,34 SK significantly reduced mortality
only in anterior and multiple site infarcts. There was a progressive
increase in the mortality rate based on infarct size (6.5% in small
infarcts to 9.6% in the modest, 14.3% in large and 21.7% in extensive).
EFFECT OF FIBRINOLYTIC THERAPY
ON MORTALITY
Early intravenous fibrinolysis undoubtedly improves survival in
patients with STEMI.17 Mortality varies considerably, depending
on the patients included for study and the adjunctive therapies
used. As previously mentioned, the benefit of fibrinolytic therapy
appears to be the greatest when agents are administered as early as
possible, with the most dramatic results obtained when the drug is
given less than 2 hours after symptoms begin. Fibrinolytic therapy
trialists collaboration group indicated an 18% reduction in shortterm mortality with thrombolytics but as much as a 25% reduction in
mortality for the subset patients with ST-segment elevation or bundle
branch block. Two trials, Late Assessment of Thrombolytic Efficacy
(LATE) and Estudio Multicéntrico Estreptoquinasa Repúblicas
de América del Sur (EMERAS), provide evidence that a mortality
reduction may still be observed in patients treated with thrombolytic
agents between 6 hours and 12 hours from the onset of ischemic
symptoms.
CHOICE OF AGENT
The clinicians must weigh the risk of mortality and the risk of
ICH when confronting a fibrinolytic-eligible patient with STEMI.
Constraints are placed on physicians by the health care system
in which they practice. In patients, presenting within 4 hours of
symptom onset, the speed of reperfusion of the infarct vessel is of
paramount importance and a high-intensity fibrinolytic regimen
such as accelerated t-PA is the preferred treatment, except in those
for whom the risk of death is low [e.g. a young patient with a small
inferior myocardial infarction (MI)] and the risk of ICH is increased
(e.g. acute hypertension), in whom SK and accelerated t-PA are
approximately equivalent choices. For those, presenting between
4 hours and 12 hours after the onset of chest discomfort, the speed
of reperfusion of the infarct vessel is of lesser importance, and SK
and accelerated t-PA are therefore generally equivalent options,
given the difference in costs. Of note, for those presenting between
4 hours and 12 hours from symptom onset with a low-mortality risk
but an increased risk of ICH (e.g. older patients with inferior MI,
systolic pressure > 100 mm Hg and heart rate < 100 beats/minutes),
SK is probably preferable to t-PA because of cost considerations if
fibrinolytic therapy is prescribed at all in such patients.20
In those patients considered as appropriate candidates for
fibrinolysis and for whom t-PA would have been selected as the
agent of choice in the past, clinicians should now consider as
using a bolus fibrinolytic such as rPA or TNK. The rationale for this
recommendation is that bolus fibrinolysis has the advantage of
ease of administration, a lower chance of medication errors (and
the associated increase in mortality when such medication errors
occur) and less noncerebral bleeding, and also offers the potential
for prehospital treatment.6
INTRACORONARY THROMBOLYTIC THERAPY
Rentrop first reported IC administration of SK in the management of
patients with AMI. The efficacy of IC fibrinolytic therapy was studied
among patients undergoing primary PCI. In a study by Sezer, IC SK
(250 kU of IC SK over 3 minutes) was associated with significantly
better coronary flow reserve compared to the control group 2 days
following the procedure.35 However, this did not translate into
improvements in left ventricular size and function at 6 months.
Intracoronary TNK is a safe, well-tolerated and effective treatment for
the management of thrombotic complications in high-risk complex
PCI. Kelly and coworkers demonstrated that TNK-supported PCI
significantly improved the no-reflow phenomenon among high-risk
PCI patients.36
RECOMMENDATIONS
For the patients with STEMI, as per American College of Cardiology
(ACC)/American Heart Association (AHA) guidelines fibrinolysis is
preferred if patients present early (≤ 3 hours from symptoms onset),
invasive strategy is not an option or delay to invasive strategy is
expected (prolonged transport, door to balloon—door to needle time
more than 1 hour or medical contact to balloon or door to balloon >
90 minutes). Moreover, for those presenting to non-PCI centers, it is
reasonable for high-risk patients who receive fibrinolytic therapy as
primary reperfusion therapy to be transferred as soon as possible to a
PCI-capable facility where PCI can be performed either when needed
or as a pharmacoinvasive strategy (Class IIa recommendation, Level
of Evidence: B).37
CONCLUSION
In the setting of STEMI, fibrinolysis continues to be an option for
reperfusion in non-PCI centers and in patients presenting early (≤
3 hours) where delay to invasive strategy is expected. The evolution
of thrombolytic drugs over the last 2 decades has seen transition
from first generation (SK, urokinase) to fibrin-specific, nonantigenic,
second (alteplase, t-PA) and third generation thrombolytics (rPA,
TNK) with longer half lives, resistance to PAI-1, better 90 minutes
patency rates and TFG3. In a given clinical setting, the choice of
thrombolytic agent should consider risk of mortality, ICH, age,
timing of thrombolytic treatment and cost effectiveness in a given
health care system. Future research might see development of
optimal thrombolytic strategy with ability of maximal reperfusion
and with minimal bleeding and reocclusion complications.
REFERENCES
1.Vijayalakshmi Kunadian, C Michael Gibson. Thrombolytics and
Myocardial Infarction. Cardiovascular Therapeutics 2012; 30:e81–e88.
2. Fletcher AP, Alkjaersign N, Smyrniotis FE, Sherry S. The treatment
of patients suffering from early myocardial infarction with massive
and prolonged streptokinase therapy. Trans Assoc Am Physicians.
1958;71:287–96.
3.Gruppo Italiano per lo Studio della Streptochinasi nell’Infarto
Miocardico (GISSI). Effectiveness of intravenous thrombolytic
treatment in acute myocardial infarction. Lancet. 1986;1:397-402.
4. ISIS-2 (Second International Study of Infarct Survival) Collaborative
Group. Randomised trial of intravenous streptokinase, oral aspirin,
both, or neither among 17,187 cases of suspected acute myocardial
infarction: ISIS-2. Lancet. 1988;2:349-60.
5. Baigent C, Collins R, Appleby P, et al. The ISIS-2 (Second International
Study of Infarct Survival) Collaborative Group. ISIS-2: 10 year survival
115
Cardiology
among patients with suspected acute myocardial infarction in
randomised comparison of intravenous streptokinase, oral aspirin,
both, or neither. BMJ. 1998;316:1337-43.
6. Van de Werf FJ, Topol EJ. Sobel BE: The impact of fibrinolytic therapy for
ST-segment-elevation acute myocardial infarction. J Thromb Haemost
2009; 7:14.
7.Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto
Miocardico. GISSI-2: A factorial randomised trial of alteplase versus
streptokinase and heparin versus no heparin among 12,490 patients
with acute myocardial infarction. Lancet. 1990;336:65-71.
8. ISIS-3 (Third International Study of Infarct Survival) Collaborative
Group. ISIS-3: A randomised comparison of streptokinase vs tissue
plasminogen activator vs anistreplase and of aspirin plus heparin
vs aspirin alone among 41,299 cases of suspected acute myocardial
infarction. Lancet. 1992;339:753-70.
9.The GUSTO Angiographic Investigators. The effects of tissue
plasminogen activator, streptokinase, or both on coronary-artery
patency, ventricular function, and survival after acute myocardial
infarction. N Engl JMed .1993;329:1615-22.
10. TIMI Study Group. The Thrombolysis in Myocardial Infarction (TIMI)
trial. Phase I findings. N Engl J Med. 1985;312:932–6.
11. The Global Use of Strategies to Open Occluded Coronary Arteries
(GUSTO III) Investigators. A comparison of reteplase with alteplase for
acute myocardial infarction. N Engl J Med. 1997;337:1118-23.
12. Topol EJ. Reperfusion therapy for acute myocardial infarction with
fibrinolytic therapy or combination reduced fibrinolytic therapy and
platelet glycoprotein IIb/IIIa inhibition. The GUSTO V randomized
trial. Lancet. 2001;357:1905–14.
13.Randomised, double-blind comparison of reteplase double-bolus
administration with streptokinase in acute myocardial infarction
(INJECT): Trial to investigate equivalence. Inter national Joint Efficacy
Comparison of Thrombolytics. Lancet. 1995;346:329-36.
14. Cannon CP, McCabe CH, Gibson CM, et al. TNK-tissue plasminogen
activator in acute myocardial infarction. Results of the Thrombolysis
in Myocardial Infarction (TIMI) 10A dose-ranging trial. Circulation.
1997;95:351-56.
15.Cannon CP, Gibson CM, McCabe CH, et al. the Thrombolysis
in Myocardial Infarction (TIMI) 10B Investigators. TNK-tissue
plasminogen activator compared with front-loaded alteplase in
acute myocardial infarction: Results of the TIMI 10B trial. Circulation
1998;98:2805-14.
16. Van de WF, Cannon CP, Luyten A, et al. Safety assessment of singlebolus administration of TNK tissue-plasminogen activator in acute
myocardial infarction: The ASSENT-1 trial. The ASSENT-1 Investigators.
Am Heart J. 1999;137:786-91.
17. Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for
the management of patients with ST-elevation myocardial infarction:
A report of the American College of Cardiology/American Heart
Association Task Force on Practice Guidelines (Committee to Revise the
1999 Guidelines for the Management of Patients with Acute Myocardial
Infarction). Circulation. 2004;110:e82.
18. Efficacy and safety of tenecteplase in combination with enoxaparin,
abciximab, or unfractionated heparin: The ASSENT-3 randomised trial
in acute myocardial infarction. Lancet. 2001;358:605-13.
19.Dundar Y, Hill R, Dickson R, Walley T. Comparative efficacy of
thrombolytics in acute myocardial infarction: A systematic review. QJM
2003;96:103-13.
20. Elliott M, Antman, David A Morrow. ST-segment Elevation Myocardial
Infarction: Management. Braunwald Heart Disease A Textbook of
Cardiovascular Medicine Ninth Edition. 1111-1171.
21. Vanderschueren S, Barrios L, Kerdsinchai P, et al. The STAR Trial Group.
A randomized trial of recombinant staphylokinase versus alteplase for
116
Section 4
coronary artery patency in acute myocardial infarction. Circulation.
1995;92:2044-9.
22. Armstrong PW, Burton J, Pakola S, et al. Collaborative angiographic
patency trial of recombinant staphylokinase (CAPTORS II). Am Heart. J
2003;146:484-8.
23. Intravenous NPA for the treatment of infarcting myocardium early:
In TIME-II, a double-blind comparison of single-bolus lanoteplase
vs accelerated alteplase for the treatment of patients with acute
myocardial infarction. Eur Heart J. 2000;21:2005-13.
24. Cannon CP, Bahit M, Haugland JM, et al. Under-utilization of evidence
based medications in acute ST elevation myocardial infarction. Results
of the Thrombolysis in Myocardial Infarction (TIMI 9) registry. Crit
Pathways Cardiol. 2002;1:44-52.
25. Weaver WD, Cerqueira M, Hallstrom AP, et al. Prehospital-initiated
vs hospital-initiated thrombolytic therapy. The Myocardial Infarction
Triage and Intervention Trial. JAMA. 1993;270:1211-6.
26. Morrison LJ, Verbeek PR, McDonald AC, Sawadsky BV, Cook DJ.
Mortality and prehospital thrombolysis for acute myocardial infarction:
A meta-analysis. JAMA 2000;283:2686-92.
27. Boersma E, Maas AC, Deckers JW, et al. Early thrombolytic treatment
in acute myocardial infarction: Reappraisal of the golden hour. Lancet.
1996;348:771.
28. Fibrinolytic Therapy Trialists’ (FTT) Collaborative Group. Indications
for fibrinolytic therapy in suspected acute myocardial infarction:
Collaborative overview of early mortality and major morbidity
results from all randomized trials of more than 1000 patients. Lancet.
1994;343:311-22.
29. Gore JM, Granger CB, Simoons ML, et al. Stroke after thrombolysis.
Mortality and functional outcomes in the GUSTO-I trial. Global use of
strategies to open occluded coronary arteries. Circulation 1995;92:2811-8.
30. Gurwitz JH, Gore JM, Goldberg RJ, et al. Risk for intracranial hemorrhage
after tissue plasminogen activator treatment for acute myocardial
infarction. Participants in the National Registry of Myocardial Infarction
2. Ann Intern Med. 1998;129: 597-604.
31. Hudson MP, Granger CB, Topol EJ, et al. Early reinfarction after
fibrinolysis: Experience from the global utilization of streptokinase and
tissue plasminogen activator (alteplase) for occluded coronary arteries
(GUSTO I) and global use of strategies to open occluded coronary
arteries (GUSTO III) trials. Circulation. 2001;104:1229-35.
32. White HD, Barbash GI, Califf RM, et al. Age and outcome with
contemporary thrombolytic therapy. Results from the GUSTO-I trial.
Global Utilization of Streptokinase and TPA for Occluded coronary
arteries trial. Circulation. 1996;94:1826-33.
33. Weaver WD, Litwin PE, Martin JS, et al. The MITI Project Group. Effect
of age on use of thrombolytic therapy and mortality in acute myocardial
infarction. J Am Coll Cardiol. 1991;18:657-62.
34. Mauri F, Gasparini M, Barbonaglia L, et al. Prognostic significance of
the extent of myocardial injury in acute myocardial infarction treated
by streptokinase (the GISSI trial). Am J Cardiol. 1989;63:1291-5.
35. Sezer M, Oflaz H, Goren T, et al. Intracoronary streptokinase after primary
percutaneous coronary intervention. N Engl J Med 2007;356:1823-34.
36.Kelly RV, Crouch E, Krumnacher H, et al. Safety of adjunctive
intracoronary thrombolytic therapy during complex percutaneous
coronary intervention: Initial experience with intracoronary
tenecteplase. Catheter Cardiovasc Interv. 2005;66:327-32.
37. Kushner FG, Hand M, Smith SC, Jr., et al. 2009 focused updates: ACC/AHA
guidelines for the management of patients with ST-elevation myocardial
infarction (updating the 2004 guideline and 2007 focused update) and
ACC/AHA/SCAI guidelines on percutaneous coronary intervention
(updating the 2005 guideline and 2007 focused update) a report of the
American College of Cardiology Foundation/American Heart Association
Task Force on Practice Guidelines. J Am Coll Cardiol. 2009;54:2205–41.