THEMED ARTICLE y Disorders of the Myocardium Review

Fibrinolytic therapy in
patients with ST-elevation
myocardial infarction
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Expert Rev. Cardiovasc. Ther. 12(2), 201–215 (2014)

Amirreza Solhpour*1 ST-elevation myocardial infarction (STEMI) is related to acute occlusion of a coronary artery by
and Syed W Yusuf2 a fibrin-rich thrombus. Early reperfusion in STEMI reduces infarct size and improves prognosis.
1 Acute reperfusion may be achieved with percutaneous coronary intervention (PCI) and/or
Department of Cardiology, University
of Texas Health Science Center at fibrinolytic agents. When performed in a timely manner, primary PCI is the preferred method
Houston and Memorial Hermann Heart of reperfusion; however, due to logistic reasons, including lack of PCI-capable hospitals and
and Vascular Institute, Houston, delay in the first medical contact-to-balloon time, this simplified approach lacks universal
77030-1503 TX, USA
2
Department of Cardiology, MD Ander-
applicability. Due to clinical efficacy and the ease of administration, fibrinolysis is still an
son Cancer Center, Houston, TX, USA important reperfusion modality in patients with STEMI who cannot have primary PCI within
*Author for correspondence: guideline-recommended time. This review focuses on the role of fibrinolysis in patients
Tel.: +1 713 500 6577 with STEMI.
Fax: +1 832 218 4062
[email protected]
For personal use only.

KEYWORDS: fibrinolysis • percutaneous coronary intervention • pharmacoinvasive strategy • prehospital • ST-elevation

myocardial infarction

Despite advanced technology and improvement step-by-step processing of patients with STEMI
in interventional techniques, ST-elevation myo- for reperfusion therapy of choice.
cardial infarction (STEMI) is still a major Timely intervention with PCI in patients
cause of morbidity and mortality in the USA with STEMI leads to decreased mortality and
with an in-hospital mortality of 8% [1]. In the reduced cardiac dysfunction [5,7,9]. Since most
treatment of STEMI, time is muscle because patients present to a non-PCI–capable hospi-
ischemic time is directly associated with both tal, this issue is still a major logistic challenge
infarct size and mortality [2]. Hence, to limit or in many geographic areas [10].
prevent myocardial damage, the immediate re- Several studies have shown time dependence
establishment of blood flow in the infarct- of the benefit of PCI versus fibrinolysis [11–13].
related artery, with either fibrinolysis or An analysis of 21 trials demonstrated that the
primary percutaneous coronary intervention benefit of PPCI over fibrinolysis in absolute
(PPCI) is imperative. In patients presenting to mortality reduction at 4–6 weeks decreases, as
a PCI-capable hospital, PPCI is the treatment PCI-related time delay increases (0.94%
of choice [3–5]. PPCI is preferred for these decrease per additional 10-min delay; p =
patients due to established higher rates of 0.006) (FIGURE 2), with apparent equivalence
infarct-related artery patency and TIMI 3 flow after a PCI-related time delay of 62 min [13].
compared with fibrinolytic therapy [6,7]. Cur- The PCI-related time delay has significant
rent European and American guidelines recom- effect on the composite endpoint of death,
mend that in patients presenting to a non- stroke or reinfarction (FIGURE 3).
PCI–capable facility, if there is an anticipated Although extensive work has been directed
delay of >120 min from first medical contact toward resolving this PCI-related delay, there
to primary PCI, then fibrinolytic therapy are still large number of patients with STEMI
should be started within 30 min of hospital who do not receive PPCI within guideline rec-
arrival in all eligible patients, followed by a ommended times [14]. This delay increases
transfer to a PCI-capable facility [3,8]. FIGURE 1 morbidity and mortality [15,16]. Based on the
shows current American Heart Association/ current data, in the USA, the mean time to
American College of Cardiology guidelines in a PCI is 253 min, and the mean time to hospital

www.expert-reviews.com 10.1586/14779072.2014.867805 Ó 2014 Informa UK Ltd ISSN 1477-9072 201

 Review Solhpour & Yusuf

STEMI patient
substance, which was later named strepto-
appropriate for kinase [21]. In 1957, Sherry and col-
reperfusion leagues recommended a protocol for
Can you get them
to PCI hospital and intravenous fibrinolysis with a loading
device activation Give thrombolytics dose of streptokinase, followed by a con-
Seen at PCI in catheterization No within 30 min of tinuous infusion [22]. This resulted in the
No arrival
capable laboratory within first human study of intravenously strep-
hospital 120 min?
tokinase for the treatment of acute myo-
r tiate

cardial infarction [22]. The investigators

i
Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by University of Southern California on 04/06/14

min ut)
tran e to in

also found that when streptokinase was

or i sfe
≤ 30 door
tim

Yes administered early, within 14 h of symp-

Failed reperfusion
n
get

or reocclusion tom onset, there was lower in-hospital

Tar

(do

Transfer to mortality; however, the in-hospital mor-

catheterization Yes tality of those receiving delayed fibrinoly-
laboratory No sis and those without treatment was
for primary PCI Transfer to
Target for device catheterization similar [22].
Transfer for
activation in laboratory for Transfer to angiography and In 1971, a multicenter trial conducted
catheterization primary PCI catheterization revascularization by Marc Verstraete, who was the leader
laboratory ≤90 min Target ≤120 min laboratory for PCI within 3–24 hours as of a European Working Party [23],
from first medical from first medical part of an invasive
contact contact
showed that the use of streptokinase with
strategy
myocardial infarction decreased the rate
of hospital mortality from 26.3 to
Figure 1. Current American Heart Associaiton/American College of Cardiology
guidelines regarding reperfusion therapy for patients with ST-elevation 18.5%. Subsequently, in 1981, Markis
myocardial infarction. and colleagues [24] demonstrated that
For personal use only.

STEMI: ST elevation myocardial infarction; PCI: Percutaneous coronary intervention. intracoronary streptokinase administration
salvaged ischemic myocardium in patients
administered fibrinolysis is 54 min [1]. Door-to-balloon times with evolving myocardial infarction. Collen and Rijken [25],
within the recommended 90 min was reported in only 35% of during the early 1980s, were able to purify a substance called
hospitals and no real improvement in the door-to-balloon time human extrinsic plasminogen activator from melanoma cell
has been seen in the USA during the last several years [17]. Reduc- lines, which was renamed tissue plasminogen activator (tPA).
ing ischemic time, which is time from symptom onset to reperfu- In 1984, melanoma-derived tPA was evaluated in seven patients
sion, is the key factor to reduce 1-year mortality [18]. Among with acute myocardial infarction, and prompt thrombolysis was
patients undergoing PCI, it has been shown that each 30 min of noted in six patients [26].
delay is associated with an 8% increase in the risk of death dur-
ing 1 year [18]. Fibrinolytic agents
It has been shown that patients with STEMI who have Fibrinolysis is mediated by plasmin, which is a nonspecific
TIMI 3 flow prior to angioplasty have greater myocardial sal- serine protease and degrades clot-associated fibrin and fibri-
vage and improved early and late survival [19]. This finding led nogen and finally disrupts evolving thrombus. Fibrinolytic
to the design of several prospective randomized trials testing agents are plasminogen activators, which convert the plasmi-
pharmacological approaches such as fibrinolysis to achieve ear- nogen to plasmin either directly or indirectly. Plasmin
lier reperfusion before definitive mechanical intervention degrades several proteins such as fibrin, fibrinogen, factors V
is performed. and VII and prothrombin.
One important cause of prolonged ischemic time is the delay Four fibrinolytic agents (streptokinase and three plasminogen
from the time of symptom onset to hospital arrival [20]. To activators: alteplase, tenecteplase and reteplase) are approved for
address this issue, prehospital care has been implemented includ- use in the USA (TABLE 1).
ing performance of prehospital electrocardiography, the adminis- Streptokinase is a 415 amino acid bacterial protein. It has
tration of prehospital fibrinolysis and the informed triage of such no intrinsic enzymatic activity but forms a stable, noncovalent
patients to PCI-capable hospitals when appropriate [20]. 1:1 complex with plasminogen. It is the least expensive fibrino-
Our objective in this manuscript is to review the role of lytic agent and given by short-term infusions. This enzyme is
fibrinolytic therapy including prehospital fibrinolysis in the antigenic and has little fibrin specificity, and it has systemic
treatment of patients with STEMI. lytic effects in clinical doses. Since hemolytic streptococci pro-
duces streptokinase, antibodies against streptococci develop in
History of coronary fibrinolysis those receiving streptokinase, which precludes re-administration
In 1933, Tillet and Garner reported that Lancefield Group A of the enzyme. Since the advent of newer agents, streptokinase
beta-hemolytic streptococci were able to produce a fibrinolytic is rarely used clinically for fibrinolysis.

202 Expert Rev. Cardiovasc. Ther. 12(2), (2014)

 Fibrinolytic therapy in patients with STEMI Review

Alteplase is a tPA produced by 15

Absolute risk difference in death (%)

recombinant DNA technology. It consists
of 527 amino acids and synthesized with
the complementary DNA for natural 10
human tissue-type plasminogen activator
obtained from a human melanoma cell
p = 0.006
line. Alteplase binds to fibrin in a throm- 5
bus leading to conversion of plasminogen
to plasmin. This initiates local fibrinolysis
Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by University of Southern California on 04/06/14

with limited systemic proteolysis. Alte- 0

plase rapidly clears from the plasma in
patients with acute myocardial infarction
with an initial half-life of <5 min requir- -5
ing long weight-based infusion. Fibrin 0 20 40 60 80 100
specificity of alteplase is lower than that PCl-related time delay
of tenecteplase.
Tenecteplase is currently the most com- Figure 2. Absolute risk reduction in 4- to 6-week mortality rates with primary
monly used fibrinolytic in the USA. It percutaneous coronary intervention as a function of percutaneous coronary
has different structure with triple-site sub- intervention-related time delay. Circle size reflects the sample size of the individual
study. The solid line represents the weighted meta-regression. Values >0 favor PCI and
stitution providing longer plasma half-life; values <0 favor fibrinolysis.
therefore, single-bolus administration is PCI: Percutaneous coronary intervention.
possible. Fibrin specificity of tenecteplase Modified with permission of Elsevier from [13].
is higher than all other fibrinolytic agents.
Reteplase is also a mutant version of
For personal use only.

tPA, but with a single-chain deletion mutation. This deletion statistically nonsignificant reduction of 13/1000 when treated
provides longer half-life, which allows double-bolus after 12 h.
administration. Subsequent clinical trials then compared the efficacy of dif-
ferent fibrinolytic agents. The outcomes of the main trials com-
The effect of fibrinolysis on mortality paring fibrinolytic agents are summarized in TABLE 2. There was
The key trials of fibrinolysis evaluating the effect of fibrinolytic no significant difference in mortality between streptokinase and
agents on mortality were performed in the 1980s. The effect of tPA in GISSI-2 [31] and ISIS-3 [32] studies. In the Global Use
fibrinolytic agents on mortality reduction in acute myocardial of Streptokinase and tPA for Occluded Coronary Arteries-1
infarction was initially shown in the prospective Gruppo (GUSTO-1) study [33,34], there was a small reduction in mortal-
Italiano per lo Studio della Streptochinasi nell’Infarto ity (14% risk reduction) with tPA compared with streptokinase.
Miocardico-1 trial [27]. Gruppo Italiano per lo Studio della Publication of the GUSTO-l results led to much discussion
Streptochinasi nell’Infarto Miocardico-1 reported a significant and debate about thrombolytic therapy in acute myocardial
reduction in overall in-hospital mortality in those treated with infarction [35–43]. Some of the controversy concerns the proper
streptokinase within 12 h of the onset of symptoms [27]. The interpretation of the magnitude of differences between agents,
anisoylated plasminogen streptokinase activator complex the potential impact of an open-label design and the meaning
(APSAC) Interventional Mortality Study (AIMS; effect of intra- of observed effects in prespecified subgroups.
venous ASPAC on mortality after acute myocardial infarction:
preliminary report of a placebo-controlled trial) demonstrated a Intravenous infusion versus bolus fibrinolytics
significant decrease in 30-day and 1-year mortality rate with The main trials assessing intravenous versus bolus fibrinolytic
the use of APSAC [28]. The Second International Study of agents are shown in TABLE 3. The Assessment of the Safety and
Infarct Survival (ISIS-2) trial compared the 35-day cardiac Efficacy of a New Thrombolytic- 2 trial [44] showed similar
mortality rate with aspirin, streptokinase or combination of 30-day mortality and intracranial hemorrhage (ICH) rates
both. It showed 23% reduction by aspirin alone, 25% reduc- between weight-adjusted tenecteplase and accelerated tPA. In
tion by streptokinase alone and 42% reduction by combined the GUSTO-III trial [45], double-bolus reteplase did not
streptokinase and aspirin [29]. improve survival when compared with accelerated tPA. Lanote-
The Fibrinolytic Therapy Trialists’ Collaborative Group [30] plase or tPA had similar 30-day mortality rate in the Intrave-
pooled data from nine controlled trials of patients with sus- nous nPA for Treating Infarcting Myocardium Early-2
pected acute myocardial infarction, with enrollment of trial [46]; however, intracranial hemorrhage rate was significantly
45,000 patients, showed that in patients with STEMI, there higher in those who received lanoteplase, which led to its with-
was an absolute mortality reduction of 30/1000 when treated drawal from the market. Therefore, the bolus fibrinolytic agents
within the first 6 h, 20/1000 when treated in 7–12 h and a do not have better efficacy than the accelerated tPA, but

www.expert-reviews.com 203
 Review Solhpour & Yusuf

symptoms). [47] A review of two random-

Absolute risk difference in death/MI/stroke (%)

ized trials, the Which Early STEMI (Can-

ada) and the Comparison of Angioplasty
15 and Prehospital Thrombolysis in acute
Myocardial infarction (France) compared
PPCI and fibrinolysis in those with
10 STEMI who present early after symptom
p = 0.016
onset and confirmed the results from pre-
vious work showing the benefit of fibrino-
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5
lytic agents over PPCI [48]. In this study, a
better survival was seen (which was sus-
0 tained up to 1 year) in those who pre-
sented within 2 h of symptom onset and
received fibrinolysis compared with PPCI
-5 performed in large volume PCI facili-
0 20 40 60 80 100 ties [48]. There were 646 patients who
PCl-related time delay were randomized within 2 h of symptom
onset. Those patients who received fibri-
Figure 3. Absolute risk reduction in the 4- to 6-week combined end point of nolysis had 67% reduction in 1-year mor-
death, reinfarction or stroke with primary percutaneous coronary intervention
tality compared with those receiving PPCI
as a function of percutaneous coronary intervention-related time delay. Circle
sizes reflect the sample size of the individual study. Values >0 represent benefit and val- (fibrinolysis 10/358 [2.8%] vs PCI 20/288
ues <0 represent harm. The solid line represents the weighted meta-regression. [6.9%]; p = 0.021; hazard ratio: 0.43;
MI: Myocardial infarction; PCI: Percutaneous coronary intervention. 95% CI: 0.20–0.91) [48]. It should be
Modified with permission of Elsevier from [13]. noted that, in these trials, a pharmacoinva-
For personal use only.

sive strategy was conducted in the group

reteplase and tenecteplase have the similar efficacy to tPA. undergoing pharmacological reperfusion. Rescue PCI was
These agents, especially tenecteplase, are currently used as employed in 26% of patients, and 70% of the patients had PCI
standard fibrinolytics because they can be easily administered within 30 days. Therefore, one of the factors that needs to be
and require less transfusion. considered when choosing the reperfusion modality should be
time from symptom onset to medical presentation.
Role of fibrinolysis in patients who present early The recently published Strategic Reperfusion Early After
after STEMI Myocardial Infarction (STREAM) study was a large
It is still unclear which reperfusion modality is the best in randomized trial evaluating those STEMI patients present-
patients with STEMI who present to hospital early after symp- ing within 3 h of symptom onset [49]. In this study, inves-
tom onset (<3 h). Fibrinolysis within first few hours in patients tigators utilized half-dose fibrinolytic therapy with
with STEMI has shown optimal outcomes with low incidence tenecteplase and compared prehospital fibrinolysis followed
rate of morbidity and mortality. Of note, no clinically significant by routine or rescue PCI with PPCI alone, and there was
myocardial damage was seen in 25% of the patients who receive no significant difference in mortality between the two
fibrinolysis very early (within the first hour of the onset of groups [49].

Table 1. Fibrinolytic agent characteristics.

Fibrinolytic Dose Relative Plasminogen Antigenic Plasma
fibrin activator half-life
specificity (min)
Alteplase (tPA) 15 mg bolus + 90 min weight-based infusion† ++ Direct No 4–6
Lanoteplase 120 KU/kg single bolus + Direct Unknown 37
Reteplase (rPA) 10 MU + 10 MU iv. boluses given 30 min apart ++ Direct No 18
Streptokinase 1.5 MU iv. given over 30–60 min 0 Direct Yes 23
Tenecteplase (TNK-tPA) Single iv. weight-based bolus‡ ++++ Direct No 20
†
Infusion 0.75 mg/kg for 30 min (maximum 50 mg), then 0.5 mg/kg (maximum 35 mg) over next 60 min; total dose not to excess 100 mg.
‡
30 mg for weight <60 kg; 35 mg for 60–69 kg; 40 mg for 70–79 kg; 45 mg for 80-89 kg; and 50 mg for >90 kg.
iv.: Intravenous; KU: Thousand units; MU: Million units.
Data adapted from [3,123].

204 Expert Rev. Cardiovasc. Ther. 12(2), (2014)

 Fibrinolytic therapy in patients with STEMI Review

Table 2. Comparative trials of fibrinolytic agents.

Trial Sample Compared 30-day 30-day Total Total Intracranial Intracranial Ref.
size (n) interventions mortality mortality stroke stroke hemorrhage hemorrhage
(%) p-value rates (%) p-value rates (%) p-value
GUSTO-1 41,021 SK 7.3 0.001 1.31 0.09 0.52 0.03 [33]
tPA 6.3 1.55 0.72
SK 7.3 0.352 1.31 0.02 0.52 <0.001
SK + tPA 7.0 1.64 0.94
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tPA 6.3 0.04 1.55 N/A 0.72 N/A

SK + tPA 7.0 1.64 0.94
ISIS-3 41,299 SK 10.6 NS 1.04 2p† = 0.24 2p < 0.0001 [32]
APSAC 10.5 1.26 0.08 0.55
SK 10.6 NS 1.04 2p < 0.01 0.24 2p < 0.00001
tPA 10.3 1.39 0.66
GISSI-2 12,490 SK 8.6 NS 0.9 NS 0.25 NS [31]
tPA 9.0 1.1 0.30
†
2p indicates two-sided p-value.
APSAC: Anisoylated plasminogen-streptokinase activator complex (anistreplase); N/A: Not applicable (not reported in the study); NS: Not statistically significant;
SK: Streptokinase, tPA: Tissue plasminogen activator.

Prehospital fibrinolysis symptom [52]. This finding matches with the results of the
Fibrinolysis has the most benefit when given soon after the onset randomized comparison of angioplasty and prehospital throm-
For personal use only.

of symptoms and then this benefit diminishes as the time from bolysis in acute myocardial infarction trials [53] and primary
symptom onset to fibrinolysis increases [2]. There is a meta- angioplasty in patients transferred from general community hos-
analysis of 6 clinical trials including 6434 patients comparing the pitals to specialized PTCA units with or without emergency
outcomes of prehospital versus in-hospital fibrinolysis. This anal- thrombolysis study [12]. To date, the results of prehospital fibri-
ysis showed a reduced all-cause hospital mortality with prehospi- nolysis for acute myocardial infarction are promising; however,
tal fibrinolysis [50]. Pooled data from meta-analysis were not there are some logistic limitations in different areas of the world,
sufficient to reach a statistically significant difference in 1 or which prevents its widespread application in real practice. This
2-year mortality between two groups. However, longer term ben- approach is most suitable for rural areas with prolonged transfer
efit of prehospital fibrinolysis at 5 years was seen in the Gram- time to the hospitals.
pian Region Early Anistreplase Trial [51] study’s follow-up results,
in those treated out of hospital with prolonged transfer time to Rational for prehospital fibrinolysis
hospital. Another study [52] showed lower mortality rate with Over 75% of the US hospitals do not have PCI capability
fibrinolysis in the first 2 h of symptom onset compared with requiring patient transfer for PPCI [54]. It has been shown that
PPCI (5.1 vs 7.8%); however, there was no statistically signifi- the benefit of PPCI over fibrinolysis is lost in those patients
cant difference (p = 0.37). It should be noted that only 34 of the with STEMI if first medical contact to balloon is prolonged to
1,053 consecutive patients evaluated in this study received preho- 62 min [13]. Current data show that only minority of those
spital fibrinolysis at a median of 76 min following the onset of STEMI patients who are transferred for PPCI have guidelines

Table 3. Comparative trials with bolus fibrinolytic agents.

Trial Sample Compared 30-day 30-day Total Total Intracranial Intracranial Ref.
size (n) interventions mortality mortality stroke stroke hemorrhage hemorrhage
(%) p-value rates (%) p-value rates (%) p-value
In TIME-II 15,060 tPA 6.61 NS 1.53 NS 0.64 0.004 [46]
Lanoteplase 6.75 1.87 1.12
ASSENT-2 16,949 tPA 6.151 NS 1.66 NS 0.94 NS [44]
Tenecteplase 6.179 1.78 0.93
GUSTO-III 15,059 tPA 7.24 NS 1.79 NS 0.87 NS [45]
Reteplase 7.47 1.64 0.91
ASSENT-2: Assessment of the Safety and Efficacy of a New Thrombolytic- 2; GUSTO-III: Global Use of Streptokinase and tPA for Occluded Coronary Arteries;
NS: Not statistically significant; tPA: Tissue plasminogen activator.

www.expert-reviews.com 205
 Review Solhpour & Yusuf

showed that fibrinolytic therapy saved

65, 37, 26 and 29 lives per 1000 treated
patients in the 0–1, 1–2, 2–3 and 3–
Absolute 40 6 h intervals, respectively, after symp-
benefit per 3000
tom onset [2]. There was significantly
1000 patients Change in benefit
with ST elevation 14000 per hour of delay larger reduction in mortality in those
or BBB allocated 30 to randomization: treated within 2 h of symptom onset
fibrinolytic therapy 12000 -1.6 ± 0.6 lives per (44%; 95% CI: 32–53) than patients
(±1 standard 1000 patients treated later (20%; 95% CI: 15–25;
Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by University of Southern California on 04/06/14

deviation) 9000
20 p = 0.001). There are many studies
showing better cardiac function and less
mortality by using prehospital fibrinoly-
10
sis in appropriate patients and reducing
the time from symptom onset to reper-
7000
fusion [50,51,53,58–69]. Many studies have
shown that prehospital fibrinolysis
0
0 6 12 18 24
reduces the time to reperfusion signifi-
cantly when compared with in-hospital
Hours from symptom onset to randomization
fibrinolysis [59,62–64,66,67,69,70].
Figure 4. Increased benefit of early fibrinolysis in reducing mortality in patients It was also noted that in the Compar-
with ST-elevation or bundle-branch block. The Fibrinolytic Therapy Trialists’ Collabo- ison of Angioplasty and Prehospital
rative Group, Indications for fibrinolytic therapy in suspected acute myocardial infarction: Thrombolysis in Acute Myocardial
collaborative overview of early mortality and major morbidity results from all randomized Infarction trial, despite no significant
trials of more than 1000 patients.
difference in short-term mortality
For personal use only.

BBB: bundle-branch block.

Modified with permission of Elsevier from [30]. between those given prehospital fibrinol-
ysis within first 2 h of symptom onset
and those who had PPCI, there was a
recommended medical contact-to-balloon time leading to significantly lower cardiogenic shock in those who received pre-
delays in reperfusion therapy and subsequent increase in hospital fibrinolysis than those who had PPCI [11]. Further-
mortality [3,54]. more, the Myocardial Infarction Triage and Intervention study
When a STEMI occurs, there is a short but ‘golden’ time of also showed better improvement in ejection fraction and a sig-
opportunity within the first 2–3 h, when time to reperfusion nificant decrease in infarct size and mortality in those patients
is more important than the method of reperfusion. It has previ- with STEMI given prehospital fibrinolysis within 70 min of
ously been shown that every 30 min delay during this 2–3 h symptom onset compared with those received fibrinolytic at
window, is associated with an 8% increase in relative mortality later time [69]. These findings further emphasize that reduced
at 1 year [18]. ischemic time using prehospital fibrinolysis plays an important
Taken together, ischemic time, which is the time from role in the outcomes of patients with STEMI.
symptom onset to reperfusion, can be reduced by shortening of It is worth mentioning that most of the studies designed to
the transportation time to the hospital using a prehospital elec- assess the benefit of prehospital fibrinolysis were performed in
trocardiography assessment and patient evaluation [55,56]. The Europe with the presence of a doctor when fibrinolytic agent
ischemic time can be further reduced using fibrinolytic agents was administered in the ambulance [51,53,58–62,66,67]. However, in
in prehospital setting for appropriate patients by specially one Swedish study and few North American studies in which
trained medical emergency staff. In fact, ESC guidelines recom- fibrinolytic agents were given by emergency medical services
mend to start fibrinolytic therapy, particularly prehospital fibri- (EMSs) personnel, ischemic time was also reduced, and led to
nolysis (e.g., In the ambulance) if anticipated delay of similar or even better outcomes compared with in-hospital
performing PCI is >120 min [8]. FIGURE 4 shows a linear relation- fibrinolysis [64,69–73].
ship between mortality and time of reperfusion with a fibrino- A ‘facilitated’ PCI strategy with reduced dose fibrinolysis fol-
lytic, which equates 1.6 lives lost per 1000 patients per hour of lowed by immediate PCI (termed FAST-PCI) may improve
delay in treatment [2,57]. patency of the infarct-related artery prior to initial angioplasty
and decrease mortality in those who are not able to have PPCI
Evidence for prehospital fibrinolysis within recommended time frame [49,74,75].
There have been several studies showing reduction in myocar- The Alliance for Myocardial Infarction Care Optimization
dial damage and improvement in patient outcome with rapid (AMICO) [71] found that prehospital half-dose fibrinolytic
reperfusion using fibrinolysis in STEMI patients compared administration coupled with urgent PCI led to lower 30-day
with delayed treatment [2]. A meta-analysis including 22 studies mortality compared with PPCI, without any bleeding penalty.

206 Expert Rev. Cardiovasc. Ther. 12(2), (2014)

 Fibrinolytic therapy in patients with STEMI Review

In this study, the 30-day mortality rate was 3.8% with It has been shown that medical staff may under or overesti-
FAST-PCI compared with 6.4% with PPCI (p = 0.002). mate patients’ weights in the emergency setting, which can
Bhatt et al. [72] also reported in-hospital mortality rate similar results in dosing error [85,86].
to AMICO study for FAST-PCI versus PPCI (2.8% in FAST- This medication error may also be seen in those with very
PCI vs 10.5% in PPCI). Importantly, in AMICO study, pre- high or low body weight. When a patient with high body
hospital administration of half-dose fibrinolytic was safe, and it weight receives a maximum recommended dose from a fibri-
was able to re-establish blood flow in infarct-related arteries in nolytic agent requiring weight-based dosing, there is a possi-
approximately 80% of patients prior to PCI [71]. bility that the administered dosage is below that specific
In STEARM study, a recent randomized trial that utilized patient’s requirement due to his high body weight leading to
Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by University of Southern California on 04/06/14

half-dose fibrinolytic therapy with tenecteplase and compared suboptimal treatment. On the other hand, when a patient
prehospital fibrinolysis followed by routine or rescue PCI with with very low body weight receives a bolus agent with no
PPCI alone, there was no significant difference in mortality weight adjustment, there is possibility that administered dos-
between two groups [49]. age is more than required dose for that specific patient’s low
body weight, which can results in bleeding complications.
Which fibrinolytic agents should be used in prehospital Reteplase in a nonweight-based dosing, in those with weight
setting? <65 kg, has resulted in more in-hospital overall bleeding
Since fibrinolytic agents have a narrow therapeutic window, events with no significant difference in stroke rate or bleeding
therefore, the accuracy of dosage and administration plays an events requiring blood transfusion [87]. Furthermore, clear-
important role in a safe and effective prehospital care of ance of tenecteplase decreases in those with lower body
STEMI patients wherein medication error should be avoided weight or higher age [88].
[76,77]. In fact, the successful use of prehospital fibrinolysis in In brief, as discussed earlier, the bolus fibrinolytic agents do
many studies was secondary to ability of giving the fibrinolytic not have better efficacy than the accelerated tPA, but reteplase
agents not requiring weight-based dosing [50,53,61,64,65]. Inaccu- and tenecteplase have the similar efficacy to tPA. These agents
rate dosing of fibrinolytic agents may lead to complications should currently be preferred to be used as standard fibrinolysis
For personal use only.

requiring resources for treatment, which are not available in because they can be easily administered, and the simplicity of
prehospital setting. Therefore, simplicity of fibrinolytic agent the administration will result in the least medication errors,
administration needs to be considered in prehospital care sys- which is very important in this setting.
tem. Drugs like streptokinase and alteplase have short half-life;
therefore, their administration requires intravenous infusion, The pharmacoinvasive strategy
making them hard to use in prehospital setting. As noted previ- The term pharmacoinvasive therapy refers to the administration
ously, tenecteplase and reteplase have different structure from of fibrinolytic therapy either in the prehospital setting or at a
native plasminogen activator, which provides half-life longer non-PCI-capable hospital, followed by immediate transfer to a
than that of other fibrinolytic agents; hence, they can be given PCI-capable hospital for emergent rescue PCI if pharmacologic
as bolus injection [78]. therapy has failed or early routine angiography and PCI in
There is a potential high risk of medication error when fibri- those with successful pharmacologic treatment. The current
nolytic agents are administered. Those given incorrect dosage criteria for successful pharmacologic treatment after administra-
of alteplase and streptokinase had worse outcome with an tion of fibrinolytic agent are ST resolution >50% on a
increase in mortality rate [79]. There has been significantly less 60–90 min ECG, absence of symptoms and hemodynamically
error in dosage with bolus fibrinolytic compared with agents stable. The currently recommended time for early routine
requiring intravenous infusion [77,80–82]. In addition, fibrinolytic angiography and PCI in this group of patients is between
agents requiring weight-based dosing may lead to more treat- 3 and 24 h after fibrinolytic administration.
ment complexity in the prehospital setting where a simple drug Current data from randomized trials showed that when
administration is necessary [83,84]. Both tenecteplase and alte- compared with fibrinolysis, the pharmacoinvasive strategy led
plase need to be dosed based on patients’ weight. Tenecteplase to a lower risk of death (odds ratio [OR]: 0.55; 95% CI:
have five dose levels based on the weight: 30 mg for those with 0.34–0.90) and re-infarction (OR: 0.53; 95% CI: 0.33–0.89)
weight <60 kg, 35 mg for those weighing >60 to <70 kg, [89]. In a combined data overview (n = 2,961) comparing the
40 mg for those weighing >70 to <80 kg, 45 mg for those pharmacoinvasive strategy with fibrinolysis and standard of
with weight >80 to <90 kg and finally 50 mg for those with care, significant decrease in re-infarction (OR: 0.55; 95% CI:
weight >90 kg [201]. Alteplase has two different dosage protocol 0.36–0.82; p = 0.003) and recurrent ischemia (OR: 0.25; 95%
based on patients’ weight. For those with weight >67 kg, a CI: 0.13–0.49; p = 0.001) at 30 days were seen with the phar-
15 mg bolus is given, followed by 50 mg over the next 30 min macoinvasive strategy, but no benefit was achieved on 30-day
and then 35 mg over the next 60 min, and for those with (OR: 0.87; 95% CI: 0.59–1.30) or 6-month (OR: 0.88; 95%
weight <67 kg, a 15 mg bolus should be given, followed by CI: 0.62–1.25) mortality [90]. These benefits were seen without
0.75 mg/kg (maximum 50 mg) over the next 30 min and then an increased risk of stroke (OR: 0.63; 95% CI: 0.31–1.26) or
0.50 mg/kg (maximum 35 mg) over the next 60 min [202]. major bleeding (OR: 0.93; 95% CI: 0.67–1.31).

www.expert-reviews.com 207
 Review Solhpour & Yusuf

Table 4. Absolute and relative contraindications for fibrinolytic therapy in ST-elevation myocardial infarc-
tion patients.
Absolute contraindications Relative contraindications
• Any prior intracranial hemorrhage • History of prior ischemic stroke >3 months
• Known structural cerebral vascular lesion • Dementia
• Known malignant intracranial neoplasm • Known intracranial pathology not covered in absolute
• Ischemic stroke within past 3 months (except acute contraindications
ischemic stroke within past 4.5 h) • Traumatic or prolonged (>10 min) CPR
Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by University of Southern California on 04/06/14

• Significant closed-head or facial trauma within past • Major surgery within past 3 weeks
3 months • Noncompressible vascular punctures
• Intracranial or intraspinal surgery within past 2 months • History of chronic, severe, poorly controlled hypertension
• Suspected aortic dissection • SBP >180 mmHg or DBP >110 mmHg on presentation
• Active bleeding or bleeding diathesis (excluding menses) • Recent (within 2–4 weeks) internal bleeding
• Severe uncontrolled hypertension unresponsive to • Pregnancy
emergency therapy • Active peptic ulcer
• For streptokinase, prior treatment within past 3 months • Oral anticoagulant therapy
CPR: Cardiopulmonary resuscitation; DBP: Diastolic blood pressure; SBP: Systolic blood pressure.
Data adapted from [3].

Recently, published STREAM trial showed that fibrinolysis is the main complication of fibrinolysis. Intracranial hemor-
with tenecteplase and contemporary antithrombotic therapy rhage is the worst bleeding complication, with a possible conse-
given prior to transport to a PCI-capable hospital followed by quence of disability or fatality [100]. The following patients are
timely coronary angiography using pharmacoinvasive strategy is at increased risk of intracranial hemorrhage: elderly people;
as effective as PPCI in patients with STEMI who present those weighing <70 kg; women; and those with hypertension
For personal use only.

within 3 h of symptom onset and PPCI cannot be performed on admission [101].

within 1 h of first medical contact [49]. There was a significant Serious anaphylaxis or bronchospasm is uncommon with
increase in intracranial hemorrhage in the fibrinolysis group, streptokinase use with an incidence rate of 0.2–0.5% [29]. In the
which led to the dose of tenecteplase being halved in people ISIS-3 trial [32], 3.6% of those administered streptokinase and
aged 75 years and older, fairly early on in the course of the 0.8% of those receiving tPA had allergic reaction. If a complica-
trial, after which the intracranial hemorrhage rate in the fibri- tion is seen secondary to antigenic reaction with streptokinase
nolysis group was reduced to 0.5%, which was not significantly use, then it should not be used in future, and other fibrinolytic
different from the PCI group [49]. agents such as an alteplase-based or nonstreptokinase-based
Some STEMI reperfusion centers have been using the pharma- agent should be used if fibrinolysis is indicated. Some relative
coinvasive approach with acceptable outcomes. However, there is contraindications to using streptokinase are history of prior
no certain answer yet to the following question: “when is the exposure (not within last 5 days) and history of any allergic
best exact time of early cardiac catheterization in those who have reaction [28].
had successful reperfusion with pharmacologic therapy?”
Historically, fibrinolysis followed by early PCI has been associ- Fibrinolysis in the elderly
ated with platelet activation, coronary reocclusion and an increased Majority of the earlier trials of fibrinolytic therapy have
rate of bleeding [91–93]. Subsequently, the stenting technique signifi- excluded patients >75 years of age. The elderly population with
cantly decreased the rate of these complications [94,95]. Since there is acute coronary syndrome has not been studied as extensively as
improved patency with PCI, it is recommended to transfer these the younger population [102]. Fibrinolytics are administered cau-
STEMI patients to PCI-capable hospitals immediately following tiously to this population, since ICH is a possible complication
fibrinolytic administration [3]. This recommendation was con- of treatment [103], especially in those with risk factors such as
firmed in several randomized clinical trials such as NORDISTEMI, uncontrolled hypertension, low body weight and female gender.
GRACIA-1, TRANSFER-AMI and CARESS-in-AMI [96–99]. This has led to the impression that PPCI may be a better reper-
In brief, all STEMI patients should be transferred to PCI- fusion modality over full-dose fibrinolysis in elderly population.
capable hospitals following fibrinolytic therapy (when appropri- The two largest trials evaluating these two reperfusion
ate). Further studies need to be conducted to better determine modalities in the elderly, the ‘Senior PAMI’ trial (481 patients)
the best time of cardiac catheterization in those with successful and the Tratamiento del Infarto Agudo de Miocardio en
pharmacological reperfusion. Ancianos trial (266 patients) were terminated early due to slow
enrollment [104,203]. Although neither trial demonstrated superi-
Complications of fibrinolysis ority of PPCI over full-dose intravenous fibrinolysis with the
Absolute and relative contraindications of fibrinolytic agents in enrollment numbers obtained, numerically, the results seemed
patients with STEMI are summarized in TABLE 4. Major bleeding to favor PPCI. A pooled analysis of available randomized

208 Expert Rev. Cardiovasc. Ther. 12(2), (2014)

 Fibrinolytic therapy in patients with STEMI Review

STEMI patients >75 years of age (n = 834) included with the of pharmacoinvasive therapy by using evidence from random-
Tratamiento del Infarto Agudo de Miocardio en Ancianos ized clinical trials. Bleeding complications may be higher in
report indicated a nonsignificant reduction in mortality for patients in acute setting undergoing emergent intervention
PPCI over full-dose intravenous fibrinolysis (10.7 vs 13.8%; compared with those undergoing the same intervention, but in
OR: 0.74; 95% CI: 0.49–1.13; p = 0.16). However, the pooled an elective setting [109,110], and therefore, more cautions should
analysis also revealed a benefit of PPCI over full-dose fibrinoly- be taken to avoid bleeding in the acute setting [110]. Some alter-
sis in these elderly patients for the composite endpoint of mor- native strategies such as use of both radial artery access and
tality, reinfarction and disabling stroke (14.9 vs 21.5%; OR: bivalirudin may decrease the bleeding complications [111,112];
0.64; 95% CI: 0.45–0.91; p = 0.013). however, these strategies should be tested in randomized clini-
Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by University of Southern California on 04/06/14

Another analysis showed that there may be a harm to elderly cal trials in those treated with pharmacoinvasive approach.
patients aged >75 years with fibrinolysis [105]. Conversely, a PPCI in a timely fashion is the preferred option in patients
large registry performed in Sweden reported a 12% risk reduc- with STEMI. However, this may not be logistically possible in
tion in the composite endpoint of cerebral bleeding and 1-year all centers and may never be a realistic goal worldwide. Thus,
mortality in elderly patients treated with fibrinolytic agents [106]. we suggest that pharmacoinvasive therapy should be used for a
The Fibrinolytic Therapy Trialists’ overview of randomized large minority of patients with STEMI who are not able to
trial data in those >75 years similarly showed a reduction in undergo immediate PPCI. The optimal window or timing for
35-day mortality with fibrinolysis [30]. cardiac catheterization for the pharmacoinvasive approach
In ISIS-2 study, 401 patients >80 years were randomized to remains undefined and need more investigations (currently
receive streptokinase or placebo [29]. The results showed a within 3–24 h). Based on the current evidence from random-
reduction in mortality from 34.2% in the placebo arm to ized trials, all PCI-capable hospitals should implement proto-
20.1% in the streptokinase arm, a relative risk reduction of cols to achieve a door-to-balloon time <90 min in all eligible
41% and an absolute risk reduction of 14.1%. Importantly, patients with STEMI.
there was greater reductions in both relative and absolute risk It should also be noted that current PCI era is different
in patients >80 years compared with any other age group (<60, from the PCI era when some studies performed on the role of
For personal use only.

60–69 and 70–79), and that the benefits were with no increase fibrinolysis in the patients with STEMI. The introduction of
in the risk of major bleeding, intracranial hemorrhage or other new generations of stents and antiplatelet medications in the
strokes. Interestingly, the number of lives saved per 100 patients current and future PCI era may lead to the better outcomes of
was higher in very elderly compared with other age groups the patients undergoing PCI. Hence, more investigations are
(14.1 lives saved per 100 patients in >80 vs 1.6 in <60; 3.8 in needed to focus on the role of fibrinolysis in the future and
60–69 and 1.9 in 70–79) [29]. Despite the fact that octogenar- more advanced PCI era.
ians included in ISIS-2 comprised a selected patient popula- One more important aspect needs to be considered while
tion, the results showed that fibrinolytic therapy may offer comparing the different strategies in the treatment of patients
substantial benefit in even elderly people [29]. with STEMI is the cost–effectiveness of each strategy.
The elderly population is growing due to enhanced survival, Several studies have assessed this aspect in different treatment
and specific data regarding this subset of patients are needed. strategies [113,114]. A systematic review of 22 randomized clinical
The STREAM study provided further information specific to trials into the cost–effectiveness of PPCI compared with
fibrinolysis in the elderly. In this large randomized clinical trial, thrombolysis in the UK concluded that PPCI was more cost-
half-dose fibrinolytic therapy with tenecteplase was utilized and effective than thrombolysis when carried out within 80 min of
compared prehospital fibrinolysis and PPCI in STEMI patients STEMI diagnosis [115]. One study demonstrated the cost–effec-
[49]. Intracranial hemorrhage rates between the two groups were tiveness of introducing earlier administration of thrombolytics
comparable after the study changed their protocol from full- to by paramedics in the field compared with the current practice
half-dose fibrinolytic administered to patients aged >75 years [49]. of administering thrombolytics only in hospital [113]. As dis-
However, the efficacy of this approach was not investigated cussed earlier, there are potentially large costs to establish a
specifically in the elderly population. In brief, reperfusion service where paramedics administer thrombolysis. These costs
should never be disregarded in elderly on the basis of age include stocking ambulances with thrombolytics and the train-
alone, but we should consider the higher risk of bleeding, ing of staff to administer thrombolytics. However, these costs
especially if there are other features of bleeding risk. occur early in the establishment phase and may be considered
as an initial investment to provide long-term future health
Expert commentary gains. In one study, patients presenting with inferior STEMI
Overall, we recommend that non-PCI-capable hospitals should who received fibrinolytic therapy, a routine invasive strategy
be designated as Pharmacoinvasive therapy referral facilities with early coronary angiography and intended revascularization,
where door to fibrinolytic therapy of <30 min is achieved in as achieved a clinical outcome similar to an ischemia-guided strat-
many patients as possible; PPCI referral facilities where meas- egy; yet, at a significantly higher cost [116].
urement of transfer time is the main indicator of quality of One should take into account the long-term cost–effective-
care [107,108]. There is a need for simplification of the definition ness of these different strategies and also compares the cost–

www.expert-reviews.com 209
 Review Solhpour & Yusuf

effectiveness of combined therapy, fibrinolytic therapy followed the reduction of total ischemic time and achievement of better
by PCI, using large randomized clinical trials. outcomes in patients with STEMI patients. Further random-
ized clinical trials need to be conducted to evaluate the efficacy
Five-year view and safety of the strategy of using prehospital-reduced dose
Data show that the time from symptom onset to hospital fibrinolysis followed by urgent PCI compared with PPCI alone
arrival is one of the key opportunities to reduce total ischemic or pharmacoinvasive strategy. The optimal time of cardiac
time, as there is still a delay around 2 h before first medical catheterization and PCI for those with successful reperfusion
contact in patients with STEMI [117,118]. Future strategies using fibrinolysis in pharmacoinvasive approach needs further
should focus on shortening of this time in addition to improv- investigation.
Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by University of Southern California on 04/06/14

ing door-to-needle or door-to-balloon time. Furthermore, To be able to have an active prehospital fibrinolysis system
EMSs are currently used by less than one-third of patients with with the least possible medical error, an organized integration
STEMI, and the majority of patients are transported by friends and collaboration between different systems of care are
or family members to the hospital [119]. Of particular note, this required. These systems include emergency centers of both PCI
delay to hospital presentation results in a delay in fibrinolytic and non-PCI-capable hospitals, emergency personnel and medi-
administration and subsequently most of the patients under- cal services, in a local area and cardiac catheterization laborato-
going fibrinolytic-facilitated PCI, will receive treatment on the ries. This strategy must be sensitive to critical care access
‘flat’ part of the curve when the golden window for reperfusion hospitals in rural area with the goal being the most expedient
to significantly improve cardiac function or reduce mortality care for the STEMI patient. A patient with STEMI is a critical
has already passed [120]. Hence, it is crucial to educate people patient and even a delay of minutes can increase patient mor-
to call EMS as soon as they become symptomatic and use bidity or mortality; therefore, it is important to implement the
ambulance as a transportation tool. strategies to expedite the process to reach the shortest total
One important strategy to shorten total ischemic time is an ischemic time to improve patients’ outcomes and survival.
earlier diagnosis using a prehospital electrocardiogram [121] with
protocols and systems to bypass the emergency centers of hos- Financial & competing interests disclosure
For personal use only.

pitals with PCI capability and transport patients with STEMI The authors have no relevant affiliations or financial involvement with
directly to the cardiac catheterization laboratory to reduce any organization or entity with a financial interest in or financial conflict
door-to-balloon time. However, there are some challenges with with the subject matter or materials discussed in the manuscript. This
major regional and national differences [122]. includes employment, consultancies, honoraria, stock ownership or options,
The important role of prehospital fibrinolysis has been expert testimony, grants or patents received or pending or royalties.
shown, especially in Europe [61], and this plays a pivotal role in No writing assistance was utilized in the production of this manuscript.

Key issues
• Fibrinolysis is an important mode of reperfusion in patients with ST-elevation myocardial infarction (STEMI) when primary percutaneous
coronary intervention (PPCI) cannot be performed within guideline recommended time.
• In patients with STEMI presenting to non-PCI-capable hospitals, If first medical contact to PPCI delay is expected to be >120 min,
fibrinolysis should be started within 30 min of hospital arrival followed by immediate transfer to a PCI-capable hospital.
• The bolus fibrinolytic agents do not have better efficacy than the accelerated tissue plasminogen activator (tPA), but reteplase and
tenecteplase have the similar efficacy to tPA. These agents, especially tenecteplase, are currently used as standard fibrinolysis because
they can be easily administered.
• In patients with STEMI, prehospital diagnosis is required and should be combined with field triage directly to cardiac catheterization
laboratory in PPCI centers if available, bypassing local hospitals, coronary care units and emergency centers.
• The time taken for transportation by emergency medical services (EMSs) to the hospital is an opportunity to reduce total ischemic time
through active prehospital patient evaluation and prehospital fibrinolytic administration by trained EMSs.
• Fibrinolytic therapy is more effective within first few hours after STEMI occurs. Optimal balance between safety and efficacy in STEMI
patients who are not able to undergo immediate PPCI can be achieved by using pharmacoinvasive strategy. This was recently confirmed
by the Strategic Reperfusion Early After Myocardial Infarction trial.
• One of the strategies to achieve the goal of total ischemic time <120 min will be prehospital diagnosis and initiation of reperfusion with reduced
dose of fibrinolytic agents immediately at the scene by trained EMSs providers acting under protocol, followed by urgent infarct artery PCI after
the patient is transported. Randomized clinical trials need to be conducted to further investigate the efficacy and safety of this approach.
• Intracranial hemorrhage is the worst bleeding complication of fibrinolytic therapy, especially in elderly, patients with weight <70 kg,
women and those with hypertension on admission. Although some data show that fibrinolytic therapy may offer some benefits even in
elderly patients, more randomized clinical trials evaluating the efficacy and safety of fibrinolytic agents in elderly are required.

210 Expert Rev. Cardiovasc. Ther. 12(2), (2014)

 Fibrinolytic therapy in patients with STEMI Review

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