R-tPA and Thrombolysis in STEMI : Pro and Cons

Hariadi Hariawan
Department of Cardiology and Vascular Medicine
Faculty of Medicine Universitas Gadjah Mada
Dr. Sardjito General Hospital Yogyakarta, Indonesia

Abstract
Reperfusion therapy is the standard treatment for ST-segment elevation
myocardial infarction.1 The objective of the treatment is to restore the coronary
flow in the infarct related artery quickly, completely and in a sustained manner.
Reperfusion or revascularization strategies are pharmacological reperfusion as
thrombolytic (fibrinolytic) therapy and mechanical reperfusion by primary
Percutaneous Coronary Intervention (Primary PCI)

STEMI presentation in up to 33% of ACS cases. Diagnosis based on typical ST

changes, usually represent an acute thrombotic occlusion of an epicardial coronary
artery, that requires prompt recognition, triage, and reperfusion.2 The presence of
ST-elevation prompts the decision to proceed with rapid reperfusion therapy, in
order to decrease the mortality rate of STEMI patients. In Indonesia, based on
basic health research data, the prevalence of acute coronary syndrome was 7.2%
in, and ST-segment Elevation Myocardial Infarction (STEMI) was a spectrum of
acute coronary syndrome with the highest severity.

However, in the real world, timely reperfusion therapy cannot be applied in

all STEMI patients, particularly in a developing country with several barriers still
in existence. For logistic reasons, primary-PCI cannot be implemented quite often,
and thrombolytic therapy continues to be the frequently performed reperfusion
therapy across the globe.

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 There are 3 generations of the thrombolytic agents for use in STEMI, and one
has to choose an agent that suits the situation best. It is also important to
remember that thrombolytic therapy is not the end of the management of STEMI.
One of the thrombolytic agent is recombinant tissue Plasminogen Activator
(R-tPA).3 An how is advantage and disadvantage of R-tPA for thrombolysis in
STEMI patients.

Keywords: STEMI, reperfusion therapy, thrombolytic agent, R-tPA.

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Introduction
Plaque rupture and thrombus formation remain the primary cause of acute
vessel occlusion that leads to STEMI. Fibrinolytic therapy was a major advance in
the treatment of acute STEMI since > 90% of STEMI is due to plaque rupture and
subsequent thrombus formation. The proximate cause of acute ST elevation
myocardial infarction (STEMI) is the total occlusion of the coronary artery lumen
following errosion of rupture of the coronary atheromatous plaque. The presence
of ST-elevation prompts the decision to proceed with rapid reperfusion therapy.4
Primary PCI is the preferred reperfusion therapy for acute STEMI, because of
superior in efficacy (over 90% restoration of TIMI 3 flow), superior in safety (less
stroke / bleeding), and superior for long term outcomes as less reinfaction and
restenosis.2 As logistic and resourses reasons, primary-PCI cannot be
implemented quite often, and thrombolytic therapy continues to be the important
and frequently performed as reperfusion therapy. Thrombolytic treatment is one of
the rapid methode of revascularization.

Thrombolytic Therapy
Fibrin plays an essential role in hemostasis as both the primary product of the
coagulation cascade and the ultimate substrate for fibrinolysis. Fibrinolysis
efficiency is greatly influenced by clot structure, fibrinogen isoforms and
polymorphisms, the rate of thrombin generation, the reactivity of
thrombus-associated cells such as platelets, and the overall biochemical
environment. Fibrinolytic activity can be generated either on the surface of a
fibrin-containing thrombus, or on cells that express profibrinolytic receptors.5
Administer thrombolytic treatment as soon as possible after onset of symptoms.

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Figure 1. Action of Fibrinolytic agent (Copyright 2015 by Elsevier Inc)

Thrombolytic agents
Generations of thrombolytic agents consists of :
1. Streptokinase
2. Alteplase (Recombinant tissue Plasminogen Activator = R-tPA)
3. Reteplase (Recombinant Plasminogen Activator = rPA)
4. Tenecteplase (TNK tPA)

Streptokinase
Streptokinase is the first thrombolytic agent to be used in the management of
STEMI, initially by the intracoronary route and subsequently as an intravenous
infusion. Streptokinase has antigenic property as allergic reactions and
hypotension.

Alteplase
The R-tPA (Alteplase) is the second generation of fibrinolytic agent. That agent is
fibrin specific, not associated with any alergic adverse event and hypotension. The

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half life is very short about 4 minutes, is needed intra venous heparin for
maintenance the patency of vascular.2

Alteplase is a tissue plasminogen activator produced by recombinant DNA

technology. It is a sterile, purified glycoprotein of 527 amino acids. It is
synthesized using the complementary DNA (cDNA) for natural human tissue-type
plasminogen activator obtained from a human melanoma cell line.3 About 3
years ago, two fibrinolytic agent are R-tPA as Alteplase and streptokinase, are
available for revascularization therapy in Indonesia.

Figure 2. Genentech USA, Inc. 1 DNA Way. 2017

Alteplase is non antigenic, second generation thrombolytic. It is administered

in accelerated dose regimen over 90 minutes, and it produces more rapid
thrombolysis than the standard 3 hours infusion. With alteplase 90 minutes
patency rate is seen in 75%, and TIMI 3flow in 54%. The accelerated dose regime
of t-PA is 15mg intravenous bolus, followed by an infusion of 0.75mg/kg
(maximum of 50mg) over 30 minutes, followed by an infusion of 0.5mg/kg

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(maximum of 35mg) over 60 minutes.6

Reteplase
Reteplase is a recombinant mutant form t-PA. The Global Utilization of
Streptokinase and t-PA for Occluded Coronary Artery (GUSTO) III Trial, which
compared reteplase with t-PA in 15.059 patients, did not demonstrate superiority
of reteplase over or equivalence with t-PA. These two agents to be equivalent or
similar outcome, and reteplase has the advantage of 1 “double bolus”
administration (10+10 units). Ninety minutes of infarct related artery is seen in
75% and TIMI 3 flow in 60%.6 Reteplase is less fibrin selective and has a longer
half life than alteplase

TNK-tPA (Tenecteplase)
Its genetically engineered, multiple point mutant of recombinant tissue-type
plasminogen activator (tPA), Has longer plasma half-life allowing for a single
intravenous bolus injection. 14 times more fibrin specific, and 80-fold higher
resistance to inhibition by plasminogen activator inhibitor 1 (PAI-1) than standard
tPA. Efficacy has similar when compared to tPA. The good safety with modestly
less bleeding risk and easier for administration. With tenecteplase, 90 minutes
patency of IRA is 79%, and TIMI 3 flow is seen in 63%.6

What Are the Feature of an Ideal Thrombolytic Agent ?

It would be difficult for any one thrombolytic agent to fulfill all the
requirements of an ideal thrombolytic agent. Some might come close to the ideal.
The thrombolytic agent should be safe, effective producing TIMI 3 flow in 100%,
fibrin specific, resistent to PAI-1, should have low risk of systemic and cerebral
bleeding, should be non-antigenic and should have ease and convinience of
administration, i.e. intravenous single bolus. It should be less procoagulant and

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produce less reocclusion. Most importantly it should be reasonably prised and
widely available. ACC/AHA guidelines recommend use of fibrin specific
thrombolytic agents for pharmacologic reperfusion therapy in STEMI.7
Nowadays one of them are available in Indonesia namely Alteplase. Alteplase
is enough expensive, is not a bolus thrombolytic, has a complex dosing schedule
and more likely to lead dosing errors.
According to the discussion of the study, Tenecteplase appears to be right
choice of thrombolytic agent for the management of STEMI in patients who do
not undergo primary PCI. It is fibrin specific, non-antigenic and has ease and
convinience of administration. It has proved safety and efficacy in international
studies.7

Conclusions
Pros: R-tPA is fibrin specific, non antigenic, not associated with any alergic
adverse event and hypotension. Efficacy has similar when compared to another
tPA. With alteplase 90 minutes patency rate is seen in 75%, and TIMI-3 flow in
54%. The good safety with modestly less bleeding risk. Widely available in most
hospitals and EDs. Also is covered by BPJS-Kesehatan.
Cons: Not enough easy of administration. The half life is very short about 4
minutes, is needed intra venous heparin for maintenance the patency of vascular.
Price is expensive (One package-2 vial Alteplase ; IDR 9.000.000).
Important to remember that thrombolytic therapy is not the end of the
management of STEMI. Primary PCI is the preferred reperfusion therapy for acute
STEMI, in order to get superior in efficacy, safety, and superior for long term
outcomes.

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