Fibrinolytic Therapy

Dr. Nathania Marliani Kristanti, SpJP, FIHA. 3rd Pekanbaru Cardiology Update, August 24th 2013. Pangeran Hotel Pekanbaru. Learn more at PerkiPekanbaru.com

1. FIBRINOLYTIC THERAPY
ACS - Medical Treatment

2. STEMI
•a clinical syndrome defined by characteristic
symptoms of myocardial ischemia in association
with persistent electrocardiographic (ECG) ST
elevation and subsequent release of biomarkers of
myocardial necrosis.
•new ST elevation at the J point in at least 2
contiguous leads of ≥2 mm (0.2 mV) in men or
≥1.5 mm (0.15 mV) in women in leads V 2–V3
and/or of ≥1 mm (0.1 mV) in other contiguous
chest leads or the limb leads

3. •Any patients with symptoms of chest
pain suspected to be cardiac origin
•ECG should be obtained within 10
minutes
•interpreted promptly
•determine eligibility for reperfusion
therapy

4. •acute myocardial infarction (MI) should be used when there is
evidence of myocardial necrosis in a clinical setting consistent
with acute myocardial ischaemia
•Detection of a rise and/or fall of cardiac biomarker values [preferably cardiac
troponin (cTn)] with at least one value above the 99 th percentile upper reference
limit (URL) and with at least one of the following:
•Symptoms of ischaemia
•New or presumed new significant ST-segment–T wave (ST–T) changes or new left bundle
branch block (LBBB).
•Development of pathological Q waves in the ECG.
•Imaging evidence of new loss of viable myocardium or new regional wall motion
abnormality.
•Identification of an intracoronary thrombus by angiography or autopsy.
Third universal definition of myocardial infarction; Thygesen et al; European Heart Journal 2012

5. LBBB, the nearest PCI hospital is informed of the expected time of
patient arrival. During the ambulance transfer, the catheterization
laboratory is prepared and staff summoned, if necessary, allowing
direct transfer of the patient to the catheterization laboratory
table (bypassing the emergency department and coronary care
unit). In cases where the diagnostic ECG has been done elsewhere
(e.g. in a non-PCI hospital, at a physician’s office, etc.), the EMS is
called for transfer and the above chain followed. This scenario is
best accomplished in a regional network with one high-volume
PCI centre, several surrounding non-PCI hospitals and a single re-
gional EMS. Such regional networks should have predefined man-
agement protocols for STEMI patients.
3.5 Reperfusion therapy
3.5.1 Restoring coronary flow and myocardial tissue
reperfusion
For patients with the clinical presentation of STEMI within 12 h
of symptom onset and with persistent ST-segment elevation or
new or presumed new LBBB, early mechanical (PCI) or pharma-
cological reperfusion should be performed as early as possible
(Table9).
There is general agreement that reperfusion therapy should be
considered if there is clinical and/or electrocardiographic evidence
of ongoing ischaemia, even if, according to the patient, symptoms
started.12 h before as the exact onset of symptoms is often
unclear, or when the pain and ECG changes have been stuttering.
59
There is, however, no consensus as to whether PCI is also bene-
ficial in patients presenting.12 h from symptom onset in the
absence of clinical and/or electrocardiographic evidence of
ongoing ischaemia. In such asymptomatic late-comers, a small (n!
347) randomized study has shown myocardial salvage and improved
4-year survival resulting from primary PCI, compared with conserva-
tive treatment alone, in patients without persistent symptoms 12–
48 h after symptom onset.
60,61
However, in stable patients with per-
sistent occlusion of the infarct-related artery, the large (n!2166)
Occluded Artery Trial (OAT) revealed no clinical benefit from
routine coronary intervention with medical management,
62,63
beyond that from medical management alone, when the occlusion
was identified 3–28 days after acute myocardial infarction, including
in the subgroup of 331 patients randomized between 24 and 72 h
after onset of infarction.
64
A meta-analysis of trials, testing
whether late re-canalization of an occluded infarct artery is benefi-
cial, provided results consistent with those from OAT.
51
Yes No
No
Preferably
<60 min
Immediately
Preferably 3–24 h
Preferably
!90 min
(!60 min in early presenters) Preferably
!30 min
a
The time point the diagnosis is confirmed with patient
history and ECG ideally within 10 min from the first
medical contact (FMC).
All delays are related to FMC (first medical contact).
Immediate transfer
to PCI center
Immediate transfer
to PCI center
Yes
STEMI diagnosis
a
Primary-PCI capable center
Primary-PCI
Coronary angiography
Rescue PCI
EMS or non primary-PCI
capable center
Immediate
fibrinolysis
Successful
fibrinolysis?
PCI possible <120 min?
Cath = catheterization laboratory; EMS = emergency medical system; FMC = first medical contact; PCI = percutaneous coronary intervention; STEMI = ST-segment elevation myocardial infarction.
Figure 2Prehospital and in-hospital management, and reperfusion strategies within 24 h of FMC (adapted from Wijnset al.).
4
ESC GuidelinesPage 12 of 51

6. hospitals when the anticipated FMC-to-device time at a PCI-
capable hospital exceeds 120 minutes because of unavoidable
delays (16,22,23). (Level of Evidence: B)
8. When fibrinolytic therapy is indicated or chosen as the primary
reperfusion strategy, it should be administered within 30
minutes of hospital arrival* (24 –28). (Level of Evidence: B)
CLASS IIA
1. Reperfusion therapy is reasonable for patients with STEMI and
symptom onset within the prior 12 to 24 hours who have
clinical and/or ECG evidence of ongoing ischemia. Primary PCI
is the preferred strategy in this population (16,29,30). (Level
of Evidence: B)
2.2.Evaluation and Management of Patients
With STEMI andOut-of-Hospital Cardiac Arrest
CLASS I
1. Therapeutic hypothermia should be started as soon as possible in
comatose patients with STEMI and out-of-hospital cardiac arrest
caused by ventricular fibrillation or pulseless ventricular tachycar-
dia, including patients who undergo primary PCI (31–33). (Level
of Evidence: B)
2. Immediate angiography and PCI when indicated should be per-
formed in resuscitated out-of-hospital cardiac arrest patients
whose initial ECG shows STEMI (34 – 49). (Level of Evidence: B)
3. Reperfusion at a PCI-Capable Hospital:
Recommendations
3.1. Primary PCI in STEMI
SeeTable 2for a summary of recommendations from this
section.
Figure 1.Reperfusion therapy for patients with STEMI. The bold arrows and boxes are the preferred strategies. Performance of PCI is
dictated by an anatomicallyappropriate culprit stenosis.!Patients with cardiogenic shock or severe heart failure initially seen at a non–PCI-
capable hospital should be transferred for cardiac catheterization and revascularization as soon as possible, irrespective of time delay from
MI onset (Class I, LOE: B). †Angiography and revascularization should not be performed within the first 2 to 3 hours after administration of
fibrinolytic therapy. CABG indicates coronary artery bypass graft; DIDO, door-in– door-out; FMC, first medical contact; LOE, Level of Evi-
dence; MI, myocardial infarction; PCI, percutaneous coronary intervention; and STEMI, ST-elevation myocardial infarction.
Table 2. Primary PCI in STEMI
COR LOE References
Ischemic symptoms!12 h I A ( 17,50,51)
Ischemic symptoms!12 h and
contraindications to fibrinolytic therapy
irrespective of time delay from FMC
IB( 52,53)
Cardiogenic shock or acute severe HF
irrespective of time delay from MI onset
IB( 54–57)
Evidence of ongoing ischemia 12 to 24 h
after symptom onset
IIa B ( 29,30)
PCI of a noninfarct artery at the time of
primary PCI in patients without
hemodynamic compromise
III: Harm B ( 58–60)
COR indicates Class of Recommendation; FMC, first medical contact; HF,
heart failure; LOE, Level of Evidence; MI, myocardial infarction; PCI, percuta-
neous coronary intervention; and STEMI, ST-elevation myocardial infarction.
6 O’Gara et al. JACC Vol. 61, No. 4, 2013
2013 ACCF/AHA STEMI Guideline Executive Summary January 29, 2013:xxx–xxx
Downloaded From: http://content.onlinejacc.org/ on 12/26/2012

7. ECG in patients after cardiac arrest, immediate angiography should
be considered in survivors of cardiac arrest having a high index of
suspicion of ongoing infarction (such as the presence of chest pain
before arrest, history of established CAD, and abnormal or uncer-
tain ECG results).
31,33
Additionally, there is evidence that survivors
of out-of-hospital cardiac arrest who are comatose have improved
neurological outcomes when cooling is provided early after resus-
citation. Therefore, these patients should rapidly receive thera-
peutic hypothermia.
34–36
The optimal sequence of cooling and
primary PCI in these patients is unclear.
The implementation of local/regional protocols to optimally
manage out-of-hospital cardiac arrest is pivotal to providing
prompt cardiopulmonary resuscitation, early defibrillation (if
needed), and effective advanced cardiac life support. Availability of
automated external defibrillators is a key factor in increasing sur-
vival. Prevention and improved treatment of out-of-hospital
cardiac arrest is key to reductions in mortality related to CAD.
For a more detailed discussion of these issues, refer to the recent
European Resuscitation Council Guidelines for Resuscitation.
37
3.4 Pre-hospital logistics of care
3.4.1 Delays
Prevention of delays is critical in STEMI for two reasons: first, the
most critical time of an acute myocardial infarction is the very
early phase, during which the patient is often in severe pain and
liable to cardiac arrest. A defibrillator must be made available to
the patient with suspected acute myocardial infarction as soon as
possible, for immediate defibrillation if needed. In addition, early
provision of therapy, particularly reperfusion therapy, is critical to
its benefit.
38
Thus, minimizing delays is associated with improved
outcomes. In addition, delays to treatment are the most readily avail-
able, measurable index of quality of care in STEMI; they should be
recorded in every hospital providing care to STEMI patients and
be monitored regularly, to ensure that simple quality-of-care indica-
tors are met and maintained over time. Although still debated,
public reporting of delays may be a useful way of stimulating im-
provement in STEMI care. If targets are not met, then interventions
are needed to improve performance. There are several components
of delay in STEMI and several ways to record and report them. For
simplicity, it is advised to describe and report as shown inFigure1.
†Patient delay:that is, the delay between symptom onset and
FMC. To minimize patient delay, the public should be made
aware of how to recognize common symptoms of acute myo-
cardial infarction and to call the emergency services, but the ef-
fectiveness from public campaigns has not yet been clearly
established.
38
Patients with a history of CAD, and their families,
should receive education on recognition of symptoms due to
acute myocardial infarction and the practical steps to take,
should a suspected acute coronary syndrome (ACS) occur. It
may be wise to provide stable CAD patients with a copy of
their routine baseline ECG for comparison purposes by
medical personnel.
†Delay between FMC and diagnosis:a good index of the quality of
care is the time taken to record the first ECG. In hospitals and
emergency medical systems (EMSs) participating in the care of
STEMI patients, the goal should be to reduce this delay to
10 min or less.
†Delay between FMC and reperfusion therapy:This is the ‘system
delay’. It is more readily modifiable by organizational measures
than patient delay. It is an indicator of quality of care and a pre-
dictor of outcomes.
39
If the reperfusion therapy is primary PCI,
the goal should be a delay (FMC to wire passage into the culprit
artery) of!90 min (and, in high-risk cases with large anterior
infarcts and early presenters within 2 h, it should be
Symptom onset FMC Diagnosis Reperfusion therapy
10 min
Patient delay
System delay
Wire passage in culprit artery
if primary PCI
Bolus or infusion
start if thrombolysis
Time to reperfusion therapy
All delays are related to FMC (first medical contact)
Figure 1Components of delay in STEMI and ideal time intervals for intervention.
ESC Guidelines Page 9 of 51

11. CONTRAINDICATIONS TO
FIBRINOLYTIC TXAbsolute
Previous intracranial haemorrhage or stroke of unknown origin at any time
Ischaemic stroke in the preceding 6 months
Central nervous system damage or neoplasms or atrioventricular malformation
Recent major trauma/surgery/head injury (within the preceding 3 weeks)
Gastrointestinal bleeding within the past month
Known bleeding disorder (excluding menses)
Aortic dissection
Non-compressible punctures in the past 24 h (e.g. liver biopsy, lumbar puncture)

12. CONTRAINDICATIONS TO
FIBRINOLYTIC TXRelative
Transient ischaemic attack in the preceding 6 months
Oral anticoagulant therapy
Pregnancy or within 1 week postpartum
Refractory hypertension (systolic blood pressure >180 mmHg and/or diastolic blood pressure >110 mmHg)
Advanced liver disease
Infective endocarditis
Active peptic ulcer
Prolonged or traumatic resuscitation

14. Alteplase (tPA)
•Tissue plasminogen activator (Actilyse®)
•enzyme that binds to fibrin with a greater affinity than
streptokinase or urokinase
•convert plasminogen to plasmin on the fibrin surface.
•relatively “clot selective”
•The very short half-life of alteplase mandates co-therapy with
intravenous heparin to avoid reocclusion.
•In the GUSTO trial mortality was 14% lower (1% absolute
decrease) with tPA compared with streptokinase.

15. Alteplase (tPA)
•Accelerated regimen (weight-based)
•Patients > 67 kg
•15 mg bolus over 1-2 minutes
•infusion 50 mg over 30 minutes, 35 mg over 1 hour
•Patients ≤ 67 kg
•15 mg bolus over 1-2 minutes
•0.75 mg/kg over 30 minutes, 0.5 mg/kg over 1 hour
O’Gara, 2013 ACCF/AHA

16. RETEPLASE
•recombinant plasminogen activator (rPA) - Retavase®
•less fibrin-specific mutation
•has a longer half-life
•no mortality benefit
•Double bolus regiment :
•10 U over 10 minutes and another 10 U 30 minutes apart

17. TENECTEPLASE
•Tenecteplase (TNK-tPA) is a genetically engineered,
multiple point mutant of tPA
•Longer plasma half-life allowing for a single intravenous
bolus injection
•It is also 14 times more fibrin specific and has an 80 fold
higher resistance to inhibition by plasminogen activator
inhibitor 1 (PAI-1) than standard tPA.
•Easier and faster to administer
•These advantages have made tenecteplase the fibrinolytic
agent of choice in many hospitals in the United States.

18. STREPTOKINASE
•a single chain polypeptide derived from culture
filtrate of beta- haemolytic streptococci of group C
•high doses are necessary to neutralize the
plasma levels of antistreptococcal antibodies
•Form a 1:1 complex with plasminogen that
convert to plasmin

21. StreptokinaseAlteplase ReteplaseTenecteplase
Fibrin selectiveNo Yes Yes Yes > tPA
Plasminogen
binding
Indirect Direct Direct Direct
Duration of
infusion (min)
60 90 10 + 10 5-10 sec
Half-life (min)23 <5 13-16 20
Fibrinogen
breakdown
4+ 1-2+ Not known >tPA
Early heparinProbably yes Yes Yes Yes
Hypotension Yes No No No
Allergic
reactions
Yes No No No
Approximate
current cost/
dose
$750 $5863 $5212 $3848
TIMI flow grade
3 in 90 min
32% 45%-54% 60% ≈tPA
Opie, 2013

22. HOW TO PREPARE
1.Slowly add 5 mL Sodium Chloride Injection or 5% Dextrose Injection to the
Streptokinase vial, directing the diluent at the side of the vacuum-packed
vial rather than into the drug powder.
2.Roll and tilt the vial gently to reconstitute. Avoid shaking. (Shaking may
cause foaming.)
3.Withdraw the entire reconstituted contents of the vial; slowly and carefully
dilute further to a total volume of 100 mL. Avoid shaking and agitation on
dilution.
4.Because Streptokinase, contains no preservatives, it should be
reconstituted immediately before use. The solution may be used for direct
intravenous administration within eight hours following reconstitution if
stored at 2-8°C.
5.Do not add other medication to the container of Streptase, Streptokinase.
6.Unused reconstituted drug should be discarded.

26. MONITORING
•Tanda vital
•Keluhan nyeri dada
•EKG - aritmia reperfusi
•Tanda-tanda perdarahan

27. COMPLICATIONS
•most serious - intracerebral hemorrhage (0.5-0.7%)
•major risk factors :
•age > 75 years
•hypertension
•low body weight
•female gender
•coagulopathy (prior use of anticoagulants)

28. SUCCESSFULL REPERFUSION?
•resolution of chest pain -- sometimes inaccurate
•serial assessment of 12-lead ECG -- more reliable
•> 70% resolution of ST elevation
•arrhythmia reperfusion -- AIVR

30. AIVR

31. •complete resolution of chest pain
•ECG changes (>70% resolution of ST elevation)
•a run of AIVR
Highly specific for successful reperfusion
<10%

32. RESCUE PCI