Fibrinolytic Therapy in STEMI

Abdul Hakim

MCVU XVI 2017

 ACS

Acute coronary syndromes

(ACS) is a term used to describe
a group of conditions resulting
from acute myocardial ischemia
(insufficient blood flow to heart
muscle) and ranging from
unstable angina (increasing,
unpredictable chest pain) to
myocardial infarction (heart
attack).
Acute Coronary Syndromes

› Unstable Angina
Similar pathophysiology

› Non-ST-Segment Similar presentation and early

Elevation MI management rules
(NSTEMI)
STEMI requires evaluation for
acute reperfusion
› ST-Segment intervention
Elevation MI
(STEMI)
Overview

› Selection of reperfusion therapy

› Eligibility and complications

› Fibrinolytic agents

› Adjunctive therapies

› Patient transfer after fibrinolysis

Epidemiology

› CHD is the leading cause of death in men and

women

› Estimated 600,000 new Mls in the US

annually and 320,000 recurrent Mls

› STEMI accounts for 30-40%

› The financial impact of CHD is $156 billion

STEMI: time is muscle
Why Thrombolysis

"the appropriate and timely use of some form of

reperfusion therapy is likely more important
than the choice of therapy"
ACC/AHA guidelines

Only a minority of US hospitals are capable of

performing primary PCI

Hence, familiarity with thrombolytic agents and

regimens is essential
Selecting Reperfusion Therapy
› The time from onset of symptoms
› The risk of complications related to STEMI
(CHF, cardiogenic shock)
› The risk of bleeding with fibrinolysis
› The time required for transfer to a PCI hospital
Eligibility for Thrombolysis

› Patients with STEMI and onset of symptoms

within 12 hours if PCI delay> 120 minutes
(class I)
› Patients with STEMI and onset of symptoms
between 12-24 hours if continued symptoms
or ECG changes and PCI unavailable
(class IIa)
› Door to needle time <30 minutes
› Not indicated for patients with ST depression
Absolute and Relative Contraindications
to Fibrinolytic Therapy
Intracranial Hemorrhage

› The most feared complication of fibrinolysis

› Fatal in up to 8o% of cases
› Usually within the first 24 hour with an
incidence of 0.5 -1%
› Risk factors:
• Age > 65 years
• Weight < 70 kg
• HTN on admission
• Female gender
› The risk is similar for the different agents
Fibrinolytic Agents
The Goals of Fibrinolysis

Short-term goals Longer term goals

• To lyse the thrombus • To limit myocardial tissue damage and/ or
and rapidly restore tissue death
blood flow to the • To preserve ventricular function
affected coronary
artery • To decrease the risk of other complications
associated with acute myocardial infarction
• To limit myocardial
damage • To reduce mortality

Van de Werf et al, Eur Heart J 2003

Assessment of Reperfusion

› Thrombolysis in Myocardial Infarction (TIMI)

Flow Grades
The ideal thrombolytic agent
› Rapid acting
› High efficacy in terms of both 60-90 minute
vessel patency and TIMI grade 3 flow
› Low incidence of adverse reactions,
particularly bleeding and stroke
› Low reocclusion rate
› Easily administered (bolus vs infusion)
› Simple, patient-tailored dosage regimen
› Good long term effects on clinical outcome
› Cost-effective
Currently available thrombolytic agents

Third-generation thrombolytics
tenecteplase (TNK-tPA)

Second-generation thrombolytics
recombinant tissue plasminogen activator (rt-PA), reteplase
(rPA)

First-generation thrombolytics
streptokinase, anistreplase
 Alteplase (Actilyse)
• The “gold standard”
3 fibrinolytic agent
4
– 14% relative decrease
in 30-day deaths
(absolute reduction
2 from 7.3 to 6.3%) with
1
accelerated regimen in
5 GUSTO I
• But some limitations:
NH2
– IV infusion precludes
1 Finger COOH
pre-hospital use
2 Growth Factor
3 Kringle 1 – Even the “accelerated”
4 Kringle 2 dose takes 90 minutes
5 Protease to administer
 Reteplase

› Longer plasma half-life

than alteplase (18
1
minutes vs 4-6 minutes)
NH2
› 10+10 MU double-bolus
30 minutes apart
› Possible improvement in
2
vessel patency
› But no clinical benefit
over alteplase
COOH

1 Kringle
2 Protease
 Tenecteplase (Metalyse)
“N” Gln for
Asn at 117
Y 3
disulphide bonds

4
“T” Y “K”
Asn for Ala-Ala-Ala-Ala
Thr at 103 for Lys-His-Arg-Arg
2 between 296 and 299
1
• Greater fibrin specificity than
5
alteplase
• Longer plasma half-life than
NH2 Active site at 478
alteplase (20 minutes vs
1 Finger COOH 4-6 minutes)
2 Growth Factor • ±0.5 mg/kg single bolus
3 Kringle 1
Y • Resistance to PAI-1
448
4 Kringle 2
5 Protease glycosylation sites
 Key characteristics of newer thrombolytics
compared to alteplase

Characteristic Alteplase Reteplase Tenecteplase

(rt-PA) (rPA) (TNK-tPA)
Immunogenicity No No No
Plasminogen activation Direct Direct Direct
Fibrin specificity ++ + +++
Plasma half-life 4-6 min 18 min 20 min
Dose 15 mg bolus plus 90 min 10+10MU double ±0.5 mg/kg
infusion up to 85 mg bolus 30 min apart single bolus
PAI-1 resistance No ? Yes
Genetic alteration to No Yes Yes
native t-PA (recombinant version)

Based on Ross AM, Clin Cardiol 1999

21
Mechanism of Action
Mechanism of Action

› All fibrinolytic agents activate plasminogen

directly or indirectly
› They differ in fibrin specificity (clot bound vs.
circulating) and in half life
› All fibrinolytic agents activate platelets
› Four agents are approved by the FDA
Fibrinolytic Agents
Major Clinical Trials of Thrombolysis
 Actilyse vs. other thrombolytic agents
Feature Actilyse Streptokinase Urokinase
Show no difference from naturally
occuring substance Yes No Yes

Free from possible allergic reactions Yes No Yes

Free from possible antigenic reactions Yes No Yes
Fibrin -Specific, preventing
generalized lysing Yes No

Short half life Yes No

Efficacy obtained with intravenous
administration is equal to or better
than found with intracoronary Yes No
administration

•Braunwald, E., Circulation 1985

•De Bono, D.P., Pharmaceutical Journal 1985
•Fox, K.A.A., Biochem Pharmacol 1984
•Van de Wert,F.,et al., Circulation 1984 26
Adjunctive Therapy
Antiplatelet Therapy
› Aspirin loading dose (162-325 mg) should be given
to all patients (class I)
› Aspirin should be continued indefinitely (preferably
81 mg daily)
› Clopidogrel (loading dose of 300 mg in pts < 75
years and 75 mg in pts > 75 years) (class I)
• CLARITY-TIMI 28 trial
• COMMIT/CCS-2 trial
› Clopidogrel should be continued for at least 14 days
and up to 1 year (class I)
› No data on other P2Y12 antagonists with
fibrinolysis
CLARITY-TIMI 28 Trial
COMMIT/CCS-2 - Clopidogrel
Anticoagulant Therapy

› All pts should receive anticoagulant therapy

for at least 48 hours and preferably for the
duration of the index hospitalization up to 8
days or until revascularization (class I)
• UFH weight-based bolus and infusion
• Enoxaparin IV bolus followed in 15 min by
subcutaneous injections
• Fondaparinux IV bolus followed in 24 hours by
subcutaneous injections
• Bivalirudin can be used in pts with HIT
Enoxaparin with Fibrinolysis
ExTRACT-TIMI 25
Enoxaparin with Fibrinolysis
Lessons from the ExTRACT Trial
› Longer anticoagulation is needed (8 days vs. 48 hours)
› Pts <75 years
• IV bolus 30 mg follovved by 1 mg/kg subcu every 12 hours
› Pts > 75 years
• No IV bolus and reduced dose of 0.75 mg/kg subcu every 12
hours
› The dose of subcu enoxaparin was capped at 100 mg
for the first 2 doses
› Pts with renal insufficiency received the bolus and the 1
mg/kg subcu but the interval was increased to 24 hours
› There was no increase in ICH with this dosing regimen
Fondaparinux with Fibrinolysis
The Oasis-6Trial
Glycoprotein IIb/IIIA Inhibitors
› Large trials done with half-dose fibrinolysis+ GP
› lIb/lIlA inhibitors
• GUST0-5
• ASSENT-3
› Small improvement in secondary ischemic
endpoints but no improvement in mortality
› Increased major bleeding including ICH in the
elderly
› Current guidelines recommend against the routine
use of GP IIb/IIIA inhibitors with fibrinolysis
Transfer After Fibrinolysis
Assessment of Reperfusion

› Ischemic symptoms are not reliable indicators

especially when morphine is used
› >70% ST segment resolution in the index lead
is helpful indicator of successful reperfusion
› Complete or near complete resolution of ST
elevation at 60-90 minutes is indicative of a
patent artery
› <50% ST resolution and absence of
reperfusion arrhythmia at 2 hours reliably
predicts <TIMI3 flow
Transfer for PCI After Fibrinolysis
› Immediate transfer for cardiogenic shock or
acute severe HF irrespective of time delay
(class I)
• The SHOCK triaI (nearly 50% of pts had fibrinolytic
therapy prior to PCI with similar benefit)
› Urgent transfer for failed reperfusion or re-
occlusion (class IIa) (rescue PCI)
• The REACT trial
› As part of an invasive strategy in stable pts
with PCI between 3 and 24 hours after
successful fibrinolysis (class IIa)
(pharmacoinvasive strategy)
Rescue PCI

› The benefit was driven mainly by a reduction in re-infarction rate

› No difference in major bleeding but higher rate of minor bleeding with rescue PCI
Pharmaco-invasive Strategy
Pharmaco-invasive Strategy
Community Preparedness and
System Goals
Community Preparedness and
System Goals

› All communities should create and maintain a

regional system of STEM I care that includes
assessment and continuous quality
improvement of EMS and hospital based
activities. Performance can be facilitated by
participating in programs such as Mission:
Lifeline and the D2B Alliance

ACC/AHA guidelines class I

Guideline
 Patients Distribution from
Jakarta Acute Coronary Syndrome Registry

1. Adapted from Dharma S, et al. Acute myocardial infarction system of care in the third world. Neth Heart J 2012. 20; 254-259
In Hospital Mortality of STEMI patients based on
Jakarta Acute Coronary Syndrome (ACS) registry

1. Adapted fromDharma S, et al. Acute myocardial infarction system of care in the third world. Neth Heart J 2012. 20; 254-259
 Conclusions
› Fibrinolytic therapy is still an important option for
reperfusion in many STEMI pts
› When administered within 3 hours of symptom
onset to pts at low risk for bleeding, fibrinolytic
(Actilyse) therapy is as effective as primary PCI
› Familiarity with the different fibrinolytic agents and
different adjunctive therapy options is critical to
reduce the risk of bleeding complications
› Systems of care with written protocols based on
evidence based national guidelines to direct
appropriate initial therapy and transfer of pts are of
paramount importance to improve outcomes