1. health and fitness
2. therapy

Fibrinolytic Therapy for STEMI
Patricia Howard, Pharm. D., BCPS,
AQ Cardiology
Professor and Vice Chair Pharmacy Practice
Professor Cardiovascular Medicine
University of Kansas Medical Center
Presenter Disclosure Information
Patricia Howard, PharmD
Fibrinolytics for STEMI
FINANCIAL DISCLOSURE:
No relevant financial relationship exists
UNLABELED/UNAPPROVED USES DISCLOSURE:
None to disclose
2
Acute Coronary
Syndromes*
1.57 Million Hospital Admissions in US
70 %
UA/NSTEMI†
1.10 million
Admissions/year
30% STEMI
470,000
Admissions/year
Heart Disease and Stroke Statistics – 2013 Update. Circulation 2013;127:143-152
Spectrum of ACS
No ST elevation
Stable
angina
Unstable
angina
NSTEMI
ST elevation
STEMI
ACUTE CORONARY SYNDROMES
Tissue damage after Infarction
(wavefront inside to outside of muscle)
Timeline for Loss of Viable Myocardium
after Infarction
Normal heart: elliptical
Larger infarcts lead to greater damage, extensive
remodeling and poorer outcomes
Remodeling results in more spherical shape with
hypertrophy, collagen deposition and fibrosis
STEMI Early Reperfusion is the most Critical Step
Plan A: Mechanical Primary PCI
• Highly Effective but………..
• Available at only 25% of U.S. hospitals
Plan B: Pharmacologic (fibrinolytics)
• Lesser efficacy but….
• Widely available at U.S. hospitals and
can be administered in the field
9
PCI vs Lytics: Comparison from Clinical Trials
Keeley et al. Lancet 2003;361:13-20
Outcomes with PCI vs tPA in Real World Setting
Percent
NRMI 2 Cohort: n=2,958, lytic eligible, no
shock at presentation
PTCA
8
6
5.2
5.4
t-PA
6.2
5.6
4
2
0
In-hospital mortality
P=NS
In-hospital mortality or
nonfatal stroke
P=NS
Tiefenbrunn AJ, et al. J Am Coll Cardiol. 1998;31:1240-1245.
Time from Symptom Onset to Treatment
Predicts 1-year Mortality after Primary PCI
Relative Risk for 1 year mortality increases 8% with
Each 30 minute delay to Reperfusion
DeLuca et al. Circulation 2004;109:1223-1225
A hypothetical patient develops chest pain at 1000 h.
As commonly happens, the patient does not call for
help immediately, and phones the emergency number
only because of persistent pain at 1130 h. Paramedics
arrive at 1145 h—the first medical contact. They do a
full assessment and an ECG, which shows obvious
anterior ST-segment elevation. This assessment takes
25 min. The patient lives in a semirural area, and the
time to hospital is about 65 min. If the paramedics
radio ahead the patient could be on the cath table with
a vascular sheath deployed within 40 min of arrival at
the hospital door. These fairly commonplace events
equate to a total ischemic time of 235 min and FMC to
device time of 130 min.
Adapted from Gershlick et al. Lancet 2013;382:624-32
In many parts of the US, achieving timely
mechanical reperfusion is nearly impossible
• The patient
- Failure to promptly recognize symptoms
- Hesitation to seek medical attention
• Time to transport
- Mandated delivery to the closest hospital,
regardless of PCI capabilities
- Long transport in rural areas
• Decision process on arrival
- Clot-busting drugs vs. PCI
- Off hours
- Transfer to PCI facility
• Time to implement treatment strategy
- Procedural factors
- Team assembly
Reperfusion Algorithm for STEMI
*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.
ACCF/AHA 2013 guidelines
2013 ACCF/AHA Guideline for the
Management of STEMI
• Reperfusion therapy should be administered to all eligible
patients with STEMI with symptom onset within the prior 12 hours
(Class I:A)
• Primary PCI is the recommended method of reperfusion when it can be
performed in a timely fashion by experienced operators (Class I:A)
• In the absence of contraindications, fibrinolytic therapy should be
administered to patients with STEMI at non–PCI-capable hospitals
when the anticipated FMC-to-device time at a PCIcapable hospital
exceeds 120 minutes because of unavoidable delays (Class I:B)
• When fibrinolytic therapy is indicated or chosen as the primary
reperfusion strategy, it should be administered within 30 minutes of
hospital arrival (Class I:B)
Fibrinolysis
Goals: reestablish perfusion by opening the artery
minimize infarct size and salvage myocardium
Lytics
activate
Fibrinolytics: Activate Plasminogen
Fibrin-bound
Plasminogen
Fibrin-bound
Plasmin
Fibrin split prod
Dissolves clot
Circulating
Plasminogen
Circulating
Plasmin
Degrades
Fibrinogen
V, VIII, others
Systemic bleeds
Fibrinolytic Agents Available in US
• streptokinase (SK)
• alteplase (TPA or rTPA)
• reteplase (rPA)
• tenecteplase (TNK)
Characteristics of Ideal Fibrinolytic Drugs
• Fibrin Selective: greater selectivity reduces the
risk of systemic bleeding
• Longer Half-Life: generally enhances efficacy
• Non-antigenic
• Ease of administration: faster drug delivery and
less nursing time
TIMI Flow as Indicator of Reperfusion
(Thrombolysis in Myocardial Infarction)
Levels of coronary blood flow assessed during PCI
Graded 0-3
0
1
2
3*
no perfusion
dye penetration but no distal perfusion
partial reperfusion – delayed or slow
normal flow
* Correlates with survival and improved LV function
Comparison of Fibrinolytic Agents
Property
SK
TPA
rPA
Fibrin select.
Half-life min.
Antigenic
Dosing method*
Wt. Adjusted
-15-25
yes
IVF
no
+++
++
4-8
13-16
no
no
SB/IVF DB
yes
no
TIMI 2 or 3 flow %
TIMI 3 flow %
60-68
32
73-84
54
84
60
* IVF=intravenous infusion; SB=single bolus; DB=double bolus
TNK
++++
20-25
no
SB
yes
85
63
Is the Patient Eligible for Fibrinolysis?
•
•
•
•
ECG consistent with STEMI
Time from symptom onset less than 12 hours
Estimated time FMC to device > 120 min
No evidence of cardiogenic shock, PE or recurrent
VT/VF
• No known contraindications to lytics
• Acceptable Bleeding risk
Absolute Contraindications
Who should NOT get Fibrinolytics?
•
•
•
•
•
•
•
•
•
•
•
•
Any prior ICH
Known structural cerebral vascular lesion (e.g., arteriovenous
malformation)
Known malignant intracranial neoplasm (primary or metastatic)
Ischemic stroke within 3 mo EXCEPT acute ischemic stroke within 4.5 h
Suspected aortic dissection
Active bleeding or bleeding diathesis (excluding menses)
Significant closed-head or facial trauma within 3 mo
Intracranial or intraspinal surgery within 2 mo
Severe uncontrolled hypertension (unresponsive to emergency
therapy)
For streptokinase, prior treatment within the previous 6 mo
ACCF/AHA 2013 Guideline
Relative Contraindications
Must weigh benefits/risks
•
•
•
•
•
•
•
•
•
•
•
•
History of chronic, severe, poorly controlled hypertension
Significant hypertension on presentation (SBP > 180 mm Hg or
DBP > 110 mm Hg)
History of prior ischemic stroke > 3 mo
Dementia
Known intracranial pathology not covered in absolute contraindications
Traumatic or prolonged (> 10 min) CPR
Major surgery (< 3 wk)
Recent (within 2 to 4 wk) internal bleeding
Noncompressible vascular punctures
Pregnancy
Active peptic ulcer
Oral anticoagulant therapy
ACCF/AHA 2013 guideline
Fibrinolytic Dosing for STEMI (1 of 2)
SK:
1.5 MU infused over 60 min
rTPA:
Front Loaded: max 100 mg over 90 min
15 mg IV bolus
0.75 mg/kg over 30 min (max. 50 mg)
0.5 mg/kg over 60 min (max. 35 mg)
Fibrinolytic Dosing for STEMI (2 of 2)
rPA:
10 U bolus over 2 min; repeat in 30 min
TNK:
Weight based single bolus over 5 sec
<60 kg
30 mg
60-69 kg
35 mg
70-79 kg
40 mg
80-89 kg
45 mg
> 90 kg
50 mg
Adjunct Antiplatelet Therapy
• To prevent platelet activation and aggregation
• Aspirin : 162-325 mg daily
• Clopidogrel:
– < 75 yrs 300 mg loading dose
– > 75 yrs omit loading dose
– Maintenance dose: 75 mg daily
Adjunct Anticoagulant Therapy
• To prevent additional clot formation
Heparin: weight adjusted bolus to achieve aPTT 1.5-2.0
times control for > 48h
Typical: 60 U/kg bolus (max 4000 U, then 12 U/kg/hr
(max 1000 U/hr) OR
LMWH (e.g. enoxaparin)
< 75 yr: IV bolus 30 mg; wait 15 min then 1 mg/kg q 12 hr
> 75 yr: No bolus; 0.75 mg/kg q 12 hr
Patients with Cr Cl < 30 ml/min: 1 mg/kg daily
Fibrinolytics: Bleeding Risks
• Minor bleeding (20%) —
Surface or superficial: invaded or disturbed sites
(e.g., injection site, venous cutdowns, arterial
punctures including catheterization site, location
of recent surgical intervention)
• Major bleeding (2-3%) —typically Internal:
gastrointestinal, genitourinary, retroperitoneal,
pericardial and intracranial
• Intracranial bleeding (1%)
Monitoring for Adverse Events
• Monitor ECG for arrhythmias
• Monitor BP and pulse
e.g. q 15 min for 2 hr, then q 30 min for 6 hr,
then hourly for 16 hr (total of 24 hr)
• Bedrest; Minimize handling and moving patient
• No unnecessary punctures, IM injections,
catheters, invasive procedures for 24 hr
• Monitor for bleeding; check secretions for blood
• Assess for signs of neurologic dysfunction
• Monitor for allergy (<1%) /anaphylaxis (<0.1%)
Management of bleeding complications
• Attempts should be made to manage minor bleeds
without stopping treatment via compression and
other supportive strategies
• Major life-threatening bleeds or possible ICH:
Stop the Fibrinolytic and call for immediate
medical expertise
Discontinue other anticoagulants/antiplatelets
(Heparin can be reversed with Protamine)
Achieving the Target DTN Time < 30 min
• Availability of drug onsite or in ER
• Mix the drug while completing assessment
• Procedures for determining weight, calculating
dose, administration of lytic and adjunct therapy
(UH or LMWH, ASA etc.)
• Monitoring plan: signs and symptoms of bleeding
or neurological dysfunction, labs needed etc.
• Protocols must be in place!!
Assessing Reperfusion
• Relief of chest pain
• Resolution of ST elevation
• Reperfusion arrhythmias
• Note: all these are imprecise but lack of >50%
resolution of ST elevation in the worst lead 60-90
min after treatment is strong indicator of need for
rescue PCI
Indications for Transfer for Angiography after
Fibrinolytic Therapy
• Immediate transfer for cardiogenic shock or severe
acute HF
• Urgent transfer for failed fibrinolysis or
reocclusion
• 3-24 hr after fibrinolysis in stable patients as part
of invasive strategy
ACCF/AHA 2013 Guidelines
In this age of Mechanical Reperfusion,
Fibrinolytics remain an Effective Alternative
• “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 can perform
primary PCI
• Difficulties achieving FMC to device time goals
• After approx. 20 minutes of occlusion, thousands
of cells begin to die every minute
In conclusion, through effective partnerships, proper
planning, infrastructure development, protocols and
education we can significantly improve the care of
STEMI patients in Kansas
Early recognition, early reperfusion and continuous
quality improvement is key
Initiatives such as Kansas Mission: Lifeline and Project
10-30 (10 min to read ECG and 30 min DIDO or DTN
times) provide valuable tools and resources that
SAVE LIVES and IMPROVE QUALITY OF LIFE