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Thrombolytics

Interventional Fellow
Thrombolytics-overview
• Characteristics
• Thrombolytics trials overview
• Thrombolytics vs PCI
• Adjuvant Therapy
Characteristics
• Streptokinase
– Purified from streptococci bacteria
– Binds to plasminogen for activation
– Not specific for clot bound-plasminogen
• More systemic side-effects
• Need for higher dose
– Antigenic---can last upto 7 years
• Repeat administration can cause anaphylaxis rare—0.5 %
• But may have other immune reaction upto 10%
Characteristics
• tPA Analogs
– Alteplase(naturally occurring), Retaplase, TNK-tPA (genetically
engineered)
– Tissue specific
• Less fibrinogen depletion
Trials Overview
• Streptokinase
– GISSI-1, ISSI-2
• Alteplase
– GUSTO-1
• Retaplase
– RAPID I, GUSTO III
• TNK-tPA
– TIMI 10A-B, ASSENT-1, 2
Streptokinase
GISSI-1, ISIS-2
• GISSI-1 (1986-first landmark study)
– Streptokinase (1.5mil unit over 1 hr) vs Placebo
– 13% RRR. (10.7% vs 13%) at 21 days
– Benefit persist for 1 year: 17% vs 19%.

• ISIS-2 (1998)
– Streptokinase vs placebo w/ or w/o ASA
– SK+ASA vs placebo: 8% vs 13.2% (42% RRR)---additive effect
– With associated 0.5% bleed risk.
Alteplase
GUSTO-1
• SK vs tPA (Alteplase)
– SK + SQ Heparin
– SK + IV Heparin
– tPA+ IV Heparin
• Mortality: 7.2% vs 7.4% vs 6.3% 14% RRR
– 24 hrs till 30 day mortality benefit
• IC bleeding: 0.5% vs 0.7%
• 2,400 patient radomized to late Angiography
– Significant higher patency rate and TIMI 3 flow (50% vs 75%)
– Reason for improved benefit
• Identified high risk patient characteristics
Alteplase
GUSTO-1
Alteplase
ISIS-3, GISSI-2
• ISIS-3
– Alteplase vs SK
– No heparin or suboptimal Heparin dose
– No mortality difference between two

• GISSI-2
– Alteplase vs SK
– Also randomized to Heparin 12,500 SQ heparin bid
– No difference between Alteplase and SK
– Heparin did not make a difference in mortality (due ASA benefit)
Retaplase
GUSTO III
• Alteplase vs Retaplase
– 30 day mortality: 7.4% vs 7.2% no difference
– CVA 1.5% no difference
TNK-tPA
• ASSENT I and TIMI 10B
– Safely trial. Comparing dosages 30, 40mg, 50mg single bolus
• Equal efficacy, higher patency of artery with higher dose

• ASSENT II
– TNK vs Alteplase
– Single bolus is equal and in-different to Alteplase
– 30 day motality: 6.2% vs 6.3%
– CVA similar: 1.6% vs 1.7%
– Minor bleed less common: 26% vs 28.1% P<.002
TNK-tPA
ASSENT 3
• TNK + Enoxaparin (7 days)
• ½ TNK + Abciximab (12 hours)
• TNK + UFH (48 hours)
• 30 day events:
– 11.4% vs 11.1% vs 15.4%
• Bleeding/CVA
– 3% vs 4.4% vs 2.2%
• Abciximab (doubled the bleeding risk to UFH)
• No difference between UFH and LMWH
– Abciximab also did worse in DM patients and elderly patients
9 RCT ANALYSIS: Mortality differences
Comparison of lytics
LIMITATIONS OF
THROMBOLYSIS
1. Time dependent benefit
– Most benefit if given within 4 hrs
– Absolute mortality benefit:
• 3% for with 6 hrs
• 2% for 6-12 hrs
• 1% for 12-18 hrs
• No benefit after 24 hrs
LIMITATIONS OF
THROMBOLYSIS
1. Patency of Artery
1. 75%-80% success of Thrombolytics but only 50% have TIMI III flow
on angiogram.
2. PCI achieve TIMI flow 96%
LIMITATIONS OF
THROMBOLYSIS
1. Re-infarction, Ischemia
1. Recurrent ischemia observed in 20-30% patients
2. Re-infarction observed in 15% of patients

2. Bleeding
1. Major Bleeding incidence is 2-3% and Hemorrhagic CVA 1%

3. Ineligibility
1. 20-30% of patient are not candidate for thrombolysis.

4. No Benefit in Shock patients


CONTRAINDICATIONS
Absolute contraindications
Thrombolysis vs PCI
• PAMI
• GUSTO IIb
PAMI
• Primary angioplasty in Acute MI.
• 395 pt, within 12 hours of acute MI
– Either Angioplasty vs 100mg of Alteplase (within 60 min)
• PTCA possible in 90% of patient with success rate of 97%

• All received asa/heparin/beta blockers


PAMI RESULTS
• In hospital death: 2.6% vs 5.9%
• 2 year Death/MI: 14.9% vs 23%
• 2 year recurrent ischemia: 36.4% vs 48%
• 2 year re intervention: 26% vs 46%

• Intra cranial bleed: 0% vs 2%

• No difference in ejection fraction between the two group.


META ANALYSIS:
PCI vs Thrombolytics

Jama. 1997
META ANALYSIS:
PCI vs Thrombolytics
META ANALYSIS:
PCI vs Thrombolytics
• A lower mortality at 30 days (4.4 versus 6.5 percent, odds ratio 0.66, 95% CI
0.46-0.94)
– the effect was similar among the different thrombolytic regimens used.

• A lower rate of death or nonfatal reinfarction (7.2 versus 11.9 percent, odds
ratio 0.58, 95% CI 0.44-0.76).

• A lower rate of total stroke (0.7 versus 2.0 percent) and hemorrhagic stroke
(0.1 versus 1.1 percent).
PCI vs Thrombolytics

ACC-guidelines. 05
PCI vs Thrombolytics:
Time Factor
PCI vs Thrombolytics:
Time Factor

ACC guidelines. 05
Adjuvant Therapy
• ASA
• Plavix
• Beta Blockers
• ACE
• Heparin
• Pentasaccharides
• IIbIIIa Inhibitors
• GIK
Streptokinase, aspirin, both, or neither for mortality in acute MI. (1998)

25% Risk reduction with ASA alone. 45% with ASA + Streptokinase
Plavix
• 2 New trial since 05 Guidelines
– CLARITY
– COMMIT-CCS 2
Plavix
PLAVIX
• Class I
– Clopidogrel 75 mg per day orally should be added to aspirin in
patients with STEMI regardless of whether they undergo
reperfusion with fibrinolytic therapy or do not receive reperfusion
therapy.
– Treatment with clopidogrel should continue for at least 14 days.
• Class IIa
– In patients less than 75 years of age who receive fibrinolytic
therapy or who do not receive reperfusion therapy, it is
reasonable to administer an oral loading dose of clopidogrel 300
mg.
– Long-term maintenance therapy (e.g., 1 year) with clopidogrel
(75 mg per day orally) is reasonable in STEMI patients
regardless of whether they undergo reperfusion with fibrinolytic
therapy or do not receive reperfusion therapy..

ACC 07. GUIDELINES


Beta Blockers
• Class I
– Oral beta blocker therapy should be
administered
• (significant benefit w/o thrombolytics in pre-lytics
era)
• Class IIa
– IV beta blockers
• (GUSTO I-did not show mortality benefit with IV
beta blockers)
ACE
• Class I
– Oral ACE/ARB within 24 hours of STEMI, with Anterior MI, pulmonary
edema, or LVEF <40
• ISIS-4, GISSI-3, and other major trials combine show
– 6% relative risk reduction: 4.6 lives saved per 1000.
– Benefit limited to patient with anterior MI, LVEF<40, pulmonary edema

• Class III
– IV ACE
• CONSENSUS II, with IV Enalapril (trial early termination showing potential
harm)
2005 Guideline for Anticoagulation
• UFH
– Class I
• Undergoing PCI, give UFH.
• Lytics with tPA, give 4000U UFH
– (majority of benefit derived from increase artery patency,
recurrent ischemia/infarction)
– (Mortality benefit small)
– IIb
• Streptokinase + UFH
2005 Guideline for Anticoagulation
• LMWH
– Class IIb
• LMWH acceptable alternative to UFH in lytics and
age <75
– III
• LMWH in age>75
ExTRACT-TIMI 25: Primary End Point (ITT)
Death or Nonfatal MI

Lost to follow-up = 3

Days after
Randomization
OASIS-6 Trial: Results
STEMI patient: 2.5mg Fondaparinux vs Reduction in Death/MI at 30 days:
control, for 8 days threatment. Stratum 1 (No UFH indicated)
P<.05 14%
14%
Primary End Point: 12% 11.2%
Death/Reinfarction (%)
10%
14.8%
15% 8%
13.4%
6%
12% 11.2%
9.7% 4%
Frequency

8.9%
9% 2%
7.4%
0%
6% Fondaparinux Placebo
Reduction in Death/MI: Stratum 2
3% 14% (UFH Indicated)
P=.008 P=.003 P=.008 12% P=NS
0% 10% 8.7%
8.3%
30 days 9 days 3-6 months 8%
p=0.
Fondaparinux (n=6036) Control (n=6056) 6%
97
4%
2%
0%
Fondaparinux UFH
Yusuf S, et al. JAMA. 2006;295:1519-1530. Adapted with
permission from www.clinicaltrialresults.org
Anticoagulants: 07 UPDATE
I IIa IIb III Patients undergoing reperfusion with
fibrinolytics should receive anticoagulant
therapy for a minimum of 48 hours (Level of
Evidence: C) and preferably for the duration of
I IIa IIb III the index hospitalization, up to 8 days
(regimens other than unfractionated heparin
[UFH] are recommended if anticoagulant
therapy is given for more than 48 hours
because of the risk of heparin-induced
thrombocytopenia with prolonged UFH
treatment). (Level of Evidence: A)

Anticoagulant regimens with established


efficacy include:
♥ UFH (LOE: C)
Anticoagulants
For patients undergoing PCI after having
received an anticoagulant regimen, the
following
dosing recommendations should be
followed:
I IIa IIb III
a. For prior treatment with UFH: administer
additional boluses of UFH as needed to
support the procedure taking into
account whether GP IIb/IIIa receptor
antagonists have been administered.
(Level of Evidence: C) Bivalirudin may
also be used inRecommendation continues on the next slide.
patients treated
previously with UFH. (Level of Evidence:
Anticoagulants

I IIa IIb III b. For prior treatment with enoxaparin: if


the last SC dose was administered within
the prior 8 hours, no additional
enoxaparin should be given; if the last
SC dose was administered at least 8 to
12 hours earlier, an IV dose of 0.3 mg/kg
of enoxaparin should be given.
I IIa IIb III
c. For prior treatment with fondaparinux:
administer additional intravenous
treatment with an anticoagulant
possessing anti-IIa activity taking into
account whether GP IIb/IIIa receptor
antagonists have been administered.
Anticoagulants
I IIa IIb III Because of the risk of catheter thrombosis,
fondaparinux should not be used as the
sole
anticoagulant to support PCI. An additional
anticoagulant with anti-IIa activity should
be
administered.
Unfractionated Heparin

Advantages Disadvantages
 Immediate  Indirect thrombin
anticoagulation inhibitor so does not
inhibit clot-bound
 Multiple sites of action thrombin
in coagulation cascade  Nonspecific binding to:
― Serine proteases
 Long history of
― Endothelial cells
successful clinical use
(can lead to variability
 Readily monitored by in level of
aPTT and ACT anticoagulation)

 Reduced effect in ACS


― Inhibited by PF-4
 Causes platelet
aggregation

 Nonlinear
Hirsh J, et al. Circulation. 2001;103:2994-3018. aPTT = activated partial thromboplastin time; ACT = activated coagulation time; PF-4 =
platelet factor 4; HIT = heparin-induced thrombocytopenia.
pharmacokinetics
LMWH
Advantages Disadvantages
 Increased anti-Xa to anti-IIa  Indirect thrombin inhibitor
activity → inhibits thrombin  Less reversible
generation more effectively  Difficult to monitor
 Induces ↑ release of TFPI vs (no aPTT or ACT)
UFH  Renally cleared
 Not neutralized by platelet
 Long half-life
factor 4
 Risk of HIT
 Less binding to plasma
proteins (eg, acute-phase
reactant proteins) → more
consistent anticoagulation
 Lower rate of HIT vs UFH
 Lower fibrinogen levels
 Easy to administer (SC
administration)
 Long history of clinical
studies and experience, FDA-
Hirsh J, et approved indications
al. Circulation. 2001;103:2994-3018. TFPI = tissue factor pathway inhibitor; UFH = unfractionated heparin;
SC = subcutaneous; aPTT
 Monitoring typically = activated partial thromboplastin time;
ACT = activated coagulation time.
unnecessary
Fondaparinux
Advantages Disadvantages
• SC administration
― Potential exists for • Difficult to monitor (no
outpatient aPTT or ACT)
management • Long half-life
• Once-daily • Catheter thrombosis
administration during PCI
• Predictable
anticoagulant response
• Fixed dose
• No antigenicity
• Potentially no need for
serologic parameters
• Does not cross the
placenta
• HIT antibodies do not
cross-react
• Decreased
Simoons ML, bleeding
et al. J Am Coll Cardiol. 2004;43:2183-2190.
complications vs UFH or
Yusuf S, et al. N Engl J Med. 2066;354:1464-1476.
IIbIIIa Inhibitors
• IIb
– Abciximab + ½ dose reteplase or TNK in Anterior MI, no bleeding risk,
and <75 yr old
• ASSENT-3, GUSTO-V: Similar 30 day mortality
Reinfarction reduced at cost of higher Bleed (2.3% to 4.6%)

• Class III
– Abciximab + ½ dose retaplase or TNK in age >75
Glucose-insulin-potassium
• There is mixed study results.

• No definite recommendation in 05 and 07


updated ACC guidelines
• Questions?

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