Transcript Treatment in Acute MI

PCI and platelet activation

The early response to arterial wall injury is platelet
activation and deposition over the injured arterial
surface, creating the substrate for thrombosis

Stent implantation appears to be associated with
greater platelet activation than balloon angioplasty
alone

The magnitude of platelet activation is associated with
an increased risk for adverse clinical events after
coronary intervention
S. Banai, M.D.
Kabbani SS: Circulation. 2002;104:181–186
Myocardial necrosis after PCI
 Myocardial
necrosis, assessed by CK-MB
elevation, is relatively frequent after coronary
intervention, occurring in up to 40% of cases
 Although
most patients remain asymptomatic
with no changes in cardiac function, even a
mild release of CK-MB is associated with higher
mortality during follow-up
S. Banai, M.D.
Klein LW: J Am Coll Cardiol. 1991; 17: 621–626
Abdelmeguid AE: Circulation. 1996; 94: 1528–1536
Brener SJ: Eur Heart J. 2002; 23: 869–876
Nallamothu BK: J Am Coll Cardiol. 2003; 42: 1412–1414
Ioannidis JPA: J Am Coll Cardiol. 2003; 42: 1406–1411
PCI-related myocardial injury
 The
 Can
most frequent complication after PCI
be significantly reduced and outcome
improved with appropriate pharmacological
treatment before PCI
S. Banai, M.D.
The ARMYDA Study
Atorvastatin for Reduction of
MYocardial Damage during Angioplasty
Randomized, placebo-controlled trial to evaluate
the effect of pretreatment with atorvastatin
(40mg) started 1 week before elective PCI on
the release of markers of cardiac damage (CKMB, troponin I, and myoglobin) in patients
with stable angina
S. Banai, M.D.
Pasceri V: Circulation 2004;110:674-678
Conclusions: Pretreatment with atorvastatin significantly
reduces procedural myocardial injury in elective PCI
Incidence of postprocedural increase
of CK-MB and troponin I >1, 2 to 5,
and >5 times above upper normal
limit (UNL)
Peak values of CK-MB,
troponin I, and myoglobin in
statin vs placebo group
S. Banai, M.D.
Pasceri, V. et al. Circulation
2004;110:674-678
The ARMYDA-2 Study
Antiplatelet therapy for Reduction of MYocardial
Damage during Angioplasty
To evaluate whether aggressive antiplatelet therapy with
clopidogrel in patients undergoing PCI will reduce
periprocedural MI and improve outcome
S. Banai, M.D.
Patti, G. et al. Circulation 2005;111:2099-2106
ARMYDA-2 Study
Antiplatelet therapy for Reduction of
Myocardial Damage during Angioplasty
255 pts with stable CAD or non-ST ACS, randomized to
300 or 600 mg of Clopidogrel 4-8 h before PCI
Primary end point: A composite of death, MI or TVR at 30 days
non-ST-elevation MI - 25%
complex lesions 75%
DES 20%
IIb/IIIa blockers 13%
S. Banai, M.D.
Patti, G. et al. Circulation 2005;111:2099-2106
ARMYDA-2: Number of events
Event
Clopidogrel
300 mg
Clopidogrel
600 mg
Death
0
0
Target vessel
revascularization
0
1
15
5
MI
S. Banai, M.D.
ARMYDA-2 STUDY Results: 30-day occurrence of
death, MI, or TVR in patients receiving 600-mg versus the
300-mg loading regimen of clopidogrel
The primary end points
occurred in:
4% of pts with 600 mg
versus
12% with 300 mg
S. Banai, M.D.
Patti, G. et al. Circulation 2005;111:2099-2106
ARMYDA-2 STUDY Results:
Comparison of postprocedural
elevation of CK-MB and troponin I in the 2 study arms
S. Banai, M.D.
Patti, G. et al. Circulation 2005;111:2099-2106
ARMYDA-2 STUDY Results:
Baseline and peak values of CK-MB, troponin I, and myoglobin
S. Banai, M.D.
Patti, G. et al. Circulation 2005;111:2099-2106
ARMYDA-2 STUDY Results:
Multivariable analysis
Pretreatment with 600-mg loading dose of clopidogrel
significantly reduced the risk of periprocedural MI
(OR 0.48; 95% CI 0.15 to 0.97; P=0.044)
S. Banai, M.D.
Patti, G. et al. Circulation 2005;111:2099-2106
Percentage of patients with any
elevation of CKMB/troponin I
Marker
Clopidogrel
300 mg (%)
Clopidogrel
600 mg (%)
p
CKMB
26
14
0.036
Troponin I
44
26
0.004
S. Banai, M.D.
Bleeding events
Event
S. Banai, M.D.
Clopidogrel
300 mg
Clopidogrel
600 mg
Major bleed
(Hgb>5g/dL)
0
0
Minor bleed
(Hgb<5g/dL)
1 (0.8%)
1 (0.8%)
The ARMYDA-2 trial
Conclusions:
Pretreatment
with a 600-mg loading dose of
clopidogrel given 6 hours before the procedure is safe
and, as compared with the 300-mg dose, reduces
periprocedural MI and improves short-term prognosis in
patients undergoing PCI
The
low risk of this pharmacological regimen may
support its routine use in patients before planned
coronary angioplasty and may influence practice
patterns with regard to antiplatelet therapy before PCI
S. Banai, M.D.
The active metabolite exerts its antiplatelet effect by
noncompetitive inhibition of the platelet ADP receptor
subtype P2Y12
CLOPIDOGREL
Clopidogrel: An inactive
prodrug requires in vivo
conversion in the liver by
the cytochrome P450 (CYP)
3A4 enzyme system
C
ADP
ADP
GPllb/llla
Activation
(Fibrinogen receptor)
ASA
Collagen thrombin
TXA 2
COX
TXA 2
S. Banai, M.D.
COX (cyclo-oxygenase)
ADP (adenosine diphosphate)
TXA2 (thromboxane A2)
Jarvis B, Simpson K. Drugs 2000; 60: 347–77
The thienopyridine clopidogrel
 A prodrug
that needs to be metabolized to an active compound
that targets the platelet Gi-coupled adenosine diphosphate
(ADP) P2Y12 receptor
 Clopidogrel is oxidized in a cytochrome P450 (CYP)
monooxygenase-dependent way to 2-oxo-clopidogrel, an
intermediate metabolite that is further hydrolyzed to the active
thiol metabolite of clopidogrel
 The active metabolite irreversibly binds to the P2Y12 receptor
 The
major circulating metabolite of clopidogrel is a carboxylic
acid derivate that completely lacks antiaggregatory activity
S. Banai, M.D.
Pharmacology of Clopidogrel
Absorption
(oral): rapid, not affected by food or antacids
Metabolism:
Half-life:
rapid and extensive hepatic metabolism
8 hours (but has an irreversible effect on platelets,
with a lifespan of approximately 7–10 days)
Excretion:
S. Banai, M.D.
50% in urine and 46% in feces, after 5 days
Jarvis B, Simpson K. Drugs 2000; 60: 347–77
Clopidogrel Dosing
1977:
The 75-mg once-daily dose was approved by the FDA
after the CAPRIE trial showed superior reduction of adverse
cardiovascular events with clopidogrel versus aspirin
The 75-mg once-daily dose had been used in CAPRIE because it
produced inhibition of platelet aggregation equivalent to that
produced by ticlopidine 250 mg administered twice daily
2002:
FDA approval for the 300-mg loading dose in patients
with ACS after the CURE trial demonstrated a reduction of
adverse cardiovascular events with dual antiplatelet therapy
versus aspirin
S. Banai, M.D.
Loading Dose
Without
a loading dose, clopidogrel 75 mg daily induces
inhibition of ADP-induced platelet aggregation as early as 2
hours after the first dose but requires 3 to 7 days to achieve
maximal inhibition of platelet aggregation
The
3- to 7-day delay can be shortened to 6 hours with a
loading dose of 300 mg
 With
600 mg loading (as compared with the 300-mg dose):
the maximal platelet inhibition is achieved at 2 hours
the level of inhibition of platelet aggregation is increased
the number of low responders decreased
Bates ER: Circulation 2005;111:2557-2559
S. Banai, M.D.
Hochholzer W: Circulation 2005;111:2560-2564
The benefit of a higher loading dose
The
advantage of using the higher loading dose is the
maximal drug effect during the periprocedural period
when pretreatment has not been given, a common
occurrence with ad hoc PCI
The
clinical benefit is measured by lower biomarkerdefined periprocedural MI rates, as has been seen with
periprocedural platelet inhibition with GP IIb/IIIa inhibitor
agents, and with the 600 mg Clopidogrel pre-treatment in
the ARMYDA-2 trial
S. Banai, M.D.
Should patients who are on chronic clopidogrel
therapy receive the 600 mg pretreatment regimen?
Many patients presenting for PCI are already treated with
clopidogrel. Should these patients receive the 600-mg
pretreatment regimen?
The answer is yes!
Additional, significant inhibition of platelet aggregation is
achieved when a 600-mg dose is administered to patients
already receiving clopidogrel 75 mg daily
S. Banai, M.D.
Further platelet inhibition can be achieved with 600-mg
Re-loading in patients with chronic clopidogrel therapy
In both groups, 600 mg clopidogrel
loading significantly inhibited ADPinduced expression of GP IIb/IIIa and Pselectin receptors
In the chronic therapy group, loading
with 600 mg clopidogrel yielded further
inhibition of platelet aggregation in
addition to that achieved by the
maintenance dose of 75 mg/d, from
52±14% to 33±12% (P<0.001)
S. Banai, M.D.
Adnan Kastrati Circulation. 2004;110:1916-1919
Abciximab offers no additional benefit in the
setting of Clopidogrel pretreatment
S. Banai, M.D.
Kastrati A: N Engl J Med 2004;350:232-238
Study design and objectives
2159 patients with CAD who underwent a PCI:
All patients were pretreated with a 600-mg dose of clopidogrel
at least two hours before the procedure
N=1079 - abciximab
N=1080 - placebo
Primary end point:
Composite of death, MI, and urgent TVR within 30 days
S. Banai, M.D.
Kastrati A: N Engl J Med 2004;350:232-238
Results: 4% event rate in both patient groups
S. Banai, M.D.
Kastrati A: N Engl J Med 2004;350:232-238
conclusion
In patients at low and intermediate risk who
undergo elective PCI after pretreatment
with a 600-mg loading dose of clopidogrel at least
two hours before the procedure, the additional
use of abciximab is associated with no clinically
measurable benefit within the first 30 days
S. Banai, M.D.
Kastrati A: N Engl J Med 2004;350:232-238
Abciximab offers no additional benefit in the
setting of Clopidogrel pretreatment in Diabetics
Randomized Clinical Trial of Abciximab in Diabetic Patients Undergoing
Elective PCI After Treatment With a High Loading Dose of Clopidogrel
Study: 701 diabetic patients with CAD who underwent elective
PCI after pretreatment with a 600-mg dose of clopidogrel
>2 hours before the procedure
351 patients - abciximab
350 patients - placebo
Primary end point: composite of death and MI at 1 year
S. Banai, M.D.
Julinda Mehilli, Circulation. 2004;110:3627-3635
Conclusions:
There is no significant impact of abciximab on the risk of
death and MI in diabetic patients undergoing PCI after
pretreatment with a 600-mg loading dose of clopidogrel at
least 2 hours before the procedure
S. Banai, M.D.
Mehilli J, Circulation
2004;110:3627-3635
How High Should We Go?
Absorption, Metabolization, and Antiplatelet Effects of 300,
600, and 900-mg Loading Doses of Clopidogrel:
Results of the ISAR-CHOICE (Intracoronary Stenting and
Antithrombotic Regimen: Choose Between 3 High Oral Doses for
Immediate Clopidogrel Effect) Trial
Primary end point:
Maximal ADP-induced (5 µmol/L) platelet aggregation
4 hours after administration of clopidogrel
S. Banai, M.D.
Nicolas von Beckerath: Circulation 2005;112: 2946 - 2950
Antiplatelet Effects of 300-, 600-, and 900-mg
Loading Doses of Clopidogrel
Sixty patients with suspected or documented CAD
admitted for coronary angiography were included
They were allocated to clopidogrel loading doses of 300,
600, or 900 mg in a double-blinded, randomized manner
Plasma concentrations of the active thiol metabolite,
unchanged clopidogrel, and the inactive carboxyl
metabolite of clopidogrel were determined before and
serially after drug administration
S. Banai, M.D.
Nicolas von Beckerath: Circulation 2005;112: 2946 - 2950
Plasma concentrations
active metabolite
clopidogrel
carboxyl metabolite
Loading with 600 mg resulted in
higher plasma concentrations of
active metabolite, clopidogrel, and
carboxyl metabolite compared with
loading with 300 mg (P 0.03)
With 900 mg, no further increase in
plasma concentrations of active
metabolite and clopidogrel (P 0.38)
was achieved
300 mg (blue)
600 mg (red)
900 mg (cyan)
S. Banai, M.D.
von Beckerath, N. et al. Circulation 2005;112:2946-2950
Maximal ADP-induced platelet aggregation 4 hours after
administration of a 300-, 600-, and 900- mg loading dose
An increase of the clopidogrel loading
dose from 600 to 900 mg does not
result in further suppression of platelet
aggregation caused by a failed increase
in plasma concentration of the drug
This suggests that intestinal absorption
becomes the bottleneck when single
doses exceeding 600 mg are
administered
S. Banai, M.D.
von Beckerath, N. et al. Circulation 2005;112:2946-2950
Should we split the high dose?
Administering
900 mg Clopidogrel in 2 separate
doses may allow more complete absorption and,
consequently, additional platelet inhibition compared
with 600 mg
However, the practicability of such an approach as a
pretreatment before PCI is limited
S. Banai, M.D.
Nicolas von Beckerath Circulation. 2005;112:2946-2950
What can we reasonable conclude about
antiplatelet therapy and PCI?
1.
2.
3.
4.
augmenting aspirin with additional antiplatelet therapy
reduces myonecrosis after PCI
according to the information currently available, if clopidogrel
is selected, the dose should be 600 mg and the drug should
be administered at least 2 hours before PCI
for the types of patients evaluated thus far, intravenous GP
IIb/IIIa inhibitors appear unnecessary when clopidogrel has
been administered
if circumstances restrict clopidogrel pretreatment, intravenous
GP IIb/IIIa is a reasonable alternative
S. Banai, M.D.
Thank You
S. Banai, M.D.