Antiplatelet
Therapy in
General Overview
Prof. Lale Tokgözoğlu MD, FACC, FESC
Hacettepe University Faculty of Medicine
Department of Cardiology
Cause of Death by Gender in
Europe:
WHO 2008
Platelets are important in
atherothrombosis
 After release from
bone marrow,
circulate for 7-10
days without
interaction with
vessel wall
 If exposed to
subendothelium,
platelets activated
Plaque
Fissure or
Rupture
Unstable
plaques activate
platelets
Platelet
Adhesion
Platelet
Activation
Platelet
Aggregation
Thrombotic
Occlusion
Adhesion mediated by vWF, agonists like ADP, secreted
granules and TXA2 cause aggregation, exposed GPIIbIIIa
receptors crosslink with fibrinogen to form platelet aggregates
1
Adhesion
3
Aggregation
2 Activation
Reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: www.theheart.org.
THROMBUS
FIBRIN
THROMBOCYTE
AGGREGATION
THROMBOCYTE
ADHESION
ENDOTHELIUM
MACROPHAGE
SMOOTH MUSCLE CELL
MONOCYTE
Platelet surface membrane receptors
play important role
Platelets also important in stent thrombosis:
Mechanism of AMI after stent implantation
Relative frequency
12%
Atherothrombosis at new
location (after 27 months)
48%
Restenosis (after 19 months)
Stent thrombosis (after 9 months)
40%
Alexopoulos D. Am Heart J 2010; 159: 439-445
Different mechanisms of
antiplatelet drugs:
1. COX-1 inhibitors
ASA, Omega 3
2. Phosphodiesterase inhibitors
Dipyrdamole, Cilostazol
3. ADP-P2Y12 interaction blokers
Ticlopidine, Clopidogrel, Prasugrel,
Cangrelor, Ticagelor
4. GP IIb/IIIa blokers
5. Thrombin receptor antagonists
Blocking different pathways for
additional clinical benefit:
Clopidogrel
Prasugrel
Cangrelor
Heparin, hirudin
Epinephrine Collagen
ADP
AA
Aspirin
TxA2
PLATELET
GPIIb/IIIa
Aggregation
GP IIb/IIIa
antagonists
ASA
 Inactivates COX irreversibly blocking
TXA2 formation (potent mediator of
aggregation and vasoconstriction)
 Effective 15-30 minutes after oral
administration
 Large dose over 10 gr
eicosapentaenoic acid also blocks
TXA2
Phosphodiesterase Inhibitors
 Dipyridamole stimulates PGI2
synthesis, blocks uptake of adenosine
 Clinical trials failed to show efficacy
alone, enhances warfarin and ASA
 MR form useful for stroke prevention
 Cilostazol may be useful in claudicatio
and has vasodilatory and antiplatelet
effects
Thienopyridines
 Bind to P2Y12
receptor
inhibiting
interaction with
ADP that would
result in
activation and
aggregation
 Prodrugs
requiring
transformation
to active
metabolites
Ticlopidine dramatically changed
interventional cardiology by making stent
implantation safe
14
12
10
8
6
4
2
0
Prim. Cardiac EP
Abrupt vessel
closure
Ticlo + ASA
Schomig, NEJM 1996
Prim. Noncardiac
EP
UFH + Warfarin + ASA
Bleeding
Ticlopidine replaced by clopidogrel: more
effective, safer
5
4
Ticlopidine
Clopidogrel
3
2
1
0
MACE
Bhatt, JACC 2002
Mortality
Antiplatelet Resistance:
 Genetic polymorphism in platelet proteins
(CYP2C19 reduced function alleles have 30
% decrease in active clopidogrel)
 Drug interaction
(NSAID , drugs metabolized with
Cytochrome P450 )
 Environmental factors
(Smoking, DM, HTN, HLP, ACS)
VARIABILITY IN RESPONSE NOT ALWAYS
RESISTANCE:
Insufficent dosing, differences in assays and
cutoffs, no gold standart
Is Aspirin Resistance Clinically
Significant?
 326 stable CAD
 5.2 % Aspirin resistance
 In HOPE study, @ 5 year follow up
MI, stroke, death rate 1.8 % increased in the
group with 11- deoxythromboxane B2 level !
Circulation 2002, 105: 1650
JACC 2003:41; 961
ASA resistance vs. clopidogrel
resistance vs. dual resistance
The prevalence of drug resistance: ASA 16%, CLOPI 15%, dual 9%
The risk is 7x higher with dual resistence and 4.5x higher with multivessel PCI
40
37%
35
Percentage
30
26%
No resistance
25
ASA resistance
20
CLOPI resistance
15
Dual resistance
10
5
0
Periprocedur.MI
Eshtehardi P, Am Heart J 2010; 159: 891-898
Ischaemic events within
30 days
Definition of Resistance Varies with
Method Used: ASA Resistance Measured
by PFA-100 and Aggregometry
Stable AP n= 325 patients
Partial response
23.8 %
Routine
assessment of platelet
RESISTANT
5.5 %not
9.5 %
aggregation
recommended
(II-B)
70.7 %
Aspirin Sensitive
Aggregometry
Response to ADP and AA
Gum P. Am J Cardiol 2001;88:230-235
90.5 %
Aspirin Resistant
PFA-100
600 mg clopidogrel loading is
faster and more effective !
Aggregation inhibition (%)
0
*P=0.01
** P=0.02
‡ P=0.0008
20
40
**
*
60
‡
Clopidogrel, 300 mg
Clopidogrel, 600 mg
80
0
2
*
**
4
6
Hours
Zidar F, et al. J Am Coll Cardiol. 2004;43(5, suppl A);Abstract 1100-1159.
ARMYDA-II
Circulation 2005;111:2099
Doubling loading and maintenance dose of
clopidogrel in ACS patients undergoing PCI
CV death, MI or stroke
Clopidogrel standard
15% RRR
Cumulative hazard
0.04
Clopidogrel double
0.03
0.02
HR 0.85
95% CI: 0.74-0.99
p=0.036
0.01
0.00
0
3
6
9
12
15
18
Days
21
24
27
30
Clopidogrel to Prasugrel Crossover Study:
Less variability with prasugrel since it produces
higher concentrations of active metabolite
Healthy volunteers Crossover study
IPA (20 µM ADP) 24 hours
Platelet aggregation inhbition (%)
100
N=66
80
60
40
20
Clopidogrel effective
0
Clopidogrel resistant
-20
Clopidogrel reply
Prasugrel reply
Brandt et al. J Am Coll Cardiol 2005;45(3 Suppl 1):87A – abstract 868-5
TRITON-TIMI 38:
13608 patients with ACS
Prasugrel
60 mg LD/ 10 mg MD
ASA
UA/NSTEMI
(TIMI Risk Score ≥ 3)
& Planned PCI
12.0 month
planned median
R
Double-blind treatment
6 - 15 months planned follow-up
STEMI
(Primary PCI ≤ 12
hours of symptoms or
post-STEMI within 14
days)
ASA
14.5 month
actual median
Clopidogrel
300 mg LD/ 75 mg MD
= Primary efficacy end point: a composite of the rate of death from cardiovascular causes,
nonfatal MI, or nonfatal stroke
= Key secondary end points at 30 and 90 days included primary efficacy end point and a composite
of the rate of death from cardiovascular causes, nonfatal MI, or UTVR
Key safety end point: non-CABG related TIMI Major Bleeding
Wiviott SD et al. New Engl J Med 2007;357:2001-2015; Wiviott SD et al. Am Heart J 2006;152:627-635
TRITON TIMI-38:
Balance of efficacy and safety in patients
< 75 Yrs, ≥ 60 kg, and without prior TIA/Stroke (N=10,804)
16
CV death, NF MI, or NF stroke
14
Endpoint (%)
12
Clopidogrel 11.0%
HR 0.74
(95% CI: 0.66-0.84)
p<0.001, NNT 37
10
8
Prasugrel 8.3%
6
4
HR 1.24
(95% CI: 0.91-1.69)
p=0.17, NNH 222
2
TIMI major bleeding
Prasugrel 1.9%
Clopidogrel 1.5%
0
0
30
90
Wiviott SD et al. Circulation 2010;122:394-403
180
Days
270
360
450
Prevention of bleeding just as
important as prevention of ischemia:
Efficacy
Safety
In Clopidogrel group ,30 % of subjects had reduced
function allele for CYP, these had 3X more stent
thrombosis
Genetic and Platelet Fx Tests
are Complementary
Genome
Genetics Transcriptome
Environment
Proteome
Phenotype
Platelet function
testing
Variable Response to Clopidogrel
Test:
Genetic,
platelet
function
Increase
dose
+ Personalise
+ Easy
- Complex
- Efficacy, safety ?
Alternative
treatment:
+ Efficacy
- Cost ?
Bleeding ?
Patients undergoing PCI with high platelet
activity randomised to 75 mg C or 600
loading plus 150 mg C: GRAVITAS Study
Primary end point
End point
High-dose
clopidogrel (%)
Standard-dose
clopidogrel (%)
HR (95% CI)
p
Cardiovascular death/MI/stent
thrombosis
2.3
2.3
1.01 (0.58-1.76)
0.98
Outcome
High-dose
clopidogrel (%)
Standard-dose
clopidogrel (%)
p
GUSTO severe/moderate bleeding
1.4
2.3
0.10
Any GUSTO bleeding
12.0
10.2
0.18
Bleeding results
Percentage of patients with persistently high platelet reactivity at 30
days
Platelet reactivity units
High-dose
clopidogrel (%)
Standard-dose clopidogrel (%)
p
>230
62
40
<0.001
AHA 2010
Cangrelor
 Potent inhibitor of ADP
induced aggregation
 ATP analogue that inhibits
P2Y12 by 100 %
 No renal/hepatic
metabolism to be activated
 İv,rapid action, platelets
back to normal in 60
minutes
 Has additive effects to
clopidogrel
 Two short term trials
discontinued for less than
expected efficacy
Ticagrelor
 Stable, high affinity inhibitor of ADP
induced aggregation
 Oral agent acting directly on P2Y12
receptor without transformation
 Rapid and greater action
 Reversibility
 180 mg loading ,90 mg bid
 Higher doses cause dyspnea and
ventricular pause
PLATO Study
 . Lancet. 2002;359:189-198
NEJM 2009; 361:1045
Glycoprotein IIb/IIIa Inhibitors Block
the Common Final Pathway to Platelet Aggregation
regardless of the stimulus for activation
Glycoprotein IIb/IIIa Inhibitors
 Monoclonal Ab against IIb/IIIa:
Abciximab
 Peptide antagonist: Eptifibatid
 Nonpeptide antagonist: Tirofiban
GP IIb/IIIa Inhibitors in ACS:
30 day death / MI (N=31,402)
Study
PRISM
Placebo
Gp IIb/IIIa
Odds Ratio 95% CI
7.1%
5.8%*
0.80
0.60-1.06
PRISM-PLUS
12.0%
(*)
8.7%
(† ) 13.6%*
0.70
1.17
0.50-0.98
0.80-1.70
PARAGON-A
11.7%
(l)
(h)
10.3%
12.3%
0.87
1.06
0.58-1.29
0.72-1.55
PURSUIT
15.7%
(l)
(h)
13.4%
14.2%
0.83
0.89
0.70-0.99
0.79-1.00
PARAGON-B
11.4%
10.6%
0.92
0.77-1.09
GUSTO-IV
8.0%
(24h) 8.2%
(48h) 9.1%
1.02
1.15
0.83-1.24
0.94-1.39
Overall
11.8%
-High risk
10.8%t
- Diabetic
0
1.0
Gp IIb/IIIa iyi
Boersma E, et al. Lancet. 2002;359:189-198.
0.91 0.85-0.98
2.0
Placebo iyi
P=.015
- ASA use on admission
PRISM-PLUS: Thrombus size
50
Probable
40
Odds Ratio:
0.77
P=0.022
Probable
30
Small
Cumulative
(%)
20
Small
Medium
Medium
10
Big
0
Occlusion
Tirofiban + Heparin
(n=608)
Circulation. 1999;100:1609-1615.
24.1%
17.1%
Big
Occlusion
Heparin
(n=622)
ACUITY, timing GP IIb/IIIa at the time
of PCI vs. upstream in everyone
Routine Upstream
GP IIb/IIIa
(N=4,605)
Deferred PCI
GP IIb/IIIa
(N=4,602)
98.3%
55.7%
Rand. to angio/interv (h)
6.2
6.2
Rand. to GP IIb/IIIa (h)
0.6
4.6
Net clinical benefit
11.7
11.7
Ischaemic EP
7.1
7.9
Bleeding EP
6.1
4.9
Overall exposure
Stone GW et al. JAMA 2007;297:591-602
TARGET: Benefit of triple
antiplatelet therapy
6 months death/MI
Clopidogrel and tirofiban
Clopidogrel and abciximab
No clopidogrel only tirofiban
No clopidogrel only abciximab
18
16
15.5%
14
12
10.9%
Patients 10
(%)
8.4%
7.2%
8
6
4
2
0
0
30
60
90
Days
Chan A, et al. J Am Coll Cardiol. 2003;42:1188-1195.
120
150
180
Major bleeding %
Excess dose %
Relation between age, dosing and bleeding
Eur Heart J Suppl 2007, 9 (Suppl A) A23-A31.
Age
Antithrombotic treatment options in
myocardial revascularisation: STEMI
Classa
Levelb
ASA
I
B
Clopidogrelc (with 600 mg loading dose as soon as possible)
I
C
Prasugreld
I
B
Ticagrelord
I
B
Abciximab
IIa
A
Eptifibatide
IIa
B
Tirofiban
IIb
B
Upstream GPIIb–IIIa antagonists
III
B
Bivalirudin (monotherapy)
I
B
UFH
I
C
Antiplatelet therapy
+ GPIIb–IIIa antagonists (in patients with evidence of high
intracoronary thrombus burden)
Anticoagulation
Fondaparinux
III
B
a: Class of recommendation; b: Level of evidence; c: Primarily if more efficient antiplatelet agents are contraindicated; d:
Depending on approval and availability. Direct comparison between prasugrel and ticagrelor is not available. Long term
follow-up is awaited for both drugs
Eur Heart J 2010. On line
Antithrombotic treatment options in
myocardial revascularisation: NSTE-ACS
Classa
Levelb
ASA
I
C
Clopidogrelc (with 600 mg loading dose as soon as possible)
I
C
Clopidogrelc (for 9–12 months after PCI)
I
B
Prasugreld
IIa
B
Ticagrelord
I
B
Abciximab (with DAPT)
II
B
Tirofiban, Eptifibatide
IIa
B
Upstream GPIIb–IIIa antagonists
III
B
Antiplatelet therapy
+ GPIIb–IIIa antagonists (in patients with evidence of high
intracoronary thrombus burden)
a: Class of recommendation; b: Level of evidence; c: Primarily if more efficient antiplatelet agents are contraindicated; d:
Depending on approval and availability. Direct comparison between prasugrel and ticagrelor is not available. Long term
follow-up is awaited for both drugs
Eur Heart J 2010. On line
Antiplatelets for ischemic stroke
or preventing systemic embolism
Warfarin vs placebo
Warfarin vs low dose Warfarin
Warfarin vs ASA
Warfarin vs ASA + clopidogrel
0
0.3
0.6
Warfarin better
Camm, ESC 2009
0.9
1.2
1.5 1.8 2.0
Other better
What is the ideal antiplatelet
drug?






Effective platelet inhibition without bleeding
Uniformly effective in all patients (no resistance)
Simple dosage
No side effects
No drug interactions
Reasonable price
FOR NOW:
 Beware of drug interactions and bleeding
 Keep ASA dose low in combination
 Calculate GPI dose meticulously
New Horizons in Antiplatelet
Therapy:
- TRA thrombin receptor antagonists
- Antagonists to A1 domain on vWF:
ARC1779
- Collagen induced platelet aggregation
blockers : CTRP-1
TRITON-TIMI 38:
Therapeutic considerations for
subgroups
Age ≥75 years or weight <60 kg:
Prasugrel 10 mg equivalent to clopidogrel
(Prasugrel 5 mg under investigation)
Majority of patients:
Significant benefit
with prasugrel 10 mg
(MD)
16%
4%
80%
Prior stroke/TIA:
Prasugrel is
contraindicated
PRAGUE-8 (with 600 mg load):
Patients undergoing elective PCI
Percentage patients
20
Pre-treatment
Clop 600 mg
(n=155)
No Pre-treatment
Clop 600 mg
(n=143)
p=NS
15
11.9
p=0.006
10
8.4
7.1
p=NS
5
2.8
1.3
0.7
0
D/MI/CVA/UTVR
Widimsky P et al. Eur Heart J 2008;29:1495-1503
Troponin >3XULN
Major + Minor
Bleeding
Activated platelets express CD 40L triggering
inflammation and thrombosis
ISAR-CHOICE
Circulation 2005;112:2946
30th DAY DEATH / MI WITH GPI
18
Placebo
16.7
GP IIb-IIIa Inhibitor
14.1
14
11.6
10.9
9
10
% Parients
10.2
10.1
5.9
4.8
6
3.6
3.9
1.8
2
0
EPIC
CAPTURE
EPILOG
EPISTENT
PRISM-PLUS
PURSUIT
JUMBO - TIMI 26 (Phase II)
PCI + Stent (n= 904)
ASA 325 + % 70 GP2b/3a
Clopidogrel
Klopidogrel
Prasugrel
300/75
40/7.5 60/10 60/15
2
9,4
10
1,7
%
%
7,2
1,2
1
5
0
0
Major, minor bleeding
Circulation 2005;111:3366
MACE
Variable Clopidogrel Response
At 5 Days
UA Patients* (n = 32)
Nonresponders
22%
Responders
47%
Low responders
32%
*Received an oral loading dose of 300 mg of clopidogrel followed by 75 mg daily.
Gurbel PA, et al. Circulation. 2003;107(23):2908-2913; Lau WC, et al. Circulation. 2004;109(2):166-171.