Dr Tan Huay Cheem
MBBS, M Med(Int Med), FRCP(UK), FAMS, FACC, FSCAI
Director, National University Heart Centre, Singapore (NUHCS)
Associate Professor of Medicine, Yong Loo Lin School of Medicine
National University of Singapore
Evidence Based Medicine: Role of Antiplatelet In Reducing
Cardiovascular Mortality in ACS Patients
13th Vietnam National Congress of Cardiology
National University Heart Centre, Singapore
(NUHCS)
Singapore Myocardial Infarction Registry (SMIR)
AMI National Trends 2007-2010
Mortality Rates in Acute Coronary Syndromes
• Despite advancements in the treatment of ACS over the past decade,
ACS mortality and morbidity rates remain high
– Among ACS patients with a diagnosis of UA, 30% evolved to a
myocardial infarction (MI) – 24% to NSTEMI and 6% to STEMI
– Rates of recurrent MI in NSTEMI patients after 5 years are
12%-14% and is 7% for cardiovascular (CV) death
– In-hospital and 6-month death from STEMI rates are nearly 5%
Fox KA et al JAMA 2007;297:1892-1902; Fox KA et al Eur Heart J 2002; 23:1177-1189;
Damman P et al J Am Coll Cardiol 2010; 55: 858-864
Milestones in ACS Management
Anti-thrombin Rx
Antiplatelet Rx
Treatment Strategy
PCI
1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2010
Ischemic Risk
Heparin
Aspirin
Conservative
Bleeding Risk
LMWH Bivalirudin Fondaparinux
GP IIb/IIIa
blockers Clopidogrel Prasugrel Ticagrelor
Early invasive
PRISM-PLUS
PURSUIT
ESSENCE TACTICS TIMI-18
REPLACE 2
CURE
SYNERGY
QASIS-5 TRITON
ACUITY
HORIZON MI
PLATO
5% Stents 85% Stents Drug-Eluting Stents 2nd Gen DES
Targets for Antithrombotic Drugs
Eur Heart Journal 2011; 32: 2999-3054
Antiplatelet Therapy
• Aspirin
• Clopidogrel
• Prasugrel
• Ticagrelol
Sir John Vane (1927-2004)
Nobel Prize in Medicine 1982
for work on prostaglandins &
discovery of prostacyclin,
leading to understanding of the
mechanism of action of aspirin
Irreversible inhibition of the cyclo-oxygenase
pathway in platelets, blocking formation of
thromboxane A2, and platelet aggregation
Aspirin Discovery and Mechanism of Action
17.1
6.5*
Placebo ASA 0
5
10
15
20
Pat
ien
ts (
%)
Unstable Angina
25.0
11.0*
ASA 0
10
20
30
3.3
1.9*
ASA 0
1
2
3
4
11.8
9.4*
ASA 0
5
10
15
Acute MI
Aspirin in Acute Coronary Syndromes
*P <0.0001 Death or MI
*P =0.003 Reocclusion
*P =0.012 MI
*P <0.001 Death
N= 397 399 513 419 8587 8600 8587 8600
Placebo Placebo Placebo
62% 42%
20%
RISC Group Lancet 1990; Roux S et al J Am Coll Cardiol 1992; ISIS-2 Lancet 1988
Antiplatelet Therapy
• Aspirin
• Clopidogrel
• Prasugrel
• Ticagrelol
Platelet P2Y Receptors/Inhibitors
G protein
Molecular structure Intrinsic ion
channel
G protein
Receptor subtype
P2X1
P2Y1 P2Y12
GPCR Gj
GPCR Gq
PLC/IP3 [Ca2+]j
AC [cAMP]
Shape change Transient
aggregation
Sustained aggregation
Secondary Messenger system
Functional response
[Na+/Ca2+]i
Shape Change
Aggregation
ADP
Ticlopidine
Clopidogrel
Prasugrel
Cangrelor
AZD-6140
X
Bhatt and Topol, Nature Reviews Drug Disc 2003; 2:15-28
Clopidogrel in CURE Trial:
Primary Endpoints (Death, MI, Stroke)
0 1 2 3 4 5 6 7 8 9 10 11 12
Months of follow-up
20% RRR
p=0.00009
n=12,562
Aspirin
Clopidogrel + Aspirin
0
10
14
12
4
8
6
2
9.3%
11.4%
The CURE Investigators N Eng J Med August 2001; 345: 494-502
CURE: Death/MI/Stroke/Severe Ischemia 24 Hours
The CURE Investigators N Eng J Med August 2001; 345: 494-502
CURE – Bleeding Complications
0.02 2.2 2.8 • Transfusion
0.002 0.9 1.5 Non life threatening
ns 1.8 2.2 Life threatening
0.001 2.7 3.7 • Major
P Standard therapy
alone including
ASA (%)
Clopidogrel +
Std therapy
Including ASA (%)
The CURE Investigators N Eng J Med August 2001; 345: 494-502
Aspirin dose Placebo + Aspirin Clopidogrel + Aspirin
75-100 mg 1.9% 3.0%
101-199 mg 2.8% 3.4%
200-325 mg 3.7% 4.9%
CURE: Major Bleeding By Aspirin Dose
Through Follow-Up (1 Year)
Variability in Clopidogrel Response
Change in ADP-Induced platelet
aggregation 75 mg chronic dosing
N=544
0 2 4 6 8 10
0
20
40
60
80
100
Time from loading dose to cath (h)
Maximal aggregation 5µmol/L ADP (%)
following 600 mg loading dose
N=1001
Serebruany. J Am Coll Cardiol 2005; 45:246 Hochholzer W et al Circulation 2005
Red dot: nonresponder
Mechanism of Clopidogrel Response Variability
Intestinal
Absorption
Highly variable absorption capacity with ceiling effect at 600 mg leading dose
Inactive Carboxylic Acid
Metabolite
Clopidogrel
(prodrug)
P-glycoprotein
(MDR1 34357 genotype)
Esterases
85%
15% Multistep Conversion
CYP1A2
CYP2B6
CY3A4/5
CYP2C9
CYP2C19
Hepatic Cytochrome
P450 Isoforms Drug-drug interaction with lipophilic statins
Genetic polymorphisms
Drug-drug interaction with protein pump Inhibitors
Genetic polymorphisms
Active Thiol Metabolite
P2Y12 Receptor Genetic Polymorphism
Genetic polymorphisms
Smoking
Prevalence of CYP2C19 Polymorphisms in 300 Asian Subjects
0
10
20
30
40
50
60
70
Non-carriers Loss-of-function carriers Gain-of-function carriers
Pre
vale
nce,
%
Chinese
Malay
Indian
• Within-group P <0.05
• Loss-of-function – 1 or more *2/*3 Alleles
• Gain-of-function – 1 or more *17 alleles
Chinese and Malay subjects demonstrated an East Asian genotype with a high prevalence of
CYP2C19*2 and *3 loss-of-function polymorphisms and low prevalence of the CYP2C19*17
gain-of-function polymorphism. In contrast, Indian subjects demonstrated a South Asian genotype,
with a lower prevalence of loss-of-function polymorphisms but a higher prevalence of the
*17 gain-of-function polymorphism
0
10
20
30
40
50
60
70
Chinese (n = 100) Malay (n = 100) Indians (n = 100)
Per
cen
tag
e (%
)
PM
NM
RM
Clopidogrel Pharmacogenetic Differences
Among 3 Major Asian Ethnicities
Mark Y Chan et al Pharmacogenomics 2012 (in press)
Antiplatelet Therapy
• Aspirin
• Clopidogrel
• Prasugrel
• Ticagrelol
More Efficient and Less Variable Activation of
Prasugrel Compared to Clopidogrel
Clopidogrel
CYP1A2,
2B6, 2C19
Intermediate
Active Metabolite
CYP3A, 2B6,
2C9, 2C19 Liver
CYP2C19 variants and inhibitors affect
the PK and PD of clopidogrel
Liver
85%
Inactive
Metabolite
hCE1
Prasugrel has no clinically relevant
interactions with CYP2C19 variants
or inhibitors
Prasugrel
Gut hCE2
Intermediate
Active Metabolite
Liver
Gut
and CYP3A, 2B6,
2C9, 2C19
Prasugrel in PRINCIPLE-TIMI 44
Wiviott SD et al Circulation 2007; 116: 2923-2932
Prasugrel loading with 60mg resulted in greater platelet inhibition than 600mg clopidogrel,
and maintenance with prasugrel 10mg has greater antiplatelet effect than 150mg/d clopidogrel
TRITON TIMI 38 Main Trial Design
ASA
Prasugrel
60 mg LD/ 10 mg MD
Clopidogrel
300 mg LD/ 75 mg MD
1o endpoint: CV death, MI, stroke
2o endpoint: Stent thrombosis
Safety endpoints: TIMI major bleeds, life-threatening bleeds
Duration of therapy: 6–15 months
n = 13,608
Double-blind
ACS (STEMI or UA/NSTEMI) and planned PCI
Wiviott SD et al Am Heart J 2006;152: 627-35
TRITON TIMI 38: Balance of Efficacy and Safety
Wiviott SD et al N Engl J Med 2007; 357: 2001--15
TRITON TIMI 38 Bleeding Events (n=13 457) E
ven
ts (
%)
ARD 0.6%
HR 1.32
P = 0.03
NNH = 167
Clopidogrel Prasugrel
ARD 0.5%
HR 1.52
P = 0.01
ARD 0%
P = 0.74
ARD 0.3%
P = 0.002
ICH in patients with
prior stroke/TIA
(n = 518)
Clopidogrel 0 (0%)
Prasugrel 6 (2.3%)
(P = 0.02)
ARD 0.2%
P = 0.23
1.8
0.9 0.9
0.1 0.3
2.4
1.4
1.1
0.4 0.3
0
2
4
TIMI major
bleeds
Life-
threatening
Non-fatal Fatal ICH
Wiviott SD et al N Engl J Med 2007; 357: 2001--15
TRITON-TIMI 38: CABG-Related Bleeding
Safety Endpoint
Prasugrel
N=213
n (%)
Clopidogrel
N=224
n (%) p-value
CABG-related TIMI Major Bleeding 24 (11.27) 8 (3.57) 0.002
Wiviott SD et al N Engl J Med 2007; 357: 2001--15
YD Li, Mark Chan et al J Thrombosis and Thrombolysis (in press)
• 65 consecutive Asian patients with STEMI received
60mg of prasugrel before primary PCI
• Pre- and post-PCI corrected TIMI frame count (CTFC)
and 8-hour post-treatment platelet VASP index
compared with a matched historical Asian STEMI
cohort (n = 65) receiving 600 mg of clopidogrel
pretreatment
Prasugrel 60mg vs Clopidogrel 600mg During PPCI
YD Li, Mark Chan et al J Thrombosis and Thrombolysis (in press)
Prasugrel
(n=65)
Clopidogrel
(n=65) p value
Mean post-PCI VASP index (%; SD) 22.2 (24.5) 70.5 (17.5) <0.001
VASP>50(%) 13.8 84.3 0.001
PlateletReactivityEndpoints
• Clopidogrel pre-treatment was associated with greater high on-treatment platelet reactivity
than prasugrel pretreatment
• Treatment with 60 mg of prasugrel before primary PCI was associated with significantly lower platelet
reactivity, modestly better pre-PCI angiographic outcomes, less pre-PCI coronary thrombi and
less rescue platelet glycoprotein inhibitor use compared with 600 mg of clopidogrel.
• This suggests greater pharmacodynamic efficacy with 60 mg of prasugrel than 600 mg of clopidogrel.
Antiplatelet Therapy
• Aspirin
• Clopidogrel
• Prasugrel
• Ticagrelol
Ticagrelor
• New chemical class of P2Y12 inhibitors
- Cyclo-pentyl-triazole-pyrimidine (CPTP): not a thienopyridine or
ATP analogue
- Inhibits adenosine reuptake
• Direct-acting
- Not a prodrug; does not require metabolic activation
- Onset (within 2 hours); peak plasma levels within 2-3 hours
- Greater and more consistent inhibition of platelet aggregation vs
clopidogrel
• Reversibly bound
- Degree of inhibition reflects plasma concentration
- Offset of effect (36-48 hours)
- Functional recovery of all circulating platelets
O H
O H
O
O H
N
F
S
N H
N N
N N
F
Onset/Offset: Inhibition of Platelet Aggregation
Onset of IPA for ticagrelor was rapid, with IPA evident at
0.5 h after first dose (40% vs 8%; P<0.001)
At 1 and 2 h after first dose, IPA for ticagrelor was
statistically significantly higher than for clopidogrel
Ticagrelor demonstrated greater IPA that was sustained during
maintenance (P<0.0001 at all times)
Ticagrelor IPA at day 3 (72hrs) post dosing was similar
to clopidogrel IPA at day 5 (120hrs) post dosing
Gurbel PA et al Circulation 2009; 120: 2577-2585
Primary endpoint: CV death + MI + Stroke
Primary safety endpint: Total major bleeding
6–12-month exposure
Clopidogrel
If pre-treated, no additional loading dose;
if naive, standard 300 mg loading dose,
then 75 mg qd maintenance;
(additional 300 mg allowed pre PCI)
Ticagrelor
180 mg loading dose, then
90 mg bid maintenance;
(additional 90 mg pre-PCI)
NSTE-ACS (moderate-to-high risk) STEMI (if primary PCI)
Clopidogrel-treated or -naive;
randomised within 24 hours of index event
(N=18,624)
PCI = percutaneous coronary intervention; ASA = acetylsalicylic acid; CV = cardiovascular; TIA = transient ischaemic attack
PLATO Study Design
Wallentin L et al N Engl J Med 2009; 361:1045-1057
PLATO: Planned Invasive vs Medically Managed Patients
All Patients (N = 18,624)
Planned Invasive (n = 13,408) Planned Non-invasive (n = 5216)
Ticagrelor (n = 6732)
STEMI (n = 3278)
NSTEMI (n = 2564)
Other (n = 197)
Unknown (n = 17)
Clopidogrel (n = 6676)
STEMI (n = 3297)
NSTEMI (n = 2481)
Unstable angina
(n = 710)
Other (n = 177)
Unknown (n = 11)
Ticagrelor (n = 2601)
STEMI (n = 218)
NSTEMI (n = 1441)
Other (n = 62)
Unknown (n = 7)
Clopidogrel (n = 2615)
NSTEMI (n = 1469)
Unstable angina
(n = 853)
Other (n = 53)
Unknown (n = 7)
STEMI (n = 233)
James SK et al BMJ 2011; 342: 3527
Unstable angina
(n = 676)
Unstable angina
(n = 873)
PLATO: Time to First Primary Efficacy Event
(Composite of CV Death, MI or Stroke)
No. at risk
Clopidogrel
Ticagrelor
9,291
9,333
8,521
8,628
8,362
8,460
8,124
Days after randomisation
6,743
6,743
5,096
5,161
4,047
4,147
0 60 120 180 240 300 360
12
11
10
9
8
7
6
5
4
3
2
1
0
13
Cum
ula
tive
inci
den
ce (
%)
9.8
11.7
8,219
HR 0.84 (95% CI 0.77–0.92), p=0.0003
Clopidogrel
Ticagrelor
Wallentin L et al N Engl J Med 2009; 361:1045-1057
8688
8763
0 10 20 30
8
6
4
2
0
Cu
mu
lati
ve
inci
den
ce (
%)
Clopidogrel
Ticagrelor
4.8
5.4
(HR, 0.88; 95% CI, 0.77-1.00; P=0.045)
No. at risk
Clopidogrel
Ticagrelor
9291
9333
8875
8942
8763
8827
Days after randomization
31 90 150 210 270 330
8
6
4
2
0
Clopidogrel
Ticagrelor
5.3
6.6
8688
8673
8286
8397
6379
6480
Days after randomization*
(HR, 0.80; 95% CI, 0.70-0.91; P<0.001)
8437
8543
6945
7028
4751
4822
Cu
mu
lati
ve
inci
den
ce (
%)
*Excludes patients with any primary event during the first 30 days
PLATO: Primary Efficacy Endpoint Over Time
(Composite of CV Death, MI or Stroke)
0-30 days 31-360 days
Wallentin L et al N Engl J Med 2009; 361:1045-1057
PLATO: Hierarchical Testing of Major Efficacy Endpoints
All Patients* Ticagrelor
(n=9333)
Clopidogrel
(n=9291)
HR for
ticagrelor (95%
CI)
P value†
Primary endpoint, n (%/year)
CV death + MI + stroke 864 (9.8) 1014 (11.7) 0.84 (0.77-0.92) <0.001
Secondary endpoints, n (%/yr)
Total death + MI + stroke 901 (10.2) 1065 (12.3) 0.84 (0.77-0.92) <0.001
CV death + MI + stroke + severe
recurrent ischemia + recurrent ischemia
+ TIA + arterial thrombus
1290 (14.6) 1456 (16.7) 0.88 (0.81-0.95) <0.001
MI 504 (5.8) 593 (6.9) 0.84 (0.75-0-95) 0.005
CV death 353 (4.0) 442 (5.1) 0.79 (0.69-0.91) 0.001
Stroke 125 (1.5) 106 (1.3) 1.17 (0.91-1.52) 0.22
Death from any cause 399 (4.5) 506 (5.9) 0.78 (0.69-0.89) <0.001
Wallentin L et al N Engl J Med 2009; 361:1045-1057
PLATO Incidence of Stent Thrombosis:
Patients with Planned Invasive Treatment
*Intent for invasive or medical management declared prior to randomization.
Patients with intent for invasive treatment*
Ticagrelor (n=6732)
Clopidogrel (n=6676)
HR for ticagrelor (95% CI)
P value
Definite 71 (1.3) 106 (1.9) 0.67 (0.50-0.91) 0.0091
Probable + Definite 118 (2.1) 158 (2.8) 0.75 (0.59-0.95) 0.0167
Possible + Probable + Definite 155 (2.8) 202 (3.6) 0.77 (0.62-0.95) 0.0131
Wallentin L et al N Engl J Med 2009; 361:1045-1057
Event Ticagrelor,%
(n=2601)
Clopidogrel, %
(n=2615) p value
CV death, MI or
stroke 12.0 14.3 0.045
MI 7.2 7.8 0.555
CV death 5.5 7.2 0.019
All-cause death 6.1 8.2 0.010
Non-CV death 0.6 1.0 0.252
Stroke 2.1 1.7 0.162
PLATO Non-Invasive Management: Efficacy Outcomes
Clopidogrel better Ticagrelor better
1.0 2.0
HR (95% CI)
James S et al BMJ 2011; 342: d3527
Cardiovascular Death in TRITON and PLATO Trials
2.1
43.4
2.4
4.3
5.1
0
5
10
TRITON PLATO PLATO INVASIVE
New Drug
Clopidogrel P <001
P = .02
%
Wiovitt SD et al N Engl J Med 2007;357:2001; Wallentin L et al N Engl J
Med 2009;361:1045; Cannon CP et al Lancet 2010;375:283
PLATO: Non-CABG and CABG-Related Major Bleeding
p= 0.026
p= 0.025
NS
NS
9
K-M
est
imate
d r
ate
(%
per
yea
r)
Non-CABG
PLATO major
bleeding
8
7
6
5
4
3
2
1
0 Non-CABG
TIMI major
bleeding
CABG
PLATO major
bleeding
CABG
TIMI major
bleeding
4.5
3.8
2.8
2.2
7.4
7.9
5.3
5.8
Ticagrelor
Clopidogrel
Cannon CP et al Lancet 2010; 375: 283-93
Ticagrelor should be discontinued 5 days
(7 days in some countries) prior to surgery
Dual Anti-platelet Therapy in ACS:
Who is the best “ASA-Partner”?
Prasugrel Ticagrelor
ACS-Strategy for Treatment Invasive Invasive or conservative
Conservative Treatment 0% 28%
STEMI percentage 26% 38%
Strategy for Revascularization PCI PCI or CABG
PCI 99% 62%
Coronary Artery Bypass Surgery 1%
10% of total population
rep 14% of Invasive
Comparison of the New P2Y12 Inhibitors Pivotal Trials
Comparison of the New P2Y12 Inhibitors Pivotal Trials: All Patients Total Mortality
Prasugrel Clopidogrel
3.0 %
(Not significant)
3.2%
Ticagrelor Clopidogrel
4.5%
(significant)
5.9%
Risk Reduction by the
new drug
as compared to Clopidogrel
Risk Increase by the
new drug
as compared to Clopidogrel
1.0 1.5 0.5
Comparison of the New P2Y12 Inhibitors Pivotal Trials:
Total Mortality in Patients with Conservative Strategy
Prasugrel Clopidogrel
---- ----
Ticagrelor Clopidogrel
6.1%
(significant)
8.2%
Risk Reduction by the
new drug
as compared to Clopidogrel
Risk Increase by the
new drug
as compared to Clopidogrel
1.0 1.5 0.5
In TRITON no
conservative strategy!
In PLATO:
n = 5216 = 28%
Comparison of the New P2Y12 Inhibitors Pivotal Trials:
TIMI Major Bleeding Not Related to CABG
Prasugrel Clopidogrel
2.4 %
(significant)
1.8%
Ticagrelor Clopidogrel
2.8 %
(significant)
2.2%
Risk Reduction by the
new drug
as compared to Clopidogrel
Risk Increase by the
new drug
as compared to Clopidogrel
1.0 1.5 0.5
Comparison of the New P2Y12 Inhibitors Pivotal Trials: STEMI Primary Combined Endpoint
Prasugrel Clopidogrel
6.5 %
(significant)
9.5%
Ticagrelor Clopidogrel
9.4%
(p=0.07)
10.8%
Risk Reduction by the
new drug
as compared to Clopidogrel
Risk Increase by the
new drug
as compared to Clopidogrel
1.0 1.5 0.5
Contraindications and Warnings!
Prasugrel Ticagrelor
Increased Risk of Bleeding ! !
Contraindications (Brain) s/p stroke/ TIA s/p cerebral bleeding
Contraindications (Liver) Severe liver dysfunction Moderate or severe liver
dysfunction
Contraindications (Metabolism) None Simultaneous administration
of strong CYP3A4 inhibitors,
eg clarithromycin,
ketoconazole
Warnings Dose adjustment in pts
<60 kg / ≥75 years
Bradycardia / AV
block/dyspnoea / asthma /
COPD
What Does Guidelines Say?
What Should I Do?
Optimal Window (‘Sweet Spot’) of Platelet Inhibition
for PCI or CABG
Montalescot G et al J Am Coll Cardiol 2010; 56: 2003-2005
Eur Heart Journal 2011; 32: 2999-3054
Eur Heart Journal 2011; 32: 2999-3054
Conclusions
• Indications may differ for each of the potent P2Y12 inhibitors in terms of
patient selection, pretreatment with thienopyridines and timing of therapy;
reflecting differences in the patient populations that were studied
and the dissimilar safety profiles that emerged from these trials
• The clinical availability of potent inhibitors of P2Y12 platelet receptors
has changed the acute coronary syndrome (ACS) treatment paradigm
• Recent NSTE-ACS guidelines of the (ESC) have recommended
ticagrelor and prasugrel in preference to clopidogrel for ACS patients
at moderate to high risk of ischemic events based on large randomised
clinical trials demonstrating superior efficacy of these more potent
agents versus clopidogrel
Prasugrel for STEMI. Ticagrelol for NSTEMI.
• Mortality was reduced with ticagrelor in PLATO trial which provide a
unique advantage not seen with any other oral antiplatelet agents
Clinical trials and evidence-based medicine provide
answers for ‘average’ patient
In real life, however, there are no average patients
Thank You