New p2y12 blockers is the best anti platelet agent for patients undergoing PCI

14th Vietnam National Congress of Cardiology
Da Nang City Vietnam 2014

Great Debates on Antiplatelet and Anticoagualant Therapies

New P2Y12 Blockers is the Best Anti-platelet agent
for Patients Undergoing PCI

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
President, Asia Pacific Society of Interventional Cardioloogy


Debate At Medical Meetings

Humorous discussion for
the entertainment
of the audience with
little or no significant
scientific content


Do Not Be Misled!!

Do Not Turn blind eye to Current Evidence!


Proper Interpretation of Trial Evidence

Milestones in ACS Management
Anti-thrombin Rx
Heparin

LMWH

Bivalirudin

Fondaparinux

Antiplatelet Rx
GP IIb/IIIa
blockers

Aspirin

Clopidogrel

Treatment Strategy
Conservative

Prasugrel

Early invasive
PRISM-PLUS
PURSUIT

ESSENCE

PLATO

REPLACE 2
CURE

HORIZON MI
QASIS-5

SYNERGY

TACTICS TIMI-18

Ticagrelor

TRITON

ACUITY

1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2010

PCI
Ischemic Risk
Bleeding Risk

 5% Stents

 85% Stents

Drug-Eluting Stents

2nd Gen DES


Dual Antiplatelet Therapy is a Cornerstone of ACS Treatment
•

Dual antiplatelet therapy with ASA and P2Y12 inhibition has been shown
to be effective for secondary prevention in ACS patients

•

Clopidogrel has been core of post-ACS treatment
– CURE: NSTE-ACS (n=12,562)
• Clopidogrel vs Placebo; on top of ASA
• 1 year follow-up
• 20% RRR (2.1% ARR) in CV death/MI/stroke
– COMMIT: STEMI (n=45,852)
• Clopidogrel vs Placebo; on top of ASA
• 1 month follow-up
• 9% RRR (0.9% ARR) in CV death/MI/stroke

CURE Investigators. N Engl J Med 2001; 345: 494-502
COMMIT Investigators. Lancet 2005; 366: 1607-21


Current Dual Antiplatelet Regimen

Why Not Clopidogrel?


Variability in Clopidogrel Response
Change in ADP-Induced platelet
aggregation 75 mg chronic dosing

N=544

Maximal aggregation 5µmol/L ADP (%)
following 600 mg loading dose

100

80

N=1001

60

40

20

0
0

2

4

6

8

Time from loading dose to cath (h)
Red dot: nonresponder

Serebruany et al J Am Coll Cardiol 2005; 45:246
Hochholzer W et al Circulation 2005

10


Metabolism of P2Y12 Inhibitors

Albert Schömig et al NEJM 2009


Clopidogrel Resistance Among Asians:
Prevalence of CYP2C19 Polymorphisms in 300 Asian Subjects
70
•
•
•

60

Within-group P <0.05
Loss-of-function – 1 or more *2/*3 Alleles

Gain-of-function – 1 or more *17 alleles

Prevalence, %

50

40

Chinese

30

Malay

20

Indian

10
0
Non-carriers

Loss-of-function carriers

Gain-of-function carriers

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

Mark Y Chan et al Pharmacogenomics 2012; 13: 533-542


70

Clopidogrel Pharmacogenetic Differences
Among 3 Major Asian Ethnicities

60

Percentage (%)

50
40

PM
NM

30

RM
20
10

0
Chinese (n = 100)

Malay (n = 100)

CYP2C19 Poor Metabolisers
CYP2C19 Normal Metabolisers
CYP2C19 Rapid Metaboliser

Indians (n = 100)

CYP2C19 *2 or *3
CYP2C19 WT or combination *2/*3 and *17
CYP2C19 *17

Mark Y Chan et al Pharmacogenomics 2012; 13: 533-542


CYP2C19 and Clopidogrel Response

RM= rapid metaboliser
NM= normal metaboliser
PM= poor metaboliser

CYP2C19 only accounts for 17% of variability in
on-clopidogrel platelet reactivity

Mark Y Chan et al Pharmacogenomics 2012; 13: 533-542


% Inhibition of Platelet Aggregation During PCI
n = 48
60

Optimal

Clopidogrel 300 mg
40.9(26.2)

40

%

Sub-Optimal
25.6(22.3)

20

7.8(11.3)

Median (SD) %

0
10 min
Post-PCI

4 hrs post-PCI

24 hrs post-PCI

ACS
Diabetes
Overweight
Diffuse CAD

Bad genes

UFH 100 UI/kg
baseline
(ASA 200 mg/d)
Angiolillo DJ et al Thromb Res 2005; 115: 101-8


New P2Y12 Receptor Antiplatelet Agents

• Prasugrel
• Ticagrelor


Prasugrel vs Clopidogrel: More Effective Platelet P2Y12 Inhibition
IPA in Healthy Subjects

• More rapid

• More potent
• More consistent platelet
inhibition

• Less frequent “resistance”
• More efficient generation of
its active metabolite

Inhibition of Platelet Aggregation (%)

100

90
80
70
60
50
40
30

Pras 60/10

20

Clop 600/75
Clop 300/75

10
0
-10
1/.25 1/.5 1/1 1/2 1/4 1/6

2/0 3/0 4/0

5/0 6/0 7/0

Time Post-dose (Day/Hour)

1. Wiviott SD et al Am Heart J 2006; 152-627
2. Payne CD et al Am J Cardiol. 2006; 98: S8

8/0 9/0


TRITON TIMI 38 Main Trial Design
ACS (STEMI or UA/NSTEMI) and planned PCI

n = 13,608

ASA
Double-blind

Clopidogrel
300 mg LD/ 75 mg MD

Prasugrel
60 mg LD/ 10 mg MD

Duration of therapy: 6–15 months
1o endpoint:
CV death, MI, stroke
2o endpoint:
Stent thrombosis
Safety endpoints: TIMI major bleeds, life-threatening bleeds
Reprinted with permission from: Wiviott SD, Antman EM, Gibson CM, et al. Evaluation of prasugrel compared with clopidogrel in patients with acute coronary syndromes: design and rationale for the TRial to
assess Improvement in Therapeutic Outcomes by optimizing platelet InhibitioN with prasugrel Thrombolysis In Myocardial Infarction 38 (TRITON-TIMI 38).
Am Heart J. 2006 Oct;152(4):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)
Clopidogrel

Prasugrel
ICH in patients with
prior stroke/TIA
(n = 518)

Events (%)

4

Clopidogrel 0 (0%)
Prasugrel 6 (2.3%)
(P = 0.02)

2.4

2

1.8
1.4
0.9

1.1
0.9
0.4

0.1

0.3

0.3

0
TIMI major
bleeds

Lifethreatening

Non-fatal

Fatal

ICH

ARD 0.6%
HR 1.32
P = 0.03
NNH = 167

ARD 0.5%
HR 1.52
P = 0.01

ARD 0.2%
P = 0.23

ARD 0.3%
P = 0.002

ARD 0%
P = 0.74

Wiviott SD et al N Engl J Med 2007; 357: 2001--15


HO

N
N

N
H
N

HO
O

N

F

N

Ticagrelor

F

S
OH

•

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


Onset/Offset: Inhibition of Platelet Aggregation

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


PLATO Study Design
NSTE-ACS (moderate-to-high risk) STEMI (if primary PCI)
Clopidogrel-treated or -naive;
randomised within 24 hours of index event
(N=18,624)

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)

6–12-month exposure

Primary endpoint: CV death + MI + Stroke
Primary safety endpint: Total major bleeding
PCI = percutaneous coronary intervention; ASA = acetylsalicylic acid;
CV = cardiovascular; TIA = transient ischaemic attack

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)

Ticagrelor (n = 6732)

Clopidogrel (n = 6676)

Planned Non-invasive (n = 5216)

Ticagrelor (n = 2601)

Clopidogrel (n = 2615)

STEMI (n = 3278)

STEMI (n = 3297)

STEMI (n = 218)

STEMI (n = 233)

NSTEMI (n = 2481)

NSTEMI (n = 1441)

NSTEMI (n = 1469)

NSTEMI (n = 2564)

Unstable angina
(n = 676)

Unstable angina
(n = 710)

Unstable angina
(n = 873)

Unstable angina
(n = 853)

Other (n = 197)

Other (n = 177)

Other (n = 62)

Other (n = 53)

Unknown (n = 17)

Unknown (n = 11)

Unknown (n = 7)

Unknown (n = 7)

James SK et al BMJ 2011; 342: 3527


PLATO: Time to First Primary Efficacy Event
(Composite of CV Death, MI or Stroke)
13
12

11.7

Clopidogrel

11
10

9.8

9
Ticagrelor

8
Cumulative incidence (%)

7
HR 0.84 (95% CI 0.77–0.92), p=0.0003

6
5

4
3
2
1
0
0

60

120

180

240

300

360

Days after randomisation

No. at risk
Ticagrelor

9,333

8,628

8,460

8,219

6,743

5,161

4,147

Clopidogrel

9,291

8,521

8,362

8,124

6,743

5,096

4,047

Wallentin L et al N Engl J Med 2009; 361:1045-1057