Evidence Based Medicine: Role of Antiplatelet In Reducing ...vnha.org.vn/upload/hoinghi/A1_8_2. Antiplatelet... · pathway in platelets, blocking formation of thromboxane A 2, and

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


• 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


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 (%)


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


Active Thiol Metabolite

P2Y12 Receptor Genetic Polymorphism


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)


• 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


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


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.


• 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


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


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


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


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


1.0 1.5 0.5

Comparison of the New P2Y12 Inhibitors Pivotal Trials:

Total Mortality in Patients with Conservative Strategy


---- ----


6.1%

(significant)

8.2%


new drug



new drug


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


2.4 %

(significant)

1.8%


2.8 %

(significant)

2.2%


new drug



new drug


1.0 1.5 0.5

Comparison of the New P2Y12 Inhibitors Pivotal Trials: STEMI Primary Combined Endpoint


6.5 %

(significant)

9.5%


9.4%

(p=0.07)

10.8%


new drug



new drug


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



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

Evidence Based Medicine: Role of Antiplatelet In Reducing ...vnha.org.vn/upload/hoinghi/A1_8_2. Antiplatelet... · pathway in platelets, blocking formation of thromboxane A 2, and

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