Michael S. Lee, MD

Associate Professor

UCLA Medical Center

Los Angeles, CA

Antiplatelet Therapy in ACS

Patients: New P2Y12

Inhibitor is Preferred

Results from cross-linking of

platelets by fibrinogen at

platelet receptors GP IIb-IIIa

at site of plaque rupture

Platelet

Fibrinogen

Ruptured plaque

GP IIb-IIIa

NSTE ACS is generally

caused by partially occlusive,

platelet-rich thrombus

Unobstructed

lumen

Thrombus

Artery wall

Van de Werf F. Thromb Haemost. 1997;78(1):210-213; Moser M, et al. J Cardiovasc Pharmacol. 2003;41(4):

586-592; Davies MJ. Heart. 2000;83(3):361-366.

The Role of the Platelet in Non-ST

Elevation Acute Coronary Syndrome

The Role of Platelets in Atherothrombosis

Slide modified from Cannon CP, et al. Available at http://www.theheart.org/viewArticle.do?primaryKey=119759. Accessed April 20, 2005.

Activation 2

Adhesion 1 Aggregation 3

Months of Follow-up

Yusuf S et al. N Engl J Med. 2001;345:494-502.

CURE Study Primary End Point: MI/Stroke/CV Death

Clopidogrel

+ Aspirin

(n=6259)

Placebo

+ Aspirin

(n=6303)

P<0.001

n=12,562

3 6 9 0 12

20% Relative Risk Reduction

0.12

0.14

0.10

0.06

0.08

0.00

0.04

0.02 Cu

mu

lati

ve H

azar

d R

ate

IPA Responses to Clopidogrel

Δ 5µM ADP-Induced Platelet Aggregation (%)

≤ -20 [-10,0] [11,20] [31,40] [51,60] [71,80] [91,100]

Nu

mb

er o

f Pa

tien

ts

Greater antiplatelet effect may address

this group

What effect does greater platelet

inhibition have on bleeding?

Adapted from: Serebruany V et al. J Am Coll Cardiol. 2005.

Biotransformation of Clopidogrel

• Clopidogrel is a prodrug that requires

conversion to its active metabolite.1

• 2-step process mediated by CYP450s, with

CYP2C19 involved in both steps

• A substantial portion of absorbed clopidogrel

is shunted into a dead-end pathway by

esterases.2

10 1. Price MJ, J Am Coll Cardiol. 2014;64:1015-1018 2. Tang M et al, J Pharmacol Exp Ther. 2006;319:1467-76.

Hazard Ratio 1.53

(95% CI 1.07-2.19)

P=0.014

8.0

12.1

1064 1009 999 980 870 755 542

Number at Risk:

Days After Randomization

Non-Carrier

395 364 360 348 306 270 181Carrier

CV

De

ath

, M

I, o

r S

tro

ke

(%

)

0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

0 30 90 180 270 360 450

Non-carriers

CarriersCYP2C19 Reduced-Function

Allele Carriers

Non-carriers

HR 1.53 (95% CI, 1.07-2.19)

P=.014

Carriers ~30% of the population CV, cardiovascular; HR, hazard ratio; CI, confidence interval

CYP2C19 Genotype, Clinical Outcomes 1477 Patients w/ ACS and planned PCI Rx’d w/ clopidogrel

Hazard Ratio 3.09

(95% CI 1.19-8.00)

P=0.015

0.8

2.6

1014 1004 1001 989 885 765 547

375 368 366 359 316 279 186

Defi

nit

e o

r P

rob

ab

le S

ten

tT

hro

mb

os

is (

%)

0

1

2

3

4

0 30 90 180 270 360 450

Number at Risk:

Days After Randomization

Non-Carrier

Carrier

Non-carriers

Carriers

HR 3.09 (95% CI, 1.19-8.00)

P=.015

CYP2C19 Reduced-Function

Allele Carriers

Non-carriers

CV

De

ath

, MI,

or

Stro

ke (

%)

Ste

nt

Thro

mb

osi

s (%

)

CV events Stent Thrombosis

Mega JL. N Engl J Med 2009;360:354-362. Copyright © 2009 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

TRITON-TIMI 38: Prasugrel vs Clopidogrel

Primary endpoint: CV Death + MI + Stroke Primary safety endpoint: TIMI Major Bleeding (non-CABG)

6-15–month exposure

Clopidogrel Standard 300-mg loading dose,

after PCI 75-mg qd maintenance

Prasugrel 60-mg loading dose, then after PCI

10-mg qd maintenance

STEMI, NSTEMI, or unstable angina with known suitable coronary anatomy scheduled to undergo PCI

(N=13,608)

Randomization prior to PCI

Aspirin, recommended daily dose 75-162 mg qd Aspirin, recommended daily dose 75-162 mg qd

Wiviott SD et al. N Engl J Med. 2007;357:2001-2015.

Study Design

TRITON-TIMI, Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in MI

HR 0.81 (0.73-0.90)

P=.001

HR 1.32 (1.03-1.68)

P=.03

NNT=46

NNH=167

Wiviott SD et al. N Engl J Med. 2007;357:2001-2015. Copyright © 2007 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

5

10

15

0 30 60 90 180 270 360 450

Prasugrel

Clopidogrel

Days

End

po

int

(%)

12.1

9.9

Prasugrel

Clopidogrel 1.8 2.4

CV Death/MI/Stroke

TIMI Major Bleeds (non-CABG)

0

Life-threatening bleeding: 1.4% vs 0.9%; P=.01)

TRITON-TIMI 38: Prasugrel vs Clopidogrel

15

Balance of Efficacy and Safety

Balancing Efficacy and Bleeding TRITON TIMI-38: Net Clinical Benefit

TRITON TIMI-38 = Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction 38.

Wiviott SD, et al. NEJM. 2007;357:2001-2015.

p Risk (%)

Prior Stroke / TIA

Yes pint=0.006

+54

No -16

Age >=75

pint=0.18 -1

<75 -16

Weight <60 kg

pint=0.36 +3

>=60 kg -14

Overall -13

2 1 0.5 Hazard Ratio

Clopidogrel Better Prasugrel Better

Prasugrel Summary

• Third-generation oral thienopyridine1

• Oral prodrug, hydrolyzed more efficiently vs clopidogrel1 – Faster onset of action

– More potent antiplatelet effect

– Reduced variability

– Less impact of drug-drug interactions, genetic polymorphisms

• TRITON-TIMI 38: Significantly reduced rates of ischemic events, but increased risk of major (and fatal) bleeding, in patients with ACS scheduled for PCI1

• Contraindicated in patients with history of stroke or TIA2

• Consider dose reduction in patients with age >75 or weight <60 kg2

1. Capodanno D et al. J Thromb Haemost. 2013;11(suppl 1):316-329. 2. Eli Lilly and Co. Effient package insert. 2012.

21

PLATO: Ticagrelor vs Clopidogrel in ACS

Primary endpoint: CV death + MI + stroke Primary safety endpoint: total major bleeding

6-12–month exposure

Clopidogrel If pretreated, no additional loading dose; if naïve, 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 -naïve;

randomized within 24 hours of index event (N=18,624)

PLATO, Platelet Inhibition and Patient Outcomes Wallentin L et al. N Engl J Med. 2009;361(11):1045-1057.

Randomization

22

Study Design

PLATO: Ticagrelor vs Clopidogrel in ACS

*Composite of CV death, MI, or stroke

Number at risk:

Clopidogrel

Ticagrelor

9291

9333

8521

8628

8362

8460

8124

Days after Randomization

6650

6743

5096

5161

4047

4147

0 60 120 180 240 300 360

12 11 10 9 8 7 6 5 4 3 2 1 0

13 C

um

ula

tive

Inci

de

nce

(%

)

9.8%

11.7%

8219

HR 0.84 (95% CI, 0.77 – 0.92), P=.001

Clopidogrel

Ticagrelor

RR Reduction, ≈16%

Wallentin L et al. N Engl J Med. 2009;361(11):1045-1057. Copyright © 2009 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

Time to Primary Efficacy Endpoint*

PLATO: Clopidogrel vs Ticagrelor

*Percentages are K-M estimates of the rate of the endpoint at 12 mo; patients could have had >1 type of endpoint †By Cox regression analysis

Wallentin L et al. N Engl J Med. 2009;361(11):1045-1057.

ENDPOINT* Ticagrelor (n=9333)

Clopidogrel (n=9291)

Ticagrelor HR (95% CI)

P value†

Primary endpoint, %

Death from vascular causes/MI/ stroke 9.8 11.7 0.84 (0.77–0.92) <.001

Secondary endpoints, %

Death from any cause/MI/stroke 10.2 12.3 0.84 (0.77–0.92) <.001

Death vascular cause/MI/ stroke/SRI/TIA/arterial thrombotic events

14.6 16.7 0.88 (0.81–0.95) <.001

MI 5.8 6.9 0.84 (0.75–0.95) .005

Death vascular causes 4.0 5.1 0.79 (0.69–0.91) .001

Stroke 1.5 1.3 1.17 (0.91–1.52) .22

All-cause mortality 4.5 5.9 0.78 (0.69–0.89) <.001

24

Major Efficacy Endpoints at 12 Months, Total Cohort

SRI, severe recurrent ischemia

PLATO: Ticagrelor vs Clopidogrel in ACS

25 Wallentin L et al. N Engl J Med. 2009;361(11):1045-1057.

P=.66

P=.70

P=.03

P=.96

P=.57

P=.43

Major Bleeding

CV

de

ath

, MI

or

stro

ke (

%)

Days after randomization

James S et al. BMJ. 2011;342:d3527.

0

5

10

15

20

0 60 120 180 240 300 360

PLATO: Ticagrelor vs Clopidogrel in ACS

Invasive Ticagrelor 6732 6236 6134 5972 4889 3735 3048 Clopidogrel 6676 6129 6034 5881 4815 3680 2965

Non-Invasive Ticagrelor 2601 2392 2326 2247 1854 1426 1099 Clopidogrel 2615 2392 2328 2243 1835 1416 1109

Number at risk:

Non-Invasive vs Invasive Strategy

Reproduced from BMJ, James S et al, 342, d3527, © 2011 with permission from BMJ Publishing Group Ltd.

*Percentages are K-M estimates of the rate of the endpoint at 12 mo; patients could have had >1 type of endpoint

PLATO: Clopidogrel vs Ticagrelor

27

0% 2% 4% 6% 8% 10% 12% 14% 16%

Any dyspnea

Discontinuation (dyspnea)

Pacemaker placement

Syncope

Bradycardia

Heart block

Clopidogrel (n=9186) Ticagrelor (n=9235)

P=1.0

P=.21

P=.08

P=.87

P<.001

P<.001

Bra

dyc

ard

ia-r

ela

ted

ev

ents

Other Safety Endpoints*

Wallentin L et al. N Engl J Med. 2009;361(11):1045-1057.

Ticagrelor Summary

• Directly, reversibly inhibits P2Y12 receptor1 – More potent, consistent antiplatelet effect

– Requires twice-daily dosing

• In PLATO, ticagrelor resulted in improved ischemic benefit, decreased CV mortality in patients with ACS; significant increase in non-CABG bleeding, but not CABG-related bleeding.2 – High-dose ASA (≥300 mg) associated with possible harm in

combination with ticagrelor3; recommended ASA dose ≤100mg QD

– Demonstrated less efficacy in US population in PLATO; may be related to higher ASA dose in US or play of chance3

1. Capodanno D et al. J Thromb Haemost . 2013;11(suppl 1):316-329. 2. Wallentin L et al. N Engl J Med. 2009;361(11):1045-1057. 3. Mahaffey KW et al. Circulation. 2011;124:544-554. 28

CURRENT GUIDELINES FOR DUAL ANTIPLATELET THERAPY IN ACS

Guidelines for Antiplatelet Therapy in NSTEMI

Recommended LD of P2Y12 inhibitors at the time of PCI:

• Clopidogrel 600 mg (LOE: B), or

• Prasugrel* 60 mg (LOE: B) who are not at high risk of bleeding (LOE: B), or

• Ticagrelor† 180 mg (LOE: B)

Duration and maintenance dose of P2Y12 receptor inhibitors after stent placement:

• In NSTE-ACS patients: • Either clopidogrel 75 mg/d, prasugrel 10 mg/d, or ticagrelor 90 mg BID, ≥12 mo (LOE: B)

• If risk of morbidity due to bleeding outweighs anticipated benefits afforded by P2Y12 receptor inhibitor therapy, consider earlier discontinuation (LOE: C)

*Loading dose of prasugrel indicated if not pretreated with another P2Y12 receptor inhibitor; should not be used in patients with a h/o stroke or TIA †The recommended dose of aspirin to be used with ticagrelor is 81 mg/d LOE, level of evidence Amsterdam EA et al. Circulation. 2014;Epub ahead of print Sept 23. 30

2014 AHA/ACC Guideline for the Management of NSTE-ACS

Adjunctive Antiplatelet Therapy to Support Reperfusion with Primary PCI for STEMI

Aspirin:

• 162 to 325 mg given before primary PCI (LOE: B), and

• 81 mg to 325 mg maintenance dose continued indefinitely after PCI (LOE: A)

• Preferred maintenance dose is 81 mg/d (Class IIa, LOE: B)*

*The recommended dose of aspirin to be used with ticagrelor is 81 mg/d O’Gara PT et al. Circulation. 2013;127:e362-425.

2013 ACCF/AHA Guidelines

Adjunctive Antiplatelet for

Primary PCI for STEMI

P2Y12 receptor inhibitors:

• Loading dose as early as possible or at time of PCI • Clopidogrel, 600 mg

• Prasugrel, 60 mg

• Ticagrelor, 180 mg

• Maintenance therapy for 1 y (minimum 1 mo with BMS) in patients who receive a stent (DES or BMS)*

• Clopidogrel, 75 mg/d (LOE: B)

• Prasugrel, 10 mg/d (LOE: B)

• Ticagrelor, 90 mg BID (LOE: B)

• Prasugrel contraindicated in patients with history of stroke or TIA

32

2013 ACCF/AHA Guidelines

BMS, bare-metal stent; DES, drug-eluting stent

*Balloon angioplasty without stent placement may be used in selected patients. It might be reasonable to provide

P2Y12 inhibitor therapy to patients with STEMI undergoing balloon angioplasty alone per recommendations listed

for BMS .

O’Gara PT et al. Circulation. 2013;127:e362-425.

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