Antiplatelet Therapy

Briain Mac Neill

Galway University Hospital & National University of Ireland Galway

Milestones in ACS Management

Anti-Thrombin Rx

Anti-Platelet Rx

Treatment Strategy

Heparin

Aspirin

Conservative

LMWH

Ticaglelor

Early invasive

Bleeding risk

Ischemic risk

Bivalirudin

Prasugrel Cangrelor Clopidogrel

2020 2010 2000 1990

GP!!b!!!a Inhib

Interventional Techniques

POBA Stenting (5%)

Stenting (85%) DES 4th Generation DES Radial

IVUS OCT

Impact of Pharmacoinvasive Therapy in PCI and ACS

Reduction of death+MI in high-risk patients

Increased mortality

Benefit Risk

Bleeding

Minimizing infarct size Clinical Stabilization

Prevention of early (re)infarction Protection of microcirculation

ACS is a “Platelet-Centric Disease”

Shear Stress, PCI Plaque Rupture

Platelet Platelet

ADP

TxA2

Granule Secretion

Membrane PL’s

Platelet Aggregation

Microaggregates

Myocardial Infarction

GPIIb/IIIa Activation

X

X X

Initial Activation

Sustained Activation

P-selectin CD-40L

PLT-WBC Aggregation/

Microparticles

Inflammation

Cytokine Release

Growth Factor

Release

Restenosis

Stent Thrombosis

Procoagulant State

Hypercoagulability

Thrombin

TF

Aspirin

Clopidogrel

GP IIb/IIIa Inhibitor

TF

Thrombosis RIsk Progression (TRIP) Study Relation Between Platelet Physiology, Inflammation and Disease Activity

Inflammation

CRP

(ug/

mL)

p=.006

p=0.2

0 5

10 15 20 25

AS SA UA

Inte

rleuk

in-8

(pg

/mL)

0

4

8

12

16

AS SA UA

P<.001 p=.11

Plat

elet-F

ibrin

60 63 66 69 72

AS SA UA

Clot

-Stre

ngth

(mm

)

P=.002

P=.053

AS SA UA 0

1.5

3

4.5

6

Fibr

inog

en (

mg/

mL)

P=.15 P=.22

Prothrombotic State Reactive Platelets

0

14

28

42

56

AS SA UA

GPIIb

/IIIa-

Un

stim

ulat

ed (M

FI)

p=.051

P<.001

0 60

120 180 240 300

AS SA UA

GPIIb

/IIIa-

AD

P-St

imul

ated

(MFI

)

P=.14 P=.002

AS = Asymptomatic Patients, SA= Stable Angina, UA= Unstable Angina

A distinct pathophysiological state of heightened platelet reactivity to ADP, platelet activation, hypercoagulability, and inflammation marks the development of symptomatic cardiovascular disease from

chronic stable disease

Inflammation

? ? Prothrombotic State (Hypercoagulability)

Unstable Coronary Artery Disease

Reactive Platelets

Gurbel PA et al. J Am Coll Cardiol. 2007;49:196A.

Aspirin Effect: COX-1 Inhibition

ADP, Collagen, Thrombin

Arachidonic Acid

TxA2

Tx A2 Receptor

Aspirin

Receptor

COX-1

Membrane Phospholipids

Platelet Activation

Gurbel PA et al. J Am Coll Cardiol. 2007;50:1822-1834.

Non-COX-1 Pathway

10.1

5.0*

Placebo

ASA

0

4

8

12

Patie

nts

(%)

11.9

3.3*

Placebo ASA 0

5

10

15 12.9

6.2*

Placebo ASA 0

5

10

15

Lewis HD Jr: NEJM 1983 309:396-403

Theroux P: NEJM 1988

319:1105-1111

Cairns JA: NEJM 1985

313:1369-1375

17.1

6.5*

Placebo ASA 0

5

10

15

20

The RISC Group: Lancet 1990 336:827-830

Death or MI *p = .0005 *p = .012 *p = .008 * p<.0001

ASA in UA/NSTEMI

Platelet Inhibition With GPIIb/IIIa Inhibitors

GPIIb/IIIa Antagonists in PCI

Risk Ratio & 95% CI EPIC IMPACT-II EPILOG CAPTURE

Trial 9.6% 8.5% 9.1% 9.0% 6.3% RESTORE

Placebo IIb/IIIa6.6% 7.0% 4.0% 4.8% 5.1%

2,099

4,010

2,792

1,265

2,141

N

10.2% EPISTENT 5.2% 2,399

Placebo Better

IIb/IIIa Antag Better

0.62 (0.55, 0.71) p < 0.000000001 8.8% Pooled 5.6% 16,770

0 0.5 1 1.5 2

ESPRIT 2,064 10.2% 6.3%

30 Day Death / MI

12

4.6

10.5

5

14.7

7.3 74.6

10.5

4.5

0

10

20

30

Rapport ISAR 2 Admiral Cadillac ACE

No AbciximabAbciximab

%

GP IIb/IIIa in Acute MI

Abciximab PCI in Acute MI Trials 30 Day Endpoint (D, Re-MI, Urg TVR)

p=0.023

p<0.05 p=0.005

PTCA N = 483

Stent N = 401

Stent N = 301

PTCA or Stent N = 2082

Stent N = 400

p=0.038

p=0.01

P2Y12 – A Pivotal Platelet Receptor

Gurbel PA et al. Rev Cardiovasc Med. 2006;7:S20-S28.

Shear

GPIIb/IIIa Activation Platelet Aggregation

Inflammation

ADP

TxA2 Membrane

Phospholipids

Granule Secretion

Sustained Activation

Collagen

Thrombin

P2Y12 Receptor Activation ADP

Procoagulant Surface Coagulation

Clopidogrel Prasugrel

Tricagrelor Cangrelor PRT128

X

TxA2 Amplification

Amplification

CURE Primary End Point: MI/Stroke/CV Death

Months of Follow-up

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

Cum

ulat

ive

Haz

ard

Rat

e

* In addition to other standard therapies

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

Clopidogrel Across Spectrum of CAD

COMMIT†

(CCS-2)

CAPRIE§

Lancet 1996

MI/Stroke/PAD High-Risk Vascular Disease

STEMI

Acute STEMI Long-term 2o (1º) prevention UA/NSTEMI

PCI UA/NSTEMI

+ Benefit + Benefit

1 Year 1 Year + Benefit

1-3 Years 30 Days + Benefit

CLARITY* CURE† CREDO† CHARISMA†

*Clopidogrel vs. placebo. †Clopidogrel + ASA. §Clopidogrel vs. ASA.

CLARITY $ 20%CV death/MI/ re-isch COMMIT !9%death/MI/stroke

$ 18.4%CV death/MI/

stroke

$ 26.9% death/MI/

stroke

$ 8.7% risk reduction death/MI/

stroke

$ 7%CV death/MI/

stroke

PCI

Up to 3.5 years Benefit in symptomatic

patients only

GP IIb/IIIa receptor expression

P2Y12 receptor (irreversible inhibition)

Active metabolite

Hepatic metabolism Cytochrome P450 pathway

Intestinal absorption Variable absorption

Drug-drug interactions

Genetic polymorphisms CYP enzymes

Drug-drug interactions

Genetic polymorphisms P2Y12 receptor

Alternate pathways of platelet activation

↑ release of circulating ADP

Higher baseline platelet reactivity

Genetic polymorphisms

Poor compliance

Inadequate administration

Potential Sites for Response Variability

O’Donoghue M and Wiviott SD Circulation 2007

Clopidogrel Response Variability: Change the Agent?

Prasugrel

Pro-drug

Oxidation (Cytochrome

P450)

HOOC * HS

N

O

F

Active Metabolite

N

S

O

F O

Hydrolysis (Esterases)

N

S

O

C H 3

C O

F O N

S

O

Cl

O CH3 C

Clopidogrel

85% Inactive Metabolites Esterases

N

S

O

Cl

O CH3 C

O N

S

O

Cl

O CH3 C

Active Metabolite

HOOC * HS

N

O

Cl

OCH3

Herbert JM, Savi P. Sem Vasc Med. 2003;3:113-122.

Prasugrel More Effective Platelet Inhibition

Prasugrel vs Clopidogrel1 •  More potent •  More rapid in onset •  More consistent inhibition

of platelet aggregation (IPA)

•  Less frequent poor IPA response

•  More efficient generation of its active

1.  Wiviott SD et al. Am Heart J. 2006;152:627-635. 2.  Payne CD et al. Am J Cardiol. 2006;98:S8.

Time Post-dose (Day/Hour)

IPA in healthy subjects2

- 1 0

0

1 0

2 0

3 0

4 0

5 0

6 0

7 0

8 0

9 0

1 0 0

1 / . 2 5 1 / . 5 1 / 1 1 / 2 1 / 4 1 / 6 2 / 0 3 / 0 4 / 0 5 / 0 6 / 0 7 / 0 8 / 0 9 / 0

Pras 60/10 Clop 600/75 Clop 300/75 In

hibi

tion

of P

latele

t Agg

rega

tion

(%)

TRITON-TIMI-38 Primary Endpoint- CV Death, MI, Stroke

Prim

ary E

ndpo

int (

%)

0

5

10

15

0 30 60 90 180 270 360 450

HR 0.81 p=0.0004

Prasugrel

Clopidogrel

HR 0.80 P=0.0003

HR 0.77 P=0.0001

Days

12.1 %

9.9 % ~ 10% Recurrent Ischemic Events

- What is the Reason for Treatment Failure? - Ceiling effect of P2Y12 blocker? - Selected patients with high platelet reactivity? - Other unblocked pathways? e.g. Thrombin - PAR-1?

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

Bleeding Events = Prasugrel (1.4%) vs. Clopidogrel (0.9%), p=0.01

DISPERSE 2 Effect of Ticagrelor on Platelet Aggregation in ACS

Storey et al. J Am Coll Cardiol. 2007;50:1852.

PLATO study design

Primary endpoint: CV death + MI + Stroke Primary safety endpint: Total major bleeding

6–12-month exposure

ClopidogrelIf pre-treated, no additional loading dose;if naive, standard 300 mg loading dose,then 75 mg qd maintenance;(additional 300 mg allowed pre PCI)

Ticagrelor180 mg loading dose, then90 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

K-M estimate of time to first primary efficacy event

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 C

umul

ativ

e in

cide

nce

(%) 9.8

11.7

8,219

HR 0.84 (95% CI 0.77–0.92), p=0.0003

Clopidogrel

Ticagrelor

K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval

Change the Route of Administration

Cangrelor •  ATP derivative that is a selective

and reversible PGY12 inhibitor •  Administered intravenously •  Dose-dependent platelet inhibition •  At high dose achieves nearly 100%

of ADP-induced platelet aggregation

N N

N N

N H

S

C F 3

O H O H

O

O P O

O P

P

O O

O Cl Cl

O O

O

S

4Na +

Increased affinity

Increased stability

Adapted from: O’Donoghue M, Wiviott SD. Circulation. 2006;114:e600-e606.

CHAMPION Trials Study Designs

1 2 hours 0

PCI ~30’

Cangrelor bolus then infusion Clopidogrel 600 mg oral

CHAMPION PHOENIX n=10,942 mITT SA / NSTE-ACS / STEMI P2Y12 naïve Placebo or clopidogrel before or after PCI

CHAMPION PCI n=8667 mITT SA / NSTE-ACS / STEMI Placebo or clopidogrel before PCI

CHAMPION PLATFORM n=5301 mITT SA / NSTE-ACS P2Y12 naïve Placebo or clopidogrel after PCI

Cangrelor bolus then infusion

Cangrelor bolus then infusion

Clopidogrel 600 mg oral

Clopidogrel 600 mg oral

Clopidogrel 600 mg oral

Clopidogrel 600 mg or 300 mg oral

Clopidogrel 600 mg oral

OR

Randomised, Double Blind, Controlled Trials of patients undergoing PCI

Death / MI / IDR / ST OR (95% CI) p value p for

interaction PLATFORM 0.72 (0.53, 0.97) 0.0330 PCI 0.90 (0.72, 1.14) 0.3859 PHOENIX 0.79 (0.67, 0.93) 0.0055 Pooled 0.81 (0.71, 0.91) 0.0007 0.4537

ST PLATFORM 0.31 (0.11, 0.85) 0.0157 PCI 0.73 (0.33, 1.59) 0.4242 PHOENIX 0.62 (0.43, 0.90) 0.0101 Pooled 0.59 (0.43, 0.80) 0.0008 0.3716

Death / MI / IDR PLATFORM 0.72 (0.53, 0.97) 0.0330 PCI 0.90 (0.72, 1.14) 0.3859 PHOENIX 0.80 (0.67, 0.95) 0.0115 Pooled 0.81 (0.71, 0.92) 0.0014 0.4681

Death / QMI / IDR PLATFORM 0.55 (0.33, 0.93) 0.0224 PCI 0.66 (0.42, 1.05) 0.0779 PHOENIX 0.76 (0.53, 1.11) 0.1558 Pooled 0.68 (0.52, 0.87) 0.0022 0.6093

Summary of Clinical Efficacy: Pooled Analysis

Comparator betterCangrelor better

Steg GS, Bhatt DL, Hamm CW et al…. Harrington RA. Lancet 2013 at www.thelancet.com

•  Vorapaxar / Atopaxar: §  First-in-class §  Oral PAR-1 inhibitor

•  Metabolism: §  Primarily hepatic

via CYP 3A4 §  Terminal half-life:

~126–269 hrs •  Prior trials:

§  No increase in bleeding and fewer MIs

Protease-activated receptor-1 (PAR-1) antagonists

Chackalamannil S, J Med Chem, 2006

Platelet

PAR-4

TBX A2TBXA2-R

Thrombin

Anionicphospholipidsurfaces

GP IIb/IIIa

ADP P2Y12

PAR-1

Clopidogrel Prasugrel Ticagrelor Cangrelor

ASA

VorapaxarAtopaxar

Trial Design

1:1 Randomized Double-blind

NSTE Acute Coronary Syndromes

Vorapaxar Loading: 40 mg

Maintenance: 2.5 mg daily

Placebo

Follow-up: 1, 4, 8, 12 months, then every 6 months Standard of care based on practice guidelines

Key inclusion criteria•  Within 24 hrs of symptoms•  ábiomarkers or ECG changes•  1 other high-risk feature

Efficacy Endpoints Primary: CV death, MI, stroke, hospitalization for ischemia, urgent revascularization Key Secondary: CV death, MI, stroke Bleeding Endpoints: GUSTO moderate or severe and clinically significant TIMI bleeding

0%

5%

10%

15%

20%

0 1 4 8 12 18 24

Even

t Rat

e

Months from Randomization

Placebo

Vorapaxar

Primary Endpoint CV Death, MI, Stroke, Hospitalization for Ischemia, Urgent Revascularization

No. at risk Placebo 6471 5844 5468 5121 3794 2291 795 Vorapaxar 6473 5897 5570 5199 3881 2318 832

HR (95% CI): 0.92 (0.85, 1.01)P-value= 0.072

Placebo Vorapaxar 2-year KM rate 19.9% 18.5%

Future Developments – New Targets

Future Developments – Individualised Targets

Impact of Pharmacoinvasive Therapy in PCI and ACS

Reduction of death+MI in high-risk patients

Increased mortality?

Benefit Risk

Bleeding

Minimizing infarct size Clinical Stabilization

Prevention of early (re)infarction Protection of microcirculation

Ischemic vs Bleeding Risk in ACS

Aggressiveness of Antithrombotic Therapy

Antiplatelet Therapy

Briain Mac Neill

Galway University Hospital & National University of Ireland Galway

~30% 75mg/day for 30days

Post-PCI

~30%-40% 300 mg load

Post-PCI

~1.4x 150mg/d vs. 75mg/d for 30days Post-PCI3

Inhibition of Platelet Aggregation (Wide Response Variability)1

Mechanism of Clopidogrel Response Variability

Clopidogrel Bisulfate

Intestinal Absorption

Inactive Carboxylic Acid Metabolite

CYP3A4 CYP3A5 CYP2C19

Active Thiol Metabolite

P2Y12 Receptor

Limited absorption capacity with ceiling effect at 600mg loading dose

Hepatic P450 Cytochromes

lipophilic statins

Genetic polymorphisms Genetic polymorphisms

Multistep Conversion

15%

Esterases

85%

1. Gurbel PA et al. Thromb Res. 2007;120:311-21. 2. Taubert et al. Clin Pharmacol. 2006;80:486-501. 3. von Beckerth et al. Eur Heart J.2007;28:1814-9.

P-glycoprotein (MDR1 3435T genotype)2

?

Smoking, proton pump inhibitors CYP1A2 CYP2B6, 2C19

Mortality

Major Bleeding

Transfusion Hypotension Cessation of ASA/Clopidogrel

Ischemia Stent Thrombosis Inflammation

Bhatt DL et al. In Braunwald: Harrison’s Online 2005.

Potential Relationship Between Bleeding and Mortality

Milestones in ACS Management Anti-Thrombin Rx

Anti-Platelet Rx

Treatment Strategy

Heparin

Aspirin

Conservative

LMWH

ESSENCE

Ticaglelor

REPLACE 2

OASIS-5

[ Fondaparinux ]

GP IIb/IIIa

PRISM-PLUS

PURSUIT CURE

Clopidogrel

TACTICS TIMI-18

Early invasive

ICTUS

ISAR-REACT 2

ACUITY SYNERGY

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

PCI ~ 5% stents ~85% stents Drug-eluting stents

Bleeding risk

Ischemic risk

2007 2008

Bivalirudin

Prasugrel Cangrelor Clopidogrel