5/17/2016

1

Classification of Atrial Fibrillation (AF)

2

Recurrent AF*

(≥2 episodes)

Paroxysmal Persistent

Permanent

• Arrhythmia terminates spontaneously

• AF is sustained ≤7 days

• Arrhythmia does not terminate spontaneously

• AF is sustained >7 days

• Both paroxysmal and persistent AF can become permanent

*Termination with pharmacologic therapy or direct-current cardioversion does not change the designation.

Fuster V, et al. Circulation. 2006;114(7):e257-e354.

Platelet Biology

Tailored to the Acute

Coronary Syndrome

No Disclosures

Outline

1. Platelet Biology

1. Drug Therapy

• Aspirin

• Prasugrel

• Ticagrelor

• Cangrelor

• GP 2b/3a inhibitors

2. Preloading

3. Duration of DAPT

5/17/2016

2

Platelet

Thrombus Formation Involves Both Platelet

Activation and Blood Coagulation

INITIATION AMPLIFICATION PROPAGATION

Activated platelet

Fibrinogen (I)

Fibrin

Clot

X Xa

TF-VIIa

TF-VIIa

IX

IXa

Free vWF

VIII/vWF

VIIIa

Prothrombin (II)

Prothrombin

V

Va

XIa Xa Va

XIa

XI

IXa VIIIa

XIIIa

XIII Va

P-selectin

CD40L PAR1;4

Gp IIb/IIIa

P2Y12/ADP

X

TF-expressing cell/ microparticle

Xa

Xa

Thrombin (IIa)

Thrombin (IIa)

De Caterina R et al. Thromb Haemost 2013;109:569–79

No currently approved

antiplatelet agents specifically target

Adhesion

Most approved antiplatelet agents

affect different aspects of platelet

Activation

GP IIb/IIIa inhibitors inhibit the “final

common pathway,” Aggregation

Platelet-Mediated Thrombosis Targets

Meadows et al. Circulation Res. 2007;100:1261-1275

Platelet vWF Receptor (GP1b)

Intact Endothelium

Endothelial Damage

Collagen vWF

(Α2β3 Integrin) Platelet Collagen

Receptor (GPIa)

TXA2

ADP

Aspirin

ticlopidine, clopidogrel, prasugrel,

ticagrelor TXA2

Receptor

ADP (P2Y12)

Receptor

abciximab, eptifibatide,

tirofiban

GP IIb/IIIa

Receptor

GP = glycoprotein; vWF = von Willebrand factor; ADP = adenosine diphosphate; TX = thromboxane.

Desai NR, Bhatt DL. JACC CV int. 2010;3:571-83

Antiplatelet Agents

5/17/2016

3

Outline

1. Platelet Biology

1. Drug Therapy

• Aspirin

• Prasugrel

• Ticagrelor

• Cangrelor

• GP 2b/3a inhibitors

2. Preloading

3. Duration of DAPT

Platelet Inhibition by Low-Dose Aspirin

Patrono et al. JACC 2015 66(1): 74-85

Aspirin is Effective in Acute

Coronary Syndromes NSTE-ACS STEMI

Lancet 1988;2:349-60 Cairns JA et al. NEJM 1985;313:1369-76

Vascu

lar

Death

, n

35

200

300

400

500

100

ASA 461/4295 (10.7%)

SK 448/4300 (10.4%)

Placebo

568/4300 (13.2%)

SK + ASA 343/4292 (8.0%)

7 14 21 28

Days after STEMI

0

20 No aspirin

10

0

MI o

r C

ard

iac D

eath

, %

0 6

Months after NSTEMI

12 18 24

Aspirin

0

5/17/2016

4

PCI Without Aspirin

Kenaan M et al. JACC 2013:on-line

No ASA given w/i 24 hrs prior PCI in 4,640 (7.1%) of 65,175 pts. Propensity-matched in-hospital outcomes in 4,008 pt pairs:

Imbalances

↑ ASA use

• Prior PCI

↑ No ASA use

• Prior GI bleed

• STEMI

• Shock or

post arrest

• Prasugrel or

ticagrelor

Only 10.7%

contraindication

No difference in CIN between the groups (falsification endpoint)

Increase in mortality was robust in sensitivity analyses

P=0.0005

P=0.007

Death

No ASA ASA

>>favors ASA

Transfusion

Nephropathy requiring dialysis

CABG

Contrast induced nephropathy

Vascular complication

Stroke/CVA

Repeat PCI (same lesion)

Emergent CABG

0.25

Post procedural MI

<<favors no ASA

1.89 (1.32, 2.71)

1.08 (0.84, 1.39)

0.79 (0.38, 1.64)

1.52 (0.97, 2.40)

1.17 (0.89, 1.54)

0.89 (0.68, 1.17)

4.24 (1.49, 12.11)

1.13 (0.55, 2.34)

0.94 (0.26, 3.43)

1.54 (0.77, 3.05)

2.79%

5.54%

0.60%

1.00%

4.14%

4.07%

0.15%

0.47%

0.20%

0.50%

0.5 1 2 4 8

3.87%

5.71%

0.47%

1.65%

4.37%

3.47%

0.52%

0.50%

0.20%

0.70%

Incidence

Antithrombotic Trialists’ Collaboration. Lancet 2009;373:1849–60

Aspirin in primary and secondary prevention

Aspirin better Aspirin Worse

0.5 0.75 1.0 1.25 1.5 99% CI 95% CI

p<0.00001 0.81 (0.75-0.87) 1801 (8.19) 1505 (6.69) Total

Serious vascular event* (X2 1=0.0; p=1.0)

p=0.04 0.78 (0.61-0.99) 176 (0.77) 140 (0.61) Total

Ischemic stroke (X2 1=0.7; p=0.4)

p<0.00001 0.80 (0.73-0.88) 1214 (5.30) 995 (4.30) Total

Events per year

Major coronary event (X2 1=0.6; p=0.4)

0.81 (0.64-1.02) 314 (7.14) 250 (5.88) Female

0.81 (0.73-0.90) 1487 (8.45) 1255 (6.88) Male

0.73 (0.50-1.06) 123 (0.67) 95 (0.51) Male

0.91 (0.52-1.57) 53 (1.17) 45 (1.04) Female

0.81 (0.72-0.92) 1057 (5.79) 880 (4.70) Male

0.73 (0.51-1.03) 157 (3.36) 115 (2.59) Female

Aspirin Control RR (CI)

Meta-analyses of 16 secondary prevention trials (n=17,000)

Efficacy of Aspirin at Various Doses in Reducing

Vascular Events (Death from Vascular Causes, MI,

or Stroke) in High-risk Patients

Antithrombotic Trialists’ Collaboration, BMJ, 2002;342:71-86.

Aspirin

(mg daily)

No. of

Trials

% Odds

Reduction

Odds Ratio

500-1500

160-325

75-150

<75

Any aspirin

34

19

12

3

65

19

26

32

13

23

Treatment effect

P<0.0001

Aspirin better

0 0.5 1.0 1.5 2.0

Aspirin worse

5/17/2016

5

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

ASA Dose Placebo

+ ASA

Clopidogrel

+ ASA

<100 mg 2.0% 2.6%

100 – 200 mg 2.3% 3.5%

>200 mg 4.0% 4.9%

CURE:

Major Bleeding by ASA Dose

The therapeutic target for

thienopyridines and CPTPs is the

platelet P2Y12 receptor

Ticagrelor Prasugrel

Esterification and

2-step oxidation to

active metabolite

1-step oxidation to active metabolite

Active metabolite

P2Y12 Receptor Antagonists

Agent Class

IPA (20 uM ADP)

mean

Time to peak

onset

Reversibility (d/c before

CABG)

Ticlopidine 250 mg bid thienopyridine

(pro-drug) 25% 48 hrs

non reversible

5 days

Clopidogrel 300 mg LD Clopidogrel 600 mg LD

Clopidogrel 75 mg qd

Clopidogrel 150 mg qd

thienopyridine(pro-drug)

30% - 40% 35% - 50%

30% - 35%

45% - 50%

12 hrs 6 hrs

-

-

non reversible 5 days

Prasugrel 60 mg LD* Prasugrel 10 mg qd*

Prasugrel 5 mg qd*

thienopyridine(pro-drug)

80% 60%

40%

1-2 hrs -

-

non reversible 7 days

Ticagrelor 180 mg LD*

Ticagrelor 90 mg bid*

cyclo-pentyl-triazolo-

pyrimidine*

80%

70%

1-2 hrs

-

reversible

2-5 days

*Less affected by genetic polymorphisms and drug interactions (e.g. PPIs)

**not a pro-drug

5/17/2016

6

CURE Trial Investigators. N Engl J Med 2001;345:494–502.

Months

0.00

0.02

0.04

0.06

0.08

0.10

0.12

0.14

CV

Death

, M

I o

r str

oke

3 6 9 0 12

Placebo + Aspirin*

(n = 6303)

11.4%

Clopidogrel + Aspirin*

(n = 6259)

9.3%

P<0.001

20%↓

* In combination with standard therapy

CURE 12,562 pts with NSTE-ACS were treated with aspirin and randomized

to clopidogrel vs. placebo and followed for up to 12 months

Primary endpoint = CV Death, MI, or Stroke

PCI was performed

in 2658 pts (21%): 1 Yr CV Death or MI

A=median time to PCI; B=open label clopidogrel for 30 d after PCI

0.0

0.05

0.10

0.15

0 40 100 200 300 400 10

A B Days following PCI

CV

Death

or

MI

P=0.002 Clopidogrel

Placebo 12.6%

8.8%

31% Relative Risk

Reduction

10 days

Mehta SR et al. Lancet 2001;21:2033–41

CURE 12,562 pts with ACS were treated with aspirin and randomized to

clopidogrel vs. placebo and followed for up to 12 months

ASA + Clopidogrel ASA + Placebo P

CV death, MI, stroke 9.3% 11.4% <0.001

CV death, MI, stroke, refractory ischemia

16.5% 18.8% <0.001

- CV death 5.1% 5.5% NS

- MI 5.2% 6.7% <0.05

- Stroke 1.2% 1.4% NS

- Refractory ischemia 8.7% 9.3% NS

Non CV death 0.7% 0.7% NS

Bleeding events, any 8.5% 5.0% <0.001

- Major 3.7% 2.7% 0.001

- Minor 5.1% 2.4% <0.001

Primary endpoint = CV Death, MI, or Stroke

CURE Trial Investigators. N Engl J Med 2001;345:494–502

5/17/2016

7

Variability in Clopidogrel Response

Serebruany V et al. JACC 2005;45:246-51

Hochholzer W et al. Circ 20051;11:2560-4

0

20

40

60

80

100

120

-20 0 20 40 60 80 100

Nu

mb

er

of

Pati

en

ts

Change in 5 µmol/L ADP-induced

platelet aggregation with

75 mg chronic dosing

N=544

100

0 2 4 6 8 10 0

20

40

60

80

Time from loading dose to cath (h)

Maximal aggregation to

5 µmol/L ADP (%) after

600 mg loading dose

N=1001

Max A

gg

reg

ati

on

(%

)

Hypo

responders

Hyper

responders

ADAPT-DES: Stent thrombosis (definite or

probable) according to post-PCI PRU

HR [95%CI] = 2.54 [1.55, 4.16]

P=0.0001

PRU >208 (n=3610) PRU ≤208 (n=4839)

Ste

nt

thro

mb

osis

(def/p

rob

) (%

)

0

1

2

Months 0 3 6 9 12

3610 3450 3420 3380 3152

4839 4688 4654 4631 4341

Number at risk:

PRU > 208

PRU ≤ 208

1.3%

0.5%

Stone GW et al. Lancet 2013:on-line

Mechanisms of Individual Variability

in Clopidogrel Responsiveness

Angiolillio DJ et al. JACC 2007;49:1505-1516

Cellular Factors

• Accelerated platelet turnover

• Reduced CYP3A metabolic activity

• Increased ADP exposure

• Up-regulation of the P2Y12 pathway

• Up-regulation of the P2Y1 pathway

• Up-regulation of the P2Y–independent pathways (collagen, epinephrine, thomboxane A2, thrombin)

Clinical Factors • Failure to prescribe/poor compliance

• Under-dosing

• Poor absorption

• Drug-drug interactions involving CYP3A4 (?PPIs)

• Acute coronary syndrome

• Diabetes mellitus/insulin resistance

• Elevated body mass index

Suboptimal

Clopidogrel

Response

Genetic Factors

• Polymorphisms of CYP, GPIa, P2Y12, GPIIIa

5/17/2016

8

CYP2C19 Genetic Polymorphisms

and Outcomes With Clopidogrel 9 studies (91% PCI, 55% ACS)

MACE (N=9,684) Risk Ratio

(95% CI) P Value

Carriers vs Noncarriers 1.61 (1.28-2.02) <0.001

Heterozygotes vs Wildtype 1.50 (1.08-2.08) 0.016

Homozygotes vs Wildtype 1.81 (1.21-2.71) 0.004

Stent Thrombosis (N=5,772)

Carriers vs Noncarriers 2.76 (1.77-4.30) <0.001

Heterozygotes vs Wildtype 2.51 (1.59-3.98) <0.001

Homozygotes vs Wildtype 4.78 (2.01-11.39) <0.001

Risk Higher With

CYP2C19 Variant

Risk Lower With

CYP2C19 Variant

0.5 1.0 15.0

Mega JL et al. JAMA 2010; 304:1821-30

Metabolism of P2Y12 Receptor Blockers

Schomig A. NEJM 361;11:1108-11

Ticagrelor

Prasugrel

Clopidogrel

Active compound

Intermediate metabolite

Prodrug

CYP-dependent

oxidation

CYP1A2

CYP2B6

CYP2C19

CYP-dependent

oxidation

CYP2C19

CYP3A4/5

CYP2B6

CYP-

dependent

oxidation

CYP3A4/5

CYP2B6

CYP2C19

CYP2C9

CYP2D6 Hydrolysis

By esterase

Binding

Platelet

P2Y12

No in vivo biotransformation

O

O CI O

N S

F F

N

O Prasugrel Ticagrelor Clopidogrel

O

N

N N

N

F N

S

O

O S

O O

N

Ticagrelor and prasugrel have more rapid and consistently

greater IPA

5/17/2016

9

TRITON-TIMI-38 13,608 pts with ACS (unstable angina, NSTEMI, acute STEMI, or recent STEMI) undergoing PCI with known coronary anatomy (except for primary PCI pts) were

treated with aspirin and randomized to clopidogrel 300 mg load + 75 mg qd vs.

prasugrel 60 mg load + 10 mg qd and followed for 6-15 mos (median 12 mos)

Wiviott SD et al. NEJM 2007;357:2001-15

0

5

10

15

0 30 60 90 180 270 360 450

HR 0.81

(0.73-0.90)

P=0.0004

Prasugrel

Days

Pri

mary

En

dp

oin

t

CV

death

, M

I, o

r str

oke (

%)

12.1%

9.9%

Clopidogrel

HR 0.77 P=0.0001

HR 0.80 P=0.0003

7.4%

5.7%

Ste

nt

thro

mb

osis

(%

)

TRITON-TIMI-38 Definite or probable stent thrombosis

in 12,844 pts receiving any stent

0

0.5

1.0

1.5

2.0

2.5

0 50 100 150 200 250 300 350 400 450

HR [95%CI]

0.48 [0.36-0.64]

P<0.0001

2.4%

1.1%

DAYS

Wiviott SD et al. Lancet. 2008;371:1353-63

Definite ST: 0.9% vs. 2.0%

HR 0.42 [0.31, 0.59

P<0.0001

CLOPIDOGREL PRASUGREL

TRITON-TIMI-38

Prasugrel

(n=6813)

Clopidogrel

(n=6795) HR [95%CI] P

TIMI bleed, major or minor 5.0% 3.8% 1.31 [1.11, 1.56] 0.002

- Major, CABG related 13.4% 3.2% 4.73 [1.90, 11.82] <0.001

- Major, non CABG related 2.4% 1.8% 1.32 [1.03, 1.68] 0.03

- Life-threatening 1.4% 0.9% 1.52 [1.08, 2.13] 0.01

- Fatal 0.4% 0.1% 4.19 [1.58, 11.11] 0.002

- Requiring transfusion 4.0% 3.0% 1.34 [1.11, 1.63] <0.001

Death, all-cause 3.0% 3.2% 0.95 [0.78, 1.16] 0.64

Wiviott SD et al. NEJM 2007;357:2001-15

5/17/2016

10

Net Clinical Benefit CV Death / MI / CVA / TIMI Major Bleeding

OVERALL

≥60 kg

<60 kg

<75

≥75

No

Yes

0.5 1 2

Prior

Stroke / TIA

Age (years)

Weight

Risk (%)

+37

-16

-1

-16

+3

-14

-13

Prasugrel Better Clopidogrel Better HR

Pint = 0.006

Pint = 0.18

Pint = 0.36

Post-hoc analysis

Wiviott SD et al. NEJM 2007;357:2001-15

Prasugrel – FDA Label “Boxed Warning”

TRILOGY ACS: Study Design Medically managed UA or NSTEMI (68%)

(n=9,326)

Clopidogrel*

75 mg MD

Prasugrel*

5 or 10 mg MD

Minimum Rx Duration: 6 months; Maximum Rx Duration: 30 months

Primary Efficacy Endpoint: CV Death, MI, Stroke

Randomization stratified by:

age, country, prior clopidogrel treatment

(Primary analysis cohort — Age <75 years; n=7,243)

Clopidogrel* 300 mg LD

+ 75 mg MD

Prasugrel*

30 mg LD +

5 or 10 mg MD

Medical Management Decision ≤72 hrs (No prior clopidogrel given) — 4% of total

Medical Management Decision ≤ 10 days (Clopidogrel started ≤ 72 hrs in-hospital OR

on chronic clopidogrel) — 96% of total

*All patients were on aspirin and low-dose aspirin (< 100 mg) was strongly recommended. For patients <60 kg or ≥75 years, 5 mg MD of prasugrel was given.

Among pts <75 years, 7.9% underwent revascularization (median 113 [40-334] days)

Median time from presentation to

enrollment = 4.5 days

With (42%) or w/o prior angiography;

if with, required CAD

with DS ≥30%

Adapted from Chin CT et al. Am Heart J 2010;160:16-22.

5/17/2016

11

Primary Efficacy: CV death,

MI, or stroke (Age < 75 years)

HR (95% CI):

0.91 (0.79, 1.05)

P = 0.21

Roe MT et al. NEJM 2012:on-line

Median FU 17 months

Ticagrelor (AZD 6140): an Oral Reversible P2Y12 Antagonist

Ticagrelor is a cyclo-pentyl-triazolo-pyrimidine (CPTP)

O H

O H

O

O H

N

F

S

N

H

N N

N

N

F

• Direct acting

� Not a prodrug; does not require metabolic activation

� Rapid onset of inhibitory effect on the P2Y12 receptor

� Greater inhibition of platelet aggregation than clopidogrel

• Reversibly bound

� Degree of inhibition reflects plasma concentration

� Faster offset of effect than clopidogrel

� Functional recovery of all circulating platelets

� Off-target effects

� Blocks red blood cell adenosine re-uptake

Clopidogrel vs. Ticagrelor ONSET/OFFSET Study

Hours

0

20

40

60

80

100

0 4 8 12 16 20 24

Clopidogrel 600 mg

Ticagrelor 180mg

IPA

(%

; 20 m

M A

DP, F

inal)

.5

*

* * * *

Loading Maintenance and Offset

Ticagrelor vs clopidogrel.

* P<0.0001; † P<0.005; ‡, P<0.05

Gurbel PA et al. Circulation. 2009;120:2577-85.

Time (hours)

Offset Maintenance

Ticagrelor (n=54) Clopidogrel (n=50)

IPA

% (

20µM

AD

P –

Fin

al E

xte

nt)

100

80

70

50

10

0

6 weeks 24

‡

†

20

30

40

60

90

0 2 4 8 24 48 72 120 168 240

*

* *

* †

5/17/2016

12

Ticagrelor Increases Extracellular Adenosine

Concentrations by Blocking the Cellular ENT1 Receptor

ATP

ADP

AMP

Adenosine

Inosine

Hypoxanthine

Xanthine

Uric Acid

Cell

Adenosine kinase

Adenosine deaminase

Ticagrelor cAMP

Tissue damage

Hypoxia

ATP

ADP

AMP CD73

CD39

Adenylyl Cyclase

Cattaneo M et al. JACC 2014;63:2503–9

ENT1

Adenosine

Effects Mediated by Ticagrelor and Adenosine

Cattaneo M et al. JACC 2014;63:2503–9

Ticagrelor Adenosine

Adenosine-induced increases in coronary blood flow (dogs and humans)

Endothelial function (ACS patients)

Incidence of MACE (ACS patients) CV and all cause mortality (ACS patients)

Incidence of ventricular pauses (ACS patients)

Infarct size (animals models)

Adenosine-induced platelet inhibition (in vitro)

Mortality (ACS patient with

pulmonary infection)

Creatinine levels (ACS patients)

Vasodilation Endothelial progenitor cell migration

Ichemia/reperfusion injury Induces pharmacological reconditioning

Electrical conduction

Platelet inhibition Modulates inflammation

Glomerular filtration

Incidence of dyspnea

HO OH

HO O N N

N

N N

S

F

F HN

OH

O

OH

HO N

N

N

NH2

N

Incidence of dyspnea (ACS patients)

Adenosine-induced dyspnea (healthy subjects)

Primary Efficacy Endpoint

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 randomization

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

CV

death

, M

I o

r str

oke

(%)

9.8%

11.7%

8,219

HR[95%CI] =

0.84 [0.77–0.92]

P=0.0003

Clopidogrel

Ticagrelor

Wallentin L et al. NEJM 2009;361:1045-57

5/17/2016

13

PLATO

Stent Thrombosis

1.9

2.8

3.6

1.3

2.1

2.8

0

1

2

3

4

5

Definite Denite or probable Definite, probable

or possible

12 M

on

th E

ven

tRate

(%

)

Clopidogrel (n=5,649) Ticagrelor (n=5,640)

HR(95%CI) = 0.67 (0.50–0.91)

P=0.009

HR(95%CI) = 0.77 (0.62–0.95)

P=0.01

HR(95%CI) = 0.75 (0.59–0.95)

P=0.02

Wallentin L et al. NEJM 2009;361:1045-57

PLATO

Primary and Secondary Endpoint Events

11.7

5.1

6.9

1.3

5.9

9.8

4.0

5.8

1.5

4.5

0

5

10

15

CV death,

MI, stroke

CV death MI Stroke All death

12 M

on

th E

ven

t R

ate

(%

)

Clopidogrel (n=9,291) Ticagrelor (n=9,333)

HR(95%CI) = 0.84 (0.77–0.92)

P<0.001

HR(95%CI) = 0.84 (0.75–0.95)

P=0.005

HR(95%CI) = 0.78 (0.69–0.89))

P<0.001

HR(95%CI) = 0.79 (0.69–0.91)

P=0.001

HR(95%CI) = 1.17 (0.91–1.52)

P=0.22

Wallentin L et al. NEJM 2009;361:1045-57

PLATO: Non-CABG and

CABG-related Major Bleeding

P=0.026

P=0.025

P=0.32 9

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

P=0.32

Ad

vers

e e

ven

t ra

te (

%)

Clopidogrel (n=9,291)

Ticagrelor (n=9,333)

Wallentin L et al. NEJM 2009;361:1045-57

5/17/2016

14

Percentage of Patients With High On-

Treatment Platelet Reactivity:

Ticagrelor vs. Clopidogrel

Angiolillo, et al. JACC 2016;67:603-13