Karlis TRUSINSKIS

Interventional Cardiologist

Pauls Stradins Clinical University Hospital

Riga, LATVIA

ANTIAGREGANTS

IN ACUTE CORONARY SYNDROME

Dual Antiplatelet Therapy

ASA + Clopidogrel

I Class of evidence in treatment of ACS

Beneficial, effective and useful in acute and long term treatment of ACS

Current standard in patients after stent implantation

Possible problems:

Increased risk of bleeding

Risk of stent thrombosis and MI in poor responders

Stent thrombosis of LAD bifurcation

Thrombosuction

Kissing balloon dilatation

Final Result

Days

Cu

mu

lati

ve H

azar

d

0.0

0.00

40.

008

0.01

2

0 3 6 9 12 15 18 21 24 27 30

Clopidogrel Standard Dose

Clopidogrel Double Dose

42% RRR

HR 0.5895% CI 0.42-0.79

P=0.001

Clopidogrel: Double (600mg and 150mg/d 1wk) vs Standard Dose (300mg) Definite Stent Thrombosis

Days

Cu

mu

lati

ve H

azar

d

0.0

0.01

0.02

0.03

0.04

0 3 6 9 12 15 18 21 24 27 30

Clopidogrel: Double vs Standard Dose Primary Outcome: PCI Patients

Clopidogrel Standard

Clopidogrel Double

HR 0.8595% CI 0.74-0.99

P=0.036

15% RRR15% RRR

CV Death, MI or StrokeCV Death, MI or Stroke

Clopidogrel Double vs Standard DoseBleeding PCI Population

Clopidogrel

Standard

N= 8684

Double

N=8548

Hazard

Ratio

95% CI P

TIMI Major1 0.5 0.5 1.06 0.70-1.61 0.79

CURRENT Major2 1.1 1.6 1.44 1.11-1.86 0.006

CURRENT Severe3 0.8 1.1 1.39 1.02-1.90 0.034

Fatal 0.15 0.07 0.47 0.18-1.23 0.125

ICH 0.035 0.046 1.35 0.30-6.04 0.69

RBC transfusion ≥ 2U 0.91 1.35 1.49 1.11-1.98 0.007

CABG-related Major 0.1 0.1 1.69 0.61-4.7 0.31

1ICH, Hb drop ≥ 5 g/dL (each unit of RBC transfusion counts as 1 g/dL drop) or fatal2Severe bleed + disabling or intraocular or requiring transfusion of 2-3 units3Fatal or ↓Hb ≥ 5 g/dL, sig hypotension + inotropes/surgery, ICH or txn of ≥ 4 units

1ICH, Hb drop ≥ 5 g/dL (each unit of RBC transfusion counts as 1 g/dL drop) or fatal2Severe bleed + disabling or intraocular or requiring transfusion of 2-3 units3Fatal or ↓Hb ≥ 5 g/dL, sig hypotension + inotropes/surgery, ICH or txn of ≥ 4 units

Conclusions

1.1. Double-dose clopidogrel significantly reduced stent Double-dose clopidogrel significantly reduced stent thrombosis and major CV events (CV death, MI or thrombosis and major CV events (CV death, MI or stroke) in PCI.stroke) in PCI.

2.2. In patients not undergoing PCI, double dose clopidogrel In patients not undergoing PCI, double dose clopidogrel was not significantly different from standard dose (70% was not significantly different from standard dose (70% had no significant CAD or stopped study drug early for had no significant CAD or stopped study drug early for CABG).CABG).

3.3. There was a modest excess in CURRENT-defined major There was a modest excess in CURRENT-defined major bleeds but no difference in TIMI major bleeds, ICH, fatal bleeds but no difference in TIMI major bleeds, ICH, fatal bleeds or CABG-related bleeds.bleeds or CABG-related bleeds.

4.4. No significant difference in efficacy or bleeding between No significant difference in efficacy or bleeding between ASA 300-325 mg and ASA 75-100 mgASA 300-325 mg and ASA 75-100 mg

Platelet Aggregation after Clopidogrel Loading

Hochholzer W et al, Circulation 2005

Survival free of cardiovascular death, infarction and stent thrombosis depending on platelet

reactivity

Price MJ et al. Eur heart J 2008

Inhibition of Platelet Aggregation

Double-blind

ACS (STEMI or UA/NSTEMI) & Planned PCI

ASA

PRASUGREL60 mg LD/ 10 mg MD

CLOPIDOGREL300 mg LD/ 75 mg MD

1o endpoint: CV death, MI, Stroke2o endpoint: Stent Thrombosis Safety endpoints: TIMI major bleeds, Life-threatening bleeds

Duration of therapy: 6-15 months

N= 13,608

Wiviott SD, Antman EM et al AHJ 2006

STENT ANALYSIS

0

5

10

15

0 30 60 90 180 270 360 450

HR 0.81(0.73-0.90)P=0.0004

Prasugrel

Clopidogrel

Days

En

dp

oin

t (%

)

12.1

9.9

HR 1.32(1.03-1.68)

P=0.03

Prasugrel

Clopidogrel1.82.4

Main Trial: Main Trial: Primary ResultsPrimary Results

CV Death / MI / Stroke

TIMI Major NonCABG Bleeds

Wiviott SD, Braunwald E, McCabe CH et al NEJM2007

Prasugrel in STEMI and UA/NSTEMI

Wiviott SD, Braunwald E, McCabe CH et al NEJM2007

Safety Profile of Prasugrel in STEMI vs UN/NSTEMI

Wiviott SD, Braunwald E, McCabe CH et al NEJM2007

Net Clinical Benefit in STEMI

Montalescot G et al. Lancet 2009

Diabetic SubgroupDiabetic Subgroup

0

2

4

6

8

10

12

14

16

18

0 30 60 90 180 270 360 450

HR 0.70P<0.001

Days

En

dp

oin

t (%

)

CV Death / MI / Stroke

TIMI Major NonCABG Bleeds

NNT = 21

N=3146N=3146

17.0

12.2

Prasugrel

Clopidogrel

Prasugrel

Clopidogrel 2.6

2.5

Wiviott et al NEJM 2007

Stent ThrombosisStent Thrombosis((Definite + Probable)Definite + Probable)

0

1

2

3

0 30 60 90 180 270 360 450

HR 0.48P <0.0001

Prasugrel

Clopidogrel2.4

(142)

NNT= 77

1.1 (68)

Days

En

dp

oin

t (%

)

Any Stent at Index PCIAny Stent at Index PCI N= 12,844 N= 12,844

Definite/Probable ST: Definite/Probable ST: Any Stent (N=12844)Any Stent (N=12844)

0

0.5

1

1.5

2

2.5

0 5 10 15 20 25 300

0.5

1

1.5

2

2.5

30 90 150 210 270 330 390 450

% o

f S

ubje

cts

HR 0.41 [0.29-0.59]P<0.0001

HR 0.60 [0.37-0.97]P=0.03

DAYS

EARLY ST LATE ST

STENT ANALYSIS

1.56%

0.64%

59% 0.82%

0.49%

40%

CLOPIDOGREL

PRASUGREL

Death Following STDeath Following ST

Mortality During Follow up (%) Post-Stent Thrombosis

STENT ANALYSIS

N=210 N=12634

HR 13.1 (9.8 – 17.5) P<0.0001

% o

f S

ubje

cts

Net Clinical BenefitNet Clinical BenefitBleeding Risk SubgroupsBleeding Risk Subgroups

OVERALL

>=60 kg

< 60 kg

< 75

>=75

No

Yes

0.5 1 2

Prior Stroke / TIA

Age

Wgt

Risk (%)

+ 54

-16

-1

-16

+3

-14

-13

Prasugrel Better Clopidogrel BetterHR

Pint = 0.006

Pint = 0.18

Pint = 0.36

Post-hoc analysisPost-hoc analysis

Wiviott et al NEJM 2007

• Thienopyridines act by binding covalently to the P2Y12 receptor, causing a structural change, and rendering the receptors

permanently inactivated

Irreversible inhibition - Thienopyridines

Reversible inhibition – Ticagrelor

P Savi, et al. Proc Natl Acad Sci USA 2006; 103:11069-11074.

ST

RIC

TLY

CO

NF

IDE

NT

TIA

L, F

OR

IN

TE

RN

AL

US

E O

NLY

.NO

T T

O B

E U

SE

D F

OR

SA

LES

PR

ES

EN

TA

TIO

NS

ST

RIC

TLY

CO

NF

IDE

NT

TIA

L, F

OR

IN

TE

RN

AL

US

E O

NLY

.NO

T T

O B

E U

SE

D F

OR

SA

LES

PR

ES

EN

TA

TIO

NS

0 2 4 6 8 10 120

20

40

60

80

**

*

*

**

*

**

**

*

Time postdose (h)

Mea

n P

late

let

Ag

gre

ga

tio

n

Clopidogrel 75 mg (n=12)

Ticagrelor 180 mg (n=7)

Ticagrelor 90 mg (n=9)

Ticagrelor 270 mg (n=16)

*P<0.05 for AZD6140 vs clopidogrel.Storey RF et al. J Am Coll Cardiol. 2007;50:1852-1856.

DISPERSE-2 PK/PD Substudy: Suppression of Platelet Aggregation in Clopidogrel-Pretreated Patients (N=44)

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 (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

1211109876543210

13

Cum

ula

tive inci

dence

(%

)

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

No. at risk

Clopidogrel

Ticagrelor

9,291

9,333

8,560

8,678

8,405

8,520

8,177

Days after randomisation

6,703

6,796

5,136

5,210

4,109

4,191

0 60 120 180 240 300 360

6

5

4

3

2

1

0

7

Cum

ula

tive in

cid

en

ce (

%)

Clopidogrel

Ticagrelor

5.8

6.9

8,279

HR 0.84 (95% CI 0.75–0.95), p=0.005

0 60 120 180 240 300 360

6

4

3

2

1

0

Clopidogrel

Ticagrelor

4.0

5.1

HR 0.79 (95% CI 0.69–0.91), p=0.001

7

5

9,291

9,333

8,865

8,294

8,780

8,822

8,589

Days after randomisation

7079

7119

5,441

5,482

4,364

4,4198,626

Myocardial infarction Cardiovascular death

Cum

ula

tive in

cid

en

ce (

%)

Secondary efficacy endpoints over time

Stent thrombosis

Ticagrelor

(n=5,640)

Clopidogre

l

(n=5,649)

HR

(95% CI)

p

value

Stent thrombosis, n (%)

Definite

Probable or definite

Possible, probable,

definite

71 (1.3)

118 (2.1)

155

(2.8)

106 (1.9)

158 (2.8)

202 (3.6)

0.67 (0.50–

0.91)

0.75 (0.59–

0.95)

0.77 (0.62–

0.95)

0.009

0.02

0.01

(evaluated in patients with any stent during the study)

*Time-at-risk is calculated from first stent insertion in the study or date of randomisation

Time to major bleeding – primary safety event

No. at risk

Clopidogrel

Ticagrelor

9,186

9,235

7,305

7,246

6,930

6,826

6,670

Days from first IP dose

5,209

5,129

3,841

3,783

3,479

3,433

0 60 120 180 240 300 360

10

5

0

15

Clopidogrel

Ticagrelor

11.2011.58

6,545

HR 1.04 (95% CI 0.95–1.13), p=0.434

K-M

est

imate

d r

ate

(%

per

year)

Holter monitoring & Bradycardia related events

Holter monitoring at first weekTicagrelor(n=1,451)

Clopidogrel(n=1,415) p value

Ventricular pauses ≥3

seconds, %

Ventricular pauses ≥5

seconds, %

5.8

2.0

3.6

1.2

0.01

0.10

Holter monitoring at 30 daysTicagrelor(n= 985)

Clopidogrel(n=1,006) p value

Ventricular pauses ≥3

seconds, %

Ventricular pauses ≥5

seconds, %

2.1

0.8

1.7

0.6

0.52

0.60

Bradycardia-related event, %

Ticagrelor(n=9,235)

Clopidogrel(n=9,186) p value

Pacemaker Insertion

Syncope

Bradycardia

Heart block

0.9

1.1

4.4

0.7

0.9

0.8

4.0

0.7

0.87

0.08

0.21

1.00

Other findings

All patientsTicagrelor(n=9,235)

Clopidogrel(n=9,186) p value*

Dyspnoea, %

Any

With discontinuation of study

treatment

13.8

0.9

7.8

0.1<0.001

<0.001

Neoplasms arising during treatment,

%

Any

Malignant

Benign

1.4

1.2

0.2

1.7

1.3

0.4

0.17

0.69

0.02

*p values were calculated using Fischer’s exact test

Conclusions

• Reversible, more intense P2Y12 receptor inhibition for one

year with ticagrelor in comparison with clopidogrel in a broad population with ST- and non-ST-elevation ACS provides

– Reduction in myocardial infarction and stent thrombosis

– Reduction in cardiovascular and total mortality

– No change in the overall risk of major bleeding

Funnel plots comparing prasugrel vs. ticagrelor for the risk of key Funnel plots comparing prasugrel vs. ticagrelor for the risk of key clinical events. Odds ratios (OR) <1.0 favor prasugrel, whereas odds clinical events. Odds ratios (OR) <1.0 favor prasugrel, whereas odds

ratios>1.0 favor ticagrelor.ratios>1.0 favor ticagrelor.

Indirect comparison Prasugrel vs. Ticagrelor

Zoccai GB. EuroPCR 2010

CYP2C19 Polymorphism and Response to Clopidogrel

Mega et al. N Engl J Med 2009;360:354-62.

CYP2C19 Polymorphism and Response to Prasugrel

Mega et al. Circulation. 2009;119:2553-2560

Cangrelor (AR-C69931MX)

Parenteral ADP-P2Y12 receptor antagonist

ATP analogue

Direct and Reversible P2Y12 inhibitor

More potent than clopidogrel ~90% inhibition of platelet

aggregation at 1 - 4 mcg/kg/min iv

Plasma half-life of 5-9 min.; 20 min. for return to normal platelet

function

O- O- O-

O-O OHO OH

P P PO O

N

HN

NN

N

N

S

S

CF3

O

Cl

Cl-O

CHAMPION Trial: Cangrelor versusStandard Therapy to Achieve Optimal Management

of Platelet Inhibition PCI

Harrington et al. N Engl J Med 2009;361:2318-29.

INNOVATE PCI: treatment with oral and intravenous Elinogrel

in setting of non-urgent PCI

• Second phase trial • Evaluation of clinical effectiveness, safety and

tolerability

Rao et al. ESC Congress 2010

Karlis TRUSINSKIS

Interventional Cardiologist

Pauls Stradins Clinical University Hospital

Riga, LATVIA

ANTIAGREGANTS

IN ACUTE CORONARY SYNDROME