UCR Uppsala Clinical

Research Center

Practical Application Of New

Developments In Antithrombotic And

Antiplatelet Therapy In ACS

Stefan James, MD, PhD

Associate Professor

Head of Interventional Cardiology

Uppsala Clinical Research Center

University Hospital

Uppsala, Sweden

Grant/Research Support

Consulting Fees/Honoraria

Astra Zeneca, Daiichi Sankyo, Eli Lilly, BMS, Terumo,

Merck, Medtronic, Boston Scientific

STE- / NSTE-ACS

Clopidogrel 300 mg Pre / post cath

Ticagrelora Pre / post cath

Bivalirudin

11 anti-thrombotic agents with 384 possible treatment combinations

Parenteral anticoagulant

UFH Bolus / infusion

LMWH Fondaparinux

Primary PCI / Lytics Early Invasive/ Early Conservative

Aspirin loading

Parenteral antiplatelet

Abciximab Pre / post cath

Eptifibatide Pre / post cath

Tirofiban Pre / post cath

Clopidogrel 600 mg Pre / post cath

Prasugrel Pre / post cath

Oral antiplatelet

aTicagrelor is not currently approved for use in any market.

ESC = European Society of Cardiology, LMWH = low-molecular-weight heparin, UFH = unfractionated heparin.

Bassand JP, et al. Eur Heart J. 2007;28:1598-660. Van de Werf F, et al. Eur Heart J. 2008;29:2909-45

ESC guidelines NSTE-ACS I-A, STE-ACS I-B

1

2

Targets for Antithrombotic Treatment

Fibrin

Thrombus

Platelet aggregation

Conformational activation of GPIIb/IIIa

Collagen Thrombin

Tx A2

ADP

Aspirin

Clopidogrel

Prasugrel

Ticagrelor

Cangrelor

Elinogrel

GPIIb/IIIa

inhibitors

PAR1

PAR1-inhib

Vorapaxar

Atopaxar

ADP = adenosine diphosphate, AT = antithrombin , GP = glycoprotein, inhib =

inhibitor, PAR1 = protease activated receptor, TxA2 = thromboxane A2.

Platelet activation

Tissue factor

Plasma clotting

cascade

Prothrombin

Thrombin

Fibrinogen

AT

AT

Bivalirudin

Dabigatran

Factor

Xa

Fondaparinux

LMWH

Heparin

Rivaroxaban

Apixaban

Edoxaban

Coagulation

Warfarin

3

Targets for Antithrombotic Treatment

Fibrin

Thrombus

Platelet aggregation

Conformational activation of GPIIb/IIIa

Collagen Thrombin

Tx A2

ADP

Aspirin

Clopidogrel

Prasugrel

Ticagrelor

Cangrelor

Elinogrel

GPIIb/IIIa

inhibitors

PAR1

PAR1-inhib

Vorapaxar

Atopaxar

ADP = adenosine diphosphate, AT = antithrombin , GP = glycoprotein, inhib =

inhibitor, PAR1 = protease activated receptor, TxA2 = thromboxane A2.

Platelet activation

Tissue factor

Plasma clotting

cascade

Prothrombin

Thrombin

Fibrinogen

AT

AT

Bivalirudin

Dabigatran

Factor

Xa

Fondaparinux

LMWH

Heparin

Rivaroxaban

Apixaban

Edoxaban

Coagulation

Warfarin

Variability in Inter-Individual

Clopidogrel Response

ADP, adenosine diphosphate.

Hochholzer W, et al. Circulation. 2005;111:2560-4.

Clopidogrel

Mehta SR, et al. NEJM 2010 and Lancet 2010

0.14 0.95 - 1.44 1.17 4.9 4.2 No PCI (2N=7855)

0.74 - 0.99 0.85 3.9 4.5 PCI (2N=17,232)

CV Death / MI / Stroke

Int P P 95% CI HR Double Standard

0.14 0.95 - 1.44 1.17 4.2 No PCI (2N=7855)

0.016 0.74 - 0.99 0.86 4.5 PCI (2N=17,232)

CV Death / MI / Stroke

P P 95% CI HR Double Standard

0.04

300 (-600) mg

5

Days

Cu

mu

lati

ve H

azard

0.0

0.01

0.02

0.03

0.04

0 3 6 9 12 15 18 21 24 27 30

Clopidogrel Standard

Clopidogrel Double

HR= 0.86 (95% CI, 0.74-0.99)

P=0.039

CV Death / MI / Stroke in PCI Patients

0.37 0.84 - 1.07 0.95 4.2 4.4 Overall (2N=25,087) 0.84 - 1.07 0.95 4.4 Overall (2N=25,087)

Days

Cu

mu

lati

ve H

azard

0.0

0.01

0.02

0.03

0.04

0 3 6 9 12 15 18 21 24 27 30

Clopidogrel Standard

Clopidogrel Double

HR= 0.85 (95% CI, 0.74-0.99)

P=0.036

CV Death / MI / Stroke

6

Clopidogrel dosing

Class Level

www.escardio.org/guidelines

Class Level

Class Level

PRINCIPLE-TIMI44

(Wiviott SD et al. Circulation 2007) (Gurbel PA et al. Circulation 2009)

ONSET-OFFSET

Prasugrel 60 mg

TRITON-TIMI 38: study design

ASA N=13,608

Wiviott S, et al. N Engl J Med 2007;357:2001–15 UTVR = urgent target vessel revascularisation

Clopidogrel

300mg loading dose/75mg maintenance

(N=6,795)

ACS (STEMI or UA/NSTEMI) and planned PCI

Double-blind randomisation

Prasugrel

60mg loading dose/10mg maintenance

(N=6,813)

Median duration of therapy: 12 months

1o endpoint: CV death, MI, stroke

2o endpoints: CV death, MI, stroke, recurrent ischaemia with rehospitalisation

CV death, MI, UTVR

stent thrombosis (ARC definite/probable)

Safety endpoints: TIMI major bleeds, life-threatening bleeds

Key substudies: pharmacokinetic, genomic

Efficacy endpoints

Prasugrel Clopidogrel

Days

12.1

9.9

1.8

2.4

CV death/MI/stroke

TIMI major

non-CABG bleeds

CV death, MI, stroke

and major non-CABG bleeding

HR=0.41 (0.29–0.59)

p<0.0001

HR=0.60 (0.37–0.97)

p=0.03

Early Late

Wiviott S, et al. N Engl J Med 2007;357:2001–15; Wiviott S, et al. Lancet 2008;371:1353–1363

15

10

5

0

0 90 180 270 360 450

Endpoin

t (%

)

0 5 10 15 20 25 30

2.5

2.0

1.5

1.0

0.5

0

1.56

0.64 40%

0.82

0.49

CABG = coronary artery bypass grafting

Early and late

stent thrombosis

Days

59%

2.5

2.0

1.5

1.0

0.5

0

Endpoin

t (%

)

Endpoin

t (%

)

0 90 270 450

Days

Montalescot G, et al. Lancet 2009;373:723–31.

STEMI cohort

10

Days

15

10

5

0 0 50 100 150 200 250 300 350 400 450

Pro

po

rtio

n o

f p

ati

ents

, %

9.5

6.5

12.4

10.0

HR = 0.79 (0.65–0.97); NNT = 42

P = 0.02 RRR = 21%

P = 0.002 RRR = 32%

2.1

2.4

HR = 1.11 (0.70–1.77); NNH = 333

P = 0.65

Clopidogrel Prasugrel

CV Death / MI / stroke

TIMI major non-CABG bleeds

Montalescot et al. Lancet 2009; 373, 723-31

Prasugrel

Conclusions on Prasugrel in ACS

In patients with ACS and planned PCI

Prasugrel 60/10mg vs Clopidogrel 300/75mg for 15 months

l reduces the composite: CV death + MI + stroke

l reduces MI (especially produre related MI)

l reduces stent thrombosis

l raises the risk of major (including fatal) bleeding

with

l higher risk of bleedings at age >75 years, <65 kg,

history of stroke or TIA and at CABG

l net clinical benefit larger at STEMI and DM

13

Prasugrel

www.escardio.org/guidelines

PLATO study design

Primary endpoint : • Composite of CV death, MI or stroke

Key secondary • CV death, MI, or stroke in patients intended for invasive management

• Total mortality, MI or stroke

• CV death, MI, stroke, recurrent ischemia, TIA, or arterial thrombosis

• Components of primary endpoint - CV death; MI; stroke

• Death from any cause

Primary safety: • Total Major bleeding

6–12 month exposure

Clopidogrel

If pretreated, no additional loading dose;

if naive, standard 300mg loading dose,

then 75mg q.d maintenance;

(additional 300mg allowed pre PCI)

Ticagrelor

180mg loading dose, then

90mg b.i.d maintenance;

(additional 90mg prePCI)

NSTE-ACS (moderate-to-high risk) STEMI (if primary PCI)

Clopidogrel-treated or -naive;

randomised within 24 hours of index event

(N=18,624)

James S, et al. Am Heart J 2009;157:599–605

HR 0.84

(0.77–0.92)

p=0.0003

NNT = 54

Days after randomization

0 60 120 180

12

11

10

9

8

7

6

5

4

3

2

1

0

Cu

mu

lati

ve i

ncid

en

ce (

%) 9.8

11.7 Clopidogrel

Ticagrelor

Wallentin L, et al. N Engl J Med. 2009;361:1045-57.

Primary Endpoint

(CV death, MI, Stroke)

Ticagrelor vs. Clopidogrel

Clopidogrel

Ticagrelor

2.3

2.8

HR 1.25

(1.03–1.53)

p=0.03

NNH=167

TIMI Major

Non CABG bleeds

N=18,624

HR 0.84

(0.77–0.92)

p=0.0003

NNT = 54

Days after randomization

0 60 120 180

12

11

10

9

8

7

6

5

4

3

2

1

0

Cu

mu

lati

ve

in

cid

en

ce

(%

)

9.8

11.7 Clopidogrel

Ticagrelor

Wallentin L, et al. N Engl J Med. 2009;361:1045-57.

Primary Endpoint

(CV death, MI, Stroke)

CV death Clopidogrel

Ticagrelor

4.0

5.1

HR 0.79

(0.69–0.91)

p=0.001

NNT = 90

N=18,624

Ticagrelor vs. Clopidogrel

Cannon CP, et al. Lancet. 2010;375:283-293.

Definite Stent Thrombosis

Days Since PCI

Invasive

Ticagrelor D

efi

nit

e s

ten

t th

rom

bo

sis

, %

0 5 10 15 20 25 30

2

1

0

1.41

1.42

0.87

0.96

Clopidogrel, <600 mg

Ticagrelor, <600 mg clopidogrel

Clopidogrel, ≥600 mg

Ticagrelor, ≥600 mg clopidogrel

James S et al. ESC abstract 2010

Mortality reduction in invasive and non-

invasive treatment strategies

Invasive

HR, 0.81, 95% CI: (0.68–0.95)

Number at risk

Invasive

Ticagrelor 6732 6439 6375 6241 5141 3951 3233

Clopidogrel 6676 6376 6331 6209 5114 3917 3164

Days after randomization

All

-cau

se m

ort

ali

ty (

%)

3.9%

5.0%

0

2

4

6

8

10

0 60 120 180 240 300 360

Non-

Invasive

N=13408

Non-invasive

HR, 0.75, 95% CI: (0.61–0.93)

6.1%

8.2%

N=5216

Non-invasive

Ticagrelor 2601 2485 2447 2385 1978 1531 1186

Clopidogrel 2615 2488 2448 2380 1965 1524 1200

0

2

4

6

8

10

12

14

0 60 120 180 240 300 360

Clopidogrel

Ticagrelor

Clopidogrel

Ticagrelor

588 542 530 507 397 314 246

564 534 525 511 411 332 254

8699 8318 8245 8078 6679 5124 4115

8761 8382 8289 8107 6701 5143 4162

Prior stroke

No prior stroke

Patient at risk

Clopidogrel

Clopidogrel

Ticagrelor

Ticagrelor

Prior stroke

No prior stroke

James, S et al, ESC 2011

Prior stroke or TIA

N=1052

HR, 0.62 (0.42, 0.91)

All

ca

use

de

ath

Stroke

20

Primary endpoint in ONSET/OFFSET study: Onset: IPA (20 M ADP, final extent) at 2 h after the first dose of study drug. Offset: Slope of IPA between 4 and 72 h after the last dose of study drug. Ticagrelor (180 mg load, 90 mg bd maintenance dose), clopidogrel (600 mg load, 75 mg/day maintenance dose) or placebo on top of aspirin 75-100 mg/day.

*P<0.001; †P<0.005; ‡P<0.05 ticagrelor vs clopidogrel.

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

20 M ADP (Final Extent)

6 Weeks

IPA

, %

Onset Maintenance Offset

Time, h

0 0.5 1 2 4 8 24 0 2 4 8 24 48 120 168 240 0

10

20

30

40

50

60

70

80

90

100

Clopidogrel (n=50)

Ticagrelor (n=54)

Placebo (n=12)

*

*

* * *

* *

* * †

‡

†

Loading Dose

Last Maintenance Dose

72

IPA in the ONSET/OFFSET Study

Following Last Maintenance Dose

21

Time from CABG to CV Death

(CABG Population)

130

119

Clopidogrel

No. at Risk

Ticagrelor

629

629

565

583

539

557

472 404

415

269

291 491

8

7

6

5

4

3

2

1

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

Months from CABG procedure

HR 0.52

(95% CI, 0.32-0.85)

P<0.01

7.9

4.1

Clopidogrel

Ticagrelor

K-M

esti

mate

d r

ate

, %

Held C, et al. J Am Coll Cardiol. 2011;57:672-84.

CABG

22

PLATO dyspnoea

AE, adverse event; CI, confidence interval; HR, hazard ratio.

Storey RF, et al. Eur Heart J 2011;108:1542–1546.

Ticagrelor Clopidogrel

On

se

t o

f a

ny d

ysp

no

ea

AE

(%

) p for interaction <0.001

Days from first dose

First 30 days 10

8

6

4

2

0

0 10 20 30

8.29

3.84

HR(95% CI) = 2.24(1.97–2.54)

Days from randomisation

All-c

au

se

mo

rta

lity

(%

)

p for interaction <0.001

Days from randomisation

20

15

10

5

0

31 90 150 210 270 330

8.51

3.39 All-c

au

se

mo

rta

lity

(%

)

p for interaction =0.659

20

15

10

5

0

31 90 150 210 270 330

3.04

2.54

HR(95% CI) = 1.11(0.69–1.78) HR(95% CI) = 2.73(1.82–4.09)

Dyspnoea No dyspnoea

Ticagrelor mortality Clopidogrel mortality

Dyspnoea No dyspnoea

23

Ticagrelor

www.escardio.org/guidelines

30-Day Major Adverse CV Events

Time, Days

5.5%

5.5%

Bivalirudin Should Probably Always Be Combined with UFH CV = cardiovascular.

Stone GW, et al. N Engl J Med. 2008;358:2218-30.

Ma

jor

Ad

ve

rse

CV

Eve

nts

, %

*

HR=1.00 (95% CI, 0.75, 1.32)

P=0.98

Heparin + GPIIb/IIIa inhibitor (n=1802) Bivalirudin monotherapy (n=1800)

Bivalirudin

24

0

1

2

3

4

5

6

7

8

0 5 10 15 20 25 30

Days After PCI

Perc

en

t

SCAAR

30 25 20 15 10 5 0

0.12

0.10

0.08

0.06

0.04

0.02

0.00

Bivalirudin Plus UFH, N=1068

Bivalirudin, N=1928

Adjusted N=2996

OR; 0.63, 95% CI (0.42-0.94), P=0.025

Koutouzis M, et al. Presented at: EuroPCR 2010; 25-28 May 2010; Paris, France.

Death or Target Lesion Stent Thrombosis

Bivalirudin

30 Day Mortality

Number at risk

Bivalirudin 1800 1758 1751 1746 1742 1729 1666

Heparin + GPIIb/IIIa 1802 1764 1748 1736 1728 1707 1630

Dea

th (

%)

Time in Days

3.1%

2.1%

HR [95%CI] =

0.66 [0.44, 1.00]

P=0.048

Heparin + GPIIb/IIIa inhibitor (n=1802)

Bivalirudin monotherapy (n=1800)

27

Bivalirudin

Months After Randomization

PRIMARY EFFICACY ENDPOINT: CV Death / MI / Stroke

Rivaroxaban (both doses)

Es

tim

ate

d C

um

ula

tiv

e In

cid

en

ce

(%

)

Placebo

5113 4307 3470 2664 1831 1079 421

10229 8502 6753 5137 3554 2084 831

Placebo

Rivaroxaban

No. at Risk

HR and 95% confidence interval estimates from Cox model stratified by thienopyridine use are provided per mITT approach; Stratified log-rank p-values

are provided for both mITT and ITT approaches.

HR

0.68

p=0.04

2.9%

4.5% Placebo

Rivaroxaban (2.5 mg)

All Cause Death

HR 0.84

(0.74-0.96)

10.7%

8.9%

2 Yr KM

Estimate

HR 3.46

(95% CI 2.08-

5.77; p<0.001)

No

of

pati

en

ts (

%)

1.8%

0.6%

HR 4.47

(95% CI 2.71-

7.36; p<0.001)

Rivaroxaban 5 mg

(n=5115)

2.4%

Rivaroxaban 2.5 mg

(n=5114)

Placebo (n=5113)

1.5

0.5

1.0

ICH: 32 (0.6%) with rivaroxaban vs 5 (0.2%) with placebo

2.0

2.5

Mega et al. N Engl J Med 2011.

ATLAS-ACS-2

Primary Safety Outcome (Major bleeding)

hjärtinfarkt med ST-höjning, utskrivna levande, alla åldrar, 1995-2008.

Figur 22b. Utveckling av användningen av blodproppshämmande behandling vid

ASA ASA+(Plavix eller Ticlid)

Plavix eller Ticlid Waran

Waran+(Plavix eller Ticlid) Waran+ASA

Waran+ASA+(Plavix eller Ticlid) Övrigt

Andel B

lo

dpro

ppshäm

mande (%

)

0

10

20

30

40

50

60

70

80

90

100

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008

ST-elevation, discharged alive, all ages, 1995-2008.

Figure 23a. Platelet inhibiting therapy among AMI patients without

ASA ASA+(Clopidogrel)

Clopidogrel Warfarin

Warfarin+(Clopidogrel) Warfarin+ASA

Warfarin+ASA+(Clopidogrel) Other

Pro

po

rtio

n inhibito

rs (%

)

0

10

20

30

40

50

60

70

80

90

100

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008

Uppsala Clinical Research Centre 2006

Antithrombotic treatment at discharge 2009 P

rop

ort

ion

tre

ate

d %

Clopidogrel

+ ASA

ASA

Warfarin

Pro

po

rtio

n t

rea

ted

%

Uppsala Clinical Research Centre 2009

Clopidogrel

+ ASA

ASA

Warfarin

STEMI NSTEMI

ST-elevation or left bundle branch block, <80 years, 1995-2008.

Figure 7a. Acute reperfusion therapy among AMI patients with

Alteplase Tenecteplase Reteplase

Streptokinase Acute CABG Acute angio without PCI

Facilitated PCI Primary PCI

Pro

po

rtio

n a

cute

reperf

usi

on t

hera

py (

%)

0

10

20

30

40

50

60

70

80

90

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008

Uppsala Clinical Research Centre 2006

2009 Reperfusion treatment in STEMI < 80 yrs

Primary PCI Streptokinase

Actilyse-tPA

rPA

TNK

Uppsala Clinical Research Centre 2009

Pro

po

rtio

n r

ep

erf

us

ion

tre

atm

en

t %

Mortality in STEMI

In Hospital

30-days

1 year

Observed

Standardized according to baseline data 2007

0

5

10

15

20

25

%

JAMA. 2011;305(16):1677-1684

Long-term mortality in STEMI

2.6 years

JAMA. 2011;305(16):1677-1684

Long-term mortality in NSTEMI

1.7 years

Conclusions

• Outcome has improved considerably and mortality has been reduced by almost 50% the last decade

• With the introduction of new more potent anti thrombotic agents with a favourable balance between efficacy and safety mortality can be reduced further

36