should we use bivalirudin ? fibrin 2 1 thrombin 2 1 thrombin 2 1 trombina 2 1 trombina bivalirudin...

Should we use bivalirudin ?

FibrinFibrin

2

1

ThrombinThrombin2

1

ThrombinThrombin

2

1

TrombinaTrombina

2

1

TrombinaTrombina

BivalirudinBivalirudin

ADVANTAGES

- No requirement for anti-thrombin III- Effective on clot-bound thrombin- Plasma half-life 25 minutes- No anticoagulation monitoring

Primary Endpoint in the ACUITY trial

11,7%

7,3%5,7%

3,0%

10,1%

7,8%

Net clinicaloutcome

Ischemiccomposite

Major bleeding

30

da

y e

ve

nts

(%

)

UFH/Enoxaparin+GPI (N=4603) Bivalirudin alone (N=4612)

UFH/Enoxaparin + GPI vs. Bivalirudin AloneUFH/Enoxaparin + GPI vs. Bivalirudin Alone

PNI <0.0001PSup = 0.015

PNI = 0.011PSup = 0.32

PNI <0.0001PSup <0.0001

0 1 2

Net Clinical Outcome CompositeUFH/Enoxaparin + IIb/IIIa vs. Bivalirudin AloneUFH/Enoxaparin + IIb/IIIa vs. Bivalirudin Alone

Yes (n=3197)No (n=6008)

Low (0-2) (n=1291)Intermed (3-4) (n=4407)

High (5-7) (n=2449)

Elevated (n=5368)Normal (n=3841)

Risk ratio±95% CI

Risk ratio±95% CI

BivalAlone

UFH/Enox+ IIb/IIIa

9.2%11.3%

12.2%11.1%

P Pint

0.76 (0.65-0.89)1.02 (0.86-1.21)

12.2%7.1%

13.3%9.4%

0.92 (0.80-1.06)0.75 (0.61-0.93)

0.230.01

<0.0010.83

0.35

0.02

0.18

13.0%8.6%

13.7%10.6%

0.96 (0.80-1.14)0.81 (0.69-0.95)

0.610.01 0.42

Biomarkers (CK/Trop)

ST Deviation

TIMI Risk Score

Pre Thienopyridine

6.4% 10.2% 0.63 (0.43-0.91) 0.019.4% 10.2% 0.92 (0.77-1.10) 0.34

13.9% 15.2% 0.92 (0.76-1.11) 0.36

Yes (n=5192)No (n=4023)

RR (95% CI)

Bivalirudin alone betterBivalirudin alone better UFH/Enox + IIb/IIIa betterUFH/Enox + IIb/IIIa better

Effetto della bivalirudina sui sanguinamenti non legati al sito di accesso arterioso all’analisi cumulativa degli studi REPLACE-2,

ACUITY e HORIZONS.

Landmark Analysis: 30-Day Stent Thrombosis (N=3,124)

Bivalirudin: 1749 1714 1711 1673 1663 1591

UFH + GP IIb/IIIa: 1818 1805 1804 1746 1724 1625

Patients at Risk

Bivalirudin UFH + GP IIb/IIIa

Est

ima

ted

Ev

ent

Rat

e (%

)

Days from Randomisation

0

1

2

3

4

5

5 10 15 20 25 300 0.5 1

23

4

30

19

Data on file: The Medicines Company Analysis of safety population in all patients receiving stents

Platelet Activation Mechanisms

ThrombinThrombin

ThromboxaneThromboxaneAA 22

5HT5HT

P2Y12

ADPADP ADPADPADPADP

5HT5HT

PLATELETPLATELETACTIVATIONACTIVATION

P2Y15HT2A

PAR1

PAR4

Densegranule

ThrombinThrombingenerationgeneration

ShapeShapechangechange

IIb3

IIb3

FibrinogenFibrinogenIIb3

AggregationAggregation

AmplificationAmplificationAlpha

granule

Coagulation factorsCoagulation factorsInflammatory mediatorsInflammatory mediators

TPa

CoagulationCoagulation

GPVI

CollagenCollagen

ATPATPATPATP

P2X1

ASPIRINASPIRIN

x TICLOPIDINETICLOPIDINECLOPIDOGRELCLOPIDOGRELPRASUGRELPRASUGREL

ACTIVE ACTIVE METABOLITEMETABOLITE

x TICAGRELORTICAGRELOR CANGRELORCANGRELOR

GP IIb/IIIa ANTAGONISTSGP IIb/IIIa ANTAGONISTS

xx

Storey RF. Curr Pharm Des. 2006;12:1255-59.

PRIMARY COMPOSITE ENDPOINT* IN TRITON AND PLATO TRIALS

9,9

12,1

9,8

11,7

0,00

5,00

10,00

15,00

20,00

TRITON PLATO

CLOPIDOGREL

NEW DRUG

P<.001 P<.001

*Death,MI,Stroke

CLINICAL CHARACTERISTICS OF TRITON AND PLATO POPULATION

TRITON (N=13608 pts )

PLATO ( N= 18624 pts )

% PCI 99 64

% CABG 1 10

% NON-INVASIVE 0 29

% STEMI 26 38

Prasugrel (studio TRITON) e’ stato confrontato con clopidogrel 300 mg LD + 75 mg MD.

Ticagrelor (studio PLATO) e’ stato confrontato con clopidogrel 300-600 mg LD + 75mg MD.

Study Design, Flow and Compliance

25,087 ACS Patients (UA/NSTEMI 70.8%, STEMI 29.2%)Planned Early (<24 h) Invasive Management with intended PCIIschemic ECG Δ (80.8%) or ↑cardiac biomarker (42%)

25,087 ACS Patients (UA/NSTEMI 70.8%, STEMI 29.2%)Planned Early (<24 h) Invasive Management with intended PCIIschemic ECG Δ (80.8%) or ↑cardiac biomarker (42%)

PCI 17,232(70%)

Angio 24,769(99%)

Angio 24,769(99%) No PCI 7,855

(30%)

No Sig. CAD 3,616 CABG 1,809 CAD 2,430

Randomized to receive (2 X 2 factorial):

CLOPIDOGREL: Double-dose (600 mg then150 mg/d x 7d then 75 mg/d) vs Standard dose (300 mg then 75 mg/d)

ASA: High Dose (300-325 mg/d) vs Low dose (75-100 mg/d)

Efficacy Outcomes: CV Death, MI or stroke at day 30Stent Thrombosis at day 30

Safety Outcomes: Bleeding (CURRENT defined Major/Severe and TIMI Major)Key Subgroup: PCI v No PCI

Efficacy Outcomes: CV Death, MI or stroke at day 30Stent Thrombosis at day 30

Safety Outcomes: Bleeding (CURRENT defined Major/Severe and TIMI Major)Key Subgroup: PCI v No PCI

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

TICAGRELOR

8,688

8,763

0 10 20 30

8

6

4

2

0

Cu

mu

lati

ve i

nci

de

nce

(%

)

Clopidogrel

Ticagrelor

4.77

5.43

HR 0.88 (95% CI 0.77–1.00), p=0.045

No. at risk

Clopidogrel

Ticagrelor

9,291

9,333

8,875

8,942

8,763

8,827

Days after randomisation

31 90 150 210 270 330

8

6

4

2

0

Clopidogrel

Ticagrelor

5.28

6.60

8,688

8,673

8,286

8,397

6,379

6,480

Days after randomisation*

HR 0.80 (95% CI 0.70–0.91), p<0.001

8,437

8,543

6,945

7,028

4,751

4,822

Cu

mu

lati

ve i

nci

de

nce

(%

)

Primary efficacy endpoint over time (composite of CV death, MI or stroke)

*Excludes patients with any primary event during the first 30 days

CARDIOVASCULAR DEATH IN TRITON AND PLATO TRIALS

2,12,4

4

5,1

0

5

10

TRITON PLATO

NEW DRUG

CLOPIDOGREL

P<.001

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 = 20 (46)

N=3146N=3146

17.0

12.2

Prasugrel

Clopidogrel

Prasugrel

Clopidogrel 2.6

2.5

ARC Definite or Probable Late Stent Thrombosis* in Patients Receiving DES

HR 0.46 (0.22-0.97); P=0.04

ARC = Academic Research Consortium; DES = drug-eluting stent

Days

30 90 150 210 270 330 390 450

% o

f S

ub

jec

ts

0.0

0.5

1.0

1.5

2.0

2.5

Prasugrel

Clopidogrel0.91

0.42

P=.04P=.04

NON-CABG RELATED TIMI MAJOR BLEEDING IN TRITON AND PLATO TRIALS

2,41,8

2,82,2

0

5

TRITON PLATO

CLOPIDOGREL

NEW DRUG

P=.03P=.03

FATAL BLEEDING IN TRITON AND PLATO TRIALS

0,4

0,1

0,30,3

0

1

TRITON PLATO

CLOPIDOGREL

NEW DRUG

P=.002

INTRACRANIAL HEMORRAGES IN TRITON AND PLATO TRIALS

0,30,3

0,20,1

0,3

0,1

0

1

TRITON PLATO PLATO (+Unknown origin)

CLOPIDOGREL

NEW DRUG

P=.06 P<.05

Balance of Efficacy and Safety in Patients Balance of Efficacy and Safety in Patients <75 Yrs, ≥60 kg, and Without TIA/Stroke<75 Yrs, ≥60 kg, and Without TIA/Stroke

En

dp

oin

t (%

)

0

2

4

6

8

1 0

1 2

1 4

1 6

0 30 90 180 270 360 450

Hazard Ratio, 1.240(95% CI, 0.91-1.69)

P=0.17

Hazard Ratio, 0.75(95% CI, 0.66-0.84)

P<0.001

Clopidogrel

Prasugrel

Clopidogrel

Prasugrel 1.95%

1.50%

11%

8.4%

CV Death / NF MI / NF Stroke

Non-CABG TIMI Major Bleeding

Days

NNT37

NNH222

Adapted from Wiviott SD et al NEJM 357: 2001, 2007Presented at TCT 2009, San Francisco, CA

CLINICAL CHARACTERISTICS OF TRITON AND PLATO POPULATION

Variable\\\\ TRITON PLATO

AGE (years) 61 62

% FEMALE SEX 26 28

% Cl Creat <60 ml/min 11 4

% DIABETES 23 25

% PRIOR MI 18 20

% PRIOR CABG 8 6

For High Risk,RR=0.58

[ 0.34, 0.98]P= 0.037

Parodi G. TCT 2009

COMPOSITE ENPOINT IN CURRENT-OASIS 7

4,4 4,24,2

4,9

4,53,9

0

2

4

6

ALL PATIENTS NO PCI PCI

DOUBLE

STANDARD

P=NS

P=NSP=0.036

CARDIOVASCULAR DEATH IN STEMI PATIENTS INCLUDED IN TRITON

2,4

3,43,3

4,3

0

5

10

CV DEATH ALL DEATHS

PRASUGREL

CLOPIDOGREL

STENT THROMBOSIS IN TRITON AND PLATO TRIALS

1,1

2,42,2

2,9

0

2

4

TRITON PLATO

CLOPIDOGREL

NEW DRUG

P<.001P=.02

COMPOSITE ENPOINT IN DIABETIC PATIENTS

12,2

17

14,1

16,2

0

5

10

15

20

25

TRITON PLATO

CLOPIDOGREL

NEW DRUG

P<.001NS

CARDIOVASCULAR DEATH IN TRITON AND PLATO TRIALS

2,12,4

4

5,1

0

5

10

TRITON PLATO

NEW DRUG

CLOPIDOGREL

P<.001

MYOCARDIAL INFARCTION IN TRITON AND PLATO TRIALS

7,3

9,5

5,8

6,9

0

5

10

15

TRITON PLATO

CLOPIDOGREL

NEW DRUG

P<.001

P=.005

CABG RELATED TIMI MAJOR BLEEDING IN TRITON AND PLATO TRIALS

13,4

3,25,3

5,8

0

5

10

15

20

TRITON PLATO

CLOPIDOGREL

NEW DRUG

P<.001

STROKE IN TRITON AND PLATO TRIALS

11

1,5 1,31,2 1,1

0

5

TRITON PLATO PLATO INVASIVE

CLOPIDOGREL

NEW DRUG

FATAL HEMORRAGES IN PLATO

0,10,01

0,1

0,3

0

1

INTRACRANIAL NON-INTRACRANIAL

CLOPIDOGREL

NEW DRUG

P=.03

P=.02

NON-ADHERENCE TO STUDY DRUG

( MEDIAN TREATMENT TIME FOR PLATO 9 MONTHS , FOR TRITON 14.5 MONTHS )

16,3 15,7

23,4 21,5

0

5

10

15

20

25

30

TRITON PLATO

CLOPIDOGREL

NEW DRUG

COMPOSITE ENPOINT IN CURRENT-OASIS 7

4,53,9 4,2

4,9

0

2

4

6

PCI NO PCI

DOUBLE

STANDARD

P=.036

P=NS

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 vs Standard DoseDefinite Stent Thrombosis (Angio confirmed)

Ticagrelor better Clopidogrel better

Ti. Cl.Total

Patients

KM % atMonth 12

HR (95% CI)Hazard Ratio

(95% CI)

Yes

Yes

Revascularization History of CABG

Sex

Weight Group

≥65 Years

Characteristic

0.5 1.0 2.0

17256 9.5 11.2 0.86 (0.78, 0.94)<80 kg

1312 13.1 17.3 0.75 (0.60, 0.99)≥60 kg

5288 11.2 13.2 0.83 (0.71, 0.97)

<60 kg

13336 9.2 11.1 0.85 (0.76, 0.95)Female

2878 16.8 18.3 0.94 (0.78, 1.12)

Male

15744 8.6 10.4 0.82 (0.74, 0.91)≥75 Years

7979 13.2 16.0 0.83 (0.74, 0.94)<75 Years

10643 7.2 8.5 0.85 (0.74, 0.97)<65 Years

1152 19.0 20.8 0.87 (0.66, 1.13)Age Group

17462 9.2 11.1 0.84 (0.76, 0.93)No

1106 19.5 21.7 0.88 (0.67, 1.15)Previous TIA/Non-hemorrhagic Stroke

17518 9.2 11.0 0.84 (0.77, 0.93)No

Yes

Central/South America

≥80 kg

North America

1237 15.2 17.9 0.86 (0.65, 1.13)Europe/Middle East/Africa

1714 11.4 14.8 0.80 (0.61, 1.04)Asia/Australia

4662 14.1 16.2 0.88 (0.76, 1.03)Region

13962 8.4 10.2 0.83 (0.74, 0.92)No

9513 8.3 10.5 0.79 (0.69, 0.90)Medical History of DM

9055 11.4 12.8 0.90 (0.79, 1.01)

0.2

p- value(Interaction)

0.76

0.84

0.86

0.22

0.82

0.36

0.17

0.05

1814 11.9 9.6 1.25 (0.93, 1.67)13859 8.8 11.0 0.80 (0.72, 0.90)

0.49

Primary endpoint in pre-defined subgroups (cont’d)

Ticagrelor better Clopidogrel better

Ti. Cl.Total

Patients

KM % atMonth 12

HR (95% CI)Hazard Ratio

(95% CI)

Yes

Yes

Revascularization History of CABG

Sex

Weight Group

≥65 Years

Characteristic

0.5 1.0 2.0

17086 11.5 10.9 1.06 (0.96, 1.16)<80 kg

1296 12.6 15.2 0.82 (0.60, 1.12)≥60 kg

5237 10.7 10.5 1.01 (0.85, 1.21)

<60 kg

13184 11.9 11.4 1.05 (0.94, 1.16)Female

2846 14.2 13.3 1.04 (0.84, 1.29)

Male

15574 11.1 10.8 1.04 (0.94, 1.15)≥75 Years

7892 14.4 13.6 1.07 (0.95, 1.22)<75 Years

10528 9.5 9.5 1.00 (0.87, 1.13)<65 Years

1136 14.6 14.9 0.99 (0.71, 1.37)Age Group

17284 11.4 11.0 1.04 (0.95, 1.14)No

1092 7.3 7.8 0.94 (0.60, 1.49)Previous TIA/Non-hemorrhagic Stroke

17329 11.8 11.4 1.04 (0.95, 1.14)No

Yes

Central/South America

≥80 kg

North America

1230 15.6 13.2 1.22 (0.89, 1.66)Europe/Middle East/Africa

1692 10.6 10.8 1.03 (0.76, 1.40)Asia/Australia

4621 14.1 14.8 0.95 (0.81, 1.12)Region

13800 10.8 10.0 1.08 (0.97, 1.20)No

9423 11.4 10.5 1.08 (0.95, 1.23)Medical History of DM

8959 11.7 11.9 0.99 (0.88, 1.13)

0.2

P value(Interaction)

0.68

0.77

0.42

1.00

0.76

0.12

0.35

0.75

1752 12.9 12.2 1.06 (0.80, 1.40)13747 11.1 11.0 1.01 (0.91, 1.13)

0.21

HRs and cumulative incidence of major bleeding in pre-defined subgroups (cont’d)

FATAL BLEEDING IN TRITON AND PLATO TRIALS

0,4

0,1

0,30,3

0,2

0,3

0

1

TRITON PLATO PLATO INVASIVE

CLOPIDOGREL

NEW DRUG

P=.002

MAJOR BLEEDING

Preliminary Results

Safety outcomes at 1 monthSafety outcomes at 1 month Safety outcomes at 1 monthSafety outcomes at 1 month

NSTE-ACS NSTE-ACS 2 of 3 Criteria: Ischemic symptom, ST-T change, troponin rise2 of 3 Criteria: Ischemic symptom, ST-T change, troponin rise

with TIMI score with TIMI score >> 3 3

Immediate cathImmediate cath Next day cathNext day cath

All PCIs on abciximabAll PCIs on abciximab

1-month Follow-up1-month Follow-up

IVRS RANDOMIZATIONIVRS RANDOMIZATION

85% of radial access

Preliminary Results

Safety outcomes at 1 monthSafety outcomes at 1 monthSafety outcomes at 1 monthSafety outcomes at 1 month

Immediate Delayed PP

Major bleeding at 1 month, (%)Major bleeding at 1 month, (%) 4.0 6.8 0.250.25

Non-CABG major bleedingNon-CABG major bleeding 2.3 5.1 0.260.26

CABG-related major bleedingCABG-related major bleeding 1.7 1.7 1.001.00

Transfusion Transfusion >> 2 units 2 units 3.4 5.6 0.320.32

Transfusion Transfusion >> 5 units 5 units 1.1 1.1 1.001.00

Thrombocytopenia at 1 month, (%)Thrombocytopenia at 1 month, (%) 2.9 4.5 0.410.41

Non-CABG Non-CABG thrombocytopenia,thrombocytopenia, (%) (%) 2.3 4.0 0.540.54

Post-CABG Post-CABG thrombocytopenia,thrombocytopenia, (%) (%) 0.6 0.6 1.001.00

Preliminary Results

Sites of Major BleedingsSites of Major BleedingsSites of Major BleedingsSites of Major Bleedings

1- Gastro-Intestinal1- Gastro-Intestinal 44

2- Puncture-related2- Puncture-related 44

3- Hemopericardium3- Hemopericardium 22

4- Intracranial4- Intracranial 11

5- Epistaxis5- Epistaxis 11

6- Hematoma (not puncture-related)6- Hematoma (not puncture-related) 11

unknownunknown 77

One patient had 2 bleeding events

n

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

Holter monitoring at first week , %

Ventricular pauses =>3 sec ,%

Ventricular pauses =>5 sec ,%

(n=1451)

5.8

2.0

(N=1415)

3.6

1.2

0.01

0.10

*p values were calculated using Fischer’s exact test

TCT 2009

3.0% 3.0%

3.8% 3.8%

HR [95%CI] = HR [95%CI] = 1.30 [0.86-1.95]1.30 [0.86-1.95]

P = 0.10P = 0.10

1-Year Stent Thrombosis1-Year Stent Thrombosis: Impact of : Impact of Clopidogrel Loading Dose (all pts)Clopidogrel Loading Dose (all pts)

19831983 19061906 18811881 18581858 18321832 1653165310341034 983983 974974 965965 952952 871871

Number at riskNumber at risk600 mg600 mg300 mg300 mg

600mg Clopidogrel600mg Clopidogrel

300mg Clopidogrel300mg Clopidogrel

Def

/Pro

b S

ten

t T

hro

mb

osi

s (%

)D

ef/P

rob

Ste

nt

Th

rom

bo

sis

(%)

00

11

22

33

44

55

Time in daysTime in days

00 3030 6060 9090 120120 150150 180180 210210 240240 270270 300300 330330 365365

TCT 2009

0.8%0.8%

2.2% 2.2%

3.2% 3.2%

0.8%0.8%

HR [95%CI] = HR [95%CI] = 0.96 [0.41-2.23]0.96 [0.41-2.23]

P = 0.92P = 0.92

HR [95%CI] = HR [95%CI] = 1.47 [0.93,2.33]1.47 [0.93,2.33]

P = 0.18P = 0.18

19831983

1034103419781978 19201920 18811881 18581858 18321832 16531653

10271027 990990 974974 965965 952952 871871

Number at riskNumber at risk

600 mg600 mg

300 mg300 mg

Def

/Pro

b S

ten

t T

hro

mb

osi

s (%

)D

ef/P

rob

Ste

nt

Th

rom

bo

sis

(%)

00

11

22

33

44

55

Time in DaysTime in Days

00 11 3030 9090 180180 270270 365365

Stent Thrombosis 1-Day Landmark Stent Thrombosis 1-Day Landmark Analysis:Analysis: Impact of Clopidogrel Loading Impact of Clopidogrel Loading

600mg Clopidogrel600mg Clopidogrel

300mg Clopidogrel300mg Clopidogrel

TCT 2009

2.8% 2.8%

3.6% 3.6%

HR [95%CI] =HR [95%CI] =0.78 [0.44-1.37]0.78 [0.44-1.37]

P = 0.38P = 0.38

727727 693693 685685 678678 668668 592592829829 793793 778778 768768 759759 698698

Number at riskNumber at riskEptifibatideEptifibatideAbciximabAbciximab

Def

/Pro

b S

ten

t T

hro

mb

osi

s (%

)D

ef/P

rob

Ste

nt

Th

rom

bo

sis

(%)

00

11

22

33

44

Time in daysTime in days

00 3030 6060 9090 120120 150150 180180 210210 240240 270270 300300 330330 365365

EptifibatideEptifibatide

AbciximabAbciximab

1-Year Stent Thrombosis: 1-Year Stent Thrombosis: Impact of Impact of GPI in the UFH Group GPI in the UFH Group

November 15, 2007

August 30, 2009

Conclusioni (1)

• La bivalirudina riduce i sanguinamenti locali e d’organo nei pazienti con SCA sottoposti a PCI , soprattutto in quelli a maggior rischio emorragico ( anziani ).

• Per una efficace copertura antiischemica deve essere associata ad un regime di doppia anti-aggregazione piastrinica (aspirina + bloccante recettore P2Y12).

Conclusioni (2)

- I nuovi farmaci che bloccano il recettore P2Y12 ( prasugrel, ticagrelor ) sono risultati piu’ efficaci del clopidogrel grazie alla loro migliore farmacocinetica e farmacodinamica. Ad essi si associa tuttavia un maggior rischio emorragico .

- L’analisi di efficacia e di rischio in particolari sottogruppi di pazienti con SCA potra’ permettere di utilizzare il farmaco piu’ vantaggioso per la condizione clinica del singolo paziente .

TCT 2009

Independent Predictors of Subacute ST Independent Predictors of Subacute ST (Cox Model)(Cox Model)

Variable HR [95% CI] P-value

Insulin-treated diabetes 4.43 [2.03, 9.65] 0.0002

History of CHF 4.16 [1.61, 10.76] 0.003

Pre-PCI TIMI flow 0/1 2.21 [1.05, 4.63] 0.04

Final TIMI flow 0/1 3.72 [1.10, 12.55] 0.03

Stent to lesion length ratio 1.44 [1.20, 1.71] <0.0001

Clopidogrel loading dose 600 mg (vs. 300 mg)

0.49 [0.27, 0.89] 0.01

Montalescot et al. ESC 2008

Stent thrombosis (ARC Definite/probable )

HR=0.58 (0.36–0.93) NNT=83

p=0.02 RRR=42%

0 100 200 300 4000

1

2

3

Pro

po

rtio

n o

f p

atie

nts

(%

)

Time (Days)

2.4

1.2

2.8

1.6p=0.008RRR=51%

Clopidogrel

Prasugrel

Age-adjusted HR=0.59 (0.37-0.96)

ARC Definite or Probable Stent Thrombosis (day 0 to day 450)

2.35

1.13

HR 0.48 (0.36-0.64); P<0.0001

Prasugrel

Clopidogrel

1 year: 1.06 vs. 2.15%HR 0.48 (0.36-0.65); P<0.0001

ARC = Academic Research Consortium

Days

0 50 100 150 200 250 300 350 400 450

% o

f S

ub

jec

ts

0.0

0.5

1.0

1.5

2.0

2.5

52% RRR

3

9.5

8.1

4.2

0

2

4

6

8

10

30-day 1 year

BIVALIRUDIN

UFH + GPIIbIIIa INH.

DEATH RATE IN ELDERLY PATIENTS IN THE ACUITY TRIAL

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 (%)

+ 37

-16

-1

-16

+3

-14

-13

Prasugrel Better Clopidogrel BetterHR

Pint = 0.006

Pint = 0.18

Pint = 0.36

Post-hoc analysisPost-hoc analysis

TCT 2009

2.8% 2.8%

3.6% 3.6%

HR [95%CI] =HR [95%CI] =0.78 [0.44-1.37]0.78 [0.44-1.37]

P = 0.38P = 0.38

727727 693693 685685 678678 668668 592592829829 793793 778778 768768 759759 698698

Number at riskNumber at riskEptifibatideEptifibatideAbciximabAbciximab

Def

/Pro

b S

ten

t T

hro

mb

osi

s (%

)D

ef/P

rob

Ste

nt

Th

rom

bo

sis

(%)

00

11

22

33

44

Time in daysTime in days

00 3030 6060 9090 120120 150150 180180 210210 240240 270270 300300 330330 365365

EptifibatideEptifibatide

AbciximabAbciximab

1-Year Stent Thrombosis: 1-Year Stent Thrombosis: Impact of Impact of GPI in the UFH Group GPI in the UFH Group

TCT 2009

3.0% 3.0%

3.8% 3.8%

HR [95%CI] = HR [95%CI] = 1.30 [0.86-1.95]1.30 [0.86-1.95]

P = 0.10P = 0.10

1-Year Stent Thrombosis1-Year Stent Thrombosis: Impact of : Impact of Clopidogrel Loading Dose (all pts)Clopidogrel Loading Dose (all pts)

19831983 19061906 18811881 18581858 18321832 1653165310341034 983983 974974 965965 952952 871871

Number at riskNumber at risk600 mg600 mg300 mg300 mg

600mg Clopidogrel600mg Clopidogrel

300mg Clopidogrel300mg Clopidogrel

Def

/Pro

b S

ten

t T

hro

mb

osi

s (%

)D

ef/P

rob

Ste

nt

Th

rom

bo

sis

(%)

00

11

22

33

44

55

Time in daysTime in days

00 3030 6060 9090 120120 150150 180180 210210 240240 270270 300300 330330 365365

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

Cu

mu

lati

ve i

nci

de

nce

(%

)

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

Cu

mu

lati

ve i

nci

de

nce

(%

)

Secondary efficacy endpoints over time

TICAGRELOR (AZD6140)

A non-thienopyridine, in the chemical class CPTP (CycloPentylTriazoloPyrimidine)

1) First oral reversible ADP P2Y12 receptor antagonist

2) Direct acting via the P2Y12 receptor - metabolism not

required for activity ( not a pro-drug ) 3) More potent platelet inhibitor than clopidogrel

HO

HN

HO OH

O S

F

F

NN

N

NN

2.6

7.76.8

3.2

0123456789

30-day 1 year

BIVALIRUDIN

UFH + GPIIbIIIa INH.

DEATH RATE IN ELDERLY PATIENTS UNDERGOING PCI

Messaggi finali (1)

- La doppia terapia antiaggregante e’ un cardine fondamentale del trattamento delle sindromi coronariche acute.

- Lo studio CURRENT ha mostrato che nei pazienti con sindrome coronarica acuta il doppio dosaggio di clopidogrel ( 600 mg seguito da 150 mg per una settimana ) migliora i risultati clinici ad 1 mese solo nei pazienti sottoposti a PCI.

Messaggi finali (2)

- I nuovi farmaci che bloccano il recettore P2Y12 ( prasugrel, ticagrelor ) sono risultati piu’ efficaci del clopidogrel negli studi di confronto a lungo termine grazie alla loro migliore farmacocinetica e farmacodinamica. Da non sottovalutare tuttavia il maggior rischio emorragico ad essi associato.

- L’analisi di efficacia e di rischio di questi nuovi farmaci antipiastrinici in particolari sottogruppi di pazienti con SCA potra’ permettere di utilizzare il farmaco piu’ vantaggioso per la condizione clinica del singolo paziente .

TRITON TIMI-38 STEMI cohort

Efficacy endpoints at 30 days

Montalescot et al. ESC 2008

* ARC def/probable

0

2

4

6

8

10

All Death MI UTVR StentThrombosis*

CV Death/MI

CV Death/MI/UTVR

CV Death/MI/Stroke

Pro

po

rtio

n o

f p

op

ula

tio

n (

%)

p= 0.04

p= 0.01

p= 0.13p= 0.008

p= 0.004 p= 0.02p= 0.002

Clopidogrel

Prasugrel

Other findings – laboratory parameters

All patientsTicagrelor(n=9,235)

Clopidogrel(n=9,186) p value*

% increase in creatinine from baseline

At 1 month

At 12 months

Follow-up visit

10 22

11 22

10 22

8 21

9 22

10 22

<0.001

<0.001

0.59

% increase in uric acid from baseline

At 1 month

At 12 months

Follow-up visit

14 46

15 52

7 43

7 44

7 31

8 48

<0.001

<0.001

0.56

Values are mean % SD; *p values were calculated using Fisher’s exact test

CREDO: Benefits of Clopidogrel Plus Aspirin CREDO: Benefits of Clopidogrel Plus Aspirin to 1 Year Following PCI to 1 Year Following PCI

CV Death, MI or Stroke

* Plus ASA and other standard therapies .Steinhubl S, et al. JAMA. 2002;288:2411-2420

Co

mb

ined

En

dp

oin

t O

ccu

rren

ce (

%)

Months From Randomization

27% RRR

P=.02

Placebo*Clopidogrel*

0

5

10

15

8.5%

11.5%

0 3 6 9 12

2485 PATIENTS WITH STENT PLACEMENTPRETREATED WITH CLOPIDOGREL 600 mg

August 30, 2009 at 08.00 CET

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 = 20 (46)

N=3146N=3146

17.0

12.2

Prasugrel

Clopidogrel

Prasugrel

Clopidogrel 2.6

2.5

990 patients with ACS990 patients with ACS

Patients with age <75 , weight >60 Kg Patients with age <75 , weight >60 Kg

and no prior CVA/TIAand no prior CVA/TIA

CLOPIDOGRELCLOPIDOGREL

(n=5383)(n=5383)PRASUGREL PRASUGREL

(n=5421)(n=5421)

CV EVENTS CV EVENTS 11% 11% (12,1%)(12,1%) 8,3% 8,3% (9,9%)(9,9%)

(DEATH ,MI,STROKE)(DEATH ,MI,STROKE)P<.001

NNT=37 (46)

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

3.6

1.2

0.4

0.17

0.69

0.02

*p values were calculated using Fischer’s exact test

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

Kaplan Meier estimates of non-CABG-related TIMI Major bleeding

Non-ideal population Ideal population

TIMI major non-CABG bleeding

Montalescot et al. ESC 2008

0.5

1.0

2.0

2.5

1.5

2.1

2.4

HR=1.11 (0.70–1.77) NNH=333Pro

po

rtio

n o

f p

atie

nts

(%

)

Time (Days)

p=0.65

0 100 200 300 4000

ClopidogrelPrasugrel

Age-adjusted HR=1.19 (0.75-1.89)

Montalescot et al. ESC 2008

Stent thrombosis

ARC Definite/probable

HR=0.58 (0.36–0.93) NNT=83

p=0.02 RRR=42%

0 100 200 300 4000

1

2

3

Pro

po

rtio

n o

f p

atie

nts

(%

)

Time (Days)

2.4

1.2

2.8

1.6p=0.008RRR=51%

Clopidogrel

Prasugrel

Age-adjusted HR=0.59 (0.37-0.96)

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 = 20 (46)

N=3146N=3146

17.0

12.2

Prasugrel

Clopidogrel

Prasugrel

Clopidogrel 2.6

2.5

ARC Definite or Probable Early Stent Thrombosis (0–30 days)

Prasugrel

Clopidogrel

1.56

0.64

HR 0.41 (0.29-0.59); P<0.0001

Days

0 5 10 15 20 25 30

% o

f S

ub

ject

s

0.0

0.5

1.0

1.5

2.0

2.5

ARC = Academic Research Consortium

ARC Definite or Probable Late Stent Thrombosis* in Patients Receiving DES

HR 0.46 (0.22-0.97); P=0.04

ARC = Academic Research Consortium; DES = drug-eluting stent

Days

30 90 150 210 270 330 390 450

% o

f S

ub

jec

ts

0.0

0.5

1.0

1.5

2.0

2.5

Prasugrel

Clopidogrel0.91

0.42

P=.04P=.04

COMPOSITE ENPOINT IN CURRENT-OASIS 7

4,53,9 4,2

4,9

0

2

4

6

PCI NO PCI

DOUBLE

STANDARD

P=.036

P=NS

Clopidogrel: Double vs Standard DosePrimary Outcome and Components

Standard Double HR 95% CI P Intn P

CV Death/MI/Stroke

PCI (2N=17,232) 4.5 3.9 0.85 0.74-0.99 0.0360.016

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

Overall (2N=25,087) 4.4 4.2 0.95 0.84-1.07 0.370

MI

PCI (2N=17,232) 2.6 2.0 0.78 0.64-0.95 0.0120.025

No PCI (2N=7855) 1.4 1.7 1.25 0.87-1.79 0.23

Overall (2N=25,087) 2.2 1.9 0.86 0.73-1.03 0.097

CV Death

PCI (2N=17,232) 1.9 1.9 0.96 0.77-1.19 0.681.0

No PCI (2N=7855) 2.8 2.7 0.96 0.74-1.26 0.77

Overall (2N=25,087) 2.2 2.1 0.96 0.81-1.14 0.628

Stroke

PCI (2N=17,232) 0.4 0.4 0.88 0.55-1.41 0.590.50

No PCI (2N=7855) 0.8 0.9 1.11 0.68-1.82 0.67

Overall (2N=25,087) 0.5 0.5 0.99 0.70-1.39 0.950

Death, MI , urgent revascularization

Clopidogrel in ACSClopidogrel in ACS

0,00

0,02

0,04

0,06

0,08

0,10

0,12

0,14

Cum

ulat

ive

Haz

ard

Rat

e

Clopidogrel Clopidogrel + ASA*+ ASA*

33 66 99

Placebo Placebo + ASA*+ ASA*

Months of Follow-UpMonths of Follow-Up

pp = 0.00009 = 0.00009N = 12,562N = 12,562

00 1212

* In addition to other standard therapies.* In addition to other standard therapies.The CURE Trial InvestigatorsThe CURE Trial Investigators. . N Engl J Med.N Engl J Med. 2001;345:494 2001;345:494

20%20%Relative RiskRelative Risk

ReductionReduction

Primary End Point – MI/Stroke/CV DeathPrimary End Point – MI/Stroke/CV Death

TIMI major and minor bleeding TIMI major and minor bleeding

Should we use bivalirudin ?

FibrinFibrin

2

1

ThrombinThrombin2

1

ThrombinThrombin

2

1

TrombinaTrombina

2

1

TrombinaTrombina

BivalirudinBivalirudin

Bivalirudin as an Alternative to UFH/LMWHBivalirudin as an Alternative to UFH/LMWH

• Advantages of the direct thrombin inhibitor bivalirudin

– No requirement for anti-thrombin III– Effective on clot-bound thrombin– Inhibits thrombin-mediated platelet activation– Plasma half-life 25 minutes– No requirement for anticoagulant monitoring

• Advantages of the direct thrombin inhibitor bivalirudin

– No requirement for anti-thrombin III– Effective on clot-bound thrombin– Inhibits thrombin-mediated platelet activation– Plasma half-life 25 minutes– No requirement for anticoagulant monitoring

3.4

4.7

1.4

5.9

4.8

10.6

0,0

5,0

10,0

15,0

Inability to cross Crossover Failure

RADIAL ACCESS

FEMORAL ACCESS