The Landscape of Oral The Landscape of Oral Antiplatelet Agents 2009Antiplatelet Agents 2009

George D. Dangas, MD, PhD, FSCAI, FACCGeorge D. Dangas, MD, PhD, FSCAI, FACC

Associate Professor of MedicineAssociate Professor of Medicine

Columbia University Medical CenterColumbia University Medical Center

DisclosuresDisclosures

• Advisory Board: Accumetrics, Astra-Advisory Board: Accumetrics, Astra-ZenecaZeneca

• Consultant: Lilly, Daichi-SankyoConsultant: Lilly, Daichi-Sankyo

• Speaker honoraria: Sanofi-Aventis, Speaker honoraria: Sanofi-Aventis, BMSBMS

EPISTENT: IV vs po Anti-Platelet RxEPISTENT: IV vs po Anti-Platelet Rx

IV placebo/abciximab & po ticlopidine preRx/no-preRxIV placebo/abciximab & po ticlopidine preRx/no-preRx

Steinhubl SR, Steinhubl SR, CirculationCirculation 1998;98:I-573 1998;98:I-573

0

5

10

15

% MACE% MACE(Death, MI,(Death, MI,

Urgent Urgent Revasc)Revasc)

Placebo/Placebo/No PreRxNo PreRx

N=343N=343

Abciximab/Abciximab/No PreRxNo PreRx

N=328N=328

Abciximab/Abciximab/ PreRxPreRxN=466N=466

Placebo/Placebo/PreRxPreRxN=466N=466

13.413.4

8.98.9

5.55.5 5.25.2

33% 33% P=0.033P=0.033

38% 38% P=0.028P=0.028

Currently Ticlopidine is reserved for clopidogrel allergy. Requires frequent CBCCurrently Ticlopidine is reserved for clopidogrel allergy. Requires frequent CBC

Pro

po

rtio

n E

ven

t-F

ree

Benefit of Clopidogrel Therapy at Early and Late Time Intervals

Months

0.90

0.92

0.94

0.96

0.98

1.00

1 4 6 8 10 12Weeks

Pro

po

rtio

n E

ven

t-F

ree

0.90

0.92

0.94

0.96

0.98

1.00

0 1 2 3 4

RRR 21%RRR 21%95% CI 0.67–0.92 P=0.003P=0.003

Clopidogrel + ASA

Placebo + ASA

MI, stroke, CV Death: 0–30 days

Yusuf S et al for the CURE Trial Investigators. Yusuf S et al for the CURE Trial Investigators. CirculationCirculation. 2003;107:966-972.. 2003;107:966-972.

MI, stroke, CV Death: 31 d - 1 y

RRR 18%RRR 18%95% CI 0.70–0.95 P=0.009P=0.009

Clopidogrel + ASA

Placebo + ASA

CUREACS pts

CLARITY trial of APT in STEMI:CLARITY trial of APT in STEMI:Occluded Artery Occluded Artery (or D/MI thru Angio/HD)(or D/MI thru Angio/HD)

15.0

21.7

0

5

10

15

20

25

Occ

lud

ed A

rter

y o

r D

eath

/MI

(%

)

PlaceboPlaceboClopidogrelClopidogrel

P=0.00000036P=0.00000036P=0.00000036P=0.00000036

Odds Ratio 0.64Odds Ratio 0.64(95% CI 0.53-0.76)(95% CI 0.53-0.76)

Odds Ratio 0.64Odds Ratio 0.64(95% CI 0.53-0.76)(95% CI 0.53-0.76)

1.00.4 0.6 0.8 1.2 1.6

ClopidogrelClopidogrelbetterbetter

PlaceboPlacebobetterbetter

n=1752 n=1739

36%Odds Reduction

36%Odds Reduction

Safety of Long-Term Clopidogrel3 Placebo Controlled Trials3 Placebo Controlled Trials

3.7%

8.8%

3.8%2.7%

6.7%

2.6%

0%

2%

4%

6%

8%

10%

CURE CREDO CHARISMA

Sig

nif

ica

nt

ble

edin

g (

%) ASA + Clopidogrel

ASA + Placebo

3.7%

8.8%

3.8%2.7%

6.7%

2.6%

0%

2%

4%

6%

8%

10%

CURE CREDO CHARISMA

Sig

nif

ica

nt

ble

edin

g (

%) ASA + Clopidogrel

ASA + Placebo

P=0.001P=0.001

NEJM 2006;354:1706-17NEJM 2006;354:1706-17

N=15,603N=15,6032.5 year FU2.5 year FU

GUSTO major GUSTO major + moderate bleed+ moderate bleed

N=12,563N=12,5631 year FU1 year FU

CURE major bleedCURE major bleedNEJM 2001;345;494-502NEJM 2001;345;494-502

N=2,116N=2,1161 year FU1 year FU

TIMI major bleedTIMI major bleedJAMA 2002;288:2411-20JAMA 2002;288:2411-20

P=0.07P=0.07

P<0.001P<0.001

Placebo+ ASA*

Clopidogrel+ ASA*

Major Bleeding by ASA DoseMajor Bleeding by ASA Dose

<100 mg<100 mg 2.6% 2.6% 2.0%2.0%

100–200 mg 100–200 mg 3.5% 3.5% 2.3% 2.3%

>200 mg>200 mg 4.9% 4.9% 4.0% 4.0%

ASA Dose

CURE

Mean ±SD Control VASP-guided p

VASP after first LD, % 68 ±11 69 ±10 0.4

VASP after adjustment, % 38 ±14* *<0.001

Bonello et al. J Am Coll Cardiol 2008

MACE: CV death, MI, revascularization

Log rank p =0.007

Step-wise reloading increased % Inhibition and % responders

After a 600mg clopidogrel LD, poor responders (PRI ≥ 50%) received additional 600mg bolus (max 2400 mg) until reaching therapeutic target.

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

Clop in 1st 7d (median) 7d 7 d 2 d 7d

Complete Followup

99.8%

Complete Followup

99.8%

Compliance:Compliance:

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 0.311ICH, 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

Definite Stent Thrombosis in 4 Groups (Angiographically Proven)

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

C Standard, A Low

C Standard, A High

C Double, A Low

C Double, A High

Standard Clop

Double Clop

HR PP

Intn

High ASA 1.2 0.6 0.49 0.003

Low ASA 1.2 0.8 0.6 0.058 0.35

45.4

61.9

0

20

40

60

80

100

30.8

64.574.8

69.3

4.9 20.3

31.8

32.6

0

20

40

60

80

100

0 4 8 12 16 20 24 28

PRINCIPLE-TIMI 44: Comparison of Prasugrel with Higher Dose Clopidogrel

P<0.0001 for eachP<0.0001 for each

IPA (%; 20 M ADP)

Hours 14 Days

IPA (%; 20 M ADP)

P<0.0001P<0.0001

Prasugrel 10 mg

Clopidogrel 150 mg

Wiviott et al Circ 2007

N=201

Prasugrel 60 mg

Clopidogrel 600 mg

Balance of Efficacy and Safety

0

5

10

0 30 60 90 180 270 360 450

HR 0.81(0.73-0.90)P=0.0004P=0.0004

Prasugrel

Clopidogrel

Days

En

dp

oin

t (%

)

12.1

9.9

HR 1.32(1.03-1.68)

P=0.03P=0.03

Prasugrel

Clopidogrel1.82.4

138 events

35 events

CV Death / MI / Stroke

TIMI Major NonCABG Bleeds

NNT = 46

NNH = 167

15

TIMI-38 STENT ANALYSISTIMI-38 STENT ANALYSISDefinite/Probable ST: DES Only (N=5743)Definite/Probable ST: DES Only (N=5743)

% o

f S

ub

jec

ts

HR 0.29 [0.15-0.56]P=0.0001P=0.0001

HR 0.46 [0.22-0.97]P=0.04P=0.04

DAYS

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

EARLY ST LATE ST

1.44%

0.42%

71% 0.91%

0.42%

54%

CLOPIDOGREL

PRASUGREL

Wiviott et al, SCAI-ACCi2 2008

TIMI-38 STENT ANALYSISTIMI-38 STENT ANALYSISDefinite/Probable ST: BMS Only (N=6461)Definite/Probable ST: BMS Only (N=6461)

% o

f S

ub

jec

ts

HR 0.45 [0.28-0.73] P=0.0009P=0.0009

HR 0.68 [0.35-1.31]P=0.24P=0.24

DAYS

0

0.5

1

1.5

2

2.5

30 90 150 210 270 330 390 4500

0.5

1

1.5

2

2.5

0 5 10 15 20 25 30

EARLY ST LATE ST

1.66%

0.75%

55% 0.78%

0.53%

32%

CLOPIDOGREL

PRASUGREL

Wiviott et al, SCAI-ACCi2 2008

AZD6140: Inhibition of Platelet aggregation Compared With Clopidogrel in NSTEMI ACS

Patients (DISPERSE-2)Inhibition of platelet aggregation after initial doses

Storey, RF et al. J Am Coll Cardiol.2007;50:1852-6

*P<0.05

Mean % inhibition of platelet aggregation derived from maximum aggregation response after addition of ADP 20 mol/l (optical aggregometry).

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, then

90 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

121110

9876543210

13

Cu

mu

lati

ve in

cid

ence

(%

)

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

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

Non-CABG and CABG-related major bleeding

p=0.026

p=0.025

NS

NS

9K

-M e

stim

ated

rat

e (

% p

er y

ear)

Non-CABGPLATO major

bleeding

8

7

6

5

4

3

2

1

0Non-CABGTIMI major bleeding

CABGPLATO major

bleeding

CABG TIMI major bleeding

4.5

3.8

2.8

2.2

7.4

7.9

5.3

5.8

TicagrelorClopidogrel

Safety of New DAPT Regimens3 Active Controlled Trials (vs Standard Clop) 3 Active Controlled Trials (vs Standard Clop)

2.0%3.8% 3.8% 3.2%

7.9%

2.5%

5.0% 4.5%

13.4%

7.4%

0%

3%

6%

9%

12%

15%

CURRENT TRITON PLATO TRITONCABG

PLATOCABG

Sign

ifica

nt b

leed

ing

(%)

ASA + ClopidogrelNew Regimen

2.0%3.8% 3.8% 3.2%

7.9%

2.5%

5.0% 4.5%

13.4%

7.4%

0%

3%

6%

9%

12%

15%

CURRENT TRITON PLATO TRITONCABG

PLATOCABG

Sign

ifica

nt b

leed

ing

(%)

ASA + ClopidogrelNew Regimen

P=0.001P=0.001

N=25,087N=25,0871-month FU1-month FUCURRENT CURRENT major bleedmajor bleedNEJM 2009NEJM 2009

P<0.001P<0.001 P=0.32P=0.32

N=13,608N=13,60815-month FU15-month FU

TIMI major+minor TIMI major+minor bleedbleed

NEJM 2007NEJM 2007

N=18,864N=18,86412-month FU12-month FU

PLATOPLATOMajor bleedMajor bleedNEJM 2009NEJM 2009

TIMI major+minor TIMI major+minor bleedbleed

NEJM 2007NEJM 2007

PLATOPLATOMajor bleedMajor bleedNEJM 2009NEJM 2009

P=0.03P=0.03P=0.002P=0.002

Non-CABG related bleedingNon-CABG related bleeding

Efficacy of New DAPT Rx in ACS3 Active Controlled Trials (vs Standard Clop) 3 Active Controlled Trials (vs Standard Clop)

4.4%

12.1% 11.7%

2.3% 2.4% 2.8%

4.2%

9.9% 9.8%

1.6% 1.1%2.1%

0%

3%

6%

9%

12%

15%

CURRENT TRITON PLATO CURR. ST TRITON ST PLATO ST

Sign

ifica

nt E

vent

s (%

)

ASA + Clopidogrel

New Regimen

4.4%

12.1% 11.7%

2.3% 2.4% 2.8%

4.2%

9.9% 9.8%

1.6% 1.1%2.1%

0%

3%

6%

9%

12%

15%

CURRENT TRITON PLATO CURR. ST TRITON ST PLATO ST

Sign

ifica

nt E

vent

s (%

)

ASA + Clopidogrel

New Regimen

P=0.37P=0.37

N=25,087N=25,0871-month FU1-month FUD/MI/CVAD/MI/CVAESC 2009ESC 2009

P=0.02P=0.02

N=13,608N=13,60815-month FU15-month FU

D/MI/CVAD/MI/CVANEJM 2007NEJM 2007

Def/ProbDef/ProbESC 2009ESC 2009

Def/ProbDef/ProbNEJM 2007NEJM 2007

Def/ProbDef/ProbNEJM 2009NEJM 2009

P=0.0003P=0.0003

P=0.002P=0.002 P<0.001P<0.001

P<0.001P<0.001

N=18,864N=18,8641- Year FU1- Year FUD/MI/CVAD/MI/CVANEJM 2009NEJM 2009

Efficacy of New DAPT Rx: ACS+PCI3 Active Controlled Trials (vs Standard Clop) 3 Active Controlled Trials (vs Standard Clop)

4.5%

12.1%

0.0%

2.3% 2.4% 2.8%3.9%

9.9%

0.0%

1.6% 1.1%2.1%

0%

3%

6%

9%

12%

15%

CURRENT TRITON PLATO CURR. ST TRITON ST PLATO ST

Sign

ifica

nt E

vent

s (%

)

ASA + Clopidogrel

New Regimen

4.5%

12.1%

0.0%

2.3% 2.4% 2.8%3.9%

9.9%

0.0%

1.6% 1.1%2.1%

0%

3%

6%

9%

12%

15%

CURRENT TRITON PLATO CURR. ST TRITON ST PLATO ST

Sign

ifica

nt E

vent

s (%

)

ASA + Clopidogrel

New Regimen

P=0.04P=0.04

N=17,232N=17,2321-month FU1-month FUD/MI/CVAD/MI/CVA

ESC 2009ESC 2009

P<0.001P<0.001 P=0.02P=0.02

N=13,608N=13,60815-month FU15-month FU

D/MI/CVAD/MI/CVANEJM 2007NEJM 2007

Def/ProbDef/Prob

ESC 2009ESC 2009

Def/ProbDef/Prob

NEJM 2007NEJM 2007

Def/ProbDef/Prob

NEJM 2009NEJM 2009

P=0.0P=0.0

P=0.002P=0.002

P<0.001P<0.001

N=11,289N=11,2891-year FU1-year FUD/MI/CVAD/MI/CVATCT 2009TCT 2009

ACC/AHA/SCAI Guideline Update for PCIOral Antiplatelet Adjunctive Therapies

In patients in whom subacute thrombosis may be catastrophic or lethal (unprotected left main, bifurcating left main, or last patent coronary vessel), platelet aggregation studies may be considered and the dose of clopidogrel increased to 150 mg per day if less than 50% inhibition of platelet aggregation is demonstrated.

I IIa IIb III

C

Antiplatelet Therapy SummaryAntiplatelet Therapy Summary

• Major recent advances in clinical research have Major recent advances in clinical research have established the value of early + sustained therapy with established the value of early + sustained therapy with combination oral antiplatelet agents for CADcombination oral antiplatelet agents for CAD

• More complex combination regimens are under More complex combination regimens are under investigations that address the different clinical investigations that address the different clinical situations situations

• Prasugrel: newest addition as an FDA approved agent. Prasugrel: newest addition as an FDA approved agent. Improved efficacy. Drawback bleeding. Need for risk Improved efficacy. Drawback bleeding. Need for risk stratificationstratification

• Ticagrelor: newest clinical results with improved Ticagrelor: newest clinical results with improved efficacy. Reversibility likely related to less CABG efficacy. Reversibility likely related to less CABG bleeding. bleeding.

• CilostazolCilostazol 3ple combination therapy investigational3ple combination therapy investigational