The Role of New Anti-Platelet Agents: Will Prasugrel and …summitmd.com/pdf/pdf/1134_3.DAPT and DES.pdf · The Role of New Anti-Platelet Agents: Will Prasugrel and Ticagrelor Change

Columbia University Medical CenterColumbia University Medical CenterThe Cardiovascular Research FoundationThe Cardiovascular Research Foundation

The Role of New Anti-Platelet Agents:Will Prasugrel and Ticagrelor Change the DES Landscape?

The Role of New Anti-Platelet Agents:Will Prasugrel and Ticagrelor Change the DES Landscape?

Roxana Mehran, MDAssociate Professor of Medicine

Roxana Mehran, MDAssociate Professor of Medicine

Clinical Research Support to Columbia: Clinical Research Support to Columbia: Sanofi/Aventis, BMS, BraccoSanofi/Aventis, BMS, Bracco

Educational/Research Support to CRF: TMC, Educational/Research Support to CRF: TMC, Boston Scientific, Abbott, Medtronic, Cordis, Boston Scientific, Abbott, Medtronic, Cordis, Lilly/Diachi Sankyo, BMS, AZLilly/Diachi Sankyo, BMS, AZ

Consultant/Honoraria: TMC, Sanofi/Aventis, Consultant/Honoraria: TMC, Sanofi/Aventis, Astra Zeneca, Cordis, Therox, Bracco, Astra Zeneca, Cordis, Therox, Bracco, Guerbert, Regado, GileadGuerbert, Regado, Gilead

Clinical Research Support to Columbia: Clinical Research Support to Columbia: Sanofi/Aventis, BMS, BraccoSanofi/Aventis, BMS, Bracco

Educational/Research Support to CRF: TMC, Educational/Research Support to CRF: TMC, Boston Scientific, Abbott, Medtronic, Cordis, Boston Scientific, Abbott, Medtronic, Cordis, Lilly/Diachi Sankyo, BMS, AZLilly/Diachi Sankyo, BMS, AZ

Consultant/Honoraria: TMC, Sanofi/Aventis, Consultant/Honoraria: TMC, Sanofi/Aventis, Astra Zeneca, Cordis, Therox, Bracco, Astra Zeneca, Cordis, Therox, Bracco, Guerbert, Regado, GileadGuerbert, Regado, Gilead

Disclosures: Roxana Mehran

CollagenTXA2

ADPADP

TXA2

ADP PDEPDE

ADP

(Fibrinogen(Fibrinogenreceptor)receptor)

GP IIb/IIIaGP IIb/IIIa

Activation

COX

TiclopidineClopidogrelPrasugrelAZD6140Cangrelor

PRT060128

ASA

Dipyridamole

↑cAMP

Targets for antiplatelet therapies

Thrombin PAR-1

SCH 530348

AbciximabEptifibatide

Tirofiban

Courtesy of BM Scirica, MD.Adapted from Schafer AI.

Am J Med. 1996;101:199-209.cAMP = cyclic adenosine monophosphate, COX = cyclooxygenase, PAR = protease-activated receptor, PDE = phosphodiesterase

2.72.7

6.26.2

3.63.6

3.93.9

0.50.5

1.61.6

5.7 5.7

0.8 0.8

00 3.03.0 5.05.0 8.08.0 1212

STARS (1998)STARS (1998)33

ISAR (1997)ISAR (1997)22

MATTIS (1998)MATTIS (1998)44

Hall (1996)Hall (1996)11

11 Hall P, et al. Hall P, et al. CirculationCirculation. 1996;93:215. 1996;93:215--222.222.22 Schömig A, et al. Schömig A, et al. N Engl J MedN Engl J Med. 1996;335:1084. 1996;335:1084--1089.1089.33 Leon M, et al. Leon M, et al. N Engl J MedN Engl J Med. 1998:339:1665. 1998:339:1665--71.71.44 Urban P, et al. Urban P, et al. CirculationCirculation. 1998 98:2126. 1998 98:2126--2132.2132.5 5 Bertrand M, et al. Bertrand M, et al. Circulation. Circulation. 1998;98:15971998;98:1597--1603. (Events include death, Q1603. (Events include death, Q--wave or nonwave or non--QQ--wave MI).wave MI).

Combination Antiplatelet Therapy Combination Antiplatelet Therapy Reduces Coronary Events after StentingReduces Coronary Events after Stenting

ASA + TiclopidineASA + TiclopidineASA onlyASA onlyASA + WarfarinASA + Warfarin

11.011.0

FANTASTIC (1998)FANTASTIC (1998)55

N =485N =485

5.65.6

8.38.3

N=226N=226

N=517N=517

N=1653N=1653

N=350N=350

P=0.1P=0.1

P=0.01P=0.01

P<0.001P<0.001

Cumulative Event Rate (%)Cumulative Event Rate (%)

P=0.07P=0.07

P=0.37P=0.37

Clopidogrel Trials – ACS/CAD

COMMITCOMMIT(CCS(CCS--2)2)

CAPRIECAPRIELancet 1996Lancet 1996

MI / stroke PAD

2.5 yearsBenefit

selected 2o Prev

STEMI

Acute STEMI Long-term 2o 1 1o preventionUA/NSTEMI PCI

PCIUA/ NSTEMI

+ Benefit + Benefit

1 Year 1 Year

+ Benefit1-3 Years30 Days

+ Benefit

PCI –

ARMYDA-2 Study: Design and Primary End PointPrimary composite of death, MI,

or target vessel revasc. at 30 daysP=.041

4%

0%

2%

4%

6%

8%

10%

12%

14%

600 mg 300 mg

12%

High Loading Dose of

Clopidogrel600 mgPre-PCI

Standard Loading Dose of

Clopidogrel 300 mgPre-PCI

255 patients with stable CAD or NSTEMI prior to PCI

13% received GP IIb/IIIa inhibitors20% received drug-eluting stents

Randomized 4-8 Hours Pre-PCI

ARMYDA-2, Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty.Patti G, et al. Circulation. 2005;111(16):2099-2106.

Study Design, Flow and Compliance25,087 ACS Patients (UA/NSTEMI 70.8%, STEMI 29.2%)

ü Planned Early (<24 h) Invasive Management with intended PCIü Ischemic ECG Δ (80.8%) or ↑cardiac biomarker (42%)

25,087 ACS Patients (UA/NSTEMI 70.8%, STEMI 29.2%)ü Planned Early (<24 h) Invasive Management with intended PCIü Ischemic 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

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

Complete Followup

99.8%

Compliance:

Days

Cum

ulat

ive

Haz

ard

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)

Days

Cum

ulat

ive

Haz

ard

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% RRR

CV Death, MI or Stroke

Definite Stent Thrombosis in 4 Groups (Angiographically Proven)

Days

Cum

ulat

ive

Haz

ard

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 P

PIntn

High ASA 1.2 0.6 0.49 0.003

Low ASA 1.2 0.8 0.6 0.058 0.35

0

5

10

15

0 30 60 90 180 270 360 450

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

Prasugrel

Clopidogrel

HR 0.80P=0.0003P=0.0003

HR 0.77P=0.0001P=0.0001

Days

Prim

ary

Endp

oint

(%)

12.1(781)

9.9 (643)

NNT= 46

ITT= 13,608ITT= 13,608 LTFU = 14 (0.1%)LTFU = 14 (0.1%)

Primary Endpoint CV Death,MI,Stroke

Stent Thrombosis(ARC Definite + Probable)

0

1

2

3

0 30 60 90 180 270 360 450

HR 0.48P <0.0001P <0.0001

Prasugrel

Clopidogrel 2.4(142)

NNT= 77

1.1 (68)

Days

Endp

oint

(%)

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

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 Sub

ject

s

0

5

10

15

0 30 60 90 180 270 360 450

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

Prasugrel

Clopidogrel

Days

Endp

oint

(%)

12.1

9.9

HR 1.32(1.03-1.68)

P=0.03P=0.03

Prasugrel

Clopidogrel1.82.4

138events

35events

CV Death / MI / Stroke

TIMI Major NonCABG Bleeds

NNT = 46

NNH = 167

Balance of Efficacy and Safety

Ticagrelor (AZD 6140): an oral reversible P2Y12 antagonist

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

OH

OH

O

OH

N

F

S

NH

NN

NN

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

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

ClopidogrelTicagrelor

9,2919,333

8,5218,628

8,3628,460

8,124

Days after randomisation

6,7436,743

5,0965,161

4,0474,147

0 60 120 180 240 300 360

121110

9876543210

13

Cum

ulat

ive

inci

denc

e (%

)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


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

ulat

ive

inci

denc

e (%

)

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


7079

7119

5,441

5,482

4,364

4,4198,626

Myocardial infarction Cardiovascular death

Cum

ulat

ive

inci

denc

e (%

)

Secondary efficacy endpoints over time

Stent thrombosis

Ticagrelor(n=5,640)

Clopidogrel(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

ClopidogrelTicagrelor

9,1869,235

7,3057,246

6,9306,826

6,670

Days from first IP dose

5,2095,129

3,8413,783

3,4793,433

0 60 120 180 240 300 360

10

5

0

15

Clopidogrel

Ticagrelor11.2011.58

6,545

HR 1.04 (95% CI 0.95–1.13), p=0.434K-M

est

imat

ed ra

te (%

per

yea

r)

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

Sig

nif

ican

t b

leed

ing

(%

) ASA + ClopidogrelNew Regimen

P=0.001P=0.001

N=25,087N=25,08711--month FUmonth FUCURRENT CURRENT major bleedmajor bleed

NEJM 2009NEJM 2009

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

N=13,608N=13,6081515--month FUmonth FU

TIMI major+minor TIMI major+minor bleedbleed

NEJM 2007NEJM 2007


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

NonNon--CABG related bleedingCABG 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

Sig

nif

ica

nt

Ev

en

ts (

%) ASA + Clopidogrel

New Regimen

P=0.37P=0.37


D/MI/CVAD/MI/CVAESC 2009ESC 2009

P=0.02P=0.02


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

Def/ProbDef/ProbESC 2009ESC 2009

Def/ProbDef/ProbNEJM 2007NEJM 2007


P=0.0003P=0.0003

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

P<0.001P<0.001

N=18,864N=18,86411-- Year FUYear 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%10.7%

2.3% 2.4% 2.3%3.9%

9.9%9.0%

1.6% 1.1% 1.7%

0%

3%

6%

9%

12%

15%

CURRENT TRITON PLATO CURR. ST TRITON ST PLATO ST

Sig

nif

ican

t E

ven

ts (

%) ASA + Clopidogrel

New Regimen

P=0.04P=0.04


D/MI/CVAD/MI/CVAESC 2009ESC 2009

P<0.001P<0.001 P=0.01P=0.01


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

Def/ProbDef/ProbESC 2009ESC 2009



P=0.003P=0.003

P=0.002P=0.002

P<0.001P<0.001

N=11,289N=11,28911--year FUyear FUD/MI/CVAD/MI/CVATCT 2009TCT 2009

How will these results change the landscape?

ischemic ischemic events events bleedingbleedingThrombosis Bleeding

25

Stent thrombosis: Past and present trial results

02468

1012141618

0-30d

CoumadinHigh-pressure

balloons and Ticlid®

SES BMS PES BMS

0-30d 30d-1y 1y-4y

30 day resultsBMS Trials 1991-1997

4 year results definite and probable ARCPooled DES vs BMS Trials 2002-2006

16%

0.6%

Schatz et al. Circulation.1991;83:148; Fischman et al. N Engl J Med. 1994;331496; Colombo et al. Circulation.1995;91:1676; Schömig et al.Circulation.1994,90:2716; Leon et al. N Engl J Med. 1998;339:1665; Mauri et al. N Engl J Med. 2007;356:1020-9.

26Cutlip et al. Circulation 2004; 110: 1226–1230.

18.3%

2.3%1.3% 1.5% 1.4%

5.6%7.0%

5.7%6.7%

12.4%

0%

5%

10%

15%

20%

25%

Year 1 Year 2 Year 3 Year 4 Year 5

Haz

ard

Rat

e

Target Lesion EventNon-target Lesion Event

bbbbbbbbbbb

Non Target Lesion Events outnumber stent Non Target Lesion Events outnumber stent specific outcomes in long term follow upspecific outcomes in long term follow upHCRI database N=6186 with complete 5y follow upHCRI database N=6186 with complete 5y follow up

27

Stent thrombosis accounts for a minority of Stent thrombosis accounts for a minority of clinical eventsclinical events

SESSES BMSBMS PESPES BMSBMS

DeathDeath 57 (6.7%)57 (6.7%) 45 (5.3%)45 (5.3%) 86 (6.1%)86 (6.1%) 92 (6.6%)92 (6.6%)

ST DeathST Death 4 (0.5%)4 (0.5%) 5 (0.6%)5 (0.6%) 7 (0.5%)7 (0.5%) 5 (0.4%)5 (0.4%)

ST death/ST death/total deathtotal death

7%7% 11%11% 8%8% 6 %6 %

ST represents less about 10% of mortality, and a smaller proportion of death/MI composite.

Clinical endpoints may not distinguish differences in ST

Mauri, L. N Engl J Med 2007;356:1020-9.

Bleeding and Mortality

Major Bleeding

TransfusionHypotension

Ischemia Stent Thrombosis Inflammation

Mortality

Cessation of ASA/Clop

Bhatt DL. In Braunwald EB, Harrison’s Online. 2005.

HR [95% CI] P-valueAttributable

DeathsRisk Factor

TimeTime--updated covariate adjusted Cox model updated covariate adjusted Cox model relating 30relating 30--day events to 30day events to 30--day mortalityday mortality

-- Complete modelComplete model in 3,124 pts with successfully implanted stents in 3,124 pts with successfully implanted stents --

Hazard Ratio [95% CI]Hazard Ratio [95% CI]0.01 0.1 1 10 100

CC--statistic = 0.87. statistic = 0.87. Attributable deaths = N deaths among pts Attributable deaths = N deaths among pts with the time updated event (attribute) X (adj. HR with the time updated event (attribute) X (adj. HR –– 1)/adj. HR1)/adj. HR

*8.3% of 54 total deaths*8.3% of 54 total deaths**28.0% of 54 total deaths**28.0% of 54 total deaths

Major bleeding(non CABG)Incidence 195 (6.2%)18 deaths with event

6.22[3.33, 11.60]

<0.001 15.1** 15.1** [12.6, 16.4][12.6, 16.4]

Stent thrombosis(definite)Incidence 57 (1.8%)5 deaths with event

10.62[3.96, 28.48]

<0.001 4.5* 4.5* [3.7, 4.8][3.7, 4.8]

Definitions of Major/Severe Bleeding Definitions of Major/Severe Bleeding in Randomized Controlled Clinical Trialsin Randomized Controlled Clinical Trials

PLATOACUITYHORIZONSSTEEPLECUREOASIS-5

ESSENCEREPLACE-2TIMI phase II

TIMI phase IGUSTOType of bleeding

+++++++++Intracranial/intracerebral

++++++---Intraocular

-+++++---Retroperitoneal

+-++----+Bleeding causing hemodynamic compromise

+-----++-Cardiac tamponade

++++-----Bleeding requiring surgical intervention

-+-------Hematoma >5cm at the puncture site

≥4≥1≥1≥2≥2≥2≥1≥1≥1Transfusion, units

≥5.0≥3.0≥3.0-≥3.0≥3.0≥3.0≥5.0*-Decrease in Hgb with overt bleeding, g/dL

-≥4.0-≥5.0-≥4.0---Decrease in Hgb withoutovert bleeding, g/dL

*Or decrease in Hct ≥15%

Type of BleedType of Bleed HR (95% CI)HR (95% CI) PP--valuevalue

Attributable Attributable deaths deaths

within 1 yrwithin 1 yr

TIMI major bleedTIMI major bleed 4.85 (3.564.85 (3.56--6.60)6.60) <0.001<0.001 5353

ACUITY major (non TIMI ACUITY major (non TIMI major) bleed with major) bleed with transfusion*transfusion*

2.98 (2.102.98 (2.10--4.24)4.24) <0.001<0.001 4040

ACUITY major (non TIMI ACUITY major (non TIMI major) bleed without major) bleed without transfusion*transfusion*

1.79 (1.091.79 (1.09--2.93)2.93) 0.020.02 1717

Hematoma ≥5 cm onlyHematoma ≥5 cm only 1.30 (0.581.30 (0.58--2.92)2.92) 0.530.53 66

Influence of Bleeding Severity within 30 Days Influence of Bleeding Severity within 30 Days After PCI on the Risk of Death Over 1 YearAfter PCI on the Risk of Death Over 1 Year

Baseline covariateBaseline covariate--adjusted timeadjusted time--updated Cox multivariable modelupdated Cox multivariable model

HR (HR (95%CI95%CI))

* Excluding hematomas if the only criteria* Excluding hematomas if the only criteriaEach patient is represented only once according to their most severe bleedEach patient is represented only once according to their most severe bleed

D 5mkM ADP Platelet Aggregation

Patient Numbers112

32

0

48

64

16

< 0

80

96

(0,10)(11,20)

(21,30)(31,40)

(41,50)(51,60)

(61,70)(71,80)

(81,90)(91,100)

>100

D 5mkM ADP Platelet Aggregation

Patient Numbers112

32

0

48

64

16

< 0

80

96

(0,10)(11,20)

(21,30)(31,40)

(41,50)(51,60)

(61,70)(71,80)

(81,90)(91,100)

>100

Change in Platelet Aggregation between Pre- and Post-Clopidogrel Time Points: Distribution

Mean 41.9%

Hypo

(-2 SD)Hyper

(+2 SD)

From Serebruany, et al. JACC 2005;45:246-251

Impact of clopidogrel hyporesponsiveness Impact of clopidogrel hyporesponsiveness after stents: after stents: 683 pts with ACS after BMS or DES were 683 pts with ACS after BMS or DES were tested by the VerifyNow P2Y12 assay within 24 hrs after tested by the VerifyNow P2Y12 assay within 24 hrs after

600 mg clopidogrel load. By ROC, pts with PRU ≥240 600 mg clopidogrel load. By ROC, pts with PRU ≥240 defined as nonresponders. defined as nonresponders.

MarcucciMarcucci R et al. Circulation 2009;119:237R et al. Circulation 2009;119:237--242242

P=0.01P=0.01 P=0.23P=0.23P=0.006P=0.006P=0.03P=0.03

Impact of clopidogrel hyporesponsiveness Impact of clopidogrel hyporesponsiveness after DES: after DES: 804 pts after PES or SES were tested by LTA 804 pts after PES or SES were tested by LTA

1212--18 hrs after 600 mg clopidogrel load. Pts with platelet 18 hrs after 600 mg clopidogrel load. Pts with platelet aggregation by 10 umol ADP ≥90th percentile of controls aggregation by 10 umol ADP ≥90th percentile of controls

(70%) were defined as non responders. (70%) were defined as non responders.

Buonamici P et al. JACC 2007;49:2312Buonamici P et al. JACC 2007;49:2312––77

P<0.001P<0.001P<0.001P<0.001 P<0.001P<0.001

P=0.61P=0.61

N=2N=9

Impact of clopidogrel Impact of clopidogrel hyporesponsiveness after DEShyporesponsiveness after DES

Price MJ et al. Price MJ et al. EHJEHJ 2008;29:9922008;29:992––10001000

Clopidogrel responsiveness in loaded pts was assessed in Clopidogrel responsiveness in loaded pts was assessed in 380 pts receiving SES by the Accumetrics VerifyNow 380 pts receiving SES by the Accumetrics VerifyNow P2Y12P2Y12assay. assay. Hyporesponsiveness was defined as postHyporesponsiveness was defined as post--treatment treatment reactivity reactivity PRUPRU ≥235 (~ the upper tertile) by ROC analysis to ≥235 (~ the upper tertile) by ROC analysis to

optimize prediction of 6 month MACE. optimize prediction of 6 month MACE.

P=0.04

P=0.008P=0.004

P=0.04

N=5

ADAPTADAPT--DESDESAAssessment of ssessment of DDual ual AAntintiPPlateletlatelet TTherapy with herapy with DDrugrug--EEluting luting SStentstents

11,000 11,000 –– 15,000 pts15,000 pts1010--15 sites in US, Germany, Italy15 sites in US, Germany, Italy

Clinical FU ≥2 yrs (5 yrs max)Clinical FU ≥2 yrs (5 yrs max)Angio core lab assessment all STs w/1:3 matching controlsAngio core lab assessment all STs w/1:3 matching controls

Assessment of platelet function: Assessment of platelet function: Accumetrics VerifyNow Aspirin, VerifyNow Accumetrics VerifyNow Aspirin, VerifyNow P2Y12P2Y12, and VerifyNow IIb/IIIa assays (results blinded to investigators), and VerifyNow IIb/IIIa assays (results blinded to investigators)

Aspirin: Aspirin: ≥300 mg oral ≥6 hrs or 324 mg chewed or 250 mg IV ≥30 mins prior to PCIClopidogrel: Clopidogrel: Assess ≥6’ after 600 mg or ≥12’ after 300 mg or ≥5d after 75 mg qd

GP IIb/IIIa inhibitor: GP IIb/IIIa inhibitor: Optional per standard of care, but washout required

PCI with non investigational DESPCI with non investigational DES(IVUS/VH substudy; n=3000)(IVUS/VH substudy; n=3000)

ACC/AHA/SCAI 2005 Guideline Update for PCIOral Anti-platelet 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

Adapted from Smith SC Jr, et al. Available at: www.acc.org/clinical/guidelines/percutaneous/update/index_rev.pdf

“Standard Therapy”clopidogrel 75mg +placebo/day

“Standard Therapy”clopidogrel 75mg +placebo/day

“Tailored Therapy”clopidogrel 150-mg/day

Successful PCI with DES without major complication or GPIIb/IIIa use

Post-PCI VerifyNow P2Y12 Assay (PRU) 12-24 hours post-PCI

PRU ≥ 230?

Non-Responder

Clinical Follow-up And VerifyNow Assessment at 30 days, 6 months

Primary Endpt: 6 month CV Death, Non-Fatal MI, ARC Def/Prob Stent Thrombosis

Yes No

N ~ 6600

N = 1100 N = 583

Responder

A B C

Random Selection

N = 1100

G R A V T A S

Coordinating Center: Scripps Advanced Clinical TrialsStudy PI: Matthew J. Price, MD

ACC/AHA/SCAI 2005 Guideline Update for PCIOral Antiplatelet Adjunctive Therapies

In patients who have undergone PCI, clopidogrel 75 mg daily should be given for at least 1 month after bare-metal stent implantation (unless the patient is at increased risk of bleeding; then it should be given for a minimum of 2 weeks), 3 months after sirolimus stent implantation, and 6 months after paclitaxel stent implantation, and ideally up to 12 months in patients who are not at high risk of bleeding.

I IIa IIb III

B

Adapted from Smith SC Jr, et al. Available at: www.acc.org/clinical/guidelines/percutaneous/update/index_rev.pdf

Clopidogrel

Clopidogrel for >1-year?

41

DAPT Study DesignDAPT Study Design

4141

50% of patients continue onDual Antiplatelet Therapy

18 mos.12 mos.

50% of patients receive aspirin + placebo

Total 33 month patient evaluation including additional 3-month follow-up

All patients onaspirin +open-label

thienopyridinetherapy for 12 months

DES n =

15,245BMS n =

5,400 1:1 Randomization at month 12

MI, Bleeding and AllMI, Bleeding and All--Cause MortalityCause Mortality

TrialTrial MIMI Major bleed*Major bleed* Death (time)Death (time)

OASISOASIS--5 (n=20,078)5 (n=20,078) 6 months6 months-- EnoxaparinEnoxaparin 4.1%4.1% 5.0%5.0% 6.5%6.5%-- FondaparinuxFondaparinux 3.9%3.9% 3.1%3.1% 5.8%5.8%

HORIZONS (n=3,602)HORIZONS (n=3,602) 1 year1 year-- UFH/GPIUFH/GPI 1.8%1.8% 10.8%10.8% 4.8%4.8%-- BivalirudinBivalirudin 1.8%1.8% 6.8%6.8% 3.5%3.5%

PLATO (n=18,624)PLATO (n=18,624) 1 year1 year-- ClopidogrelClopidogrel 6.9%6.9% 11.2%11.2% 5.9%5.9%-- TicagrelorTicagrelor 5.8%5.8% 11.6%11.6% 4.5%4.5%

Large RCTs Large RCTs withwith significant reductions in deathsignificant reductions in death

*TIMI major + minor or protocol major*TIMI major + minor or protocol major

-- ↓↓ ↓↓

-- ↓↓↓↓ ↓↓

↓↓ -- ↓↓

Stone, GW NEJM 2010

TrialTrial MIMI Major bleed*Major bleed* Death (time)Death (time)CHARISMA (n=15,603)CHARISMA (n=15,603) 28 28 mosmos

-- PlaceboPlacebo 2.0%2.0% 1.3%1.3% 4.8%4.8%-- ClopidogrelClopidogrel 1.9%1.9% 1.7%1.7% 4.8%4.8%

CURRENT (n=25,807)CURRENT (n=25,807) 30 days (CV)30 days (CV)-- LD ClopidogrelLD Clopidogrel 2.2%2.2% 2.0%2.0% 2.2%2.2%-- HD ClopidogrelHD Clopidogrel 1.9%1.9% 2.5%2.5% 2.1%2.1%

SYNERGY (n=10,027)SYNERGY (n=10,027) 1 year1 year-- UFHUFH 12.7%12.7% 7.6%7.6% 7.3%7.3%-- Enoxaparin Enoxaparin 11.7%11.7% 9.1%9.1% 7.7%7.7%

REPLACEREPLACE--2 (n=6,010) 2 (n=6,010) 1 year1 year-- UFH/GPIUFH/GPI 6.2%6.2% 4.1%4.1% 1.4%1.4%-- BivalirudinBivalirudin 7.0%7.0% 2.4%2.4% 1.0%1.0%

ACUITY (n=9,215)ACUITY (n=9,215) 1 year1 year-- UFH/GPIUFH/GPI 4.9%4.9% 11.8%11.8% 3.9%3.9%-- BivalirudinBivalirudin 5.4%5.4% 9.1%9.1% 3.8%3.8%

CURE (N=12,562)CURE (N=12,562) 1 year1 year-- PlaceboPlacebo 6.7%6.7% 2.7%2.7% 6.2%6.2%-- ClopidogrelClopidogrel 5.2%5.2% 3.7%3.7% 5.8%5.8%

TRITON (n=13,608)TRITON (n=13,608) 15 15 mosmos-- ClopidogrelClopidogrel 9.5%9.5% 3.8%3.8% 3.2%3.2%-- PrasugrelPrasugrel 7.3%7.3% 5.0%5.0% 3.0%3.0%

MI, Bleeding and AllMI, Bleeding and All--Cause MortalityCause MortalityLarge RCTs Large RCTs withoutwithout significant reductions in deathsignificant reductions in death

-- -- --

↓↓ ↑↑ --

-- --↑↑ --

↓↓ ↑↑ --

--↓↓ ↑↑ --

--↑↑ ↓↓ --

--↑↑ ↓↓ --

Stone, GW NEJM 2010

ConclusionsvvPharmacologic treatment of patients Pharmacologic treatment of patients

undergoing PCI has improved over the years undergoing PCI has improved over the years to decrease ischemic and bleeding to decrease ischemic and bleeding complicationscomplications

vvAs most drugs which ↓ ischemia also ↑ As most drugs which ↓ ischemia also ↑ bleeding, the offsetting impact of adverse bleeding, the offsetting impact of adverse ischemic and hemorrhagic events must be ischemic and hemorrhagic events must be carefully examined carefully examined

vvThe net balance of ischemia and bleeding The net balance of ischemia and bleeding should be strongly considered when should be strongly considered when choosing APT for individual pts in an attempt choosing APT for individual pts in an attempt to minimize complicationsto minimize complications

Documents

The Role of New Anti-Platelet Agents: Will Prasugrel and …summitmd.com/pdf/pdf/1134_3.DAPT and DES.pdf · The Role of New Anti-Platelet Agents: Will Prasugrel and Ticagrelor Change