Tim Henry, MD Director, Division of Cardiology Professor ...€¦ · Director, Division of Cardiology Professor, Department of Medicine Cedars-Sinai Heart Institute. Implications

Tim Henry, MDDirector, Division of Cardiology

Professor, Department of MedicineCedars-Sinai Heart Institute

Implications of Pre-loading on Patients

Undergoing Coronary Angiography

Heart Disease and Stroke Statistics--2014 Update.Circulation. 2013;129:e28-e292.

Angiography

Define coronary anatomy

Medical therapyPCICABG

In 2010: ~397,000 CABG procedures, ~954,000 PCI procedures,and ~diagnostic 1,029,000 angiograms were performed in the US

All-cause MortalityNo. of Events No. of Patients

PretreatmentNo

Pretreatment PretreatmentNo

PretreatmentOR

(95% CI)Favors

PretreatmentFavors No

Pretreatment HeterogeneityP for

Trend x2

Odds Ratio (95%CI)0.1 1.0 10

0.1 0.75

Presenting featureElective PCINSTE ACSSTEMI

25014

25528

82023661097

81624081101

1.12 (0.17-7.27)0.93 (0.63-1.36)0.50 (0.26-0.96)

Loading dose≤300 mg600-900 mg

633

796

3299984

3338987

0.79 (0.54-1.17)0.62 (0.15-2.61)

2.66 0.02

MACENo. of Events No. of Patients

PretreatmentNo

Pretreatment PretreatmentNo

PretreatmentOR

(95% CI)Favors

PretreatmentFavors No

Pretreatment HeterogeneityP for

Trend x2

Odds Ratio (95%CI)0.1 1.0 10

1.18 0.28

Presenting featureElective PCINSTE ACSSTEMI

5332939

5041470

82023661097

81624081101

1.05 (0.70-1.57)0.78 (0.66-0.91)0.54 (0.36-0.81)

Loading dose≤300 mg600-900 mg

36358

47262

3299984

3338987

0.74 (0.63-0.87)0.93 (0.64-1.36)

5.1 0.08

Clopidogrel Pre-treatment in PCI:

Bellemain-Appaix A et al. JAMA 2012;308:2507-16.

Timing of Clopidogrel Loadingin US Practice

Dean BB et al. Am J Health-Syst Pharm 2010;67:1430-7

EMR Review from 112 US hospitals between 1/2006 and 3/2008 (n=6,253)

Pe

rce

nt

29

43

30

1216

33

59

4137

0

20

40

60

80

100

Elective(n=3922)

NSTE-ACS(n=972)

STEMI(n=1359)

Before PCI (up to 12 hours prior to PCI)At PCI (in the cath lab)After PCI (up to 6 hours after PCI)

Cangrelor

NN

NN

NH

SCF3

OHOH

OO

PO

O

PP

OO

OCl

Cl

OO

O

S

4Na+

Cangrelor: Pharmacokinetics andPlatelet Inhibition

Platelet recovery time ~60 minutes

Ca

ng

relo

r(n

g/m

L) Pharmacokinetics

Imp

ed

an

ce

(Oh

ms)

Whole Blood Impedance Aggregometry

Time (min)

Time (min)

0

16

0 20 40 60 80 100 120 140 160

141210

8642

0

200

400

600

800

0 20 40 60 80 100 120 140 160

Group A: 15 mcg/kg bolus + 2 mcg/kg/min (n=9)Group B: 30 mcg/kg bolus + 4 mcg/kg/min (n=9) - Clinical dose

Group AGroup B

Akers WS et al. J Clin Pharm. 2010;50:27-35

Cangrelor

One obvious huge advantage

PCI pts unable to take oral meds(sedation, intubation, vomiting,

shock, etc.)

Cangrelor

But what about routine

cangrelor use?It may depend if you routinely

pre-load DAPT

CHAMPION PHOENIX Study Design

1 2 to 4 hours0

Cangrelor2 bolus & infusion (30 ug/kg; 4 ug/kg/min)Clopidogrel600 mg oral

OR

Placebo2 bolus & infusion Placebo oral

PCI ~30’

OR Clopidogrel3 (600 mg or 300 mg oral, per physician)

1 Randomization occurred once suitability for PCI was confirmed either by angiography or STEMI diagnosis.Double blind study medication was administered as soon as possible following randomization.

2 Study drug infusion (cangrelor or matching placebo) was continued for 2-4 hours at the discretion of thetreating physician. At the end of the infusion patients received a loading dose of clopidogrel or matching

placebo and were transitioned to maintenance clopidogrel therapy.3 Clopidogrel loading dose (or matching placebo) was administered as directed by the investigator. At the time

of patient randomization, a clopidogrel loading dose of 600 mg or 300 mg was specified by the investigator.MITT = modified intent-to-treat.

Rand

Placebo3 oral (right before PCI or right after, per physician)

Phoenix: Death, MI, IDR, StentThrombosis within 48 Hrs (n=10,942)

0

1

2

3

4

5

6

7

8

0 6 12 18 24 30 36 42 48

Patient at Risk

Cangrelor: 5472 5233 5229 5225 5223 5221 5220 5217 5213

Clopidogrel: 5470 5162 5159 5155 5152 5151 5151 5147 5147

Ev

en

tR

ate

(%)

Hours from Randomization

5.9%

4.7%

P=0.006NNT = 84

Cangrelor (n=5,472)

Clopidogrel (n=5,470)

Death, MI, IDR or ST:Landmark analysis from Phoenix

CangrelorClopidogrel

5.4%

4.1%

0.7%0.6%

HR (95% CI):1.16 (0.70, 1.90)

p=0.57

HR (95% CI):0.76 (0.64, 0.90)

p=0.002

Eve

nt

Ra

te(%

)

Hours from RandomizationPatients at risk:

0

0 1 2 6 12 18 24 30 36 42 48

54725470

Cangrelor:Clopidogrel:

52955214

52495177

52335162

52295159

52255155

52235152

52215151

52205151

52175147

52125146

6

5

4

3

2

1

End of cangrelor infusion

600 mg clopidogrel given (or placebo)

Efficacy Outcomes w/i 2 HoursChampion PHOENIX (mITT)

Primary endpointCangrelor

N=5470Clopidogrel

N=5469OR (95% CI)

Pvalue

Death/MI/IDR/ST 224 (4.1%) 293 (5.4%) 0.75 (0.63, 0.90) 0.002

Secondary endpoints

Stent thrombosis 37 (0.7%) 70 (1.3%) 0.53 (0.35, 0.78) 0.001

- IPST 35 (0.6%) 54 (1.0%) 0.65 (0.42, 0.99) 0.04

- ARC-ST 2 (0.0%) 17 (0.3%) 0.12 (0.03, 0.51) 0.001

MI 192 (3.5%) 243 (4.4%) 0.78 (0.64, 0.95) 0.01

- MB ≥10x ULN 50 (0.9%) 78 (1.4%) 0.64 (0.45, 0.91) 0.01

- Q-MI 9 (0.2%) 13 (0.2%) 0.69 (0.30, 1.62) 0.39

IDR 2 (0.0%) 12 (0.2%) 0.17 (0.04, 0.74) 0.008

Death 7 (0.1%) 6 (0.1%) 1.17 (0.39, 3.47) 0.78

Death, MI, IDR, ST at 48 Hours

5.01.00.2Cangrelor Better Clopidogrel Better

Phoenix: Stent Thrombosiswithin 48 Hours (n=10,942)

0.0

0.5

1.0

1.5

2.0

0 6 12 18 24 30 36 42 48

Hours from Randomization

Ev

en

tR

ate

(%)

Patient at Risk

Cangrelor: 5472 5426 5421 5419 5419 5418 5417 5416 5414

Clopidogrel: 5470 5392 5389 5388 5386 5385 5385 5383 5383

1.4%

0.8%

Cangrelor (n=5,472)


OR [95%CI] =0.62 (0.43, 0.90)

P=0.01

Landmark analysis from Phoenix


0.2%0.1%

p=0.18

Ste

nt

Th

rom

bo

sis

(%)

Hours from RandomizationPatients at risk:

0.0

0 1 2 6 12 18 24 30 36 42 48

54725470

Cangrelor:Clopidogrel:

54355413

54325396

54265392

54215389

54195388

54195386

54185385

54175385

54165383

54135382

2.0

1.8

1.4

1.0

0.8

0.2

1.6

1.2

0.6

0.4

1.3%

0.7%

HR [95%CI] =0.53 [0.35, 0.79]

p=0.002

End of cangrelor infusion

600 mg clopidogrel or placebo given

Comparative Efficacy vs. Safety

Outcomes: Champion PHOENIXE

ve

nt

Ra

te(%

)

HoursPatients at risk:

55295527

Cangrelor SafetyClopidogrel Safety

55165511

55165511

55125507

55115505

55095502

55085502

55055500

55015500

Cangrelor

Clopidogrel

Cangrelor0.16%

Clopidogrel0.11%0.0

1.0

2.0

3.0

4.0

5.0

6.0

7.0

0 6 12 18 24 30 36 42 48

54725470

Cangrelor EfficacyClopidogrel Efficacy

52335162

52295159

52255155

52235152

52215151

52205151

52175147

52135147

Death/MI/IDR/ST

GUSTO Severe Bleeding

5.9%

4.7%

Beigel R et al. Am J Cardiol 2013;112:1551-56

Suboptimal IPA (<70%) attime of primary PCI:

Clopidogrel: 71%Prasugrel: 53%

ADPaggregarton

Clopn=49 (%)

Prasn=30 (%)

Pvalue

Baseline 79 ± 10 76 ± 9 0.2

At PPCI 74 ± 12 63 ± 18 0.002

At 72 hours 47 ± 18 33 ± 16 0.002

AD

P-i

nd

uc

ed

pla

tele

ta

gg

reg

ati

on

(%)

P=0.2100

90

80

70

30

0

60

50

40

Admission PPCI 72 hours

20

10

Clopidogrel

Prasugrel

P<0.1 P<0.1

230208

All P=NS,except at day 5

(P<0.05)

0%(0,0)

0%(0,0)

0%(0,5)

0%(0,5) 48%

(0,72)12%(0,54) 85%

(65,94)76%

(61,89)

90%(78,97)

84%(72,93)

83%(62,97)

95%(92,97)

PR

U

450

400

350

250

100

200

0

300

150

0 Hour

50

1 Hour 2 Hours 6 Hours 24 Hours Day 5

Ticagrelor

Prasugrel

One hour DBT →No intra-procedural effect

Delayed peak effect

Franchi F et al. JACC CV Int 2015;8:1457–67

PK/PD nalysesperformed before and 30 min, 1, 2, 4, 8, and 24 hrs after 3 randomized

ticagrelor LD regimens (180 mg, 270 mg, 360 mg) in PPCI (N=52)




irculation. 2013;128:1055-65

Timing of STHR [95%CI]

favoring ticagrelor

Acute (≤24 hours) 0.94 [0.43 – 2.05]

Subacute (1-30 days) 0.60 [0.39 – 0.93]

Late (30 days-1 year) 0.48 [0.24 – 0.96]

0.0

0.5

1.0

1.5

2.0

2.5

3.0

0 60 120 180 240 300 360

Def

ST

(%)

HR [95%CI] =0.67 [0.50-0.91]

P=0.009

Clopidogrel (n=5,648)Ticagrelor (n=5,636)

1.9%

1.4%

30

No reduction in acute stent thrombosis!

1,840 ptsnot randomized

Uses for Cangrelor Across the

Spectrum of CAD

Uses for Cangrelor Across the

Spectrum of CAD

( , ) , p

All-cause mortality day 7-30 (all pts)

Bellemain-Appaix A et al. BMJ 2014;349:g6269

1010.10.01

Odds Ratio(95% CI)

12 value (%)(P value)

StudyRandomized controlled trials

Odds Ratio(95% CI)

Weight(%)

5%, P=0.35

Observational analysis of randomized controlled trial

Observational studiesAssali et alFeldman et al

Chan et alSubtotalTotal

*Follow-up at 9 months†Follow-up at 1 year

2/2352/467

19/447723/5179

594/20128

3/643/574

3/3329/970

477/11954

0%, P=0.48

10%, P=0.35

11.912.2

26.250.3100.0

0.17 (0.03 to 1.07)0.82 (0.14 to 4.92)

0.47 (0.14 to 1.59)0.42 (0.18 to 1.02)0.90 (0.75 to 1.07)

ACCOASTCREDO

CURE*Subtotal

8/20370/900

359/6259367/6196

10/19964/915

390/6303404/9214

3.60.462.866.8

0.78 (0.31 to 1.99)0.11 (0.01 to 2.09)0.92 (0.80 to 1.07)0.88 (0.09 to 2.61)

ACUITY† 204/5753 64/1770 29.1 0.98 (0.74 to 1.30)

Pre-treat No pre-treat

Pre-treatment better No pre-treatment better



( , ) , p

All-cause mortality day 7-30 (PCI pts – 55%)


1010.10.01

Odds Ratio(95% CI)



Odds Ratio(95% CI)

Weight(%)

13%, P=0.32




*Follow-up at 9 months†Follow-up at 1 year

2/2352/467

19/447723/5179

146/12300

3/643/574

3/3329/970

79/6121

0%, P=0.48

6%, P=0.38

3.43.5

7.314.3100.0

0.17 (0.03 to 1.07)0.82 (0.14 to 4.92)

0.47 (0.14 to 1.59)0.42 (0.18 to 1.02)0.83 (0.59 to 1.17)

ACCOASTCREDO

PCI-CURESubtotal

4/13940/900

14/131318/3610

4/13764/915

13/134521/3636

5.81.3

17.824.9

0.98 (0.25 to 3.95)0.11 (0.01 to 2.09)

1.10 (0.52 to 2.36)0.92 (0.43 to 1.98)

ACUITY-PCI† 105/3511 49/1515 60.9 0.92 (0.65 to 1.30)



( , ) , p

Ischemic MACE* day 7-30 (all pts)


1010.10.01

Odds Ratio(95% CI)


StudyOdds Ratio

(95% CI)Weight

(%)

48%, P=0.15


Observational studiesAssali et alFeldman et alChan et alSubtotalTotal

13/23539/467

292/4477244/5179

1294/20128

9/6441/57434/33284/970

968/13488

74%, P=0.02

52%, P=0.05

2.68.2

10.821.6100.0

0.36 (0.15 to 0.88)1.18 (0.75 to 1.87)

0.61 (0.42 to 0.89)0.69 (0.38 to 1.26)0.84 (0.72 to 0.98)

ACCOASTCREDO

CURE*Subtotal

203/203761/900

275/6259539/9196

195/199676/915

346/6303617/9214

19.911.8

23.355.0

1.02 (0.83 to 1.26)0.80 (0.57 to 1.14)

0.79 (0.67 to 0.93)0.87 (0.73 to 1.04)

ACUITY 411/5753 267/3304 23.4 0.88 (0.75 to 1.03)

Randomized controlled trials

*D, MI, UTVR for all except:D, MI, CVA for CURED, MI, UTVR, CVA for FeldmanD, MI, UTVR, CVA, bail-out GPII for ACCOAST



( , ) , p

Ischemic MACE* day 7-30 (PCI pts – 55%)


1010.10.01

Odds Ratio(95% CI)



Odds Ratio(95% CI)

Weight(%)

44%, P=0.17




13/23539/467

292/4477344/5179937/12300

9/6441/574

34/33284/970

556/6134

74%, P=0.02

55%, P=0.04

9.713.9

14.738.3100.0

0.36 (0.15 to 0.88)1.18 (0.75 to 1.87)0.61 (0.42 to 0.89)0.69 (0.38 to 1.26)0.83 (0.69 to 1.01)

ACCOASTCREDO

PCI-CURESubtotal

183/139761/900

59/1313303/3610

180/137676/915

86/1345342/3636

20.714.7

15.150.4

0.98 (0.25 to 3.95)0.11 (0.01 to 2.09)

1.10 (0.52 to 2.36)0.92 (0.43 to 1.98)

ACUITY-PCI 290/3511 130/1528 20.9 0.92 (0.65 to 1.30)

*D, MI, UTVR for all except:D, MI, CVA for CURED, MI, UTVR, CVA for FeldmanD, MI, UTVR, CVA, bail-out GPII for ACCOAST



( , ) , p

Major bleeding day 7-30 (all pts)


1010.10.01

Odds Ratio(95% CI)


StudyOdds Ratio

(95% CI)Weight

(%)

0%, P=0.40


Observational studiesAssali et alFeldman et alChan et alSubtotalTotal

*CABG) and non-CABG†Non-CABG

26/2354/467

36/447766/5179

551/20128

7/647/5743/332

17/970305/13636

0%, P=0.89

0%, P=0.52

2.71.4

1.55.5

100.0

1.01 (0.42 to 2.45)0.70 (0.20 to 2.41)

0.89 (0.27 to 2.90)0.89 (0.48 to 1.65)1.27 (1.10 to 1.47)

ACCOAST*CREDO*

CURESubtotal

52/203750/1053

125/6259227/9349

27/199638/1063

95/6303160/9362

9.511.3

28.949.7

1.91 (1.20 to 3.05)1.34 (0.87 to 2.07)

1.33 (1.02 to 1.74)1.43 (1.16 to 1.76)

ACUITY 258/5753 128/3304 44.7 1.16 (0.94 to 1.45)

Randomized controlled trials



( , ) , p

Major bleeding day 7-30 (PCI pts – 55%)


1010.10.01

Odds Ratio(95% CI)



Odds Ratio(95% CI)

Weight(%)

25%, P=0.27




26/2354/467

36/447766/5179

344/12453

7/647/574

3/33217/970

151/6282

0%, P=0.89

0%, P=0.58

5.22.7

2.910.8100.0

1.01 (0.42 to 2.45)0.70 (0.20 to 2.41)

0.89 (0.27 to 2.90)0.89 (0.48 to 1.65)1.23 (1.00 to 1.50)

ACCOAST†

CREDO†

PCI-CURESubtotal

19/139750/1053

21/131390/3763

7/137638/1063

19/134564/3784

5.421.910.437.7

2.70 (1.13 to 6.44)1.34 (0.87 to 2.07)1.13 (0.61 to 2.12)1.45 (0.97 to 2.15)

ACUITY-PCI 188/3511 70/1528 51.5 1.18 (0.89 to 1.56)

*CABG) and non-CABG†Non-CABG

Largest Pre-loading Trials: Efficacy (ITT)

N pts randomized:Pts – Stable/ACS:

% PCI:Drug:

Primary endpoint

Follow-up:Published:

2,11633% / 67%

86%Clopidogrel 300 mg

D/MI/UTVR

28 days2002

1,02887% / 13%


D/MI/CVA/TIA/revasc

7 days2008

4,033100%

69%Prasugrel 30 mg

CD/MI/CVA/urg revasc/GPI

30 days2013

P=0.23

P=0.98

P=0.75

8.3%

1.0%

10.8%

6.8%

0.8%

10.8%

0%

2%

4%

6%

8%

10%

12%

CREDO PRAGUE 8 ACCOAST

Eve

nt

rate

(%)

No pre-loading Pre-loading

Largest Pre-loading Trials: Major/minorBleeding

N pts randomized:Pts – Stable/ACS:

% PCI:Drug:

Follow-up:

Published:

2,11633% / 67%


28 days

2002

1,02887% / 13%


7 days

2008

4,033100%

69%Prasugrel 30 mg

30 days

2013

P=0.02

P<0.001P=0.025

5.9%

1.4%

7.8%

3.5% 3.5%

0%

2%

4%

6%

8%

10%

CREDO PRAGUE 8 ACCOAST

Eve

nt

rate

(%)

1.2%

No pre-loading Pre-loading

Cangrelor:

Novel Uses of a Rapidly Acting

IV P2Y12 Inhibitor in PCI

Cangrelor (n=5,472)


Ste

nt

thro

mb

os

is(%

)

0.0

0.5

1.0

1.5

2.0

0 1 2

54325396

Hours after Randomization

54355413

54725470


OR [95%CI] =0.53 [0.35-0.79]

P=0.0020.7%

1.3%

N at risk

0.8%

0.5%

1.2% 1.2%

0.0%

0.5%

1.0%

1.5%

All Stable CAD NSTE -ACS STEMI

89/10,939

P=0.0006

32/6138 33/2810 24/1991

IPST No IPST

No at risk:

0

2

4

6

8

10

12

0 5 10 15 20 25 30

Mo

rta

lity

(%)

IPST: 89 84 82 80 80 80 79

No IPST: 10850 10781 10759 10741 10735 10727 10688

Days from Randomization

10.1%

1.0%

HR [95%CI] =11.04 [5.59 ,21.79]

P<0.0001

0

1

2

3

4

5

6

7

8

0 5 10 15 20 25 30

AR

CS

T(%

)

Days from Randomization

IPST: 89 82 79 77 77 77 76

No IPST: 10850 10755 10722 10708 10699 10691 10653

5.6%

0.8%

IPST in Champion PHOENIX

IPST No IPST

No at risk:

HR [95%CI]=7.66 [3.11, 18.85]

P<0.0001

1 31.4

1.0

0

0.5

1

1.5

2

2.5

All Stable Angina NSTE-ACS STEMI

Clopidogrel (n=5470)

Cangrelor (n=5469)

OR [95%CI] =0.65 [0.42,0.99]

p=0.04

OR [95%CI] =0.50 [0.24,1.05]

p=0.06

OR [95%CI] =0.75 [0.38,1.50]

p=0.42

OR [95%CI] =0.76 0.34,1.73]

p=0.52

P Int = 0.77

IPS

T(%

)

1 31.4

1.0

0

0.5

1

1.5

2

2.5

All Stable Angina NSTE-ACS STEMI


Cangrelor (n=5469)

OR [95%CI] =0.65 [0.42,0.99]

p=0.04 OR [95%CI] =0 50 [0 24 1 05]

OR [95%CI] =0.75 [0.38,1.50]

OR [95%CI] =0.76 0.34,1.73]

P Int = 0.77

IPS

T(%

)

Phoenix: Outcomes in Patients Treated

with Heparin vs. Bivalirudin (n=9,628)

6.7

0

1

2

3

4

5

6

7

8

Bivalirudin only Heparin only

Clopidogrel Cangrelor

5.6

0

2

4

6

8

Bivalirudin only Heparin only Bivalirudin only Heparin only


Phoenix: Outcomes in Patients Treated

with Heparin vs. Bivalirudin (n=9,628)

Outcomes in PtsTreated with Heparin vs. Bivalirudin (n=21,818)

5.44 7

0

1

2

3

4

5

6

7

8

Bivalirudin only Heparin only


4.6

0

2

4

6

8

Bivalirudin only Heparin only Bivalirudin only Heparin only


Outcomes in PtsTreated with Heparin vs. Bivalirudin (n=21,818)

Safety: Non-CABG Bleeding at 48 Hours

Clopidogrel Pre-loading Before PCI37,814 pts with stable CAD, NSTE-ACS or STEMI in 15 studies;

7 RCTs (8,608 pts), 2 observational analyses of RCTs (10,945 pts), and6 observational studies (18,261 pts).

Bellemain-Appaix A et al. JAMA 2012;308:2507-16

Results in 7 RCTs according to clinical presentation

Stable CAD NSTEACS STEMI

OR (95% CI) P OR (95% CI) P OR (95% CI) P

N=1636 N=4774 N=2198

Majorcoronaryevent

1.05 (0.70-1.57) 0.82 0.78 (0.66-0.91) 0.002 0.54 (0.36-0.81) 0.003

Death 1.12 (0.17-7.27) 0.91 0.93 (0.63-1.36) 0.69 0.50 (0.26-0.96) 0.04

Majorbleeding 1.18 (0.31-4.55) 0.81 1.28 (0.98-1.67) 0.07 0.78 (0.42-1.45) 0.42

Prasugrel 30 mg

Prasugrel 60 mgPrasugrel 30 mg

Prasugrel 10 mg or 5 mg (based on weight and age) for 30 days

PCI

1° Endpoint: CV Death, MI, Stroke, Urg Revasc, GP IIb/IIIa bailout, at 7 days

Placebo

CoronaryAngiography

n~4100 (event driven)Stopped after 4033 randomized

CoronaryAngiography

PCI

CABGor

MedicalManagement

(no prasugrel)

CABGor

MedicalManagement

(no more prasugrel)

Randomize 1:1Double-blind

NSTEMI + Troponin ≥ 1.5 times ULN local lab valueClopidogrel naive or on long term clopidogrel 75 mg

0

5

10

15

1996

2037

1788

1821

1775

1809

1769

1802

1762

1797

1752

1791

1621

1616

No. at Risk:

No pre-treatment

Pre-treatment

Pre-treatment 10.810.0

HR 0.997(95% CI 0.83, 1.20)

P=0.98

P=0.81(95% CI 0.84, 1.25)

HR 1.02

No Pre-treatment10.8

9.8

0 5 10 15 20 25 30

0 5 10 15 20 25 30

0

1

2

3

4

5

Pre-treatment2.9

2.6

No Pre-treatment

1.51.4

1996

2037

1947

1972

1328

1339

1297

1310

1288

1299

1284

1297

1263

1280

No. at Risk::

No pre-treatment

Pre-treatment

HR 1.97(95% CI 1.26, 3.08)

P=0.002

HR 1.90(95% CI 1.19, 3.02)

P=0.006

Dangas GD et al. Circulation. 2011;123:1745-56

Delayed Clopidogrel Activity in STEMI600 mg load in 11 STEMI pts compared to 10 healthy controls

LTA with 20 μmol/l ADPagonist

Blood sampled pre-dose, and at0.5, 1, 1.5, 2, 3, 4, 6 and 24 hours post-dose

Median

75%

25%

90%

10%

Heestermans AACM et al. Thromb Res 2008;122:776-81

STEMI

p<0.001

Cm

ax

(activ

em

eta

bo

lite,

ng

/ml)

Healthycontrol

0

6

12

16

14

10

8

4

2

Mean

STEMI

p=0.023

Tm

ax

(activ

em

eta

bo

lite

,m

in)

Healthycontrol

0

100

250

350

300

200

150

50

STEMI4 hours

post-dose

p<0.001

60

80

40

20

0

100

STEMI24 hours

post-dose

Healthycontrol

6 hourspostdose

p<0.001

p=0.029

p g pp<5 days prior to CABG

p g pp>5 days prior to CABG

0

11.3

0

5

10

15

TIMI Fatal TIMI Major

Clopidogrel (n=224)

Prasugrel (n=213)

Clopidogrel

Prasugrel

30%

20%

10%

0%1 2 3 4 5 6 7 8 9 10 11 12 13

Beigel R et al. Am J Cardiol 2013;112:1551-56

AD

P-in

du

ced

pla

tele

tag

gre

gati

on

at

pri

mary

PC

I(%

)

r2 = 0.1, p = 0.03

r2 = 0.15, p = 0.04

Time from thienopyridine loading to primary PCI (min)

Clopidogrel

Prasugrel

100

80

60

40

20

0 50 100

TRITON-TIMI 38 STEMI

5

10

15

0

0 50 100 150 200 250 300 350 400 450

9.5

6.5

12.4%

10.0%

HR [95%CI] =0.79 0.65–0.97]

P=0.02


Prasugrel (n=1769)

Days

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

CV

de

ath

,M

I,str

ok

e(%

)

97% underwent PCIPrimary PCI (<12 ; n=2,438)

Secondary PCI (12 - 14d; n=1,094)

ancet. 2008;371:1353-63

HR 0.41 [0.29-0.59]P<0.0001

HR 0.60 [0.37-0.97]P=0.03

Early stent thrombosis

1.6%

0.6%

0.8%

0.5%

Clopidogrel Prasugrel

Late stent thrombosis

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

No reduction in acute stent thrombosis!




HPRNo morphine

(n=205)Morphine

(n=95)Adjusted

RR (95% CI)P value

Hour 1 (N=154) (N=67)

≥208 PRU 92 (59.7) 53 (79.1) 1.32 (1.10-1.59) 0.003

≥230 PRU 84 (54.5) 44 (65.7) 1.17 (0.93-1.49) 0.23

Hour 2 (N=202) (N=89)

≥208 PRU 59 (29.2) 47 (52.8) 1.89 (1.40-2.56) <0.001

≥230 PRU 49 (24.3) 42 (47.2) 2.06 (1.46-2.89) <0.001

Hour 4 (N=126) (N=70)

≥208 PRU 12 (9.5) 17 (24.3) 2.11 (1.06-4.21) 0.03

≥230 PRU 7 (5.6) 13 (18.6) 2.77 (1.14-6.73) 0.03

82 pts randomized to crushed vs intact ticagrelor180 mg tablets LD before primary PCI

52 pts randomized to crushed vs. intact prasugrel60 mg tablets LD before primary PCI (morphine in 75%)

P2Y

12

Reactio

nU

nits

(PR

U)

300

200

0

250

p<0.001p=0.053

150

0

100

50

p=0.02

p=0.02

p=0.10

ANOVA p=0.008

p=0.18

Hours30´1 2 4 6 24

*

TRITON-TIMI 38 STEMI

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

Primary PCI (<12 ; n=2,438)Secondary PCI (12 - 14d; n=1,094)

Clopidogrel

Prasugrel

Clopidogrel

Prasugrel

2.8% 2.7%

3.1%

1.6% 1.5%

1.9%

All PCI Primary PCI Secondary PCI

0.63 [0.28-1.39]P = 0.02

0.55 [0.30-1.00]P = 0.048

0.58 [0.36-0.93]P = 0.02

2.4% 2.5%2.2%

1.2% 1.1%1.3%

0%

1%

2%

3%

4%

All PCI Primary PCI Secondary PCI

0.58 [0.23-1.54]P = 0.28

0.44 [0.22-0.87]P = 0.01

0.49 [0.28-0.84]P = 0.008

0%

2%

4%

6%

8%

10%

12%

0 2 4 6 8 10 12

CV

de

ath

,M

Ior

str

ok

e

Months

11.0%

9.3%


0.0

1.0

2.0

3.0

4.0

0 60 120 180 240 300 3600.0

0.5

1.0

1.5

2.0

2.5

3.0

0 60 120 180 240 300 360

PLATO STEMI: Stent thrombosis

Steg PG et al. Circulation. 2010;122:2131-2141

De

fS

T(%

)

HR [95%CI] =0.67 [0.50-0.91]

P=0.009


1.9%

1.4%

2.9%

2.2%

Time from PCI/randomization (days)


Time from PCI/randomization (days)

Def/

pro

bS

T(%

)

3030

HR [95%CI] =0.75 [0.59-0.95]

P=0.02

irculation. 2013;128:1055-65.

Timing of ST HR [95%CI] favoring ticagrelor

Acute (within 24 hours) 0.94 [0.43 – 2.05]

Subacute (1 – 30 days) 0.60 [0.39 – 0.93]

Late (30 days – 1 year) 0.48 [0.24 – 0.96]

2.4

1.41.6

1.1

0

1

2

3

4

STEMI NSTEMI

Clopidogrel Ticagrelor

HR[95%CI] =

0.71 [0.43-1.17]

HR[95%CI] =

0.66 [0.45-0.95]

HT

PR

Ra

te(%

)

100

75

50

25

01 Hour 2 Hour 6 Hour 24 Hour Day 5

Prasugrel

230 PRU Threshold

208 PRU Threshold

468 AU/min Threshold

Ticagrelor

230 PRU Threshold

208 PRU Threshold

468 AU/min Threshold

1

82.2% 80.4%

0%

20%

40%

60%

80%

100%

STR ≥70% pre-PCI

TIMI-3 flow pre-PCI

STR ≥70% post-PCI

TIMI-3 flow post-PCI

Pre-hospital ticagrelor (n=906)

C th l b ti l ( 952)

P=0.34

30-day MACE(MITT)

Pre-hospitalticagrelor (n=906)

Cath-labticagrelor (n=952)

Pvalue

D, MI, CVA, UR, def ST 4.5% 4.4% 0.91

D, MI, urgent revasc 4.3% 3.6% 0.42

ST – definite, <24 hrs 0% 0.8% 0.008

ST – definite, 30 days 0.2% 1.2% 0.02

ST – def/prob, 30 days 2.3% 2.1% 0.75

Death 3.3% 2.0% 0.08

MI 0.8% 1.1% 0.53

Stroke 0.4% 0.2% 0.39

Urgent revascularization 0.6% 0.8% 0.46

GPI bail-out 8.6% 10.5% 0.17

30-day MACE(MITT)

Pre-hospitalticagrelor (n=906)

Cath-labticagrelor (n=952)

Pvalue

D, MI, CVA, UR, def ST 4.5% 4.4% 0.91

D, MI, urgent revasc 4.3% 3.6% 0.42

ST – definite, <24 hrs 0% 0.8% 0.008

ST – definite, 30 days 0.2% 1.2% 0.02

ST – def/prob, 30 days 2.3% 2.1% 0.75

Death 3.3% 2.0% 0.08

MI 0.8% 1.1% 0.53

Stroke 0.4% 0.2% 0.39

Urgent revascularization 0.6% 0.8% 0.46

GPI bail-out 8.6% 10.5% 0.17

Documents

Tim Henry, MD Director, Division of Cardiology Professor ...€¦ · Director, Division of Cardiology Professor, Department of Medicine Cedars-Sinai Heart Institute. Implications