progress in oral anti- platelet therapy rabih r. azar, md, msc, facc division of cardiology hotel...

Progress in Oral Anti-Platelet Therapy

Rabih R. Azar, MD, MSc, FACC

Division of Cardiology

Hotel Dieu de France Hospital

1

Role of the Platelets in ThrombosisRole of the Platelets in ThrombosisRole of the Platelets in Thrombosis

UA/NQMI:Partially-occlusive thrombus (primarily

platelets)

Intra-plaque thrombus (platelet dominated)

Plaque core

ST MI:occlusive thrombus (platelets,

red blood cells, and fibrin)

Intra-plaque thrombus (platelet dominated)

Plaque core

SUDDEN DEATHAdapted from Davies MJ. Circulation.1990; 82 (supl II): 30-46.

Pathogenesis of UA and Acute MIPathogenesis of UA and Acute MI

GP IIb/IIIa Receptor Activation Pathway

ASPIRIN

ASPIRIN

HEPARINS

ASPIRIN

ASPIRIN

ASPIRIN

ASPIRIN

GP IIb/IIIa

GP IIb/IIIa

Thickness of lineindicates strengthof activator

5HT

PAF

Epi

Thrombin ADPTXA2

ASPIRIN Vasopressin

Collagen

Fibrinogen

PLATELET

PLATELET

CLOPIDOGREL

Thienopyridine Structures

Ticlopidine(1st generation)

N

SCl

N

SCl

Prasugrel(CS-747, LY640315)

S

N

F

O

OCH3

O

Clopidogrel(2nd generation)

OCH3

N

SCl

N

SCl

O

Meadows TA, et al. Circulation Research 2007;100:1261-1275; Sugidachi A, et al. J Thromb Haemost 2007;5:1545-1551

Ticlopidine (ticlid) and clopidogrel (plavix)

Ticlopidine Clopidogrel

twice / day once / day

Neutropenia No neutropenia

CBC monitoring No need for CBC monitoring

Skin reactions (rash) No skin reactions

Delayed onset of effect Rapid onset of effect

Role of Thienopyridines

¨ Inhibit platelet aggregation

¨ Improve cardiovascular outcome• Decrease the risk of MI

• Decrease the risk of stent thrombosis

• Decrease the risk of death

What is the Effect of Clopidogrel on Platelet

Aggregation?

Adapted from Angiolillo DJ et al. Am J Cardiol. 2006;97:38-43.

Individual Response Variability to Dual Individual Response Variability to Dual AntiplateletAntiplateletTherapy in the Steady State Phase of TreatmentTherapy in the Steady State Phase of Treatment

% % PlateletPlatelet AggregationAggregation (LTA(LTA--ADP 20ADP 20mol/L)mol/L)

97.597.5

92.592.5

87.587.5

82.582.5

77.577.5

72.572.5

67.567.5

62.562.5

57.557.5

52.552.5

47.547.5

42.542.5

37.537.5

32.532.5

27.527.5

22.522.5

17.517.5

12.512.5

7.57.5

2.52.5

2020

1515

1010

55

00

Nu

mb

erN

um

ber

of

of

Pat

ien

tsP

atie

nts

Bleeding riskBleeding risk Ischemic riskIschemic risk

Mean aggregation = 80% at 2 hours, 60% at 24 hours, 57% at 5 days and 52% at 30 days (or 48% inhibition at 30 days)

Incidence of resistance = 35% at 24 hours and 21% at 30 days (defined as < 10% reduction in aggregation compared to baseline)

Why is the onset of action of clopidogrel late and why

is the response to clopidogrel variable?

Change the Agent?

Prasugrel

Sankyo Ann Report 51:1,1999

Pro-drug

Oxidation(Cytochrome P450)

HOOC* HS

N

O

F

Active Metabolite

N

S

O

FO

Sem Vasc Med 3:113, 2003

Hydrolysis(Esterases)

N

S

O

CH3

CO

FON

S

O

Cl

O CH3C

Clopidogrel

85% Inactive Metabolites

Esterases

N

S

O

Cl

O CH3C

ON

S

O

Cl

O CH3C

Active Metabolite

HOOC* HS

N

O

Cl

OCH3

Is There a Correlation Between Poor Platelet Inhibition and Adverse

Cardiovascular Outcome?

Clinical Relevance Clinical Relevance of Clopidogrel Nonof Clopidogrel Non--responsivenessresponsiveness

Clinical RelevanceFunctional ParameterN

Stent thrombosis↑shear-induced platelet aggregation49Ajzenberg et al.JACC 2005

Stent thrombosis↑P2Y12 reactivity ratio; ↑platelet

aggregation;

↑stimulated GPIIb/IIIa expression

120Gurbel et al.JACC 2005

Stent thrombosis↑P2Y12 reactivity ratio (VASP-levels)36Barragan et al. CCI 2003

Stent thrombosis↓inhibition of platelet aggregation105Mueller et al.

Thromb Haemost2003

Angiolillo DJ et al. Am J Cardiov Drugs. 2007.

Stent ThrombosisStent Thrombosis

Clinical RelevanceFunctional ParameterN

Post-PCI ischemic events (30 days)

↑ platelet aggregation292Cuisset et al.JACC 2006


Post-PCI ischemic events (3 months)

Post-PCI ischemic events (12 months)

↑ platelet aggregation (3rd & 4th quartiles)

↓ platelet inhibition

↑ platelet aggregation

802

379

100

Hocholzer et al.JACC 2006

Geisler et al.Eur Heart J 2006

Bliden et al.JACC 2007

Post PCI-myonecrosis↑ clopidogrel/aspirin-resistant patients120Lev et al.JACC 2006


↑ platelet aggregation106Cuisset et al.J Thromb Haemost2006

Myonecrosis and inflammation marker release

↑ periprocedrual platelet aggregation 120Gurbel et al.Circulation 2005

Post-PCI ischemic events(6 months)

↑ periprocedrual platelet aggregation 192Gurbel et al.JACC 2005

Post-primary PCI ischemic events (6 months)

↑ platelet aggregation (4th quartile)60Matezky et al.Circulation 2004

Angiolillo DJ et al. Am J Cardiov Drugs. 2007.

PostPost-- Stent Ischemic Events and Stent Ischemic Events and PeriproceduralPeriprocedural InfarctionInfarction

Clinical Relevance Clinical Relevance of Clopidogrel Nonof Clopidogrel Non--responsivenessresponsiveness

Can We Improve the Outcome by Improving

Platelet Inhibition?

TAILORED CLOPIDOGREL LOADING DOSE ACCORDING TO PLATELET REACTIVITY MONITORING DECREASE EARLY

STENT THROMBOSIS

L Bonello, L Camoin-Jau, S Arques, , P . Rossi, C. Boyer, D Panagides, O Wittenberg, P Barragan, F Dignat-George, F Paganelli.

Service de cardiologie, Hôpital Universitaire Nord, Marseille; FRANCELaboratoire d’hématologie, INSERM UMRS 608, Hôpital conception; Marseille; FRANCEService de cardiologie, Hôpital d’aubagne, Aubagne; FRANCEService de cardiologie, Clinique clairval, Marseille; FRANCEService de cardiologie, Clinique Bouchard, Marseille; FRANCEService de cardiologie, Hôpital Privé Beauregard, Marseille; FRANCELaboratoire de statistique, Faculté de la Timone, Marseille; FRANCEService de cardiologie, Polyclinique les Fleurs, Ollioules, FRANCE

Am J Cardiol 2009;103:5-10

DESIGN

Non-emergent PCI : ACS and Stable angina (n= 1122)

Loading dose (LD) -ASA 250mg -Clopidogrel 600mg

VASP ≥ 50%

Randomization(n=429)

CONTROL (n =215)

VASP-guided LD (n =214)

Up-to 3 additional LD of 600 mg every 24 hours until VASP < 50% before PCIMaintenance dose -ASA 160 mg

-Clopidogrel 75 mg

1° endpoint: Definite stent thrombosis (ARC definition)

2° endpoints: MACE including CV death, MI and U-TVRTIMI major and minor bleeding at 30 days

Platelet reactivity monitoring

VASP after first LD 66 ± 11 67 ± 10

VASP after sensitization 37 ± 12†

17 patients (8%)

† p <0.01

Timing of early stent thrombosis

All early stent thrombosis occured during the first 7 days

Am J Cardiol 2009;103:5-10

How Can We Solve the Problem Caused by

Clopidogrel Resistance?

Is the answer by increasing the dose?

P < 0.05 vs. 300 mg LD

A Faster Onset of Action Was Seen with Higher Clopidogrel Loading Regimens

A Faster Onset of Action Was Seen with Higher A Faster Onset of Action Was Seen with Higher ClopidogrelClopidogrel Loading RegimensLoading Regimens

The ALBION trial

0

10

20

30

40

50

1 2 3 4 5 6

300 mg LD600 mg LD900 mg LD

Maximum Inhibition of Platelet Aggregation (5 µM ADP)

Time (h)

(%) Inhibition

Shortened time to reach the highest level of inhibition of the 300 mg LD

Montalescot G et al. J Am Coll Cardiol 2006;48:931-8

Change the Agent?

Prasugrel

Sankyo Ann Report 51:1,1999

Pro-drug

Oxidation(Cytochrome P450)

HOOC* HS

N

O

F

Active Metabolite

N

S

O

FO

Sem Vasc Med 3:113, 2003

Hydrolysis(Esterases)

N

S

O

CH3

CO

FON

S

O

Cl

O CH3C

Clopidogrel

85% Inactive Metabolites

Esterases

N

S

O

Cl

O CH3C

ON

S

O

Cl

O CH3C

Active Metabolite

HOOC* HS

N

O

Cl

OCH3

Inhibition of Platelet Aggregation(IPA) at 24 Hours (Healthy Volunteers)

-20.0

0.0

20.0

40.0

60.0

80.0

100.0

Inhi

bitio

n of

Pla

tele

t Ag

gre

gat

ion

(%)

Response to Prasugrel

Response to Clopidogrel

Clopidogrel ResponderClopidogrel Non-responder

*Responder = 25% IPA at 4 and 24 h

Inte

rpat

ient

Var

iabi

lity

Interpatient V

ariability

Brandt, Payne, Wiviott et al AHJ 2007

Inhibition of Platelet Aggregation After Loading Dose in Patients With Elective PCI

Hours

IPA

% (

20

µM

AD

P) Prasugrel 60 mg

***p<0.0001 Prasugrel vs. Clopidogrel

Clopidogrel 600 mg

*********

***

0.5 4 8 12 16 20 24

0

20

40

60

80

100

62

IPA=inhibition of platelet aggregation; PCI=Percutaneous coronary intervention Wiviott SD et al. Circulation 2007;116(25):2923-2932

Inhibition of Platelet Aggregation in Healthy Volunteers

• Data are expressed as mean ± SEM. Arrows (↓) indicate day of dose administration

Payne CD et al. J Cardiovasc Pharmacol 2007;50(5):555-562

IPA

% (

20

M

AD

P)

Loading Dose Maintenance Doses

Time

-10

0

10

20

30

40

50

60

70

80

90

100

2 3 4 5 6 7 8 90.25 0.5 1 2 4 6

‡

*

* * * * * * * * * * *†

†

‡ ‡‡

*

Pre-doseIPA

Day 1, Hours Days

Clopidogrel 600 mg/75 mg

Clopidogrel 300 mg/75 mg

Prasugrel 60 mg/10 mg

IPA=Inhibition of platelet aggregation; ADP=Adenosine diphosphate

* p<0.001 Prasugrel vs Clopidogrel† p<0.05 Clopidogrel 600 mg vs 300 mg‡ p<0.001 Clopidogrel 600 mg vs 300 mg

TRial to Assess Improvement in Therapeutic Outcomes by

Optimizing Platelet InhibitioN with Prasugrel

TRITON-TIMI 38

Study funded by Daiichi Sankyo Company, Limited and Eli Lilly and Company

ACS=Acute Coronary Syndrome; CV=Cardiovascular; IPA=Inhibition of Platelet Aggregation; MI=Myocardial Infarction; PCI=Percutaneous Coronary Intervention

1.Wiviott SD et al. New Engl J Med 2007;357:2001-20152. Wiviott SD et al. Am Heart J 2006;152:627-635

TRITON-TIMI 38: Study Objective and Hypothesis

¨ To test the hypothesis that an antiplatelet agent that results in higher and less variable IPA reduces ischemic events1

¨ To evaluate the safety of a regimen that produces higher IPA1

¨ To determine in ACS subjects with planned PCI whether:2

• Prasugrel is superior to clopidogrel in reducing occurrence of CV death, nonfatal MI, or nonfatal stroke

• Prasugrel has a similar safety profile to clopidogrel

TRITON-TIMI 38: Study Design and Primary Efficacy End Points

& Planned PCI

ASA

ASA

ASA=Acetylsalicylic Acid; CABG=Coronary Artery Bypass Graft surgery; LD=Loading Dose; MD=Maintenance Dose; MI=Myocardial Infarction; NSTEMI=Non-ST-Elevation Myocardial Infarction; PCI=Percutaneous Coronary Intervention; R=Randomization; STEMI=ST-Elevation Myocardial Infarction; TIMI=Thrombolysis In Myocardial Infarction; UA=Unstable Angina; UTVR=Urgent Target Vessel Revascularization

Primary efficacy end point: a composite of the rate of death from cardiovascular causes, nonfatal MI, or nonfatal stroke

=

UA/NSTEMI (TIMI Risk Score ≥ 3)

STEMI (Primary PCI ≤ 12 hours of symptoms or post-STEMI within 14 days)

RD

ay 3

Day

30

Day

90

Prasugrel60 mg LD/ 10 mg MD

Clopidogrel300 mg LD/ 75 mg MD

Day

450

Key secondary end points at 30 and 90 days included primary efficacy end point and a composite of the rate of death from cardiovascular causes, nonfatal MI, or UTVR

=

14.5 month actual

median

12.0 month planned median

Double-blind treatment 6 - 15 months planned follow-up

Key safety end point: non-CABG related TIMI Major Bleeding

Wiviott SD et al. New Engl J Med 2007;357:2001-2015Wiviott SD et al. Am Heart J 2006;152:627-635

TIMI Category

Intracranial hemorrhage

Clinically Overt (including imaging)

Hgb drop (g/dL)

Major X X ≥5

Minor X 3 to <5

Minimal X <3

TRITON-TIMI 38: TIMI Bleeding Definitions

Wiviott SD et al. Am Heart J 2006;152:627-635Hgb=Hemoglobin; PRBC=Packed Red Blood Cells; TIMI=Thrombolysis In Myocardial Infarction

Life Threatening: Any TIMI major bleeding event meeting any of the following criteria:

• Fatal

•Leads to hypotension requiring I.V. inotropic agents

• Requires surgical intervention for ongoing bleeding

• Necessitates transfusion of ≥ 4 units of blood (whole or PRBC) over 48 hour time period

• Any symptomatic intracranial bleed

ACS=Acute Coronary Syndrome; NSTEMI=Non–ST-Elevation Myocardial Infarction; CI=Percutaneous Coronary Intervention; STEMI=ST-Elevation Myocardial Infarction; TIMI=Thrombolysis In Myocardial Infarction; UA=Unstable Angina; NSAID=Non-steroidal Anti-Inflammatory Drug

Wiviott SD et al. Am Heart J 2006;152:627-635

TRITON-TIMI 38: Key Enrollment Criteria

Inclusion Criteria

¨ Moderate-high risk ACS patients with planned PCI:

• UA/NSTEMI (TIMI Risk Score ≥3) within 72 hours of symptom onset

• STEMI: Primary PCI (within 12 hours)

• STEMI: Primary PCI not planned (>12 hours to ≤14 days)

Exclusion Criteria

¨ Any thienopyridine within 5 days of randomization

¨ Daily treatment with NSAID or Cox-2 inhibitor

¨ Fibrin-specific fibrinolytic therapy <24 hours

¨ Increased bleeding risk

¨ History of hemorrhagic stroke; or ischemic stroke ≤3 months

TRITON-TIMI 38: Baseline Characteristics

Clopidogrel (n=6,795)

Prasugrel (n=6,813)

UA/NSTEMI (%)1 74 74

STEMI (%)1 26 26

Median age (years)1

≥75 years (%)6113

6113

Median weight (kg)2

<60 kg (%)835.3

844.6

Female (%)1 27* 25

NSTEMI=Non–ST-Elevation Myocardial Infarction; STEMI=ST-Elevation Myocardial Infarction; UA=Unstable Angina

1. Wiviott SD et al. New Engl J Med 2007;357:2001-20152. Antman EM et al. American Heart Association Scientific Sessions; 2007, Nov 4-7; Orlando, FL

* P=0.02

TRITON-TIMI 38: Study Drug and Pharmacotherapies

Clopidogrel(n=6,795)

%

Prasugrel(n=6,813)

%

Timing of study drug loading dose

Pre-PCI (before 1st wire) 25 26

During PCI (1st wire to 1 hr after leaving lab) 74 73

Post-PCI (>1 h after leaving lab) 1 1

Pharmacotherapies (during index event)

Angiotensin-Converting Enzyme Inhibitor or Angiotensin Receptor Blocker

75* 76

Beta-blocker 88 88

Statin 92 92

Calcium channel blocker 17 18

Aspirin 99 99

PCI=Percutaneous Coronary Intervention

*P=0.03 Wiviott SD et al. New Engl J Med 2007;357:2001-2015

ACS=Acute Coronary Syndrome; ARR=Absolute Risk Reduction; CV=Cardiovascular; HR=Hazard Ratio; MI=Myocardial Infarction; NNT=Number Needed to Treat

10

15

Days

0

5

0 30 60 90 180 270 360 450

Prasugrel

Clopidogrel

Intent To Treat: n=13,608; Lost to Follow-Up: n=14 (0.1%)

HR 0.81 (0.73-0.90)

P<0.001ARR=2.2NNT=46

12.1(n=781)

9.9 (n=643)

HR 0.77 (0.67-0.88)

P<0.001

HR 0.80 (0.71-0.90)

P<0.001

CV

Dea

th/M

I/S

tro

ke

(%)

Wiviott SD et al. New Engl J Med 2007;357:2001-2015

TRITON-TIMI 38: Primary End Point All ACS Population

ARR=Absolute Risk Reduction; CV=Cardiovascular; HR=Hazard Ratio; MI=Myocardial Infarction; RRR=Relative Risk Reduction

Days

CV

Dea

th/M

I/S

tro

ke (

%)

Loading Dose Maintenance Dose0 1 2 3 3 30 90 180 270 360 450

HR 0.82 (0.71-0.96)

P=0.01

RRR 18%ARR 0.9%

5.6

4.7

HR 0.80 (0.70-0.93)

P=0.003

RRR 20%ARR 1.3%

6.9

5.6Clopidogrel Clopidogrel

Prasugrel Prasugrel

0

2

4

6

8


TRITON-TIMI 38: Timing of Benefit (Primary Endpoint, All ACS– 3-Day Landmark Analysis)

CABG=Coronary Artery Bypass Graft surgery; CV=Cardiovascular; MI=Myocardial Infarction; TIMI=Thrombolysis In Myocardial Infarction

Prasugrel

Clopidogrel

TRITON-TIMI 38: Rates of Key Study End Points (All ACS)


5

10

15

00 30 60 90 180 270 360 450

Days After Randomization

En

d P

oin

t (%

)

120

1.8 (n=111)

2.4(n=146)

Non-CABG TIMI Major Bleeds

CV Death, MI, Stroke

P=0.03

P<0.001↓138 events

↑ 35 events

12.1(n=781)

9.9 (n=643)

Prasugrel

Clopidogrel

Days After RandomizationMI=Myocardial Infarction; CABG=Coronary Artery Bypass Graft surgery; Hazard Ration; ITT=Intent To Treat; TIMI=Thrombolysis In Myocardial Infarction

0

5

10

15

0 30 60 90 180 270 360 450

En

d P

oin

t (%

)

HR 0.87 (0.79-0.95)

P=0.004

13.9

12.2

ITT=13,608

Prasugrel

Clopidogrel

TRITON-TIMI 38: Net Clinical Benefit(All Cause Death, MI, Stroke, Non-CABG TIMI Major Bleed)


TRITON-TIMI 38: ARC Definite/Probable Stent Thrombosis: Any Stent

ARC=Academic Research Consortium; ARR=Absolute Risk Reduction; HR=Hazard Ratio; NNT=Number Needed to Treat; PCI=Percutaneous Coronary Intervention; RRR=Relative Risk Reduction Wiviott SD et al. Lancet 2008;371:1353-1363

0 30 60 90 180 270 360 450

HR 0.48 (0.36-0.64)

P<0.001

RRR 52%ARR 1.22%

Prasugrel

Clopidogrel2.4

1.1

Days

Ste

nt

Th

rom

bo

sis

(%)

Any Stent at Index PCI n=12,844

0

1

2

3

NNT=77

TRITON-TIMI 38: Primary Endpoint (CVD/MI/Stroke) Not Related to Stent Thrombosis

Days

% o

f S

ub

ject

s

10.3%

8.7%

RRR 15%

HR 0.85p=0.005

Clopidogrel

Prasugrel

0

2

4

6

8

10

12

0 50 100 150 200 250 300 350 400 450

CVA=cerebrovascular accident; HR=hazard ratio; MI=myocardial infarction Wiviott SD et al. Lancet 2008;371:1353-1363

TRITON-TIMI 38: Net Clinical Benefit: MI and Non-CABG TIMI Major Bleeds

Myocardial Infarction

Non-CABG TIMI Major

Bleed

Events per 1,000 patients on prasugrelversus clopidogrel

CABG=Coronary Artery Bypass Graft surgery; MI=Myocardial Infarction; TIMI=Thrombolysis In Myocardial Infarction

+6

-23

# o

f E

ven

ts


TRITON-TIMI 38: Diabetic Subgroup Analysis (n=3,146)

CABG=Coronary Artery Bypass Graft surgery; CV=Cardiovascular; HR=Hazard Ratio; MI=Myocardial Infarction; NNT= Number Needed to Treat; TIMI=Thrombolysis In Myocardial Infarction

Adapted from Antman EM et al. American Heart Association Scientific Sessions; 2007, Nov 4-7; Orlando, FL

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

d P

oin

t (%

)

CV Death, MI, Stroke

NNT=21

17.0

12.2

2.62.5

Non-CABG TIMI Major Bleeds

Prasugrel

Clopidogrel

Eff-SK-2-MENA-07/10

Cumulative Kaplan-Meier estimates of the rates of primary end points during the follow-up periodCV=Cardiovascular; HR=Hazard Ratio; NF=Nonfatal; MI=Myocardial Infarction; NNT=Number Needed to Treat ;STEMI=ST Segment Elevation Myocardial InfarctionMontalescot G et al. Lancet 2009 Feb 28;373(9665):723-31

STEMI Cohort: Primary End Point(CV Death, NF MI or NF Stroke)15

Days from Randomization

Pati

en

ts (

%)

5

10

00 50 100 150 200 250 300 350 400 450

9.5

6.5

12.4(n = 216)

10.0(n = 174)

Clopidogrel

Prasugrel

HR 0.68 (0.54–0.87) P = 0.0017

HR 0.79 (0.65–0.97) P = 0.0221

NNT = 41

30

TRITON TIMI 38

Eff-SK-2-MENA-07/10

Cumulative Kaplan-Meier estimates of the safety end point non-CABG TIMI major bleedingCABG=Coronary Artery Bypass Graft; HR=Hazard Ratio; NNH=Number Needed to Harm;STEMI=ST Segment Elevation Myocardial Infarction; TIMI=Thrombolysis in Myocardial InfarctionMontalescot G et al. Lancet 2009 Feb 28;373(9665):723-31

STEMI Cohort:Non-CABG TIMI Major Bleeding

2.4(n = 38)

Pati

en

ts (

%)

Days from Randomization

0.5

1.0

2.0

2.5

1.5

2.1(n = 34)

HR 1.11 (0.70–1.77)P = 0.6451

0 100 200 300 4000

Clopidogrel

Prasugrel

15050 250 350 450

TRITON TIMI 38

TRITON-TIMI 38: Net Clinical BenefitPost-hoc Analyses in Selected Subgroups

Prasugrel Better Clopidogrel Better

P* value

P**interaction

0.04 -

<0.001 0.006

0.43 -

<0.001 0.006

MI=Myocardial infarction; HR=Hazard Ratio; TIA=Transient Ischemic Attack; TIMI=Thrombolysis In Myocardial Infarction

HR0.8 1.3 1.8 2.30.5 1.0 1.5 2.0 2.5

History of stroke or TIA

Yes

No

Any of the following:

Age >75 y, Body wt. <60 kg, History stroke/TIA

Yes

No


*Tests hazard ratio =1.0 within subgroups; **Tests equality hazard ratio between subgroups

All Cause Death, MI, Stroke, Non-CABG TIMI Major Bleed

CABG=Coronary Artery Bypass Graft surgery; CV=Cardiovascular; MI=Myocardial Infarction; TIMI=Thrombolysis In Myocardial Infarction

TRITON-TIMI 38: Clinical Implications

¨ For every 1,000 patients treated with prasugrel compared with clopidogrel• 23 MI’s are prevented

• 6 more non-CABG TIMI major bleeds are experienced

¨ Over 15 months • Number needed to treat is 46 to prevent one CV

death, nonfatal MI or nonfatal stroke

• Number needed to harm is 167 to cause one non-CABG TIMI major bleed


Conclusions

¨ The TRITON-TIMI 38 Trial demonstrated that prasugrel is more effective at preventing ischemic events than clopidogrel in moderate to high-risk patients with ACS with scheduled PCI

¨ Prasugrel was also more effective at preventing stent thrombosis

¨ The beneficial effect of intensive inhibition of platelet aggregation is accompanied by increased risk of major bleeding

¨ Analysis of net clinical benefit favored prasugrel over clopidogrel

¨ In patients with STEMI and those with Diabetes the superiority of prasugrel compared to clopidogrel was more important with SAME bleeding risk

ACS= Acute Coronary Syndrome; PCI=Percutaneous Coronary Intervention Wiviott SD et al. New Engl J Med 2007;357:2001-2015

ACC/AHA 2009 Joint STEMI/PCI Guidelines Focused Update

47

ACC/AHA 2009 STEMI/PCI Guidelines Focused Update

Based on the ACC/AHA Guidelines for the Management of Patients With ST-Elevation

Myocardial Infarction (STEMI) and the ACC/AHA/SCAI Guidelines on Percutaneous Coronary Intervention (PCI): A Report of the ACC/AHA Task Force on Practice Guidelines


48

Recommendations for the use of Thienopyridines STEMI

A loading dose of thienopyridine is recommended for STEMI patients for

whom PCI is planned. Regimens should be one of the following:

MODIFIED Recommendation

III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII

Clopidogrel at least 300 mg to 600mg† should be given as early as possible before or at the time of primary or non-primary PCI.


Prasugrel 60 mg should be given

as soon as possible for primary

PCI.


49

Recommendations for the timing of Angiography and

Antiplatelet Therapy in UA/NSTEMI


Patients with definite UA/NSTEMI at medium or high risk and in whom an initial invasive strategy is selected should receive

The choice of a second antiplatelet therapy to be added to ASA on presentation includes 1 of the following:

Before PCI:

● Clopidogrel; or

● An IV GP IIb/IIIa inhibitor. (Level of Evidence: A) IV eptifibatide or tirofiban

are the preferred GP IIb/IIIa inhibitors.

At the time of PCI:

● Clopidogrel if not started before PCI; or

● Prasugrel; or

● An IV GP IIb/IIIa inhibitor (Level of Evidence: A)

50JACC Vol. 57, No. 18, March 2011


…dual-antiplatelet therapy on presentation, ASA should be initiated on presentation




progress in oral anti- platelet therapy rabih r. azar, md, msc, facc division of cardiology hotel...

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