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Progress in Oral Anti-Platelet Therapy. Rabih R. Azar, MD, MSc, FACC Division of Cardiology Hotel Dieu de France Hospital. GP IIb/IIIa Receptor Activation Pathway. ADP. Thrombin. TXA 2. PAF. PLATELET. ASPIRIN. Vasopressin. Epi. ASPIRIN. ASPIRIN. HEPARINS. ASPIRIN. CLOPIDOGREL.

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Progress in Oral Anti-Platelet Therapy

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Progress in oral anti platelet therapy

Progress in Oral Anti-Platelet Therapy

Rabih R. Azar, MD, MSc, FACC

Division of Cardiology

Hotel Dieu de France Hospital


Gp iib iiia receptor activation pathway

GP IIb/IIIa Receptor Activation Pathway

ADP

Thrombin

TXA2

PAF

PLATELET

ASPIRIN

Vasopressin

Epi

ASPIRIN

ASPIRIN

HEPARINS

ASPIRIN

CLOPIDOGREL

ASPIRIN

ASPIRIN

5HT

ASPIRIN

Collagen

GP IIb/IIIa

Thickness of lineindicates strengthof activator

Fibrinogen

GP IIb/IIIa

PLATELET


Role of thienopyridines

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

What is the Effect of Clopidogrel on Platelet Aggregation?


Progress in oral anti platelet therapy

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

Why is the onset of action of clopidogrel late and why is the response to clopidogrel variable?


Is there a correlation between poor platelet inhibition and adverse cardiovascular outcome

Is There a Correlation Between Poor Platelet Inhibition and Adverse Cardiovascular Outcome?


Can we improve the outcome by improving platelet inhibition

Can We Improve the Outcome by Improving Platelet Inhibition?


Progress in oral anti platelet therapy

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; FRANCE

Laboratoire d’hématologie, INSERM UMRS 608, Hôpital conception; Marseille; FRANCE

Service de cardiologie, Hôpital d’aubagne, Aubagne; FRANCE

Service de cardiologie, Clinique clairval, Marseille; FRANCE

Service de cardiologie, Clinique Bouchard, Marseille; FRANCE

Service de cardiologie, Hôpital Privé Beauregard, Marseille; FRANCE

Laboratoire de statistique, Faculté de la Timone, Marseille; FRANCE

Service 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

DESIGN

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 PCI

Maintenance dose -ASA 160 mg

-Clopidogrel 75 mg

1° endpoint: Definite stent thrombosis (ARC definition)

2° endpoints: MACE including CV death, MI and U-TVR

TIMI major and minor bleeding at 30 days


Platelet reactivity monitoring

VASP after first LD

66 ± 11

67 ± 10

VASP after sensitization

37 ± 12†

† p <0.01

Platelet reactivity monitoring

17 patients (8%)


Timing of early stent thrombosis

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

How Can We Solve the Problem Caused by Clopidogrel Resistance?

Is the answer by increasing the dose?


Progress in oral anti platelet therapy

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


Triton timi 38 study objective and hypothesis

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

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 design and primary efficacy end points

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

R

Prasugrel

60 mg LD/ 10 mg MD

ASA

UA/NSTEMI (TIMI Risk Score ≥ 3)

12.0 month planned median

& Planned PCI

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

14.5 month actual median

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

ASA

Clopidogrel

300 mg LD/ 75 mg MD

Day 3

Day 30

Day 90

Day 450

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

=

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

=

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

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

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


Triton timi 38 timi bleeding definitions

TRITON-TIMI 38: TIMI Bleeding Definitions

Hgb=Hemoglobin; PRBC=Packed Red Blood Cells; TIMI=Thrombolysis In Myocardial Infarction

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


Triton timi 38 key enrollment criteria

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

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 baseline characteristics

TRITON-TIMI 38: Baseline Characteristics

* P=0.02

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

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

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


Triton timi 38 study drug and pharmacotherapies

TRITON-TIMI 38: Study Drug and Pharmacotherapies

*P=0.03

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

PCI=Percutaneous Coronary Intervention


Progress in oral anti platelet therapy

TRITON-TIMI 38: Primary End Point All ACS Population

15

HR 0.77 (0.67-0.88)P<0.001

Clopidogrel

12.1(n=781)

9.9 (n=643)

10

Prasugrel

CV Death/MI/Stroke (%)

HR 0.81 (0.73-0.90)P<0.001ARR=2.2NNT=46

HR 0.80 (0.71-0.90)P<0.001

5

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

0

0

30

60

90

180

270

360

450

Days

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

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


Triton timi 38 timing of benefit primary endpoint all acs 3 day landmark analysis

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

8

6.9

5.6

6

Clopidogrel

5.6

Clopidogrel

4.7

CV Death/MI/Stroke (%)

Prasugrel

Prasugrel

4

HR 0.82 (0.71-0.96)P=0.01

RRR 18%

ARR 0.9%

HR 0.80 (0.70-0.93)P=0.003

RRR 20%

ARR 1.3%

2

0

0

1

2

3

3

30

90

180

270

360

450

Loading Dose

Maintenance Dose

Days

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

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


Triton timi 38 rates of key study end points all acs

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

15

12.1(n=781)

Clopidogrel

CV Death, MI, Stroke

9.9 (n=643)

10

P<0.001

Prasugrel

↓138 events

End Point (%)

P=0.03

5

↑ 35 events

Non-CABG TIMI Major Bleeds

2.4

(n=146)

Prasugrel

1.8 (n=111)

Clopidogrel

0

0

30

60

90

180

270

360

450

120

Days After Randomization

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

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


Triton timi 38 net clinical benefit all cause death mi stroke non cabg timi major bleed

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

15

13.9

12.2

Clopidogrel

HR 0.87 (0.79-0.95)P=0.004

10

Prasugrel

End Point (%)

5

ITT=13,608

0

0

30

60

90

180

270

360

450

Days After Randomization

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

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


Triton timi 38 arc definite probable stent thrombosis any stent

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

3

2

1

0

0

30

60

90

180

270

360

450

Any Stent at Index PCI n=12,844

2.4

Clopidogrel

Stent Thrombosis (%)

1.1

Prasugrel

HR 0.48 (0.36-0.64)P<0.001

RRR 52%

ARR 1.22%

NNT=77

Days

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


Triton timi 38 primary endpoint cvd mi stroke not related to stent thrombosis

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

0

50

100

150

200

250

300

350

400

450

12

10.3%

10

RRR 15%

Clopidogrel

8.7%

8

HR 0.85p=0.005

% of Subjects

6

Prasugrel

4

2

0

Days

CVA=cerebrovascular accident; HR=hazard ratio; MI=myocardial infarction

Wiviott SD et al. Lancet2008;371:1353-1363


Triton timi 38 net clinical benefit mi and non cabg timi major bleeds

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

Events per 1,000 patients on prasugrelversus clopidogrel

Myocardial Infarction

+6

# of Events

-23

Non-CABG TIMI Major Bleed

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

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


Triton timi 38 diabetic subgroup analysis n 3 146

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

18

17.0

Clopidogrel

CV Death, MI, Stroke

16

Prasugrel

14

12.2

12

HR 0.70P<0.001

10

End Point (%)

NNT=21

8

6

Non-CABG TIMI Major Bleeds

4

2.6

2.5

2

0

0

30

60

90

180

270

360

450

Days

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


Triton timi 38 net clinical benefit post hoc analyses in selected subgroups

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

P*

value

P**

interaction

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

Yes

0.04

-

History of stroke or TIA

No

<0.001

0.006

Any of the following:

Age >75 y, Body wt. <60 kg,

History stroke/TIA

0.43

-

Yes

<0.001

0.006

No

0.5

0.8

1.0

1.3

1.5

1.8

2.0

2.3

2.5

HR

Clopidogrel Better

Prasugrel Better

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

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

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


Triton timi 38 clinical implications

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

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

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


Conclusions

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 stemi pci guidelines focused update

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


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MODIFIED Recommendation

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:

Prasugrel 60 mg should be given as soon as possible for primary PCI.

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.


Progress in oral anti platelet therapy

Recommendations for the timing of Angiography and Antiplatelet Therapy in UA/NSTEMI


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

…dual-antiplatelet therapy on presentation,

ASA should be initiated on presentation

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)

JACC Vol. 57, No. 18, March 2011


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