Post pci mi thrombotic events a plateletcentric problem
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Post-PCI/MI Thrombotic Events – A Plateletcentric Problem!!!!. Platelet Adhesion/Activation. PCI/MI. Aspirin. x. P2Y 12 Blockers. ADP. TxA 2. Thrombin. Vorapaxar. x. x. Sustained GPIIb / IIIa Activation. Ischemic Events/Stent Thrombosis. Hypercoagulability. Inflammation.

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Post-PCI/MI Thrombotic Events – A Plateletcentric Problem!!!!

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Post pci mi thrombotic events a plateletcentric problem

Post-PCI/MI Thrombotic Events – A Plateletcentric Problem!!!!

Platelet Adhesion/Activation

PCI/MI

Aspirin

x

P2Y12Blockers

ADP

TxA2

Thrombin

Vorapaxar

x

x

Sustained GPIIb/IIIa Activation

Ischemic Events/Stent Thrombosis

Hypercoagulability

Inflammation

ADP = adenosine diphosphate. GP = glycoprotein. MI = myocardial infarction. PCI = percutaneous coronary intervention. TxA2 = thromboxane A2.

Gurbel PA, Tantry US. Circulation. 2012;125:1276-1287.

Platelet Aggregation


Aggregation on aspirin aspirin clopidogrel and aspirin ticagrelor

Aggregation on Aspirin, Aspirin + Clopidogrel, and Aspirin + Ticagrelor

Aggregation in 42% of pts on clopidogrel + aspirin:

In same range as 50% of pts treated with aspirin alone!

In Asians, it will be even higher than 42%

100

42%

50%

80

8 hrs post-600 mg clopidogrel

8 hrs post-180 mg ticagrelor load

60

Aspirin 75-100 mg QD

Cumulative Frequency (%)

40

20

0

0

20

40

60

80

100

120

20uM ADP-induced Aggregation

GurbelPA, TantryUS. Circulation.2012;125:1276-1287.


Verifynow p2y 12 patient based meta analysis 2 year outcomes

VerifyNow P2Y12Patient-based Meta-analysis: 2-year Outcomes

Very low ST rate ~ immunity

6 studies; n=3059

2-year MACE by PRU Quartile

2-year ST by PRU Quartile

~8x risk between Q1 and Q4

~3x risk between Q1 and Q4

MACE = major adverse cardiovascular event. PRU = platelet reactivity unit. ST = stent thrombosis.

Brar SS, et al. J Am CollCardiol. 2011;58:1945-1954.


The platelet function therapeutic window and the concept of thrombosis immunity

The Platelet Function Therapeutic Window and the Concept of Thrombosis Immunity

Post-PCI Ischemic/Thrombotic Clinical Events

100

Patients with ischemic events

Immunity Thresholds~170 PRU

~50% VASP-PRI

~35% 5 M ADP~46% 20 M ADP

~416 AU MULTIPLATE

~65 mm MAKH-TEG

90

80

BleedingThreshold

<85 PRU<188 AU<31mm MAKH

70

60

Cumulative Frequency of Patients (%)

50

Most ischemic events occur above a platelet reactivity cutoff

Small increase above cutoff: increased ischemic risk

40

30

Too lowplatelet reactivity?

20

Bleeding?

10

0

ADP-induced Platelet Reactivity (%)

The sigmoid cumulative frequency curve in patients with post-PCI ischemic/thrombotic clinical events relative to platelet reactivity to ADP; these data support the concept of a therapeutic window for P2Y12 blockade.

Gurbel PA, et al. J Am CollCardiol. 2007;50:1822-1834. Gurbel PA, et al. Am Heart J. 2010;160:346-354. Campo G, et al. J Am CollCardiol. 2011;57:2474-2483. Jeong YH, et al. Presented at: European Society of Cardiology Congress 2011; August 27-31, 2011; Paris, France. Gurbel PA, et al. ThrombHaemost. 2011;106:263-264. Sibbing D, et al. ThrombHaemost 2010;103:151-159. Sibbing D, et al. J ThrombHaemost. 2010;8:250-256.


Post pci mi thrombotic events a plateletcentric problem

ARCTIC Trial Design

Coronary angiogram

  • Primary endpoint at 12 months:

  • Death, MI, stroke, ST, urgent revascularization

Randomized

VerifyNow

P2Y12 + ASA

Standard of care

  • Statistical considerations:

  • Assuming an annual risk of 9% and a 33% relative risk reduction (α risk at 5% and error βof 20%, bilateral test), 2466 patients were necessary to demonstrate the superiority of the strategy of monitoring and adjustment

Drug (ASA, clopidogrel, prasugrel, GPIIbIIIai) and doseadjustments if high platelet reactivity

Stent-PCI

ARCTIC study protocol - Collet JP, et al. Am Heart J 2011;161:5-12

Stent-PCI

Standard of care

Druganddoseadjustments if high platelet reactivity at Day 14

12-month FU


Post pci mi thrombotic events a plateletcentric problem

Primary Endpoint to 1 year

Death, MI, stroke, stent thrombosis, urgent revascularization


Post pci mi thrombotic events a plateletcentric problem

Other Ischemic Endpoints


Post pci mi thrombotic events a plateletcentric problem

Key Safety Outcomes

STEEPLE definitions - Montalescot G, et al. N Engl J Med 2006; 355:1006–17


Platelet function substudy design

Platelet Function Substudy Design

UA/NSTEMI (N = 9326, 52 countries) planned medical management without revascularization

Prasugrelvs.Clopidogrel 10 mg (< 75 years and ≥ 60 kg)75 mg (for all)5 mg (≥ 75 years; < 75 years and < 60 kg)

Aspirin ≤ 100 mg(strongly recommended) for all

PFS: 2690 (28% of total) participants from 25 countries

VerifyNow P2Y12Assay At baseline, at 2 h, and at 1, 3, 6, 12, 18, 24, and 30 mos after randomization

Primary efficacy endpoint:-Composite of CV death, MI, and stroke through 30 months

Key secondary endpoints:- All-cause death - MI

126 without valid PRU measurement excluded from analysis

2564 participants (prasugrel, n = 1286 and clopidogrel, n = 1278) included in final analysis


Kaplan meier event curves landmark at 30 days hpr cut point 208 pru

Kaplan-Meier Event Curves: Landmark at 30 Days HPR Cut-Point > 208 PRU

Primary Efficacy Endpoint

With HPR

Without HPR

The P values for each panel compare the hazard between the two groups throughout the time period represented.

All MI Events

All-Cause Death


Relationship of pru values with ischemic event occurrence through 30 months

Relationship of PRU Values with Ischemic Event Occurrence Through 30 Months


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