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

ADP = adenosine diphosphate. GP = glycoprotein. MI = myocardial infarction. PCI = percutaneous coronary intervention. TxA2 = thromboxane A2.Gurbel PA, Tantry US. Circulation. 2012;125:1276-1287.

Ischemic Events/Stent Thrombosis

PCI/MIPlatelet Adhesion/Activation

Platelet Aggregation

Hypercoagulability Inflammation

ThrombinADP TxA2

Sustained GPIIb/IIIa Activation

P2Y12 Blockers

xVorapaxar

x

Aspirinx

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

0 20 40 60 80 100 12020uM ADP-induced Aggregation

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

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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%

2-year MACE by PRU Quartile

MACE = major adverse cardiovascular event. PRU = platelet reactivity unit. ST = stent thrombosis. Brar SS, et al. J Am Coll Cardiol. 2011;58:1945-1954.

2-year ST by PRU Quartile

Very low ST rate ~ immunity

6 studies; n=3059

~3x risk between Q1 and Q4 ~8x risk between Q1 and Q4

VerifyNow P2Y12 Patient-based Meta-analysis: 2-year Outcomes

Gurbel PA, et al. J Am Coll Cardiol. 2007;50:1822-1834. Gurbel PA, et al. Am Heart J. 2010;160:346-354. Campo G, et al. J Am Coll Cardiol. 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. Thromb Haemost. 2011;106:263-264. Sibbing D, et al. Thromb Haemost 2010;103:151-159. Sibbing D, et al. J Thromb Haemost. 2010;8:250-256.

The Platelet Function Therapeutic Window and the Concept of Thrombosis Immunity

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.

Post-PCI Ischemic/Thrombotic Clinical Events

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ADP-induced Platelet Reactivity (%)

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2030405060708090

100

Too lowplatelet reactivity?

Bleeding?

1. Most ischemic events occur above a platelet reactivity cutoff

2. Small increase above cutoff: increased ischemic risk

Patients with ischemic events

Bleeding Threshold

<85 PRU<188 AU<31mm MAKH

Immunity Thresholds~170 PRU~50% VASP-PRI~35% 5 M ADP~46% 20 M ADP~416 AU MULTIPLATE~65 mm MAKH-TEG

Standard of care

VerifyNow P2Y12 + ASA

Drug (ASA, clopidogrel, prasugrel, GPIIbIIIa i) and dose adjustments if high

platelet reactivity

Coronary angiogram

Stent-PCI

Randomized

Standard of careDrug and dose adjustments

if high platelet reactivity at Day 14

12-month FU

Stent-PCI

ARCTIC Trial Design

Primary endpoint at 12 months:• Death, MI, stroke, ST, urgent

revascularization

Statistical considerations:• Assuming an annual risk of 9% and a

33% relative risk reduction (α risk at 5% and error β of 20%, bilateral test), 2466 patients were necessary to demonstrate the superiority of the strategy of monitoring and adjustment

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

Primary Endpoint to 1 yearDeath, MI, stroke, stent thrombosis, urgent revascularization

  Conventional Monitoring HR [95%CI]  P

Death or myocardial Infarction - % 28.8 31.7 1.11 [0.96; 1.29] 0.15

Any death - % 1.6 2.3 1.41 [0.79; 2.50] 0.24

Myocardial infarction - % 28.4 30.3 1.08 [0.93; 1.25] 0.32

Stent thrombosis - % 0.7 1 1.34 [0.56; 3.18] 0.51

Stroke or TIA- % 0.6 0.7 1.15 [0.42; 3.18] 0.78

Urgent revascularization - % 4.2 4.5 1.06 [0.73; 1.55] 0.76

Other Ischemic Endpoints

  Conventional Monitoring HR [95%CI] P

Major bleeding - % 3.3 2.3 0.70 [0.43; 1.14] 0.15

Minor bleeding - % 1.7 1.0 0.57 [0.28; 1.16] 0.12

Major or minor bleeding - % 4.5 3.1 0.69 [0.46; 1.05] 0.08

Key Safety Outcomes

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

Platelet Function Substudy DesignUA/NSTEMI (N = 9326, 52 countries)

planned medical management without revascularization

Prasugrel vs. 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 allPFS: 2690 (28% of total) participants from 25 countries

Primary efficacy endpoint: - Composite of CV death, MI, and stroke through 30 monthsKey secondary endpoints: - All-cause death

- MI

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

126 without valid PRU measurement excluded from analysis

VerifyNow P2Y12 Assay At baseline, at 2 h, and at 1, 3, 6, 12, 18, 24, and 30 mos after randomization

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

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

All MI Events All-Cause Death

Primary Efficacy Endpoint With HPR

Without HPR

Relationship of PRU Values with Ischemic Event Occurrence Through 30 Months

Unadjusted Results

HR (95% CI) p-value

PRU as time-dependent covariate (per 60-unit increase)

CVD/MI/stroke 1.09 (1.02-1.16) 0.008

All-cause death 1.09 (1.01-1.18) 0.03

All MI 1.02 (0.94-1.11) 0.60

30-day HPR PRU cut-point > 208

CVD/MI/stroke 1.43 (1.10-1.86) 0.01

All-cause death 1.38 (0.99-1.91) 0.06

All MI 1.37 (0.96-1.95) 0.08

30-day HPR PRU cut-point > 178

CVD/MI/stroke 1.35 (1.05-1.73) 0.02

All-cause death 1.27 (0.92-1.75) 0.15

All MI 1.34 (0.96-1.86) 0.09

Adjusted Results

HR (95% CI) p-value

1.03 (0.96-1.11) 0.44

0.99 (0.90-1.08) 0.79

0.97 (0.88-1.07) 0.53

1.16 (0.89-1.52) 0.28

1.03 (0.74-1.44) 0.84

1.13 (0.79-1.62) 0.50

1.13 (0.87-1.45) 0.35

0.99 (0.71-1.38) 0.95

1.13 (0.80-1.58) 0.49