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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Sustained GPIIb/IIIa Activation
Ischemic Events/Stent Thrombosis
ADP = adenosine diphosphate. GP = glycoprotein. MI = myocardial infarction. PCI = percutaneous coronary intervention. TxA2 = thromboxane A2.
Gurbel PA, Tantry US. Circulation. 2012;125:1276-1287.
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%
8 hrs post-600 mg clopidogrel
8 hrs post-180 mg ticagrelor load
Aspirin 75-100 mg QD
Cumulative Frequency (%)
20uM ADP-induced Aggregation
GurbelPA, TantryUS. Circulation.2012;125:1276-1287.
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.
Post-PCI Ischemic/Thrombotic Clinical Events
Patients with ischemic events
Immunity Thresholds~170 PRU
~35% 5 M ADP~46% 20 M ADP
~416 AU MULTIPLATE
~65 mm MAKH-TEG
<85 PRU<188 AU<31mm MAKH
Cumulative Frequency of Patients (%)
Most ischemic events occur above a platelet reactivity cutoff
Small increase above cutoff: increased ischemic risk
Too lowplatelet reactivity?
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.
ARCTIC Trial Design
P2Y12 + ASA
Standard of care
Drug (ASA, clopidogrel, prasugrel, GPIIbIIIai) and doseadjustments if high platelet reactivity
ARCTIC study protocol - Collet JP, et al. Am Heart J 2011;161:5-12
Standard of care
Druganddoseadjustments if high platelet reactivity at Day 14
Primary Endpoint to 1 year
Death, MI, stroke, stent thrombosis, urgent revascularization
Other Ischemic Endpoints
Key Safety Outcomes
STEEPLE definitions - Montalescot G, et al. N Engl J Med 2006; 355:1006–17
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
Primary Efficacy Endpoint
The P values for each panel compare the hazard between the two groups throughout the time period represented.
All MI Events