Tailored Clopidogrel Loading Dose According to Platelet Reactivity Monitoring to Reduce 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 Presented at AHA 2008

Introduction Large inter-individual variability in response to clopidogrel in CAD patients when 300mg loading dose (LD) used Large inter-individual variability in response to clopidogrel in CAD patients when 300mg loading dose (LD) used 600mg LD decreases the mean platelet reactivity, but STILL does not overcome inter-individual variability 600mg LD decreases the mean platelet reactivity, but STILL does not overcome inter-individual variability Variability is related to many factors Variability is related to many factors Genetic variations to form metabolite Genetic variations to form metabolite Response to clopidogrel is UNPREDICTABLE Response to clopidogrel is UNPREDICTABLE Statins/PPI

EndpointAuthorPlatelet assayn Stent thrombosisBarraganVASP index36 GurbelVASP index, ADP aggregometry120 BuonamiciADP- aggregometry804 BlindtVASP index, ADP aggregometry99 Ischemic events CV death, MI, unstable angina, stroke GurbelADP aggregometry192 Death, MI, stent thrombosis, stroke, ischemia BlidenADP aggregometry100 CV death, acute or subacute ST, ACS, ischemic stroke CuissetADP aggregometry, VASP index195 Death, MI, TLRTrenkADP aggregometry802 CV death, MI, urgent TVRBonelloVASP index144 CV death, acute and subacute stent thrombosis, MI PriceVerifyNow P2Y12380 Link btw Low-Responders and Thrombotic Events/MACE

To assess the utility of a vasodilator-associated stimulated phosphoprotein (VASP) index to guide management in patients undergoing PCI for non- emergent causes. To assess the utility of a vasodilator-associated stimulated phosphoprotein (VASP) index to guide management in patients undergoing PCI for non- emergent causes. Essentially…tailored clopidogrel loading in patients who are clopidogrel non-responders Essentially…tailored clopidogrel loading in patients who are clopidogrel non-responders Objective

+ ADP AC cAMP PKA VASP VASP-P GP 2b/3a complex Fibrinogen binding Inactivated Platelets VASP-P>VASP PGE1 - Activated platelets VASP>VASP-P P2Y 12 ADP-receptor Monoclonal Ab specific for the VASP-P Quantified by flow cytometry Highly specific of the response to clopidogrel. Horstrup et al. Eur J Biochem 1994;225:21-7 Geiger et al. Arterioscler Thromb Vasc Biol. 1999;19: Vasodilator-Associated Stimulated Phosphorylation Index

Threshold of PR to Prevent Thrombotic Events AuthorTestEnd-pointnFollow-upCut-off BarraganVASP indexST461 month50% BonelloVASP indexMACE1446 months50% FrereVASP indexMACE+ stroke 1951 months53% LTA70% BlindtVASP indexST996 months48% PriceVerifyNowCVD + ST3806 months52% GurbelLTACVE29724 months46% LTA59%

Study Design Non-emergent PCI : ACS and Stable angina (n= 1122) Loading dose: 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 PCI (over 4d) 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

Baseline Characteristics n of treated vessels*1.5 ± ± n of stents1.8 ± 11.9 ± n of DES0.9 ± ± 10.9 GP IIb/IIIa inhibitors51 (23.8)51 (23.7)0.1 n, (%)Control (n = 214) VASP-guided (n = 215) p Sex, male168 (78.5)177 (82)0.4 Age, yrs*66.8 ± ± BMI, kg/m 2 *28 ± ± Previous MI56 (26)65 (30)0.4 Present smoking115 (53.7)123 (57)0.9 Dyslipidemia126 (58.9)129 (60)0.8 Diabetes84 (39)71 (33)0.5 Hypertension132 (61.7)132 (61.4)0.2 ACS112 (52.3)109 (50.7)1

Platelet Reactivity Monitoring VASP after first LD66 ± 1167 ± 10 VASP after sensitization  37 ± 12 † 17 patients (8%) VASP Index > 50% † p <0.01

Early Definite Stent Thrombosis at 1 month GP IIb/IIIa inhibitor were used in half of pts presenting with early stent thrombosis. All early stent thrombosis occurred during the first 7 days

Secondary Endpoint: MACE Endpoint n, (%)Control (n= 214) VASP-guided (n= 215) p Cardiovascular death4 (1.8)00.06 Myocardial infarction10 (4.8)1 (0.5)0.01 Urgent revascularization5 (2.3)00.06 All MACE19 (8.9)1 (0.5)< 0.001

Secondary Endpoint: TIMI Bleeding No difference in bleeding complication between the 2 groups NO intracerebral bleeding, NO fatal bleeding Majority of patients had PCI through the radial access (55.6%) Control (n= 214) VASP-guided (n= 215) p Major bleeding2 (0.9) 1 Minor bleeding4 (1.9)6 (2.8)0.8 All6 (2.8)8 (3.7)0.8

Conclusions Adjusted LD of clopidogrel according to platelet response (PR) decreases the rate of stent thrombosis and MACE at 1mo in clopidogrel low-responders without increasing bleeding.Adjusted LD of clopidogrel according to platelet response (PR) decreases the rate of stent thrombosis and MACE at 1mo in clopidogrel low-responders without increasing bleeding. Patients could be divided in 3 groups according to VASP index:Patients could be divided in 3 groups according to VASP index: Good-responders: VASP<50 % after a first bolus of 600 mg of clopidogrel (55%)Good-responders: VASP<50 % after a first bolus of 600 mg of clopidogrel (55%) Low-responders: VASP>50 % after the first bolus but could be sensitized with up-to three additional LD (37%)Low-responders: VASP>50 % after the first bolus but could be sensitized with up-to three additional LD (37%) Resistant: VASP>50 % despite up-to 2400 mg of clopidogrel (8%)Resistant: VASP>50 % despite up-to 2400 mg of clopidogrel (8%) Authors suggest a Paradigm shift:Authors suggest a Paradigm shift: Need to assess PR in ALL pts receiving clopidogrelNeed to assess PR in ALL pts receiving clopidogrel

Potential bias: VASP-guided arm had a relatively longer time until PCI (up to 4 days) which could have allowed for important meds (ie statins) to be used for a longer duration Potential bias: VASP-guided arm had a relatively longer time until PCI (up to 4 days) which could have allowed for important meds (ie statins) to be used for a longer duration Role of >50% radial approach: potentially safer at higher clopidogrel doses Role of >50% radial approach: potentially safer at higher clopidogrel doses Unclear how MI was defined: main driver of MACE Unclear how MI was defined: main driver of MACE What happened to the clopidogrel-resistant pts? What happened to the clopidogrel-resistant pts? VASP Assay: expensive and need for extensive sample preparation, flow cytometry, and experienced technicians VASP Assay: expensive and need for extensive sample preparation, flow cytometry, and experienced technicians Limitations

Alternative Agents: Prasugrel (TIMI 38), AZD 6140 (PLATO), Cangrelor (CHAMPION) Alternative Agents: Prasugrel (TIMI 38), AZD 6140 (PLATO), Cangrelor (CHAMPION) Alternative test: Point-of-Care test - VerifyNow Alternative test: Point-of-Care test - VerifyNow Tailored vs. STD Clopidogrel dosing post PCI (GRAVITAS) Tailored vs. STD Clopidogrel dosing post PCI (GRAVITAS) Empiric High vs. STD dose Clopidogrel Load pre PCI (OASIS 7) Empiric High vs. STD dose Clopidogrel Load pre PCI (OASIS 7) On the Horizon