High Versus Standard Clopidogrel Maintenance Dose After Percutaneous Coronary Intervention: Effects on Platelet Inhibition, Endothelial Function and Inflammation. Results of the ARMYDA-150 mg (Antiplatelet Therapy for Reduction of MYocardial Damage During Angioplasty) Randomized Study Giuseppe Patti, MD, FACC Department of Cardiovascular Sciences, Campus Bio-Medico University of Rome

GOAL OF THE STUDY To investigate whether a 150 mg/day clopidogrel maintenance dose exerts, in addition to a stronger antiplatelet effect, a more intense anti-inflammatory action and is associated with improvement of endothelial function vs the conventional regimen (75 mg/day) in patients receiving percutaneous coronary intervention (PCI)

Inclusion criteria: Consecutive patients (N=50) with non ST-segment elevation acute coronary syndrome or chronic stable angina undergoing PCI Exclusion criteria: Primary PCI for STEMI Active bleeding or bleeding diathesis Gastro-intestinal bleeding <6 months Cerebro-vascular accident <3 months Indication to oral anticoagulant therapy History of malignancy Severe liver disease or chronic renal failure with serum creatinine >2 mg/dL Platelet count <70x10 9 /L ARMYDA-150 study

One month N=50 patients treated with PCI (600 mg clopidogrel load before the procedure) R N=25 Clopidogrel 75 mg/day T-1T-2T-0 PRU FMD, NMD HS-CRP ARMYDA-150: Study design N=25 Clopidogrel 75 mg/day Clopidogrel 150 mg/day Clopidogrel 75 mg/day Clopidogrel 150 mg/day PRU FMD, NMD HS-CRP PRU FMD, NMD HS-CRP PRU= P2Y12 Reaction Units FMD= Flow-mediated dilation NMD= Nitroglycerin-mediated dilation HS-CRP= High sensitivity C-reactive protein One month

ARMYDA-150 End-points evaluated in the two clopidogrel doses: Platelet reactivity expressed by P2Y12 Reaction Units (PRU) with the point-of-care VerifyNow assay:  Absolute PRU values  Percent inhibition of PRU values from estimated baseline (measured by the TRAP-channel)  Percentage of patients with absolute PRU values ≥240 Brachial artery reactivity:  Percent Flow-mediated dilation (FMD) values  Incidence of patients with FMD <7%  Percent Nitroglycerin-mediated dilation (NMD) values Inflammation:  Absolute High-sensitivity C-reactive protein (HS-CRP) values  Variations of HS-CRP levels across study time points

150 then 75 mg/day (N=25) 75 then 150 mg/day (N=25) P Age (yrs) 60.8± ± Male gender21 (84) 1 Diabetes mellitus 11 (44)9 (36)0.77 Systemic hypertension 23 (92)22 (88)1 Hypercolesterolemia 21 (84) 1 Body mass index 30.3± ± Previous myocardial infarction 12 (48)8 (32)0.39 Previous PCI 12 (48)13 (52)1 NSTEMI/Unstable angina 10 (40)8 (32)0.77 Left ventricular ejection fraction (%) 57± ± Serum creatinine (mg/dl) 0.83± ± Multivessel coronary disease 11 (44)12 (48)0.77 Multivessel PCI 4 (16)6 (24)0.72 Use of DES 16 (64) 1 Medical Rx Aspirin 25 (100) - Statins 25 (100) - Proton pump inhibitors --- ARMYDA-150. Main characteristics in the two arms

ARMYDA-150 results Outcome measures: Platelet reactivity, Brachial artery reactivity, Inflammation High dose 150 mg/day Standard dose 75 mg/day P Platelet reactivity PRU value 141±73198± PRU inhibition from baseline (%) 50±2031±20< Patients with PRU ≥240 (%) Brachial artery reactivity FDM (%) 16.9± ± Patients with FMD <7% (%) NMD (%) 18.2± ± Inflammation HS-CRP (mg/L) 3.6±3.07.0± Delta HS-CRP (mg/L) -3.3± ± Patients with HS-CRP >3 mg/L (%)

Individual data of Platelet reactivity, Brachial artery reactivity, Inflammation Platelet ReactivityBrachial Artery Reactivity FMD (%) PRU mg 150 mg mg 150 mg 7% mg 150 mg HS-CRP (mg/L) 3 mg/L Inflammation P=0.001 P= P=0.07

HS-CRP >3 mg/L FMD <7% PRU ≥ % -60% -40% -20% 0 Difference in percentage of patients with PRU ≥240, FMD <7% and HS-CRP >3 mg/L (150 mg/day vs 75 mg/day clopidogrel)

T-0 T-1 T-2 PRU 75 mg 150 mg Cross-over * * * P=0.004 Variations of PRU, FMD, NMD and HS-CRP at different time points T-0 T-1 T-2 FMD (%) 75 mg 150 mg Cross-over * * * P= T-0 T-1 T T-0 T-1 T-2 NMD (%) mg 150 mg Cross-over 75 mg 150 mg Cross-over HS-CRP (mg/L) * P=0.07 * * * * * P=0.016 Patients initially randomized to 75 mg/day clopidogrelPatients initially randomized to 150 mg/day clopidogrel

 In patients receiving PCI, high clopidogrel maintenance dose (150 mg/day) compared with the standard regimen (75 mg/day) is associated with stronger platelet inhibition and reduction of low-responders  Use of the higher maintenance dose improved endothelial function (evaluated by brachial artery reactivity) and reduced inflammation (evaluated by HS-CRP levels)  In addition to more intense antiplatelet action, “pleiotropic effects” may further explain mechanisms of the clinical benefit observed in recent trials with the 150 mg vs the 75 mg daily dose of clopidogrel CONCLUSIONS