Proton Pump Inhibitor (PPI) Studies Speaker to refer to slide for presentation.

Study Design: Clopidogrel + Omeprazole Interaction Studies* Sequence: Clopidogrel or Placebo + Omeprazole → Clopidogrel or Placebo Screening Day –28 to Day –7 ≤21 days Omeprazole Day –5 to Day 5 Wash-out period† Clopidogrel or Placebo Day 1 to Day 5 Follow-up at least 7 to 10 days post-dose Clopidogrel or Placebo Day 1 to Day 5 Day 6 Admission Inclusion Procedures Day –1 Admission Inclusion Procedures Day 6 Discharge Day 6 Discharge End-of-Study Visit Day –5 Inclusion Randomization Omeprazole Administration Day –1 Clopidogrel or Placebo Administration All 3 studies were randomized, placebo-controlled, 2-period, 2-sequence, crossover, pharmacokinetic and pharmacodynamic interaction studies. Primary objective: To assess the effects of clopidogrel, given either alone or concomitantly with omeprazole, on platelet aggregation induced by adenosine diphosphate (ADP). Primary criteria: Maximum platelet aggregation intensity (MAI) as stimulated by ADP 5 µM, after 5 days of clopidogrel repeated dosing. Subjects received a loading dose of clopidogrel for 1 day followed by 4 days of clopidogrel maintenance doses for both periods. Omeprazole was given once daily for 10 days in the period of clopidogrel or placebo + omeprazole administration; administration for 5 days prior to clopidogrel and then concomitantly with clopidogrel for 5 days. Total duration per subject from screening: from 8 to 9 weeks. Screening: 2 to 21 days before the first dosing (clopidogrel or omeprazole) Period of clopidogrel or placebo: 5 days Period of clopidogrel or placebo + omeprazole: 12 days Wash-out period: at least 14 days with respect to clopidogrel treatment End of study: at 7 to 10 days after the last dosing Note that this slide presents only 1 treatment sequence. Patients could also be randomized to the sequence of Clopidogrel or Placebo followed by Clopidogrel or Placebo + Omeprazole. Reference 1. Angiolillo DA, et al. Clin Pharmacol Ther 2010; in press. Day 1 Clopidogrel or Placebo Administration *Design is similar for 3 different comparisons: Standard-dose clopidogrel (300-mg loading dose/75-mg/day maintenance dose)+ omeprazole 80 mg/day given concomitantly vs standard-dose clopidogrel alone Standard-dose clopidogrel + omeprazole 80 mg/day given 12 hours apart vs standard-dose clopidogrel alone Double-dose clopidogrel (600-mg loading dose/150-mg/day maintenance dose) + omeprazole 80 mg/day given concomitantly vs double-dose clopidogrel alone †At least 14 days Angiolillo DA, et al. Clin Pharmacol Ther. 2010 Sep 15. [Epub ahead of print] 2

Standard-Dose Clopidogrel + Omeprazole Administered Together: Pharmacodynamic Data Mean ± SEM of Maximum Platelet Aggregation (%) Induced by ADP 5 µM This was a randomized, placebo-controlled, two-period, two-sequence, cross-over pharmacokinetic and pharmacodynamic interaction study after 5-day repeated oral doses of clopidogrel (300-mg loading dose followed by 75 mg/d for 4 days) administered alone or given concomitantly with omeprazole 80 mg/d in 72 healthy men and women. The pharmacodynamic population included all 72 subjects. The graph on the slide shows the mean values of maximum platelet aggregation (MPA) (%) induced by adenosine diphosphate (ADP) at each timepoint for up to 5 days after treatment with clopidogrel in the presence and absence of omeprazole. In the presence of omeprazole, there was a decrease of the antiplatelet activity of clopidogrel after both the loading and maintenance doses. On Day 5, there was an absolute increase of 8.0% (90% confidence interval [CI], 4.7-11.3; P<0.0001) in the MPA induced by ADP 5 µM under combined treatment, compared with the value observed under clopidogrel alone. The decreased antiplatelet activity of clopidogrel when coadministered with omeprazole was also reflected in increases in vasodilator-stimulated phosphoprotein (VASP) phosphorylation and decreases in bleeding time. Reference 1. Angiolillo DA, et al. Clin Pharmacol Ther 2010; in press. Estimated Treatment Difference in MPA (%) Induced by ADP 5 µM at Day 5 Parameter Comparison Estimate 90% CI P-value MPA (%), ADP 5 µM Clopidogrel + Omeprazole minus Clopidogrel Alone at D5 8.0 4.7 to 11.3 <0.0001 ADP, adenosine diphosphate; CI, confidence interval; D, day; MPA, maximum platelet aggregation; SEM, standard error of the mean; T, sampling time. 3 Angiolillo DA, et al. Clin Pharmacol Ther. 2010 Sep 15. [Epub ahead of print]

Standard-Dose Clopidogrel + Omeprazole Administered Together: Effect on Clopidogrel Active Metabolite H4 Mean (SD) Plasma Concentration of Clopidogrel Active Metabolite H4 After a 300-mg Loading Dose (Left) and 75-mg Maintenance Dose (Right) 60 Day 5 – 75 mg Nominal Time (h) 0.0 0.5 1.0 1.5 2.0 5 10 15 20 25 Clopidogrel alone Clopidogrel + omeprazole LOQ = 0.500 ng/mL* Day 1 – 300 mg 50 Clopidogrel alone Clopidogrel + omeprazole 40 LOQ = 0.500 ng/mL Mean (SD) Active Metabolite H4 Concentration (ng/mL) 30 Mean (SD) Active Metabolite H4 Concentration (ng/mL) 20 10 The pharmacokinetic population included 66 subjects. Based on AUC(0-24) ratios (standard-dose clopidogrel + omeprazole vs standard-dose clopidogrel alone), the active metabolite H4 exposure was decreased by 45% following a 300-mg loading dose of clopidogrel given concomitantly with 80 mg omeprazole (AUC0-24 ratio of 0.55; 90% CI, 0.51-0.59; P<0.001) and by 40% following an additional 4-day 75-mg maintenance dose of clopidogrel + omeprazole (AUC0-24 ratio of 0.60; 90% CI, 0.56-0.65; P<0.001). After a 300-mg clopidogrel loading dose given concomitantly with omeprazole, the Cmax ratio was 0.54 (90% CI, 0.51-0.58; P<0.001); after an additional 4 days of clopidogrel 75 mg/day given concomitantly with omeprazole, the Cmax ratio was 0.58 (90% CI, 0.53-0.65; P<0.001). Simultaneous administration of a 300-mg clopidogrel loading dose with omeprazole increased exposure of unchanged clopidogrel (AUC0-24 ratio, 1.19; 90% CI, 1.06-1.33; P=0.012), and after 4 days of clopidogrel 75 mg/day, unchanged clopidogrel exposure increased by 51% (AUC0-24 ratio, 1.51; 90% CI, 1.35-1.69; P<0.001). Reference 1. Angiolillo DA, et al. Clin Pharmacol Ther 2010; in press. 0.0 0.5 1.0 1.5 2.0 2.5 3.0 Nominal Time (h) After coadministering omeprazole with clopidogrel (300-mg LD/75-mg/day MD), the clopidogrel active metabolite H4 pharmacokinetic parameters were consistently decreased by: 46% on Day 1 (P<0.001) and 42% on Day 5 (P<0.001) for maximum plasma concentration (Cmax), and 45% on Day 1 (P<0.001) and 40% on Day 5 (P<0.001) for area under the concentration–time curve from time zero to 24 hours (AUC0-24). LD, loading dose; LOQ, lower limit of quantification.; MD, maintenance dose; SD, standard deviation. Angiolillo DA, et al. Clin Pharmacol Ther. 2010 Sep 15. [Epub ahead of print] 4

Standard-Dose Clopidogrel + Omeprazole Administered 12 Hours Apart: Pharmacodynamic Data Mean ± SEM of Maximum Platelet Aggregation (%) Induced by ADP 5 µM This was a randomized, placebo-controlled, two-period, two-treatment, two-sequence, cross-over pharmacodynamic and pharmacokinetic interaction study after 5-day repeated oral doses of clopidogrel (300-mg loading dose followed by 75 mg/d) administered alone or given with omeprazole 80 mg/d (12 hours apart on the same days) in 72 healthy men and women. The pharmacodynamic population included all 72 subjects. The graph shows mean values of MPA (%) induced by ADP 5 µM at each time point for up to 5 days after treatment with clopidogrel (300-mg loading dose followed by 4 additional days of 75 mg/d) administered alone or given with omeprazole 80 mg/d at a 12-hour interval. In the presence of omeprazole, given 12 hours apart from clopidogrel, there was a decrease of clopidogrel antiplatelet activity after both the loading and maintenance doses. On Day 5, there was an absolute increase of 5.6% (90% CI, 2.8 to 8.5; P=0.0014) in the MPA induced by ADP 5 µM under combined treatment, compared with the value observed under clopidogrel alone. The decreased antiplatelet activity of clopidogrel when administered 12 hours apart from omeprazole was also reflected in increases in vasodilator-stimulated phosphoprotein (VASP) phosphorylation and decreases in bleeding time. Reference 1. Angiolillo DA, et al. Clin Pharmacol Ther 2010; in press. Estimated Treatment Difference in MPA (%) Induced by ADP 5 µM at Day 5 Parameter Comparison Estimate 90% CI P-value MPA (%), ADP 5 µM Clopidogrel + Omeprazole minus Clopidogrel Alone at D5 5.6 2.8 to 8.5 0.0014 ADP, adenosine diphosphate; CI, confidence interval; D, day; MPA, maximum platelet aggregation; SEM, standard error of the mean; T, sampling time. 5 Angiolillo DA, et al. Clin Pharmacol Ther. 2010 Sep 15. [Epub ahead of print]

Standard-Dose Clopidogrel + Omeprazole Administered 12 Hours Apart: Effect on Clopidogrel Active Metabolite H4 Mean (SD) Plasma Concentration of Clopidogrel Active Metabolite H4 After a 300-mg Loading Dose (Left) and 75-mg Maintenance Dose (Right) 50 25 Day 1 - 300 mg Day 5 - 75 mg 40 20 Clopidogrel alone Clopidogrel alone Clopidogrel + omeprazole Clopidogrel + omeprazole 30 LOQ = 0.500 ng/mL LOQ = 0.500 ng/mL 15 Mean (SD) Active Metabolite H4 Concentration (ng/mL) Mean (SD) Active Metabolite H4 Concentration (ng/mL) 20 10 10 5 The pharmacokinetic population included 65 subjects. Based on AUC(0-24) ratios (standard-dose clopidogrel + omeprazole vs standard-dose clopidogrel alone), the active metabolite H4 exposure was decreased by 53% following a 300-mg loading dose of clopidogrel given 12 hours before 80 mg omeprazole (AUC0-24 ratio of 0.47; 90% CI, 0.44-0.50; P<0.001) and by 47% following an additional 4-day 75-mg maintenance dose of clopidogrel + omeprazole (AUC0-24 ratio of 0.53; 90% CI, 0.50-0.57; P<0.001). After a 300-mg clopidogrel loading dose given 12 hours before omeprazole, the Cmax ratio was 0.45 (90% CI, 0.42-0.49; P<0.001); after an additional 4 days of clopidogrel 75 mg/day given 12 hours before omeprazole, the Cmax ratio was 0.44 (90% CI, 0.40-0.49; P<0.001). Administration of a 300-mg clopidogrel loading dose 12 hours before omeprazole increased exposure of unchanged clopidogrel (AUC0-24 ratio, 1.19; 90% CI, 1.09-1.30; P=0.001), and after 4 days of clopidogrel 75 mg/day, unchanged clopidogrel exposure increased by 37% (AUC0-24 ratio, 1.37; 90% CI, 1.22-1.54; P<0.001). Reference 1. Angiolillo DA, et al. Clin Pharmacol Ther 2010; in press. 0.0 0.5 1.0 1.5 2.0 2.5 3.0 0.0 0.5 1.0 1.5 2.0 Nominal Time (h) Nominal Time (h) After separating the administration of omeprazole and clopidogrel (300-mg LD/75-mg/day MD) by 12 hours, the clopidogrel active metabolite H4 pharmacokinetic parameters were consistently decreased by: 55% on Day 1 (P<0.001) and 56% on Day 5 (P<0.001) for maximum plasma concentration (Cmax), and 53% on Day 1 (P<0.001) and 47% on Day 5 (P<0.001) for area under the concentration–time curve from time zero to 24 hours (AUC0-24). LD, loading dose; LOQ, lower limit of quantification.; MD, maintenance dose; SD, standard deviation. 6 Angiolillo DA, et al. Clin Pharmacol Ther. 2010 Sep 15. [Epub ahead of print]

Double-Dose Clopidogrel + Omeprazole Administered Together: Pharmacodynamic Data Mean ± SEM of Maximum Platelet Aggregation (%) Induced by ADP 5 µM This was a randomized, double-blind, placebo-controlled, two-period, two-treatment, two-sequence, cross-over pharmacodynamic and pharmacokinetic interaction study after 5-day repeated oral doses of clopidogrel (600-mg loading dose followed by 150 mg/d) administered alone or given concomitantly with omeprazole 80 mg/d in 72 healthy men and women. The pharmacodynamic population included 71 subjects. The graph shows the mean values of maximum platelet aggregation (MPA) (%) induced by adenosine diphosphate (ADP) 5 µM at each time point for up to 5 days after treatment with clopidogrel in the presence or absence of omeprazole. In the presence of omeprazole, there was a decrease of the antiplatelet activity of clopidogrel after both the loading and maintenance doses. On Day 5, there was an absolute increase of 8.1% (90% CI, 5.7% to 10.6%; P<0.0001) in the MPA induced by ADP 5 µM under combined treatment, compared with the value observed under clopidogrel alone. The decreased antiplatelet activity of clopidogrel when coadministered with omeprazole was also reflected in increases in vasodilator-stimulated phosphoprotein (VASP) phosphorylation and decreases in bleeding time. Reference 1. Angiolillo DA, et al. Clin Pharmacol Ther 2010; in press. Estimated Treatment Difference in MPA (%) Induced by ADP 5 µM at Day 5 Parameter Comparison Estimate 90% CI P-value MPA (%), ADP 5 µM Clopidogrel + Omeprazole minus Clopidogrel Alone at D5 8.1 5.7 to 10.6 <0.0001 ADP, adenosine diphosphate; CI, confidence interval; D, day; MPA, maximum platelet aggregation; SEM, standard error of the mean; T, sampling time. 7 Angiolillo DA, et al. Clin Pharmacol Ther. 2010 Sep 15. [Epub ahead of print]

Double-Dose Clopidogrel + Omeprazole Administered Together: Effect on Clopidogrel Active Metabolite H4 Mean (SD) Plasma Concentration of Clopidogrel Active Metabolite H4 After a 600-mg Loading Dose (Left) and 150-mg Maintenance Dose (Right) Plasma Active Metabolite Concentrations (ng/mL) 60 0 1 2 3 4 Nominal time (h) Day 1: 600 mg 50 40 30 20 10 Nominal time (h) Day 5: 150 mg 0 1 2 3 4 25 20 15 10 5 Plasma Active Metabolite Concentrations (ng/mL) Clopidogrel alone Clopidogrel + omeprazole LOQ = 0.500 ng/mL Clopidogrel alone Clopidogrel + omeprazole LOQ = 0.500 ng/mL The pharmacokinetic population included 65 subjects. Based on AUC(0-24) ratios (double-dose clopidogrel + omeprazole vs double-dose clopidogrel alone), the active metabolite H4 exposure was decreased by 48% following a 600-mg loading dose of clopidogrel given concomitantly with 80 mg omeprazole (AUC0-24 ratio of 0.52; 90% CI, 0.49-0.56; P<0.001) and by 41% following an additional 4-day 150-mg maintenance dose of clopidogrel + omeprazole (AUC0-24 ratio of 0.59; 90% CI, 0.56-0.63; P<0.001). After a 600-mg clopidogrel loading dose given concomitantly with omeprazole, the Cmax ratio was 0.54 (90% CI, 0.49-0.59; P<0.001); after an additional 4 days of clopidogrel 150 mg/day given concomitantly with omeprazole, the Cmax ratio was 0.50 (90% CI, 0.46-0.56; P<0.001). Simultaneous administration of a 600-mg clopidogrel loading dose with omeprazole increased exposure of unchanged clopidogrel (AUC0-24 ratio, 1.19; 90% CI, 1.09-1.31; P=0.002), and after 4 days of clopidogrel 150 mg/day, unchanged clopidogrel exposure increased by 44% (AUC0-24 ratio, 1.44; 90% CI, 1.27-1.63; P<0.001). Reference 1. Angiolillo DA, et al. Clin Pharmacol Ther 2010; in press. After coadministering omeprazole with clopidogrel (600-mg LD/150-mg/day MD), the clopidogrel active metabolite H4 pharmacokinetic parameters were consistently decreased by: 46% on Day 1 (P<0.001) and 50% on Day 5 (P<0.001) for maximum plasma concentration (Cmax), and 48% on Day 1 (P<0.001) and 41% on Day 5 (P<0.001) for area under the concentration–time curve from time zero to 24 hours (AUC0-24). LD, loading dose; LOQ, lower limit of quantification.; MD, maintenance dose; SD, standard deviation. 8 Angiolillo DA, et al. Clin Pharmacol Ther. 2010 Sep 15. [Epub ahead of print]

Study Design: Pantoprazole + Clopidogrel Interaction Study Omeprazole Interaction Studies Sequence: Clopidogrel or Placebo → Clopidogrel or Placebo + Pantoprazole Screening Day –21 to Day –2 ≤21 days Clopidogrel or Placebo Day 1 to Day 5 Wash-out period* Pantoprazole Day –7 to Day 5 Follow-up at least 7 to 10 days post-dose Day –1 Admission Inclusion Procedures Day 6 Discharge Day –8 Admission Inclusion Procedures Clopidogrel or Placebo Day 1 to Day 5 Day 1 Inclusion Randomization Clopidogrel or Placebo Administration Speaker to refer to slide for presentation. Note that this slide presents only 1 sequence. Patients could also be randomized to the sequence of Clopidogrel or Placebo + Pantoprazole followed by Clopidogrel or Placebo Alone. Reference 1. Angiolillo DA, et al. Clin Pharmacol Ther 2010; in press. Day 6 Discharge End-of-Study Visit Day –7 Pantoprazole Administration *At least 14 days Angiolillo DA, et al. Clin Pharmacol Ther. 2010 Sep 15. [Epub ahead of print] 9

Standard-Dose Clopidogrel + Pantoprazole Administered Together: Pharmacodynamic Data Mean ± SEM of Maximum Platelet Aggregation (%) Induced by ADP 5 µM This was a randomized, placebo-controlled, 2-period, 2-sequence, cross-over pharmacodynamic and pharmacokinetic interaction study after 5 days repeated oral doses of clopidogrel (300-mg loading dose followed by 75 mg/day) alone or given concomitantly with pantoprazole 80 mg/day in 66 healthy men. The pharmacodynamic population included 64 men. The graph on the slide shows the mean values of maximum platelet aggregation (MPA) (%) induced by adenosine diphosphate (ADP) 5 µM at each timepoint for up to 5 days after treatment with clopidogrel in the presence or absence of pantoprazole. In the presence of pantoprazole, there was a slight decrease of the antiplatelet activity of clopidogrel. On Day 5, there was an absolute increase of 4.3% (90% CI, 1.4% to 7.1%; P=0.0136) in the MPA induced by ADP 5 µM under combined treatment, compared with the value observed under clopidogrel alone. The decreased antiplatelet activity of clopidogrel when coadministered with pantoprazole was not reflected in a significant increase in vasodilator-stimulated phosphoprotein (VASP) phosphorylation at Day 5. These small pharmacodynamic effects are consistent with a 14% reduction in AUC0-24 of the clopidogrel active metabolite H4 after 5 days of coadministration of clopidogrel and pantoprazole. Reference 1. Angiolillo DA, et al. Clin Pharmacol Ther 2010; in press. Estimated Treatment Difference in MPA (%) Induced by ADP 5 µM at Day 5 Parameter Comparison Estimate 90% CI P-value MPA (%), ADP 5 µM Clopidogrel + Pantoprazole minus Clopidogrel Alone at D5 4.3 1.4 to 7.1 0.0136 ADP, adenosine diphosphate; CI, confidence interval; D, day; MPA, maximum platelet aggregation; SEM, standard error of the mean; T, sampling time. 10 Angiolillo DA, et al. Clin Pharmacol Ther. 2010 Sep 15. [Epub ahead of print]

Standard-Dose Clopidogrel + Pantoprazole Administered Together: Effect on Clopidogrel Active Metabolite H4 Mean (SD) Plasma Concentration of Clopidogrel Active Metabolite H4 After a 300-mg Loading Dose (Left) and 75-mg Maintenance Dose (Right) 0.0 0.5 1.0 1.5 2.0 3.0 Mean (SD) Active Metabolite H4 Concentration (ng/mL) 10 20 30 40 50 Clopidogrel alone Clopidogrel + pantoprazole LOQ = 0.5 (ng/mL) Day 1 – 300 mg Nominal Time (hr) Clopidogrel alone Clopidogrel + pantoprazole LOQ = 0.5 (ng/mL) Day 5 – 75 mg 0.0 0.5 1.0 1.5 2.0 5 10 15 20 Nominal Time (hr) Mean (SD) Active Metabolite H4 Concentration (ng/mL) The pharmacokinetic population included 58 men. Based on AUC(0-24) ratios (standard-dose clopidogrel + pantoprazole vs standard-dose clopidogrel alone), the active metabolite H4 exposure was decreased by 20% following a 300-mg loading dose of clopidogrel given concomitantly 80 mg pantoprazole (AUC0-24 ratio of 0.80; 90% CI, 0.76-0.85; P<0.001) and by 14% following an additional 4-day 75-mg maintenance dose of clopidogrel + pantoprazole (AUC0-24 ratio of 0.86; 90% CI, 0.79-0.93; P=0.002). After a 300-mg clopidogrel loading dose given concomitantly with pantoprazole, the Cmax ratio was 0.76 (90% CI, 0.70-0.82; P<0.001); after an additional 4 days of clopidogrel 75 mg/day given concomitantly with pantoprazole, the Cmax ratio was 0.72 (90% CI, 0.65-0.79; P<0.001). Simultaneous administration of a 300-mg clopidogrel loading dose with pantoprazole did not affect exposure of unchanged clopidogrel (AUC0-24 ratio, 1.00; 90% CI, 0.90-1.10; P=0.942), but after 4 days of clopidogrel 75 mg/day, unchanged clopidogrel exposure increased by 19% (AUC0-24 ratio, 1.19; 90% CI, 1.07-1.33; P=0.011). Reference 1. Angiolillo DA, et al. Clin Pharmacol Ther 2010; in press. After coadministering pantoprazole with clopidogrel (300-mg LD/75-mg/day MD), the clopidogrel active metabolite H4 pharmacokinetic parameters were decreased by: 24% on Day 1 (P<0.001) and 28% on Day 5 (P<0.001) for maximum plasma concentration (Cmax), and 20% on Day 1 (P<0.001) and 14% on Day 5 (P=0.001) for area under the concentration–time curve from time zero to 24 hours (AUC0-24). LD, loading dose; LOQ, lower limit of quantification.; MD, maintenance dose; SD, standard deviation. 11 Angiolillo DA, et al. Clin Pharmacol Ther. 2010 Sep 15. [Epub ahead of print]

Standard-Dose Clopidogrel + Omeprazole versus Standard-Dose Clopidogrel + Pantoprazole: VASP-PRI Data Mean ± SEM of Vasodilator-Stimulated Phosphoprotein Phosphorylation-Platelet Reactivity Index (%) Clopidogrel ± Omeprazole Clopidogrel ± Pantoprazole VASP-PRI (%) was higher in the clopidogrel + omeprazole group (left panel): omeprazole decreased the effect of clopidogrel on platelet reactivity at Day 5. There was a numerically small, statistically insignificant increase in VASP-PRI when clopidogrel was coadministered with pantoprazole, with the CI for the effect including zero (increase of 3.86% with 90% CI, -2.71 to 10.44) (P=0.3319). Reference 1. Angiolillo DA, et al. Clin Pharmacol Ther 2010; in press. After coadministering omeprazole (left panel) or pantoprazole (right panel) with clopidogrel (300-mg LD/75-mg/day MD), the estimated treatment differences (90% CIs) at Day 5 were: 20.7% (90% CI, 14.1% to 27.2%; P<0.0001) for omeprazole and 3.9% (–2.7% to 10.4%; P=0.3319) for pantoprazole. Angiolillo DA, et al. Clin Pharmacol Ther. 2010 Sep 15. [Epub ahead of print] D, day; LD, loading dose; LOQ, lower limit of quantification; MD, maintenance dose; SEM, standard error of the mean; T, sampling time; VASP-PRI, vasodilator-stimulated phosphoprotein phosphorylation-platelet reactivity index. 12