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ALBION

ALBION. A ssessment of the best L oading dose of clopidogrel to B lunt platelet activation, I nflammation and O ngoing N ecrosis. Optimal and rapid platelet inhibition in ACS: crucial in the context of urgent care

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ALBION

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  1. ALBION Assessment of the bestLoading doseof clopidogrel toBlunt platelet activation, Inflammation and OngoingNecrosis

  2. Optimal and rapid platelet inhibition in ACS: crucial in the context of urgent care Clopidogrel (300 mg LD) has been shown to be of clinical benefit in the treatment of ACS1 A LD of 300 mg administered early is of proven clinical benefit2,3 Ex vivo measurements of platelet aggregation suggest that a higher loading dose can shorten the time to reach the plateau of antiplatelet efficacy 4,5 Q: What is the effect of higher loading doses on the pharmacokinetics and pharmacodynamics of clopidogrel ? Background and Rationale 1.Yusuf S et al. NEJM 2001;345(7):494-502 2.Steinhubl Set al., JAMA 2002; 2411-2420 3.Mehta S. R. Lancet, 2001, 358(9281), 527-5334 Müller I et al. Heart 2001; 85: 92-93 5. Seyfarth HJ et al. Am Heart J2002; 143:118-123

  3. Study Design Randomized, open-label trial with blind centralized laboratory assessment inpatients aged 1885 years with UA/NSTEMI (onset < 48 h) Clopidogrel 300 mg LD then 75 mg qd D2 n=35 LD Clopidogrel 600 mg LD then 75 mg qd LMWH and ASA* D2 Clinical follow-up at 30 days R n=34 Clopidogrel 900 mg LD then 75 mg qd D2 n=34 Sampling Time Hours post-LD 0 1/2 1 2 3 4 5 6 24 *ASA=250-500 mg on admission, then  100 mg/day plus other standard care

  4. Inclusion/Exclusion Criteria Inclusion criteria • Age 1885 years • UA/NSTEMI within 48 hours • Planned treatment with clopidogrel Major exclusion criteria • Intention of angiography within 24 hours • Contraindication to the use of clopidogrel or ASA • BP > 180/ 100mmHg despite therapy • Platelet count < 100 000/ mm3 • Neutrophil count < 1800/ mm3 • Severe risk of bleeding • Patients treated with a thienopyridine, dipyridamole, NSAID, cilostazol, GPIIb/IIIa inhibitor within the previous 10 days before randomization or planned to receive any of these products within the 24 h post-randomization • Evolving cancer • NYHA class IV heart failure • Venous status incompatible with an indwelling catheter

  5. Primary: Platelet aggregation induced by 5 µM/L ADP (T0  T24) Secondary: Platelet aggregation induced by 20 µM/L ADP (T0  T24) Flow cytometry (T0  T24): PAC1, anti-P selectin, VASP Inflammation markers (T0, T6, T24) : hsCRP, wWF Ag, PAI-1 Ag, sCD40-L Myonecrosis markers (T0, T6, T24): Troponin I, CK MACE* at Day 30 Safety Evaluation Criteria MACE: Major Adverse Cardiac Events

  6. Baseline Characteristics

  7. Patients Invasive Management *No statistically significant differences between groups

  8. Shortened time to reach the highest level of inhibition of the 300 mg LD Primary Endpoint: Faster Onset of Action and Higher Level of Platelet Inhibition p< 0.05 vs. 300 mg LD

  9. Secondary Endpoint: Faster Onset of Action and Higher Level of Platelet Inhibition p< 0.05 vs. 300 mg LD

  10. AUC Inhibition: Baseline to 24 hours Areas Under the IPA* - Time Curves p < 0.05 6 p < 0.05 p < 0.05 5 300mg 4 3 600mg 2 900mg 1 0 20 µM/L ADP 5 µM/L ADP IPA: Inhibition of Platelet Aggregation

  11. Flow Cytometry p< 0.05 vs. 300 mg LD

  12. Flow cytometry (cont.) p< 0.05 vs. 300 mg LD

  13. VASP : MFI (PGE 1 +ADP) at 6 and 24 Hours p < 0.05 p < 0.05 p < 0.05 VASP= Vasodilator-Stimulated Phosphoprotein MFI = Median Fluorescence Intensity

  14. VASP Index at 6 and 24 Hours p < 0.05 p < 0.05 p < 0.05 VASP Index = [(MFI PGE1 – MFI PGE1 +ADP)/ MFI PGE1] X 100

  15. Inflammatory and Myonecrosis Markers No statistically significant differences between the three LDs at 6 and 24 hours • Inflammatory Markers • hs CRP • von Willebrand factor Ag • PAI-1 Ag • sCD40-L • Myonecrosis Markers: CK and Troponin-I

  16. Patients with Increasing Troponin-I at Day 2 p = NS • Increasing Troponin defined as: • either within normal range at Day 1 and > normal range at Day 2 • or, > normal range on Day 1 and increased by  30% at Day 2

  17. Major Adverse Cardiac Events * New Q wave or CK > 3 times the ULN

  18. Safety *GUSTO Classification

  19. In patients with NSTE-ACS, ALBION has shown that 600 and 900 mg LDs compared to the conventional 300-mg LD provided: More rapid and higher levels of IPA during the first 24 h Greater reductions in some markers of platelet activation (PAC-1 and VASP) during the first 24 hours No statistically significant differences in various inflammatory and myonecrosis markers Potential favorable trends on troponin release and ischemic events Comparable safety profiles Summary IPA: Inhibition of Platelet Aggregation

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