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Randomized Double-Blind Assessment of the ONSET and OFFS et of the Antiplatelet E ffects of T icagrelor Versus Clopidogrel in Patients with Stable Coronary Artery Disease: The ONSET/OFFSET Study.

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  1. Randomized Double-Blind Assessment of the ONSET and OFFSet of the Antiplatelet Effects of Ticagrelor Versus Clopidogrel in Patients with Stable Coronary Artery Disease: The ONSET/OFFSET Study Gurbel PA, Bliden KP, Butler K, Tantry US, Gesheff T, Wei C, Teng R, Antonino MJ, Patil SB, Karunakaran A, Kereiakes DJ, Parris C, Purdy D, Wilson V, Ledley GS, Storey RF

  2. Disclosures Research GrantsHonoraria/Consultant - Astra Zeneca - Astra Zeneca - Sanofi/Aventis - Sanofi/Aventis - Portola - Portola - Daiichi Sankyo - Daiichi Sankyo - Pozen - Pozen - Lilly - Bayer - Schering Plough

  3. Introduction • Clopidogrel: - slow, variable, irreversible pharmacodynamic effect - non-responsiveness ~15% to 30% • - non-responsiveness associated with ischemic events • - irreversibility problematic: - patients treated prior to angiography then needing CABG - other unanticipated surgery1 • Ticagrelor (formerly AZD6140): - first reversibly binding oral, direct-acting P2Y12 antagonist2 - faster onset and greater IPA compared to low dose clopidogrel (300 mg load)3,4 - clinical efficacy studied in ACS (PLATO trial)5 • Onset and Offset of ticagrelor vs. high dose clopidogrel (600 mg load) never comprehensively characterized 1. Gurbel PA et al. Expert Opin Drug Metab Toxicol. 2009;5:989-1004 2. Tantry US et al. Expert Opin Investig Drug. 2007;16:225-229 3. Husted S et al. Eur Heart J. 2006;27:1038-1047. 4. Storey RF et al. J Am Coll Cardiol. 2007;50:1852-1856. 5. Wallentin L et al. N Engl J Med. 2009;361:1045-1057.

  4. Aims of ONSET/OFFSET Study • To determine the onset and offset of the antiplatelet effect of ticagrelor using the PLATO trial dose compared to high loading dose clopidogrel and placebo in stable CAD patients on background aspirin therapy • To determine cardiopulmonary effects of ticagrelor by objective testing • To measure the pharmacokinetics of ticagrelor therapy

  5. Methods Primary end point: Onset:IPA (20 M ADP, final extent) at 2 hours after the first dose of study drug Offset: Slope of IPA (20 M ADP, final extent) between 4 and 72 hours after the last dose of study drug

  6. Methods Inclusion Criteria:- 18 years of age with documented stable CAD on aspirin therapy (75 to 100 mg/d) Exclusion Criteria: - ACS within 12 mo. - Indication for antithrombotic therapy (eg, warfarin, clopidogrel, or aspirin dose other than 75 to 100 mg/d during the study period) - CHF- EF <35%- FEV1- FVC < normal- Bleeding diathesis or severe pulmonary disease- Pregnancy - Current smoking - Moderate or strong cytochrome P450 3A inhibitors, substrates, or inducers - Platelet count <100 000/mm3; Hb<10 g/dL; HbA1c >10% - Drug addiction or alcohol abuse- NSAID - Creatinine clearance <30 mL/min.

  7. Multicenter, Randomized, Double-blind, Double-dummy, Parallel Group Study Visit 1 Screening/Washout Period (n=154) - 21 days Screen Failures (n=31) Visits 2-3 Randomization (n=123) Platelet Function Testing (Pre-dose and 0.5,1,2,4,8,24 hours post-dose) Onset 1 day Placebo (n=12) 180 mg Ticagrelor (n=57) PM: 90 mg Ticagrelor 600 mg Clopidogrel (n=54) 6 weeks ± 3 days Maintenance 90 mg Ticagrelor bid 75 mg Clopidogrel qd Placebo Visit 4 Last Dose Platelet Function Testing(0,2, 4,8 hours post last dose) Offset 10 days Visits 5-10 Platelet Function TestingDay 1-3,5, 7 and 10 after last dose

  8. Methods Platelet Function Measurements Light Transmittance Aggregometry (Chronolog)* - 5 and 20 M ADP-, and 2ug/ml collagen, 2mM arachidonic acid-induced - Maximum and final extent (6 minutes) VerifyNow P2Y12 Assay *- Platelet reaction units (PRU) and % inhibition (Accumetrics) Vasodilator-stimulated Phosphoprotein (VASP) Phosphorylation * - Platelet reactivity index (PRI, Biocytex) ADP-induced GPIIb/IIIa and P-selectin Expression by Flow Cytometry

  9. Statistical Methods • ITT analysis • Primary comparison between ticagrelor and clopidogrel by Wilcoxon rank sum test • Slope of onset and offset by random coefficients model fitted to: - IPA at 0.5, 1, and 2 h post-loading (onset) - IPA at 4, 8, 24, 48, and 72 hours after last dose (offset) • Model included fixed effects for: treatment group, hour (relative to last dose or first dose), treatment group by hour interaction, center, center-by-treatment interaction, and random coefficients for the patient and patient by hour interaction • Statistical analyses carried out by QDS (King of Prussia, PA) using SAS™ (version 8.2).

  10. Demographics

  11. 20 µM ADP- Final Extent Loading Dose Last Maintenance Dose Ticagrelor (n=54) * * * * * † Clopidogrel (n=50) * * Placebo (n=12) *   * ‡ †  100 90 80 70 60 IPA % 50 40 30 20 10 10 Endpoint for Onset was met. IPA at 2hrs after first dose (loading):88% ticagrelor vs. 38% clopidogrel, p<0.0001  0 0 .5 1 2 4 8 24 6 weeks 0 2 4 8 24 48 72 120 168 240 Onset Maintenance Offset Time (hours)

  12. Ticagrelor (n=54) Clopidogrel (n=50) Last Maintenance Dose Placebo (n=12) Loading Dose   * * * * *  * VerifyNow P2Y12 Assay 450 400 350 300 250 P2Y12 Reaction Units (PRU) 200 150 100 50  0 0 2 8 24 6 weeks 0 8 24 48 120 240 Onset Maintenance Offset Time (hours)

  13. VASP-P Assay Ticagrelor (n=54)  Clopidogrel (n=50) Placebo (n=12)  Loading Dose †  * * * * * Last Maintenance Dose 100 90 80 70 60 Platelet Reactivity Index (PRI) (%) 50 40 30 20 10  0 0 2 8 24 6 weeks 0 8 24 48 120 240 Onset Maintenance Offset Time (hours)

  14. Maximum Extent Final Extent 75 Slope (IPA,%/h) p<0.0001 60 ONSET (0-2 hrs After Loading Dose) 43.57 p<0.0001 45 31.44 30 19.45 11.98 15 0 TicagrelorClopidogrel TicagrelorClopidogrel 0 Slope (IPA,%/h) -0.3 - 0.29 OFFSET (4-72 hrs After Last Dose) -0.6 - 0.48 p<0.0001 - 0.74 -0.9 - 1.04 -1.2 p<0.0001 -1.5 Slope of Onset and Offset (20 µM ADP) 10 Endpoint for Offset was met. Slope of IPA (20 µM ADP, final extent) between 4-72 hrs after last dose): -1.04 (IPA,%/h) ticagrelor vs. -0.74 (IPA,%/h) clopidogrel, p<0.0001

  15. Clopidogrel Ticagrelor Final Extent 250 200 Hours 150 196 100 116 109 80 50 56 53 0 Time to IPA = 10% Time(30-10%) Time to IPA = 30% Maximum Extent 180 150 120 156 Hours 90 130 60 85 30 49 36 26 0 Time for IPA (20 µM ADP) to Decrease From 30% to 10% p<0.001 p=0.004 p=0.06 p<0.001 p=0.003 p=0.13

  16. Conclusions • First study to comprehensively characterize onset and offset of the antiplatelet effect of ticagrelor compared with clopidogrel in stable CAD patients. • 3 Major Findings: - Ticagrelor onset is very rapid and markedly greater than high loading dose clopidogrel - Greater inhibitory effect of ticagrelor is sustained during maintenance - Ticagrelor offset as determined by IPA slope was significantly faster than clopidogrel • These effects may explain the lower occurrence of the primary endpoint with ticagrelor therapy as compared to clopidogrel therapy in PLATO whereas numerically less CABG-related bleeding occurred in the ticagrelor group despite greater platelet inhibition.

  17. Investigators and Centers Paul A Gurbel, Kevin P Bliden, Udaya S Tantry, Tania Gesheff, Mark J Antonino - Sinai Center for Thrombosis Research, Baltimore, Maryland KathleenButler, Cheryl Wei, RenlyTeng - AstraZeneca LP, Wilmington, Delaware Rob FStorey, Shanker B Patil, ArunKarunakaran - University of Sheffield, Sheffield, United Kingdom Dean J Kereiakes - The Christ Hospital Heart and Vascular Center and The Lindner Research Center, Cincinnati, Ohio Cordel Parris - Dolby Research LLC, Baton Rouge, Louisiana Drew Purdy - Black Hills Clinical Research Center, Rapid City, South Dakota Vance Wilson - Cardiology Consultants, Daytona Beach, Florida Gary Ledley - Drexel University College of Medicine, Philadelphia, Pennsylvania

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