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Novel Antiplatelet Agents: AZD6140, Cangrelor, TRA

Novel Antiplatelet Agents: AZD6140, Cangrelor, TRA . Meadows TA, Bhatt DL. Circ Res . 2007;100:1261. AZD6140 Characteristics. The first reversible oral adenosine diphosphate ( ADP) receptor antagonist 1 New class of P2Y 12 inhibitors Cyclo-pentyl-triazolo-pyrimidine (CPTP)

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Novel Antiplatelet Agents: AZD6140, Cangrelor, TRA

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  1. Novel Antiplatelet Agents: AZD6140, Cangrelor, TRA

  2. Meadows TA, Bhatt DL. Circ Res. 2007;100:1261

  3. AZD6140 Characteristics • The first reversible oral adenosine diphosphate (ADP) receptor antagonist1 • New class of P2Y12 inhibitors • Cyclo-pentyl-triazolo-pyrimidine (CPTP) • Not a thienopyridine or ATP analog • Direct-acting (not a prodrug); does not require metabolic activation • Reversible binding; degree of inhibition reflects plasma concentration • half-life of approximately 12 h • More rapid reversal of effect—full recovery of platelet function • Rapid onset (within 2 hours); peak plasma levels within 2 to 3 hours • Greater and more consistent inhibition of ADP-induced platelet aggregation versus clopidogrel 1. van Giezen JJ, Humphries RG. Semin Thromb Hemost 2005;31:195-204. Cannon CP, et al. J Am Coll Cardiol2007;50:1844-51.

  4. DISPERSE2 Main Study Design ACS Patients; Onset of chest pain and 48 h maximum to randomization AZD6140 90 mg bid (n = 334) • All patients received aspirin (≤325 mg first dose, then 75–100 mg qd) and heparin/LMWH and/or a GPIIb/IIIa antagonist • 50% of AZD6140 patients in each arm received a 270-mg loading dose • In the clopidogrel group, thienopyridine-naïve patients received a 300-mg loading dose N = 990 AZD6140 180 mg bid (n = 323) Clopidogrel 75 mg qd (n = 327) Randomization V1 V2 V3 V4 Follow-up Day 1 Week 4 Week 8 Week 12 Final Visit +7 days *Of the 990 randomized patients, 984 who received ≥1 dose of study drug and were included in the safety analysis dataset. GP = glycoprotein; LMWH = low-molecular-weight heparin. Cannon CP, et al. J Am Coll Cardiol2007;50:1844-51.

  5. AZD6140 270 mg * * * * * * * * * * * * * * * * * * * * * * * * AZD6140 90 mg AZD6140 180 mg Clopidogrel 300 mg DISPERSE2 PK/PD Substudy: Inhibition of Platelet Aggregation After Initial Doses on Day 1 in Clopidogrel Naïve patients Maximum Aggregation Response Final Aggregation Response 100 100 80 75 60 Mean % inhibition Mean % inhibition 50 40 25 20 0 0 0 2 4 6 8 10 12 0 2 4 6 8 10 12 Time postdose (h) Time postdose (h) *p < 0.05 for AZD6140 versus clopidogrel. Mean ± SD. Storey R, et al. J Am Coll Cardiol 2007;50:1852-6.

  6. AZD6140 270 mg DISPERSE2 PK/PD Substudy: Suppression of Platelet Aggregation in Clopidogrel-Pretreated Patients 80 AZD6140 90 mg AZD6140 180 mg 60 Clopidogrel 75 mg Mean % platelet aggregation 40 20 * * * * * * * * * * 0 * * 0 2 4 6 8 10 12 *p < 0.05 for AZD6140 versus clopidogrel. Time postdose (h) Storey R, et al. J Am Coll Cardiol 2007;50:1852-6.

  7. DISPERSE2 Protocol-Defined Bleeding Rates (%) Week 4 and Overall (Week 12) • Protocol-defined total bleeding rates were similar for all groups • No evidence of dose-response pattern for major bleeds Minor* Week 4 (Primary End Point) Overall Major 12 12 10.2 10.2 9.6 9.2 10 10 8.0 Total Bleeding Rate, % Total Bleeding Rate, % 7.7 8 8 6 6 4 4 2 2 0 0 AZD6140 90 mg bid AZD6140 180 mg bid Clopidogrel 75 mg qd AZD6140 90 mg bid AZD6140 180 mg bid Clopidogrel 75 mg qd *Minor bleeding without major bleeding. Cannon CP, et al. J Am Coll Cardiol2007;50:1844-51.

  8. 20% AZD6140 90 mg bid AZD6140 180 mg bid Clopidogrel 75 mg daily 15% Cumulative Risk of an Event 10% 5% 0 1 11 21 31 41 51 61 71 81 91 Study Day DISPERSE2 Cumulative Adjudicated Clinical End Point of CV Death/MI/StrokeKaplan-Meier Estimates Cannon CP, et al. J Am Coll Cardiol2007;50:1844-51.

  9. DISPERSE2 Crude Incidence ofNon-Bleeding Adverse Events (%) • Discontinuation rates due to adverse events were low and similar among all groups • 6%, 7%, and 6% discontinued in the AZD6140 90 mg bid, AZD6140 180 mg bid, and clopidogrel 75 mg qd groups, respectively *p < 0.05 vs. clopidogrel. All other values are not significant. Cannon CP, et al. J Am Coll Cardiol2007;50:1844-51.

  10. DISPERSE2 Arrhythmia Events Detected From Post-Hoc Analysis of ECG Monitoring (%) • Ventricular pauses were mostly asymptomatic • Continuous ECG monitoring began at randomization for 885 patients (89.4% of patients enrolled) • There was no difference in rates of VT among the 3 groups ECG = electrocardiogram; NSVT = nonsustained ventricular tachycardia; VT = ventricular tachycardia. Cannon CP, et al. J Am Coll Cardiol2007;50:1844-51.

  11. DISPERSE2 Conclusions • AZD6140 had greater platelet inhibition than clopidogrel • AZD6140 shows similar safety and tolerability to clopidogrel • AZD6140, a reversible inhibitor of the P2Y12 receptor, offers potential for flexibility by allowing rapid initiation of surgical procedures following discontinuation of drug • With lack of increased major bleeding and encouraging trends in efficacy, this agent is now being studied in the PLATlet inhibition and patient Outcomes (PLATO) outcomes study Cannon CP, et al. J Am Coll Cardiol2007;50:1844-51.

  12. Study Design End of Treatment Follow-up V1 V2 V3 V4 V5 V6 EOT + 1 mo 1 mo 3 mo 6 mo 9 mo 12 mo 6 to 12 mo Onset of chest pain <24h AZD6140 90 mg bid ®* Clopidogrel 300/600mg load: 75mg od * N=9000 per treatment arm

  13. Cangrelor (AR-C69931MX) S H N N + 4Na N O O O C F O N 3 N S O P P P O O O O O Cl Cl O H H O Parenteral ADP-P2Y12 receptor antagonist ATP analogue Molecular weight 800 Daltons Plasma half-life of 5-9 minutes 20 minutes for return to normal platelet function

  14. Double-blind randomized trial performed in US Cangrelor Phase II Clinical Data: Compared with Abciximab in PCI 6% Abciximab (N=94) 5.7% 5.4% 5% Cangrelor (N=105) 4% 3% 2% 2.1% 1% 1.0% 0% Major bleed (TIMI criteria) Death, MI, revascularization Incidence of events up to 7 days P=NS Greenbaum, AB et al. Am Heart J. 2006;151;689.e1-689.e10.

  15. CHAMPION Program • Phase III program underway 1O Endpoint – superiority for ischemic events vs. clopidogrel 600 mg at the start of PCI vs. clopidogrel 600 mg at the end of PCI N = 9,000 pts N = 6,300 pts

  16. TRANSCENDENCE-PCI Subjects Undergoing Non-Urgent PCI or Cardiac Catheterization Randomization #1  3:1 SCH 530348 : Placebo Single Loading Dose Prior to Catheterization Cardiac Catheterization No PCI** PCI - Subjects Receive Clopidogrel and Antithrombin No** Medical Management CABG Randomization #2 Quantify Postoperative Chest-Tube Drainage, Transfusions, and Re-exploration 0.5 mg n~100 1 mg n~100 2.5 mg n~100 Placebo n~100 Safety: TIMI Major plus Minor Bleeding Efficacy: Death/MACE Safety: TIMI Major plus Minor Bleeding TRANSCENDENCE-PCI, Thrombin Receptor Antagonist for Clinical Event Reduction Over Standard Concominant therapies in Percutaneous Coronary Intervention.

  17. Thrombin Receptor Antagonist in SecondaryPrevention of Atherothrombotic Ischemic Events (TRA 2°P)-TIMI 50 Prior MI, Ischemic CVA, or PAD Standard care, including oral antiplt rx RANDOMIZE 1:1 DOUBLE BLIND Stratify by CAD, CVD or PADand intent to use thienopyridine SCH 530348 Placebo Trial Features Global: 31 countries ~1000 sites ~19,500 subjects Double-blind Event-driven Follow up VisitsDay 30, Mo 4, Mo 8, Mo 12Q6 months Primary EPCV Death, MI, Stroke, Urgent Coronary Revascularization Final Visit Major Secondary EP: CV death, non-fatal MI, non-fatal stroke

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