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Rob Storey Senior Lecturer and Honorary Consultant in Cardiology, University of Sheffield, Sheffield UK

Adjunctive Therapy New Agents – Will They Have A Role?. Rob Storey Senior Lecturer and Honorary Consultant in Cardiology, University of Sheffield, Sheffield UK. My Conflicts of Interest Are:. Company Name Relationship AstraZeneca Research grant, honoraria, consultant

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Rob Storey Senior Lecturer and Honorary Consultant in Cardiology, University of Sheffield, Sheffield UK

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  1. Adjunctive Therapy New Agents – Will They Have A Role? Rob Storey Senior Lecturer and Honorary Consultant in Cardiology, University of Sheffield, Sheffield UK

  2. My Conflicts of Interest Are: Company NameRelationship AstraZeneca Research grant, honoraria, consultant Eli Lilly / Daiichi Sankyo Research grant, honoraria The Medicines Company Honoraria, consultant Schering-Plough Research grant

  3. Targets for Platelet Inhibition ASPIRIN HEPARINS FONDAPARINUX BIVALIRUDIN RIVAROXABAN APIXABAN DABIGATRAN x 5HT 5HT Thromboxane TICLOPIDINE CLOPIDOGREL PRASUGREL A Coagulation Collagen ADP ADP ADP 2 x ATP ATP GPVI 5HT P2Y 2A Thrombin 1 TP a x P2X ACTIVE METABOLITE 1 PAR-4 PAR-1 x Dense SCH 530348 E5555 TICAGRELOR CANGRELOR granule PLATELET P2Y 12 Thrombin generation ACTIVATION Amplification Shape change Alpha granule x x Aggregation a b IIb 3 a b a b IIb 3 IIb 3 Fibrinogen Coagulation factors Inflammatory mediators GP IIb/IIIa ANTAGONISTS GP = glycoprotein; PAR = protease-activated receptor; TP = thromboxane A2 / prostaglandin H2. Storey RF. Curr Pharm Des. 2006;12:1255-1259.

  4. Irreversible P2Y12 Receptor Inhibition: Thienopyridine active metabolite Savi P, et al. Proc Natl Acad Sci USA. 2006;103:11069-11074.

  5. PRINCIPLE-TIMI 44: Effects of Clopidogrel and Prasugrel Loading on VASP Phosphorylation 100 Prasugrel 60 mg Clopidogrel 600 mg 80 75.0 60 68.4 64.3 VASP PRI, % 40 21.5* 20 7.4* 10.3* 0 0 4 8 12 16 20 24 Time, h *P<0.0001 vs clopidogrel. Data are mean ± SD. PRI = platelet reactivity index; PRINCIPLE-TIMI 44 = Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation - Thrombolysis in Myocardial Infarction 44; VASP = vasodilator-stimulated phosphoprotein. Wiviott SD, et al. Circulation. 2007;116:2923-2932.

  6. Stent Thrombosis(ARC Definite + Probable) 3 Any Stent at Index PCI N= 12,844 2.4(142) Clopidogrel 2 Endpoint (%) 1.1 (68) 1 Prasugrel HR 0.48P <0.0001 NNT= 77 0 0 30 60 90 180 270 360 450 Days Wiviott SD et al. N Engl J Med. 2007 Nov 15;357(20):2001-15

  7. Pts w/ Prior Stroke / TIA (N=518) P=0.02 Events, % ICH TRITON-TIMI 38: Bleeding Events Safety Cohort (N=13,457) 4 ClopidogrelPrasugrel 2.4 1.8 Events, % 2 1.4 1.1 0.9 0.9 0.4 0.3 0.3 0.1 0 TIMI MajorBleeds LifeThreatening Nonfatal Fatal ICH ARD 0.6%HR 1.32P=0.03NNH=167 ARD 0.5%HR 1.52P=0.01 ARD 0.2%P=0.23 ARD 0.3% P=0.002 ARD 0% P=0.74 ARD = absolute risk difference; HR = hazard ratio; ICH = intracranial haemorrhage; NNH = number needed to harm; TIA = transient ischemic attack; TIMI = Thrombolysis in Myocardial Infarction. Adapted from Wiviott SD, et al. Presented at: American Heart Association Scientific Sessions 2007; 4-7 November, 2007; Orlando, FL. Wiviott SD, et al. N Engl J Med. 2007;357:2001-2015.

  8. Ticagrelor (AZD6140)The first oral reversible P2Y12 antagonist

  9. Reversible P2Y12 Receptor Inhibition: CPTPs CPTP = cyclo-pentyl-triazolo-pyrimidine.

  10. Effect of ticagrelor on thrombus formation Laser-Injury Model: Mean Thrombus Area in P2Y12 +/+, +/–, and –/– Mice +/+ +/– 3000 3000 2500 2500 2000 2000 Area, µm2 Area, µm2 1500 1500 1000 1000 500 500 0 0 0 20 40 60 80 100 0 20 40 60 80 100 3000 3000 –/– +/+ Ticagrelor treated 2500 2500 2000 2000 Area, µm2 Area, µm2 1500 1500 1000 1000 500 500 0 0 0 20 40 60 80 100 0 20 40 60 80 100 Time, s Time, s Data are means ± standard deviation (SD). n=4 animals per group. Patil SBG, et al. Presented at: International Society on Thrombosis and Haemostasis XXIst Congress; 6-12 July, 2007; Geneva, Switzerland.

  11. DISPERSE: AUC for IPA at Day 28 (Final Extent) 1500 1250 1000 AUC (IPA 0-12 h, Final) 750 500 250 0 AZD6140 50 mg bd AZD6140 100 mg bd AZD6140 200 mg bd AZD6140 400 mg od Clopidogrel 75 mg od AUC = area under the curve; DISPERSE = Dose confirmatIon Study assessing anti-Platelet Effects of AZD6140 vs clopidogRel in NSTEMI; NSTEMI = non-ST-segment elevation myocardial infarction. Storey RF, et al. Presented at: American Heart Association 2006 Scientific Sessions; November 12-15, 2006; Chicago, Ill, USA.

  12. 100 75 Ticagrelor 90 mg Ticagrelor 180 mg Ticagrelor 270 mg Clopidogrel 300 mg 50 IPA, % (Mean ± SEM) 25 0 0 2 4 6 8 10 12 Time Postdose, h DISPERSE2 Substudy: Clopidogrel 300 mg ld vs Ticagrelor (AZD6140) 90-270 mg ld* in NSTE-ACS Inhibition of Platelet Aggregation Induced by ADP 20 μM (Final Extent, Day 1) *~50% of ticagrelor patients in each arm received a 270-mg loading dose. NSTE = non-ST-segment elevation. Storey RF, et al. J Am Coll Cardiol. 2006;47(suppl A):204A. Abstract 821-3.

  13. Ticagrelor and dyspnoea: DISPERSE2 25 20 15.8 15 Patients with Dyspnoea, % 10.5 10 6.4 5 0 AZD6140 90 mg bd (n=334) AZD6140 180 mg bd (n=323) Clopidogrel 75 mg od (n=327) Cannon CP, et al. Presented at: American Heart Association 2005 Scientific Sessions; November 13-16, 2005; Dallas, TX, USA.

  14. PLATO Study Design Moderate- to High-Risk ACS patients (UA/NSTEMI/STEMI, PCI, Medically-Managed, or CABG) (N=18,500) ASA + Clopidogrel 300 mg ld/75 mg od 600 mg ld allowed in PCI ASA + Ticagrelor 180 mg ld/90 mg bd 12-month maximum exposure (Min = 6 mo, Max = 12 mo, Mean = 11 mo) Primary end point: CVD/MI/stroke Secondary end point: CVD/MI/stroke/revascularisation with PCI; CVD/MI/stroke, severe recurrent ischaemia Recruitment October 2006 to July 2008; estimated final data collection March 2009 and study completion June 2009 STEMI = ST-segment elevation myocardial infarction; UA = unstable angina.

  15. Cangrelor The first intravenous reversible P2Y12 antagonist

  16. NH2 SMe HN N N O O O N Cl N –O O O O O O O N P P P N –O O O O CF3 N P P P S N O– O– O– O Cl O– O– O– 4Na+ 4Na+ HO OH HO OH Cangrelor: Stabilised Analogue of ATP ATP Cangrelor (IV) IV = intravenous. van Giezen JJJ, Humphries RG. Semin Thromb Hemost. 2005;31:195-204.

  17. Inactivation by Dephosphorylation S HN N N F F 4Na + Cl N N S F _ O O O O O O O P P P _ Cl _ _ O O O OH OH S HN N N F F N N S F HO O OH OH

  18. Effect of Cangrelor on ADP-Induced Platelet Aggregation in Patients with NSTE-ACS Whole Blood Impedance Aggregometry 100 80 60 IPA, % (Mean ± SEM) 40 Infusion dose 20 0.2 mg/kg/min 0.5 mg/kg/min 0.05 mg/kg/min 2.0 mg/kg/min 0 0.5 1.5 2.5 3.5 5 24 20 m 1 h Post Post Time after onset of infusion, h Time after terminationof infusion Storey RF, et al. Thromb Haemost. 2001;85:401-407.

  19. Clinical interaction of cangrelor with clopidogrel Whole-Blood Impedance Aggregometry Clopidogrel Clopidogrel (T=0) + 2 h cangrelor 1 h cangrelor, then clopidogrel 16 14 12 10 Impedance, ohms 8 6 4 2 0 0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 Time, h Cangrelor = 30 μg/kg IV bolus + 4 μg/kg/min infusion; clopidogrel = 600 mg loading dose. Data are means ± standard error. Steinhubl SR, et al. Thromb Res. 2008;121:527-534.

  20. CHAMPION Studies Program Clopidogrel PCI Placebo Placebo infusion • N = 9000 • SA/NSTEMI/STEMI • April 2008: 5800 enrolled PCI R Cangrelor infusion Clopidogrel Placebo Clopidogrel PLATFORM Placebo Placebo infusion • N = 6400 • SA/NSTEMI • April 2008: 2300 enrolled PCI R Cangrelor infusion Placebo Clopidogrel Randomization Treatment

  21. CHAMPION Program Endpoints

  22. Platelets and inflammation Monocyte • Chemotactic Molecules: MCP-1 • Proteolytic Enzymes: MMPs, PA’s • Pro-thrombotic molecules : Tissue Factor • Cytokines: Il-1, Il-8, TNF- • Adhesion Molecules: Mac-1, PSGL-1 PSGL-1 Mac-1 P-Selectin GP1b • Inflammatory mediators: Il-1, TGF- , PDGF, FGF-2, RANTES, CD40L. • Platelet Activation/aggregation: ADP, ATP, Thrombin. • Adhesion Molecules: P-Selectin, GPIIb/IIIa,, Fibrinogen, Fibronectin, vWF. • Coagulation Factors: PAI-1, Plasminogen, protein S, Factor V, Factor XI. Platelet GPIIb/IIIa 21 Integrin Collagen vWF

  23. Role of P2Y12 in Neointima Formation P2Y12+/+ P2Y12 –/– 30 Min Post-injury Alcian Blue / Elastic van Gieson stain 21 Days Post-injury Alcian Blue / Elastic van Gieson stain 21 Days Post-injury -smooth-muscle actin antibody Representative sections. Scale bar = 500 μm. Evans DJW, et al. Circulation 2009

  24. Neointima at 21 Days Post-injury 3 2 Intima : Media Ratio 1 * 0 P2Y12 +/+ P2Y12–/– Data are mean ± standard error of the mean (SEM); n=4. *P<0.05 vs wild type (Mann-Whitney). Evans DJW, et al. Circulation 2009

  25. Targets for Platelet Inhibition ASPIRIN TERUTROBAN HEPARINS FONDAPARINUX BIVALIRUDIN RIVAROXABAN APIXABAN DABIGATRAN x 5HT 5HT Thromboxane TICLOPIDINE CLOPIDOGREL PRASUGREL A Coagulation Collagen ADP ADP ADP 2 x x ATP ATP GPVI 5HT P2Y 2A Thrombin 1 TP a x P2X ACTIVE METABOLITE 1 PAR-4 PAR-1 x Dense SCH 530348 E5555 TICAGRELOR CANGRELOR granule PLATELET P2Y 12 Thrombin generation ACTIVATION Amplification Shape change Alpha granule x x Aggregation a b IIb 3 a b a b IIb 3 IIb 3 Fibrinogen Coagulation factors Inflammatory mediators GP IIb/IIIa ANTAGONISTS GP = glycoprotein; PAR = protease-activated receptor; TP = thromboxane A2 / prostaglandin H2. Storey RF. Curr Pharm Des. 2006;12:1255-1259.

  26. TRA.PCI studyPCIcohort: Bleeding results Moliterno D, et al. American College of Cardiology 2007 Scientific Sessions. March 24, 2007

  27. TRA.PCI study PCI cohort: Cardiac events MACE= MI/ischemia requiring hospitalization/coronary revascularization Moliterno D, et al. American College of Cardiology 2007 Scientific Sessions. March 24, 2007

  28. TRACER Study Design Moderate- to High-Risk ACS patients (UA/NSTEMI, PCI, Medically-Managed, or CABG) (N=10,000) Standard therapy + placebo Standard therapy + SCH 530548 40 mg LD then 2.5 mg od 12-month minimum exposure Primary end point: CV death/MI/stroke/recurrent ischaemia with rehospitalisation/urgent coronary revascularisation Study started December 2007 Estimated study completion July 2011

  29. Targets for Platelet Inhibition ASPIRIN TERUTROBAN HEPARINS FONDAPARINUX BIVALIRUDIN RIVAROXABAN APIXABAN DABIGATRAN x 5HT 5HT Thromboxane TICLOPIDINE CLOPIDOGREL PRASUGREL A Coagulation Collagen ADP ADP ADP 2 x x ATP ATP GPVI 5HT P2Y 2A Thrombin 1 TP a x P2X ACTIVE METABOLITE 1 PAR-4 PAR-1 x Dense SCH 530348 E5555 TICAGRELOR CANGRELOR granule PLATELET P2Y 12 Thrombin generation ACTIVATION Amplification Shape change Alpha granule x x Aggregation a b IIb 3 a b a b IIb 3 IIb 3 Fibrinogen Coagulation factors Inflammatory mediators GP IIb/IIIa ANTAGONISTS GP = glycoprotein; PAR = protease-activated receptor; TP = thromboxane A2 / prostaglandin H2. Storey RF. Curr Pharm Des. 2006;12:1255-1259.

  30. Discussion ASPIRIN TERUTROBAN HEPARINS FONDAPARINUX BIVALIRUDIN RIVAROXABAN APIXABAN DABIGATRAN x 5HT 5HT Thromboxane TICLOPIDINE CLOPIDOGREL PRASUGREL A Coagulation Collagen ADP ADP ADP 2 x x ATP ATP GPVI 5HT P2Y 2A Thrombin 1 TP a x P2X ACTIVE METABOLITE 1 PAR-4 ? PAR-1 x Dense SCH 530348 E5555 TICAGRELOR CANGRELOR granule P2Y 12 Thrombin generation Amplification Shape change Alpha granule x x Aggregation a b IIb 3 a b a b IIb 3 IIb 3 Fibrinogen Coagulation factors Inflammatory mediators GP IIb/IIIa ANTAGONISTS GP = glycoprotein; PAR = protease-activated receptor; TP = thromboxane A2 / prostaglandin H2. Storey RF. Curr Pharm Des. 2006;12:1255-1259.

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