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Rob Storey Reader and Honorary Consultant in Cardiology, University of Sheffield

Rob Storey Reader and Honorary Consultant in Cardiology, University of Sheffield. The changing world of adjunctive pharmacology. Disclosures. Company Name Relationship AstraZeneca Research grants, speaker fees, consultant, travel

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Rob Storey Reader and Honorary Consultant in Cardiology, University of Sheffield

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  1. Rob Storey Reader and Honorary Consultant in Cardiology, University of Sheffield The changing world of adjunctive pharmacology

  2. Disclosures • Company NameRelationship • AstraZeneca Research grants, speaker fees, consultant, travel • Eli Lilly / Daiichi Sankyo Research grant, speaker fees, consultant, travel • Schering-Plough Research grant, consultant • Teva Consultant • Novartis Consultant • The Medicines Company Consultant • Dynabyte Research consumables

  3. 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.

  4. P2Y12 as a therapeutic target 5HT 5HT Thromboxane TICLOPIDINE CLOPIDOGREL PRASUGREL A Coagulation Collagen ADP ADP ADP 2 ATP ATP GPVI 5HT P2Y 2A Thrombin 1 TP a P2X ACTIVE METABOLITE 1 PAR-4 PAR-1 x Dense TICAGRELOR CANGRELOR granule PLATELET P2Y 12 Thrombin generation ACTIVATION Amplification Shape change Alpha granule Aggregation a b IIb 3 a b a b IIb 3 IIb 3 Fibrinogen Coagulation factors Inflammatory mediators GP = glycoprotein; PAR = protease-activated receptor; TP = thromboxane A2 / prostaglandin H2. Storey RF. Curr Pharm Des. 2006;12:1255-1259.

  5. Activation/inactivation of clopidogrel OCH O OCH O O OCH 3 3 C O O H 3 CYPs N N CYPs N O S S H S Cl Cl Cl Esterases Clopidogrel 2-Oxo-clopidogrel R-130964 O O H N S Cl SR26334 (Inactive) CYP = cytochrome P450. Farid NA, et al. Clin Pharmacol Ther. 2007;81:735-741.

  6. Platelet aggregation before and 4 hours after clopidogrel 600 mg in patients undergoing PCIWhole blood single platelet counting in response to ADP 10 uM Patient with subacute stent thrombosis Smith SMG et al. Platelets 2006; 17: 250-258

  7. VerifyNow P2Y12 assay

  8. Multiplate MEA

  9. Clinical outcomes according to platelet aggregometry results with MEA Sibbing, D. et al. JACC 2009; 53: 849-56

  10. Clopidogrel, CYP 2C19 and stentthrombosis Sibbing, D. et al. Eur Heart J 2009 30:916-922

  11. Prasugrel

  12. Comparison of prasugrel with higher dose clopidogrel IPA (%; 20 mM ADP) IPA (%; 20 mM ADP) P<0.0001 N=201 P<0.0001 for each Prasugrel 60 mg Clopidogrel 600 mg Clopidogrel 150 mg Prasugrel 10 mg Hours 14 Days Wiviott et al Circ 2007

  13. TRITON Study Design ACS (STEMI or UA/NSTEMI) & Planned PCI N= 13,600 ASA Double-blind CLOPIDOGREL 300 mg LD/ 75 mg MD PRASUGREL 60 mg LD/ 10 mg MD Median duration of therapy - 12 months 1o endpoint: CV death, MI, Stroke 2o endpoints: CV death, MI, Stroke, Rehosp-Rec Isch, CV death, MI, UTVR Stent Thrombosis (ARC definite/prob.) Safety endpoints: TIMI major bleeds, Life-threatening bleedsKey Substudies: Pharmacokinetic, Genomic

  14. TRITON-TIMI study Balance of Efficacy and Safety 15 138 events Clopidogrel HR 0.81(0.73-0.90)P=0.0004 12.1 CV Death / MI / Stroke 9.9 10 NNT = 46 Prasugrel Endpoint (%) 5 35 events TIMI Major NonCABG Bleeds Prasugrel 2.4 HR 1.32(1.03-1.68)P=0.03 1.8 Clopidogrel 0 NNH = 167 0 30 60 90 180 270 360 450 Days

  15. TRITON-TIMI study 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

  16. TRITON Diabetic Subgroup N=3146 18 Clopidogrel 17.0 16 CV Death / MI / Stroke 14 12.2 12 HR 0.70P<0.001 Endpoint (%) Prasugrel 10 NNT = 46 8 6 TIMI Major NonCABG Bleeds Clopidogrel 4 2.6 2.5 2 Prasugrel 0 0 30 60 90 180 270 360 450 Days

  17. Clopidogrel Prasugrel 15 12.4 p=0.02 RRR=21% 10.0 10 9.5 p=0.002 RRR=32% Proportion of patients (%) 6.5 5 HR=0.79 (0.65–0.97) NNT=42 0 Age-adjusted HR=0.81 (0.66-0.99) 0 50 100 150 200 250 300 350 400 450 Time (Days) TRITON STEMI cohortPrimary EP (CV death, MI and stroke at 15 months) Montalescot et al. ESC 2008

  18. TRITON Net Clinical BenefitBleeding Risk Subgroups Post-hoc analysis Risk (%) + 37 Yes Prior Stroke / TIA -16 No Pint = 0.006 -1 >=75 Age -16 Pint = 0.18 < 75 +3 < 60 kg Wgt Pint = 0.36 -14 >=60 kg -13 OVERALL 0.5 1 2 Prasugrel Better Clopidogrel Better HR

  19. Ticagrelor The first oral reversible P2Y12 antagonist

  20. ONSET/OFFSET Study IPA with ADP 5uM (final extent) Ticagrelor 180mg LD / 90 mg bd (n=54) * * * * * † Clopidogrel 600mg LD / 75 mg od (n=50) * * *   * ‡ † 100 90 80 70 60 IPA % 50 40 30 20 10  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) Gurbel PA et al. Circulation 2009

  21. PLATO PLATELET – VerifyNow P2Y12 assay comparing maintenance therapy with clopidogrel (C) vs ticagrelor (T) Storey RF et al. Presented at American Heart Association annual scientific sessions Nov 2009

  22. Secondary efficacy endpoints over time Cardiovascular death Myocardial infarction 7 7 6.9 Clopidogrel 6 6 5.8 Clopidogrel 5.1 5 5 Ticagrelor 4.0 4 4 Ticagrelor Cumulative incidence (%) Cumulative incidence (%) 3 3 2 2 1 1 HR 0.84 (95% CI 0.75–0.95), p=0.005 HR 0.79 (95% CI 0.69–0.91), p=0.001 0 0 0 60 120 180 240 300 360 0 60 120 180 240 300 360 Days after randomisation Days after randomisation No. at risk 9,333 8,294 8,822 8,626 7119 5,482 4,419 Ticagrelor 9,333 8,678 8,520 8,279 6,796 5,210 4,191 9,291 8,865 8,780 8,589 7079 5,441 4,364 Clopidogrel 9,291 8,560 8,405 8,177 6,703 5,136 4,109

  23. Total major bleeding 13 NS Ticagrelor Clopidogrel 12 11.6 11.2 11 NS 10 8.9 8.9 NS 9 7.9 7.7 8 NS 7 K-M estimated rate (% per year) 5.8 5.8 6 5 4 3 2 NS 1 0.3 0.3 0 PLATO major bleeding TIMI major bleeding Red cell transfusion* PLATO life-threatening/fatal bleeding Fatal bleeding Major bleeding and major or minor bleeding according to TIMI criteria refer to non-adjudicated events analysed with the use of a statistically programmed analysis in accordance with definition described in Wiviott SD et al. NEJM 2007;357:2001–15; *Proportion of patients (%); NS = not significant

  24. Non-CABG and CABG-related major bleeding 9 Ticagrelor Clopidogrel NS 7.9 8 7.4 7 NS 5.8 6 5.3 p=0.026 5 K-M estimated rate (% per year) 4.5 3.8 4 p=0.025 2.8 3 2.2 2 1 0 Non-CABGPLATO majorbleeding Non-CABGTIMI major bleeding CABGPLATO major bleeding CABG TIMI major bleeding

  25. PLATO - Dyspnoea *p values were calculated using Fischer’s exact test

  26. PLATO Conclusions • Reversible, more intense P2Y12 receptor inhibition for one year with ticagrelor in comparison with clopidogrel in a broad population with ST- and non-ST-elevation ACS provides • Reduction in myocardial infarction and stent thrombosis • Reduction in cardiovascular and total mortality • No change in the overall risk of major bleeding • Ticagrelor is a more effective alternative than clopidogrel for the continuous prevention of ischaemic events, stent thrombosis and death in the acute and long-term treatment of patients with ACS • Clinicians will need to learn how to identify and manage dyspnoea associated with ticagrelor

  27. CangrelorIntravenous reversible P2Y12 antagonist

  28. 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

  29. BRIDGE study design (provisional) ACS treated with clopidogrel, scheduled for CABG Stop clopidogrel x days prior to CABG Cangrelor infusion Placebo infusion PD measurements Stop x hours prior to CABG surgery Primary objective: To assess safety of cangrelor compared to placebo prior to CABG surgery 1o end point: Bleeding 2o end points: Inhibition of platelet function, ischaemic events

  30. ElinogrelIntravenous and oral reversible P2Y12 antagonist

  31. Elinogrel • Reversible P2Y12 inhibitor in phase 2/3 development • IV and oral formulations • Half-life ~12 hours • Competitive mechanism of action – competes with ADP for binding to receptor, greater IPA for low vs high concentrations of ADP

  32. Targeting PAR-1

  33. 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.

  34. No significant compromise to haemostasis with SCH 530348 Cynomolgus monkey model. Chintala M et al. Arterioscl Thromb Vasc Biol. 2008; 28: e138–e139 T-1 = SCH 530348 1 mg/kg T-2 = Aspirin (10 mg/kg) plus Clopidogrel (2 mg/kg) T-3 = SCH 530348, Aspirin plus Clopidogrel

  35. 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

  36. Questions 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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