Practical Application Of New Developments In Antithrombotic And - PowerPoint PPT Presentation

UCR Uppsala Clinical Research Center Practical Application Of New Developments In Antithrombotic And Antiplatelet Therapy In ACS Stefan James, MD, PhD Associate Professor Head of Interventional Cardiology Uppsala Clinical Research Center University Hospital Uppsala, Sweden Astra Zeneca, Daiichi Sankyo, Eli Lilly, BMS, Terumo, Grant/Research Support Consulting Fees/Honoraria Merck, Medtronic, Boston Scientific

STE- / NSTE-ACS Primary PCI / Lytics Early Invasive / Early Conservative Aspirin loading Parenteral anticoagulant UFH LMWH Fondaparinux Bivalirudin Bolus / infusion Parenteral antiplatelet Abciximab Eptifibatide Tirofiban Pre / post cath Pre / post cath Pre / post cath Oral antiplatelet Clopidogrel 600 mg Prasugrel Ticagrelor a Clopidogrel 300 mg Pre / post cath Pre / post cath Pre / post cath Pre / post cath ESC guidelines NSTE-ACS I-A, STE-ACS I-B 11 anti-thrombotic agents with 384 possible treatment combinations a Ticagrelor is not currently approved for use in any market. 1 ESC = European Society of Cardiology, LMWH = low-molecular-weight heparin, UFH = unfractionated heparin. Bassand JP, et al. Eur Heart J . 2007;28:1598-660. Van de Werf F, et al. Eur Heart J . 2008;29:2909-45

Targets for Antithrombotic Treatment Coagulation Platelet activation Warfarin Tissue factor Collagen Thrombin PAR1 - inhib Vorapaxar Aspirin Rivaroxaban Atopaxar Plasma clotting Apixaban Tx A 2 PAR1 cascade Edoxaban Clopidogrel ADP Prasugrel Ticagrelor Prothrombin Fondaparinux Cangrelor AT Factor Conformational LMWH Elinogrel Xa AT activation of GPIIb/IIIa Heparin GPIIb/IIIa inhibitors Thrombin Platelet aggregation Bivalirudin Dabigatran Fibrinogen Fibrin Thrombus 2 ADP = adenosine diphosphate, AT = antithrombin , GP = glycoprotein, inhib = inhibitor, PAR1 = protease activated receptor, TxA 2 = thromboxane A 2 .

Targets for Antithrombotic Treatment Coagulation Platelet activation Warfarin Tissue factor Collagen Thrombin PAR1 - inhib Vorapaxar Aspirin Rivaroxaban Atopaxar Plasma clotting Apixaban Tx A 2 PAR1 cascade Edoxaban Clopidogrel ADP Prasugrel Ticagrelor Prothrombin Fondaparinux Cangrelor AT Factor Conformational LMWH Elinogrel Xa AT activation of GPIIb/IIIa Heparin GPIIb/IIIa inhibitors Thrombin Platelet aggregation Bivalirudin Dabigatran Fibrinogen Fibrin Thrombus 3 ADP = adenosine diphosphate, AT = antithrombin , GP = glycoprotein, inhib = inhibitor, PAR1 = protease activated receptor, TxA 2 = thromboxane A 2 .

Variability in Inter-Individual Clopidogrel Response ADP, adenosine diphosphate. Hochholzer W, et al. Circulation. 2005;111:2560-4.

Clopidogrel 300 (-600) mg Standard Standard Double Double HR HR 95% CI 95% CI P P Int P P CV Death / MI / Stroke CV Death / MI / Stroke 0.37 Overall (2N=25,087) Overall (2N=25,087) 4.4 4.4 4.2 0.95 0.95 0.84 0.84 - - 1.07 1.07 0.016 PCI (2N=17,232) PCI (2N=17,232) 4.5 4.5 3.9 0.86 0.85 0.74 0.74 - - 0.99 0.99 0.04 No PCI (2N=7855) No PCI (2N=7855) 4.2 4.2 4.9 1.17 1.17 0.95 0.95 - - 1.44 1.44 0.14 0.14 CV Death / MI / Stroke in PCI Patients CV Death / MI / Stroke Clopidogrel Standard Clopidogrel Standard Cumulative Hazard 0.04 Cumulative Hazard 0.04 Clopidogrel Double Clopidogrel Double 0.03 0.03 0.02 0.02 HR= 0.86 (95% CI, 0.74-0.99) 0.01 HR= 0.85 (95% CI, 0.74-0.99) 0.01 P =0.039 P =0.036 0.0 0.0 Days 0 3 6 9 12 15 18 21 24 27 30 Days 0 3 6 9 12 15 18 21 24 27 30 5 Mehta SR, et al. NEJM 2010 and Lancet 2010

Clopidogrel dosing Class Level Level Class Class Level www.escardio.org/guidelines 6

PRINCIPLE-TIMI44 ONSET-OFFSET Prasugrel 60 mg (Wiviott SD et al. Circulation 2007) (Gurbel PA et al. Circulation 2009)

TRITON-TIMI 38: study design ACS (STEMI or UA/NSTEMI) and planned PCI ASA N=13,608 Double-blind randomisation Clopidogrel Prasugrel 300mg loading dose/75mg maintenance 60mg loading dose/10mg maintenance (N=6,795) (N=6,813) Median duration of therapy: 12 months 1 o endpoint: CV death, MI, stroke 2 o endpoints: CV death, MI, stroke, recurrent ischaemia with rehospitalisation CV death, MI, UTVR stent thrombosis (ARC definite/probable) Safety endpoints: TIMI major bleeds, life-threatening bleeds Key substudies: pharmacokinetic, genomic Wiviott S, et al. N Engl J Med 2007;357:2001 – 15 UTVR = urgent target vessel revascularisation

Efficacy endpoints CV death, MI, stroke Early and late and major non-CABG bleeding stent thrombosis Clopidogrel Prasugrel 15 2.5 2.5 Early Late CV death/MI/stroke HR=0.41 (0.29 – 0.59) HR=0.60 (0.37 – 0.97) 12.1 p<0.0001 p=0.03 2.0 2.0 10 1.56 Endpoint (%) Endpoint (%) Endpoint (%) 9.9 1.5 1.5 59% 1.0 1.0 0.82 5 TIMI major 40% non-CABG bleeds 2.4 0.64 0.5 0.5 0.49 1.8 0 0 0 0 5 10 15 20 25 30 0 90 270 450 0 90 180 270 360 450 Days Days Days CABG = coronary artery bypass grafting Wiviott S, et al. N Engl J Med 2007;357:2001 – 15; Wiviott S, et al. Lancet 2008;371:1353 – 1363

STEMI cohort Clopidogrel Prasugrel 15 12.4 CV Death / MI / stroke P = 0.02 Proportion of patients, % RRR = 21% 10.0 10 9.5 P = 0.002 RRR = 32% HR = 0.79 (0.65 – 0.97); NNT = 42 6.5 5 TIMI major 2.4 non-CABG bleeds P = 0.65 2.1 HR = 1.11 (0.70 – 1.77); NNH = 333 0 0 50 100 150 200 250 300 350 400 450 Days 10 Montalescot G, et al. Lancet 2009;373:723 – 31.

Prasugrel Montalescot et al. Lancet 2009; 373, 723-31

Conclusions on Prasugrel in ACS In patients with ACS and planned PCI Prasugrel 60/10mg vs Clopidogrel 300/75mg for 15 months reduces the composite: CV death + MI + stroke l reduces MI (especially produre related MI) l reduces stent thrombosis l raises the risk of major (including fatal) bleeding l with higher risk of bleedings at age >75 years, <65 kg, l history of stroke or TIA and at CABG net clinical benefit larger at STEMI and DM l

Prasugrel www.escardio.org/guidelines 13

James S, et al. Am Heart J 2009;157:599 – 605 PLATO study design NSTE-ACS (moderate-to-high risk) STEMI (if primary PCI) Clopidogrel-treated or -naive; randomised within 24 hours of index event (N=18,624) Clopidogrel Ticagrelor If pretreated, no additional loading dose; 180mg loading dose, then if naive, standard 300mg loading dose, 90mg b.i.d maintenance; then 75mg q.d maintenance; (additional 90mg prePCI) (additional 300mg allowed pre PCI) 6 – 12 month exposure Primary endpoint : • Composite of CV death, MI or stroke Key secondary • CV death, MI, or stroke in patients intended for invasive management • Total mortality, MI or stroke • CV death, MI, stroke, recurrent ischemia, TIA, or arterial thrombosis • Components of primary endpoint - CV death; MI; stroke • Death from any cause Primary safety: • Total Major bleeding

Ticagrelor vs. Clopidogrel N=18,624 Primary Endpoint 12 Clopidogrel HR 0.84 (CV death, MI, Stroke) 11.7 11 (0.77 – 0.92) 10 p=0.0003 9.8 Cumulative incidence (%) 9 NNT = 54 Ticagrelor 8 7 6 5 TIMI Major 4 HR 1.25 Ticagrelor Non CABG bleeds (1.03 – 1.53) 3 2.8 p=0.03 2 2.3 NNH=167 1 Clopidogrel 0 0 60 120 180 Days after randomization Wallentin L, et al. N Engl J Med. 2009;361:1045-57.

Ticagrelor vs. Clopidogrel Primary Endpoint HR 0.84 12 Clopidogrel (CV death, MI, Stroke) 11.7 (0.77 – 0.92) 11 p=0.0003 10 9.8 NNT = 54 9 Cumulative incidence (%) Ticagrelor 8 7 CV death 6 5 Clopidogrel HR 0.79 5.1 (0.69 – 0.91) 4 4.0 p=0.001 Ticagrelor 3 NNT = 90 2 1 N=18,624 0 0 60 120 180 Days after randomization Wallentin L, et al. N Engl J Med. 2009;361:1045-57.

Ticagrelor Invasive Definite Stent Thrombosis 2 Clopidogrel, ≥600 mg Definite stent thrombosis, % 1.42 Clopidogrel, <600 mg 1.41 Ticagrelor, ≥600 mg clopidogrel 1 0.96 0.87 Ticagrelor, <600 mg clopidogrel 0 0 5 10 15 20 25 30 Days Since PCI Cannon CP, et al. Lancet. 2010;375:283-293.

Mortality reduction in invasive and non- invasive treatment strategies Non- Invasive 10 N=5216 All-cause mortality (%) Non-invasive 8.2% 8 HR, 0.75, 95% CI: (0.61 – 0.93) 6.1% 6 5.0% 4 3.9% 2 Invasive N=13408 HR, 0.81, 95% CI: (0.68 – 0.95) 0 0 60 120 180 240 300 360 Number at risk Days after randomization Invasive Ticagrelor 6732 6439 6375 6241 5141 3951 3233 Clopidogrel 6676 6376 6331 6209 5114 3917 3164 Non-invasive Ticagrelor 2601 2485 2447 2385 1978 1531 1186 Clopidogrel 2615 2488 2448 2380 1965 1524 1200 James S et al. ESC abstract 2010

Prior stroke or TIA 14 Stroke Prior stroke Clopidogrel 12 HR, 0.62 (0.42, 0.91) All cause death 10 N=1052 8 Ticagrelor 6 No prior stroke Clopidogrel Ticagrelor 4 2 0 Patient at risk 0 60 120 180 240 300 360 Clopidogrel Prior stroke 588 542 530 507 397 314 246 Ticagrelor 564 534 525 511 411 332 254 No prior stroke 8699 8318 8245 8078 6679 5124 4115 Clopidogrel Ticagrelor 8761 8382 8289 8107 6701 5143 4162 James, S et al, ESC 2011