Cairo, Egypt 2010 New antiplatelets in NSTEMI Steen D. Kristensen, FESC Department of Cardiology Aarhus University Hospital Skejby Denmark Overview: dual anti-platelet oral therapy Aspirin Clopidogrel New P2Y12 blockers: prasugrel and ticagrelor Thrombin receptor antagonists 1
Coagulation Acute myocardial infarction: coronary thrombus Platelets E Falk 1983 and 1985 Platelet adhaesion and aggregation Scanning electron micrograph of discoid, dormant platelets Adhering platelets Aggregating Platelets 2
Targets for Platelet Inhibition HEPARINS FONDAPARINUX BIVALIRUDIN RIVAROXABAN APIXABAN DABIGATRAN SCH 530348 E5555 Thrombin generation TERUTROBAN Thromboxane Coagulation A 2 x x Thrombin PAR-1 x TPα PAR-4 x ASPIRIN 5HT Collagen GPVI 5HT 2A PLATELET ACTIVATION ADP P2Y 1 ATP P2X 1 5HT ADP ATP Dense granule ADP TICLOPIDINE CLOPIDOGREL PRASUGREL ACTIVE METABOLITE x TICAGRELOR CANGRELOR P2Y 12 ELINOGREL Shape change Alpha granule Coagulation factors Inflammatory mediators Amplification α IIb β 3 α IIb β 3 Fibrinogen x Aggregation α IIb β 3 GP IIb/IIIa ANTAGONISTS GP = glycoprotein; PAR = protease-activated receptor; TP = thromboxane A 2 / prostaglandin H 2. Storey RF. Curr Pharm Des. 2006;12:1255-1259. New ESC Guidelines on Revascularization expected 2010. 3
Aspirin Aspirin for ever (75 to 100 mg daily) in all patients t without t allergy IA Conclusions ASA Dose Comparison No significant difference in efficacy or bleeding between ASA 300-325325 mg and ASA 75-100 mg. 4
Oral antiplatelet drugs: clopidogrel For all patients, immediate 300mg loading dose of clopidogrel is recommended, followed by 75mg clopidogrel daily (I-A). Clopidogrel should be maintained for 12 months unless there is an excessive risk of bleeding (I-A). Clopidogrel: Double vs Standard Dose Primary Outcome: PCI Patients CV Death, MI or Stroke Clopidogrel Standard Cu umulative Hazard 0.02 0.03 0.04 0.0 0.01 15% RRR Clopidogrel Double HR 0.85 95% CI 0.74-0.99 P=0.036 0 3 6 9 12 15 18 21 24 27 30 Days S Mehta. ESC 2009 5
Antithrombotic therapy in ACS and after PCI Thrombosis Bleeding 6
Dual anti-platelet therapy: any problems? Clopidogrel (+ Aspirin) and CABG 8/10 Bleeding 1-8 8/10 Transfusion rate 1-4,6-9 PRBC / Cryo / Platelets 4/10 Re-exploration rate 1,3,5,6 (OR 5.7 6 ) 1/10 ICU and Hospital Stay 7 1/10 In-Hospital Mortality 5 10 1) Yende S et al. Crit Care Med 2001;29:2271-5. 1/10 No complications 2) Hongo RH et al. JACC 2002;40:231-7. 231 Jan Van der Linden 3) Chen L et al. J Thorac Cardiovasc Surg 2004;128:425-31 4) Chu MW et al. Ann Thorac Surg 2004;78:1536-41. 5) Ascione R et al. Ann Thorac Surg 2005;79:1210-6 6) Kapetanakis E et al. Eur Heart J 2005;26:576-583 7) Leong J et al. Ann Thorac Surg 2005;80:928-33 8) Ray JG et al. BMC Cardiovasc Disord. 2003;3:3. 9) Metha RH et al. JACC 2006;48:281-6 10) Karabulut H et al. Eur J Cardiothac Surg 2004;25:419-23 3 mars 2010 14 7
Oral antiplatelet drugs: clopidogrel In patients pretreated with clopidogrel who need to undergo CABG, surgery should be postponed for 5 days for clopidogrel withdrawal if clinically feasible (IIa- C). Dosing Problems: clopidogrel Duration Irreversibility Low-response Onset of effect 8
Ex-vivo addition of the clopidogrel metabolite: full response in low responders Wallentin, L et al., Eur Heart J 2007 Healthy Volunteer Crossover Study IPA at 24 hours (%) 100 80 60 40 20 N=66 Interpatient Variability Inter rpatient Var iability 0 Clopidogrel Responder Clopidogrel Non-responder -20 Response to Clopidogrel 300 mg Response to 60 mg From Brandt JT AHJ 153: 66e9,2007 9
Antiplatelet Therapy for PCI Clinical need to improve on benefits observed ed with clopidogrel Novel thienopyridine Efficient generation of active metabolite High levels of IPA achieved rapidly High IPA in clopidogrel hyporesponders Encouraging Phase 2 data PRIMARY EP Acute Phase: IPA 20 um ADP P<0.0001 for each DP) IPA (%; 20 μm AD 60 mg Hours Wiviott SD et al, Circulation 2007 Copyright 2007 American Heart Association 10
TRITON TIMI 38 NEJM 357: 2001-2015, 2007 www.nejm.org TRITON TIMI 38 study design ACS (STEMI or UA/NSTEMI) and planned PCI (n=13,608) Aspirin Clopidogrel 300mg loading dose/ 75mg maintenance dose Primary endpoint: Secondary endpoints: Safety endpoints: Key substudies: double-blind 60mg loading dose/ 10mg maintenance dose Median duration of therapy: 14.5 months CV death, MI, stroke All-cause death, MI, stroke CV death, MI, stroke, rehospitalisation due to ischaemia CV death, MI, urgent target-vessel revascularisation Stent thrombosis (ARC: definite/probable) TIMI major bleeds, life-threatening bleeds Pharmacokinetic, genomic STEMI = ST-segment elevation MI; TIMI = thrombolysis in myocardial infarction; UA = unstable angina; NSTEMI = non-st-segment elevation MI ARC = Academic Research Consortium Wiviott SD, et al. N Engl J Med 2007;357:2001 15 11
JD124857 Kristensen Slides 03/03/2010 11:46 23 Primary endpoint CV death, MI, stroke Primary endpoint (%) 15 10 5 0 HR 0.77 p=0.0001 HR 0.80 p=0.0003 Clopidogrel l ITT=13,608 LTFU=14 (0.1%) 12.1 (781) 9.9 (643) HR 0.81 (0.73 0.90) p=0.0004 NNT=46 0 30 60 90 180 270 360 450 Days HR = hazard ratio; NNT = number needed-to-treat ITT = intent-to-treat; LTFU = long-term follow-up Wiviott SD, et al. N Engl J Med 2007;357:2001 15 JD124857 Kristensen Slides 03/03/2010 11:46 24 Stent thrombosis (ARC definite and probable) 3 Any stent at index PCI (n=12,844) Clopidogrel 24% 2.4% (142) Endpoint (%) 2 1 1.1% (68) HR 0.48 p<0.0001 0 0 30 60 90 180 270 360 450 Days Wiviott SD, et al. Lancet 2008;370:1353 63 12
JD124857 Kristensen Slides 03/03/2010 11:46 25 Balance of efficacy and safety Endpoint (%) 15 10 5 CV death/mi/stroke TIMI major Non-CABG bleeds 138 events HR 0.81 (0.73 0.90) Clopidogrel 12.1% p=0.0004 9.9% 2.4% Clopidogrel 1.8% 0 0 30 60 90 180 270 360 450 Days NNT = number needed to treat NNT=46 35 events HR 1.32 (1.03 1.68) p=0.03 NNT= 67 Wiviott SD, et al. N Engl J Med 2007;357:2001 15 JD124857 Kristensen Slides 03/03/2010 11:46 26 Bleeding events (non-cabg) (n=13,457) Events (%) 4 2 0 1,8 Clopidogrel 2,4 TMI major bleeds ARD 0.6% HR 1.32 p=0.03 NNT=167 1,4 0,9 0,9 Lifethreatening ARD 0.5% HR 1.52 p=0.01 1,1 ARD 0.2% p=0.23 0,1 ICH in patients with prior stroke/tia (n=518) Clopidogrel: 0 (0)% : 6 (2.3)% (p=0.02) ARD 0.3% p=0.002 0,4 0,3 0,3 Non-fatal Fatal ICH ARD 0% p=0.74 TIA = transient ischaemic attack Wiviott SD, et al. N Engl J Med 2007;357:2001 15 13
Bleeding Risk Subgroups Therapeutic Considerations 16% 4% MD 10 mg Significant Net Clinical Benefit with 80% Has been approved by EMEA and FDA Should prasugrel be used in ACS patients undergoing PCI? 14
Patients NSTEMI scheduled for angio? Pretreatment? Patients NSTEMI scheduled for PCI? Pretreatment? 15
Patients NSTEMI scheduled for PCI? When should we start therapy? Switching which dose of prasugrel (loading)? STEMI patients? Montelascot et al, Lancet 2009 16
STEMI patients? Pretreatment? ACS Diabetes patients? Wiviott et al, Circulation 2008 17
Patients with stent thrombosis? in ACS/PCI Should we test for clopidogrel low response? Functional test? Genetic test? 18
Ticagrelor (AZD 6140): an oral reversible P2Y 12 antagonist HO HO O N N N S N N H N F F Ticagrelor is a cyclo-pentyl- triazolo-pyrimidine (CPTP) OH Direct acting Not a prodrug; does not require metabolic activation Rapid onset of inhibitory effect on the P2Y 12 receptor Greater inhibition of platelet aggregation than clopidogrel Reversibly bound Degree of inhibition reflects plasma concentration Faster offset of effect than clopidogrel Functional recovery of all circulating platelets 19
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 If pre-treated, no additional loading dose; if naive, standard 300 mg loading dose, then 75 mg qd maintenance; (additional 300 mg allowed pre PCI) Ticagrelor 180 mg loading dose, then 90 mg bid maintenance; (additional 90 mg pre-pci) 6 12-month exposure Primary endpoint: CV death + MI + Stroke Primary safety endpint: Total major bleeding PCI = percutaneous coronary intervention; ASA = acetylsalicylic acid; CV = cardiovascular; TIA = transient ischaemic attack K-M estimate of time to first primary efficacy event (Composite of CV death, MI or stroke) (%) Cumulative incidence No. at risk Ticagrelor 9,333 Clopidogrel 9,291 Completeness of follow-up 99.97% = five patients lost to follow-up 13 12 Clopidogrel 11 10 9 Ticagrelor 8 7 6 5 4 3 2 1 HR 0.84 (95% CI 0.77 0.92), p=0.0003 0 0 60 120 180 240 300 360 8,628 8,521 Days after randomisation 8,460 8,362 K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval 8,219 8,124 6,743 6,650 5,161 5,096 11.7 98 9.8 4,147 4,047 20
K-M estimates of time to secondary efficacy endpoints Myocardial infarction Cardiovascular death 7 Clopidogrel 6.9 7 Cumulative incidence (%) 6 5 4 3 2 1 0 5.8 Ticagrelor HR 0.84 (95% CI 0.75 0.95), 0.95), p=0.005 Cumulative incidence (%) 6 5 4 3 2 1 0 Clopidogrel 5.1 4.0 Ticagrelor HR 0.79 (95% CI 0.69 0.91), 0.91), p=0.001 No. at risk 0 60 120 180 240 300 360 Days after randomisation 0 60 120 180 240 300 360 Days after randomisation Ticagrelor 9,333 8,678 8,520 8,279 6,796 5,210 4,191 9,333 8,678 8,520 8,279 6,796 5,210 4,191 Clopidogrel 9,291 8,560 8,405 8,177 6,703 5,136 4,109 9,291 8,560 8,405 8,177 6,703 5,136 4,109 K-M estimates of time to primary safety event (Major bleeding) 15 Completeness of follow-up 99.97% = five patients lost to follow-up Cumulative incidence ( %) Ticagrelor 11.58 11.20 10 Clopidogrel 5 HR 1.04 (95% CI 0.95 1.13), p=0.434 0 0 60 120 180 240 300 360 Days from first IP dose No. at risk Ticagrelor 9,235 7,246 6,826 6,545 5,129 3,783 3,433 Clopidogrel 9,186 7,305 6,930 6,670 5,209 3,841 3,479 21
Non-CABG and CABG-related major bleeding 9 8 7.4 NS 7.9 Ticagrelor Clopidogrel estimated rate (% per year) K-M 7 6 5 4 3 2 p=0.0264 4.5 3.8 p=0.0246 2.8 2.2 5.3 NS 5.8 1 0 Non-CABG PLATO major bleeding Non-CABG TIMI major bleeding CABG PLATO major bleeding CABG TIMI major bleeding TICAGRELOR Benefit in the invasive group Benefit in the STEMI population p 22
PROBLEMS Compliance, dyspnoea and AV-conduction PROBLEMS Compliance, dyspnoea and AV-conduction 23
TRA Background SCH 530348 is an oral, potent, selective thrombin receptor antagonist (TRA) being developed for the prevention and treatment of atherothrombosis. Preclinical and early clinical studies have demonstrated SCH 530348 to have antithrombotic properties, with no increase in bleeding time or clotting times. Galbulimima baccata Bark of the Australian Rhododedron. TRA CER Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome NSTEACS N = 10,000 SCH 530348 Placebo 40 mg bolus, 2.5 mg daily (and usual therapy) n=5000 n=5000 1-Year Cardiovascular Death, MI, Stroke, Recurrent Ischemia with Rehosp, Urgent Coronary Revas www.clinicaltrials.gov 24
TRA 2P TIMI 50 Thrombin Receptor Antagonist for 2º Prevention Hx MI, CVA, PVD N ~ 18,000 SCH 530348 Placebo 2.5 mg daily (and usual therapy) N~9,000 N~9000 1-Year Cardiovascular Death, MI, Stroke, Recurrent Ischemia with Rehosp, Urgent Coronary Revas www.clinicaltrials.gov 25
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