Anti-platlets from clopidogrel to the new agents


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Antiplatlets controversy

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  • PrasugrelThe main advantage of prasugrel over clopidogrel appears to be the prevention of non-fatal MI and stent thrombosis in ACS patients who undergo PCI.51 The cost of this prevention is excess bleeding. The improved efficacy of prasugrel may be exploited in the setting of STEMI referred for primary PCI or after coronary angiography in patients with NSTE-ACS undergoing PCI.47 The use of prasugrel should also be considered in patients who develop stent thrombosis despite aspirin and clopidogrel therapy. The place of prasugrel in the initial medical management of ACS remains uncertain until further ongoing studies are completed.90A lower maintenance dose of 5 mg in the elderly (>75 years) and the underweight (<60 kg) would seem logical, but formal testing of this hypothesis is necessary before such a strategy can be recommended.90 The ongoing TRILOGY trial and other studies are designed to answer this question
  • GPIIb/IIIa antagonists prevent fibrinogen binding to activated GPIIb/IIIa receptors and, thus, formation of fibrinogen bridges between platelets (reviewed in detail in ref. 2). Activation of GPIIb/IIIa constitutes the final common pathway of platelet aggregation. Currently, three GPIIb/IIIa blockers are available for intravenous administration: abciximab, eptifibatide, and tirofiban (reviewed in detail in ref.2). Abciximab, a non-competitive inhibitor of GPIIb/IIIa, is the humanized chimeric Fab-fragment of the monoclonal mouse antibody 7E3. Abciximab cross-reacts with the αvβ3integrin on endothelial cells and smooth muscle cells and with the αMβ2integrin (CD11b/CD18) on granulocytes and monocytes. Two small-molecule GPIIb/IIIa blockers act specifically on the αIIb-chain of GPIIb/IIIa: eptifibatide, a cyclic heptapeptide, and tirofiban, a non-peptide (‘peptidomimetic’) antagonist. Eptifibatide and tirofiban are competitive inhibitors. Their effect on platelet aggregation is closely linked to plasma concentrations.1 Owing to their short plasma half-lives, continuous infusion is needed for sustained platelet inhibition
  • Anti-platlets from clopidogrel to the new agents

    1. 1. Antithrombotic therapy between clinical trials and guidelines By Ashraf Reda, MD, FESC Prof and head of Card. Dep., Menofiya University President of WGLVA
    2. 2. One of the big stories in the last few years • RE-LY: • ROCKET: • ARISTOTLE: • • • • • Dabigatran Rivaroxaban Apixaban AF Triology/TRITON : Prasugrel DISPERSE?PLATO: Tecagrelor ACS/PCI ATLAS: Rivaroxaban Oasis Fodaparinux HORIZON-AMI bivalirudin Vit.K antagonist: • Narrow therapeutic range • Drug &food interaction • Bleeding • • • • Clopidogrel resistance MACEs Stent thrombosis Variable response
    4. 4. OASIS • Fondaparinux 2.5 mg bid Vs Enoxaparin 1mg/kg bid • Pts wit ACS • Non inferiority DBRT • Same protective effect • Significantly less bleeding with fondaparinux 2.2% compared to Enoxaparin 4,15 • PCI thrombosis?
    5. 5. Bivalirudin: Main Results From HORIZONS-AMI Bonaca, M. P. et al. J Am Coll Cardiol 2009;54:969-984 Copyright ©2009 American College of Cardiology Foundation. Restrictions may apply.
    6. 6. ACC/ AHA guide lines • Fonda is preferred only in: • Conservative non invasive strategy • Renal dysfunction
    7. 7. Antiplatelets
    8. 8. Anti platelets • COX-1 inhibitors Irreversible: aspirin Reversible: indobufen, triflusal • P2Y12 inhibitors Irreversible: ticlopidine, clopidogrel, prasugrel Reversible: Ticagrelor, cangrelora, elinogrela • Phosphodiesterase inhibitors Dipyridamole Cilostazol • GPIIb/IIIa blockers Abciximab Eptifibatide Tirofiban • Thromboxane receptor (TP) antagonists Terutrobana • Thrombin receptor (PAR-1) antagonists Vorapaxara Atopaxara
    9. 9. Current problems with anti platelet drugs • • • • • Resistance Bleeding On treatment platelet reactivity Drug interactions Variable efficacy and liver enzyme genetic variations • Duration of therapy • Preoperative management
    10. 10. Wiviott SD, Braunw ald E, McCabe CH, et al. N Eng J Med 2007; 357:20012015. TRITON-TIMI 38 results (ACS for PCI) End point Prasugrel (%) Clopidogrel (%) HR (95% CI) p Cardiovascular death/MI/ stroke* 9.9 12.1 0.81 (0.73–0.90) <0.001 Cardiovascular death 2.1 2.4 0.89 (0.70–1.12) 0.31 Nonfatal MI 7.3 9.5 0.76 (0.67–0.85) <0.001 Nonfatal stroke 1.0 1.0 1.02 (0.71–1.45) 0.93 Death from any cause 3.0 3.2 0.95 (0.78–1.16) 0.64 Urgent TVR 2.5 3.7 0.66 (0.54–0.81) <0.001 Stent thrombosis 1.1 2.4 0.48 (0.36–0.64) 1.34 (1.11–1.63) <0.001 Bleed requiring 4.0 3.0 CABG-related TIMI major bleedb 13.4 3.2 *Primary end point transfusion 4.73 (1.90–11.82) <0.001 <0.001
    11. 11. Prasugrel • Better prevention of MI and stent thrombosis in ACS Pts under going PCI (More bleeding) • For stent TH despite ASP/clopidogrel therapy • High risk in the elderly, low body Wt. and HO CVA • TRIOLOGY 51 ( high risk medically managed population/
    12. 12. PLATO: Patient disposition in the trial Ticagrelor Versus Clopidogrel in Patients With ST-Elevation Acute Coronary Syndromes Intended for Reperfusion With Primary Percutaneous Coronary Intervention A Platelet Inhibition and Patient Outcomes (PLATO) Trial Subgroup Analysis 7544 STEMI Steg P G et al. Circulation 2010;122:2131-2141 Copyright © American Heart Association
    13. 13. Time-related Kaplan–Meier estimates of the time to first occurrence of (A) the primary end point (incidence of MI, stroke, or vascular death; HR, 0.87; 95% CI, 0.75 to 1.01; P=0.07) and each of its components; B, cardiovascular death (HR, 0.83; 95% CI, 0.67... Steg P G et al. Circulation 2010;122:2131-2141 Copyright © American Heart Association
    14. 14. Time-related Kaplan–Meier estimate for major bleeding according to the PLATO definition (HR, 0.98; 95% CI, 0.83 to 1.14; P=0.76). Steg P G et al. Circulation 2010;122:2131-2141 Copyright © American Heart Association
    15. 15. Clopidogrel
    16. 16. Glycoprotein (GP)IIb/IIIa blockers • No routine up-stream • For high risk PCI (=ve Troponin- Thrombus) and low bleeding risk
    17. 17. Clopidogrel, Prasugrel, or Tecagrelor A major across Atlantic differences
    18. 18. STEMI: 2013 ACCF/AHA guideline1 • A loading dose of a P2Y12 receptor inhibitor should be given as early as possible or at time of primary PCI to patients with STEMI. Options include: • Clopidogrel 600 mg (Level of Evidence: B); or • Prasugrel 60 mg (Level of Evidence: B); or • Ticagrelor 180 mg (Level of Evidence: B) • P2Y12 inhibitor therapy should be given for 1 year to patients with STEMI who receive a stent (bare metal stent or drug-eluting stent) during primary PCI, using the following maintenance doses: • Clopidogrel 75 mg daily (Level of Evidence: B); or • Prasugrel 10 mg daily (Level of Evidence: B); or • Ticagrelor 90 mg twice a day. (Level of Evidence: B)
    19. 19. UA/NSTEMI invasively or noninvasively 2012 ACCF/AHA guideline: Class I • For patients with definite UA/NSTEMI at medium or high risk and in whom an initial invasive strategy is selected: Patients should receive dual antiplatelet therapy on presentation. (Level of Evidence: A) Aspirin should be initiated on presentation. (Level of Evidence: A) The choice of a second antiplatelet therapy to be added to aspirin on presentation includes 1 of the followinga: Before PCI: • • • • • • • • Clopidogrel (Level of Evidence: B); or Ticagrelorb (Level of Evidence: B); or An IV glycoprotein (GP) IIb/IIIa inhibitor (Level of Evidence: A) At the time of PCI: Clopidogrel if not started before PCI (Level of Evidence: A); or Prasugrel (Level of Evidence: B); or Ticagrelorb (Level of Evidence: B); or An IV GP IIb/IIIa inhibitor (Level of Evidence: A
    20. 20. UA/NSTEMI conservative 2012 ACCF/AHA guideline: Class I • For UA/NSTEMI patients in whom an initial conservative (ie, noninvasive) strategy is selected: Clopidogrel or ticagrelorb (loading dose followed by daily maintenance dose) should be added to aspirin and anticoagulant therapy as soon as possible after admission and administered for up to 12 months. (Level of Evidence B) For UA/NSTEMI patients for whom PCI is plannedc: A loading dose of P2Y12receptor inhibitor therapy is recommended. One of the following regimens should be used: • Clopidogrel 600 mg should be given as early as possible before or at the time of PCI (Level of Evidence: B); or • Prasugrel 60 mg should be given promptly and no later than 1 hour after PCI once coronary anatomy is defined and a decision is made to proceed with PCI (Level of Evidence: B); or • Ticagrelorb 180 mg should be given as early as possible before or at the time of
    21. 21. 2 more problems • Pre operative management • Triple therapy
    22. 22. The Safety and Efficacy Of Cangrelor, a Short Acting, IV, Reversible, Platelet P2Y12 Inhibitor In Patients Awaiting Cardiac Surgery: Results Of the BRIDGE Trial Dominick J. Angiolillo MD, PhD, Michael S. Firstenberg MD, Matthew J. Price MD, Pradyumna E. Tummala MD, Martin Hutyra MD, Ian J. Welsby MD, Michele D. Voeltz MD, Harish Chandna MD, Chandrashekhar Ramaiah MD, Miroslav Brtko MD, PhD, Louis Cannon MD, Cornelius Dyke MD Tiepu Liu MD, PhD, Gilles Montalescot MD, Steven V. Manoukian MD, Jayne Prats PhD, Eric J. Topol MD for the BRIDGE Investigators 28
    23. 23. Unmet need & rationale • Surgery is frequent in patients presenting with an ACS or treated with stents (1-2) – 10–15% of patients presenting with ACS have to undergo CABG – 5% to 25% of patients have to undergo non-cardiac surgery • Oral P2Y12 therapy following ACS and coronary stenting is Guideline-recommended for up to 12 months (3-4) • Continue or stop P2Y12 therapy? (5-10) – Continuation puts patients at ∼35% incidence of bleeding. Bleeding and transfusion are associated with increased risk of mortality – Preoperative discontinuation of anti-platelet therapy is associated with ∼20% incidence of ischemic events • No proven and efficacious alternative solution for bridging to surgery is currently available (11-12) 1. Vicenzi MN, et al. Br J Anaesth 2006; 96: 686–693; 2. Ebrahimi R., et al. J ACC 2009; 53: 1965–19724;3. King, S.B., 3rd, et al. JACC 2008; 51: 172–209; 4. Patrono C, et al. Chest 2008; 133: 199S-233S; 5. Berger JS, et al. JACC 2008; 52: 1693–1701; 6. Kaluza GL, et al. JACC 2000; 35: 1288–1294; 7. Berger PB, et al. JACC Cardiovasc Interv 2010; 3:.920-7; 8. Rao SV, et al. Eur Heart J 2007; 28: 1193–1204; 9. Hajjar LA, et al. J Am Med Assoc 2010; 304: 1559–1567; 10. Murphy GJ, et al. Circulation 2007; 116: 2544–255; 11.Hamm C et al Eur Heart J 2011 Sep 21. [Epub ahead of print]; 12. Anderson J et al. Circulation. 2011;123:e426-e579. 29
    24. 24. BRIDGE Conclusions • The results of the BRIDGE trial support the hypothesis that IV cangrelor is a feasible and safe management strategy in patients who require prolonged platelet P2Y12 inhibition after thienopyridine discontinuation prior to cardiac surgery. • Larger patient samples are warranted to more definitively assert the safety and efficacy of cangrelor as a bridging therapy in patients with ACS or treated with coronary stents who require surgery. 30
    25. 25. TOAT (triple oral antithrombotic therapy) • DAPT: ACS, PCI • OAC: AF, prosthetic valves, venous thromboembolism (VTE) • Risk of bleeding with TOAT against risk of stent thrombosis or stroke • 5-10% of Pts scheduled for PCI are on OAC • Population aging with more prevalence of AF increase the need to consider TOAT • Should we decrease the dose of OAC? • Should we avoid new agents with high bleeding risk as Prasugrel? • Could we consider Clopidogrel + OAC without ASP?