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Antiplatelet Therapy in General Overview

Antiplatelet Therapy in General Overview. Prof. Lale Tokgözoğlu MD, FACC, FESC Hacettepe University Faculty of Medicine Department of Cardiology. Cause of Death by Gender in Europe:. WHO 2008. Platelets are important in atherothrombosis.

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Antiplatelet Therapy in General Overview

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  1. Antiplatelet Therapy in General Overview Prof. Lale Tokgözoğlu MD, FACC, FESC Hacettepe University Faculty of Medicine Department of Cardiology

  2. Cause of Death by Gender in Europe: WHO 2008

  3. Platelets are important in atherothrombosis • After release from bone marrow, circulate for 7-10 days without interaction with vessel wall • If exposed to subendothelium, platelets activated

  4. Platelet Adhesion Platelet Activation Platelet Aggregation Thrombotic Occlusion Unstable plaques activate platelets Plaque Fissure or Rupture

  5. Adhesion mediated by vWF, agonists like ADP, secreted granules and TXA2 cause aggregation, exposed GPIIbIIIa receptors crosslink with fibrinogen to form platelet aggregates Adhesion Aggregation 1 3 Activation 2 Reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: www.theheart.org.

  6. THROMBUS FIBRIN THROMBOCYTE AGGREGATION THROMBOCYTE ADHESION ENDOTHELIUM MONOCYTE MACROPHAGE SMOOTH MUSCLE CELL

  7. Platelet surface membrane receptors play important role

  8. Platelets also important in stent thrombosis:Mechanism of AMI after stent implantation Relative frequency 12% Atherothrombosis at newlocation (after 27 months) Restenosis (after 19 months) 48% Stent thrombosis (after 9 months) 40% Alexopoulos D. Am Heart J 2010; 159: 439-445

  9. Different mechanisms of antiplatelet drugs: • COX-1 inhibitorsASA, Omega 3 • Phosphodiesterase inhibitorsDipyrdamole, Cilostazol • ADP-P2Y12 interaction blokersTiclopidine, Clopidogrel, Prasugrel, Cangrelor, Ticagelor • GP IIb/IIIa blokers • Thrombin receptor antagonists

  10. Blocking different pathways for additional clinical benefit: Clopidogrel Prasugrel Cangrelor Epinephrine Collagen ADP Heparin, hirudin AA Aspirin TxA2 GPIIb/IIIa PLATELET GP IIb/IIIa antagonists Aggregation

  11. ASA • Inactivates COX irreversibly blocking TXA2 formation (potent mediator of aggregation and vasoconstriction) • Effective 15-30 minutes after oral administration • Large dose over 10 gr eicosapentaenoic acid also blocks TXA2

  12. Phosphodiesterase Inhibitors • Dipyridamole stimulates PGI2 synthesis, blocks uptake of adenosine • Clinical trials failed to show efficacy alone, enhances warfarin and ASA • MR form useful for stroke prevention • Cilostazol may be useful in claudicatio and has vasodilatory and antiplatelet effects

  13. Thienopyridines • Bind to P2Y12 receptor inhibiting interaction with ADP that would result in activation and aggregation • Prodrugs requiring transformation to active metabolites

  14. Ticlopidine dramatically changed interventional cardiology by making stent implantation safe Schomig, NEJM 1996

  15. Ticlopidine replaced by clopidogrel: more effective, safer Bhatt, JACC 2002

  16. Antiplatelet Resistance: • Genetic polymorphism in platelet proteins (CYP2C19 reduced function alleles have 30 % decrease in active clopidogrel) • Drug interaction (NSAID , drugs metabolized with Cytochrome P450 ) • Environmental factors(Smoking, DM, HTN, HLP, ACS) VARIABILITY IN RESPONSE NOT ALWAYS RESISTANCE: Insufficent dosing, differences in assays and cutoffs, no gold standart

  17. Is Aspirin Resistance Clinically Significant? • 326 stable CAD • 5.2 % Aspirin resistance • In HOPE study, @ 5 year follow up MI, stroke, death rate 1.8 % increased in the group with 11- deoxythromboxane B2 level ! Circulation 2002, 105: 1650 JACC 2003:41; 961

  18. No resistance ASA resistance CLOPI resistance Dual resistance ASA resistance vs. clopidogrel resistance vs. dual resistance The prevalence of drug resistance: ASA 16%, CLOPI 15%, dual 9% The risk is 7x higher with dual resistence and 4.5x higher with multivessel PCI 40 37% 35 30 26% 25 Percentage 20 15 10 5 0 Periprocedur.MI Ischaemic events within 30 days Eshtehardi P, Am Heart J 2010; 159: 891-898

  19. Definition of Resistance Varies with Method Used: ASA Resistance Measured by PFA-100 and Aggregometry Stable AP n= 325 patients Partial response Routine assessment of platelet aggregation not recommended (II-B) 23.8 % RESISTANT 5.5 % 9.5 % 90.5 % Aspirin Resistant 70.7 % Aspirin Sensitive Aggregometry Response to ADP and AA PFA-100 Gum P. Am J Cardiol 2001;88:230-235

  20. 600 mg clopidogrel loading is faster and more effective ! 0 *P=0.01 ** P=0.02 ‡ P=0.0008 20 40 Aggregation inhibition (%) ** * 60 ‡ * Clopidogrel, 300 mg Clopidogrel, 600 mg ** 80 0 2 4 6 Hours Zidar F, et al. J Am Coll Cardiol. 2004;43(5, suppl A);Abstract 1100-1159.

  21. ARMYDA-II Circulation 2005;111:2099

  22. Doubling loading and maintenance dose of clopidogrel in ACS patients undergoing PCI CV death, MI or stroke Clopidogrel standard 15% RRR 0.04 Clopidogrel double 0.03 Cumulative hazard 0.02 HR 0.85 95% CI: 0.74-0.99 p=0.036 0.01 0.00 0 3 6 9 12 15 18 21 24 27 30 Days

  23. Clopidogrel to Prasugrel Crossover Study: Less variability with prasugrel since it produces higher concentrations of active metabolite Healthy volunteers Crossover study IPA (20 µM ADP) 24 hours Platelet aggregation inhbition (%) N=66 Clopidogrel effective Clopidogrel resistant Clopidogrel reply Prasugrel reply Brandt et al. J Am Coll Cardiol 2005;45(3 Suppl 1):87A – abstract 868-5

  24. TRITON-TIMI 38: 13608 patients with ACS R Prasugrel 60 mg LD/ 10 mg MD ASA UA/NSTEMI (TIMI Risk Score ≥ 3) 12.0 month planned median & Planned PCI Double-blind treatment 6 - 15 months planned follow-up 14.5 month actual median STEMI (Primary PCI ≤ 12 hours of symptoms or post-STEMI within 14 days) ASA Clopidogrel 300 mg LD/ 75 mg MD Day 3 Day 30 Day 90 Day 450 Primary efficacy end point: a composite of the rate of death from cardiovascular causes, nonfatal MI, or nonfatal stroke = Key secondary end points at 30 and 90 days included primary efficacy end point and a composite of the rate of death from cardiovascular causes, nonfatal MI, or UTVR = Key safety end point: non-CABG related TIMI Major Bleeding Wiviott SD et al. New Engl J Med 2007;357:2001-2015; Wiviott SD et al. Am Heart J 2006;152:627-635

  25. TRITON TIMI-38: Balance of efficacy and safety in patients < 75 Yrs, ≥ 60 kg, and without prior TIA/Stroke (N=10,804) 16 CV death, NF MI, or NF stroke 14 Clopidogrel 11.0% 12 HR 0.74 (95% CI: 0.66-0.84) p<0.001, NNT 37 10 Endpoint (%) 8 Prasugrel 8.3% 6 TIMI major bleeding 4 HR 1.24 (95% CI: 0.91-1.69) p=0.17, NNH 222 Prasugrel 1.9% 2 Clopidogrel 1.5% 0 0 30 90 180 270 360 450 Days Wiviott SD et al. Circulation 2010;122:394-403

  26. Prevention of bleeding just as important as prevention of ischemia: Efficacy Safety

  27. In Clopidogrel group ,30 % of subjects had reduced function allele for CYP, these had 3X more stent thrombosis

  28. Genetic and Platelet Fx Tests are Complementary Genome Transcriptome Environment Genetics Proteome Phenotype Platelet function testing

  29. Variable Response to Clopidogrel Test: Increase dose Alternative treatment: Genetic, platelet function + Personalise - Complex + Easy - Efficacy, safety ? + Efficacy - Cost ? Bleeding ?

  30. Patients undergoing PCI with high platelet activity randomised to 75 mg C or 600 loading plus 150 mg C: GRAVITAS Study Primary end point Bleeding results Percentage of patients with persistently high platelet reactivity at 30 days AHA 2010

  31. Cangrelor • Potent inhibitor of ADP induced aggregation • ATP analogue that inhibits P2Y12 by 100 % • No renal/hepatic metabolism to be activated • İv,rapid action, platelets back to normal in 60 minutes • Has additive effects to clopidogrel • Two short term trials discontinued for less than expected efficacy

  32. Ticagrelor • Stable, high affinity inhibitor of ADP induced aggregation • Oral agent acting directly on P2Y12 receptor without transformation • Rapid and greater action • Reversibility • 180 mg loading ,90 mg bid • Higher doses cause dyspnea and ventricular pause

  33. PLATO Study • . Lancet. 2002;359:189-198 NEJM 2009; 361:1045

  34. Glycoprotein IIb/IIIa Inhibitors Block the Common Final Pathway to Platelet Aggregation regardless of the stimulus for activation

  35. Glycoprotein IIb/IIIa Inhibitors • Monoclonal Ab against IIb/IIIa: Abciximab • Peptide antagonist: Eptifibatid • Nonpeptide antagonist: Tirofiban

  36. High risk • Diabetic • - ASA use on admission GP IIb/IIIa Inhibitors in ACS:30 day death / MI (N=31,402) Study Placebo Gp IIb/IIIa Odds Ratio 95% CI PRISM 7.1% 5.8%*0.80 0.60-1.06 PRISM-PLUS 12.0% (*) 8.7% 0.70 0.50-0.98(† ) 13.6%*1.17 0.80-1.70 PARAGON-A 11.7% (l) 10.3% 0.87 0.58-1.29(h) 12.3% 1.06 0.72-1.55 PURSUIT 15.7% (l) 13.4% 0.83 0.70-0.99(h) 14.2% 0.89 0.79-1.00 PARAGON-B 11.4% 10.6% 0.92 0.77-1.09 GUSTO-IV 8.0% (24h) 8.2% 1.02 0.83-1.24(48h) 9.1% 1.15 0.94-1.39 Overall 11.8% 10.8%t 0.91 0.85-0.98 0 1.0 2.0 Gp IIb/IIIa iyi Placebo iyi P=.015 Boersma E, et al. Lancet. 2002;359:189-198.

  37. 50 40 30 20 10 0 PRISM-PLUS: Thrombus size Odds Ratio: 0.77 P=0.022 Probable Probable Small Cumulative (%) Small Medium 24.1% Medium 17.1% Big Big Occlusion Occlusion Tirofiban + Heparin (n=608) Heparin (n=622) Circulation. 1999;100:1609-1615.

  38. ACUITY, timing GP IIb/IIIa at the time of PCI vs. upstream in everyone Deferred PCI Routine Upstream GP IIb/IIIa GP IIb/IIIa (N=4,605) (N=4,602) Overall exposure 98.3% 55.7% 6.2 Rand. to angio/interv (h) 6.2 Rand. to GP IIb/IIIa (h) 0.6 4.6 Net clinical benefit 11.7 11.7 Ischaemic EP 7.1 7.9 Bleeding EP 6.1 4.9 Stone GW et al. JAMA 2007;297:591-602

  39. TARGET: Benefit of triple antiplatelet therapy 6 months death/MI Clopidogrel and tirofiban 18 16 14 12 10 8 6 4 2 0 Clopidogrel and abciximab No clopidogrel only tirofiban 15.5% No clopidogrel only abciximab 10.9% Patients (%) 8.4% 7.2% 0 30 60 90 120 150 180 Days Chan A, et al. J Am Coll Cardiol. 2003;42:1188-1195.

  40. Relation between age, dosing and bleeding Age Excess dose % Major bleeding % Eur Heart J Suppl 2007, 9 (Suppl A) A23-A31.

  41. Antithrombotic treatment options in myocardial revascularisation: STEMI a: Class of recommendation; b: Level of evidence; c: Primarily if more efficient antiplatelet agents are contraindicated; d: Depending on approval and availability. Direct comparison between prasugrel and ticagrelor is not available. Long term follow-up is awaited for both drugs Eur Heart J 2010. On line

  42. Antithrombotic treatment options in myocardial revascularisation: NSTE-ACS a: Class of recommendation; b: Level of evidence; c: Primarily if more efficient antiplatelet agents are contraindicated; d: Depending on approval and availability. Direct comparison between prasugrel and ticagrelor is not available. Long term follow-up is awaited for both drugs Eur Heart J 2010. On line

  43. Antiplatelets for ischemic stroke or preventing systemic embolism Warfarin vs placebo Warfarin vs low dose Warfarin Warfarin vs ASA Warfarin vs ASA + clopidogrel 0 0.3 0.6 0.9 1.2 1.5 1.8 2.0 Warfarin better Other better Camm, ESC 2009

  44. What is the ideal antiplatelet drug? Effective platelet inhibition without bleeding Uniformly effective in all patients (no resistance) Simple dosage No side effects No drug interactions Reasonable price FOR NOW: Beware of drug interactions and bleeding Keep ASA dose low in combination Calculate GPI dose meticulously

  45. New Horizons in Antiplatelet Therapy: TRA thrombin receptor antagonists Antagonists to A1 domain on vWF: ARC1779 Collagen induced platelet aggregation blockers : CTRP-1

  46. TRITON-TIMI 38: Therapeutic considerations for subgroups Age ≥75 years or weight <60 kg: Prasugrel 10 mg equivalent to clopidogrel (Prasugrel 5 mg under investigation) Majority of patients: Significant benefit with prasugrel 10 mg (MD) 16% Prior stroke/TIA: Prasugrel is contraindicated 4% 80%

  47. PRAGUE-8 (with 600 mg load): Patients undergoing elective PCI 20 Pre-treatment No Pre-treatment Clop 600 mg Clop 600 mg (n=155) (n=143) p=NS 15 11.9 p=0.006 Percentage patients 10 8.4 7.1 p=NS 5 2.8 1.3 0.7 0 D/MI/CVA/UTVR Troponin >3XULN Major + Minor Bleeding Widimsky P et al. Eur Heart J 2008;29:1495-1503

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