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

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Presentation on theme: "Antiplatelet Therapy in General Overview Prof. Lale Tokgözoğlu MD, FACC, FESC Hacettepe University Faculty of Medicine Department of Cardiology Prof. Lale."— Presentation transcript:

1 Antiplatelet Therapy in General Overview Prof. Lale Tokgözoğlu MD, FACC, FESC Hacettepe University Faculty of Medicine Department of Cardiology 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  After release from bone marrow, circulate for 7-10 days without interaction with vessel wall  If exposed to subendothelium, platelets activated

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

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

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

7 Platelet surface membrane receptors play important role

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

9 Different mechanisms of antiplatelet drugs: 1.COX-1 inhibitors ASA, Omega 3 2.Phosphodiesterase inhibitors Dipyrdamole, Cilostazol 3.ADP-P2Y12 interaction blokers Ticlopidine, Clopidogrel, Prasugrel, Cangrelor, Ticagelor 4.GP IIb/IIIa blokers 5.Thrombin receptor antagonists 1.COX-1 inhibitors ASA, Omega 3 2.Phosphodiesterase inhibitors Dipyrdamole, Cilostazol 3.ADP-P2Y12 interaction blokers Ticlopidine, Clopidogrel, Prasugrel, Cangrelor, Ticagelor 4.GP IIb/IIIa blokers 5.Thrombin receptor antagonists

10 AA TxA 2 GPIIb/IIIa Aggregation Aspirin PLATELET Clopidogrel Prasugrel Cangrelor Heparin, hirudin Blocking different pathways for additional clinical benefit: GP IIb/IIIa antagonists Epinephrine Collagen ADP Epinephrine Collagen ADP

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

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13 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  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

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

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

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

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18 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  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

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

20 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 Eshtehardi P, Am Heart J 2010; 159: % 37% Periprocedur.MIIschaemic events within 30 days No resistance ASA resistance CLOPI resistance Dual resistance 0 Percentage

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

22 Zidar F, et al. J Am Coll Cardiol. 2004;43(5, suppl A);Abstract Aggregation inhibition (%) Clopidogrel, 600 mg Clopidogrel, 300 mg *P=0.01 ** P=0.02 ‡ P= * ** ‡ * Hours 600 mg clopidogrel loading is faster and more effective !

23 ARMYDA-II Circulation 2005;111:2099

24 Doubling loading and maintenance dose of clopidogrel in ACS patients undergoing PCI CV death, MI or stroke Days Clopidogrel standard Clopidogrel double HR % CI: p= % RRR Cumulative hazard

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

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

27 TRITON TIMI-38: Balance of efficacy and safety in patients < 75 Yrs, ≥ 60 kg, and without prior TIA/Stroke (N=10,804) Endpoint (%) HR 1.24 (95% CI: ) p=0.17, NNH 222 HR 0.74 (95% CI: ) p<0.001, NNT 37 Clopidogrel 11.0% Prasugrel 8.3% Clopidogrel 1.5% Prasugrel 1.9% Days CV death, NF MI, or NF stroke TIMI major bleeding Wiviott SD et al. Circulation 2010;122:

28 Prevention of bleeding just as important as prevention of ischemia: Safety Efficacy

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

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

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

32 Patients undergoing PCI with high platelet activity randomised to 75 mg C or 600 loading plus 150 mg C: GRAVITAS Study End pointHigh-dose clopidogrel (%) Standard-dose clopidogrel (%) HR (95% CI)p Cardiovascular death/MI/stent thrombosis ( )0.98 Primary end point Bleeding results OutcomeHigh-dose clopidogrel (%) Standard-dose clopidogrel (%) p GUSTO severe/moderate bleeding Any GUSTO bleeding Percentage of patients with persistently high platelet reactivity at 30 days Platelet reactivity unitsHigh-dose clopidogrel (%) Standard-dose clopidogrel (%)p > <0.001 AHA 2010

33 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  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

34 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  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

35 PLATO Study . Lancet. 2002;359: NEJM 2009; 361:1045

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

37 Glycoprotein IIb/IIIa Inhibitors  Monoclonal Ab against IIb/IIIa: Abciximab  Peptide antagonist: Eptifibatid  Nonpeptide antagonist: Tirofiban  Monoclonal Ab against IIb/IIIa: Abciximab  Peptide antagonist: Eptifibatid  Nonpeptide antagonist: Tirofiban

38 GP IIb/IIIa Inhibitors in ACS: 30 day death / MI (N=31,402) PRISM7.1%5.8%* PRISM-PLUS12.0%(*)8.7% ()13.6%* PRISM-PLUS12.0%(*)8.7% ( † )13.6%* PARAGON-A11.7%(l)10.3% (h)12.3% PURSUIT15.7%(l)13.4% (h)14.2% PURSUIT15.7%(l)13.4% (h)14.2% PARAGON-B11.4%10.6% GUSTO-IV8.0%(24h)8.2% (48h)9.1% GUSTO-IV8.0%(24h)8.2% (48h)9.1% Overall11.8%10.8% t Overall11.8%10.8% t Odds Ratio Placebo Gp IIb/IIIa 95% CI Placebo iyiGp IIb/IIIa iyi Study P=.015 Boersma E, et al. Lancet. 2002;359: High risk - Diabetic - ASA use on admission

39 PRISM-PLUS: Thrombus size Heparin (n=622) Big Tirofiban + Heparin (n=608) Probable Small Medium Probable Small Medium Odds Ratio: 0.77 P= % 24.1% Big Occlusion Circulation. 1999;100: Cumulative (%)

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

41 Days 6 months death/MI 15.5% 10.9% 8.4% 7.2% Chan A, et al. J Am Coll Cardiol. 2003;42: TARGET: Benefit of triple antiplatelet therapy Patients (%) Patients (%) No clopidogrel only tirofiban No clopidogrel only abciximab Clopidogrel and tirofiban Clopidogrel and abciximab

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

43 Antithrombotic treatment options in myocardial revascularisation: STEMI Antiplatelet therapyClass a Level b ASAIB Clopidogrel c (with 600 mg loading dose as soon as possible)IC Prasugrel d IB Ticagrelor d IB + GPIIb–IIIa antagonists (in patients with evidence of high intracoronary thrombus burden) AbciximabIIaA EptifibatideIIaB TirofibanIIbB Upstream GPIIb–IIIa antagonistsIIIB Anticoagulation Bivalirudin (monotherapy)IB UFHIC FondaparinuxIIIB 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 On line

44 Antithrombotic treatment options in myocardial revascularisation: NSTE-ACS Antiplatelet therapyClass a Level b ASAIC Clopidogrel c (with 600 mg loading dose as soon as possible)IC Clopidogrel c (for 9–12 months after PCI)IB Prasugrel d IIaB Ticagrelor d IB + GPIIb–IIIa antagonists (in patients with evidence of high intracoronary thrombus burden) Abciximab (with DAPT)IIB Tirofiban, EptifibatideIIaB Upstream GPIIb–IIIa antagonistsIIIB 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 On line

45 Antiplatelets for ischemic stroke or preventing systemic embolism Camm, ESC 2009 Warfarin vs placebo Warfarin vs low dose Warfarin Warfarin vs ASA Warfarin vs ASA + clopidogrel Warfarin betterOther better

46 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

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

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

50 PRAGUE-8 (with 600 mg load): Patients undergoing elective PCI Widimsky P et al. Eur Heart J 2008;29: Pre-treatment Clop 600 mg (n=155) No Pre-treatment Clop 600 mg (n=143) 0 20 D/MI/CVA/UTVRTroponin >3XULNMajor + Minor Bleeding p=NS p= Percentage patients

51 Activated platelets express CD 40L triggering inflammation and thrombosis

52 ISAR-CHOICE Circulation 2005;112:2946

53 30th DAY DEATH / MI WITH GPI % Parients EPICCAPTUREEPILOGEPISTENTPRISM-PLUSPURSUIT PlaceboGP IIb-IIIa Inhibitor

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55 KlopidogrelPrasugrel 300/7540/7.560/1060/15 JUMBO - TIMI 26 (Phase II) PCI + Stent (n= 904) ASA % 70 GP2b/3a ClopidogrelPrasugrel 300/7540/7.560/1060/15 Circulation 2005;111:3366 % % % %

56 Variable Clopidogrel Response At 5 Days UA Patients* (n = 32) At 5 Days UA Patients* (n = 32) Responders 47% Low responders 32% Nonresponders 22% *Received an oral loading dose of 300 mg of clopidogrel followed by 75 mg daily. Gurbel PA, et al. Circulation. 2003;107(23): ; Lau WC, et al. Circulation. 2004;109(2):


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