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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 Unstable plaques activate platelets
Fissure or Rupture Platelet Adhesion Platelet Activation Platelet Aggregation Platelets are recognized to play an integral role in acute coronary syndromes and arterial thrombosis. After plaque fissure or rupture, there is platelet adhesion and activation. This leads to platelet aggregation within the coronary artery, and ultimately partial or complete occlusion of the coronary artery. Thrombotic Occlusion

5 Adhesion mediated by vWF, agonists like ADP, secreted granules and TXA2 cause aggregation, exposed GPIIbIIIa receptors crosslink with fibrinogen to form platelet aggregates 1 Adhesion 3 Aggregation Scanning electron microscope photographs showing platelet adhesion and activation (left photo) and early platelet aggregation (right photo) 2 Activation Reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at:

6 THROMBUS SMOOTH MUSCLE CELL 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 new location (after 27 months) Restenosis (after 19 months) 48% Stent thrombosis (after 9 months) 40% Alexopoulos D. Am Heart J 2010; 159:

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

10 GP IIb/IIIa antagonists
Blocking different pathways for additional clinical benefit: Clopidogrel Prasugrel Cangrelor Heparin, hirudin Epinephrine Collagen ADP 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 minutes after oral administration Large dose over 10 gr eicosapentaenoic acid also blocks TXA2

12

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

14 Thienopyridines 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

17

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

19 Is Aspirin Resistance Clinically Significant?
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 ! Circulation 2002, 105: 1650 JACC 2003:41; 961

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 40 37% 35 30 26% No resistance ASA resistance CLOPI resistance Dual resistance 25 Percentage 20 15 10 5 Periprocedur.MI Ischaemic events within 30 days Eshtehardi P, Am Heart J 2010; 159:

21 Routine assessment of platelet aggregation not recommended (II-B)
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 % 5.5 % RESISTANT 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:

22 600 mg clopidogrel loading is faster and more effective !
*P=0.01 ** P=0.02 ‡ P=0.0008 20 40 Aggregation inhibition (%) ** * The objective of this study was to determine the response to a 300 mg clopidogrel loading dose versus a 600 mg loading on the course of aggregation and inflammation suppression. 12 healthy volunteers were given 300 mg of clopidogrel and blood samples were obtained 2, 4, and 6 hours later. After a 2-week washout period, the subjects were given 600 mg clopidogrel and blood samples were drawn again. These data demonstrate that the higher loading dose of 600 mg of clopidogrel works much more rapidly to suppress platelet inflammatory markers.1 1. Zidar F, Moliterno D, Bhatt D, Kottke-Marchant K, Goormastic M, Plow E, Topol E. High-dose clopidogrel loading rapidly reduces both platelet inflammatory marker expression and aggregation. J Am Coll Cardiol. 2004;43:5-suppl A;Abstract 60 * Clopidogrel, 300 mg Clopidogrel, 600 mg ** 80 2 4 6 Hours Zidar F, et al. J Am Coll Cardiol. 2004;43(5, suppl A);Abstract

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 Clopidogrel standard 15% RRR 0.04 Clopidogrel double 0.03 Cumulative hazard 0.02 HR 0.85 95% CI: 0.01 p=0.036 0.00 3 6 9 12 15 18 21 24 27 30 Days

25 Platelet aggregation inhbition (%)
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 25

26 TRITON-TIMI 38: 13608 patients with ACS
Prasugrel 60 mg LD/ 10 mg MD ASA UA/NSTEMI (TIMI Risk Score ≥ 3) 12.0 month planned median R & Planned PCI Double-blind treatment months planned follow-up 14.5 month actual median STEMI (Primary PCI ≤ 12 hours of symptoms or post-STEMI within 14 days) ASA Day 3 Clopidogrel 300 mg LD/ 75 mg MD THIS SLIDE HAS BEEN THROUGH QUALITY REVIEW Wiviott: Wiviott: 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: ; Wiviott SD et al. Am Heart J 2006;152: 1Wiviott SD et al. NEJM 2007;357: 2Data on File, Eli Lilly and Company / Daiichi Sankyo, Inc (H7TJAN2008A) Wiviott SD et al. Am Heart J 2006;152: 4Antman EM et al. JAMA 2000;284:835-42 26 26

27 TRITON TIMI-38: CV death, NF MI, or NF stroke TIMI major bleeding
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: ) p<0.001, NNT 37 10 Endpoint (%) 8 Prasugrel 8.3% 6 TIMI major bleeding 4 HR 1.24 (95% CI: ) p=0.17, NNH 222 Prasugrel 1.9% 2 Clopidogrel 1.5% 30 90 180 270 360 450 Days Wiviott SD et al. Circulation 2010;122:

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

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 Environment Genetics Proteome Phenotype 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 Primary end point End point High-dose clopidogrel (%) Standard-dose clopidogrel (%) HR (95% CI) p Cardiovascular death/MI/stent thrombosis 2.3 1.01 ( ) 0.98 Bleeding results Outcome High-dose clopidogrel (%) Standard-dose clopidogrel (%) p GUSTO severe/moderate bleeding 1.4 2.3 0.10 Any GUSTO bleeding 12.0 10.2 0.18 Percentage of patients with persistently high platelet reactivity at 30 days Platelet reactivity units High-dose clopidogrel (%) Standard-dose clopidogrel (%) p >230 62 40 <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

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

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

38 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%* PRISM-PLUS 12.0% (*) 8.7% († ) 13.6%* PARAGON-A 11.7% (l) 10.3% (h) 12.3% PURSUIT 15.7% (l) 13.4% (h) 14.2% PARAGON-B 11.4% 10.6% GUSTO-IV 8.0% (24h) 8.2% (48h) 9.1% Overall 11.8% 10.8%t High risk Diabetic - ASA use on admission 1.0 2.0 Gp IIb/IIIa iyi Placebo iyi P=.015 Boersma E, et al. Lancet. 2002;359: References Boersma, E. et al. Platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes: a meta-analysis of all major randomized clinical trials. Lancet. 2002;359:

39 PRISM-PLUS: Thrombus size
10 20 30 40 50 Odds Ratio: 0.77 P=0.022 Probable Probable Small Cumulative (%) Small Medium 24.1% Shown here is data from PRISM-PLUS of the analysis of thrombus grade, classified as possible, small, moderate, large thrombus or a recent total occlusion. There was an overall reduction in thrombus burden with tirofiban plus heparin compared with heparin alone; the odds ratio was 0.77, which was statistically significant (P=0.022). The incidence of definitive thrombus (grades moderate to recent total occlusion), was reduced from 24.1% in patients receiving heparin to 17.1% in patients receiving tirofiban plus heparin.1 1. Zhao XQ, Theroux P, Snapinn SM, Sax FL. Intracoronary thrombus and platelet glycoprotein IIb/IIIa receptor blockade with tirofiban in unstable angina or non-Q-wave myocardial infarction. Angiographic results from the PRISM-PLUS trial (Platelet receptor inhibition for ischemic syndrome management in patients limited by unstable signs and symptoms). PRISM-PLUS Investigators. Circulation. 1999;100: Medium 17.1% Big Big Occlusion Occlusion Tirofiban + Heparin (n=608) Heparin (n=622) Circulation. 1999;100:

40 ACUITY, timing GP IIb/IIIa at the time of PCI vs. upstream in everyone
Routine Upstream Deferred PCI GP IIb/IIIa GP IIb/IIIa (N=4,605) (N=4,602) Overall exposure 98.3% 55.7% Rand. to angio/interv (h) 6.2 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: 40

41 TARGET: Benefit of triple antiplatelet therapy
6 months death/MI Clopidogrel and tirofiban 18 16 14 12 10 8 6 4 2 Clopidogrel and abciximab No clopidogrel only tirofiban No clopidogrel only abciximab 15.5% 10.9% Patients (%) 8.4% 7.2% This graph from TARGET demonstrates that triple anti-platelet drug therapy during PCI is associated with improved outcomes. Patients who received aspirin and a GP IIb/IIIa inhibitor and were pre-treated with clopidogrel had markedly reduced mortality rates compared with those patients who were not pre-treated with clopidogrel.1 1. Chan A, Moliterno D, Berger P, Stone G, DiBattiste P, Yakubov S, Sapp S, Wolski K, Bhatt D, Topol E for the TARGET Investigators. Triple antiplatelet therapy during percutaneous coronary intervention is associated with improved outcomes including one-year survival. Results from the Do Tirofiban and ReoPro Give Similar Efficacy Outcome Trial (TARGET). J Am Coll Cardiol. 2003;42: Days Chan A, et al. J Am Coll Cardiol. 2003;42:

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

43 Antithrombotic treatment options in myocardial revascularisation: STEMI
Antiplatelet therapy Classa Levelb ASA I B Clopidogrelc (with 600 mg loading dose as soon as possible) C Prasugreld Ticagrelord + GPIIb–IIIa antagonists (in patients with evidence of high intracoronary thrombus burden) Abciximab IIa A Eptifibatide Tirofiban IIb Upstream GPIIb–IIIa antagonists III Anticoagulation Bivalirudin (monotherapy) UFH Fondaparinux 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 therapy Classa Levelb ASA I C Clopidogrelc (with 600 mg loading dose as soon as possible) Clopidogrelc (for 9–12 months after PCI) B Prasugreld IIa Ticagrelord + GPIIb–IIIa antagonists (in patients with evidence of high intracoronary thrombus burden) Abciximab (with DAPT) II Tirofiban, Eptifibatide Upstream GPIIb–IIIa antagonists III 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
Warfarin vs placebo Warfarin vs low dose Warfarin Warfarin vs ASA Warfarin vs ASA + clopidogrel 0.3 0.6 0.9 1.2 1.5 1.8 2.0 Warfarin better Other better Camm, ESC 2009

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

48

49 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% On the basis of these observations we have formulated several potential therapeutic considerations. 1. The 4% of patients with a prior stroke, shown in red are at increased risk for bleeding and had worse outcomes--they should not receive prasugrel 2. Patients age >= 75 or with a weight < 60 kg, shown in yellow and representing 16% of the trial may benefit from a reduced MD to minimize bleeding. 3. The 80% of remaining patients had a significant net clinical benefit with prasugrel at 10 mg MD. 80% 49 49 49

50 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 D/MI/CVA/UTVR Troponin >3XULN Major + Minor Bleeding Widimsky P et al. Eur Heart J 2008;29: 50

51 Activated platelets express CD 40L triggering inflammation and thrombosis

52 ISAR-CHOICE Circulation 2005;112:2946

53 30th DAY DEATH / MI WITH GPI
18 Placebo GP IIb-IIIa Inhibitor 16.7 14.1 14 11.6 10.9 10.1 10.2 % Parients 9 10 5.9 6 4.8 3.9 3.6 1.8 2 EPIC CAPTURE EPILOG EPISTENT PRISM-PLUS PURSUIT 53

54

55 JUMBO - TIMI 26 (Phase II) PCI + Stent (n= 904) ASA 325 + % 70 GP2b/3a
Clopidogrel Prasugrel 300/75 40/7.5 60/10 60/15 Klopidogrel Prasugrel 300/75 40/7.5 60/10 60/15 % % Circulation 2005;111:3366

56 Variable Clopidogrel Response
At 5 Days UA Patients* (n = 32) Nonresponders 22% Responders 47% Individual variability of platelet inhibition after aspirin or clopidogrel administration has been reported. In addition, aspirin and clopidogrel resistance has been reported due to their variable response across patients. In this study by Lau and colleagues, clopidogrel response was compared between UA patients (n = 32) and healthy volunteers (n = 25). Among healthy volunteers, 16% were nonresponders, 12% were low responders, and 72% were responders to clopidogrel administration. Among UA patients, 22% were nonresponders, 32% were low responders, and 47% were responders. In this study, a majority of patients (54%) were either nonresponders or low responders. This study demonstrates the importance of administering alternative antithrombotic therapies to reduce the incidence of thrombotic events that continue to occur for clopidogrel nonresponders and low responders despite oral antiplatelet therapy. Gurbel PA, et al. Circulation. 2003;107(23): ; Lau WC, et al. Circulation. 2004;109(2): ; Steinhubl SR, et al. Circulation. 2001;103(21): Low responders 32% *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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