ANTIPLATELET TREATMENTS JL DAVID Unité Thrombose- Hémostase CHU Liège 1
INDICATIONS OF ANTIPLATELET DRUGS. Ischemic stroke TIA. unstable / stable amgina myocardial infarction percutaneous coronary intervention ( stenting ) Coronary Artery By-pass Graft. peripheral arterial disease 2
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IMPACT OF ANTIPLATELET DRUGS. COX-1 prostaglandins synthesis Aspirine and other anti-cox 1. thromboxane receptor. P2Y12 - ADP receptor Ticlopidine, Clopidogrel. GPIIb-IIIa receptor Abciximab / Integrilin / Fibans ( Tiro-, Frada-, Lami- ) 4
METABOLISM OF ASA 1/ rapid absorbtion in stomach and upper small intestine ( enteric form intestine ) partial déacétylation fasting: 30-60 min. / post-prandial : +/- 2h 2/ into contact with platelets in portal circulation contact ASA platelets irreversible inhibition of TXA2 synthesis 3/ deacetylation in liver and in plasma : half-life of ASA 15-20 min. salicylic acid : no antiplatelet effect 5
PHARMACOLOGICAL PROPERTIES OF ASA irreversible inhibition of COX-1 CH 3 -OH Ser 529 - polypeptide PGH synthase no inhibition of Hydroxyperoxydase prevention of TXA2 production inhibition of. Endothelin ETA receptor platelet aggregation vasoconstriction. T cells adhesion and transmigration on endothelium. NFκB activation including that induced by Chlamydia pneumoniae on EC 6
DURATION OF THE ANTIPLATELET EFFECT OF ASA irreversible inhibition of platelets 8-10 d production of new platelets depending on consumption 10 % / d reappearance of thrombotic risk recovery of hemostatic potential 2 d 3-4 d 7
METABOLISM OF ARACHIDONIC ACID 8
INHIBITION OF PROSTACYCLINE BY ASA. acetylation of platelet COX -1 in portal circulation. half-life ½ de l ASA in circulation 20 min impact of ASA in portal > systemic circulation. de novo synthesis of endothelial COX-1 transient inhibition of PGI2 production = no reduction of urinary 6-kéto PGF1a / 24 h ( Inhibition dose-dependent?) 9
LIMITS OF THE ANTITHROMBOTIC EFFECTS OF ASA ASA is a antiplatelet agent blocking only TXA2 dependent aggregation. no inhibition of platelet adhesion. no or poor inhibition of platelet aggregation induced by strong stimuli. very weak inhibition of COX-2 inductible following inflammatory and mitogen stimuli 10
RISK FACTORS OF ATHEROTHROMBOSIS > 65 years old * overweight * smoking hypertension * diabetes * hypercholestérolemia* LDL / hypo- HDL hyperhomocysteinemia inflammatory diseases familal history of premature myocardial infarction* * criteria of PPP 11
PRIMARY PREVENTION Studies end-point RR CI 95% PHS 1989 IM 0,56 0,45-0,70 Meta-anal. 2001 CV 0,85 0,78-0,94 PPP 2001 CV 0,77 0,62-0,95 mort. CV 0,56 0,31-0,99 12
INDICATIONS OF ASA FOR PRIMARY PREVENTION Eur.Soc. Hypert.-Eur. Soc. Card.2003 hypertension (controlled ) in > 50 years old and risk of CV event or creatinine > 1.3 mg/dl Am.Diab. Ass 2002 diabetes and 30 y.o. or add.cv risk High risk of CV event > 3% (Eu) or >/=10% (USA) 13
SECONDARY PREVENTION BY AA 135.640 pts at high risk ( > 3% /y ) : AMI, UA,SA, past-mi, IS, TIA, PAD, FA RRR vasc. event -1/4 nonfatal IM - 1/3 non fatal stoke - 1/4 vascular death - 1/6 Antithrombotic Trialist Collaboration 2002 14
SECONDARY PREVENTION traitement abs.reduction / 1000 MI 2 y - 36 MI 1 mo - 38 stroke/ TIA 2 y - 36 stroke 1 mo - 9 stable angin. 2 y - 22 periph art.. atr. fibrill. 15
ASA DOSES acute event prevention 160-200 mgr 75 150 mg / daily 325 mg every other day enteric form 90% bioavailable additive dose- dépendent effect 30-50 mg / 24 h Interference with Ibuprofen, Naproxen,.! 16
ASA IN WOMEN Secondary prevention ASA effective in both sexes but benefit related to CV risk Primary prevention ( Women s Health study) ASA 100 mg /alt.day vs placebo 10 years in 39.876 women >/= 45 y.o. major CV events - 9 % strokes - 17 % isch. strokes - 24 % MI ns except in sub-group >/= 65 y.o CV deaths ns Ridker et al. NEJM 2005 352 1293-1304 17
ASA and SEX Women s Health Study (ASA 100mg / alt.d) Physician s Health Study ( ASA 325 mg /alt.d) In the placebo group rate / 100.000 p/yr MI 97.3 439.7 stroke 134.3 179.4 ratio MI/ stroke 0.72 2.45 18
RESISTANCE TO ASPIRIN. clinical trials ASA treatment is statistically effective but no apparent prevention in a great number of patients. ex vivo tests aggregometry, PFA, P-selectin expression, insufficient effect in 5.5-9.8 % to 36-60 % of the treated patients depending on the population studied, the assay utilized and the criteria of resistance McKee SA et al. Thromb Haemost 2002 88 711-5 19
RESISTANCE TO ASPIRIN : WHAT DOES IT MEAN? Relationship between ex-vivo testing of some pharmacological effects and the clinical issue? Need for increasing the dosage or for shifting to an alternative treatment? 20
CLINICAL OUTCOME OF PATIENTS WITH RESISTANCE TO ASA Aspirin treated patients in case-control study from HOPE trial urin. conc. of 11-dehydroTXB2 OR for MI, stroke or CV death p upper/ lower quartile 1.8 (1.2-2.7 ) 0.009 OR for MI upper quartile 2 ( 1.2-3.4 ) 0.006 OR for CV death upper quartile 3.5 (1.7-7.4 ) < 0.001 Eickelboom JW et al. Circulation 2002 105 1650-55 21
POSSIBLE CAUSES OF RESISTANCE TO AAS Extrinsic mechanisms. hyperstimulation of platelets hyperreactive platelets ( increased turn-over). insufficient dosage lack of information about individual dose-effect relationship. interference with other inhibitors of COX-1 ( ibuprofen,..) McKee S.A et al. Thromb Haemost 2002 88 711-5 Haluska MK and Halushka PV Circulation 2002 105 1620-22 22
Intrinsic mechanisms POSSIBLE CAUSES OF RESISTANCE TO AAS. bypass of inhibited platelet COX-1 by PGH2 shunted into platelets from nucleated cells in which COX-1 has been regenerated. induction of COX-2 insensitive to ASA in platelets, monocytes and macrophages allowing for TXA2 production. polymorphism of COX-1 affecting the response to ASA. other polymorphism(s) regulating platelet activity. expression of COX-2 messenger RNA (controversial). PLA2 allele greater affinity of GPIIbIIIa receptor for fibrinogen McKee S.A et al. Thromb Haemost 2002 88 711-5 Haluska MK and Halushka PV Circulation 2002 105 1620-22 23
AGGREGATING EFFECTS OF ADP ADP released from activated platelets, red cells, EC platelet receptors tyrosine phosphorylation of proteins P2Y1 Gq protein PLc activation Ca release aggregation P2Y12 Gi2 protein adenylcyclase inhibition camp full aggregation and release amplification of the response to other agonists and recruitment of other platelets 24
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PHARMACOLOGICAL PROPERTIES OF THIENOPYRIDINES Ticlopidine Clopidogrel (T carboxy methylated in benzilic position ) active metabolite covalent modification of the receptor P2Y12 inhibition of. ADP binding GPIIbIIIa activation fibrinogen binding bridges between platelets. P- selectin expression of platelets platelet - monocyte / platelet - neutrophil conjugate formation Storey et al. Thromb Haemost 2002 88 488-94 26
Muller I et al. Heart 2001 85 92-95 27
CAPRIE Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events Clopidogrel 75 mg/j vs ASA 375 mgr/j 19185 pt for 1,91 years. IS in the past 6 mo. MI within 35 days of randomization. APAD annual composite risk = MI, IS, vascular death 28
CAPRIE Clopidogrel vs ASA history of annual risk (%) selected sub-groups p IS - 7.3 0.26 MI + 3.7 0.66 PAD - 23.8 0.0028 total - 8.7 % ( IC 95% 0.3-16.5) 5.83 % 5.32 % 29
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CAPRIE clopidogrel vs ASA Reduction in composite IS-MI-VD or re-hospitalization for ischemia or bleeding RRR (%) ARR (%) NTT Total 7.9 1.1 91 previous CABG 28.9 6.4 16 >/= 1 isch.event 10 2 50 mult.vasc.beds 12.4 2.45 41 diabetes 12.5 2.1 48 insulin-dep. 16.7 3.8 26.3 hypercholesterolemia 9.7 1.3 77 31
CURE Clopidogrel in Unstable angina to prevent Recurrent Events 12.562 pt previously treated by AAS by 3-12 mo </= 100 or 101-<200 or >/=200 mg/ d within 24 h of symptom onset of ACS without - ST elevation : + placebo vs + clopidogrel 300mg then 75 mg/d composite risk = MI, IS, CVD 32
CURE ASA mg/d + placebo % + clopidogrel % RRR IC 95% 300 mg 75mg/d 75-100 10,5 8,6 0,81 0.68-0.97 101< 200 9,8 9,5 0,97 0.77-1.22 325 13,6 9,8 0,71 0.59-0.85 ASA. no more protective effect > 100 mg/j. bleeding risk hémorragique related to dose Clopidogrel. significant benefit for 12 mo greatest in patients with high TIMI high score or previous revascularization ( RRR 45%). increased risk of bleeding 33
PCI CURE Percutaneous Coronary Intervention - Sub group of 2.658 pts from CURE PCI 1/ pretreatment clopidogrel 300 mg vs placebo + AAS 75 à 325 mg 2/ post - PCI ( stents 80%) clopidogrel 75 mg / d + AAS for 2-4 weeks 3/ then clopidogrel 75 mg / d vs placebo CVD, IM after +/- 8 mo 34
PCI CURE placebo % clopidogrel % RRR p 30 d 59 (6,4) 38 ( 2,9) 0,66 ( 0,44-0,99 ) 0.04 8 mo 108 ( 8 ) 79 (6 ) 0,75 ( 0,56-1 ) 0.047 pré-post 169 (12,6) 116 (8,8) 0,69 ( 0,54-0,87) 0.002 35
CURE and PCI-CURE AAS (%) ASA + Clopidogrel (%) RRR ARR NNT CURE 11,4 9,3 20 2,1 48 PCI-CURE 12,6 8,8 31 3,8 26 36
ENHANCED RISK REDUCTION WITHCLOPIDOGREL Subgroups might be more responsive to clopidogrel than to ASA CAPRIE not pre-specified overestimation? previous CABG history of >/= 1 ischemic event involvement of multiple vascular beds diabetes hypercholesterolemia CAPRA patients with atherosclerosis are at much higher risk compared with those enrolled in clinical trials such as CAPRIE more likely to derive benefit CURE not pre-specified overestimation high TIMI risk score history of revascularization PCI-CURE prespecified from CURE 37
CREDO Clopidogrel to Reduce Events During Observation 2.116 pts pré-pci post-pci 28j 12 mo Gp 1 clopid.300 clopid. 75 mg/d clopid. 75 mg/d + ASA 81-325 mg/d ASA 75 325 mg/d Gp2 - clopid. 75 mg/d - + ASA 75-325 mg/d ASA 81-325 mg/d composite risk of death MI, stroke 38
CREDO Composite risk of death, MI, stroke Gp1 Gp2 RRR % IC 95% p 8,5 11,5 26,9 3,9-44,5 0.02 39
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PLATELET GP RECEPTORS ( Integrins ) ADHESION GP Ib / IX / V vwf GP VI collagen GP Ia/ IIa collagen AGGREGATION GPIIbIIIa fibrinogen binding (defect in Glanzmann s thrombasthenia) = complex cross-talking between the various integrins 41
STRUCTURE AND PROPERTIES of GP IIb IIIa INHIBITORS Abciximab ( ReoPro) Fab fragment of a humanized murine mab (c7e3) also recognizing the vitronectin receptor αvβ3 (EC ; SMC) and the leucocyte integrin αmβ2 Tirofiban ( Aggrastat ) small mol.weight synthetic non-peptide ( tyrosine derivative) containing the RDG sequence of fibrinogen (= 2 binding sequences) Eptifibatide ( Integrilin ) cyclic synthetic heptafibatide containing the KGD sequence of fibrinogen ( = 1 binding sequence) 42
PHARMACODYNAMICS OF GP IIb IIIA INHIBITORS During infusion equilibrium between platelet receptors ( pl. number ) and plasma according to the affinities for platelet GPIIb IIIa / plasma half-life KD in nm min. abciximab 5 10-30 tirofiban 15 120 eptifibatide 120 150 43
PHARMACODYNAMICS OF GP IIb IIIa INHIBITORS After the end of infusion delay of functional recovery of platelets. abciximab 12-36 h but detectable bound to platelets more than 2 weeks. tirofiban 30 min - 4 h. eptifibatide idem 44
OPTIMAL DOSES OF GPIIbIIIa INHIBITORS For an optimal efficiency in Acute Coronary Intervention a high and sustained level of receptor blockade is required > 80 % ( determined in animal experiences) > 90% : high risk of bleeding! 45
BENEFICIAL PROPERTIES OF GPIIbIIIa INHIBITORS AT THERAPEUTIC LEVEL ANTITHROMBOTIC PROPERTIES. inhibition of the final common pathway of platelet aggregation fibrinogen and vwf binding to GPIIbIIIa complex. inhibition of platelet procoagulant activities prothrombinase / platelet - derived microparticules. inhibition of phenotypic resistance to APC by activated platelets 46
BENEFICIAL PROPERTIES OF GPIIbIIIa ANTAGONISTS AT THERAPEUTIC LEVEL ANTIINFLAMMATORY PROPERTIES. suppression of CD 40 L expression by platelets. suppression of platelet- leucocytes aggregates. blunting of the raise of CRP, IL6, TNFα occurring 24-48 h after PCI 47
SIDE-EFFECTS OF GPIIbIIIa INHIBITORS AT SUB -THERAPEUTICAL DOSAGE. partial agonist effect ( platelet escape ). increase of CD 40 ligand able to mediate GPIIbIIIa binding. increase of P-selectin expression worse outcome in PCI 48
OPTIMAL TIMING FOR INITIATION OF GPIIbIIIa INHIBITORS ISAR- COOL In patients with UA ( - ST depression or elevated troponin T level ) treated by an intense antiplatelet treatment ( ASA + Clopidogrel + Tirofiban) and Heparin, deferral of intervention ( 3-5 days ) vs less than 6 hours does not improve the composite 30 days incidence ( large non fatal MI or death from any cause) RR 1. 96 p 0.04 in favour of early intervention Neumann et al. JAMA 2003 290 1593-99 49
THROMBOCYTOPENIA DUE TO GPIIbIIIa ANTAGONISTS.Thrombocytopenia due to GP IIbIIIa antagonist < 50.000 to < 20.000 platelets / µl onset from 1 h ( within 24h ) to days after exposure to abciximab 0.4-1 % * tirofiban 0.1-0.3 eptifibatide 0-0.2 lamifiban 0-0.1 Control of platelet count : within the first 2-4h after the onset of the treatment and at least daily during treatment Lincoff et al. J Am Coll Card 2000 35 1103-15 Diff.diagnosis:.EDTA-induced pseudothrombocytopenia corrected in citrated blood.heparin-induced thrombocytopenia 50