תרופות נוגדות קרישה וטסיות בחולים העוברים צנתור כלילי התערבותי

  • View
    43

  • Download
    0

Embed Size (px)

DESCRIPTION

. ' " , . 3 Major systems involved in thrombosis and hemostasis. Vessel wall Endothelium Platelets Coagulation cascade. - PowerPoint PPT Presentation

Transcript

  • ' " ,

  • 3 Major systems involved in thrombosis and hemostasisVessel wallEndothelium

    Platelets

    Coagulation cascade

  • Anti-platelet and Anti-coagulant Properties of the EndotheliumCovers highly thrombogenic basement membrane (collagen, TF). Uninjured endothelium does not bind platelets

    NO from uninjured endothelium inhibit platelet aggregation and adhesion, PGI2 (prostacyclin) inhibits platelet aggregation

    TFPI tissue factor pathway inhibitor released from endothelial cells

    Endothelial cells produce t- PA which activates fibrinolysis via plasminogen to plasmin

  • Platelet AdhesionPlatelets are the first cells to adhere to injured vascular wall (subendothelium)

    Adhesion is mediated by vWF

    Binding occurs only under high shear stress conditions !

  • Platelet Activation(Plasma)(Plasma)(released from activated cells) (ECM)

  • Platelet Aggregation1. Kuwahara M et al. Arterioscler Thromb Vasc Biol 2002; 22: 32934.FIRM, BUT REVERSIBLEADHESIONIRREVERSIBLEADHESIONScanning electron micrograph of discoid, dormant plateletsActivated, aggregating platelets illustrating fibrin strands

  • 3 Major systems involvedVessel wallEndothelium

    Platelets

    Coagulation cascade

  • FibrinogenFibrinThrombinProthrombinXaVaVIIaTFExtrinsic PathwayIXaVIIIaXIaXIIaIntrinsic pathwayXIIIaSoft clotFibrinHard clotClassic Coagulation Cascade

  • Classic Coagulation CascadeRosenberg et al NEJM 19994 major Anti-thrombotic Pathways (TFPI, Prot C/S,ATIII, Plasmin)Localization to sitesof vascular injury.Protease complexes assemble on PLmembranes of activated platelets,endothelial cells andmonocytes. (The coagulationcascade occurs veryslowly in fluid phaseplasma and withresting cells)

  • From Classic to Current View

  • Current View of the Coagulation SystemInitiation by vessel wall injury which exposes blood to cells with TF on their surface TF/FVIIa activates FX Xa + Va cleaves II small amounts of IIa (thrombin)

    Minute amounts of thrombin produced initially than lead to a marked increase in activation of FXI, FIX, FVIII, FV and marked generation of thrombin.

    Priming invloves adherence and activation of platelets.The small amounts of initial thrombin activates platelets release of FV + PL surface for protease activation

    Propagation an explosive increase in thrombin generation mediated by the classic intrinsic system FXI, FIX Fxa/VIIIa/Va on activated platelets IIa + fibrin formation

    Schneider D et al, Circulation 2007

  • The Great BalanceThrombotic ComplicationsBleeding Complications

  • Mortality (%)Days from Randomization03060901201501802102402703003303603900515301025201 year EstimateSignificance of bleeding: Impact of MI and Major Bleeding (non-CABG) in first 30 Days on Risk of Death Over 1 Year28.9%12.5%8.6%3.4%ACUITY 1 year

  • Courtesy of Dr S. Steinhubl, U. Kentucky

  • Aspirin in Acute Myocardial Infarction: ISIS-2 (Lancet 1988;2:349-60)

  • Aspirin in the Treatment of ACSWallentin LC, et al. JACC 1991;18:1587-93.036912MonthsProbability of Death or MIPlaceboAspirin 75 mgRisk ratio 0.52 95% CL 0.37-0.72

  • Comparison of ASA Doses on Vascular Events in High-Risk Patients*Odds reduction. Treatment effect P
  • Clopidogrel

  • Efficacy of anti-platelet agents in reducing coronary events after stentingCumulative event rate (%)

  • CURE TRIAL ACS pts 20 % reduction in primary endpoint (N Engl J Med. 2001;345:494-502)

  • PCI-CURE TRIAL ACS pts Pretreatment with clopidogrel vs. no pretreatmentReduction in CV death, MI or urgent TVRCURE Investigatots, Lancet 2001 358: 527-33

  • Distribution of Response to Clopidogrel (544 patients, platelet aggregation)Change in Aggregation to 5M ADPNumber of patients0163248648096112
  • PLATELET FUNCTION ASSAYS REVEALE EXTREME INTER-PATIENT VARIABILITY*Courtesy of Aradi, Collet. * After 600 mg clopidogrel loading dose, in patients with stable angina undergoing PCI

  • ADAPT-DES: DEFINITE / PROBABLE ST @ 30 daysStone et al, Lancet 2013

  • Low response to clopidogrel in patients with ACS: RECLOSE-2P=0.003P
  • Prasugrel: Active Metabolite FormationFaster Onset of IPANSOCH3COFPrasugrelPro-drugHepatic Metabolism Cytochrome P450Active MetaboliteSem Vasc Med 3:113, 2003Pre-hepatic metabolism - Hydrolysis Esterases in blood O85% Inactive Metabolites (hydrolysis)Clopidogrel

  • ********Prasugrel 10 mg MD vs. Clopidogrel 75 mg MD: Higher IPA During Maintenance Dosing mean SEM 20 M ADPInhibition of Platelet Aggregation (%)020406080100Loading DoseMaintenance DosesTimeHoursDays0.250.512462434567890Clop 300 mgClop 75 mg !!* P
  • CABG=Coronary Artery Bypass Graft surgery; CV=Cardiovascular; MI=Myocardial Infarction; TIMI=Thrombolysis In Myocardial InfarctionPrasugrel ClopidogrelTRITON-TIMI 38: Rates of Key Study End Points (13,500 pts with ACS)Wiviott SD et al. New Engl J Med 2007;357:2001-20155101500306090180270360450Days After RandomizationEnd Point (%)1201.8 (111)2.4(146)Non-CABG TIMI Major Bleeds CV Death, MI, StrokeP=0.03P
  • TRITON-TIMI 38: ARC Definite/Probable Stent Thrombosis:ARC=Academic Research Consortium; ARR=Absolute Risk Reduction; HR=Hazard Ratio; NNT=Number Needed to Treat; PCI=Percutaneous Coronary Intervention; RRR=Relative Risk ReductionWiviott SD et al. Lancet 2008;371:1353-1363 HR 0.48 (0.36-0.64) P
  • ACS=Acute Coronary Syndrome; CABG=Coronary Artery Bypass Graft surgery; HR=Hazard Ratio; TIMI=Thrombolysis In Myocardial InfarctionP=0.002Odds Ratio 4.73 P
  • Bleeding Risk SubgroupsTherapeutic ConsiderationsSignificant Net Clinical Benefit with Prasugrel 80%Reduced MD Guided by PK Age > 75 or Wt < 60 kg16%Avoid Prasugrel Prior CVA/TIA4%TRITON-TIMI 38, NEJM 2007

    Chart1

    16

    4

    80

    Sheet1

    Age >=75Wgt < 60 kgNo Bleeding Risks

    16480

  • TRITON-TIMI 38: Diabetic Subgroup Analysis (n=3,146)CABG=Coronary Artery Bypass Graft surgery; CV=Cardiovascular; HR=Hazard Ratio; MI=Myocardial Infarction; NNT= Number Needed to Treat; TIMI=Thrombolysis In Myocardial InfarctionAdapted from Antman EM et al. American Heart Association Scientific Sessions; 2007, Nov 4-7; Orlando, FL 0246810121416180306090180270360450HR 0.70 P
  • TRITON-TIMI 38: STEMI Subgroup Analysis (n=3,534)P=0.05P=0.045P=0.01P=0.01P=0.4

  • Ticagrelor (AZD 6140): an oral reversibleP2Y12 antagonistTicagrelor is a cyclo-pentyl-triazolo-pyrimidine (CPTP)Direct acting Not a prodrug; does not require metabolic activationRapid onset of inhibitory effect on the P2Y12 receptorGreater and more consistent inhibition of platelet aggregation versus clopidogrelReversibly boundDegree of inhibition reflects plasma concentrationFaster offset of effect than clopidogrel Functional recovery of all circulating platelets

  • Time (hours) Onset Maintenance Offset1009080706050403020100 IPA % 0 .5 1 2 4 8 24 6 weeks 0 2 4 8 24 48 72 120 168 240Onset / Offset Study, IPA to 5uM ADP Gurbel PA et al. Circulation 2009

  • PLATO study primary efficacy event - CV death, MI or stroke (18,600 pts with ACS)No. at riskClopidogrelTicagrelor9,2919,3338,5218,6288,3628,4608,124Days after randomisation6,7436,7435,0965,1614,0474,147060120180240300360121110987654321013Cumulative incidence (%)9.811.78,219HR 0.84 (95% CI 0.770.92), p=0.0003ClopidogrelTicagrelorK-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval

  • K-M estimates of time to secondary efficacy endpointsNo. at riskClopidogrelTicagrelor9,2919,3338,5608,6788,4058,5208,177Days after randomisation6,7036,7965,1365,2104,1094,19106012018024030036065432107Cumulative incidence (%)ClopidogrelTicagrelor5.86.98,279HR 0.84 (95% CI 0.750.95), p=0.005060120180240300360643210ClopidogrelTicagrelor4.05.1HR 0.79 (95% CI 0.690.91), p=0.001759,2919,3338,8658,2948,7808,8228,589Days after randomisation707971195,4415,4824,3644,4198,626Myocardial infarctionCardiovascular death !!!Cumulative incidence (%)

  • Stent thrombosisEvaluated in patients with any stent during the studyWallentin et al, N Engl J Med 2009P=0.01P=0.02%

  • Major bleeding primary safety event No. at riskClopidogrelTicagrelor9,1869,2357,3057,2466,9306,8266,670Days from first IP dose5,2095,1293,8413,7833,4793,433060120180240300360105015ClopidogrelTicagrelor11.2011.586,545HR 1.04 (95% CI 0.951.13), p=0.434K-M estimated rate (% per year)

  • Non-CABG and CABG-related major bleedingp=0.026p=0.025NSNS9K-M estimated rate (% per year)Non-CABG PLATO major bleeding876543210Non-CABG TIMI major bleedingCABG PLATO major bleedingCABG TIMI major bleeding4.53.82.82.27.47.95.35.8TicagrelorClopidogrel

  • Dyspnoea with TicagrelorTicagrelor-related dyspnoea is usually mild or moderate in intensity, self-limiting and does not appear to be associated with differences in any efficacy or safety outcomes with ticagrelor compared with clopidogrel therapy in ACS pts.

    Storey et al, Eur Heart J 2011

    All patientsTicagrelor(n=9,235) Clopidogrel(n=9,186)p value*Dyspnoea, % Any Requiring discontinuation of study Rx 13.80.97.80.1

  • PLATO STEMI - Primary endpoint: CV death, MI or stroke01234567891011121211109876543210MonthsHR: 0.85 (95% CI = 0.740.97), p=0.02No. at riskClopidogrelTicagrelor4,2294,2013,8923,8873,8233,8343,7303,0223,0112,3332,2971,8681,8913,73211.09.3ClopidogrelTicagrelorK-M estimated rate (% per year)Steg et al, Circulation 2010

  • PLATO STEMI - All cause mortality012345678910111276543210K-M esti