קורס השתלמות לאחיות ו טכ נאים מחדרי צנתור תרופות נוגדות קרישה וטסיות בחולים העוברים צנתור כלילי התערבותי

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1 קורס השתלמות לאחיות ו טכ נאים מחדרי צנתור 06/2010 תרופות נוגדות קרישה וטסיות בחולים העוברים צנתור כלילי התערבותי בי""י ד"ר אלי לב מנהל שרות הצנתורים רבין מרכז רפואי ח השרון,

2 3 Major systems involved in thrombosis and hemostasis Vessel wall Endothelium Platelets Coagulation cascade

3 Anti-platelet Properties of the Endothelium Covers highly thrombogenic basement membrane (type IV 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

4 3 Major systems involved Vessel wall Endothelium Platelets Coagulation cascade

5 Platelets Adhesion Activation Aggregation

6 Platelet Adhesion Platelets are the first cells to adhere to injured vascular wall (subendothelium( subendothelium) Adhesion is mediated by vwf Binding occurs only under high shear stress conditions!

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

8 Platelet Aggregation Flowing disc-shaped platelet Rolling ball-shaped platelet Hemisphere-shaped platelet Spreading platelet FIRM, BUT REVERSIBLE ADHESION IRREVERSIBLE ADHESION Scanning electron micrograph of discoid, dormant platelets Activated, aggregating platelets illustrating fibrin strands 1. Kuwahara M et al. Arterioscler Thromb Vasc Biol 2002; 22:

9 Platelet Aggregation

10 3 Major systems involved Vessel wall Endothelium Platelets Coagulation cascade

11 Intrinsic pathway XIIa Classic Coagulation Cascade Extrinsic Pathway XIa IXa VIIIa Prothrombin Xa Va VIIa TF Fibrinogen Thrombin Fibrin Soft clot XIIIa Hard clot Fibrin

12 Classic Coagulation Cascade Enzymatic cascade (amplification) Several serine protease complexes Produced by liver (most) Several require Vit K (IIa( IIa, VIIa, IXa, Xa) Requires Ca 2+ Localized to site of injury Reversible (via production of plasmin)

13 Classic Coagulation Cascade Localization to sites of vascular injury. Protease complexes assemble on PL membranes of activated platelets, endothelial cells and monocytes. (The coagulation cascade occurs very slowly in fluid phase plasma and with resting cells) 4 major Anti-thrombotic Pathways (TFPI, Prot C/S, ATIII, Plasmin) Rosenberg et al NEJM 1999

14 The Great Balance Thrombotic Complications Bleeding Complications

15 Significance of Major Bleeding ACUITY Trial: bivalirudin vs. bivalirudin + GPIIb/IIIa inhibitors vs. heparin + GPIIb/IIIa inhibitors in 13,819 moderate-high risk ACS patients Major bleeding was an independent predictor of death at 30 days (OR 7.6!! 95% CI , P<0.0001) 8% 7% 6% 5% 4% 3% 2% 1% 0% P< P< day Death 30 day Stent Thrombosis Major Bleeding No Bleeding Manoukian et al, JACC 2007

16 An original package of Bayer Aspirin sold in the United States from Each pill is 5 grains, or ~ 325mg. Developed by Felix Hoffrman, Bayer Co., 1897

17 Courtesy of Dr S. Steinhubl, U. Kentucky

18 Early Citations Predicted the Value of Aspirin Therapy to Inhibit Platelet Aggregation we might use salicylic acid for the treatment of coronary thrombosis: it could do no harm and might well do good. Lancet 1948;1:965

19 Aspirin Usage In the US Today ,000,000 Americans receive chronic aspirin therapy for cardioprotection. Percentage of Use Heart Disease Arthritis Headache Body Ache Other

20 Antithrombotic Trialists Collaboration Overview of 195 randomized trials, including 212,000 patients (135,640 high-risk). Overall odds reduction 22%. % MI, Stroke or Vascular Death 21.4 Aspirin Control Acute Stroke Acute MI Prior Stroke/TIA Antithrombotic Trialists Collaboration. BMJ 2002; 324: Prior MI

21 Aspirin in Acute Myocardial Infarction: ISIS-2 (Lancet 1988;2:349-60) Cumulative Number of Vascular Deaths Placebo alone: 568/4300 (13.2%) Aspirin alone: 461/4295 (10.7%) Streptokinase alone: 448/4300 (10.4%) Streptokinase plus aspirin: 343/4292 (8.0%) Days From Randomization

22 Aspirin in the Treatment of ACS 0.25 Probability of Death or MI Placebo Aspirin 75 mg Risk ratio % CL Months Wallentin LC, et al. JACC 1991;18:

23 Aspirin in Primary Prevention Data from 5 randomized trials, with over 50,000 individuals, with doses of mg daily, 3-7 years f/u. 3 OR = Control Aspirin OR = Death or MI Hemorrhagic Stroke

24 ATT Collaboration Lancet primary prevention trials 12% proportional reduction in serious vascular events

25 Comparison of ASA Doses on Vascular Events in High-Risk Patients OR* Aspirin Dose No. of Trials (%) Odds Ratio mg mg mg <75 mg 3 13 Any aspirin * Odds reduction. Treatment effect P< ASA, acetylsalicylic acid. Antiplatelet Better Antiplatelet Worse Adapted with permission from BMJ Publishing Group. Antithrombotic Trialists Collaboration. BMJ. 2002;324:71-86.

26 CLOPIDOGREL (PLAVIX) A thienopyridine, inhibits ADP induced platelet aggregation The specific target of inhibition appears to be the P2Y 12 receptor Fewer side effects than ticlopidine

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

28 Pharmacokinetic properties Requires metabolism by the hepatic cytochrome P450-1A enzyme system to acquire activity Peak plasma concentrations of the main circulating metabolite, an inactive carboxylic acid derivative occur at 1 hour. Platelet inhibition effect of 600 mg bolus after hrs, of 300 mg bolus after 6 6 hrs

29 Clopidogrel metabolism

30 Efficacy of anti-platelet agents in reducing coronary events after stenting Cumulative event rate (%)

31 Stent Thrombosis

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

33 PCI-CURE TRIAL ACS pts Pretreatment with clopidogrel vs. no pretreatment Reduction in CV death, MI or urgent TVR CURE Investigatots, Lancet :

34 CLARITY TRIAL STEMI pts % with endpoint (CV Death, MI, Urgent Revasc) Placebo Odds ratio 0.80 (95% CI ) P=0.026 Days Clopidogrel % Sabatine et al. N Engl J Med 2005;352:

35 Distribution of Response to Clopidogrel (544 patients, platelet aggregation) Number of patients Variability in response due to several factors - one of the important ones is rate of drug metabolism by cyt. P <= -20 [-10,0] [11,20] [31,40] [51,60] [71,80] [91,100] Change in Aggregation to 5µM ADP Serebrauny V et al. JACC 2004

36 Impact of Clopidogrel Response on Stent Thrombosis 804 pts who had successful PCI with DES implantation Loaded with 600 mg clopidogrel,, platelet reactivity to ADP assessed hrs after loading 105 pts (13%) not responsive to clopidogrel ST incidence: 8.6% vs. 2.3% (non responders vs responders) P<0.001 ST non responders responders Buonamici et al, JACC 2007

37 S Prasugrel: Active Metabolite Formation Faster Onset of IPA 85% Inactive Metabolites (hydrolysis) O O N C C Cl O CH 3 Clopidogrel O CH 3 Pro-drug Pre-hepatic metabolism - Hydrolysis Esterases in blood O C CH 3 O Sem Vasc Med 3:113, 2003 O S S O N F Prasugrel O N F O S N Cl HOOC * HS O N Cl OCH 3 Hepatic Metabolism Cytochrome P450 Active Metabolite HOOC * HS O N F

38 Inhibition of Platelet Aggregation (%) Healthy Volunteer Crossover Study (n=68) Interpatient Variability N = 68 IPA (20 µm M ADP) at 24 H Clopidogrel 300 mg Brandt J et al. AHJ 2007 Clopidogrel Responder* Clopidogrel Nonresponder *Responder = 25% IPA at 4 and 24 h Prasugrel 60 mg Interpatient Variability

39 15 TRITON-TIMI 38: Rates of Key Study End Points (13,500 pts with ACS) End Point (%) CV Death, MI, Stroke Non-CABG TIMI Major Bleeds Clopidogrel Prasugrel Prasugrel Clopidogrel Days After Randomization 12.1 (781) 9.9 (643) P< events P= events 2.4 (146) 1.8 (111) CABG=Coronary Artery Bypass Graft surgery; CV=Cardiovascular; MI=Myocardial Infarction; TIMI=Thrombolysis In Myocardial Infarction Wiviott SD et al. New Engl J Med 2007;357:

40 Stent Thrombosis (%) TRITON-TIMI 38: ARC Definite/Probable Stent Thrombosis: Any Stent at Index PCI n=12,844 Clopidogrel Prasugrel HR 0.48 ( ) P< RRR 52% NNT=77 ARR 1.22% Days ARC=Academic Research Consortium; ARR=Absolute Risk Reduction; HR=Hazard Ratio; NNT=Number Needed to Treat; PCI=Percutaneous Coronary Intervention; RRR=Relative Risk Reduction Wiviott SD et al. Lancet 2008;371:

41 TRITON-TIMI 38: Other TIMI Bleeds at 15 Months (All ACS) (n=6,716) (n=6,741) Odds Ratio 4.73 P< % At risk 24/179 End Point (%) P= % 3.8% n=303 n=231 P< % 3.0% n=244 n= % At risk 6/189 TIMI Major or Minor Requiring Transfusion CABG-related TIMI Major Bleeding ACS=Acute Coronary Syndrome; CABG=Coronary Artery Bypass Graft surgery; HR=Hazard Ratio; TIMI=Thrombolysis In Myocardial Infarction Wiviott SD et al. New Engl J Med 2007;357:

42 Bleeding Risk Subgroups Therapeutic Considerations Reduced MD Guided by PK Age > 75 or Wt < 60 kg 16% Avoid Prasugrel Prior CVA/TIA 4% Significant Net Clinical Benefit with Prasugrel 80% TRITON-TIMI 38, NEJM 2007

43 Ticagrelor (AZD 6140): an oral reversible P2Y 12 antagonist HO HO O N N N N N H N F Ticagrelor is a cyclo-pentyltriazolo-pyrimidine (CPTP) S F OH Direct acting Not a prodrug; does not require metabolic activation Rapid onset of inhibitory effect on the P2Y 12 receptor Greater and more consistent inhibition of platelet aggregation versus clopidogrel Reversibly bound Degree of inhibition reflects plasma concentration Faster offset of effect than clopidogrel Functional recovery of all circulating platelets

44 PLATO study primary efficacy event - CV death, MI or stroke (18,600 pts with ACS) Cumulative incidence (%) Clopidogrel Ticagrelor HR 0.84 (95% CI ), p= No. at risk Ticagrelor Clopidogrel Days after randomisation 9,333 8,628 8,460 8,219 6,743 5,161 4,147 9,291 8,521 8,362 8,124 6,743 5,096 4,047 K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval

45 K-M estimates of time to secondary efficacy endpoints 7 Myocardial infarction Cardiovascular death!!! Clopidogrel Cumulative incidence (%) Ticagrelor HR 0.84 (95% CI ), p=0.005 Cumulative incidence (%) Clopidogrel Ticagrelor HR 0.79 (95% CI ), p= No. at risk Days after randomisation Days after randomisation Ticagrelor 9,333 8,678 8,520 8,279 6,796 5,210 4,191 9,333 8,294 8,822 8, ,482 4,419 Clopidogrel 9,291 8,560 8,405 8,177 6,703 5,136 4,109 9,291 8,865 8,780 8, ,441 4,364

46 Major bleeding primary safety event 15 K-M estimated rate (% per year) Ticagrelor Clopidogrel HR 1.04 (95% CI ), p= No. at risk Days from first IP dose Ticagrelor 9,235 7,246 6,826 6,545 5,129 3,783 3,433 Clopidogrel 9,186 7,305 6,930 6,670 5,209 3,841 3,479

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

48 GP IIb/IIIA Inhibitors Abciximab (ReoPro ) the first inhibitor developed and approved for clinical use. Chimeric monoclonal antibody 7E3, the murine constant region was replaced by its human counterpart Eptifibatide (Integrilin ) synthetic cyclic hepta-peptide derived from a sequence found in the venom of the southeastern pygmy rattlesnake Tirofiban (Aggrastat ) synthetic small molecule with structure similar to that of the RGD sequence of the snake venom echistatin

49 Antibody abciximab GP IIbIIIa inhibitors Cyclic peptide eptifibatide Nonpeptide tirofiban HCI (Aggrastat, Merck)

50 Glycoprotein IIb/IIIa Receptor Antagonists Abciximab Tirofiban Eptifibatide Pharma Fab portion of chimeric monoclonal antibody Synthetic non-peptide Cyclic heptapeptide Plasma ½ life 30 minutes 1.8 hours 2.5 hours Specificity Not specific Highly specific Highly specific Dose 0.25 mcg/kg bolus followed by mcg/kg/min drip (max 10 mcg/min) for hours 0.4 mcg/kg/min for 30 minutes followed by 0.1 mcg/kg/min drip for hours 180 mcg/kg bolus (x2) followed by 2.0 mcg/kg/min drip for hours

51 PCI Trials - 30-Day Mortality 0.73 ( ) 0.96) Am J Cardiol 2003;92:651-5

52 GP IIb/IIIa Inhibition in ACS Trial N Placebo 7.1% GP IIb- IIIa Inhibitor PRISM 5.8% 3, Day Death or MI PRISM PLUS 1, % 8.7% PARAGON A 2, % 10.6% PURSUIT 15.7% 14.2% 9,461 GUSTO-IV ACS 7, % 8.7% Overall 26, (0.82, 0.94) 11.9% P < GP IIb-IIIa IIIa Inhibitor Better Placebo Better 10.5%

53 Meta-Analysis of Risk-Adjusted Mortality in GP IIb-IIIa Inhibitor NSTE ACS Trials Odds ratio for mortality Odds Ratio 95% CI NRMI NSTEMI 1 (n=60,770) In-hospital mortality ,0.97 Boersma 2 (n=31,402) Mortality at 30 days , GP IIb-IIIa inhibitor favored (aspirin + heparin) NRMI=National Registry of Myocardial Infarction 1 Peterson ED, et al. J Am Coll Cardiol. 2003;42(1): Boersma E, et al. Lancet. 2002;359: Control arm favored (aspirin + heparin)

54 ISAR-REACT REACT 2 High-risk ACS Patients 30 Days 10% p=0.34 p= % 8.1% p= % 8.6% Placebo Abciximab p=0.64 5% 1.6% 1.1% 1.2% 1.0% 0% Death MI Death/MI Urg Revac JAMA 2006;295:

55 GP IIb/IIIA Inhibitors GP IIb/IIIa inhibitor price :: increased risk of bleeding (mainly access site + GI, not intracranial hemorrhages) Increased risk of thrombocytopenia 1-2% (mainly with abciximab) Two specific populations probably benefit most from GP IIb/IIIa administration

56 GP IIb/IIIa Inhibitors in STEMI Trials of PCI with abcixiamb and stenting that included long-term follow-up Death or re-infarction over 3 yrs of f/u 3 year mortality P = Montalescot, G. et al. Eur Heart J : % 14% 12% 10% 8% 6% 4% 2% 0% P = Placebo Abciximab

57 GP IIB/IIIA inhibitors and Diabetes Meta-analysis analysis of non-stemi ACS trials with GP IIb/IIIa inhib.. (PRISM, PRISM-PLUS, PLUS, PARAGON, PURSUIT, GUSTO-IV) 6,458 diabetic pts significant mortality reduction at 30 dys: : 6.2% vs. 4.6% (placebo vs. IIb/IIIa,, P=0.007) 23,072 non diabetic pts no survival benefit (3% vs. 3%) Main benefit in diabetics among those who underwent PCI (4% vs. 1.2%, P=0.002) Roffi et al, Circulation 2001

58 Bivalirudin - Angiomax Direct inhibitor of thrombin Very short half life (25 min)

59 Bivalirudin Bivalirudin a direct thrombin inhibitor - binds bivalently and with high affinity to thrombin s s active site 2 D-Phe-Pro-Arg-Pro (active-site-binding moiety) portion) (Gly) 4 Thrombin 1 C-terminal dodecapeptide (Exosite 1-binding portion) A/BR//259.a.1

60 Bivalirudin Bivalirudin can displace fibrin bound to thrombin Bivalirudin has high specificity for thrombin. 2 Thrombin 1 A/BR//260.a.1

61 Bivalirudin Bivalirudin is slowly cleaved by thrombin at the active site. 2 Thrombin 1 A/BR//261.a.1

62 Bivalirudin Bivalirudin is cleared from plasma by a combination of renal mecahnisms and proteolytic cleavage Plasma half life = 25 minutes (norm renal funct) Mod. renal impairment, half life = 34 minutes (dose reduced) Almost immediate prolongation of ACT. aptt Coagulation times return to normal after about 1 hour following drug d/c

63 ACUITY TRIAL 13,819 patients with ACS randomized to one of 3 antithrombotic regimens: heparin (or enoxaparin) ) + GP IIb/IIIa inhibitor, bivalirudin + GP IIb/IIIa inhibitor, or bivalirudin alone The primary end points were a composite ischemia end point (death, MI, or revasc. for ischemia), major bleeding. Stone G et al, NEJM 2006

64 Ischemic Composite Endpoint (Death, MI, unplanned revascularization for ischemia) UFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin Alone Ischemic Composite (%) UFH/Enoxaparin + IIb/IIIa Bivalirudin + IIb/IIIa Bivalirudin alone day Estimate 7.4% 7.8% 7.9% P (log rank) year Estimate 16.3% 16.5% 16.4% Days from Randomization P (log rank) Bivalirudin+GPI vs. Hep+GPI HR [95% CI] = 1.05 ( ) Bivalirudin alone vs. Hep+GPI HR [95% CI] = 1.05 ( ) p=0.55