1. תרופות נוגדות קרישה וטסיות בחולים העוברים צנתור כלילי התערבותי פרופ' אלי לב מנהל יחידת הצנתורים בי"ח השרון, מרכז רפואי רבין

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

3. Anti-platelet and Anti-coagulant Properties of the Endothelium –Covers 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

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

5. Platelet Activation (Plasma) (released from activated cells) (ECM)

6. Platelet Aggregation 1. Kuwahara M et al. Arterioscler Thromb Vasc Biol 2002; 22: 329–34. FIRM, BUT REVERSIBLE ADHESION IRREVERSIBLE ADHESION Scanning electron micrograph of discoid, dormant platelets Activated, aggregating platelets illustrating fibrin strands Flowing disc-shaped platelet Rolling ball-shaped platelet Hemisphere-shaped platelet Spreading platelet

7. 3 Major systems involved Vessel wall –Endothelium Platelets Coagulation cascade

8. FibrinogenFibrin Thrombin Prothrombin Xa Va VIIa TF Extrinsic Pathway IXa VIIIa XIa XIIa Intrinsic pathway XIIIa Soft clot Fibrin Hard clot “Classic Coagulation Cascade”

9. Rosenberg et al NEJM 1999 4 major Anti-thrombotic Pathways (TFPI, Prot C/S, ATIII, Plasmin) 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)

10. From “Classic” to Current View

11. Current View of the Coagulation System Initiation 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

12. “The Great Balance” Thrombotic Complications Bleeding Complications

13. Mortality (%) Days from Randomization 0306090120150180210240270300330360390 0 5 15 30 10 25 20 1 year Estimate Major Bleed only (without MI) (N=551)12.5% 28.9%Both MI and Major Bleed (N=94) 3.4%No MI or Major Bleed (N=12,557) MI only (without Major Bleed) (N=611)8.6% Significance of bleeding: Impact of MI and Major Bleeding (non-CABG) in first 30 Days on Risk of Death Over 1 Year 28.9% 12.5% 8.6% 3.4% ACUITY – 1 year

14. Courtesy of Dr S. Steinhubl, U. Kentucky

15. 100 200 300 400 500 600 0714212835 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%) Cumulative Number of Vascular Deaths Days From Randomization Aspirin in Acute Myocardial Infarction: ISIS-2 (Lancet 1988;2:349-60)

16. Aspirin in the Treatment of ACS Wallentin LC, et al. JACC 1991;18:1587-93. 0.00 0.05 0.10 0.15 0.20 0.25 036912 Months Probability of Death or MI Placebo Aspirin 75 mg Risk ratio 0.52 95% CL 0.37-0.72

17. Comparison of ASA Doses on Vascular Events in High-Risk Patients *Odds reduction. Treatment effect P<.0001. ASA, acetylsalicylic acid. Adapted with permission from BMJ Publishing Group. Antithrombotic Trialists’ Collaboration. BMJ. 2002;324:71-86. 0.51.01.52.0 500-1500 mg34 19 160-325 mg19 26 75-150 mg12 32 <75 mg 3 13 Any aspirin65 23 Antiplatelet BetterAntiplatelet Worse Aspirin DoseNo. of Trials (%) Odds Ratio 0 OR*

18. Clopidogrel

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

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

21. PCI-CURE TRIAL – ACS pts Pretreatment with clopidogrel vs. no pretreatment Reduction in CV death, MI or urgent TVR CURE Investigatots, Lancet 2001 358: 527-33

22. Distribution of Response to Clopidogrel (544 patients, platelet aggregation) Change in Aggregation to 5µM ADP Number of patients 0 16 32 48 64 80 96 112 <= -20[-10,0][11,20][31,40][51,60][71,80][91,100] Serebrauny V et al. JACC 2004

23. 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

24. ADAPT-DES: DEFINITE / PROBABLE ST @ 30 days Stone et al, Lancet 2013

25. Low response to clopidogrel in patients with ACS: RECLOSE-2 P=0.003 P<0.001 1789 patients with ACS High on treatment platelet reactivity (low response) determined by LTA in response to ADP 14% of pts had HTPR Primary endpoint = cardiac death, MI, urgent revasc. or stroke Antoniucci et al, JAMA 2011

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

27. * * * * * * * * Prasugrel 10 mg MD vs. Clopidogrel 75 mg MD: Higher IPA During Maintenance Dosing mean ± SEM 20 μM ADP mean ± SEM 20 μM ADP Inhibition of Platelet Aggregation (%) 0 20 40 60 80 100 Loading Dose Maintenance Doses Time HoursDays 0.250.512462434567890 Clop 300 mg Clop 75 mg † † ! ! † § P<0.001 vs. Clop 300 mg or 600 mg LD * P<0.001 vs. Clop 300 mg or 600 mg LD P<0.001 vs. Clop 300 † P<0.001 vs. Clop 300 P<0.05 vs. Clop 300 P<0.05 vs Clop 300/75 ! P<0.05 vs. Clop 300 § P<0.05 vs Clop 300/75 Clop 600 mg Clop 75 mg * * * * * Pras 60 mg Pras 10 mg Payne CD et al. Presented at TCT 2006.

28. CABG=Coronary Artery Bypass Graft surgery; CV=Cardiovascular; MI=Myocardial Infarction; TIMI=Thrombolysis In Myocardial Infarction Prasugrel Clopidogrel TRITON-TIMI 38: Rates of Key Study End Points (13,500 pts with ACS) Wiviott SD et al. New Engl J Med 2007;357:2001-2015 5 10 15 0 0306090180270360450 Days After Randomization End Point (%) 120 1.8 (111) 2.4 (146) Non-CABG TIMI Major Bleeds CV Death, MI, Stroke P=0.03 P<0.001 ↓138 events ↑ 35 events 12.1 (781) 9.9 (643) Prasugrel Clopidogrel

29. 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 Reduction Wiviott SD et al. Lancet 2008;371:1353-1363 0306090180270360450 HR 0.48 (0.36-0.64) P<0.0001 RRR 52% ARR 1.22% Prasugrel Clopidogrel 2.35 1.13 Days Stent Thrombosis (%) Any Stent at Index PCI n=12,844 0 1 2 3 NNT=77

30. ACS=Acute Coronary Syndrome; CABG=Coronary Artery Bypass Graft surgery; HR=Hazard Ratio; TIMI=Thrombolysis In Myocardial Infarction P=0.002 Odds Ratio 4.73 P<0.001 TIMI Major or Minor CABG-related TIMI Major Bleeding Requiring Transfusion P<0.001 At risk 6/189 At risk 24/179 (n=6,716) (n=6,741) End Point (%) 3.2% 13.4% n=244 n=182 n=231 n=303 3.8% 5.0% 3.0% 4.0% Wiviott SD et al. New Engl J Med 2007;357:2001-2015 TRITON-TIMI 38: TIMI Bleeds at 15 mo (all ACS) TIMI major bleeding: 1.8% vs. 2.4%, (P=0.03), Pras vs. Clop

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

32. 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 Infarction Adapted from Antman EM et al. American Heart Association Scientific Sessions; 2007, Nov 4-7; Orlando, FL 0 2 4 6 8 10 12 14 16 18 0306090180270360450 HR 0.70 P<0.001 Days End Point (%) CV Death, MI, Stroke NNT=21 17.0 12.2 2.6 2.5 Non-CABG TIMI Major Bleeds Prasugrel Clopidogrel

33. TRITON-TIMI 38: STEMI Subgroup Analysis (n=3,534) P=0.05 P=0.045 P=0.01 P=0.4

34. Ticagrelor (AZD 6140): an oral reversible P2Y 12 antagonist Ticagrelor is a cyclo-pentyl- triazolo-pyrimidine (CPTP) 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

35. Last Maintenance Dose Loading Dose Time (hours) Onset Maintenance Offset 100 90 80 70 60 50 40 30 20 10 0 IPA % Ticagrelor (n=54) Clopidogrel (n=50) Placebo (n=12) 0.5 1 2 4 8 24 6 weeks 0 2 4 8 24 48 72 120 168 240 * * * * * * * * * ‡ † † Onset / Offset Study, IPA to 5uM ADP Gurbel PA et al. Circulation 2009

36. PLATO study primary efficacy event - CV death, MI or stroke (18,600 pts with ACS) No. at risk Clopidogrel Ticagrelor 9,291 9,333 8,521 8,628 8,362 8,460 8,124 Days after randomisation 6,743 5,096 5,161 4,047 4,147 060120180240300360 12 11 10 9 8 7 6 5 4 3 2 1 0 13 Cumulative incidence (%) 9.8 11.7 8,219 HR 0.84 (95% CI 0.77–0.92), p=0.0003 Clopidogrel Ticagrelor K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval

37. K-M estimates of time to secondary efficacy endpoints No. at risk Clopidogrel Ticagrelor 9,291 9,333 8,560 8,678 8,405 8,520 8,177 Days after randomisation 6,703 6,796 5,136 5,210 4,109 4,191 060120180240300360 6 5 4 3 2 1 0 7 Cumulative incidence (%) Clopidogrel Ticagrelor 5.8 6.9 8,279 HR 0.84 (95% CI 0.75–0.95), p=0.005 060120180240300360 6 4 3 2 1 0 Clopidogrel Ticagrelor 4.0 5.1 HR 0.79 (95% CI 0.69–0.91), p=0.001 7 5 9,291 9,333 8,865 8,294 8,780 8,822 8,589 Days after randomisation 7079 7119 5,441 5,482 4,364 4,4198,626 Myocardial infarction Cardiovascular death !!! Cumulative incidence (%)

38. Stent thrombosis Evaluated in patients with any stent during the study Wallentin et al, N Engl J Med 2009 P=0.01 P=0.02 %

39. Major bleeding – primary safety event No. at risk Clopidogrel Ticagrelor 9,186 9,235 7,305 7,246 6,930 6,826 6,670 Days from first IP dose 5,209 5,129 3,841 3,783 3,479 3,433 060120180240300360 10 5 0 15 Clopidogrel Ticagrelor 11.20 11.58 6,545 HR 1.04 (95% CI 0.95–1.13), p=0.434 K-M estimated rate (% per year)

40. Non-CABG and CABG-related major bleeding p=0.026 p=0.025 NS 9 K-M estimated rate (% per year) Non-CABG PLATO major bleeding 8 7 6 5 4 3 2 1 0 Non-CABG TIMI major bleeding CABG PLATO major bleeding CABG TIMI major bleeding 4.5 3.8 2.8 2.2 7.4 7.9 5.3 5.8 Ticagrelor Clopidogrel

41. Dyspnoea with Ticagrelor All patients Ticagrelor(n=9,235)Clopidogrel(n=9,186) p value * Dyspnoea, % Any Any Requiring discontinuation of study Rx Requiring discontinuation of study Rx13.80.97.80.1<0.001<0.001 “Ticagrelor-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

42. PLATO STEMI - Primary endpoint: CV death, MI or stroke 0123456789101112 12 11 10 9 8 7 6 5 4 3 2 1 0 Months HR: 0.85 (95% CI = 0.74–0.97), p=0.02 No. at risk Clopidogrel Ticagrelor 4,229 4,201 3,892 3,887 3,823 3,834 3,7303,022 3,011 2,333 2,297 1,868 1,8913,732 11.0 9.3 Clopidogrel Ticagrelor K-M estimated rate (% per year) Steg et al, Circulation 2010

43. PLATO STEMI - All cause mortality 0123456789101112 7654321076543210 K-M estimated rate (% per year) 4,2014,0053,9623,8763,1502,4131,993 4,2294,0293,9893,9123,1952,4711,980 Months No. at risk Ticagrelor Clopidogrel Ticagrelor 4.9 6.0 HR 0.82 (95% CI = 0.68–0.99), p=0.04

44. K-M estimated rate (% per year) 0123456789101112 10 8 6 4 2 0 Months No. at risk Ticagrelor Clopidogrel 4,1653,4313,2543,1372,4401,7861,640 4,1813,4303,2973,1592,4411,8041,635 Clopidogrel Ticagrelor 9.0 9.3 PLATO STEMI - Primary safety event: major bleeding HR 0.96 (95% CI = 0.83–1.12), p=0.63 Steg et al, Circulation 2010

45. Platelet Activation (Plasma) (released from activated cells) (ECM)

46. 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

47. Glycoprotein IIb/IIIa Receptor Antagonists 0.25 mcg/kg bolus followed by 0.125 mcg/kg/min drip (max 10 mcg/min) for 12-24 hours Synthetic non-peptide 0.4 mcg/kg/min for 30 minutes followed by 0.1 mcg/kg/min drip for 48-96 hours Cyclic heptapeptide 180 mcg/kg bolus (x2) followed by 2.0 mcg/kg/min drip for 18-24 hours Fab portion of chimeric monoclonal antibody 30 minutes 1.8 hours2.5 hours Not specific Highly specific AbciximabTirofibanEptifibatide Pharma Plasma ½ life Specificity Dose

48. ISAR-REACT 2 High-risk ACS Patients – 30 Days p=0.06 p=0.03 p=0.34p=0.64 JAMA 2006;295:1531-38

49. Abciximab in Primary PCI Meta-analysis 8 RCTs – 3,949 pts with AMI w/i 12  undergoing primary (7) or rescue (1) PCI rand to abciximab vs. placebo or control p=0.06 RR 0.71 [0.49,1.02] p=0.01 RR 0.72 [0.55,0.94] 6–12 months De Luca G et al. JAMA 2005;293:1759–1765

50. Updated meta-analysis of effect of GPIs on 30 day mortality in pts with STEMI De Luca rt al, EHJ 2009 Favors GPIsFavors Control

51. Updated meta-analysis of effect of GP IIb/IIIa inhibitors on 30 day re-MI De Luca rt al, EHJ 2009 Favors GPIsFavors control

52. Updated meta-analysis of effect of GP IIb/IIIa inhibitors on major bleeding De Luca rt al, EHJ 2009

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

54. 2 1 Thrombin Bivalirudin can displace fibrin bound to thrombin— Bivalirudin has high specificity for thrombin. Bivalirudin A/BR//260.a.1

55. Bivalirudin Bivalirudin is cleared from plasma by 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 No HIT !!

56. HORIZONS 1-Year Major Adverse CV Events 3602 patients with STEMI undergoing 1 o PCI Number at risk Bivalirudin alone Heparin+GPIIb/IIIa ) Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802) 18001627157915441394 18021619157315401380 MACE (%) 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Time in Months 0123456789101112 11.9% 11.9% Diff [95%CI] = 0.0% [-2.1, 2.2] HR [95%CI] = 1.00 [0.83, 1.21] P=0.98 * *MACE = All cause death, reinfarction, ischemic TVR or stroke

57. 9.2% 5.8% Diff [95%CI] = -3.4% [- 5.2, -1.7] 2 HR [95%CI] = 0.61 [0.48, 0.78] P<0.0001 1-Year Major Bleeding (non-CABG) Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802)

58. 1-Year Mortality: Cardiac and Non Cardiac Number at risk Bivalirudin alone Heparin+GPIIb/IIIa Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802) 18001705168416691520 18021678166316461486 Cardiac Non Cardiac Mortality (%) 0 1 2 3 4 5 Time in Months 0123456789101112 3.8% 2.1% 1.3% 1.1% HR [95%CI] = 0.57 [0.38, 0.84] P=0.005 2.9% 1.8% Δ = 1.1% P=0.03 Δ = 1.7%

59. NCDR PCI registry including >1,500,000 pts undergoing PCI in 955 US hospitals 23% of the patients treated with bivalirudin 50% elective, 36% urgent, 14% emergent PCI Bivalirudin associated with OR 0.67 (0.63-0.70) for bleeding events !! (Bleeding defined as requiring blood transfusion, prolonged hospital stay, or ↓ 3 g/dL in Hg)

60. THANK YOU