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תרופות נוגדות קרישה וטסיות בחולים העוברים צנתור כלילי התערבותי

תרופות נוגדות קרישה וטסיות בחולים העוברים צנתור כלילי התערבותי. פרופ' אלי לב מנהל יחידת הצנתורים בי " ח השרון, מרכז רפואי רבין. 3 Major systems involved in thrombosis and hemostasis. Vessel wall Endothelium Platelets Coagulation cascade.

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תרופות נוגדות קרישה וטסיות בחולים העוברים צנתור כלילי התערבותי

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  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) (Plasma)

  6. Flowing disc-shaped platelet Rolling ball-shaped platelet Hemisphere-shaped platelet Spreading platelet Platelet Aggregation IRREVERSIBLE ADHESION FIRM, BUT REVERSIBLE 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: 329–34.

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

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

  9. “Classic Coagulation Cascade” Localization to sites of vascular injury. Protease complexes assemble on PL membranes of activatedplatelets, 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

  10. From “Classic” to Current View

  11. 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 thrombinproduced initially than lead to a marked increase in activation of FXI, FIX, FVIII, FV and marked generation of thrombin. Priminginvloves 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 Current View of the Coagulation System Schneider D et al, Circulation 2007

  12. “The Great Balance” Thrombotic Complications Bleeding Complications

  13. Major Bleed only (without MI) (N=551) 12.5% MI only (without Major Bleed) (N=611) 8.6% No MI or Major Bleed (N=12,557) Both MI and Major Bleed (N=94) 28.9% 3.4% Significance of bleeding:Impact of MI and Major Bleeding (non-CABG) in first 30 Days on Risk of Death Over 1 Year 1 yearEstimate 30 28.9% 25 20 Mortality (%) 15 12.5% 10 8.6% 5 3.4% 0 0 30 60 90 120 150 180 210 240 270 300 330 360 390 Days from Randomization ACUITY – 1 year

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

  15. Placebo alone: 568/4300 (13.2%) 600 Aspirin alone: 461/4295 (10.7%) 500 Streptokinase alone: 448/4300 (10.4%) 400 Streptokinase plus aspirin: 343/4292 (8.0%) Cumulative Number of Vascular Deaths 300 200 100 0 7 14 21 28 35 Days From Randomization Aspirin in Acute Myocardial Infarction: ISIS-2(Lancet 1988;2:349-60)

  16. 0.25 0.20 0.15 0.10 0.05 0.00 Aspirin in the Treatment of ACS Placebo Probabilityof Death or MI Aspirin 75 mg Risk ratio 0.5295% CL 0.37-0.72 0 3 6 9 12 Months Wallentin LC, et al. JACC 1991;18:1587-93.

  17. Comparison of ASA Doses on Vascular Events in High-Risk Patients OR* Aspirin Dose No. of Trials (%) Odds Ratio 500-1500 mg 34 19 160-325 mg 19 26 75-150 mg 12 32 <75 mg 3 13 Any aspirin 65 23 0 0.5 1.0 1.5 2.0 * Odds reduction. Treatment effect P<.0001. ASA, acetylsalicylic acid. Adapted with permission from BMJ Publishing Group. Antithrombotic Trialists’ Collaboration. BMJ. 2002;324:71-86. Antiplatelet Better Antiplatelet Worse

  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) 112 96 80 Number of patients 64 48 32 16 0 <= -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

  23. LIMITATIONS OF CLOPIDOGREL PLATELET FUNCTION ASSAYS REVEALE EXTREME INTER-PATIENT VARIABILITY* * After 600 mg clopidogrel loading dose, in patients with stable angina undergoing PCI Courtesy of Aradi, Collet.

  24. POOR RESPONSE to CLOPIDORGEL (HPR) and THROMBOTIC EVENTS 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 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 P<0.001 Antoniucci et al, JAMA 2011

  26. Prasugrel: Active Metabolite FormationFaster Onset of IPA O O O CH3 CH3 CH3 O O O C C C N N N S S S Cl Cl Cl O O O N N HOOC N HOOC O O * HS S F OCH3 * HS F Cl Sem Vasc Med 3:113, 2003 O Pro-drug N O O C S F Prasugrel Clopidogrel Pre-hepatic metabolism - HydrolysisEsterases in blood C H 3 85% Inactive Metabolites(hydrolysis) Hepatic MetabolismCytochrome P450 Active Metabolite

  27. Prasugrel 10 mg MD vs. Clopidogrel 75 mg MD: Higher IPA During Maintenance Dosing Maintenance Doses Loading Dose 100 * * * * Pras 10 mg * * * * * * * 80 * Clop 600 mg Pras 60 mg † † † § Clop 75 mg ! * 60 Inhibition of Platelet Aggregation (%) 40 Clop 75 mg ! *P<0.001 vs. Clop 300 mg or 600 mg LD †P<0.001 vs. Clop 300 !P<0.05 vs. Clop 300§P<0.05 vs Clop 300/75 Clop 300 mg 20 mean ± SEM 20 μM ADP 0 0 0.25 0.5 1 2 4 6 24 3 4 5 6 7 8 9 Hours Days Time Payne CD et al. Presented at TCT 2006.

  28. TRITON-TIMI 38: Rates of Key Study End Points (13,500 pts with ACS) 15 12.1(781) Clopidogrel CV Death, MI, Stroke 9.9 (643) 10 P<0.001 Prasugrel ↓138 events End Point (%) P=0.03 5 ↑ 35 events Non-CABG TIMI Major Bleeds 2.4 (146) Prasugrel 1.8 (111) Clopidogrel 0 0 30 60 90 180 270 360 450 120 Days After Randomization 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;357:2001-2015

  29. TRITON-TIMI 38: ARC Definite/Probable Stent Thrombosis: 3 2 1 0 0 30 60 90 180 270 360 450 Any Stent at Index PCI n=12,844 2.35 Clopidogrel Stent Thrombosis (%) 1.13 Prasugrel HR 0.48 (0.36-0.64)P<0.0001 RRR 52% ARR 1.22% NNT=77 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;371:1353-1363

  30. TRITON-TIMI 38: TIMI Bleeds at 15 mo (all ACS) Odds Ratio 4.73P<0.001 13.4% (n=6,716) At risk 24/179 (n=6,741) TIMI major bleeding: 1.8% vs. 2.4%, (P=0.03), Pras vs. Clop P=0.002 End Point (%) P<0.001 5.0% 3.8% 4.0% n=303 3.2% 3.0% n=244 n=231 At risk 6/189 n=182 Requiring Transfusion CABG-related TIMI Major Bleeding TIMI Major or Minor 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;357:2001-2015

  31. Bleeding Risk SubgroupsTherapeutic Considerations Reduced MDGuided by PKAge > 75 or Wt < 60 kg Avoid PrasugrelPrior CVA/TIA 16% 4% Significant Net Clinical Benefit with Prasugrel80% TRITON-TIMI 38, NEJM 2007

  32. TRITON-TIMI 38: Diabetic Subgroup Analysis (n=3,146) 18 17.0 Clopidogrel CV Death, MI, Stroke 16 Prasugrel 14 12.2 12 HR 0.70P<0.001 10 End Point (%) NNT=21 8 6 Non-CABG TIMI Major Bleeds 4 2.6 2.5 2 0 0 30 60 90 180 270 360 450 Days 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

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

  34. Ticagrelor (AZD 6140): an oral reversibleP2Y12 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 P2Y12 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. Onset / Offset Study, IPA to 5uM ADP Loading Dose Last Maintenance Dose Ticagrelor (n=54) * * * * * † Clopidogrel (n=50) * * Placebo (n=12) * * ‡ † 100 90 80 70 60 IPA % 50 40 30 20 10 0 0 .5 1 2 4 8 24 6 weeks 0 2 4 8 24 48 72 120 168 240 Onset Maintenance Offset Time (hours) Gurbel PA et al. Circulation 2009

  36. PLATO study primary efficacy event - CV death, MI or stroke (18,600 pts with ACS) 13 12 11.7 Clopidogrel 11 10 9.8 9 Ticagrelor 8 7 Cumulative incidence (%) 6 5 4 3 2 HR 0.84 (95% CI 0.77–0.92), p=0.0003 1 0 0 60 120 180 240 300 360 Days after randomisation No. at risk Ticagrelor 9,333 8,628 8,460 8,219 6,743 5,161 4,147 Clopidogrel 9,291 8,521 8,362 8,124 6,743 5,096 4,047 K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval

  37. K-M estimates of time to secondary efficacy endpoints Myocardial infarction Cardiovascular death !!! 7 7 6.9 Clopidogrel 6 6 5.8 Clopidogrel 5.1 5 5 Ticagrelor 4.0 4 4 Ticagrelor Cumulative incidence (%) Cumulative incidence (%) 3 3 2 2 1 1 HR 0.84 (95% CI 0.75–0.95), p=0.005 HR 0.79 (95% CI 0.69–0.91), p=0.001 0 0 0 60 120 180 240 300 360 0 60 120 180 240 300 360 Days after randomisation Days after randomisation No. at risk 9,333 8,294 8,822 8,626 7119 5,482 4,419 Ticagrelor 9,333 8,678 8,520 8,279 6,796 5,210 4,191 9,291 8,865 8,780 8,589 7079 5,441 4,364 Clopidogrel 9,291 8,560 8,405 8,177 6,703 5,136 4,109

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

  39. Major bleeding – primary safety event 15 Ticagrelor 11.58 11.20 10 Clopidogrel K-M estimated rate (% per year) 5 HR 1.04 (95% CI 0.95–1.13), p=0.434 0 0 60 120 180 240 300 360 Days from first IP dose No. at risk 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

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

  41. Dyspnoea with Ticagrelor “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 12 11 10 9 8 7 6 5 4 3 2 1 0 Clopidogrel 11.0 9.3 Ticagrelor K-M estimated rate (% per year) HR: 0.85 (95% CI = 0.74–0.97), p=0.02 0 1 2 3 4 5 6 7 8 9 10 11 12 Months No. at risk Ticagrelor 4,201 3,887 3,834 3,732 3,011 2,297 1,891 Clopidogrel 4,229 3,892 3,823 3,730 3,022 2,333 1,868 Steg et al, Circulation 2010

  43. PLATO STEMI - All cause mortality 7 6 5 4 3 2 1 0 Clopidogrel 6.0 4.9 Ticagrelor K-M estimated rate (% per year) HR 0.82 (95% CI = 0.68–0.99), p=0.04 0 1 2 3 4 5 6 7 8 9 10 11 12 Months No. at risk Ticagrelor Clopidogrel 4,201 4,005 3,962 3,876 3,150 2,413 1,993 4,229 4,029 3,989 3,912 3,195 2,471 1,980

  44. PLATO STEMI - Primary safety event: major bleeding 10 8 6 4 2 0 Clopidogrel 9.3 9.0 Ticagrelor K-M estimated rate (% per year) HR 0.96 (95% CI = 0.83–1.12), p=0.63 0 1 2 3 4 5 6 7 8 9 10 11 12 Months No. at risk Ticagrelor Clopidogrel 4,165 3,431 3,254 3,137 2,440 1,786 1,640 4,181 3,430 3,297 3,159 2,441 1,804 1,635 Steg et al, Circulation 2010

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

  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 snakevenomechistatin

  47. Glycoprotein IIb/IIIa Receptor Antagonists Abciximab Tirofiban Eptifibatide Fab portion of chimeric monoclonal antibody Pharma Synthetic non-peptide Cyclic heptapeptide Plasma ½ life 30 minutes 1.8 hours 2.5 hours Specificity Highly specific Highly specific Not specific Dose 0.25 mcg/kg bolus followed by 0.125 mcg/kg/min drip (max 10 mcg/min) for 12-24 hours 0.4 mcg/kg/min for 30 minutes followed by 0.1 mcg/kg/min drip for 48-96 hours 180 mcg/kg bolus (x2) followed by 2.0 mcg/kg/min drip for 18-24 hours

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

  49. Abciximab in Primary PCI Meta-analysis8 RCTs – 3,949 pts with AMI w/i 12 undergoing primary (7) or rescue (1) PCI rand to abciximab vs. placebo or control p=0.01 RR 0.72 [0.55,0.94] p=0.06 RR 0.71 [0.49,1.02] 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 Favors GPIs Favors Control De Luca rt al, EHJ 2009

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