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State of the Art in Hospital Management of Non-ST-Elevation

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State of the Art in Hospital Management of Non-ST-Elevation State of the art in hospital management of non‐ST‐elevation myocardial infarction (NSTEMI) / unstable angina Professor Bernhard Meier (Switzerland) State of the Art in Hospital Management of NSTEMI / Unstable Angina Bernhard Meier, Stephan Windecker Department of Cardiology Bern University Hospital, Switzerland Risk Stratification Use of DES Antiplatelet Acute Therapy Coronary SdSyndromes Invasive Antithrombotic Management Therapy GRACE Risk Score Mortality, In‐Hospital and at 6 Months Relationship of Troponin Level to Early Mortality in ACS Antman EM et al. NEJM 1996;335:1342-49 8 7.5 p <0.001 ) 6 %% 6 days ( 22 3.7 4 343.4 1.7 ath by 4 by ath 2 ee 1 D 0 0<040-<0.4 04<100.4-<1.0 10<201.0-<2.0 20<502.0-<5.0 50<905.0-<9.0 9 cTnl at baseline (ng/ml) Risk ratio 1.0 1.8 3.5 3.9 6.2 7.8 Accuracy of Cardiac Troponin Assays AdiAccording to Time of OtOnset of Ches t PiPain Reichlin T et al, N Engl J Med 2009;361:858-67 Differential Diagnos is Non‐Cardiac Causes of Troponin Elevation Hamm C et al. Eur Heart J 2001 High‐Risk Indicators ElEarly IiInvasive Stra tegy WtdWarranted Class IA Indication for Early Invasive Strategy (ESC) Primary • Relevant rise or fall in troponin • Dynamic ST- or T-wave changes Secondary • Diabetes mellitus • Renal insufficiency (eGFR < 60 ml/min) • Reduced LV function (LVEF <40%) • Early post infarction angina • Recent PCI • Prior CABG • Intermediate to high GRACE risk score 24,045 Patients Major Bleeding: 3.9% HR=1.64, 95% CI 1.2-2.3 Assessment of Bleeding‐Risk Hamm C et al. ESC Guidelines UA/NSTEMI Eur Heart J 2011 . Age (>75y) . Renal failure . Low body weight (<60kg) . Female gender . Anemia . High dose antithrombotic agents . Duration of antithrombotic Rx . Combination of several antithrom bo tic agents . Change between various antithrombotic agents Risk Stratification Use of DES Antiplatelet Acute Therapy Coronary SdSyndromes Invasive Antithrombotic Management Therapy (P2Y12) Ticagrelor Cangrelor (iv) Elinogrel (po/iv) - Thrombi n recept or bl ock ers - Thrombin inhibitors - heparin - low molecular weight heparin - bivalirudin - dabigatran (po) - Xa inhibitors - fondaparinux, otamixaban (iv) - rivaroxaban - apixaban Benefit of Aspirin in Unstable Angg/ina/NSTEMI: Four Randomized Trials P<0.0001 20 P=0.0005 P=0.012 P=0.008 17.1 %) 15 12. 9 11.9 10.1 d MI ( d MI 10 nn 6.2 6.5 5 ath a 5 3.3 ee D 0 Lewis et al Cairns et al Theroux et al RISC group Aspirin Placebo NEJM 1983 NEJM 1985 NEJM 1988 Lancet 1990 (N=333) (N=555) (N=239) (N=796) CURRENT OASIS 7 –Acute Coronary Syndromes AiiAspirin “Dbl”Double” Dosage Mehta SR et al. N Engl J Med 2010;363:930‐42 Primary outcome: CV death, MI or stroke at 30 days High dose (300-325 mg) versus Qa low dose (75-100 mg) Aspirin Major GI Bleeding: 0.4% (high dose) vs 0.2% (low dose), P=0.04 CURE: Early and Long‐Term Benefits of Clopidogrel The CURE Trial Investigators. N Engl J Med 2001;345:494–502 CV Death, Myocardial Infarction, or Stroke 0.14 RR 20% Aspirin alone: 11.4% ate 0.12 rr (n = 6, 303) p < 0.0001 0.10 hazard 0080.08 Dual antiplatelet therapy 0.06 Clopidogrel and Aspirin: 9.3% ulative (n = 6,259) mm 0040.04 First 30 days 30 days – End of Study Cum 0.02 HR079(067HR 0.79 (0.67-0. 92) HR 008.82 (0 .7 0-0.95) 0.00 036912 Months of follow-up Clopidogrel loading dose: 300 mg in CURE CURRENT OASIS 7 ‐ PCI Population Mehta SR et al Lancet 2010;376 :1233 ‐43 Primary outcome: CV death, MI or Stroke at 30 days Clopidogrel 300mg loading dose and 75mg/d Clopidogrel 600mg loading dose and 150mg/d for 7d QuickTime?and a decompressor are needed to see this picture. Inhibition of Platelet Aggregation After Loading Dose in Pati ents With Elect ive PCI 100 *** *** *** 80 Prasugrel 60 mg DP) AA 60 *** 20 µM (( 40 Clopidogrel 600 mg IPA % IPA 20 ***p<0.0001 Prasugrel vs. Clopidogrel 0 0.52 46 8 12 16 20 24 IPA=inhibition of platelet aggregation; Hours PCI=Percutaneous coronary intervention Wiviott SD et al. Circulation 2007;116(25):2923-2932 Triton TIMI 38 – Prasugrel vs. Clopidogrel Wiviott SD et al. N Engl J Med 2007;357:2001‐15 15 Primary Endpoint: CV Death, MI, Stroke Clopidogrel ) 12.1 %% (781) point ( 10 9.9 dd (643) Prasugrel ary En HR 0.81 mm HR 0.80 (0.73-0.90) Pri P=0.0003 P=0.0004 5 HR 0.77 P=0. 0001 NNT= 46 ITT= 13,608 LTFU = 14 (0.1%) 0 0 30 60 90 180 270 360 450 Days Triton TIMI 38 –Prasugrel vs. Clopidogrel Wiviott SD et al. N Engl J Med 2007;357:2001‐15 Individual Ischemic Endpoints HR= 0.95 HR=0.89 HR=0.76 HR=0.48 HR=1.02 (0.78–1.16) (0.70-1.12) (0.67–0.85) (0.36-0.64) (0.71-1.45) 12 PP0=064.64 PP0=031.31 P<0. 001 P<0. 001 PP0.93=0.93 9.5 8 737.3 4 3 3.2 2.1 2.4 2.4 1.1 1 1 0 All Cause Death CV Death MI Stent Thrombosis Stroke Prasugrel Clopidogrel Triton TIMI 38 –Prasugrel vs. Clopidogrel Wiviott SD et al. N Engl J Med 2007;357:2001‐15 CABG and Non-CABG Related Bleeding 15 13.4 HR= 4734.73 HR= 1321.32 (1.90–11.82) (1.03–1.68) 10 P<0.001 P= 0.03 5 323.2 2.4 1.8 0 CABG TIMI Major Bleeding Non-CABG TIMI Major Bleeding Clopidogrel Prasugrel PLATO ‐ Ticagrelor versus Clopidogrel in ACS Wallentin L, et al. N Engl J Med 2009;361:1045‐57 Primaryyp Endpoint: CV Death, MI or Stroke 11.7% 98%9.8% p=0.0003 HR 0.84 (95% CI 0.77–0.92) RRR = 16%, ARR = 1.87%, NNT = 54 Ticagrelor versus Clopidogrel in ACS Wallentin L, et al. N Engl J Med 2009;361:1045‐57 Individual Ischemic Endpoints HR= 0.78 HR=0.79 HR=0.84 HR=1.17 (0.69–0.89) (0.69–0.91) (0.75–0.95) (0.91–1.52) P=0.74 12 P<0010.01 P=0. 001 P=0000.005P=0220.22 8 6.9 5.9 5.8 5.1 454.5 4 4 115.5 131.3 111.1 111.1 0 All Cause Dea th CV Dea th MI Stro ke IhIschem iStkic Stroke Ticagrelor Clopidogrel PLATO – Ticagrelor vs. Clopidogrel Wallentin L, et al. N Engl J Med 2009;361:1045‐57 CABG and Non-CABG Related Bleeding 15 HR= 0950.95 HR= 1251.25 (0.85–1.06) (1.03–1.53) 10 P=0.32 P= 0.03 5.8 5.2 5 2.8 2.2 0 CABG TIMI Major Bleeding Non-CABG TIMI Major Bleeding Clopidogrel Prasugrel Ticagrelor vs. Clopidogrel for ACS in PtiPatien ts ItInten ddded to TtTreat Non‐IilInvasively James SK et al. BMJ 2011, 342:d3527. doi: 10.1136/bmj.d3527 NON‐ INVASIVE INVASIVE NON ‐ INVASIVE STRATEGY HR 0.85, 95%CI 0.73 to 1.00 MI , NON‐ EATH NVASIVE (%) I D ROKE ULAR TT INVASIVE S R O ARDIOVASC CC | Prasugrel vs. Clopidogrel for ACS Withou t RlitiRevascularization – TRILOGY ACS Roe MT et al. N Eng J Med 2012 Primary EP: CV Death, MI, or Stroke at 30 Months % HR 0.91 (0.79‐1.05) HR 1.31 (0.81‐2.11) Prasugrel N=3620 Days Clopidogrel N=3623 Net Clinical Benefit: Bleedingggp Risk Subgroups PostPost--hochoc analysis Ris k (%) Yes + 54 Prior Stroke / TIA No -16 Pint = 0.006 >=75 -1 Age -16 < 75 Pint = 0.18 < 60 kg +3 Wgt >=60 kg Pint = 0.36 -14 OVERALL -13 0.5 1 2 Prasugrel Better Clopidogrel Better HR Ticagrelor versus Clopidogrel ‐ PLATO Wallentin L, et al. N Engl J Med 2009;361:1045‐57 Outcomes byygpyp Geography and Aspirin Dose Prasugrel and Ticagrelor loading doses (LD) in PCI for STEMI (RAPID) 50 pts with PCI for STEMI (bivalirudin monotherapy) • randomized to - 60 mg prasugrel LD - 180 mg ticagrelor LD • platelet reactivity assessed by VerifyNow Inhibition of Platelet Aggregation Percentage of High Residual Platelet Reactivity *p<0.01 vs Ticagrelor Parodi G, Antoniucci D, J Am Coll Cardiol 2013;61:1601–6 CHAMPION PHOENIX Bhatt DL, N Engl J Med 2013;368:1303-13 Death / MI / ILR / Stent Thrombosis within 48 Hours clopidogrel 5.9% te (%) aa 47%4.7% cangrelor vent R EE Log Rank P Value = 0.006 Patient at Risk Hours from Randomization Cangrelor: 5472 5233 5229 5225 5223 5221 5220 5217 5213 Clopidogrel: 5470 5162 5159 5155 5152 5151 5151 5147 5147 Vorapaxar (Thrombin-Receptor (PAR-1) Antagonist) in ACS (TRACER) • Death (cardiovascular) • MI • Stroke Merck (MSD) Tricoci P, N Engl J Med 2012;366:20-33 Vorapaxar (Thrombin-Receptor (PAR-1) Antagonist) in ACS (TRACER) TIMI Bleeding Tricoci P, N Engl J Med 2012;366:20-33 Risk Stratification Use of DES Antiplatelet Acute Therapy Coronary SdSyndromes Invasive Antithrombotic Management Therapy Antithrombin Agents in Acute Coronary Syndromes • UFH – Glyygycosaminoglycan MW 3000-30 000 – UFH inhibits factor II and Xa via binding AT III – Unpredictable pharmacokinetics requiring monitoring of coagulation status – Intravenous infusion • LMWH – Short chain (18 saccharides) fragments MW 4000 – 6000 – Anti-factor Xa:factor IIa ratio: 1.9-3.8 – Predictable pharmacokinetic profile – No monitoring of anticoagulation – Ease of administration Acute Non-ST Elevation Myocardial Infarction Unfractionated Heparin versus Low Molecular Weight Heparin Death or MI RR Unfractionated heparin 33% vs placebo * LMWH vs placebo ** 47% LMWH vs unfractionated heparin ** 12% * JAMA 1996;276:811-5 0 0.2 0.4 0.6 0.8 1.0 1.2 ** Lancet 2000;355:1936-1942 Fondaparinux A Synthetic Inhibitor of Factor Xa, Mechanism of Action Intrinsic Extrinsic pathway pathway Antithrombin AT AT AT Xa Xa FdFondapari nux II IIa THROMBIN Recycled Fibrinogen Fibrin clot Turpie AGG et al.
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