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Should we use bivalirudin ?. 2. 2. Trombina. Thrombin. 1. 2. 2. 1. Thrombin. Trombina. Bivalirudin. 1. ADVANTAGES - No requirement for anti-thrombin III - Effective on clot-bound thrombin - Plasma half-life 25 minutes - No anticoagulation monitoring. 1. Fibrin.
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Should we use bivalirudin ? 2 2 Trombina Thrombin 1 2 2 1 Thrombin Trombina Bivalirudin 1 • ADVANTAGES • - No requirement for anti-thrombin III • - Effective on clot-bound thrombin • - Plasma half-life 25 minutes • - No anticoagulation monitoring 1 Fibrin
Primary Endpoint in the ACUITY trial UFH/Enoxaparin + GPI vs. Bivalirudin Alone PNI <0.0001 PSup = 0.015 PNI = 0.011 PSup = 0.32 PNI <0.0001 PSup <0.0001
12.2% 13.7% <0.001 13.0% 0.61 9.2% 0.96 (0.80-1.14) 0.23 12.2% 0.92 (0.80-1.06) 0.76 (0.65-0.89) 13.3% 0.01 10.6% 7.1% 11.3% 11.1% 1.02 (0.86-1.21) 0.81 (0.69-0.95) 8.6% 9.4% 0.75 (0.61-0.93) 0.01 0.83 6.4% 10.2% 0.63 (0.43-0.91) 0.01 0.34 9.4% 10.2% 0.92 (0.77-1.10) 13.9% 15.2% 0.92 (0.76-1.11) 0.36 Net Clinical Outcome Composite UFH/Enoxaparin + IIb/IIIa vs. Bivalirudin Alone UFH/Enox + IIb/IIIa Risk ratio ±95% CI Bival Alone RR (95% CI) P Pint Biomarkers (CK/Trop) Elevated (n=5368) Normal (n=3841) 0.35 ST Deviation Yes (n=3197) No (n=6008) 0.42 TIMI Risk Score Low (0-2) (n=1291) Intermed (3-4) (n=4407) High (5-7) (n=2449) 0.18 Pre Thienopyridine Yes (n=5192) No (n=4023) 0.02 Bivalirudin alone better UFH/Enox + IIb/IIIa better
Effetto della bivalirudina sui sanguinamenti non legati al sito di accesso arterioso all’analisi cumulativa degli studi REPLACE-2, ACUITY e HORIZONS.
Landmark Analysis: 30-Day Stent Thrombosis (N=3,124) Bivalirudin UFH + GP IIb/IIIa 5 4 3 Estimated Event Rate (%) 30 2 23 19 1 4 0 0 0.5 1 5 10 15 20 25 30 Days from Randomisation Patients at Risk Data on file: The Medicines Company Analysis of safety population in all patients receiving stents
Dense granule P2Y 12 Alpha granule a b IIb 3 Platelet Activation Mechanisms ASPIRIN x 5HT 5HT Thromboxane TICLOPIDINE CLOPIDOGREL PRASUGREL Coagulation Collagen ADP ADP ADP A 2 ATP ATP GPVI 5HT Thrombin P2Y 2A 1 TP a P2X ACTIVE METABOLITE 1 PAR4 PAR1 x TICAGRELOR CANGRELOR PLATELET Thrombin generation ACTIVATION Amplification Shape change x x Aggregation a b a b IIb 3 IIb 3 Fibrinogen Coagulation factors Inflammatory mediators GP IIb/IIIa ANTAGONISTS Storey RF. Curr Pharm Des. 2006;12:1255-59.
PRIMARY COMPOSITE ENDPOINT* IN TRITON AND PLATO TRIALS P<.001 P<.001 CLOPIDOGREL *Death,MI,Stroke NEW DRUG
CLINICAL CHARACTERISTICS OF TRITON AND PLATO POPULATION Prasugrel (studio TRITON) e’ stato confrontato con clopidogrel 300 mg LD + 75 mg MD. Ticagrelor (studio PLATO) e’ stato confrontato con clopidogrel 300-600 mg LD + 75mg MD.
Study Design, Flow and Compliance • 25,087 ACS Patients (UA/NSTEMI 70.8%, STEMI 29.2%) • Planned Early (<24 h) Invasive Management with intended PCI • Ischemic ECG Δ (80.8%) or ↑cardiac biomarker (42%) Randomized to receive (2 X 2 factorial): CLOPIDOGREL: Double-dose(600 mg then150 mg/d x 7d then 75 mg/d) vsStandard dose (300 mg then 75 mg/d) ASA: High Dose (300-325 mg/d) vsLow dose(75-100 mg/d) Angio 24,769 (99%) PCI 17,232 (70%) No PCI 7,855 (30%) No Sig. CAD 3,616 CABG 1,809 CAD 2,430 Efficacy Outcomes: CV Death, MI or stroke at day 30 Stent Thrombosis at day 30 Safety Outcomes:Bleeding (CURRENT defined Major/Severe and TIMI Major) Key Subgroup:PCI v No PCI
Clopidogrel: Double vs Standard Dose Primary Outcome: PCI Patients CV Death, MI or Stroke Clopidogrel Standard 15% RRR 0.04 Clopidogrel Double 0.03 Cumulative Hazard 0.02 HR 0.85 95% CI 0.74-0.99 P=0.036 0.01 0.0 0 3 6 9 12 15 18 21 24 27 30 Days
TICAGRELOR CLOPIDOGREL
Primary efficacy endpoint over time (composite of CV death, MI or stroke) 8 8 6.60 Clopidogrel 6 6 Clopidogrel 5.43 5.28 4.77 4 Cumulative incidence (%) Cumulative incidence (%) 4 Ticagrelor Ticagrelor 2 2 HR 0.88 (95% CI 0.77–1.00), p=0.045 HR 0.80 (95% CI 0.70–0.91), p<0.001 0 0 31 90 150 270 330 0 10 20 30 210 Days after randomisation Days after randomisation* No. at risk Ticagrelor 9,333 8,942 8,827 8,763 8,543 7,028 4,822 8,673 8,397 6,480 Clopidogrel 9,291 8,875 8,763 8,688 8,437 6,945 4,751 8,688 8,286 6,379 *Excludes patients with any primary event during the first 30 days
CARDIOVASCULAR DEATH IN TRITON AND PLATO TRIALS P<.001 CLOPIDOGREL NEW DRUG
Diabetic Subgroup N=3146 18 Clopidogrel 17.0 16 CV Death / MI / Stroke 14 12.2 12 HR 0.70P<0.001 Endpoint (%) Prasugrel 10 NNT = 20 (46) 8 6 TIMI Major NonCABG Bleeds Clopidogrel 4 2.6 2.5 2 Prasugrel 0 0 30 60 90 180 270 360 450 Days
ARC Definite or Probable Late Stent Thrombosis* in Patients Receiving DES 2.5 2.0 HR 0.46 (0.22-0.97); P=0.04 P=.04 1.5 % of Subjects 0.91 1.0 Clopidogrel 0.5 Prasugrel 0.42 0.0 30 90 150 210 270 330 390 450 Days ARC = Academic Research Consortium; DES = drug-eluting stent
NON-CABG RELATED TIMI MAJOR BLEEDING IN TRITON AND PLATO TRIALS P=.03 P=.03 CLOPIDOGREL NEW DRUG
FATAL BLEEDING IN TRITON AND PLATO TRIALS P=.002 CLOPIDOGREL NEW DRUG
INTRACRANIAL HEMORRAGES IN TRITON AND PLATO TRIALS P<.05 P=.06 CLOPIDOGREL NEW DRUG
Balance of Efficacy and Safety in Patients <75 Yrs, ≥60 kg, and Without TIA/Stroke 1 6 CV Death / NF MI / NF Stroke 1 4 NNT37 Clopidogrel 11% 1 2 Hazard Ratio, 0.75 (95% CI, 0.66-0.84) P<0.001 1 0 Endpoint (%) 8 Prasugrel 8.4% 6 Non-CABG TIMI Major Bleeding Hazard Ratio, 1.240 (95% CI, 0.91-1.69) P=0.17 NNH222 4 Prasugrel 1.95% 2 Clopidogrel 1.50% 0 0 30 90 180 270 360 450 Days Adapted from Wiviott SD et al NEJM 357: 2001, 2007 Presented at TCT 2009, San Francisco, CA
For High Risk, RR=0.58 [ 0.34, 0.98] P= 0.037 Parodi G. TCT 2009
COMPOSITE ENPOINT IN CURRENT-OASIS 7 P=NS P=NS P=0.036 DOUBLE STANDARD
CARDIOVASCULAR DEATH IN STEMI PATIENTS INCLUDED IN TRITON CLOPIDOGREL PRASUGREL
STENT THROMBOSIS IN TRITON AND PLATO TRIALS P=.02 P<.001 CLOPIDOGREL NEW DRUG
COMPOSITE ENPOINT IN DIABETIC PATIENTS P<.001 NS CLOPIDOGREL NEW DRUG
CARDIOVASCULAR DEATH IN TRITON AND PLATO TRIALS P<.001 CLOPIDOGREL NEW DRUG
MYOCARDIAL INFARCTION IN TRITON AND PLATO TRIALS P<.001 P=.005 CLOPIDOGREL NEW DRUG
CABG RELATED TIMI MAJOR BLEEDING IN TRITON AND PLATO TRIALS P<.001 CLOPIDOGREL NEW DRUG
STROKE IN TRITON AND PLATO TRIALS CLOPIDOGREL NEW DRUG
FATAL HEMORRAGES IN PLATO P=.02 P=.03 CLOPIDOGREL NEW DRUG
NON-ADHERENCE TO STUDY DRUG( MEDIAN TREATMENT TIME FOR PLATO 9 MONTHS , FOR TRITON 14.5 MONTHS ) CLOPIDOGREL NEW DRUG
COMPOSITE ENPOINT IN CURRENT-OASIS 7 P=NS P=.036 DOUBLE STANDARD
Clopidogrel: Double vs Standard Dose Definite Stent Thrombosis (Angio confirmed) Clopidogrel Standard Dose 0.012 42% RRR 0.008 Cumulative Hazard Clopidogrel Double Dose 0.004 HR 0.58 95% CI 0.42-0.79 P=0.001 0.0 0 3 6 9 12 15 18 21 24 27 30 Days
Primary endpoint in pre-defined subgroups (cont’d) KM % atMonth 12 Hazard Ratio(95% CI) TotalPatients p- value(Interaction) Characteristic Ti. Cl. HR (95% CI) Revascularization History of CABG 0.76 No 17518 9.2 11.0 0.84 (0.77, 0.93) Yes 1106 19.5 21.7 0.88 (0.67, 1.15) Previous TIA/Non-hemorrhagic Stroke 0.84 17462 9.2 11.1 0.84 (0.76, 0.93) No Yes 1152 19.0 20.8 0.87 (0.66, 1.13) Age Group <65 Years 0.86 10643 7.2 8.5 0.85 (0.74, 0.97) 7979 13.2 16.0 0.83 (0.74, 0.94) ≥65 Years <75 Years 0.22 15744 8.6 10.4 0.82 (0.74, 0.91) ≥75 Years 2878 16.8 18.3 0.94 (0.78, 1.12) 0.82 Sex 13336 9.2 11.1 0.85 (0.76, 0.95) Male Female 5288 11.2 13.2 0.83 (0.71, 0.97) Weight Group <60 kg 1312 13.1 17.3 0.75 (0.60, 0.99) 0.36 17256 9.5 11.2 0.86 (0.78, 0.94) ≥60 kg <80 kg 9055 11.4 0.90 (0.79, 1.01) 0.17 12.8 ≥80 kg 9513 8.3 10.5 0.79 (0.69, 0.90) Medical History of DM 0.49 13962 8.4 10.2 0.83 (0.74, 0.92) No Yes 4662 14.1 16.2 0.88 (0.76, 1.03) 0.05 Region 1714 11.4 14.8 0.80 (0.61, 1.04) Asia/Australia Central/South America 1237 15.2 17.9 0.86 (0.65, 1.13) 13859 8.8 11.0 0.80 (0.72, 0.90) Europe/Middle East/Africa North America 1814 11.9 9.6 1.25 (0.93, 1.67) 0.2 0.5 1.0 2.0 Ticagrelor better Clopidogrel better
HRs and cumulative incidence of major bleeding in pre-defined subgroups (cont’d) KM % atMonth 12 Hazard Ratio(95% CI) TotalPatients P value(Interaction) Characteristic Ti. Cl. HR (95% CI) Revascularization History of CABG 0.68 No 17329 11.8 11.4 1.04 (0.95, 1.14) Yes 1092 7.3 7.8 0.94 (0.60, 1.49) Previous TIA/Non-hemorrhagic Stroke 0.77 17284 11.4 11.0 1.04 (0.95, 1.14) No Yes 1136 14.6 14.9 0.99 (0.71, 1.37) Age Group <65 Years 0.42 10528 9.5 9.5 1.00 (0.87, 1.13) 7892 14.4 13.6 1.07 (0.95, 1.22) ≥65 Years <75 Years 1.00 15574 11.1 10.8 1.04 (0.94, 1.15) ≥75 Years 2846 14.2 13.3 1.04 (0.84, 1.29) 0.76 Sex 13184 11.9 11.4 1.05 (0.94, 1.16) Male Female 5237 10.7 10.5 1.01 (0.85, 1.21) Weight Group <60 kg 1296 12.6 15.2 0.82 (0.60, 1.12) 0.12 17086 11.5 10.9 1.06 (0.96, 1.16) ≥60 kg <80 kg 8959 11.7 0.99 (0.88, 1.13) 0.35 11.9 ≥80 kg 9423 11.4 10.5 1.08 (0.95, 1.23) Medical History of DM 0.21 13800 10.8 10.0 1.08 (0.97, 1.20) No Yes 4621 14.1 14.8 0.95 (0.81, 1.12) 0.75 Region 1692 10.6 10.8 1.03 (0.76, 1.40) Asia/Australia Central/South America 1230 15.6 13.2 1.22 (0.89, 1.66) 13747 11.1 11.0 1.01 (0.91, 1.13) Europe/Middle East/Africa North America 1752 12.9 12.2 1.06 (0.80, 1.40) 0.2 0.5 1.0 2.0 Ticagrelor better Clopidogrel better
FATAL BLEEDING IN TRITON AND PLATO TRIALS P=.002 CLOPIDOGREL NEW DRUG
Safety outcomes at 1 month NSTE-ACS 2 of 3 Criteria: Ischemic symptom, ST-T change, troponin rise with TIMI score > 3 IVRS RANDOMIZATION Next day cath Immediate cath 85% of radial access All PCIs on abciximab 1-month Follow-up
Sites of Major Bleedings n One patient had 2 bleeding events
Other findings *p values were calculated using Fischer’s exact test
1-Year Stent Thrombosis: Impact of Clopidogrel Loading Dose (all pts) 600mg Clopidogrel 300mg Clopidogrel 5 3.8% 4 3.0% 3 Def/Prob Stent Thrombosis (%) 2 HR [95%CI] = 1.30 [0.86-1.95] P = 0.10 1 0 0 30 60 90 120 150 180 210 240 270 300 330 365 Time in days Number at risk 600 mg 1983 1906 1881 1858 1832 1653 300 mg 1034 983 974 965 952 871