Should we use bivalirudin ? Fibrin 2 1 Thrombin 2 1 Thrombin 2 1 Trombina 2 1 Trombina Bivalirudin ADVANTAGES - No requirement for anti-thrombin III - Effective on clot-bound thrombin - Plasma half-life 25 minutes - No anticoagulation monitoring

Primary Endpoint in the ACUITY trial UFH/Enoxaparin + GPI vs. Bivalirudin Alone P NI < P Sup = P NI = P Sup = 0.32 P NI < P Sup <0.0001

Net Clinical Outcome Composite UFH/Enoxaparin + IIb/IIIa vs. Bivalirudin Alone Yes (n=3197) No (n=6008) Low (0-2) (n=1291) Intermed (3-4) (n=4407) High (5-7) (n=2449) Elevated (n=5368) Normal (n=3841) Risk ratio ±95% CI Risk ratio ±95% CI Bival Alone UFH/Enox + IIb/IIIa 9.2% 11.3% 12.2% 11.1% PP int 0.76 ( ) 1.02 ( ) 12.2% 7.1% 13.3% 9.4% 0.92 ( ) 0.75 ( ) < % 8.6% 13.7% 10.6% 0.96 ( ) 0.81 ( ) Biomarkers (CK/Trop) ST Deviation TIMI Risk Score Pre Thienopyridine 6.4%10.2%0.63 ( ) %10.2%0.92 ( ) %15.2%0.92 ( )0.36 Yes (n=5192) No (n=4023) RR (95% CI) Bivalirudin alone better UFH/Enox + IIb/IIIa better

Effetto della bivalirudina sui sanguinamenti non legati al sito di accesso arterioso allanalisi cumulativa degli studi REPLACE-2, ACUITY e HORIZONS.

Landmark Analysis: 30-Day Stent Thrombosis (N=3,124) Bivalirudin: UFH + GP IIb/IIIa: Patients at Risk BivalirudinUFH + GP IIb/IIIa Estimated Event Rate (%) Days from Randomisation Data on file: The Medicines Company Analysis of safety population in all patients receiving stents

Platelet Activation Mechanisms Thrombin Thromboxane A 2 5HT P2Y 12 ADPADPADP 5HT PLATELET ACTIVATION P2Y 1 5HT 2A PAR1 PAR4 Dense granule Thrombingeneration Shapechange IIb 3 IIb 3 Fibrinogen IIb 3 Aggregation Amplification Alpha granule Coagulation factors Inflammatory mediators TP a Coagulation GPVI Collagen ATPATP P2X 1 ASPIRIN x TICLOPIDINECLOPIDOGRELPRASUGREL ACTIVEMETABOLITE x TICAGRELORCANGRELOR GP IIb/IIIa ANTAGONISTS xx Storey RF. Curr Pharm Des. 2006;12:

PRIMARY COMPOSITE ENDPOINT* IN TRITON AND PLATO TRIALS CLOPIDOGREL NEW DRUG P<.001 *Death,MI,Stroke

CLINICAL CHARACTERISTICS OF TRITON AND PLATO POPULATION TRITON (N=13608 pts ) PLATO ( N= pts ) % PCI % CABG 1 10 % NON-INVASIVE 0 29 % STEMI Prasugrel (studio TRITON) e stato confrontato con clopidogrel 300 mg LD + 75 mg MD. Ticagrelor (studio PLATO) e stato confrontato con clopidogrel 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%) 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%) PCI 17,232 (70%) Angio 24,769 (99%) Angio 24,769 (99%) No PCI 7,855 (30%) No Sig. CAD 3,616CABG 1,809CAD 2,430 Randomized to receive (2 X 2 factorial): CLOPIDOGREL: Double-dose (600 mg then150 mg/d x 7d then 75 mg/d) vs Standard dose (300 mg then 75 mg/d) ASA: High Dose ( mg/d) vs Low dose ( mg/d) 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

Days Cumulative Hazard Clopidogrel: Double vs Standard Dose Primary Outcome: PCI Patients Clopidogrel Standard Clopidogrel Double HR % CI P= % RRR CV Death, MI or Stroke

CLOPIDOGREL TICAGRELOR

TCT % 3.4% 1.5% 1.2% HR [95%CI] = 1.30 [ ] P = 0.56 HR [95%CI] =2.11 [1.07,4.17] P = Number at risk 600 mg 300 mg Def/Prob Stent Thrombosis (%) Time in Days Stent Thrombosis 1-Day Landmark Analysis: Impact of Clopidogrel Loading (Bivalirudin) 600mg Clopidogrel 300mg Clopidogrel

8,688 8, Cumulative incidence (%) Clopidogrel Ticagrelor HR 0.88 (95% CI 0.77–1.00), p=0.045 No. at risk Clopidogrel Ticagrelor 9,291 9,333 8,875 8,942 8,763 8,827 Days after randomisation Clopidogrel Ticagrelor ,688 8,673 8,286 8,397 6,379 6,480 Days after randomisation * HR 0.80 (95% CI 0.70–0.91), p< ,437 8,543 6,945 7,028 4,751 4,822 Cumulative incidence (%) Primary efficacy endpoint over time (composite of CV death, MI or stroke) *Excludes patients with any primary event during the first 30 days

CARDIOVASCULAR DEATH IN TRITON AND PLATO TRIALS NEW DRUG CLOPIDOGREL P<.001

Diabetic Subgroup HR 0.70 P<0.001 Days Endpoint (%) CV Death / MI / Stroke TIMI Major NonCABG Bleeds NNT = 20 (46) N= Prasugrel Clopidogrel Prasugrel Clopidogrel

ARC Definite or Probable Late Stent Thrombosis* in Patients Receiving DES HR 0.46 ( ); P=0.04 ARC = Academic Research Consortium; DES = drug-eluting stent Days % of Subjects Prasugrel Clopidogrel P=.04

NON-CABG RELATED TIMI MAJOR BLEEDING IN TRITON AND PLATO TRIALS CLOPIDOGREL NEW DRUG P=.03

FATAL BLEEDING IN TRITON AND PLATO TRIALS CLOPIDOGREL NEW DRUG P=.002

INTRACRANIAL HEMORRAGES IN TRITON AND PLATO TRIALS CLOPIDOGREL NEW DRUG P=.06 P<.05

Balance of Efficacy and Safety in Patients <75 Yrs, 60 kg, and Without TIA/Stroke Endpoint (%) Hazard Ratio, (95% CI, ) P=0.17 Hazard Ratio, 0.75 (95% CI, ) P<0.001 Clopidogrel Prasugrel Clopidogrel Prasugrel 1.95% 1.50% 11% 8.4% CV Death / NF MI / NF Stroke Non-CABG TIMI Major Bleeding Days NNT 37 NNH 222 Adapted from Wiviott SD et al NEJM 357: 2001, 2007 Presented at TCT 2009, San Francisco, CA

CLINICAL CHARACTERISTICS OF TRITON AND PLATO POPULATION Variable\\\\ TRITON PLATO AGE (years) % FEMALE SEX % Cl Creat <60 ml/min 11 4 % DIABETES % PRIOR MI % PRIOR CABG 8 6

For High Risk, RR=0.58 [ 0.34, 0.98] P= Parodi G. TCT 2009

COMPOSITE ENPOINT IN CURRENT- OASIS 7 DOUBLE STANDARD P=NS P=0.036

CARDIOVASCULAR DEATH IN STEMI PATIENTS INCLUDED IN TRITON PRASUGREL CLOPIDOGREL

STENT THROMBOSIS IN TRITON AND PLATO TRIALS CLOPIDOGREL NEW DRUG P<.001 P=.02

COMPOSITE ENPOINT IN DIABETIC PATIENTS CLOPIDOGREL NEW DRUG P<.001 NS

CARDIOVASCULAR DEATH IN TRITON AND PLATO TRIALS NEW DRUG CLOPIDOGREL P<.001

MYOCARDIAL INFARCTION IN TRITON AND PLATO TRIALS CLOPIDOGREL NEW DRUG P<.001 P=.005

CABG RELATED TIMI MAJOR BLEEDING IN TRITON AND PLATO TRIALS CLOPIDOGREL NEW DRUG P<.001

STROKE IN TRITON AND PLATO TRIALS CLOPIDOGREL NEW DRUG

FATAL HEMORRAGES IN PLATO CLOPIDOGREL NEW DRUG P=.03 P=.02

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 DOUBLE STANDARD P=.036 P=NS

Days Cumulative Hazard Clopidogrel Standard Dose Clopidogrel Double Dose 42% RRR HR % CI P=0.001 Clopidogrel: Double vs Standard Dose Definite Stent Thrombosis (Angio confirmed)

Ticagrelor betterClopidogrel better Ti.Cl. Total Patients KM % at Month 12 HR (95% CI) Hazard Ratio (95% CI) Yes Revascularization History of CABG Sex Weight Group 65 Years Characteristic (0.78, 0.94) <80 kg (0.60, 0.99) 60 kg (0.71, 0.97) <60 kg (0.76, 0.95) Female (0.78, 1.12) Male (0.74, 0.91) 75 Years (0.74, 0.94) <75 Years (0.74, 0.97) <65 Years (0.66, 1.13) Age Group (0.76, 0.93) No (0.67, 1.15) Previous TIA/Non-hemorrhagic Stroke (0.77, 0.93)No Yes Central/South America 80 kg North America (0.65, 1.13) Europe/Middle East/Africa (0.61, 1.04) Asia/Australia (0.76, 1.03) Region (0.74, 0.92) No (0.69, 0.90) Medical History of DM (0.79, 1.01) 0.2 p- value (Interaction) (0.93, 1.67) (0.72, 0.90) 0.49 Primary endpoint in pre-defined subgroups (contd)

Ticagrelor betterClopidogrel better Ti.Cl. Total Patients KM % at Month 12 HR (95% CI) Hazard Ratio (95% CI) Yes Revascularization History of CABG Sex Weight Group 65 Years Characteristic (0.96, 1.16) <80 kg (0.60, 1.12) 60 kg (0.85, 1.21) <60 kg (0.94, 1.16) Female (0.84, 1.29) Male (0.94, 1.15) 75 Years (0.95, 1.22) <75 Years (0.87, 1.13) <65 Years (0.71, 1.37) Age Group (0.95, 1.14) No (0.60, 1.49) Previous TIA/Non-hemorrhagic Stroke (0.95, 1.14)No Yes Central/South America 80 kg North America (0.89, 1.66) Europe/Middle East/Africa (0.76, 1.40) Asia/Australia (0.81, 1.12) Region (0.97, 1.20) No (0.95, 1.23) Medical History of DM (0.88, 1.13) 0.2 P value (Interaction) (0.80, 1.40) (0.91, 1.13) 0.21 HRs and cumulative incidence of major bleeding in pre-defined subgroups (contd)

FATAL BLEEDING IN TRITON AND PLATO TRIALS CLOPIDOGREL NEW DRUG P=.002

MAJOR BLEEDING

Preliminary Results Safety outcomes at 1 month Safety outcomes at 1 month NSTE-ACS 2 of 3 Criteria: Ischemic symptom, ST-T change, troponin rise with TIMI score > 3 Immediate cath Next day cath All PCIs on abciximab 1-month Follow-up IVRS RANDOMIZATION 85% of radial access

Preliminary Results Safety outcomes at 1 month ImmediateDelayedP Major bleeding at 1 month, (%) Major bleeding at 1 month, (%) Non-CABG major bleeding Non-CABG major bleeding CABG-related major bleeding CABG-related major bleeding Transfusion > 2 units Transfusion > 2 units Transfusion > 5 units Transfusion > 5 units Thrombocytopenia at 1 month, (%) Thrombocytopenia at 1 month, (%) Non-CABG thrombocytopenia, (%) Non-CABG thrombocytopenia, (%) Post-CABG thrombocytopenia, (%) Post-CABG thrombocytopenia, (%)

Preliminary Results Sites of Major Bleedings 1- Gastro-Intestinal 4 2- Puncture-related 4 3- Hemopericardium 2 4- Intracranial 1 5- Epistaxis 1 6- Hematoma (not puncture-related) 1 unknown7 One patient had 2 bleeding events n

Other findings All patients Ticagrelor (n=9,235) Clopidogrel (n=9,186) p value * Dyspnoea, % Any With discontinuation of study treatment <0.001 Holter monitoring at first week, % Ventricular pauses =>3 sec,% Ventricular pauses =>5 sec,% (n=1451) (N=1415) *p values were calculated using Fischers exact test

TCT mg Clopidogrel 300mg Clopidogrel 2.8% 2.9% 0.4% 0.4% 0% HR=0.21CI= P = 0.30 HR=1.08 CI= [0.57,2.05] P = Number at risk 600 mg 300 mg Def/Prob Stent Thrombosis (%) Time in Days P int antithrombin x clopidogrel LD = 0.16 Stent Thrombosis 1-Day Landmark Analysis: Impact of Clopidogrel Loading (UFH+GPI)

TCT % 3.8% HR [95%CI] = 1.30 [ ] P = Year Stent Thrombosis: Impact of Clopidogrel Loading Dose (all pts) Number at risk 600 mg 300 mg 600mg Clopidogrel 300mg Clopidogrel Def/Prob Stent Thrombosis (%) Time in days

TCT % 2.2% 3.2% 0.8% HR [95%CI] = 0.96 [ ] P = 0.92 HR [95%CI] = 1.47 [0.93,2.33] P = Number at risk 600 mg 300 mg Def/Prob Stent Thrombosis (%) Time in Days Stent Thrombosis 1-Day Landmark Analysis: Impact of Clopidogrel Loading 600mg Clopidogrel 300mg Clopidogrel

TCT % 3.6% HR [95%CI] = 0.78 [ ] P = Number at risk Eptifibatide Abciximab Def/Prob Stent Thrombosis (%) Time in days Eptifibatide Abciximab 1-Year Stent Thrombosis: Impact of GPI in the UFH Group

November 15, 2007

August 30, 2009

Conclusioni (1) La bivalirudina riduce i sanguinamenti locali e dorgano nei pazienti con SCA sottoposti a PCI, soprattutto in quelli a maggior rischio emorragico ( anziani ). Per una efficace copertura antiischemica deve essere associata ad un regime di doppia anti-aggregazione piastrinica (aspirina + bloccante recettore P2Y12).

Conclusioni (2) - I nuovi farmaci che bloccano il recettore P2Y12 ( prasugrel, ticagrelor ) sono risultati piu efficaci del clopidogrel grazie alla loro migliore farmacocinetica e farmacodinamica. Ad essi si associa tuttavia un maggior rischio emorragico. - Lanalisi di efficacia e di rischio in particolari sottogruppi di pazienti con SCA potra permettere di utilizzare il farmaco piu vantaggioso per la condizione clinica del singolo paziente.

TCT 2009 Independent Predictors of Subacute ST (Cox Model) VariableHR [95% CI]P-value Insulin-treated diabetes4.43 [2.03, 9.65] History of CHF4.16 [1.61, 10.76]0.003 Pre-PCI TIMI flow 0/12.21 [1.05, 4.63]0.04 Final TIMI flow 0/13.72 [1.10, 12.55]0.03 Stent to lesion length ratio1.44 [1.20, 1.71]< Clopidogrel loading dose 600 mg (vs. 300 mg) 0.49 [0.27, 0.89]0.01

Montalescot et al. ESC 2008 Stent thrombosis (ARC Definite/probable ) HR=0.58 (0.36–0.93) NNT=83 p=0.02 RRR=42% Proportion of patients (%) Time (Days) p=0.008 RRR=51% Clopidogrel Prasugrel Age-adjusted HR=0.59 ( )

ARC Definite or Probable Stent Thrombosis (day 0 to day 450) HR 0.48 ( ); P< Prasugrel Clopidogrel 1 year: 1.06 vs. 2.15% HR 0.48 ( ); P< ARC = Academic Research Consortium Days % of Subjects % RRR

BIVALIRUDIN UFH + GPIIbIIIa INH. DEATH RATE IN ELDERLY PATIENTS IN THE ACUITY TRIAL

Net Clinical Benefit Bleeding Risk Subgroups OVERALL >=60 kg < 60 kg < 75 >=75 No Yes Prior Stroke / TIA Age Wgt Risk (%) Prasugrel BetterClopidogrel Better HR P int = P int = 0.18 P int = 0.36 Post-hoc analysis

TCT % 3.6% HR [95%CI] = 0.78 [ ] P = Number at risk Eptifibatide Abciximab Def/Prob Stent Thrombosis (%) Time in days Eptifibatide Abciximab 1-Year Stent Thrombosis: Impact of GPI in the UFH Group

TCT % 3.8% HR [95%CI] = 1.30 [ ] P = Year Stent Thrombosis: Impact of Clopidogrel Loading Dose (all pts) Number at risk 600 mg 300 mg 600mg Clopidogrel 300mg Clopidogrel Def/Prob Stent Thrombosis (%) Time in days

TCT % 3.4% 1.5% 1.2% HR [95%CI] = 1.30 [ ] P = 0.56 HR [95%CI] =2.11 [1.07,4.17] P = Number at risk 600 mg 300 mg Def/Prob Stent Thrombosis (%) Time in Days Stent Thrombosis 1-Day Landmark Analysis: Impact of Clopidogrel Loading (Bivalirudin) 600mg Clopidogrel 300mg Clopidogrel

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, Cumulative incidence (%) Clopidogrel Ticagrelor ,279 HR 0.84 (95% CI 0.75–0.95), p= Clopidogrel Ticagrelor HR 0.79 (95% CI 0.69–0.91), p= ,291 9,333 8,865 8,294 8,780 8,822 8,589 Days after randomisation ,441 5,482 4,364 4,4198,626 Myocardial infarction Cardiovascular death Cumulative incidence (%) Secondary efficacy endpoints over time

TICAGRELOR (AZD6140) A non-thienopyridine, in the chemical class CPTP (CycloPentylTriazoloPyrimidine) 1) First oral reversible ADP P2Y 12 receptor antagonist 2) Direct acting via the P2Y 12 receptor - metabolism not required for activity ( not a pro-drug ) 3) More potent platelet inhibitor than clopidogrel HO HN HO OH OS F F N N N N N

BIVALIRUDIN UFH + GPIIbIIIa INH. DEATH RATE IN ELDERLY PATIENTS UNDERGOING PCI

Messaggi finali (1) - La doppia terapia antiaggregante e un cardine fondamentale del trattamento delle sindromi coronariche acute. - Lo studio CURRENT ha mostrato che nei pazienti con sindrome coronarica acuta il doppio dosaggio di clopidogrel ( 600 mg seguito da 150 mg per una settimana ) migliora i risultati clinici ad 1 mese solo nei pazienti sottoposti a PCI.

Messaggi finali (2) - I nuovi farmaci che bloccano il recettore P2Y12 ( prasugrel, ticagrelor ) sono risultati piu efficaci del clopidogrel negli studi di confronto a lungo termine grazie alla loro migliore farmacocinetica e farmacodinamica. Da non sottovalutare tuttavia il maggior rischio emorragico ad essi associato. - Lanalisi di efficacia e di rischio di questi nuovi farmaci antipiastrinici in particolari sottogruppi di pazienti con SCA potra permettere di utilizzare il farmaco piu vantaggioso per la condizione clinica del singolo paziente.

TRITON TIMI-38 STEMI cohort Efficacy endpoints at 30 days Montalescot et al. ESC 2008 * ARC def/probable All DeathMIUTVRStent Thrombosis* CV Death/ MI CV Death/ MI/UTVR CV Death/ MI/Stroke Proportion of population (%) p= 0.04 p= 0.01 p= 0.13 p= p= p= 0.02 p= Clopidogrel Prasugrel

Other findings – laboratory parameters All patients Ticagrelor (n=9,235) Clopidogrel (n=9,186) p value * % increase in creatinine from baseline At 1 month At 12 months Follow-up visit < % increase in uric acid from baseline At 1 month At 12 months Follow-up visit < Values are mean % SD; *p values were calculated using Fishers exact test

CREDO: Benefits of Clopidogrel Plus Aspirin to 1 Year Following PCI CV Death, MI or Stroke *Plus ASA and other standard therapies. Steinhubl S, et al. JAMA. 2002;288: Combined Endpoint Occurrence (%) Months From Randomization 27% RRR P=.02 Placebo* Clopidogrel* % 11.5%

2485 PATIENTS WITH STENT PLACEMENT PRETREATED WITH CLOPIDOGREL 600 mg

August 30, 2009 at CET

Diabetic Subgroup HR 0.70 P<0.001 Days Endpoint (%) CV Death / MI / Stroke TIMI Major NonCABG Bleeds NNT = 20 (46) N= Prasugrel Clopidogrel Prasugrel Clopidogrel

990 patients with ACS

Patients with age 60 Kg and no prior CVA/TIA Patients with age 60 Kg and no prior CVA/TIA CLOPIDOGREL(n=5383) PRASUGREL (n=5421) CV EVENTS 11% (12,1%) 11% (12,1%) 8,3% (9,9%) (DEATH,MI,STROKE) P<.001 NNT=37 (46)

Other findings All patients Ticagrelor (n=9,235) Clopidogrel (n=9,186) p value * Dyspnoea, % Any With discontinuation of study treatment <0.001 Neoplasms arising during treatment, % Any Malignant Benign *p values were calculated using Fischers exact test

Holter monitoring & Bradycardia related events Holter monitoring at first week Ticagrelor (n=1,451) Clopidogrel (n=1,415)p value Ventricular pauses 3 seconds, % Ventricular pauses 5 seconds, % Holter monitoring at 30 days Ticagrelor (n= 985) Clopidogrel (n=1,006)p value Ventricular pauses 3 seconds, % Ventricular pauses 5 seconds, % Bradycardia-related event, % Ticagrelor (n=9,235) Clopidogrel (n=9,186) p value Pacemaker Insertion Syncope Bradycardia Heart block

Kaplan Meier estimates of non-CABG-related TIMI Major bleeding Non-ideal populationIdeal population

TIMI major non-CABG bleeding Montalescot et al. ESC HR=1.11 (0.70–1.77) NNH=333 Proportion of patients (%) Time (Days) p= Clopidogrel Prasugrel Age-adjusted HR=1.19 ( )

Montalescot et al. ESC 2008 Stent thrombosis ARC Definite/probable HR=0.58 (0.36–0.93) NNT=83 p=0.02 RRR=42% Proportion of patients (%) Time (Days) p=0.008 RRR=51% Clopidogrel Prasugrel Age-adjusted HR=0.59 ( )

Diabetic Subgroup HR 0.70 P<0.001 Days Endpoint (%) CV Death / MI / Stroke TIMI Major NonCABG Bleeds NNT = 20 (46) N= Prasugrel Clopidogrel Prasugrel Clopidogrel

ARC Definite or Probable Early Stent Thrombosis (0–30 days) Prasugrel Clopidogrel HR 0.41 ( ); P< Days % of Subjects ARC = Academic Research Consortium

ARC Definite or Probable Late Stent Thrombosis* in Patients Receiving DES HR 0.46 ( ); P=0.04 ARC = Academic Research Consortium; DES = drug-eluting stent Days % of Subjects Prasugrel Clopidogrel P=.04

COMPOSITE ENPOINT IN CURRENT- OASIS 7 DOUBLE STANDARD P=.036 P=NS

Clopidogrel: Double vs Standard Dose Primary Outcome and Components StandardDoubleHR95% CIPIntn P CV Death/MI/Stroke PCI (2N=17,232) No PCI (2N=7855) Overall (2N=25,087) MI PCI (2N=17,232) No PCI (2N=7855) Overall (2N=25,087) CV Death PCI (2N=17,232) No PCI (2N=7855) Overall (2N=25,087) Stroke PCI (2N=17,232) No PCI (2N=7855) Overall (2N=25,087)

Death, MI, urgent revascularization

Clopidogrel in ACS Clopidogrel + ASA* 369 Placebo + ASA* Months of Follow-Up p = N = 12, * In addition to other standard therapies. The CURE Trial Investigators. N Engl J Med. 2001;345:494 20% Relative Risk Reduction Primary End Point – MI/Stroke/CV Death

TIMI major and minor bleeding

Should we use bivalirudin ? Fibrin 2 1 Thrombin 2 1 Thrombin 2 1 Trombina 2 1 Trombina Bivalirudin

Bivalirudin as an Alternative to UFH/LMWH Advantages of the direct thrombin inhibitor bivalirudin –No requirement for anti-thrombin III –Effective on clot-bound thrombin –Inhibits thrombin-mediated platelet activation –Plasma half-life 25 minutes –No requirement for anticoagulant monitoring Advantages of the direct thrombin inhibitor bivalirudin –No requirement for anti-thrombin III –Effective on clot-bound thrombin –Inhibits thrombin-mediated platelet activation –Plasma half-life 25 minutes –No requirement for anticoagulant monitoring

RADIAL ACCESS FEMORAL ACCESS