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Luigi Oltrona Visconti Divisione di Cardiologia IRCCS Fondazione Policlinico S. Matteo Pavia HEARTLINE 2014 IRCCS S. Martino Genoa Cardiology Meeting SCA-NSTEMI.

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Presentation on theme: "Luigi Oltrona Visconti Divisione di Cardiologia IRCCS Fondazione Policlinico S. Matteo Pavia HEARTLINE 2014 IRCCS S. Martino Genoa Cardiology Meeting SCA-NSTEMI."— Presentation transcript:

1 Luigi Oltrona Visconti Divisione di Cardiologia IRCCS Fondazione Policlinico S. Matteo Pavia HEARTLINE 2014 IRCCS S. Martino Genoa Cardiology Meeting SCA-NSTEMI Trattamento antipiastrinico ed eccesso di sanguinamento : dove portano i risultati dell’ ACCOAST ?

2 2011

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6 PCI-CURE Principali risultati

7 PCI-CURE - Disegno dello studio (2) * La terapia in aperto comprendeva un antagonista del recettore dell'ADP in associazione a ASA § La terapia tradizionale comprendeva sempre ASA, e poteva anche includere eparina, LMWH, inibitori della GP IIa/IIIb post randomizzazione, beta-bloccanti, ACE inibitori, ipolipidemizzanti e/o altre terapie o interventi (ad es. PTCA, CABG), a discrezione del medico LMWH, eparina a basso peso molecolare; GP, glicoproteina; PTCA, angioplastica coronarica transluminale percutanea; CABG, bypass coronarico The CURE Investigators. N Eng J Med August 2001 PCI Mesi 12 Clopidogrel 75 mg/die + terapia tradizionale § (n=1313) Placebo 1 cpr/die + terapia tradizionale § (n=1345) PCI = Intervento coronarico percutaneo Giorno 30 Tienopiridina +ASA in aperto* per 2-4 settimane Mesi 12Giorno 30

8 *On top of standard therapy (including ASA) PCI-CURE: 31% Riduzione del Rischio Relativo a Lungo Termine 1 1. Mehtra SR et al. Lancet 2001; 358: 527–33. Endpoint: Infarto Miocardico o Morte Cardiovascolare Giorni di follow-up Tasso di rischio cumulativo Placebo * (n = 1,345) Riduzione del rischio relativo p < Clopidogrel * (n = 1,313) Tempo mediano dalla PCI 10 31%

9 The CREDO Trial Clopidogrel for the Reduction of Events During Observation

10 Disegno dello studio Braccio Clopidogrel Braccio Placebo PCI 28 Giorni LD Placebo # Pre-trattaento LD Clopidogrel # Clopidogrel # LD=dose di carco, PT= Pre-trattamento, R= Randomizzatzione # in aggiunta alla terapia standard comprendente ASA (325 mg) in aggiunta alla terapia standard comprendente ASA ( mg) R Clopidogrel * Placebo * 12 Mesi Steinhubl S, et al. JAMA, November 20, 2002 – Vol 288, No 19: 2411 – 2420

11 Precoce effetto del pretrattamento con Clopidogrel: risultati “ Per – Protocollo » 18.5 % RRR p = 0.23 *Dal PCI sino al 28 giorno, In aggiunta alla terapia standard comprendente ASA (325mg dalla randomizzazione al 28° giorno) PT= Pre-trattamento UTVR: Target Vessel Revascularization Urgente GIORNI DALLA RANDOMIZZAZIONE PT con Clopidogrel* Senza PT con Clopidogrel* 6.8% 8.3% (Morte, IM e TVR urgente) Risultati a 28 giorni Steinhubl S, et al. JAMA, November 20, 2002 – Vol 288, No 19: 2411 – 2420 COMPARSA DELL’ ENDPOINT COMPOSITO (%)

12 Momento della dose di carico risultato a 28 giorni Hazard ratio (95% CI) < 6 hrs to 24 hr RRR p=NS RRR 38.6 p=0.05 RRR 18.5 p=0.23 Risultati globali dello studio CREDO n PT-Clopidogrel* Senza-PT Clopidogrel* Eventi (%) Senza-PT Clopidogrel migliore PT-Clopidogrel migliore * In aggiunta alla terapia standard comprendente ASA, PT= Pre-trattamento Steinhubl S, et al. JAMA, November 20, 2002 – Vol 288, No 19: 2411 – 2420

13 Study Design Double-blind ACS (STEMI or UA/NSTEMI) & Planned PCI ASA PRASUGREL 60 mg LD/ 10 mg MD CLOPIDOGREL 300 mg LD/ 75 mg MD 1 o endpoint: CV death, MI, Stroke 2 o endpoints:CV death, MI, Stroke, Rehosp-Rec IschCV death, MI, UTVR Stent Thrombosis (ARC definite/prob.) Safety endpoints: TIMI major bleeds, Life-threatening bleeds Key Substudies:Pharmacokinetic, Genomic Median duration of therapy - 12 months N= 13,600 Nuovi antiaggreganti orali : prasugrel – evidenze cliniche di efficacia

14 HR 0.81 ( ) P= Prasugrel Clopidogrel HR 0.80 P= HR 0.77 P= Days Primary Endpoint (%) 12.1 (781) 9.9 (643) Primary Endpoint CV Death,MI,Stroke NNT= 46 ITT= 13,608 LTFU = 14 (0.1%) Nuovi antiaggreganti orali : prasugrel – evidenze cliniche di efficacia

15 A Comparison of Prasugrel at the Time of Percutaneous Coronary Intervention Or as Pre-treatment At the Time of Diagnosis in Patients with Non-ST-Elevation Myocardial Infarction (NSTEMI)

16 ACCOAST Trial design Prasugrel 30 mg Prasugrel 60 mg Prasugrel 30 mg Prasugrel 10 mg or 5 mg (based on weight and age) for 30 days PCI 1° Endpoint: CV Death, MI, Stroke, Urg Revascularization, GP IIb/IIIa bailout at 7 days Placebo Coronary Angiography n~4100 (event driven) Coronary Angiography PCI CABG or Medical Management (no prasugrel) CABG or Medical Management (no more prasugrel) Montalescot G et al. Am Heart J 2011;161: Randomize 1:1 Double-blind NSTEMI + Troponin ≥ 1.5 times ULN local lab value Clopidogrel naive or on long term clopidogrel 75 mg

17 NEJM 2013;369:

18 To answer the question: IN NSTEMI patients, does having good inhibition of P2Y12 mediated platelet activation and aggregation prior to the start of PCI reduce the incidence of ischemic events compared to administration of a fast acting inhibitor (prasugrel) on the table?” Potential benefits of pretreatment: Prevention of ischemic events in NSTEMI patients while waiting for the PCI, during and after PCI. Potential risks of pretreatment: Bleeding risks need to be considered when starting platelet inhibition in NSTEMI patients before the coronary anatomy is known (eg, the patient will not be a candidate for PCI- medical management or CABG). Clinical questions and rationale of the study

19 Enrollment: >4,000 patients in 19 Countries Enrollment: >4,000 patients in 19 Countries Canada: 146 Finland: 42 Hungary: 134 Netherlands: 142 Sweden: 4 Belgium: 81 France: 586 Austria: 172 Italy: 628 Israel: 131 Poland: 847 Czech Rep: 292 Germany: 529 Romania: 85 Turkey: 112 Lithuania: 73 Portugal: 17 Slovakia: 47 Latvia: 5 Montalescot et al. NEJM 2013; epub Sept 1

20 Toni Badia, Ospedale Misericordia e Dolce, Prato; Sergio Berti, Fondazione Toscana G. Monasterio -Ospedale del Cuore G. Pasquinucci, Massa; Leonardo Bolognese, Cardiovascular and Neurological Department Azienda Ospedaliera Arezzo; Francesco Maria Bovenzi, Ospedale Campo di Marte, Lucca; Paola Camisasca,Nuovo Ospedale San Gerardo, Monza, Milano; Claudio Cavallini, Ospedale Santa Maria della Misericordia,Perugia; Raffaele De Caterina, Ospedale SS. Annunziata, Chieti; Stefano De Servi, Ospedale di Legnano, Legnano,Milano; Giuseppe Fantini, Policlinico Universitario Modena, Modena; Claudio Fresco, Azienda Ospedaliero Universitaria Santa Maria della Misericordia, Udine; Antonio Manari, Azienda Ospedaliera-IRCCS S. Maria Nuova, Reggio Emilia; Sebastiano Marra, Azienda Ospedaliera S.Giovanni Battista, Torino; Ciro Mauro, AziendaOspedaliera Antonio Cardarelli, Napoli; Luca Olivotti, Ospedale Santa Corona, Pietra Ligure; Anna Sonia Petronio, Stabilimento Ospedaliero di Cisanello, Pisa; Francesco Prati, S. Giovanni Hospital, Rome; Bernhard Reimers, Ospedale Civile di Mirano, Venezia; Massimo Santini, Ospedale S. Filippo Neri, Roma; Silva Severi, Ospedale Misericordia, Grosseto; Luigi Oltrona Visconti, Division of Cardiology, Fondazione IRCCS Policlinico San Matteo, Pavia; Corrado Tamburino, Ospedale Ferrarotto, Catania; Roberto Zanini, Ospedale Civile Carlo Poma, Mantova.

21 Main Inclusion/Exclusion Criteria Inclusion  NSTEMI symptoms within 48 hours prior to study entry  Elevated troponin (≥1.5 times ULN) per local lab(s)  Patient to be scheduled for coronary angiography and PCI within 2 hours to 24 hours of randomization and no later than 48 hours after randomization Exclusion  STEMI patients  Medical history contraindicating therapy with prasugrel  History of stroke or transient ischemic attack (TIA)  LD of any P2Y 12 antagonist ≤ 7 days of study entry Montalescot G et al. Am Heart J 2011;161: e1

22 Patient Disposition Pre-treatment N=2037 Lost to Follow-up 1 (0.05) ITT and All Treated N= 4033 Total Randomized N= Subjects Revoked Consent Day 30 Visit N=1958 (96.12%) Day 7 N=2009 (98.63%) No Pre-treatment N=1996 Lost to Follow-up 2 (0.10) Day 30 Visit N=1924 (96.39%) Day 7 N=1964 (98.40%) Montalescot et al. NEJM 2013; epub Sept 1

23 Baseline Characteristics Characteristics Pre-treatment (N =2037) No Pre-treatment (N =1996) Age (mean, yrs) Female sex (%) Weight (mean, kg) BMI ≥ 30 (%) CV risk factors (%) Diabetes mellitus Dyslipidemia Hypertension Current smoker Region of enrolment (%) Eastern Europe/Israel Western Europe/Canada Montalescot et al. NEJM 2013; epub Sept 1

24 Characteristics Pre-treatment (N =2037) No Pre-treatment (N =1996) GRACE score (%) < ≥ CRUSADE score n, (median)1899 (34.0)1941 (34.0) Timing (hr)  Symptom onset to 1st LD, median2036 (14.6)1996 (15.2)  1 st LD to coronary angiogram, median2017 (4.4)1985 (4.2) Access (%) ‖ Femoral 1140 (56.6) 1136 (57.3) Radial 869 (43.2) 842 (42.5) Baseline Characteristics Montalescot et al. NEJM 2013; epub Sept 1

25 Concomitant medications through 7 days (%) Pre-treatment (N =2037) No Pre-treatment (N =1996) Aspirin, (%) Antithrombin Use, (%) * UFH LMWH Bivalirudin Fondaparinux Proton pump inhibitor Beta blockers Statins89.5 ARBs ACE inhibitors Calcium channel blockers On a MD of clopidogrel at randomization** 2.2 Baseline Characteristics *Monotherapy is reported; N=1323 for pre-treatment and N=1275 for no pre-treatment **75-mg dose allowed per the protocol Montalescot et al. NEJM 2013; epub Sept 1

26 Efficacy Results

27 1° Efficacy End days (All Patients) Montalescot et al. NEJM 2013; epub Sept 1

28 Secondary Efficacy Endpoint of CV Death, MI, Stroke (All Patients) Montalescot et al. NEJM 2013; epub Sept 1

29 1° Efficacy Endpoint (PCI Patients) Montalescot et al. NEJM 2013; epub Sept 1

30 Major Efficacy Endpoints Through 7 Days (All Patients) *Hazard ratio and two-sided 95% CI are from a Cox proportional hazards model with treatment as a fixed effect. †Two-sided P-value based on the log rank test. Endpoint Pre-treatment (n = 2037) No pre-treatment (n = 1996) HR* (95% CI)P-Value † CVD, MI, stroke, UR or GPIIb/IIIa bailout (primary endpoint) 203 (10.0)195 (9.8)1.02 (0.84, 1.25)0.81 Death All cause 8 (0.4)10 (0.5)0.78 (0.31, 1.98)0.61 CV 7 (0.3)10 (0.5)0.69 (0.26, 1.80)0.44 MI 119 (5.8)109 (5.5)1.07 (0.83, 1.39)0.60 Stroke 8 (0.4)10 (0.5)0.78 (0.31, 1.98)0.60 UR 22 (1.1)26 (1.3)0.83 (0.47, 1.46)0.52 GPIIb/IIIa bailout 76 (3.7)78 (3.9)0.96 (0.70, 1.31)0.79 Montalescot et al. NEJM 2013; epub Sept 1

31 1° Efficacy Endpoint Through 7 Days for Prespecified Subgroups (All Patients) *Hazard ratio not evaluated for <10 events. †Interaction P-value is from a Cox proportional hazards model with treatment, subgroup, and the treatment-by-subgroup interaction as fixed effects; PCI includes 11 patients with PCI + CABG. Montalescot et al. NEJM 2013; epub Sept 1

32 Safety Results

33 All TIMI (CABG or non-CABG) Major Bleeding (All Treated patients) Days From First Dose Endpoint (%) Pre-treatment 2.9 No Pre-treatment 1.5 Hazard Ratio, 1.97 (95% 1.26, 3.08) P=0.002 All TIMI Major Bleeding Hazard Ratio, 1.90 (95% 1.19, 3.02) P=0.006 Pre-treatment 2.6 No Pre-treatment No. at Risk, All TIMI Major Bleeding: No pre-treatment Pre-treatment Montalescot et al. NEJM 2013; epub Sept 1

34 All TIMI Major Bleeding (PCI Patients) Montalescot et al. NEJM 2013; epub Sept 1

35 Non-CABG TIMI Major Bleeding Endpoints Through 7 Days (All Treated Patients) Most Frequent Locations of Major Bleed P=0.003 NE* P=0.002 *not evaluable N= < Montalescot et al. NEJM 2013; epub Sept 1

36 *Hazard ratio not evaluated for <10 events. †Interaction P-value is from a Cox proportional hazards model with treatment, subgroup, and the treatment-by-subgroup interaction as fixed effects; ‡CRUSADE score is a post-hoc analysis; PCI includes 11 patients with PCI + CABG. All TIMI Major Bleeding for Prespecified Subgroups Through 7 days (All Treated Patients) Montalescot et al. NEJM 2013; epub Sept 1

37 GUSTO, STEEPLE Bleeding Endpoints/ TIMI Transfusion Through 7 Days (All Treated Patients) GUSTO, STEEPLE Bleeding Endpoints/ TIMI Transfusion Through 7 Days (All Treated Patients) Endpoint Pre- treatment (n = 2037) No pre- treatment (n = 1996) HR* (95% CI)P-Value † GUSTO moderate or severe, CABG or non-CABG 70 (3.4)35 (1.8)1.98 (1.32, 2.97)<0.001 STEEPLE major (non-CABG)46 (2.3)18 (0.9)2.52 (1.46, 4.35)<0.001 STEEPLE minor (non-CABG)58 (2.8)38 (1.9)1.50 (1.00, 2.26)0.05 Total Transfusion ‖ 41 (2.0)22 (1.1)1.84 (1.09, 3.08)0.02 Non-CABG TIMI major ‖ 20 (1.0)7 (0.4)2.81 (1.19, 6.63)0.01 *Hazard ratio and two-sided 95% CI are from a Cox proportional hazards model with treatment as a fixed effect. †Two-sided P-value based on the log rank test. ‖ Transfusion includes: any transfusion, fresh frozen plasma, packed red blood cells, platelets, whole blood cells. Event rates are raw percents. Montalescot et al. NEJM 2013; epub Sept 1

38 Overall Conclusions  In NSTEMI patients managed invasively within 48 hours of randomization, pre-treatment with prasugrel does not reduce major ischemic events up to 30 days and increases major bleeding complications.  The efficacy and safety results are consistent among patients undergoing PCI  No subgroup appears to have a favorable risk/benefit ratio with pre-treatment.

39 Considerations

40 Overall Conclusions (L. Oltrona)  in intermediate risk NSTEMI patients  early invasively managed (median 4.3 hrs post randomisation)  pre-treatment with 30 mg of prasugrel (+ 30 mg at the time of PCI) does not reduce major ischemic events up to 30 days but increases major bleeding complications.  ( The efficacy and safety results are consistent among patients undergoing PCI. No subgroup appears to have a favorable risk/benefit ratio with pre-treatment)  Drug failure or strategy failure ?

41 The most frequent questions 1. Risk-level of population 2. Timing of PCI 3. Drug dosage (pharmacodynamic considerations) 4. Clopidogrel pretreated 5. Medically managed pts 6. Femoral vs radial approach

42 The most frequent questions 1. Risk-level of population 2. Timing of PCI 3. Drug dosage (pharmacodynamic considerations) 4. Clopidogrel pretreated 5. Medically managed pts 6. Femoral vs radial approach

43 Baseline Characteristics Age < 75 Years (N = 7243)Overall Population (N = 9326) Prasugrel (N = 3620) Clopidogrel (N = 3623) Prasugrel (N = 4663) Clopidogrel (N = 4663) Age—yr62 (56–68) 66 (58–74)66 (59–73) Female sex—% Body weight < 60 kg—% Disease classification—% NSTEMI Unstable angina Medical History—% Diabetes mellitus Current/recent smoking Prior myocardial infarction Prior PCI Prior CABG Baseline risk assessment GRACE risk score 114 (101–128)115 (102–128) 122 (105–140)121 (106–138) Creatinine clearance—mL/min81 (63–104) 81 (63–102)73 (54–97) 73 (54–96) Angiography performed pre-randomization—% Post-randomization revascularization performed in 7.5% of patients

44 CrCl <50 ml/min (n=1730) CrCl ≥50 ml/min (n=7257) Excess dose (n=594) Adjusted dose (n=1136) Standard dose (n=7257) Baseline characteristics (%) Median age, yrs*77.5 (72.0, 81.7) 78.0 (72.0, 82.5) 65.1 (58.4, 71.9) Female sex Region of enrollment North America Western Europe Eastern Europe Middle East, Africa, Asia Diabetes Dyslipidemia Hypertension Prior CABG Prior MI Prior PCI Baseline CrCl (ml/min)*43.9 (37.3, 47.3) 38.8 (31.7, 44.9) 81.4 (66.3, 101.7) TIMI risk categories > Baseline Characteristics by CrCl and Dose of Study Drug

45 ECG Abnormalities: Ischemia/ ST Depression at Baseline ECG abnormality at baseline; n (%) Pre-treatment (N=2037) n (%) No Pre-treatment (N=1996) n (%) Total (N=4033) n (%) Ischemic abnormalities1118 (55)1061 (54)2179 (54) ST depression 0.5 to <1 mm420 (38)353 (33)773 (35) ST depression ≥ 1 mm289 (26)240 (23)529 (24) Montalescot et al. NEJM 2013; epub Sept 1

46 Montalescot et al. Am Heart J 2011; 161 :

47 The most frequent questions 1. Risk-level of population 2. Timing of PCI 3. Drug dosage (pharmacodynamic considerations) 4. Clopidogrel pretreated 5. Medically managed pts 6. Femoral vs radial approach

48 Time to Angiography/PCI Montalescot et al. NEJM 2013; epub Sept 1 Mehta SR, et al. N Engl J Med. 2010;363(10): Bhatt DL, et al. N Engl J Med. 2013;368(14): Tricoci P, et al. N Engl J Med. 2012;366(1): Cannon CP, et al. Lancet. 2010;375(9711): Stone GW, et al. N Engl J Med. 2006;355(21):

49 No differences between quartiles of time to PCI (highest quartile > 15 hours)

50 LOV 13 Time intervals to angio/PCI Hospital admission Hours days ACCOAST PCI- CURE CREDO Real world ?? IR median mean

51 The most frequent questions 1. Risk-level of population 2. Timing of PCI 3. Drug dosage (pharmacodynamic considerations) 4. Clopidogrel pretreated 5. Medically managed pts 6. Femoral vs radial approach

52 ACCOAST PFS: Results VerifyNow P2Y12 PRU Montalescot et al. NEJM 2013; epub Sept 1 *P<0.05 Placebo LD1 30 mg LD1 Approximate time of PCI 60 mg LD2 30 mg LD2

53 Inhibition of Platelet Aggregation After a Single Prasugrel 30 mg Dose Time Post-dose (Hours) Inhibition of Platelet Aggregation (%) Prasugrel 30 mg Mean ± SD Non-responders: IPA <20% ±2 SD (representing 95% of the data) 14 healthy Caucasian subjects, IPA (LTA 20 µM ADP), mean ± SD Small DS, et al. Clin Ther 2010;32:

54 The most frequent questions 1. Risk-level of population 2. Timing of PCI 3. Drug dosage (pharmacodynamic considerations) 4. Clopidogrel pretreated 5. Medically managed pts 6. Femoral vs radial approach

55 Montalescot et al. Am Heart J 2011; 161 :

56 Backups

57 Treatment Emergent Adverse Event Through 30 Days From First LD Reported in >1% of Total Population Pre- treatment N=2037 No Pre- treatment N=1996 Total N=4033 P- value Treatment Emergent Adverse Event (System organ class and preferred term) n % Respiratory, thoracic and mediastinal disorders Epistaxis38 (1.88)30 (1.50)68 (1.69)0.371 Vascular disorders Hematoma102 (5.01)60 (3.01)162 (4.02)0.001 Montalescot et al. NEJM 2013; epub Sept 1

58 Primary and Secondary Efficacy Endpoints Prior to Angiography Primary Composite Components Pre- treatment N=2014 No Pre- treatment N=1981 Total N=3995 P- value* CVD/MI/Stroke/UR/GPIIb/IIIa Bailout 16 (0.79) 18 (0.91) 34 (0.85)0.926 CVD 0 (0.00) MI 6 (0.30) 8 (0.40) 14 (0.35)0.852 Stroke 0 (0.00) UR 5 (0.25) 7 (0.35) 12 (0.30)0.832 GPIIb/IIIa Bailout 5 (0.25) 10 (0.25)1.000 *P-value based on two-sided Pearson Chi-square test. Montalescot et al. NEJM 2013; epub Sept 1

59 Non-CABG Related Bleeding: 1. Major Any intracranial bleeding (excluding microhemorrhages <10 mm evident only on gradient-echo MRI)intracranial bleeding Clinically overt signs of hemorrhage associated with a drop in hemoglobin of ≥5 g/dL or a ≥15% absolute decrease in haematocrithemorrhagehaematocrit Fatal bleeding (bleeding that directly results in death within 7 d) 2. Minor Clinically overt (including imaging), resulting in hemoglobin drop of 3 to <5 g/dL or ≥10% decrease in haematocrit haematocrit No observed blood loss: ≥4 g/dL decrease in the haemoglobin concentration or ≥12% decrease in haematocrit haematocrit Any overt sign of hemorrhage that meets one of the following criteria and does not meet criteria for a major or minor bleeding event, as defined abovehemorrhage Requiring intervention (medical practitioner-guided medical or surgical treatment to stop or treat bleeding, including temporarily or permanently discontinuing or changing the dose of a medication or study drug)bleeding Leading to or prolonging hospitalization Prompting evaluation (leading to an unscheduled visit to a healthcare professional and diagnostic testing, either laboratory or imaging) 3. Minimal Any overt bleeding event that does not meet the criteria above Any clinically overt sign of haemorrhage (including imaging) associated with a <3 g/dL decrease in haemoglobin concentration or <9% decrease in haematocrithaemorrhagehaematocrit TIMI Bleeding Criteria

60 Bleeding in the Setting of CABG: Fatal bleeding (bleeding that directly results in death) Perioperative intracranial bleedingintracranial bleeding Reoperation after closure of the sternotomy incision for the purpose of controlling bleeding Transfusion of ≥5 U PRBCs or whole blood within a 48-h period; cell saver transfusion will not be counted in calculations of blood products. Chest tube output >2 L within a 24-h period

61 Major Bleeding Fatal bleedingbleeding Retroperitoneal, intracranial, or intraocular bleedingintraocular bleeding Bleeding that causes hemodynamic compromise requiring specific treatment Bleeding that requires intervention (surgical or endoscopic) or decompression of a closed space to stop or control the event Clinically overt bleeding, requiring any transfusion of ≥1 U PRBC or whole blood Clinically overt bleeding, causing a decrease in hemoglobin of ≥3 g/dL (or, if hemoglobin level is not available, a decrease in hematocrit of ≥10%) Minor Gross hematuria not associated with trauma (eg, from instrumentation)hematuriatrauma Epistaxis that is prolonged, is repeated, or requires plugging or interventionEpistaxis Gastrointestinal hemorrhage Hemoptysis Subconjunctival hemorrhage Hematoma >5 cm or leading to prolonged or new hospitalizationHematoma Clinically overt bleeding, causing a decrease in hemoglobin of 2 to 3 g/dL Uncontrolled bleeding requiring protamine sulfate administration Steeple Bleeding Criteria

62 MI Summary through 7 Days ITT Population CEC adjudicated Pre-treatment (N=2037) No Pre-treatment (N=1996) Total subjects with MI Type of MIn (%) Type 14 (3.36)7 (6.42) Type 21 (0.84)2 (1.83) Type 31 (0.84)1 (0.92) Type 4a110 (92.44)98 (89.91) Type 4b0 (0.0)1 (0.92) Type 53 (2.52)0 (0.0) Other0 (0.00) Data on File, Daiichi Sankyo, Inc. and Eli Lilly and Company

63 Cohort or Subcohort Pre-treatment N=2037 No Pre-treatment N=1996 Total N=4033 HR a (95% CI) P value b Nn / %N N Overall (9.97) (9.77) (9.87)1.02 (0.84, 1.25)0.812 PCI Only (13.13) (13.08) (13.10)1.01 (0.82, 1.24)0.927 PCI+CABG62 (33.33)51 (20.00)113 (27.27)NE CABG Only1219 (7.44)1178 (6.84)23817 (7.14)1.08 (0.42, 2.79)0.879 MM5169 (1.74)4986 (1.20) (1.48)1.45 (0.528, 4.09)0.475 Abbreviations: CVD = cardiovascular death; GP = glycoprotein; HR = hazard ratio based on Cox proportional hazard model with no pre-treatment in denominator and pre-treatment in numerator; LD = loading dose; MI = myocardial infarction; NE = not estimable; UR = urgent revascularization. a HR (pre-treatment/no pre-treatment) and two-sided 95% CI are from a Cox proportional hazards model with treatment as a fixed effect. b Two-sided P-value based on the log rank test. Primary Efficacy Composite Endpoint (CVD, MI, Stroke, UR, GPIIb/IIIa Bailout through 7 Days from 1st LD) Overall and by Subcohort Data on File, Daiichi Sankyo, Inc. and Eli Lilly and Company

64 Major and Other Efficacy Endpoints Through 30 days (All Patients) *Hazard ratio and two-sided 95% CI are from a Cox proportional hazards model with treatment as a fixed effect. †Two-sided P-value based on the log rank test. Endpoint Pre-treatment (n = 2037) No pre-treatment (n = 1996) HR* (95% CI)P-Value † 30 Days CVD, MI, stroke, UR, or GPIIb/IIIa bailout 219 (10.8)216 (10.8)1.00 (0.83, 1.20)0.98 CVD, MI, or stroke144 (7.1)144 (7.2)0.98 (0.78, 1.23)0.86 CVD or MI135 (6.6)130 (6.5)1.02 (0.80, 1.30)0.88 CVD, MI, or UR157 (7.7)146 (7.3)1.06 (0.85, 1.33)0.62 CVD14 (0.7)22 (1.1)0.62 (0.32, 1.22)0.16 MI126 (6.2)116 (5.8)1.07 (0.83, 1.37)0.62 Montalescot et al. NEJM 2013; epub Sept 1

65 Major Efficacy Endpoints Through 30 Days (All Patients) *Hazard ratio and two-sided 95% CI are from a Cox proportional hazards model with treatment as a fixed effect. †Two-sided P-value based on the log rank test. Montalescot et al. NEJM 2013; epub Sept 1

66 Primary and Secondary Efficacy Endpoints Prior to Angiography Primary Composite Components Pre-treatment N=2014 No Pre- treatment N=1981 Total N=3995 P-value* CVD/MI/Stroke/UR/GPIIb/IIIa Bailout 16 (0.79) 18 (0.91) 34 (0.85)0.926 CVD 0 (0.00) MI 6 (0.30) 8 (0.40) 14 (0.35)0.852 Stroke 0 (0.00) UR 5 (0.25) 7 (0.35) 12 (0.30)0.832 GPIIb/IIIa Bailout 5 (0.25) 10 (0.25)1.000 *P-value based on two-sided Pearson Chi-square test. Montalescot et al. NEJM 2013; epub Sept 1

67 All TIMI (CABG or non-CABG) Major or Minor Bleeding (All Treated Patients) Montalescot et al. NEJM 2013; epub Sept 1

68 TIMI Bleeding Endpoints Through 7 Days (All Treated Patients) TIMI Bleeding Endpoints Through 7 Days (All Treated Patients) Endpoint Pre-treatment (n = 2037) No pre- treatment (n = 1996) HR* (95% CI) P- Value † All CABG or non-CABG TIMI major bleeding (key safety endpoint) 52 (2.6)27 (1.4)1.90 (1.19, 3.02)0.006 Non-CABG TIMI major bleeding27 (1.3)9 (0.5)2.95 (1.39, 6.28)0.003 Fatal bleeding1 (<0.1)0 (0.00)NE Life threatening bleeding17 (0.8)3 (0.2)5.56 (1.63,19.0)0.002 Non-CABG TIMI major/minor bleeding61 (3.0)20 (1.0)3.02 (1.82, 5.01)<0.001 CABG Only TIMI major bleeding (n=121) 25 (20.7) (n=117) 16 (13.7) 1.59 (0.85, 2.98)0.14 *Hazard ratio and two-sided 95% CI are from a Cox proportional hazards model with treatment as a fixed effect. †Two-sided P-value based on the log rank test. Event rates are raw percents. Montalescot et al. NEJM 2013; epub Sept 1

69 Number of Patients with Life Threatening Bleeding Through 7 Days (PCI Cohort) Location of Life Threatening Bleed Montalescot et al. NEJM 2013; epub Sept 1

70 TIMI Non-CABG Major Bleeding for Prespecified Subgroups Through 7 days (All Treated Patients) *Hazard ratio not evaluated for <10 events. †Interaction P-value is from a Cox proportional hazards model with treatment, subgroup, and the treatment-by-subgroup interaction as fixed effects; PCI includes 11 patients with PCI + CABG. Montalescot et al. NEJM 2013; epub Sept 1

71 TIMI, GUSTO, STEEPLE Bleeding Endpoints Through 7 Days (All Treated Patients) P=0.003 P=0.001 P<0.001 N= Montalescot et al. NEJM 2013; epub Sept 1

72 P=0.002 NE* P<0.001 *not evaluable Non-CABG TIMI Major Bleeding Endpoints Through 30 Days (All Treated Patients) Most Frequent Locations of Major Bleed N= Montalescot et al. NEJM 2013; epub Sept 1

73 TIMI Bleeding Endpoints Through 30 Days (All Treated Patients) TIMI Bleeding Endpoints Through 30 Days (All Treated Patients) Endpoint Pre- treatment (n = 2037) No pre- treatment (n = 1996) HR* (95% CI) P- Value † All CABG or non-CABG TIMI major bleeding (key safety endpoint) 58 (2.8)29 (1.5)1.97 ( 1.26, 3.08)0.002 Non-CABG TIMI major bleeding32 (1.6)11 (0.6)2.86 (1.44, 5.68)0.002 Fatal bleeding3 (0.1)0 (0)NE Life threatening bleeding22 (1.1)4 (0.2)5.40 (1.86,15.68)<0.001 Non-CABG TIMI major/minor bleeding73 (3.6)23 (1.2)3.15 (1.97, 5.03)<0.001 CABG Only TIMI major bleeding (n=157) 27 (17.2) (n=157) 16 (10.2) 1.77 (0.95, 3.28)0.07 *Hazard ratio and two-sided 95% CI are from a Cox proportional hazards model with treatment as a fixed effect. †Two-sided P- value based on the log rank test. Event rates are raw percents. Montalescot et al. NEJM 2013; epub Sept 1


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