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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 Trattamento antipiastrinico ed eccesso di sanguinamento : dove portano i risultati dell’ ACCOAST ?. Luigi Oltrona Visconti Divisione di Cardiologia IRCCS Fondazione Policlinico S. Matteo Pavia. 2011.

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Luigi Oltrona Visconti Divisione di Cardiologia IRCCS Fondazione Policlinico S. Matteo Pavia

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

  2. 2011

  3. PCI-CURE Principali risultati

  4. PCI-CURE - Disegno dello studio (2) Giorno 30 Mesi 12 Clopidogrel 75 mg/die +terapia tradizionale § (n=1313) PCI Placebo 1 cpr/die + terapia tradizionale § (n=1345) Tienopiridina +ASA in aperto* per 2-4 settimane Giorno 30 Mesi 12 PCI = Intervento coronarico percutaneo * 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

  5. Placebo*(n = 1,345) 0.15 31% Tempo mediano dalla PCI Riduzionedel rischio relativo p < 0.002 0.10 Tasso di rischio cumulativo Clopidogrel*(n = 1,313) 0.05 0.00 10 0 100 200 300 400 Giorni di follow-up PCI-CURE: 31% Riduzione del Rischio Relativo a Lungo Termine1 Endpoint: Infarto Miocardico o Morte Cardiovascolare *On top of standard therapy (including ASA) 1. Mehtra SR et al.Lancet 2001; 358: 527–33.

  6. The CREDO TrialClopidogrel for the Reduction of EventsDuring Observation

  7. Disegno dello studio PCI 28 Giorni 12 Mesi Pre-trattaento Braccio Clopidogrel Clopidogrel# Clopidogrel* LDClopidogrel# R Placebo* Clopidogrel# Braccio Placebo LD Placebo# • 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 (81-325 mg) Steinhubl S, et al. JAMA, November 20, 2002 – Vol 288, No 19: 2411 – 2420

  8. Precoce effetto del pretrattamento con Clopidogrel: risultati “ Per – Protocollo » Risultati a 28 giorni (Morte, IM e TVR urgente) 8.3% 18.5 % RRR p = 0.23 6.8% COMPARSA DELL’ ENDPOINT COMPOSITO (%) PT con Clopidogrel* Senza PT con Clopidogrel* 0 7 14 21 28 GIORNI DALLA RANDOMIZZAZIONE *Dal PCI sino al 28 giorno, In aggiunta alla terapia standard comprendente ASA (325mg dalla randomizzazione al 28° giorno) PT= Pre-trattamentoUTVR: Target Vessel Revascularization Urgente Steinhubl S, et al. JAMA, November 20, 2002 – Vol 288, No 19: 2411 – 2420

  9. 0.6 0.8 1.0 1.2 Momento della dose di carico risultato a 28 giorni Eventi (%) Senza-PT Clopidogrel migliore PT-Clopidogrel migliore Senza-PT Clopidogrel* PT-Clopidogrel* n RRR -13.4 p=NS < 6 hrs 7.9 7.0 893 6 to 24 hr 5.8 9.4 851 RRR 38.6 p=0.05 RRR 18.5 p=0.23 Risultati globali dello studio CREDO Hazard ratio (95% CI) * In aggiunta alla terapia standard comprendente ASA, PT= Pre-trattamento Steinhubl S, et al. JAMA, November 20, 2002 – Vol 288, No 19: 2411 – 2420

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

  11. Nuovi antiaggreganti orali : prasugrel – evidenze cliniche di efficacia Primary Endpoint CV Death,MI,Stroke 15 Clopidogrel 12.1(781) 9.9 (643) 10 Primary Endpoint (%) Prasugrel HR 0.81(0.73-0.90)P=0.0004 HR 0.80P=0.0003 HR 0.77P=0.0001 5 NNT= 46 LTFU = 14 (0.1%) ITT= 13,608 0 0 30 60 90 180 270 360 450 Days

  12. AComparison 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)

  13. ACCOAST Trial design NSTEMI + Troponin ≥ 1.5 times ULN local lab value Clopidogrel naive or on long term clopidogrel 75 mg n~4100 (event driven) Randomize 1:1 Double-blind Prasugrel 30 mg Placebo CABG or Medical Management (no more prasugrel) CABG or Medical Management (no prasugrel) Coronary Angiography Coronary Angiography Prasugrel 60 mg Prasugrel 30 mg PCI PCI Prasugrel 10 mg or 5 mg (based on weight and age) for 30 days 1° Endpoint: CV Death, MI, Stroke, Urg Revascularization, GP IIb/IIIa bailout at 7 days Montalescot G et al. Am Heart J 2011;161:650-656

  14. NEJM 2013;369:999-1010

  15. Clinical questions and rationale of the study 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).

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

  17. 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.

  18. 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 P2Y12 antagonist ≤ 7 days of study entry Montalescot G et al. Am Heart J 2011;161:650-656.e1

  19. Patient Disposition Total Randomized N=4038 5 Subjects Revoked Consent ITT and All Treated N= 4033 No Pre-treatment N=1996 Pre-treatment N=2037 Day 7 N=1964 (98.40%) Day 7 N=2009 (98.63%) Day 30 Visit N=1958 (96.12%) Day 30 Visit N=1924 (96.39%) Lost to Follow-up 2 (0.10) Lost to Follow-up 1 (0.05) Montalescot et al. NEJM 2013; epub Sept 1

  20. Baseline Characteristics Montalescot et al. NEJM 2013; epub Sept 1

  21. Baseline Characteristics Montalescot et al. NEJM 2013; epub Sept 1

  22. 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

  23. Efficacy Results

  24. 1° Efficacy End Point @ 7 + 30 days (All Patients) Montalescot et al. NEJM 2013; epub Sept 1

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

  26. 1° Efficacy Endpoint (PCI Patients) Montalescot et al. NEJM 2013; epub Sept 1

  27. 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. Montalescot et al. NEJM 2013; epub Sept 1

  28. 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

  29. Safety Results

  30. All TIMI (CABG or non-CABG) Major Bleeding (All Treated patients) 5 Hazard Ratio, 1.90 Hazard Ratio, 1.97 (95% 1.19, 3.02) (95% 1.26, 3.08) 4 P=0.006 P=0.002 Pre-treatment 2.9 3 Pre-treatment 2.6 Endpoint (%) 2 All TIMI Major Bleeding 1 No Pre-treatment 1.5 0 No Pre-treatment 1.4 0 5 10 15 20 25 30 Days From First Dose No. at Risk, All TIMI Major Bleeding: No pre-treatment 1947 1328 1284 1263 1996 1297 1288 Pre-treatment 1972 1339 1297 1280 2037 1310 1299 Montalescot et al. NEJM 2013; epub Sept 1

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

  32. Non-CABG TIMI Major Bleeding Endpoints Through 7 Days (All Treated Patients) Most Frequent Locations of Major Bleed P=0.003 1.3 P=0.002 0.8 NE* 0.5 <0.1 0 0.2 1 0 N= 27 9 17 3 *not evaluable Montalescot et al. NEJM 2013; epub Sept 1

  33. All TIMI 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; ‡CRUSADE score is a post-hoc analysis; PCI includes 11 patients with PCI + CABG. Montalescot et al. NEJM 2013; epub Sept 1

  34.   GUSTO, STEEPLE Bleeding Endpoints/TIMI Transfusion Through 7 Days (All Treated 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. ‖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

  35. 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.

  36. Considerations

  37. 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 ?

  38. The most frequent questions 1. Risk-level of population 2. Timing of PCI3. Drug dosage (pharmacodynamic considerations)4. Clopidogrel pretreated 5. Medically managed pts 6. Femoral vs radial approach

  39. The most frequent questions 1. Risk-level of population 2. Timing of PCI3. Drug dosage (pharmacodynamic considerations)4. Clopidogrel pretreated 5. Medically managed pts 6. Femoral vs radial approach

  40. Baseline Characteristics Post-randomization revascularization performed in 7.5% of patients

  41. Baseline Characteristics by CrCl and Dose of Study Drug

  42. ECG Abnormalities: Ischemia/ ST Depression at Baseline Montalescot et al. NEJM 2013; epub Sept 1

  43. Montalescot et al. Am Heart J 2011; 161 : 650-656

  44. The most frequent questions 1. Risk-level of population 2. Timing of PCI3. Drug dosage (pharmacodynamic considerations)4. Clopidogrel pretreated 5. Medically managed pts 6. Femoral vs radial approach

  45. Time to Angiography/PCI Montalescot et al. NEJM 2013; epub Sept 1 Mehta SR, et al. N Engl J Med. 2010;363(10):930-942. Bhatt DL, et al. N Engl J Med. 2013;368(14):1303-1013. Tricoci P, et al. N Engl J Med. 2012;366(1):20-33. Cannon CP, et al. Lancet. 2010;375(9711):283-293. Stone GW, et al. N Engl J Med. 2006;355(21):2203-2016.

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

  47. Time intervals to angio/PCI Hospital admission Real world ?? Hours 0 2 4 6 8 10 12 14 16 18 20 22 24 48 72 96 120 10 days IR median mean CREDO PCI-CURE median ACCOAST LOV 13

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