Gestione della DAPT nel primo anno dopo SCA o PCI : bastano le attuali Linee Guida?

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1 Gestione della DAPT nel primo anno dopo SCA o PCI : bastano le attuali Linee Guida? Luigi Oltrona Visconti Divisione di Cardiologia IRCCS Fondazione Policlinico S. Matteo Pavia

3 Gestione della DAPT nel primo anno dopo SCA o PCI : bastano le attuali Linee Guida? Novara 7 Giugno 2018 The question is : how long? Reducing or prolonging the recommended period of treatment? LOV 2015

5 Haemorragic risk Thrombotic risk

6 Gestione della DAPT nel primo anno dopo SCA o PCI : bastano le attuali Linee Guida? Novara 7 Giugno 2018 Definitions a) stented stable coronary disease b) acute coronary syndromes LOV 2016

7 Gestione della DAPT nel primo anno dopo SCA o PCI : bastano le attuali Linee Guida? Novara 7 Giugno 2018 a) stented stable coronary disease Considerations stent-related strategy (neither disease nor patient) clopidogrel only available (beyond clopidogrel?) duration of treatment LOV 2016

8 Gestione della DAPT nel primo anno dopo SCA o PCI : bastano le attuali Linee Guida? Novara 7 Giugno 2018 The future Trial Population Reference Tx Experimental Tx 1 E-point GLOBAL LEADERS 16,000 pts All-comers PCI (stable pts) 12 M asa+clopidogrel + 24 M asa (stable pts) 1 M asa+ticagrelor + 23 M ticagrelor 2 year death/mi TWILIGHT 9,000 pts All-comers PCI (h-risk stable) 15 M asa+ticagrelor 3 M asa+ticagrelor + 12 M ticagrelor BARC bleeding ALPHEUS 1,900 pts Stable pts PCI 30-D asa+clopidogrel 30-D asa+ticagrelor 48h ischemic episodes

11 Gestione della DAPT nel primo anno dopo SCA o PCI : bastano le attuali Linee Guida? Novara 7 Giugno 2018 DAPT administration after stenting with respect to the recommemded time Short? stent thrombosis? MACCE* reduced? bleeding Prolonged * = mortality (total, CV, non-cv), MI, stroke LOV 2016

12 Randomized Trials of DAPT Duration (DES stents) Trial Pts N Months Randomization Design % ACS 1 EP Abbreviated DAPT *Plus a 3M washout EXCELLENT 1,443 6 vs. 12 asa vs. asa + clop ISAR-SAFE 4,000 6 vs. 12* asa vs. asa + clop ITALIC 3,700 6 vs. 12 asa vs. asa + clop OPTIMIZE 3,120 3 vs. 12 asa vs. asa + clop Noninfer iority Noninfer iority Noninfer iority Noninfer iority 52 D/MI/TVR 40 D/MI/CVA/ST, Bleed 24 D/MI/CVA/Rev/MB 32 D/MI/CVA/MB RESET 2,148 3 vs. 12 asa vs. asa + clop Strategy 54 CVD/MI/ST/TVR, Bleed SECURITY 1,399 6 vs 12 asa vs. asa + clop Noninfer iority 38 CD/MI/CVA/ST, Bleed

13 Gestione della DAPT nel primo anno dopo SCA o PCI : bastano le attuali Linee Guida? Novara 7 Giugno 2018 LOV 2015 Giustino G et al JACC 2015;65:

14 Gestione della DAPT nel primo anno dopo SCA o PCI : bastano le attuali Linee Guida? Novara 7 Giugno 2018 LOV 2015 Giustino G et al JACC 2015;65:

15 Gestione della DAPT nel primo anno dopo SCA o PCI : bastano le attuali Linee Guida? Novara 7 Giugno 2018 LOV 2015 Giustino G et al JACC 2015;65:

16 Gestione della DAPT nel primo anno dopo SCA o PCI : bastano le attuali Linee Guida? Novara 7 Giugno 2018 LOV 2015 Giustino G et al JACC 2015;65:

18 Gestione della DAPT nel primo anno dopo SCA o PCI : bastano le attuali Linee Guida? Novara 7 Giugno 2018 Compared to 12 months of DAPT administration short unchanged unchanged reduced stent thrombosis MACCE* bleeding prolonged * = mortality (total, CV, non-cv), MI, stroke LOV 2015

20 Gestione della DAPT nel primo anno dopo SCA o PCI : bastano le attuali Linee Guida? Novara 7 Giugno 2018 Definitions a) stented stable coronary disease b) acute coronary syndromes LOV 2016

21 Gestione della DAPT nel primo anno dopo SCA o PCI : bastano le attuali Linee Guida? Novara 7 Giugno 2018 b) acute coronary syndromes Considerations not stent-related strategy (?) not only clopidogrel available duration of treatment LOV 2016

22 Gestione della DAPT nel primo anno dopo SCA o PCI : bastano le attuali Linee Guida? Novara 7 Giugno 2018 The question is : how long? Reducing or prolonging the recommended period of treatment? LOV 2015

Primary Endpoint (%) Nuovi antiaggreganti orali : prasugrel evidenze cliniche di efficacia 15 Primary Endpoint CV Death,MI,Stroke Clopidogrel 12.

27 Primary Endpoint (%) Nuovi antiaggreganti orali : prasugrel evidenze cliniche di efficacia 15 Primary Endpoint CV Death,MI,Stroke Clopidogrel 12.1 (781) 10 5 HR 0.77 P= HR 0.80 P= Prasugrel 9.9 (643) HR 0.81 ( ) P= NNT= 46 0 ITT= 13,608 LTFU = 14 (0.1%) Days

28 K-M estimate of time to first primary efficacy event (composite of CV death, MI or stroke) Cumulative incidence (%) No. at risk Ticagrelor Clopidogrel ,333 9,291 8,628 8,521 HR 0.84 (95% CI ), p= Days after randomisation 8,460 8,362 8,219 8,124 6,743 6,743 K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval Clopidogrel Ticagrelor 5,161 5,096 4,147 4,

% Events 4 Clopidogrel Prasugrel Bleeding

w Prior Stroke/TIA (N=518) 2 1,8 2,4 1,4

02) 0 TIMI Major Bleeds Life Threatening

6% HR 1.32 P=0.03 NNH=167 ARD 0.5% HR 1.

29 % Events 4 Clopidogrel Prasugrel Bleeding Events Safety Cohort (N=13,457) ICH in Pts w Prior Stroke/TIA (N=518) 2 1,8 2,4 1,4 0,9 0,9 1,1 Clop 0 (0) % Pras 6 (2.3)% (P=0.02) 0 TIMI Major Bleeds Life Threatening 0,1 0,4 0,3 0,3 Nonfatal Fatal ICH ARD 0.6% HR 1.32 P=0.03 NNH=167 ARD 0.5% HR 1.52 P=0.01 ARD 0.2% P=0.23 ARD 0.3% P=0.002 ARD 0% P=0.74

30 K-M estimated rate (% per year) Non-CABG and CABG-related major bleeding NS 7.9 Ticagrelor Clopidogrel p= NS p= Non-CABG PLATO major bleeding Non-CABG TIMI major bleeding CABG PLATO major bleeding CABG TIMI major bleeding

31 CURE Safety Bleeding complications Clopidogrel + Standard therapy standard therapy alone including including ASA (%) ASA (%) Major * life-threatening non-life-threatening ** Transfusion *** The CURE Investigators. N Eng J Med August 2001 Data on file *p=0.001; **p=0.002; ***p=0.02

32 Palmerini T et al EurHJ 2017;38:

33 Randomized Trials of DAPT Duration (DES stents) Trial Pts N Months Randomization Design % ACS 1 EP Abbreviated DAPT *Plus a 3M washout EXCELLENT 1,443 6 vs. 12 asa vs. asa + clop ISAR-SAFE 4,000 6 vs. 12* asa vs. asa + clop ITALIC 3,700 6 vs. 12 asa vs. asa + clop OPTIMIZE 3,120 3 vs. 12 asa vs. asa + clop Noninfer iority Noninfer iority Noninfer iority Noninfer iority 52 D/MI/TVR 40 D/MI/CVA/ST, Bleed 24 D/MI/CVA/Rev/MB 32 D/MI/CVA/MB RESET 2,148 3 vs. 12 asa vs. asa + clop Strategy 54 CVD/MI/ST/TVR, Bleed SECURITY 1,399 6 vs 12 asa vs. asa + clop Noninfer iority 38 CD/MI/CVA/ST, Bleed

34 Gestione della DAPT nel primo anno dopo SCA o PCI : bastano le attuali Linee Guida? Novara 7 Giugno 2018 Optimal duration of antiplatelet treatment after DES (or ACS) What to do? LOV 2015

35 Il progetto SCA e Diabete : dal documento di consenso al Registro GISE Inibitori P2Y12 alla dimissione (89% dei pazienti) STEMI NSTEMI

36 Gestione della DAPT nel primo anno dopo SCA o PCI : bastano le attuali Linee Guida? Novara 7 Giugno 2018 Optimal duration of antiplatelet treatment after DES (or ACS) Changing the perspective : treat the patient not the stent LOV 2015

37 Levine GN et al Circulation 2017;135:

38 TRACER NSTEMI pts Valgimigli M et al. EurHJ 2017; 38:

NSTEMI STEMI I A I A 2015 2017 12 months 12 months

43 DAPT therapy (ACS patients) Guidelines Condition Recommandation/ Evidence Level Year Duration ESC NSTEMI STEMI I A I A months 12 months AHA/ACC NSTEMI STEMI I B I B months 12 months LOV 2017

44 STEMI ESC 2017

45 La durata della DAPT dopo SCA : dallo stent al paziente The question is : how long? Prolonging the recommended period of treatment? LOV 2017

46 Randomized Trials of DAPT Duration (DES stents) Trial Pts N Months Randomization Design 1 EP Abbreviated DAPT *Plus a 3M washout EXCELLENT 1,443 6 vs. 12 asa vs. asa + clop Noninferiority D/MI/TVR ISAR-SAFE 4,000 6 vs. 12* asa vs. asa + clop Noninferiority D/MI/CVA/ST, Bleed ITALIC 3,700 6 vs. 12 asa vs. asa + clop Noninferiority D/MI/CVA/Rev/MB OPTIMIZE 3,120 3 vs. 12 asa vs. asa + clop Noninferiority D/MI/CVA/MB RESET 2,148 3 vs. 12 asa vs. asa + clop Strategy CVD/MI/ST/TVR, Bleed SECURITY 1,399 6 vs 12 asa vs. asa + clop Noninferiority CD/MI/CVA/ST, Bleed Prolonged DAPT *Plus a 3M washout REAL/ZEST Late 2, vs. 24 asa vs. asa + clop Superiority D/MI DAPT 20, vs. 30* asa vs. asa + clop (pras) NI and Sup D/MI/CVA/ST, Bleed PRODIGY 1,800 6 vs. 24 asa vs. asa + clop Superiority D/MI/CVA ARCTIC Interr 1, vs 18 asa vs. asa + clop Superiority D/MI/CVA/TVR/ST

54 MACE reduction greater for patients with MI (3.9% vs. 6.8% HR 0.42 p < 0.001) compared with those with no MI (4.4% vs. 5.3% HR 0.60 p = 0.08) Yeh RW, et al. J Am Coll Cardiol 2015;65:

55 La durata della DAPT dopo SCA : dallo stent al paziente Changing the perspective : treat the patient not the stent LOV 2017

56 MACE (%) PROSPECT: MACE (N=697) All Culprit lesion (CL) related Non culprit lesion (NCL) related Indeterminate 20.4% % % 5 2.7% Time in Years Number at risk ALL CL related NCL related Indeterminate MACE = cardiac death, cardiac arrest, MI, or rehospitalization for unstable or progressive angina

58 Jernberg T et al. EurHJ 2015; 36:

59 Bhatt DL et al. JAMA 2010;304: %

60 Fox KAA et al. EurHJ 2010;31: %

61 PEGASUS-TIMI 54: Study Design Patients aged 50 years with a history of spontaneous MI 1 3 years prior to enrolment AND at least one additional atherothrombosis risk factor* (N=21,162) Ticagrelor 90 mg bid + ASA mg/day Ticagrelor 60 mg bid + ASA mg/day Placebo + ASA mg/day Minimum of 12 months follow up: Every 4 months in Year 1, then semi-annually Primary efficacy endpoint: CV death, MI or stroke Primary safety endpoint: TIMI-defined major bleeding *Age 65 years, diabetes mellitus, second prior MI, multivessel CAD or chronic non-end stage renal disease bid, twice daily; CAD, coronary artery disease; TIMI, Thrombolysis in Myocardial Infarction Bonaca MP et al. Am Heart J 2014;167: Bonaca MP et al. N Engl J Med 2015;372: FOR REACTIVE MEDICAL USE ONLY 61

62 LOV 2017

64 PEGASUS-TIMI 54: Efficacy Endpoints Endpoint 3-year KM event rates (%) Ticagrelor Placebo HR (95% CI) P value Primary CV death, MI or stroke (1558 events) CV death (566 events) MI (898 events) Stroke (313 events) ( ) ( ) ( ) ( ) ( ) ( ) ( ) 0.01* ( ) 0.03* ( ) 0.005* ( ) 0.14* ( ) 0.03* ( ) 0.03* Ticagrelor better Placebo better Ticagrelor 90 mg bid Ticagrelor 60 mg bid Ticagrelor pooled *Indicates nominal P value; P<0.026 indicates statistical significance Bonaca MP et al. N Engl J Med 2015;372: FOR REACTIVE MEDICAL USE ONLY 64

65 PEGASUS-TIMI 54: Primary Endpoint * by Subgroup (1) Subgroup Patients Ticagrelor 90 mg 3-year KM (%) Ticagrelor 60 mg 3-year KM (%) Placebo 3-year KM (%) HR (95% CI) ticagrelor 90 mg bid vs placebo HR (95% CI) Interaction P value HR (95% CI) ticagrelor 60 mg bid vs placebo HR (95% CI) Interaction P value All patients 21, ( ) 0.84 ( ) Age at randomisation <75 years 18, ( ) 0.86 ( ) 75 years ( ) 0.77 ( ) Sex Female ( ) 0.98 ( ) Male 16, ( ) 0.79 ( ) Qualifying MI NSTEMI ( ) 0.89 ( ) STEMI 11, ( ) 0.81 ( ) Unknown ( ) 0.74 ( ) Time from qualifying MI <2 years 12, ( ) 0.77 ( ) 2 years ( ) 0.96 ( ) History of diabetes Diabetes ( ) 0.83 ( ) No diabetes 14, ( ) 0.84 ( ) *Composite of CV death, MI or stroke KM, Kaplan-Meier Ticagrelor 90 mg better Placebo better Ticagrelor 60 mg better Placebo better Bonaca MP et al. N Engl J Med 2015;372: FOR REACTIVE MEDICAL USE ONLY 65

Bhatt DL, et al. JACC 2016;67:2732-2740 Magnani G, et al.

66 Bhatt DL, et al. JACC 2016;67: Magnani G, et al. EurHJ 2015;doi /eurheartj/ehv482 Bonaca M et al. JACC 2016;67:

68 Number of Patients Discontinued for Bleeding Discontinuation over time for Bleeding by Randomization Group 500 Placebo Ticagrelor 60 mg twice daily Ticagrelor 90 mg twice daily 450 P<0.01 for each dose vs. placebo Median Days to Discontinuation Days From Randomization An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School Bonaca M et al. JAMA Cardiol 2016;1:

69 Number of events per 10,000 patients initiated on treatment per year PEGASUS-TIMI 54: Estimates of First Efficacy and Bleeding Events Prevented and Caused Annualized from 3-year Kaplan-Meier event rates in the intention-to-treat population Irreversible harm CV death, MI or stroke CV death MI Stroke Fatal bleeding ICH TIMI major bleeding Ticagrelor 90 mg bid Ticagrelor 60 mg bid -50 Net clinical benefit is defined as the comparison of first occurrence of CV death, MI or stroke with first occurrence of TIMI major bleeding; irreversible events are defined as CV death, MI, stroke, fatal bleeding and ICH Note these are estimated events based on calculations made from the observed ARRs in the PEGASUS-TIMI 54 study and therefore should be viewed as estimates of events prevented and caused rather than specific indicators of efficacy. Also note that these analyses are based on Kaplan-Meier time to first event curves, and therefore the sum of the events for CV death, MI and stroke individually do not equal that for the composite of CV death/mi/stroke Bonaca MP et al. N Engl J Med 2015;372: , Supplementary Appendix Data on file: ATLAS approval ID 773, FOR REACTIVE MEDICAL USE ONLY 69

70 La durata della DAPT dopo SCA : dallo stent al paziente Pegasus N events/1000 patients/year Ticagrelor 90 mg 60 mg Ischemic ev. prevented Bleeding LOV 2017

71 pts Charisma Prodigy Arctic-Int 323 DAPT DES-Late Pegasus

72 La durata della DAPT dopo SCA : dallo stent al paziente Who and when to treat after 12 months LOV 2017

73 La durata della DAPT dopo SCA : dallo stent al paziente Who Patients with prior MI at high risk: Diabetes mellitus Multiple prior MIs Renal dysfunction Multiple vascular disease Prior CABG PAD Not at high risk for bleeding Prior/risk of ICH Recent major Bleeding Bleeding diathesis On anticoagulation Anemia LOV 2017

The DAPT Score Variable Patient Characteristic Age Points Distribution of DAPT Scores among all randomized subjects in the DAPT Study 75-2 65 - <75-1 < 65 0 Diabetes

75 The DAPT Score Variable Patient Characteristic Age Points Distribution of DAPT Scores among all randomized subjects in the DAPT Study <75-1 < 65 0 Diabetes Mellitus 1 Current Cigarette Smoker 1 Prior PCI or Prior MI 1 CHF or LVEF < 30% 2 Index Procedure Characteristic MI at Presentation 1 Vein Graft PCI 2 Stent Diameter < 3mm 1 75

76 Cumulative Incidence of GUSTO Moderate/ Severe Bleed Cumulative Incidence of ST/MI Cumulative Incidence of MACCE Continued Thienopyridine vs. Placebo DAPT Score 2 (High); N=5917 Myocardial Infarction or Stent Thrombosis 10% 8% Continued Thienopyridine Placebo Death, MI or Stroke (MACCE) 10% 8% Continued Thienopyridine Placebo 6% 4% 2.7% vs. 5.7% P< % 4% 4.9% vs. 7.6% P< % 2% 0% GUSTO Moderate/ Severe Bleeding Months After Enrollment 10% 8% 6% 4% 2% Continued Thienopyridine Placebo 1.8% vs. 1.4% P=0.26 0% Months After Enrollment 0% Months After Enrollment 76

77 Cumulative Incidence of GUSTO Moderate/ Severe Bleed Cumulative Incidence of ST/MI Cumulative Incidence of MACCE Continued Thienopyridine vs. Placebo DAPT Score <2 (Low); N=5731 Myocardial Infarction or Stent Thrombosis 10% 8% Continued Thienopyridine Placebo Death, MI, or Stroke (MACCE) 10% 8% Continued Thienopyridine Placebo 6% 6% 4% 1.7% vs. 2.3% P=0.07 4% 3.7% vs. 3.8% P=0.73 2% 2% 0% GUSTO Moderate/ Severe Bleeding Months After Enrollment 10% 8% 6% 4% 2% Continued Thienopyridine Placebo 3.0% vs. 1.4% P< % Months After Enrollment 0% Months After Enrollment 77

78 Complex PCI was defined (at least 1 of the following features) : 3 vessels treated 3 stents implanted 3 lesions treated bifurcation with 2 stents implanted total stent length >60 mm or chronic total occlusion Giustino G et al. JACC 2016;68:

79 La durata della DAPT dopo SCA : dallo stent al paziente When Continue after started for MI and re-evaluate at each visit: Recent bleeding? Are they tolerating? Are they adherent? Contraindications? (e.g. AF requiring anticoagulation) LOV 2017

80 Bonaca M et al. EurHJ 2016;37:

81 Bonaca M et al. EurHJ 2016;37:

83 La durata della DAPT dopo SCA : dallo stent al paziente Prolonging DAPT duration in ACS pts treat the patient not the stent one size may not fit all (carefully assessing the balance between thrombotic and bleeding risk) LOV 2016

84 Reed GW et al. Lancet 2017; 389:

85 Backup

87 Bonaca M et al. JAMA Cardiol 2016;1:

89 PEGASUS-TIMI 54: Safety Endpoints Endpoint Ticagrelor 90 mg bid N=6988; n (%) Ticagrelor 60 mg bid N=6958; n (%) Placebo N=6996; n (%) Ticagrelor 90 mg bid vs placebo HR (95% CI) Ticagrelor 60 mg bid vs placebo HR (95% CI) Primary safety endpoint TIMI major bleeding 127 (2.60) 115 (2.30) 54 (1.06) 2.69 ( ) P< ( ) P<0.001 Secondary safety endpoints ICH 29 (0.56) 28 (0.61) 23 (0.47) 1.44 ( ) P=0.19 Haemorrhagic stroke 4 (0.07) 8 (0.19) 9 (0.19) 0.51 ( ) P=0.26 Fatal bleeding 6 (0.11) 11 (0.25) 12 (0.26) 0.58 ( ) P=0.27 Fatal bleeding or nonfatal ICH 32 (0.63) 33 (0.71) 30 (0.60) 1.22 ( ) P= ( ) P= ( ) P= ( ) P= ( ) P=0.47 Rates are presented as 3-year Kaplan-Meier estimates n = number of patients with events, not the number of events Bonaca MP et al. N Engl J Med 2015;372: FOR REACTIVE MEDICAL USE ONLY 89

90 PEGASUS-TIMI 54: Safety Endpoints Endpoint Ticagrelor 90 mg bid N=6988; n (%) Ticagrelor 60 mg bid N=6958; n (%) Placebo N=6996; n (%) Ticagrelor 90 mg bid vs placebo HR (95% CI) Ticagrelor 60 mg bid vs placebo HR (95% CI) Secondary safety endpoints TIMI minor bleeding 66 (1.31) 55 (1.18) 18 (0.36) 4.15 ( ) P< ( ) P<0.001 Bleeding requiring transfusion Bleeding leading to study drug discontinuation 122 (2.43) 105 (2.09) 37 (0.72) 3.75 ( ) P< (7.81) 354 (6.15) 86 (1.50) 5.79 ( ) P< ( ) P< ( ) P<0.001 Rates are presented as 3-year Kaplan-Meier estimates n = number of patients with events, not the number of events Bonaca MP et al. N Engl J Med 2015;372: FOR REACTIVE MEDICAL USE ONLY 90

91 yspnea Bleeding E) Serious (SAE) 5% mild or moderate TIMI Major Med Attention TIMI Minor Minimal % mild or moderate icagrelor 0 mg BID 8 11 Ticagrelor 60 mg BID Placebo Ticagrelor 90 Ticagrelor 60 mg BID mg BID Bonaca M et al. JAMA Cardiol 2016;1:

Optimal duration of antiplatelet treatment

unchanged MACCE* reduced reduced bleeding

93 Optimal duration of antiplatelet treatment after ACS Compared to 12 months of DAPT administration short (3 or 6 m) > 12 (30?) m unchanged stent thrombosis reduced unchanged MACCE* reduced reduced bleeding increased * = mortality (total, CV, non-cv), MI, stroke LOV 2015

94 Jernberg T et al. EurHJ 2015; 36:

95 PEGASUS-TIMI 54: Primary Endpoint * by Subgroup (2) Subgroup Patients Ticagrelor 90 mg 3-year KM (%) Ticagrelor 60 mg 3-year KM (%) Placebo 3-year KM (%) HR (95% CI) ticagrelor 90 mg bid vs placebo HR (95% CI) Interaction P value HR (95% CI) ticagrelor 60 mg bid vs placebo HR (95% CI) Interaction P value All patients 21, ( ) 0.84 ( ) ASA dose mg ( ) 0.82 ( ) >75 mg 16, ( ) 0.85 ( ) History of PCI Prior PCI 17, ( ) 0.83 ( ) No prior PCI ( ) 0.87 ( ) Region North America ( ) 0.75 ( ) South America ( ) 0.90 ( ) Europe 12, ( ) 0.85 ( ) Asia ( ) 0.90 ( ) Ticagrelor 90 mg better Placebo better Ticagrelor 60 mg better Placebo better *Composite of CV death, MI or stroke Bonaca MP et al. N Engl J Med 2015;372: FOR REACTIVE MEDICAL USE ONLY 95

96 PEGASUS-TIMI 54: Primary Endpoint * by Subgroup (3) Subgroup Patients Ticagrelor 90 mg 3-year KM (%) Ticagrelor 60 mg 3-year KM (%) Placebo 3-year KM (%) HR (95% CI) ticagrelor 90 mg bid vs placebo HR (95% CI) Interaction P value HR (95% CI) ticagrelor 60 mg bid vs placebo HR (95% CI) Interaction P value All patients 21, ( ) 0.84 ( ) Race Caucasian 18, ( ) 0.81 ( ) Non-Caucasian ( ) 1.07 ( ) Weight < Median (81 kg) 10, ( ) 0.77 ( ) Median (81 kg) 10, ( ) 0.91 ( ) Second prior MI Second MI ( ) 0.85 ( ) No second MI 17, ( ) 0.83 ( ) Multivessel disease Multivessel 12, ( ) 0.81 ( ) disease No multivessel disease ( ) 0.88 ( ) Non-endstage renal dysfunction Renal dysfunction No renal dysfunction ( ) 0.81 ( ) 16, ( ) 0.88 ( ) *Composite of CV death, MI or stroke n = number of patients with events, not the number of events Bonaca MP et al. N Engl J Med 2015;372: Ticagrelor 90 mg better Placebo better Ticagrelor 60 mg better Placebo better FOR REACTIVE MEDICAL USE ONLY 96

97 Storey RF, et al. JACC 2016;67:

98 La doppia antiaggregazione prolungata : gli aggiornamenti dal PEGASUS robusto disegno e risultati convincenti coerenza dei risultati in numerosi sottogruppi prespecificati spalanca il focus sul paziente stabile nella fase successiva a una sindrome coronarica acuta LOV 2016

99 DAPT Duration for Complex PCI Patient-level meta-analysis of 9,577 pts from 6 PCI trials of DAPT duration Definite or probable stent thrombosis P for interaction = ,6% 0,8% 0,5% 0,5% Complex PCI Noncomplex PCI Long DAPT Short DAPT Complex PCI was defined as having at least 1 of the following features: 3 vessels treated, 3 stents implanted, 3 lesions treated, bifurcation with 2 stents implanted, total stent length >60 mm, or chronic total occlusion Giustino G et al. JACC 2016;68:

100 DAPT a lungo termine : un nuovo paradigma Il rischio residuo del paziente nella pratica clinica It s time to re-focus our attention and resources on the chronic phase after an acute coronary event LOV 2017

101 The EYESHOT Post-MI Snapshot EYESHOT (EmploYEd antithrombotic therapies in patients with acute coronary Syndromes HOspitalized in italy) Post-MI Registry 230 centers 3 months duration

Number of Patients Discontinued for Dyspnea Discontinuation over time for Dyspnea by Randomization Group 500 Placebo Ticagrelor 60 mg twice daily Ticagrelor 90 mg twice daily 450 P<0.

102 Number of Patients Discontinued for Dyspnea Discontinuation over time for Dyspnea by Randomization Group 500 Placebo Ticagrelor 60 mg twice daily Ticagrelor 90 mg twice daily 450 P<0.01 for each dose vs. placebo Median Days to Discontinuation Days From Randomization An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School Bonaca M et al. JAMA Cardiol 2016;1:

Protease-activated receptor (PAR)-1 Thrombin

selective antagonist of PAR-1 Metabolism by CYP3A4

half-life (T1/2 > 100 hrs) XSignal Shape Change

103 Protease-activated receptor (PAR)-1 Thrombin Vorapaxar C C C C Vorapaxar is an oral, potent, and selective antagonist of PAR-1 Metabolism by CYP3A4 enzymes No meaningful renal clearance Long half-life (T1/2 > 100 hrs) XSignal Shape Change Activation Aggregation Adapted from Vu TH et al. Cell 1991;64:

Event Rate (%) CV Death, MI, or Stroke 12% 10% 8% 6% N = 26449 Mean f/u: 2.5 years Hazard Ratio 0.

3% 4% 2% GUSTO Mod/Sev at 3 yrs 4.2 v. 2.5%, HR 1.66, p<0.

104 Event Rate (%) CV Death, MI, or Stroke 12% 10% 8% 6% N = Mean f/u: 2.5 years Hazard Ratio 0.87 p < Background 1 Efficacy Evaluation Overall Population Placebo Vorapaxar 10.5% 9.3% 4% 2% GUSTO Mod/Sev at 3 yrs 4.2 v. 2.5%, HR 1.66, p< % Days since randomization Morrow et al. N Engl J Med 2012 ClinicalTrials.gov NCT c

Event Rate (%) Primary Efficacy Evaluation Prior MI Cohort 12% 10% 8% 6% CV Death, MI, or Stroke N = 17,779 Mean f/u: 2.5 years Hazard Ratio 0.80; 95% CI 0.72-0.89 p < 0.

105 Event Rate (%) Primary Efficacy Evaluation Prior MI Cohort 12% 10% 8% 6% CV Death, MI, or Stroke N = 17,779 Mean f/u: 2.5 years Hazard Ratio 0.80; 95% CI p < Placebo 9.7% 8.1% Vorapaxar 4% 2% 0% Vora Plac HR P-value CV Death MI <0.001 Stroke Days since Randomization

Razionale ed evidenze scientifiche di Doppia Antiaggregazione Piastrinica a lungo termine nel Paziente con Sindrome Coronarica Acuta

Razionale ed evidenze scientifiche di Doppia Antiaggregazione Piastrinica a lungo termine nel Paziente con Sindrome Coronarica Acuta Giuseppe Musumeci SC Cardiologia Ospedale Santa Croce e Carle Cuneo