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

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1 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

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3 Proportion of patients (%) 40% of recurrent MIs occur 2 5 years after the index event Observational study of 307 consecutive patients experiencing a second MI >1 month after the first event Year Figueras J et al. Am J Cardiol 2002;89:

4 MACE (%) About the same rate of recurrent events is attributable to target and non-target vessels PROSPECT: prospective study of 697 ACS patients undergoing three-vessel angiography and gray-scale and radiofrequency intravascular ultrasonographic imaging after PCI All Culprit lesion related Non culprit lesion related Indeterminate 18.1% 20.4% % 7.9% 11.4% 9.4% 12.9% 11.6% % 0.9% 1.9% Time in Years 2.7% Stone GW, et al. N Engl J Med. 2011;364:226-35

5 DAPT: Shorter or Longer after PCI? 15 studies, ~40,000 patients randomized RESET JACC 2012 N=2,117 3 months noninferior to 12 months OPTIMIZE JAMA 2013 N=2,199 3 months noninferior to 12 months SECURITY JACC 2016 N=1,399 6 months noninferior to 12 months ISAR SAFE EHJ 2015 N=4,000 6 months similar to 12 months I-LOVE-IT 2 CIRC CV 2016 N=1,829 6 months noninferior to 12 months OPTIMA-C TCTAP 2015 N=1,368 6 months noninferior to 12 months EXCELLENT Circulation 2015 N=1,443 6 months noninferior to 12 months IVUS XPL NEW! JACC: CI 2016 N=1,400 6 months similar to 12 months NIPPON NEW! ESC 2016 N=2,772 6 months noninferior to 18 months ITALIC JACC 2015 N=1,822 6 months similar to 24 months PRODIGY Circulation 2012 N=1,970 6 months noninferior to 24 months DES LATE Circulation 2014 N=5, months similar to months ARCTIC NEJM 2012 N=1, months noninferior to 12 months DAPT NEJM 2014 N=9, months inferior to 30 months OPTIDUAL EHJ 2015 N=1, months similar to 48 months Capodanno D. Personal communication

6 DAPT Trial Randomiza on Primary Analysis Period Study Drug Treatment Ends 12-Month Observa onal Period: Open-Label Thienopyridine + Aspirin Required Thienopyridine + Aspirin Placebo + Aspirin 3-Month Observa onal Period: Off Thienopyridine, On Aspirin 0 (mos) Inclusion: FDA-approved DES or BMS, candidates for thienopyridine Excluded: Oral anticoagulant therapy; life expectancy < 3y Randomized: Free from MI, stroke, repeat revascularization, moderate/severe bleeding, and adherent with therapy at 12 months Mauri, Kereiakes et al. AHJ. 2010;160(6): ClinicalTrials.gov number NCT

7 DAPT trial Thienopyridine vs Placebo 12 m after DES

8 Benefits of Extended DAPT in Patients with Previous MI 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 Yen RW, et al. J Am Coll Cardiol 2015

9 CV Death, MI, or Stroke (%) CHARISMA: Clopidogrel+ASA vs ASA 15,603 patients with qualifying CAD, CVD or PAD or multiple risk factors randomized to DAPT or ASA 10 Prior MI subgroup 8 6 N=3,846 Placebo + ASA Clopidogrel + ASA 8.3% 6.6% 4 2 HR=0.774 (95% CI [ ]) P= Months Since Randomization Bhatt DL, et al. J Am Coll Cardiol. 2007;49:

10 PEGASUS: Ticagrelor vs Placebo 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. N Engl J Med 2015;372:

11 PEGASUS: Ticagrelor vs Placebo Inclusion criteria Age 50 years old History of a spontaneous MI 1 3 years prior to enrolment and one additional high-risk feature Age 65 years old Diabetes mellitus requiring medication A second prior spontaneous MI Angiographic evidence of multivessel CAD Chronic, non-end-stage renal dysfunction (CrCl <60 ml/min) Prescribed and tolerating ASA at the time of enrolment Bonaca MP, et al. N Engl J Med 2015;372:

12 Death/MI/Stroke (%) PEGASUS: Ticagrelor vs Placebo 21,162 patients with prior MI randomized to ticagrelor 90 mg bid, ticagrelor 60 mg bid, or placebo Placebo Ticagrelor 90 mg bid Ticagrelor 60 mg bid 9.04% Placebo 7.85% 90 mg bid % 60 mg bid Ticagrelor 90 mg vs placebo HR 0.85 (95% CI ) P=0.008 Ticagrelor 60 mg vs placebo HR 0.84 (95% CI ) P= No. at risk Placebo 90 mg bid 60 mg bid Months from randomisation Bonaca MP, et al. N Engl J Med 2015;372:

13 PEGASUS: Ticagrelor vs Placebo 21,162 patients with prior MI randomized to ticagrelor 90 mg bid, ticagrelor 60 mg bid, or placebo 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

14 3-year KM event rate PEGASUS: Ticagrelor vs Placebo 21,162 patients with prior MI randomized to ticagrelor 90 mg bid, ticagrelor 60 mg bid, or placebo P< P< TIMI major bleeding TIMI minor bleeding Ticagrelor 90 mg bid Ticagrelor 60 mg bid Placebo P=NS P=NS P=NS Fatal bleeding or ICH ICH Fatal bleeding Bonaca MP, et al. N Engl J Med 2015;372:

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17 Events by Time of P2Y 12 Inhibitor Withdrawal 21,162 patients with prior MI randomized to ticagrelor 90 mg bid, ticagrelor 60 mg bid, or placebo Time from P2Y 12 inhibitor withdrawal to randomization 30 days N=7,181 > 30 days To 1 year N=6,501 > 1 year N=5,079 27% RRR 14% RRR No RRR HR (95% CI) P value 0.70 ( ) 0.75 ( ) 0.73 ( ) < ( ) 0.82 ( ) 0.86 ( ) ( ) 1.06 ( ) 1.01 ( ) 0.96 P for interaction < Ticagrelor better 1.0 Placebo better Ticagrelor 90 Ticagrelor 60 Pooled Bonaca MP, t al. Eur Heart J. 2015

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20 Resor Circulation 2016

21 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 Long DAPT Short DAPT Noncomplex PCI 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. J Am Coll Cardiol [Epub ahead of print]

22 PRODIGY LAD prox/left Main (n=953) 6 months 24 months F. Costa Eurointervention August 2015

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24 MACE with Ticagrelor in MVD

25 CV Death, MI, Stroke (%) MACE with Ticagrelor in Diabetics Ticagrelor (doses pooled) Placebo Ticagrelor in Diabetic Patients HR 0.84 (95% CI ) ARR 1.5%; P= % 10.1% Benefit in Diabetic vs. Non-Diabetic Patients: Interaction P= % 6.7% Ticagrelor in Non-Diabetic Patients HR 0.84 (95% CI ) ARR 1.1%; P=0.01 Days from Randomization Bhatt DL, Bonaca MP, Bansilal S, et al. Steg PG. JACC

26 3-yr KM % Efficacy of ticagrelor by egfr 16 Primary Endpoint: CV death, MI, stroke egfr < 60 Placebo (N = 1,649) egfr < 60 Ticagrelor Pooled (N = 3,200) egfr 60 Placebo (N = 5,336) egfr 60 Ticagrelor Pooled (N = 10,713) 13.99% HR 95% CI 0.81 ( ) ARR = 2.70% 11.29% NNT % 6.80% HR 95% CI 0.88 ( ) ARR = 0.63% Months since randomization Magnani G et al. and Bonaca MP EHJ 2015

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28 Udell Eur Heart J 2016

29 Irreversible harm HR = 0.85 Udell Eur Heart J 2016

30 All Cause Mortality with Prolonged Intensive Antiplatelet Therapy after MI ~11% rededication in all cause mortality ~17% reduction in CV Mortality (about 60% of deaths) No excess in non-cv Mortality (about 40% of deaths) Bonaca MP and Sabatine MS. JAMA Cardiology 2016

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32 PEGASUS-TIMI 54 EU label population: Primary and secondary outcomes patients 2 years from qualifying MI or 1 year from prior ADP receptor inhibitor treatment (efficacy cohort) Outcome Ticagrelor 60 mg bid N=5388 n 3 year KM% n Placebo N=5391 Hazard ratio (95% CI) 3 year KM% P value Composite of CV death, MI or stroke ( ) CV death ( ) MI ( ) Stroke ( ) All-cause mortality ( ) Dellborg M et al. Eur Heart J 2017;38(suppl): Abs P3670 (Presented at ESC 2017) 32

33 Conclusions Trials investigating DAPT duration beyond 1 year are more likely to capture atherothrombotic manifestations, particularly outside the stented coronary segments. Accordingly, the optimal DAPT duration will largely be determined by the prevention of new atherothrombotic events rather than the nuisance of stent-related thrombotic complications. Prior MI may be a treatment modifier with respect to DAPT duration after stenting. The DAPT trial suggests that patients with prior MI have more to gain from extended DAPT than patients without. Secondary prevention with antiplatelet therapy after an MI decreases recurrent ischemia but increases bleeding (even in patients at low risk). The trade-off between ischemic and bleeding events with long-term DAPT should be carefully evaluated when the decision to continue DAPT after a recommended period is considered.

34 Primary endpoint (%) PEGASUS-TIMI 54 EU label population: Primary endpoint (CV death, MI, stroke) patients 2 years from qualifying MI or 1 year from prior ADP receptor inhibitor treatment (efficacy cohort) 10 8 Ticagrelor 60 mg bid, EU label [373 events; N=5388] Placebo, EU label [463 events; N=5391] 9.56% 7.85% Number at risk: Placebo, EU Ticagrelor 60 mg bid, EU Days from randomization The EU label subgroup includes patients with 2 years from qualifying MI or 1 year from last dose of prior ADP receptor inhibitor treatment to randomization Dellborg M et al. Eur Heart J 2017;38(suppl): Abs P3670 (Presented at ESC 2017) 34

35 Question: Who, when and why to treat after 12 months Who Patients with prior MI at high risk: Diabetes mellitus Multiple prior MIs Renal dysfunction MVD / prior CABG PAD Smoker CHF / low EF Not at high risk for bleeding Prior/risk of ICH Recent major Bleeding Bleeding diathesis On anticoagulation Low BMI / anemia When Continue after started for MI and re-evaluate at each visit: Recent bleeding? Are they tolerating? Are they adherent? Contraindications (e.g. new dx of AF requiring anticoagulation) Why To reduce long-term ischemic risk including: New spontaneous MI including STEMI Ischemic stroke including disabling events Limb ischemic events in PAD CV mortality as predominant cause of death Slide by Marc Bonaca

36 DAPT trial Randomized treatment effects on ischemia and bleeding (DES cohort)

37 NNT and NNH in PEGASUS Ticagrelor 90 mg bid Ticagrelor 60 mg bid Endpoint Estimated risk difference NNT Estimated risk difference NNT Primary endpoint: CV death, MI or stroke 1.19% % 79 Primary safety endpoint: TIMI major bleeding 1.22% % 107 Estimated risk difference is the difference in 3-year Kaplan-Meier percent between ticagrelor and placebo based on intention-to-treat analyses NNH, number needed to harm; NNT, number needed to treat Data on file: ATLAS approval ID 773,

38 Yeh JAMA 2016

39 Yeh JAMA 2016

40 Kereiakes JACC 2016

41 Rate at 3 years Rate at 3 years Events at 3 Years by Prior Coronary Stent 21,162 5% 4% 4% 3% 3% 2% 2% 1% 1% 0% Placebo Patients N=7, % 16,891 (80%) With Coronary Stent 91% of PEP Events Spontaneous Unrelated to Coronary Stent 4.1% Event 1.7% 0.7% CV Death Type 1 MI Stroke Definite Stent Thrombosis 9% 8% 7% 6% 5% 4% 3% 2% 1% 0% Placebo Patients N=1, % 4,271 (20%) No Coronary Stent 4.4% Event 3.1% 0.0% CV Death Type 1 MI Stroke Definite Stent Thrombosis

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43 DAPT Duration in Clinical Guidelines Population ESC Guidelines ACCF/AHA/SCAI 2016 Acute Coronary Syndrome (BMS or DES) Stable Ischemia and BMS Maximum of 12 months (Class I-A) Shorter or longer durations may be considered (Class IIb-A) At least 1 month (Class I-A) At least 12 months (Class I-BR) Shorter (Class IIb-C-LD) or longer (Class IIb-A SR ) durations may be considered At least 1 month (Class I-A) >1 month if no HBR (Class IIb-A) Stable Ischemia and DES 6 months (Class I-B) At least 6 months (Class I-B-NR) >6 months if no HBR (Class IIb-A) HBR: 3 months (Class IIb-C-LD) Secondary Prevention Selected patients at high ischemic risk Prior MI (1-3 yrs), no HBR: May be reasonable (Class IIb-A) Roffi M, et al ESC Guidelines for Management of ACS. EHJ 2015 (Online Aug 29, 2015). Windecker S, et al ESC/EACTS Guidelines on Myocardial Revascularization. EHJ 2014;35: Amsterdam EA, et al AHA/ACC Guideline for Management of NSTE-ACS. JACC 2014;64:e Montalescot G, et al ESC Guidelines on Management of Stable CAD. EHJ 2013;34: Levine GN, et al ACCF/AHA/SCAI Guidelines for PCI. JACC 2011;58:e Smith SC Jr, et al AHA/ACCF Secondary Prevention Guidelines. JACC 2011;58: Levine GN, et al ACC/AHA Guidelines for DAPT. JACC AOP

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