Quale, Quando e per Quanto DAPT in NSTE-ACS? Leonardo De Luca, MD, - PowerPoint PPT Presentation

VII CONGRESSO REGIONALE SIMEU LAZIO OVERVIEW IN EMERGENCY MEDICINE Roma, Hotel Villa Pamphili 5-6 Novembre 2015 Quale, Quando e per Quanto DAPT in NSTE-ACS? Leonardo De Luca, MD, PhD, FACC, FESC Department of Cardiovascular Sciences Department of Cardiovascular Sciences Interventional Cardiology Unit European Hospital Rome, Italy Rome, Italy leo.deluca@libero.it

Conflicts of Interest of Interest I’ve received honoraria for advisory boards or as speaker/chairman at scientific congresses from the speaker/chairman at scientific congresses from the following companies: Abbott Vascular, AstraZeneca, Bayer, Boehringer Ingelheim, Correvio, Daiichi Sankyo, Eli Lilly, Menarini, The Medicines Company

~1 in 5 Pts who are Event-free for the First Year Post- MI, will Suffer an MI, Stroke or Death within 3 yrs MI, will Suffer an MI, Stroke or Death within 3 yrs APOLLO 4-country analysis: adjusted incidence* y y j MI/stroke/all-cause death Adjusted risk (%) Shaded areas correspond to 95% confidence intervals *Adjusted for differences in study populations; MI, myocardial infarction. Shaded areas / figures in brackets [95%CI] Rapsomaniki E et al . ESC Late Breaking Registry presentation 2014.

PEGASUS: Study Design Study Design Patients with history of prior MI within 1–3 years + ≥ 1 additional atherothrombotic risk factor (age ≥ 65 years, >1 prior MI, multivessel CAD, diabetes, or chronic non-end-stage renal dysfunction) N ~21,000 Concurrent treatment with ASA 75–150 mg + standard background care Randomized, double-blind Ticagrelor Ticagrelor Placebo 90 mg BID 60 mg BID BID Duration: Minimum 12 months up to ~44 months (median ~34 months) Duration: Minimum 12 months up to 44 months (median 34 months) Primary efficacy endpoint: CV death, non-fatal MI or non-fatal stroke P i Primary safety endpoint: TIMI major bleeding f t d i t TIMI j bl di Bonaca MP, et al. Am Heart J 2014;167:437

PEGASUS-TIMI 54: Primary Endpoint Primary Endpoint 10 Placebo 9.04% Placebo Ticagrelor 90 mg bid Ticagrelor 90 mg bid 9 Ticagrelor 60 mg bid 7.85% 90 mg bid 8 7 7 7.77% 60 mg bid 6 rate (%) 5 5 Event r 4 3 Ticagrelor 90 mg vs placebo Ticagrelor 90 mg vs placebo HR 0.85 (95% CI 0.75–0.96) P=0.008 2 Ticagrelor 60 mg vs placebo 1 HR 0.84 (95% CI 0.74–0.95) P=0.004 0 0 3 6 9 12 15 18 21 24 27 30 33 36 Months from randomisation No. at risk Placebo Pl b 7067 6979 6892 6823 6761 6681 6508 6236 5876 5157 4343 3360 2028 90 mg bid 7050 6973 6899 6827 6769 6719 6550 6272 5921 5243 4401 3368 2038 60 mg bid 7045 6969 6905 6842 6784 6733 6557 6270 5904 5222 4424 3392 2055 Bonaca MP, et al. N Engl J Med 2015;372:1791

PEGASUS-TIMI 54: Efficacy Endpoints Efficacy Endpoints Ticagrelor Ticagrelor Ticagrelor Ticagrelor Ticagrelor Ticagrelor Placebo 90 mg bid vs 60 mg bid vs Endpoint 90 mg bid 60 mg bid N=7067; n (%) placebo placebo N=7050; n (%) N=7045; n (%) HR (95% CI) HR (95% CI) Primary endpoint P i d i t 0.85 (0.75–0.96) 0.84 (0.74–0.95) CV death, MI or 493 (7.85) 487 (7.77) 578 (9.04) stroke P=0.008 P=0.004 Secondary endpoints y p 0.87 (0.71–1.06) 0.83 (0.68–1.01) CV death 182 (2.94) 174 (2.86) 210 (3.39) P=0.15 P=0.07 1.00 (0.86–1.16) 0.89 (0.76–1.04) Death from any 326 (5.15) 289 (4.69) 326 (5.16) cause cause P 0 99 P=0.99 P 0 14 P=0.14 Other efficacy endpoints 0.81 (0.69–0.95) 0.84 (0.72–0.98) MI 275 (4.40) 285 (4.53) 338 (5.25) P=0.01 P=0.03 0.82 (0.63–1.07) 0.75 (0.57–0.98) All stroke 100 (1.61) 91 (1.47) 122 (1.94) P=0.14 P=0.03 0.85 (0.64–1.14) 0.76 (0.56–1.02) Ischaemic stroke 88 (1.41) 78 (1.28) 103 (1.65) P=0.28 P=0.06 Bonaca MP, et al. N Engl J Med 2015;372:1791

Evidence-Based Pharmacological Therapies in MI Survivors in MI Survivors Agent ASA β -blockers ACE-I/ARB Statins Aldost. Ant. ADP Ant. Pivotal Trial ATT BHAT SMILE CARE EPHESUS** PEGASUS Year Year ‘70-’80 70- 80 1982 1995 1996 2003 1982 1995 1996 2003 2015 2015 Duration 4,5 y 25 m 6 w 5 y 16 m 3 y Background Rx Background Rx None Aspirin (21%) Aspirin (53%) Aspirin (83%) Aspirin (88%) Aspirin (99%) ~None Aspirin (21%) Aspirin (53%) Aspirin (83%) Aspirin (88%) Aspirin (99%) β -block (18%) β -block (41%) β -block (75%) β -block (83%) CCBs (10%) CCBs (40%) ACE-I (87%) ACE-I (81%) ACE-I (15%) Statins (47%) Statins (93%) PCI None None None* 32% 24% 83% Mortality 23% 26% 29% 15% 11% p<.02 p p p<.005 p<.01 p p<.008 p P=NS @1y Reinfarction 16% 34% 37% 24% 16% N/A p<.02 p=NS p<.01 p<.003 P=.003 @1y @1y * Pts not eligible for thrombolysis ** Pts with LV dysfunction or HF

Long-term DAPT in patients with previous MI: a collaborative meta-analysis of RCTs collaborative meta analysis of RCTs Udell JA, et al. Eur Heart J 2015, in press

PEGASUS-TIMI 54: Analysis of Net Clinical Benefit Analysis of Net Clinical Benefit Ticagrelor 90 mg bid Ti l 90 bid Ticagrelor 60 mg bid Ti l 60 bid versus placebo versus placebo Characteristic Characteristic RRR RRR HR (95%CI) HR (95%CI) P value P value RRR RRR HR (95%CI) HR (95%CI) P value P value Irreversible harm: 12% 0.88 0.0372 14% 0.86 0.0160 CV death, MI, stroke, , , , (0.78–0.99) ( ) (0.77–0.97) ( ) ICH and fatal bleeding Bonaca MP, et al. N Engl J Med 2015;372:1791 ‘the superiority of a drug involves the irreversible harm’ FDA Rivaroxaban package approval FDA Cangrelor package approval

Reduction in MACE with Ticagrelor by Time from P2Y 12 Inhibitor Withdrawal Time from P2Y 12 Inhibitor HR (95% CI) P-value withdrawal to randomization 0.70 (0.57 – 0.87) ≤ 30 days 0.75 (0.61 – 0.92) N=7 181 N=7,181 27% RRR 0.73 (0.61 – 0.87) <0.001 0.90 (0.72 – 1.12) >30 days y to 1 year 0.82 (0.65 – 1.02) 14% RRR 0.86 (0.71 – 1.04) 0.11 N=6,501 0.96 (0.73 – 1.26) >1 year 1.06 (0.81 – 1.38) N=5079 ∅ RRR 1.01 (0.80 – 1.27) 0.96 P-interaction 0.0097 Ticagrelor 90 mg 0.90 1.10 0.70 Ticagrelor 60 mg Ticagrelor 60 mg Ticagrelor Better Placebo Better 1.0 Pooled

MACE in Patients Randomized to Placebo by Time from P2Y 12 Inhibitor Withdrawal ≤ 30 days Adj. HR 1.47 30 days – ≤ 1 Year 1.46% (95% CI >1 Year >1 Year 1.12 – 1.93) 9.9% P-trend 0.0097 0.60% Adj. HR 1.28 0.55% 8.7% (95% CI ) 0 98 0.98 – 1.67) 1 67) Stroke (% 6.9% Ref. CVD/MI/S Adjusted for baseline characteristics that differed between Adjusted for baseline characteristics that differed between groups including age, sex, race, region, time from qualifying MI, diabetes, multivessel disease, hypertension, hypercholesterolemia, and history of PCI/stent. Days from Randomization An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School

PLATO NSTE-ACS: Composite of CV death, MI or stroke Composite of CV death, MI or stroke Lindholm D, et al. Eur Heart J, 2014 in press

TRITON TIMI-38 NSTE-ACS Population NSTE ACS Population HR for the Primary Endpoint HR for the Primary Endpoint De Servi S, et al. Eur Heart J:ACC 2014

New ESC Guidelines for NSTE-ACS Oral Antiplatelet Therapy Oral Antiplatelet Therapy Eur Heart J 2015; doi:10.1093/eurheartj/ehv320

Pre-Treatment in Phase III Trials on Novel P2Y12 Inhibitors on Novel P2Y12 Inhibitors Pre-Rx PCI CABG Conserv. Trial Study Drug 1 Ticagrelor 2 Prasugrel g 1. Wallentin L, et al. N Engl J Med. 2009;361:1045 15 2. Wiviott SD, et al. N Engl J Med 2007;357:2001 Confidential for AstraZeneca Discussion Purposes Only

Comparison of Ticagrelor Versus Prasugrel to Prevent Periprocedural Myonecrosis in ACS Prevent Periprocedural Myonecrosis in ACS 213 patients with NSTE-ACS @ intermediate-high risk randomized to a 180 180 mg of ticagrelor LD given as soon as possible after admission and before PCI (LD-PCI: 13.4 hrs) f ti l LD i ibl ft d i i d b f PCI (LD PCI 13 4 h ) or to a 60 mg LD of prasugrel given at the time of PCI (admission-PCI: 17.8 hrs for tica vs 18.2 hrs for prasu) Bonello L, et al. Am J Cardiol 2015, in press

Patients Presenting with NSTE-ACS in the United States NSTE-ACS in the United States Burke MA, et al. Am Heart J 2011;161:832

CABG-Related Bleeding Complications in Patients Treated with Ticagrelor or Clopidogrel Treated with Ticagrelor or Clopidogrel All ACS patients in Sweden on dual antiplatelet therapy with aspirin and ticagrelor (n=1266) or clopidogrel (n=978) who underwent CABG during 2012–13 were included in a retrospective observational study retrospective observational study. Hansson EC, et al. Eur Heart J 2015, in press

Time to Coronary Angiography y g g p y PCI CURE FRISC II RITA 3 EYESHOT FAST ‐ MI GRACE APTOR TACTICS TACTICS TIMI ‐ 18 CRUSADE SYNERGY ACUITY FUTURA/ OASIS ‐ 8 CHAMPION CURRENT/ CURRENT/ ACCOAST PLATFORM OASIS ‐ 7 PLATO RCT Registries Year of publication De Luca L, et al. Am J Cardiol 2015;116:660

Pre-Treatment with DAPT with DAPT EYESHOT Registry 79 3% (1807/2280) 79.3% (1807/2280) 79.5% (1395/1755) De Luca L, et al. Eur Heart J: ACC 2015,;4:441