Optimal antithrombotic treatment after acute coronary syndrome: the (complicated) near future Jur ten Berg Associate Professor, PhD, MSc, FESC, FACC St. Antonius Hospital, Nieuwegein, the Netherlands; University Hospital Groningen, the Netherlands
Disclosures Research Grants: ZonMw, AstraZeneca Advisory/consulting/speakers fees : Accu-Metrics, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, Ferrer, Idorsia, Pfizer, The Medicines Company
Optimal antithrombotic treatment after acute coronary syndrome: the near future • Duale therapie: aspirine plus clopidogrel, prasugrel of ticagrelor - 1, 3, 6, 12, >12 maanden Keuze P2Y12 remmer obv gentyping? • Ticagrelor monotherapy na 3 maanden DAPT? •
Recommendation Class Level Oral antiplatelet therapy A P2Y 12 inhibitor is recommended in addition to aspirin, for 12 months unless there are I A contraindications such as excessive risk of bleeds. • Ticagrelor (180 mg loading dose, 90 mg twice daily) is recommended in the absence of contraindications, for all patients at moderate-to-high risk of ischaemic events (e.g. elevated I B cardiac troponins), regardless of initial treatment strategy and including those pretreated with clopidogrel (which should be discontinued when ticagrelor is started). • Prasugrel (60 mg loading dose, 10 mg daily dose) is recommended in patients who are I B proceeding to PCI if no contraindications. • Clopidogrel (300-600 mg loading dose, 75 mg daily dose) is recommended for patients who I B cannot receive ticagrelor or prasugrel or who require oral anticoagulation. Roffi et al. Eur Heart J. 2015;doi:10.1093/eurheartj/ehv320;
Casus I-duur DAPT • Vrouw 78 jaar, 57 kg, hypertensie • Opname ivm NONSTEMI, trop T pos, Hb 6,9 mmol/l , GFR=58, L 5.6, • PCI DES prox LAD succesvol a)1 jaar DAPT b)6 maanden DAPT c) 3 maanden DAPT
Casus I-welke P2Y12 remmer • Vrouw 78 jaar, 57 kg, hypertensie • Opname ivm NONSTEMI, trop T pos, Hb 6,9 mmol/l, GFR=58, L 5.6, • PCI DES prox LAD succesvol a) ticagrelor b) prasugrel c) clopidogrel
Reasons for dual antiplatelet therapy (DAPT): prevention of ST 44 yr female STEMI due to ST after discontinuing ticagrelor after 2 months
Reasons for DAPT: prevention of spontaneous MI DAPT Trial (N=10,000) Study drug Randomization* treatment ends 12-month 3-month Thienopyridine + Aspirin observational period: observational period: open label Off Thienopyridine, Thienopyridine + Placebo + Aspirin On Aspirin Aspirin required Time in months after index stent procedure (not to scale) 12 30 33 0 * Free from MI, stroke, repeat revascularization and bleeeding, adherent to P2Y12 Mauri L, et al. Am Heart J 2010;160:1035-1041.e1
Both ST related and spontaneous MI % 10 HR 95% CI P value n 12 months 8 0,59 0,45 – 0,78 <0,001 9.961 30 months 6 55% of the MI 2,9 benefit is NOT 4 related to stent thrombosis 1,8 0 0 12 15 18 21 24 27 30 33 Months post randomisation Mauri L, et al. Am Heart J 2010;160:1035-1041.e1
DAPT is not innocent! CURE: Major Bleeding at 1 year clopidogrel + ASA Placebo Clopidogrel + ASA + ASA (N=6303) (N=6259) ASA Dose <100 mg (N=5320) 1.9% 3.0% 100-199 mg (N=3109) 2.8% 3.4% >200 mg (N=4110) 3.7% 4.9% P value for trend .0001 .0009 Adapted from Peters RJG, et al. Circulation. 2003;108:1682-1687.
Especially spontaneous bleeding increased mortality Analysis in 17 393 patients who underwent PCI as part of the REPLACE-2, ACUITY, and HORIZONS-AMI trials Relative risk (95% CI) One-year mortality (%) P value compared with no bleed No bleed 2.54 – – Access site only 6.16 2.33 (1.53–3.53) <0.001 All nonaccess site 14.4 5.40 (4.32–6.74) <0.0001 Nonaccess only 14.1 5.52 (3.62–8.40) <0.001 Both access and nonaccess 14.5 5.70 (3.78–8.61) <0.001 Indeterminate 14.6 5.18 (3.82–7.03) <0.001 Unadjusted one-year mortality rates and relative risks associated with experiencing a 30-day TIMI bleed. Verheugt et al. JACC 2001
ASA plus P2Y12 inhibitor clopidogrel for 12 months • Predominantly conservative treatment • BMS, first generation DES • Clopidogrel: weaker and variable response N Engl J Med 2001; 345:494-502
Stronger P2Y12 inhibitors: prasugrel and ticagrelor • Stronger P2Y12 inhibition • Rapid onset • Very few low responders Wiviott, et al. N Engl J Med 2007; 357:2001-2015 Wallentin, et al. N Engl J Med 2009; 361:1045-1057
Prasugrel and ticagrelor superior in large outcome trials • Post PCI • All comers ACS treated at admittance Wiviott, et al. N Engl J Med 2007; 357:2001-2015 Wallentin, et al. N Engl J Med 2009; 361:1045-1057
Stronger P2Y12 preferred in all patients? Recommendation Class Level Oral antiplatelet therapy A P2Y 12 inhibitor is recommended in addition to aspirin, for 12 months unless there are contraindications such as excessive I A risk of bleeds. • Ticagrelor (180 mg loading dose, 90 mg twice daily) is recommended in the absence of contraindications, for all patients at moderate-to-high risk of ischaemic events (e.g. elevated cardiac troponins), regardless of initial treatment I B strategy and including those pretreated with clopidogrel (which should be discontinued when ticagrelor is started). • Prasugrel (60 mg loading dose, 10 mg daily dose) is recommended in patients who are proceeding to PCI if no I B contraindications. Adapted from Roffi et al. 2015 1 • Clopidogrel (300-600 mg loading dose, 75 mg daily dose) is recommended for patients who cannot receive ticagrelor I B or prasugrel or who require oral anticoagulation. Roffi et al. Eur Heart J. 2015;doi:10.1093/eurheartj/ehv320;
Need to individualise Class Level Oral antiplatelet therapy A P2Y 12 inhibitor is recommended in addition to aspirin, for 12 months I A Ticagrelor (180 mg loading dose, 90 mg twice daily) is recommended in the absence of high bleeding • risk , for all patients at moderate-to-high risk of ischaemic events (e.g. elevated cardiac I B troponins), regardless of initial treatment strategy and including those pretreated with clopidogrel (which should be discontinued when ticagrelor is started). • Prasugrel (60 mg loading dose, 10 mg daily dose) is recommended in patients who are proceeding to PCI if no I B contraindications. • Clopidogrel (300-600 mg loading dose, 75 mg daily dose) is recommended for patients who cannot receive ticagrelor Adapted from Roffi et al. 2015 1 I B or prasugrel or who require oral anticoagulation. Who are these patients? 1. Roffi et al. Eur Heart J. 2015;doi:10.1093/eurheartj/ehv320; 2. Lip et al. Eur Heart J.2014;35:3155–3179;
Can we rely on gut feeling? Old, fragile platelets Highly activated platelets Peacefully and shorter DAPT Aggressive and long DAPT clopidogrel ticagrelor or prasugrel
Choice of P2Y12 inhibition based on age Randomised comparison of clopidogrel versus ticagrelor or prasugrel in patients of 70 years or older with non-ST -elevation acute coronary syndrome POPular AGE trial (N=1000) Marieke E. Gimbel MD St. Antonius hospital, Nieuwegein, the Netherlands Jurriën ten Berg, Vera Deneer (PIs)
Primary safety outcome Ticagrelor/prasugrel 23.1% Clopidogrel 17.6% HR 0.74 (95%CI 0.56-0.97) P=0.03
Secondary efficacy outcome Clopidogrel 12.8% Ticagrelor/prasugrel 12.5% HR 1.02 (95% CI 0.72-1.45) P=0.91
Can we rely on gut feeling? Average patients Highly activated platelets Old, fragile platelet Peacefully and shorter DAPT Aggressive and long DAPT Risk for bleeding? clopidogrel ticagrelor or prasugrel Risk for thrombosis?
Introductie Ticagrelor 60 mg BID Valgimigli, et all. European Heart Journal , Volume 39, Issue 3, 14 January 2018, Pages 213–260,
Individualise DAPT duration Valgimigli, et all. European Heart Journal , Volume 39, Issue 3, 14 January 2018, Pages 213–260,
Valgimigli, et all. European Heart Journal , Volume 39, Issue 3, 14 January 2018, Pages 213–260,
Antwoord Casus 1- DAPT 6 maanden
Casus II • Man 55 jaar, DM II, hypertensie met GFR = 48 ml/min, rookt nog • 2015- 1 PCI RCA voor OWI DAPT 12 maanden • 2016- 12 PCI DES proximale LAD, PCI Cx en diffuus RCA herstart DAPT • 2018- 1 geen AP, geen bloeding a) P2Y12 remmer had al gestopt moeten zijn b) Nog jaren continueren 28
Casus II • Man 55 jaar, DM II, hypertensie met GFR = 48 ml/min, rookt nog • 2015- 1 PCI RCA voor OWI DAPT 12 maanden • 2016- 12 PCI DES proximale LAD, PCI Cx en diffuus RCA herstart DAPT • 2018- 1 geen AP, geen bloeding a) P2Y12 remmer had al gestopt moeten zijn b) Nog jaren continueren DAPT score : no event first year, score 3 (DM, prior MI or PCI, smoking) PEGASUS : age of 65 years or older, diabetes mellitus, a second prior spontaneous MI, multivessel CAD, or GFR < 60 ml/min 29
• Woman 78 yrs, 57 kg, hypertension, no prior bleeding • Hb 11.1 g/dl, L 5.6, GFR=58 • NON-STEMI, PCI DES LAD successful • PRECISE-DAPT score ≧ 25, prolonged DAPT was associated with no ischemic benefit but increased bleeding with NNH = 38 • DAPT duration 6 months Costa F, at all Lancet. 2017 Mar 11;389(10073):1025-1034 . 30
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