P2Y 12 blockade. To load or not to load before the cath lab?

Transcription

1 UPDATE ON ANTITHROMBOTICS IN ACUTE CORONARY SYNDROMES P2Y 12 blockade. To load or not to load before the cath lab? Franz-Josef Neumann

2 Personal: None Institutional: Conflict of Interest Speaker honoraria, consultancy fees and research grants from Lilly, Daiichi Sankyo, Sanofi-Aventis, Bristol, Novartis, Roche, Boston Scientific, Cordis, Biotronik, Medtronic

3 UPDATE ON ANTITHROMBOTICS IN ACUTE CORONARY SYNDROMES P2Y 12 blockade. To load or not to load before the cath lab? Lessons from early studies: Role of platelet inhibition during PCI Evidence for loading with clopidogrel Evidence for loading with new P2Y 12 blockers Loading with unkown coronary anatomy

4 UPDATE ON ANTITHROMBOTICS IN ACUTE CORONARY SYNDROMES P2Y 12 blockade. To load or not to load before the cath lab? Lessons from early studies: Role of platelet inhibition during PCI Evidence for loading with clopidogrel Evidence for loading with new P2Y 12 blockers Loading with unkown coronary anatomy

5 Impact of Platelet Inhibition During PCI on Early MACE 7-Day MACE (%) 2 P= < 95 % > 95% Inhibition of platelet aggregation at 1 min after anti-gp IIb/IIIa bolus Steinhubl S et al., Circulation 21

6 Platelet Aggregation and Time after Loading % inhibition of platelet aggregation (%) 1 75 Tirofiban (TACTICS dosage) Abciximab minutes 2 hours Time After Bolus Lakkis N et al., Catheter Cardiovasc Interv. 22; Neumann FJ et al., J Am Coll Cardiol 21

7 Outcome Depending on Early Platelet Inhibition Early Incidence of MI (%) Tirofiban Abciximab Time (Hours) Cannon C et al., N Engl J Med 21

8 UPDATE ON ANTITHROMBOTICS IN ACUTE CORONARY SYNDROMES P2Y 12 blockade. To load or not to load before the cath lab? Lessons from early studies: Role of platelet inhibition during PCI Evidence for loading with clopidogrel Evidence for loading with new P2Y 12 blockers Loading with unkown coronary anatomy

9 Clopidogrel Pretreatment and Early Risk of PCI 3-Day Death, MI & Urg. TVR (%) PCI-CURE CREDO P= P= No Pretreatment Pretreatment 2 3 mg + 75 mg for 3 mg median of 1 days < 6 h 6-24 h

10 Reduced Risk of PCI after Loading with Thienopyridine PCI-CURE, n = 2658 CREDO (full effect), n = 473 EPISTENT, n = 89 ESPRIT, n = 124 Early Risk for Efficacy Endpoint PRAGUE-8, n = Pooled, n = Mehta SR, Lancet 21; Steinhubl SR, Circulation 21 & JAMA 22; Tcheng JE, pers. comm.; Widimsky P, ESC 27

11 Clopidogrel pretreatment plus GP IIb/IIIa Blockade? 3-Day Death, MI & Urg. TVR (%) 15 P=.17 P= P= No Pretreatment Pretreatment Abciximab TARGET Tirofiban Eptifibatide ESPRIT* *1-year Death&MI Chan AW et al., J Am Coll Cardiol 23; Tcheng JE, pers. comm.

12 Efficacy of Thienopyridines with GP IIb/IIIa Blockade Ticlopidin EPISTENT (Abciximab), n=794 Clopidogrel ESPRIT* (Eptifibatid), n=14 TARGET (Abciximab), n=2411 TARGET (Tirofiban), n=2398 CREDO (Mixed), n=378 Relative 3-Day Risk of Death, MI & Urg. TVR Pooled, n=7,21 *1-year Death&MI Steinhubl SR, Circulation 21 & JAMA 22; Chan AW et al., J Am Coll Cardiol 23; Tcheng JE, pers. comm

13 Benefit of clopidogrel before PCI after fibrinolysis - PCI-CLARITY - Event rate [%] 8 P =.8 P =.21 Clopidogrel 6 6.2% Placebo 4 3.6% 2 Death, MI, Stroke post PCI.5% 1.1% Major Bleed Sabatine MS et al., JAMA 25

14 Cumulative Hazard Benefit of clopidogrel loading in large regristry.5 Loading dose after stenting Pre-treatment.1 N = 4.16 P =.1 Szük T et al., Am Heart J Time to Major Adverse Events (Days)

15 Highly variable platelet responses after clopidogrel Maximal aggregation 5 µmol/l ADP (%) Time from loading dose to catheterisation (h) Hochholzer W et al., Circulation 25

16 Impact of insufficient platelet inhibition during PCI Incidence of MACE (%) P =.4 1 Residual platelet aggregation > 14% 14% 1 2 Days after PCI 3 Hochholzer W et al., J Am Coll Cardiol 26

17 UPDATE ON ANTITHROMBOTICS IN ACUTE CORONARY SYNDROMES P2Y 12 blockade. To load or not to load before the cath lab? Lessons from early studies: Role of platelet inhibition during PCI Evidence for loading with clopidogrel Evidence for loading with new P2Y 12 blockers Loading with unkown coronary anatomy

18 Prasugrel: Faster and stronger than high-dose clopidogrel Inhibition of Platelet Aggregation - 2 mm ADP (%) P<.1 for each Prasugrel 6 mg 4 Clopidogrel 6 mg Hours Wiviott SD et al., Circulation 27

19 Ticagrelor: Faster and stronger than clopidogrel Storey R et al., J Am Coll Cardiol 27

20 Attenuated effect of clopidogrel in STEMI Schäfer A et al., Thromb Haemost 211

21 Delayed effect of prasugrel and ticagrelor in ACS Inhibition, % Inhibition RPA ADP 2µM Time from Loading to PCI, min. STEMI - Pras STEMI - Tica NonSTEMI - Pras NonSTEMI - Tica PRINCIPLE TIMI range clopidogrel 2- range prasugrel Trenk D et al., unpublished

22 Circumstantial evidence for preloading with novel P2Y 12 -receptor blockers from TRITON or PLATO? Overall benefit with PCI? Peri-interventional benefit? Frequency of preloading during study?

23 Benefit of prasugrel in TRITON-TIMI 38 Incidence (%) 15 P < P =.3 Clopidogrel Prasugrel 5 Death, MI, stroke Wiviott SD et al., N Engl J Med TIMI major Non-CABG bleed NNT 46 NNH 167

24 Benefit of ticagrelor in PLATO Incidence (%) 15 P < P =.3 P = Clopidogrel Ticagrelor 5 Death, MI, stroke Wallentin L et al., N Engl J Med TIMI major Non-CABG bleed NNT 53 NNH 167 PLATO major bleed

25 Wiviott et al. N Engl J Med 27 Prasugrel: Prevention of periinterventional events Incidence of death, MI and stroke (%) 1 P= Clopidogrel Prasugrel Days

26 Wiviott et al. N Engl J Med 27 Minority with upstream treatment in TRITON Timing of study drug administration Before PCI 26% During PCI 73% After PCI 1%

27 Ticagrelor: Prevention of delayed events Incidence of death, MI and stroke (%) Clopidogrel Ticagrelor P= Wallentin L et al., N Engl J Med Days

28 Ticagrelor: Lack of periinterventional efficacy? Consequence of pretreatment with clopidogrel? 54 % without pretreatment Stronger benefit in the absence of pretreatment with clopidogrel? Not in STEMI Not reported in NSTE-ACS Steg G et al., Circulation 21; Wallentin L et al., N Engl J Med 29

29 Efficacy independent of clopidogrel pretreatment Steg G et al., Circulation 21

30 Trial Design Upstream + Transfer to PCI (>2h to 24h) NON-STEMI / Troponin +, n=41+ (Clopid. naive or long term 75mg) Transfer for planned PCI (>2h and <24h) Randomize Placebo P 3 Cathlab CAG PCI CAG P 6 PCI P 3 3d FU PE: CV-D, MI, Stroke, utvr, GPI SE: All TIMI major NetClinOutcome@3d

31 UPDATE ON ANTITHROMBOTICS IN ACUTE CORONARY SYNDROMES P2Y 12 blockade. To load or not to load before the cath lab? Lessons from early studies: Role of platelet inhibition during PCI Evidence for loading with clopidogrel Evidence for loading with new P2Y 12 blockers Loading with unkown coronary anatomy

32 Bleeding Risk of CABG After Clopidogrel Early Major/Life Threatening Bleeding (%) 1 P= P= Placebo Clopidogrel < 4 Days > 4 Days After Discontinuation of Study Drug Fox KA et al., Circulation 24

33 Risk/Benefit Ratio of Clopidogrel in CURE CV Death, MI, Stroke & Life Threatening Bleeding (%) 15 P< Events Prevented/Incurred per 1 1 Life Threatening 5 Bleeding Placebo Clopidogrel CV Death, Infarction, Stroke Fox KA et al., Circulation 24

34 Safety of CABG 5 days after stopping clopidogrel - ACUITY - 3-day event rate (%) 5 P=.4 P= Transfusion Ebrahimi R et al., J Am Coll Cardiol 29 P=.3 P= Ischemic complications No clopidogrel before CABG Clopidogrel stopped for > 5 days Clopidogrel stopped < 5 days

35 Superior CABG outcome after treatment with clopidogrel - ACUITY - 3-day incidence of myocardial infarction (%) P < No clopidogrel before CABG Clopidogrel before CABG Ebrahimi R et al., J Am Coll Cardiol 29

36 Increased risk of CABG bleed with prasugrel vs. clopidogrel High overall risk in PLATO Rate of TIMI major CABG bleeds (%) 7 P <.1 P = TRITON PLATO Clopidogrel Prasugrel Ticagrelor Wiviott SD et al., N Engl J Med 27; Wallentin L et al., N Engl J Med 29

37 Superior CABG survival after treatment with prasugrel All Cause Death Rate (%) 1 8 Clopidogrel 8.7% N = 346 Adjusted Odds Ratio:.26 ( ) p =.25 Prasugrel Days from Isolated CABG 2.3% Smith PK et al. American Heart Association Scientific Sessions, 21

38 K-M estimated rate (%) Superior CABG survival after treatment with ticagrelor Clopidogrel Ticagrelor HR:.49 (95% CI.32.77), p< Months Held C et al., J Am Coll Cardiol 211

39 Loading with P2Y 12 blockers before the cath lab - ESC Practice Guidelines on NSTE-ACS - A P2Y 12 inhibitor should be added to aspirin as soon as possible.., unless there are contraindications. Ticagrelor is recommended for all patients at moderate-to-high risk of ischaemic events Prasugrel is recommended for P2Y 12 -inhibitor-naïve patients who are proceeding to PCI Clopidogrel is recommended for patients who cannot receive ticagrelor or prasugrel. I A I B I B I A Eur Heart J 211

40 Loading with P2Y 12 blockers before the cath lab - ESC Practice Guidelines on STEMI - An ADP-receptor blocker is recommended in addition to aspirin: Prasugrel if no history of prior stroke/tia, age < 75 yrs Ticagrelor Clopidogrel.. when prasugrel or ticagrelor are either not available or contraindicated I A I B I B I C Eur Heart J 212