LA TERAPIA ANTIAGGREGANTE PER VIA PARENTERALE

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1 LA TERAPIA ATIAGGREGATE PER VIA PARETERALE Sergio Leonardi, MD, MHS, FESC Cardiovascular Clinical Research Center Fondazione IRCCS Policlinico San Matteo Pavia, Italy 28 March 2015 Induno, BG CI-1

2 Terapia antiaggregante E.V. Via di somministrazione razionale in caso di mancato/scarso assorbimento per via orale: Shock Intubati Vomito/ausea Altri problemi gastrointestinali (gastroresezione, sdr da malassorbumento, etc) Antiaggreganti disponibili per via parenterale TXA 2 Aspirin IIb/IIIa Abciximab, Tirofiban, Eptifibatide P2Y 12 Cangrelor CI-2

3 ausea and/or Vomiting in Acute MI Year Country Patients utcome Inferior STEMI Anterior STEMI 1978 US 62 ausea or Vomiting 69% 27% 1980 England 58 Vomiting 31% 58% 1987 US 94 ausea or Vomiting 51% 66% 2001 Croatia 1646 Vomiting 28% 19% 2009 US 180 Vomiting 33% 26% Fuller EE et al, Am J Cardiol 2009;104: CI-3

4 IV Aspirin? Aspirin should preferably be given orally (preferably mg) including chewing, to ensure complete inhibition of TXA 2 -dependent platelet aggregation, but may be given intravenously in patients who are unable to swallow. There is little clinical data on the optimal i.v. dosage, but pharmacological data suggest that a lower dose range than orally may avoid inhibition of prostacyclin and therefore a bolus dose range of mg should be preferred for i.v. aspirin. Steg PG, James SK, et al. ESC STEMI Guidelines 2012 CI-4

5 GP IIb/IIIa in STEMI undergoing ppci In the event of angiographic evidence of large thrombus, slow- or no-reflow, and other thrombotic complications, use of GP IIb/IIIa inhibitors as bail-out therapy appears reasonable, although this has not been tested in a randomized trial. Steg PG, James SK, et al. ESC STEMI Guidelines 2012 CI-5

6 GP IIb/IIIa in STEMI undergoing ppci Steg PG, James SK, et al. ESC STEMI Guidelines 2012 CI-6

7 GP IIb/IIIa in STEACS: ESC vs ACC/AHA ESC 2014 Myocardial Revasc GL: verall, there is no evidence for an additional benefit of routine upstream use of GP IIb/IIIa inhibitors in STE-ACS patients scheduled for coronary angiography. ACC/AHA 2014 nsteacs GL: In patients with STE-ACS and high-risk features (e.g., elevated troponin) T adequately pretreated with clopidogrel or ticagrelor, it is useful to administer a GP IIb/IIIa inhibitor (abciximab, double-bolus eptifibatide, or highdose bolus tirofiban) at the time of PCI. (Class I, Level of Evidence: A) CI-7

8 Cangrelor, an ATP analogue H S 4a + P Cl Cl P P H H S C F 3 Angiolillo DJ, Schneider DJ, Bhatt DL, et al..j Thromb Thrombolysis 2012;34: CI-8

9 Cangrelor Metabolism Independent of renal or hepatic function Mechanism of inactivation: sequential dephosphorylation to the nucleoside major circulating metabolite 10,000-fold less active than parent Cangrelor H S P + 4a Cl Cl P P H H S C F 3 Dephosporylated major metabolite H H H H S S C F 3 CI-9

10 Cangrelor: Summary of Characteristics A P2Y 12 receptor inhibitor that is: Intravenous and quickly acting Immediate onset and rapid offset T 1/2 3 to 6 minutes Platelet function return to baseline in 60 minutes Potent Reversible, direct acting Linear PK, metabolism independent of renal or hepatic function CI-10

11 Summary of Clinical Efficacy 48-hour Events R [95% CI] P value PLATFRM Death/MI/IDR 0.87 (0.71,1.07) 0.17 Death/Q-MI/IDR 0.55 (0.33,0.93) 0.02 Death/Q-MI/ST 0.38 (0.20,0.72) PCI Death/MI/IDR 1.05 (0.89,1.24) 0.57 Death/Q-MI/IDR 0.66 (0.42,1.05) 0.08 Death/Q-MI/ST 0.74 (0.43,1.27) 0.27 PLED Death/MI/IDR 0.97 (0.86,1.11) 0.68 Death/Q-MI/IDR 0.61 (0.43,0.86) Death/Q-MI/ST 0.55 (0.36,0.83) Cangrelor better Comparator better 1. Bhatt DL et al. Engl J Med. 2009;361: Harrington RA et al. Engl J Med. 2009;361: White HD et al. Am Heart J. 2012;163: CI-11

12 CHAMPI PHEIX Study Design CHAMPI PHEIX = 10,900 MITT SA/ STE-ACS/ STEMI Patients requiring PCI 1 P2Y 12 inhibitor naïve Rand R Placebo 3 oral (right before PCI or right after, per physician) Cangrelor 2 bolus & infusion (30ug/kg; 4ug/kg/min) PCI ~30 Placebo 2 bolus & infusion R Clopidogrel 600 mg oral Placebo oral Clopidogrel 3 (600 mg or 300 mg oral, per physician) to 4 hours 1 Randomization occurred once suitability for PCI was confirmed either by angiography or STEMI diagnosis. Double blind study medication was administered as soon as possible following randomization. 2 Study drug Infusion (cangrelor or matching placebo) was continued for 2-4 hours at the discretion of the treating physician. At the end of the infusion patients received a loading dose of clopidogrel or matching placebo and were transitioned to maintenance clopidogrel therapy. 3 Clopidogrel loading dose (or matching placebo) was administered as directed by the investigator. At the time of patient randomization, a clopidogrel loading dose of 600 mg or 300 mg was specified by the investigator. MITT=modified intent-to-treat; STE-ACS=non-ST-elevation acute coronary syndrome; PCI=percutaneous coronary intervention; SA=stable angina; STEMI=ST-elevation MI. Leonardi S, Mahaffey KW, et al. Am Heart J CI

13 Primary Efficacy utcomes at 48 Hours, mitt Cangrelor (=5472) Clopidogrel (=5470) R (95% CI) P-value Death/MI/IDR/ST 257/5470 (4.7%) 322/5469 (5.9%) 0.78 (0.66, 0.93) Secondary Efficacy utcomes at 48 Hours, MITT Stent thrombosis (key secondary endpoint) 46/5470 (0.8%) 74/5469 (1.4%) 0.62 (0.43,0.90) 1. The logistic model was adjusted for baseline status and clopidogrel dose. P value of shown on the KM curve is log rank p value. Bhatt DL, Stone GW, Mahaffey KW, et al. Harrington RA. EJM 2013 at CI MI 207/5470 (3.8) 255/5469 (4.7) 0.80 (0.67,0.97) 0.02 Q-wave MI 11/5470 (0.2) 18/5469 (0.3) 0.61 (0.29,1.29) 0.19 IDR 28/5470 (0.5) 38/5469 ( 0.7) 0.74 (0.45,1.20) 0.22 Death 18/5470 (0.3) 18/5469 (0.3) 1.00 (0.52,1.92) >0.99 CV Death 18/5470 (0.3) 18/5469 (0.3) 1.00 (0.52,1.92) >0.99

14 ARC ST only on Clinical Composite EP CI-14

15 on-cabg Bleeding at 48 Hours Bleeding Scale Cangrelor (=5529) Clopidogrel (=5527) R (95% CI) P Value GUST Severe 9 (0.16%) 6 (0.11%) 1.50 (0.53,4.22) 0.44 GUST Moderate 22 (0.4%) 13 (0.2%) 1.69 (0.85,3.37) 0.13 GUST Severe + Moderate 31 (0.6%) 19 (0.3%) 1.63 (0.92,2.90) 0.09 TIMI Major 5 (0.1%) 5 (0.1%) 1.00 (0.29,3.45) >0.999 TIMI Minor 9 (0.2%) 3 (0.1%) 3.00 (0.81,11.10) 0.08 TIMI Major + Minor 14 (0.3%) 8 (0.1%) 1.75 (0.73,4.18) 0.2 Any Blood Transfusion 25 (0.5%) 16 (0.3%) 1.56 (0.83,2.93) 0.16 ACUITY Major 235 (4.3%) 139 (2.5%) 1.72 (1.39,2.13) <0.001 ACUITY w/out hematoma 42 (0.8%) 26 (0.5%) 1.62 (0.99,2.64) 0.05 CI-15

16 Conclusion IV antiplatelet therapy should be always considered in the acute setting surrounding PCI, with special consideration in case of presumed impaired oral absorption ie nausea/vomiting, hypotension/shock, intubation. CI-19