Antiplatelet Agents in Acute Coronary Syndromes, NSTE-ACS

Transcription

1 Antiplatelet Agents in Acute Coronary Syndromes, NSTE-ACS Is There Still a Role for IV Antiplatelet Agents (Cangrelor, GPIIbIIIA inhibitors)? François Schiele, MD, PhD Department of Cardiology, University Hospital Jean Minjoz, Besançon, France. Potential conflicts of interest Research grant : GlaxoSmithKline, St Jude Medical, Sanofi-Aventis, Servier, Daiichi-Sankyo/Lilly Speaker : Boehringer Ingelheim, Daiichi-Sankyo/Lilly, Novartis, Sanofi-Aventis, Servier, The Medicines Company, Astra Zeneca Consulting : Sanofi, Astra Zeneca, Lilly

2 Antiplatelet Agents in Acute Coronary Syndromes, NSTE-ACS Is There Still a Role for IV Antiplatelet Agents (Cangrelor, GPIIbIIIA inhibitors)? 1. Oral or intra venous route in ACS? 2. P2Y12 receptor inhibitors? 3. GPIIbIIIa receptor inhibitors?

3 Oral or intravenous route in NSTE-ACS? #1 Acute stress induces Gastro Intestinal disorders, that might affect drug absoption* : Stress ulcer Stimulation of intestine motility Alteration of intestine mucine secretion Bacterial translocation. Opioids have GI effects ** *Soderholm Am J Physiol 2001;280:G7-13 **Rees-Parrish Practical Gastro Enterology 2008

4 Oral or intravenous route in NSTE-ACS? #2 180 consecutive patients with acute MI Consistent with the results of 4 previous studies Nausea in 2/3 patients with STEMI, vomiting in 1/3 More often in STEMI than in NSTEMI and more frequent in inferior vs anterior MIs Fuller Am J Cardiol 2009;104:

5 Oral or intravenous route in NSTE-ACS? #3 Impaired gastro intestinal absorption, time to maximal platelet inhibition of clopidogrel in STEMI patients as compared with controls. Shunting of blood to vital organs and ANP release have an impact on intestinal motility and gastric emptying. Heestermans Thromb Res 2008;122:776-81

6 Oral or intravenous route in NSTE-ACS? #4 Aspirin is available as oral or IV: change in doses? NSTE-ACS guidelines recommend a loading dose of chewed mg. «IV loading dose is an alternative mode of application, but has not been evaluated»* mg oral aspirin allows complete inhibition of TXA2 dependent aggregation. Higher doses (like mg) lead to an inhibition of PGI2 biosythesis and lowers the platelet inhibition** Translation of mg oral aspirin to IV is mg. Recommended IV aspirin dose is mg ***. *Hamm Eur Heart J 2011;32: ** Fitzgerald J Clin Invest 1983;71: ***Patrono Eur Heart J 2011; 32,

7 Is There Still a Role for Cangrelor? #1 Cangrelor: direct parenteral P2Y12 antagonist, analog of ATP, high affinity for P2Y12 receptors, no conversion to active metabolite, Intravenous injection, half life 2.9 to 5.5 min Dose dependent platelet inhibition. Onset within 2 min and offset 60 min after infusion cessation Akers J Pharmacology 2010;50:27-35

8 Is There Still a Role for Cangrelor? #2 Cangrelor: greater inhibition than clopidogrel Phase II dose ranging study : 4µg/kg produce 100% platelet inhibition within 15 min, similar to abciximab, but with a return to normal within 15 min. Simultaneous administration of cangrelor and clopidogrel prevents clopidogrel from inhibiting P2Y12 receptor => to maintain inhibition after cangrelor administration, clopidogrel LD must be administered after cessation of cangrelor. Greenbaum Am Heart J 2006;151:689 Steinhubl Thromb Res 2008;121:527

9 Is There Still a Role for Cangrelor? #3 CHAMPION-PCI and CHAMPION-PLATFORM: phase III studies to test cangrelor during PCI (stable and ACS patients), vs clopidogrel. Early termination (8882 patients) due to low likelihood to achieve superiority in the primary endpoint. Negative results: no difference in composite all-cause death, MI, ischemia-driven revascularization (p=0.59) and more «non severe» bleedings (p=0.06). Kastrati NEJM 2009;361

10 Is There Still a Role for Cangrelor? #5 1. No difference in the combined endpoint, but mainly driven by a raise of CPK MB/troponin. Harrington NEJM 2009;361:1

11 Is There Still a Role for Cangrelor? #5 1. No difference in the combined endpoint, but mainly driven by a raise of CPK MB/troponin. 2. In patients not pre treated with clopidogrel (CHAMPION- PLATFORM), two pre specified endpoints without biology were positive, including death from any cause. Bhatt NEJM 2009;361:2330

12 Is There Still a Role for Cangrelor? #5 1. No difference in the combined endpoint, but mainly driven by a raise of CPK MB/troponin. 2. In patients not pre treated with clopidogrel (CHAMPION- PLATFORM), two pre specified endpoints without biology were positive, including death any cause. 3. The pooled data from CHAMPION-PCI and CHAMPION- PLATFORM suggest benefit of cangrelor over clopidogrel. White Am Heart J 2012;163:182

13 Is There Still a Role for Cangrelor? #5 1. No difference in the combined endpoint, but mainly driven by a raise of CPK MB/troponin. 2. In patients not pre treated with clopidogrel (CHAMPION- PLATFORM), two pre specified endpoints without biology were positive, including death any cause. 3. The pooled data from CHAMPION-PCI and CHAMPION- PLATFORM suggest benefit of cangrelor over clopidogrel. 4. Were the CHAMPION trials given an optimal chance to compare cangrelor and clopidogrel? No baseline troponin assessment => non discriminating raise explain the lack of difference in the combined endpoint Unclear bleeeding definitions, including elements from ACUITY Potential GAP in P2Y12 inhibition in the transition IV-oral 5. The CHAMPION-PHOENIX trial will answer this question : patients, stable or ACS with PCI

14 Is There Still a Role for GPIIbIIIa inhibitors? #1 1. Class I, Level B: NSTEMI and high risk PCI 2. Class III, Level A: not in patients with conservative management Kastrati JAMA 2006; 295: Roffi Eur Heart J 2002;23: Hamm Eur Heart J 2011;32:

15 Is There Still a Role for GPIIbIIIa inhibitors? #1 3. Class IIa, Level C: high risk PCI without pre tx with DAPT 4. Class IIb, Level C: high risk going to PCI early with DAPT Marmur J Invasive Cardiol 2008;20:53-58 Hamm Eur Heart J 2011;32:

16 Is There Still a Role for GPIIbIIIa inhibitors? #1 5. Class I, Level C: high thrombotic/low bleeding risk 6. Class III, Level A: not upstream, before angiography Stone NEJM 2006;355: Giugliano NEJM 2009;360:21 Hamm Eur Heart J 2011;32:

17 Is There Still a Role for IV antiplatelet agents in NSTE-ACS? Yes, definitely! 1. IV route has several advantages over oral administration, more reliable and quicker. Gastro intestinal function might be altered through different ways at the early phase of ACS. 2. Cangrelor is the only IV P2Y12 antagonist. It has many theoretical advantages, but clinical benefit needs to be confirmed through the CHAMPION-PHOENIX trial. 3. GPIIbIIIa inhibitors still needed during PCI in patients with high thrombotic risk, low bleeding risk or in those admitted for angiography/pci without effective DAPT.