Robert Storey. Sheffield, United Kingdom

Transcription

1 Antiplatelet in ACS Moving beyond clopidogrel Robert Storey Professor of Cardiology, Department of Cardiovascular Science, University of Sheffield and Academic Director and Honorary Consultant Cardiologist, Cardiology and Cardiothoracic Surgery Directorate, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom 1

2 My Conflicts of Interest Are: Company Name Relationship AstraZeneca Research grant, honoraria, consultant Eli Lilly / Daiichi Sankyo Research/educational grants, honoraria, consultant The Medicines Company Consultant Merck Research grant, consultant Novartis Consultant Sanofi aventis /BMS Consultant Eisai Consultant Medscape Honoraria Accumetrics Educational grant, research consumables, consultant Iroko Honorarium

3 Mechanisms of Platelet Inhibition Thrombin generation Coagulation Thrombin PAR-1 Thromboxane A 2 PAR-4 TPα x ASPIRIN 5HT Collagen GPVI 5HT 2A PLATELET ACTIVATION ADP P2Y 1 ATP P2X 1 5HT ADP ATP Dense granule ADP x TICAGRELOR P2Y 12 CLOPIDOGREL PRASUGREL ACTIVE METABOLITE Shape change Alpha granule Coagulation factors Inflammatory mediators Amplification α IIb β 3 α IIb β 3 Fibrinogen x Aggregation α IIb β 3 GP IIb/IIIa ANTAGONISTS GP = glycoprotein; PAR = protease-activated receptor; TP = thromboxane A 2 / prostaglandin H 2. Storey RF. Curr Pharm Des. 2006;12:

4 Platelet aggregation before and 4 hours after clopidogrel 600 mg in patients undergoing PCI Whole blood single platelet counting in response to ADP 10 um 100 % ag ggregatio on Patient t with subacute stent thrombosis 20 0 Baseline Smith SMG et al. Platelets 2006; 17: Post clopidogrel

5 Activation/inactivation of clopidogrel O OCH 3 O OCH O OCH 3 3 COOH N CYPs N CYPs O S Cl S Cl HS N Cl Clopidogrel Esterases 2-Oxo-clopidogrel R Esterases O OH O OH S N Cl O S N Cl SR26334 (Inactive) Inactive 5 CYP = cytochrome P450. Farid NA, et al. Clin Pharmacol Ther. 2007;81:

6 P2Y 12 inhibitors 6

7 PRINCIPLE TIMI 44 Inhibition of ADP-induced platelet aggregation P< for each ADP) IPA (%; 20 μm A Prasugrel 60 mg Hours Wiviott SD et al. Circulation 2007

8 3 TRITON Stent Thrombosis (ARC Definite it + Probable) bl Any Stent at Index PCI N= 12,844 Clopidogrel 2.4 (142) Endpo oint (%) 2 1 Prasugrel 1.1 (68) HR 0.48 P < NNT= 77 Wiviott SD et al. N Engl J Med Nov 15;357(20): Days

9 Ev vents, % TRITON-TIMI TIMI 38: Bleeding Events Safety Cohort (N=13,457) 4 Pts w/ Prior Stroke / TIA (N=518) Clopidogrel Prasugrel P= TIMI Major Bleeds ARD 0.6% HR 1.32 P=0.03 NNH= Life Threatening ARD 0.5% HR 1.52 P= nts, % Eve ICH Nonfatal Fatal ICH ARD 0.2% P=0.23 ARD 0.3% P=0.002 ARD 0% P=0.74 ARD = absolute risk difference; HR = hazard ratio; ICH = intracranial haemorrhage; NNH = number needed to harm; TIA = transient ischemic attack; TIMI = Thrombolysis in Myocardial Infarction. 9 Adapted from Wiviott SD, et al. Presented at: American Heart Association Scientific Sessions 2007; 4-7 November, 2007; Orlando, FL. Wiviott SD, et al. N Engl J Med. 2007;357:

10 ONSET/OFFSET Study IPA with ADP 5uM (final extent) 100 Ticagrelor 180mg LD /90mgbd(n=54) * * * * * 90 Clopidogrel 600mg LD / 75 mg od (n=50) * * // * I PA % * // 10 0 Onset Maintenance Offset Gurbel PA et al. Circulation 2009 Time (hours) // weeks

11 PLATO Invasive Definite it Stent t Thrombosis 2 tent throm mbosis, % 1 Clopidogrel, 600 mg Clopidogrel, <600 mg Ticagrelor, 600 mg clopidogrel Ticagrelor, <600 mg clopidogrel Definite st Days Since PCI Cannon CP, et al. Lancet. 2010;375:

12 PLATO All-cause mortality planned invasive vs non-invasive strategy All-ca ause mor rtality (% %) Non-invasive HR, 0.75, 95% CI: ( ) Invasive HR, 0.81, 95% CI: ( ) 8.2% 6.1% Number at risk Invasive Days after randomization Ticagrelor Clopidogrel Non-invasive Ticagrelor Clopidogrel James S et al. Brit Med J 2011

13 Time from CABG to any death 10 9 (CABG population) Clopidogrel 9.7 -M estima ated rate (%) Ticagrelor K- 3 2 HR: 0.49 (95% CI ), p< No. at risk 0 Months Ticagrelor Clopidogrel Held C. J Am Coll Cardiol 2011

14 PLATO PLATELET: VerifyNow P2Y 12 Assay Comparing Maintenance Therapy with Clopidogrel vs Ticagrelor 500 **** **** tion Unit ts Platel let Reac PRU ***P< Clopidogrel Ticagrelor Clopidogrel Ticagrelor Trough Peak Storey RF et al. J Am Coll Cardiol

15 PLATO Non-CABG and CABG-related major bleeding 9 8 NS Ticagrelor Clopidogrel % per ye ear) p= NS K-M estimate ed rate ( p= Non-CABG PLATO major bleeding Non-CABG TIMI major bleeding CABG PLATO major bleeding CABG TIMI major bleeding

16 Primary Efficacy Outcome US and Non-US and by ASA Dose *Hazard ratio not calculated due to small number of events.

17 A PLATO: Any dyspnoea AE ( 30 days) ntage (% %) Kap plan Mei ier perce 9 Ticagrelor (T) (742/9235) 8.29% 8 Clopidogrel (C) (339/9186) % HR 95% CI P-value T vs. C < Days from first IP dose n at risk T C Storey RF et al. Eur Heart J AE = adverse event; CI = confidence interval; HR = hazard ratio; IP = investigational product.

18 D Clopidogrel: total death in patients with dyspnoea AE within 30 days ntage (% %) Kap plan Mei ier perce Dyspnoea yp event (DE)(26/331) No dyspnoea event (NDE) (250/8557) 8.51% % 39% HR 95% CI P-value DE vs. NDE < Days from randomisation n at risk DE NDE Storey RF et al. Eur Heart J CI = confidence interval; HR = hazard ratio.

19 C Ticagrelor: total death in patients with dyspnoea AE within 30 days ntage (% %) Kap plan Mei ier perce Dyspnoea yp event (DE)(19/726) No dyspnoea event (NDE) (190/8221) 3.04% 2.54% 2 1 HR 95% CI P-value DE vs. NDE Days from randomisation n at risk DE NDE Storey RF et al. Eur Heart J CI = confidence interval; HR = hazard ratio.

20 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation Class Level 20

21 ESC Guidelines for Prasugrel the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation Class Level 21

22 ESC Guidelines Clopidogrel for the management dosing of acute coronary syndromes in patients presenting without persistent ST-segment elevation Class Level Class Level 22

23 Sheffield NSTEMI protocol 23

24 Admitted with ischaemic chest pain consistent with MI and elevated troponin Contraindication to antithrombotic therapy (active bleeding, Yes Consider risk vs. benefit of iron deficiency anaemia, bleeding diathesis etc.)? therapy for individual patient, avoid ticagrelor and prasugrel No 1. Aspirin 300 mg loading dose then 75 mg daily longterm 2. Fondaparinux 2.5 mg s/c stat t then daily s/c until discharge/day before coronary angiogram, max 8 days (if creatinine > 265 μm use unfractionated heparin) 3. If no contraindication, start ticagrelor 180mg loading dose then 90 mg twice daily for 1 year; if ticagrelor contraindicated, consider clopidogrel 300mg loading dose followed by 75 mg daily for 1 year. If already on clopidogrel l when NSTEMI diagnosed, d ticagrelor should be started t in place of clopidogrel using above regimen unless contraindicated Planned coronary angiography +/- PCI? Yes 1. Continue aspirin and ticagrelor (or clopidogrel) 2. Ticagrelor: if more than 24 hours since loading dose, give an additional No 1. Specify duration of aspirin and P2Y 12 inhibitor on discharge sheet 2. Consider proton pump inhibitor if previous history 90mg pre procedure. 3. of peptic ulcer disease or increased risk of gastrooesophageal bleeding; avoid omeprazole with clopidogrel Atorvastatin 80mg od or simvastatin 40 mg on Ticagrelor contra-indicated or not tolerated: If cumulative clopidogrel dose <600 mg, give further 300 mg at least 4 hrs pre procedure; if PCI (warn about myopathy, check drug interactions) 4. Ramipril target dose 10 mg daily with U&E monitoring 5. Consider beta blocker +/- other antihypertensive medication 6. Consider aldosterone antagonist if NSTEMI complicated by heart failure performed and candidate for prasugrel, consider platelet function testing and/or switch to prasugrel 3. Omit fondaparinux on day of procedure if possible and use standard anticoagulation for PCI; usually stopped if PCI performed 24

25 Thank you for listening! HEPARINS FONDAPARINUX BIVALIRUDIN RIVAROXABAN APIXABAN DABIGATRAN VORAPAXAR ATOPAXAR Thrombin generation Coagulation Thromboxane A 2 x ASPIRIN 5HT Collagen ADP x GPVI 5HT Thrombin 2A P2Y 1 TPα PAR-4 x PAR-1 ATP P2X 1 5HT ADP ATP Dense granule ADP x TICAGRELOR P2Y 12 TICLOPIDINE CLOPIDOGREL PRASUGREL ACTIVE METABOLITE CANGRELOR Shape change Alpha granule Coagulation factors Inflammatory mediators Amplification α IIb β 3 α IIb β 3 Fibrinogen x Aggregation α IIb β 3 GP IIb/IIIa ANTAGONISTS