Antiplatelet Therapy: how, why, when? For Coronary Stenting

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1 Antiplatelet Therapy: how, why, when? For Coronary Stenting Dominick J. Angiolillo, MD, PhD, FACC, FESC, FSCAI Director of Cardiovascular Research Associate Professor of Medicine University of Florida College of Medicine - Jacksonville

2 Presenter Disclosure Information Name: Dominick J Angiolillo Within the past 12 months, the presenter or their spouse/partner have had a financial interest/arrangement or affiliation with the organization listed below. Honoraria/Lectures: Bristol-Myers Squibb, Sanofi-Aventis, Eli Lilly Co, Daiichi Sankyo, Inc., Advisory Board: Bristol-Myers Squibb, Sanofi-Aventis, Eli Lilly Co, Daiichi Sankyo, Inc., The Medicines Company, Portola Pharmaceuticals, Novartis, Arena Pharmaceuticals, Accumetrics, Medicure, Evolva, Abbott Vascular Research Grants: GlaxoSmithKline, Otsuka, Accumetrics, Eli Lilly Co, Daiichi Sankyo, Inc., The Medicines Company, Portola Pharmaceuticals, Schering-Plough, AstraZeneca, Johnson & Johnson, Bristol-Myers Squibb, Sanofi-Aventis

3 ANTITHROMBOTIC DRUGS USED IN ACS/PCI I. ANTIPLATELET DRUGS COX-1 inhibitor (aspirin) P2Y 12 inhibitors (ticlopidine; clopidogrel; prasugrel; ticagrelor) Glycoprotein IIb/IIIa inhibitors (abciximab; eptifibatide; tirofiban) II. ANTICOAGULANT DRUGS Anti-Factor II (anti-thrombins) - Indirect Thrombin Inhibitors (UFH & LMWH) - Direct Thrombin Inhibitors (Bivalirudin) Anti-Factor X - Fondaparinux

4 ANTITHROMBOTIC DRUGS USED IN ACS/PCI What s Your Cocktail?

5 ASA Dose Comparison Primary Outcome and Bleeding ASA mg ASA mg HR 95% CI P CV Death/MI/Stroke PCI (2N=17,232) No PCI (2N=7855) Overall (2N=25,087) Stent Thrombosis TIMI Major Bleed CURRENT Major Bleed CURRENT Severe Bleed GI Bleeds: 30 (0.24%) v 47 (0.38%), P=0.051 No other significant differences between ASA dose groups

6 First and Second Generation Thienopyridine N S Cl Ticlopidine (1 st generation) Solution to these problems: S N C O Cl Clopidogrel (2 nd generation) O C H 3 P2Y 12 ADP receptor antagonism: antithrombotic treatment of choice for coronary stenting Side effects: neutropenia, thrombocytopenia, rash, diarrhea, etc Delayed time frame to achieve full antiplatelet effects Better Safety profile - Fewer side effects (CLASSICS trial. Bertrand NE et al. Circulation 2000; 102: 624 9). Rapid onset of action with a loading dose (Cadroy Y et al. Circulation. 2000;101: ). Better clinical outcomes (Bhatt DL et al. J Am Coll Cardiol 2002; 39: 9 14.).

7 % Positive Cells High Clopidogrel Loading Dose Regimen Activated GP IIb/IIIa (ADP 2 M) mg loading dose (n=27) 600 mg loading dose (n=23) p< p=0.001 (MANOVA) p=0.009 p= Basal 4h 24h Post - PCI 48h Angiolillo DJ, et al. Eur Heart Journal 2004;25:

8 ARMYDA-2 Trial: Primary endpoint Primary Composite of death, MI, and TVR at 30 days Clopidogrel pre-treatment 4-8 hrs before PCI 14% p = % 12% There 10% is no reason why not to give 8% clopidogrel 600 mg loading dose! 6% 4% 4% 2% 0% 600 mg 300 mg n=126 n=129 Patti G et al. Circulation 2005

9 Optimal Antithrombotic Cocktail When to consider: 1. GP IIb/IIIa inhibitors 2. Bivalirudin 3. New P2Y12 receptor antagonists

10 Optimal Antithrombotic Cocktail Stable CAD UA/NSTEMI STEMI

11 Optimal Antithrombotic Cocktail Stable CAD UA/NSTEMI STEMI

12 ISAR REACT: Abciximab vs. Placebo in Low- Moderate Risk PCI All patients pretreated with 600mg clopidogrel at least 2 hrs prior to PCI. 30-Day Event Rate (%) Pretreatment equally efficacious if initiated 2 to 24 hours prior to a PCI Abciximab (n=1079) Placebo (n=1080) Death, Death Q MI Non-Q MI TVR Major MI, TVR bleeding 0.7 Kastrati A et al. NEJM 2004;350:232-8.

13 Optimal Antithrombotic Cocktail In the setting of elective PCI, there is no need for GPI use, particulalry on a background of 600mg clopidogrel loading dose Is there a role for bivalirudin in this low risk setting?

14 ISAR-REACT 3 All patients pretreated with 600mg clopidogrel at least 2 hrs prior to PCI. Primary (Quadruple) Endpoint: Death, MI, UTVR, Major Bleeding Cumulative incidence (%) 10 8 UFH Bivalirudin 8.7% 8.3% 6 4 UFH 140 IU/kg (higher than standard) Lower doses of UFH just as fine (ISAR-REACT 3A) 2 0 RR=0.94 [95% CI, ], P=0.57 N= Days after randomization ISAR-REACT 3, NEJM 2008

15 What s MY Antithrombotic Cocktail Stable CAD Aspirin 325mg LD / 81mg maintenance + Clopidogrel 600mg LD / 75mg maintenance + UFH ( IU/kg)

16 Optimal Antithrombotic Cocktail Stable CAD UA/NSTEMI STEMI

17 NSTEMI: The Role of GP IIb/IIIa inhibitors in the era of clopidogrel and direct thrombin inhibitors Shifting the paradigm!! IIb or not IIb? Major Considerations: 1) Trials performed in the good old days - Less experience; not all with stents; devices 2) Antiplatelet therapy - 1 st generation thienopyridine (ticlopidine) 3) Anticoagulant therapy William Shakespeare ( ) - indirect thrombin inhibitors

18 ISAR-REACT 2: Abciximab vs. Placebo in ACS All patients pretreated with 600mg clopidogrel at least 2 hrs prior to PCI. 20 Death/MI/UTVR, % 15 Troponin-Positive: RR=0.71 [ ] 10 Abciximab vs. Placebo 5 0 Troponin-Negative: RR=0.99 [ ] Days after randomization Kastrati et al. JAMA. 2006;295:

19 ACUITY: Primary Results UFH/Enox + GP IIb/IIIa Bivalirudin + GP IIb/IIIa Bivalirudin alone Observed Rate Rate P Endpoint Value Rate P Value Net clinical outcome Ischemic events Major bleeding 11.7% 11.8% <0.001 NI 10.1% Sup 7.3% 7.7% NI 7.8% NI 5.7% 5.3% NI 3.0% <0.001 Sup NI = non-inferiority; Sup = superiority

20 Mortality (%) Impact of MI and Major Bleeding (Non-CABG) in the First 30 Days on Risk of Death Over 1 Year 30 Both MI and Major Bleed (N=94) Major Bleed Only (Without MI) (N=551) MI Only (Without Major Bleed) (N=611) No MI or Major Bleed (N=12,557) 1 Year Estimate 28.9% 12.5% 8.6% 3.4% Mehran R, et al. Eur Heart J. 2009;30(12): Days From Randomization

21 Net Clinical Outcome Composite UFH/Enoxaparin + IIb/IIIa vs. Bivalirudin Alone Risk ratio ±95% CI Bival Alone UFH/Enox + IIb/IIIa RR (95% CI) P P int Biomarkers (CK/Trop) Elevated (n=5368) Normal (n=3841) 12.2% 7.1% 13.3% 9.4% 0.92 ( ) 0.75 ( ) ST Deviation Yes (n=3197) No (n=6008) 13.0% 8.6% 13.7% 10.6% 0.96 ( ) 0.81 ( ) TIMI Risk Score Low (0-2) (n=1291) Intermed (3-4) (n=4407) High (5-7) (n=2449) Pre Thienopyridine Yes (n=5192) No (n=4023) 6.4% 10.2% 0.63 ( ) % 10.2% 0.92 ( ) % 15.2% 0.92 ( ) % 11.3% 12.2% 11.1% 0.76 ( ) 1.02 ( ) < Bivalirudin alone better UFH/Enox + IIb/IIIa better

22 20 20 EARLY-ACS Trial: Death or MI at 30 days 15 Death/MI (%) 10 Delayed Provisional 15 Death/MI (%) Early Routine 10 Delayed Provisional Early Routine 5 5 Treatment Upstream Clopidogrel Delayed provisional eptifibatide Early upstream eptifibatide Time Since Randomization (Days) days Time Since Randomization days (Days) Treatment adjusted OR 0.85; 95% CI 0.73 to 0.99 adjusted OR 1.02; 95% CI 0.80 to 1.30 P-interaction: 0.23 Delayed provisional eptifibatide Early upstream eptifibatide No Upstream Clopidogrel

23 What s MY Antithrombotic Cocktail UA/NSTEMI (# 1) Aspirin 325mg LD / 81mg maintenance + Clopidogrel 600mg LD / 75mg maintenance + UFH /LMWH

24 What s MY Antithrombotic Cocktail UA/NSTEMI (# 2) Bivalirudin: - High bleeding risk (elderly, CKD, diabetes) - Pre-treated w/clopidogrel - Unclear prior anticoagulation (safe to switch) GPI: - Already on upstream GPI - Not pre-treated w/clopidogrel (especially if high thrombotic burden) - ACS while on DAPT

25 What s MY Antithrombotic Cocktail UA/NSTEMI (# 3) New P2Y12 Receptor Antagonists?

26 Strategies of ADP P2Y12 mediated platelet inhibition Angiolillo DJ et al. JACC Interv 2011

27 TRITON vs PLATO: Is there a winner? Prasugrel and ticagrelor both showed favorable efficacy and safety profiles in their respective trials and only a head-to-head comparison will be able to define the winner. Subgroup analysis will allow to define their best niche. Prasugrel. Particularly efficacious in reducing stent thrombosis, MI, utvr and great benefit in diabetics and STEMI. Contraindicated: high-risk bleeding; prior TIA/stroke Considerations: elderly, low-weight; CABG/surgery (7days). Ticagrelor. Particularly efficacious in reducing mortality (offtarget effects), OK for patients with prior TIA/ ischemic stroke. Contraindicated: high-risk bleeding; prior hemorrhagic stroke Considerations: COPD/asthma, bradyarrythmia, gout syndromes, ESRD, compliance (b.i.d. administration), CABG/surgery (7days), regional differences (North America?).

28 Prasugrel /Ticagrelor: Working Algorithm in UA/NSTEMI undergoing PCI UA/NSTEMI Coronary angiography STEMI (primary or delayed PCI) Can be considered before coronary anatomy established if need for CABG is determined to be unlikely Loading dose: Prasugrel 60 mg / Ticagrelor 180mg Do not start or continue prasugrel in these patients PCI If not started prior to diagnostic angiography, administer loading dose of prasugrel anytime after diagnostic angiogram but prior to leaving the cath lab Medical therapy CABG Maintenance dose: Prasugrel 10mg/day (5mg <60kg >75 y) Ticagrelor 90mg/twice daily Do not use prasugrel in patients with active pathological bleeding and history of TIA/stroke. No indication in patients managed medically and CABG. Do not use ticagrelor in patients with active pathological bleeding and history of intracranial hemorrhage. Indication in patients managed medically and CABG. Warning on aspirin dose (<100mg). In patients undergoing CABG, discontinue prasugrel /ticagrelor 7 days prior to surgery.

29 SWAP: SWITCHING ANTIPLATELET THERAPY Maximum Platelet Aggregation (20 µm ADP) Maximum Platelet Aggregation (%) * Mean±SE Time, hours Placebo LD/Clopidogrel 75 mg MD (n=33) Placebo LD/Prasugrel 10 mg MD (n=36) Prasugrel 60 mg LD/10 mg MD (n=31) * * * * p< vs clopidogrel 75 mg MD p< vs prasugrel 10 mg MD Time, days Similar findings obtained with MPA to 5 µm ADP, VASP PRI, and Verify Now PRU Angiolillo DJ et al. J Am Coll Cardiol 2010; 56: *

30 Cost-effectiveness analysis will dictate the use of more expensive drugs, particularly in socialized medical systems (e.g. UK NICE: Prasugrel OK only in Primary PCI for STEMI; Stent thrombosis on clopidogrel treatment; Diabetes mellitus)

31 Optimal Antithrombotic Cocktail Stable CAD UA/NSTEMI STEMI

32 All-cause mortality or reinfarction (%) 3-Year All-Cause Mortality or Reinfarction Landmark analysis day HR (95% CI) 0.84 ( ) 4.5% 3.8% Heparin + GPIIb/IIIa (n=1802) Bivalirudin (n=1800) 3-year HR (95% CI) 0.72 ( ) p=0.005 p= % 7.8% Months Stone, GW Lancet 2011 Published online June 13. DOI: /S (11)

33 Def/Prob Stent Thrombosis (%) Stent Thrombosis 1-Day Landmark Analysis: Impact of Antithrombin 3.5 Bivalirudin monotherapy Heparin + GPIIb/IIIa inhibitor HR [95%CI] = 5.93 [ ] P = % 0.3% 3.0% 2.2% HR [95%CI] = 1.73 [ ] P = 0.06 Number at risk Bivalirudin UFH+GPIIb/IIIa Time in Days

34 What s MY Antithrombotic Cocktail STEMI (# 1) Aspirin 325mg LD + Prasugrel 60mg LD + UFH (4000 IU)

35 What s MY Antithrombotic Cocktail STEMI (# 2) Bivalirudin in all my Primary PCI patients. Consider GPI: - STEMI while on DAPT - Already on upstream GPI - Not pre-treated w/prasugrel - Bail-out

36 NOT in my Antithrombotic Cocktail what s not good for me, may be good for others.it s a matter of taste! LMWH (enoxaparin) STEEPLE, ATOLL High dose aspirin - OASIS-7 High maintenance dose clopidogrel - OASIS-7 Fondaparinox - OASIS-5, OASIS-6, OASIS-8

37 Thienopyridines MODIFIED Recommendation The duration of thienopyridine therapy should be as follows: I IIa IIb III I IIa IIb III III a. In patients receiving a stent (BMS or DES) during PCI for ACS, clopidogrel 75 mg daily or prasugrel 10 mg daily should be given for at least 12 months; (prior stated with BMS give for at least 1 month, ideally 12 mo) b. If the risk of morbidity from bleeding outweighs the anticipated benefit afforded by thienopyridine therapy, earlier discontinuation should be considered. ACC/AHA 2009 Joint STEMI/PCI Guidelines Focused Update 37

38 Balancing Safety and Efficacy High risk of ischemic events Sweet spot High risk of bleeding events Phenotypes: ACS, DM, CKD Intermediate phenotypes: PD/ PK Genotypes Inhibition of platelet aggregation Ischemic risk Bleeding risk Ferreiro & Angiolillo. Thromb Haemost 2010