Timing of Anti-Platelet Therapy for ACS (EARLY-ACS & ACUITY) Mitchell W. Krucoff, MD, FACC

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1 Timing of Anti-Platelet Therapy for ACS (EARLY-ACS & ACUITY) Mitchell W. Krucoff, MD, FACC Professor, Medicine/Cardiology Duke University Medical Center Director, Cardiovascular Devices Unit Duke Clinical Research Institute

2 With special thanks: q Sunil Rao q Kristin Newby q George Dangas

3 Choices Impacting Anti-PLT Therapy Anticoagulants: UFH LMWH Fonda Bival Antiplatelets: Antiplatelets: ASA (dose) Clopidogrel (time/dose) Prasugrel IV antiplatelets: None Abcix Ept/Tiro (timing) Cath strategy: Early Delayed Never >100 Different Combinations!

4 When to start? Anti-PLT RX Chronic Oral Rx Pre-Hosp ED Unknown Anatomy Plaque Rupture Cath Lab PCI Post-PCI Known Anatomy Plaque Rupture Benefit: Death MI Stroke Bleeding: CABG Arteriotomy GI CNS

5 Delay of Invasive Therapy: Should We Prolong The Upstream Window? Can we passify plaque & improve PCI & clinical outcomes?

6 Study Design 2 of 3 high-risk criteria: 1. Age > 60 years 2. + CKMB or TnT/I 3. ST or transient ST (Or age 50-59, h/o CVD and + CKMB or TnT/I) High-risk NSTE ACS n = 10,500 Routine, early eptifibatide (180/2/180) Placebo / delayed provisional eptifibatide pre-pci Randomize within 12 hours of presentation Invasive strategy: 12 to 96 hours after randomization Primary Endpoint: 96-hr Death, MI, Recurrent ischemia Safety requiring Endpoints at urgent revascularization, 120 hrs: Bleeding (GUSTO or Thrombotic and TIMI bailout scales), Transfusions, Stroke, Non-hemorrhagic SAEs Key Secondary Endpoint: 30-d Death or MI

7 15 Kaplan-Meier Curves for Primary Endpoint Death, MI, RIUR or TBO (%) Delayed provisional eptifibatide Routine early eptifibatide P = 0.23 Time Since Randomization (Hours) 10.0% 9.3% (stratified for intended early clopidogrel use)

8 Secondary Endpoint: 30-day Death or MI 15 Death or MI (%) 10 5 Delayed provisional eptifibatide Routine early eptifibatide P = % 11.2% Time Since Randomization (Days)

9 Secondary Endpoint: Bleeding Routine Early Eptifibatide (n=4686) Delayed Provisional Eptifibatide (n=4643) OR (95% CI) P Bleeding (all patients, %) TIMI major ( ) GUSTO moderate or severe ( ) <0.001 PRBC transfusion ( ) 0.001

10 Upstream Clopidogrel Use in EARLY-ACS l l l Clopidogrel use and timing were determined by treating physician Randomization in the EARLY-ACS Trial was stratified by declared intent for upstream clopidogrel use Does addition of early thienopyridine to early eptifibatide passify ACS lesions?

11 Study Population EARLY-ACS Patients N = 9,406 No cardiac catheterization (n=240) Final Study Population N =9,166 (97%) Median time to angiography 21 hrs (IQR 17-33) Upstream Clopidogrel N = 6895 (75%) No upstream Clopidogrel N = 2271 (25%)

12 15 Death or MI at 30 days Death/MI (%) Delayed Provisional 10 Delayed Provisional 10 Early Routine Early Routine 5 5 Treatment Delayed provisional eptifibatid Upstream Clopidogrel Early upstream eptifibatide Time Since Randomization (Days) days Treatment Delayed provisional eptifibati No Upstream Clopidogrel Early upstream eptifibatid Time Since Randomization (Days) days

13 Bleeding (adjusted) TIMI Major Bleeding Upstream Clopidogrel No Clopidogrel p for interaction = 0.31 Adjusted OR (95% CI) 1.54 ( ) 1.13 ( ) GUSTO Mod/Severe Bleeding Upstream Clopidogrel No Clopidogrel p for interaction = 0.13 Transfusion Upstream Clopidogrel No Clopidogrel p for interaction = ( ) 1.29 ( ) 1.38 ( ) 1.23 ( ) Early eptifibatide better Provisional eptifibatide better

14 Can Need for Upstream Anti-Platelet Therapy Be Eliminated by Selective Anti-Thrombotics? Can we passify thrombin signaling for better PCI & clinical outcomes?

15 Thrombus formation Thrombin plays a central role among tissue injury, coagulation, and platelet response. ADP Platelet activation Platelet aggregation Collagen TXA 2 Thrombin Fibrinogen Fibrin Tissue Factor Plasma Clotting cascade Prothrombin THROMBUS

16 ACUITY - Study design Moderate-high risk unstable angina or NSTEMI undergoing an invasive strategy (N = 13,800) Moderatehigh risk ACS Aspirin in all Clopidogrel dosing and timing per local practice R* UFH or Enoxaparin + GP IIb/IIIa Bivalirudin + GP IIb/IIIa Bivalirudin Alone Angiography within 72h Medical management PCI CABG Primary endpoint: Net Clinical Composite Death, MI, TVR, Bleeding ACUITY Design. Stone GW et al. AHJ 2004;148:764 75

17 ACUITY: Net Clinical Outcome Composite Endpoint: Death, MI, TVR, Bleeding UFH/enoxaparin+GPI vs bivalirudin+gpi vs bivalirudin alone 15 Cumulative Events (%) 10 5 Estimate P (log rank) UFH/enoxaparin+GPI (N=4603) 11.7% Bivalirudin+GPI (N=4604) 11.8% 0.89 Bivalirudin alone (N=4612) 10.1% Days from Randomization UFH, unfractionated heparin; GPI, glycoprotein IIb/IIIa inhibitor. Stone GW. NEJM 2007.

18 ACUITY: Major Bleeding Endpoint UFH/enoxaparin+GPI vs bivalirudin+gpi vs bivalirudin alone Cumulative Events (%) UFH/enoxaparin+GPI (N=4603) Estimate 5.7% Days from Randomization P (log rank) Bivalirudin+GPI (N=4604) 5.3% 0.41 Bivalirudin alone (N=4612) 3.0% < UFH, unfractionated heparin; GPI, glycoprotein IIb/IIIa inhibitor. Stone GW. NEJM 2007.

19 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 Stone GW. NEJM 2007 UFH/Enox + IIb/IIIa better

20 Clopidogrel Timing and Incidence of 30-Day Composite Ischemic Outcome Similar rates of composite ischemia were demonstrated with bivalirudin monotherapy vs heparin + GP IIb/IIIa inhibitor when clopidogrel was administered either before or within 30 minutes after PCI Composite Ischemia (%) P=.46 Bivalirudin monotherapy* Heparin(s) + GP IIb/IIIa inhibitor P= *In the bivalirudin monotherapy group, 91% of PCI patients received bivalirudin monotherapy. Pre-PCI = patients who received clopidogrel either prehospital, prerandomization, postrandomization, or preangiography. Peri-PCI= patients who received clopidogrel after angiography and within 30 minutes after PCI procedure. Post-PCI = patients who received clopidogrel any time >30 minutes after PCI within the index hospitalization. None= patients who had no documentation of receiving clopidogrel at any time before or after the PCI procedure. Lincoff AM et al. JACC Cardiovasc Interv. 2008;1: P= Pre-PCI Peri-PCI Post-PCI None (n=5,131) (n=1,572) (n=814) (n=129) Timing of Clopidogrel Exposure Hold for CABG! P=.08 PCI Subgroup

21 JAMA. 2007;297:

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23 Optimal Dosing, Duration, & New Novel Agents

24 ACS+PCI: 3 RCTs vs. Std Clopidogrel Significant Events (%) 15% 12% 9% 6% 3% P= % 3.9% P< % 9.9% P= % 9.0% P=0.002 ASA + Clopidogrel New Regimen P<0.001 P= % 2.4% 2.3% 1.6% 1.7% 1.1% 0% CURRENT TRITON PLATO CURR. ST TRITON ST PLATO ST N=17,232 D/MI/CVA N=13,608 D/MI/CVA N=11,289 D/MI/CVA Def/Prob Def/Prob Def/Prob TRITON NEJM 2007 PLATO NEJM 2009 CURRENT ESC 2009

25 2007 ACC/AHA UA/NSTEMI Guideline Revision Initial Invasive Strategy: Antiplatelet, Anticoagulant Therapy Aspirin Initiate anticoagulant therapy as soon as possible after presentation (I, A). Regimens with established efficacy: Enoxaparin or UFH (I, A) Bivalirudin or fondaparinux (I, B) Prior to angiography, initiate one (I, A) or both (IIa, B) Clopidogrel Changes coming? IV GP IIb/IIIa inhibitor Use both if: Prasugrel? ndelay to angiography nhigh-risk features nearly recurrent ischemic syndromes Anderson JL, et al. J Am Coll Cardiol. 2007;50(7):e1-e157. Bivalirudin + later thienopyridine?

26 Optimal Use of Anti-PLT Therapies: Conclusions 1. Cath should not be delayed to passify lesions with IIbIIIa therapy (EARLY-ACS, ACS, ACUITY) 2. Combined/prolonged thienopyridine and eptifibatide might provide benefit, but clearly with added bleeding (EARLY-ACS) ACS) 3. Specific thrombin inhibitors may obviate the need for upstream platelet inhibition, but are not sufficient as solo therapy (ACUITY) 4. Reduced arteriotomy site bleeding through trans- radial approach might improve net clinical benefit

27 Cleveland Clinic Columbia University Duke University Harvard Johns Hopkins Washington Heart Ctr U.S. FDA AHRQ NIH ACC SCAI SOLACI ESC

28 Timing of Anti-Platelet Therapy for ACS (EARLY-ACS & ACUITY) Mitchell W. Krucoff, MD, FACC Professor, Medicine/Cardiology Duke University Medical Center Director, Cardiovascular Devices Unit Duke Clinical Research Institute