Dual Oral Antiplatelet Therapy for ACS: Improving Standards of Care to Optimize Outcomes

Transcription

1 Agenda Welcome and Introduction Pathophysiology of ACS Is Aspirin Enough? Overview of Antiplatelet Agents Clopidogrel Prasugrel Ticagrelor New Guideline Recommendations for Dual Antiplatelet Therapy in ACS Q&A With Faculty Discussion 2 1

2 PATHOPHYSIOLOGY OF ACS Michelle O Donoghue, MD, MPH Central Role of Platelets Shear, PCI Plaque Rupture Tissue Factor Thrombin Fibrinogen X Collagen vwf Initial Activation ADP TxA 2 Amplification P2Y 12 X TP Amplification PAR-1 Granule Secretion Activation X X COX-1 Amplification GPIIb/IIIa Activation X Fibrin + Platelet Aggregation Platelet-Fibrin Clot Formation ADP, adenosine diphosphate; PCI, percutaneous coronary intervention GurbelPA et al. J Am Coll Cardiol.2007;50:

3 ACS Associated With Substantial Morbidity, Mortality Prevalence estimated at >1.1 million pts in US 1 57% hospitalized for MI 28% hospitalized for UA 15% hospitalized for MI/UA 38% of pts present with STEMI 2 30% of pts with STEMI die within 24 h of symptom onset 3 30-day mortality rate is 11% for STEMI, 1.7% for UA, and 7.4% for NSTEMI 4 MI, myocardial infarction; UA, unstable angina; NSTEMI, non-st-segment elevation MI 1. Go AS et al. Circulation. 2013;127:e6-e Chan PS et al. JAMA. 2009;302: Kolansky DM. Am J Manag Care. 2009;15(2 suppl):s36- S Kumar A et al. Mayo ClinProc. 2009;84: All-Cause 30-Day Readmissions After AMI Risk-adjusted 30-d Readmission Rate (%) No Change Between 2003 and % of ACS pts are readmitted within 1 y 2 Readmission accounts for 60% of ACS cost 2 >$150 billion spent on ACS care annually AMI, acute myocardial infarction 1. Joynt KE. N EnglJ Med. 2012;366; KolanskyDM. Am J ManagCare. 2009;15(2 suppl):s36-s

4 IS ASPIRIN ENOUGH? Michelle O Donoghue, MD, MPH Is ASA Enough? Despite clinical practice guidelines, 45% of pts with STEMI receive only ASA upon discharge 1 Common reason: no evidence/guidelines to support use of P2Y 12 inhibitors 2 68% of physicians indicate that they are not confident in their ability to follow ACCF/AHA guideline recommendations for UA/STEMI 3 ASA, aspirin; ACCF, American College of Cardiology Foundation; AHA, American Heart Association 1. Maddox TM et al. Circulation.2012;5: BagnallAJ et al. Circulation. 2010;3: Paradigm CME Pretest Survey

5 ASA Dose and Vascular Events in High-risk Patients No Benefit of Higher Doses OR Aspirin Dose No. of Trials (%) Odds Ratio mg mg mg <75 mg 3 13 Any aspirin dose P<.0001 OR, odds reduction Antiplatelet Better Antiplatelet Worse Antithrombotic Trialists Collaboration. BMJ. 2002;324: CURRENT-OASIS 7: Randomized ASA Dose Comparison Death/MI/Stroke at 30 Days Primary Endpoint ASA mg ASA mg CV death/mi/stroke 4.4% 4.2% HR (95% CI) 0.97 ( ) PValue.61 Higher doses of ASA increased risk of GI bleeding, but not major bleeding HR, hazard ratio; GI, gastrointestinal The CURRENT OASIS 7 Investigators. N Engl J Med. 2010;363:

6 ASA Dosing Recommendations 2011 ACCF/AHA/SCAI Guideline for PCI 1 Class IIaIndication After PCI, it is reasonable to use aspirin 81 mg per day in preference to higher maintenance doses AHA/ACC Guideline for Management of NSTE-ACS 2 Class IIaIndication After PCI, it is reasonable to use 81 mg per day of aspirin in preference to higher maintenance doses. SCAI, Society for Cardiac Angiography and Interventions; ACC, American College of Cardiology; NSTE-ACS, non-stsegment elevation acute coronary syndromes 1. Levine GN et al. J Am Coll Cardiol2011;58:e44-e Amsterdam EA et al. Circulation. 2014;Epub ahead of print Sept CLOPIDOGREL Matthew J. Price, MD, FACC, FSCAI 6

7 CURE Trial: Clopidogrel in NSTE-ACS Randomized, Double-Blind Trial Evaluated Clopidogrel + ASA vs Placebo + ASA CV Death, MI, Stroke (%) % 9.3% RR, 0.80 (95% CI, ; P<.001) Placebo + Aspirin Clopidogrel + Aspirin Relative risk reduction of 20% over 12 mo *N=12,563 presenting within 24 h symptom onset randomized to clopidogrel (300 mg immediately, then 75 mg qd) (n=6259) or placebo (n=6303) plus aspirin for 3-12 mo CURE, Clopidogrel in Unstable Angina to Prevent Recurrent Events Yusuf S et al. N EnglJ Med. 2001;345(7): CURE Trial: Clopidogrel in NSTE-ACS CV Death, MI, or Stroke by Management Strategy RR reduction in primary endpoint consistent regardless of treatment strategy Strategy Clopidogrel Placebo RR (95% CI) PCI 9.6% 13.2% CABG 14.5% 16.2% Medical therapy 8.1% 10.0% 0.72 ( ) 0.89 ( ) 0.80 ( ) CABG, coronary artery bypass graft; RR, relative risk Fox KA et al. Circulation. 2004;110:

8 CURE Trial: Clopidogrel in NSTE-ACS Bleeding Event Rates Major Bleeding RR, 1.38 (95% CI, ; P=.001) Major Bleeding Clopidogrel (%) Placebo (%) RR (95% CI) Life-threatening ( ; P=.13) Required blood transfusion 2 U ( ; P=.02) Major ( ; P=.001) Minor ( ; P<.001) Any ( ; P<.001) Yusuf S et al. N EnglJ Med. 2001;345: Antiplatelet Effect of Clopidogrel Inter-individual Differences in Antiplatelet Activity N=380 Patients (n) PRU, platelet reactivity units Price MJ et al. Eur Heart J. 2008;29: PRU 16 8

9 Factors Linked to Clopidogrel On-treatment Platelet Reactivity Intestinal absorption Poor compliance Inadequate administration Variable absorption Drug-drug interactions Hepatic metabolism CYP450 family variants Drug-drug interactions P2Y12 receptor Receptor polymorphisms Alternate pathways of platelet activation Increased release of circulating ADP Higher baseline platelet reactivity O Donoghue M et al. Circulation 2006;114:e600-e Association of P2Y 12 -Mediated Platelet Reactivity and Events After PCI PCI Patients Treated With ClopidogrelWith Higher Platelet Reactivity (PRU >208) Are at Higher Risk of CV Events Event ST, def/prob. ST, definite MI Clinically relevant bleeding Mortality, all-cause Adj HR (95% CI) 2.49 ( ; P=.001) 3.05 ( ; P=.0006) 1.42 ( ; P=.01) 0.73 ( ; P=.002) 1.20 ( ; P=.30) ADAPT-DES Study (N=8583): adj. risk in patients with PRU >208 CI, confidence index; ST, stent thrombosis Stone GW et al. Lancet. 2013;382:

10 Biotransformation of Clopidogrel Inactive metabolites (85% of dose) Clopidogrel CYP1A2 CYP2B6 CYP2C19 2-oxo-clopidogrel CYP2B6 CYP2C9 CYP2C19 CYP3A4 Clopidogrel is a prodrugthat requires conversion to its active metabolite 2-step process mediated by CYP450 with CYP2C19 involved in both steps The majority of absorbed clopidogrelis shunted into a dead-end pathway by esterases (HCE-1) Active metabolite 1. Price MJ. J Am Coll Cardiol. 2014;64: Tang M et al. J Pharmacol Exp Ther. 2006;319: PK, PD Responses to Clopidogrel According to CYP2C19 Genotype A Gradient of Effect 162 healthy volunteers MPA measured by ADP 20 μm ΔMPA at 24 h CYP2C19 reducedfunction allele carriers had 32% relative reduction in plasma exposure to AM compared with noncarriers Carriers had 25% relative reduction in ΔMPA compared with noncarriers PK, pharmacokinetic; PD, pharmacodynamic; ΔMPA, reduction in maximal platelet aggregation; UM, ultrarapid metabolizers; EM, extensive metabolizers; IM, intermediate metabolizers, PM, poor metabolizers Mega JL et al. N EnglJ Med.2009;360: Copyright 2009 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society

11 CYP2C19 Reduced-function Alleles and Major Adverse Events Carriers of 1 or 2 CYP2C19 Reduced- Function Alleles vs Noncarriers 1.57 ( ) Carriers of 1 CYP2C19 Reduced-Function Alleles vs Noncarriers 1.55 ( ) Carriers of 2 CYP2C19 Reduced-Function Alleles vs Noncarriers 1.76 ( ) HR (95% CI) Meta-analysis of 9685 patients (91.3% underwent PCI). 71.5% noncarriers, 26.3% 1 reducedfunction CYP2C19 allele, 2.2% had 2 reduced-function CYP2C19 alleles. Mega J et al. JAMA. 2010;304: Clopidogrel Recommendations FDA Drug Safety Communication: Reduced effectiveness of clopidogrelin patients who are poor metabolizers of the drug 1 Clinical Policy Bulletin: Pharmacogenetic and Pharmacodynamic Testing 2 (Number 0715; 6/15/2012) Aetna considers one genotyping for CYP2C19polymorphisms medically necessary for persons who have been prescribed clopidogrel (Plavix). 1. FDA Safety Announcement Accessed 10/23/ Aetna. Clinical Policy Bulletin Accessed 10/23/

12 Variability in Clopidogrel Response Unexplained Majority of Variability Remains Unexplained by CYP2C19 and Clinical Factors Characteristic Partial η 2 P value CYP2C19 genotype*.097 <.0001 Body mass index Diabetes mellitus Age, y Sex < History of CHF (6 mos) CYP2C19 genotype could only explain 10% of the variability in clopidogrel response. N=707, 30 days after maintenance clopidogrel therapy *CYP2C19 genotype was classified according to 0, 1, or 2 loss-of-function allele(s) specific portion of variance explained by the characteristic Price MJ et al. J Am Coll Cardiol. 2012;59: GRAVITAS: Study Design Elective or Urgent PCI With DES 1 * VerifyNowP2Y 12 Test hours post-pci 1 PRU R High-Dose Clopidogrel clopidogrel 600-mg, then clopidogrel150-mg daily X 6 mo 1 Standard-Dose Clopidogrel clopidogrel75-mg daily X 6 mo 1 Primary Efficacy Endpoint: CV Death, Non-Fatal MI, Stent Thrombosis at 6 mo 1 Key Safety Endpoint: GUSTO Moderate or Severe Bleeding at 6 mo 2 Pharmacodynamics: Repeat VerifyNowP2Y 12 at 1 and 6 mo 2 *Peri-PCI clopidogrel per protocol-mandated criteria to ensure steady-state at hrs Placebo-controlled; all patients received aspirin (81-162mg daily) 1. Price MJ et al. Circulation 2011;124: Price MJ et al. JAMA 2011;305:

13 GRAVITAS: Primary Endpoint CV Death, MI, or Stent Thrombosis HR, 1.68; 95% CI, ; P=.20 Observed event rates are listed; P value by log-rank test. Price MJ et al. JAMA 2011;305: American Medical Association. All rights reserved. 25 GRAVITAS: Platelet Reactivity and Outcomes Lower Reactivity Associated With Lower CV Death, MI, Stent Thrombosis *On-treatment reactivity treated as a time-varying covariate CrCl, creatinine clearance Price MJ et al. Circulation 2011;124: Price MJ et al, Platelet Reactivity and Cardiovascular Outcomes After Percutaneous Coronary Intervention: A Time-Dependent Analysis of the Gauging Responsiveness With a VerifyNowP2Y12 Assay: Impact on Thrombosis and Safety (GRAVITAS) Trial, Circulation, 124(10), Used with permission

14 Platelet Reactivity With Higher Dose of Clopidogrel* Noncarriers CYP2C19*2 Heterozygotes CYP2C19*2 Homozygotes PRU Clopidogrel Daily Dose (mg) *Study performed in CYP2C19 reduced-function allele carriers Mega JL et al. JAMA. 2011;306: PRASUGREL Michelle O Donoghue, MD, MPH 14

15 Biotransformation of Prasugrel Into its Active Metabolite Esterases CYP3A CYP2B6 CYP2D6 CYP2C9 CYP2C19 Prasugrel R Prasugrel is a prodrug Undergoes hydrolysis to produce an intermediate, which is converted to an active metabolite in a single step by oxidation via the CYP450 system Active metabolite R Price MJ. Platelet Inhibitor Agents. In: TopolE, TeirsteinP, ed. Textbook of Interventional Cardiology. 6 th Ed. Philadelphia, PA: Elsevier Saunders; 2012: TRITON-TIMI 38: Prasugrel vs Clopidogrel Study Design STEMI, NSTEMI, unstable angina with known suitable coronary anatomy scheduled to undergo PCI (N=13,608) Randomization prior to PCI Clopidogrel Standard 300-mg loading dose, after PCI 75-mg qd maintenance Prasugrel 60-mg loading dose, then after PCI 10-mg qd maintenance ASA, recommended daily dose mg qd ASA, recommended daily dose mg qd 6-15 month exposure Primary endpoint: CV Death + MI + Stroke Primary safety endpoint: TIMI Major Bleeding (non-cabg-related) WiviottSD et al. N EnglJ Med. 2007;357:

16 TRITON-TIMI 38: Prasugrel vs Clopidogrel Balance of Efficacy and Safety CV Death/MI/Stroke HR 0.81 ( ) P=.001 NNT=46 NNT, number needed to treat; NNH, number needed to harm Life-threatening bleeding: 1.4% vs 0.9%; P=.01 TIMI Major Bleeds (non-cabg) HR 1.32 ( ) P=.03 NNH=167 WiviottSD et al. N EnglJ Med. 2007;357: Copyright 2007 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. 31 Considerations for Prasugrel Prior Stroke/TIA Yes No P int = Age* 75 y <75 y P int =.18 2 Body Weight* <60 kg 60 kg P int =.36 2 OVERALL Prasugrel Better HR Clopidogrel Better 1. WiviottSD et al. N EnglJ Med. 2007;357: Eli Lilly and Company. FDA Briefing Document. Accessed 11/12/

17 Bleeding Events: Prasugrel vs Clopidogrel TRITON-TIMI 38 TIMI non-cabg-related major bleeding: 2.4% prasugrel vs 1.8% clopidogrel HR, 1.32; 95% CI, ; P=.03 Nonfatal bleeding: 1.1% prasugrel vs 0.9% clopidogrel HR, 1.25; 95% CI, ; P=.23 Fatal bleeding: 0.4% prasugrel vs 0.1% clopidogrel HR, 4.19; 95% CI, ; P=.002 WiviottSD et al. N EnglJ Med. 2007;357: TRILOGY ACS: Prasugrel vs Clopidogrel STEMI, NSTEMI, unstable angina to receive medical management without revascularization within 10 d of index event; N=9326 Clopidogrel Randomized within 72 h: Standard 300-mg loading dose, then 75-mg qd maintenance After 72 h: Open-label clopidogrel until randomization, then maintenance clopidogrel ASA, recommended daily dose 100 mg qd Study Design Randomization 6-30 months exposure Prasugrel Randomized within 72 h: 30-mg loading dose, then after PCI 10-mg qd maintenance After 72 h: Open-label clopidogrel until randomization, then maintenance prasugrel ASA, recommended daily dose 100 mg qd Roe MT et al. N EnglJ Med. 2012;367: Primary endpoint: CV death + MI + stroke Primary safety endpoint: non-cabg-related major bleeding (TIMI, GUSTO) 34 17

18 TRILOGY ACS: Prasugrel vs Clopidogrel Primary Efficacy Endpoint and Non-CABG TIMI Major Bleeding to 30 Mo Endpoint (%) HR (95% CI): 0.91 ( ) P=.21 HR (95% CI): 1.31 ( ) P=.27 TRILOGY ACS, The Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes Roe MT et al. N EnglJ Med. 2012;367: Copyright 2007 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. 35 ACCOAST Trial: Prasugrel Upstream or Downstream in NSTEMI Pretreatment: (time of diagnosis) No pretreatment: (time of PCI) Prasugrel30 mg Placebo Study Design NSTEMI + Troponin 1.5 times ULN local lab value Clopidogrel-naïve or on long-term clopidogrel 75 mg Double-blind, randomize 1:1 N 4100 (event driven) Coronary angiography Coronary angiography Median time LD angiogram: 48 h Prasugrel 30 mg Prasugrel 60 mg PCI All patients received prasugrel 10 mg or 5 mg (based on weight, age) for 30 d Primary endpoint: CV death, MI, stroke, urgent revasc, GP IIb/IIIa bailout, at 7 d ULN, upper limit of normal; LD, loading dose MontalescotG et al. Am Heart J. 2011;161:

19 ACCOAST Trial: Prasugrel Upstream or Downstream in NSTEMI Primary Efficacy and Safety Endpoints 12 At 7 days Event Rate (%) Pretreatment Time of PCI 0 CV Death, MI, Stroke, UR, GP IIb/IIa Bailout All TIMI Major Bleeding* UR, urgent revascularization *CABG and non-cabg-related bleeding MontalescotG et al. N EnglJ Med. 2013;369: Prasugrel Summary 2 nd -generationthienopyridine with more efficient active metabolite generation than clopidogrel, leading to greater antiplatelet effect 1-2 TRITON-TIMI 38: Significantly reduced rates of ischemic events, but increased risk of major (and fatal) bleeding, in patients with ACS undergoing PCI 1 ACCOAST: Pretreatment of invasively managed NSTE-ACS patients did not reduce ischemic events, but increased major bleeding 2 TRILOGY: No evidence that prasugrelreduces ischemic events in patients with ACS managed conservatively Contraindicatedin patients with history of stroke, TIA 3 Considerdose reduction in patients with body weight <60 kg 3 1. CapodannoD et al. J ThrombHaemost. 2013;11(suppl 1): MontalescotG et al. N EnglJ Med. 2013;369: Eli Lilly and Co. Effient package insert

20 TICAGRELOR MATTHEW J. PRICE, MD, FACC, FSCAI Ticagrelor: Oral Reversible P2Y 12 Antagonist Direct acting Not a prodrug; does not require metabolic activation Rapid onset of P2Y 12 receptor inhibition Greater inhibition of platelet aggregation than clopidogrel Reversibly bound Different mechanism of action than thienopyridines Different binding site, allosteric inhibition of P2Y 12 signal transduction 40 20

21 PLATO: Ticagrelor vs Clopidogrel Study Design NSTEMI-ACS (moderate-to-high risk), STEMI (if primary PCI) Clopidogrel treated or naïve; randomized within 24 h of index event (N=18,624) Randomization Clopidogrel If pretreated, no additional loading dose; if naïve, standard 300-mg loading dose, then 75-mg qd maintenance (additional 300 mg allowed pre-pci) Ticagrelor 180-mg loading dose, then 90-mg BID maintenance (additional 90 mg pre-pci) 6-12 month exposure PLATO, Platelet Inhibition and Patient Outcomes WallentinL et al. N Engl J Med. 2009;361: Primary endpoint: CV death + MI + stroke Primary safety endpoint: total major bleeding 41 PLATO: Ticagrelor vs Clopidogrel Cumulative Incidence (%) Number at risk: Ticagrelor 9333 Clopidogrel 9291 Time to Primary Efficacy Endpoint* Clopidogrel 11.7% % 9 8 Ticagrelor RRR 16% 3 HR 0.84 (95% CI, );P< Days after Randomization *Composite of CV death, MI, or stroke WallentinL et al. N Engl J Med. 2009;361: Copyright 2009 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society

22 PLATO: Ticagrelor vs Clopidogrel Events (%) Major Secondary Endpoints at 12 Mo, Total Cohort P< % 12.3% Death, any cause, MI, stroke P= % 4% Death, vascular causes Ticagrelor (N=9333) P= % 6.9% P= % 1.3% MI Stroke All-cause mortality Clopidogrel (N=9291) P< % 4.5% *Percentages are K-M estimates of the rate of the endpoint at 12 mo; patients could have had >1 type of endpoint By Cox regression analysis WallentinL et al. N Engl J Med. 2009;361: PLATO: Ticagrelor vs Clopidogrel Major Bleeding P=.66 P=.03 P=.70 P=.96 P=.57 P=.43 WallentinL et al. N Engl J Med. 2009;361:

23 PLATO: Clopidogrel vs Ticagrelor P=.01 Ventricular pauses* 3 s P=.10 Ventricular pauses* 5 s Ticagrelor (N=3719) Clopidogrel (N=3752) Percentages are K-M estimates of the rate of the endpoint at 12 mo; patients could have had >1 type of endpoint *As measured by Holter monitoring at first week Steg PG et al. Circulation. 2010;122: PLATO: Clopidogrel vs Ticagrelor P< P=.0004 P=.20 P=.18 P=.83 P=.64 0 Any dyspnea Discont., dyspnea Pacemaker placement Syncope Bradycardia Heart Block Ticagrelor (N=3719) Clopidogrel (N=3752) Percentages are K-M estimates of the rate of the endpoint at 12 mo; patients could have had >1 type of endpoint Steg PG et al. Circulation. 2010;122:

24 PLATO: Ticagrelor vs Clopidogrel Primary Endpoint: Non-invasive vs Invasive Strategy* HR, 0.85 (95% CI, ) CV death, MI or stroke (%) HR, 0.84 (95% CI, ) 0 Non-invasive Ticagrelor Clopidogrel *Data from supplementary material as opposed to main article Invasive WallentinL et al. N Engl J Med. 2009;361: ATLANTIC: Pre-hospital Ticagrelor in STEMI Study Design STE-ACS planned for PCI Onset of ischemic symptoms within 6 h, initially managed in ambulance or ED of non-pci hospitals (N=1862) Double-blind, Randomize 1:1 Pretreatment: No pretreatment: Pre-hospital: Ticagrelor 180 mg loading dose Placebo Loading dose Median time 1 st LD 2 nd LD: 31 m In-hospital Placebo Loading dose Ticagrelor 180 mg loading dose All patients received ticagrelor 90 mg BID for 30 d after PCI Co-primary endpoint: 70% STEMI resolution pre-pci OR TIMI flow grade 3 of culprit MI vessel at initial angiography ED, emergency department; STE-ACS, ST-elevation-acute coronary syndromes Montalescot G. ATLANTIC Administration of Ticagrelor in the cath Lab or in the Ambulance for New ST elevation myocardial infarction to open the coronary artery. Presented at: European Society of Cardiology Congress; Sept 1, 2014; Barcelona, Spain. PCI 48 24

25 ATLANTIC: Pre-hospital Ticagrelor in STEMI Absence of TIMI Flow Grade 3 or ST-Segment Resolution ( 70%) OR 0.97 (95% CI, ; P=.82) 82.6% 83.1% Events (%) OR 0.93 (95% CI, ; P=.63) 86.8% 87.6% Pre-PCI TIMI Flow Grade 3* Patients (%) Pre-hospital In-hospital *In infarct-related artery at ini al angiography; primary co-endpoint Montalescot G et al. N Engl J Med. 2014;371: ATLANTIC: Pre-hospital Ticagrelor in STEMI Major Adverse CV Events Event Rate (KM %) 30 days OR (95% CI) MACE 1 Ticagrelor pre-hospital 4.5 Ticagrelor in-hospital 4.4 Definite stent thrombosis 2 Ticagrelor pre-hospital 0.2 Ticagrelor in-hospital ( ; P=.91) 0.19 ( ; P=.0225) MACE, death, MI, stent thrombosis, stroke, urgent revascularization, or definite stent thrombosis; KM, Kaplan-Meier; OR, odds ratio 1. Montalescot G et al. N Engl J Med. 2014;371: Montalescot G. ATLANTIC Administration of Ticagrelor in the cath Lab or in the Ambulance for New ST elevation myocardial infarction to open the coronary artery. Presented at: European Society of Cardiology Congress; Sept 1, 2014; Barcelona, Spain

26 Ticagrelor Summary Directly, reversibly inhibits P2Y 12 receptor 1 Greater antiplatelet effect than clopidogrel In PLATO, ticagrelor improved ischemic benefit, decreased CV mortality in patients with ACS; significant increase in non-cabg bleeding, but not CABG-related bleeding 2 Maintenance ASA doses >100 mg appeared to attenuate treatment effect of ticagrelor 3 In ATLANTIC, pre-and in-hospital ticagrelor resulted in similar safety and efficacy for patients with STEMI 4 1. CapodannoD et al. J ThrombHaemost. 2013;11(suppl 1): WallentinL et al. N EnglJ Med. 2009;361: Mahaffey KW et al. Circulation. 2011;124: Montalescot G et al. Am Heart J. 2013;165: CURRENT GUIDELINES FOR DUAL ANTIPLATELET THERAPY IN ACS Michelle O Donoghue, MD, MPH 26

27 Guidelines for Antiplatelet Therapy in UA/NSTEMI New 2014 AHA/ACC Guideline Recommended LD of P2Y 12 inhibitors prior to procedure at the time of PCI (Class I): Clopidogrel 600 mg, or Prasugrel* 60 mg who are not at high risk of bleeding, or Ticagrelor 180 mg Clopidogrel or ticagrelor can be used upstream Ticagrelor and prasugrel should be used preferentially over clopidogrel for P2Y 12 therapy (Class IIa) Ticagrelor is preferential to clopidogrel in NSTE-ACS patients undergoing noninvasive or invasive strategy and for maintenance after PCI Prasugrel is preferential to clopidogrel in NSTE-ACS patients undergoing PCI and for maintenance after PCI who are not at high-risk of bleeding *Loading dose of prasugrel indicated if not pretreated with another P2Y 12 receptor inhibitor; should not be used in patients with a h/o stroke or TIA The recommended dose of aspirin to be used with ticagrelor is 81 mg/d LOE, level of evidence Amsterdam EA et al. Circulation. 2014;Epub ahead of print Sept Guidelines for Antiplatelet Therapy in UA/NSTEMI (continued) New 2014 AHA/ACC Guideline Duration and maintenance dose of P2Y 12 receptor inhibitors after stent placement: In NSTE-ACS patients (Class I): Either clopidogrel 75 mg/d, prasugrel 10 mg/d, or ticagrelor 90 mg BID, 12 mo If risk of morbidity due to bleeding outweighs anticipated benefits afforded by P2Y 12 receptor inhibitor therapy, consider earlier discontinuation (Class IIa) 54 27

28 Adjunctive Antiplatelet Therapy 2013 ACCF/AHA Guidelines for Support of Reperfusion With Primary PCI for STEMI P2Y 12 receptor inhibitors: Loading dose as early as possible or at time of PCI (Class I) Clopidogrel, 600 mg Prasugrel, 60 mg Ticagrelor, 180 mg Maintenance therapy for 1 year (minimum of 1 month with DES) in patients who receive a stent (DES or BMS; Class I)* Clopidogrel, 75 mg/d Prasugrel, 10 mg/d Ticagrelor, 90 mg BID Prasugrel contraindicated in patients with history of stroke or TIA (Class III) BMS, bare-metal stent; DES, drug-eluting stent *Balloon angioplasty without stent placement may be used in selected patients. It might be reasonable to provide P2Y 12 inhibitor therapy to patients with STEMI undergoing balloon angioplasty alone per recommendations listed for BMS. O Gara PT et al. Circulation. 2013;127:e362-e Balancing Safety and Efficacy High risk of ischemic events Sweet spot High risk of bleeding events Inhibition of platelet aggregation Ischemic Risk Bleeding Risk Ferreiro JL et al. Thromb Haemost. 2010;103: Reproduced with permission

29 Conclusions Recurrent atherothrombotic events in patients with ACS and/or those undergoing PCI are driven by platelets. Therefore, effective/safe use of antiplatelets is critical. Dual antiplatelet therapy with aspirin and clopidogrel has been the standard of care for more than a decade and is currently recommended in US guidelines. The newer P2Y 12 inhibitors, prasugrel and ticagrelor, are also approved for clinical use and may provide benefit in some patients. Ensure all appropriate patients receive evidence-based antiplatelet therapy based on individual benefits and risks. 57 FOR MORE COMPLIMENTARY CME ACTIVITIES, VISIT 29