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2 Agenda New Rapid Rule Out Strategy General Guidelines and Therapies Assessing Patient Risk Timing of Catheterization Navigating Anticoagulant/Antiplatelet Choices Newer Choices and new data The Future

3 New European and US Guidelines This Year for NSTEMI First time a 1B recommendation for rapid rule out protocol with blood test at 0 and 1 hour using HS-Troponin with additional testing at 3-6 hrs if the first 2 are not conclusive and the clinical condition is still suggestive of ACS Prospective validation of a 1-hour algorithm to rule-out and rule-in acute myocardial infarction using a highsensitivity cardiac troponin T assay. CMAJ 2015;187:E243 E252.

4 Rapid Rule Out 1320 Patients treated according to the algorithm AMI was the final diagnosis in 17.3% of patients. 786 (59.5%) patients were classified as rule-out, 216 (16.4%) were classified as rule-in 318 (24.1%) were classified to the observational. Prospective validation of a 1-hour algorithm to rule-out and rule-in acute myocardial infarction using a highsensitivity cardiac troponin T assay. CMAJ 2015;187:E243 E252.

5 Rapid Rule Out The negative predictive value for acute MI in the rule-out zone was 99.9%. The positive predictive value for acute MI in the rulein zone was 78.2%. Cumulative 30-day mortality was 0.0, 1.6, and 1.9% in patients classified in the rule-out, observational, and rule-in groups, respectively. Prospective validation of a 1-hour algorithm to rule-out and rule-in acute myocardial infarction using a highsensitivity cardiac troponin T assay. CMAJ 2015;187:E243 E252.

6 New European and US Guidelines This Year for NSTEMI First time a 1B recommendation for rapid rule out protocol with blood test at 0 and 1 hour using HS-Troponin with additional testing at 3-6 hrs if the first 2 are not conclusive and the clinical condition is still suggestive of ACS Prospective validation of a 1-hour algorithm to rule-out and rule-in acute myocardial infarction using a highsensitivity cardiac troponin T assay. CMAJ 2015;187:E243 E252.

7 Immediate Management The history, physical examination, 12-lead ECG, and initial cardiac biomarker tests should be integrated Assign patients with chest pain into 1 of 4 categories Noncardiac diagnosis Chronic stable angina Possible ACS Definite ACS 7

8 Universal Definition of MI

9 Universal Definition of MI

10 Goals for the Management of Non-ST Elevation Acute Coronary Syndromes Unstable Angina Prevent immediate risk of MI and improve longterm outcome Non-STEMI Minimize extent of MI to improve long-term outcome Prevent repeat MI to improve long-term outcome

11 General Therapies Anti Ischemic Therapy & Pain Control Oxygen Nitrates Unless BP <90 HR <50 and if SBP >100 without CHF Morphine Oral Beta Blockade within 24 hrs Unless HF, Low output state, PR >0.24, Heart Block, Active Asthma/Reactive Airway Disease ACE-I within 24 hrs if HF or LVEF <=40% Unless BP <100 or >30 mm Hg below baseline

12 Aspirin in the Treatment of ACS Probability of Death or MI Months Wallentin LC, et al. JACC 1991;18: Placebo Aspirin 75 mg Risk ratio % CL

13 Beta Blockers It may be harmful to administer intravenous beta blockers to UA/NSTEMI patients who have contraindications to beta blockade, signs of HF or low-output state, or other risk factors* for cardiogenic shock. *Risk factors for cardiogenic shock (the greater the number of risk factors present, the higher the risk of developing cardiogenic shock): 1.age >70 years SBP <120 mmhg 2.sinus tachycardia >110 or heart rate >60 3.increased time since onset of symptoms of UA/NSTEMI. Chen ZM, et al. Lancet 2005;366:

14 Goals for Therapy During NSTEMI Patient risk dictates management Goals: Unstable Angina: Prevent Progression to Infarct NSTEMI: Minimize Infarct Size and Recurrent MI Therapeutic agents Anticoagulants Anti Platelets Invasive Management Angiography to further clarify risk Revascularization to arrest thrombus progression

15 I m Confused What Dose of ASA? 600 mg vs. 300 mg Clopidogrel? What if Pt. needs a CABG? Early Invasive vs. Selective Invasive NSTEMI Which Stent? Drug Eluting vs. Bare Metal Stent Which Anticoagulant? LMWH UFH DTI Start Meds Upstream vs. In Cath Lab? Which Antiplatelet? Clopidogrel Prasugrel LMWH=Low Molecular Weight Heparin UFH= Unfractionated Heparin DTI= Direct Thrombin Inhibitor

16 EARLY INVASIVE STRATEGY WHO AND WHEN?

17 TIMI Risk Score TIMI Risk Score All-Cause Mortality, New or Recurrent MI, or Severe Recurrent Ischemia Requiring Urgent Revascularization Through 14 Days After Randomization % Antman EM, et al. JAMA 2000;284: Copyright 2000, American Association. All Rights reserved. The TIMI risk calculator is available at AndersonJL, et al. J Am Coll Cardiol 2007;50:e1 e157, Table8. TIMI= Thrombolysisin Myocardial Infarction.

18 Mortality and the TIMI Risk Score NSTEMI is generally caused by a partially occlusive, platelet-rich thrombus in a coronary artery JAMA 2000;284: (159).

19 Relative Risk for All-Cause Mortality: Early Invasive vs Selective Invasive Therapy Study FRISC-II TRUCS TIMI-18 VINO RITA-3 ISAR-COOL ICTUS Invasive Deaths, n Conservative Overall RR (95% CI) 0.75 ( ) Favors Early Invasive Therapy Favors Conservative Therapy Follow-up, Months Bavry A, et al. J Am Coll Cardiol. 2006;48:

20 Time to catheterization (hrs) EARLY LATE FRISC 2 (1999) TRUCS (2000) TIMI-18 (2001) VINO (2002) RITA 3 (2002) ELISA (2003) 6 50 ISAR-COOL (2003) 3 86 ICTUS (2005) TIME-ACS (2009) 14 50

21 TIMACS Primary Outcome Death, MI, or Stroke Cumulative Hazard No. at Risk Delayed Early Death/MI/Stroke at 180 days Days HR % CI P= Delayed Early N Engl J Med May 21;360(21):

22 ESC Guideline 2016 Immediate Invasive Strategy within 2 hours for very high risk patients Shock, severe heart failure, arrhythmia, ongoing chest pain Early invasive within 24 hours for high risk Invasive (within 72 hours) for intermediate risk

23 Summary Risk stratify patients with UA/NSTEMI using simple clinical scores (TIMI, GRACE) Select for further invasive work-up those who are at moderate and high risk for ischemic complications Catheterization should be urgent but not emergent for high risk individuals Low risk individuals should have noninvasive work-up first

24 MEDICATIONS FOR UA/NSTEMI PLATELETS AND THROMBUS

25 Questions Which patients for more aggressive antiplatelet medications? When to administer (pre-cath, at cath, postcath etc)? Which ones (oral, IV or both)? Newer agents?

26 Embolism in NSTEMI

27 P2Y 12 Inhibitors Clopidogrel Prasugrel Ticagrelor Class Thienopyridine Thienopyridine Triazolopyrimidine Binding to Receptor Activation Irreversible Irreversible Reversible Prodrug, limited by metabolisation Prodrug, not limited by metabolisation Active drug Nonresponders Yes No No Onset of Effect 2 4 h 30 min 30 min Duration of Effect 3 10 days 5 10 days 3 4 days Withdrawal Before Major Surgery Hamm CW, et al. Eur Heart J. 2011;32: days 7 days 5 days

28 Clopidogrel During UA/NSTEMI CV death, MI, stroke (%) Placebo (n=6303) Days After Enrollment RR = 0.80 P<.001 Clopidogrel (n=6259) CURE investigators. N Engl J Med. 2001;345:

29 Endpoint (%) CV Death / MI / Stroke Clopidogrel Prasugrel TIMI Major NonCABG Bleeds Days Prasugrel Clopidogrel Wiviott et al NEJM events HR 0.81 ( ) P= NNT = events HR 1.32 ( ) P=0.03 NNH = 167

30 Post-hoc analysis Prior Stroke / TIA Age Wgt TRITON-TIMI 38: Net Clinical Benefit Bleeding Risk Subgroups Yes No 75 < 75 < 60 kg 60 kg P int =.006 P int =.18 P int =.36 Risk (%) OVERALL Prasugrel Better Clopidogrel Better HR Wiviott SD, et al. N Engl J Med. 2007;357:

31 ESC Guideline 2016 Class III indication for Prasugrel before anatomy is known based on the ACCOAST Trial

32 Ticagrelor: PLATO Myocardial infarction Cardiovascular death Cumulative incidence (%) Clopidogrel Ticagrelor HR 0.84 (95% CI ), p=0.005 Cumulative incidence (%) Clopidogrel 1 HR 0.79 (95% CI ), p= Ticagrelor No. at risk Days after randomisation Days after randomisation Ticagrelor 9,333 8,678 8,520 8,279 6,796 5,210 4,191 9,333 8,294 8,822 8, ,482 4,419 Clopidogrel 9,291 8,560 8,405 8,177 6,703 5,136 4,109 9,291 8,865 8,780 8, ,441 4,364 N Engl J Med Sep 10;361(11): Epub 2009 Aug 30.

33 Timing of Clopidogrel Loading In US Practice Dean BB et al. Am J Health-Syst Pharm 2010; 67:

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35 2014 ACCF/AHA Select Recommendations for Oral Antiplatelet Agents with NSTE-ACS Recommendation COR LOE Initial Therapy: Aspirin ( mg) as soon as possible after hospital presentation, followed by 81 mg daily I A A P2Y 12 inhibitor (clopidogrel or ticagrelor) in addition to aspirin to all patients with NSTE-ACS without contraindications I B Ticagrelor in preference to clopidogrel IIa B Therapy at the time of PCI: P2Y 12 at the time of PCI: clopidogrel (LOE=A), prasugrel (LOE=B), ticagrelor (LOE=B,) or GPI (LOE=A) I B Prasugrel or ticagrelor in preference to clopidogrel in patients undergoing coronary stenting IIa B Prasugrel potentially harmful as part of DAPT in patients with a prior III: history of CVA and/or TIA Harm B Post-Discharge: Aspirin indefinitely I A Aspirin 81 mg in preference to higher doses IIa B If treated medically (no revascularization): clopidogrel or ticagrelor added to aspirin and continued for up to 12 months I B If treated with PCI: clopidogrel, prasugrel, or ticagrelor added to aspirin and continued at least 12 months I B Ticagrelor (PCI or med Rx) or prasugrel (PCI) in preference to clopidogrel IIa B Amsterdam E, et al. Circulation

36 Preloading May Not Actually Be Preloading

37 Circulation Volume 130(21): November 18, 2014

38 Cangrelor Now Approved for PCI Direct platelet P2Y 12 receptor antagonist ATP analogue MW=800 Daltons Parenteral administration Rapid inhibition (> 90%) at 4 mg/kg/min after a weight-based bolus Full recovery of platelet function in <60 minutes t 1/ minutes Putative metabolism by endothelial-associated ectonucleotidases/cd 39 O O O P C l 4N a C l + O P O O P O O O HO O N N OH Meadows TA, Bhatt DLCirc Res 2007;100: ; Akers J Clin Pharmacol. 2010;50:27-35; Steinhubl Thromb Res. 2008;121: HN N N S S CF3

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40 Summary: What to Do for Oral and Intravenous Antiplatelets ASA 325 mg orally, uncoated, chew-ok Clopidogrel 600 mg, Ticagrelor OK esp if you think will not need CABG Prasugrel OK but NO if prior TIA/Stroke and caution age >75, weight <60 kg ASA 81 mg a day with ticagrelor GPI: OK to wait for cath lab but start if fail above (recurrent chest pain, ECG changes)

41 Unfractionated heparin Anticoagulant choices LMW Heparin Fondaparinux Bivalirudin

42 Enoxaparin vs UFH in UA/NSTEMI: A Systematic Overview Death or MI at 30 Days Trial ESSENCE TIMI 11B ACUTE II INTERACT A to Z SYNERGY Overall OR (95% CI) 0.76 ( ) 0.88 ( ) 0.97 ( ) 0.54 ( ) 0.94 ( ) 0.96 ( ) 0.91 ( ) Favors Enoxaparin (N=21,946) Favors UFH OR (95% CI) Peterson JL, et al. JAMA. 2004;292:89-96.

43 Cumulative Events (%) ACUITY: Bivalirudin Ischemic Composite Endpoint UFH/enoxaparin + GPI vs bivalirudin + GPI vs bivalirudin alone Estimate P (log rank) UFH/enoxaparin + GPI (N=4603) 7.4% Bivalirudin + GPI (N=4604) 7.9% 0.37 Bivalirudin alone (N=4612) 8.0% Days from Randomization Stone GW, et al. N Engl J Med. 2006;355:

44 Cumulative Events (%) ACUITY: Bivalirudin Major Bleeding Endpoint UFH/enoxaparin + GPI vs bivalirudin + GPI vs bivalirudin alone Estimate UFH/enoxaparin + GPI (N=4603) 5.7% Bivalirudin + GPI (N=4604) 5.3% 0.41 Bivalirudin alone (N=4612) 3.1% < Days from Randomization P (log rank) Stone GW, et al. N Engl J Med. 2006;355:

45 MATRIX Program NCT NSTEACS or STEMI with invasive management Aspirin+P2Y12 blocker Trans-Radial Access Bivalirudin Mono-Tx 1:1 1:1 ACCESS 1:1 Trans-Femoral Access Lancet. 2015; 385(9986): ANTITHROMBIN TYPE Heparin GPI ACC 2015, oral presentation Stop Infusion Prolong 4 hs infusion TREATMENT DURATION

46 Primary EP: NACE NNTB: % 9.8% Rate Ratio 0.83; 95% CI, 0.73 to 0.96; p= Femoral Radial

47 New Guideline Recommendation Europeans Radial Preferred in experienced centers Americans Radial an option

48 MATRIX: Antithrombin Comparison Bivalirudin UFH 95% CI P-Value MACE NACE BARC 3, Death Definite ST

49 Summary Anticoagulants Unfractionated Heparin HIT Risk, Need to Titrate, Variable Response, platelet activation, inferior outcomes LMWH Main advantage is ease of administration. Not cath lab friendly. Avoid if think going to CABG Avoid in renal failure Fondaparinux Good for medical management esp. if bleeding risk Not favored if invasive management selected Bivalirudin Not a platelet activator Less bleeding and similar outcomes when compared to heparin paired with IV antiplatelets

50 WOEST Primary Endpoint: Total number of TIMI bleeding events Cumulative incidence of bleeding 50 % 40 % 30 % 20 % 10 % 0 % Triple therapy group Double therapy group 44.9% 19.5% p<0.001 HR= %CI[ ] Days n at risk:

51 Duration of DAPT New Insights from the PEGASUS- TIMI 54 and DAPT study Prolonged DAPT most logical when there is a diagnosis of obstructive CAD and there are few bleeding complications DAPT Study Investigators. Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. N Engl J Med 2014;371: PEGASUS-TIMI 54 Steering Committee and Investigators. Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med 2015;372:

52 Variable Patient Characteristic Age <75-1 < 65 0 Diabetes Mellitus 1 Current Cigarette Smoker 1 Prior PCI or Prior MI 1 CHF or LVEF < 30% 2 Index Procedure Characteristic MI at Presentation 1 Vein Graft PCI 2 Stent Diameter < 3mm 1 The DAPT Score Points Distribution of DAPT Scores among all randomized subjects in the DAPT Study 52

53 Continued Thienopyridine vs. Placebo, by DAPT Score, Excluding Paclitaxel-Eluting Stent Risk Difference (Continued Thienopyridine Placebo), 12-30M 4.0% 3.0% 2.0% 1.0% 0.0% -1.0% -2.0% -3.0% Stent Thrombosis or MI NNT 192 NNT 53 NNH 70 NNH 264 NNH 97 NNT 60 P=0.06 P=0.07 P= % -1.90% GUSTO Moderate Or Severe Bleed 1.44% 0.38% DAPT Score < 2 DAPT Score 2 Net Adverse Events 1.03% -1.67% -4.0% P values are for comparison of risk differences across DAPT Score category (interaction). 53

54 So Hot Off The Presses, I Didn t Know The Results When The Syllabus was Made! Presented at LBCT AHA Nov 12-16

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56 CHA 2 DS 2 -VASc 2009 Birmingham Schema Expressed as a Point-Based Scoring System Risk Factor Congestive heart failure/lv dysfunction 1 Hypertension 1 Age 75 y 2 Diabetes mellitus 1 Stroke/TIA/TE 2 Vascular disease myocardial infarction, peripheral artery disease, or aortic plaque) (prior Age y 1 Sex category (i.e. female gender) LV = left ventricular; TE = thromboembolism Score 1 1 Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Chest Feb;137(2): Pub Med PMID:

57 Stroke or Other TE at One Year CHA 2 DS 2 - VASc Score # CHA 2 DS 2 -VASc #TE Events TE Rate During 1 yr (95% CI) TE Rate During 1 yr, Adjusted for AspirinRX % (0-0) 0% % ( ) 0.7% % ( ) 1.9% % ( ) 4.7% % ( ) 2.3% % ( ) 3.9% % ( ) 4.5% % ( ) 10.1% % ( ) 14.2% % ( ) 100% Total 1, P Value for trend Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Chest Feb;137(2): Pub Med PMID:

58 HAS-BLED SCORE HAS-BLED Hypertension 4 1 Abnormal Renal 5 or Liver 1 function 6 1 Stroke 1 Bleeding 1 Labile INR 8 1 Elderly (>65 yrs) 1 Drugs 9 or Alcohol 1 1 HAS-BLED Low Risk (<3) 1,739 (75.9) 159 (9.1) 22 (1.3) High Risk ( 3) 553 (24.1) 92 (16.6) 17 (3.1) TOTAL 2, (11.0) 39 (1.7) Apostolakis S, Lane DA, Guo Y, Buller H, Lip GY. J Am Coll Cardiol 2012;60: Jul 24. [Epub ahead of print] Online Appendix. PMID:

59 References: ESC and American Guidelines Roffi M, et al. Eur Heart J 2016;37: Amsterdam EA. Circulation 2014;130: