UPDATE ACUTE CORONARY SYNDROMES. Dr. Wayne Tymchak April 7, 2017

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1 UPDATE ACUTE CORONARY SYNDROMES Dr. Wayne Tymchak April 7, 2017

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3 Spontaneous Rupture Unstable Angina Myocardial Infarction

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6 Classification: Acute Coronary Syndromes Ischemic Discomfort Non-ST ST Unstable Angina Non-Q Q Wave MI* Wave MI* * positive cardiac enzymes/markers

7 Declining AMI Mortality Over Four Decades 1960s % short-term mortality Resuscitation recognition & R x of dysrhythmia 1970s Prehospital care 30 Infarct size limitation 1980s Hemodynamic monitoring vasodilators/mechanical assist Reperfusion thrombolysis PTCA s Evidence-based practice Process of care Early testing/intervention/ combination therapies s 5 0 Pre-CCU era CCU era Reperfusion era Adapted from Armstrong P. Can J Cardiol 1996;12:909

8 OBJECTIVES ACS Risk Assessment Invasive vs. Conservative Therapy for ACS ACS Dual Antiplatelet NSTEACS ACS Dual Antiplatelet STEMI ACS Dual Antiplatelet Duration Pharmaco Invasive Approach To STEMI STEMI Systems Of Care

9 ACS Risk Scoring TIMI Age Use of aspirin Risk Factors Known CAD > 1 episode rest pain ST segment deviation Cardiac risk markers PURSUIT Age, Sex CCS class in last 6/52 Signs of CCF ST depression on ECG GRACE Age Heart rate and systolic BP Creatinine CCF (Killip class) Cardiac arrest at admission Elevated cardiac markers ST segment deviation Eduard van den Berg, cardio.nl 9

10 TIMI Risk Score for Patients with Definite ACS Age > 65 Documented CAD Cardiac risk factors ASA usage previous 7 days >2 anginal events in past 24 hours ST deviation Elevated cardiac markers Cardiac Events (%) p<0.001 by x 2 for trend N= / /7 Risk Score Key point: People have can significant disease with low scores. Must continuously reassess risk stratification TIMI ESSENCE Antman EM, et al. JAMA.2000;284(7):

11 At Admission Risk Model >140=high risk Eduard van den Berg, cardio.nl 11

12 OBJECTIVES Invasive vs. Conservative Therapy for ACS

13 Invasive Therapy for Non ST Segment Elevation ACS New trials support an invasive approach in high risk patients with Non ST Segment Elevation ACS High risk Recurrent chest pain Dynamic ST T changes Positive markers for myocardial injury Hemodynamic instability Invasive Therapy Planned catherization in all suitable high risk patients without contraindication Subsequent revascularization where feasible

14 FRISC II - % of Patients Primary Endpoint: Death or MI at 6 months Invasive vs. Non-Invasive 12.1 p= % 0.0 Non-Invasive (n=1226) Death or MI Invasive (n=1207) Lancet 1999; 354:

15 Primary Endpoint TACTICS Death, MI, Rehosp for ACS at 6 Months % % Patients O.R % CI (0.62, 0.97) p=0.025 CONS INV Time (months) 15.9%

16 TIMING OF INTERVENTION

17 TIMACS Design, Eligibility Criteria and Protocol UA or NSTEMI 2 of 3 Criteria: Age > 60, ischemic ECG or biomarker AND suitable for revascularization RANDOMIZE* *Randomization ratio 1:1, 1:2 or 2:1 Early Invasive Coronary angio as soon as possible (<24 hours) Delayed Invasive Coronary angio >36 hrs Follow-up up to 180 days Preliminary Results as of Nov 7, 2008

18 TIMACS Primary Outcome Death, MI, or Stroke Death/MI/Stroke at 180 days Delayed Cumulative Hazard HR % CI P= 0.15 Early No. at Risk Delayed Early Days Preliminary Results as of Nov 7, 2008

19 TIMACS HIGH RISK > 141 VS. LOW RISK Primary Outcome Cumulative Hazard Delayed Early Early Delayed High Risk GRACE Score >140 Low/Intermediate Risk GRACE Score Days Mehta SR et al. N Engl J Med 2009;360:

20 OBJECTIVES ACS Dual Antiplatelet NSTEACS

21 Timing of Randomization in Dual Antiplatelet Trials < 24 hrs CURE Clopidogrel PLATO Ticagrelor Selective Invasive Medical Management Symptom Onset Presentation Early Invasive Coronary Angiography PCI CABG TRITON Prasugrel NSTE ACS < 72 hrs STEMI < 12 hrs James SK, et al. BMJ. 2011;342:d3527. Wiviott SD, et al. N Engl J Med. 2007;357(20): Yusuf S, et al. N Engl J Med. 2001;345(7):

22 CURE Primary End Point - MI/Stroke/CV Death Cumulative Hazard Rate * In combination with standard therapy Placebo + ASA* Clopidogrel + ASA* Months of Follow-Up The CURE Trial Investigators. N Engl J Med. 2001;345: % 9.3% 20% RRR P < N = 12,562

23 PCI- CURE Overall Long-Term Results Composite of cardiovascular death or MI from randomization to end of follow-up % Placebo + ASA* Cumulative Hazard Rate * In combination with standard therapy Clopidogrel + ASA* 8.8% 31% RRR P = N = Days of follow-up Mehta, SR. et al for the CURE Trial Investigators. Lancet. August 2001.

24 PLATO study design NSTEMI ACS (moderate-to-high risk) STEMI (if primary PCI) (N=18,624) Clopidogrel-treated or -naive; randomized <24 hours of index event At randomization, 13,408 (72%) of patients were specified by the Investigator: intent for invasive strategy Clopidogrel (n=6,676) If pre-treated, no additional loading dose; if naive, standard 300 mg loading dose, then 75 mg qd maintenance; (additional 300 mg allowed pre-pci) Ticagrelor (n=6,732) 180 mg loading dose, then 90 mg bid maintenance; (additional 90 mg pre-pci) 6 12 months treatment Primary endpoint: CV death + MI + Stroke Primary safety endpoint: Total major bleeding PCI = percutaneous coronary intervention; CV = cardiovascular; PI = principal investigator Wallentin L, et al. N Engl J Med. 2009;361:

25 PLATO: Secondary Efficacy Outcomes Ticagrelor Reduced Mortality in ACS Cardiovascular Death All Cause Mortality 7 6 Clopidogrel (n=9291) Cumulative incidence (%) HR % CI p=0.001 Clopidogrel (n=9291) Ticagrelor (n=9333) 21% RRR Incidence (%) Ticagrelor (n=9333) HR % CI p<0.001 (nominal) Months after randomization Incidence at 1 year (%) Wallentin L, et al. N Engl J Med. 2009;361:

26 PLATO: Noninvasive Management Subgroup Analysis of 5216 Patients (28% of overall cohort) 20 Noninvasive Subgroup Ticagrelor (n=2601) Clopidogrel (n=2615) Invasive Subgroup Ticagrelor (n=6732) Clopidogrel (n=6676) CV Death/MI/Stroke (%) HR % CI p=0.045 HR % CI p= p for interaction = Days after randomization James SK, et al. BMJ. 2011;342:d3527 doi: /bmj.d3527. Cannon CP, et al. Lancet.2010;375:

27 Figure 9: Rates of bleeding according to different definitions Invasive p= Non-CABG-related bleeding only Both non-cabg-related and CABG-related bleeding CABG-related bleeding only 11 Kaplan-Meier estimated rate (% per year) p= p= Ticagrelor Clopidogrel Ticagrelor Clopidogrel Ticagrelor Clopidogrel PLATO-defined major bleeding TIMI-defined major bleeding GUSTO-defined severe bleeding CABG=coronary artery bypass graft; PLATO=PLATelet inhibition and patient Outcomes TIMI=Thrombolysis In Myocardial Infarction GUSTO=Global Use of Strategies To Open occluded coronary arteries. Cannon CP, et al. Lancet 2010;375:

28 Fondaparinux vs Enoxaparin in NSTE ACS Similar Ischemic Outcomes but Less Major Bleeding Death/MI/Refractory Ischemia Major Bleeding Cumulative Hazard (%) HR % CI p=0.007 Fondaparinux (n=10,057) Enoxaparin (n=10,021) Cumulative Hazard (%) HR % CI p<0.001 Enoxaparin (n=10,021) Fondaparinux (n=10,057) Days 30 Day and 6 Month Results Days Event Fondaparinux (n=10,057) Enoxaparin (n=10,021) HR (95% CI) p value Mortality (30 day) 2.9% 3.5% 0.83 ( ) 0.02 Mortality (6 mo) 5.8% 6.5% 0.89 ( ) 0.05 OASIS-5 Yusuf S, et al. N Eng J Med. 2006;354:

29 Algorithm for Management of Patients With Definite or Likely NSTE-ACS

30 In patients who have been treated with fondaparinux (as upfront therapy) who are undergoing PCI, an additional anticoagulant with anti-iia activity should be administered at the time of PCI because of the risk of catheter thrombosis.

31 OBJECTIVES ACS Dual Antiplatelet STEMI

32 Study Design Double-blind, randomized, placebo-controlled trial in 3491 patients, age yrs with STEMI < 12 hours Fibrinolytic, ASA, Heparin randomize Study Drug Open-label clopidogrel per MD in both groups Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) 30-day clinical follow-up Placebo Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio

33 Primary Endpoint: Occluded Artery, D, MI at ANGIOGRAPHY Occluded Artery or Death/MI (%) % Odds Reduction Odds Ratio 0.64 (95% CI ) P= n=1752 n=1739 Clopidogrel Placebo Clopidogrel better Placebo better

34 CV Death, MI, RI Urg Revasc 30 Days Percentage with endpoint (%) Placebo Odds Ratio 0.80 (95% CI ) P=0.026 Clopidogrel 20% days

35 M A R C H 9, Conclusion Clopidogrel offers an effective, simple, inexpensive, and safe means by which to improve infarct-related artery patency and reduce ischemic complications. Bleeding complications were not increased Sabatine MS, Cannon CP, Gibson CM, Lopez-Sendon JL, Montalescot G, Theroux P, Claeys MJ, Cools F, Hill KA, Skene AM, McCabe CH and Braunwald E for the CLARITY-TIMI 28 Investigators.

36 COMMIT/CCS-2 (ClOpidogrel & Metoprolol in Myocardial Infarction Trial) 45,852 patients from 1250 centres in China Heilongjiang (53) Xinjiang (7) Qinghai (4) Jilin (50) Liaoning (92) Beijing (48) Nei Mongol (38) Tianjin (21) Hebei (115) Ningxia (8) Shanxi (58) Shandong (148) Gansu (25) Henan (121) Jiangsu (63) Shaanxi (43) Anhui (28) Shanghai (16) Sichuan (49) Hubei (54) Zhejiang (12) Chongqing (11) Jiangxi (20) Hunan (37) Guizhou (11) Fujian (22) Yunnan (12) Guangdong (49) Guangxi (30) Hainan (7)

37 COMMIT: Study design TREATMENT: INCLUSION: EXCLUSION: Clopidogrel 75 mg daily vs placebo, (aspirin 162mg daily in both groups) Suspected acute MI (ST change or LBBB) within 24 h of symptom onset Primary PCI or high-risk of bleeding 1 OUTCOMES: Death & death, re-mi or stroke up to 4 weeks in hospital (or prior discharge) Mean treatment and follow-up: 16 days

38 COMMIT: Effects of CLOPIDOGREL on Death, Re-MI or Stroke Placebo + ASA: 2311 events (10.1%) Clopidogrel + ASA: 2125 events (9.3%) Event (%) 9% (SE3) relative risk reduction (2P=0.002) Days since randomisation (up to 28 days)

39 COMMIT: Major bleed in hospital Type Clopidogrel Placebo (n=22,958) (n=22,891) Cerebral Fatal Non-fatal Non-cerebral Fatal Non-fatal Any major bleed (0.58%) (0.54%)

40 COMMIT: Conclusions Adding 75 mg daily CLOPIDOGREL to aspirin in acute MI prevents major vascular events No excess of cerebral, fatal or transfused bleeds (even with fibrinolytic therapy and in older people) Each million MI patients treated for ~2 weeks would avoid 5000 deaths and 5000 non-fatal events

41 OBJECTIVES ACS Dual Antiplatelet Duration

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51 PEGASUS Stable patients with history of MI 1 3 years prior + 1 additional atherothrombosis risk factor P2Y 12 inhibitor therapy may have been stopped at any time prior to randomization RANDOMIZED DOUBLE-BLIND Planned treatment with ASA mg/d & standard background care Ticagrelor 90 mg bid Ticagrelor 60 mg bid Placebo Follow-up visits Q4 months for 1st year, then Q6 months Followed for median of 33 months Primary endpoint: CV death, MI, stroke Bonaca MP et al. N Engl J Med 2015;372: These slides have been provided, on request by AstraZeneca Scientific Affairs. AstraZeneca does not, under any circumstances, promote its products for off-label or unapproved uses.

52 CV death, MI, or stroke (%) N=21,162 Median follow-up 33 months from randomization Background Bonaca MP et al. N Engl J Med 2015;372: Months from randomization CVD / MI / Stroke Ticagrelor 90 mg BD HR 0.85 (95% CI 0.75, 0.96) P=0.008 Ticagrelor 60 mg BD HR 0.84 (95% CI 0.74, 0.95) P=0.004 Placebo (9.0%) Ticagrelor 90 mg (7.8%) Ticagrelor 60 mg (7.8%) These slides have been provided, on request by AstraZeneca Scientific Affairs. AstraZeneca does not, under any circumstances, promote its products for off-label or unapproved uses.

53 Reduction in CV death, MI or stroke with ticagrelor by time from P2Y 12 inhibitor withdrawal Time from P2Y 12 inhibitor withdrawal to randomization HR (95% CI) P value 30 days n= % RRR 0.70 (0.57, 0.87) 0.75 (0.61, 0.92) 0.73 (0.61, 0.87) <0.001 >30 days to 1 year n= % RRR 0.90 (0.72, 1.12) 0.82 (0.65, 1.02) 0.86 (0.71, 1.04) 0.11 >1 year n=5079 RRR P-interaction Ticagrelor better 1.0 Placebo better 0.96 (0.73, 1.26) 1.06 (0.81, 1.38) 1.01 (0.80, 1.27) 0.96 Ticagrelor 90 mg Ticagrelor 60 mg Pooled Bonaca MP. Presented at ESC Congress 2015 (Abstract 3918) These slides have been provided, on request by AstraZeneca Scientific Affairs. AstraZeneca does not, under any circumstances, promote its products for off-label or unapproved uses.

54 TIMI major bleeding at 3 years with ticagrelor by dose Time from P2Y 12 inhibitor withdrawal to randomization P trend NS 3-year Kaplan-Meier rate (%) Ticagrelor Placebo HR (95% CI) P value 30 days n=7093 >30 days to 1 year n=6446 >1 year n= (1.88, 6.28) (1.80, 6.03) (1.91, 5.92) < (1.59, 5.10) (1.66, 5.22) (1.69, 4.94) < (1.70, 6.33) (1.05, 4.22) (1.43, 4.98) Ticagrelor better 1.0 Placebo better Bonaca MP. Presented at ESC Congress 2015 (Abstract 3918) Ticagrelor 90 mg Ticagrelor 60 mg Pooled These slides have been provided, on request by AstraZeneca Scientific Affairs. AstraZeneca does not, under any circumstances, promote its products for off-label or unapproved uses.

55 Conclusions Continuing P2Y 12 inhibition beyond 1 year after MI offers robust ischaemic benefit Re-initiation of P2Y 12 inhibition in patients who have been stable on aspirin alone for more than a year does not appear to offer benefit and increases bleeding Ongoing research using clinical, biochemical and genetic factors may enable us to further refine, in a prospective manner, the optimal patient populations for long-term therapy Bonaca MP. Presented at ESC Congress 2015 (Abstract 3918) These slides have been provided, on request by AstraZeneca Scientific Affairs. AstraZeneca does not, under any circumstances, promote its products for off-label or unapproved uses.

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58 Two Recent Meta Analysis With Second Generation DES Shorter term 3 6 months Did not disadvantage patients No Increase in Mortality No Increase in In stent thrombosis Resulted in less bleeding Extended Term > 12 months Improved Mortality Reduced in stent thrombosis More bleeding events Risk stratify using tools such as DAPT SCORE

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64 OBJECTIVES Pharmaco Invasive Approach To STEMI

65 Pharmaco-Invasive Approach to STEMI Pharmaco-invasive approach to STEMI care has now become widely accepted as standard therapy Primary PTCA still preferred mode of therapy, must be done in a timely fashion with first medical contact to balloon inflation of < 90 minutes 65

66 CARESS-IN-AMI: Primary Outcome primary outcome (composite of all cause mortality, reinfarction, & refractory MI within 30 days) 10.7% 4.4% HR=0.40 ( ) Di Mario et al. Lancet 2008;371. ACC/AHA 2009 Joint STEMI/PCI Guidelines Focused Update 64

67 CAPITAL AMI Trial 170 patients presenting with ST elevation acute MI with chest pain 30 minutes and within six hours of symptom onset Randomized, open-label, multicenter Thrombolytic Therapy Full-dose Tenectaplase (TNK) n=84 Thrombolytic Therapy, Transfer, and PCI Full-dose Tenectaplase (TNK) followed by transfer and subsequent percutaneous coronary intervention (PCI) n=86 Endpoints (30 days and 6 months): Composite of death, reinfarction, recurrent unstable ischemia, or stroke www. Clinical trial results.org Presented at ACC Scientific Sessions 20

68 CAPITAL AMI Trial 25% 20% In-Hospital Composite Event Rate p= % 20% 15% 10% In-Hospital Reinfarction p= % In-Hospital Recurrent Unstable Ischemia p= % % 15% 10% 5% 0% TNK www. Clinical trial results.org 8.1% TNK+PCI 5% 0% TNK 3.5% TNK +PCI TNK 5.8% TNK +PCI The composite in-hospital event rate of death, reinfarction, recurrent unstable ischemia, or stroke was lower in the TNK+PCI arm compared with the TNK alone arm, driven by a reduction in reinfarction and recurrent unstable ischemia. Presented at ACC Scientific Sessions 20

69 CAPITAL AMI Trial 25% Primary Composite Endpoint at 30 days p= % 20% 15% 30-Day Reinfarction % 30-Day Recurrent Unstable Ischemia % 20% 10% 5% 4.7% 7.0% % 15% 0% TNK TNK +PCI TNK TNK +PCI 10% 5% 0% TNK 9.3% TNK+PCI Composite event rate remained lower in the TNK+PCI arm at 30 days, again driven by reductions in reinfarction and recurrent unstable ischemia, with no difference in mortality (2.3% vs. 3.6%). Length of hospital stay shorter in the TNK+PCI arm (5 vs. 6 days, p=0.009). www. Clinical trial results.org Presented at ACC Scientific Sessions 20

70 High Risk ST Elevation MI within 12 hours of symptom onset TNK + ASA + Heparin / Enoxaparin + Clopidogrel Community Hospital Emergency Department Pharmacoinvasive Strategy Urgent Transfer to PCI Centre Standard Treatment Assess chest pain, ST resolution at minutes after randomization Failed Reperfusion* Successful Reperfusion PCI Centre Cath Lab Cath / PCI within 6 hrs regardless of reperfusion status Cath and Rescue PCI GP IIb/IIIa Inhibitor Elective Cath PCI > 24 hrs later Repatriation of stable patients within 24 hrs of PCI * ST segment resolution < 50% & persistent chest pain, or hemodynamic instability Randomization stratified by age ( 75 vs. > 75) and by enrolling site 9803mo01, 70

71 % of Patients Standard PCI > 24 hrs (n=496) Invasive < 6 hrs (n=508) n=496 n=508 Primary Endpoint: 30-Day Death, re- MI, CHF, Severe Recurrent Ischemia, Shock OR=0.537 (0.368, 0.783); p= Days from Randomization RR= 0.64, 95 CI% ( ) mo01, 71

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73 OBJECTIVES STEMI Systems Of Care

74 F. Van de Werf, ACC 2013

75 STUDY AIM A strategy of early fibrinolysis followed by coronary angiography within 6-24 hours or rescue PCI if needed was compared with standard primary PCI in STEMI patients with at least 2 mm ST-elevation in 2 contiguous leads presenting within 3 hours of symptom onset and unable to undergo primary PCI within 1 hour. Pharmaco-Invasive vs. Primary PCI In STEMI F. Van de Werf, ACC 2013

76 MEDIAN TIMES TO TREATMENT (min) Sx onset 1st Medical contact Randomize IVRS Rx TNK min Sx onset 1st Medical contact Randomize IVRS 78 min difference Rx PPCI n= Hour 2 Hours 178 min F. Van de Werf, ACC 2013

77 PRIMARY ENDPOINT Dth/Shock/CHF/ReMI (%) TNK vs PPCI Relative Risk 0.86, 95%CI ( ) PPCI 14.3% TNK 12.4% p=0.24 The 95% CI of the observed incidence in the pharmaco-invasive arm would exclude a 9% relative excess compared with PPCI F. Van de Werf, ACC 2013

78 CONCLUSIONS A strategy of fibrinolysis with bolus tenecteplase and contemporary antithrombotic therapy given before transport to a PCI-capable hospital coupled with timely coronary angiography : circumvents the need for an urgent procedure in about two thirds of fibrinolytic treated STEMI patients. is associated with a small increased risk of intracranial bleeding. is as effective as primary PCI in STEMI patients presenting within 3 hours of symptom onset who cannot undergo primary PCI within one hour of first medical contact. F. Van de Werf, ACC 2013

79 VHR Vital Heart Response Evidence Based Guidelines (ACCF/AHA and ESC) Developing a System of Care approach to STEMI First Medical Contact (FMC) to fibrinolysis in < 30 minutes FMC to PPCI in < 90 minutes Early reperfusion provides best outcomes 1 in 3 patients reperfused within 1 hr of onset have negligable myocardial damage 79

80 Alberta, Canada 661,848 km 2 (255,500 mi 2 ) 4.1 million people Edmonton, Alberta 782,439 city 1,155,383 metro million referral population Texas: 268,820 square miles (696,200 km 2 ), and a pop of 25.1 million residents 80

81 Avoid reperfusion decision paralysis 81

82 VHR Protocol Overview 82

83 STEMI Acute Care Overview 83

84 Adding GP 2b 3a Inhibitors to ASA, Anticoagulation and DAPT in ACS patients implies a very high risk patient which require invasive investigation in a timely fashion.patients implies ve 2b 3a Inhibitors to ASA, GP 2b 3a Inhibitors not to be used concomitantly with Thrombolytics Major increase in serious bleeding Ticagrelor not to be used concomitantly with Thrombolytics Not studied If using Fondaparinux for ACS Must reload with unfractionated heparin in patients going for invasive approach Increase catheter thrombosis

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