STEMI Oct. 31, 2011 Core Curriculum Adjunctive/Conjunctive pharmacological therapy

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1 STEMI Oct. 31, 211 Core Curriculum Adjunctive/Conjunctive pharmacological therapy Robert C. Welsh, MD, FRCPC Associate Professor, University of Alberta Director, Adult Cardiac Catheterization and Interventional Cardiology Co-Director, University of Alberta Chest Pain Program Co-Chair, Vital Heart Response

2 Disclosures Research funding: Abiomed, Astra Zeneca, Boringher Ingelheim, BMS, geli Lilly, Johnson and Johnson, Pfiser, Portola, Regado, Roche, sanofi aventis Consultant/honorarium: Astra Zeneca, Bristol Myers-Squibb, Eli Lilly, Medtronic, Roche, sanofi-aventis 2

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4 How do you assess patient risk in STEMI?

5 CRUSADE bleeding risk score GRACE ACS risk model Baseline HCT.34 Elevated cardiac markers + ST segment deviation + GFR (Cockcroft Gault) 58 Creatinine 82 Heart Rate 58 Heart Rate 58 Systolic BP 155 Systolic BP 155 Prior vascular disease - Diabetes Mellitus - Heart Failure - Heart Failure - Sex F age 8 Cardiac arrest on admission - CRUSADE bleeding score = 4 Risk of in-hospital major bleeding 9.2% GRACE risk score in-hospital death = 6% In-hospital death or MI = 21%

6 Dilemma Balancing Ischemic and Bleeding Risks 25 Baseline risk estimates Ischemia risk In-hospital death and re-mi Bleeding risk In-hospital major bleeding Armstrong & Welsh JACC Int, Dec. 21.

7 Dilemma Balancing Ischemic and Bleeding Risks 25 2 Baseline risk estimates Intervention risk/benefit estimates Ischemia risk In-hospital death and re-mi Bleeding risk In-hospital major bleeding Armstrong & Welsh JACC Int, Dec. 21.

8 Anti-thrombotic therapy in STEMI What is the optimal anti-thrombotic agent in patients with STEMI undergoing: 1. Primary PCI 2. Fibrinolysis 3. Receiving no reperfusion

9 OASIS 6 Trial: Study Design 12,92 patients presenting with STEMI within 24 hours of symptom onset (shortened to 12 hours of symptom onset midway through trial) Randomized. Blinded. Factorial. 28% female, mean age 62 years, mean follow-up months Stratum 1 (No UFH) Stratum 2 (UFH) Fondaparinux 2.5mg/day for up to 8 days or hospital discharge Placebo Fondaparinux 2.5mg/day for up to 8 days or hospital discharge UFH Primary Endpoint: Composite of death or reinfarction at 3 days Secondary Endpoint: Composite of death or reinfarction at 9 days and at final follow-up JAMA. 26 Apr 5;295(13): Epub 26 Mar 14.

10 OASIS 6 Trial: Primary Endpoint Reduction in Death/MI: Stratum 1 (No UFH indicated) p<.5 Reduction in Death/MI: Stratum 2 (UFH Indicated) p=ns p=.97 There was no difference in Stratum 2, comparing those patients who received Fondaparinux vs those who received UFH (8.3% vs. 8.7%, HR.96, p=ns) JAMA. 26 Apr 5;295(13): Epub 26 Mar 14.

11 OASIS - 6 Trial: PCI Sub-study at 3 Days Primary Endpoint = Death or MI p=.19 Guiding Catheter Thrombosis p<.1 JAMA. 26 Apr 5;295(13): Epub 26 Mar 14.

12 ExTRACT TIMI 25: Study profile Enoxaparin (n = 1,256) ExTRACT TIMI 25 (N = 2,479) UFH (n = 1,223) Death/MI (%) RRR = 17% P <.1 UFH 12.% Enox 9.9% UFH 13.8% PCI by 3 days (n = 2,272) PCI by 3 days (n = 2,44) Death/MI (%) RRR = 23% P =.1 Enox 1.7% Antman EM, et al. N Engl J Med 26;354: Gibson CM, et al. J Am Coll Cardiol 27;49: Days

13 Primary Endpoint - PCI cohort 3 day death or MI Death or MI (%) Major bleeding: enox 1.4% vs. 1.6%, NS Net clinical benefit: death/nonfatal MI/nonfatal RR.77 major bleed Enox 11.5% vs. 14.8%, p<.1 (.78 (.67.9)) OR adj.72 95% CI (p=.1) ExTRACT Parent trial bleeding UFH 13.8% ENOX 1.7% Major bleeding (including ICH): 211 (2.1) vs. 138 (1.4) 1.53 ( ) <.1 ICH: 84 (.8) vs. 66 (.7) 1.27 ( ).14 Minor bleeding: (2.6) vs (1.8) ( ) 25 <.13 Major or minor bleeding: 464 (4.6) vs. 315 (3.1) 1.47 ( ) <.1 Days Adjusted for age, prior ASA use, time to PCI, smoking, time from symptom onset to lytic, type of lytic and propensity to undergo PCI Gibson et al, JACC 27, Antman et al, NEJM 26

14 ExTRACT-TIMI TIMI 25 TRIAL ASA STEMI < 6 h Lytic Eligible Double-blind Double-dummy Lytic Choice by MD (TNK, tpa, rpa, SK) Enoxaparin < 75 y: 3 mg IV bolus sc 1. mg/kg q 12h (Hosp DC) > 75 y: No bolus sc.75 mg/kg q 12h (Hosp DC) UFH bolus 6 U/kg Inf 12 U/kg/h for > 48 h Day 3 Primary Efficacy Endpoint: Death / MI Primary Safety Endpoint: TIMI Major Hemorrhage Antman EM et al. Am Heart J, 25

15 WEST Anti-Xa sub-study Results: 1 st anti-xa sample fibrinolysis arm 153 min. Total study population N=45.65 U/ml.48 U/ml 179 min. Fibrinolysis with sq enox (1mg/kg) only 875 min..42u/ml 139 min. Sub-therapeutic N=23 <.5 U/ml 157 min. 2.6 hours 186 min. 178 min. Note: all times are presented as median values Therapeutic N=21 >.5 U/ml 645 min hours 1196 min. Welsh et al, CJC (abstract), 27

16 Bivalirudin vs UFH with SK for STEMI 14 p = NS p < UFH Percent of patients p =.1 Bivalirudin p = p = Death ReMI 96 H Severe Mod Mild Bleeding Lancet 358: 1855,21

17 HORIZONS-AMI main results Stone G et al, NEJM, May 28

18 HORIZONS-AMI main results Stone G et al, NEJM, May 28

19 ATOLL Trial design Randomization as early as possible (MICU +++) Real life population (shock, cardiac arrest included) No anticoagulation and no lytic before Rx Similar antiplatelet therapy in both groups STEMI Primary PCI ENOXAPARIN IV.5 mg/kg with or without GPIIbIIIa ENOXAPARIN SC IVRS Primary PCI UFH IV 5-7 IU with GP IIbIIIa 7-1IU without GP IIbIIIa (Dose ACT-adjusted) UFH IV or SC 3 days 1 EP: Death, Complication of MI, Procedure Failure, Major Bleeding Main 2 EP: Death, recurrent MI/ACS, Urgent Revascularization

20 Primary Endpoint Death, Complication of MI, Procedure Failure or Major Bleeding 4 ts n tie a p f o % RRR = 17% P =.7 UFH ENOX 5

21 Main Secondary Endpoint (ischemic) Death, Recurrent MI/ACS or Urgent Revascularization 3d rate (%) te ra P E ry a d n o c e s in a M UFH ENOX Log-Rank Test p= % 6.7% Days

22 Death or Complication of MI Death, resuscitated cardiac arrest, recurrent MI/ACS, Urg Revasc, stroke, peripheral or pulmonary embolism 3d rate (%) te I ra M f o n tio a lic p m o C r o th a e D UFH ENOX Log-Rank Test p= % Days 7.8%

23 Death (any) Death or resuscitated cardiac arrest te r a th a e D UFH ENOX Log-Rank Test p= Days te r a t s r e a c ia rd a c d te ita c s u s r e o th a e D 3d rate (%) % % 2.. UFH ENOX Log-Rank Test p= Days

24 Main Safety Endpoint Non-CABG Major Bleeding (STEEPLE definition) ts n tie a p f o % P = NS

25 All Safety Endpoints ts n tie a p f o % P = NS for all Protocole definitions (STEEPLE)

26 Death, Complication of MI or Major bleeding 16 Net clinical benefit ts n tie a p f o % ,2 RRR = 32% P =.3 UFH ENOX 2

27 Enoxaparin vs. unfractionated heparin in patients undergoing primary PCI: Insights from a comprehensive prospective reperfusion registry of STEMI patients (VITAL HEART RESPONSE) Welsh, S Sookram, B Tyrrell, S Garg, W Tymchak, B O'Neill, N Brass

28 Results: in-hospital clinical events P=.3 Composite endpoint: death, re-mi, CHF and major bleeding requiring transfusion P=.2 P=.5 P=.4 composite endpoint adjusted for: gender, age, height, weight and diabetes

29 Antiplatelet therapy in STEMI What antiplatelet strategies have been shown to reduce mortality in STEMI patients? 1. ASA vs. no antiplatelets 2.ASA/clopidogrel vs. ASA 3.ASA/double dose clopidogrel vs ASA/clopidogrel 4.ASA/prasugrel vs. ASA/clopidogrel 5. ASA/ticagrelor vs. ASA/clopidogrel

30 % mortality ISIS-2 Reperfusion Synergy 35-day Vascular Mortality 13.2 n = 17, Placebo ASA SK ASA + SK p <.1 Treatment ASA vs placebo SK vs placebo Combination vs either ISIS-2. Lancet 1988;2:349

31 Percentage with endpoint (%) CLARITY CV Death, MI, RI Urg Revasc Clopidogrel and Fibrinolysis Placebo Clopidogrel N=3491 Odds Ratio.8 (95% CI ).97) P=.26 2% No increase in major bleeding COMMIT CV Death, re-mi, Stroke Placebo Clopidogrel N=45,852 9% (SE3) relative risk reduction (2P=.2) 9% No increase in major bleeding days Days

32 COMMIT: Effect of Clopidogrel on Death in Hospital Placebo + ASA: 1846 deaths (8.1%) Clopidogrel + ASA: 1728 deaths (7.7%) Dead (%) 7% (SE3) relative risk reduction (2P=.3) Days since randomisation (up to 28 days) Chen Z. Presentation at ACC 25; Orlando, FL; March 9, 25

33 CURRENT OASIS 7 A 2 X 2 factorial randomized trial of optimal clopidogrel and aspirin dosing in patients with ACS undergoing an early invasive strategy with intent for PCI CURRENT Study Design Patients with UA/NSTEMI or STEMI planned for early invasive strategy, i.e. intend for PCI as early as possible within 72 hrs RANDOMIZE (n=25,87) Clopidogrel High Dose Group Clopidogrel 6mg loading dose Day 1 followed by 15mg from Day 2 to Day 7; 75mg from Day 8 to 3 Clopidogrel Standard Dose Group Clopidogrel 3mg (+placebo) Day 1 followed by 75mg (+placebo) from Day 2 to Day 7; 75mg from Day 8 to 3 RANDOMIZE RANDOMIZE ASA low dose group At least 3mg Day1; 75 1mg from D2 to D3 ASA high dose group At least 3mg Day1; 3mg 325mg from D2 to D3 ASA low dose group At least 3mg Day1; 75 1mg from D2 to D3 ASA high dose group At least 3mg Day1; 3mg 325mg from D2 to D3

34 Results of the aspirin dose comparison: Efficacy and bleeding Measure Aspirin 75 1 mg Aspirin mg Hazard ratio (95% CI) Cardiovascular death, MI, and stroke (n=25 87) ( ) PCI cohort (n=17 232) ( ) No PCI cohort (n=7855) ( ) Stent thrombosis ( ) TIMI major bleed ( ) CURRENT major bleed ( ) CURRENT severe bleed ( ) CURRENT-OASIS 7 investigators, NEJM, Sept.2, 21

35 Double vs standard dose of clopidogrel: Primary outcome and components Measure (n=25 87) Standard clopidogrel therapy Double clopidogrel therapy Hazard ratio (95% CI) Cardiovascular death, MI, ( ) and stroke, overall cohort CV death ( ) MI, overall cohort ( ) Stroke (.7-1.4) Recurrent ischemia ( ) CURRENT-OASIS 7 investigators, NEJM, Sept.2, 2

36 Double vs standard dose of clopidogrel: Safety outcomes Measure (n=25 87) Standard clopidogrel therapy Double clopidogrel therapy Hazard ratio (95% CI) CURRENT major ( ) RBC transfusion 2 units ( ) CABG related ( ) Severe ( ) TIMI major ( ) CURRENT Minor ( ) CURRENT-OASIS 7 investigators, NEJM, Sept.2, 21

37 Clinical outcomes, stent thrombosis and bleeding events in PCI population Outcome Standard clopidogrel (n=8684) Double clopidogrel (n=8548) Hazard ratio (95% CI) CV death, MI, Stroke ( ) CV death ( ) MI (.64.96) Stroke ( ) Definite stent thrombosis (.42.79) TIMI major bleeding ( ) CURRENT major bleeding ( ) CURRENT severe bleeding ( ) Fatal bleeding ( ) Red blood cell transfusion 2U ( ) CABG-related major bleeding ( ) Mehta S. et al, Lancet, sept 1, online, 21

38 Clopidogrel Prasugrel Mechanism of Action Irreversible Irreversible Dosing route oral oral Onset of action 3-8 h (prodrug) 1-4 h (prodrug) Inhibition irreversible irreversible Maximum Inhibition ~4% Full Variability Selectivity Loading Dose Inhibition of Platelet Aggregation (Mean ± SEM, 2 µm ADP) Maintenance Doses Inhibition of Platelet Aggregation (%) * * * * * 6 mg * 6 mg 3 mg * * * 75 mg 1 mg * * * * Clopidogrel Clopidogrel Prasugrel *P<.1 vs Clop 3 mg 6 mg and 75 mg P <.5 vs Clop 3 mg/75 mg P <.1 vs Clop 3 mg/75 mg Time Day 1, Hours Days Jakubowski et al. Cardiovasc Drug Rev. 27;25: ADP=adenosine diphosphate Clop=clopidogrel Pras=prasugrel

39 TRITON TIMI-38 Main Trial Design Adapted from Wiviott SD, et al. Am Heart J. 26;152:

40 TRITON-TIMI 38: Follow-up Duration for Major Efficacy End Points % Risk Reduction P-value Primary Endpoint 19 <.1 CV Death Nonfatal MI 24 <.1 Nonfatal stroke -.93 All Cause Death 5.64 CV Death/Nonfatal MI/UTVR 19 <.1 All Cause Death/Nonfatal MI/ Nonfatal Stroke 17 <.1 UTVR 34 <.1 CV Death/Nonfatal MI/Nonfatal Stroke/ Rehospitalization for ischemia 16 <.1 Stent Thrombosis 52 < Prasugrel Better Clopidogrel Better ACS=Acute Coronary Syndrome; CV=Cardiovascular; HR=Hazard Ratio; MI=Myocardial Infarction; UTVR=Urgent Target Wiviott SD et al. New Engl Vessel J Revascularization Med 27;357: HR

41 % Events 4 2 Bleeding Events: Safety Cohort 1.8 Clopidogrel Prasugrel 2.4 (N=13,457) ICH in Pts w/ Prior Stroke/TIA (N=518) Clop () % Pras 6 (2.3)% (P=.2) TIMI Major Bleeds Life Threatening Nonfatal Fatal ICH ARD.6% HR 1.32 P=.3 NNH=167 ARD.5% HR 1.52 P=.1 ARD.2% P=.23 ARD.3% P=.2 ARD % P=.74

42 Patients with STEMI Efficacy of Prasugrel TRITON-TIMI 38 1 Acute ACS patients undergoing planned PCI. Prespecified analysis of STEMI patients Prasugrel (6 mg LD, 1 mg/day MD), n=1765 Clopidogrel (3 mg LD, 75 mg/day MD), n=1769 Primary Endpoint* Hazard Ration 3 Days.68 (95% CI ) p=.17 Hazard Ratio 15 Months.79 (95% CI ) p=.221 Number at risk Clopidogrel Prasugrel LD, loading dose; MD, maintenance dose. * Composite primary endpoint of death from CV causes, MI or stroke; Dotted line represents 3 days. 1. Montalescot et al. Lancet. 29;373:723-31;

43 TIMI Major Bleeding Unrelated to CABG Safety of Prasugrel vs. Clopidogrel Patients with STEMI Number at risk idogrel rasugrel TIMI major bleeding unrelated to CABG was similar in clopidogrel and prasugrel groups at 3 days and 15 months. In patients who underwent CABG (<4%) prasugrel was associated with significantly increased risk of TIMI major bleeding after CABG at 15 months, compared to clopidogrel. Dotted line represents 3 days. 1. Montalescot et al. Lancet. 29;373:

44 Ticagrelor and clopidogrel: Metabolism Ticagrelor: Orally active; does not require metabolic activation 1 Ticagrelor CYP-dependent oxidation CYP3A4/5 Binding Platelet Clopidogrel Active compound Active metabolite Intermediate metabolite Prodrug CYP-dependent oxidation CYP1A2 CYP2B6 CYP2C19 CYP-dependent oxidation CYP2C19 CYP3A4/5 CYP2B6 Clopidogrel: A produg; requires hydrolysis by esterase followed by CYP-dependent oxidation to generate active compound. 2 ADP P2Y12 recept or

45 Ticagrelor has a faster rate of offset of IPA as compared to clopidogrel in patients with stable CAD Ticagrelor IPA is similar between ticagrelor (58%) and clopidogrel (52%)

46 PLATO Study Design UA/NSTEMI (moderate-to-high risk) STEMI (if primary PCI) All receiving ASA; clopidogrel-treated or naive; randomised within 24 hours of index event (N=18,624) Clopidogrel If pre-treated, no additional loading dose; if naive, standard 3 mg loading dose, then 75 mg qd maintenance; (additional 3 mg allowed pre PCI) Ticagrelor 18 mg loading dose, then 9 mg bid maintenance; (additional 9 mg pre-pci) 6 12 month exposure Primary endpoint: CV death + MI + Stroke Key secondary: CV death + MI + Stroke in patients intended for invasive management Total mortality + MI + Stroke CV death + MI + Stroke + recurrent ischaemia + TIA + arterial thrombotic events MI alone / CV death alone / Stroke alone / Total mortality Primary safety: Total major bleeding James S, et al. Am Heart J. 29;157: UA = unstable angina; PCI = percutaneous coronary intervention; ASA = acetylsalicylic acid; CV = cardiovascular; TIA = transient ischaemic attack

47 PLATO Hierarchical Testing of Major Efficacy Endpoints All Patients* Ticagrelor (n=9,333) Clopidogrel (n=9,291) HR for ticagrelor (95% CI) P value Primary Objective, n (%/yr) CV death + MI + stroke 864 (9.8) 1,14 (11.7).84 ( ) <.1 Secondary Objectives, n (%/yr) Total death + MI + stroke 91 (1.2) 1,65 (12.3).84 ( ) <.1 CV death + MI + stroke + 1,29 (14.6) 1,456 (16.7).88 ( ) <.1 severe + recurrent ischemia + TIA + arterial thrombus MI 54 (5.8) 593 (6.9).84 ( ).5 CV death 353 (4.) 442 (5.1).79 ( ).1 Stroke 125 (1.5) 16 (1.3) 1.17 ( ).22 Total Death 399 (4.5) 56 (5.9).78 ( ) <.1 *The percentages are K-M estimates of the rate of the endpoint at 12 months. Patients could have had more than one type of endpoint. Death from CV causes and fatal bleeding, as only traumatic fatal bleeds were excluded from the CV death category. By Cox regression analysis using treatment as factor. CV=cardiovascular; MI=myocardial infarction; yr=year; HR=hazard ratio; CI=confidence intervals; K-M=Kaplan-Meier; TIA=transient ischemic attack Wallentin L, et al.new Engl J Med. 29;361.

48 K-M estimated rate (% per year) PLATO Non-CABG and CABG-related Major Bleeding p= p= NS Ticagrelor Clopidogrel NS 5.8 For patients requiring CABG recommended that the study drug be withheld clopidogrel group, for 5 days, and in the ticagrelor group, for 24 to 72 hours Non-CABG PLATO major bleeding Non-CABG TIMI major bleeding CABG PLATO major bleeding CABG TIMI major bleeding NS = not significant; K-M=Kaplan-Meier; CABG=coronary-artery bypass grafting Wallentin L, et al.new Engl J Med. 29;361.

49 Patients with STEMI Efficacy of Ticagrelor PLATO 2 Acute ACS patients Subgroup analysis of STEMI patients Ticagrelor (18 mg LD, 1 mg/day MD BID), n=3752 Clopidogrel (3 mg LD, 75 mg/day MD), n=3792 Primary Endpoint* Hazard Ratio.87 (95% CI ) p=.7 Number at risk Clopidogrel Ticagrelor LD, loading dose; MD, maintenance dose. * Composite primary endpoint of death from CV causes, MI or stroke; Dotted line represents 3 days.. Steg et al. Circulation. 21;122:

50 Safety of Ticagrelor vs. Clopidogrel Patients with STEMI Major bleeding and TIMI bleeding were similar in the clopidogrel and ticagrelor groups. *TIMI bleeding rates were calculated, not adjudicated; Primary safety endpoint,. 1. Steg et al. Circulation. 21;122:

51 Vital Heart Response Regional reperfusion protocol Pharmacological reperfusion ASA, clopidogrel, enoxaparin and TNK Adjusted for age >75 (clopid and enox) Mechanical reperfusion Ambulance protocol ASA, clopidogrel (6 mg), enoxaparin (IV 3 mg & SQ 1 mg/kg) GP IIb/IIIa in cath lab In-hospital protocol ASA, clopidogrel (3-6 mg), UFH 7 U/kg/bivalirudin/enoxaparin GP IIb/IIIa in cath lab

52 . Canadian Cardiovascular Society Working Group: Providing a perspective on the 27 focused update of the American College of Cardiology and American Heart Association 24 guidelines for the management of ST elevation myocardial infarction. with the exception of aspirin, both nonselective and cyclooxygenase-2 selective nonsteroidal antiinflammatory drugs have been associated with increased risk of mortality, reinfarction, hypertension, heart failure, and myocardial rupture 3. Therefore, patients that present with STEMI who are routinely taking nonsteroidal anti-inflammatory agents should have these drugs discontinued immediately and for those requiring ongoing therapy for pain aspirin and/or morphine sulfate are appropriate alternatives. Welsh et al, Can J Cardiol. 29 Jan;25(1):25-32.

53 . Canadian Cardiovascular Society Working Group: Providing a perspective on the 27 focused update of the American College of Cardiology and American Heart Association 24 guidelines for the management of ST elevation myocardial infarction. Early aggressive beta blocker therapy (intravenous and oral) was not associated with clinical benefit but was actually associated with increased risk when delivered to a broad spectrum of STEMI patients within the ClOpidogrel and Metoprolol in Myocardial Infarction Trial (COMMIT II) 4. Evidence still supports the administration of oral beta blocker therapies initiated within the first 24 hours in patients who do not have signs of heart failure, low output states, increased risk for cardiogenic shock, or other relative contraindications for beta blockers (first, second, or third degree heart block, active asthma, or reactive airway disease). Welsh et al, Can J Cardiol. 29 Jan;25(1):25-32.

54 . Canadian Cardiovascular Society Working Group: Providing a perspective on the 27 focused update of the American College of Cardiology and American Heart Association 24 guidelines for the management of ST elevation myocardial infarction. Beta blockers should be initiated at low to moderate doses and titrated consistent with patient stability, heart rate and blood pressure response. Intravenous beta-blockers maintain clinical utility in selected patient populations, especially those with ongoing myocardial ischemia associated with significant hypertension and in the absence of high-risk features for congestive heart failure or cardiogenic shock. Welsh et al, Can J Cardiol. 29 Jan;25(1):25-32.

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56 STEMI Oct. 31, 211 Core Curriculum Adjunctive/Conjunctive pharmacological therapy Robert C. Welsh, MD, FRCPC Associate Professor, University of Alberta Director, Adult Cardiac Catheterization and Interventional Cardiology Co-Director, University of Alberta Chest Pain Program Co-Chair, Vital Heart Response