Patient Oriented Therapy for STE-MI Seçkin Pehlivanoğlu, MD Başkent University, İstanbul Hospital

Patient Oriented Therapy for STE-MI Q: What are the spesific conditions that will make a difference with individual patient’s treatmet ? Diagnostic level Prognostic level (risk stratification) Therapeutic level

2008 2010 3

Patient Oriented Therapy for STE-MI M. Cohen et al. JACC 2010 55: 1895-1906

Patient Oriented Therapy for STE-MI Choice of Reperfusion Therapy Primary PCI vs FLT Acceptable time-window for PPCI ?

STE-AMI : Reperfusion Therapy (2007) STEMI patients presenting to a hospital with PCI capability should be treated with Primary PCI within 90 minutes of first medical contact (FMC) I IIa IIb III A I IIa IIb III B STEMI patients presenting to a hospital without PCI capability and who cannot be transfered to a PCI center and undergo PCI within 90 minutes of FMC should be tretated with Fibrinolytic therapy (FLT) within 30 minutes of hospital presentation as a system goal unless FLT is contraindicated

STE-AMI : Reperfusion Therapy (2008)

Primary PCI vs Fibrinolysis Time dependant benefit Meta-analysis of 23 trials of 1ry PCI vs fibrinolysis relating 4-6 week death difference to PCI-related time delay. Mortality benefit of Primary PCI may be lost if door-to-balloon time is delayed by >60 min compared with door-to-needle time Am J Cardiol 2003; 92:824

Primary PCI vs Fibrinolysis Time dependant benefit NRMI (National Registry of Myocardial Infarction) 192 509 patient Primary PCI related delay (min) (Door-Balloon – Door- Needle) 60 75 90 105 114 135 150 165 180 2.0 1.5 1.25 1.0 0.8 0.5 PCI better Fibrinolysis Better Odds of Death with Fibrinolysis Conclusions—As DB-DN times increase, the mortality advantage of PPCI over fibrinolysis declines, and this advantage varies considerably depending on patient characteristics. Circulation. 2006;114:2019-2025

Time to Reperfusion - Mortality In hospital mortality (%) Circulation. 2006;113:2398-2405 10

What has changed with Primary PCI patients? Percent of PPCI patiens of DBT<90 min Analysis according to the transfer status NRMI 2 NRMI 3 NRMI 4 NRMI 5 %52.6 Not Transfered %34.3 Patients (%) Transfered %9.0 %3.7 Discharged year 11

Untimely reperfusion (after hospital presentation): Fibrinolytic therapy > 30 min (54%) Primary PCI > 90 min (68%) JAMA 2010; 303(21):2148-2155

Patient Oriented Therapy for STE-MI Choice of Reperfusion Therapy Primary PCI vs FLT Regardless of the mode of the therapy, primary goal should be to “minimize total ischemic time”; time from onset of symptoms to initiation of reperfusion therapy “TIMELY REPERFUSION”

Fibrinolytic Therapy – Secondary PCI “Triage and Transfer for PCI” Patient Oriented Therapy for STE-MI Fibrinolytic Therapy – Secondary PCI “Triage and Transfer for PCI”

STE-AMI : “Triage and Transfer for PCI”

STE-AMI : Pharmacoinvasive strategy The high risk patients who receive FLT as a primary reperfusion therapy at a non-PCI hospital can be transfered to a PCI-hospital inorder to perform PCI as a part of “pharmacoinvasive strategy”

CARESS-IN-AMI primary outcome :composite of all cause mortality, reinfarction, & refractory MI within 30 days Non-PCI hospital: half-dose lytic (reteplase) + abciximab + UFH High risk STEMI (<12 hours) With one or more high-risk features: extensive ST-segment elevation new-onset left bundle branch block previous MI Killip class >2, or left ventricular ejection fraction <35% for inferior MIs; Anterior MI alone with 2 mm or more ST-elevation in 2 or more leads 10.7% 4.4% HR=0.40 (0.21-0.76) Di Mario et al. Lancet 2008;371. 17

or worsening CHF, or shock within 30 days primary end point: composite of death, reinfarction, recurrent ischemia, new or worsening CHF, or shock within 30 days Non-PCI hospital: TNK + ASA + Heparin / Enoxaparin + Clopidogrel High risk STEMI (<12 hours) ANTERIOR MI ≥ 2 mm ST-segment elevation in 2 anterior leads INFERIOR MI ≥ 1 mm ST-segment elevation in 2 inferior leads and at least one of the following: SBP < 100 HR > 100 Killip Class II-III ≥ 2mm ST-segment depression in anterior leads ≥ 1 mm ST-segment elevation in V4R 17.2% 11.0% Cumulative Incidence Days p=0.004 RR= 0.64, 95 CI% (0.47-0.87) ACC/2008 N Engl J Med 2009;360:2705-18

Faciliated PCI   Pharmacoinvasive strategy STE-AMI : “Triage and Transfer for PCI” Faciliated PCI   Pharmacoinvasive strategy Fibrinolytic therapy Rescue PCI Faciliated PCI Risc of Death Systematic PCI Late PCI for occluded IRA Benefit 0-3 h Harm >3 h Benefit 12 h Benefit 24 h Benefit No Benefit Hours Harvey White; Circulation 2008;118:219-222 19

Fibrinolytic Therapy – Secondary PCI “Clopidogrel pretreatment” Patient Oriented Therapy for STE-MI Fibrinolytic Therapy – Secondary PCI “Clopidogrel pretreatment”

Fibrinolytic, ASA, Heparin 30-day clinical follow-up Clopidogrel in STEMI Double-blind, randomized, placebo-controlled trial in 3491 patients, age 18-75 yrs with STEMI < 12 hours Fibrinolytic, ASA, Heparin randomize Placebo Clopidogrel 300 mg + 75 mg qd Study Drug Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio Coronary Angiogram (2-8 days) Open-label clopidogrel per MD in both groups 30-day clinical follow-up Sabatine MS et al. NEJM 2005; 352

Clopidogrel in STEMI 36%  P<0.0001 Placebo 20% Clopidogrel 15 36%  P<0.0001 Placebo 20% 10 Clopidogrel CV Death, MI, or Urg Revasc (%) 5 Odds Ratio 0.80 (95% CI 0.65-0.97) P=0.026 Clopidogrel Placebo 5 10 15 20 25 30 days Coronary Angiogram (2-8 days) Sabatine MS et al. NEJM 2005; 352: 1179

CV Death, MI, or Stroke following PCI Clopidogrel in STEMI PCI-CLARITY CV Death, MI, or Stroke following PCI 8 Odds Ratio 0.54 (95% CI 0.35-0.85) P=0.008 No Pretreatment – 6.2% 6 46% Percentage with outcome (%) 4 Clopidogrel – 3.6% Pretreatment 2 10 20 30 Days post PCI Sabatine MS et al. JAMA 2005;294:1224-32

45,851 Patients STEMI w/in 24 hrs; ASA; lytic therapy (~1/2) Clopidogrel in STEMI 45,851 Patients STEMI w/in 24 hrs; ASA; lytic therapy (~1/2) Placebo (10.1%) Placebo (8.1%) 9 8 7 6 5 4 3 2 1 7 6 5 4 3 2 1 Clopidogrel (9.3%) Clopidogrel (7.5%) Death, MI, Stroke (%) 9% relative risk reduction (P=.002) Mortality (%) 7% relative risk reduction (P=.03) 7 14 21 28 7 14 21 28 Days Days COMMIT Collaborative Group. Lancet. 2005;366:1607.

Fibrinolytic Therapy – Secondary PCI “Clopidogrel pretreatment”

“Adjunctive Antiplatelet Therapy” Clopidorel vs Prasugrel /Ticagrelor Patient Oriented Therapy for STE-MI “Adjunctive Antiplatelet Therapy” Clopidorel vs Prasugrel /Ticagrelor

TRITON-TIMI 38 : Main study cohort Wiviott et al. New Engl J Med 2007;357:2001-2015 5 10 15 30 60 90 180 270 360 450 HR 0.81 (0.73-0.90) Days CV Death, MI, Stroke (%) 12.1 9.9 NNT= 46 Prasugrel Clopidogrel P<0.001 P=0.002 P=0.03 P=0.01 TRITON allowed recruitment of STEMI patients undergoing primary PCI when they presented < 12 hours of symptom onset or secondary PCI when they presented late 27

Clopidogrel Under Fire: Is Prasugrel in Primary PCI or Recent MI Superior? Insights From TRITON-TIMI-38 Gilles Montalescot, Stephen D. Wiviott, Eugene Braunwald, Sabina A. Murphy, C. Michael Gibson, Carolyn H. McCabe and Elliott M. Antman, for the TRITON–TIMI 38 Investigators All ACS/PCI patients N=13608 UA/NSTEMI patients N=10074 STEMI patients N=3534 Primary PCI N=2438 (69%) Secondary PCI N=1094 (31%)* Clopidogrel N=1235 Prasugrel N=1203 N=530 N=564 Montalescot et al. ESC 2008 28

TRITON-TIMI 38 : STEMI TRITON-TIMI 38 : STEMI Primary EP (CV death, MI and stroke at 15 months) Time (Days) 5 10 15 50 100 150 200 250 300 350 400 450 Proportion of patients (%) 9.5 6.5 12.4 10.0 HR=0.79 (0.65–0.97) NNT=42 p=0.02 RRR=21% p=0.002 RRR=32% Clopidogrel Prasugrel Age-adjusted HR=0.81 (0.66-0.99) 30 days Montalescot et al. ESC 2008 29

Proportion of population (%) TRITON-TIMI 38 : STEMI TRITON-TIMI 38 : STEMI Efficacy endpoints at 30 days * ARC def/probable 2 4 6 8 10 All Death MI UTVR Stent Thrombosis* CV Death/ MI CV Death/ MI/UTVR MI/Stroke Proportion of population (%) p= 0.04 p= 0.01 p= 0.13 p= 0.008 p= 0.004 p= 0.02 p= 0.002 Clopidogrel Prasugrel Montalescot et al. ESC 2008 30

Conclusions In STEMI patients undergoing PCI TRITON-TIMI 38 : STEMI TRITON-TIMI 38 : STEMI Conclusions In STEMI patients undergoing PCI Prasugrel was superior to standard dose clopidogrel to prevent ischaemic events Prasugrel did not have more bleeding events compared to those who were treated with clopidogrel, and this was equally true for: Primary PCI Secondary PCI Major bleeding Minor bleeding These data make prasugrel an especially attractive alternative to clopidogrel in PCI for STEMI Montalescot et al ESC 2008 31

STE-AMI : Adjunctive Antiplatelet Therapy (2009) Choice of Thienopyridine for PCI in STEMI: Prasugrel is not not endorsed explicitly over Clopidogrel - Benefit is predominantly by reduction in non-fatal MI (Death & nonfatal stroke similar + increased hemorraghic risk) - Loading dose of Cloidogrel (300 mg – TRINITON TIMI 38) was lower tha currently recommended doses

PLATO STEMI STEMI 8,430 pts 18,758 patients enrolled in PLATO 134 patients not randomized 18,624 patients randomized NSTEMI/UA/other: 10,194 patients STEMI 8,430 pts Randomized to ticagrelor: efficacy population N= 4,201 Randomized to clopidogrel: efficacy population N= 4,229 No intake of study medication: 36 patients No intake of study medication: 48 patients Safety population N=4,165 Safety population N=4,181 33 33

PLATO STEMI Primary endpoint: CV death, MI or stroke 11.0 9.3 0 1 2 3 4 5 6 7 8 9 10 11 12 12 11 10 9 8 7 6 5 4 3 2 1 Months HR: 0.85 (95% CI = 0.74–0.97), p=0.02 No. at risk Clopidogrel Ticagrelor 4,229 4,201 3,892 3,887 3,823 3,834 3,730 3,022 3,011 2,333 2,297 1,868 1,891 3,732 11.0 9.3 K-M estimated rate (% per year)

K-M estimated rate (% per year) PLATO STEMI K-M estimated rate (% per year) 0 1 2 3 4 5 6 7 8 9 10 11 12 10 8 6 4 2 Months Clopidogrel Ticagrelor 9.0 9.3 Primary safety event: major bleeding HR 0.96 (95% CI = 0.83–1.12), p=0.63

PLATO STEMI Hierarchical testing of major efficacy endpoints Endpoint* Ticagrelor (n=4,201) Clopidogrel (n=4,229) HR for ticagrelor (95% CI) p-value† Primary endpoint, % CV death + MI + stroke 9.3 11.0 0.85 (0.74–0.97) 0.02 Secondary endpoints, % Total death + MI + stroke CV death + MI + stroke + ischaemia + TIA + arterial thrombotic events MI CV death Stroke 9.7 13.4 4.7 4.5 1.6 11.5 15.4 6.1 5.4 1.0 0.84 (0.73–0.96) 0.86 (0.76–0.96) 0.77 (0.63–0.93) 0.84 (0.69–1.03) 1.45 (0.98–2.17) 0.01 0.09 0.07 All-cause mortality 4.9 6.0 0.82 (0.68–0.99) 0.04 36 36

PLATO STEMI Conclusions Reversible, more intense P2Y12 receptor inhibition for one year with ticagrelor in comparison with clopidogrel in patients with STEMI intended for reperfusion with primary PCI provides Reduction in composite of CV death, MI or stroke Reduction in MI and stent thrombosis Reduction in total mortality No increase in the risk of major bleeding The mortality reduction is afforded on top of modern care Ticagrelor may become a new standard of care for the management of patients with STEMI intended for primary PCI 37 37

Patient Oriented Therapy for STE-MI “Adjunctive Antiplatelet Therapy” Clopidogrel: Double dose vs Standart dose

Clopidogrel: Double vs Standard Dose 25,087 ACS Patients (UA/NSTEMI 70.8%, STEMI 29.2% ) Planned Early (<24 h) Invasive Management with intended PCI Ischemic ECG Δ (80.8%) or ↑cardiac biomarker (42%) Randomized to receive (2 X 2 factorial): CLOPIDOGREL: Double-dose (600 mg then150 mg/d x 7d then 75 mg/d) vs Standard dose (300 mg) then 75 mg/d) ASA: High Dose (300-325 mg/d) vs Low dose (75-100 mg/d) Angio 24,769 (99%) PCI 17,232 (70%) No PCI 7,855 (30%) No Sig. CAD 3,616 CABG 1,809 CAD 2,430 Compliance: Clop in 1st 7d (median) 7d 7 d 2 d 7d Complete Followup 99.8% Efficacy Outcomes: CV Death, MI or stroke at day 30 Stent Thrombosis at day 30 Safety Outcomes: Bleeding (CURRENT defined Major/Severe and TIMI Major) Key Subgroup: PCI v No PCI

Primary Outcome: PCI vs No-PCI Clopidogrel: Double vs Standard Dose Primary Outcome: PCI vs No-PCI Standard Double HR 95% CI P Intn P CV Death/MI/Stroke PCI (2N=17,232) 4.5 3.9 0.85 0.74-0.99 0.036 0.016 No PCI (2N=7855) 4.2 4.9 1.17 0.95-1.44 0.14 Overall (2N=25,087) 4.4 0.95 0.84-1.07 0.370 MI 2.6 2.0 0.78 0.64-0.95 0.012 0.025 1.4 1.7 1.25 0.87-1.79 0.23 2.2 1.9 0.86 0.73-1.03 0.097 CV Death 0.96 0.77-1.19 0.68 1.0 2.8 2.7 0.74-1.26 0.77 2.1 0.81-1.14 0.628 Stroke 0.4 0.88 0.55-1.41 0.59 0.50 0.8 0.9 1.11 0.68-1.82 0.67 0.5 0.99 0.70-1.39 0.950

Primary Outcome: PCI Patients Clopidogrel: Double vs Standard Dose Primary Outcome: PCI Patients CV Death, MI or Stroke Clopidogrel Standard 15% RRR 0.04 Clopidogrel Double 0.03 Cumulative Hazard 0.02 HR 0.85 95% CI 0.74-0.99 P=0.036 0.01 0.0 3 6 9 12 15 18 21 24 27 30 Days

Comparison of CURRENT and TRITON CURRENT PCI N=17,232 TRITON N=13,608 CV Death, MI or Stroke ↓ 15% ↓ 21% (w high dose ASA) ↓ 19% Definite Stent Thrombosis ↓ 42% ↓ 51% (w high dose ASA) ↓ 58% TIMI Major Bleed No increase ↑ 32% CABG-related Bleeding ↑ 4-fold Fatal bleeding

STE-AMI : Adjunctive Antiplatelet Therapy (2010) 43

STE-AMI : Adjunctive Antiplatelet Therapy (2011) Clopidogrel: Class I-B (PCI) 600 mg loading dose now recommended No spesific recommendation for STE-MI GP IIb/IIIa inhibitor : Class II-A May be most appropriate with large anterior MI and/or large thrombus burden IC abciximab (Class IIb-B) Precatheterization lab. GPI administration (Class III-no benefit) Antithrombin agents (UFH-Bivaluridine-Enoxaparine):