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Patient Oriented Therapy for STE-MI

Patient Oriented Therapy for STE-MI. Seçkin Pehlivanoğlu, MD Başkent University, İstanbul Hospital. Patient Oriented Therapy for STE-MI. Diagnostic level Prognostic level (risk stratification) Therapeutic level.

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Patient Oriented Therapy for STE-MI

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  1. Patient Oriented TherapyforSTE-MI Seçkin Pehlivanoğlu, MD Başkent University, İstanbul Hospital

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

  3. 2008 2010

  4. PatientOrientedTherapyfor STE-MI M. Cohen et al. JACC 2010 55: 1895-1906

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

  6. I I I I I I IIa IIa IIa IIa IIa IIa IIa IIa IIb IIb IIb IIb IIb IIb IIb IIb III III III III III III III III I I I I I I IIa IIa IIa IIa IIa IIa IIa IIa IIb IIb IIb IIb IIb IIb IIb IIb III III III III III III III III I I I I I I IIa IIa IIa IIa IIa IIa IIa IIa IIb IIb IIb IIb IIb IIb IIb IIb III III III III III III III III B A STE-AMI : ReperfusionTherapy (2007) STEMI patientspresentingto a hospitalwith PCI capability should be treatedwithPrimary PCI within 90 minutes of firstmedicalcontact (FMC) STEMI patientspresentingto a hospitalwithout PCI capability andwhocannot be transferedto a PCI centerandundergo PCI within 90 minutes of FMC should be tretatedwithFibrinolytictherapy (FLT) within 30 minutes of hospitalpresentationas a systemgoalunless FLT is contraindicated

  7. STE-AMI : ReperfusionTherapy (2008)

  8. Primary PCIvsFibrinolysisTime dependantbenefit • 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

  9. PCI better 2.0 1.5 1.25 Odds of Death with Fibrinolysis 1.0 Fibrinolysis Better 0.8 0.5 60 75 90 105 114 135 150 165 180 Primary PCI related delay (min) (Door-Balloon – Door- Needle) Primary PCIvsFibrinolysisTime dependantbenefit NRMI (NationalRegistry of MyocardialInfarction) 192 509 patient Conclusions—As DB-DN timesincrease, themortalityadvantage of PPCI overfibrinolysisdeclines, andthisadvantage variesconsiderablydepending on patientcharacteristics. Circulation. 2006;114:2019-2025

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

  11. What has changedwithPrimary PCI patients? Percent of PPCI patiens of DBT<90 min Analysisaccordingtothe transfer status NRMI 2 NRMI 3 NRMI 4 NRMI 5 %52.6 Not Transfered %34.3 Patients (%) Transfered %9.0 %3.7 Discharged year

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

  13. Choice of Reperfusion Therapy Primary PCIvsFLT Patient Oriented Therapyfor STE-MI 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”

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

  15. STE-AMI :“Triage and Transfer for PCI”

  16. STE-AMI :Pharmacoinvasivestrategy 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”

  17. 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 10.7% • 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 4.4% HR=0.40 (0.21-0.76) Di Mario et al. Lancet 2008;371. 17

  18. 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% Cumulative Incidence 11.0% p=0.004 RR= 0.64, 95 CI% (0.47-0.87) Days ACC/2008 N Engl J Med 2009;360:2705-18

  19. STE-AMI :“Triage andTransfer 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 12 h Benefit 24 h Benefit >3 h Benefit No Benefit Hours Harvey White; Circulation 2008;118:219-222

  20. Patient Oriented Therapyfor STE-MI Fibrinolytic Therapy – Secondary PCI “Clopidogrel pretreatment”

  21. Clopidogrel in STEMI Double-blind, randomized, placebo-controlled trial in3491 patients, age 18-75 yrs with STEMI < 12 hours Fibrinolytic, ASA, Heparin randomize Placebo Clopidogrel 300 mg + 75 mg qd Study Drug Primary endpoint: Occludedartery (TIMI Flow Grade 0/1) or D/MI by timeof angio Coronary Angiogram (2-8 days) Open-label clopidogrel per MD inboth groups 30-day clinical follow-up Sabatine MS et al. NEJM 2005; 352

  22. Clopidogrel in STEMI 15 36%  P<0.0001 Placebo 20% Clopidogrel 10 CV Death, MI, or Urg Revasc (%) 5 Odds Ratio 0.80 (95% CI 0.65-0.97) P=0.026 0 Clopidogrel Placebo 0 5 10 15 20 25 30 days Coronary Angiogram (2-8 days) Sabatine MS et al. NEJM 2005; 352: 1179

  23. CV Death, MI, or StrokefollowingPCI 46% Clopidogrel – 3.6% Pretreatment Clopidogrel in STEMI PCI-CLARITY 8 Odds Ratio 0.54 (95% CI 0.35-0.85) P=0.008 No Pretreatment – 6.2% 6 Percentage with outcome (%) 4 2 0 0 10 20 30 Days post PCI Sabatine MS et al. JAMA 2005;294:1224-32

  24. 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 0 7 6 5 4 3 2 1 0 Clopidogrel (7.5%) Clopidogrel (9.3%) 9% relative risk reduction (P=.002) 7% relative risk reduction (P=.03) Mortality (%) Death, MI, Stroke (%) 0 7 14 21 28 0 7 14 21 28 Days Days COMMIT Collaborative Group. Lancet. 2005;366:1607.

  25. Fibrinolytic Therapy – Secondary PCI “Clopidogrel pretreatment”

  26. Patient Oriented Therapyfor STE-MI “Adjunctive Antiplatelet Therapy” Clopidorel vs Prasugrel /Ticagrelor

  27. TRITON-TIMI 38 :Main study cohort 15 12.1 Clopidogrel 9.9 10 P<0.001 Prasugrel CV Death, MI, Stroke (%) 5 HR 0.81 (0.73-0.90) NNT= 46 0 0 30 60 90 180 270 360 450 Days Wiviott et al. New Engl J Med 2007;357:2001-2015 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

  28. 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 Clopidogrel N=530 Prasugrel N=564 Montalescot et al. ESC 2008

  29. Clopidogrel Prasugrel 15 12.4 p=0.02 RRR=21% 10.0 10 9.5 p=0.002 RRR=32% Proportion of patients (%) 6.5 5 HR=0.79 (0.65–0.97) NNT=42 0 Age-adjusted HR=0.81 (0.66-0.99) 0 50 100 150 200 250 300 350 400 450 Time (Days) TRITON-TIMI 38 :STEMI TRITON-TIMI 38 :STEMI Primary EP (CV death, MI and stroke at 15 months) 30 days Montalescot et al. ESC 2008

  30. Clopidogrel Prasugrel p= 0.002 10 p= 0.004 p= 0.02 8 p= 0.01 6 Proportion of population (%) 4 p= 0.008 p= 0.04 p= 0.13 2 0 All Death MI UTVR Stent Thrombosis* CV Death/MI CV Death/ MI/UTVR CV Death/ MI/Stroke * ARC def/probable TRITON-TIMI 38 :STEMI TRITON-TIMI 38 :STEMI Efficacy endpoints at 30 days Montalescot et al. ESC 2008

  31. 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 Conclusions In STEMI patients undergoing PCI TRITON-TIMI 38 :STEMI TRITON-TIMI 38 :STEMI These data make prasugrel an especially attractive alternative to clopidogrel in PCI for STEMI Montalescot et al ESC 2008

  32. STE-AMI : AdjunctiveAntiplateletTherapy (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

  33. 134 patients not randomized 18,624 patients randomized NSTEMI/UA/other: 10,194 patients PLATOSTEMI 18,758 patients enrolled in PLATO 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=4,181 Safety population N=4,165

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

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

  36. PLATOSTEMI Hierarchical testing of major efficacy endpoints

  37. PLATOSTEMI Conclusions • Reversible, more intense P2Y12 receptor inhibition for one year with ticagrelorin 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

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

  39. 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) vsStandard dose (300 mg) then 75 mg/d) ASA: High Dose (300-325 mg/d) vsLow dose (75-100 mg/d) Angio 24,769 (99%) PCI 17,232 (70%) No PCI 7,855 (30%) CABG 1,809 CAD 2,430 No Sig. CAD 3,616 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

  40. Clopidogrel: Double vs Standard Dose Primary Outcome: PCI vs No-PCI

  41. 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 0 3 6 9 12 15 18 21 24 27 30 Days

  42. Comparison of CURRENT and TRITON

  43. STE-AMI : Adjunctive Antiplatelet Therapy (2010)

  44. 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): No spesific recommendation for STE-MI

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