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

2. 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

3. 2008
2010 3

4. Patient Oriented Therapy for STE-MI
M. Cohen et al. JACC :

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

6. 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 minutes of FMC
should be tretated with Fibrinolytic therapy (FLT) within 30 minutes of hospital presentation as a system goal unless FLT is contraindicated

7. STE-AMI : Reperfusion Therapy
(2008)

8. 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

9. Primary PCI vs Fibrinolysis Time dependant benefit
NRMI
(National Registry of Myocardial Infarction)
patient
Primary PCI related delay (min) (Door-Balloon – Door- Needle)
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:

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

11. 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

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

13. 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”

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

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

16. 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”

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
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 ( )
Di Mario et al. Lancet 2008;371. 17

18. 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% ( )
ACC/2008
N Engl J Med 2009;360:

19. 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: 19

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

21. Fibrinolytic, ASA, Heparin 30-day clinical follow-up
Clopidogrel in STEMI
Double-blind, randomized, placebo-controlled trial in 3491 patients, age 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

22. Clopidogrel in STEMI 36%  P<0.0001 Placebo 20% Clopidogrel15
36% 
P<0.0001
Placebo
20% 10
Clopidogrel
CV Death, MI, or Urg Revasc (%) 5
Odds Ratio 0.80
(95% CI )
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

23. 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 )
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:

24. 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.

25. Fibrinolytic Therapy – Secondary PCI “Clopidogrel pretreatment”

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

27. TRITON-TIMI 38 : Main study cohort
Wiviott et al. New Engl J Med 2007;357: 5 10 15 30 60 90
180
270
360
450
HR 0.81
( )
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

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

29. 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 ( )
30 days
Montalescot et al. ESC 2008 29

30. 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

31. 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

32. 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

33. 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

34. PLATO STEMI Primary endpoint: CV death, MI or stroke 11.0 9.3 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)

35. K-M estimated rate (% per year)
PLATO STEMI
K-M estimated rate (% per year) 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

36. 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

37. 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

38. Patient Oriented Therapy for 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) vs Standard dose (300 mg) then 75 mg/d)
ASA: High Dose ( mg/d) vs Low dose ( 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 d d d
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. 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
0.036
0.016
No PCI (2N=7855)
4.2
4.9
1.17
0.14
Overall (2N=25,087)
4.4
0.95
0.370 MI
2.6
2.0
0.78
0.012
0.025
1.4
1.7
1.25
0.23
2.2
1.9
0.86
0.097
CV Death
0.96
0.68
1.0
2.8
2.7
0.77
2.1
0.628
Stroke
0.4
0.88
0.59
0.50
0.8
0.9
1.11
0.67
0.5
0.99
0.950

41. 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
P=0.036
0.01
0.0 3 6 9 12 15 18 21 24 27 30
Days

42. 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

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

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):