Patient Oriented Therapyfor 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 ?
1) Diagnostic level
2) Prognostic level (risk stratification)
3) Therapeutic level
2008
2010
M. Cohen et al. JACC 2010 55: 1895-1906
Patient Oriented Therapy for STE-MI
Patient Oriented Therapy for STE-MI
Choice of Reperfusion Therapy
Primary PCI vs FLT
Acceptable time-window for PPCI ?
STE-AMI : STE-AMI : Reperfusion TherapyReperfusion Therapy(2007)(2007)
STEMI patients presenting to a hospital with PCI capability
should be treated with Primary PCI
within 90 minutes of first medical contact (FMC)
III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII
III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIIISTEMI 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 : STE-AMI : Reperfusion TherapyReperfusion Therapy(2008)(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.
Am J Cardiol 2003; 92:824
Mortality benefit of Primary PCI may be lost if door-to-balloon time is delayed by >60 min compared with door-to-needle time
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 18060 75 90 105 114 135 150 165 180
2.02.0
1.51.5
1.251.25
1.01.0
0.80.8
0.50.5
PC
I bet
ter
Fib
rin
oly
sis
Be
tte
r
Od
ds
of
Dea
th w
ith
Fib
rin
oly
sis
Primary PCI vs FibrinolysisTime dependant benefit
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
Circulation. 2006;113:2398-2405
In hospital
mortality (%)
Time to Reperfusion - Mortality
Pa
tient
s (%
) What has changed with Primary PCI patients?
Percent of PPCI patiens of DBT<90 min Analysis according to the transfer status
What has changed with Primary PCI patients?Percent of PPCI patiens of DBT<90 min Analysis according to the transfer status
0
10
20
30
40
50
60
1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005
%34.3
%52.6
Discharged year
%3.7%9.0
Not Transfered
Transfered
NRMI 2NRMI 2 NRMI 3NRMI 3 NRMI 4NRMI 4 NRMI 5NRMI 5
Untimely reperfusion (after hospital presentation): - Fibrinolytic therapy > 30 min (54%)- Primary PCI > 90 min (68%)
Untimely reperfusion (after hospital presentation): - Fibrinolytic therapy > 30 min (54%)- Primary PCI > 90 min (68%)
JAMA 2010; 303(21):2148-2155JAMA 2010; 303(21):2148-2155
Patient Oriented Therapy for 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”
Choice of Reperfusion Therapy
Primary PCI vs FLT
Patient Oriented Therapy for STE-MI
Fibrinolytic Therapy – Secondary PCI
““Triage Triage and and Transfer for PCITransfer for PCI””
STE-AMI :STE-AMI : ““Triage Triage and and Transfer for PCITransfer for PCI””
STE-AMI :STE-AMI : Pharmacoinvasive strategyPharmacoinvasive 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-AMIprimary outcome :composite of all cause mortality, reinfarction, & refractory MI within 30 days
10.7%
4.4%
HR=0.40 (0.21-0.76)
Di Mario et al. Lancet 2008;371.
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
Non-PCI hospital: Non-PCI hospital: half-dose lytic (reteplase) + abciximab + UFH
17.2%
11.0%
Cumulative
Incidence
Days
p=0.004
RR= 0.64, 95 CI% (0.47-0.87)
ACC/2008N Engl J Med 2009;360:2705-18
primary end point: composite of death, reinfarction, recurrent ischemia, newor worsening CHF, or shock within 30 days
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
Non-PCI hospital: Non-PCI hospital: TNK + ASA TNK + ASA + Heparin / + Heparin / Enoxaparin + ClopidogrelEnoxaparin + Clopidogrel
Benefit 0-3 hHarm
>3 hBenefit
12 hBenefit
24 hBenefit
Hours
Risc ofDeath
Fibrinolytic therapy
Rescue PCI
Faciliated PCI
Systematic PCI
Late PCI for occluded IRA
Harvey White; Circulation 2008;118:219-222
Faciliated PCI Pharmacoinvasive strategy
No Benefit
STE-AMI :STE-AMI : ““Triage Triage and and Transfer for PCITransfer for PCI” ”
Patient Oriented Therapy for STE-MI
Fibrinolytic Therapy – Secondary PCI
““Clopidogrel pretreatment”Clopidogrel pretreatment”
Clopidogrel in STEMI
Fibrinolytic, ASA, Heparin
Clopidogrel300 mg + 75 mg qd
Coronary Angiogram(2-8 days)
Primary endpoint:Occludedartery (TIMI Flow Grade 0/1)or D/MI by timeof angio
randomize
Placebo
Double-blind, randomized, placebo-controlled trial in3491 patients, age 18-75 yrs with STEMI < 12 hours
StudyDrug
30-day clinical follow-up
Open-labelclopidogrelper MD in
both groupsSabatine MS et al. NEJM 2005; 352
15,0
21,7
0
5
10
15
20
25
Oc
clu
de
d A
rte
ry o
r D
ea
th/M
I (
%)
PlaceboPlaceboClopidogrelClopidogrel
36% P<0.0001
36% P<0.0001
Sabatine MS et al. NEJM 2005; 352: 1179
days
CV
Dea
th, M
I, o
r U
rg R
evas
c (%
)0
510
15
0 5 10 15 20 25 30
PlaceboPlacebo
ClopidogrelClopidogrel
Odds Ratio 0.80(95% CI 0.65-0.97)
P=0.026
20%20%20%20%
Clopidogrel in STEMI
Coronary Angiogram(2-8 days)
CV Death, MI, or Stroke following PCI
02
46
8
0 10 20 30Days post PCI
Per
cen
tag
e w
ith
ou
tco
me
(%) No Pretreatment – 6.2%No Pretreatment – 6.2%
Clopidogrel – 3.6%Clopidogrel – 3.6%Pretreatment Pretreatment
46%46%46%46%
Odds Ratio 0.54Odds Ratio 0.54(95% CI 0.35-0.85)(95% CI 0.35-0.85)
P=0.008P=0.008
Odds Ratio 0.54Odds Ratio 0.54(95% CI 0.35-0.85)(95% CI 0.35-0.85)
P=0.008P=0.008
Sabatine MS et al. JAMA 2005;294:1224-32
PCI-CLARITYPCI-CLARITY
Clopidogrel in STEMIClopidogrel in STEMI
9% relative risk reduction (P=.002)
Placebo (10.1%)
Clopidogrel (9.3%)
Days
Dea
th, M
I, S
tro
ke (
%)
9
8
7
6
5
4
3
2
1
0
0
Mo
rtal
ity
(%)
Days
Placebo (8.1%)
Clopidogrel (7.5%)
7% relative risk reduction (P=.03)
7
6
5
4
3
2
1
0
7 14 21 28 0 7 14 21 28
COMMIT Collaborative Group. Lancet. 2005;366:1607.
45,851 Patients STEMI w/in 24 hrs; ASA; lytic therapy (~1/2)
Clopidogrel in STEMI
Fibrinolytic Therapy – Secondary PCI
““Clopidogrel pretreatment”Clopidogrel pretreatment”
Patient Oriented Therapy for STE-MI
“Adjunctive Antiplatelet Therapy”
Clopidorel vs Prasugrel /Ticagrelor
TRITON allowed recruitment of STEMI patients undergoing primary PCI when they presented < 12 hours of symptom
onset or secondary PCI when they presented late
0
1
2
3
4
5
6
TIMI majorbleed
Lifethreatening
TIMI majoror minor
clopidogrel
prasugrel
P=0.03P=0.03
P=0.01P=0.01
P=0.002P=0.002
Wiviott et al. New Engl J Med 2007;357:2001-2015
0
5
10
15
0 30 60 90 180 270 360 450
HR 0.81(0.73-0.90)
Days
CV
Dea
th, M
I, S
tro
ke (
%)
12.1
9.9
NNT= 46
Prasugrel
Clopidogrel
P<0.001
TRITON-TIMI 38 : Main study cohort
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
Montalescot et al. ESC 2008
Montalescot et al. ESC 2008
Time (Days)
5
10
15
00 50 100 150 200 250 300 350 400 450
Pro
po
rtio
n o
f p
atie
nts
(%
)
9.5
6.5
12.4
10.0
HR=0.79 (0.65–0.97) NNT=42
p=0.02RRR=21%
p=0.002RRR=32%
Clopidogrel
Prasugrel
Age-adjusted HR=0.81 (0.66-0.99)
TRITON-TIMI 38 : STEMITRITON-TIMI 38 : STEMI
Primary EP (CV death, MI and stroke at 15 months)
30 days30 days
Montalescot et al. ESC 2008
* ARC def/probable
0
2
4
6
8
10
All Death MI UTVR StentThrombosis*
CV Death/
MI
CV Death/MI/UTVR
CV Death/MI/Stroke
Pro
po
rtio
n o
f p
op
ula
tio
n (
%)
p= 0.04
p= 0.01
p= 0.13p= 0.008
p= 0.004 p= 0.02p= 0.002
Clopidogrel
Prasugrel
Efficacy endpoints at 30 days
TRITON-TIMI 38 : STEMITRITON-TIMI 38 : STEMI
Montalescot et al ESC 2008
• 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 : STEMITRITON-TIMI 38 : STEMI
These data make prasugrel an especially attractive alternative to clopidogrel
in PCI for STEMI
These data make prasugrel an especially attractive alternative to clopidogrel
in PCI for STEMI
STE-AMI : STE-AMI : Adjunctive Antiplatelet TherapyAdjunctive Antiplatelet Therapy(200(20099))
• 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
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
PLATO STEMI
Primary endpoint: CV death, MI or stroke
0 1 2 3 4 5 6 7 8 9 10 1112
12
11
10
9
8
7
6
5
4
3
2
1
0 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
1,8913,732
11.0
9.3
Clopidogrel
Ticagrelor
K-M
est
imat
ed r
ate
(% p
er y
ear)
PLATO STEMI
K-M
est
imat
ed r
ate
(% p
er y
ear)
0 1 2 3 4 5 6 7 8 9 10 11 12
10
8
6
4
2
0
Months
Clopidogrel
Ticagrelor 9.09.3
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
0.01
0.01
0.09
0.07
All-cause mortality 4.9 6.0 0.82 (0.68–0.99) 0.04
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
PLATO STEMI
Patient Oriented Therapy for STE-MI
“Adjunctive Antiplatelet Therapy”
Clopidogrel: Double dose vs Standart dose
25,087 ACS Patients (UA/NSTEMI 70.8%, 25,087 ACS Patients (UA/NSTEMI 70.8%, STEMI 29.2%STEMI 29.2% ))Planned Early (<24 h) Invasive Management with Planned Early (<24 h) Invasive Management with intended PCIintended PCIIschemic ECG Ischemic ECG ΔΔ (80.8%) (80.8%) or ↑cardiac biomarker (42%) or ↑cardiac biomarker (42%)
25,087 ACS Patients (UA/NSTEMI 70.8%, 25,087 ACS Patients (UA/NSTEMI 70.8%, STEMI 29.2%STEMI 29.2% ))Planned Early (<24 h) Invasive Management with Planned Early (<24 h) Invasive Management with intended PCIintended PCIIschemic ECG Ischemic ECG ΔΔ (80.8%) (80.8%) or ↑cardiac biomarker (42%) or ↑cardiac biomarker (42%)
PCI 17,232(70%)
Angio 24,769Angio 24,769(99%)(99%)
Angio 24,769Angio 24,769(99%)(99%) No PCI 7,855 (30%)
No Sig. CAD 3,616 CABG 1,809 CAD 2,430
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)
Efficacy Outcomes: CV Death, MI or stroke at day 30Stent Thrombosis at day 30
Safety Outcomes: Bleeding (CURRENT defined Major/Severe and TIMI Major)Key Subgroup: PCI v No PCI
Efficacy Outcomes: CV Death, MI or stroke at day 30Stent Thrombosis at day 30
Safety Outcomes: Bleeding (CURRENT defined Major/Severe and TIMI Major)Key Subgroup: PCI v No PCI
Clop in 1st 7d (median) 7d 7 d 2 d 7d
Complete Followup 99.8%
Complete Followup 99.8%
Compliance:Compliance:
Clopidogrel: Double vs Standard Dose
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 0.0360.016
No PCI (2N=7855) 4.2 4.9 1.17 0.95-1.44 0.14
Overall (2N=25,087) 4.4 4.2 0.95 0.84-1.07 0.370
MI
PCI (2N=17,232) 2.6 2.0 0.78 0.64-0.95 0.0120.025
No PCI (2N=7855) 1.4 1.7 1.25 0.87-1.79 0.23
Overall (2N=25,087) 2.2 1.9 0.86 0.73-1.03 0.097
CV Death
PCI (2N=17,232) 1.9 1.9 0.96 0.77-1.19 0.681.0
No PCI (2N=7855) 2.8 2.7 0.96 0.74-1.26 0.77
Overall (2N=25,087) 2.2 2.1 0.96 0.81-1.14 0.628
Stroke
PCI (2N=17,232) 0.4 0.4 0.88 0.55-1.41 0.590.50
No PCI (2N=7855) 0.8 0.9 1.11 0.68-1.82 0.67
Overall (2N=25,087) 0.5 0.5 0.99 0.70-1.39 0.950
Clopidogrel: Double vs Standard DosePrimary Outcome: PCI vs No-PCI
Days
Cu
mu
lati
ve H
azar
d
0.0
0.01
0.02
0.03
0.04
0 3 6 9 12 15 18 21 24 27 30
Clopidogrel Standard
Clopidogrel Double
HR 0.8595% CI 0.74-0.99
P=0.036
15% RRR15% RRR
CV Death, MI or StrokeCV Death, MI or Stroke
Clopidogrel: Double vs Standard DosePrimary Outcome: PCI Patients
CURRENT PCIN=17,232
TRITONN=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 No increase ↑ 4-fold
Fatal bleeding No increase ↑ 4-fold
Comparison of CURRENT and TRITON
STE-AMI : Adjunctive Antiplatelet Therapy(2010)
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