Transcript Slayt 1

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 ?
1) Diagnostic level
2) Prognostic level (risk stratification)
3) Therapeutic level
2008
2010
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)
I IIa IIb III
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
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
Odds of Death with Fibrinolysis
NRMI
(National Registry of Myocardial Infarction)
192 509 patient
PCI better
2.0
Conclusions—As
DB-DN times increase, the mortality advantage of PPCI
1.5
over fibrinolysis declines,
and this advantage
Fibrinolysis Better
1.25
varies considerably
depending on patient characteristics.
1.0
0.8
0.5
60
75
90
105
114
135
150
165
180
Primary PCI related delay (min) (Door-Balloon – Door- Needle)
Circulation. 2006;114:2019-2025
Time to Reperfusion - Mortality
In hospital
mortality (%)
Circulation. 2006;113:2398-2405
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
%52.6
Patients (%)
60
Not Transfered
50
40
NRMI 5
%34.3
30
20
10
Transfered
%9.0
%3.7
0
1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005
Discharged year
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”
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;
10.7%
4.4%
HR=0.40 (0.21-0.76)
Anterior MI alone with 2 mm
or more ST-elevation in 2 or
more leads
Di Mario et al. Lancet 2008;371.
17
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
SBP < 100
HR > 100
Killip Class II-III
≥ 2mm ST-segment
depression in anterior
leads
≥ 1 mm ST-segment
elevation in V4R
Cumulative Incidence
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:
17.2%
p=0.004
11.0%
Days
RR= 0.64, 95 CI% (0.47-0.87)
ACC/2008
N Engl J Med 2009;360:2705-18
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
Patient Oriented Therapy for STE-MI
Fibrinolytic Therapy – Secondary PCI
“Clopidogrel pretreatment”
Clopidogrel in STEMI
Double-blind, randomized, placebo-controlled trial in
3491 patients, age 18-75 yrs with STEMI < 12 hours
Fibrinolytic, ASA, Heparin
randomize
Clopidogrel
300 mg + 75 mg qd
Study
Drug
Coronary Angiogram
(2-8 days)
Open-label
clopidogrel
per MD in
both groups
30-day clinical follow-up
Placebo
Primary endpoint:
Occluded
artery (TIMI Flow
Grade 0/1)
or D/MI by time
of angio
Sabatine MS et al. NEJM 2005; 352
15
10
Clopidogrel
Odds Ratio 0.80
(95% CI 0.65-0.97)
P=0.026
0
5
20%
10
15,0
Placebo
5
20
36% 
P<0.0001
21,7
CV Death, MI, or Urg Revasc (%)
Occluded Artery or Death/MI (%)
25
15
Clopidogrel in STEMI
0
Clopidogrel Placebo
Coronary Angiogram
(2-8 days)
0
5
10
15
20
days
25
30
Sabatine MS et al. NEJM 2005; 352: 1179
Clopidogrel in STEMI
PCI-CLARITY
8
CV Death, MI, or Stroke following PCI
Odds Ratio 0.54
No Pretreatment – 6.2%
6
P=0.008
4
46%
2
Clopidogrel – 3.6%
Pretreatment
0
Percentage with outcome (%)
(95% CI 0.35-0.85)
0
10
Days post PCI
20 Sabatine MS et al. JAMA 2005;294:1224-32
30
Clopidogrel in STEMI
45,851 Patients STEMI w/in 24 hrs; ASA; lytic therapy (~1/2)
Placebo (10.1%)
Placebo (8.1%)
9
7
8
6
7
Mortality (%)
Death, MI, Stroke (%)
Clopidogrel (7.5%)
Clopidogrel (9.3%)
6
5
9% relative risk reduction
(P=.002)
4
3
5
4
7% relative risk reduction
(P=.03)
3
2
2
1
1
0
0
0
7
14
Days
21
28
0
7
14
21
28
Days
COMMIT Collaborative Group. Lancet. 2005;366:1607.
Fibrinolytic Therapy – Secondary PCI
“Clopidogrel pretreatment”
Patient Oriented Therapy for STE-MI
“Adjunctive Antiplatelet Therapy”
Clopidorel vs Prasugrel /Ticagrelor
TRITON-TIMI 38 : Main study cohort
6
CV Death, MI, Stroke (%)
15
Clopidogrel
12.1 5
9.9
4
Prasugrel P<0.001
3
10
5
HR 0.81
(0.73-0.90)
NNT= 46
0
0 30 60 90
180
270
360
Days
Wiviott et al. New Engl J Med 2007;357:2001-2015
450
P=0.002
clopidogrel
prasugrel
P=0.03
P=0.01
2
1
0
TIMI major
bleed
Life
TIMI major
threatening or minor
TRITON allowed recruitment of STEMI patients undergoing
primary PCI when they presented < 12 hours of symptom
onset or secondary PCI when they presented late
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
Prasugrel
Clopidogrel
Prasugrel
N=1235
N=1203
N=530
N=564
Montalescot et al. ESC 2008
TRITON-TIMI 38 : STEMI
Primary EP (CV death, MI and stroke at 15 months)
Clopidogrel
Prasugrel
Proportion of patients (%)
15
12.4
10.0
10
p=0.02
RRR=21%
9.5
p=0.002
RRR=32%
6.5
5
HR=0.79 (0.65–0.97) NNT=42
Age-adjusted HR=0.81 (0.66-0.99)
0
0
50
30 days
100
150
200
250
300
350
400
450
Time (Days)
Montalescot et al. ESC 2008
TRITON-TIMI 38 : STEMI
Efficacy endpoints at 30 days
Clopidogrel
Proportion of population (%)
Prasugrel
10
p= 0.004
8
p= 0.002
p= 0.02
p= 0.01
6
4
p= 0.04
p= 0.13
p= 0.008
2
0
All Death
MI
UTVR
Stent
CV
Thrombosis* Death/
MI
CV Death/ CV Death/
MI/UTVR MI/Stroke
* ARC def/probable
Montalescot et al. ESC 2008
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
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
18,758 patients enrolled
in PLATO
134 patients not
randomized
18,624 patients
randomized
NSTEMI/UA/other:
10,194 patients
STEMI
Randomized to
ticagrelor: efficacy
population N= 4,201
No intake of study
medication: 36 patients
Safety population
N=4,165
8,430 pts
Randomized to
clopidogrel: efficacy
population N= 4,229
No intake of study
medication: 48 patients
Safety population
N=4,181
PLATO
STEMI
Primary endpoint: CV death, MI or stroke
12
Clopidogrel
11
11.0
K-M estimated rate (% per year)
10
9.3
9
Ticagrelor
8
7
6
5
4
3
HR: 0.85 (95% CI = 0.74–0.97), p=0.02
2
1
0
No. at risk
Ticagrelor
Clopidogrel
0 1
4,201
4,229
2
3
3,887
3,892
4
5
3,834
3,823
6
7
Months
3,732
3,730
8
9
3,011
3,022
10
11
2,297
2,333
12
1,891
1,868
PLATO
STEMI
K-M estimated rate (% per year)
Primary safety event: major bleeding
10
Clopidogrel
8
Ticagrelor
6
4
2
0
HR 0.96 (95% CI = 0.83–1.12), p=0.63
01
2
3
4
5
6
7
8
Months
9
10
11
12
9.3
9.0
PLATO
STEMI
Hierarchical testing of major efficacy endpoints
Ticagrelor
(n=4,201)
Clopidog
rel
(n=4,229)
HR for
ticagrelor
(95% CI)
pvalue†
Primary endpoint, %
CV death + MI + stroke
9.3
11.0
0.85 (0.74–0.97)
0.02
Secondary endpoints, %
Total death + MI + stroke
9.7
11.5
0.84 (0.73–0.96)
0.01
CV death + MI + stroke +
ischaemia + TIA + arterial
thrombotic events
13.4
15.4
0.86 (0.76–0.96)
0.01
MI
4.7
6.1
0.77 (0.63–0.93)
0.01
CV death
Stroke
4.5
5.4
0.84 (0.69–1.03)
0.09
1.6
1.0
1.45 (0.98–2.17)
0.07
4.9
6.0
0.82 (0.68–0.99)
0.04
Endpoint*
All-cause mortality
Conclusions
PLATO
STEMI
• 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
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)
PCI 17,232
(70%)
No Sig. CAD 3,616
Compliance:
Clop in 1st 7d (median) 7d
Efficacy Outcomes:
Safety Outcomes:
Key Subgroup:
Angio 24,769
(99%)
7d
No PCI 7,855 (30%)
CABG 1,809
2d
CV Death, MI or stroke at day 30
Stent Thrombosis at day 30
Bleeding (CURRENT defined Major/Severe and TIMI Major)
PCI v No PCI
CAD 2,430
7d
Complete
Followup 99.8%
Clopidogrel: Double vs Standard Dose
Primary Outcome: PCI vs No-PCI
Standard
Double
HR
95% CI
P
PCI (2N=17,232)
4.5
3.9
0.85
0.74-0.99
0.036
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
PCI (2N=17,232)
2.6
2.0
0.78
0.64-0.95
0.012
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
PCI (2N=17,232)
1.9
1.9
0.96
0.77-1.19
0.68
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
PCI (2N=17,232)
0.4
0.4
0.88
0.55-1.41
0.59
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
Intn P
CV Death/MI/Stroke
0.016
MI
0.025
CV Death
1.0
Stroke
0.50
Clopidogrel: Double vs Standard Dose
Primary Outcome: PCI Patients
CV Death, MI or Stroke
Clopidogrel Standard
0.02
0.03
Clopidogrel Double
0.01
HR 0.85
95% CI 0.74-0.99
P=0.036
0.0
Cumulative Hazard
0.04
15% RRR
0
3
6
9
12
15
Days
18
21
24
27
30
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
No increase
↑ 4-fold
Fatal bleeding
No increase
↑ 4-fold
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