Patient Oriented Therapy for STE-MI

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



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


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


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” ”



““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%


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 pretreatment”Clopidogrel pretreatment”


“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


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


* 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


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


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


“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

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Patient Oriented Therapy for STE-MI

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