Santa Margherita Ligure TIGULLIO CARDIOLOGIA 2012 16-17 ... · Il trattamento dell’infarto miocardico acuto ad ST spraslivellato: dal territorio al laboratorio di emodinamica Il

Il trattamento dell’infarto miocardico acuto ad ST spraslivellato: dal territorio al laboratorio di emodinamica

Il punto sulla terapia antitrombotica nelle sindromi coronariche acute

Santa Margherita LigureTIGULLIO CARDIOLOGIA 2012

16-17 Febbrajo 2012

Diego ArdissinoParma

Divisione di CardiologiaParma

Antithrombotic therapy in ACS

Aggressiveness of Antithrombotic therapy

Ischemic Risk

Bleeding Risk

Ischemic vs Bleeding Risk in ACS

Today’s practiceOptimal practice

Risk



Aspirin in Acute Myocardial InfarctionCumulative vascular mortality in days 0 - 35

Cum

ulat

ive n

umbe

r of v

ascu

lar d

eath

s

Days from randomisation0 7 14 21 28 35

0

100

200

300

400

500

600Placebo

Streptokinase + aspirin

Streptokinase

The Lancet 1988

Aspirin

ESC/ EACTS Guidelines on myocardial revascularization 2010Antithrombotic treatment options in myocardial revascularization

Options for anticoagulation include UFH 60 IU/Kg iv boluswith GPIIb/IIIa inhibitor or UFH 100 IU/Kg iv bolus withoutGPIIb/IIIa inhibitor, (I C) or bivalirudin 0.75 mg/Kg bolusfollowed by 1.75 mg/kg/h (I B). Antithrombins can be stoppedafter PCI for STEMI.

EUROPEAN SOCIETY OF CARDIOLOGY GUIDELINESMANAGEMENT OF ACUTE MYOCARDIAL INFARCTION

Unfractionated heparin is standard anticoagulant therapy duringPCI.

• i.v. bolus: 100 U/Kg (60 U/Kg if GP IIb/IIIa antagonists are used)•target ACT during procedure: 250-350 seconds (200-250 seconds if GP IIb/IIIaantagonists are used)

CLASS I EVIDENCE C

ANTITHROMBOTIC THERAPY IN PRIMARY PCI

EUROPEAN SOCIETY OF CARDIOLOGY GUIDELINESMANAGEMENT OF ACUTE MYOCARDIAL INFARCTION

CLASS IIa EVIDENCE A

ANTITHROMBOTIC THERAPY IN PRIMARY PCI

Abiciximab can be administered in primary PCI.•i.v. bolus: 0.25 mg/kg

•Infusion: 0.125 mcg/Kg/min (maximum 10 mcg/min for 12 hours)

Abciximab as Adjunctive Therapy to Reperfusion in STEMI30-day mortality

Divisione di CardiologiaParma�De Luca G. et al, JAMA 2005; 293: 1759-65

RAPPORTISAR-2ADMIRALCADILLACPetronio et alZorman et alACEPetronio et alASSENT-3ENTIRE-TIME 23GUSTO VPrimary PCIFibrinolysis

Overall

P Value

0.750.240.160.490.360.100.79

> 0.990.150.790.430.0470.95

0.61

0.1 101Abciximab better Control better

Odds Ratio (95% CI)

Abciximab as Adjunctive Therapy to Reperfusion in STEMILong-term (6 and 12 month) mortality

Divisione di CardiologiaParma�De Luca G. et al, Jama 2005; 293: 1759-65

P Value

0.830.330.130.830.150.040.040-090.990.010.41

0.98

0.1 101Abciximab better Control better

Odds Ratio (95% CI)

RAPPORTISAR-2ADMIRALCADILLACPetronio et alZorman et alACEASSENT-3GUSTO VPrimary PCIFibrinolysis

Overall

Abciximab vs Placebo in Primary PCIDeath or re-infarction over 3 years of follow-up


Time

Surv

ival d

istrib

utio

n fu

nctio

n

0 400 600 1000

Montalescot G. et al, Eur Heart J 2007; 28: 443-449

200 800

Trials: ACE, ADMIRAL and ISAR

0.80

0.85

0.90

0.95

1

P = 0.008

AbciximabPlacebo


CLASS III EVIDENCE B

….the controversial literature data, the negative outcome of theonly prospecitve RCT and the beneficial effects of faster acting andmore efficacious ADP receptor blockers in primary PCI do notsupport pre-hospital or pre-catheterization use of GPIIb/IIIainhibitors.

UPSTREAM GP IIb/IIIa INHIBITORS

0

2

4

6

8

10

12

14

16

Facilitated PCI in Patients with STEMIThe FINESSE trial


Days

Patie

nts w

ith P

rimar

y Com

posit

eEn

d Po

int p

erce

nt

0 30 60 90

Ellis SG. et al, N Engl J Med 2008; 358: 2205-17

Primary PCIAbciximab-facilitated PCICombination-facilitated PCI

P = NS

0

5

10

15

20

25

30


TIMI Bleeding through Discharge/Day 7

Perc

enta

ge

TIMI major TIMI minor TIMI major or minor

Facilitated PCI in Patients with STEMIThe FINESSE trial

2.64.1 4.8 4.3

6

9.7

6.9

10.1

14.5

P < 0.001

P < 0.001

P = 0.025

P = 0.127P = 0.547

P = 0.141

P = 0.006P = 0.025

P = 0.008

Primary PCI with in Lab Abciximab ( n = 795 )Abciximab facilitated PCI ( n = 805 )Abciximab/Reteplase facilitated ( n = 814 )

Ellis SG. et al, N Engl J Med 2008; 358: 2205-17

STEMIplanned for 1° PCI

ENOXAPARIN IV0.5 mg/kg

(± GP IIb/IIIa inhibitor)

UFH IV50 – 70 IU/kg if GP IIb/IIIa

70 – 100 IU/kg if no GP IIb/IIIaDose adjusted to ACT

Randomization (N = 850)

1° PCI and stenting1° EP: Death, complication of MI, procedure failure

or non-CABG major bleeding at 30 daysMain 2° EP: Death, MI, refractory ischemia, urgent revasc.

6-month follow-upPatients who have already received UFH or LMWH or any other anticoagulant are excluded.

All concomitant drugs accepted, except lytics; cross-over to other anticoagulant NOT accepted.

Enoxaparin vs UFH in primary PCIATOLL Study Design


Montalescot, ESC 2010


28

33,7

0

10

20

30

40

Montalescot, ESC 2010

RRR=17% P=0.07

Per

cent

of p

atie

nts

Enoxaparin vs UFH in primary PCIATOLL trial Primary endpoint

Death, complication of MI, procedure failure or maior bleeding


CLASS I EVIDENCE B

….a recent study suggested bivalirudin monotherapy as analterantive to UFH plus a GPIIb/IIIa inhibitor.

ANTICOAGULATION

0

3

6

9

12

15

Bivalirudin During Primary PCI in STEMIThe HORIZONS-AMI trial


Days

Net A

dver

se C

linica

l Eve

nts p

erce

nt

0 10 20 30

�Stone GW. et al, N Engl J Med 2008; 358: 2218-30

5 15 25

Net adverse clinical events

Heparin plus GP IIB/IIIaBivalirudin alone P = 0.006

12.2

9.3

0

1

2

3

4

5

6

7

8



Days

Majo

r Adv

erse

card

iova

scul

arEv

ents

per

cent

0 10 20 30

Stone GW. et al, N Engl J Med 2008; 358: 2218-30

5 15 25

Major adverse cardiovascular events

Heparin plus GP IIB/IIIaBivalirudin alone

P = 0.985.5

5.5

0

3

6

9

12



Days

Majo

r Blee

ding

per

cent

0 10 20 30

�Stone GW. et al, N Engl J Med 2008; 358: 2218-30

5 15 25

Major bleeding

Heparin plus GP IIB/IIIaBivalirudin alone P < 0.0001

8.4

5.0

0

1

2

3

4

5



Days

Deat

h pe

rcen

t

0 10 20 30

Stone GW. et al, N Engl J Med 2008; 358: 2218-30

5 15 25

Death from cardiac and non cardiac causes

Heparin plus GP IIB/IIIaBivalirudin alone

P = 0.032.9

1.8

0.3

0.2

Cardiac

Noncardiac

Bivalirudin During Primary PCI in STEMIThe HORIZONS-AMI trial 3-years follow up

Divisione di CardiologiaParmaStone GW. et al, TCT 2010

0.1 0.5 1.0 1.5 2.0

Major bleeding

All-cause mortality

Cardiac mortality

Reinfarction

6.9

5.9

2.9

6.2

10.5

7.7

5.1

8.2

0.64 (0.51-0.80)

0.75 (0.58-0.97)

0.56 (0.40-0.80)

0.76 (0.59-0.92)

<0.001

0.03

0.001

0.04

Endpoint Bival HR (95% CI) pHep+GP IIb/IIIa(%) (%)

ANTITHROMBOTIC THERAPY IN STEMIAbciximab vs bivalirudin


High ischemic risk

High bleeding risk

AGGRESSIVENESS OF ANTITHROMBOTIC THERAPY

Abciximab

+Heparin

Biva

lirud

in

Heparin


Dual antiplatelet therapy consists of aspirin 150-300mg per os or 250-500 mg bolus iv followed by 75-100 mg daily, and prasugrel 60 mgloading dose, followed by 10 mg daily, or ticagrelor 180 mg loadingdose, followed by 90 mg twice daily, depending on drug availability.

Clopidogrel 600 mg loading dose, followed by 75 mg daily should beused primarily if the more effective ADP receptor blockers arecontroindicated or unavailable.

STEMI ANTITHROMBOTIC THERAPY

012345

6789

1011

COMMIT / CCS-2In-hospital death


Time since randomization (up to 28 days)

Deat

h pe

rcen

t

0 14

COMMIT Collaborative Group Lancet 2005; 366: 1607-21

7 14 21

Placebo + ASA: 1845 deaths (8.1%)Clopidogrel + ASA: 1726 deaths (7.5%)

7 % (SE) relative risk reduction (2P = 0.03)


Hours prior to PCI of study drug loading doseSteirhubl SR et al Circulation 2003;108:374

MACE

5 150 10 20 25

PlaceboClopidogrel

p = 0.02for treatment/timing interaction

Prevention of Myocardial Infarction During PCIEffect of Clopidogrel 300 mg Loading Dose

Divisione di CardiologiaParmaFefer P et al. Am J Cardiol 2009; 104: 514-518

Patie

nts (

%)

Clopidogrel 600 mg Clopidogrel 300 mg n=116 n=80 n=97 n=64

p<0.01

Primary composite endpoint at 30 days ( death, recurrent ACS, stent thrombosis, CHF)

Impact of pre-treatment with clopidogrel on outcome in STEMI


CLASS I EVIDENCE B

Prasugrel is superior to clopidogrel in reducing combinedischaemic endpoints and stent thrombosis in STEMI patientswithout increasing the risk of severe bleeding.

Prasugrel vs clopidogrel in primary PCI TRITON TIMI-38

Primary endpoint: Cardiovascular death, non-fatal MI, non-fatal stroke

0

5

10

15

Montalescot G et al, Lancet 2009; 373: 723-31Divisione di Cardiologia

Parma

Cum

ulat

ive in

ciden

ce (%

)

50 150 250 350 450

Days from randomization

p=0.0017 p=0. 0221

ClopidogrelPrasugrel

0

5

10

15TIMI major bleeding

TRITON TIMI-38Prasugrel vs clopidogrel in primary PCI

Montalescot G et al, Lancet 2009; 373: 723-31Divisione di Cardiologia

Parma

Days from randomization50 150 250 350 450

p=0.3359 p=0. 6451

Cum

ulat

ive in

ciden

ce (%

) ClopidogrelPrasugrel

Net Clinical BenefitBleeding Risk Subgroups Post-hoc Analysis

YesNo

≥ 75< 75

< 60 Kg≥ 60 Kg

Overall

+54-16

-1-16

+3-14

-13

0.5 1 2

Pinter = 0.36

HRPrasugrel better Clopidogrel better

Risk percent

PriorStroke / TIA

Age

Wgt

Pinter = 0.18

Pinter = 0.006


CLASS I EVIDENCE B

…A predefinite subgroup analysis has demonstrated that STEMIpatients referred to PCI significantly benefit from ticagrelor vsclopidogrel, with similar bleeding rates.



Greater and More Consistent IPAwith AZD6140 than Clopidogrel

Final Extent

Mean

per

cent

inhi

bitio

n

Hours

AZD6140 100 mg bd

0

20

40

60

80

100

0 2 4 8 12 242 4 8 12Day 1 Day 14

Hours

Clopidogrel

0

20

40

60

80

100

0 2 4 8 12 242 4 8 12Day 1 Day 14

0123456789

101112


Months

Cum

ulat

ive in

ciden

ce (%

)

0 1 3 5 7 9 12

Clopidogrel

Ticagrelor

2 4 6 8 10

T 3752 3476 3424 3331 2687 2049 1675

C 3792 3501 3438 3356 2726 2097 1679

11

Ticagrelor vs clopidogrel in STEMI treated with primary PCIPrimary efficacy endpoint

Steg PG et al, Circulation 2010, 122:2131-2141

HR 0.87 95%CI 0.75-1.01 p=0.07

0123456789

101112


Months

Cum

ulat

ive in

ciden

ce (%

)

0 1 3 5 7 9 12

Clopidogrel

Ticagrelor

2 4 6 8 10

T 3752 3581 3539 3461 2812 2154 1766

C 3792 3614 3580 3511 2872 2216 1773

11

Ticagrelor vs clopidogrel in STEMI treated with primary PCICardiovascular death


HR 0.83 95% CI 0.67-1.02 p=0.07

0

1

2

3

4

5

6

7

8

9

10


Months

Cum

ulat

ive in

ciden

ce (%

)

0 1 3 5 7 9 12

Clopidogrel

Ticagrelor

HR 0.98 95%CI 0.83-1.14 p=0.76

2 4 6 8 10 11

Ticagrelor vs clopidogrel in STEMI treated with primary PCI


Major bleeding according to PLATO definition

T 3719 3079 2920 2812 2183 1592 1459

C 3752 3092 2972 2850 2202 1624 1471


Pre-hospital vs. In-hospital initiation of ticagrelor therapy in STEMIATLANTIC study design

Primary endpoint: TIMI flow grade 3 of MI culprit vessel at initial angiography; ST-segment resolution up to pre PCI >70%

Secondary endpoint: 30-days death, MI, urgent revascularization, stent thrombosis, life threatening bleeding, major and minor bleeding

(n = 1.770)

Pre-hospital Ticagrelor loading dose (180 mg) followed by in-hospital matching placebo

Randomized, Parallel-group, Double blind, Placebo controlled phase IV trial

STEMI patients planned for primary PCI(symptom onset < 6 hours)

R

Pre-hospital placebo followed by in-hospital Ticagrelor loading dose (180mg)

Primary Efficacy Endpoint: CV death, MI or strokePrimary Safety Endpoint: TIMI major Bleeding

Follow up VisitsQ4 mos for 1st ys, then Q6 mos

(n = 21,000)

Ticagrelor 90 mg BID Placebo


History of MI 1-3 years prior +

Randomize double blind

* Age≥ 65yrs, diabetes, 2nd prior MI, multivessel CAD, PAD or chronic non-end stage renal dysfunction

PEGASUS TIMI 54 Study design

Min 12 mos and average 24 mos follow-up

Event driven trial

Standard background care (ASA 75-100 mg recommended)

Ticagrelor 60 mg BID

> 1 additional atherothrombosis risk factor


The cycle of continuous quality improvement

Concept

Clinical Trials

Guidelines

PerformanceIndicators

Outcomes

Performance

Califf RM et al. JACC 2002;40:1895-901

Documents

Santa Margherita Ligure TIGULLIO CARDIOLOGIA 2012 16-17 ... · Il trattamento dell’infarto miocardico acuto ad ST spraslivellato: dal territorio al laboratorio di emodinamica Il