Preparazione Farmacologica alla PCI Primaria. Dalle Linee Guida ai Dati Degli Studi e dei Registri: sul Territorio

Leonardo De Luca, M.D., Ph.D., F.A.C.C.

Department of Cardiovascular SciencesInterventional Cardiology UnitEuropean HospitalRome, Italyleo.deluca@libero.it

Conflict of interest: none

Convegno Area Emergenza-Urgenza ANMCO

Preparazione alla PTCA nelle Sindromi Coronariche Acute

Roma, 20 Marzo 2010

Symptoms onset and

identification

Call EMS ER Cath LabPre-hospital phase

Increasing Loss of Myocytes

Factors Associated with Delays in Factors Associated with Delays in Mechanical Reperfusion TxMechanical Reperfusion Tx

Symptoms onset and

identification

Call EMS ER Cath LabPre-hospital phase

Factors Associated with Delays in Factors Associated with Delays in Mechanical Reperfusion TxMechanical Reperfusion Tx

Increasing Loss of Myocytes

Symptoms onset and

identification

Call EMS ER Cath LabPre-hospital phase

Factors Associated with Delays in Factors Associated with Delays in Mechanical Reperfusion TxMechanical Reperfusion Tx

Increasing Loss of Myocytes

Practical Limitations of Primary PCI as a Universal Reperfusion Strategy

Time delays (DBT, transfer time, waiting time for next available ambulance etc.)

Availability of invasive facilities

Operators’ skillness and cath lab volume load

Reorganization of EMS systems not conductive to making PPCI

EMS lacking 12-lead ECG capabilities

Not all patients having STEMI are transported by EMS

Mandates to transport patients to the nearest facility

Transport in STEMI Transport in STEMI NetworksNetworks::a Continous Odissey a Continous Odissey

Is it my

ECG?

No, It Is

Your

Route

Organization of ambulance systems, prehospital management, and adequate PCI capacity appear now to be the key issues in providing

reperfusion therapy for AMI.

Terkeisen et al. J Electrocardiology 2005; 36: 187

Sym

pto

m o

nse

t to

bal

loo

n in

flat

ion

(m

inu

tes)

No prehospital diagnosisAdmission to local hospitalSubsequently transferredto interventional hospital

Prehospital diagnosisAdmission to local hospitalSubsequently transferredto interventional hospital

Prehospital diagnosisLocal hospital bypassed.Patients rerouted directlyto interventional hospital

PRAGUE-1

PRAGUE-2

MAASTRICT

DANAMI-2

Terkelsen et al.

Aashein et al.

Clinical Impact of Direct Referral to PCI Clinical Impact of Direct Referral to PCI Following pre-H Diagnosis of STEMIFollowing pre-H Diagnosis of STEMI

Is Possible to Apply These Findings in a Is Possible to Apply These Findings in a ““Real World”Real World” Setting? Setting?

0

50

100

66%

86.6%

PRE POST0

5

10

15

20

PRE POST

16%

9.5%

Implementation of Guidelines Improve the Standard of Care

The Vienna STEMI RegistryREPERFUSION THERAPY MORTALITY

Kalla K, et al. Circulation 2006;113:2398

%

EMS coordinated with 5 Heart Hospitals Rotated 24 hr PCI availability Evaluated frequency of PCI and Lytics Evaluated Mortality

The Ottawa Hospital Institute The Ottawa Hospital Institute STEMI Regional ProgramSTEMI Regional Program

95,979,7

44,9

11,9

0

50

100

150

DTB<90 min DTB<120 min

%

Le May RM et al. N Engl J Med 2008;358:231

Field transf

Inter-hosp. transf

Interhospitaltransfers

Fieldtransfers

P<0.001

Minutes

EC

G t

o B

allo

on

Tim

eP

rop

ort

ion

of

Pat

ien

ts (

%)

The Citywide Ottawa ProgramThe Citywide Ottawa ProgramTime to TreatmentTime to Treatment

p<0.001 p<0.001

0

10

20

30

40

50

60

70

80

90

37.5%

51%

85.7%

EMS12 LeadPre-Arrival Activation

No EMS12 Lead

EMS12 Lead

Prehosp Emerg Care 2006;10:374-377

Door to Balloon Time < 90 min

Establishing Infarct NetworksMedical Response Delay

Comparison of Existing Prehospital ECG Programs

Location Prehospital ECG Interpretation

Activate Catheterization Lab en Route to Hospital

Bypass Non-PCI Hospitals

BostonAm J Emerg Med. 2005;23:443

Paramedic interpretation Yes (activation by emergency department physician based on paramedic interpretation)

Yes (for all patients with “definite STEMI” or “possible STEMI”)

Los Angeles CountyAm Heart J. 2006;152:661

Computer algorithm interpretation

Yes (activation by emergency department physician based on computer algorithm interpretation)

Yes (for all patients with acute MI)

North CarolinaJAMA. 2007;298:2371

Mixed (used computer algorithm interpretation, paramedic interpretation, or wireless transmission)

Mixed (activation by paramedics or emergency department physician)

Mixed (paramedics occasionaly diverted patients with STEMI to nearest PCI hospital)

OttawaN Engl J Med. 2008;358:231

Paramedic interpretation Mixed (activation by paramedic through a central page operator)

Yes (for all patients with STEMI)

Time from Ambulance Arrival (min)

% T

reat

ed P

ts

5%

49%

97%

48%

In-H Thrombolysis

Pre-H Thrombolysis

0 20 40 60 80 100 120 140

Morrow DA, et al. J Am Coll Cardiol. 2002;40:71

# of Pts Treated Earlier with Prehospital Thrombolysis

Data from the ER-TIMI-19 Trial

(n=19) (n=18) (n=23)

(p=0.003, Group B vs. C+DNT)

% P

ts w

ith

An

gio

gra

ph

ic

Per

fusi

on

Sco

re

10

A B CPre-H Thrombolysis

Full DosePre-H Thrombolysis½ Dose + Urgent PCI

Primary PCI(not eligible to

lysis or excluded)

Smalling RW, et al. J Am Coll Cardiol. 2007;50:1612

Pre-hospital Thrombolysis Pre-hospital Thrombolysis as Facilitation to Primary PCIas Facilitation to Primary PCI

* ST segment resolution < 50% & persistent chest pain, or hemodynamic instability* ST segment resolution < 50% & persistent chest pain, or hemodynamic instability

PCI CentreCath Lab

CommunityHospitalEmergencyDepartment

Cath / PCI within 6 Cath / PCI within 6 hrs regardless of hrs regardless of reperfusion statusreperfusion status

Cath and Cath and Rescue PCI Rescue PCI GP IIb/IIIa GP IIb/IIIa InhibitorInhibitor

TNK + ASA + Heparin / Enoxaparin + ClopidogrelTNK + ASA + Heparin / Enoxaparin + Clopidogrel

““PharmacoinvasivePharmacoinvasiveStrategy”Strategy”UrgentUrgent Transfer to PCI Transfer to PCI CentreCentre

Assess chest pain, STAssess chest pain, ST resolution resolution at 60-90 minutes after randomizationat 60-90 minutes after randomization

‘‘High Risk’ ST Elevation MI within 12 hours High Risk’ ST Elevation MI within 12 hours of symptom onset of symptom onset

Failed Reperfusion*Failed Reperfusion* Successful ReperfusionSuccessful Reperfusion

Elective Cath Elective Cath PCIPCI> 24 hrs later> 24 hrs later

““Standard Standard Treatment”Treatment”

Repatriation of stable patients within 24 hrs of PCI

The TRANSFER AMI Trial

Cantor WJ, et al. N Engl J Med 2009;360:2705

00

22

44

66

88

1010

1212

1414

1616

1818

00 55 1010 1515 2020 2525 3030

10.6

16.6

Days from Randomization

% of Patients% of Patients

n=496n=508

422468

415466

415463

414461

414460

412457

30-Day Death, re-MI, CHF, Severe 30-Day Death, re-MI, CHF, Severe Recurrent Ischemia, Shock Recurrent Ischemia, Shock

OR=0.537 (0.368, 0.783); p=0.0013

Cantor WJ, et al. N Engl J Med 2009;360:2705

TIMI 3 Patency Before Primary PCI in TIMI 3 Patency Before Primary PCI in Randomized Trials on GP IIb/IIIa InhibitorsRandomized Trials on GP IIb/IIIa Inhibitors

TIMI 3 Flow (%)

Abciximab Tirofiban Integrilin Lysis

16

25

11

29

17

32 32

19

34

60

2

16

8 7 5

20

1015

10

0

10

20

30

40

50

60

70

Zorman

Reo-Mobile

ERAMI

ReoPro-bridging

ADMIRAL

Cutlip

TIGER-PA

On-TIME

INTAMI TNK

Early Late or no GP IIb/IIIa blocker use

27

14

TITAN

Acute myocardial infarctionAcute myocardial infarctiondiagnosed in ambulance or referral centerdiagnosed in ambulance or referral center

ASA + 600 mg Clopidogrel + UFHASA + 600 mg Clopidogrel + UFH

AngiogramAngiogram

Tirofiban *Tirofiban *PlaceboPlacebo

Transportation

PCI centerAngiogramAngiogram

TirofibanTirofibanprovisionalprovisional

Tirofiban Tirofiban cont’dcont’d

N=9846/2006-11/2007

PCI

*Bolus: 25 µg/kg & 0.15 µg/kg/min infusion

Ongoing Tirofiban In Myocardial Infarction Ongoing Tirofiban In Myocardial Infarction Evaluation: ON-TIME 2 TrialEvaluation: ON-TIME 2 Trial

Van’t Hof AW, et al. Lancet. 2008;372:537

Cumulative ST- Deviation over Time

0

4

8

12

16

Diagnosis pre Angio 60min 90 min

Placebo Tirofiban 14.3±9.1

12.1±9.4

5.9±8.1

4.8±6.3

14.5±9.1

10.9±9.2

4.4±5.3

3.3±4.3

0.0020.0220.028p=0.84

[mm]

Ongoing Tirofiban In Myocardial Infarction Ongoing Tirofiban In Myocardial Infarction Evaluation: ON-TIME 2 TrialEvaluation: ON-TIME 2 Trial

Van’t Hof AW, et al. Lancet. 2008;372:537

Ongoing Tirofiban In Myocardial Infarction Ongoing Tirofiban In Myocardial Infarction Evaluation: ON-TIME 2 TrialEvaluation: ON-TIME 2 Trial

Residual ST-Deviation and Mortality

%

Van’t Hof AW, et al. Lancet. 2008;372:537

Dudek D, et al. Am Heart J 2008;156:1147

The EUROTRANSFER Registry:Impact of Prehospital Abciximab on TIMI flow

Before PCI After PCI

p<0.0001 p<0.001

Mehran R, et al. Lancet 2009;374:1149

Bivalirudin in Primary PCI. Bivalirudin in Primary PCI. 1-Year Results of the HORIZONS-AMI1-Year Results of the HORIZONS-AMI

18.3%

15.6%

HR 0.83 (95% CI 0.71-0.97)p=0.022

0

5

10

20

0 6 12

Bivalirudin (n=1800)

Control (n=1802)

HR 0.61 (95% CI 0.48-0.78)p=0.0001

9.2%

5.8%

0

4

8

12

0 6 12

HR 1.00 (95% CI 0.82-1.21)p=0.98

11.9%11.9%

0

5

10

15

15

0 6 12

Time (months) Time (months)

Time (months)

Feasibility and Safety of Prehospital Feasibility and Safety of Prehospital Administration of BivalirudinAdministration of Bivalirudin During STEMIDuring STEMI

Sejersten, M, et al. Am J Cardiol 2009;103:1635

%

**

* *

*: p<0.05

Clopidogrel LD in Pts Undergoing Primary PCI Clopidogrel LD in Pts Undergoing Primary PCI Results from the HORIZONS-AMIResults from the HORIZONS-AMI

Dangas G, et al. J Am Coll Cardiol 2009;54:1438

300 mg Loading Dose

600 mg Loading Dose

p=0,07

p=0,02

p=0,004

p=0,0007

p=0,0497 p=0,004Bivalirudin

Unfractioned Heparinplus GlycoproteinIIb/IIIa Inhibitors

Clopidogrel: Double vs SD.Clopidogrel: Double vs SD.STEMI PCI CohortSTEMI PCI Cohort

S. Mehta @ TCT 2009; September 24; San Francisco, CA

Outcome Standard clopidogrel

(n=3175)

Double-dose clopidogrel

(n=3171)

Hazard ratio (95% CI)

Definite stent thrombosis

1.8 1.0 0.54 (0.35–0.84)

All stent thrombosis

3.5 2.5 0.72 (0.54–0.96)

MI 1.9 1.2 0.63 (0.41–0.94)

MI or stent thrombosis

4.0 2.8 0.70 (0.54–0.92)

CURRENT major 1.2 1.4 1.16 (0.75–1.78)

CURRENT severe 0.9 1.1 1.18 (0.72–1.93)

Clopidogrel Administered Pre-h to Improve Clopidogrel Administered Pre-h to Improve Primary PCI: the CPrimary PCI: the CIPAMI StudyIPAMI Study

Pre-hospital Hospital until discharge or day 7

Prim

ary

angi

ogra

phy

Prim

ary

endp

oint

PC

I

(Sec

onda

ry e

ndpo

ints

)D

eath

, Re-

MI,

TV

R

RAspirin +

UFH/enoxaparin

n = 327Clopidogrel 600 mg

n = 327No loading

Treatment according to investigator

Clopidogrel loading prior to PCI strongly recommended

n = 654with STEMI

Acute STEMI <6hAngina >20 minST elevation >2

leadsor

new/presumed LBBB

Zeymer U et al. Cardiology 2007;108:265

Pre-hospitalP

CI

(Pri

mar

y en

dp

oin

ts)

TM

PG

R

Clopidogrel 600 mgn = 150

with STEMIAcute STEMI <12h

Angina >30 minST elevation >0.2

mV in >2 leadsor

new/presumed LBBB

P.I.s: Leonardo Bolognese and Kenneth DucciOspedale S. Donato, Arezzo

Three Different LD of Clopidogrel Administered Three Different LD of Clopidogrel Administered at FMC in AMI. The LOAD & GO Trialat FMC in AMI. The LOAD & GO Trial

Clopidogrel 900 mg

None

Clopidogrel

300 mg

Aspirin +UFH/enoxaparin

Prasugrel in Primary PCI.Prasugrel in Primary PCI.Data from Data from TRITON-TIMI 38TRITON-TIMI 38

Montalescot G, et al. Lancet 2009;373:723

p=0.0084p=0.0232 p=0.3359 p=0.6451

p=0.0017 p=0.0221p=0.0205 p=0.0250

Prasugrel

Clopidogrel

Days after Randomization Days after Randomization

0

5

10

15

0

5

10

15

CV death/non-fatal MI/non-fatal stroke CV death/non-fatal MI/urgent TVR

Stent Thrombosis TIMI major bleeding (no CABG)

0 200 450

0 200 450 0 200 450

0 200 450

PLATO Randomized Trial.PLATO Randomized Trial.STEMI CohortSTEMI Cohort

@ AHA 2009; November 14-18 2009; Orlando, FL

End point Ticagrelor

(180 mg+90 mg BID)

Clopidogrel

(300 mg+75 mg daily)

Hazard ratio for ticagrelor

p

Primary end point: death from vascular causes, MI, or stroke

9.3 11.0 0.85 0.02

All-cause mortality 4.9 6.0 0.82 0.04

CV mortality 4.5 5.4 0.84 0.09

Definite stent thrombosis

1.6 2.5 0.61 0.01

MI 4.7 6.1 0.77 0.01

Primary safety event: major bleeding

9.0 9.3 0.96 0.63

The need to shorten delays and to improve the quality of care for STEMI pts is urgent. We cannot wait! It’s up to us!!

Prehospital management is a key issue in 2010!

Emulating successful organizations can speed effective improvement.

A combined strategy of immediate thrombolysis or potent antithrombotic agents in the ambulance followed by PCI could theoretically provide early, complete and successful myocardial reperfusion.

The Tension Between Needing to Improve Care and Knowing How to Do it!