Dott. Antonio Butera

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Preparazione farmacologica alla PTCA STEMI
Negli ospedali senza emodinamica

• Dott. Antonio Butera
• Lamezia Terme

Roma, 20 marzo 2010
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2009

• Facilitaded and Rescue PCInon longer
  usedpotentially misleading labels

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Scopi del trattamento farmacologico pre PTCA

• Limitazione di eventi e riduzione del danno
  ischemico pre-PCI
• Facilitazione dellangioplastica
• Riduzione delle complicanze peri e
  post-procedurali (trombosi dello stent, ischemia)
• (Il tutto con minori effetti pro-emorragici) -I
  sanguinamenti maggiori moltiplicano MACE GRACE
  EHJ 2003 Eikelboom JW et al Circulation 2006
  Nikolski E et al EHJ 2007 CRUSADE
  Circulation 2009-

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Facilitata
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Razionale dellAngioplastica facilitata

• La maggiore pervietà dellIRA prima
  dellangioplastica migliora loutcome

6 months mortality
TIMI 3 (n375)
100 98 96 94 92 90
0.5
TIMI 2 (n295)
2.8
Survival ()
TIMI 0/1 (n1,657)
4.4
log-rank p for trend 0.009
0 1 2 3
4 5 6
Stone GW Circulation 2001104636
Months
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ASSENT- 4 PCI study design
n 2000
n 2000
ASA UFH (bolus 40U/kg) TNK-tPA
ASA UFH (bolus 70u/Kg)
Immediate PTCA
Immediate PTCA
Stent or clopidogrel at researchers
discretion No anti-GP IIb/IIIa
Stent, clopidogrel or anti-GP IIb/IIIa at
researchers discretion
Primary endpoints death, heart failure or
cardiogenic shock at 90 days
Lancet 2006
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ASSENT- 4 PCI Trial TIMI Flow Grade
TIMI grade 3 flow prior to PCI and TIMI grade 2/3
flow post-PCI ()
p0.03

• TIMI grade 3 flow prior to PCI was present more
  frequently in the TNK PCI arm (43.6 vs 15.0)
• TIMI grade 2/3 post-PCI was slightly higher in
  the PCI alone group (95.3 vs 97.6)

plt0.001

Lancet 2006
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ASSENT-4 Primary Endpointmortality, CHF, Shock
at 90 days
p0.04
Lancet 2006
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ASSENT-4 PCI in-hospital cardiac events
Event TNKPCI () PCI alone () p
Re-MI 4.1 1.9 0.01
Abrupt vessel closure 1.9 0.1 lt0.001
Repeat TVR 4.4 1.0 lt0.001
Pericarditis 0.7 0.1 0.07
Tamponade 0.6 0.4 0.50
Cardiac rupture 0.9 0.2 0.11
EM dissociation 1.7 1.0 0.20
Pulmonary edema 3.4 3.1 0.78
Ventricular fibrillation 5.6 3.7 0.08
Lancet 2006
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ASSENT-4 PCI in-hospital stroke rates
Outcome TNKPCI () PCI alone () p
Total stroke 1.81 0 lt0.001
Intracranial hemorrhage 0.97 0 0.004
Ischemic stroke 0.60 0 0.03
Hemorrhagic conversion 0.12 0 0.50
Unclassified 0.24 0 0.25
van de Werf F. European Society of Cardiology
Congress 2005 September 4-7, 2005 Stockholm,
Sweden.
Lancet 2006
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Conclusioni ASSENT - 4
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Major Objectives
1 - To test if Reteplase/Abciximab Facilitated
PCI is superior to Primary PCI with in lab
Abciximab Primary end-pointmortality, CHF, VF,
Shock at 90 days
Primary PCI with in lab Abciximab
R
?
Reteplase/Abciximab Facilitated Primary PCI
NEJM 2008
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TIMI Flow in IRA Pre-PCI
Subjects with TIMI 2/3 (Patency) Pre-PCI

p lt 0.0001
p lt 0.0001
61
Percentage
25
TIMI 2 TIMI 3
26
25
11
36
12
15
13
Abciximab Facilitated PCI (n809)
Primary PCI (in lab Abciximab) (n790)
Reteplase/Abciximab Facilitated PCI (n815)
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Primary Endpointmortality, CHF, VF, Shock at 90
days
p0.55
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TIMI Major or Minor Bleeding (nonintracranial)
through Discharge/Day7
plt0.001
plt0.001
p0.025
p0.008
p0.006
p0.547
p0.025
p0.141
p0.127
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CONCLUSIONI

• il rapporto rischio/beneficio della pPCI con
  Abciximab somministrato direttamente in
  emodinamica è migliore delle due strategie di
  facilitazione

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(19 studi)
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Ma se la pPCI non si potesse proprio
fare.specialmente nei pazienti ad alto rischio
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CARESS Study design
STEMI patients lt12 hrs from symptom
onset Admitted to centres without PCI facilities
and at least one high risk feature gt15 mm ST
Elevation new onset LBBB, previous MI, Killip
Class gt2, lt 35 LVEF
ASA 300-500 mg iv Reteplase half dose UFH (40
U/kg -max 3000- 7 U/kg/h) Abciximab 0.25 mg/kg
bolus 0.125 mg/kg/min x 12 h
Urgent transfer after lysis to nearest PCI centre
for PCI plus stenting
Admit to CCU and only transfer for PCI if
persistent ST elevation at 90 min (gt50 basal
ECG), chest pain or haemodynamic compromise
Primary outcome Death, Reinfarction, Refractory
Ischemia at 30 Days
Lancet 2008
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Primary outcome Death, Reinfarction, Refractory
Ischemia at 30 Days
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Il beneficio del trasferimento immediato si è
ottenuto malgrado 1/3 dei pazienti del braccio
di controllo sia stato trattato con la Rescue.
Il rischio di sanguinamento non è stato
differente nei due Gruppi (e comunque basso solo
5 ICH nei 598 pz )
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High Risk ST Elevation MI within 12 hours of
symptom onset
Community Hospital Emergency Department
TNK ASA Heparin / Enoxaparin Clopidogrel
Pharmacoinvasive Strategy Urgent Transfer to
PCI Centre
Standard Treatment
Assess chest pain, ST? resolution at 60-90
minutes after randomization
Failed Reperfusion
Successful Reperfusion
PCI Centre Cath Lab
Cath / PCI within 6 hrs regardless of reperfusion
status
Cath and Rescue PCI ? GP IIb/IIIa Inhibitor
Elective Cath ? PCI gt 24 hrs later
Repatriation of stable patients within 24 hrs of
PCI
ST segment resolution lt 50 persistent chest
pain, or hemodynamic instability
Randomization stratified by age (75 vs. gt 75)
and by enrolling site
NEJM 2009
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Primary end-point 30-day composite Death,
Reinfarction, recurrent ischemia, CHF, Shock
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Conclusioni

• In paz con STEMI ad alto rischio sottoposti alla
  fibrinolisi in centri periferici, il
  trasferimento entro 6 ore al centro hub per
  eseguire la PCI si associa ad una riduzione
  significativa di eventi ischemici, (malgrado il
  ricorso in circa il 40 dei pazienti alla PCI
  rescue)
• senza incrementare gli eventi emorragici,
• La PCI precoce dopo trombolisi, si è dimostrata
  più safe che nei precedenti trials (progressi
  con gli stent ed altra terapia concomitante
  Clopidogrel-?)

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1.Se possibile pPCI
2.Se non possibile pPCI
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2009
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Anti IIB/IIIA pre-cathlab

• Molti studi eseguiti prima della doppia
  antiaggregazione non più attuali.
• BRAVE-3 (Abciximab) clinicamente neutro ON-TIME
  2 (Tirofiban) clinicamente neutro.
• MULTISTRATEGY Abciximab vs Tirofiban e BMS vs
  DES (Sirolimus) vantaggio del DES.
• FINESSE Braccio abciximab clinicamente neutro
  (con emorragie rispetto alla somministrazione
  in emodinamica)

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2009
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Come identificare, eventualmente, i pazienti
della Classe 2B?
Am Heart J 2008
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Early abciximab administration before primary
percutaneous coronary intervention improves
clinical outcome in elderly patients transferred
with ST-elevation myocardial infarction Data
from the EUROTRANSFER registry
30-day death Reinfarction
30-day death


P 0.001
P 0.001
Nessuna differenza per emorragie nel gruppo gt/
65 aa
Dziewiers et al Int J Cardiol 2009
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2009
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ISIS-2ISIS-2 (Second International Study of
Infarct Survival) Collaborative Group, Randomised
trial of intravenous streptokinase, oral aspirin,
both, or neither among 17,187 cases of suspected
acute myocardial infarctions ISIS-2. Lancet
1988 ii 349-360
-20
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Collaborative metaanalysis of randomised trials
ofantiplatelet therapy for prevention of death,
myocardial infarction, and stroke in high risk
patients. BMJ 2002 32471-86
NNT 26
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ACC/AHA Guidelines 2004 (invariate per lASA)
ESC Guidelines 2008
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Biotransformation and Mode of Action of
Clopidogrel, Prasugrel, and Ticagrelor
Schomig A. N Engl J Med 2009
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Il beneficio del Clopidogrel (300gt75) è maggiore
nei pazienti sottoposti a PCI
CURE Primary end-point CVDMIStroke)
CVD/MI/Stroke
CVD/MI/Stroke
Clopidogrel
-30
-19
NEJM 2001
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The CURE Investigators Lancet 2001
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Clarity TIMI 28 (Fibrinolisi)
PCI- Clarity TIMI 28
-36
-46
NEJM 2005
JAMA 2005
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Meta-Analysis of Clopidogrel Pretreatment
Clopidogrel No Trial Pretreatment Pretreatment
PCI-CURE 3.6 5.1 CREDO n/a n/a PCI-CLARITY 4.
0 6.1 Overall 3.7 5.5 Clopidogrel No Trial Pre
treatment Pretreatment PCI-CURE 2.9 4.4 CREDO 6.0
7.1 PCI-CLARITY 3.3 5.4 Overall 3.9 5.5
MI before PCI ()
Favors Pretreatment
Favors No Pretreatment
OR 0.67 P0.005
CVD or MI after PCI ()
1.0
0.25
2.0
0.5
OR (95 CI)
OR 0.71 P0.004
1.0
0.25
2.0
0.5
OR (95 CI)
Sabatine MS et al. JAMA 2005
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CURRENT OASIS Study Design, Flow and Compliance

• 25,087 ACS Patients (UA/NSTEMI 70.8, STEMI
  29.2)
• Planned Early (lt24 h) Invasive Management with
  intended PCI
• Ischemic ECG ? (80.8) or ?cardiac biomarker (42)

Randomized to receive (2 X 2 factorial) CLOPIDOGR
EL 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)
Angio 24,769 (99)
PCI 17,232 (70)
No PCI 7,855 (30)
No Sig. CAD 3,616
CABG 1,809
CAD 2,430
Efficacy Outcomes CV Death, MI or stroke at day
30 Stent Thrombosis at day 30 Safety
Outcomes Bleeding (CURRENT defined
Major/Severe and TIMI Major) Key Subgroup PCI
v No PCI
Complete Followup 99.8
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CURRENT OASIS Double vs Standard Dose Primary
Outcome (CV Death, MI or Stroke) PCI Patients
Clopidogrel Standard
15 RRR
0.04
Clopidogrel Double
0.03
Cumulative Hazard
0.02
HR 0.85 95 CI 0.74-0.99 P0.036
0.01
0.0
0
3
6
9
12
15
18
21
24
27
30
Days
ESC 2009
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CURRENT OASIS 7 Double vs Standard DoseDefinite
Stent Thrombosis (Angio confirmed)
Clopidogrel Standard Dose
0.012
42 RRR
0.008
Cumulative Hazard
Clopidogrel Double Dose
0.004
HR 0.58 95 CI 0.42-0.79 P0.001
0.0
0
3
6
9
12
15
18
21
24
27
30
Days
ESC 2009
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Clopidogrel Double v Standard DosePCI Cohort
Subgroups
CV Death, MI or Stroke
MI or Stent Thrombosis
Std
Double
Std
Double
Intxn P
Intxn P
2N
Overall
17232
4.5
3.9
3.7
3.0
NSTEMI/UA
10886
4.2
3.6
3.6
3.1
0.805
0.248
STEMI
6346
5.0
4.2
4.0
2.8
Male
13009
4.1
3.6
3.5
3.0
0.419
0.148
Female
4223
5.8
4.6
4.6
3.0
Age lt 65 yrs
10975
3.0
2.7
2.9
2.2
0.702
0.418
Age gt 65 yrs
6257
7.1
6.0
5.2
4.4
Non-Diabetic
13400
4.2
3.6
3.6
2.8
0.836
0.567
Prev Diabetic
3831
5.6
4.9
4.1
3.6
No Inhosp GPIIb/IIIa
12288
3.9
3.5
3.1
2.5
0.465
0.894
GPIIb in hosp
4936
6.0
4.7
5.2
4.1
No Prot Pump Inhib
7675
3.8
3.2
3.1
2.3
0.408
0.613
Prot Pump Inhib
5557
5.7
4.2
4.8
3.3
Non-smoker
10845
4.9
4.6
3.9
3.5
0.045
0.050
Current Smoker
6380
3.8
2.6
3.4
2.1
ASA Low
8620
4.2
4.3
3.6
3.2
0.024
0.191
ASA High
8612
4.8
3.5
3.8
2.7
Double Dose Better
Double Dose Better
0.50
1.50
0.50
1.50
50
Clopidogrel Double vs Standard DoseBleeding
Overall Population
Clopidogrel Clopidogrel
Standard N12579 Double N12508 Hazard Ratio 95 CI P

TIMI Major 0.95 1.04 1.09 0.85-1.40 0.50
CURRENT Major 2.0 2.5 1.25 1.05-1.47 0.01
CURRENT Severe 1.5 1.9 1.23 1.02-1.49 0.03
Fatal 0.11 0.13 1.15 0.56-2.35 0.71
ICH 0.05 0.03 0.67 0.19-2.37 0.53
RBC transfusion 2U 1.76 2.21 1.26 1.06-1.51 0.01
CABG-related Major 0.9 1.0 1.10 0.85-1.42 0.48
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TRITON TIMI 38 Study Design
ACS STEMI (35) or UA/NSTEMI) Planned PCI
N 13,608
ASA
Double-blind
PRASUGREL 60 mg LD/ 10 mg MD
CLOPIDOGREL 300 mg LD/ 75 mg MD
Median duration of therapy - 12 months
1o endpoint CV death, MI, Stroke 2o
endpoints CV death, MI, Stroke, Rehosp-Rec
Isch CV death, MI, UTVR Stent
Thrombosis (ARC definite/prob.) Safety
endpoints TIMI major bleeds, Life-threatening
bleedsKey Substudies Pharmacokinetic, Genomic
NEJM 2007
NEJM 2009
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TRITON TIMI 38 Primary Endpoint CV Death, MI,
Stroke
15

Clopidogrel
12.1(781)
9.9 (643)
10
Primary Endpoint ()
Prasugrel
HR 0.81(0.73-0.90)P0.0004
HR 0.80P0.0003
HR 0.77P0.0001
5
NNT 46
Days
0
0
30
60
90
180
270
360
450
Days
NEJM 2007
NEJM 2009
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TRITON TIMI 38 Stent Thrombosis (Definite
Probable)

3
Any Stent at Index PCI N 12,844
2.4(142)
Clopidogrel
2
Endpoint ()
1.1 (68)
1
Prasugrel
HR 0.48P lt0.0001
NNT 77
0
0
30
60
90
180
270
360
450
Days
NEJM 2007
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TRITON TIMI 38 CV Death, MI, StrokeMajor
Subgroups
Reduction in risk ()
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UA/NSTEMI


B
21
STEMI
21
Male
12
Female
25
lt65
14
65-74
Age
6
gt75
14
No DM
30
DM
20
BMS
18
DES
21
GPI
16
No GPI
14
CrCl lt 60
20
CrCl gt 60
Pinter NS
19
OVERALL
0.5
1
2
Prasugrel Better
Clopidogrel Better
HR
NEJM 2007
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TRITON TIMI 38 (STEMI 3534 pt)
CVD nf MI nf Stroke
CVD nf MI Urg target v revas.
TIMI Major bleeding
Stent thrombosis
Lancet 2009
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TRITON TIMI 38 Bleeding Events
ICH in Pts w Prior Stroke/TIA (N518)
Clopidogrel
Prasugrel
Clop 0 (0) Pras 6 (2.3) (P0.02)
Events
P0.01
P0.74
P0.002
P0.03
P0.23
NEJM 2007
NEJM 2007
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PLATO study design
NSTE-ACS (mod-to-high risk) STEMI 37 (if primary
PCI) Clopidogrel-treated or -naive randomised
within 24 hours of index event (N18,624)
Clopidogrel If pre-treated, no additional loading
dose if naive, standard 300 mg loading
dose, then 75 mg qd maintenance (additional 300
mg allowed pre PCI)
Ticagrelor 180 mg loading dose, then 90 mg bid
maintenance (additional 90 mg pre-PCI)
612-month exposure
Primary endpoint CV death MI Stroke Primary
safety endpint Total major bleeding
NEJM 2009
NEJM 2009
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PLATO Risultati end-point primario
(CVDMIStroke)
8
8
6.60
Clopidogrel
6
6
Clopidogrel
5.43
5.28
4.77
4
Cumulative incidence ()
4
Cumulative incidence ()
Ticagrelor
Ticagrelor
2
2
HR 0.88 (95 CI 0.771.00), p0.045
HR 0.80 (95 CI 0.700.91), plt0.001
0
0
0
10
20
30
31
90
150
210
270
330
Days after randomisation
Days after randomisation
No. at risk
8,763
Ticagrelor
9,333
8,942
8,827
8,673
8,397
6,480
8,543
7,028
4,822
8,688
Clopidogrel
9,291
8,875
8,763
8,437
6,945
4,751
8,688
8,286
6,379
Excludes patients with any primary event during
the first 30 days
NEJM 2009
Wallentin L et al. N Engl J Med 200910.1056
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PLATO Time to major bleeding primary safety
event
15
Ticagrelor
11.58
11.20
10
Clopidogrel
K-M estimated rate ( per year)
5
HR 1.04 (95 CI 0.951.13), p0.434
0
0
60
120
180
240
300
360
Ticagrelor
9,235
7,246
6,826
5,129
3,783
3,433
6,545
Clopidogrel
9,186
7,305
6,930
6,670
5,209
3,841
3,479
NEJM 2009
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PLATO-STEMI
18,758 patients enrolled in PLATO
STEMI 8,430 patients
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 N4,181
Safety population N4,165
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PLATO-STEMI Primary endpoint CV death, MI or
stroke
12 11 10 9 8 7 6 5 4 3 2 1 0
Clopidogrel
11.0
9.3
Ticagrelor
K-M estimated rate ( per year)
HR 0.85 (95 CI 0.740.97), p0.02
0 1 2 3 4 5 6 7 8 9 10 11 12
Months
Steg PG ESC 2009
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PLATO Stent thrombosis
NEJM 2009
PLATO-STEMI Stent thrombosis
Steg PG ESC 2009
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PLATO-STEMI Primary safety event major bleeding
10 8 6 4 2 0
Clopidogrel
9.3
9.0
Ticagrelor
K-M estimated rate ( per year)
HR 0.96 (95 CI 0.831.12), p0.63
0 1 2 3 4 5 6 7 8 9 10 11 12
Months
Steg PG ESC 2009
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PCI Recommendations Class I
(Classe I Evidenza C)
2008
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Ancillary Therapy to Reperfusion (2004)

• Unfractionated heparin (UFH) should be given
• intravenously in
• Patients undergoing PCI or surgical
  revascularization
• After alteplase, reteplase, tenecteplase
• After streptokinase, anistreplase, urokinase in
  patients at high risk for systemic emboli.

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Considerazioni finali (1)

• La PTCA va considerata sempre e comunque un
  trattamento Farmaco-invasivo
• Forse è meglio abbandonare i termini Facilitata
  e Rescue perché potentially misleading
  labels as-soon-as-possible o timely
  dovrebbero diventare il nuovo parametro di
  riferimento.
• La trombolisi rimane una buona scelta nei
  pazienti che si presentano presto con un tempo
  D2B lungo, con valutazione angiografica
  as-soon-as-possible
• Il calcolo del rischio emorragico deve assumere
  la stessa rilevanza del calcolo del rischio
  ischemico

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Considerazioni finali (2)

• Le Linee Guida forniscono elementi utilissimi per
  la preparazione corretta e linvio alla PTCA, ma
• limplementazione delle stesse va coniugata
  sempre con
• Condizioni logistiche
• Fruibilità di risorse adeguate (SUEM 118,
  Emodinamica H24 ecc)
• Condizioni del paziente (classe Killip),
  insorgenza e durata dei sintomi, sede
  dellinfarto, età, rischio emorragico,
  comorbilità.

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Ospedale Giovanni Paolo II Lamezia Terme
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