1. Degli Studi e dei Registri: sul Territorio
Convegno Area Emergenza-Urgenza ANMCO
Preparazione alla PTCA nelle
Sindromi Coronariche Acute
Roma, 20 Marzo 2010
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 Sciences
Interventional Cardiology Unit
European Hospital
Rome, Italy
Conflict of interest: none

2. Symptoms onset and identification
Factors Associated with Delays in
Mechanical Reperfusion Tx
Cath Lab
Symptoms onset and identification
Call EMS
Pre-hospital phase ER
Increasing Loss of Myocytes 2

3. Symptoms onset and identification
Factors Associated with Delays in
Mechanical Reperfusion Tx
Cath Lab
Symptoms onset and identification
Call EMS
Pre-hospital phase ER
Increasing Loss of Myocytes 3

4. Symptoms onset and identification
Factors Associated with Delays in
Mechanical Reperfusion Tx
Cath Lab
Symptoms onset and identification
Call EMS
Pre-hospital phase ER
Increasing Loss of Myocytes 4

5. 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

6. Transport in STEMI Networks: 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.

7. Symptom onset to balloon inflation
Clinical Impact of Direct Referral to PCI Following pre-H Diagnosis of STEMI
PRAGUE-1
PRAGUE-2
MAASTRICT
DANAMI-2
Terkelsen et al.
Aashein et al.
Symptom onset to balloon inflation
(minutes) .
No prehospital diagnosis
Admission to local hospital
Subsequently transferred
to interventional hospital
Prehospital diagnosis
Admission to local hospital
Subsequently transferred
to interventional hospital
Prehospital diagnosis
Local hospital bypassed.
Patients rerouted directly
to interventional hospital
Terkeisen et al. J Electrocardiology 2005; 36: 187

8. Is Possible to Apply These Findings in a “Real World” Setting?8

9. The Vienna STEMI Registry
Implementation of Guidelines Improve the
Standard of Care
The Vienna STEMI Registry
REPERFUSION THERAPY
MORTALITY
86.6%
16%
66%
9.5% %
Another exaple is the this large city Vienna (1.8 million inhabitants), where a strict implementation of the ESC guidelines for the management of STEMI was put in place. A network of hospitals with catheterization facilities offer primary PCI on a round-the-clock basis. A differential strategy is used based on delay from onset of symptoms, first medical contact, and predicted transfer time. Most patients are submitted to primary PCI (the rate increased from 16 to 60%), but patients presenting within 2 h following onset of symptoms, and patients with a long transfer time are submitted to thrombolytic treatment. This has led to a reduction in mortality from 16 to 9.5%, including patients who are not submitted to any reperfusion for whatever reason,
PRE
POST
PRE
POST
EMS coordinated with 5 Heart Hospitals
Rotated 24 hr PCI availability
Evaluated frequency of PCI and Lytics
Evaluated Mortality
Kalla K, et al. Circulation 2006;113:2398

10. The Ottawa Hospital Institute STEMI Regional Program
We developed a care delivery model to improve survival of patients with ST-segment elevation myocardial infarction with the use of systematic primary PCI for the 800,000 people living in the Ottawa metropolitan area. This project required a redesign of the traditional care of these patients, the development of new protocols for ambulance transport, changes in physician-referral patterns, and changes in emergency department protocols.
We sought to determine whether there was a difference in door-toballoon times between patients who were referred directly from the field by paramedics trained in the interpretation of electrocardiograms and patients who were referred by emergency department physicians. 10

11. The Citywide Ottawa Program Time to Treatment
Field transf
Inter-hosp. transf
p<0.001
p<0.001
Proportion of Patients (%)
ECG to Balloon Time
Field
transfers
Interhospital
transfers %
The median door-to-balloon time was shorter in patients referred from the field (69 minutes; interquartile range, 43 to 87) than in patients needing interhospital transfer (123 minutes; interquartile range, 101 to 153; P<0.001). Door-to-balloon times of less than 90 minutes were achieved in 79.7% of patients who were transferred from the field and in 11.9% of those transferred from emergency departments (P<0.001).
Guideline door-to-balloon-times were more often achieved when trained paramedics independently triaged and transported patients directly to a designated primary PCI center than when patients were referred from emergency departments
P<0.001
DTB<90 min
DTB<120 min
Minutes
Le May RM et al. N Engl J Med 2008;358:231

12. Establishing Infarct Networks Medical Response Delay
Door to Balloon Time < 90 min
85.7%
51%
37.5%
No EMS
12 Lead
EMS
12 Lead
EMS12 Lead
Pre-Arrival Activation
Prehosp Emerg Care 2006;10:

13. Comparison of Existing Prehospital ECG Programs
Location
Prehospital ECG Interpretation
Activate Catheterization Lab en Route to Hospital
Bypass Non-PCI Hospitals
Boston
Am 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 County
Am 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 Carolina
JAMA. 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)
Ottawa
N Engl J Med. 2008;358:231
Mixed (activation by paramedic through a central page operator)
Yes (for all patients with STEMI)
Several studies have examined the feasibility of EMS providers identifying STEMI using prehospital ECGs with or without wireless transmission. 13

14. # of Pts Treated Earlier with Prehospital Thrombolysis
Data from the ER-TIMI-19 Trial
97%
49%
% Treated Pts
48%
Pre-H Thrombolysis
In-H Thrombolysis 5% 20 40 60 80
100
120
140
Time from Ambulance Arrival (min)
Morrow DA, et al. J Am Coll Cardiol. 2002;40:71

15. % Pts with Angiographic
Pre-hospital Thrombolysis
as Facilitation to Primary PCI
(p=0.003, Group B vs. C+DNT)
% Pts with Angiographic
Perfusion Score 10
(n=19)
(n=18)
(n=23) A B C
Pre-H Thrombolysis
Full Dose
Pre-H Thrombolysis
½ Dose + Urgent PCI
Primary PCI
(not eligible to
lysis or excluded)
Smalling RW, et al. J Am Coll Cardiol. 2007;50:1612

16. ‘High Risk’ ST Elevation MI within 12 hours
The TRANSFER AMI
Trial
‘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 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
> 24 hrs later
Repatriation of stable patients within 24 hrs of PCI
* ST segment resolution < 50% & persistent chest pain, or hemodynamic instability
Cantor WJ, et al. N Engl J Med 2009;360:2705

17. 30-Day Death, re-MI, CHF, Severe Recurrent Ischemia, Shock
% of Patients 18
16.6 16 14
OR=0.537 (0.368, 0.783); p=0.0013 12
10.6 10 8 6 4
Standard (n=496)
Pharmacoinvasive (n=508)
32.5 vs 2,8 hours after randomization
There were no significant differences between the groups in the incidence
of major bleeding.
Conclusions
Among high-risk patients who had a myocardial infarction with ST-segment elevation
and who were treated with fibrinolysis, transfer for PCI within 6 hours after
fibrinolysis was associated with significantly fewer ischemic complications than
was standard treatment 2 5 10 15 20 25 30
Days from Randomization
n=496
n=508
422
468
415
466
415
463
414
461
414
460
412
457
Cantor WJ, et al. N Engl J Med 2009;360:2705

18. TIMI 3 Patency Before Primary PCI in
Randomized Trials on GP IIb/IIIa Inhibitors
TIMI 3 Flow (%)
Early
Late or no GP IIb/IIIa blocker use 70 60 60 50 40 34 32 32 29 30 27 25 20 19 20 16 16 17 15 11 10 10 14 10 8 7 5 2
Zorman
ERAMI
ADMIRAL
TIGER-PA
INTAMI
TNK
Reo-Mobile
ReoPro-
Cutlip
On-TIME
TITAN
bridging
Abciximab
Tirofiban
Integrilin
Lysis

19. Ongoing Tirofiban In Myocardial Infarction Evaluation: ON-TIME 2 Trial
Acute myocardial infarction
diagnosed in ambulance or referral center
ASA mg Clopidogrel + UFH
N=984
6/ /2007
Placebo
Tirofiban *
Transportation
Angiogram
PCI center
Angiogram
Tirofiban
provisional
PCI
Tirofiban
cont’d
*Bolus: 25 µg/kg & 0.15 µg/kg/min infusion
Van’t Hof AW, et al. Lancet. 2008;372:537 19

20. Cumulative ST- Deviation over Time
Ongoing Tirofiban In Myocardial Infarction Evaluation: ON-TIME 2 Trial
Cumulative ST- Deviation over Time
[mm]
14.5±9.1
14.3±9.1
12.1±9.4
10.9±9.2
5.9±8.1
4.8±6.3
4.4±5.3
3.3±4.3
p=0.84
0.028
0.022
0.002
Van’t Hof AW, et al. Lancet. 2008;372:537 20

21. Residual ST-Deviation and Mortality
Ongoing Tirofiban In Myocardial Infarction Evaluation: ON-TIME 2 Trial
Residual ST-Deviation and Mortality %
Van’t Hof AW, et al. Lancet. 2008;372:537 21

22. The EUROTRANSFER Registry:
Impact of Prehospital Abciximab on TIMI flow
p<0.0001
p<0.001
Before PCI
After PCI
Dudek D, et al. Am Heart J 2008;156:1147

23. Bivalirudin in Primary PCI. 1-Year Results of the HORIZONS-AMI15 12
11.9%
11.9%
9.2% 10 8
5.8% 5
HR 1.00 (95% CI )
p=0.98 4
HR 0.61 (95% CI )
p=0.0001 6 12 6 12
Time (months)
Time (months) 20
direct thrombin inhibitor bivalirudin
In high-risk patients with STEMI undergoing primary PCI, anticoagulation with bivalirudin reduced the rates of net adverse clinical events and major bleeding at 1 year compared with treatment with heparin plus a GPI. This finding has important clinical implications for the selection of optimum treatment strategies for patients with STEMI.
All-cause mortality and cardiac mortality at 1 year were also substantially reduced in patients assigned to bivalirudin compared with those assigned to heparin plus a GPI. Although the benefits of bivalirudin treatment were present at 30 days (including improved survival), cardiac death, reinfarction, and composite death or reinfarction also occurred less frequently in the bivalirudin group than in the control group between 30 days and 1 year, contributing to the improved outcomes at 1 year.
18.3%
Bivalirudin (n=1800) 15
15.6%
Control (n=1802) 10
HR 0.83 (95% CI )
p=0.022 5 6 12
Time (months)
Mehran R, et al. Lancet 2009;374:1149 23

24. Feasibility and Safety of Prehospital
Administration of Bivalirudin During STEMI * * * * %
*: p<0.05
Sejersten, M, et al. Am J Cardiol 2009;103:1635

25. Clopidogrel LD in Pts Undergoing Primary PCI Results from the HORIZONS-AMI
Bivalirudin
300 mg Loading Dose
p=0,004
600 mg Loading Dose
p=0,02
Unfractioned Heparin
plus Glycoprotein
IIb/IIIa Inhibitors
p=0,07
Dangas G, et al. J Am Coll Cardiol 2009;54:1438

26. Standard clopidogrel (n=3175) Double-dose clopidogrel (n=3171)
Clopidogrel: Double vs SD.
STEMI PCI Cohort
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
1.4
1.16 (0.75–1.78)
CURRENT severe
0.9
1.1
1.18 (0.72–1.93)
the study is a 2x2 factorial, randomized trial studying the optimal doses of clopidogrel and aspirin
Of the original 17 232 patients undergoing PCI, 6346 patients presented with STEMI, a significant majority of whom underwent primary PCI.
S. TCT 2009; September 24; San Francisco, CA 26

27. Clopidogrel Administered Pre-h to Improve Primary PCI: the CIPAMI Study
Clopidogrel 600 mg
Treatment according to investigator
n = 654
with STEMI
Acute STEMI <6h
Angina >20 min
ST elevation >2 leads or
new/presumed LBBB
Primary angiography
Primary endpoint
(Secondary endpoints)
Death, Re-MI, TVR
PCI R
Aspirin + UFH/enoxaparin
Topic: Pre-treatment with clopidogrel in primary PCI
Clopidogrel, in combination with acetylsalicylic acid (ASA), has become a mainstay of the pharmacological therapy for patients with acute coronary syndromes, especially in those undergoing percutaneous coronary interventions (PCI). Although studies have shown that pre-treatment with a loading dose of clopidogrel 300 or 600 mg before PCI is effective in reducing cardiovascular complications, the optimal dose and timing in various patient groups is still unclear.
The primary objective of the present randomised, open-label Clopidogrel to Improve Primary percutaneous coronary Intervention in Acute Myocardial Infarction (CIPAMI) study is to evaluate the efficacy and the safety of a 600 mg loading dose of clopidogrel in addition to standard ASA/heparin treatment in the pre-hospital setting in 654 patients with acute ST-elevation myocardial infarction scheduled for primary PCI. The primary efficacy endpoint is the TIMI 2/3 patency of the infarct-related artery immediately prior to PCI.
n = 327
No loading
Clopidogrel loading prior to PCI strongly recommended
Pre-hospital
Hospital until discharge or day 7
Zeymer U et al. Cardiology 2007;108:265
Zeymer U et al. Cardiology 2007;108:265–272

28. Three Different LD of Clopidogrel Administered
at FMC in AMI. The LOAD & GO Trial
Clopidogrel 600 mg
n = 150
with STEMI
Acute STEMI <12h
Angina >30 min
ST elevation >0.2 mV in >2 leads or
new/presumed LBBB
Clopidogrel
300 mg
None
(Primary endpoints)
TMPG
PCI R
Aspirin + UFH/enoxaparin
Clopidogrel 900 mg
Pre-hospital
P.I.s: Leonardo Bolognese and Kenneth Ducci
Ospedale S. Donato, Arezzo 28

29. Prasugrel in Primary PCI. Data from TRITON-TIMI 38
CV death/non-fatal MI/non-fatal stroke
CV death/non-fatal MI/urgent TVR
Clopidogrel
Prasugrel 15 10 5
p=0.0017
p=0.0221
p=0.0205
p=0.0250
Stent Thrombosis
TIMI major bleeding (no CABG) 15
3534 participants presenting with STEMI
third-generation thienopyridine and a more potent blocker of the platelet P2Y12 receptor than clopidogrel, producing consistent platelet inhibition 10 5
p=0.0084
p=0.0232
p=0.3359
p=0.6451
Days after Randomization
Days after Randomization
Montalescot G, et al. Lancet 2009;373:723 29

30. PLATO Randomized Trial. STEMI Cohort
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
Primary safety event: major bleeding
9.0
0.96
0.63
Ticagrelor is an oral, reversible, direct-acting inhibitor of the adenosine diphosphate
receptor P2Y12 that has a more rapid onset and more pronounced platelet
inhibition than clopidogrel.
Methods
In this multicenter, double-blind, randomized trial, we compared ticagrelor (180-mg
loading dose, 90 mg twice daily thereafter) and clopidogrel (300-to-600-mg loading
dose, 75 mg daily thereafter) for the prevention of cardiovascular events in 18,624
patients admitted to the hospital with an acute coronary syndrome, with or without
ST-segment elevation.
@ AHA 2009; November ; Orlando, FL

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

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