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 leo.deluca@libero.it Conflict of interest: none

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

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

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

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 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.

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

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

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

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

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

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;10:374-377

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

# 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

% 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

‘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 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 > 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

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

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

Ongoing Tirofiban In Myocardial Infarction Evaluation: ON-TIME 2 Trial Acute myocardial infarction diagnosed in ambulance or referral center ASA + 600 mg Clopidogrel + UFH N=984 6/2006-11/2007 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

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

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

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

Bivalirudin in Primary PCI. 1-Year Results of the HORIZONS-AMI 15 12 11.9% 11.9% 9.2% 10 8 5.8% 5 HR 1.00 (95% CI 0.82-1.21) p=0.98 4 HR 0.61 (95% CI 0.48-0.78) 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 0.71-0.97) p=0.022 5 6 12 Time (months) Mehran R, et al. Lancet 2009;374:1149 23

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

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

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. Mehta @ TCT 2009; September 24; San Francisco, CA 26

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

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

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 0 200 450 0 200 450 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 0 200 450 0 200 450 Days after Randomization Days after Randomization Montalescot G, et al. Lancet 2009;373:723 29

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 14-18 2009; Orlando, FL

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.

32

33

34