STEMI: ΥΠΑΡΧΕΙ ΘΕΣΗ ΓΙΑ ΤΗ ΘΡΟΜΒΟΛΥΣΗ;

Transcript

1 STEMI: ΥΠΑΡΧΕΙ ΘΕΣΗ ΓΙΑ ΤΗ ΘΡΟΜΒΟΛΥΣΗ; AΘΑΝΑΣΙΟΣ Ν. ΚΑΡΤΑΛΗΣ ΕΠΙΜΕΛΗΤΗΣ Α ΚΑΡΔΙΟΛΟΓΙΚΗ ΚΛΙΝΙΚΗ Γ.Ν. ΧΙΟΥ

2 DISCLOSURE -

3 REPERFUSION THERAPY IN STEMI PRIMARY PCI is defined as percutaneous intervention in the setting of STEMI without previous or concomitant fibrinolytic treatment. FIBRINOLYSIS

4 Quantitative review of 23 trials of primary angioplasty versus thrombolysis (n=7739) Short-term clinical outcomes 15,0% 10,0% 5,0% 14,0% Primary PCI Thrombolysis p= ,0% p< p< ,0% 5,0% 3,0% 8,0% p= ,0% 1,0% 0,0% Death Re-MI Stroke p< ,0% 0,1% Haem stroke Any event Keeley, Lancet 2003;361:13

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6 If cardiogenic shock, immediate transfer to PCI center

7 2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction Reperfusion Therapy for Patients with STEMI *Patients with cardiogenic shock or severe heart failure initially seen at a non PCI-capable hospital should be transferred for cardiac catheterization and revascularization as soon as possible, irrespective of time delay from MI onset (Class I, LOE: B). Angiography and revascularization should not be performed within the first 2 to 3 hours after administration of fibrinolytic therapy.

8 It is currently estimated that about 66% of patients achieve a guidelinerecommended overall first-hospital-door-to-balloon time of 120 minutes.

9 In settings where primary PCI cannot be performed in a timely fashion, fibrinolysis should be considered, particularly if it can be administered prehospital (e.g. in the ambulance) within the first 120minutes after symptom onset. It should be followed by transfer to PCI-capable centers for routine coronary angiography in all patients and for rescue PCI in case of unsuccessful fibrinolysis.

10 Twenty-five trials, which enrolled 7743 patients. The primary endpoint of this pooled analysis was all-cause mortality at 30 days.

11 Sensitivity analyses of the use of accelerated t-pa and of the inclusion of trials with tabular data The Primary Coronary Angioplasty vs. Thrombolysis (PCAT)-2 Trialists' Collaborative Group FMCTB <90 min FL<120 min Boersma E et al. Eur Heart J 2006;27:

12 In settings where primary PCI cannot be performed in a timely fashion, fibrinolysis should be considered, particularly if it can be administered prehospital (e.g. in the ambulance) within the first 120minutes after symptom onset.

13 Time is Muscle

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15 Mortality and Prehospital Thrombolysis for Acute Myocardial Infarction: A Meta-analysis 6 randomized trials (n=6434) 0.83 (95% CI, ; P=.03) Prehospital thrombolysis reduced the relative risk of all-cause hospital mortality by 17%. The absolute risk reduction of 2% translates into 1 life saved for every 62 patients with overt AMIs who accessed the regional prehospital system and were treated with thrombolytics in the prehospital rather than in-hospital setting. Diagonal line represents equal rates. Above diagonal, favors in-hospitalthrombolysis; below diagonal, favors prehospital thrombolysis. Rate is measured as total number of deaths per total number of patients treated in either group. Laurie J. Morrison et al. JAMA. 2000;283(20):

16 Comparison of primary PCI and prehospital thrombolysis in acute MI (CAPTIM n=840) Events at 30 days 10% 8% 6% Primary PCI Pre-hospital alteplase (rescue PCI 26%) 6,2% 4,8% 4% 2% 0% 8,2% 3,8% P=0.61 P=0.29 Death Death, re-mi, CVA Symptoms to lysis 130 min Symptoms to balloon 190 min Bonnefoy, Lancet 2002;360:825

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19 Pre-hospital FL p=ns Primary PCI Survival according to randomized treatment assignment. [Pre-hospital fibrinolysis group (broken line) and PCI group (solid line).] Underneath the graph are the numbers of patients at risk for each time point (those who survived and had been at least followed up to this point). Bonnefoy E et al. Eur Heart J 2009;30: The 5-year follow up analysis of the CAPTIM trial confirms the initial trends observed at 30 days. A strategy of prehospital fibrinolysis with immediate transfer to an interventional facility for rescue angioplasty if needed appears to yield long-term survival similar to that of primary angioplasty. Those results do not challenge the general consensus concerning the superiority of timely PCI over inhospital fibrinolysis.

20 p=0.04 For patients treated within 2 h of symptom onset, 5-year mortality was lower with prehospital lysis. p=ns Bonnefoy E et al. Eur Heart J 2009;30:

21 1 Year Mortality

22 ΑΧΙΛΛΕΙΟΣ ΠΤΕΡΝΑ ΤΗΣ ΘΡΟΜΒΟΛΥΣΗΣ Ασθενείς με καρδιογενές shock. Ασθενείς που εμφανίζονται μετά από 6 ώρες από την έναρξητων συμπτωμάτων (late presenters). Ασθενείς με αντενδείξεις θρομβόλυσης.

23 STEMI: Fighting with the clot Fibrin Platelets Plasminogen activators - t-pa - r-pa - TNK-tPA Antiplatelet therapy - aspirin - dihydropyridines - GP IIb/IIIa inhibitors Thrombin Antithrombin therapy - Heparin -LMWH -Fondaparinux -Bivalirudin

24 Brief Review of Thrombolytic Trials GISSI-1: Streptokinase 18% reduction in mortality at 21 d GUSTO-1: tpa 15% reduction in 30-day mortality compared to Streptokinase GUSTO-3: Reteplase had no benefit over tpa but is easier to use (double bolus) ASSENT-2: TNK was similar to tpa but with less non-cerebral bleeding : Single bolus, fibrin selective, resistance to PAI-1 *Overall risk of ICH is 0.7%; Strokes occurred in 1.4%

25 over 2 min over 5 sec

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28 ΚΙΝΔΥΝΟΣ ΓΙΑ ΕΓΚΕΦΑΛΙΚΗ ΑΙΜΟΡΡΑΓΙΑ ΑΠΟ ΘΡΟΜΒΟΛΥΣΗ 0,025 0,02 2,17% 0, ΑΥΞΗΜΕΝΗ ΗΛΙΚΙΑ 1,32% 0,96% 0,01 0,005 ΠΑΡΑΓΟΝΤΕΣ ΚΙΝΔΥΝΟΥ: Μέσο ποσοστό ενδοκρανιακής αιμορραγίας 0,75% 2. ΥΠΕΡΤΑΣΗ ΚΑΤΑ ΤΗΝ ΠΡΟΣΕΛΕΥΣΗ 3. ΧΑΜΗΛΟ ΣΩΜΑΤΙΚΟ ΒΑΡΟΣ 0,26% ΑΡΙΘΜΟΣ ΠΑΡΑΓΟΝΤΩΝ ΚΙΝΔΥΝΟΥ ΓΙΑ ΕΓΚΕΦΑΛΙΚΗ ΑΙΜΟΡΡΑΓΙΑ Simons et al: Lancet 1993

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30 Fibrinolytic Therapy in Patients 75 Years and Older With ST-Segment Elevation Myocardial Infarction: One-Year Follow-up of a Large Prospective Cohort 13% p=0.001 (n = 6891) by multiple Cox regression analysis at the mean of all covariates; relative risk, 0.87; 95% confidence interval, 0.80 to 0.94; P =.001. Adjusted probability of death or cerebral bleeding in patients receiving and not receiving fibrinolytic therapy at 30 days was 23% and 26% and at 1 year was 32% and 36%, respectively. Arch Intern Med. 2003;163(8):

31 Reinfarction:Repeat Fibrinolysis vs Conservative Treatment REACT trial Outcomes If there is evidence of reinfarction with recurrence of ST-segment elevation the patient should be immediately transferred to a hospital with PCI capabilities. If PCI is not available, a second administration of a non-immunogenic fibrinolytic agent may be considered, if there is a large infarct and if the risk of bleeding is not high 20 p = 0.14 Patients (%) 15, ,7 p = 0.03 p = ,6 11,8 p = ,5 4,3 5 7,8 2,7 0 Mortality ReMI Repeat fibrinolysis Repeat fibrinolysis was not associated with significant improvements in allcause mortality or reinfarction, and it also showed an increased risk for minor bleeding. Major Bleed Minor Bleed Conservative treatment Wijeysundera HC, et al. JACC. 30 Jan 2007:49(4):

32 2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction Adjunctive Antiplatelet Therapy With Fibrinolysis I IIa IIb III Aspirin (162- to 325-mg loading dose) and clopidogrel (300-mg loading dose for patients 75 years of age, 75-mg dose for patients >75 years of age) should be administered to patients with STEMI who receive fibrinolytic therapy. I IIa IIb III aspirin should be continued I IIa IIb III clopidogrel (75 mg daily) for at least 14 days I IIa IIb III o and up to 1 year

33 2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction Adjunctive Antithrombotic Therapy to Support Reperfusion With Fibrinolytic Therapy

34 2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction Adjunctive Antithrombotic Therapy to Support PCI After Fibrinolytic Therapy (cont.) *Balloon angioplasty without stent placement may be used in selected patients. It might be reasonable to provide P2Y 12 inhibitor therapy to patients with STEMI undergoing balloon angioplasty after fibrinolysis alone according to the recommendations listed for BMS. (Level of Evidence: C)

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36 Benefit seen despite high cath/pci rates in Standard Treatment group (~40% rescue PCI)

37 ACC, 2013

38 1892 patients randomized by 99 sites in 15 countries After 20% of the planned recruitment, the TNK dose was reduced by 50% among patients 75 years of age.

39 STREAM STUDY - 30 days RESULTS Pharmaco-invasive PPCI (N=944) (N=948) All cause death (43/939) 4.6% (42/946) 4.4% 0.88 Cardiac death (31/939) 3.3% (32/946) 3.4% 0.92 Congestive heart failure (57/939) 6.1% (72/943) 7.6% 0.18 Cardiogenic shock (41/939) 4.4% (56/944) 5.9% 0.13 Reinfarction (23/938) 2.5% (21/944) 2.2% ,4% 14,3% 0,21 Primary end poind (all cause death,chf,remi, shock) P-value

40 STREAM STUDY: STROKE RATES Pharmaco-invasive PPCI P-value 15/939 (1.60%) 5/946 (0.53%) /939 (0.75%) 4/946 (0.42%) /939 (0.96%) 2/946 (0.21%) /939 (0.64%) 2/946 (0.21%) /747 (1.20%) 5/756 (0.66%) /747 (0.40%) 4/756 (0.53%) > /747 (0.54%) 2/756 (0.26%) /747 (0.27%) 2/756 (0.26%) >0.999 TOTAL POPULATION (N=1892) Total stroke fatal stroke Haemorrhagic stroke fatal haemorrhagic stroke POST AMENDMENT POPULATION (N=1503) Total stroke fatal stroke Haemorrhagic stroke fatal haemorrhagic stroke

41 STREAM STUDY:IN-HOSPITAL BLEEDING COMPLICATIONS Major non-ich Pharmacoinvasive (N=944) PPCI (N=948) P-value 6.5% 4.8% % 20.2% % 2.3% 0.47 bleeding Minor non-ich bleeding Blood transfusions

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44 Thrombolysis per inhabitants in 37 ESC countries 2010/2011 2η Kristensen S D et al. Eur Heart J 2014;35:

45 No reperfusion therapy per inhabitants in 37 ESC Countries 2010/2011 5η Kristensen S D et al. Eur Heart J 2014;35:

46 REPERFUSION THERAPIES IN GREECE 100% 90% 32% 80% 70% 60% 50% 50% NO THERAPY THROMBOLYSIS 40% P-PCI 40% 30% 41% 20% 10% 0% Rescue PCI: 7,4% Pharmacoinvasive: 6,4% 28% 9% HELIOS 2006 Thrombolysis pts: STENT FOR LIFE 2011

47 H πρωτογενής αγγειοπλαστική είναι στο STEMI η θεραπεία εκλογής. Στην Ελλάδα των πολλών νησιών και των ορεινών απομακρυσμένων περιοχών με κακό οδικό δίκτυο, είναι δύσκολο οι ασθενείς με STEMI να διακομίζονται και να υποβάλλονται σε πρωτογενή αγγειοπλαστική.

48 49 Centers with cath-lab Επιπλέον, τα περισσότερα Αιμοδυναμικά Εργαστήρια στη χώρα, δεν λειτουργούν 24 ώρες το 24ωρο / 7 μέρες την εβδομάδα or only 1 Non STOP(24H/7D) p-pci CENTERS? 1 2

49 Μια καθυστερημένη πρωτογενής αγγειοπλαστική, είναι πιο καθυστερημένη από την πρωτογενή επαναιμάτωση, ειδικά στην περίπτωση που αναβάλλεται η θρομβολυτική θεραπεία σε ασθενή που προσήλθε τις 3 πρώτες ώρες, προκειμένου να διακομιστεί. PHARMACO-INVASIVE STRATEGY? Μία θεραπεία δεν ταιριάζει σε όλους, ο χρόνος μετράει.

50 ΣΥΜΠΕΡΑΣΜΑΤΑ H πρωτογενής αγγειοπλαστική είναι η θεραπεία εκλογής στο STEMI. Από την άλλη, η θρομβολυτική θεραπεία μπορεί να αποτελέσει εναλλακτική επιλογή για το STEMI, όταν η πρωτογενής αγγειοπλαστική δεν μπορεί να διενεργηθεί στους προβλεπόμενους χρόνους DI-DO<30 min και FMCTB<120 min. Όμως, είναι σημαντικό: α) H θρομβόλυση να γίνεται προνοσοκομειακά. β) Nα μπορεί ο ασθενής να διακομιστεί επειγόντως αγγειοπλαστική διάσωσης όταν απαιτείται. για γ) Nα υποβάλλονται όλοι οι ασθενείς μετά από επιτυχημένη θρομβόλυση σε στεφανιογραφία εντός 3-24 ωρών.

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52 Back up slides

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54 FL still remains a viable treatment strategy when timely PPCI is not available particularly if it can be administered pre-hospital (e.g. in the ambulance) within the first 120minutes after symptom onset. Μία θεραπεία δεν ταιριάζει σε όλους, ο χρόνος μετράει. One treatment does not fit all: time matters.

55 Primary PCI is the preferred treatment of ST-elevation myocardial infarction. However, in many areas of the world, like Greece primary PCI cannot be performed within the recommended time limits (DIDO<30 - FMCTB<120 min for non-pci hospitals). In these remote areas, thrombolysis is still the treatment of choice.

56 Fibrinolytic Therapy Trialists Collaborative Group 35 Day Outcome in patients (9 trials review) 18% reduction in mortality 25% reduction in pts with ST elevation or BBB

57 FIBRINOLYTIC THERAPY

58 Στην Ελλάδα των πολλών νησιών και των απομακρυσμένων ορεινών περιοχών με κακό οδικό δίκτυο, είναι δύσκολο οι ασθενείς με STEMI να διακομίζονται και να υποβάλλονται σε πρωτογενή αγγειοπλαστική. Επιπλέον, τα περισσότερα αιμοδυναμικά εργαστήρια στη χώρα μας δεν λειτουργούν 24 ώρες το 24ωρο/ 7 μέρες την εβδομάδα. Μια καθυστερημένη πρωτογενής αγγειοπλαστική, είναι πιο καθυστερημένη από την πρωτογενή επαναιμάτωση, ειδικά στην περίπτωση που αναβάλλεται η θρομβολυτική θεραπεία σε ασθενή που προσήλθε τις 3 πρώτες ώρες, προκειμένου να διακομιστεί. Μία θεραπεία δεν ταιριάζει σε όλους, ο χρόνος μετράει. PHARMACOINVASIVE STRATEGY?

59 Molecular structure of alteplase, reteplase, and TNK-tPA. Τα θρομβολυτικά φάρμακα στοχεύουν στη διάλυση πρόσφατα σχηματισμένων θρόμβων, ενεργοποιώντας το πλασμινογόνο σε πλασμίνη, η οποία αποδoμεί το ινώδες των θρόμβων. White H D, and Van de Werf F J J Circulation 1998;97:

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61 0,14 13% 0,12 0,1 GISSI trial ,08 10,70% 18% reduction in mortality at 21 days p= pts 0,06 0,04 0,02 0 SK Control

62 Fibrinolytic Therapy Trialists Collaborative Group 35 Day Outcome in patients (9 trials review) 11,5% 11,2% 9,6% 18% p<0.001 fibrinolytic control 1,2% Mortality 0,8% Stroke 1,1% 0,4% Major bleed Lancet 1994:343;311

63 STEMI: In hospital mortality in Greece HELIOS STENT FOR LIFE ,12 10% 0,1 0,08 0,06 0,04 M.O 0,02 TL P-PCI 0 4,70% 5,70% 11%

64 Armstrong et al.: Circulation 2001

65 DANAMI-2: Study Design High-risk ST elevation MI patients (>4 mm elevation), Sx < 12 hrs 5 PCI centers (n=443) and 22 referring hospitals (n=1,129), transfer in < 3 hrs Lytic therapy Front-loaded tpa 100 mg (n=782) Primary PCI with transfer Primary PCI without transfer (n=567) (n=223) Death / MI / Stroke at 30 Days Stopped early by safety and efficacy committee

66 DANAMI-2: Results 8% Death Recurrent MI P=0.35 P< ,6% 8% 6,6% Stroke P=0.15 8% 6,3% 6% 6% 6% 4% 4% 4% 2% 2% 0% 0% Lytic Primary PCI 1,6% Lytic Primary PCI 2% 0% 2,0% 1,1% Lytic Primary PCI

67 DANAMI-2: Primary Results Death / MI / Stroke (%) 16% P= % 12% 16% RRR 45% P=0.048 P= % 12% 8% 8% Non-Transfer Sites Transfer Sites Combined 16% RRR 40% 12% 8% 4% 4% 4% 0% 0% 0% Primary PCI RRR 45% 9% 8% Lytic 12% Lytic Primary PCI 7% Lytic Primary PCI

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71 Thrombolysis: the golden hour Absolute reduction in 35 day mortality per 1000 patients treated Lives saved per 1000 treated patients FTT data - closed circles Smaller trials - open circles Treatment delay (h) Boersma, Lancet 1996;348:771

72 RESIDUAL STENOSIS IN THE INFRACT-RELATED ARTERY AT 90 MINUTES AFTER THROMBOLYSIS 0,3 TIMI 4, 10A, 10B,14, trials, 2119 pts 25% 0,25 20% 0,2 20% 16% 0,15 10% 0,1 0,05 5% 2% 90 AFTER THROMBOLYSIS: 62% TIMI 3 FLOW IN PRIMARY PCI: 88% TIMI 3 FLOW 2% 0 Residual infract artery stenosis (%) Llevadot J, Giugliano R et al. Am J Cardiol 85:1409,2000

73 GUSTO-I Angiographic Investigators: Post-lytic TIMI Flow Predicts Mortality TIMI Flow 0,1,2 vs TIMI 3 : ~ ΜORTALITY X2 Patient Mortality (%) Days 2 Years TIMI 3 TIMI 0,1,2 90 min TIMI Flow Post-fibrinolytic Ross AM, et al. Circulation. 1998;97:

74 Coagulation and Fibrinolysis Tissue Plasminogen Activator Coagulation Factors Plasminogen Fibrinogen Plasmin Fibrin Fibrinolysis

75 The absolute mortality reduction by PPCI increased from 1.3% in patients randomized in the first hour after symptom onset to 4.2% in those randomized after 6 h. Consequently, with increasing delay, the number needed treat to prevent a death, decreased from 77 to 24 patients

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77 Primary percutaneous coronary interventions per inhabitants in 37 ESC countries. Kristensen S D et al. Eur Heart J 2014;35:

78 2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction I IIa IIb III Reperfusion therapy is reasonable for patients with STEMI and symptom onset within the prior 12 to 24 hours who have clinical and/or ECG evidence of ongoing ischemia. Primary PCI is the preferred strategy in this population. If PCI is not available, a fibrinolytic agent may be considered, if there is a large infarct and the patient is young and the risk of bleeding is not high

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80 Thrombolysis equivalence trials ceiling of benefit? 30 d mortality 10% acc alteplase lanoteplase 8% 6% 7,3% streptokinase tenecteplase 7,2% 7,5% 6,3% 6,6% 6,8% reteplase 6,2% 6,2% 4% 2% 0% GUSTO-I GUSTO-III In-TIME Assent-2

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82 1. ΠΟΙΟ ΑΠΟ ΤΑ ΠΑΡΑΚΑΤΩ ΔΕΝ ΕΙΝΑΙ ΑΠΟΛΥΤΗ ΑΝΤΕΝΔΕΙΞΗ ΘΡΟΜΒΟΛΥΣΗΣ ; Α. Διαχωριστικό ανεύρυσμα αορτής Β. Γαστρορραγία τον τελευταίο μήνα Γ. Ανθεκτική υπέρταση (συστολική> 180mmHg και διαστολική> 110mmHg) Δ. Ισχαιμικό εγκεφαλικό τους τελευταίους 6 μήνες Ε. Προηγούμενο αιμορραγικό εγκεφαλικό επεισόδιο 2 χρόνια πριν

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85 2. Ασθενής με πρόσθιο STEMI προσήλθε 1ώρα από την έναρξη των ενοχλημάτων σε non-pci Νοσοκομείο, που βρίσκεται σε απόσταση 130 λεπτών από PCI Νοσοκομείο. Τρεις ώρες μετά από την αρχικά επιτυχημένη θρομβόλυση ο ασθενής παρουσιάζει επανέμφραγμα. Ποια είναι η επόμενη ενέργεια του εφημερεύοντα με βάση τις τελευταίες κατευθυντήριες οδηγίες; Α. Να περιμένει και να αξιολογήσει εκ νέου το ΗΚΓ σε 30 λεπτά Β. Να χορηγήσει αναστολείς αιμοπεταλίων IIb IIIa Γ. Να διακομίσει άμεσα τον ασθενή για αγγειοπλαστική Δ. Να χορηγήσει ξανά θρομβόλυση

86 3. Ασθενής με πλάγιο STEMI θρομβολύθηκε σε non-pci Νοσοκομείο. Στα 60 λεπτά μετά τη χορήγηση θρομβολυτικής θεραπείας οι αρχικές ανασπάσεις έχουν ελαττωθεί 30%. Ποια είναι η επόμενη ενέργεια του εφημερεύοντα με βάση τις τελευταίες κατευθυντήριες οδηγίες, με δεδομένο ότι το πλησιέστερο PCIΝοσοκομείο βρίσκεται σε απόσταση 130 λεπτών; Α. Να περιμένει και να αξιολογήσει εκ νέου το ΗΚΓ στα 90 λεπτά Β. Να διακομίσει άμεσα τον ασθενή για αγγειοπλαστική διάσωσης Γ. Να χορηγήσει αναστολείς αιμοπεταλίων IIb IIIa Δ. Να διακομίσει τον ασθενή για αγγειοπλαστική 3 ώρες μετά τη χορήγηση της θρομβόλυσης

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88 used for AMI. Reteplase First, reconstitute two 10-U vials with sterile water (10 ml) to 1 U/mL. The adult dose of reteplase for AMI of 2 IV boluses of 10 units each; there is no weight adjustment. The first 10 U IV bolus is given over 2 minu minutes later, a second 10 U IV bolus is given over 2 minutes. Administer normal saline (NS) flush before an each bolus. Tenecteplase To reconstitute tenecteplase, mix the 50-mg vial in 10 ml sterile water (5 mg/ml). Tenecteplase is adminis a mg IV bolus over 5 seconds. The dosage is calculated on the basis of the patient s weight, as follow < 60 kg - 30 mg (6 ml) 60 to 69 kg - 35 mg (7 ml) 70 to 79 kg - 40 mg (8 ml) 80 to 89 kg - 45 mg (9 ml) 90 kg - 50 mg (10 ml) Streptokinase The adult dose of streptokinase for AMI is 1.5 million U in 50 ml of 5% dextrose in water (D5W) given IV ov minutes. Allergic reactions force the termination of many infusions before a therapeutic dose can be administered. APSAC The adult dose of APSAC (anistreplase) for AMI is 30 U given IV over 2-5 minutes

89 Fibrinolytic Therapy in Patients 75 Years and Older With ST-Segment Elevation Myocardial Infarction: One-Year Follow-up of a Large Prospective Cohort Complications of fibrinolytic therapy in relation to age. Numbers above bars are numbers of patients. Arch Intern Med. 2003;163(8):

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91 RECURRENT MI RATES IN RECENT FIBRINOLYTIC TRIALS WHICH UTILIZED A CONJUNCTIVE ANTITHROMBIN STRATEGY. Armstrong P W et al. Circulation 2003;107:

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93 Σχέση TIMI Ροής (90 min) και Θνητότητας p= ,9 7,4 4,4 TIMI 0-1 TIMI 2 MORTALITY % Simes, Circulation TIMI 3 Mortality (%)

94 APPROPRIATE PROCEDURAL VOLUME FOR p-pci Operators More than 75 interventional procedures per year, ideally at least 11 p-pci per year. Cath lab More than 200 coronary interventional procedures are performed each year, at least 36 of them being primary in nature. An institution with a volume of fewer than 200 procedures per year, unless in a region that is underserved because of geography, should carefully consider whether it should continue to offer this service. (Level of Evidence: B)

95 From: 2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines J Am Coll Cardiol. 2013;61(4):e78-e140. doi: /j.jacc Age- and sex-adjusted incidence rates of acute MI, 1999 to I bars represent 95% confidence intervals. MI indicates myocardial infarction; STEMI, ST-elevation myocardial infarction.

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97 Convincing evidence of the effectiveness of aspirin was demonstrated by the ISIS-2 trial,79 in which the benefits of aspirin and streptokinase were additive. The first dose of mg should be chewed (no enteric-coated aspirin because of slow onset of action) and a lower dose ( mg) given orally daily thereafter. If oral ingestion is not possible, aspirin can be given i.v. ( mg). In the CLARITY trial, patients 75 years were treated with a standard fibrinolytic regimen and randomized to 300 mg clopidogrel loading dose followed by 75 mg per day or placebo on top of aspirin up to and including the day of angiography with a maximum of 8 days (mean duration 3 days). By 30 days, clopidogrel therapy reduced the odds of the composite end-point of death from cardiovascular causes, recurrent myocardial infarction, or recurrent ischaemia, leading to a reduction of the need for urgent revascularization of 20%. The rates of major bleeding and intracranial haemorrhage were similar in the two groups.52 In the COMMIT study, Chinese patients of any age (but <1000 patients >75 years) with suspected myocardial infarction (93% with STEMI) were randomized to clopidogrel 75 mg (no loading dose) or placebo in addition to aspirin. Clopidogrel significantly reduced the odds of the composite of death, myocardial infarction, or stroke, corresponding to nine fewer events per 1000 patients treated for 2 weeks. Accordingly, there is a good case for the routine use of clopidogrel in the acute phase

98 MORTALITY AMONG FIBRINOLYTIC-TREATED AND CONTROL PATIENTS ACCORDING TO TREATMENT DELAY White H D, and Van de Werf F J J Circulation 1998;97:

99 STREAM STUDY - CONCLUSIONS A strategy of fibrinolysis with bolus tenecteplase and contemporary antithrombotic therapy given before transport to a PCI-capable hospital coupled with timely coronary angiography : circumvents the need for an urgent procedure in about two thirds of fibrinolytic treated STEMI patients. is associated with a small increased risk of intracranial bleeding. is as effective as primary PCI in STEMI patients presenting within 3 hours of symptom onset who cannot undergo primary PCI within one hour of first medical contact.

100 2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction Reperfusion at a Non PCI-Capable Hospital Fibrinolytic Therapy When There Is an Anticipated Delay to Performing Primary PCI Within 120 Min of FMC I IIa IIb III When fibrinolytic therapy is indicated or chosen as the primary reperfusion strategy, it should be administered within 30 minutes of hospital arrival.*

101 Indications for Fibrinolytic Therapy When There Is a >120Minute Delay From FMC to Primary PCI

102 REPERFUSION THERAPY IN STEMI

103 In this trial, 1572 STEMI patients were randomized within 12 hours of symptom onset to a fibrinolytic versus a primary percutaneous coronary intervention (PCI) strategy in both community (n=1129) and primary PCI (n=443) hospitals.19 This study integrated an inter-institutional transfer policy for those randomized to primary PCI if it could be achieved within 3 hours. The Data and Safety Monitoring Board prematurely terminated DANAMI 2 because of the perception of clear benefit of primary PCI. Although DANAMI 2 did show a substantial reduction in the composite 30-day endpoint of death, re-mi, and disabling stroke (13.7% versus 8.0%; P=0.003) in favor of the primary PCI strategy, this outcome was overwhelmingly influenced by the reduction in reinfarction (from 6.3% to 1.6%; P<0.0001). Importantly, this reduction in reinfarction occurred in a clinical environment where transfer from a community hospital was considered investigational if a mechanical intervention after fibrinolysis was needed. Hence, urgent PCI occurred in only 2.5% of patients, even though 28% of the patients were randomized in interventional institutions. An additional study, interpreted by some as impetus to move to an overall primary PCI strategy, was conducted by the Cardiovascular Patients Outcomes Research Team (C-PORT) investigators who randomized 451 STEMI patients within 12 hours of symptom onset to primary PCI versus tpa.20 Although there was no difference in mortality, there was a substantial reduction in the composite endpoints of death, re-mi, and stroke with primary PCI (17.7% versus 10.7% with tpa; P=0.03); this was again largely accounted for by a reduction in an unusually high reinfarction rate amongst fibrinolytic-treated versus PCI-treated patients (8.8% versus 4%; P=0.04). Hence, in both the aforementioned studies, which used unfractionated heparin as the antithrombin fibrinolytic partner, the recurrent infarction rate was by far the most important element in the composite endpoint and seemed unusually high relative to other trials. This is well demonstrated in Figure 2, where we compare the incidence of recurrent infarction in a number of recent STEMI studies that evaluated fibrinolysis and antithrombin therapy; it is useful to evaluate them in the context of the frequency with which mechanical cointervention with PCI was used.

104

105 J Am Coll Cardiol 2010;55:102 10

106 Kaplan-Meier curve for Secondary Endpoint 12-month Death, Reinfarction or Stroke HR =0.36 ( ); p= 0.01 Conservative Early invasive

107 Clinical outcome at 30 days RR 0.49 ( ) Conservative p=0.03 Invasive RR 0.45 ( ) p=0.14 Death, re-mi, stroke, new ischemia Death, re-mi, stroke Death

108 CARESS-in-AMI: Major results Outcome Immediate PCI (%) Rescue PCI p (%) Death, re-mi, or 4.4 refractory ischemia at 30 days* Major bleed Stroke *Primary outcome Di Mario C et al. Lancet 2008; 371:

109 ENROLMENT AND KEY DATES First patient in: March 19, 2008 Last patient in: July 26, 2012 Last patient out: Sep 7, 2012 Enrolment setting

110 PATIENTS PER COUNTRY

111 MEDIAN TIMES TO TREATMENT (min) 1st Medical Randomize IVRS contact Sx onset Rx TNK min 1st Medical contact Randomize IVRS Sx onset 61 n= min difference 31 1 Hour Rx PPCI 86 2 Hours 178 min

112 Fibrinolysis with tenecteplase and contemporary antithrombotic therapy given before transport to a PCI-capable hospital coupled with timely coronary angiography is as effective as primary PCI in STEMI patients presenting within three hours of symptom onset who cannot undergo primary PCI within one hour of first medical contact

113 INVASIVE PROCEDURES PCI performed Stents Pharmaco-invasive (N=944) PPCI (N=948) P-value 80% 90% < % 96% % 2.1% deployed CABG performed

114 MEDIAN TIMES TO TREATMENT (min) 1st Medical Randomize IVRS contact Sx onset Rx TNK 36% Rescue PCI at 2.2h min 64% non-urgent cath at 17h 1st Medical contact Randomize IVRS Sx onset 61 n=1892 Rx PPCI 31 1 Hour 86 2 Hours 178 min

115 There was a significant increase in intracranial hemorrhage (ICH) in the fibrinolysis group, which led to the dose of tenecteplase being halved in people aged 75 years and older fairly early on in the course of the trial, after which the intracranial hemorrhage rate in the fibrinolysis group was reduced to 0.5%, which was not significantly different from the PCI group.

116 Individual studies Danami II trial long term follow up.

117 Long term follow up CAPTIM trial

118 Prospective registries RIKS - HIA

119 Prospective registries RIKS - HIA

120 Prospective registries - Vienna

121 Indications for Transfer for Angiography After Fibrinolytic Therapy *Although individual circumstances will vary, clinical stability is defined by the absence of low output, hypotension, persistent tachycardia, apparent shock, high-grade ventricular or symptomatic supraventricular tachyarrhythmias, and spontaneous recurrent ischemia.

122 Individual studies Prague 2