«STEMI - Τρέχουσα θέση της Θρομβόλυσης»

«STEMI - Τρέχουσα θέση της Θρομβόλυσης» Aθανάσιος Ν. Καρτάλης Επιμελητής Α Καρδιολογική Κλινική Γ.Ν. Χίου Αμφιθέατρο Ελληνικής Καρδιολογικής Εταιρείας Παρασκευή 21 Ιουνίου 2013, Αθήνα

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

Quantitative review of 23 trials of primary angioplasty versus thrombolysis (n=7739) Short-term clinical outcomes 15,0% Primary PCI Thrombolysis p<0.0001 14,0% 10,0% 5,0% 0,0% p=0.002 p<0.0001 7,0% 7,0% 5,0% 3,0% p=0.0004 2,0% 1,0% p<0.0001 1,0% 0,1% Death Re-MI Stroke Haem stroke 8,0% Any event Keeley, Lancet 2003;361:13

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.

Time is Muscle

GISSI trial 1986 18% reduction in mortality at 21 days p=0.0002

Fibrinolytic Therapy Trialists Collaborative Group 35 Day Outcome in 58 600 patients (9 trials review) 9,6% 11,5% 11,2% fibrinolytic control 1,2% 0,8% 1,1% 0,4% Mortality Stroke Major bleed Lancet 1994:343;311

Fibrinolytic Therapy Trialists Collaborative Group 35 Day Outcome in 58 600 patients (9 trials review) 18% reduction in mortality 25% reduction in 45.000 pts with ST elevation or BBB

Lives saved per 1000 treated patients 80 60 40 20 0 0 Thrombolysis: the golden hour Absolute reduction in 35 day mortality per 1000 patients treated FTT data - closed circles Smaller trials - open circles 3 6 9 12 15 18 21 24 Treatment delay (h) Boersma, Lancet 1996;348:771

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

GUSTO-I Angiographic Investigators: Post-lytic TIMI Flow Predicts Mortality P a tie n t M o r ta lity (% ) TIMI Flow 0,1,2 vs TIMI 3 : ~ ΜORTALITY X2 16 14 12 10 8 6 4 2 0 4.6 30 Days 2 Years 7.9 TIMI 3 TIMI 0,1,2 90 min TIMI Flow Post-fibrinolytic 8 15.7 Ross AM, et al. Circulation. 1998;97:1549-1556.

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

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;97:1632-1646

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%

Armstrong et al.: Circulation 2001

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

over 2 min over 5 sec

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

2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction Adjunctive Antiplatelet Therapy With Fibrinolysis I IIa IIb III 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. aspirin should be continued indefinitely and I IIa IIb III clopidogrel (75 mg daily) for at least 14 days I IIa IIb III o and up to 1 year

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

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)

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

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 Patients (%) 20 15 10 5 0 10,7 p = 0.14 15,7 11,8 p = 0.09 6,5 p = 0.42 4,3 2,7 p = 0.03 14,6 7,8 Mortality ReMI Major Bleed Minor Bleed Repeat fibrinolysis was not associated with significant improvements in all- cause mortality or reinfarction, and it also showed an increased risk for minor bleeding. Repeat fibrinolysis Conservative treatment Wijeysundera HC, et al. JACC. 30 Jan 2007:49(4): 422-30.

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

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):965-971.

Comparison of primary PCI and prehospital thrombolysis in acute MI (CAPTIM n=840) Events at 30 days 10% 8% 6% 4% Primary PCI Pre-hospital alteplase (rescue PCI 26%) 6,2% 4,8% 3,8% 8,2% 2% P=0.61 0% Death Planned 1200 patients Symptoms to lysis 130 min Symptoms to balloon 190 min P=0.29 Death, re-mi, CVA Bonnefoy, Lancet 2002;360:825

Indications for fibrinolytic therapy

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

ACC, 2013

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.

STREAM STUDY - 30 days RESULTS:

STREAM STUDY: STROKE RATES

STREAM STUDY:IN-HOSPITAL BLEEDING COMPLICATIONS

STEMI: In hospital mortality in Greece HELIOS - 2006 STENT FOR LIFE - 2011 M.O TL P-PCI

REPERFUSION THERAPIES IN GREECE THROMBOLYSIS P-PCI Thrombolysis pts: Rescue PCI: 7,4% Pharmacoinvasive: 6,4%

42 3 Centers with cath-lab 1 ONLY 12 Non STOP(24H/7D) 1 2 8 p-pci CENTERS 2 1 1 25 1 1 1 1 2

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 (<90-120 min). In these remote areas, thrombolysis is still the treatment of choice.

IN GREECE: Most cath labs non 24h/day, 7d/week p-pci facility centers. Often Early Admission in non p-pci Centers and difficult to transfer. Delayed Primary PCI is more DELAYED than PRIMARY Reperfusion especially in the case of postponed lytic therapy due to planned Primary PCI PHARMACOINVASIVE STRATEGY?

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

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

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 PCI- Νοσοκομείο 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

Back up slides

total dose is 100 mg for patients weighing more than 67 kg. This is the most common alteplase inf parameter used for AMI. Reteplase First, reconstitute two 10-U vials with sterile water (10 ml) to 1 U/mL. The adult dose of reteplase consists of 2 IV boluses of 10 units each; there is no weight adjustment. The first 10 U IV bolus is g minutes; 30 minutes later, a second 10 U IV bolus is given over 2 minutes. Administer normal salin before and after each bolus. Tenecteplase To reconstitute tenecteplase, mix the 50-mg vial in 10 ml sterile water (5 mg/ml). Tenecteplase is in a 30-50 mg IV bolus over 5 seconds. The dosage is calculated on the basis of the patient s weigh < 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) gi minutes. Allergic reactions force the termination of many infusions before a therapeutic dose can administered. APSAC The adult dose of APSAC (anistreplase) for AMI is 30 U given IV over 2-5 minutes

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. Number s above bars are numbers of patients. Arch Intern Med. 2003;163(8):965-971.

RECURRENT MI RATES IN RECENT FIBRINOLYTIC TRIALS WHICH UTILIZED A CONJUNCTIVE ANTITHROMBIN STRATEGY. Armstrong P W et al. Circulation 2003;107:2533-2537

10 9 8 7 6 5 4 3 2 1 0 Σχέση TIMI Ροής (90 min) και Θνητότητας p=0.009 8,9 7,4 4,4 Mortality (%) TIMI 0-1 TIMI 2 TIMI 3 MORTALITY % Simes, Circulation 1995.

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)

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:10.1016/j.jacc.2012.11.019 Age- and sex-adjusted incidence rates of acute MI, 1999 to 2008. I bars represent 95% confidence intervals. MI indicates myocardial infarction; STEMI, ST- eleva on myocardial infarc on.

1/4 1/3 1/2

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 150 325 mg should be chewed (no enteric-coated aspirin because of slow onset of action) and a lower dose (75 100 mg) given orally daily thereafter. If oral ingestion is not possible, aspirin can be given i.v. (250 500 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, 80 45 852 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

MORTALITY AMONG FIBRINOLYTIC-TREATED AND CONTROL PATIENTS ACCORDING TO TREATMENT DELAY White H D, and Van de Werf F J J Circulation 1998;97:1632-1646

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.

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.*

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

REPERFUSION THERAPY IN STEMI

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.

J Am Coll Cardiol 2010;55:102 10

Kaplan-Meier curve for Secondary Endpoint 12-month Death, Reinfarction or Stroke HR =0.36 (0.16 0.81); p= 0.01 Conservative 15.9 Early invasive 6.0

Clinical outcome at 30 days RR 0.49 (0.27-0.89) p=0.03 Conservative Invasive RR 0.45 (0.18-1.16) p=0.14 Death, re-mi, stroke, new ischemia Death, re-mi, stroke Death

Outcome Death, re-mi, or refractory ischemia at 30 days* CARESS-in-AMI: Major results Immediate PCI (%) Rescue PCI (%) 4.4 10.7 0.004 Major bleed 3.4 2.3 0.47 Stroke 0.7 1.3 0.50 *Primary outcome p Di Mario C et al. Lancet 2008; 371: 559 568.

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

PATIENTS PER COUNTRY

MEDIAN TIMES TO TREATMENT (min) Sx onset 1st Medical contact Randomize IVRS Rx TNK 62 29 9 100 min Sx onset 1st Medical contact Randomize IVRS 78 min difference Rx PPCI 61 31 86 n=1892 1 Hour 2 Hours 178 min

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

INVASIVE PROCEDURES

MEDIAN TIMES TO TREATMENT (min) Sx onset 62 1st Medical contact Randomize IVRS 29 9 Rx TNK 36% Rescue PCI at 2.2h 100 min 64% non-urgent cath at 17h Sx onset 1st Medical contact Randomize IVRS Rx PPCI 61 31 86 n=1892 1 Hour 2 Hours 178 min

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.

Individual studies Danami II trial long term follow up.

Long term follow up CAPTIM trial

Prospective registries RIKS - HIA

Prospective registries RIKS - HIA

Prospective registries - Vienna

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.

Individual studies Prague 2