ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation ESC Annual Congress Munich, 2012 Thrombolysis, adjunctive pharmacology and interventions Francisco Fdez-Avilés, MD, PhD Department of Cardiology Hospital General Universitario Gregorio Marañón Complutense University of Madrid School of Medicine faviles@secardiologia.es NO CONFLICTS OF INTEREST TO DISCLOSE
2012 Issues addressed Thrombolytic drugs Angiography and intervention after lysis ( pharmacoinvasive strategy) Adjunctive antithrombotic therapy
Deaths per 1000 pts treated ESC Guidelines for STEMI Thrombolysis Evidence Highly effective, but intracranial bleeding in 1% ABSOLUTE MORTALITY REDUCTION - 30 n = 58.600-20 - 10 FTT. Lancet 1994 0-6 7-12 13-24 Delay from onset (hours) Moderate or severe 12% Bleeding GUSTO 1 (N=41021) 14% Hemo. Stroke 11.1% 13.4% 0.46% 0.54% 0.72%* 0.94%** Predictors: Advanced age Low weight Female Hypertension Prior stroke SK + SQH SK + IVH tpa + IVH Combo *P=0.003 vs SK **P<0.001 vs SK
Thrombolysis Evidence GUSTO 1 (N=41021) Highly effective, but intracranial bleeding in 1% Better outcome with fibrin-specific agents (t-pa, rt-pa, TNK). TNK: lower rate of non-cerebral bleedings and simple administration (pre-hospital) 7.2% 7.4% 7.0% 6.3%* SK + SQH SK + IVH tpa + IVH Combo *p=0.001vs SK 30-day mortality GUSTO 3 (N=15059) Reteplase Altelplase Death or disabling stroke TNK 7.4% SK Groups *p=0.006 10 deaths +1 stroke /1000 pts treated 6.9%* tpa ASSENT 2 (N=16949) Altelplase 7.24% 7.47% 26.43% P=0.0002 28.95% 30-day mortality 0.91% 0.87 % ICH 6.18% 6.15% 30-day mortality 0.93% ICH 0.94% Non Cerebral Bleeding P=0.0003 4.25% 5.45% Transfusion
Aborted Infarctions (%) ESC Guidelines for STEMI Thrombolysis Evidence Highly effective, but intracranial bleeding in 1% Better outcome with fibrin-specific agents (t-pa, rt-pa, TNK). TNK: lower rate of non-cerebral bleedings and simple administration (pre-hospital) Higher benefit if administered in < 2 hours and in a pre-hospital basis 35-day mortality according to treatment delay 22 RCTs 52246 pts Boersma E. Lancet 1996 ASSENT-ECG N = 727 (Taher T. JACC 2004) Pre-hospital vs In-hospital TL (6 RCTs, N=6434) P=0.007 104 min 162 min P=0.03 8.59% 10.23% Time to TL Pre - H JAMA 2000 Mortality In - H
Thrombolysis Recommendations
Thrombolysis Contraindications CONTRAINDICATIONS TO FIBRINOLITIC THERAPY ABSOLUTE Previous ICH or stroke of unknown origin at any time Ischemic stroke in the preceding 6 months Central nervous system damage, neoplasms or atrioventrcular malformations Recent major trauma/surgery/head injury Gastrointestinal bleeding within the past month Known bleeding disorder Aortic dissection Non-compressible punctures in the past 24 hours RELATIVE TIA in less than 3 months Oral anticoagulants Pregnancy or within 1 week post partum Refractory hypertension (systolic BP >180 mm Hg and/or diastolic BP >110 mm HG) Advanced liver disease Infective endocarditis Active peptic ulcer Prolonged or traumatic resuscitation
Thrombolysis Agents and doses
Pharmacoinvasive Strategy Evidence
Survival Percent survival ESC Guidelines for STEMI Pharmacoinvasive Strategy Evidence Postlysis TIMI & Survival (Cigarroa. AJC 2004) Lysis strongly limited by reopening failure and reocclusion TIMI 2-3 TIMI 0-1 (20-50%) years Postlysis Reocclusion & Survival. (Gibson. JACC 2004) 1 P<0.0001 No early Re-MI 0,75 Reocclusion-related Re-MI Reocclusion:5-30% Years Years 0,5 0,0 0,5 1,0 1,5 2,0
Pharmacoinvasive Strategy Evidence Lysis strongly limited by reopening failure and reocclusion Stone G. Circulation 2008. (5 RCTsTrials; N=920) Rescue-PCI is better than conservative treatment or second lysis REACT 4 Primary Composite Endpoint at 6 Months (Death, MI, CVA, or severe heart failure) p<0.001 p=0.002 31.0% 29.8% 15.3% Repeat Thrombolysis Rescue PCI Conservative Management
Primary Clinical Endpoint* One-year Survival (%) DEATH, RE-MI OR REVASCULARIZATION ESC Guidelines for STEMI Pharmacoinvasive Strategy Evidence Lysis strongly limited by reopening failure and reocclusion Rescue-PCI is better than conservative treatment or second lysis Early routine post-lysis angio/pci is better than watchful waiting strategy and could be equivalent to Primary-PCI (answer ongoing: STREAM, GRACIA-4) 1,0 0,8 0,6 0,4 0,2 0,0 0 GRACIA -1 PRIMARY ENDPOINT AT 1 YEAR GRACIA 2 (N=212) Log rank test = 0.576 Post-lysis PCI Primary PCI 90.4% 87.9% Time since randomization (months) 1 2 3 4 5 6 *: Probability of death, re-mi stroke or ischemia driven revascularization Conservative: 21% Intervention: 9% Hazard ratio 0.44 (95%CI 0.27-0.72), p=0.004 Log-rank test: p=0.0008 0 6 12 Time since randomization (months) 100 90 80 70 60 50 0 EARLY ROUTINE POST-LYSIS PCI (1.6-17 hh) (8 RCTs, 2 MA, N=3195) Rapid risk stratification Sorter stay Less acute ischemia Less early re-mi Less 1-year MACE FAST AMI (N=1714) p<0.001 Pre-hospital lysis: 94.8% Primary PCI: 91.8% In-hospital lysis: 91.8% No reperfusion: 78% Days 90 180 270 360 30 60 120 150 210 240 300 330 390
Pharmacoinvasive strategy Recommendations
Adjunctive therapy to lysis Evidence
Adjunctive therapy to lysis Evidence ANTIPLATELETS Better outcome with aspirin plus clopidogrel No evidence with prasugrel or tricagrelor Role of GP 2b/3a unclear 14% Death, re-mi or stroke 11.9% 10% 9.9% 8.8% 9,1% ISIS 2 ASA vs Placebo COMMIT CLARITY Clopidogrel vs Placebo + ASA GRACIA -3 (Tirofiban and DES in postlysis PCI) Full Perfusion Partial perfusion Failed perfusion Major Bleeding 6.1% P=0.14 2.7% Tirofiban No Tirofiban Tirofiban No Tirofiban
Adjunctive therapy to lysis Evidence ANTIPLATELETS Better outcome with aspirin plus clopidogrel No evidence with prasugrel or tricagrelor Role of GP 2b/3a unclear PARENTERAL ANTICOAGULATION Fibrin-specific lyitcs: UFH improves arterial patency (aptt > 70 deleterious) Enoxaparin better than UFH, with more noncerebral bleeding but higher net benefit SK: Fondaparinux better than UFH/Placebo in preventing re-mi and death with no excess of bleeding P<0.001 12.0%% Death or re-mi EXTRACT-TIMI 25 (UFH vs Enox in 16283 pts; fibrin-specific TL) 9.8%% UFH 0.60% P<0.001 1.14% Major bleeding (No ICH) P<0.04 ICH ENOX 0.6% 0.9% 12.7% OASIS 6 (TL Sub study; N=5436) P<0.001 10.8% Net Benefit (all deaths, MI, major bleeding) Death and Re-MI in TL pts
Adjunctive therapy to lysis Recommendations
Antithrombotics Agents and doses
Thrombolysis SUMMARY Thrombolysis is an effective therapy indicated, in the absence of contraindications, when Primary-PCI cannot be performed. It should be given very soon, preferably in the pre-hospital setting and with fibrinspecific agents Successful TL is not a final treatment and should be complemented in all patients with early angiography (3-24 h) and intervention if indicated. All TL pts should be transfer immediately to a PCI-centre (ST-based rescue PCI?). Dual antiplatelet therapy (aspirin + clopidogrel) and parenteral anticoagulation are recommended in all TL patients. UFH or preferibly Enoxaparin should be used with fibrin-specific agents, whereas Fondaparinux should be considered with SK
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