MANAGEMENT OF ACUTE MYOCARDIALINFARCTION AND THE RATIONALE FOR EARLY REPERFUSION “TIME IS MUSCLE!” Strategies for reducing time to treatment Strategy: •Public education to shorten the delay in summoning help Re-establish myocardialAims: reperfusion before •Implementation of • Prevent death irreversible damage emergency department • Limit the extent of occurs: thrombolysis protocols myocardial damage • mechanically (PCI) •Use of rapid diagnostic • Minimise patient´s • pharmacologically techniques to confirm AMI discomfort and (induction of •Implementation of pre- distress thrombolysis by hospital thrombolysis by thrombolytic agent) trained emergency personnel Van de Werf et al. Eur Heart J 2003; 24: 28–66.
Primary PCI for AMI AMI Treatment ObjectivesGeneral Objectives:1) Stabilize patient2) Open artery to TIMI-3 flow3) Reduce cardiac work4) Prevent recurrent thrombosis Reduce Recurrent Triggering Specific Objectives - Bed RestRestore Epicardial Flow - BP Control Promote Vasodilation - - Blocker - Nitrate - Calcium channel blocker Treat and Prevent Complications of Acute Open Artery Ischemic or Necrotic - Fibrinolysis Myocardium - Primary PCI - - Blocker Prevent Thrombosis - Anti-arrhythymic - Anti-Platelet Agents - GP IIb/IIIa Inhibitor - Anti-Thrombin Agent Adapted from Califf RM. In: Braunwald E., ed. Atlas of Heart Diseases. 1996:Ch. 1, with permission
Drop of rt-PA breaking down the surface of thrombus.Scanning electron microscopic photograph by Dr. h.c Lennart Nilsson
For every 30-minute delay from onset of symptoms to primary PCI, there is an 8 percent increase in the relative risk of 1-year mortalityImportance of time to reperfusion in patients undergoing primary percutaneous coronaryintervention (PCI) for ST segment elevation myocardial infarction (STEMI). This plot is basedon the pooled data from 1791 patients undergoing primary PCI for STEMI. After adjusting forbaseline risk, there is a curvilinear relationship between the time elapsed from the onset ofsymptoms to balloon inflation and the rate of mortality at 1 year. For every 30-minute delayfrom onset of symptoms to primary PCI, there is an 8 percent increase in the relative risk of1-year mortality.(From De Luca G, Suryapranata H, Ottervanger JP, et al: Time-delay to treatment and mortality in primary angioplastyfor acute myocardial infarction: Every minute counts. Circulation 109:1223, 2004
Generally caused by a Results from stabilization of a platelet aggregate at site of Pathophysiology of STEMI1 completely occlusive thrombus in a coronary artery plaque rupture by fibrin mesh Platelet RBC Fibrin mesh GPIIb/IIIa RBC=red blood cell• The common link between UA/NSTEMI and STEMI is that thrombus formation occurs secondary to the rupture or fissuring of an atherosclerotic plaque in the coronary arteries• This leads to thrombotic occlusion of the coronary artery with interruption of blood flow, resulting in myocardial ischemia and/or necrosis (death of myocardial cells)• Patients with ACS are at high risk of subsequent life-threatening atherothrombotic events such as MI, stroke or vascular death 1. Adapted from Antman EM. In: Califf RM, ed. Atlas of Heart Diseases, VIII. Philadelphia, PA: Current Medicine, 1996.
GOALS IN REPERFUSION IN AMI RAPID COMPLETE - TIMI III - EPICARDIAL ARTERY INTEGRITY OF MICROCIRCULATION MYOCARDIAL PERFUSION TIMI GRADE - III SUSTAINED
12M 10 9.3%or 8 p = 0.003 vs TIMI 0/1ta 6.1 % 6 p < 0.0001 vs TIMI 0/1l P < 0.0001 vs TIMI 2i 4 3.7 %ty 2% 0
Assessing Reperfusion Options for Patients with STEMI1STEP 1: Assess time and risk (time from symptom onset, risk of STEMI, risk of thrombolysis, time for transport to PCI lab)STEP 2: Determine whether fibrinolysis or invasive strategy is preferred* Fibrinolysis preferred if: Invasive strategy preferred if: • Early presentation (<3 hours) • Skilled PCI lab with surgical backup • Invasive strategy not an option available • Delay to invasive strategy • High risk (i.e. cardiogenic shock) • Contraindications to fibrinolysis • Late presentation (>3 hours) • Diagnosis of STEMI is in doubt*If presentation is <3 hours from onset and there is no delay to an invasivestrategy, there is no preference for either strategy 1. Antman EM et al. Circulation 2004; 110: 588–636.
Because the benefits of fibrinolytic therapy are directly related to the time from symptom onset, treatment benefit is maximized by the earliest possible application of therapy1Contraindications and cautions for fibrinolysis in patients with STEMI include:1 1. Any prior intracranial hemmorrhage (ICH) 2. A known structural cerebral vascular lesion or malignant intracranial neoplasm 3. Ischemic stroke within 3 months EXCEPT acute ischemic stroke within 3 hours 4. Suspected aortic dissection 5. Active or recent bleeding or bleeding diathesis 6. Systolic blood pressure (SBP) >180 mm Hg or diastolic blood pressure (DBP) >110 mm Hg 7. Current use of anticoagulants 8. Traumatic or prolonged cardiopulmonary resuscitation (CPR) or major surgery Reference 1. Antman EM et al. Circulation 2004; 110: 588–636.
Common thrombolytics regimens for STEMI1 Initial treatment Co-therapy ContraindicationsStreptokinase (SK) 1.5 million U in 100 mL None or iv Prior SK or D5W or NS over 3060 min heparin x 2448 hrs anistreplaseAlteplase (tPA) 15 mg iv bolus, then iv heparin x 2448 hrs 0.75 mg/kg over 30 min, then 0.5 mg/kg iv over 60 min Total dose not over 100 mgReteplase (r-PA) 10 U + 10 U iv bolus given iv heparin x 2448 hrs 30 min apartTenecteplase Single iv bolus iv heparin x 2448 hrs(TNK-tPA) 30 mg if <60 kg 35 mg if 60 kg to <70 kg 40 mg if 70 kg to <80 kg 45 mg if 80 kg to <90 kg 50 mg if ≥90 kg Note: ASA should be given to all patients without contraindications 1. Van de Werf F et al. Eur Heart J 2003; 24: 2866.
Prothrombotic effects of fibrinolytic therapy.Coronary thrombus is composed of a platelet core with fibrin-thrombin admixture (“white” and “red” clot)
CONTRAINDICATIONS TO FIBRINOLYTIC THERAPYAbsolute contraindications Hemorrhagic stroke or stroke of unknown origin at anytime Ischemic stroke in preceding 6 months Central nervous system trauma or neoplasms Recent major trauma/surgery/head injury (within preceding 3 weeks) Gastrointestinal bleeding within the last month Known bleeding disorder Aortic dissection Non-compressible punctures (e.g. liver biopsy, lumbar puncture)
Primary PCI versus fibrinolysis for MI Meta analysis of 23 trials 15 14 10Percentage 8 7 7 5 5 3 2 1 0 Death Re MI Total Stroke Total fibrinolysis prim PCI P<0.0001 Keeley EC. Lancet 2003;361:13-20
Contemporary Mortality Differences Between Primary PCI and Thrombolysis in STEMI 5,295 Belgian STEMI patients stratified by TIMI risk profile. Primary PCI ThrombolysisIn-Hospital Mortality (n = 4,574) (n = 721) P ValueHigh Risk 23.7% 30.6% 0.03Intermediate Risk 2.9% 3.1% 0.30Low Risk 0.3% 0.4% 0.60 The mortality benefit of primary PCI over early thrombolysis was offset if the door-to-balloon time exceeded 60 min.Conclusion: Primary PCI in patients with STEMI reduces in-hospital mortalitycompared with initial thrombolysis, but the benefit is restricted to high-riskpatients. Claeys MJ, et al. Arch Intern Med. 2011;171:544-549.
IMPACT OF TIME-TO-TREATMENT AND 30 DAY MORTALITY : PCI VS. THROMBOLYSIS Thrombolysis PCI 1230-35-DAY MORTALITY (%) 10 8 6 4 2 0 1 2 8 3 4 5 6 7 TIME FROM ONSET OF PAIN TO THERAPY IN HOURS The figure shows the increase in mortality over time in relation to the start of reperfusion therapy with pharmacological vs. mechanical means, compiling data from a meta-analysis of thrombolysis trials and the NRMI-2 results for mechanical reperfusion. Cannon et al. J Thromb Thrombol 1994; 1: 27–34. Cannon et al. JAMA 2000; 283: 2941–2947. Huber et al. Eur Heart J 2005; 26: 1063–1074.
CONTRAINDICATIONS TO FIBRINOLYTIC THERAPYRelative contraindications Transient ischaemic attack in preceding 6 months Oral anticoagulant therapy Pregnancy or within 1 week post-partum Refractory hypertension (systolic blood pressure > 180 mm Hg and/or diastolic blood pressure > 110 mm Hg) Advanced liver disease Infective endocarditis Active peptic ulcer Refractory resuscitation
Strategies for improving pharmacological reperfusion• Despite the success of thrombolysis in clinical practice, various strategies have been investigated in order to improve the effectiveness of pharmacological reperfusion.• The following sections consider the experience to date with strategies such as: 1. Improved fibrinolytic agents offering increased convenience and safety 2. Improved antithrombotic co-therapies 3. Improved antiplatelet co-therapies.
Strategies for improving pharmacological reperfusion Improved antiplatelet co-therapy i.v. glycoprotein IIb/IIIa inhibitors Clopidogrel Improved Improved fibrinolytic antithrombotic Agents co-therapy convenience Direct thrombin inhibitors (tenecteplase, retepla) (hirudin, bivalirudin) Low mol. Risk of major bleeds weight heparins (tenecteplase) (enoxaparin)
Enoxaparin improves infarct-related artery patency at 90 minutes Enoxaparin improves infarct- TIMI 2 related artery patency at 90 100 minutes TIMI 3 In the HART II study, 90 % of patients 80 27.2 minutes after starting 60 27.5 therapy, patency rates (TIMI 40 flow grade 2/3) were 80.1% 20 52.9 and 75.1% in the enoxaparin 47.6 0 and UFH groups, respectively. Enoxaparin Overall, enoxaparin Unfractionated heparin appeared to be at least as effective as UFH as an TIMI flow at 90 minutes adjunct to thrombolysis, with a trend toward higher recanalization rates and less reocclusion at 5 to 7 days.Therefore, such a regimen was evaluated in ASSENT-3, the first large-scale trial to compare the twoantithrombotics in combination with fibrinolysis. The ASSENT-3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT-3 randomised trial in acute myocardial infarction. Lancet 2001; 358: 605–13. Ross et al, Circulation 2001
TRANSFER – AMI STUDY DESIGN - I• 52 sites in canad with no pci capability• randomised, nonblinded• within 12 hours of chest pain• Higher risk killip class ii or iii• BP < 100 AND HR > 100,RV inf.• Shock, cabg exclude N. Eng. J. Med. 2009, 360, 2705
TRANSFER – AMI STUDY DESIGN - I AMI Stent 1059 Patients TR. TO PCI CENTER IMM.Standard treatment Early pci within 6 hours (522) + Stent TNK, CLOP. ± GP II b / III a Blockers ASP, HEP. Angio meantime 32.5 HRS (89 %) PCI – 67 % N. Eng. J. Med. 2009, 360, 2705
CLINICAL ENDPOINTS – TRANSFER - AMI End Point Standard Routine Early Relative Risk with Treatment PCI (N=536) Routine Early PCI (N=522) (95 % CI) P ValueEfficacy end points at 30days – no (%)Primary end point 90 (17.2) 59 (11.0) 0.64 (0.47-0.87) 0.004Death 18 (3.4) 24 (4.5) 1.30 (0.71-2.36) 0.39Reinfarction 30 (5.7) 18 (3.4) 0.57 (0.33-1.04) 0.06Death or reinfarction 47 (9.0) 38 (7.1) 0.79 (0.52-1.19) 0.25Recurrent ischemia 11 (2.1) 1 (0.2) 0.09 (0.01-0.68) 0.003Death, reinfarction, or 58 (11.1) 39 (7.3) 0.65 (0.44-0.96) 0.03recurrent ischemiaNew or worsening 29 (5.6) 16 (3.0) 0.54 (0.30-0.98) 0.04congestive heart failureCardiogenic shock 16 (3.1) 24 (4.5) 1.46 (0.79-2.72) 0.23 N. Eng. J. Med. 2009, 360, 2705
1.0 0.12 TRANSFER-AMI Standard treatment Cumulative Incidence of Death or Reinfarction 0.10 0.8 0.08 0.06 Routine early PCI 0.6 0.04 0.02 0.4 0.00 0 1 2 3 4 5 6 P=0.36 0.2 0.0 0 1 2 3 4 5 6 Months from Randomization No. at risk Standard treatment 522 473 465 462 462 460 458 Routine early PCI 537 497 487 487 484 483 481 N. Eng. J. Med.Kaplan-Meir Curves for Death or Reinfarction and for Reinfarction Only at 6 Months 2009, 360, 2705
1.0 0.20 TRANSFER-AMI Cumulative Incidence of Primary End Point Standard treatment 0.15 0.8 0.10 Routine early PCI 0.6 0.05 0.4 0.00 0 1 2 3 4 5 6 0.2 P=0.04 0.0 0 5 10 15 20 25 30 Days from RandomizationNo. at riskcStandard treatment 522 442 434 434 433 433 432Routine early PCI 537 488 486 483 481 480 478 Primary End Points at 30 Days N. Eng. J. Med.Composite of Death, reinfarction, worsening heart failure or cardiogenic shock 2009, 360, 2705
TRANSFER-AMI Summary• Compared with ‘Standard Treatment’, a ‘Pharmacoinvasive Strategy’ of routine early PCI within 6 hrs after thrombolysis is associated with a 6% absolute (46% relative) reduction in the composite of death, reinfarction, recurrent ischemia, heart failure and shock• The pharmacoinvasive strategy is not associated with any increase in transfusions, severe bleeding or intracranial hemorrhage despite high use of GP IIb/IIIa inhibitors during PCI• In contrast to older trials, routine early PCI after thrombolysis using stents and contemporary pharmacotherapy is safe and effective – Benefit seen despite high cath/PCI rates in Standard Treatment group (including ~40% rescue PCI) N. Eng. J. Med. 2009, 360, 2705
DANAMI-2: Study Design High-risk ST elevation MI patients (>4 mm elevation), Sx < 12 hrs5 PCI centers (n=443) and 22 referring hospitals (n=1,129), transfer in < 3 hrs Lytic therapy Primary PCI Primary PCIFront-loaded tPA with transfer without transfer 100 mg (n=567) (n=223) (n=782) Death / MI / Stroke at 30 Days Stopped early by safety and efficacy committee
DANAMI-2: transfer for primary PCI vs on-site Alteplase (n=1572) P=0.000315.0% Primary angioplasty 13.7% Thrombolysis P=0.3510.0% 7.8% P<0.001 8.0% 6.6% 6.3% p=0.002 5.0% 1.6% 2.0% 1.1% 0.0% Death Re-MI Stroke Any event Anderson 2003;349:733
PRAGUE-2 study design• Randomised 850 patients with acute ST-elevation myocardial infarction (STEMI) presenting within 12 h of symptom onset to the nearest community hospital.• Thrombolysis group, n=421 or• Immediate transport for primary percutaneous coronary intervention (PCI group, n=429).
Prague-2: Transfer for PCI vson-site thrombolysis in acute MI (n=850) Mortality at 30 days20% Transfer for PCI 15.3%15% Streptokinase 10.0%10% 6.8% 7.3% 7.4% 6.0%5% p=0.12 p=0.020% All patients Rx <3hrs of Rx >3hrs of symptoms symptoms Symptoms to balloon 277 min Symptom to lysis 195 min Planned 1200 patients Widimsky, Eur Heart J 2003;24:94
Transfer for primary PCI vs on-site lytic Quantitative review of 5 trials* *LIMI, Prague I & II, Air PAMI, DANAMI-2 Primary PCI (n=1466) 15.0%15.0% Thrombolysis (n=1443)10.0% 8.9% P<0.0001 8.2% 7.0% 6.7% 5.0% P=0.057 P<0.0001 1.8% 2.2% 1.1% 0.0% Death Re-MI Stroke Any event Keeley, Lancet 2003;361:13
REACT TRIAL DESIGN STEMI – Within 6 hours of chest pain 427 with failed thrombolysis RPCI 144 Rethrombolysis RoutineWithin 12 hours 142 Treatment For symptoms 141 Heparin
REACT Trial (Rescue PCI) 1-Year Revascularization HRsRepeated thrombolysis HR=1.05vs Conservative 95% 0.68 to 1.62R-PCI vs HR=1.05Repeated thrombolysis 95% 0.32 to 0.86 HR=0.50R-PCI vs Conservative 95% 0.30 to 0.83 0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2.0 Favors Comparative Group Favors Reference Group Hazard Ratio Absolute revascularization : Repeat thrombolysis n=41; Conservative n=4(20); R-PCI n=25 JACC 2009, 54, 118
RESCUE PCI – Death Odds Ratio, random model Bilateral CI, 95 % for trials, 95 % for MA Treatment Better Control BetterConservative vs rescue balloon PTCA Invasive Cons. 5/74 6/75 LIMI 1/16 4/12 Belinkie RESCUE 4/78 7/73 Total 0.53 p=0.18 10/160 17/168Conservative vs rescue stent PCI REACT 7/141 15/144 MERLIN 15/153 17/154 Total 0.68 p=0.19 22/294 32/298 Total 32/462 49/458 0.63 p=0.055 Relative Risk 0 0.5 1 1.5 2 2.5 3 events / size Metanalysis Collect et al, JACC
RESCUE PCI – Death or Reinfarction Odds Ratio, random model Bilateral CI, 95 % for trials, 95 % for MA Treatment Better Control BetterConservative vs rescue balloon PTCA Invasive Cons. 10/74 12/75 LIMI 2/16 4/12 Belinkie RESCUE 4/78 7/73 Total 0.62 p=0.18 16/168 23/160Conservative vs rescue stent PCI REACT 8/141 22/144 MERLIN 26/153 32/154 Total 0.60 p=0.033 34/294 54/298 Total 50/462 77/458 0.60 p=0.012 Relative Risk 0 0.5 1 1.5 2 2.5 3 events / size Metanalysis Collect et al, JACC 2006, 48, 136
Major components of time delay between onset of infarction and restoration of flow in the infarct-related artery.
The previous figure shows infarction and restoration of flow in the infarct-related artery. Plotted sequentially from left to right are the time for patientsto recognize symptoms and seek medical attention, transportation to thehospital, in-hospital decision-making and implementation of reperfusionstrategy, and time for restoration of flow once the reperfusion strategy hasbeen initiated. The time to initiate fibrinolytic therapy is the “ door-to-needle”(D-N) time; this is followed by the period of time required for pharmacologicalrestoration of flow. More time is required to move the patient to thecatheterization laboratory for a percutaneous coronary interventional (PCI)procedure, referred to as the “ door-to-balloon” (D-B) time, but restoration offlow in the epicardial infarct-related artery occurs promptly after PCI. At thebottom are shown a variety of methods for speeding the time to reperfusionalong with the goals for the time intervals for the various components of thetime delay. (Adapted from Cannon CP, Antman EM, Walls R, Braunwald E: Timeas adjunctive agent to thrombolytic therapy. J Thromb Thrombolysis 1:27,1994.)