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Update on Intravenous Fibrinolytic Therapy for Acute Myocardial Infarction

      Intravenous fibrinolytic therapy is used widely in the treatment of ST-elevation-elevation acute myocardial infarction. Advances in this therapeutic modality during the past 5 years include new third-generation fibrinolytic agents and creative strategies to enhance administration and efficacy of fibrinolytic therapy. Several of the new agents allow for single- or double-bolus injection. A number of ongoing large randomized trials are attempting to determine whether the combination of therapy with low-molecular-weight heparin or a glycoprotein IIb/IIIa antagonist enhances coronary reperfusion and reduces mortality and late reocclusion. One large prospective trial is investigating the potential benefit of prehospital administration of fibrinolytic therapy. This article summarizes recent safety and efficacy data on fibrinolytic therapy, with particular emphasis on the new third-generation fibrin-specific agents; reviews the preliminary data on facilitated fibrinolysis; and discusses the rationale for prehospital administration of fibrinolytic therapy.
      GUSTO (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries), LMWH (low-molecular-weight heparin MI heparin), MI (myocardial infarction), PCI (percutaneous coronary intervention), TIMI (Thrombolysis in Myocardial Infarction), t-PA (tissue type plasminogen activator), UFH (unfractionated heparin)
      Acute myocardial infarction (MI) remains a leading cause of death in the Western world. Classification of acute MI is based on the electrocardiographic presence of ST-segment-segment elevation or absence of ST-segment elevation (non-ST elevation), and that criterion generally directs distinct approaches to therapy. This review focuses on patients with ST-segment-segment MI. elevation MI. Early reperfusion therapy with intravenous fibrinolysis or primary percutaneous coronary intervention (PCI) remains the mainstay of therapy for ST-elevation MI and reduces short-term and long-term mortality when administered within 6 to 12 hours of symptom onset.
      • Yusuf S
      • Collins R
      • Peto R
      • et al.
      Intravenous and intracoronary fibrinolytic therapy in acute myocardial infarction: overview of results on mortality, reinfarction and side-effects from 33 randomized controlled trials.
      • Lau J
      • Antman EM
      • Jimenez-Silva J
      • Kupelnick B
      • Mosteller F
      • Chalmers TC
      Cumulative meta-analysis of therapeutic trials for myocardial infarction.
      • Weaver WD
      • Simes RJ
      • Betriu A
      • et al.
      Comparison of primary coronary angioplasty and intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review [published correction appears in JAMA. 1998;279:1876].
      Worldwide, most patients with acute ST-elevation MI receive intravenous fibrinolytic therapy (thrombolytic therapy), which has been widely tested and used for more than 3 decades and has proven efficacy and safety. Advances in intravenous fibrinolytic therapy over the past 5 years include new third-generation fibrinolytic agents
      • GUSTO Investigators
      An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction.
      • Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO III) Investigators
      A comparison of reteplase with alteplasc for acute myocardial infarction.

      Neuhaus KL. A phase three trial of novel bolus thrombolytic lanoteplase (nPA): Intravenous nPA for Treatment of Infarcting Myocardium Early (InTIME-II). Paper presented at: 48th Annual Scientific Session, American College of Cardiology; March 9, 1999; New Orleans, La.

      • Assessment of the Safety and Efficacy of a New Thrombolytic Investigators
      Single-bolus tenecleplase compared with front-loaded alleplase in acute myocardial infarction; the ASSENT-2 double-blind randomised trial.
      • Cannon CP
      • Gibson CM
      • McCabe CH
      • et al.
      Thrombolysis in Myocardial Infarction (TIM I) 10b Investigators. TNK-lissue plas-minogen activator compared with front-loaded altcplase in acute myocardial infarction: results of the T1MI 10B trial.
      • Bode C
      • Smalling RW
      • Berg G
      • et al.
      RAPID II Investigators. Randomized comparison of coronary thrombolysis achieved with double-bolus reteplase (recombinant plasminogen activator) and front-loaded, accelerated alteplase (recombinant tissue plasminogen activator) in patients with acute myocardial infarction.
      • International Joint Efficacy Comparison of Thrombolytics
      Randomised, double-blind comparison of reteplase double-bolus administration with streptokmase in acute myocardial infarction (INJECT): trial to investigate equivalence [published correction appears in Lancet. 1995;346;980j.
      • Vanderschueren S
      • Dens J
      • Kerdsinchai P
      • et al.
      Randomized coronary patency trial of double-bolus recombinant staphylokinase versus front loaded alteplase in acute myocardial infarction.
      • Armstrong PW
      • Burton JR
      • Palisaitis D
      • et al.
      Collaborative angiographie patency trial of recombinant staphylokinase (CAPTORS).
      and creative strategies that may enhance the administration and efficacy of fibrinolytic therapy.

      Tatu-Chitoiu G, Guran M, Tatu-Chitoiu A, et al. Bolus administration of 750000 l.U. streptokinase in association with enoxaparin in the pthospital management of acute myocardial infarction. Paper presented at: 1st International Congress on Heart Disease-New Trends in Research, Diagnosis and Treatment; May 18, 1999; Washington, DC.

      Ross A. A randomized comparison of low-molecular-weight hep-arin and unfractionatcd heparin adjunctive to t-PA thrombolysis and aspirin (HART II). Paper presented at: 49th Annual Scientific Session, American College of Cardiology; March 14, 2000; Anaheim, Calif.

      • Amman EM
      • Giugliano RP
      • Gibson CM
      • et al.
      TIMl 14 Investigators. Abciximab facilitates the rate and extent of thrombolysis: results of the thrombolysis in myocardial infarction (TIMl) 14 trial.
      • Strategies for Patency Enhancement in the Emergency Department (SPEED) Group
      Trial of abciximab with and without low-dose reteplase for acute myocardial infarction.

      Brener SJ. Integrelin and Reduced-dose Thrombolytics in Acute Myocardial Infarction (INTRO AMI). Paper presented at: American Heart Association Meeting; November 10, 1999; Atlanta, Ga.

      • Ross AM
      • Coyne KS
      • Reiner JS
      • et al.
      PACT Investigators. A randomized trial comparing primary angioplasty with a strategy of short-acting thrombolysis and immediate planned rescue angioplasty in acute myocardial infarction: the PACT Trial.
      • Morrison LJ
      • Verbeek PR
      • McDonald AC
      • Sawadsky BV
      • Cook DJ
      Mortality and prehospital thrombolysis for acute myocardial infarction: a meta-analysis.
      • Canto JG
      • Rogers WJ
      • Bowlby LJ
      • French WJ
      • Pearce DJ
      • Weaver WD
      • National Registry of Myocardial Infarction 2 Investigators
      The prehospital electrocardiogram in acute myocardial infarction: is its full potential being realized?.
      • Cannon CP
      • Sayah AJ
      • Walls RM
      Prehospital thrombolysis: an idea whose time has come.
      • Weaver WD
      • Cerqueira M
      • Hallstrom AP
      • et al.
      Myocardial Infarction Triage and Intervention Project Group. Prehospital-initi ated vs hospital-initiated thrombolytic therapy: the Myocardial Infarction Triage and Intervention Trial.
      This review highlights the new developments of intravenous fibrinolytic therapy, including recently approved agents and novel strategies for administration.

      AGENTS IN CURRENT USE

      Five fibrinolytic agents have been approved by the US Food and Drug Administration for treatment of acute MI, and several other agents are undergoing clinical investigation. Streptokinase, the oldest fibrinolytic, is a fibrin-non-specific agent that indirectly activates plasminogen and promotes a systemic state of fibrinolysis. Anistreplase, a derivative of the streptokinase-plasminogen activator complex, is similar to streptokinase in its mechanisms of action. The remaining agents, all fibrin-specific and direct plasminogen activators, include recombinant tissue-type plasminogen activator (t-PA), reteplase, and tenecteplase. Reteplase, modified from wild-type t-PA, is a smaller molecule. Each of these agents is efficacious and reduces mortality and infarct size when appropriately administered for acute MI. The GUSTO (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries) I trial compared 4 thrombolytic strategies involving streptokinase and t-PA in patients with acute MI. The results from GUSTO I demonstrated a slight benefit favoring treatment with t-PA: mortality at 30 days was 7.3% in the streptokinase group and 6.3% in the t-PA group.
      • GUSTO Investigators
      An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction.
      Both the absolute reduction in 30-day mortality (1%) and the relative risk reduction (14%) were statistically significant. Although fewer hemorrhagic strokes were reported in patients treated with streptokinase than in those in the t-PA group, the overall benefit still favored treatment with t-PA. Some of the benefit associated with t-PA appeared to be secondary to earlier time to treatment, an observation that underscores the importance of prompt treatment with intravenous fibrinolytic therapy for acute MI. For patients who present more than 4 hours after symptom onset, difference in efficacy among the agents appears to be minimal.
      The GUSTO III trial, designed to test whether reteplase is superior to t-PA, demonstrated no significant demonstrated no significant difference in 30-day mortality between the agents (7.47% vs 7.24%, respectively; adjusted P=.54).
      • Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO III) Investigators
      A comparison of reteplase with alteplasc for acute myocardial infarction.
      The 2 agents have not been tested for equivalency. While the comparative efficacy of these agents in reducing 30-day mortality in acute MI remains technically unclear, many centers, including ours, believe that reteplase is clinically equivalent to t-PA. Given as 2 bolus injections 30 minutes apart (Table 1), reteplase is easier to administer than t-PA.
      Table 1Comparison of Currently Available Intravenous Fibrinolytic Agents
      Anis = anistreplase; FDA = Food and Drug Administration; IV = intravenous; NA = not available; n-PA = lanoteplase; r-PA = reteplase; SAK42D = staphylokinase; SK = streptokinase; SQ = subcutaneous; TIMI = Thrombolysis in Myocardial Infarction; TNK-tPA = tenecteplase; l-PA = tissue-type plasminogen activator.
      SKt-PAr-PAAnisTNK-tPAn-PASAK42D
      Molecular weight (d)47,00070,00039,000131,00070,00053,50016,500
      Plasma half-life (min)∼254-81570-12020-24376
      Dose1.5 million U over 30-60 min
      Dosing of t-PA: 15-mg IV bolus, followed by a 30-minute infusion of 0,75 mg/kg (not to exceed 50 rug), followed by a 60-minute infusion of 0.5 mg/kg (not to exceed 35 mg) for a total dose of <100 mg administered over 90 minutes.
      Two 10-U injections 30 min apart30 U over 5 min
      Dosing of TNK-tPA; single-bolus administration, body weight <60 kg, 30 mg; 60-70 kg, 35 mg; 70-80 kg, 40 mg; 80-90 kg, 45 mg; >90 kg, 50 mg; all given over 5 seconds.
      120U/kg15-45mg over 30 min
      This agent remains in phase 2 clinical testing.
      Fibrin specificityNoYesYes but weakNoYesYesYes
      Currently FDA approvedYesYesYesYesYesNoNn
      90-min TIM! 3 flow rate (%)20-3050-6050-6050-60
      Patency rates reported only as the sum of TIMI 2 plus TIMI 3 flow in 2 studies. TIMI 3 flow, complete, brisk filling of entire vessel. TIMI 2 flow, delayed but complete filling of entire vessel. TIMI 1 flow, delayed, incomplete filling of vessel. TIMI 0 flow, no contrast seen in vessel.
      50-6050-6060-65
      Cost ($)
      (Average wholesale price for administration of the appropriate dose of the drug to 1 patient.
      5432750275028362750NANA
      Hcparin therapySQ or IVIVIVSQ or IVIVIVIV
      * Anis = anistreplase; FDA = Food and Drug Administration; IV = intravenous; NA = not available; n-PA = lanoteplase; r-PA = reteplase; SAK42D = staphylokinase; SK = streptokinase; SQ = subcutaneous; TIMI = Thrombolysis in Myocardial Infarction; TNK-tPA = tenecteplase; l-PA = tissue-type plasminogen activator.
      Dosing of t-PA: 15-mg IV bolus, followed by a 30-minute infusion of 0,75 mg/kg (not to exceed 50 rug), followed by a 60-minute infusion of 0.5 mg/kg (not to exceed 35 mg) for a total dose of <100 mg administered over 90 minutes.
      Dosing of TNK-tPA; single-bolus administration, body weight <60 kg, 30 mg; 60-70 kg, 35 mg; 70-80 kg, 40 mg; 80-90 kg, 45 mg; >90 kg, 50 mg; all given over 5 seconds.
      § This agent remains in phase 2 clinical testing.
      Patency rates reported only as the sum of TIMI 2 plus TIMI 3 flow in 2 studies. TIMI 3 flow, complete, brisk filling of entire vessel. TIMI 2 flow, delayed but complete filling of entire vessel. TIMI 1 flow, delayed, incomplete filling of vessel. TIMI 0 flow, no contrast seen in vessel.
      (Average wholesale price for administration of the appropriate dose of the drug to 1 patient.

      NEW AGENTS

      Several new fibrinolytic agents (all fibrin specific) have been tested recently for use in acute ST-elevation-elevation MI, including tenecteplase, lanoteplase, and staphylokinase. Approved by the Food and Drug Administration in June 2000 for use in acute MI, tenecteplase was compared with t-PA in the Assessment of the Safety and Efficacy of a New Thrombolytic (ASSENT-2) trial.
      • Assessment of the Safety and Efficacy of a New Thrombolytic Investigators
      Single-bolus tenecleplase compared with front-loaded alleplase in acute myocardial infarction; the ASSENT-2 double-blind randomised trial.
      An equivalency analysis demonstrated that the agents were of equal efficacy: 30-day mortality in the tenecteplase group was 6.17% vs 6.15% in the t-PA group (P=.006 for equivalence), and rates of hemorrhagic stroke were less than 1% in both groups.
      Lanoteplase was evaluated in the Intravenous nPA [lanoteplase] for Treatment of Infarcting Myocardium Early-II (InTIME-II) trial, which compared lanoteplase with t-PA in acute ST-elevation MI.

      Neuhaus KL. A phase three trial of novel bolus thrombolytic lanoteplase (nPA): Intravenous nPA for Treatment of Infarcting Myocardium Early (InTIME-II). Paper presented at: 48th Annual Scientific Session, American College of Cardiology; March 9, 1999; New Orleans, La.

      Thirty-day mortality rates were 6.77% for lanoteplase and 6.60% for t-PA (P=NS). The rates of hemorrhagic stroke were 1.13% for lanoteplase and 0.62% for t-PA (P=.003), and hemorrhagic stroke mortality rates were 0.66% for lanoteplase and 0.44% for t-PA (P=.051). Because of the observed increased risks of intracranial hemorrhage and death from intracranial hemorrhage, lanoteplase is unlikely to be investigated further.
      Staphylokinase, a 136-amino acid, highly fibrin-specific agent derived from Staphylococcus aureus, is currently under phase 2 clinical trial testing. It is too early to comment conclusively on its efficacy and safety (Table 2). Potential advantages of staphylokinase include high fibrin specificity, capacity for bolus administration, and expected reduced acquisition costs compared with currently available agents.
      Table 2Major Thrombolytic Trials
      ASSENT-2 = Assessment of the Safety and Efficacy of a New Thrombolytic; BSTG = Bolus Staphytokinase Trial Group; CAPTORS = Collaborative Angiographic Patency Trial of Recombinant Staphylokinase; GUSTO = Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries; ICH = intracranial hemorrhage; INJECT = International Joint Efficacy Comparison of Thrombolytics; InTIME-II = Intravenous nPA for Treatment of Infarcting Myocardium Early-II; NA = not available; RAPID II = Reteplase vs Altepla.se Infusion in Acute Myocardial Infarction II; STA = staphylokinase. For expansion of other abbreviations, see Table 1.
      Trial (enrollment of patients)Agents tested30-day mortality (%)ICH rates (%)TIMI3 flow rates at 90 min (%)Reference
      GUSTO 1 (N=41,021)t-PA6.30.7254
      Based on angiographic substudy in a limited number of patients.
      • GUSTO Investigators
      An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction.
      SK7.30.5439
      GUSTO III (N= 15,059)t-PA7.240.87NA
      • Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO III) Investigators
      A comparison of reteplase with alteplasc for acute myocardial infarction.
      r-PA7.470.91NA
      ASSENT-2 (N=16,949)t-PA6.150.94NA
      • Assessment of the Safety and Efficacy of a New Thrombolytic Investigators
      Single-bolus tenecleplase compared with front-loaded alleplase in acute myocardial infarction; the ASSENT-2 double-blind randomised trial.
      TNK-tPA6.180.93NA
      InTIME-II (N= 15,078)n-PA6.771 1357.l
      Bascd on InTIME-I trial.23

      Neuhaus KL. A phase three trial of novel bolus thrombolytic lanoteplase (nPA): Intravenous nPA for Treatment of Infarcting Myocardium Early (InTIME-II). Paper presented at: 48th Annual Scientific Session, American College of Cardiology; March 9, 1999; New Orleans, La.

      t-PA6.600.6246.4
      Bascd on InTIME-I trial.23
      T1M1 10B (N=886)t-PA5.71 963
      • Cannon CP
      • Gibson CM
      • McCabe CH
      • et al.
      Thrombolysis in Myocardial Infarction (TIM I) 10b Investigators. TNK-lissue plas-minogen activator compared with front-loaded altcplase in acute myocardial infarction: results of the T1MI 10B trial.
      TNK-tPA (50 me)3.83.866
      RAPID II (N=324)r-PA4.11.259.9
      • Bode C
      • Smalling RW
      • Berg G
      • et al.
      RAPID II Investigators. Randomized comparison of coronary thrombolysis achieved with double-bolus reteplase (recombinant plasminogen activator) and front-loaded, accelerated alteplase (recombinant tissue plasminogen activator) in patients with acute myocardial infarction.
      t-PA8.41.945.2
      INJECT (N=6010)r-PA9.020.77NA
      • International Joint Efficacy Comparison of Thrombolytics
      Randomised, double-blind comparison of reteplase double-bolus administration with streptokmase in acute myocardial infarction (INJECT): trial to investigate equivalence [published correction appears in Lancet. 1995;346;980j.
      SK9.530.37NA
      BSTG (N=102)t-PA1.9057
      • Vanderschueren S
      • Dens J
      • Kerdsinchai P
      • et al.
      Randomized coronary patency trial of double-bolus recombinant staphylokinase versus front loaded alteplase in acute myocardial infarction.
      STA, 15 mg + 15 mg0068
      CAPTORS (N=82)SAK42D
      • Armstrong PW
      • Burton JR
      • Palisaitis D
      • et al.
      Collaborative angiographie patency trial of recombinant staphylokinase (CAPTORS).
       15 mg2.4062
       30 mg0065
       45 mg0063
      * ASSENT-2 = Assessment of the Safety and Efficacy of a New Thrombolytic; BSTG = Bolus Staphytokinase Trial Group; CAPTORS = Collaborative Angiographic Patency Trial of Recombinant Staphylokinase; GUSTO = Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries; ICH = intracranial hemorrhage; INJECT = International Joint Efficacy Comparison of Thrombolytics; InTIME-II = Intravenous nPA for Treatment of Infarcting Myocardium Early-II; NA = not available; RAPID II = Reteplase vs Altepla.se Infusion in Acute Myocardial Infarction II; STA = staphylokinase. For expansion of other abbreviations, see Table 1.
      Based on angiographic substudy in a limited number of patients.
      Bascd on InTIME-I trial.
      • den Heijer P
      • Vermeer F
      • Ambrosioni E
      • et al.
      Evaluation of a weight-adjusted single-bolus plasminogen activator in patients with myocardial infarction: a double-blind, randomized angiographic trial of lanoteplase versus alteplase.

      INDICATIONS FOR FIBRINOLYTIC THERAPY

      All eligible patients presenting within 12 hours of onset of symptoms of acute MI who meet electrocardiographic criteria outlined in Figure 1 should be considered for fibrinolytic therapy. Patients with minor hemorrhage, menstruation, advanced age, or a history of diabetic retinopathy can receive fibrinolytic therapy; however, absolute benefit for those older than 75 years is controversial.
      • Thiemann DR
      • Coresh J
      • Schulman SP
      • Gerstenblilt G
      • Oetgen WJ
      • Powe NR
      Lack of benefit for intravenous thrombolysis in patients with myocardial infarction who are older than 75 years.
      • Ayanian JZ
      • Braunwald E
      Thrombolytic therapy for patients with myocardial infarction who are older than 75 years: do the risks outweigh the benefits? [editorial].
      Figure thumbnail gr1
      Figure 1Thrombolytic guidelines for patients with acute myocardial infarction. BP = blood pressure; H/O = history of; LBBB = left bundle branch block; NTG = nitroglycerin; SL = sublingual.

      CONTRAINDICATIONS TO THERAPY

      Fibrinolytic therapy is contraindicated in patients with acute MI who have only ST-segment-segment depression on an electrocardiogram, except those with acute posterior MI (abnormalities in leads V1 and V2). The generally accepted contraindications to intravenous fibrinolytic therapy are outlined in Figure 1.

      DOSING AND ADMINISTRATION

      Table 1 outlines dosing for the currently available fibrinolytic agents, each of which is administered intravenously. Tissue-type plasminogen activator is given in a weight-adjusted, front-loaded format over 90 minutes. A 15-mg bolus is followed by a dose of 0.75 mg/kg (maximum dose ≤50 mg) infused over 30 minutes, followed by a dose of 0.50 mg/kg (maximum ≤35 mg) over 60 minutes (total dose ≤100 mg over 90 minutes). With reteplase, a 10- U bolus injection is given over 1 to 2 minutes, and a second 10-U bolus is administered 30 minutes after the first injection (total dose is 20 U, 30 minutes apart). Streptokinase is administered as 1.5 million U intravenously over 30 to 60 minutes; administration of intravenous fluids or reduction of the streptokinase infusion rate may be necessary if hypotension develops. Anistreplase is given as a 30-U intravenous bolus over 5 minutes. Tenecteplase is administered as a single weight-adjusted bolus: patient weight less than 60 kg, 30 mg; 60 to 70 kg, 35 mg; 70 to 80 kg, 40 mg; 80 to 90 kg, 45 mg; greater than 90 kg, 50 mg. No patient with acute MI should receive more than 50 mg of intravenous tenecteplase. The bolus should be administered over a 5-second period.
      Fibrinolytic agents that require only single- or double-bolus injections appear to offer an advantage over the agents that necessitate a constant infusion because bolus injections are associated with lower error rates and are easier to administer. Fibrin-specific agents generally result in greater reperfusion to the infarct artery, but the trade-off for greater restoration of patency is an increased risk of hemorrhagic stroke (Table 2), especially in elderly patients,
      • GUSTO Investigators
      An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction.
      • Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO III) Investigators
      A comparison of reteplase with alteplasc for acute myocardial infarction.

      Neuhaus KL. A phase three trial of novel bolus thrombolytic lanoteplase (nPA): Intravenous nPA for Treatment of Infarcting Myocardium Early (InTIME-II). Paper presented at: 48th Annual Scientific Session, American College of Cardiology; March 9, 1999; New Orleans, La.

      • Assessment of the Safety and Efficacy of a New Thrombolytic Investigators
      Single-bolus tenecleplase compared with front-loaded alleplase in acute myocardial infarction; the ASSENT-2 double-blind randomised trial.
      • Cannon CP
      • Gibson CM
      • McCabe CH
      • et al.
      Thrombolysis in Myocardial Infarction (TIM I) 10b Investigators. TNK-lissue plas-minogen activator compared with front-loaded altcplase in acute myocardial infarction: results of the T1MI 10B trial.
      • Bode C
      • Smalling RW
      • Berg G
      • et al.
      RAPID II Investigators. Randomized comparison of coronary thrombolysis achieved with double-bolus reteplase (recombinant plasminogen activator) and front-loaded, accelerated alteplase (recombinant tissue plasminogen activator) in patients with acute myocardial infarction.
      • International Joint Efficacy Comparison of Thrombolytics
      Randomised, double-blind comparison of reteplase double-bolus administration with streptokmase in acute myocardial infarction (INJECT): trial to investigate equivalence [published correction appears in Lancet. 1995;346;980j.
      • Vanderschueren S
      • Dens J
      • Kerdsinchai P
      • et al.
      Randomized coronary patency trial of double-bolus recombinant staphylokinase versus front loaded alteplase in acute myocardial infarction.
      • Armstrong PW
      • Burton JR
      • Palisaitis D
      • et al.
      Collaborative angiographie patency trial of recombinant staphylokinase (CAPTORS).
      The GUSTO I study demonstrated no benefit for t-PA over streptokinase in patients older than 75 years. A recent meta-analysis
      • Thiemann DR
      • Coresh J
      • Schulman SP
      • Gerstenblilt G
      • Oetgen WJ
      • Powe NR
      Lack of benefit for intravenous thrombolysis in patients with myocardial infarction who are older than 75 years.
      criticized the use of fibrinolytic therapy for patients older than age 75 years, but this criticism is not accepted unanimously.
      • Ayanian JZ
      • Braunwald E
      Thrombolytic therapy for patients with myocardial infarction who are older than 75 years: do the risks outweigh the benefits? [editorial].
      Patients previously treated with streptokinase should receive a fibrin-specific agent for any subsequent administration of fibrinolytic therapy. For patients who present in cardiogenic shock (Killip class IV), PCI is preferred to lytic therapy. Figure 2 outlines 1 approach to agent selection for patients with acute MI.
      Figure thumbnail gr2
      Figure 2Choice of thrombolytic drug based on patient risk factors. CABO = coronary artery bypass grafting; CV = cardiovascular; ECO = electrocardiogram; Hx =history; Int = intermediate; MI = myocardial infarction; SK = streptokinase; TNK-tPA = tenecteplase. Alteplase is the trade name for recombinant tissue-type plasminogen activator (t-PA). Rales >1/3 means that rales were present in greater than one third of the lung field.

      COMPARISON WITH PRIMARY PCI

      Several small trials, including a study from the Mayo Clinic in Rochester, Minn.
      • Gibbons RJ
      • Holmes DR
      • Reeder GS
      • Bailey KR
      • Hopfenspirger MR
      • Gersh BJ
      • Mayo Coronary Care Unit and Catheterization Laboratory Groups
      Immediate angioplasty compared with the administration of a thrombolytic agent followed by conservative treatment for myocardial infarction.
      have compared primary PCI with intravenous fibrinolytic therapy. A meta-analysis of all major randomized trials comparing fibrinolytic therapy with PCI reported significantly reduced rates of death, reinfarction, and stroke with PCI
      • Weaver WD
      • Simes RJ
      • Betriu A
      • et al.
      Comparison of primary coronary angioplasty and intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review [published correction appears in JAMA. 1998;279:1876].
      . Rates of Thrombolysis in Myocardial Infarction (TIMI) 3 flow are greater with PCI than with fibrinolysis. Few contraindications to PCI have been identified; the major limitation lies in availability of primary PCI 24 hours a day, 7 days a week. At medical centers (like Mayo Clinic) with ready availability of a catheterization laboratory and skilled operators, PCI has replaced fibrinolytic therapy for acute MI. Because most US medical centers lack a fully staffed and available catheterization laboratory, this strategy is probably not widely applicable. The demonstrated benefit of fibrinolytic therapy, especially when administered early (≥3 hours after symptom onset) to patients with acute MI, cannot be overemphasized. Centers without availability of primary PCI should continue to use fibrinolytic therapy rather than transferring patients for PCI and thus delaying acute reperfusion therapy. Patients who present with acute MI should receive fibrinolytic therapy even before transfer to a nearby facility (transfer time, >30-60 minutes) is considered so that acute reperfusion therapy is not delayed. If there are signs of failed reperfusion or worsening ischemia, a patient can be transferred to a medical center with a catheterization laboratory after fibrinolytic therapy has been given and rescue PCI has been attempted.

      FACILITATED FIBRINOLYSIS

      The thrombotic occlusion responsible for acute MI is a fibrin-platelet plug attached to a fissured atherosclerotic plaque. Several recently developed potent antithrombin and antiplatelet agents target the fibrin-platelet occlusion responsible for acute MI. Facilitated fibrinolysis is a concept that combines a potent antithrombin agent, such as a low-molecular-weight heparin (LMWH), or a potent antiplatelet agent, such as a glycoprotein IIb/IIIa antagonist, with a fibrinolytic agent during initial treatment of acute MI. A number of ongoing clinical trials are investigating facilitated fibrinolysis; however, superiority over fibrinolytic therapy alone has not yet been clearly shown.

      Fibrinolytic Agent Plus LMWH

      Preliminary results have been reported for a small study from Bucharest, Romania, that examined the use of the LMWH enoxaparin in combination with streptokinase.

      Tatu-Chitoiu G, Guran M, Tatu-Chitoiu A, et al. Bolus administration of 750000 l.U. streptokinase in association with enoxaparin in the pthospital management of acute myocardial infarction. Paper presented at: 1st International Congress on Heart Disease-New Trends in Research, Diagnosis and Treatment; May 18, 1999; Washington, DC.

      The 102 patients were randomized to full-dose streptokinase and intravenous unfractionated heparin (UFH) or to a reduced dose of streptokinase (750,000 U) and enoxaparin (40 mg subcutaneously twice a day). The 30-day mortality rate was significantly decreased in the group receiving streptokinase and enoxaparin (5.7%) vs the group receiving streptokinase and UFH (10%) (P<.05). Reperfusion (determined nonangiographically) appeared better in the streptokinase-enoxaparin group (81%) than in the streptokinase-UFH group (58%) (P<.05). No differences were noted in bleeding complications. In the Heparin-Aspirin Reperfusion Trial II (HART 11), which compared enoxaparin plus t-PA with intravenous UFH plus t-PA for acute MI, coronary patency rates were similar between groups at 90-minute angiography (80.1% vs 75.1%; P=NS), but the coronary reocclusion rate was lower at 7 days in the enoxaparin group (3.1%) than than in the UFH group (9.1%) (P=.01).

      Ross A. A randomized comparison of low-molecular-weight hep-arin and unfractionatcd heparin adjunctive to t-PA thrombolysis and aspirin (HART II). Paper presented at: 49th Annual Scientific Session, American College of Cardiology; March 14, 2000; Anaheim, Calif.

      Thirty-day mortality did not differ between the groups. Each of these studies has reported only preliminary observations, and their findings should not alter current clinical practice. Advantages of the LMWH agents over UFH include (1) ease of administration, (2) elimination of need for follow-up monitoring of the activated partial thromboplastin time, (3) longer duration of anticoagulation efficacy with less frequent “swings” in overanticoagulation and underanticoagulation, and (4) cost-effectiveness. As more efficacy and safety data emerge, use of LMWH for acute MI is expected to increase.

      Fibrinolytic Agent Plus Glycoprotein IIb/IIIa Antagonist

      At least 3 trials examining the use of a glycoprotein IIb/IIIa antagonist in combination with a fibrinolytic agent for acute MI are ongoing. All reported data remain preliminary but optimistic. The TIMI 14 trial demonstrated enhanced complete reperfusion (TIMI 3 flow) using the combination of abciximab and t-PA compared with t-PA alone in acute MI.
      • Amman EM
      • Giugliano RP
      • Gibson CM
      • et al.
      TIMl 14 Investigators. Abciximab facilitates the rate and extent of thrombolysis: results of the thrombolysis in myocardial infarction (TIMl) 14 trial.
      Rates of TIMI 3 flow at 90 minutes were increased in patients who received abciximab plus t-PA (77%) compared with t-PA alone (62%) (P=.02). Similar rates of “enhanced reperfusion” have been observed in the GUSTO IV/Strategies for Patency Enhancement in the Emergency Department (SPEED) trial (which combines t-PA or reteplase with abciximab)
      • Strategies for Patency Enhancement in the Emergency Department (SPEED) Group
      Trial of abciximab with and without low-dose reteplase for acute myocardial infarction.
      and in the Integrilin and Reduced Dose of Thrombolytic in Acute Myocardial Infarction (INTRO AMI) trial (which combines eptifibatide with t-PA).

      Brener SJ. Integrelin and Reduced-dose Thrombolytics in Acute Myocardial Infarction (INTRO AMI). Paper presented at: American Heart Association Meeting; November 10, 1999; Atlanta, Ga.

      Several caveats about the use of facilitated fibrinolysis remain: (1) results are preliminary, (2) no differences have been observed in 30-day mortality rates, (3) safety and bleeding risks must be defined more accurately in a large population, (4) all studies have used reduced doses of fibrinolytic agents, and (5) reduced doses of concurrent heparin therapy are warranted to minimize bleeding and stroke risks. It is too early to conclude that facilitated fibrinolytic therapy will replace traditional fibrinolytic therapy because the safety and bleeding data are prelimi nary. However, the concept of facilitated fibrinolysis remains promising.

      Fibrinolysis-PCI Hybrid Approach

      The development of fibrin-specific agents allows PCI to be performed much more safely and successfully after fibrinolytic therapy. The recent Plasminogen-Activator Angioplasty Compatibility Trial (PACT) examined a hybrid approach to treatment of acute MI, combining bolus t-PA and delayed PCI in a treatment strategy.
      • Ross AM
      • Coyne KS
      • Reiner JS
      • et al.
      PACT Investigators. A randomized trial comparing primary angioplasty with a strategy of short-acting thrombolysis and immediate planned rescue angioplasty in acute myocardial infarction: the PACT Trial.
      Patients were given a 50-mg bolus of t-PA and transferred immediately to cardiac catheterization. If the single bolus of t-PA had restored normal flow in the infarct-related artery, a second bolus of 50 mg of t-PA was given. If the t-PA had not restored normal flow, PCI was performed immediately. The investigators observed a TIMI 3 flow rate of 33% in the group given a 50-mg bolus of t-PA and a TIMI 3 flow rate of 15% in the group treated with heparin alone. After PCI, both groups had similar TIMI 3 flow restoration rates (77% vs 79%; P=.62), and 30-day mortality was similar between the groups (3.6% vs 3.3%; P=.81). This study, in contrast to earlier published experience, demonstrated that early PCI after fibrinolytic therapy could be safely performed in the acute MI setting. The hybrid approach may emerge as a potent strategy for treatment of acute MI, but further studies are needed to clarify its safety and efficacy compared with traditional fibrinolytic therapy. Practically speaking, implementation of this strategy will require catheterization laboratory resources that are almost identical to those for primary PCI, and widespread adoption of the strategy will be limited because of this requirement.

      Prehospital Administration of Fibrinolytic Therapy

      Several trials have examined the utility of initiating intravenous fibrinolytic therapy for acute MI in the pre-hospital setting.
      • Morrison LJ
      • Verbeek PR
      • McDonald AC
      • Sawadsky BV
      • Cook DJ
      Mortality and prehospital thrombolysis for acute myocardial infarction: a meta-analysis.
      • Canto JG
      • Rogers WJ
      • Bowlby LJ
      • French WJ
      • Pearce DJ
      • Weaver WD
      • National Registry of Myocardial Infarction 2 Investigators
      The prehospital electrocardiogram in acute myocardial infarction: is its full potential being realized?.
      • Cannon CP
      • Sayah AJ
      • Walls RM
      Prehospital thrombolysis: an idea whose time has come.
      • Weaver WD
      • Cerqueira M
      • Hallstrom AP
      • et al.
      Myocardial Infarction Triage and Intervention Project Group. Prehospital-initi ated vs hospital-initiated thrombolytic therapy: the Myocardial Infarction Triage and Intervention Trial.
      The prehospital administration strategy has developed, in part, in an attempt to reduce the time to treatment for patients with acute MI. Most patients still do not seek hospital evaluation of acute MI until 1 to 2 hours after symptom onset. The Myocardial Infarction Triage and Intervention (MITI) trial in Seattle examined the potential benefit of prehospital administration of fibrinolytic therapy vs hospital administration in patients with acute ST-elevation MI.
      • Weaver WD
      • Cerqueira M
      • Hallstrom AP
      • et al.
      Myocardial Infarction Triage and Intervention Project Group. Prehospital-initi ated vs hospital-initiated thrombolytic therapy: the Myocardial Infarction Triage and Intervention Trial.
      Although no outcome differences were observed, patients treated within 70 minutes of symptom onset had significantly (P<.05) lower in-hospital mortality rates (1.2% vs 8.7%) and smaller infarct sizes (4.9% vs 11.2%) compared with patients treated more than 70 minutes after symptom onset: While most trials examining the benefit of prehospital fibrinolytic therapy have failed to demonstrate any advantage over hospital-based administration, a recent meta-analysis examining prehospital fibrinolytic therapy data from 6 randomized trials reported a benefit with prehospital treatment.
      • Morrison LJ
      • Verbeek PR
      • McDonald AC
      • Sawadsky BV
      • Cook DJ
      Mortality and prehospital thrombolysis for acute myocardial infarction: a meta-analysis.
      Mortality was reduced by 17% with an observed odds ratio of 0.83 (95% confidence interval, 0.70-0.98). From a practical standpoint, prehospital fibrinolysis is beneficial only for lengthy patient transport times, such as in large metropolitan or rural areas.
      Some ambulance-based electrocardiographic units allow portable transmission of 12-lead electrocardiograms, and many urban emergency medical service ambulances use this technology. The ongoing TIMI 19 ER (Emergency Room) study is testing the feasibility and efficacy of a strategy that includes mobile 12-lead electrocardiographic analysis and prehospital administration of fibrinolytic therapy for acute MI in several US cities. Paramedics administer the fibrinolytic agent under radio supervision of a treating physician, using a predefined checklist of eligibility and exclusion criteria to screen patients who have ST-segment elevation on the initial electrocardiogram (obtained during transport). Prehospital administration of fibrinolytic therapy could potentially emerge as an important strategy for administration of fibrinolytic therapy for acute MI.

      SUMMARY

      Fibrinolytic therapy remains an effective and important treatment of acute MI. The development of new fibrin- specific agents administered by single- or double-bolus injections reduces the likelihood of medication error and enhances administration. The key to enhanced myocardial salvage and reduced long-term mortality is quick and complete administration of fibrinolytic therapy. In light of data that demonstrate myocardial salvage with early lytic administration, an appropriate strategy is to administer fibrinolytic therapy to the patient with acute MI before a transfer for direct or delayed PCI is contemplated. Concurrent administration of intravenous heparin, aspirin, and a β-blocker at the time of fibrinolytic therapy is appropriate in almost every situation.

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