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Thrombolytic Therapy in Emergency Medicine

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Thrombolytic Therapy in Emergency Medicine

Author: Wanda L Rivera-Bou, MD, FAAEM, FACEP; Chief Editor: David FM Brown, MD more... Updated: May 3, 2012

Thrombolytic Therapy for Acute Myocardial Infarction

Myocardial infarction (MI) is a leading cause of morbidity and mortality in the United States. The estimated annual incidence of MI is 610,000 new attacks and 325,000 recurrent attacks. The average age at first MI is 64.5 years for men and 70.3 years for women.[13] Thrombolytic therapy is indicated in patients with evidence of ST-segment elevation MI (STEMI) or presumably new left bundle-branch block (LBBB) presenting within 12 hours of the onset of symptoms if there are no contraindications to fibrinolysis. Patients with STEMI usually have complete occlusion of an epicardial coronary vessel caused by an acute thrombotic obstruction.[14] Coronary atherosclerosis is a diffuse process characterized by segmental lesions called coronary plaques. The plaque ruptures, exposing the endothelial lining and allowing prothrombotic enzymes and molecular triggers to mix with the blood. Platelets are activated, and the coagulation cascade is amplified resulting in a thrombus that occludes the vessel, preventing the circulation of oxygenated blood. Irreversible ischemia-induced myocardial necrosis may occur within 20-60 minutes of occlusion. The mainstay of treatment is reperfusion therapy involving either administration of fibrinolytics (pharmacologic reperfusion) or primary percutaneous coronary intervention (PCI) (mechanical reperfusion). PCI performed within 90 minutes of patient arrival is superior to fibrinolysis with respect to combined endpoints of death, stroke, and reinfarction, but unfortunately, PCI is not widely available at acute care hospitals. Of the nearly 5000 acute care hospitals In the United States, 2200 have catheterization laboratories, and only 1200 of these (< 25%) are capable of performing PCI.[15] Fewer than 10% of patients who are transferred for primary PCI achieve a first door-to-balloon time of less than 90 minutes.[16] Although primary PCI is the preferred therapy for STEMI, it has severe logistic restraints: treatment is delayed by patient transport, emergency department (ED) delay, and preparation of the catheterization laboratory. Furthermore, a skilled intervention team must be available 24 hours a day. Thrombolysis remains the treatment of choice in STEMI when primary PCI cannot be performed within 90 minutes.
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In the 2007 STEMI Focused Update, the writing committee held that at 90 minutes after initiation of fibrinolysis, if there was less than 50% ST-segment resolution in the lead that showed the greatest degree of ST elevation at presentation, fibrinolytic therapy had likely failed to reperfuse the patient.[17] If the judgment was made that fibrinolytic therapy had not resulted in reperfusion, PCI performed at that time was labeled rescue PCI.[18] However, the best subsequent management of patients after fibrinolytic therapy remains unclear. In an effort to determine optimal patient management, the CARESS-in-AMI study evaluated 600 STEMI patients 75 years of age or younger with 1 or more high-risk features (extensive ST-segment elevation, new LBBB, previous MI, Killip class greater than 2, or left ventricular ejection fraction 35% or less) who were initially treated at a nonPCI hospital with half-dose reteplase, abciximab, heparin, and aspirin within 12 hours of symptom onset.[19] All were randomized to immediate transfer for PCI or to standard treatment with transfer for rescue PCI if needed. PCI was performed in 85.6% of patients in the immediate PCI group, and rescue PCI was performed in 30.3% of the standard treatment/transfer for rescue PCI group; the primary outcome (a composite of death, reinfarction, or refractory ischemia at 30 days) occurred significantly less often in the former group than in the latter group (4.4% and 10.7%, respectively).[19] No significant differences in the rate of major bleeding at 30 days (3.4% vs 2.3%) or stroke (0.7% vs 1.3%) were observed between groups. These results suggest that immediate transfer for PCI improves outcome in high-risk patients with STEMI treated at a non-PCI hospital with half-dose fibrinolytic therapy, abciximab, heparin, and aspirin.[19] The TRANSFER-AMI[20] study further tested the pharmacoinvasive strategy concept in high-risk STEMI patients. All patients received standard-dose tenecteplase, aspirin, and either unfractionated heparin (UFH) or enoxaparin; concomitant clopidogrel was recommended. Patients were randomized to either standard treatment (including rescue PCI, if required, or delayed angiography) or a strategy of immediate transfer to another hospital and PCI within 6 hours after fibrinolysis. The authors concluded that after treatment with fibrinolytic therapy in STEMI patients presenting to hospitals without PCI capability, transfer for PCI within 6 hours after fibrinolysis was associated with significantly fewer ischemic complications than was standard treatment.[20] Fibrinolytic therapy is a proven treatment for the management of acute MI (AMI). It is more universally available to patients without contraindications, can be administered by any properly trained health care provider, and can be given in the prehospital setting. Its efficacy declines as the duration of ischemia increases. The goal is a door-toneedle time of less than 30 minutes, and every effort must be made to minimize the time to therapy. Patients older than 75 years derive significant benefit from fibrinolytic therapy, even though their risk of bleeding is higher. Fibrinolytic agents are given in conjunction with antithrombin and antiplatelet agents, which help to maintain vessel patency once the clot has been dissolved. Aspirin inhibits platelets; the recommended dose is 160-325 mg of chewable aspirin. Clopidogrel also inhibits platelets. In patients younger than 75 years, administer an oral loading dose of 300 mg. The COMMIT-CCS-2 and CLARITY-TIMI 28 trials provided evidence for benefit of adding clopidogrel to aspirin in patients undergoing fibrinolytic therapy.[21, 22] No data are available to guide decision-making regarding the choice of an oral loading dose in patients aged 75 years or older. In this group of patients, administer 75 mg/day.[17] Heparins (UFH or low-molecular-weight heparin [LMWH]) inhibit thrombin. For UFH, the recommended dose is an intravenous (IV) bolus of 60 U/kg (maximum, 4000 U) followed by an initial infusion of 12 U/kg/h (maximum, 1000 U/h) adjusted to maintain the activated partial thromboplastin time (aPTT) at 1.5-2 times the control value. LMWH (eg, enoxaparin) is emerging as an alternative to UFH. Enoxaparin may be administered to patients younger than 75 years; the recommendation is a 30 mg IV bolus followed by 1 mg/kg subcutaneously every 12 hours. For patients at least 75 years old, the IV bolus is eliminated and the subcutaneous dose reduced to 0.75 mg/kg every 12 hours. Regardless of age, if creatinine clearance is less than 30 mL/min, the subcutaneous dose is 1 mg/kg every 24 hours.[17] Enoxaparin appeared superior to UFH in the EXTRACT-TIMI 25 trial.[23] Absolute contraindications for fibrinolytic use in STEMI include the following[14] :
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Prior intracranial hemorrhage (ICH) Known structural cerebral vascular lesion Known malignant intracranial neoplasm Ischemic stroke within 3 months Suspected aortic dissection Active bleeding or bleeding diathesis (excluding menses) Significant closed head trauma or facial trauma within 3 months Relative contraindications for fibrinolytic use in STEMI include the following[14] : History of chronic, severe, poorly controlled hypertension Severe uncontrolled hypertension on presentation (systolic blood pressure > 180 mm Hg or diastolic blood pressure > 110 mm Hg) Traumatic or prolonged (> 10 minutes) cardiopulmonary resuscitation (CPR) or major surgery less than 3 weeks previously Recent (within 2-4 weeks) internal bleeding Noncompressible vascular punctures For streptokinase and anistreplase, prior exposure (more than 5 days ago) or prior allergic reaction to these agents Pregnancy Active peptic ulcer Current use of an anticoagulant (eg, warfarin sodium) that has produced an elevated international normalized ratio (INR) higher than 1.7 or a prothrombin time (PT) longer than 15 seconds

Thrombolytic regimens
Alteplase Alteplase can be administered in an accelerated infusion (1.5 h) using 50-mg and 100-mg vials reconstituted with sterile water to 1 mg/mL. Accelerated infusion of alteplase for AMI consists of a 15-mg IV bolus followed by 0.75 mg/kg (up to 50 mg) IV over 30 minutes and then 0.5 mg/kg (up to 35 mg) IV over 60 minutes. The maximum total dose is 100 mg for patients weighing more than 67 kg. This is the most common alteplase infusion 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 for AMI consists of 2 IV boluses of 10 units each; there is no weight adjustment. The first 10 U IV bolus is given over 2 minutes; 30 minutes later, a second 10 U IV bolus is given over 2 minutes. Administer normal saline (NS) flush before and after each bolus. Tenecteplase To reconstitute tenecteplase, mix the 50-mg vial in 10 mL sterile water (5 mg/mL). Tenecteplase is administered in a 30-50 mg IV bolus over 5 seconds. The dosage is calculated on the basis of the patients weight, as follows: < 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) Streptok inase The adult dose of streptokinase for AMI is 1.5 million U in 50 mL of 5% dextrose in water (D5W) given IV over 60 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.
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Contributor Information and Disclosures

Author Wanda L Rivera-Bou, MD, FAAEM, FACEP Assistant Professor and ACLS Training Center Director, Department of Emergency Medicine, University of Puerto Rico School of Medicine Wanda L Rivera-Bou, MD, FAAEM, FACEP is a member of the following medical societies: American Academy of Emergency Medicine, American College of Emergency Physicians, American Heart Association, and Society for Academic Emergency Medicine Disclosure: Nothing to disclose. Coauthor(s) Jos G Cabaas, MD, FACEP Deputy Medical Director, Office of the Medical Director, Austin/Travis County EMS System Jos G Cabaas, MD, FACEP is a member of the following medical societies: American College of Emergency Physicians, National Association of EMS Physicians, and Society for Academic Emergency Medicine Disclosure: Nothing to disclose. Salvador E Villanueva, MD, FACEP Assistant Professor, Department of Emergency Medicine, Ponce School of Medicine, Puerto Rico Salvador E Villanueva, MD, FACEP is a member of the following medical societies: American College of Emergency Physicians and Puerto Rico Medical Association Disclosure: Nothing to disclose. Chief Editor David FM Brown, MD Associate Professor, Division of Emergency Medicine, Harvard Medical School; Vice Chair, Department of Emergency Medicine, Massachusetts General Hospital David FM Brown, MD is a member of the following medical societies: American College of Emergency Physicians and Society for Academic Emergency Medicine Disclosure: Nothing to disclose. Additional Contributors Craig F Feied, MD, FACEP, FAAEM, FACPh Professor of Emergency Medicine, Georgetown University School of Medicine; General Manager, Microsoft Enterprise Health Solutions Group Disclosure: Nothing to disclose. William G Gossman, MD Associate Clinical Professor of Emergency Medicine, Creighton University School of Medicine; Consulting Staff, Department of Emergency Medicine, Creighton University Medical Center William G Gossman, MD is a member of the following medical societies: American Academy of Emergency Medicine Disclosure: Nothing to disclose. Jonathan A Handler, MD HSG Chief Deployment Architect, Microsoft Corporation, Adjunct Associate Professor, Department of Emergency Medicine, Northwestern University, Feinberg School of Medine Disclosure: Nothing to disclose. Gary Setnik, MD Chair, Department of Emergency Medicine, Mount Auburn Hospital; Assistant Professor, Division of Emergency Medicine, Harvard Medical School
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Gary Setnik, MD is a member of the following medical societies: American College of Emergency Physicians, National Association of EMS Physicians, and Society for Academic Emergency Medicine Disclosure: SironaHealth Salary Management position; South Middlesex EMS Consortium Salary Management position; ProceduresConsult.com Royalty Other Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference Disclosure: Medscape Salary Employment

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