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Medication Safety Issues
Sound-alike/look-alike issues:
Activase® may be confused with Cathflo® Activase®, TNKase®
Alteplase may be confused with Altace®
“tPA” abbreviation should not be used when writing orders for this medication; has been misread as TNKase (tenecteplase)
High alert medication: The Institute for Safe Medication Practices (ISMP) includes this medication (I.V.) among its list of drugs which have a heightened risk of causing significant patient harm when used in error.
Pronunciation
(AL te plase)
U.S. Brand Names
Index Terms
Generic Available
No
Canadian Brand Names
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Management of ST-elevation myocardial infarction (STEMI) for the lysis of thrombi in coronary arteries; management of acute ischemic stroke (AIS); management of acute pulmonary embolism
Recommended criteria for treatment:
STEMI: Chest pain ?20 minutes duration, onset of chest pain within 12 hours of treatment (or within prior 12-24 hours in patients with continuing ischemic symptoms), and ST-segment elevation >0.1 mV in at least two contiguous precordial leads or two adjacent limb leads on ECG or new or presumably new left bundle branch block (LBBB)
AIS: Onset of stroke symptoms within 3 hours of treatment
Acute pulmonary embolism: Age ?75 years: Documented massive pulmonary embolism by pulmonary angiography or echocardiography or high probability lung scan with clinical shock
Cathflo® Activase®: Restoration of central venous catheter function
Use: Unlabeled/Investigational
Acute ischemic stroke presenting 3-4.5 hours after symptom onset; acute peripheral arterial occlusive disease
Pregnancy Risk Factor
C
Pregnancy Considerations
Teratogenic effects were not observed in animal studies. There are no adequate and well-controlled studies in pregnant women. The risk of bleeding may be increased in pregnant women. Use during pregnancy is limited; administer to pregnant women only if the potential benefits justify the risk to the fetus.
Lactation
Excretion in breast milk unknown/use caution
Contraindications
Hypersensitivity to alteplase or any component of the formulation
Treatment of STEMI or PE: Active internal bleeding; history of CVA; recent intracranial or intraspinal surgery or trauma; intracranial neoplasm; arteriovenous malformation or aneurysm; known bleeding diathesis; severe uncontrolled hypertension; suspected aortic dissection
Treatment of acute ischemic stroke: Evidence of intracranial hemorrhage or suspicion of subarachnoid hemorrhage on pretreatment evaluation; intracranial or intraspinal surgery within 3 months; stroke or serious head injury within 3 months; history of intracranial hemorrhage; uncontrolled hypertension at time of treatment (eg, >185 mm Hg systolic or >110 mm Hg diastolic); seizure at the onset of stroke; active internal bleeding; intracranial neoplasm; arteriovenous malformation or aneurysm; multilobar cerebral infarction (hypodensity >1/3 cerebral hemisphere; Adams, 2007); clinical presentation suggesting post-MI pericarditis; known bleeding diathesis including but not limited to current use of oral anticoagulants producing an INR >1.7, an INR >1.7, administration of heparin within 48 hours preceding the onset of stroke with an elevated aPTT at presentation, platelet count <100,000/mm3.
Additional exclusion criteria within clinical trials:
Presentation <3 hours after initial symptoms (NINDS, 1995): Time of symptom onset unknown, rapidly improving or minor symptoms, major surgery within 2 weeks, GI or urinary tract hemorrhage within 3 weeks, aggressive treatment required to lower blood pressure, glucose level <50 or >400 mg/dL, and arterial puncture at a noncompressible site or lumbar puncture within 1 week.
Presentation 3-4.5 hours after initial symptoms (ECASS-III; Hacke, 2008): Age >80 years, time of symptom onset unknown, rapidly improving or minor symptoms, current use of anticoagulants regardless of INR, glucose level <50 or >400 mg/dL, aggressive intravenous treatment required to lower blood pressure, major surgery or severe trauma within 3 months, baseline National Institutes of Health Stroke Scale (NIHSS) score >25, and history of both stroke and diabetes.
Warnings/Precautions
Concerns related to adverse effects:
• Arrhythmias: Coronary thrombolysis may result in reperfusion arrhythmias.
• Bleeding: Do not use doses >150 mg; associated with increased risk of intracranial hemorrhage. The total dose should not exceed 90 mg for acute ischemic stroke or 100 mg for acute myocardial infarction or pulmonary embolism. Monitor all potential bleeding sites; if serious bleeding occurs, the infusion of alteplase and heparin should be stopped.
Disease-related concerns:
• Conditions that increase bleeding risk: For the following conditions, the risk of bleeding is higher with use of thrombolytics and should be weighed against the benefits of therapy: Recent (within 10 days) major surgery (eg, CABG, obstetrical delivery, organ biopsy, pregnancy, previous puncture of noncompressible vessels), prolonged CPR with evidence of thoracic trauma, lumbar puncture within 1 week, cerebrovascular disease, recent gastrointestinal or genitourinary bleeding, recent trauma, hypertension (systolic BP >175 mm Hg and/or diastolic BP >110 mm Hg), high likelihood of left heart thrombus (eg, mitral stenosis with atrial fibrillation), acute pericarditis, subacute bacterial endocarditis, hemostatic defects including ones caused by severe renal or hepatic dysfunction, significant hepatic dysfunction, diabetic hemorrhagic retinopathy or other hemorrhagic ophthalmic conditions, septic thrombophlebitis or occluded AV cannula at seriously infected site and/or any other condition in which bleeding constitutes a significant hazard or would be particularly difficult to manage because of location.
• ST-elevation myocardial infarction (STEMI): Appropriate use: Follow standard management for STEMI while infusing alteplase.
• Stroke: Appropriate use: Patients who present within 3 hours of stroke symptom onset should be treated with alteplase unless contraindications exist. A longer time window (3-4.5 hours after symptom onset) has now been formally evaluated and shown to be safe and efficacious for select individuals (del Zoppo, 2009; Hacke, 2008).Treatment of patients with minor neurological deficit or with rapidly improving symptoms is not recommended.
Concurrent drug therapy issues:
• Anticoagulants: Use with caution in patients receiving oral anticoagulants; increased risk of bleeding. In the treatment of acute ischemic stroke, the current use of oral anticoagulants producing an INR >1.7 is a contraindication.
• Aspirin: In the treatment of acute ischemic stroke, avoid aspirin for 24 hours following administration of alteplase; administration within 24 hours increases the risk of hemorrhagic transformation.
• Heparin: Concurrent heparin anticoagulation may contribute to bleeding. In the treatment of acute ischemic stroke, concurrent use of anticoagulants was not permitted during the initial 24 hours of the <3 hour window trial (NINDS, 1995). Initiation of SubQ heparin (?10,000 units) or equivalent doses of low molecular weight heparin for prevention of DVT during the first 24 hours of the 3-4.5 hour window trial was permitted and did not increase the incidence of intracerebral hemorrhage (Hacke, 2008).
Special populations:
• Elderly: Use with caution in patients with advanced age (eg, >75 years); increased risk of bleeding. Acute ischemic stroke (within 3-4.5 hours after symptom onset): Patients >80 years were excluded from the clinical trial (Hacke, 2008).
• Pregnancy: Use with caution in pregnancy; increased risk of bleeding.
Dosage form specific issues:
• Cathflo® Activase®: When used to restore catheter function, use Cathflo® cautiously in those patients with known or suspected catheter infections. Evaluate catheter for other causes of dysfunction before use. Avoid excessive pressure when instilling into catheter.
Other warnings/precautions:
• Administration: Intramuscular injections and nonessential handling of the patient should be avoided. Venipunctures should be performed carefully and only when necessary. If arterial puncture is necessary, use an upper extremity vessel that can be manually compressed.
Adverse Reactions
As with all drugs which may affect hemostasis, bleeding is the major adverse effect associated with alteplase. Hemorrhage may occur at virtually any site. Risk is dependent on multiple variables, including the dosage administered, concurrent use of multiple agents which alter hemostasis, and patient predisposition. Rapid lysis of coronary artery thrombi by thrombolytic agents may be associated with reperfusion-related atrial and/or ventricular arrhythmia. Note: Lowest rate of bleeding complications expected with dose used to restore catheter function.
1% to 10%:
Cardiovascular: Hypotension
Central nervous system: Fever
Dermatologic: Bruising (1%)
Gastrointestinal: GI hemorrhage (5%), nausea, vomiting
Genitourinary: GU hemorrhage (4%)
Hematologic: Bleeding (0.5% major, 7% minor: GUSTO trial)
Local: Bleeding at catheter puncture site (15.3%, accelerated administration)
<1% (Limited to important or life-threatening): Intracranial hemorrhage (0.4% to 0.87% when dose is ?100 mg), retroperitoneal hemorrhage, pericardial hemorrhage, gingival hemorrhage, epistaxis, allergic reactions: anaphylaxis, anaphylactoid reactions, laryngeal edema, rash, and urticaria (<0.02%).
Additional cardiovascular events associated with use in STEMI: AV block, cardiogenic shock, heart failure, cardiac arrest, recurrent ischemia/infarction, myocardial rupture, electromechanical dissociation, pericardial effusion, pericarditis, mitral regurgitation, cardiac tamponade, thromboembolism, pulmonary edema, asystole, ventricular tachycardia, bradycardia, ruptured intracranial AV malformation, seizure, hemorrhagic bursitis, cholesterol crystal embolization
Additional events associated with use in pulmonary embolism: Pulmonary re-embolization, pulmonary edema, pleural effusion, thromboembolism
Additional events associated with use in stroke: Cerebral edema, cerebral herniation, seizure, new ischemic stroke
Drug Interactions
Anticoagulants: Thrombolytic Agents may enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Antiplatelet Agents: May enhance the anticoagulant effect of Thrombolytic Agents. Risk C: Monitor therapy
Aprotinin: May diminish the therapeutic effect of Thrombolytic Agents. Risk D: Consider therapy modification
Drotrecogin Alfa: Thrombolytic Agents may enhance the adverse/toxic effect of Drotrecogin Alfa. Bleeding may occur. Risk D: Consider therapy modification
Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Thrombolytic Agents. Bleeding may occur. Risk D: Consider therapy modification
Nitroglycerin: May decrease the serum concentration of Alteplase. Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents: May enhance the adverse/toxic effect of Thrombolytic Agents. An increased risk of bleeding may occur. Risk C: Monitor therapy
Salicylates: May enhance the adverse/toxic effect of Thrombolytic Agents. An increased risk of bleeding may occur. Risk C: Monitor therapy
Ethanol/Nutrition/Herb Interactions
Herb/Nutraceutical: Avoid cat's claw, dong quai, evening primrose, feverfew, red clover, horse chestnut, garlic, green tea, ginseng, ginkgo (all have additional antiplatelet activity).
Storage
Activase®: The lyophilized product may be stored at room temperature (not to exceed 30°C/86°F), or under refrigeration. Once reconstituted it should be used within 8 hours.
Cathflo® Activase®: Store lyophilized product in refrigerator. Once reconstituted, store at 2°C to 30°C (36°F to 86°F) and use within 8 hours.
Reconstitution
Activase®:
50 mg vial: Use accompanying diluent (50 mL sterile water for injection); do not shake. Final concentration: 1 mg/mL.
100 mg vial: Use transfer set with accompanying diluent (100 mL vial of sterile water for injection); no vacuum is present in 100 mg vial. Final concentration: 1 mg/mL.
Cathflo® Activase®: Add 2.2 mL SWFI to vial; do not shake. Final concentration: 1 mg/mL.
Compatibility
Stable in NS, sterile water for injection; incompatible with bacteriostatic water; variable stability (consult detailed reference) in D5W.
Y-site administration: Compatible: Lidocaine, metoprolol, propranolol. Incompatible: Dobutamine, dopamine, heparin, nitroglycerin.
Compatibility when admixed: Compatible: Lidocaine, morphine, nitroglycerin. Incompatible: Dobutamine, dopamine, heparin.
Mechanism of Action
Initiates local fibrinolysis by binding to fibrin in a thrombus (clot) and converts entrapped plasminogen to plasmin
Pharmacodynamics/Kinetics
Duration: >50% present in plasma cleared ~5 minutes after infusion terminated, ~80% cleared within 10 minutes
Excretion: Clearance: Rapidly from circulating plasma (550-650 mL/minute), primarily hepatic; >50% present in plasma is cleared within 5 minutes after the infusion is terminated, ~80% cleared within 10 minutes
Dosage
I.V. (Activase®):
ST-elevation myocardial infarction (STEMI): Front loading dose (weight-based):
Patients >67 kg: Total dose: 100 mg over 1.5 hours; infuse 15 mg over 1-2 minutes. Infuse 50 mg over 30 minutes. Infuse remaining 35 mg of alteplase over the next hour. See “Note.”
Patients ?67 kg: Infuse 15 mg I.V. bolus over 1-2 minutes, then infuse 0.75 mg/kg (not to exceed 50 mg) over next 30 minutes, followed by 0.5 mg/kg over next 60 minutes (not to exceed 35 mg). See “Note.”
Note: All patients should receive 162-325 mg of chewable nonenteric coated aspirin as soon as possible and then daily. Administer concurrently with heparin 60 units/kg bolus (maximum: 4000 units) followed by continuous infusion of 12 units/kg/hour (maximum: 1000 units/hour) and adjust to aPTT target of 50-70 seconds (or 1.5-2 times the upper limit of control).
Acute pulmonary embolism: 100 mg over 2 hours.
Acute ischemic stroke: Within 3 hours of the onset of symptom onset (labeled use) or within 3-4.5 hours of symptom onset (unlabeled use; del Zoppo, 2009; Hacke, 2008): Note: Initiation of anticoagulants (eg, heparin) or antiplatelet agents (eg, aspirin) within 24 hours after starting alteplase is not recommended; however, initiation of aspirin between 24-48 hours after stroke onset is recommended (Adams, 2007). Initiation of SubQ heparin (?10,000 units) or equivalent doses of low molecular weight heparin for prevention of DVT during the first 24 hours of the 3-4.5 hour window trial did not increase incidence of intracerebral hemorrhage (Hacke, 2008).
Recommended total dose: 0.9 mg/kg (maximum total dose: 90 mg)
Patients ?100 kg: Load with 0.09 mg/kg (10% of 0.9 mg/kg dose) as an I.V. bolus over 1 minute, followed by 0.81 mg/kg (90% of 0.9 mg/kg dose) as a continuous infusion over 60 minutes.
Patients >100 kg: Load with 9 mg (10% of 90 mg) as an I.V. bolus over 1 minute, followed by 81 mg (90% of 90 mg) as a continuous infusion over 60 minutes.
Intracatheter: Central venous catheter clearance (Cathflo® Activase® 1 mg/mL):
Patients <30 kg: 110% of the internal lumen volume of the catheter, not to exceed 2 mg/2 mL; retain in catheter for 0.5-2 hours; may instill a second dose if catheter remains occluded
Patients ?30 kg: 2 mg (2 mL); retain in catheter for 0.5-2 hours; may instill a second dose if catheter remains occluded
Intra-arterial: Acute peripheral arterial occlusive disease (unlabeled use): 0.02-0.1 mg/kg/hour for up to 36 hours
Advisory Panel to the Society for Cardiovascular and Interventional Radiology on Thrombolytic Therapy recommendation: ?2 mg/hour and subtherapeutic heparin (aPTT <1.5 times baseline)
Administration: I.V.
Activase®: ST-elevation MI: Accelerated infusion: Bolus dose may be prepared by one of three methods:
1) Removal of 15 mL reconstituted (1 mg/mL) solution from vial
2) Removal of 15 mL from a port on the infusion line after priming
3) Programming an infusion pump to deliver a 15 mL bolus at the initiation of infusion
Activase®: Acute ischemic stroke: Bolus dose (10% of total dose) may be prepared by one of three methods:
1) Removal of the appropriate volume from reconstituted solution (1 mg/mL)
2) Removal of the appropriate volume from a port on the infusion line after priming
3) Programming an infusion pump to deliver the appropriate volume at the initiation of infusion
Note: Remaining dose for STEMI, AIS, or total dose for acute pulmonary embolism may be administered as follows: Any quantity of drug not to be administered to the patient must be removed from vial(s) prior to administration of remaining dose.
50 mg vial: Either PVC bag or glass vial and infusion set
100 mg vial: Insert spike end of the infusion set through the same puncture site created by transfer device and infuse from vial
If further dilution is desired, may be diluted in equal volume of 0.9% sodium chloride or D5W to yield a final concentration of 0.5 mg/mL.
Administration: Other
Cathflo® Activase®: Intracatheter: Instill dose into occluded catheter. Do not force solution into catheter. After a 30-minute dwell time, assess catheter function by attempting to aspirate blood. If catheter is functional, aspirate 4-5 mL of blood in patients ?10 kg or 3 mL in patients <10 kg to remove Cathflo® Activase® and residual clots. Gently irrigate the catheter with NS. If catheter remains nonfunctional, let Cathflo® Activase® dwell for another 90 minutes (total dwell time: 120 minutes) and reassess function. If catheter function is not restored, a second dose may be instilled.
Administration: I.V. Detail
Reconstituted solution should be clear or pale yellow and transparent. Avoid agitation during dilution.
pH: 5-7.3
Monitoring Parameters
Acute ischemic stroke: In addition to monitoring for bleeding complications, the 2007 AHA/ASA Guidelines for the early management of acute ischemic stroke recommends the following:
Perform neurological assessments every 15 minutes during infusion and every 30 minutes thereafter for the next 6 hours, then hourly until 24 hours after treatment.
If severe headache, acute hypertension, nausea, or vomiting occurs, discontinue the infusion and obtain emergency CT scan.
Measure BP every 15 minutes for the first 2 hours then every 30 minutes for the next 6 hours, then hourly until 24 hours after initiation of alteplase. Increase frequency if a systolic BP is ?180 mm Hg or if a diastolic BP is ?105 mm Hg; administer antihypertensive medications to maintain BP at or below these levels.
Obtain a follow-up CT scan at 24 hours before starting anticoagulants or antiplatelet agents.
Central venous catheter clearance: Assess catheter function by attempting to aspirate blood.
ST-elevation MI: Assess for evidence of cardiac reperfusion through resolution of chest pain, resolution of baseline ECG changes, preserved left ventricular function, cardiac enzyme washout phenomenon, and/or the appearance of reperfusion arrhythmias; assess for bleeding potential through clinical evidence of GI bleeding, hematuria, gingival bleeding, fibrinogen levels, fibrinogen degradation products, prothrombin times, and partial thromboplastin times.
Reference Range
Not routinely measured; literature supports therapeutic levels of 0.52-1.8 mcg/mL
Fibrinogen: 200-400 mg/dL
Activated partial thromboplastin time (aPTT): 22.5-38.7 seconds
Prothrombin time (PT): 10.9-12.2 seconds
Test Interactions
Altered results of coagulation and fibrinolytic agents
Patient Education
This medication can only be administered by infusion; you will be monitored closely during and after treatment. You will have a tendency to bleed easily; use caution to prevent injury (use electric razor, soft toothbrush, and use caution with knives, needles, or anything sharp). Follow instructions for strict bedrest to reduce the risk of injury. If bleeding occurs, report immediately and apply pressure to bleeding spot until bleeding stops completely. Report unusual pain (acute headache, joint pain, chest pain); unusual bruising or bleeding; blood in urine, stool, or vomit; bleeding gums; vision changes; or respiratory difficulty. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Consult prescriber if breast-feeding.
Geriatric Considerations
No specific changes in use in elderly patients are necessary.
Anesthesia and Critical Care Concerns/Other Considerations
Evidence-Based Information:
Acute Ischemic Stroke (AIS):
Presentation within 0-3 hours of stroke onset (FDA approved): Based on the National Institute of Neurological Disorders and Stroke (NINDS) rt-PA stroke study, administration of alteplase within 0-3 hours after symptom onset is an established therapeutic modality in the treatment of AIS. The NINDS trial demonstrated significant neurological improvement at 24 hours and a greater number of patients experienced a favorable outcome (complete or nearly complete neurological recovery) at 90 days if they received alteplase compared to those receiving placebo. The decision to administer alteplase should be made after careful consideration of the patient's eligibility including level of neurological deficit, time of presentation, and existence of contraindications to alteplase (eg, intracranial hemorrhage). Since a powerful time-to-treatment effect exists with the administration of alteplase for AIS, any delay in treatment once a patient is identified to be a candidate for alteplase may compromise efficacy and possibly safety. With administration of alteplase for AIS, the clinician should be keenly aware of the potential serious side effect of bleeding especially intracranial hemorrhage (ICH) which occurs at a rate of approximately 6% in this population. Strict adherence to established protocols is necessary to prevent higher rates of ICH. Orolingual angioedema, a rare but serious complication, may also occur and compromise the airway.
Presentation within 3-4.5 hours of stroke onset (non-FDA approved): Administration of alteplase is currently recommended for patients with AIS who may be treated within 3 hours of symptom onset (2007 AHA/ASA guideline). However, more recently, the European Cooperative Acute Stroke Study III (ECASS III; Hacke, 2008), a double-blind, multicenter trial enrolled 821 patients with AIS presenting with onset of stroke symptoms between 3-4.5 hours. Patients were randomized to either placebo or standard-dose alteplase (total dose: 0.9 mg/kg over 60 minutes; maximum: 90 mg; with 10% of 0.9 mg/kg given as loading dose). Patients were excluded if they had evidence of brain hemorrhage or major infarction. Other notable exclusion criteria were age >80 years, oral anticoagulation regardless of INR, severe stroke as assessed clinically (eg, NIH Stroke Scale >25) and/or by appropriate imaging techniques, and history of prior stroke and concomitant diabetes. The primary endpoint was disability at 90 days, dichotomized as a favorable or unfavorable outcome (score of 0-1 or 2-6 on the modified Rankin scale, respectively). The secondary endpoint was a global outcome analysis that combined the outcomes at day 90 of four neurologic and disability scores (modified Rankin scale, Barthel Index, NIH Stroke Scale, and Glasgow Outcome Scale). Median time to alteplase treatment was 239 minutes (3.9 hours) after onset of stroke symptoms. Compared to those who received placebo, patients receiving alteplase experienced less disability at 90 days (219 [52.4%] vs 182 [45.2%], p=0.04). A favorable global outcome was statistically more frequent with alteplase compared to placebo. More cases of intracranial hemorrhage (ICH) occurred in the alteplase group compared to placebo (any ICH, 113 [27%] vs 71 [17.6%], p=0.001; symptomatic ICH 10 [2.4%] vs 1 [0.2%], p=0.008), a rate similar to that of previous clinical trials when used within 0-3 hours. Although not a primary endpoint of the trial, there was no difference in mortality between the two groups (32 [7.7%] vs 34 [8.4%], p=0.68). ECASS III suggests the extension of the time window for treatment with alteplase and is now recommended by the AHA/ASA (Class Ib recommendation; del Zoppo, 2009).
Acute Pulmonary Embolism (PE): The American College of Chest Physicians (Kearon, 2008) recommends the following:
All patients with acute PE: All patients with diagnosed PE should undergo rapid risk stratification based on risk of death from PE and bleeding. In general, the majority of patients with PE will not require treatment with thrombolytics; however, treatment with anticoagulation (eg, enoxaparin, heparin) will be necessary unless contraindicated.
Patients with acute PE without hemodynamic compromise: In general, patients without hemodynamic compromise should not receive thrombolytic therapy. However, patients without hemodynamic compromise but with poor prognostic indicators (elevated troponin, right ventricular dysfunction on echocardiogram, etc) are at high risk of an adverse outcome and may derive benefit from receiving systemic thrombolysis. Therefore, the most recent recommendation is to administer thrombolysis in these selected high-risk patients who have a low risk of bleeding. The use of regimens with short infusion times (eg, 2-hour infusion) is recommended over longer infusion times (eg, 12-hour infusions). The most widely used thrombolytic for this indication is alteplase which is administered as an infusion of 100 mg over 2 hours. Urokinase may also be used; however, the administration time for urokinase is 12 hours.
Patients with acute PE with hemodynamic compromise: Since thrombolytic therapy has been shown to accelerate thrombolysis resulting in more rapid resolution of perfusion scan abnormalities, decrement angiographic thrombus, reduction in elevated pulmonary artery pressures, and normalization of right ventricular dysfunction in patients with PE and hemodynamic compromise (usually defined as SBP <90 mm Hg requiring vasopressor therapy), the use of thrombolytic therapy via a peripheral vein is recommended unless major contraindications exist. The use of regimens with short infusion times (eg, 2-hour infusion) is recommended over longer infusion times (eg, 12-hour infusions). The most widely used thrombolytic for this indication is alteplase which is administered as an infusion of 100 mg over 2 hours. Urokinase may also be used; however, the administration time for urokinase is 12 hours.
Patients with PE experiencing cardiac arrest: According to the 2005 ACLS guidelines, when PE is responsible for cardiac arrest and the patient is unresponsive to cardiopulmonary resuscitation (CPR), it is reasonable to administer bolus thrombolytic therapy, specifically alteplase (Böttiger, 2001); however, routine use in cardiac arrest or undifferentiated pulseless electrical activity (PEA) is not recommended. Of note, ongoing CPR is not a contraindication in this setting.
Intracerebral Hemorrhage (ICH) Due to Thrombolysis: Overall management of ICH is similar regardless of cause; however, iatrogenic spontaneous ICH may have specific treatments. According to the 2007 ACC/ASA Guidelines for the Management of Spontaneous Intracerebral Hemorrhage, fibrinolytic-related ICH should be treated with infusion of platelets (6-8 units) and cryoprecipitate which contains factor VIII (Class IIb recommendation).
Peripheral Arterial Occlusive Disease (PAOD) and Deep Venous Thrombosis (DVT): The Surgery Versus Thrombolysis for Ischemia of the Lower Extremity (STILE) trial (Ann Surg, 1994) compared surgery to intra-arterial thrombolytic therapy with either urokinase (250,000 units bolus, followed by 4000 units/minute for 4 hours, followed by 2000 units/minute for ?36 hours) or alteplase (0.05 mg/kg/hour for ?12 hours) in patients with acute (<14 days) or chronic PAOD. Patients with acute PAOD who received either fibrinolytic treatment had a shorter hospital stay and an improved amputation-free survival rate. There was no difference between alteplase or urokinase with regard to efficacy or bleeding events. A group from Stanford University recently did a retrospective comparison evaluating efficacy, safety, and cost of low-dose alteplase (<2 mg/hour) and subtherapeutic heparin to urokinase and therapeutic heparin for the treatment of PAOD or DVT (Sugimoto, 2003). Efficacy was similar for both groups. The average dose of alteplase was 0.86 mg/hour and the dose of urokinase was 2250 units/minute. Alteplase infusions were shorter and less expensive than urokinase.
Cardiovascular Considerations
ST-Elevation Myocardial Infarction: The 2004 ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction recommend prehospital thrombolysis in special circumstances (eg, transport time >30 minutes). Efforts to quickly identify and safely treat appropriate candidates for therapy continue. Reducing treatment delays is very important to improve mortality. Thrombolytic therapy is indicated in patients with ST-segment elevation >1 mm in two or more contiguous leads or at least two adjacent limb leads in patients with chest discomfort >30 minutes but ?12 hours. Patients with chest discomfort suggestive of ischemia and new-onset left bundle branch block (LBBB) are also candidates for thrombolysis. Generally, there is only a small trend for benefit of therapy after a delay of more than 12-24 hours, but thrombolysis may be considered for selected patients with ongoing ischemic pain and extensive ST elevation. Additional absolute contraindications for fibrinolysis use in ST-elevation myocardial infarction from the 2004 ACC/AHA guidelines: Any prior intracranial hemorrhage, ischemic stroke within 3 months (except one within 3 hours), significant closed head or facial trauma within 3 months. Additional relative contraindications include history of chronic severe, poorly-controlled hypertension, severe uncontrolled hypertension on presentation (systolic BP >180 mm Hg or diastolic >110 mm Hg; could be an absolute contraindication in low-risk patients), history of prior ischemic stroke >3 months, dementia, or known intracranial pathology, traumatic or prolonged (>10 minutes) CPR or major surgery (<3 weeks), recent (within 2-4 weeks) internal bleeding, noncompressible vascular punctures, pregnancy, active peptic ulcer, current use of anticoagulants.
Thrombolytic and GP IIb/IIIa Inhibitor: In the GUSTO V trial, patients with STEMI were randomized to standard-dose reteplase or half-dose reteplase (two boluses of 5 units each, 30 minutes apart) and full dose abciximab. Thirty-day mortality (primary endpoint) was similar in both groups. The combination treatment group had fewer deaths or nonfatal reinfarctions, less need for urgent revascularization, and fewer major ischemic complications. More bleeding occurred in the combination treatment group, but intracranial hemorrhage and nonfatal disabling stroke were similar in both groups. All cause mortality at one year was similar in both groups. In TIMI 14, the combination of full-dose abciximab (0.25 mg/kg bolus followed by a 12-hour infusion of 0.125 mcg/kg/minute, maximum 10 mcg/minute) and half-dose alteplase (15 mg bolus followed by 35 mg infusion over 60 minutes) resulted in 74% of patients achieving TIMI grade 3 flow at 90 minutes. The 2004 ACC/AHA guidelines for the management of patients with STEMI suggests that abciximab and half-dose reteplase or tenecteplase may be considered for prevention of reinfarction in patients with an anterior MI, who are <75 years of age, and who have no risk factors for bleeding.
However, more recently, the 2008 American College of Chest Physicians guidelines recommends against the combination of half-dose reteplase or tenecteplase and standard-dose abciximab (with low dose unfractionated heparin) in any patient with STEMI due to the lack of mortality benefit and the risk of major bleeding (Goodman, 2008).
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: As with all drugs which may affect hemostasis, bleeding is the major adverse effect associated with alteplase. Hemorrhage may occur at virtually any site; risk is dependent on multiple variables, including the dosage administered, concurrent use of multiple agents which alter hemostasis, and patient predisposition. Rapid lysis of coronary artery thrombi by thrombolytic agents may be associated with reperfusion-related atrial and/or ventricular arrhythmias. See Effects on Bleeding.
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
None reported
Mental Health: Effects on Psychiatric Treatment
None reported
Nursing: Physical Assessment/Monitoring
Assess potential for interactions or toxicity with other prescriptions, OTC medications, or herbal products patient may be taking (especially those medications that may affect coagulation or platelet function). See dosing and administration details according to purpose for use. Assess vital signs, results of laboratory tests, and ECG prior to, during, and after therapy. Arrhythmias may occur; antiarrhythmic drugs should be immediately available. Infusion site (and any other potential bleeding sites) should be monitored and patient assessed for hemorrhage every 10 minutes (or according to institutional policy) during therapy and for 1 hour following therapy. Strict bedrest should be maintained and bleeding precautions should be instituted; invasive procedures and activities that could cause trauma should be avoided. Patient instructions determined by patient condition.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Injection, powder for reconstitution, recombinant:
Activase®: 50 mg [29 million int. units; contains polysorbate 80; packaged with diluent]; 100 mg [58 million int. units; contains polysorbate 80; packaged with diluent and transfer device]
Cathflo® Activase®: 2 mg [contains polysorbate 80]
References
“A Comparison of Reteplase With Alteplase for Acute Myocardial Infarction. The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO III) Investigators,” N Engl J Med, 1997, 337(16):1118-23.
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International Brand Names
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Last full review/revision July 2009
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