Alteplase is a thrombolytic agent that is manufactured by recombinant DNA technology. It is FDA approved for use in acute ischemic stroke, pulmonary embolism, acute myocardial infarction, and occluded catheters. Off-label indications include catheter-directed thrombolysis in the treatment of peripheral arterial occlusive disease and deep vein thrombosis.
Alteplase is a fibrinolytic; it also is referred to as tissue plasminogen activator (tPA). Alteplase converts plasminogen to the proteolytic enzyme plasmin, which lyses fibrin. Intravenous alteplase is cleared primarily by the liver with an initial half-life of fewer than 5 minutes and a terminal half-life of 72 minutes.
When alteplase 2 mg is instilled into occluded catheters to restore catheter function, it is unlikely that plasma will attain pharmacologic concentrations of alteplase.
Alteplase is available as a lyophilized powder in 50 mg and 100 mg vials. Each vial is packaged with diluent (sterile water for injection) for reconstitution. It also is compatible in 0.9% sodium chloride and dextrose 5% water.
Alteplase is administered intravenously at a concentration of 1 mg/mL for the treatment of acute ischemic stroke, pulmonary embolism, and myocardial infarction. Reconstituted solution is stable for 8 hours at room temperature.
For catheter clearance, the drug is instilled directly into the catheter at a concentration of 1 mg/mL.
1. Acute Ischemic Stroke
The recommended dose is 0.9 mg/kg. The total dose should not exceed 90 mg.
Ten percent of the total dose is administered as an intravenous (IV) bolus over 1 minute, and the remainder is infused over 60 minutes. It should be administered as soon as possible within 4.5 hours of symptom onset.
2. Myocardial Infarction
Alteplase may be used in conjunction with heparin and aspirin for the treatment of myocardial infarction. When used for this indication, providers may select one of the following dosing regimens: IV bolus followed by a 90-minute infusion or a 180-minute infusion.
IV bolus followed by a 90-minute infusion: Patients who weigh more than 67 kg should receive a bolus of 15 mg followed by a 30-minute infusion of 50 mg and then a 60-minute infusion of 35 mg. Patients who weigh less than or equal to 67 kg should receive a bolus of 15 mg followed by a weight-based 30-minute infusion of 0.75 mg/kg and a 60-minute infusion of 0.5 mg/kg. The total dose should not exceed 100 mg.
IV bolus followed by a 180-minute infusion: Patients weighing more than or equal to 65 kg should receive 6-10 mg administered as a bolus followed by 50-54 mg administered over the rest of the first hour and then 20 mg/hour for 2 hours. Patients who weigh less than 65 kg should receive a bolus of 0.075 mg/kg, then 0.675 mg/kg for the rest of the first hour followed by 0.25 mg/kg per hour for 2 hours. The total dose should not exceed 100 mg.
3. Pulmonary Embolism (PE)
The FDA recommended dose for PE is 100 mg infused intravenously over 2 hours. Parenteral anticoagulation should be started near the end of, or immediately following, the infusion when the partial thromboplastin time or thrombin time is equal to or lower than twice normal.
4. Catheter Clearance
Alteplase 2 mg should be instilled into the catheter at a concentration of 1 mg/mL. A second dose may be administered 2 hours after the first one if the catheter is still occluded.
The NINDS Trial was a randomized trial of IV alteplase versus placebo in patients with acute ischemic stroke treated within 3 hours of symptom onset. Alteplase improved functional outcomes at 3 months in comparison to placebo.
In the ECASS trial, alteplase administered between 3 and 4.5 hours after onset of acute ischemic stroke symptoms resulted in a lower incidence of the primary end-point, disability at 3 months, compared to placebo. However, alteplase was more frequently associated with symptomatic intracranial hemorrhage than placebo.
The MAPPET-3 trial compared heparin plus 100 mg alteplase to heparin alone, both administered over 2 hours in patients with PE and right-ventricular dysfunction or pulmonary hypertension but no hypotension or shock (submassive PE). The primary endpoint of in-hospital death or clinical deterioration was significantly lower in the group that received alteplase.
In the MOPETT trial, 121 patients with moderate PE were randomized to receive alteplase 0.5 mg/kg (maximum 50 mg), given as a 10 mg bolus followed by the remainder over 2 hours plus anticoagulation or anticoagulation alone. This dose of alteplase is lower than the FDA recommended dose of 100 mg for a massive PE. Alteplase plus anticoagulation reduced the incidence of pulmonary hypertension and the composite outcome of pulmonary hypertension and recurrent PE compared to anticoagulation alone.
In the Gusto trial, the use of alteplase and heparin compared to streptokinase plus heparin resulted in a 14% reduction in mortality. The use of alteplase resulted in significantly more hemorrhagic strokes compared to the use of streptokinase.
Adverse effects of alteplase include bleeding, angioedema, anaphylaxis, and fever.
The risk of bleeding is highest in patients with the following conditions: recent intracranial hemorrhage, major surgery, cerebrovascular disease, recent trauma or major bleeding, uncontrolled hypertension, acute pericarditis, hemorrhagic ophthalmic conditions, advanced age, concurrent anticoagulant or antiplatelet agents, and any coagulopathy that makes patients more susceptible to bleeding.
There have been case reports of cholesterol embolization in patients treated with thrombolytics, including alteplase. The incidence and clinical significance of this are not well defined.
When considering alteplase for the treatment of acute ischemic stroke, do not use in patients with the following conditions:
Stroke within the last 3 months
Intracranial or intraspinal surgery within the last 3 months
Serious head trauma within the last 3 months
Intracranial neoplasms, arteriovenous malformations, or aneurysms
Conditions that increase the risk of bleeding
Currently severe uncontrolled hypertension
Alteplase is listed in FDA pregnancy category C. It is not known if it crosses the placenta or if it is excreted in human milk. It has not been well studied in pregnant women, nursing mothers, or pediatric patients.
Patients should be assessed for bleeding and hypersensitivity reactions.
Neurological status and blood pressure should be closely monitored during intravenous therapy. Laboratory parameters to follow include hemoglobin, hematocrit, platelets, fibrinogen, and activated partial thromboplastin time. If serious bleeding occurs, stop the alteplase therapy and provide supportive care.
If a hypersensitivity reaction occurs, stop the alteplase and provide supportive therapy such as antihistamines and corticosteroids.
Coagulation tests may be unreliable during alteplase therapy because alteplase may degrade fibrinogen in blood samples.