Alteplase (Monograph)

Brand names: Activase, Cathflo Activase
Drug class: Thrombolytic Agents

Medically reviewed by Drugs.com on Feb 21, 2024. Written by ASHP.

Warning

A standardized concentration for this drug has been established through Standardize 4 Safety (S4S), a national patient safety initiative to reduce medication errors, especially during transitions of care. The drug is included in a standard concentration list which may apply to an IV or oral compounded liquid formulation. For additional information, see the ASHP website [Web].

Introduction

Thrombolytic agent;¹ ² ⁴⁶ biosynthetic (recombinant DNA origin) form of human tissue-type plasminogen activator (t-PA).⁴ ⁵ ⁸ ¹¹ ¹² ¹³ ¹⁴ ¹⁵ ¹⁹ ²¹ ³¹ ³⁵ ³⁶ ⁴⁶ ⁶² ⁶⁷

Uses for Alteplase

Acute MI

Used for reperfusion therapy in patients with acute MI,¹ ² ³⁴ ³⁷ ³⁸ ⁴¹ ⁴² ⁴³ ⁴⁶ ⁴⁷ ⁴⁸ ⁶⁵ ⁷⁵ ⁸⁰ ⁸³ ¹⁴¹ ¹⁹³ ⁵²⁷ in conjunction with appropriate anticoagulant (e.g., heparin) and antiplatelet (e.g., aspirin and clopidogrel) therapies.¹ ² ¹⁴ ³⁰ ³¹ ³² ³³ ³⁴ ³⁵ ³⁶ ³⁷ ³⁸ ³⁹ ⁴⁰ ⁴¹ ⁴² ⁴³ ⁴⁴ ⁴⁵ ⁴⁶ ⁴⁷ ⁴⁸ ⁵⁰ ⁵⁷ ⁵⁹ ⁶⁵ ⁶⁸ ⁶⁹ ⁷² ⁷⁵ ⁷⁸ ⁷⁹ ⁸⁰ ⁸³ ⁸⁴ ⁸⁵ ¹¹⁷ ¹⁴¹ ¹⁵⁴ ¹⁵⁵ ¹⁶³ ¹⁶⁸ ¹⁹³ ¹⁹⁴ ²²⁶ ⁵²⁷

Current standard of care in patients with ST-segment-elevation MI (STEMI) is timely reperfusion (with primary PCI or thrombolytic therapy).⁵²⁷ ⁹⁹⁴ The American College of Cardiology Foundation/American Heart Association (ACCF/AHA) guideline states that reperfusion therapy should be administered to all eligible patients with STEMI and onset of ischemic symptoms within the previous 12 hours.⁵²⁷ ⁹⁹⁴ Select appropriate reperfusion method based on a risk-benefit analysis, considering the time from onset of MI symptoms, patient's clinical and hemodynamic status, comorbidities (e.g., severe heart failure), bleeding risk, contraindications, and availability (and timeliness) of PCI.⁵²⁷

Primary PCI is preferred when it can be performed in a timely manner.⁵²⁷ ⁹⁹⁴ Thrombolytic therapy is recommended when it is anticipated that PCI cannot be performed within 120 minutes of first medical contact.⁵²⁷

Benefits of thrombolytic therapy in patients with STEMI are well established;⁵²⁷ resulting reperfusion can limit infarct size,¹ ⁴⁸ ¹⁹³ improve ventricular function,¹ ² ⁴ ³⁸ ⁴² ⁴⁶ ⁴⁷ ⁴⁸ ⁵⁰ ⁶⁹ ¹⁹³ and reduce the incidence of heart failure¹ ² ³⁸ and death.¹ ⁴² ⁴⁶ ¹⁹³ ¹⁹⁴ ²²⁶

Clinical benefit diminishes as the time period from symptom onset to initiation of therapy increases.⁴² ⁵¹ ⁵² ⁶⁷ ⁶⁸ ¹⁹³ ²⁰⁵ ⁵²⁷ Administer as soon as possible after acute MI.¹ ² ⁴ ¹⁴ ³¹ ³² ³³ ³⁴ ³⁵ ³⁶ ³⁷ ³⁸ ³⁹ ⁴⁰ ⁴¹ ⁴² ⁴³ ⁴⁶ ⁴⁷ ⁴⁸ ²²² ACCF and AHA recommend administration within 30 minutes of hospital arrival.⁵²⁷

Pulmonary Embolism

Lysis of acute pulmonary emboli involving obstruction of blood flow to a lobe or multiple segments of the lungs.¹ ¹⁵ ⁴⁶ ⁸⁶ ⁸⁷ ⁸⁸ ⁸⁹ ⁹⁰ ⁹¹ ⁹² ⁹³ ²⁶⁹ ²⁷⁰ ²⁷¹ ²⁷² ²⁷³ ²⁷⁴ ²⁷⁵ ²⁷⁶

Lysis of acute pulmonary emboli accompanied by unstable hemodynamics (i.e., when BP cannot be maintained without supportive measures).¹ ¹⁵ ⁴⁶ ⁸⁶ ⁸⁷ ⁸⁸ ⁸⁹ ⁹⁰ ⁹¹ ⁹² ⁹³ ²⁶⁹ ²⁷⁰ ²⁷¹ ²⁷² ²⁷³ ²⁷⁴ ²⁷⁵ ²⁷⁶

The American College of Chest Physicians (ACCP) generally recommends against the use of systemic thrombolytic therapy in most patients with acute PE; however, in patients with acute PE associated with hypotension (e.g., SBP <90 mm Hg), thrombolytic therapy may provide some benefit in terms of mortality reduction and is suggested as a possible treatment in patients without high risk of bleeding.¹⁰⁰⁵

Acute Ischemic Stroke

Management of acute ischemic stroke to improve neurologic recovery and reduce the incidence of disability.¹ ² ³ ⁴ ⁵ ⁶ ³²² ³⁵⁷ ³⁵⁸ ³⁷⁸ ³⁷⁹ ³⁸⁷ ³⁸⁸ ³⁸⁹ ³⁹⁰ ³⁹¹ ³⁹² ³⁹³ ³⁹⁴ ³⁹⁵ ³⁹⁶ ³⁹⁷ ¹⁰⁰⁹

Should be initiated within 3–4.5 hours following the onset of symptoms of acute ischemic stroke and only after intracranial hemorrhage has been excluded by cranial CT scan or other diagnostic imaging method sensitive for the presence of hemorrhage.¹ ³²² ³⁵⁷ ³⁵⁸ ³⁹² ³⁹⁴ ³⁹⁵ ³⁹⁶ ¹⁰⁰⁹ However, because benefit from thrombolytic therapy decreases substantially with time, such therapy should be administered as soon as possible following onset of stroke symptoms to obtain optimal benefit; experts recommend a “door-to-needle” time (i.e., from arrival at the treating facility until injection of alteplase) of no more than 1 hour.³⁸⁷ ³⁸⁸ ³⁸⁹ ³⁹⁰ ³⁹² ³⁹³ ³⁹⁶ ³⁹⁸

Safety of alteplase treatment administered more than 4.5 hours after symptom onset, in dosages higher than 0.9 mg/kg and without careful blood-pressure management, not established;¹ ² ³²² ³⁵⁷ ³⁹⁴ ³⁹⁵ ¹⁰⁰⁹ some data³⁸⁹ suggest increased mortality with alteplase administration more than 4.5 hours following onset of stroke symptoms.³⁸⁹ ³⁹⁰

Use of thrombolytic therapy not recommended by American Stroke Association (ASA) and other authorities in patients with major early ischemic changes on baseline CT scan (defined as clearly identifiable hypodensity involving more than one-third of the middle cerebral artery territory).³⁵⁸

Use of thrombolytic therapy not recommended in patients with minor neurologic deficit or with rapidly improving symptoms.¹

Arterial Thrombosis and Embolism

Intra-arterial thrombolytic therapy for lysis of arterial occlusions^{† [off-label]} in peripheral vessels and bypass grafts.⁹⁴ ⁹⁵ ⁹⁶ ⁹⁷ ⁹⁸

ACCP suggests the use of intra-arterial thrombolytic therapy in patients with acute limb ischemia due to arterial emboli or thrombosis; however, surgical reperfusion is preferred over thrombolytic therapy.¹⁰¹¹ If thrombolytic therapy is used, ACCP suggests that a recombinant tissue plasminogen activator (e.g., alteplase) or urokinase (no longer commercially available in the US) is preferred.¹⁰¹¹

Occluded IV Catheters

Restoration of patency to central venous catheters obstructed by a thrombus (assessed by the ability to withdraw blood).³²⁵ ¹⁰¹³

Consider causes of catheter dysfunction other than thrombus formation (e.g., catheter malposition, mechanical failure, constriction by a suture, lipid deposits, drug precipitates) before use.³²⁵

Alteplase Dosage and Administration

General

Institute therapy as soon as possible after acute MI.¹ ² ¹⁴ ³¹ ³² ³³ ³⁴ ³⁵ ³⁶ ³⁷ ³⁸ ³⁹ ⁴⁰ ⁴¹ ⁴² ⁴³ ⁴⁶ ⁴⁷ ⁴⁸ (See Acute MI under Uses.)
Initiate therapy for acute ischemic stroke within 3–4.5 hours of symptom onset.¹ ³²² ³⁵⁷ ³⁵⁸ ³⁹² ³⁹⁴ ³⁹⁵ ³⁹⁶ ¹⁰⁰⁹ Prior to administration, exclude intracranial hemorrhage by cranial CT scan or other sensitive diagnostic imaging method.¹ ³²² May initiate therapy prior to the availability of coagulation results in patients without recent anticoagulant therapy (e.g., oral anticoagulants, heparin).¹ Discontinue infusion if pretreatment coagulation results are abnormal (e.g., INR >1.7, PT >15 seconds, elevated aPTT).¹

Administration

Administer by IV infusion, preferably via a controlled-infusion device² using separate IV tubing (Activase).¹ ²

Administer by intracatheter instillation into occluded central venous catheters (Cathflo Activase).¹ ² ³²⁵

Also has been administered by intracoronary^{† [off-label]} injection,³⁰ ²²¹ selective intra-arterial^{† [off-label]} infusion,⁸⁹ ⁹⁰ ¹⁰² ¹⁰³ ¹⁰⁴ and intraocularly^{† [off-label]} via intracameral injection¹⁰⁴ in a limited number of patients.

IV Administration

For solution and drug compatibility information, see Stability: Compatibility.

For coronary artery thrombosis and MI, administer by IV infusion over 3 hours or as an “accelerated” infusion over 1.5 hours.¹ ³⁰ ³¹ ³² ³³ ³⁴ ³⁵ ³⁶ ³⁷ ³⁸ ³⁹ ⁴⁰ ⁴¹ ⁴² ⁴³ ⁴⁴ ⁴⁵ ⁴⁷ ⁴⁸ ⁵⁰ ⁵⁷ ⁷⁵ ⁸⁴ ⁸⁵ ¹¹⁷ ¹⁴¹ ¹⁵⁴ ¹⁵⁵ ¹⁶³ ¹⁸⁸ ¹⁹³ ²¹⁰ Some experts consider the accelerated infusion regimen the preferred method of administration.⁵²⁷

Reconstitution

Reconstitute vial containing 50 mg of alteplase by adding 50 mL of sterile water for injection without preservatives to provide a concentration of 1 mg/mL.¹ Use a large-bore (e.g., 18-gauge) needle and direct diluent into the lyophilized cake of powder.¹ ² Do not use diluents other than sterile water for injection without preservatives.¹ ²

Reconstitute vial containing 100 mg of alteplase with 100 mL of sterile water for injection without preservatives using supplied transfer device to provide a concentration of 1 mg/mL.¹

Slight foaming is not unusual during reconstitution.¹ Leave vial undisturbed for several minutes after addition of the diluent to allow dissipation of any large bubbles.¹

Dilution

Administer as reconstituted (1 mg/mL) or dilute further just prior to administration to a concentration of approximately 0.5 mg/mL using 0.9% sodium chloride injection or 5% dextrose injection.¹ ² More dilute solutions should not be used; drug may precipitate at concentrations of <0.5 mg/mL.²²¹ Do not use other infusion solutions (e.g., sterile water for injection without preservatives, preservative-containing solutions).¹ ² Mix solution with gentle swirling and/or slow inversion of the infusion container; avoid excessive agitation.¹ ²

Use reconstituted or diluted solutions within 8 hours.¹ Discard any unused solutions.¹

Administration into Occluded Central Venous Catheters

For clearing occluded central venous catheters, administer into occluded catheter.³²⁵

Reconstitution

Reconstitute solution for IV catheter clearance with 2.2 mL of sterile water for injection according to the manufacturer’s directions to provide a solution containing 1 mg/mL.³²⁵ Do not use bacteriostatic water for injection as a diluent.³²⁵

Slight foaming is not unusual during reconstitution.³²⁵ Leave vial undisturbed for several minutes after addition of diluent to allow dissipation of large bubbles.³²⁵

Dosage

Expressed in mg, but also may be expressed in international units (IU); each mg is equivalent to 580,000 units.¹ ²

Pediatric Patients

Occluded Central Venous IV Catheters

Intracatheter injection

Patients weighing <30 kg: 110% of the lumen volume of the catheter, with dosage not >2 mg (2 mL).³²⁵ Assess catheter function after at least 30 minutes by attempting to aspirate blood.³²⁵ If necessary, repeat aspiration attempt after 120 minutes of dwell time.³²⁵ Administer a second injection (110% of lumen volume, not >2 mg [2 mL]) in resistant cases;³²⁵ ACCP suggests a second dose of alteplase after 30 minutes of dwell time if the catheter remains occluded.¹⁰¹³ When patency is restored, aspirate 4–5 mL of blood in patients weighing ≥10 kg or 3 mL of blood in patients weighing <10 kg to remove all drug and clot residual.³²⁵ Irrigate catheter gently with 0.9% sodium chloride injection.³²⁵ If catheter patency not successfully established after 2 doses of alteplase, ACCP suggests radiologic imaging to rule out a catheter-related thrombus.¹⁰¹³

Patients weighing ≥30 kg: 2 mg (2 mL) into occluded catheter.³²⁵ Assess catheter function after at least 30 minutes by attempting to aspirate blood.³²⁵ If necessary, repeat aspiration attempt after 120 minutes of dwell time.³²⁵ Administer a second 2-mg injection (for a total of 4 mg) in resistant cases.³²⁵ ACCP suggests a second dose of alteplase after 30 minutes of dwell time if the catheter remains occluded.¹⁰¹³ When patency is restored, aspirate 4–5 mL of blood to remove all drug and clot residual.³²⁵ Irrigate catheter gently with 0.9% sodium chloride injection.³²⁵ If catheter patency not successfully established after 2 doses of alteplase, ACCP suggests radiologic imaging to rule out a catheter-related thrombus.¹⁰¹³

Adults

Acute MI

3-Hour Infusion

Infuse total of 100 mg (58 million IU) over 3 hours.¹ ² Initially, infuse 60 mg (34.8 million IU) during the first hour;¹ ² 6–10 mg of this dose is rapidly infused over 1–2 minutes.¹ ² Subsequently, infuse 20 mg (11.6 million IU) per hour for the next 2 hours.¹ ²

In adults weighing <65 kg (lean or actual body weight, whichever is less), infuse 1.25 mg/kg over 3 hours.¹ ²²¹ Initially, 0.75 mg/kg during the first hour; 0.045–0.075 mg/kg of this dose is rapidly infused over 1–2 minutes.¹⁹⁹ ²²¹ Subsequently, infuse 0.25 mg/kg per hour for the next 2 hours.¹⁹⁹ ²²¹

Accelerated Infusion

In adults weighing >67 kg, initially, infuse total dose of 100 mg.¹ ⁷ Initially, inject 15 mg rapidly over 1–2 minutes,¹ ⁷ followed by 50 mg over the next 30 minutes, then 35 mg over the next hour.¹

Alternatively, in patients weighing ≤67 kg, inject 15 mg rapidly over 1–2 minutes,¹ ⁷ followed by 0.75 mg/kg (up to 50 mg) over the next 30 minutes, then 0.5 mg/kg (up to 35 mg) over the next hour.¹

Pulmonary Embolism

IV

100 mg (58 million IU) infused over 2 hours.¹ ⁹¹ ²⁷¹ ²⁷³ Institute or reinstitute heparin therapy near the end of or immediately following alteplase infusion when aPTT or thrombin time returns to twice the normal value or less.¹

Acute Ischemic Stroke

IV

0.9 mg/kg (up to 90 mg) infused over 1 hour.¹ ³⁵⁷ Initially, administer 10% of the dose rapidly over 1 minute.¹ Do not exceed dose of 0.9 mg/kg (maximum 90 mg).¹

Occluded Central Venous IV Catheters

Intracatheter injection

2 mg (2 mL) into occluded catheter in patients weighing ≥30 kg; allow to dwell for at least 30 minutes.³²⁵ Assess catheter function after 30 minutes by attempting to aspirate blood.³²⁵ If necessary, repeat aspiration attempt after 120 minutes of dwell time.³²⁵ Administer a second 2-mg injection (for a total of 4 mg) in resistant cases.³²⁵ ACCP suggests a second dose of alteplase after 30 minutes of dwell time if the catheter remains occluded.¹⁰¹³

When patency is restored, aspirate 4–5 mL of blood to remove all drug and clot residual.³²⁵ Irrigate catheter gently with 0.9% sodium chloride injection.³²⁵

If catheter patency is not successfully established after 2 doses of alteplase, ACCP suggests radiologic imaging to rule out a catheter-related thrombus.¹⁰¹³

Arterial Thrombosis and Embolism† [off-label]

Intra-arterial†

0.05–0.1 mg/kg per hour for 1–8 hours for lysis of arterial occlusion^† in a peripheral vessel or bypass graft.⁹⁴ ⁹⁵ ⁹⁶ ⁹⁷ Even lower dosages (e.g., 0.02 mg/kg per hour over 1–7 hours) may be effective.²¹¹

Prescribing Limits

Pediatric Patients

Occluded Central Venous IV Catheters

Intracatheter Injection

Maximum 2 mg per each attempt at clearing an occluded catheter, for a total dosage of 4 mg (2 courses).³²⁵

Adults

Coronary Artery Thrombosis and MI

IV

Maximum 100 mg.¹ 150 mg dose not recommended because of possible increased incidence of intracranial bleeding.¹

Acute Ischemic Stroke

IV

Maximum 0.9 mg/kg (up to 90 mg) total dose.¹

Occluded Central Venous IV Catheters

Intracatheter Injection

Maximum 2 mg per each attempt at clearing an occluded catheter, for a total dosage of 4 mg (2 courses).³²⁵

Cautions for Alteplase

Contraindications

Active internal bleeding.¹ ²
History of cerebrovascular accident or intracranial hemorrhage.¹ ²
Intracranial neoplasm.¹ ²
Aneurysm.¹ ²
Recent intracranial or intraspinal surgery or trauma.¹ ²
Known bleeding diathesis.¹ ² ¹⁵⁴
Arteriovenous malformation.¹ ² ¹⁵⁴
Severe uncontrolled hypertension.¹ ² ¹⁵⁴
Suspected aortic dissection.¹ ² ¹⁵⁴

Evidence of active internal bleeding, intracranial hemorrhage on pretreatment evaluation, suspicion of subarachnoid hemorrhage, history of intracranial hemorrhage, or recent (within 3 weeks) GI or urinary tract hemorrhage.¹ ³²² ³⁵⁸
Known bleeding diathesis.¹ ³²² ³⁵⁸
Recent (within 3 months) intracranial or intraspinal surgery, serious head trauma, or recent previous stroke.¹ ³²² ³⁵⁸
Uncontrolled hypertension at time of treatment (e.g., SBP or DBP >185 or 110 mm Hg, respectively) or hypertension requiring aggressive treatment.¹ ³²² ³⁵⁸
Arteriovenous malformation or aneurysm.¹ ³²² ³⁵⁸
Seizure at onset of stroke.¹ ³²² ³⁵⁸
Intracranial neoplasm.¹ ³²² ³⁵⁸

Warnings/Precautions

Warnings

Effects on Hemostasis

Routine monitoring of hemostatic indices (e.g., fibrinogen concentrations, thrombin times) generally not recommended during therapy for acute MI.¹⁵ ²²¹ ²²² However, such monitoring is recommended for patients who exhibit bleeding.²²²

Possible bleeding and hemorrhagic complications,¹ ¹⁴ ⁴³ ⁴⁴ ⁶² ¹⁴⁵ ¹⁴⁶ ¹⁵⁴ ¹⁵⁵ ¹⁵⁶ including intracranial hemorrhage and other major bleeding complications.¹⁴¹ ²²² May be more common in geriatric patients⁶² ¹⁵⁴ ¹⁵⁶ and those with a history of cerebrovascular accident or severe or poorly controlled hypertension.¹⁴¹ ²²²

Weigh increased risks of therapy against anticipated benefits in patients with recent major surgery (e.g., coronary artery bypass), cerebrovascular disease, obstetric delivery, organ biopsy, previous puncture of noncompressible vessels, hypertension (SBP ≥175 mm Hg and/or DBP ≥110 mm Hg);¹ ² ³²² high likelihood of hemostatic defects (e.g., secondary to severe hepatic or renal disease), internal (e.g., GI or GU) bleeding, or recent (within 2–4 weeks) trauma.¹ ² ²²² Also, weigh risks against benefits of therapy in patients with diabetic hemorrhagic retinopathy or other hemorrhagic ophthalmic conditions.¹ ² Weigh risks against benefits in patients receiving concurrent oral anticoagulant therapy (e.g., warfarin).¹ ² Weigh risks against benefits in patients with any condition in which bleeding constitutes a substantial hazard or would be particularly difficult to manage because of its location.¹ ²

Initiate therapy only after careful screening for contraindications (e.g., previous neurologic events, severe hypertension, and potential bleeding sites).¹⁴² ²⁴⁴

Minimize risk of bleeding by carefully selecting patients and monitoring all potential bleeding sites (e.g., sites of all venous cutdowns, arterial and venous punctures, needle punctures).¹ ¹⁴ ¹⁵ ⁴⁴ ⁴⁶ ¹⁵⁴ Avoid IM injections and nonessential handling of patient.¹ ⁴⁶ Perform invasive venous procedures carefully and as infrequently as possible.¹ ⁴⁶ If bleeding from the site of an invasive procedure or other trauma is not serious, continue therapy and closely observe the patient;²²¹ ²²² initiate local measures (e.g., application of pressure) immediately.¹ Avoid arterial and venous invasive procedures in areas inaccessible to manual compression (e.g., internal jugular or subclavian punctures) before and during therapy.¹ ²²¹ ²²² Use of an artery in an upper extremity (e.g., radial or brachial) is preferable if arterial puncture is essential.¹ ⁴⁶ ²²² Apply pressure to the puncture site for ≥30 minutes, followed by a pressure dressing and frequent inspection of the puncture site for bleeding.¹ ¹⁵⁵

Possible severe and fatal spontaneous bleeding (e.g., cerebral,¹ ³⁴ ³⁷ ⁴² ⁴³ ⁴⁷ ⁴⁸ retroperitoneal,¹ ³⁷ ⁴⁴ ⁴⁷ GU,¹ ³¹ ⁴¹ ⁴⁴ ⁴⁷ respiratory tract,¹ GI bleeding).¹ ³³ ³⁶ ³⁹ ⁴¹ ⁴³ ⁴⁴ ⁴⁷ ⁴⁸ ¹⁵⁴ Less severe spontaneous bleeding (e.g., superficial hematoma or ecchymoses,¹ ⁴⁰ ⁴¹ ⁴⁸ hematuria,⁴¹ ⁴³ hemoptysis,⁴¹ ⁴³ epistaxis,¹ and gingival bleeding)¹ ⁴¹ ⁴³ also may occur.⁴⁰ ⁴¹

If serious spontaneous bleeding occurs, immediately discontinue alteplase therapy¹ ¹⁴ and initiate appropriate hemostatic therapy as needed.¹⁴ ¹⁵ ²²¹ ²²² If serious bleeding at a critical location (e.g., intracranial, GI, retroperitoneal, pericardial) occurs with intracatheter instillation of alteplase, discontinue therapy immediately and withdraw the drug from the catheter.³²⁵

Extravasation during IV infusion may cause ecchymosis and/or inflammation.¹ Terminate infusion at that IV site and apply local therapy.¹

Cardiovascular Effects

Possible fatal cardiogenic shock, heart failure, myocardial rupture, electromechanical dissociation, pericardial effusion, pericarditis, mitral regurgitation, cardiac tamponade, hypotension, pulmonary edema, thromboembolism, or recurrent thromboembolic events.¹

Weigh risks against anticipated benefits of therapy in patients with a high likelihood of left heart thrombus (e.g., mitral stenosis with atrial fibrillation, profound left ventricular dyskinesia),¹ ² ¹⁹⁶ acute pericarditis,¹ ² ¹⁹⁸ subacute bacterial endocarditis, septic thrombophlebitis, or an occluded arteriovenous cannula at a seriously infected site.¹ ² ²²²

Possible coronary artery reocclusion.⁴ ¹⁴ ³¹ ³⁴ ³⁵ ³⁷ ³⁹ ⁴⁰ ⁴¹ ⁶⁰ ⁷⁴ ²⁰⁸ Reocclusion rate greater with standard than with accelerated infusion.³¹⁶ Reduce incidence of reocclusion through concomitant anticoagulation (e.g., heparin and/or oral anticoagulants)¹ ² ³⁰ ³¹ ³² ³³ ³⁴ ³⁵ ³⁶ ³⁷ ³⁸ ³⁹ ⁴⁰ ⁴¹ ⁴² ⁴⁷ and/or platelet-aggregation inhibitor (e.g., aspirin, dipyridamole) therapy,¹ ³⁷ ³⁸ ³⁹ ⁴⁰ ⁴¹ ⁴³ ¹⁹³ prolonged infusion of the thrombolytic agent, or mechanical or surgical revascularization procedures.⁴ ¹⁴ ³⁵ ³⁷ ³⁸ ⁶² ⁶³ ¹⁷⁷

Possible thromboembolism or recurrent thromboembolic events, pleural effusion, hypotension, pulmonary edema, or fever.¹ Confirm diagnosis objectively using pulmonary angiography or a noninvasive procedure (e.g., lung scanning).¹ ²⁷⁷ Potential risk of re-embolization resulting from lysis of deep venous thrombi.¹ May not be adequate therapy for underlying DVT.¹

Potential new embolic episodes, including those involving cerebral vessels.¹⁹⁶ ²²¹ ²²² Avoid therapy in patients with arterial emboli originating from the left side of the heart (e.g., mitral stenosis accompanied by atrial fibrillation, left ventricular thrombi).¹⁹⁶ ²²¹ ²²²

Cerebrovascular Effects

Possible risk of stroke in patients with acute MI who are at low risk for cardiovascular death; risk may offset the survival benefit of thrombolytic therapy.¹

Weigh increased risks of therapy associated with cerebrovascular disease against anticipated benefits of therapy.¹ ² ²²² ³²²

Manufacturer suggests weighing risks of intracranial hemorrhage against anticipated benefits of therapy in patients with severe neurologic deficit (e.g., NIHSS score >22) on pretreatment evaluation of acute ischemic stroke¹ ³⁵⁷ and in patients with major early infarct signs on CT scan (e.g., substantial edema, mass effect, midline shift).¹ However, AHA and ASA state that thrombolytic therapy almost always should not be administered to patients with major early infarct signs.³⁵⁸

In patients with acute ischemic stroke, administer in facilities that can provide appropriate evaluation and management of intracranial hemorrhage.¹ Incidence of intracranial hemorrhage and benefits of therapy unknown in patients treated >3 hours after the onset of symptoms; use not recommended in such patients and in patients with symptoms of unknown duration.¹ ³²² ³⁵⁸ Frequently monitor and control BP during and following administration.¹ ³⁵⁷ Safety of administration without careful BP management not established.¹ ² ³²²

Cholesterol Embolization

Possibly fatal cholesterol crystal embolization associated with invasive vascular procedures (e.g., cardiac catheterization, angiography, vascular surgery) and/or anticoagulant therapy.¹ Clinical features of cholesterol embolism include livedo reticularis, “purple toe” syndrome, acute renal failure, gangrenous digits,¹ ²⁶⁷ hypertension, pancreatitis, MI, cerebral infarction, spinal cord infarction, retinal artery occlusion, bowel infarction, and rhabdomyolysis.¹ ²⁶⁷

Arrhythmias

Possible reperfusion-related atrial¹ ³² ¹⁶² ¹⁶³ ¹⁶⁴ ¹⁶⁶ and/or ventricular¹ ⁶⁷ ¹⁶² ¹⁶³ ¹⁶⁴ ¹⁶⁵ ¹⁸⁷ arrhythmias (e.g., accelerated idioventricular rhythm,⁶⁷ ¹⁵⁵ ¹⁶² ¹⁶³ ¹⁸⁷ VPCs,⁶⁷ ¹⁶² atrial fibrillation,¹⁶³ ¹⁶⁵ atrial premature complexes,¹⁶⁶ junctional rhythm,¹⁶³ VT,¹⁶² sinus bradycardia).³² ⁶⁷ ¹⁵⁵ ¹⁶² ¹⁶³ ¹⁶⁴ Such arrhythmias are usually transient.¹⁸⁷

Careful monitoring recommended.¹ ¹⁶⁴ Have appropriate antiarrhythmic therapy available during and immediately after administration.¹ ¹⁶⁴

Hepatic Effects

Weigh anticipated benefits of therapy against increased risks associated with substantial liver dysfunction.¹ ² ²²²

Sensitivity Reactions

Hypersensitivity Reactions

Allergic-type reactions (e.g., anaphylactoid reaction, laryngeal edema, orolingual edema, rash, urticaria) occur rarely.¹ ² ¹⁴⁵ Many of the patients experiencing orolingual edema were receiving concomitant ACE inhibitors.¹

Monitor patients during and several hours following infusion for signs of orolingual angioedema.¹ Administer appropriate therapy (e.g., antihistamines, epinephrine, IV corticosteroids).¹ Consider discontinuance of the drug.¹

Cautious use recommended in patients who previously received the drug.¹ Unknown risk of increased immunologic reaction with repeated administration.¹ Immediately discontinue infusion and institute appropriate therapy if an anaphylactoid reaction occurs.¹

Specific Populations

Pregnancy

Category C.¹

Weigh risks against benefits of therapy in pregnant women.¹ ² Some clinicians consider alteplase for ischemic stroke to be contraindicated in pregnant women.^a

Lactation

Not known if distributed in milk; cautious use recommended.¹

Pediatric Use

Safety and efficacy not established with IV alteplase.¹ ²²¹ However, used with some success in a few infants and children with thrombosis of the vena cava, aorta, or peripheral arteries.²⁸⁶ ²⁸⁷ ²⁸⁸

Safety and efficacy of intracatheter instillation in neonates, children, and adolescents (2 weeks to 17 years of age) with occluded central venous catheters similar to that in adults.³²⁵

Thrombolytic therapy generally not recommended for treatment of venous thromboembolism in neonates and children unless vessel occlusion is life-threatening and/or causes organ dysfunction.¹⁰¹³ If thrombolysis is required, ACCP states that alteplase is the drug of choice; alteplase exhibits greater fibrin specificity, lower immunogenicity, and more effective clot lysis in vitro compared with streptokinase or urokinase (both no longer commercially available in the US).¹⁰¹³

ACCP states that thrombolytic therapy generally not recommended in children with arterial ischemic stroke.¹⁰¹³

Geriatric Use

Assess risks against the anticipated benefits of therapy in patients >75 years of age.¹ ² Intracranial hemorrhage and other major bleeding complications more common.⁶² ¹⁵⁴ ¹⁵⁶

Hepatic Impairment

Limited data in animals suggests possible prolonged elimination half-life of t-PA in patients with severely impaired hepatic function and/or hepatic blood flow.⁴⁶ ¹⁸⁵ ²²¹ Weigh anticipated benefits against risks of possible hemostatic defects associated with severe hepatic disease.¹

Common Adverse Effects

Hemorrhage.¹ ² ³¹ ³² ³³ ³⁴ ³⁶ ³⁷ ³⁸ ³⁹ ⁴⁰ ⁴¹ ⁴³ ⁴⁴ ⁴⁵ ⁴⁶ ⁴⁷ ⁴⁸ ¹⁵⁴ ¹⁵⁵ ¹⁹⁸

Drug Interactions

Anticoagulants

Potential pharmacodynamic interaction (increased risk of hemorrhage).¹ ¹⁴ ³⁴ ⁴³ ⁴⁴ ⁶⁸ ⁷² ⁷⁴ ¹⁴⁴ ¹⁵⁵

Careful monitoring recommended, especially at arterial puncture sites.¹ ³⁴ ³⁷ ³⁸ ³⁹ ⁴⁰ ⁴¹ ⁴³ ⁴⁴ ⁴⁹ ⁵⁹ ⁶⁵ ⁷² ¹⁴⁴ ¹⁵⁵ If serious bleeding occurs, immediately discontinue anticoagulant therapy and institute appropriate treatment as necessary.¹ ¹⁴

Drugs Affecting Platelet Function

Potential pharmacodynamic interaction (increased risk of bleeding complications, notably intracranial hemorrhage).¹⁹³ ¹⁹⁴ ³⁵⁷

Specific Drugs

Drug	Interaction	Comments
Abciximab	Increased risk of hemorrhage¹
ACE inhibitors	Increased risk of orolingual angioedema¹
Aspirin	Increased risk of hemorrhage¹ ³⁵⁷	In acute stroke, use not recommended within 24 hours of a thrombolytic agent because of increased risk of bleeding³⁵⁷
Dipyridamole	Increased risk of hemorrhage¹
Heparin	Increased risk of hemorrhage¹ ¹⁴ ³⁴ ⁴³ ⁴⁴ ⁶⁸ ⁷² ⁷⁴ ¹⁴⁴ ¹⁵⁵	Monitor carefully, especially at arterial puncture sites;¹ ³⁴ ³⁷ ³⁸ ³⁹ ⁴⁰ ⁴¹ ⁴³ ⁴⁴ ⁴⁹ ⁵⁹ ⁶⁵ ⁷² ¹⁴⁴ ¹⁵⁵ if serious bleeding occurs, discontinue heparin and use protamine sulfate for reversal of effect¹ ¹⁴
Thrombolytic agents	Potential for synergistic thrombolytic effects⁴ ¹³ ¹⁸⁹ ¹⁹⁰ ¹⁹¹ ¹⁹²
Warfarin	Increased risk of hemorrhage¹	Monitor carefully, especially at arterial puncture sites;¹ ³⁴ ³⁷ ³⁸ ³⁹ ⁴⁰ ⁴¹ ⁴³ ⁴⁴ ⁴⁹ ⁵⁹ ⁶⁵ ⁷² ¹⁴⁴ ¹⁵⁵ if serious bleeding occurs, discontinue warfarin¹ ¹⁴

Alteplase Pharmacokinetics

Absorption

Onset

Thrombolysis of the infarct-related coronary artery usually occurs <1 hour after initiation of therapy.³⁰ ³¹ ³⁹ ⁴⁰ Lysis of pulmonary emboli usually occurs within 2–6 hours after initiation of therapy.⁸⁶ ⁸⁷ ⁸⁸ ⁹¹

Distribution

Extent

Not known whether alteplase crosses the placenta or distributes into milk or the CNS.³

Elimination

Metabolism

Cleared principally by the liver,¹ ³ ⁵ ⁸ ⁹ ¹⁰ ¹² ²⁷ ⁴⁶ ¹³⁰ ¹³¹ which subsequently releases degradation products into the blood.¹⁰ ¹¹ ²⁷ ¹³⁰ ¹³¹

Elimination Route

Excreted mainly in urine.¹³⁰

Half-life

Patients with acute MI: mean 3.6–4.6 minutes for initial distribution phase (t_½α) , mean 39–53 minutes for terminal elimination phase (t_½β).⁶⁵ Patients with thrombo-occlusive disease: mean 4.4 and 26.5 minutes for t_½α and t_½β, respectively.⁶⁶

Special Populations

Prolonged elimination half-life in patients with severely impaired hepatic function and/or hepatic blood flow.⁴⁶ ¹⁸⁵ ²²¹

Stability

Storage

Parenteral

Powder for Injection

≤30°C, or refrigerate at 2–8°C (Activase).¹

Lyophilized powder for intracatheter instillation (Cathflo Activase): 2–8°C, protect from light.³²⁵

Reconstituted and diluted solutions contain no preservatives.¹ ² Preferably use solutions immediately after preparation, but may be used for up to 8 hours after reconstitution or dilution.¹ ² Discard any unused solution after 8 hours.¹ ²

Compatibility

Parenteral

Solution CompatibilityHID

Compatible
Sodium Chloride 0.9%
Incompatible
Dextrose 5% in water

Drug Compatibility

Admixture Compatibility.HID
Compatible
Lidocaine HCl
Morphine Sulfate
Nitroglycerin
Incompatible
Dobutamine HCl
Dopamine HCl
Heparin Sodium

Y-Site CompatibilityHID
Compatible
Lidocaine HCl
Metoprolol Tartrate
Propranolol HCl
Incompatible
Bivalirudin
Dobutamine HCl
Dopamine HCl
Heparin Sodium
Nitroglycerin

Actions

Thrombolytic agent;⁴ ⁵ ⁸ ¹¹ ¹² ¹³ ¹⁴ ¹⁵ ¹⁹ ²¹ ³¹ ³⁵ ³⁶ ⁴⁶ ⁶² ⁶⁷ a biosynthetic (recombinant DNA origin) form of the enzyme human tissue-type plasminogen activator (t-PA).¹ ² ⁴⁶
Hydrolyzes the arginine⁵⁶⁰-valine⁵⁶¹ peptide bond in plasminogen to form the active proteolytic enzyme plasmin.⁴ ⁵ ⁷ ⁸ ¹² ¹⁰⁶
A relatively fibrin-selective plasminogen activator.¹ ² ⁴ ⁵ ⁷ ⁸ ¹¹ ¹² ¹³ ¹⁴ ¹⁹ ²¹ ⁴⁶ ¹⁰⁶ Fibrinolytic activity localized to the site of the thrombus due to formation of a ternary complex between t-PA, fibrin, and plasminogen.² ⁴ ⁵ ⁸ ¹⁹ ²⁸ Induces thrombolysis without substantially activating circulating plasminogen¹⁵ ²⁹ or degrading fibrinogen.¹⁵ ²³ ²⁸ ²⁹ ⁵⁸
May transiently activate the coagulation system and decrease the patency of successfully reperfused infarct-related arteries.³¹² ³¹³ ³¹⁶

Advice to Patients

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹¹¹ ¹¹⁸ ¹²⁰
Importance of informing clinicians of existing or contemplated therapy, including prescription and OTC drugs.²¹⁴
Importance of advising patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Alteplase (Recombinant DNA Origin)
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	For injection, for IV infusion	50 mg	Activase (with sterile water for injection diluent)	Genentech
		100 mg	Activase (with sterile water for injection diluent)	Genentech
	For solution, for IV catheter clearance	2 mg	Cathflo Activase	Genentech

† Off-label: Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

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82. Chesebro JH, Knatterud G, Braunwald E. Thrombolytic therapy. N Engl J Med. 1988; 319:1544-5.

83. Williams DO, Ruocco NA, Forman S et al. Coronary angioplasty after recombinant tissue-type plasminogen activator in acute myocardial infarction: a report from the Thrombolysis in Myocardial Infarction (TIMI) Trial. J Am Coll Cardiol. 1987; 10(Suppl):45-50B.

84. Verstraete M, Arnold AER, Brower RW et al. Acute coronary thrombolysis with recombinant human tissue-type plasminogen activator: initial patency and influence of maintained infusion on reocclusion rate. Am J Cardiol. 1987; 60:231-7. http://www.ncbi.nlm.nih.gov/pubmed/3113222?dopt=AbstractPlus

85. Jang IK, Vanhaecke J, De Geest H et al. Coronary thrombolysis with recombinant tissue-type plasminogen activator: patency rate and regional wall motion after 3 months. J Am Coll Cardiol. 1986; 8:1455-60. http://www.ncbi.nlm.nih.gov/pubmed/3097099?dopt=AbstractPlus

86. Goldhaber SZ, Vaughan DE, Markis JE et al. Acute pulmonary embolism treated with tissue plasminogen activator. Lancet. 1986; 2:886-9. http://www.ncbi.nlm.nih.gov/pubmed/2876327?dopt=AbstractPlus

87. Goldhaber SZ, Markis JE, Kessler CM et al. Perspectives on treatment of acute pulmonary embolism with tissue plasminogen activator. Semin Thromb Hemost. 1987; 13:171-7. http://www.ncbi.nlm.nih.gov/pubmed/3114885?dopt=AbstractPlus

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320. Global Use of Strategies to Open Occluded Coronary Arteries in Acute Coronary Syndromes (GUSTO IIb) Angioplasty Substudy Investigators. A clinical trial comparing primary coronary angioplasty with tissue plasminogen activator for acute myocardial infarction. N Engl J Med. 1997; 336:1621-8. http://www.ncbi.nlm.nih.gov/pubmed/9173270?dopt=AbstractPlus

321. White HD. Future of reperfusion therapy for acute myocardial infarction. Lancet. 1999; 354:695-7. http://www.ncbi.nlm.nih.gov/pubmed/10475175?dopt=AbstractPlus

322. Internation Liaison Committee on Resuscitation. Guidelines 2000 for cardiopulmonary resuscitation and emergency cardiovascular care: an international consensus on science. Part 7, section 2. Acute stroke. Circulation. 2000; 102(Suppl. I):I-204-16.

323. Weaver WD, Simes J, Betriu A et al. Comparison of primary coronary angioplasty and intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review. JAMA. 1997; 278:2093-8. http://www.ncbi.nlm.nih.gov/pubmed/9403425?dopt=AbstractPlus

324. Tiefenbrunn AJ, Chandra NC, French WJ et al. Clinical experience with primary percutaneous transluminal coronary angioplasty compared with alteplase (recombinant tissue-type plasminogen activator) in patients with acute myocardial infarction: a report from the Second National Registry of Myocardial Infarction (NRMI-2) J Am Coll Cardiol. 1998; 31:1240-5.

325. Genentech, Inc. Activase Cathflo (alteplase, recombinant) prescribing information. South San Francisco, CA; 2005 Jan.

330. Assessment of the Safety and Efficacy of a New Thrombolytic (ASSENT-2) Investigators. Single-bolus tenecteplase compared with front-loaded alteplase in acute myocardial infarction: the ASSENT-2 double-blind randomised trial. Lancet. 1999; 354:716-22.

331. Cannon CP, Gibson CM, McCabe CH et al for the Thrombolysis in Myocardial Infarction (TIMI) 10B Investigators. TNK-tissue plasminogen activator compared with front-loaded alteplase in acute myocardial infarction: results of the TIMI 10B Trial. Circulation. 1998; 98:2805-14.

332. Genentech. TNKase (tenecteplase) injection prescribing information. South San Francisco, CA; 2000 Jun.

333. Strategies for Patency Enhancement in the Emergency Department (SPEED) Group. Trial of abciximab with and without low-dose reteplase for acute myocardial infarction. Circulation. 2000; 101:2788-94. http://www.ncbi.nlm.nih.gov/pubmed/10859283?dopt=AbstractPlus

334. Antman EM, Guigliano RP, Gibson CM et al. Abciximab facilitates the rate and extent of thrombolysis: results of the Thrombolysis in Myocardial Infarction (TIMI) 14 trial. Circulation. 1999; 99:2720-32. http://www.ncbi.nlm.nih.gov/pubmed/10351964?dopt=AbstractPlus

335. Emergency Cardiac Care Guidelines. Part 7: The era of reperfusion : Section 1: Acute coronary syndromes (acute myocardial infarction). Circulation. 2000; 102:I172-I203.

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337. Kim CB, Braunwald E. Potential benefits of late reperfusion of infarcted myocardium: the open artery hypothesis. Circulation. 1993; 88:2426&#x2013;36.

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339. Cannon CP, McCabe CH, Diver DJ et al. Comparison of front-loaded recombinant tissue-type plasminogen activator, anistreplase and combination thrombolytic therapy for acute myocardial infarction: results of the Thrombolysis in Myocardial Infarction (TIMI) 4 trial. J Am Coll Cardiol. 1994; 24:1602-10. http://www.ncbi.nlm.nih.gov/pubmed/7963104?dopt=AbstractPlus

340. The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO III) Investigators. A comparison of reteplase with alteplase for acute myocardial infarction. N Engl J Med. 1997; 337:1118-23. http://www.ncbi.nlm.nih.gov/pubmed/9340503?dopt=AbstractPlus

341. Smalling RW, Bode C, Kalbfleisch J et al. More rapid, complete, and stable coronary thrombolysis with bolus admnistration of reteplase compared with alteplase infusion in acute myocardial infarction. Circulation. 1995; 91:2725-32. http://www.ncbi.nlm.nih.gov/pubmed/7758177?dopt=AbstractPlus

342. Bode C, Smalling RW, Berg G et al. Randomized compaison 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. Circulation. 1996; 94:891-8. http://www.ncbi.nlm.nih.gov/pubmed/8790022?dopt=AbstractPlus

343. Neuhaus KL, Feuerer W, Jeep-Tebbe S et al. Improved thrombolysis with a modified dose regimen of recombinant tissue-type plasminogen activator. J Am Coll Cardiol. 1989; 14:1566-9. http://www.ncbi.nlm.nih.gov/pubmed/2509531?dopt=AbstractPlus

344. Centocor, Inc. Retavase (reteplase, recombinant) injection prescribing information. Malvern, PA; 2000 Nov.

345. Topol EJ, Ohman M, Armstrong PW et al. Survival outcomes 1 year after reperfusion therapy with either alteplase or reteplase for acute myocardial infarction: results from the Global utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO) III trial. Circulation. 2000; 102:1761-5. http://www.ncbi.nlm.nih.gov/pubmed/11023929?dopt=AbstractPlus

346. International Joint Efficacy Comparison of Thrombolytics. Randomised, double-blind comparison of reteplase double-bolus administration with streptokinase in acute myocardial infarction (INJECT): trial to investigate equivalence. Lancet. 1995; 346:329-36. http://www.ncbi.nlm.nih.gov/pubmed/7623530?dopt=AbstractPlus

347. White HD, Van de Werf FJJ. Thrombolysis for acute myocardial infarction. Circulation. 1998; 97:1632-46. http://www.ncbi.nlm.nih.gov/pubmed/9593569?dopt=AbstractPlus

348. Puma JA, Sketch MH Jr, Simes RJ et al. Support for the open-artery hypothesis in survivors of acute myocardial infarction: analysis of 11,228 patients treated with thrombolytic therapy. Am J Cardiol. 1999; 83:482-7. http://www.ncbi.nlm.nih.gov/pubmed/10073847?dopt=AbstractPlus

349. Simes RJ, Topol EJ, Holmes DR Jr et al. Link between the angiographic substudy and mortality outcomes in a large randomized trial of myocardial reperfusion. Importance of early and complete infarct artery reperfusion. GUSTO-I Investigators. Circulation. 1995; 91:1923-8. http://www.ncbi.nlm.nih.gov/pubmed/7895348?dopt=AbstractPlus

350. Eyrich H, Walton T, Macon EJ et al. Alteplase versus urokinase in restoring blood flow in hemodialysis-catheter thrombosis. Am J Health Syst Pharm. 2002; 59:1437-40. http://www.ncbi.nlm.nih.gov/pubmed/12166043?dopt=AbstractPlus

351. Daeihagh P, Jordan J, Chen GJ et al. Efficacy of tissure plasminogen activator administration on patency of hemodialysis access catheters. Am J Kidney Dis. 2000; 36:75-9. http://www.ncbi.nlm.nih.gov/pubmed/10873875?dopt=AbstractPlus

357. Adams HP, Adams RJ, Brott T et al. Guidelines for the early management of patients with ischemic stroke: a scientific statement from the Stroke Council of the American Stroke Association. Stroke. 2003; 34:1056-83. http://www.ncbi.nlm.nih.gov/pubmed/12677087?dopt=AbstractPlus

358. Adams H, Adams R, Del Zoppo G et al. Guidelines for the early management of patients with ischemic stroke: 2005 guidelines update. A scientific statement from the Stroke Council of the American Heart Association/American Stroke Association. Stroke. 2005; 36:916-21. http://www.ncbi.nlm.nih.gov/pubmed/15800252?dopt=AbstractPlus

360. Lavonas EJ, Drennan IR, Gabrielli A et al. Part 10: Special Circumstances of Resuscitation: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2015; 132(18 Suppl 2):S501-18. http://www.ncbi.nlm.nih.gov/pubmed/26472998?dopt=AbstractPlus

361. Böttiger BW, Bode C, Kern S et al. Efficacy and safety of thrombolytic therapy after initially unsuccessful cardiopulmonary resuscitation: a prospective clinical trial. Lancet. 2001; 357:1583-5. http://www.ncbi.nlm.nih.gov/pubmed/11377646?dopt=AbstractPlus

362. Lederer W, Lichtenberger C, Pechlaner C et al. Recombinant tissue plasminogen activator during cardiopulmonary resuscitation in 108 patients with out-of-hospital cardiac arrest. Resuscitation. 2001; 50:71-6. http://www.ncbi.nlm.nih.gov/pubmed/11719132?dopt=AbstractPlus

363. Lederer W, Lichtenberger C, Pechlaner C et al. Long-term survival and neurological outcome of patients who received recombinant tissue plasminogen activator during out-of-hospital cardiac arrest. Resuscitation. 2004; 61:123-9. http://www.ncbi.nlm.nih.gov/pubmed/15135188?dopt=AbstractPlus

364. Janata K, Holzer M, Kürkciyan I et al. Major bleeding complications in cardiopulmonary resuscitation: the place of thrombolytic therapy in cardiac arrest due to massive pulmonary embolism. Resuscitation. 2003; 57:49-55. http://www.ncbi.nlm.nih.gov/pubmed/12668299?dopt=AbstractPlus

365. Tiffany PA, Schultz M, Stueven H. Bolus thrombolytic infusions during CPR for patients with refractory arrest rhythms: outcome of a case series. Ann Emerg Med. 1998; 31:124-6. http://www.ncbi.nlm.nih.gov/pubmed/9437356?dopt=AbstractPlus

366. Ruiz-Bailén M, Aguayo de Hoyos E, Serrano-Córcoles MC et al. Efficacy of thrombolysis in patients with acute myocardial infarction requiring cardiopulmonary resuscitation. Intensive Care Med. 2001; 27:1050-7. http://www.ncbi.nlm.nih.gov/pubmed/11497138?dopt=AbstractPlus

367. Abu-Laban RB, Christenson JM, Innes GD et al. Tissue plasminogen activator in cardiac arrest with pulseless electrical activity. N Engl J Med. 2002; 346:1522-8. http://www.ncbi.nlm.nih.gov/pubmed/12015391?dopt=AbstractPlus

369. Piazza G, Goldhaber SZ. Acute pulmonary embolism. Part II: Treatment and prophylaxis. Circulation. 2006; 114:42-7.

370. Wan S, Quinlan DJ, Agnelli G et al. Thrombolysis compared with heparin for the initial treatment of pulmonary embolism. A meta-analysis of the randomized controlled trials. Circulation. 2004; 110:744-9. http://www.ncbi.nlm.nih.gov/pubmed/15262836?dopt=AbstractPlus

371. Sasahara AA, Hyers TM, Cole CM et al. The urokinase pulmonary embolism trial: a national cooperative study. Summary, conclusions, and recommendations. Circulation. 1973; 47 (Suppl 2):7-12.

372. Dong B, Jirong Y, Liu G et al. Thrombolytic therapy for pulmonary embolism. Cochrane Database of Systematic Reviews 2006, Issue 2. Article No.: CD004437. DOI: 10.1002/14651858.CD004437.pub2.

373. Anderson DR, Levine MN. Thrombolytic therapy for the treatment of acute pulmonary embolism. Can Med Assoc J. 1992; 146:1317-24. http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=1488554&blobtype=pdf http://www.ncbi.nlm.nih.gov/pubmed/1555162?dopt=AbstractPlus

374. Dalen JE, Alpert JS, Hirsh J. Thrombolytic therapy for pulmonary embolism. Is it effective? Is it safe: When is it indicated? Arch Intern Med. 1997; 157:2550-6. Editorial.

375. Arcasoy SM, Kreit JW. Thrombolytic therapy of pulmonary embolism. A comprehensive review of current evidence. Chest. 1999; 115:1695-1707. http://www.ncbi.nlm.nih.gov/pubmed/10378570?dopt=AbstractPlus

376. Riedel M. Venous thromboembolic disease. Acute pulmonary embolism 2: treatment. Heart. 2001; 85:351-60. http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=1729663&blobtype=pdf http://www.ncbi.nlm.nih.gov/pubmed/11179282?dopt=AbstractPlus

377. Dalen JE. Pulmonary embolism: what have we learned since Virchow? Treatment and Prevention. Chest. 2002; 122:1801-17. http://www.ncbi.nlm.nih.gov/pubmed/12426286?dopt=AbstractPlus

378. Wahlgren N, Ahmed N, Dávalos A et al. Thrombolysis with alteplase for acute ischaemic stroke in the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST): an observational study. Lancet. 2007; 369:275-82. http://www.ncbi.nlm.nih.gov/pubmed/17258667?dopt=AbstractPlus

379. Albers GW, Bates VE, Clark WM, Bell R, Verro P, Hamilton SA. Intravenous tissue-type plasminogen activator for treatment of acute stroke: the Standard Treatment with Alteplase to Reverse Stroke (STARS) study. JAMA. 2000; 283:1145–50. http://www.ncbi.nlm.nih.gov/pubmed/10703776?dopt=AbstractPlus

380. Hill MD, Buchan AM. Thrombolysis for acute ischemic stroke: results of the Canadian Alteplase for Stroke Effectiveness Study. CMAJ. 2005; 172:1307–12. http://www.ncbi.nlm.nih.gov/pubmed/15883405?dopt=AbstractPlus

381. Albers GW, Olivot J-M. Intravenous alteplase for ischaemic stroke. Lancet. 2007; 369:249-50. Editorial. http://www.ncbi.nlm.nih.gov/pubmed/17258646?dopt=AbstractPlus

382. Hacke W, Donnan G, Fieschi C, et al. Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet. 2004; 363:768–74. http://www.ncbi.nlm.nih.gov/pubmed/15016487?dopt=AbstractPlus

383. Wahlgren N, Ahmed N, Dávalos A et al. Thrombolysis with alteplase 3–4.5 h after acute ischaemic stroke (SITS-ISTR): an observational study. Lancet. 2008; 372:1303-9. http://www.ncbi.nlm.nih.gov/pubmed/18790527?dopt=AbstractPlus

384. Wardlaw JM, del Zoppo G, Yamaguchi T. Thrombolysis for acute ischaemic stroke. Cochrane Database Syst Rev (database online). Issue 3, 2003.

385. Wardlaw JM. Overview of Cochrane thrombolysis meta-analysis. Neurology. 2001; 57(Suppl):S69–S76.

386. Tsivgoulis G, Alexandrov AV. Timeframe for thrombolysis in acute ischaemic stroke. Lancet. 2008; 372:1275-6. Editorial. http://www.ncbi.nlm.nih.gov/pubmed/18790526?dopt=AbstractPlus

387. Hacke W, Kaste M, Bluhmki E et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008; 359:1317-29. http://www.ncbi.nlm.nih.gov/pubmed/18815396?dopt=AbstractPlus

388. Lyden P. Thrombolytic therapy for acute stroke — not a moment to lose. N Engl J Med. 2008; 359:1393-5. Editorial. http://www.ncbi.nlm.nih.gov/pubmed/18815401?dopt=AbstractPlus

389. Lees KR, Bluhmki E, von Kummer R et al. Time to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials. Lancet. 2010; 375:1695-703. http://www.ncbi.nlm.nih.gov/pubmed/20472172?dopt=AbstractPlus

390. Saver JL, Levine SR. Alteplase for ischaemic stroke—much sooner is much better. Lancet. 2010; 375:1667-8. Commentary. http://www.ncbi.nlm.nih.gov/pubmed/20472152?dopt=AbstractPlus

391. Adams HP Jr, del Zoppo G, Alberts MJ et al. Guidelines for the early management of adults with ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups. Stroke. 2007; 38:1655-1711. http://www.ncbi.nlm.nih.gov/pubmed/17431204?dopt=AbstractPlus

392. Baldwin K, Orr S, Briand M et al. Acute ischemic stroke update. Pharmacotherapy. 2010; 30(5):493-514. http://www.ncbi.nlm.nih.gov/pubmed/20412000?dopt=AbstractPlus

393. The Canadian Stroke Strategy. Canadian best practice recommendations for stroke care (updated 2008). CMAJ. 2008; 179 (12 suppl):E1-E93.

394. del Zoppo GJ, Saver JL, Jauch EC et al on behalf of the American Heart Association Stroke Council. Expansion of the time window for treatment of acute ischemic stroke with intravenous tissue plasminogen activator: a science advisory from the American Heart Association/American Stroke Association. Stroke. 2009; 40;2945-8. http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=2782817&blobtype=pdf http://www.ncbi.nlm.nih.gov/pubmed/19478221?dopt=AbstractPlus

395. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995; 333:1581-7. http://www.ncbi.nlm.nih.gov/pubmed/7477192?dopt=AbstractPlus

396. Lyden PD. Extending the time window for thrombolytic therapy—primum non tardare. Lancet Neurol. 2009; 8:1074-5. Editorial. http://www.ncbi.nlm.nih.gov/pubmed/19850526?dopt=AbstractPlus

397. Bluhmki E, Ángel Chamorro, Antoni Dávalos et al. Stroke treatment with alteplase given 3•0–4•5 h after onset of acute ischaemic stroke (ECASS III): additional outcomes and subgroup analysis of a randomised controlled trial. Lancet Neurol. 2009; 8: 1095–102. http://www.ncbi.nlm.nih.gov/pubmed/19850525?dopt=AbstractPlus

398. The ATLANTIS, ECASS, and NINDS rt-PA Study Group Investigators. Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet. 2004; 363: 768-74. http://www.ncbi.nlm.nih.gov/pubmed/15016487?dopt=AbstractPlus

399. Hacke W, Kaste M, Fieschi C et al. Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Second European-Australasian Acute Stroke Study Investigators. Lancet. 1998 Oct 17; 352:1245-51.

400. Hacke W, Kaste M, Fieschi C et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The European Cooperative Acute Stroke Study (ECASS). JAMA. 1995 Oct 4; 274:1017-25.

527. O'Gara PT, Kushner FG, Ascheim DD et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2013; 127:e362-425. http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=3695607&blobtype=pdf

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