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Introduction ⬇

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Alteplase, a biosynthetic (recombinant DNA origin) form of the enzyme human tissue-type plasminogen activator (t-PA),1,46 is a thrombolytic agent.1,4,5,8,11,12,13,14,15,19,21,31,35,36,46,62,67

Uses ⬆ ⬇

[Section Outline]

Acute Myocardial Infarction !!navigator!!

Alteplase, a recombinant tissue-type plasminogen activator, is used as a thrombolytic agent for reperfusion therapy in patients with acute myocardial infarction (MI) to reduce mortality and to reduce the incidence of heart failure.1,34,37,38,41,42,43,46,47,48,65,75,80,83,141,193,194,226,527 The term MI is used when there is evidence of myocardial necrosis in the setting of acute myocardial ischemia.807 MI is further distinguished based on the presence or absence of ST-segment elevation on ECG.527,807,808,1100 Because patients with ST-segment-elevation MI (STEMI) typically have complete arterial occlusion, immediate reperfusion therapy is required.527,803,805 Reperfusion may be achieved with a pharmacologic (e.g., thrombolytic therapy) or mechanical (percutaneous coronary intervention [PCI]) strategy.527,803 The manufacturer states that the risk of stroke may outweigh the benefit of thrombolytic therapy in patients whose acute MI places them at low risk for death or heart failure.1

Clinical Experience

Almost all clinical studies to date of tissue-type plasminogen activator (t-PA) in patients with acute MI have been conducted using either the predominantly two-chain (prepared by Genentech roller-bottle method but not currently available) form of recombinant t-PA (rt-PA) that was used in early clinical studies4,31,32,33,35,36,38,39,40,41,46,216,226 or the currently marketed, predominantly one-chain form of rt-PA34,37,38,41,42,47,193 (alteplase)1,46 (prepared by Genentech suspension-culture methods);66,221 the manufacturer states that all Genentech-sponsored studies of rt-PA initiated since August 1985 have used the predominantly one-chain form.221 Therefore, unless otherwise specified, the term rt-PA in the Uses section refers to studies in which either alteplase or predominantly two-chain rt-PA was evaluated.

Coronary Artery Patency

The overall rate of coronary artery reperfusion or patency after rt-PA administration exceeds that of placebo4,31,33,34,38,47 or IV streptokinase (no longer commercially available in the US).4,32,36,40,43,226 Reperfusion after thrombolytic therapy may be evident by appearance of arrhythmias,163,164 relief of chest pain,162,163 and/or early peaking of serum concentrations of AST (SGOT)167 and the cardiac fraction (MB fraction) of creatine kinase (CK, creatine phosphokinase, CPK);153,167 however, these are not definitive measures of recanalization.153 Creatine kinase concentrations usually return to baseline levels rapidly after reperfusion.153 Beneficial effects of rt-PA therapy on ventricular function or mortality generally have been limited to patients with infarct-related coronary arteries that became patent with therapy.47,69,80,222,225,241,242 Analyses of data from an angiographic substudy of patients in the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO-I) trial indicate that “normal” perfusion (TIMI grade 3 flow) in an infarct-related artery at 90 minutes post-thrombolysis was associated with a lower 30-day mortality rate regardless of the thrombolytic agent used; these data support the “open-artery” hypothesis regarding early restoration of coronary artery patency and subsequent mortality reduction beyond that expected from preservation of left ventricular function (myocardial salvage) alone.299,302,303,304,347,348,349 Some evidence suggests that while the early benefit of infarct-artery patency occurs as a result of myocardial salvage, the late mortality benefit occurs independent of improvements in ventricular function.335,336,337 This late benefit appears to result from a reduction of scar formation and attenuation of ventricular dilation and infarct remodeling, particularly in areas of the myocardium that depend on collateral circulation.335,337

The extent of coronary recanalization after rt-PA therapy generally has been shown to be dose dependent.41,43,58,65,117,222 In studies employing pretreatment angiography to confirm coronary artery occlusion, rt-PA in dosages of 40-100 mg administered IV over 1-3 hours was associated with reperfusion after approximately 45-90 minutes in about 60-75% of infarct-related coronary arteries; 4,30,31,36,39,40,41,226 at these dosages, coronary artery patency rates in studies not employing pretreatment angiography have been similar or somewhat higher.32,33,34,37,38,47,57,84,85,141,222 However, patency rates may overestimate efficacy because of failure to exclude patients with patent infarct-related coronary arteries or early spontaneous recanalization.33,81,220,221,227 In dose-ranging studies conducted before the second phase of the Thrombolysis in Myocardial Infarction (TIMI) trial (TIMI-2), IV infusion of alteplase at a dose of 150 mg over 5-8 hours was associated with patency rates of 75% at 90 minutes.41,43 However, because an increased incidence of life-threatening intracranial bleeding was noted at this dose,1,41,43,59 the maximum recommended total dose was reduced to 100 mg.41,43,141,142 In phase 1 of the TIMI trial, a comparative trial of IV rt-PA and streptokinase in which both pre- and post-treatment angiography were used, the rate of reperfusion during the first 90 minutes after initiating therapy in patients with total or subtotal coronary artery occlusion was twice as high for rt-PA as for streptokinase (62 versus 31%, respectively).36,40,69 Although the average time from symptom onset until initiation of thrombolytic therapy was 4.75 hours in this study, the proportion of coronary arteries reperfused was greater for rt-PA than for streptokinase regardless of the time from symptom onset.36,40,69 An analysis of the combined results of the TIMI-1 trial36,40,69 and another randomized comparative trial32 also showed that the rate of coronary artery patency or reperfusion was greater with rt-PA than with streptokinase in patients treated both within 3 hours of symptom onset and 3-6 hours after onset of symptoms.82 These findings appear to confirm in vitro evidence indicating that the fibrinolytic efficacy of rt-PA is relatively unaffected by the age of a thrombus;14,58,94,96 however, delayed initiation of thrombolytic therapy is associated with a decreased likelihood of beneficial cardiac effects, regardless of the thrombolytic agent used.50,51,67,68,249,250,251

Effects on Mortality Reduction

Several controlled studies have demonstrated a survival benefit in patients with acute MI receiving alteplase.42,46,51,52,193,194,226,285 In a large, placebo-controlled, multicenter study (Anglo-Scandinavian Study of Early Thrombolysis; ASSET), patients with acute MI who received alteplase 100 mg IV over a 3-hour period (an initial 10-mg loading dose followed by infusions of 50, 20, and 20 mg/hour during hours 1, 2, and 3, respectively) within 5 hours of onset of symptoms had a 26% reduction in mortality (death occurred in 9.8% of placebo-treated patients versus 7.2% of patients who received alteplase) at 1 month after discharge.1,42 The mortality reductions in patients treated within 3 hours or between 3-5 hours of symptom onset (e.g., chest pain) were similar,42 and the overall mortality reduction in the ASSET study was similar42 to that in patients receiving streptokinase within 6 hours of symptom onset in several large studies.51,52 In another study, the mortality rates in patients receiving alteplase 100 mg IV over 3 hours versus placebo were 2.8 versus 5.7% (51% mortality reduction) at 14 days and 5.1 versus 7.9% (36% mortality reduction) at 3 months;46,193 patients treated within 3 hours of onset of symptoms had 14-day and 3-month mortality reductions of 82% and 59%, respectively.193 All patients in this study received concomitant therapy for 10-22 days after admission with heparin by continuous IV infusion and low-dose aspirin every other day.193

In 2 randomized, multicenter studies, >20,000 patients with acute evolving MI received either alteplase 100 mg IV over 3 hours or streptokinase 1.5 million units over 30-60 minutes, with or without subcutaneous heparin therapy (starting 12 hours after initiation of thrombolytic therapy).278,279 In-hospital mortality rates for the combined studies were low and similar in all 4 treatment groups: 9.2, 8.7, 7.9, or 9.2% in patients receiving either alteplase plus heparin, alteplase alone, streptokinase plus heparin, or streptokinase alone, respectively.278 Aspirin therapy (300-325 mg daily) and atenolol 5-10 mg IV were also administered to all study patients who had no specific contraindications to such therapy; aspirin and atenolol were given to approximately 96 and 23% of patients, respectively, in each treatment group.278 Although the overall incidence of complications and adverse effects was low, stroke was reported more often with alteplase than with streptokinase therapy (1.3 and 1% of patients, respectively), while major bleeding occurred more frequently in streptokinase-treated patients; streptokinase and heparin were both independently associated with an increased risk of bleeding.278 Adjunctive therapy with subcutaneous heparin (12,500 units twice daily during hospitalization) did not appear to provide additional benefit in patients receiving thrombolytic therapy since the incidences of stroke and reinfarction were similar whether or not concomitant heparin therapy was given.278

Improved survival with a thrombolytic regimen containing alteplase compared with streptokinase-containing regimens has been demonstrated in a multicenter study in >41,000 patients with acute MI (GUSTO-1).1,299,302,303,304 In the GUSTO-1 study, patients were randomized to receive 1 of 4 thrombolytic regimens: alteplase (maximum dose: 100 mg) in an “accelerated-dose” schedule (i.e., total dose administered IV over 1.5 rather than the usual 3 hours, with two-thirds of the dose given in the first 30 minutes) in conjunction with simultaneously initiated IV heparin therapy; streptokinase (1.5 million units over 1 hour) with IV heparin; streptokinase (1.5 million units over 1 hour) with subcutaneously administered heparin; or combined alteplase and streptokinase with IV heparin.1,302 Therapy with IV heparin (5000 units by rapid injection, then 1000-1200 units/hour) was initiated at the same time as thrombolytic therapy, while subcutaneously administered heparin (12,500 units twice daily) was begun 4 hours after initiation of thrombolytic therapy.1,302 In the combined alteplase-streptokinase regimen, streptokinase was given in a dosage of 1 million units over 1 hour; alteplase was administered in a dosage of 1 mg/kg (up to 90 mg) over 1 hour, with 10% of the dose given initially by rapid IV injection.302 The mortality rates at 30 days for the groups receiving streptokinase and subcutaneous heparin, streptokinase and IV heparin, accelerated-dose alteplase and IV heparin, and the combined alteplase-streptokinase regimen with IV heparin were 7.2, 7.4, 6.3, and 7%, respectively.1,302 The difference in these rates represent a 14% reduction in mortality with the accelerated-dose alteplase regimen compared with both streptokinase-only regimens and a 10% reduction compared with the combined alteplase-streptokinase regimen; there was no difference in 30 day-mortality between the 2 streptokinase-only regimens.302 Although hemorrhagic stroke occurred more frequently in patients receiving the accelerated-dose alteplase or combined alteplase-streptokinase regimens, the risk of the combined end point of death or disabling stroke was reduced with the accelerated-dose alteplase regimen compared with the streptokinase-only regimens, resulting in a net benefit of alteplase versus the other regimens.302

Results of the GUSTO-1 study support previous data from smaller studies305,306 that demonstrated an association between early and complete coronary artery patency, improved left ventricular function, and increased survival after acute MI.299,304 In a subset of patients enrolled in the GUSTO-1 study who were randomly assigned to undergo coronary artery angiography at 90 minutes, 180 minutes, 24 hours, or 5-7 days after initiation of thrombolytic therapy, the rate of patency of the infarct-related artery and the percentage of patients with normal blood flow through that artery at 90 minutes was higher in the group given accelerated-dose alteplase with IV heparin than in those receiving other thrombolytic regimens; patency rates were similar for all groups at 180 minutes.299 Measures of left ventricular function paralleled the rate of patency at 90 minutes; ventricular function was best in the group given accelerated-dose alteplase with heparin and in patients with normal flow through the infarct-related artery regardless of treatment group.299 Likewise, mortality at 30 days was lowest (4.4%) among patients with normal blood flow in the infarct-related artery at 90-minute angiography and highest (8.9%) among those with no coronary blood flow in that artery.299 Failure of the combined alteplase-streptokinase regimen to produce an early patency rate similar to that of the accelerated-dose alteplase regimen has been attributed to the use of only a small initial rapid-injection dose of alteplase in the combined regimen.299

Results from 2 large, comparative clinical trials (International Joint Efficacy Comparison of Thrombolytics [INJECT] trial, Global Utilization of Strategies to Open Occluded Coronary Arteries-III [GUSTO-III] trial) in patients with acute MI suggest similar effects of accelerated-dose alteplase (given as a 15-mg IV loading dose followed by 0.75 mg/kg [up to 50 mg] over 30 minutes, then 0.5 mg/kg [up to 35 mg] over 60 minutes), reteplase (2 doses of 10 units each given 30 minutes apart by direct IV injection), or streptokinase (1.5 million units IV over 60 minutes) on reduction of short-term (30 or 35 days) or long-term (6 months or 1 year) mortality.338,340,345,346 While previous studies had demonstrated improved coronary artery patency with reteplase compared with alteplase,341,342 analysis of >15,000 patients receiving the drugs in the GUSTO-III trial revealed very similar 30-day mortality rates (7.47 or 7.24% with reteplase or alteplase therapy, respectively); the incidences of other cardiovascular events, including stroke, bleeding, and intracranial hemorrhage, also were similar.340 The INJECT trial was not designed to demonstrate superiority of reteplase or streptokinase on reduction of mortality in patients with MI, only therapeutic equivalence; a trial in a larger number of patients would be required to demonstrate superiority of either agent.338,342,346 The occurrence of certain secondary clinical end points (i.e., stroke, reinfarction) was similar among patients with acute MI receiving any of the evaluated thrombolytic agents in these trials.338,340,346 The incidence of congestive heart failure also was lower in patients receiving reteplase than in those receiving streptokinase in the INJECT trial, and was similar among patients receiving reteplase or alteplase in the GUSTO-III trial.338,340,346 All patients in these trials received adjunctive antithrombotic therapy with aspirin (160-350 mg initially followed by 75-350 mg daily) and unfractionated heparin (5000 units by direct IV injection prior to reteplase administration, followed by 1000 units hourly by continuous IV infusion for at least 24 hours).338,340,341,342,345,346 Overall clinical outcomes also were improved with alteplase compared with anistreplase (no longer commercially available in the US), although the difference in mortality rate at 6 weeks was not statistically significant.339

Prevention of Reocclusion after Thrombolysis

Reocclusion of the infarct-related coronary artery following therapy with rt-PA generally has occurred in approximately 10-20% of patients,4,14,31,34,37,41,60 although higher reocclusion rates (up to 45%)35 have been reported.4,35,39,40,74,208 The reocclusion rate reported after rt-PA therapy for acute MI varies considerably77 but appears to be similar to46,84,222,317 or greater35,39,77,205,316 than that reported for streptokinase or urokinase (both no longer commercially available in the US).46,57,81,157 The rate of reocclusion is greater with a standard infusion of alteplase than with an accelerated infusion.316 Reocclusion usually occurs in the first 24 hours after thrombolysis,35,37 but may occur within 30 minutes after completion of the infusion and be clinically silent;31,34,37,153,170,208 late reocclusion (e.g., 4-10 days or longer after thrombolytic therapy) also can occur.34,35,39 The rate of reocclusion appears to depend principally on the degree of residual stenosis of the affected coronary artery,34,35,37,60,64,77,78,170,204 but also may be influenced by other factors, such as fluctuations in coronary blood flow during infusion of the thrombolytic agent,78,312,313,316,321 induction of a transient procoagulant state or possible platelet activation during thrombolytic therapy,312,313,316,321 the dosage and duration of the infusion of the thrombolytic agent,65,78,170 subsequent therapeutic measures (e.g., anticoagulant and/or platelet-aggregation inhibitor therapy),4,14,35,37,38,63,170 and the timing of angiography after thrombolytic therapy.34,35,222 In one study, all patients who developed reocclusion did so within 1 hour after discontinuance of the t-PA infusion when the plasma t-PA concentration had declined to less than 0.7 mcg/mL.35 However, in other studies, plasma rt-PA concentrations as low as 0.45 mcg/mL have been associated with prevention of reocclusion after thrombolytic therapy in patients with MI.65

Several therapeutic measures (e.g., anticoagulation and/or antiplatelet therapy, prolonged infusion of the thrombolytic agent, or mechanical or surgical revascularization procedures) have been used to reduce the incidence of reocclusion after coronary artery thrombolysis with rt-PA.4,14,35,37,38,62,63,177 Anticoagulant therapy (e.g., heparin and/or oral anticoagulants) has been used concomitantly with and/or subsequent to rt-PA therapy in most patients treated for acute MI in clinical studies.1,30,31,32,33,34,35,36,37,38,39,40,41,42,47 Platelet-aggregation inhibitors (e.g., aspirin) and P2Y12-receptor antagonists (e.g., clopidogrel) also have been administered before,527 during,193 or after1,37,38,39,40,41,43,193 rt-PA therapy in many patients for secondary prevention of recurrent ischemic events.527 In addition, a vitamin K antagonist (i.e., warfarin) is recommended in patients who have other indications for anticoagulation, such as atrial fibrillation, mechanical heart valves, venous thromboembolism, or hypercoagulable disorders.527

Since a substantial degree of coronary artery stenosis often remains even after successful thrombolysis64,79,213,225,242 and the presence of residual thrombus strongly predisposes to reocclusion,34,35,37,60,64,77,78,204 PCI also has been used after thrombolysis in an effort to maintain coronary artery patency and reduce the risk of reinfarction and recurrent ischemia.34,77,527,994

Clinical Perspective

The principal goal of therapy in patients with STEMI is to reestablish coronary blood flow; therefore, the current standard of care in such patients is timely reperfusion (with primary PCI or thrombolytic therapy).527,994 Because of a demonstrated mortality benefit and lower rates of reinfarction with PCI compared with thrombolytic therapy, primary PCI is the preferred reperfusion strategy when it can be performed in a timely manner by experienced clinicians.527,994 Due to the limited number of PCI-capable facilities in the US, thrombolytic therapy is considered an acceptable alternative.527 Experts state that the appropriate and timely use of any form of reperfusion is likely more important than the choice of therapy.527

The benefits of thrombolytic therapy in patients with STEMI are well established.527 When rt-PA is used by IV infusion in selected patients with acute MI, thrombolysis occurs usually within 1 hour after initiation of the IV infusion.4,30,31,34,37,38,39,40,41,42,43,46,47,48,50,65,75,80,83,193,527 The resulting reperfusion can limit infarct size, 48,193 improve ventricular function (e.g., decrease ventricular arrhythmias),1,4,38,42,46,47,48,50,69,193 and reduce the incidence of congestive heart failure,1,38 cardiogenic shock, and death.1,42,46,193,194,226

The American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) guideline for the management of STEMI states that reperfusion therapy should be administered to all eligible patients with STEMI and onset of ischemic symptoms within the previous 12 hours.527 The appropriate reperfusion method (thrombolytic therapy or PCI) should be selected based on a risk-benefit analysis that incorporates the time from onset of MI symptoms, the clinical and hemodynamic status of the patient, presence of comorbidities (e.g., severe heart failure), bleeding risk, contraindications, and the availability (and timeliness) of PCI.527 Primary PCI is the preferred method of reperfusion 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 Initial thrombolytic therapy is most appropriate for those patients with low bleeding risk who present early after symptom onset (less than 2-3 hours) to a non-PCI-capable hospital and who have longer delays to PCI.527 If therapy with rt-PA is selected, it should be instituted as soon as possible after acute MI1,14,31,32,33,34,35,36,37,38,39,40,41,42,43,46,47,48,527 since the potential clinical benefit diminishes as the time period from symptom onset to initiation of therapy increases.42,51,52,67,68,193,205,311,360,527 The greatest benefits of thrombolytic therapy in terms of reductions in mortality and morbidity have been observed when such therapy was initiated within the first 12 hours after symptom onset.527 Appreciable improvement of ventricular function1,4,38,42,46,47,48,50,69,193 (as assessed by left ventricular ejection fraction38,47,48,50,69,193 or regional wall motion),37,299 reduction in infarct size, 48,193 and reduction in the incidence of congestive heart failure1,38 have been apparent when rt-PA was initiated within 6 hours of the onset of symptoms of MI,38,46,48,69,193,194,299 although the greatest clinical benefit has been observed when therapy was initiated earlier.48,80,193,194,205 ACCF and AHA recommend that thrombolytic therapy be administered within 30 minutes of hospital arrival.527

Standard therapeutic measures for management of MI should be instituted concomitantly with rt-PA therapy.1,4,34,37,38,41,42,43,46,47,48,50,65,75,80,83,141,193,208,527 In all patients receiving rt-PA, the potential risk of serious hemorrhage must be weighed against the possible benefit of therapy with the drug.1,527

The relative role of alteplase versus other thrombolytic agents in acute evolving MI remains to be fully elucidated.14,15,42,60,222,266,278,279,284,285 Many clinicians suggest that the particular thrombolytic agent used is less important for patient survival than reducing the delay in initiating treatment in patients with MI.307,308 Some clinicians state that tenecteplase may be preferred over alteplase due to its ease of IV administration as a single weight- and age-adjusted dose, lower risk of non-cerebral bleeds, and decreased necessity for blood transfusion.5,415,1103 ACCF and AHA recommend the use of a fibrin-specific thrombolytic agent (e.g., alteplase, reteplase, tenecteplase).527

Pulmonary Embolism !!navigator!!

Alteplase is used in adults for lysis of acute pulmonary emboli involving obstruction of blood flow to a lobe or multiple segments of the lungs, and for lysis of pulmonary emboli accompanied by unstable hemodynamics (i.e., when blood pressure 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

Clinical Experience

rt-PA, including alteplase, has been administered IV1,15,46,86,87,88,90,91,92,93,269,270,272,274,275,276 or via the pulmonary artery†89,90,268 in patients with acute pulmonary embolism. In a comparative study in adults with symptoms of pulmonary embolism of <2 weeks (usually <5 days) duration, 100 mg of alteplase infused over 2 hours produced moderate or marked lysis of pulmonary emboli (as documented by pulmonary angiography at 2 hours) in 59% of patients compared with 13% receiving urokinase.1,91 Improvement in lung perfusion scans 24 hours after alteplase therapy was similar to that produced by a 24-hour IV infusion of urokinase,91 although the biological activity of the alteplase dosage substantially exceeded that of the urokinase dosage.182

The optimal therapeutic regimen for rt-PA in patients with pulmonary embolism has not been established.91,270,271,272,273 In IV dosages of 40-100 mg over 2-7 hours46,86,87,88,90,91,92,93 or via the pulmonary artery † in dosages of 30 or 50 mg over 1.5 or 2 hours, respectively, with89,90 or without86,87,91,92,93 concomitant heparin therapy, rt-PA produces clot lysis within 2-6 hours in more than 80% of patients with angiographically documented pulmonary emboli.86,87,88,91,273 However, substantial hemodynamic and angiographic improvement with such dosages of rt-PA has not been universally observed.276 Lysis of pulmonary emboli with rt-PA generally has been associated with early hemodynamic improvement and reversal of right ventricular dysfunction,92,269 and IV infusion appears to be as effective as administration via the pulmonary artery.90 Rapid IV injection† (e.g., over 2 minutes) of rt-PA also has been used effectively in a limited number of patients for the treatment of acute pulmonary embolism.270,271,272

Clinical Perspective

Use of systemic thrombolytic therapy in the treatment of pulmonary embolism remains controversial, in part because it has not been definitely established in randomized controlled trials that thrombolytic therapy ultimately decreases mortality or prevents recurrent pulmonary embolism and because of the high risk of bleeding associated with such therapy.369,370,371,372,373,374,375,376,377,404,1005,1102 The American College of Chest Physicians (ACCP) generally recommends against the use of systemic thrombolytic therapy in most patients with acute pulmonary embolism; however, in such patients with associated hypotension (e.g., systolic blood pressure <90 mm Hg), thrombolytic therapy may provide some benefit in terms of a reduction in mortality, and is suggested by ACCP in patients without a high risk of bleeding.1005,1102 ACCP also recommends systemic thrombolytic therapy in selected patients with acute pulmonary embolism who clinically deteriorate after starting anticoagulant therapy but have yet to develop hypotension and who have an acceptable bleeding risk.1102 For additional information on treatment of pulmonary embolism, consult the most recent American College of Chest Physicians Evidence-based Clinical Practice Guidelines on Antithrombotic Therapy and Prevention of Thrombosis available at [Web].

Further comparative studies are needed to establish the efficacy, safety, and optimum dosage of rt-PA compared with heparin, and to determine the effects of the therapies on morbidity and mortality, in the treatment of acute pulmonary embolism.86,181,273,275,404

Acute Ischemic Stroke !!navigator!!

Alteplase is used in the management of acute ischemic stroke for improving neurologic recovery and reducing the incidence of disability.1,4,5,6,322,357,358,378,379,387,388,389,390,391,392,393,394,395,396,397,1009,1101 Current data from randomized, placebo-controlled studies and pooled analyses of such studies indicate that prompt initiation of alteplase treatment (within at least 31 hours but up to 4.5 hours387,388,389,390,391,392,393,394,395 following onset of stroke symptoms†) can result in long-term (e.g., 3-month) improvements in residual neurologic deficit, disability, and functional outcome following acute ischemic stroke with no net change in mortality.1,4,5,6,322,357,379,380,384,385,387,388,389,390,391,392,393,394,395,1009,1101 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 ≤1 hour.387,388,389,390,392,393,396,398,1101 Treatment with alteplase in these studies has been associated with an increased incidence of intracranial hemorrhage, and careful diagnosis and patient selection are necessary to minimize the risk of hemorrhage and maximize benefit in patients with acute ischemic stroke.1,7,322,357,387,394,395,396 Therapy with alteplase in acute ischemic stroke should be initiated only in patients carefully selected according to history and physical examination and in whom intracranial hemorrhage has been excluded by cranial computed tomography (CT) scan or other diagnostic imaging method sensitive for the presence of hemorrhage.1,322,357,358,392,394,395,396,1101 Intracranial hemorrhage should be excluded as the primary cause of stroke signs and symptoms prior to initiation of treatment.1,1101

Clinical Experience

Reassurance regarding the safety and efficacy of alteplase in clinical practice is provided by the results of large phase 4 studies that included a variety of treatment centers, including academic and community hospitals with frequent and infrequent use of thrombolytic agents;379,380,1009 a multicenter study (Safe Implementation of Thrombolysis in Stroke-Monitoring Study) in almost 6500 patients found incidences of symptomatic intracranial hemorrhage and 3-month mortality378 similar to or lower than those in placebo-controlled trials of alteplase given within 3 hours of symptom onset in acute stroke based on analyses of pooled data from those trials.382 Postmarketing surveillance and pooled analyses of data including a randomized trial in which alteplase was administered within 3-4.5 hours of symptom onset also indicate no increase in outcomes (risk of symptomatic intracranial hemorrhage, mortality, functional independence) compared with that in randomized trials in which the drug was given within 3 hours of symptom onset.387,388,389,393,394,397

The importance of administering thrombolytic therapy as soon as possible after symptom onset is indicated by the results of a pooled analysis of data398 from 6 randomized, placebo-controlled trials of alteplase therapy in acute ischemic stroke, which found that such therapy was almost twice as effective when administered within 0-1.5 hours following onset of stroke symptoms (odds of a favorable outcome at 3 months: 2.81) as when administered 1.5-3 hours following onset of symptoms (odds of a favorable outcome at 3 months: 1.6).398 Based on a subsequent pooled analysis of data that also included a randomized study in which alteplase was administered up to 4.5 hours after symptom onset, it was estimated that substantial benefit was attained in 1 of 3 patients receiving the drug within 0-3 hours and in 1 of 6 patients receiving the drug within 3-4.5 hours after symptom onset.389,390 The safety of alteplase treatment administered >4.5 hours after symptom onset, in dosages >0.9 mg/kg and without careful blood-pressure management, has not been established;1,322,357,394,395,1009 a pooled analysis of data389 from several randomized trials of alteplase in acute ischemic stroke suggests that administration of the drug >4.5 hours following onset of stroke symptoms may even be associated with an increased risk of mortality.389,390,1009

Several randomized, controlled trials in patients with acute ischemic stroke individually have failed to show statistically significant benefits of alteplase therapy in reducing disability from stroke; possible reasons for such findings include a lack of statistical power (e.g., small sample size), inclusion of patients who received the drug up to 6 hours after symptom onset or had less severe strokes, and/or choice of end points.387,389,392,399,400 Analyses of pooled data from these trials indicated that benefit from treatment decreased as time from stroke onset to start of treatment increased.389,398 In a subsequent 2-part, randomized, placebo-controlled study conducted by the National Institute of Neurological Disorders and Stroke (NINDS) rt-PA Stroke Study Group, treatment with alteplase (0.9 mg/kg IV to a maximum dose of 90 mg) was associated with improved functional outcome in adults with acute ischemic stroke who received the drug within 3 hours of symptom onset.1,395 All patients had CT scans at 24 hours and at 7-10 days after the onset of stroke and when clinical findings suggested intracranial hemorrhage.395 Blood pressure was carefully monitored and controlled (systolic and diastolic blood pressure maintained at 185 and 110 mm Hg, respectively, or less) in the study, and concomitant administration of aspirin or heparin was not allowed.1,395 In part 1 of the NINDS study, which evaluated neurologic improvement at 24 hours after stroke onset, the proportion of patients with an improvement of at least 4 points in the NIH Stroke Scale (NIHSS) or complete recovery (NIHSS score = 0) was not significantly different with alteplase or placebo treatment, although NIHSS scores suggested improvement in the condition of alteplase-treated patients at 3 months.1,395 This long-term (3-month) clinical benefit of alteplase treatment was confirmed in part 2 of the NINDS study; patients receiving alteplase were at least 30% more likely to have minimal or no disability at 3 months (as determined by median scores on the Barthel Index, Modified Rankin Scale, Glasgow Outcome Scale, and NIHSS) than those receiving placebo.1,395 In part 2, the favorable outcome of minimal or no disability occurred in at least 11% more patients treated with alteplase than in those receiving placebo.1 Alteplase treatment resulted in a more favorable outcome than placebo regardless of the type of stroke diagnosed at study entry or of prior aspirin use.1,395

Combined analysis of the incidences of all-cause mortality, 90-day mortality, intracranial hemorrhage, and new ischemic stroke for patients in both parts of the NINDS study indicated a significant increase in intracranial hemorrhage, particularly symptomatic intracranial hemorrhage within 36 hours, with alteplase therapy compared with placebo.1 The total incidence of intracranial hemorrhage during the study follow-up period was 15.4 or 6.4% with alteplase or placebo, respectively.1 Symptomatic intracranial hemorrhage (defined as the occurrence of sudden clinical worsening followed by subsequent verification of intracranial hemorrhage on CT scan) occurred in 8 versus 1.3% of alteplase- or placebo-treated patients, respectively, while symptomatic intracranial hemorrhage within 36 hours after the onset of stroke was found in 6.4 versus 0.6% of these respective groups.1 The incidence of asymptomatic intracranial hemorrhage (defined as intracranial hemorrhage detected on a routine repeat CT scan without preceding clinical worsening) was similar among patients receiving alteplase (7.4%) or placebo (5.1%), as was the incidence of new ischemic stroke at 3 months (5.8 versus 4.5% with alteplase or placebo, respectively).1 Alteplase therapy was not associated with increases in the incidences of 90-day mortality or severe disability compared with placebo.1,395

There was a trend toward increased risk of symptomatic intracranial hemorrhage within the first 36 hours in patients with severe neurologic deficit (e.g., NIHSS score >22) or those of advanced age (e.g., patients >77 years of age).1,357 Analyses of efficacy suggested a reduced but still favorable clinical outcome for alteplase-treated patients with severe neurologic deficit or advanced age on pretreatment evaluation.1

In another randomized, placebo-controlled, phase 3 trial (ECASS-3), patients with acute ischemic stroke who received alteplase (0.9 mg/kg IV to a maximum dose of 90 mg) within up to 4.5 hours† following onset of stroke symptoms (median time: 3 hours 59 minutes following onset of symptoms) had more favorable clinical outcomes than those receiving placebo,387,394 and overall results with regard to efficacy and safety were consistent with those of an earlier trial (NINDS study)395 indicating efficacy of alteplase given within 3 hours of onset of stroke symptoms.387,394 The primary efficacy end point in the ECASS-3 trial, disability at day 90 (defined as a modified Rankin scale score of 0 or 1, indicating a favorable outcome of minimal or no disability) was achieved in 52.4 or 45.2% of those receiving alteplase or placebo, respectively.387 Alteplase recipients also had a 28% greater likelihood of attaining a favorable outcome in terms of a global composite secondary efficacy end point that assessed the patient's ability to return to an independent lifestyle.387 As in other trials of alteplase therapy for acute ischemic stroke,395 the incidence of symptomatic intracranial hemorrhage was higher with alteplase therapy (2.4%) than with placebo (0.2%); however, mortality was similar between the groups (7.7 or 8.4% with alteplase therapy or placebo, respectively).387,394 The incidence of intracranial hemorrhage was not substantially increased despite allowing the use of subcutaneous heparin to prevent deep-vein thrombosis in the first 24 hours after alteplase treatment,387,394 an exclusion criterion in earlier trials.395 Patient selection criteria for the ECASS-3 trial were similar to those of earlier trials of alteplase in acute ischemic stroke (e.g., NINDS)395 except that patients >80 years of age, those with severe stroke (a baseline NIHSS score >25), and those with a history of both stroke and diabetes were excluded.387,394 Therefore, some clinicians recommend close adherence to the ECASS-3 inclusion and exclusion criteria when treating patients with onset of stroke symptoms between 3 and 4.5 hours.392,394,396

Trials investigating alteplase treatment administered >4.5 hours after symptom onset† in patients with acute ischemic stroke using imaging biomarkers to determine eligibility for treatment have been conducted.405,406,407,1101 The MRI-Guided Thrombolysis for Stroke with Unknown Time of Onset (WAKE-UP) trial was a multicenter, randomized, double-blind, placebo-controlled trial in patients with an unknown onset of stroke † and a time since last known to be well of ≥4.5 hours.405 Patients qualified if there was a mismatch between the presence of an abnormal signal on MRI diffusion-weighted imaging and no visible signal change on diffusion-positive fluid-attenuated inversion recovery (FLAIR) in the region of the acute stroke.405 Patients were excluded if MRI showed intracranial hemorrhage or regions larger than one-third of the territory of the middle cerebral artery (MCA); if thrombectomy was planned; or if they had severe stroke (NIHSS score >25).405 The incidence of a favorable outcome (a modified Rankin scale score of 0 or 1 at 90 days) was greater in patients who received alteplase (0.9 mg/kg IV up to a maximum dose of 90 mg) compared with patients receiving placebo (53.3 versus 41.8%).405 The median time from symptom recognition to administration of alteplase was 3.1 hours, and the median interval between the time the patient was last known to be well and treatment initiation was 10.3 hours.405 There was a trend toward a higher incidence of symptomatic intracranial hemorrhage (2 versus 0.4%) and mortality (4.1 versus 1.2%) with alteplase therapy compared with placebo.405

In the Thrombolysis Guided by Perfusion Imaging up to 9 Hours after Onset of Stroke (EXTEND) clinical trial, CT-perfusion (CT-P) imaging was used to assess the eligibility for IV alteplase and suggested that the efficacy and safety of alteplase can extend to up to 9 hours† after stroke onset.406 The EXTEND trial was a multicenter, randomized, placebo-controlled trial in patients with NIHSS score of 4-26 and hypoperfused but salvageable regions of brain detected on automated perfusion imaging.406 Patients were randomly assigned to receive IV alteplase (0.9 mg/kg IV up to a maximum dose of 90 mg) or placebo between 4.5 and 9 hours after the onset of stroke or on awakening with stroke† (if within 9 hours from the midpoint of sleep).406 The incidence of a favorable outcome (a score of 0 or 1 on the modified Rankin scale at 90 days) was greater in patients who received alteplase compared with patients receiving placebo (35.4 versus 29.5%).406 As in other trials of alteplase therapy for acute ischemic stroke,395 the incidence of symptomatic intracranial hemorrhage was higher with alteplase therapy (6.2%) than with placebo (0.9%); however, mortality was similar between the groups (11.5 or 8.9% with alteplase therapy or placebo, respectively).406 Additional studies are needed to establish the safety and efficacy of IV alteplase in patients with acute ischemic stroke and unknown time of onset or time since onset of >4.5 hours.406

Clinical Perspective

Current evidence from randomized studies and pooled analyses of data indicate that initiation of alteplase up to 4.5 hours following the onset of symptoms of stroke provides a net benefit in terms of reducing disability,382,383,385,387,388,389,390,392,393,394,1101 and the American Heart Association/American Stroke Association (AHA/ASA) and other experts currently recommend administration of alteplase within up to 3-4.5 hours of the onset of symptoms in eligible patients.393,394,1009,1101 Therapy with alteplase in acute ischemic stroke should be initiated only in patients carefully selected according to history and physical examination and in whom intracranial hemorrhage has been excluded by cranial computed tomography (CT) scan or other diagnostic imaging method sensitive for the presence of hemorrhage.1,322,357,358,392,394,395,396,1101

According to the 2019 update to the 2018 guidelines for the early management of acute ischemic stroke from AHA/ASA, IV alteplase within 4.5 hours of stroke onset remains the standard of care for most patients with acute ischemic stroke.1101 AHA/ASA state that patients who are eligible for IV alteplase should receive the drug even if mechanical thrombectomy is being considered.1101 The benefits of both IV alteplase and mechanical thrombectomy are time-dependent, with greater benefits associated with treatment earlier in the time window; time from symptom onset to IV alteplase should be as short as possible, and generally never more than 4.5 hours.1101

AHA/ASA recommend IV alteplase within 3 hours of symptom onset in patients ≥18 years of age with severe stroke or mild but disabling stroke.1101 IV alteplase is recommended within 3-4.5 hours of symptom onset in patients 18-80 years of age who meet the following criteria: absence of a history of both diabetes mellitus and prior stroke; NIHSS score ≤25; not taking any oral anticoagulants; and no imaging evidence of ischemic injury involving greater than one-third of the middle cerebral artery (MCA) territory.1101 Additional eligibility criteria for treatment with IV alteplase include: ability to safely lower and maintain BP ≤185/110 mm Hg; blood glucose concentrations ≥50 mg/dL; mild to moderate early ischemic changes on noncontrast CT; and normal activated partial thromboplastin time (aPTT) in patients with end-stage renal disease.1101 AHA/ASA state that IV alteplase is recommended for patients taking antiplatelet drug monotherapy or combination therapy (eg, aspirin and clopidogrel) before stroke on the basis of evidence that the benefit of alteplase outweighs a possible small increased risk of intracranial hemorrhage.1101 IV alteplase is considered contraindicated in otherwise eligible patients with mild and nondisabling stroke (NIHSS ≤5).1101

According to AHA/ASA, individual assessment of the relative risks and benefits is required in patients with ischemic stroke presenting within 3-4.5 hours of symptom onset who: are >80 years of a have a history of both prior stroke and diabetes mellitus; have a mild but disabling stroke; or who have NIHSS >25.1101 Additional criteria which indicate a need for individual risk benefit assessment based on clinical characteristics, specifics of stroke presentation, medical history, and comorbid conditions are detailed in the guidelines and can be found at [Web].1101

AHA/ASA state that while IV alteplase remains the recommended thrombolytic agent, it may be reasonable to choose tenecteplase (single IV bolus of 0.25 mg/kg, maximum 25 mg) over IV alteplase in patients without contraindications for IV fibrinolysis who also are candidates to undergo mechanical thrombectomy.1101 AHA/ASA also state that tenecteplase administered as a 0.4-mg/kg single IV bolus has not been proven to be superior or noninferior to alteplase but might be considered as an alternative to alteplase in patients with acute ischemic stroke who have minor neurological impairment and no major intracranial occlusion.1101 However, in some studies, including a study in patients with moderate to severe stroke published after release of the AHA/ASA 2019 update, tenecteplase 0.4 mg/kg was associated with worse functional and safety outcomes compared to alteplase, and some clinicians recommend against use of this dosage of tenecteplase in patients with acute ischemic stroke.409,410,411,412 The administration of tenecteplase as a single IV bolus as opposed to the 1-hour infusion required for alteplase is mentioned by AHA/ASA as a potential advantage of tenecteplase.1101

Based on data from studies such as the WAKE-UP (Efficacy and Safety of MRI-based Thrombolysis in Wake-Up Stroke) trial,405 AHA/ASA state that in patients with acute ischemic stroke who awake with stroke symptoms † or have unclear time of onset >4.5 hours† from last known well or baseline state, MRI to identify diffusion-positive fluid-attenuated inversion recovery (FLAIR)-negative lesions can be useful for selecting those who can benefit from IV alteplase administration within 4.5 hours of stroke symptom recognition.1101

AHA/ASA state that use of intra-arterial infusion† of alteplase initiated within 6 hours of stroke onset† in carefully selected patients who have contraindications to the use of IV alteplase might be considered but that the clinical outcome of such treatment is uncertain.1101 According to AHA/ASA, mechanical thrombectomy with stent retrievers is recommended over intra-arterial fibrinolysis as first-line therapy.1101

Arterial Thrombosis and Embolism !!navigator!!

rt-PA has been administered by selective intra-arterial injection in a limited number of adults for lysis of arterial occlusions† in peripheral vessels and bypass grafts.94,95,96,97,98 1011 Angiographic and clinical improvement generally have occurred in more than 80% of patients treated with dosages of 0.05-0.1 mg/kg per hour, or even lower dosages (e.g., 0.02 mg/kg per hour) in a few patients, for 1-8 hours;94,95,96,97 however, most patients with acute arterial occlusion require further therapeutic intervention after thrombolysis.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 in such patients, ACCP suggests that a recombinant tissue plasminogen activator (e.g., alteplase) or urokinase (no longer available in the U.S.) is preferred.1011 In neonates and children with limb- or organ-threatening (via proximal extension) femoral artery thrombosis who fail to respond to initial treatment with unfractionated heparin, thrombolytic therapy is recommended unless such therapy is contraindicated.1013 Like other thrombolytic agents, rt-PA probably should be avoided in patients with arterial emboli originating from the left side of the heart (e.g., in patients with mitral stenosis accompanied by atrial fibrillation or those with left ventricular thrombi) because of the potential risk of new embolic episodes, including those involving cerebral vessels.196,221,222

Occluded Catheters !!navigator!!

Alteplase is used to restore patency to central venous catheters obstructed by a thrombus (assessed by the ability to withdraw blood).325,1013 Causes of catheter dysfunction other than thrombus formation, such as catheter malposition, mechanical failure, constriction by a suture, lipid deposits, or drug precipitates, should be considered before instillation of alteplase.325 Pooled results of a placebo-controlled study and a large open-label study indicate that about 68% of central venous catheters occluded for less than 14 days were cleared (as determined by the successful withdrawal of 3 mL of blood and infusion of 5 mL of saline through the catheter) with a single dose of alteplase (2 mg) and about 88% of occluded catheters were cleared after a second dose of alteplase, administered 120 minutes after the first dose.325 The incidence of recurrent catheter dysfunction within 30 days after treatment was 26%.325 Restoration of catheter function was similar among all catheter types studied (single, double, or triple lumen; implanted ports).325 Results of an open-label study evaluating the efficacy of the drug in restoring catheter function in pediatric patients (2 weeks to 17 years of age) indicated that 83% of the occluded catheters (defined by the inability to withdraw at least 3 mL of blood from the catheter in children weighing at least 10 kg or at least 1 mL in children weighing less than 10 kg) were cleared with up to 2 doses of alteplase (2 mg/2 mL in children weighing at least 30 kg or 110% of the estimated lumen volume not to exceed 2 mg/2 mL in children weighing less than 30 kg) in up to 120 minutes postdose.325

Alteplase has been used for clearing totally or partially occluded hemodialysis access catheters†.221,350,351 Studies of alteplase in patients with occluded hemodialysis catheters have evaluated similar dosing regimens as those currently used for clearing central venous catheters.221

Dosage and Administration ⬆ ⬇

[Section Outline]

General !!navigator!!

Pretreatment Screening

Patient Monitoring

Dispensing and Administration Precautions

Other General Considerations

Administration !!navigator!!

Alteplase is administered by IV infusion and by intracatheter instillation into occluded central venous catheters (Cathflo® Activase®), and the manufacturer states that the drug is intended for this method of administration only.1,325 When administered IV, the drug preferably should be administered via a controlled-infusion device using separate IV tubing.1 Do not add any other drugs to infusion solutions containing alteplase.1 Alteplase also has been administered by intracoronary† injection,30,221 selective intra-arterial† infusion,89,90,102,103 and intraocularly† via intracameral injection104 in a limited number of patients.

Extravasation during IV infusion of alteplase may cause ecchymosis and/or inflammation.1 If extravasation occurs, terminate the infusion at that IV site and apply local therapy.1

IV Administration

Reconstitution and Dilution

Alteplase is reconstituted by adding 50 mL of sterile water for injection without preservatives to a vial labeled as containing 50 mg of drug using a large-bore (e.g., 18-gauge) needle and directing the stream of diluent into the lyophilized cake; do not use diluents other than sterile water for injection without preservatives for reconstitution.1 Do not use the vial if a vacuum is not present.1 The resultant solution contains approximately 1 mg of alteplase per mL.1 If foaming (usually slight) occurs during reconstitution, leave the vial undisturbed for several minutes after addition of the diluent to allow dissipation of any large bubbles.1 The reconstituted solution may be used as reconstituted (1 mg/mL) or may be further diluted just prior to administration to a concentration of approximately 0.5 mg/mL with 0.9% sodium chloride injection or 5% dextrose injection, using either polyvinyl chloride bags or glass vials;1 do not use more dilute solutions since precipitation of the drug may occur at concentrations <0.5 mg/mL.221 Other infusion solutions, including sterile water for injection without preservatives or preservative-containing solutions, should not be used for dilution of the reconstituted solution.1 During dilution of the reconstituted solution, mix the solution with gentle swirling and/or slow inversion of the infusion container; avoid excessive agitation.1

Consult the manufacturer's labeling for information on the reconstitution and dilution of vials labeled as containing 100 mg of the drug and for detailed instructions on preparing doses of alteplase for IV infusion.1

Visually inspect reconstituted solutions of alteplase for particulate matter and discoloration before further dilution or administration whenever solution and container permit.1 Because alteplase powder for injection and reconstituted and diluted solutions of the drug contain no preservatives, the solutions preferably should be prepared immediately before use, but may be used for up to 8 hours after reconstitution or dilution when stored at 2-30°C; discard any unused solution.1,401

Standardize 4 Safety

Standardized concentrations for alteplase have been established through Standardize 4 Safety (S4S), a national patient safety initiative to reduce medication errors, especially during transitions of care. 401,402Multidisciplinary expert panels were convened to determine recommended standard concentrations. 401,402Because recommendations from the S4S panels may differ from the manufacturer's prescribing information, caution is advised when using concentrations that differ from labeling, particularly when using rate information from the label. 401,402 For additional information on S4S (including updates that may be available), see [Web].401,402

Table 1. Standardize 4 Safety Continuous Infusion Standards for Alteplase.401,402

Patient Population

Concentration Standard

Dosing Units

Pediatric patients (<50 kg)

1 mg/mL

mg/kg per hour

Adults

1 mg/mL

mg/hour

Administration into Occluded Central Venous Catheters

Reconstitution

Alteplase powder for restoring patency of central venous catheters (Cathflo® Activase®) is reconstituted by adding 2.2 mL of sterile water for injection to a vial labeled as containing 2 mg of alteplase to provide a concentration of 1 mg/mL.325 Do not use bacteriostatic water for injection as a diluent.325 If foaming (usually slight) occurs during reconstitution, leave the vial undisturbed for several minutes after addition of the diluent to allow dissipation of any large bubbles.325

Visually inspect reconstituted solutions of alteplase for particulate matter and discoloration before further dilution or administration whenever solution and container permit.325 Because alteplase powder intracatheter instillation and reconstituted solutions of the drug contain no preservatives117 , the drug preferably should be reconstituted immediately before use, but may be used for up to 8 hours after reconstitution when stored at 2-30°C; discard any unused solution.325

Dosage !!navigator!!

Dosage of alteplase usually is expressed in mg of drug but also may be expressed in international units (IU, units); each mg is equivalent to 580,000 units.1

Acute Myocardial Infarction

Alteplase therapy should be initiated as soon as possible after the onset of symptoms of myocardial infarction (MI) since potential clinical benefit diminishes as the time period to initiation of therapy increases.1,527 Some experts recommend that thrombolytic therapy be administered within 30 minutes of hospital arrival.527

Various dosage regimens have been employed in patients treated with rt-PA for lysis of coronary artery thrombi.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 Alteplase may be administered by IV infusion over 3 hours or as an “accelerated” infusion over 1.5 hours.1 Controlled studies comparing clinical outcomes with these regimens have not been performed.1 However, pooled analyses of data from thrombolytic trials indicate that an accelerated infusion of alteplase is associated with greater rates of patency of the infarct-related artery than with a standard 3-hour infusion,311 and some experts consider the accelerated infusion regimen of alteplase to be the preferred method of administration.527 Although a dose of 150 mg of alteplase was used in early studies with the drug, this dose should not be used for the treatment of acute MI because of its association with an increased incidence of intracranial bleeding.1

3-Hour Infusion

For lysis of coronary artery thrombi associated with acute MI, the usual adult dose (weight ≥65 kg) of alteplase currently recommended is 100 mg (58 million units) IV over a 3-hour period, given as an initial 60-mg (34.8 million units) lytic dose during the first hour (of which 6-10 mg is infused rapidly over 1-2 minutes) and a subsequent maintenance infusion at a rate of 20 mg (11.6 million units) per hour for the next 2 hours.1 For adults weighing <65 kg (lean or actual body weight, whichever is less), a dose of 1.25 mg/kg may be infused IV over 3 hours as an initial lytic dose of 0.75 mg/kg during the first hour (of which 0.075 mg/kg is infused rapidly over 1-2 minutes) and a subsequent maintenance infusion at a rate of 0.25 mg/kg per hour for the next 2 hours.1,199 The maximum recommended total dosage is 100 mg.1

Accelerated Infusion

When administered as an accelerated infusion for lysis of coronary artery thrombi associated with MI, the dose of alteplase is based on patient weight but should not exceed 100 mg.1 In adults weighing >67 kg, the usual dose of alteplase is 100 mg given by IV infusion; an initial 15-mg dose is given by rapid IV injection (e.g., over 1-2 minutes)7 followed by 50 mg IV over the next 30 minutes then 35 mg IV over the next hour.1 In patients weighing ≤67 kg, an initial 15-mg dose of alteplase is given by rapid IV injection (e.g., over 1-2 minutes),7 followed by 0.75 mg/kg (not to exceed 50 mg) over the next 30 minutes then 0.5 mg/kg (not to exceed 35 mg) over the next hour.1 The manufacturer states that the safety and efficacy of alteplase given by accelerated infusion has only been evaluated with concomitant heparin and aspirin administration.1 Although a dose of 150 mg of alteplase was used in early studies with the drug, this dose is no longer recommended because of its association with an increased incidence of intracranial bleeding.1,4,41,43

Pulmonary Embolism

Various dosage regimens of rt-PA, including alteplase, have been used in adults for the management of acute pulmonary embolism,46,86,87,88,89,90,91,92,93,270,271,272,273 and the optimal dosage regimen for rt-PA in patients with this condition has not been established.91,270,271,272,273 For lysis of acute pulmonary emboli involving obstruction of blood flow to a lobe or multiple segments of the lungs, the usual adult dose of alteplase currently recommended is 100 mg (58 million units) IV over a 2-hour period.1,91,271,273 The manufacturer states that parenteral anticoagulation should be instituted near the end of or immediately following the alteplase infusion when the activated partial thromboplastin time (aPTT) or thrombin time returns to twice the normal value or less.1 In the setting of cardiac arrest associated with pulmonary embolism, AHA guidelines suggest an alteplase dosage of 50 mg IV bolus with an option for a repeat bolus in 15 minutes; there is no consensus on the ideal dose of thrombolytic therapy in pulmonary embolism-associated cardiac arrest.360 Alteplase also has been infused via the pulmonary artery† in adults in dosages of 30 or 50 mg over 1.5 or 2 hours, respectively, with concomitant heparin therapy.89,90 Lysis of pulmonary emboli usually has occurred within 2-6 hours after initiation of the IV or intra-arterial infusion,86,87,88,91 and IV infusion of the drug appears to be as effective as administration via the pulmonary artery.90

Acute Ischemic Stroke

For the treatment of acute ischemic stroke, the recommended dosage of alteplase is 0.9 mg/kg (up to a maximum dose of 90 mg).1 Initially, administer 10% of the dose by rapid IV infusion over 1 minute; infuse the remainder of the dose by IV infusion over 60 minutes.1,357,393 The dosage of alteplase for the treatment of acute ischemic stroke should not exceed 0.9 mg/kg (maximum 90 mg).1,357 For optimum benefit, alteplase should be administered as soon as possible, but must be given within 3-4.5 hours following onset of stroke symptoms.389,393,394,398,1101 The manufacturer states that treatment should be initiated within 3 hours of onset of symptoms.1 Heparin anticoagulation that produces an elevated aPTT should not be used within 48 hours of the use of alteplase.357,358 Administration of aspirin within 24 hours of the use of a thrombolytic agent generally is not recommended by AHA and the American Stroke Association (ASA).357,1101 In patients with acute ischemic stroke who have not received recent anticoagulation therapy (e.g., oral anticoagulants, heparin), therapy with alteplase may be initiated prior to coagulation study results.1 However, infusion of alteplase should be discontinued if pretreatment coagulation study results are abnormal (as indicated by an INR >1.7 or an elevated aPTT).1

Arterial Thrombosis and Embolism

For lysis of arterial occlusion† in a peripheral vessel or bypass graft, alteplase usually has been infused intra-arterially in a dosage of 0.05-0.1 mg/kg per hour for 1-8 hours,94,95,96,97 although there is limited evidence that even lower dosages (e.g., 0.02 mg/kg per hour over 1-7 hours) may be effective.211 Regardless of the regimen used, however, some patients with acute arterial occlusion require further therapeutic intervention after thrombolysis.

Occluded Catheters

To clear an occluded central venous IV catheter, 2 mg of alteplase in 2 mL of sterile water for injection is administered into the occluded catheter in patients weighing ≥30 kg.325 In patients weighing <30 kg, a volume of the alteplase solution equal to 110% of the internal lumen volume of the catheter should be instilled, up to a maximum of 2 mg of alteplase in 2 mL of solution.325 After at least 30 minutes of dwell time, catheter function is assessed by attempting to aspirate blood.325 When patency is restored, 4-5 mL of blood in patients weighing ≥10 kg or 3 mL of blood in patients weighing <10 kg should be aspirated to remove all drug and residual clot.325 An aspiration attempt may be repeated at 120 minutes of dwell time, and a second injection of alteplase (up to 2 mg for a total of up to 4 mg) may be necessary in resistant cases.325 The American College of Chest Physicians (ACCP) suggests that a second dose of alteplase may be administered after 30 minutes of dwell time if the catheter remains occluded.1013 The catheter should then be gently irrigated with 0.9% sodium chloride injection. If catheter patency is not successfully established after 2 doses of alteplase, ACCP suggests radiologic imaging to rule out a catheter-related thrombus.1013

When alteplase has been used to clear occluded hemodialysis access catheters,† several regimens have been employed.350,351 In a limited number of studies, 1-2 mg of alteplase were injected directly into the occluded catheter and allowed to remain for at least 30 minutes of dwell time.350,351 Catheter function was assessed by measurement of blood flow rate at the next hemodialysis session; blood flow rates of 200-300 mL/minute indicated successful restoration of patency of the hemodialysis access catheter.350,351 Some patients required additional intracatheter instillations of alteplase for reocclusion of hemodialysis access catheters after successful establishment of patency.351 Some clinicians have used 2 mg of alteplase in a total volume of 2 mL by direct injection into the catheter after a hemodialysis session and then aspirated the lumen contents before the next hemodialysis session in patients with indwelling catheters.221 Other clinicians have infused 2.5-5 mg of alteplase over 2-3 hours in each access port in patients with occluded hemodialysis catheters.221

Special Populations

Geriatric Patients

Based on results of a trial with tenecteplase showing that an excess of intracranial hemorrhage in patients ≥75 years of age with acute MI was reduced after reducing the tenecteplase dosage by 50%,413 some clinicians suggest considering a 50% reduction in the dosage of alteplase in patients ≥75 years of age receiving the drug for acute MI.414

Cautions ⬆ ⬇

[Section Outline]

Contraindications !!navigator!!

Drug Interactions ⬆ ⬇

[Section Outline]

Thrombolytic Agents !!navigator!!

In vitro clot lysis studies have failed to show substantial synergistic effects with t-PA and an investigational plasminogen activator, single-chain urokinase plasminogen activator (scu-PA, prourokinase).13,191 However, in animals, simultaneous administration of t-PA and scu-PA in a molar ratio of 1:34,13 demonstrated synergistic thrombolytic effects without associated systemic fibrinogen breakdown.4,13,191 Synergistic thrombolysis also has been observed in preliminary studies in patients with acute MI who received predominantly two-chain rt-PA (no longer currently available in the US) and recombinant scu-PA4,13,189,190 in doses of each approximately one-fourth the usual doses.190 Concomitant administration of t-PA and urokinase (no longer commercially available in the US) has been associated with synergistic thrombolytic effects in animals.192 However, in a study in patients with acute MI, combined use of alteplase and urokinase was not associated with synergistic thrombolysis, although a substantial reduction in the rate of reocclusion after coronary thrombolysis did occur and was not accompanied by an increase in bleeding complications.186

Anticoagulants !!navigator!!

In almost all patients receiving alteplase for the treatment of acute MI in clinical studies, heparin, followed by oral anticoagulants in some cases, has been administered before, during, and/or after alteplase therapy to reduce the risk of coronary artery reocclusion.1,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,47,48,50,57,84,85,117,141,154,155,163 However, concomitant use of alteplase and an anticoagulant may increase the risk of hemorrhage,1,14,34,43,44,68,72,74,144,155 and careful monitoring for bleeding is necessary, especially at arterial puncture sites.1,34,37,38,39,40,41,43,44,49,59,65,72,144,155 Anticoagulant therapy should be discontinued immediately and appropriate therapy (e.g., protamine sulfate in patients receiving heparin) instituted as necessary if serious bleeding occurs.1,14

The American Heart Association (AHA) and the American Stroke Association (ASA) state that in patients with acute ischemic stroke, a follow-up CT or MRI scan should be performed at 24 hours after IV alteplase before starting treatment with anticoagulant agents.1101

Drugs Affecting Platelet Function !!navigator!!

Platelet-aggregation inhibitors (e.g., aspirin, clopidogrel) also have been administered after alteplase therapy for the treatment of acute MI to reduce the risk of reocclusion of the infarct-related artery.1,37,38,39,40,41,43,527 Drugs that affect platelet function (e.g., aspirin, dipyridamole, abciximab) may increase the risk of bleeding if administered prior to, during, or after alteplase therapy.1,357

In patients with acute stroke, the American Heart Association (AHA) and the American Stroke Association (ASA) generally do not recommend administration of aspirin within 24 hours of the use of a thrombolytic agent, as such adjunctive use of aspirin may increase the risk of bleeding from thrombolytic agents.357,1101 AHA/ASA state that concurrent administration of abciximab with IV alteplase, and administration of IV aspirin within 90 minutes of starting alteplase treatment, should be avoided.1101 AHA/ASA also state that a follow-up CT or MRI scan should be performed at 24 hours after IV alteplase before starting antiplatelet agents.1101

Angiotensin-Converting Enzyme Inhibitors !!navigator!!

Angioedema has been reported in patients (primarily with acute ischemic stroke) receiving concomitant angiotensin-converting enzyme (ACE) inhibitors with alteplase.1

Other Information ⬆ ⬇

Description

Alteplase, a recombinant DNA-derived form of human tissue-type plasminogen activator (t-PA),1,46 is a thrombolytic agent.1,4,5,8,11,12,13,14,15,19,21,31,35,36,46,62,67 The amino acid sequence and biological properties of human melanoma cell t-PA are similar or identical to those of endogenous human t-PA from uterine tissue,17 and the amino acid sequence of alteplase is identical to that of human melanoma cell t-PA;24 therefore, differences between alteplase and human uterine tissue or melanoma cell t-PA apparently relate to variability in the carbohydrate moieties of the molecules.24 In contrast to anticoagulants, which prevent propagation of thrombi,123,124,125 t-PA and other plasminogen activators such as streptokinase and urokinase (urinary-type plasminogen activator, u-PA) promote thrombolysis by hydrolyzing the arginine560-valine561 peptide bond in plasminogen to form the active proteolytic enzyme plasmin.4,5,7,8,12 Plasmin is a relatively nonspecific serine protease that is capable of degrading fibrin, fibrinogen, and other procoagulant proteins, such as factors V, VIII,4,5,13 and XII.5 Unlike streptokinase and urokinase (no longer commercially available in the US), t-PA is a relatively fibrin-selective plasminogen activator.1,4,5,7,8,11,12,13,14,19,21,46 Fibrinolytic activity is localized to the site of the thrombus due to formation of a ternary complex between t-PA, fibrin, and plasminogen.1,4,5,8,19,28 Alteplase induces thrombolysis without substantially activating circulating plasminogen15,29 or degrading fibrinogen.15,23,28,29,58 Thrombolytic therapy paradoxically may transiently activate the coagulation system, which may decrease the patency of successfully reperfused infarct-related arteries in patients with acute myocardial infarction (MI).312,313,316

Alteplase is not absorbed after oral administration and must be administered parenterally.1 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 The mechanisms involved in the elimination of t-PA from blood are poorly understood.12 t-PA appears to be cleared principally by the liver,1,5,8,9,10,12,27,46,130,131 which subsequently releases degradation products into the blood.10,11,27,130,131 In a study in patients with MI, the half-lives of alteplase in the initial distribution phase (t½α) and in the terminal elimination phase (t½β) averaged 3.6-4.6 and 39-53 minutes, respectively;65 mean t½α and t½β averaged 4.4 and 26.5 minutes, respectively, in patients with thrombo-occlusive disease.66 In healthy men receiving alteplase, t½α and t½β averaged 3.3-4.2 and 26-36 minutes, respectively.66,127 Limited evidence in animals suggests that the elimination half-life of t-PA may be prolonged in patients with severely impaired hepatic function and/or hepatic blood flow.46,185 There is limited evidence from healthy adults receiving radiolabeled human melanoma cell t-PA that exogenously administered t-PA is excreted mainly in urine, with about 80% of total radioactivity being excreted within 18 hours.130

Advice to Patients

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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

Copyright ⬆ ⬇

AHFS® Drug Information. © Copyright, 1959-2024, Selected Revisions October 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.

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

References ⬆

Only references cited for selected revisions after 1984 are available electronically.

1. Genentech, Inc. Activase (alteplase, recombinant) prescribing information. South San Francisco, CA; 2022 Sept.

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131. Nilsson S, Einarsson M, Ekvarn S et al. Turnover of tissue plasminogen activator in normal and hepatectomized rabbits. Thromb Res . 1985; 39:511-21. [PubMed 3931294]

141. Passamani E, Hodges M, Herman M et al. The Thrombolysis in Myocardial Infarction (TIMI) Phase II pilot study: tissue plasminogen activator followed by percutaneous transluminal coronary angioplasty. J Am Coll Cardiol . 1987; 10(Suppl):51-64B.

142. TIMI Operations Committee. Announcement of protocol change in Thrombolysis in Myocardial Infarction trial. J Am Coll Cardiol . 1987; 9:467.

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145. Sobel BE. Safety and efficacy of tissue-type plasminogen activator produced by recombinant DNA technology. J Am Coll Cardiol . 1987; 10(Suppl):40-4B. [PubMed 2955018]

146. Gimple LW, Gold HK, Leinbach RC et al. Correlation between template bleeding times and spontaneous bleeding during treatment of acute myocardial infarction with recombinant tissue-type plasminogen activator. Circulation . 1989; 80:581-8. [PubMed 2504511]

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154. Nazari J, Davison R, Kaplan K et al. Adverse reactions to thrombolytic agents: implications for coronary reperfusion following myocardial infarction. Med Toxicol Adverse Drug Exp . 1987; 2:274-86. [PubMed 3306267]

155. Maizel AS, Bookstein JJ. Streptokinase, urokinase, and tissue plasminogen activator: pharmacokinetics, relative advantages, and methods for maximizing rates and consistency of lysis. Cardiovasc Intervent Radiol . 1986; 9:236-44. [PubMed 3100038]

156. Willerson JT, Winniford M, Buja LM. Review: thrombolytic therapy for patients with acute myocardial infarction. Am J Med Sci . 1987; 293: 187-200. [PubMed 3105312]

157. Mathey DG, Schofer J, Sheehan FH et al. IV urokinase in acute myocardial infarction. Am J Cardiol . 1985; 55:878-82. [PubMed 3984876]

162. Goldberg S, Greenspon AJ, Urban PL et al. Reperfusion arrhythmias: a marker of restoration of antegrade flow during intracoronary thrombolysis for acute myocardial infarction. Am Heart J . 1983; 105:26-32. [PubMed 6849238]

163. Kircher BJ, Topol EJ, O'Neill WW et al. Prediction of infarct coronary artery recanalization after IV thrombolytic therapy. Am J Cardiol . 1987; 59:513-5. [PubMed 3825886]

164. Wei JY, Markis JE, Malagold M et al. Cardiovascular reflexes stimulated by reperfusion of ischemic myocardium in acute myocardial infarction. Circulation . 1983; 67:796-801. [PubMed 6825235]

165. Corr PB, Witkowski FX. Potential electrophysiologic mechanisms responsible for dysrhythmias associated with reperfusion of ischemic myocardium. Circulation . 1983; 68(Suppl 1):I-16-24. [PubMed 6305533]

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