⬇ ⬇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
⬆ ⬇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
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.
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
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
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
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
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
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
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
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 
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
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
⬆ ⬇Dispensing and Administration Precautions
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
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
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
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
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 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
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
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
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
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
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.
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
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
⬆ ⬇Alteplase can cause serious, sometimes fatal, internal and external bleeding, especially at arterial and venous puncture sites.1 Bleeding and hemorrhagic complications,1,14,43,44,145,146,154,155,156 including intracranial hemorrhage and other major bleeding complications,141 are possible in patients receiving alteplase. Hemorrhage associated with alteplase may be more common in geriatric patients1,62,154,156 and those with a history of cerebrovascular accident or severe or poorly controlled hypertension.141
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),1,322 high likelihood of hemostatic defects (e.g., secondary to severe hepatic or renal disease), internal (e.g., GI or GU) bleeding, acute pericarditis, subacute bacterial endocarditis, pregnancy, septic thrombophlebitis or occluded arteriovenous cannula at seriously infected site, recent intracranial hemorrhage, or recent (within 2-4 weeks) trauma.1 Also, weigh risks against benefits of therapy in patients with diabetic hemorrhagic retinopathy or other hemorrhagic ophthalmic conditions.1 Weigh risks against benefits in patients receiving concurrent oral anticoagulant therapy (e.g., warfarin).1 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
Initiate therapy only after careful screening for contraindications (e.g., previous neurologic events, severe hypertension, and potential bleeding sites).142,244
Minimize the 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).1,14,15,181,44,46,154 Avoid IM injections and nonessential handling of patient.1,46 Perform invasive venous procedures carefully and as infrequently as possible.1,46 Avoid arterial and venous invasive procedures in areas inaccessible to manual compression (e.g., internal jugular or subclavian punctures) before and during therapy.1 Use of an artery in an upper extremity (e.g., radial or brachial) is preferable if arterial puncture is essential.1,46 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
Severe spontaneous (i.e., unrelated to catheter or other puncture sites) bleeding, including cerebral,1,34,37,42,43,47,48 retroperitoneal,1,37,44,47 genitourinary,1,31,41,44,47 and GI bleeding,1,33,36,39,41,43,44,47,48,154 has occurred during rt-PA therapy and can be fatal (e.g., secondary to cerebral hemorrhage or other serious internal hemorrhage).1,37,41,42,43,47,48,57 Upper airway hemorrhage (sometimes fatal) at the site of traumatic intubation has been reported with alteplase therapy.1 Less severe spontaneous bleeding, such as superficial hematoma or ecchymoses,1,40,41,48 hematuria,41,43 hemoptysis,41,43 epistaxis,1 and gingival bleeding,1,41,43 also can occur in patients receiving rt-PA.40,41
Aspirin and heparin have been administered concomitantly with and following infusions of alteplase in the management of acute MI and pulmonary embolism; however, the concomitant administration of heparin and aspirin with and following infusions of alteplase for the treatment of acute ischemic stroke during the first 24 hours after symptom onset has not been studied.1 Because heparin, aspirin, or alteplase may cause bleeding complications, carefully monitor for bleeding, especially at arterial puncture sites.1 Hemorrhage can occur one or more days after administration of alteplase, while patients are still receiving anticoagulant therapy.1
If serious bleeding occurs, immediately discontinue alteplase therapy1,14 and initiate appropriate treatment.1,14,15 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
Coagulation tests and measures of fibrinolytic activity may be unreliable during alteplase therapy, unless specific precautions are taken to prevent in vitro artifacts.1 When present in blood at pharmacologic concentrations, alteplase remains active under in vitro conditions, which can result in degradation of fibrinogen in blood samples removed for analysis.1
Extravasation during IV infusion of alteplase may cause ecchymosis and/or inflammation.1 Terminate the infusion at that IV site and apply local therapy if extravasation occurs.1
Cardiovascular effects such as cardiogenic shock, heart failure, myocardial rupture, electromechanical dissociation, pericardial effusion, pericarditis, mitral regurgitation, or cardiac tamponade have occurred in patients with acute MI receiving alteplase.1 Pleural effusion has been reported in patients with pulmonary embolism receiving alteplase.1 Hypotension and pulmonary edema have been reported in patients with either acute MI or pulmonary embolism receiving alteplase.1 Potentially fatal adverse effects, such as thromboembolism or recurrent thromboembolic events (myocardial reinfarction, recurrent ischemia, or pulmonary re-embolization) have occurred in patients with acute MI or pulmonary embolism receiving alteplase in clinical trials or during postmarketing surveillance.1
Thromboembolic events may occur in patients receiving thrombolytic agents, including alteplase, who have a high likelihood of left heart thrombus, such as patients with mitral stenosis or atrial fibrillation.1 Alteplase has not been shown to adequately treat underlying deep vein thrombosis in patients with pulmonary embolism; consider the possible risk of re-embolization due to lysis of underlying deep vein thrombi in such patients.1 Weigh risks against anticipated benefits of therapy in patients with a high likelihood of left heart thrombus (e.g., mitral stenosis, atrial fibrillation, profound left ventricular dyskinesia),1,196 acute pericarditis,1,198 subacute bacterial endocarditis, septic thrombophlebitis, or an occluded arteriovenous cannula at a seriously infected site.1
New embolic episodes, including those involving cerebral vessels, may occur in patients receiving alteplase.196 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
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 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 Reduce incidence of reocclusion through concomitant anticoagulation (e.g., heparin and/or oral anticoagulants)1,30,31,32,33,34,35,36,37,38,39,40,41,42,47 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
New ischemic stroke, which may be potentially fatal, has been reported in patients with an acute ischemic stroke receiving alteplase in clinical trials or during postmarketing surveillance.1 Therefore, it is important that the benefits versus risks of rt-PA therapy be carefully considered, particularly when the potential for acute intraventricular thrombus exists.196
The manufacturer and other clinicians state that the risks of alteplase therapy for the treatment of acute ischemic stroke may be increased and should be weighed against anticipated benefits in patients with severe neurologic deficit (e.g., NIH Stroke Scale [NIHSS] score >22) on pretreatment evaluation (because of an increased risk of intracranial hemorrhage in such patients);1,358 clinicians state that this also applies to patients with major early infarct signs on CT scan (e.g., substantial edema, mass effect, midline shift).358 However, AHA and ASA state that thrombolytic therapy almost always should not be administered to patients with major early infarct signs (greater than one-third of the middle cerebral artery territory and clearly identifiable hypodensity on CT scan).358,1101
In patients with acute ischemic stroke, administer alteplase in facilities that can provide appropriate evaluation and management of intracranial hemorrhage.1 Frequently monitor and control blood pressure during and following administration.1,357 The safety of administering alteplase without careful blood pressure management has not been established.1,322
Cholesterol crystal embolization and associated serious complications in the absence of antecedent invasive vascular procedures have been reported rarely in patients receiving thrombolytic therapy, including alteplase.1,267 This serious condition, which can be fatal, also is associated with invasive vascular procedures (e.g., cardiac catheterization, angiography, vascular surgery) and/or anticoagulant therapy.1 Clinical features of cholesterol embolization may 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
Rapid lysis of coronary artery thrombi by thrombolytic agents may be associated with reperfusion-related atrial32,162,163,164,166 and/or ventricular67,162,163,164,165,187 arrhythmias. Arrhythmias most commonly associated with reperfusion include accelerated idioventricular rhythm67,155,162,163,187 and ventricular premature complexes67,162 and, less frequently, ventricular fibrillation;163,165 atrial premature complexes,166 atrial fibrillation,32,166 junctional rhythm,163 ventricular tachycardia,162 and sinus bradycardia32,67,155,162,163,164 also have been observed. Reperfusion-related arrhythmias usually are transient,187 but immediate treatment occasionally may be required.67 Monitor patients receiving rt-PA, including alteplase, for acute MI carefully for possible arrhythmias during and immediately after administration of the drug; appropriate antiarrhythmic therapy for bradycardia and/or ventricular irritability should be available during administration of the drug.164
AV block or cardiac arrest has been reported in patients with acute MI receiving alteplase in clinical trials and during postmarketing surveillance.1
Weigh the anticipated benefits of alteplase therapy against the increased risks in patients with substantial liver dysfunction.1
Hypersensitivity reactions (e.g., anaphylactoid reaction, laryngeal edema, angioedema, rash, urticaria), in rare cases fatal, have been reported with IV alteplase therapy.1,145 The onset of angioedema has occurred during and up to 2 hours after infusion of alteplase in patients with acute ischemic stroke or acute MI.1 In many instances, such patients were receiving concomitant angiotensin-converting enzyme (ACE) inhibitors.1
Monitor patients during and several hours following alteplase infusion for signs of hypersensitivity reactions.1 If signs of hypersensitivity (e.g., anaphylactic reaction, angioedema) occur, discontinue alteplase and promptly administer appropriate therapy (e.g., antihistamines, epinephrine, IV corticosteroids).1
Hypersensitivity reactions, including urticaria, angioedema, and anaphylaxis, also have been reported in patients receiving alteplase by intracatheter instillation.325 Monitor patients receiving alteplase by intracatheter instillation for hypersensitivity reactions and treat appropriately if necessary.325
Although no adequate studies have been performed in pregnant women, animal reproduction studies indicate that IV alteplase was embryocidal in rabbits given the drug at a dosage of 3 mg/kg, approximately equal to the human dosage (based on AUC) used for the treatment of acute MI.1 No maternal or fetal toxicity was evident in rabbits or rats administered alteplase during organogenesis at doses approximately 0.3 or 0.6 times the human dose (based on body weight) for acute MI, respectively.1
The risk of bleeding associated with thrombolytic therapy may be increased during pregnancy.1 Weigh the risk and benefits of alteplase prior to use during pregnancy.1
The American Heart Association (AHA) and American Stroke Association (ASA) state that IV alteplase therapy for acute ischemic stroke may be considered in pregnancy when the anticipated benefits of treating moderate or severe stroke outweigh the anticipated increased risks of uterine bleeding.1101 Therapy with rt-PA followed by IV heparin treatment has been used successfully for lysis of pulmonary emboli in a pregnant woman with congenital antithrombin III deficiency.274 Approximately 20 hours following discontinuance of rt-PA therapy, at week 35 of pregnancy, the patient delivered a male infant by cesarean section.274 No placental bleeding occurred and the infant showed no signs of bleeding, but he died later from complications related to respiratory distress syndrome.274 Another pregnant woman with massive pulmonary embolism and circulatory shock at week 31 of pregnancy who was treated successfully with rt-PA (10 mg/hour for 4 hours followed by 2 mg/hour for 1.5 hours) delivered an otherwise healthy premature infant 48 hours following thrombolytic therapy.290
AHA and ASA state that the safety and efficacy of IV alteplase for the treatment of acute ischemic stroke in the early postpartum period (<14 days after delivery) have not been established.1101
It is not known whether alteplase is distributed into human milk or whether the drug affects the breast-fed infant or affects milk production.1
Females and Males of Reproductive Potential
It is not known whether alteplase can affect fertility.1
Safety and efficacy of IV infusion of alteplase in pediatric patients have not been established.1 However, the drug has been used with some success in a few infants and children with thrombosis of the vena cava, aorta, or peripheral arteries;286,287,288,1013 successful lysis of pulmonary emboli without bleeding complications also has been reported in at least one child with angiographically documented pulmonary emboli of undetermined duration who received 0.1 mg/kg of alteplase per hour for 11 hours via the pulmonary artery†.268 Thrombolytic therapy generally is not recommended for the 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.1013
Use of thrombolytic therapy in children with arterial ischemic stroke is not recommended by ACCP outside of a research setting.1013
Safety and efficacy of intracatheter instillation of alteplase for the restoration of central venous catheters in pediatric patients (2 weeks to 17 years) is similar to that observed in adults.325
Assess the risks against the anticipated benefits of therapy with alteplase in patients >75 years of age.1 Intracranial hemorrhage and other major bleeding complications are more common in patients >75 years compared with younger adults.1,62,154,156 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
The manufacturer states that efficacy results in patients with acute ischemic stroke suggest a reduced but still favorable clinical outcome for geriatric patients receiving alteplase.1
In a large trial comparing 4 thrombolytic regimens, including accelerated-infusion alteplase, in patients with acute MI, 12% of patients were >75 years of age.1 The incidence of stroke in geriatric patients receiving accelerated-infusion alteplase was 4%, and the incidence of combined 30-day mortality or nonfatal stroke was 20.6%.1
Limited data in animals suggests the possibility of a prolonged elimination half-life of t-PA in patients with severely impaired hepatic function and/or hepatic blood flow.46,185 Weigh the anticipated benefits of alteplase therapy against the risks of possible hemostatic defects associated with severe hepatic disease.1
Adverse effects reported in >5% of patients include hemorrhage.1,31,32,33,34,36,37,38,39,40,41,43,44,45,46,47,48,154,155,198
⬆ ⬇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
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
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
Angioedema has been reported in patients (primarily with acute ischemic stroke) receiving concomitant angiotensin-converting enzyme (ACE) inhibitors with alteplase.1
⬆ ⬇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
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.
⬆ ⬇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.
⬆ ⬇ ⬆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.
4. Collen D, Stump DC, Gold HK. Thrombolytic therapy. Ann Rev Med . 1988; 39:405-23. [PubMed 3130773]
5. Tiefenbrunn AJ, Robison AK, Sobel BE. Clinical pharmacology of coronary thrombolysis. Cardiol Clin . 1987; 5:125-8. [PubMed 3103917]
6. Conard J, Samama MM. Theoretic and practical considerations on laboratory monitoring of thrombolytic therapy. Semin Thromb Hemost . 1987; 13:212-22. [PubMed 3114887]
7. Robison AK, Collen D. Activation of the fibrinolytic system. Cardiol Clin . 1987; 5:13-9. [PubMed 3103919]
8. Collen D, Lijnen HR. Tissue-type plasminogen activator: mechanism of action and thrombolytic properties. Haemostasis . 1986; 16(Suppl 3):25-32. [PubMed 3095195]
9. von Kaulla KN, Kaye H, von Kaulla E et al. Changes in blood coagulation before and after hepatectomy or transplantation in dogs and man. Arch Surg . 1966; 92:71-9. [PubMed 5322193]
10. Korninger C, Stassen JM, Collen D. Turnover of human extrinsic (tissue-type) plasminogen activator in rabbits. Thromb Haemost . 1981; 46:658-61. [PubMed 7198302]
11. Collen D, Stassen JM, Marafino BJ et al. Biological properties of human tissue-type plasminogen activator obtained by expression of recombinant DNA in mammalian cells. J Pharmacol Exp Ther . 1984; 231:146- 52. [PubMed 6541693]
12. Lijnen HR, Collen D. Molecular mechanisms of thrombolytic therapy. Haemostasis . 1986; 16(Suppl 3):3-15.
13. Collen D. Molecular mechanism of action of newer thrombolytic agents. J Am Coll Cardiol . 1987; 10(Suppl B):11B-5B. [PubMed 3117858]
14. Marder VJ, Sherry S. Thrombolytic therapy: current status (first of two parts). N Engl J Med . 1988; 318:1512-20. [PubMed 3285216]
15. Marder VJ, Sherry S. Thrombolytic therapy: current status (second of two parts). N Engl J Med . 1988; 318:1585-95. [PubMed 3287158]
17. Rijken DC, Collen D. Purification and characterization of the plasminogen activator secreted by human melanoma cells in culture. J Biol Chem . 1981; 256:7035-41. [PubMed 6787058]
19. Verstraete M, Collen D. Thrombolytic therapy in the eighties. Blood . 1986; 67:1529-41. [PubMed 2423156]
21. Verstraete M. The search for the ideal thrombolytic agent. J Am Coll Cardiol . 1987; 10(Suppl B):4B-10B. [PubMed 2959714]
23. Sobel BE. Coronary thrombolysis with tissue-type plasminogen activator (t-PA): emerging strategies. J Am Coll Cardiol . 1986; 8:1220-5. [PubMed 3093555]
24. Vehar GA, Spellman MW, Keyt BA et al. Characterization studies of human tissue-type plasminogen activator produced by recombinant DNA technology. Cold Spring Harbor Symp Quant Biol . 1986; 51:551-62. [PubMed 2953546]
27. Fuchs HE, Berger H, Pizzo SV. Catabolism of human tissue plasminogen activator in mice. Blood . 1985; 65:539-44. [PubMed 4038613]
28. Collen D. Tissue-type plasminogen activator (t-PA) and single chain urokinase-type plasminogen activator (scu-PA): potential for fibrin-specific thrombolytic therapy. Prog Hemostasis Thromb . 1986; 8:1-18.
29. Flameng W, Van de Werf F, Vanhaecke J et al. Coronary thrombolysis and infarct size reduction after IV infusion of recombinant tissue-type plasminogen activator in nonhuman primates. J Clin Invest . 1985; 75:84-90. [PubMed 4038406]
30. Van de Werf F, Ludbrook PA, Bergmann SR et al. Coronary thrombolysis with tissue-type plasminogen activator in patients with evolving myocardial infarction. N Engl J Med . 1984; 310:609-13. [PubMed 6537987]
31. Collen D, Topol EJ, Tiefenbrunn AJ et al. Coronary thrombolysis with recombinant human tissue-type plasminogen activator: a prospective, randomized, placebo-controlled trial. Circulation . 1984; 70:1012-7. [PubMed 6388898]
32. Verstraete M, Bernard R, Bory M et al. Randomised trial of IV recombinant tissue-type plasminogen activator versus IV streptokinase in acute myocardial infarction. Lancet . 1985; 1:842-7. [PubMed 2858711]
33. Verstraete M, Bleifeld W, Brower RW et al. Double-blind randomised trial of IV tissue-type plasminogen activator versus placebo in acute myocardial infarction. Lancet . 1985; 2:965-9. [PubMed 2865502]
34. Topol EJ, Morris DC, Smalling RW et al. A multicenter, randomized, placebo-controlled trial of a new form of IV recombinant tissue-type plasminogen activator (Activase) in acute myocardial infarction. J Am Coll Cardiol . 1987; 9:1205-13. [PubMed 2953770]
35. Gold HK, Leinbach RC, Garabedian HD et al. Acute coronary reocclusion after thrombolysis with recombinant human tissue-type plasminogen activator: prevention by a maintenance infusion. Circulation . 1986; 73:347-52. [PubMed 3080262]
36. The TIMI Study Group. The Thrombolysis in Myocardial Infarction (TIMI) trial: Phase I findings. N Engl J Med . 1985; 312:932-6. [PubMed 4038784]
37. Topol EJ, Califf RM, George BS et al. A randomized trial of immediate versus delayed elective angioplasty after IV tissue plasminogen activator in acute myocardial infarction. N Engl J Med . 1987; 317:581-8. [PubMed 2956516]
38. Guerci AD, Gerstenblith G, Brinker JA et al. A randomized trial of IV tissue plasminogen activator for acute myocardial infarction with subsequent randomization to elective coronary angioplasty. N Engl J Med . 1987; 317:1613-8. [PubMed 2960897]
39. Williams DO, Borer J, Braunwald E et al. IV recombinant tissue-type plasminogen activator in patients with acute myocardial infarction: a report from the NHLBI thrombolysis in myocardial infarction trial. Circulation . 1986; 73:338-46. [PubMed 3080261]
40. Chesebro JH, Knatterud G, Roberts R et al. Thrombolysis in Myocardial Infarction (TIMI) Trial, Phase I: a comparison between IV tissue plasminogen activator and IV streptokinase. Clinical findings through hospital discharge. Circulation . 1987; 76:142-54. [PubMed 3109764]
41. Mueller HS, Rao AK, Forman SA et al. Thrombolysis in Myocardial Infarction (TIMI): comparative studies of coronary reperfusion and systemic fibrinogenolysis with two forms of recombinant tissue-type plasminogen activator. J Am Coll Cardiol . 1987; 10:479-90. [PubMed 3114349]
42. Wilcox RG, von der Lippe G, Olsson CG et al. Trial of tissue plasminogen activator for mortality reduction in acute myocardial infarction. Lancet . 1988; 2:525-30. [PubMed 2900919]
43. Mueller HS. Thrombolysis in Myocardial Infarction (TIMI): update 1987. Klin Wochenschr . 1988; 66(Suppl XII):93-101. [PubMed 3126350]
44. Rao AK, Pratt C, Berke A et al. Thrombolysis in Myocardial Infarction (TIMI) Trial—Phase I: Hemorrhagic manifestations and changes in plasma fibrinogen and the fibrinolytic system in patients treated with recombinant tissue plasminogen activator and streptokinase. J Am Coll Cardiol . 1988; 11:1-11. [PubMed 3121710]
45. Collen D, Bounameaux H, De Cock F et al. Analysis of coagulation and fibrinolysis during IV infusion of recombinant human tissue-type plasminogen activator in patients with acute myocardial infarction. Circulation . 1986; 73:511-7. [PubMed 2419009]
46. Loscalzo J, Braunwald E. Tissue plasminogen activator. N Engl J Med . 1988; 319:925-31. [PubMed 3138537]
47. National Heart Foundation of Australia Coronary Thrombolysis Group. Coronary thrombolysis and myocardial salvage by tissue plasminogen activator given up to 4 hours after onset of myocardial infarction. Lancet . 1988; 1:203-8. [PubMed 2893038]
48. O'Rourke M, Baron D, Keogh A et al. Limitation of myocardial infarction by early infusion of recombinant tissue-type plasminogen activator. Circulation . 1988; 77:1311-5. [PubMed 3131040]
49. Mock MB, Chesebro JH. Thrombolysis, streptokinase, and TPA in the treatment of acute myocardial infarction. Cardiovasc Clin . 1987; 18:247- 57. [PubMed 2955892]
50. Topol EJ, Bates ER, Walton JA Jr et al. Community hospital administration of IV tissue plasminogen activator in acute myocardial infarction: improved timing, thrombolytic efficacy and ventricular function. J Am Coll Cardiol . 1987; 10:1173-7. [PubMed 3119685]
51. Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico (GISSI). Effectiveness of IV thrombolytic treatment in acute myocardial infarction. Lancet . 1986; 1:397-402. [PubMed 2868337]
52. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomised trial of IV streptokinase, oral aspirin, both, or neither among 17 187 cases of suspected acute myocardial infarction: ISIS-2. Lancet . 1988; 2:349-60. [PubMed 2899772]
57. Neuhaus KL, Tebbe U, Gottwik M et al. IV recombinant tissue plasminogen activator (rt-PA) and urokinase in acute myocardial infarction: results of the German Activator Urokinase Study (GAUS). J Am Coll Cardiol . 1988; 12:581-7. [PubMed 3042835]
58. Collen D, Stassen JM, Verstraete M. Thrombolysis with human extrinsic (tissue-type) plasminogen activator in rabbits with experimental jugular vein thrombosis: effect of molecular form and dose of activator, age of the thrombus, and route of administration. J Clin Invest . 1983; 71:368-76. [PubMed 6681615]
59. Anon. Tissue-type plasminogen activator for acute coronary thrombosis. Med Lett Drugs Ther . 1987; 29:107-9. [PubMed 3119965]
60. Yusuf S, Wittes J, Friedman L. Overview of results of randomized clinical trials in heart disease. I: treatments following myocardial infarction. JAMA . 1988; 260:2088-93. [PubMed 2901501]
62. Smith B, Kennedy JW. Thrombolysis in the treatment of acute transmural myocardial infarction. Ann Intern Med . 1987; 106:414-20. [PubMed 3101563]
63. Sobel BE. Pharmacologic thrombolysis: tissue-type plasminogen activator. Circulation . 1987; 76(Suppl II):II-39-43.
64. Harrison DG, Ferguson DW, Collins SM et al. Rethrombosis after reperfusion with streptokinase: importance of geometry of residual lesions. Circulation . 1984; 69:991-9. [PubMed 6705173]
65. Garabedian HD, Gold HK, Leinbach RC et al. Comparative properties of two clinical preparations of recombinant human tissue-type plasminogen activator in patients with acute myocardial infarction. J Am Coll Cardiol . 1987; 9:599-607. [PubMed 3102584]
66. Baughman RA Jr. Pharmacokinetics of tissue plasminogen activator. In: Sobel BE, Collen D, Grossbard EB, eds. Tissue plasminogen activator in thrombolytic therapy. New York: Marcel Dekker, Inc; 1987:41-53.
67. American College of Physicians Health and Public Policy Committee. Thrombolysis for evolving myocardial infarction. Ann Intern Med . 1985; 103:463- 9. [PubMed 3161441]
68. Sherry S. Appraisal of various thrombolytic agents in the treatment of acute myocardial infarction. Am J Med . 1987; 83(Suppl 2A):31-46. [PubMed 3115099]
69. Sheehan FH, Braunwald E, Canner P et al. The effect of IV thrombolytic therapy on left ventricular function: a report on tissue-type plasminogen activator and streptokinase from the Thrombolysis in Myocardial Infarction (TIMI Phase I) Trial. Circulation . 1987; 75:817-29. [PubMed 3103950]
72. Sherry S. Recombinant tissue plasminogen activator (rt-PA): is it the thrombolytic agent of choice for an evolving acute myocardial infarction? Am J Cardiol . 1987; 59:984-9.
74. Jaffe AS, Sobel BE. Thrombolysis with tissue-type plasminogen activator in acute myocardial infarction: potentials and pitfalls. JAMA . 1986; 255:237-9. [PubMed 3079842]
75. Simoons ML, Arnold AER, Betriu A et al. Thrombolysis with tissue plasminogen activator in acute myocardial infarction: no additional benefit from immediate percutaneous coronary angioplasty. Lancet . 1988; 1:197-203. [PubMed 2893037]
77. Schaer DH, Ross AM, Wasserman AG. Reinfarction, recurrent angina, and reocclusion after thrombolytic therapy. Circulation . 1987; 76(Suppl II):II-57-62.
78. Grines CL, Topol EJ, Bates ER et al. Infarct vessel status after IV tissue plasminogen activator and acute coronary angioplasty: prediction of clinical outcome. Am Heart J . 1988; 115:1-7. [PubMed 2962478]
79. Serruys PW, Arnold AER, Brower RW et al. Effect of continued rt-PA administration on the residual stenosis after initially successful recanalization in acute myocardial infarction—a quantitative coronary angiography study of a randomized trial. Eur Heart J . 1987; 8:1172-81. [PubMed 3121334]
80. Bates ER, Topol EJ, Kline EM et al. Early reperfusion therapy improves left ventricular function after acute inferior myocardial infarction associated with right coronary artery disease. Am Heart J . 1987; 114:261-7. [PubMed 2955688]
81. Mathey DG, Schofer J, Sheehan FH. Coronary thrombolysis with IV urokinase in patients with acute myocardial infarction. Am J Med . 1987; 83(Suppl 2A):26-30. [PubMed 3631114]
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. [PubMed 3113222]
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. [PubMed 3097099]
86. Goldhaber SZ, Vaughan DE, Markis JE et al. Acute pulmonary embolism treated with tissue plasminogen activator. Lancet . 1986; 2:886-9. [PubMed 2876327]
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. [PubMed 3114885]
88. Graor R. Fibrinolytic therapy for deep vein thrombosis and pulmonary embolism. Cardiovasc Intervention Radiol . 1988; 11:S33-7.
89. Bounameaux H, Vermylen J, Collen D. Thrombolytic treatment with recombinant tissue-type plasminogen activator in a patient with massive pulmonary embolism. Ann Intern Med . 1985; 103:64-5. [PubMed 4039905]
90. Verstraete M, Miller GAH, Bounameaux H et al. Intravenous and intrapulmonary recombinant tissue-type plasminogen activator in the treatment of acute massive pulmonary embolism. Circulation . 1988; 77:353-60. [PubMed 3123091]
91. Goldhaber SZ, Kessler CM, Heit J et al. Randomised controlled trial of recombinant tissue plasminogen activator versus urokinase in the treatment of acute pulmonary embolism. Lancet . 1988; 2:293-8. [PubMed 2899718]
92. Come PC, Kim D, Parker JA et al. Early reversal of right ventricular dysfunction in patients with acute pulmonary embolism after treatment with IV tissue plasminogen activator. J Am Coll Cardiol . 1987; 10:971-8. [PubMed 2959713]
93. Goldhaber SZ, Meyerovitz MF, Markis JE et al. Thrombolytic therapy of acute pulmonary embolism: current status and future potential. J Am Coll Cardiol . 1987; 10(Suppl):96B-104. [PubMed 3117862]
94. Graor RA, Risius B, Young JR et al. Peripheral artery and bypass graft thrombolysis with recombinant human tissue-type plasminogen activator. J Vasc Surg . 1986; 3:115-24. [PubMed 3079838]
95. Graor RA, Risius B, Lucas FV et al. Thrombolysis with recombinant human tissue-type plasminogen activator in patients with peripheral artery and bypass graft occlusions. Circulation . 1986; 74(Suppl I):1-15. [PubMed 3011308]
96. Risius B, Graor RA, Geisinger MA et al. Recombinant human tissue-type plasminogen activator for thrombolysis in peripheral arteries and bypass grafts. Radiology . 1986; 160:183-8. [PubMed 3086930]
97. Risius B, Graor RA, Geisinger MA et al. Thrombolytic therapy with recombinant human tissue-type plasminogen activator: a comparison of two doses. Radiology . 1987; 164:465-8. [PubMed 3110860]
98. Towne JB, Bandyk DF. Application of thrombolytic therapy in vascular occlusive disease. Am J Surg . 1987; 154:548-59. [PubMed 3118728]
102. Robin P, Gruel Y, Lang M et al. Complete thrombolysis of mesenteric vein occlusion with recombinant tissue-type plasminogen activator. Lancet . 1988; 1:1391. [PubMed 2898060]
103. Henze T, Boeer A, Tebbe U et al. Lysis of basilar artery occlusion with tissue plasminogen activator. Lancet . 1987; 2:1391. [PubMed 2890967]
104. Williams GA, Lambrou FH, Jaffe GA et al. Treatment of postvitrectomy fibrin formation with intraocular tissue plasminogen activator. Arch Ophthalmol . 1988; 106:1055-8. [PubMed 3135790]
117. Garabedian HD, Gold HK, Leinbach RC et al. Dose-dependent thrombolysis, pharmacokinetics and hemostatic effects of recombinant human tissue-type plasminogen activator for coronary thrombosis. Am J Cardiol . 1986; 58:673-9. [PubMed 3094354]
123. Carter BL, Jones ME, Waickman LA. Pathophysiology and treatment of deep-vein thrombosis and pulmonary embolism. Clin Pharm . 1985; 4:279-96. [PubMed 3891200]
124. Handin RI. Inherited thrombotic disorders and antithrombotic therapy. In: Braunwald E, Isselbacher KJ, Petersdorf RG et al., eds. Harrison's principles of internal medicine. 11th ed. New York: McGraw-Hill; 1987:1480-3.
125. Verstraete M, Boogaerts MA. Haematological disorders. In: Speight TM, ed. Avery's drug treatment. Auckland, New Zealand: ADIS Press Limited; 1987:968-9.
127. Seifried E, Tanswell P, Rijken DC et al. Pharmacokinetics of antigen and activity of recombinant tissue-type plasminogen activator after infusion in healthy volunteers. Arzneimittelforschung . 1988; 38:418-22. [PubMed 3132929]
130. Nilsson T, Wallen P, Mellbring G. In vivo metabolism of human tissue-type plasminogen activator. Scand J Haematol . 1984; 33:49-53. [PubMed 6431604]
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.
144. Topol EJ. Advances in thrombolytic therapy for acute myocardial infarction. J Clin Pharmacol . 1987; 27:735-45. [PubMed 3123526]
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]
153. Eisenberg PR, Jaffe AS. Coronary thrombolysis: practical considerations. Cardiol Clin . 1987; 5:129-41. [PubMed 3103918]
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]
166. Markis JE, Malagold M, Parker JA et al. Myocardial salvage after intracoronary thrombolysis with streptokinase in acute myocardial infarction. N Engl J Med . 1981; 305:777-82. [PubMed 7266630]
167. Wei JY, Markis JE, Malagold M et al. Time course of serum cardiac enzymes after intracoronary thrombolytic therapy. Arch Intern Med . 1985; 145:1596-1600. [PubMed 4026489]
170. Gold HK, Leinbach RC. Prevention of acute reocclusion after thrombolysis with IV recombinant tissue plasminogen activator. In: Sobel BE, Collen D, Grossbard EB, eds. Tissue plasminogen activator in thrombolytic therapy. New York: Marcel Dekker, Inc; 1987:115-30.
177. Kaplan K, Davison R, Parker M et al. Role of heparin after IV thrombolytic therapy for acute myocardial infarction. Am J Cardiol . 1987;59:241-4. [PubMed 3812272]
181. Sasahara AA, Henkin J, Janicki RS. Urokinase versus tissue plasminogen activator in pulmonary embolism. Lancet . 1988; 2:691. [PubMed 2901554]
182. Gaffney PJ, Thomas DP. Urokinase versus tissue plasminogen activator in pulmonary embolism. Lancet . 1988; 2:692. [PubMed 2901555]
185. Bounameaux H, Stassen JM, Seghers C et al. Influence of fibrin and liver blood flow on the turnover and the systemic fibrinogenolytic effects of recombinant human tissue-type plasminogen activator in rabbits. Blood . 1986; 67:1493-7. [PubMed 3083893]
186. Topol EJ, Califf RM, George BS et al. Coronary arterial thrombolysis with combined infusion of recombinant tissue-type plasminogen activator and urokinase in patients with acute myocardial infarction. Circulation . 1988; 77:1100-7. [PubMed 2966017]
187. Corr PB, Witkowski FX. Arrhythmias associated with reperfusion: basic insights and clinical relevance. J Cardiovasc Pharmacol . 1984; 6(Suppl 6):S903-9. [PubMed 6084147]
188. Johns JA, Gold HK, Leinbach RC et al. Prevention of coronary artery reocclusion and reduction in late coronary artery stenosis after thrombolytic therapy in patients with acute myocardial infarction. Circulation . 1988; 78:546-56. [PubMed 3136953]
189. Collen D, Stump DC, Van de Werf F. Coronary thrombolysis in patients with acute myocardial infarction by IV infusion of synergic thrombolytic agents. Am Heart J . 1986; 112:1083-4. [PubMed 3096127]
190. Collen D, Van de Werf F. Coronary arterial thrombolysis with low-dose synergistic combinations of recombinant tissue-type plasminogen activator (rt-PA) and recombinant single-chain urokinase-type plasminogen activator (rscu-PA) for acute myocardial infarction. Am J Cardiol . 1987; 60:431-4. [PubMed 3115077]
191. Collen D. Synergism of thrombolytic agents: investigational procedures and clinical potential. Circulation . 1988; 77:731-5. [PubMed 3127075]
192. Collen D, Stassen J-M, Stump DC et al. Synergism of thrombolytic agents in vivo. Circulation . 1986; 74:838-42. [PubMed 3093116]
193. Van de Werf F, Arnold AER. IV tissue plasminogen activator and size of infarct, left ventricular function, and survival in acute myocardial infarction. BMJ . 1988; 297:1374-9. [PubMed 3146370]
194. Van de Werf F, European Cooperative Study Group for Recombinant Tissue-Type Plasminogen Activator. Lessons from the European Cooperative recombinant tissue-type plasminogen activator (rt-PA) versus placebo trial. J Am Coll Cardiol . 1988; 12:14A-9. [PubMed 3142943]
195. Marder VJ, Sherry S. Thrombolytic therapy. N Engl J Med . 1988; 319:1546-7.
196. Cranston RE, Wolfson MA, Buchsbaum HW et al. Plasminogen activator and cerebral infarction. Ann Intern Med . 1988; 108:766. [PubMed 3128954]
198. Suddes KP, Thomas RD. Mediastinal haemorrhage: a complication of thrombolytic treatment. BMJ . 1988; 297:527. [PubMed 3139187]
199. Asbury WH. Guidelines for preparing and administering tissue plasminogen activator. Am J Hosp Pharm . 1988; 45:2383-5. [PubMed 3228099]
204. Schmidt WG, Uebis R, von Essen R et al. Residual coronary stenosis after thrombolysis with rt-PA or streptokinase: acute results and 3 weeks follow-up. Eur Heart J . 1987; 8:1182-8. [PubMed 3121335]
205. Hugenholtz PG. Acute coronary artery obstruction in myocardial infarction: overview of thrombolytic therapy. J Am Coll Cardiol . 1987; 9:1375-84. [PubMed 3108346]
208. Topol EJ, O'Neill WW, Langburd AB et al. A randomized, placebo-controlled trial of intravenous recombinant tissue-type plasminogen activator and emergency coronary angioplasty in patients with acute myocardial infarction. Circulation . 1987; 75:420-8. [PubMed 2948735]
210. Agnelli G, Hirsh J. Optimal dosage regimens of tissue-type plasminogen activator. Semin Thromb Hemost . 1987; 13:160-2. [PubMed 3114884]
211. Koppensteiner R, Minar E, Ahmadi R et al. Low doses of recombinant human tissue-type plasminogen activator for local thrombolysis in peripheral arteries. Radiology . 1988; 168:877-8. [PubMed 3136513]
213. Anon. Guidelines for coronary angiography. A report of the American College of Cardiology/American Heart Association Task Force on Assessment of Diagnostic and Therapeutic Cardiovascular Procedures (Subcommittee on Coronary Angiography). Circulation . 1987; 76:963A-77. [PubMed 3308168]
216. Tiefenbrunn AJ, Robison AK, Kurnik PB et al. Clinical pharmacology in patients with evolving myocardial infarction of tissue-type plasminogen activator produced by recombinant DNA technology. Circulation . 1985; 71:110-6. [PubMed 4038368]
220. DeWood MA, Spores J, Notske R et al. Prevalence of total coronary occlusion during the early hours of transmural myocardial infarction. N Engl J Med . 1980; 303:897-902. [PubMed 7412821]
221. Genentech. South San Francisco, CA: Personal communication.
222. Written communication (reviewers' comments). 1988 Dec.
225. Topol EJ, Califf RM, Kereiakes DJ et al. Thrombolysis and Angioplasty in Myocardial Infarction (TAMI) Trial. J Am Coll Cardiol . 1987; 10:65-74B.
226. Dalen JE, Gore JM, Braunwald E et al. Six- and twelve-month follow-up of the Phase I Thrombolysis in Myocardial Infarction (TIMI) Trial. Am J Cardiol . 1988; 62:179-85. [PubMed 3135737]
227. De Feyter PJ, van Eenige MJ, van der Wall EE et al. Effects of spontaneous and streptokinase-induced recanalization on left ventricular function after myocardial infarction. Circulation . 1983; 67:1039-44. [PubMed 6831668]
241. Kennedy JW, Ritchie JL, Davis KB et al. The Western Washington randomized trial of intracoronary streptokinase in acute myocardial infarction. N Engl J Med . 1985; 312:1073-8. [PubMed 3982468]
242. Sheehan FH. Determinants of improved left ventricular function after thrombolytic therapy in acute myocardial infarction. J Am Coll Cardiol . 1987; 9:937-44. [PubMed 2951424]
244. TIMI Operations Committee: Braunwald E, Knatterud GL, Passamani et al. Update from the Thrombolysis in Myocardial Infarction Trial. J Am Coll Cardiol . 1987; 10:970. [PubMed 3309009]
246. Califf RM, Topol EJ, George BS et al. Hemorrhagic complications associated with the use of intravenous tissue plasminogen activator in treatment of acute myocardial infarction. Am J Med . 1988; 85:353-9. [PubMed 3137818]
249. Mathey DG, Sheehan FH, Schofer J et al. Time from onset of symptoms to thrombolytic therapy: a major determinant of myocardial salvage in patients with acute transmural infarction. J Am Coll Cardiol . 1985; 6:518-25. [PubMed 4031265]
250. Rackley CE, Satler LF. Factors influencing myocardial preservation after recombinant tissue plasminogen activator (rt-PA) in acute myocardial infarction. J Am Coll Cardiol . 1987; 10:1178-9. [PubMed 3119686]
251. Bergmann SR, Lerch RA, Fox KAA et al. Temporal dependence of beneficial effects of coronary thrombolysis characterized by positron tomography. Am J Med . 1982; 73:573-81. [PubMed 6981998]
266. Rapaport E. Thrombolytic agents in acute myocardial infarction. N Engl J Med . 1989; 320:861-4. [PubMed 2494455]
267. Bhardwaj M, Goldweit R, Erlebacher J et al. Tissue plasminogen activator and cholesterol crystal embolization. Ann Intern Med . 1989; 111:687-8. [PubMed 2508531]
268. Pyles LA, Pierpont ME, Steiner ME et al. Fibrinolysis by tissue plasminogen activator in a child with pulmonary embolism. J Pediatr . 1990; 116:801-4. [PubMed 2109794]
269. Gore JM, Thompson MJ, Becker RC. Rapid resolution of acute cor pulmonale with recombinant tissue plasminogen activator. Chest . 1989; 96:939-41. [PubMed 2507233]
270. Levine MN, Weitz J, Turpie AG et al. A new short infusion dosage regimen of recombinant tissue plasminogen activator in patients with venous thromboembolic disease. Chest . 1990; 97(Suppl):168-71S.
271. Goldhaber SZ. Thrombolysis in venous thromboembolism: An international perspective. Chest . 1990; 97(Suppl):176-81S.
272. Levine M, Hirsh J, Weitz J et al. A randomized trial of a single bolus dosage regimen of recombinant tissue plasminogen activator in patients with acute pulmonary embolism. Chest . 1990; 98:1473-9. [PubMed 2123152]
273. Goldhaber SZ. Tissue plasminogen activator in acute pulmonary embolism. Chest . 1989; 95(Suppl 5):282-9S.
274. Baudo F, Caimi TM, Redaelli R et al. Emergency treatment with recombinant tissue plasminogen activator of pulmonary embolism in a pregnant woman with antithrombin III deficiency. Am J Obstet Gynecol . 1990; 163(4 Part 1):1274-5. [PubMed 2121034]
275. Intenzo CM, Park CH, Kim SM. Rapid resolution of pulmonary embolism by tissue plasminogen activator. Clin Nucl Med . 1989; 14:801-2. [PubMed 2513157]
276. Anon. Tissue plasminogen activator for the treatment of acute pulmonary embolism: a collaborative study by the PIOPED investigators. Chest . 1990; 97:528-33. [PubMed 2106408]
278. The International Study Group. In-hospital mortality and clinical course of 20891 patients with suspected acute myocardial infarction randomised between alteplase and streptokinase with or without heparin. Lancet . 1990; 336:71-5. [PubMed 1975322]
279. Gruppo Italiano per lo Studio della Sopravvivenza nell' Infarto Miocardico. GISSI-2: a factorial randomised trial of alteplase versus streptokinase and heparin versus no heparin among 12490 patients with acute myocardial infarction. Lancet . 1990; 336:65-71. [PubMed 1975321]
284. AIMS Trial Study Group. Effect of Intravenous APSAC on mortality after acute myocardial infarction: preliminary report of a placebo-controlled clinical trial. Lancet . 1988; 1:545-9. [PubMed 2894490]
285. AIMS Trial Study Group. Long-term effects of intravenous anistreplase in acute myocardial infarction: final report of the AIMS study. Lancet . 1990; 335:427-31. [PubMed 1968167]
286. Anderson BJ, Keeley SR, Johnson ND. Caval thrombolysis in neonates using low doses of recombinant human tissue-type plasminogen activator. Anaesth Intensive Care . 1991; 19:22-7. [PubMed 1901463]
287. Levy M, Benson LN, Burrows PE et al. Tissue plasminogen activator for the treatment of thromboembolism in infants and children. J Pediatr . 1991; 118:467-72. [PubMed 1900334]
288. Kennedy LA, Drummond WH, Knight ME et al. Successful treatment of neonatal aortic thrombosis with tissue plasminogen activator. J Pediatr . 1990; 116:798-801. [PubMed 2109793]
290. Flossdorf T, Breulmann M, Hopf HB. Successful treatment of massive pulmonary embolism with recombinant tissue type plasminogen activator (rt-PA) in a pregnant woman with intact gravidity and preterm labour. Intensive Care Med . 1990; 16:454-6. [PubMed 2125304]
299. The GUSTO Angiographic Investigators. The effects of tissue plasminogen activator, streptokinase, or both on coronary-artery patency, ventricular function, and survival after acute myocardial infarction. N Engl J Med . 1993; 329:1615-1622. [PubMed 8232430]
302. The GUSTO Investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med . 1993; 329:673-82. [PubMed 8204123]
303. Braunwald E. The open-artery theory is alive and well—again. N Engl J Med . 1993; 329:1650-2. [PubMed 8232436]
304. Bassand JP. GUSTO (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries): logic wins at last. Eur Heart J . 1994; 15:2-4. [PubMed 8174579]
305. Chesebro JH, Knatterud G, Roberts R et al. Thombolysis in Myocardial Infarction (TIMI) Trial, Phase I: a comparison between intravenous tissue plasminogen activator and intravenous streptokinase: clinical findings through hospital discharge. Circulation . 1987; 76:142-54. [PubMed 3109764]
306. Verstraete M, Bernard R, Bory M et al. Randomized trial of intravenous recombinant tissue-type plasminogen activator versus intravenous streptokinase in acute myocardial infarction: report from the European Cooperative Study Group for Recombinant Tissue-type Plasminogen Activator. Lancet . 1985; 1:842-7. [PubMed 2858711]
307. Ridker PM, Marder VJ, Hennekens CH. Large-scale trials of thrombolytic therapy for acute myocardial infarction: GISSI-2 ISIS-3, and GUSTO-1. Ann Intern Med . 1993; 119:530-2. [PubMed 8357123]
308. Hennekens CH. Thrombolytic therapy: pre- and post-GISSI-2, ISIS-3, and GUSTO-1. Clin Cardiol . 1994; 17(Suppl I):I15-7. [PubMed 8156657]
311. Ryan TJ, Antman EM, Brooks NH et al. ACC/AHA guidelines for the management of patients with acute myocardial infarction: 1999 update: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction). Circulation . 1999; 100:1016-30. [PubMed 10468535][Web]
312. Hoffmeister HM, Kastner C, Szabo S et al. Fibrin specificity and procoagulant effect related to the kallikrein-contact phase system and to plasmin generation with double-bolus reteplase and front-loaded alteplase thrombolysis in acute myocardial infarction. Am J Cardiol . 2000; 86:263-8. [PubMed 10922430]
313. Granger CB, Becker R, Tracy RP et al. Thrombin generation, inhibition and clinical outcomes in patients with acute myocardial infarction treated with thrombolytic therapy and heparin: results of the GUSTO-I trial. J Am Coll Cardiol . 1998; 31:497-505. [PubMed 9502626]
316. Barbagelata NA, Granger CB, Oqueli E et al. TIMI grade 3 flow and reocclusion after intravenous thrombolytic therapy: a pooled analysis. Am Heart J . 1997; 133:273-82. [PubMed 9060794]
317. Park SJ. Comparison of double bolus urokinase versus front-loaded alteplase regimen for acute myocardial infarction. Am J Cardiol . 1998; 82:811-3. [PubMed 9761098]
321. White HD. Future of reperfusion therapy for acute myocardial infarction. Lancet . 1999; 354:695-7. [PubMed 10475175]
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.
325. Genentech, Inc. Activase® Cathflo® (alteplase, recombinant) prescribing information. South San Francisco, CA; 2019 Feb.
335. Emergency Cardiac Care Guidelines. Part 7: The era of reperfusion : Section 1: Acute coronary syndromes (acute myocardial infarction). Circulation . 2000; 102:I172-I203.
336. Lamas GA, Flaker GC, Mitchell G et al. Survival and Ventricular Enlargement Investigators. Effect of infarct artery patency on prognosis after acute myocardial infarction. Circulation . 1995; 92:1101–9.
337. Kim CB, Braunwald E. Potential benefits of late reperfusion of infarcted myocardium: the open artery hypothesis. Circulation . 1993; 88:2426–36.
338. Wilcox RG. Clinical trials in thrombolytic therapy: what do they tell us? INJECT 6-month outcomes data. Am J Cardiol . 1996; 78:20-3. [PubMed 8990407]
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. [PubMed 7963104]
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. [PubMed 9340503]
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. [PubMed 7758177]
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. [PubMed 8790022]
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. [PubMed 11023929]
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. [PubMed 7623530]
347. White HD, Van de Werf FJJ. Thrombolysis for acute myocardial infarction. Circulation . 1998; 97:1632-46. [PubMed 9593569]
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. [PubMed 10073847]
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. [PubMed 7895348]
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. [PubMed 12166043]
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. [PubMed 10873875]
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. [PubMed 12677087]
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. [PubMed 15800252]
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. [PubMed 26472998]
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. [PubMed 15262836]
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. [PubMed 1555162]
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. [PubMed 10378570]
376. Riedel M. Venous thromboembolic disease. Acute pulmonary embolism 2: treatment. Heart . 2001; 85:351-60. [PubMed 11179282]
377. Dalen JE. Pulmonary embolism: what have we learned since Virchow? Treatment and Prevention. Chest . 2002; 122:1801-17. [PubMed 12426286]
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. [PubMed 17258667]
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. [PubMed 10703776]
380. Hill MD, Buchan AM. Thrombolysis for acute ischemic stroke: results of the Canadian Alteplase for Stroke Effectiveness Study. CMAJ . 2005; 172:1307-12. [PubMed 15883405]
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. [PubMed 15016487]
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. [PubMed 18790527]
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.
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. [PubMed 18815396]
388. Lyden P. Thrombolytic therapy for acute stroke — not a moment to lose. N Engl J Med . 2008; 359:1393-5. Editorial. [PubMed 18815401]
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. [PubMed 20472172]
390. Saver JL, Levine SR. Alteplase for ischaemic stroke—much sooner is much better. Lancet . 2010; 375:1667-8. Commentary. [PubMed 20472152]
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. [PubMed 17431204]
392. Baldwin K, Orr S, Briand M et al. Acute ischemic stroke update. Pharmacotherapy . 2010; 30(5):493-514. [PubMed 20412000]
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. [PubMed 19478221]
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. [PubMed 7477192]
396. Lyden PD. Extending the time window for thrombolytic therapy—primum non tardare. Lancet Neurol . 2009; 8:1074-5. Editorial. [PubMed 19850526]
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. [PubMed 19850525]
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. [PubMed 15016487]
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.
401. Reconstituting Guidelines for Activaste® (alteplase). Available at [Web] Accessed 2024 Feb 5.
402. ASHP. Standardize 4 Safety: pediatric continuous infusion standard. Updated 2024 Mar. From ASHP website. Updates may be available at ASHP website. [Web]
403. ASHP. Standardize 4 Safety: adult continuous infusion standard. Updated 2024 Mar. From ASHP website. Updates may be available at ASHP website. [Web]
404. Zuo Z, Yue J, Dong BR et al. Thrombolytic therapy for pulmonary embolism. Cochrane Database Syst Rev. 2021; 4:CD004437.
405. Thomalla G, Simonsen CZ, Boutitie F et al. MRI-Guided thrombolysis for stroke with unknown time of onset. N Engl J Med. 2018; 379:611-22.
406. Ma H, Campbell BCV, Parsons MW, Churilov L et al. Thrombolysis guided by perfusion imaging up to 9 hours after onset of stroke. N Engl J Med. 2019; 380:1795-1803.
407. Thomalla G, Boutitie F, Ma H et al. Intravenous alteplase for stroke with unknown time of onset guided by advanced imaging: systematic review and meta-analysis of individual patient data. Lancet. 2020; 396:1574-84.
408. Institute for Safe Medication Practices (ISMP). ISMP list of high-alert medications in acute care settings. ISMP; 2024.
409. Campbell BCV, Mitchell PJ, Churilov L et al. Tenecteplase versus alteplase before thrombectomy for ischemic stroke. N Engl J Med. 2018; 378:1573-82.
410. Kvistad CE, Næss H, Helleberg BH et al. Tenecteplase versus alteplase for the management of acute ischaemic stroke in Norway (NOR-TEST 2, part A): a phase 3, randomised, open-label, blinded endpoint, non-inferiority trial. Lancet Neurol. 2022; 21:511-19.
411. Huang J, Zheng H, Zhu X, Zhang K, Ping X. Tenecteplase versus alteplase for the treatment of acute ischemic stroke: a meta-analysis of randomized controlled trials. Ann Med. 2024; 56:2320285.
412. Alamowitch S, Turc G, Palaiodimou L et al. European Stroke Organisation (ESO) expedited recommendation on tenecteplase for acute ischaemic stroke. Eur Stroke J. 2023; 8:8-54.
413. Armstrong PW, Gershlick AH, Goldstein P et al. Fibrinolysis or primary PCI in ST-segment elevation myocardial infarction. N Engl J Med. 2013; 368:1379-87.
414. Bhatt DL, Lopes RD, Harrington RA. Diagnosis and treatment of acute coronary syndromes: a review. JAMA. 2022; 327:662-75.
415. Szummer K, Jernberg T, Wallentin L. From early pharmacology to recent pharmacology interventions in acute coronary syndromes: JACC state-of-the-art review. J Am Coll Cardiol. 2019; 74:1618-36.
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.
803. Lamas GA, Escolar E, Faxon DP. Examining treatment of ST-elevation myocardial infarction: the importance of early intervention. J Cardiovasc Pharmacol Ther . 2010; 15:6-16. [PubMed 20061507]
805. Reed GW, Rossi JE, Cannon CP. Acute myocardial infarction. Lancet . 2017; 389:197-210. [PubMed 27502078]
807. Smith JN, Negrelli JM, Manek MB et al. Diagnosis and management of acute coronary syndrome: an evidence-based update. J Am Board Fam Med . 2015 Mar-Apr; 28:283-93.
808. Anderson JL, Morrow DA. Acute Myocardial Infarction. N Engl J Med . 2017; 376:2053-2064. [PubMed 28538121]
994. Levine GN, Bates ER, Blankenship JC et al. 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. J Am Coll Cardiol . 2011; 58:e44-122. [PubMed 22070834]
1005. Kearon C, Akl EA, Comerota AJ et al. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest . 2012; 141(2 Suppl):e419S-94S. [PubMed 22315268]
1009. Lansberg MG, O'Donnell MJ, Khatri P et al. Antithrombotic and thrombolytic therapy for ischemic stroke: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest . 2012; 141(2 Suppl):e601S-36S. [PubMed 22315273]
1011. Alonso-Coello P, Bellmunt S, McGorrian C et al. Antithrombotic therapy in peripheral artery disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest . 2012; 141(2 Suppl):e669S-90S. [PubMed 22315275]
1013. Monagle P, Chan AK, Goldenberg NA et al. Antithrombotic therapy in neonates and children: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest . 2012; 141(2 Suppl):e737S-801S. [PubMed 22315277]
1100. Amsterdam EA, Wenger NK, Brindis RG et al. 2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation . 2014; 130:e344-426.
1101. Powers WJ, Rabinstein AA, Ackerson T et al. Guidelines for the early management of patients with acute ischemic stroke: 2019 update to the 2018 guidelines for the early management of acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2019; 50:e344-e418.
1102. Stevens SM, Woller SC, Kreuziger LB et al. Antithrombotic therapy for VTE disease: second update of the CHEST guideline and expert panel report. Chest. 2021; 160:e545-e608.
1103. Byrne RA, Rossello X, Coughlan JJ et al. 2023 ESC guidelines for the management of acute coronary syndromes. Eur Heart J. 2023; 44:3720-3826.
1104. Institute for Safe Medication Practices. ISMP list of error-prone abbreviations, symbols, and dose designations. 2024.