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Activase (Alteplase) - Description and Clinical Pharmacology



Activase® (Alteplase) is a tissue plasminogen activator produced by recombinant DNA technology. It is a sterile, purified glycoprotein of 527 amino acids. It is synthesized using the complementary DNA (cDNA) for natural human tissue-type plasminogen activator obtained from a human melanoma cell line. The manufacturing process involves the secretion of the enzyme alteplase into the culture medium by an established mammalian cell line (Chinese Hamster Ovary cells) into which the cDNA for alteplase has been genetically inserted. Fermentation is carried out in a nutrient medium containing the antibiotic gentamicin, 100 mg/L. However, the presence of the antibiotic is not detectable in the final product.

Phosphoric acid and/or sodium hydroxide may be used prior to lyophilization for pH adjustment.

Activase is a sterile, white to off-white, lyophilized powder for intravenous administration after reconstitution with Sterile Water for Injection, USP.

Quantitative Composition of the Lyophilized Product
100 mg Vial 50 mg Vial
Alteplase 100 mg (58 million IU) 50 mg (29 million IU)
L-Arginine 3.5 g 1.7 g
Phosphoric Acid 1 g 0.5 g
Polysorbate 80 ≤11 mg ≤4 mg
Vacuum No Yes

Biological potency is determined by an in vitro clot lysis assay and is expressed in International Units as tested against the WHO standard. The specific activity of Activase is 580,000 IU/mg.


Activase is an enzyme (serine protease) which has the property of fibrin-enhanced conversion of plasminogen to plasmin. It produces limited conversion of plasminogen in the absence of fibrin. When introduced into the systemic circulation at pharmacologic concentration, Activase binds to fibrin in a thrombus and converts the entrapped plasminogen to plasmin. This initiates local fibrinolysis with limited systemic proteolysis. Following administration of 100 mg Activase, there is a decrease (16%–36%) in circulating fibrinogen.1,2 In a controlled trial, 8 of 73 patients (11%) receiving Activase (1.25 mg/kg body weight over 3 hours) experienced a decrease in fibrinogen to below 100 mg/dL.2

The clearance of Alteplase in AMI patients has shown that it is rapidly cleared from the plasma with an initial half-life of less than 5 minutes. There is no difference in the dominant initial plasma half-life between the 3‑Hour and accelerated regimens for AMI. The plasma clearance of Alteplase is 380–570 mL/min.3,4 The clearance is mediated primarily by the liver. The initial volume of distribution approximates plasma volume.

Acute Myocardial Infarction (AMI) Patients

Coronary occlusion due to a thrombus is present in the infarct-related coronary artery in approximately 80% of patients experiencing a transmural myocardial infarction evaluated within 4 hours of onset of symptoms.5,6

Two Activase dose regimens have been studied in patients experiencing acute myocardial infarction. (Please see DOSAGE AND ADMINISTRATION.) The comparative efficacy of these two regimens has not been evaluated.

Accelerated Infusion in AMI Patients

Accelerated infusion of Activase was studied in an international, multi-center trial (GUSTO) that randomized 41,021 patients with acute myocardial infarction to four thrombolytic regimens. Entry criteria included onset of chest pain within 6 hours of treatment and ST-segment elevation of ECG. The regimens included accelerated infusion of Activase (≤ 100 mg over 90 minutes, see DOSAGE AND ADMINISTRATION) plus intravenous (IV) heparin (accelerated infusion of Alteplase, n=10,396), or the Kabikinase brand of Streptokinase (1.5 million units over 60 minutes) plus IV heparin (SK [IV], n=10,410), or Streptokinase (as above) plus subcutaneous (SQ) heparin (SK [SQ], n=9841). A fourth regimen combined Alteplase and Streptokinase. Aspirin and heparin use was directed by the GUSTO study protocol as follows: All patients were to receive 160 mg chewable aspirin administered as soon as possible, followed by 160–325 mg daily. IV heparin was directed to be a 5000 U IV bolus initiated as soon as possible, followed by a 1000 U/hour continuous IV infusion for at least 48 hours; subsequent heparin therapy was at the discretion of the attending physician. SQ heparin was directed to be 12,500 U administered 4 hours after initiation of SK therapy, followed by 12,500 U twice daily for 7 days or until discharge, whichever came first. Many of the patients randomized to receive SQ heparin received some IV heparin, usually in response to recurrent chest pain and/or the need for a medical procedure. Some received IV heparin on arrival to the emergency room prior to enrollment and randomization.

Results for the primary endpoint of the study, 30‑day mortality, are shown in Table 1. The incidence of 30‑day mortality for accelerated infusion of Alteplase was 1.0% lower than for SK (IV) and 1.0% lower than for SK (SQ). The secondary endpoints of combined 30‑day mortality or nonfatal stroke, and 24‑hour mortality, as well as the safety endpoints of total stroke and intracerebral hemorrhage are also shown in Table 1. The incidence of combined 30‑day mortality or nonfatal stroke for the Alteplase accelerated infusion was 1.0% lower than for SK (IV) and 0.8% lower than for SK (SQ).

Table 1
Event Accelerated
SK (IV) p-Value 1 SK (SQ) p-Value
30-Day Mortality 6.3% 7.3% 0.003 7.3% 0.007
30-Day Mortality
or Nonfatal Stroke
7.2% 8.2% 0.006 8.0% 0.036
24-Hour Mortality 2.4% 2.9% 0.009 2.8% 0.029
Any Stroke 1.6% 1.4% 0.32 1.2% 0.03
0.7% 0.6% 0.22 0.5% 0.02

1 Two-tailed p-value is for comparison of Accelerated Activase to the respective SK control arm.

Subgroup analysis of patients by age, infarct location, time from symptom onset to thrombolytic treatment, and treatment in the U.S. or elsewhere showed consistently lower 30‑day mortality for the Alteplase accelerated infusion group. For patients who were over 75 years of age, a predefined subgroup consisting of 12% of patients enrolled, the incidence of stroke was 4.0% for the Alteplase accelerated infusion group, 2.8% for SK (IV), and 3.2% for SK (SQ); the incidence of combined 30‑day mortality or nonfatal stroke was 20.6% for accelerated infusion of Alteplase, 21.5% for SK (IV), and 22.0% for SK (SQ).

An angiographic substudy of the GUSTO trial provided data on infarct-related artery patency. Table 2 presents 90‑minute, 180‑minute, 24‑hour, and 5–7 day patency values by TIMI flow grade for the three treatment regimens. Reocclusion rates were similar for all three treatment regimens.

Table 2
(TIMI 2 or 3)
SK (IV) p-Value SK (SQ) p-Value
90-Minute n=272 n=261   n=260  
  81.3% 59.0% < 0.0001 53.5% < 0.0001
180-Minute n=80 n=76   n=95  
  76.3% 72.4% 0.58 71.6% 0.48
24-Hour n=81 n=72   n=67  
  88.9% 87.5% 0.24 82.1% 0.79
5–7 Day n=72 n=77   n=75  
  83.3% 90.9% 0.47 78.7% 0.17

The exact relationship between coronary artery patency and clinical activity has not been established.

The safety and efficacy of the accelerated infusion of Alteplase have not been evaluated using antithrombotic or antiplatelet regimens other than those used in the GUSTO trial.

-Hour Infusion in AMI Patients

In patients studied in a controlled trial with coronary angiography at 90 and 120 minutes following infusion of Activase, infarct artery patency was observed in 71% and 85% of patients (n=85), respectively.2 In a second study, where patients received coronary angiography prior to and following infusion of Activase within 6 hours of the onset of symptoms, reperfusion of the obstructed vessel occurred within 90 minutes after the commencement of therapy in 71% of 83 patients.1

The exact relationship between coronary artery patency and clinical activity has not been established.

In a double-blind, randomized trial (138 patients) comparing Activase to placebo, patients infused with Activase within 4 hours of onset of symptoms experienced improved left ventricular function at Day 10 compared to the placebo group, when ejection fraction was measured by gated blood pool scan (53.2% vs 46.4%, p=0.018). Relative to baseline (Day 1) values, the net changes in ejection fraction were +3.6% and -4.7% for the treated and placebo groups, respectively (p=0.0001). Also documented was a reduced incidence of clinical congestive heart failure in the treated group (14%) compared to the placebo group (33%) (p=0.009).7

In a double-blind, randomized trial (145 patients) comparing Activase to placebo, patients infused with Activase within 2.5 hours of onset of symptoms experienced improved left ventricular function at a mean of 21 days compared to the placebo group, when ejection fraction was measured by gated blood pool scan (52% vs 48%, p=0.08) and by contrast ventriculogram (61% vs 54%, p=0.006). Although the contribution of Activase alone is unclear, the incidence of nonischemic cardiac complications when taken as a group (i.e., congestive heart failure, pericarditis, atrial fibrillation, and conduction disturbance) was reduced when compared to those patients treated with placebo (p < 0.01).8

In a double-blind, randomized trial (5013 patients) comparing Activase to placebo (ASSET study), patients infused with Activase within 5 hours of the onset of symptoms of acute myocardial infarction experienced improved 30‑day survival compared to those treated with placebo. At 1 month, the overall mortality rates were 7.2% for the Activase-treated group and 9.8% for the placebo-treated group (p=0.001).9,10 This benefit was maintained at 6 months for Activase-treated patients (10.4%) compared to those treated with placebo (13.1%, p=0.008).10

In a double-blind, randomized trial (721 patients) comparing Activase to placebo, patients infused with Activase within 5 hours of the onset of symptoms experienced improved ventricular function 10–22 days after treatment compared to the placebo group, when global ejection fraction was measured by contrast ventriculography (50.7% vs 48.5%, p=0.01). Patients treated with Activase had a 19% reduction in infarct size, as measured by cumulative release of HBD (α‑hydroxybutyrate dehydrogenase) activity compared to placebo-treated patients (p=0.001). Patients treated with Activase had significantly fewer episodes of cardiogenic shock (p=0.02), ventricular fibrillation (p < 0.04) and pericarditis (p=0.01) compared to patients treated with placebo. Mortality at 21 days in Activase‑treated patients was reduced to 3.7% compared to 6.3% in placebo-treated patients (1‑sided p=0.05).11 Although these data do not demonstrate unequivocally a significant reduction in mortality for this study, they do indicate a trend that is supported by the results of the ASSET study.

Acute Ischemic Stroke Patients

Two placebo‑controlled, double-blind trials (The NINDS t-PA Stroke Trial, Part 1 and Part 2) have been conducted in patients with acute ischemic stroke.12 Both studies enrolled patients with measurable neurological deficit who could complete screening and begin study treatment within 3 hours from symptom onset. A cranial computerized tomography (CT) scan was performed prior to treatment to rule out the presence of intracranial hemorrhage (ICH). Patients were also excluded for the presence of conditions related to risks of bleeding (see CONTRAINDICATIONS), for minor neurological deficit, for rapidly improving symptoms prior to initiating study treatment, or for blood glucose of < 50 mg/dL or > 400 mg/dL.

Patients were randomized to receive either 0.9 mg/kg Activase (maximum of 90 mg), or placebo. Activase was administered as a 10% initial bolus over 1 minute followed by continuous intravenous infusion of the remainder over 60 minutes (see DOSAGE AND ADMINISTRATION). In patients without recent use of oral anticoagulants or heparin, study treatment was initiated prior to the availability of coagulation study results. However, the infusion was discontinued if either a pretreatment prothrombin time (PT) > 15 seconds or an elevated activated partial thromboplastin time (aPTT) was identified. Although patients with or without prior aspirin use were enrolled, administration of anticoagulants and antiplatelet agents was prohibited for the first 24 hours following symptom onset.

The initial study (NINDS-Part 1, n=291) evaluated neurological improvement at 24 hours after stroke onset. The primary endpoint, the proportion of patients with a 4 or more point improvement in the National Institutes of Health Stroke Scale (NIHSS) score or complete recovery (NIHSS score = 0), was not significantly different between treatment groups. A secondary analysis suggested improved 3‑month outcome associated with Activase treatment using the following stroke assessment scales: Barthel Index, Modified Rankin Scale, Glasgow Outcome Scale, and the NIHSS.

A second study (NINDS-Part 2, n=333) assessed clinical outcome at 3 months as the primary outcome. A favorable outcome was defined as minimal or no disability using the four stroke assessment scales: Barthel Index (score ≥ 95), Modified Rankin Scale (score ≤ 1), Glasgow Outcome Scale (score = 1), and NIHSS (score ≤ 1). The results comparing Activase- and placebo‑treated patients for the four outcome scales together (Generalized Estimating Equations) and individually are presented in Table 3. In this study, depending upon the scale, the favorable outcome of minimal or no disability occurred in at least 11 per 100 more patients treated with Activase than those receiving placebo. Secondary analyses demonstrated consistent functional and neurological improvement within all four stroke scales as indicated by median scores. These results were highly consistent with the 3‑month outcome treatment effects observed in the Part 1 study.

Table 3 The NINDS t-PA Stroke Trial, Part 2 3-Month Efficacy Outcomes
  Frequency of Favorable Outcome Favorable Outcome is defined as recovery with minimal or no disability.
Analysis Placebo (n=165) Activase (n=168) Absolute Difference (95% CI) Relative
Frequency Value > 1 indicates frequency of recovery in favor of Activase treatment. (95% Cl)
p-Value p-Value for Relative Frequency is from Generalized Estimating Equations with log link.
Estimating Equations
1.34 (1.05, 1.72) 0.02
Barthel Index 37.6% 50.0% 12.4% (3.0, 21.9) 1.33 (1.04, 1.71) 0.02
Modified Rankin Scale 26.1% 38.7% 12.6% (3.7, 21.6) 1.48 (1.08, 2.04) 0.02
Glasgow Outcome
31.5% 44.0% 12.5% (3.3, 21.8) 1.40 (1.05, 1.85) 0.02
NIHSS 20.0% 31.0% 11.0% (2.6, 19.3) 1.55 (1.06, 2.26) 0.02

The incidences of all‑cause 90‑day mortality, ICH, and new ischemic stroke following Activase treatment compared to placebo are presented in Table 4 as a combined safety analysis (n=624) for Parts 1 and 2. These data indicated a significant increase in ICH following Activase treatment, particularly symptomatic ICH within 36 hours. In Activase‑treated patients, there were no increases compared to placebo in the incidences of 90‑day mortality or severe disability.

Table 4 The NINDS t-PA Stroke Trial Safety Outcome
  Part 1 and Part 2 Combined
  Placebo (n=312) Activase (n=312) p-Value Fisher's Exact Test
All-Cause 90-day Mortality 64 (20.5%) 54 (17.3%) 0.36
Total ICH Within trial follow‑up period. Symptomatic ICH was defined as the occurrence of sudden clinical worsening followed by subsequent verification of ICH on CT scan. Asymptomatic ICH was defined as ICH detected on a routine repeat CT scan without preceding clinical worsening. 20 (6.4%) 48 (15.4%) < 0.01
 Symptomatic 4 (1.3%) 25 (8.0%) < 0.01
 Asymptomatic 16 (5.1%) 23 (7.4%) 0.32
Symptomatic ICH within 36 hours 2 (0.6%) 20 (6.4%) < 0.01
New Ischemic Stroke (3-months) 17 (5.4%) 18 (5.8%) 1.00

In a prespecified subgroup analysis in patients receiving aspirin prior to onset of stroke symptoms, there was preserved favorable outcome for Activase‑treated patients.

Exploratory, multivariate analyses of both studies combined (n=624) to investigate potential predictors of ICH and treatment effect modifiers were performed. In Activase‑treated patients presenting with severe neurological deficit (e.g., NIHSS > 22) or of advanced age (e.g., > 77 years of age), the trends toward increased risk for symptomatic ICH within the first 36 hours were more prominent. Similar trends were also seen for total ICH and for all‑cause 90‑day mortality in these patients. When risk was assessed by the combination of death and severe disability in these patients, there was no difference between placebo and Activase groups. Analyses for efficacy suggested a reduced but still favorable clinical outcome for Activase‑treated patients with severe neurological deficit or advanced age at presentation.

Pulmonary Embolism Patients

In a comparative randomized trial (n=45),13 59% of patients (n=22) treated with Activase (100 mg over 2 hours) experienced moderate or marked lysis of pulmonary emboli when assessed by pulmonary angiography 2 hours after treatment initiation. Activase‑treated patients also experienced a significant reduction in pulmonary embolism‑induced pulmonary hypertension within 2 hours of treatment (p=0.003). Pulmonary perfusion at 24 hours, as assessed by radionuclide scan, was significantly improved (p=0.002).

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