activase use in central line clots

DESCRIPTION
Activase (Alteplase) is a tissue plasminogen activator produced by recombinantDNA technology activase use in central line clots. It is a sterile, purified glycoprotein of 527 amino acids activase use in central line clots. Itis synthesized using the complementary DNA (cDNA) for natural human tissue-typeplasminogen activator obtained from a human melanoma cell line activase use in central line clots. The manufacturingprocess involves the secretion of the enzyme alteplase into the culture mediumby an established mammalian cell line (Chinese Hamster Ovary cells) into whichthe cDNA for alteplase has been genetically inserted activase use in central line clots. Fermentation is carriedout in a nutrient medium containing the antibiotic gentamicin, 100 mg/L activase use in central line clots. However,the presence of the antibiotic is not detectable in the final product activase use in central line clots.

Phosphoric acid and/or sodium hydroxide may be used prior to lyophilizationfor pH adjustment activase use in central line clots.

Activase is a sterile, white to off-white, lyophilized powder for intravenousadministration after reconstitution with Sterile Water for Injection, USP activase use in central line clots.

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 expressedin International Units as tested against the WHO standard activase use in central line clots. The specific activityof Activase is 580,000 IU/mg activase use in central line clots.

CLINICAL PHARMACOLOGY
Activase is an enzyme (serine protease) which has the property of fibrin-enhancedconversion of plasminogen to plasmin activase use in central line clots. It produces limited conversion of plasminogenin the absence of fibrin activase use in central line clots. When introduced into the systemic circulation at pharmacologicconcentration, Activase binds to fibrin in a thrombus and converts the entrappedplasminogen to plasmin activase use in central line clots. This initiates local fibrinolysis with limited systemicproteolysis activase use in central line clots. Following administration of 100 mg Activase, there is a decrease(16%-36%) in circulating fibrinogen activase use in central line clots. 1,2 In a controlled trial, 8 of 73 patients(11%) receiving Activase (1.25 mg/kg body weight over 3 hours) experienced adecrease in fibrinogen to below 100 mg/dL activase use in central line clots. 2

The clearance of Alteplase in AMI patients has shown that it is rapidly clearedfrom the plasma with an initial half-life of less than 5 minutes activase use in central line clots. There is nodifference in the dominant initial plasma half-life between the 3-Hour and acceleratedregimens for AMI activase use in central line clots. The plasma clearance of Alteplase is 380-570 mL/min activase use in central line clots. 3,4 Theclearance is mediated primarily by the liver activase use in central line clots. The initial volume of distributionapproximates plasma volume activase use in central line clots.

Acute Myocardial Infarction (AMI) Patients
Coronary occlusion due to a thrombus is present in the infarct-related coronaryartery in approximately 80% of patients experiencing a transmural myocardialinfarction evaluated within 4 hours of onset of symptoms activase use in central line clots. 5,6

Two Activase dose regimens have been studied in patients experiencing acutemyocardial infarction activase use in central line clots. (Please see DOSAGE AND ADMINISTRATION .) The comparativeefficacy of these two regimens has not been evaluated activase use in central line clots.

Accelerated Infusion in AMI Patients
Accelerated infusion of Activase was studied in an international, multi-centertrial (GUSTO) that randomized 41,021 patients with acute myocardial infarctionto four thrombolytic regimens activase use in central line clots. Entry criteria included onset of chest pain within6 hours of treatment and ST-segment elevation of ECG activase use in central line clots. The regimens includedaccelerated infusion of Activase (</= 100 mg over 90 minutes, see DOSAGEAND ADMINISTRATION ) plus intravenous (IV) heparin (accelerated infusion ofAlteplase, n=10,396), or the Kabikinase brand of Streptokinase (1.5 millionunits over 60 minutes) plus IV heparin (SK [IV], n=10,410), or Streptokinase(as above) plus subcutaneous (SQ) heparin (SK [SQ], n=9841) activase use in central line clots. A fourth regimencombined Alteplase and Streptokinase activase use in central line clots. Aspirin and heparin use was directed bythe GUSTO study protocol as follows: All patients were to receive 160 mg chewableaspirin administered as soon as possible, followed by 160-325 mg daily activase use in central line clots. IV heparinwas directed to be a 5000 U IV bolus initiated as soon as possible, followedby a 1000 U/hour continuous IV infusion for at least 48 hours; subsequent heparintherapy was at the discretion of the attending physician activase use in central line clots. SQ heparin was directedto be 12,500 U administered 4 hours after initiation of SK therapy, followedby 12,500 U twice daily for 7 days or until discharge, whichever came first activase use in central line clots. 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 activase use in central line clots. Some received IV heparin on arrival to the emergency room prior to enrollmentand randomization activase use in central line clots.

Results for the primary endpoint of the study, 30-day mortality, are shownin Table 1 activase use in central line clots. The incidence of 30-day mortality for accelerated infusion of Alteplasewas 1.0% lower than for SK (IV) and 1.0% lower than for SK (SQ) activase use in central line clots. The secondaryendpoints of combined 30-day mortality or nonfatal stroke, and 24-hour mortality,as well as the safety endpoints of total stroke and intracerebral hemorrhageare also shown in Table 1 activase use in central line clots. The incidence of combined 30-day mortality or nonfatalstroke for the Alteplase accelerated infusion was 1.0% lower than for SK (IV)and 0.8% lower than for SK (SQ) activase use in central line clots.

Table 1 Event Accelerated
Activase SK (IV) p-Value 1 SK (SQ) p-Value 1
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
Intracerebral
Hemorrhage 0.7% 0.6% 0.22 0.5% 0.02
1 Two-tailed p-value is for comparison of Accelerated Activase to the respectiveSK control arm activase use in central line clots.

Subgroup analysis of patients by age, infarct location, time from symptom onsetto thrombolytic treatment, and treatment in the U.S activase use in central line clots. or elsewhere showed consistentlylower 30-day mortality for the Alteplase accelerated infusion group activase use in central line clots. For patientswho were over 75 years of age, a predefined subgroup consisting of 12% of patientsenrolled, the incidence of stroke was 4.0% for the Alteplase accelerated infusiongroup, 2.8% for SK (IV), and 3.2% for SK (SQ); the incidence of combined 30-daymortality or nonfatal stroke was 20.6% for accelerated infusion of Alteplase,21.5% for SK (IV), and 22.0% for SK (SQ) activase use in central line clots.

The exact relationship between coronary artery patency and clinical activityhas not been established activase use in central line clots.

The safety and efficacy of the accelerated infusion of Alteplase have not beenevaluated using antithrombotic or antiplatelet regimens other than those usedin the GUSTO trial activase use in central line clots.

3-Hour Infusion in AMI Patients
In patients studied in a controlled trial with coronary angiography at 90 and120 minutes following infusion of Activase, infarct artery patency was observedin 71% and 85% of patients (n=85), respectively activase use in central line clots. 2 In a second study, wherepatients received coronary angiography prior to and following infusion of Activasewithin 6 hours of the onset of symptoms, reperfusion of the obstructed vesseloccurred within 90 minutes after the commencement of therapy in 71% of 83 patients activase use in central line clots. 1

The exact relationship between coronary artery patency and clinical activityhas not been established activase use in central line clots.

In a double-blind, randomized trial (138 patients) comparing Activase to placebo,patients infused with Activase within 4 hours of onset of symptoms experiencedimproved 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) activase use in central line clots. Relative to baseline (Day 1) values, the net changes in ejection fractionwere +3.6% and -4.7% for the treated and placebo groups, respectively (p=0.0001) activase use in central line clots. Also documented was a reduced incidence of clinical congestive heart failurein the treated group (14%) compared to the placebo group (33%) (p=0.009) activase use in central line clots. 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 experiencedimproved left ventricular function at a mean of 21 days compared to the placebogroup, when ejection fraction was measured by gated blood pool scan (52% vs48%, p=0.08) and by contrast ventriculogram (61% vs 54%, p=0.006) activase use in central line clots. Althoughthe contribution of Activase alone is unclear, the incidence of nonischemiccardiac complications when taken as a group (i.e., congestive heart failure,pericarditis, atrial fibrillation, and conduction disturbance) was reduced whencompared to those patients treated with placebo (p < 0.01) activase use in central line clots. 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 ofsymptoms of acute myocardial infarction experienced improved 30-day survivalcompared to those treated with placebo activase use in central line clots. At 1 month, the overall mortality rateswere 7.2% for the Activase-treated group and 9.8% for the placebo-treated group(p=0.001) activase use in central line clots. 9,10 This benefit was maintained at 6 months for Activase-treatedpatients (10.4%) compared to those treated with placebo (13.1%, p=0.008) activase use in central line clots. 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 experiencedimproved ventricular function 10-22 days after treatment compared to the placebogroup, when global ejection fraction was measured by contrast ventriculography(50.7% vs 48.5%, p=0.01) activase use in central line clots. Patients treated with Activase had a 19% reductionin infarct size, as measured by cumulative release of HBD ((alpha)-hydroxybutyratedehydrogenase) activity compared to placebo-treated patients (p=0.001) activase use in central line clots. Patientstreated with Activase had significantly fewer episodes of cardiogenic shock(p=0.02), ventricular fibrillation (p < 0.04) and pericarditis (p=0.01) comparedto patients treated with placebo activase use in central line clots. Mortality at 21 days in Activase-treated patientswas reduced to 3.7% compared to 6.3% in placebo-treated patients (1-sided p=0.05) activase use in central line clots. 11 Although these data do not demonstrate unequivocally a significant reductionin mortality for this study, they do indicate a trend that is supported by theresults of the ASSET study activase use in central line clots.

Acute Ischemic Stroke Patients
Two placebo-controlled, double-blind trials (The NINDS t-PA Stroke Trial, Part1 and Part 2) have been conducted in patients with acute ischemic stroke activase use in central line clots. 12Both studies enrolled patients with measurable neurological deficit who couldcomplete screening and begin study treatment within 3 hours from symptom onset activase use in central line clots. A cranial computerized tomography (CT) scan was performed prior to treatmentto rule out the presence of intracranial hemorrhage (ICH) activase use in central line clots. Patients were alsoexcluded for the presence of conditions related to risks of bleeding (see CONTRAINDICATIONS), for minor neurological deficit, for rapidly improving symptoms prior to initiatingstudy treatment, or for blood glucose of < 50 mg/dL or > 400 mg/dL activase use in central line clots.

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

The initial study (NINDS-Part 1, n=291) evaluated neurological improvementat 24 hours after stroke onset activase use in central line clots. The primary endpoint, the proportion of patientswith a 4 or more point improvement in the National Institutes of Health StrokeScale (NIHSS) score or complete recovery (NIHSS score = 0), was not significantlydifferent between treatment groups activase use in central line clots. A secondary analysis suggested improved3-month outcome associated with Activase treatment using the following strokeassessment scales: Barthel Index, Modified Rankin Scale, Glasgow Outcome Scale,and the NIHSS activase use in central line clots.

A second study (NINDS-Part 2, n=333) assessed clinical outcome at 3 monthsas the primary outcome activase use in central line clots. A favorable outcome was defined as minimal or no disabilityusing the four stroke assessment scales: Barthel Index (score >/= 95), ModifiedRankin Scale (score </= 1), Glasgow Outcome Scale (score = 1), and NIHSS(score </= 1) activase use in central line clots. The results comparing Activase- and placebo-treated patientsfor the four outcome scales together (Generalized Estimating Equations) andindividually are presented in Table 3 activase use in central line clots. In this study, depending upon the scale,the favorable outcome of minimal or no disability occurred in at least 11 per100 more patients treated with Activase than those receiving placebo activase use in central line clots. Secondaryanalyses demonstrated consistent functional and neurological improvement withinall four stroke scales as indicated by median scores activase use in central line clots. These results were highlyconsistent with the 3-month outcome treatment effects observed in the Part 1study activase use in central line clots.

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