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Activase® is proven to reduce disability at 90 days in patients treated within 3 hours of symptom onset6

The National Institute of Neurological Disorders and Stroke (NINDS) Trial was a large, randomized, placebo-controlled trial of intravenous Activase versus placebo in patients with acute ischemic stroke (AIS) treated within 3 hours of stroke symptom onset and was carried out in 2 parts.6,14

  • Part 1 (n=291) assessed changes in neurologic deficits 24 hours after the onset of strokea
  • Part 2 (n=333) assessed whether treatment with Activase resulted in sustained clinical benefit at 3 monthsb

aComplete resolution of neurologic deficit or an improvement from baseline NIHSS score of 4 or more were defined as early improvement.6
bScores of 95 or greater on the Barthel index, ≤1 on the NIHSS and the modified Rankin Scale, and 1 on the Glasgow Outcome Scale were considered to indicate a favorable outcome.6

Trial Design Efficacy Safety
Trial Design

NINDS trial design

NINDS trial set up

aAdditional study controls; pretreatment prothrombin time >15 seconds; anticoagulant use or heparin use within the 48 hours preceding the onset of stroke (patients taking aspirin were NOT excluded); elevated activated partial thromboplastin time. Study treatment was initiated prior to the availability of coagulation study results in patients without recent use of oral anticoagulants and/or heparin and was discontinued if the pretreatment prothrombin time (PT) was greater than 15 seconds or the activated partial thromboplastin time (aPTT) was elevated.6 
bPatients were randomized (1:1) to receive either 0.9 mg/kg Activase (maximum of 90 mg) or placebo. A cranial CT scan was performed prior to treatment to rule out the presence of intracranial hemorrhage. Blood pressure was actively controlled (185/110 mm Hg or lower) for 24 hours.6
cActivase- and placebo-treated patient results for the 4 outcome scales were compared together (generalized estimating equations).6

Efficacy

Learn about Activase efficacy

Activase showed statistically significant improvement on all 4 stroke scales used in Part 2 of the NINDS Trial

NINDS Efficacy Results
  • Part 1 of the trial demonstrated no significant difference between the Activase and placebo groups in the primary outcome measure (NIHSS) at 24 hours after treatment.6
  • Patients treated with Activase within 3 hours of symptom onset had reduced disability and were at least 33% more likely to achieve minimal or no disability at 90 days vs placebo-treated patients
  • Global odds ratio for favorable outcome: 1.7 (95% CI, 1.15-2.56, P=0.02)6,b

aRelative increase was calculated based on the numbers shown in the above chart. Relative benefit increase is calculated as relative percentage-1.
bThe primary hypothesis was tested with a global statistic (the Wald test). This global test statistic simultaneously tests for effect in all 4 outcome measures specified in the primary hypothesis (the Barthel Index, NIHSS, modified Rankin Scale, and the Glasgow Outcome Scale). A favorable outcome is defined as recovery with minimal or no disability.14

Safety

Review incidences of symptomatic intracranial hemorrhage (sICH) and mortality in patients who were administered Activase

As illustrated, sICHa occurred more commonly in Activase-treated patients. In addition, 90-day mortality rates were not significantly different between the Activase and placebo groups.

NINDS Safety Results
  • Of the 6.4% of Activase-treated patients who experienced an sICH within 36 hours, 45% (9/20) were fatal and 55% (11/20) were nonfatal.14
  • There was no significant difference in 90-day mortality rates between Activase- and placebo-treated patients.6

 Additional safety information from the NINDS trial

  • Total intracranial hemorrhage rate (all time periods, both symptomatic and asymptomatic) was 15.4% for Activase- and 6.4% for placebo-treated patients (P<0.01)6
  • New ischemic stroke rate (within the first 3 months following study intervention) was 5.8% for Activase- and 5.4% for placebo-treated patients (P=1.00)6

aSymptomatic intracranial hemorrhage within 36 hours was defined as the occurrence of sudden clinical worsening followed by subsequent verification of intracranial hemorrhage on CT scan.6

NEXT: Learn how to reconstitute Activase

DID YOU KNOW?

  • The NINDS Trial showed that Activase given within 3 hours of symptom onset of AIS reduced the incidence of disability among treated patients compared with placebo at 3 months.6
Data

See data from the pivotal trial and real-world, retrospective analysis from the Get With The Guidelines®-Stroke registry.

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IMPORTANT SAFETY INFORMATION & INDICATIONS

Indications

Activase® (alteplase) is indicated for the treatment of acute ischemic stroke. Exclude intracranial hemorrhage as the primary cause of stroke signs and symptoms prior to initiation of treatment. Initiate treatment as soon as possible but within 3 hours after symptom onset.

Activase is indicated for use in acute myocardial infarction (AMI) for the reduction of mortality and reduction of the incidence of heart failure.

Limitation of Use: The risk of stroke may outweigh the benefit produced by thrombolytic therapy in patients whose AMI puts them at low risk for death or heart failure.

Activase is indicated for the lysis of acute massive pulmonary embolism (PE), defined as:

  • Acute pulmonary emboli obstructing blood flow to a lobe or multiple lung segments.
  • Acute pulmonary emboli accompanied by unstable hemodynamics, e.g., failure to maintain blood pressure without supportive measures.

Important Safety Information

Contraindications

Do not administer Activase to treat acute ischemic stroke in the following situations in which the risk of bleeding is greater than the potential benefit: current intracranial hemorrhage (ICH); subarachnoid hemorrhage; active internal bleeding; recent (within 3 months) intracranial or intraspinal surgery or serious head trauma; presence of intracranial conditions that may increase the risk of bleeding (e.g., some neoplasms, arteriovenous malformations, or aneurysms); bleeding diathesis; and current severe uncontrolled hypertension.

Do not administer Activase to treat acute myocardial infarction or pulmonary embolism in the following situations in which the risk of bleeding is greater than the potential benefit: active internal bleeding; history of recent stroke; recent (within 3 months) intracranial or intraspinal surgery or serious head trauma; presence of intracranial conditions that may increase the risk of bleeding; bleeding diathesis; and current severe uncontrolled hypertension.

Warnings and Precautions

Bleeding

Activase can cause significant, sometimes fatal internal or external bleeding, especially at arterial and venous puncture sites. Avoid intramuscular injections and trauma to the patient. Perform venipunctures carefully and only as required. Fatal cases of hemorrhage associated with traumatic intubation in patients administered Activase have been reported. Aspirin and heparin have been administered concomitantly with and following infusion with Activase in the management of acute myocardial infarction and pulmonary embolism. The concomitant administration of heparin and aspirin with and following infusions of Activase for the treatment of acute ischemic stroke during the first 24 hours after symptom onset has not been investigated. Because heparin, aspirin, or Activase may cause bleeding complications, carefully monitor for bleeding, especially at arterial puncture sites. Hemorrhage can occur 1 or more days after administration of Activase, while patients are still receiving anticoagulant therapy. If serious bleeding occurs, terminate the Activase infusion, and treat appropriately.

In the following conditions, the risks of bleeding with Activase are increased and should be weighed against the anticipated benefits: recent major surgery or procedure; cerebrovascular disease; recent intracranial hemorrhage; recent gastrointestinal or genitourinary bleeding; recent trauma; hypertension; acute pericarditis; subacute bacterial endocarditis; hemostatic defects including those secondary to severe hepatic or renal disease; significant hepatic dysfunction; pregnancy; diabetic hemorrhagic retinopathy or other hemorrhagic ophthalmic conditions; septic thrombophlebitis or occluded AV cannula at seriously infected site; advanced age; and patients currently receiving oral anticoagulants, or any other condition in which bleeding constitutes a significant hazard or would be particularly difficult to manage because of its location.

Hypersensitivity

Hypersensitivity, including urticarial / anaphylactic reactions, have been reported after administration of Activase. Rare fatal outcome for hypersensitivity was reported. Angioedema has been observed during and up to 2 hours after Activase infusion in patients treated for acute ischemic stroke and acute myocardial infarction. In many cases, patients received concomitant angiotensin-converting enzyme inhibitors. Monitor patients treated with Activase during and for several hours after infusion for hypersensitivity. If signs of hypersensitivity occur, e.g. anaphylactoid reaction or angioedema develops, discontinue the Activase infusion and promptly institute appropriate therapy (e.g., antihistamines, intravenous corticosteroids, epinephrine).

Thromboembolism

The use of thrombolytics can increase the risk of thrombo-embolic events in patients with high likelihood of left heart thrombus, such as patients with mitral stenosis or atrial fibrillation. Activase has not been shown to treat adequately underlying deep vein thrombosis in patients with PE. Consider the possible risk of re-embolization due to the lysis of underlying deep venous thrombi in this setting.

Cholesterol Embolization

Cholesterol embolism, sometimes fatal, has been reported rarely in patients treated with thrombolytic agents; the true incidence is unknown. It is associated with invasive vascular procedures (e.g., cardiac catheterization, angiography, vascular surgery) and/or anticoagulant therapy.

Coagulation Tests May be Unreliable during Activase Therapy

Coagulation tests and/or measures of fibrinolytic activity may be unreliable during Activase therapy unless specific precautions are taken to prevent in vitro artifacts. When present in blood at pharmacologic concentrations, Activase remains active under in vitro conditions, which can result in degradation of fibrinogen in blood samples removed for analysis.

Adverse Reactions

The most frequent adverse reaction associated with Activase therapy is bleeding.

Please see the full Prescribing Information for additional Important Safety Information and Instructions for Use.

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