What trials have been done on Activase (alteplase)?

From the Guidelines

Activase (Alteplase) Trials

Activase, also known as alteplase, has been extensively studied in the context of acute ischemic stroke treatment. The most notable trials include the NINDS rtPA trial, ECASS I, ECASS II, and ECASS III 1. These trials have demonstrated the efficacy and safety of IV alteplase in improving outcomes for patients with acute ischemic stroke when administered within specific time windows.

Key Findings

• ECASS III specifically evaluated the efficacy of IV alteplase within 3 to 4.5 hours after symptom onset, supporting the value of IV thrombolysis up to 4.5 hours after symptom onset 1.
• NINDS rtPA trial showed that IV alteplase is beneficial for adult patients with disabling stroke symptoms, regardless of age and stroke severity, when administered within 3 hours of stroke onset 1.
• Pooled analysis of multiple trials has confirmed the benefit of IV alteplase in reducing death and disability at 90 days, with a recommended dose of 0.9 mg/kg (maximum dose 90 mg) over 60 minutes, with an initial 10% of the dose given as a bolus over 1 minute 1.

Eligibility Criteria

The eligibility criteria for IV alteplase have evolved over time, but generally include:

• Patients who can be treated within 3 to 4.5 hours of ischemic stroke symptom onset
• Patients with a small number (1-10) of cerebral microbleeds (CMBs) on MRI
• Patients with mild stroke presenting in the 3- to 4.5-hour window, where treatment risks should be weighed against possible benefits

Other IV Thrombolytics and Sonothrombolysis

Other IV thrombolytics, such as tenecteplase, have been compared to alteplase in clinical trials, but have not been proven to be superior or noninferior 1. Sonothrombolysis as adjuvant therapy with IV thrombolysis is not recommended due to lack of clinical benefit 1.

Brain Imaging

Brain imaging studies, such as noncontrast CT (NCCT) and diffusion-weighted magnetic resonance imaging (DW-MRI), are essential in the initial evaluation of patients with suspected acute stroke 1. However, routine use of MRI to exclude cerebral microbleeds (CMBs) before administration of IV alteplase is not recommended due to lack of evidence 1.

From the FDA Drug Label

CLINICAL STUDIES Three clinical studies were performed in patients with improperly functioning central venous access devices (CVADs) A placebo‑controlled, double‑blind, randomized trial (Trial 1) and a larger open‑label trial (Trial 2) investigated the use of Alteplase in predominately adult patients who had an indwelling CVAD for administration of chemotherapy, total parenteral nutrition, or long‑term administration of antibiotics or other medications Trial 1 tested the efficacy of a 2 mg/2 mL Alteplase dose in restoring function to occluded catheters in 150 patients with catheter occlusion up to 24 hours in duration. Trial 2 was an open‑label, single arm trial in 995 patients with catheter dysfunction and included patients with occlusions present for any duration. Three hundred forty-six patients who had successful treatment outcome were evaluated at 30 days after treatment. Trial 3 In Trial 3 all serious adverse events were recorded with a specific interest in intracranial hemorrhage, major hemorrhage, thrombosis, embolic events, sepsis and catheter related complications.

The trials that have been done on Activase (alteplase) include:

• Trial 1: a placebo-controlled, double-blind, randomized trial that tested the efficacy of a 2 mg/2 mL Alteplase dose in restoring function to occluded catheters in 150 patients with catheter occlusion up to 24 hours in duration 2.
• Trial 2: an open-label, single arm trial in 995 patients with catheter dysfunction and included patients with occlusions present for any duration 2.
• Trial 3: a trial that recorded all serious adverse events with a specific interest in intracranial hemorrhage, major hemorrhage, thrombosis, embolic events, sepsis and catheter related complications 2.

From the Research

Trials on Activase (Alteplase)

• The NINDS trial showed that alteplase administered within 3 hours after stroke onset significantly improved clinical outcomes at 90 days relative to placebo 3.
• The ECASS III trial demonstrated that alteplase administered between 3 and 4.5 hours after stroke onset significantly improved clinical outcomes at 90 days relative to placebo 3.
• The ATLANTIS study found no significant benefit of alteplase when administered between 3 and 5 hours after stroke onset, with an increased risk of symptomatic intracerebral hemorrhage 4.
• The J-ACT trial assessed the efficacy and safety of alteplase at a lower dose (0.6 mg/kg) in Japanese patients with acute ischemic stroke within 3 hours of onset, showing comparable outcomes and incidence of symptomatic intracranial hemorrhage to published data for the standard dose (0.9 mg/kg) 5.
• A pooled analysis of 9 trials found that treatment with alteplase was beneficial for a delay in treatment extending to 4.5 hours after stroke onset, with a greater benefit with earlier treatment, and that the benefit was consistent across different age groups and stroke severities 6.

Key Findings

• Alteplase has been shown to be effective in improving clinical outcomes in patients with acute ischemic stroke when administered within 3-4.5 hours of stroke onset 3, 7.
• The benefit of alteplase decreases as the time between stroke onset and treatment initiation increases, with no significant benefit observed when treatment is initiated more than 4.5 hours after stroke onset 3, 6.
• Alteplase is generally well tolerated, but it increases the risk of symptomatic intracranial hemorrhage, particularly when administered between 3 and 5 hours after stroke onset 3, 4.