Effects of alteplase for acute stroke according to criteria defining the European Union and United States marketing authorizations: Individual-patient-data meta-analysis of randomized trials

Abstract

Background: The recommended maximum age and time window for intravenous alteplase treatment of acute ischemic stroke differs between the Europe Union and United States. Aims:We compared the effects of alteplase in cohorts defined by the current Europe Union or United States marketing approval labels, and by hypothetical revisions of the labels that would remove the Europe Union upper age limit or extend the United States treatment time window to 4.5 h. Methods: We assessed outcomes in an individual-patient-data meta-analysis of eight randomized trials of intravenous alteplase (0.9 mg/kg) versus control for acute ischemic stroke. Outcomes included: excellent outcome (modified Rankin score 0-1) at 3-6 months, the distribution of modified Rankin score, symptomatic intracerebral hemorrhage, and 90-day mortality.Results: Alteplase increased the odds of modified Rankin score 0-1 among 2449/6136 (40%) patients who met the current European Union label and 3491 (57%) patients who met the age-revised label (odds ratio 1.42, 95% CI 1.21À1.68 and 1.43, 1.23À1.65, respectively), but not in those outside the age-revised label (1.06, 0.90À1.26). By 90 days, there was no increased mortality in the current and age-revised cohorts (hazard ratios 0.98, 95% CI 0.76À1.25 and 1.01, 0.86-1.19, respectively) but mortality remained higher outside the age-revised label (1.19, 0.99-1.42). Similarly, alteplase increased the odds of modified Rankin score 0-1 among 1174/6136 (19%) patients who met the current US approval and 3326 (54%) who met a 4.5-h revised approval (odds ratio 1.55, 1.19À2.01 and 1.37, 1.17À1.59, respectively), but not for those outside the 4.5-h revised approval (1.14, 0.97À1.34). By 90 days, no increased mortality remained for the current and 4.5-h revised label cohorts (hazard ratios 0.99, 0.77À1.26 and 1.02, 0.87-1.20, respectively) but mortality remained higher outside the 4.5-h revised approval (1.17, 0.98-1.41).Conclusions: An age-revised European Union label or 4.5-h-revised United States label would each increase the number of patients deriving net benefit from alteplase by 90 days after acute ischemic stroke, without excess mortality.

Alteplase for Acute Ischemic Stroke in Patients Aged >80 Years

“… 6 , 21 , 23 – 25 , 27 Data were evaluated using statistical methods and outcomes similar to those described previously. 1 , 28 , 29 …”

“…However, key aspects of its regulatory approval differ by region. 1 For example, no upper age limit is stated in the US product label, but treatment must be initiated within 3 hours of stroke onset. 2 Alteplase is approved for use in Europe within 4.5 hours of stroke onset but, until recently, regulatory criteria restricted its use to patients aged 18–80 years.…”

“…2 Alteplase is approved for use in Europe within 4.5 hours of stroke onset but, until recently, regulatory criteria restricted its use to patients aged 18–80 years. 1 , 3…”

“… 16 – 19 Closer alignment of regulatory criteria with clinical guidelines could allow more patients to receive a potentially beneficial therapy for AIS. 1 , 5 , 20 …”

Five-Year Cumulative Cost Saving with Thrombolysis in Korea: 3-Month Disability-Based Estimation

“…Meta-analyses of pivotal randomized trials confirmed the benefit of intravenous thrombolysis (IVT) and mechanical thrombectomy (MT) in patients with acute ischemic stroke. 1,2 In addition to the treatment effect, the cost saved with the efficacyproven therapy should be considered in healthcare policy making for resource allocation and reimbursement. Earlier studies have already shown that IVT and MT are clearly cost-effective, but the magnitude of cost saving likely differs according to individual healthcare systems.…”