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 1.21-1.68 and 1.43, 1.23-1.65, respectively), but not in those outside the age-revised label (1.06, 0.90-1.26). By 90 days, there was no increased mortality in the current and age-revised cohorts (hazard ratios 0.98, 95% CI 0.76-1.25 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, 1.19-2.01 and 1.37, 1.17-1.59, respectively), but not for those outside the 4.5-h revised approval (1.14, 0.97-1.34). By 90 days, no increased mortality remained for the current and 4.5-h revised label cohorts (hazard ratios 0.99, 0.77-1.26 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.
Highlights
Despite the availability of reliable information about the factors determining the benefit–risk relationship for alteplase in acute ischemic stroke, there are wide regional differences in the market authorizations for the drug, which may explain variations in its use between countries
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, 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 but mortality remained higher outside the age-revised label (1.19, 0.99–1.42)
Summary
Despite the availability of reliable information about the factors determining the benefit–risk relationship for alteplase in acute ischemic stroke, there are wide regional differences in the market authorizations for the drug, which may explain variations in its use between countries. In the European Union (EU), the upper age limit for safe treatment is set at 80 years and the time window for treatment is 0–4.5 h from stroke onset.[1] These contrast with the stricter 0–3-h time window but lack of an explicit upper age limit in the United States (US).[2] In contrast to these regulatory statements, the scientific guidelines issued by the respective regional professional bodies (from the American Stroke Association/American Heart Association (ASA/AHA) and the European Stroke Organisation (ESO)) recommend treatment within 4.5 h in both regions These guidelines do not specify an age limit in Europe, but in the US they stipulate an age limit of 80 years if treating between 3 and 4.5 h (Table 1).[3,4] Marketing labels in other parts of the world vary in criteria, mostly with respect to age limit, treatment time window, and in the case of Japan, in the recommended dose.[5] Many clinicians, especially those in less specialized settings, may adhere to the more conservative regulatory labels rather than the more inclusive professional guidelines.[6,7] It is possible that modification of the labeling in the US and in the EU would enable a larger number of patients to be treated and achieve improved outcome from acute ischemic stroke.
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