Thrombolysis with alteplase 3–4.5 hours after acute ischaemic stroke: trial reanalysis adjusted for baseline imbalances

Abstract

ObjectivesAlteplase is commonly recommended for acute ischaemic stroke within 4.5 hours after stroke onset. The Third European Cooperative Acute Stroke Study (ECASS III) is the only trial reporting statistically significant efficacy for clinical outcomes for alteplase use 3–4.5 hours after stroke onset. However, baseline imbalances in history of prior stroke and stroke severity score may confound this apparent finding of efficacy. We reanalysed the ECASS III trial data adjusting for baseline imbalances to determine the robustness or sensitivity of the efficacy estimates.DesignReanalysis of randomised placebo-controlled trial. We obtained access to the ECASS III trial data and replicated the previously reported analyses to confirm our understanding of the data. We adjusted for baseline imbalances using multivariable analyses and stratified analyses and performed sensitivity analysis for missing data.SettingEmergency care.Participants821 adults with acute ischaemic stroke who could be treated 3–4.5 hours after symptom onset.InterventionsIntravenous alteplase (0.9 mg/kg of body weight) or placebo.Main outcome measuresThe original primary efficacy outcome was modified Rankin Scale (mRS) score 0 or 1 (ie, being alive without any disability) and the original secondary efficacy outcome was a global outcome based on a composite of functional end points, both at 90 days. Adjusted analyses were only reported for the primary efficacy outcome and the original study protocol did not specify methods for adjusted analyses. Our adjusted reanalysis included these outcomes, symptom-free status (mRS 0), dependence-free status (mRS 0–2), mortality (mRS 6) and change across the mRS 0–6 spectrum at 90 days; and mortality and symptomatic intracranial haemorrhage at 7 days.ResultsWe replicated previously reported unadjusted analyses but discovered they were based on a modified interpretation of the National Institutes of Health Stroke Scale (NIHSS) score. The secondary efficacy outcome was no longer significant using the original NIHSS score. Previously reported adjusted analyses could only be replicated with significant effects for the primary efficacy outcome by using statistical approaches not reported in the trial protocol or statistical analysis plan. In analyses adjusting for baseline imbalances, all efficacy outcomes were not significant, but increases in symptomatic intracranial haemorrhage remained significant.ConclusionsReanalysis of the ECASS III trial data with multiple approaches adjusting for baseline imbalances does not support any significant benefits and continues to support harms for the use of alteplase 3–4.5 hours after stroke onset. Clinicians, patients and policymakers should reconsider interpretations and decisions regarding management of acute ischaemic stroke that were based on ECASS III results.Trial registration numberNCT00153036.

European Stroke Organisation (ESO) guidelines on intravenous thrombolysis for acute ischaemic stroke

“…It has been recently argued that the evidence supporting the use of IVT 3–4.5 h after stroke is frail, and that imbalance in baseline NIHSS score may have been solely responsible for the positive results of the ECASS-3 trial. 13 However, the individual participant data meta-analysis by Emberson et al. does provide support for this time window, and did adjust for NIHSS score at baseline.…”

“…The numbers and the ORs for the two time subgroups are from the individual patient data meta-analysis of nine RCTs by Emberson et al that imbalance in baseline NIHSS score may have been solely responsible for the positive results of the ECASS-3 trial. 13 However, the individual participant data meta-analysis by Emberson et al does provide support for this time window, and did adjust for NIHSS score at baseline. 8 Although IVT is currently recommended prior to mechanical thrombectomy, 14 there is a debate about whether IVT is necessary for patients directly arriving at stroke centre with thrombectomy capability.…”

Alteplase for Acute Ischemic Stroke Beyond 3 hours: Enthusiasm Outpaces Evidence

“…In a multivariate model adjusted for both baseline National Institutes of Health Stroke Scale (NIHSS) scores ( P = .03 between groups) and prior stroke status ( P = .003 between groups) there was a non-significant difference between alteplase and placebo for all efficacy outcomes. 4 …”

“…In a multivariate model adjusted for both baseline National Institutes of Health Stroke Scale (NIHSS) scores (P = .03 between groups) and prior stroke status (P = .003 between groups) there was a non-significant difference between alteplase and placebo for all efficacy outcomes. 4 An unplanned post-hoc reanalysis risks analytical bias by nature. Limitations not considered in the original trial publication, however, support Alper et al's findings.…”

Acute Stroke Management: Overview and Recent Updates

“…Due to the clear benefits of reduced disability and undeniable positive results, the treatment was approved by the Food and Drug Administration (FDA) in 1996. Subsequent studies have been carried out in hopes of safely expanding the use of IV tPA beyond the 3-hour window [4][5][6][7][8][9][10][11][12][13][14]. For example, up to 4.5 hours, 6 hours, 9 hours, and even with wake-up strokes and unknown last well time.…”