Research in context
Evidence before this study
The treatment of ischaemic stroke with intravenous alteplase or tenecteplase has been studied in randomised trials up to 6 h after symptom onset. Findings from a systematic review and a pooled analysis of trial data suggested decreasing effectiveness over time and no beneficial effect of alteplase after 5 h. The Desmoteplase in Acute Ischemic Stroke (DIAS) and Dose Escalation of Desmoteplase for Acute Ischemic Stroke (DEDAS) trials showed higher recanalisation rates and better clinical outcomes after desmoteplase than after placebo; efficacy was not confirmed by findings from the DIAS-2 trial. A post-hoc pooled analysis suggested that patients with major artery occlusions might benefit from 90 μg/kg desmoteplase in this time window. To identify additional randomised trials of intravenous alteplase, desmoteplase, or other thrombolytic agents, we searched Medline for articles published between Jan 1, 2014, and April 1, 2015, with the terms (“stroke”[MeSH Terms] OR “stroke”[All Fields]) AND thrombolytics [All Fields] AND (“therapy”[Subheading] OR “therapy”[All Fields] OR “therapeutics”[MeSH Terms] OR “therapeutics”[All Fields]). No additional randomised controlled trials in patients being treated between 3 h and 9 h after ischaemic stroke were identified.
Added value of this study
To our knowledge this study is the first prospective, randomised, controlled phase 3 trial testing the effect of an intravenous thrombolytic drug in patients with ischaemic stroke with proven major artery occlusion, but no major ischaemic damage, treated 3–9 h after stroke onset. In this patient population, desmoteplase did not significantly improve functional outcomes at 90 days and did not increase the frequency of symptomatic brain haemorrhages, symptomatic brain oedema, or deaths. Nevertheless, we noted significant (nominal p<0·05) improvements in functional outcome in the desmoteplase group for the prespecified subgroup of patients with lesions on diffusion-weighted imaging less than 25 mL and in the prespecified ordinal analysis of patients treated more than 7 h after onset of stroke symptoms.
Implications of all the available evidence
Our findings indicate that desmoteplase is overall not beneficial when given 3–9 h after symptom onset to patients with major cerebral artery occlusion. The potential effects of desmoteplase in prespecified subgroups supports the notion that some patients could benefit from desmoteplase in an extended time window. The association between patients who achieved recanalisation and good clinical outcome in our post-hoc analysis suggests that reperfusion, even in this late time window, might be beneficial.