Elsevier

The Lancet Neurology

Volume 14, Issue 6, June 2015, Pages 575-584
The Lancet Neurology

Articles
Safety and efficacy of desmoteplase given 3–9 h after ischaemic stroke in patients with occlusion or high-grade stenosis in major cerebral arteries (DIAS-3): a double-blind, randomised, placebo-controlled phase 3 trial

https://doi.org/10.1016/S1474-4422(15)00047-2Get rights and content

Summary

Background

Current treatment of ischaemic stroke with thrombolytic therapy is restricted to 3–4·5 h after symptom onset. We aimed to assess the safety and efficacy of desmoteplase, a fibrin-dependent plasminogen activator, given between 3 h and 9 h after symptom onset in patients with occlusion or high-grade stenosis in major cerebral arteries.

Methods

In a prospective, double-blind, multicentre, parallel-group, randomised trial, we enrolled patients from 77 hospitals in 17 countries who had ischaemic stroke and occlusion or high-grade stenosis in major cerebral arteries. We randomly assigned patients in a 1:1 ratio, using computer-generated randomisation lists with stratification for baseline National Institutes of Health Stroke Scale and age, to treatment with desmoteplase (90 μg/kg) given 3–9 h after symptom onset or to placebo. Patients, investigators, staff, and the funder were masked to treatment assignment. The primary outcome was a favourable modified Rankin Scale score (0–2) at day 90 in all treated patients who had at least one postbaseline measurement of the modified Rankin Scale. Safety was assessed in all randomly assigned patients who received study drugs. This trial is registered with ClinicalTrials.gov, number NCT00790920.

Findings

Between Feb 6, 2009, and Nov 27, 2013, we enrolled 492 patients and randomly assigned 247 to desmoteplase and 245 to placebo (236 in the desmoteplase group and 237 in the placebo group were included in the analysis of the primary endpoint). Median time from stroke onset to treatment was 6·9 h (IQR 5·7–8·0) for placebo and 7·0 h (6·0–7·9) for desmoteplase. Modified Rankin Scale score (0–2) at day 90 occurred in 121 (51%) patients given desmoteplase and 118 (50%) patients given placebo (adjusted odds ratio 1·20, 95% CI 0·79–1·81, p=0·40). 24 (10%) of 240 patients given desmoteplase died compared with 23 (10%) of 238 patients given placebo. Serious adverse events occurred in 64 (27%) of 240 patients receiving desmoteplase compared with 69 (29%) of 238 patients receiving placebo; frequency of symptomatic intracranial haemorrhage (six [3%] patients in the desmoteplase group vs five [2%] in the placebo group), symptomatic cerebral oedema (five [2%] vs four [2%]), and major haemorrhage (ten [4%] vs 15 [6%]) was much the same between treatment groups.

Interpretation

Treatment with desmoteplase did not cause safety concerns and did not improve functional outcome when given to patients who had ischaemic stroke and major cerebral artery occlusion beyond 3 h of symptom onset.

Funding

H Lundbeck A/S.

Introduction

Regulatory approval for thrombolytic therapy for treatment of ischaemic stroke with alteplase is restricted to 3 h after symptom onset in the USA and 4·5 h in most European and some other countries.1, 2 There is an unmet need for patients who present beyond these time limits. Desmoteplase, a fibrin-dependent plasminogen activator, has high fibrin specificity.3 Clinical data in patients with acute ischaemic stroke have suggested that desmoteplase is associated with low risk of symptomatic brain haemorrhage and high rates of early reperfusion.4, 5 Findings from the Desmoteplase in Acute Ischemic Stroke 2 (DIAS-2) trial, a phase 3 placebo-controlled study, did not show clinical efficacy for desmoteplase 3–9 h after stroke onset.6 However, only 30% of the patients enrolled had an intracranial vessel occlusion. A post-hoc analysis of pooled data from DIAS-2 and the phase 2 studies DIAS4 and Dose Escalation of Desmoteplase for Acute Ischemic Stroke (DEDAS)5 suggested that desmoteplase was beneficial in patients with complete (or almost complete) arterial occlusion.7

Identification of an occluded major intracranial artery with CT angiography (CTA) or magnetic resonance angiography (MRA), in conjunction with evidence of little irreversible brain injury on CT or MRI, could be a useful strategy to select patients for reperfusion therapy in a late time window for which no treatment is currently approved.7 We initiated two phase 3 studies (DIAS-3 and DIAS-4)8 to assess the safety and efficacy of a single intravenous bolus injection of 90 μg/kg desmoteplase given 3–9 h after onset of ischaemic stroke in patients with occlusion or high-grade stenosis in major cerebral arteries on CTA or MRA and little ischaemic injury on CT or MRI. Both studies followed identical protocols, but were done in different countries and continents aiming to prove safety and efficacy of desmoteplase in two independent randomised controlled trials. Here, we present the primary, secondary, and safety endpoints of DIAS-3.

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.

Section snippets

Study design and participants

We undertook a multinational, randomised, double-blind, parallel-group, placebo-controlled phase 3 study, enrolling patients from 77 hospitals in 17 countries. The study design was similar to that of previous trials of desmoteplase (DIAS4, DEDAS5, and DIAS-26), and details about the methods used in this study have been published previously.8

At each study site we recruited patients with ischaemic stroke within 3–9 h of witnessed symptom onset who were aged between 18 and 85 years, had a National

Results

Between Feb 6, 2009, and Nov 27, 2013, we enrolled 492 patients (184 from Europe, 289 from Asia, and 19 from Australia) and randomly assigned them to receive either 90 μg/kg desmoteplase (n=247) or placebo (n=245). 14 patients were randomly assigned but not treated, two patients were treated but lost to follow-up, two patients were excluded because of early code-break (ie, unblinding at study site), one patient was treated but lost to follow-up, one patient's postbaseline modified Rankin Scale

Discussion

In DIAS-3, a single intravenous injection of 90 μg/kg desmoteplase did not improve functional outcome at day 90 in patients with ischaemic stroke in the primary prespecified efficacy analysis or the post-hoc intention-to-treat analysis. The lack of clinical efficiency might be accounted for by the modest differences in arterial recanalisation recorded in our study. The premise that reperfusion beyond 3 h can be beneficial is supported by the post-hoc analysis of the association between

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