Desmoteplase 3 to 9 Hours After Major Artery Occlusion Stroke: The DIAS-4 Trial (Efficacy and Safety Study of Desmoteplase to Treat Acute Ischemic Stroke)

Rüdiger von Kummer; Etsuro Mori; Thomas Truelsen; Jens-Kristian S Jensen; Bjørn A Grønning; Jochen B Fiebach; Karl-Olof Lovblad; Salvador Pedraza; Javier M Romero; Hugues Chabriat; Ku-Chou Chang; Antoni Dávalos; Gary A Ford; James Grotta; Markku Kaste; Lee H Schwamm; Ashfaq Shuaib; Gregory W Albers; DIAS-4 Investigators

doi:10.1161/STROKEAHA.116.013715

Desmoteplase 3 to 9 Hours After Major Artery Occlusion Stroke: The DIAS-4 Trial (Efficacy and Safety Study of Desmoteplase to Treat Acute Ischemic Stroke)

Stroke. 2016 Dec;47(12):2880-2887. doi: 10.1161/STROKEAHA.116.013715. Epub 2016 Nov 1.

Authors

Rüdiger von Kummer¹, Etsuro Mori², Thomas Truelsen², Jens-Kristian S Jensen², Bjørn A Grønning², Jochen B Fiebach², Karl-Olof Lovblad², Salvador Pedraza², Javier M Romero², Hugues Chabriat², Ku-Chou Chang², Antoni Dávalos², Gary A Ford², James Grotta², Markku Kaste², Lee H Schwamm², Ashfaq Shuaib², Gregory W Albers²; DIAS-4 Investigators

Affiliations

¹ From the Universitätsklinikum Carl Gustav Carus an der Technischen Universität, Dresden, Germany (R.v.K.); Tohoku University Graduate School of Medicine, Sendai, Japan (E.M.); H. Lundbeck A/S, Valby, Denmark (T.T., J.-K.S.J., B.A.G.); Center for Stroke Research Berlin, Charité-Universitätsmedizin Berlin, Germany (J.B.F.); University of Geneva, Switzerland (K.-O.L.); c IDIBGI. Hospital Dr Josep Trueta, UDG. Girona, Spain (S.P.); Department of Radiology, Harvard Medical School, Boston, MA (J.M.R.); Department of Neurology, Hopital Lariboisiere APHP, University Denis Diderot and INSERM U1161, DHU NeuroVasc, Paris, France (H.C.); Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University, Taiwan (K.-C.C.); Department of Neurosciences Hospital Germans Trias i Pujol, Universitat Autonoma, Barcelona, Spain (A.D.); Oxford University Hospitals and Medical Sciences Division, University of Oxford, United Kingdom (G.A.F.); Memorial Hermann Hospital, Houston, TX (J.G.); Department of Neurology, Helsinki University Hospital, Clinical Neurosciences, Neurology, University of Helsinki, Finland (M.K.); Department of Neurology and Stroke Service, Massachusetts General Hospital, Harvard Medical School, Boston (L.H.S.); University of Alberta, Edmonton, Canada (A.S.); and Stanford University Medical Center, Palo Alto, CA (G.W.A.). ruediger.vonkummer@uniklinikum-dresden.de.
² From the Universitätsklinikum Carl Gustav Carus an der Technischen Universität, Dresden, Germany (R.v.K.); Tohoku University Graduate School of Medicine, Sendai, Japan (E.M.); H. Lundbeck A/S, Valby, Denmark (T.T., J.-K.S.J., B.A.G.); Center for Stroke Research Berlin, Charité-Universitätsmedizin Berlin, Germany (J.B.F.); University of Geneva, Switzerland (K.-O.L.); c IDIBGI. Hospital Dr Josep Trueta, UDG. Girona, Spain (S.P.); Department of Radiology, Harvard Medical School, Boston, MA (J.M.R.); Department of Neurology, Hopital Lariboisiere APHP, University Denis Diderot and INSERM U1161, DHU NeuroVasc, Paris, France (H.C.); Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University, Taiwan (K.-C.C.); Department of Neurosciences Hospital Germans Trias i Pujol, Universitat Autonoma, Barcelona, Spain (A.D.); Oxford University Hospitals and Medical Sciences Division, University of Oxford, United Kingdom (G.A.F.); Memorial Hermann Hospital, Houston, TX (J.G.); Department of Neurology, Helsinki University Hospital, Clinical Neurosciences, Neurology, University of Helsinki, Finland (M.K.); Department of Neurology and Stroke Service, Massachusetts General Hospital, Harvard Medical School, Boston (L.H.S.); University of Alberta, Edmonton, Canada (A.S.); and Stanford University Medical Center, Palo Alto, CA (G.W.A.).

PMID: 27803391
DOI: 10.1161/STROKEAHA.116.013715

Abstract

Background and purpose: The DIAS-3 trial (Efficacy and Safety Study of Desmoteplase to Treat Acute Ischemic Stroke [phase 3]) did not demonstrate a significant clinical benefit of desmoteplase administered 3 to 9 hours after stroke in patients with major artery occlusion. We present the results of the prematurely terminated DIAS-4 trial together with a post hoc pooled analysis of the concomitant DIAS-3, DIAS-4, and DIAS-J (Japan) trials to better understand the potential risks and benefits of intravenous desmoteplase for the treatment of ischemic stroke in an extended time window.

Methods: Ischemic stroke patients with occlusion/high-grade stenosis in major cerebral arteries were randomly assigned to intravenous treatment with desmoteplase (90 μg/kg) or placebo. The primary outcome was modified Rankin Scale (mRS) score of 0 to 2 at day 90. Safety assessments included mortality, symptomatic intracranial hemorrhage, and other serious adverse events.

Results: In DIAS-4, 52 of 124 (41.9%) desmoteplase-treated and 46 of 128 (35.9%) placebo-treated patients achieved an mRS score of 0 to 2 (odds ratio, 1.45; 95% confidence interval, 0.79; 2.64; P=0.23) with equal mortality, frequency of symptomatic intracranial hemorrhage, and other serious adverse events in both the treatment arms. In the pooled analysis, mRS score of 0 to 2 was achieved by 184 of 376 (48.9%) desmoteplase-treated versus 171 of 381 (44.9%) placebo-treated patients (odds ratio, 1.33; 95% confidence interval, 0.95; 1.85; P=0.096). Treatment with desmoteplase was safe and increased the recanalization rate (107/217 [49.3%] versus 85/222 [38.3%]; odds ratio, 1.59; 95% confidence interval, 1.08-2.35; P=0.019). Recanalization was associated with favorable outcomes (mRS 0-2) at day 90 in both the treatment arms.

Conclusions: Late treatment with intravenous 90 µg/kg desmoteplase is safe, increases arterial recanalization, but does not significantly improve functional outcome at 3 months.

Clinical trial registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00856661.

Keywords: brain ischemia; cerebral arteries; goals; intracranial hemorrhage; stroke.

Publication types

Clinical Trial, Phase III
Multicenter Study
Randomized Controlled Trial

MeSH terms

Aged
Aged, 80 and over
Arterial Occlusive Diseases / complications
Brain Ischemia / drug therapy*
Brain Ischemia / etiology
Cerebral Arterial Diseases / complications
Early Termination of Clinical Trials*
Female
Fibrinolytic Agents / administration & dosage
Fibrinolytic Agents / adverse effects
Fibrinolytic Agents / pharmacology*
Follow-Up Studies
Humans
Male
Middle Aged
Outcome Assessment, Health Care*
Plasminogen Activators / administration & dosage
Plasminogen Activators / adverse effects
Plasminogen Activators / pharmacology*
Stroke / drug therapy*
Stroke / etiology

Substances

Fibrinolytic Agents
salivary plasminogen activator alpha 1, Desmodus rotundus
Plasminogen Activators

Associated data

ClinicalTrials.gov/NCT00856661