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.
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.


RESULTS
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.


CONCLUSIONS
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.


BACKGROUND
H Lundbeck A/S.
Stanford University Medical Center, Palo Alto, CA, USA. Electronic address: albers@stanford.edu.
Gregory W
GW
Albers
Universitätsklinikum Carl Gustav Carus an der Technischen Universität, Dresden, Germany.
Rüdiger
R
von Kummer
H Lundbeck A/S, Valby, Denmark.
Thomas
T
Truelsen
H Lundbeck A/S, Valby, Denmark.
Jens-Kristian S
JK
Jensen
H Lundbeck A/S, Valby, Denmark.
Gabriela M
GM
Ravn
H Lundbeck A/S, Valby, Denmark.
Bjørn A
BA
Grønning
Department of Neurology, Hôpital Lariboisière APHP, University Denis Diderot and INSERM U1161, DHU NeuroVasc, Paris, France.
Hugues
H
Chabriat
Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University, Taiwan.
Ku-Chou
KC
Chang
Department of Neurosciences Hospital Germans Trias i Pujol, Universitat Autonoma, Barcelona, Spain.
Antonio E
AE
Davalos
Oxford University Hospitals and Medical Sciences Division, University of Oxford, Oxford, UK.
Gary A
GA
Ford
Memorial Hermann Hospital, Houston, TX, USA.
James
J
Grotta
Department of Neurology, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland.
Markku
M
Kaste
Department of Neurology, Harvard Medical School, Boston, MA, USA.
Lee H
LH
Schwamm
Department of Medicine, University of Alberta, Edmonton, AB, Canada.
Ashfaq
A
Shuaib
D000368:Aged; D000369:Aged, 80 and over; D002545:Brain Ischemia / Q000188:drug therapy* / Q000209:etiology; D002539:Cerebral Arterial Diseases / Q000150:complications / Q000188:drug therapy*; D003251:Constriction, Pathologic / Q000150:complications / Q000188:drug therapy; D004311:Double-Blind Method; D005260:Female; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010960:Plasminogen Activators / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D011446:Prospective Studies; D020521:Stroke / Q000188:drug therapy* / Q000209:etiology; D015912:Thrombolytic Therapy / Q000379:methods*; D016896:Treatment Outcome
D005343:Fibrinolytic Agents; C069588:salivary plasminogen activator alpha 1, Desmodus rotundus; D010960:Plasminogen Activators