Abstract
BACKGROUND Under current guidelines, intravenous thrombolysis is used to treat acute stroke only if it can be ascertained that the time since the onset of symptoms was less than 4.5 hours. We sought to determine whether patients with stroke with an unknown time of onset and features suggesting recent cerebral infarction on magnetic resonance imaging (MRI) would benefit from thrombolysis with the use of intravenous alteplase. METHODS In a multicenter trial, we randomly assigned patients who had an unknown time of onset of stroke to receive either intravenous alteplase or placebo. All the patients had an ischemic lesion that was visible on MRI diffusion-weighted imaging but no parenchymal hyperintensity on fluid-attenuated inversion recovery (FLAIR), which indicated that the stroke had occurred approximately within the previous 4.5 hours. We excluded patients for whom thrombectomy was planned. The primary end point was favorable outcome, as defined by a score of 0 or 1 on the modified Rankin scale of neurologic disability (which ranges from 0 [no symptoms] to 6 [death]) at 90 days. A secondary outcome was the likelihood that alteplase would lead to lower ordinal scores on the modified Rankin scale than would placebo (shift analysis). RESULTS The trial was stopped early owing to cessation of funding after the enrollment of 503 of an anticipated 800 patients. Of these patients, 254 were randomly assigned to receive alteplase and 249 to receive placebo. A favorable outcome at 90 days was reported in 131 of 246 patients (53.3%) in the alteplase group and in 102 of 244 patients (41.8%) in the placebo group (adjusted odds ratio, 1.61; 95% confidence interval [CI], 1.09 to 2.36; P=0.02). The median score on the modified Rankin scale at 90 days was 1 in the alteplase group and 2 in the placebo group (adjusted common odds ratio, 1.62; 95% CI, 1.17 to 2.23; P=0.003). There were 10 deaths (4.1%) in the alteplase group and 3 (1.2%) in the placebo group (odds ratio, 3.38; 95% CI, 0.92 to 12.52; P=0.07). The rate of symptomatic intracranial hemorrhage was 2.0% in the alteplase group and 0.4% in the placebo group (odds ratio, 4.95; 95% CI, 0.57 to 42.87; P=0.15). CONCLUSIONS In patients with acute stroke with an unknown time of onset, intravenous alteplase guided by a mismatch between diffusion-weighted imaging and FLAIR in the region of ischemia resulted in a significantly better functional outcome and numerically more intracranial hemorrhages than placebo at 90 days.
| Original language | English |
|---|---|
| Journal | New England Journal of Medicine |
| Volume | 379 |
| Issue number | 7 |
| Pages (from-to) | 611-622 |
| Number of pages | 12 |
| ISSN | 0028-4793 |
| DOIs | |
| Publication status | Published - 16.08.2018 |
Funding
Supported by a grant (278276) from the European Union Seventh Framework Program. Dr. Thomalla reports receiving consulting fees from Acandis, grant support and lecture fees from Bayer, lecture fees from Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, and Daiichi Sankyo, and consulting fees and lecture fees from Stryker; Dr. Simonsen, receiving lecture fees from Bayer and Boehringer Ingelheim; Dr. Fiehler, receiving consulting fees from Acandis, Cerenovus, Medtronic, Microvention, Penumbra, and Route 92 Medical; Dr. Häusler, receiving lecture fees from Boehringer Ingelheim, Bristol-Myers Squibb, and Sanofi Aventis, grant support, lecture fees, and advisory board fees from Bayer HealthCare, advisory board fees and lecture fees from Pfizer and Daiichi Sankyo, advisory board fees from Medtronic and EIP Pharma, consulting fees from Edwards Lifesciences, and technical support for clinical studies from Getemed; Dr. Kemmling, receiving consulting fees from Siemens Healthineers; Dr. Perez de la Ossa, receiving fees per patient and coordinator contact, paid to his institution, from Medtronic, and fees per patient, paid to his institution, from Stryker, Biogen, and Pfizer; Dr. Ringleb, receiving lecture fees from Boehringer Ingelheim, Bayer, Pfizer, and Bristol-Myers Squibb; Dr. Thijs, receiving lecture fees, advisory board fees, consulting fees, and travel support from Boehringer Ingelheim, Medtronic, Bristol-Myers Squibb/Pfizer, AstraZeneca, and Bayer, and fees for serving on a steering committee from Sygnis; Dr. Endres, receiving fees for serving as a principal investigator, fees for serving on a steering committee, lecture fees, consulting fees, and advisory board fees, paid to his institution, and grant support from Bayer, lecture fees and advisory board fees, paid to his institution, from Boehringer Ingelheim and Amgen, lecture fees, paid to his institution, from Bristol-Myers Squibb/Pfizer, GlaxoSmithKline, Sanofi, Ever Pharma, and No-vartis, and advisory board fees, paid to his institution, from Daiichi Sankyo and Covidien; Dr. Fiebach, receiving consulting fees from BioClinica, Cerevast, Artemida Pharma, and Brainomix; Dr. Muir, receiving advisory board fees and drugs supplied by Boehringer Ingelheim; Dr. Pedraza, receiving fees for serving on an imaging board from Lundbeck; and Dr. Gerloff, receiving lecture fees and advisory board fees from Boehringer Ingelheim. No other potential conflict of interest relevant to this article was reported. We thank the patients and their families for participating in the trial; the members of the data and safety monitoring board (Marc Hommel, Université Grenoble Alpes; Kennedy Lees, University of Glasgow; and Karl Wegscheider, Universitätsklinikum Hamburg–Eppendorf) for their advice; and Gary Randall and Markus Wagner of the Stroke Alliance for Europe for their support.
DFG Research Classification Scheme
- 2.23-07 Clinical Neurology, Neurosurgery and Neuroradiology
