Intravenous thrombolytic treatment and endovascular thrombectomy for ischaemic wake-up stroke

Melinda B Roaldsen, Haakon Lindekleiv, Ellisiv B Mathiesen, Melinda B Roaldsen, Haakon Lindekleiv, Ellisiv B Mathiesen

Abstract

Background: About one in five strokes occur during sleep (wake-up stroke). People with wake-up strokes have previously been considered to be ineligible for thrombolytic treatment because the time of stroke onset is unknown. However, recent studies suggest benefit from recanalisation therapies in selected patients.

Objectives: To assess the effects of intravenous thrombolysis and endovascular thrombectomy versus control in people with acute ischaemic stroke presenting on awakening from sleep.

Search methods: We searched the Cochrane Stroke Group Trials Register (last search 24 of May 2021). In addition, we searched the following electronic databases in May 2021: Cochrane Central Register of Controlled Trials (CENTRAL; 2021, Issue 4 of 12, April 2021) in the Cochrane Library, MEDLINE, Embase, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform. We searched the Stroke Trials Registry (last search 7 December 2017, as the site is currently inactive). We also screened references lists of relevant trials, contacted trialists, and undertook forward tracking of relevant references.

Selection criteria: Randomised controlled trials (RCTs) of intravenous thrombolytic drugs or endovascular thrombectomy treatments in people with acute ischaemic stroke presenting upon awakening.

Data collection and analysis: Two review authors applied the inclusion criteria, extracted data, and assessed risk of bias and the certainty of the evidence using the GRADE approach. We obtained both published and unpublished data for participants with wake-up strokes. We excluded participants with strokes of unknown onset if the symptoms did not begin upon awakening.

Main results: We included seven trials with a total of 980 participants, of which five trials with 775 participants investigated intravenous thrombolytic treatment and two trials with 205 participants investigated endovascular thrombectomy in large vessel occlusion in the anterior intracranial circulation. All trials used advanced imaging for selecting patients to treat. For intravenous thrombolytic treatment, good functional outcome (defined as modified Rankin Scale score 0 to 2) at 90 days follow-up was observed in 66% of participants randomised to thrombolytic treatment and 58% of participants randomised to control (risk ratio (RR) 1.13, 95% confidence interval (CI) 1.01 to 1.26; P = 0.03; 763 participants, 5 RCTs; high-certainty evidence). Seven per cent of participants randomised to intravenous thrombolytic treatment and 10% of participants randomised to control had died at 90 days follow-up (RR 0.68, 95% CI 0.43 to 1.07; P = 0.09; 763 participants, 5 RCTs; high-certainty evidence). Symptomatic intracranial haemorrhage occurred in 3% of participants randomised to intravenous thrombolytic treatment and 1% of participants randomised to control (RR 3.47, 95% CI 0.98 to 12.26; P = 0.05; 754 participants, 4 RCTs; high-certainty evidence). For endovascular thrombectomy of large vessel occlusion, good functional outcome at 90 days follow-up was observed in 46% of participants randomised to endovascular thrombectomy and 9% of participants randomised to control (RR 5.12, 95% CI 2.57 to 10.17; P < 0.001; 205 participants, 2 RCTs; high-certainty evidence). Twenty-two per cent of participants randomised to endovascular thrombectomy and 33% of participants randomised to control had died at 90 days follow-up (RR 0.68, 95% CI 0.43 to 1.07; P = 0.10; 205 participants, 2 RCTs; high-certainty evidence).

Authors' conclusions: In selected patients with acute ischaemic wake-up stroke, both intravenous thrombolytic treatment and endovascular thrombectomy of large vessel occlusion improved functional outcome without increasing the risk of death. However, a possible increased risk of symptomatic intracranial haemorrhage associated with thrombolytic treatment cannot be ruled out. The criteria used for selecting patients to treatment differed between the trials. All studies were relatively small, and six of the seven studies were terminated early. More studies are warranted in order to determine the optimal criteria for selecting patients for treatment.

Trial registration: ClinicalTrials.gov NCT02142283 NCT04256096.

Conflict of interest statement

Melinda Roaldsen: Declaring financial interests, Other: Trial Manager for TWIST (Tenecteplase in Wake‐up Ischaemic Stroke Trial), University Hospital of North Norway (funds received by author). Declaring non‐financial/other interests, Published opinions in medical journals, the public press, broadcast and social media relevant to the interventions in the work: First author on the following article: Roaldsen MB, Lindekleiv H, Eltoft A, Jusufovic M, et al. Tenecteplase in wake‐up ischaemic stroke trial (TWIST): Protocol for a randomised‐controlled trial, 14 January 2021, International Journal of Stroke, TWIST/University Hospital of North Norway. The main source of funding for the ongoing TWIST study is Norwegian Government Funding from the Clinical Therapy Research in the Specialist Health Services Research Programme. Additional grants are from the Swiss Heart Foundation, the British Heart Foundation, and the Norwegian National Association for Public Health. The cost of tenecteplase is also covered by an unconditional grant from Boehringer Ingelheim Norway KS. The study is an investigator‐ and academically initiated study. The funders of the study had no role in the study design or data collection.

Haakon Lindekleiv: none known.

Ellisiv Mathiesen: Declaring non‐financial/other interests, Other: Co‐ordinating Investigator of the Tenecteplase in Wake‐up Ischaemic Stroke Trial (TWIST), University Hospital of North Norway, Tromsø, Norway. A protocol article about the rationale for and design of TWIST has been published in the International Journal of Stroke. TWIST is an ongoing trial and therefore not included in the current analyses, but the trial is mentioned in the article. The main funding source for TWIST is from the Norwegian Clinical Therapy Research in the Specialist Health Services Research Programme (KLINBEFORSK; funded by the Norwegian Ministry of Health and Care Services). The trial has also received funding from the Norrwegian National Association for Public Health, the British Heart Foundation, and the Swiss Heart Foundation. The cost of the investigational medicinal product used in the trial is covered by Boehringer Ingelheim GmbH.