Extending thrombolysis to 4·5–9 h and wake-up stroke using perfusion imaging: a systematic review and meta-analysis of individual patient data

Abstract

Background Stroke thrombolysis with alteplase is currently recommended 0-4•5 h after stroke onset. We aimed to determine whether perfusion imaging can identify patients with salvageable brain tissue with symptoms 4•5 h or more from stroke onset or with symptoms on waking who might benefit from thrombolysis.Methods In this systematic review and meta-analysis of individual patient data, we searched PubMed for randomised trials published in English between Jan 1, 2006, and March 1, 2019. We also reviewed the reference list of a previous systematic review of thrombolysis and searched ClinicalTrials.gov for interventional studies of ischaemic stroke. Studies of alteplase versus placebo in patients (aged ≥18 years) with ischaemic stroke treated more than 4•5 h after onset, or with wake-up stroke, who were imaged with perfusion-diffusion MRI or CT perfusion were eligible for inclusion. The primary outcome was excellent functional outcome (modified Rankin Scale [mRS] score 0-1) at 3 months, adjusted for baseline age and clinical severity. Safety outcomes were death and symptomatic intracerebral haemorrhage. We calculated odds ratios, adjusted for baseline age and National Institutes of Health Stroke Scale score, using mixed-effects logistic regression models. This study is registered with PROSPERO, number CRD42019128036. FindingsWe identified three trials that met eligibility criteria: EXTEND, ECASS4-EXTEND, and EPITHET. Of the 414 patients included in the three trials, 213 (51%) were assigned to receive alteplase and 201 (49%) were assigned to receive placebo. Overall, 211 patients in the alteplase group and 199 patients in the placebo group had mRS assessment data at 3 months and thus were included in the analysis of the primary outcome. 76 (36%) of 211 patients in the alteplase group and 58 (29%) of 199 patients in the placebo group had achieved excellent functional outcome at 3 months (adjusted odds ratio [OR] 1•86, 95% CI 1•15-2•99, p=0•011). Symptomatic intracerebral haemorrhage was more common in the alteplase group than the placebo group (ten [5%] of 213 patients vs one [<1%] of 201 patients in the placebo group; adjusted OR 9•7, 95% CI 1•23-76•55, p=0•031). 29 (14%) of 213 patients in the alteplase group and 18 (9%) of 201 patients in the placebo group died (adjusted OR 1•55, 0•81-2•96, p=0•66).Interpretation Patients with ischaemic stroke 4•5-9 h from stroke onset or wake-up stroke with salvageable brain tissue who were treated with alteplase achieved better functional outcomes than did patients given placebo. The rate of symptomatic intracerebral haemorrhage was higher with alteplase, but this increase did not negate the overall net benefit of thrombolysis.

EXTEND Trial

“…No differences were observed in the mRS distribution analysis, but a higher proportion of alteplase-treated patients had major early neurological improvement, attained independent recovery (mRS 0-2 at day 90), and had imaging evidence of recanalization and reperfusion at 24h. As expected, alteplase-treated patients had an excess of symptomatic intracranial hemorrhage (6.2% vs. 0.9%) EXTEND, 10 and an individual patient data pooled analysis of EXTEND, ECASS-4 and EPITHET, 21 provide further evidence supporting the concept that tissue viability on physiological imaging should be used for reperfusion therapy selection beyond the 4.5 h window or when onset time is uncertain, adding to 1021 evidence from WAKE-UP, 11 DAWN 14 and DEFUSE-3. 15 .…”

Brain-Derived Neurotrophic Factor and Its Potential Therapeutic Role in Stroke Comorbidities

“…However, as shown in clinical studies, treatment with tPA is only effective if administered within 4.5 hours postischemia. Although it was recently reported that the timeframe for effective thrombolysis treatment extends up to 9 hours after the onset of a stroke, this time window remains narrow [5][6][7], not to mention the side effects of tPA, which include enhanced risk of brain hemorrhage. In fact, the number of patients actually benefiting from tPA is very limited (2-5%) [16].…”

“…Thus, this disease has become an enormous threat to human health and a huge burden to the healthcare system worldwide [1][2][3][4]. So far, the only FDA-approved medication for ischemic stroke is the tissue plasminogen activator (tPA) when applied within 3 hours of an acute ischemic stroke attack, which therefore benefits only a small portion of the patients (2-5%) [5][6][7]. A great deal of effort has been made toward developing neuroprotectants, which mostly aim to block individual cytotoxic pathways in the early stages of stroke pathogenesis.…”

Pediatric Stroke: Unique Implications of the Immature Brain on Injury and Recovery

“…More recent trials have extended the time windows for such therapies, which may eventually lead to more pediatric patients being considered eligible for treatment. [5][6][7] The relative plasticity of a child's brain, however, may offer significant possibilities for targeting the recovery phase after stroke with a much larger window of opportunity for intervention.…”