Current guidelines from the American Heart Association and American Stroke Association recommend that intravenous thrombolysis (IVT) with alteplase not be used for patients with acute ischemic stroke (AIS) who have unclear or unwitnessed symptom onset time or in patients with symptom onset time exceeding the 4.5-hour window. However, a growing body of research suggests that advanced neuroimaging with validated techniques can guide the selection of patients with AIS who could gain the most benefit from reperfusion therapies regardless of the elapsed time from symptom onset, explains Georgios Tsivgoulis, MD. To determine whether IVT is a safe and effective treatment option for patients with AIS, Dr. Tsivgoulis and colleagues conducted a systematic review and meta-analysis and published their results in Neurology.

The study team assessed four randomized clinical trials of patients with AIS with unclear symptom onset time or with symptom onset outside the conventional 4.5-hour time window but with evidence of substantial viable hypoperfused tissue documented by advanced baseline neuroimaging, using either CT or MRI. The reviewed and analyzed trials evaluated the use of IVT with alteplase at a dose of 0.9 mg/kg.

The Data

The study team found that IVT treatment was associated with a higher likelihood of a favorable functional outcome (FFO) at the 3-month mark than guideline-recommended treatments. There was also no significant difference between IVT and recommended treatments in all-cause mortality at 3 months. “IVT in this population is associated with a three-fold higher chance of achieving successful recanalization of the previously occluded intracranial vessel, with a more than 40% increase in the probability of functional independence at 3 months after stroke onset,” highlights Dr. Tsivgoulis. “At the same time, IVT treatment in this population is associated with a five-fold increase in the likelihood of symptomatic intracranial hemorrhage (sICH), however, without an increase in the mortality risk (Table).”

The team developed forest plots of adjusted associations between IVT and outcomes, including 3 months FFO, 3 months functional improvement, and sICH. The results indicate that IVT was still associated with a higher rate of 3 months FFC, but also with a higher risk of sICH.

Ongoing Research

Research into the safety and efficacy of IVT for patients with AIS who have unclear or unwitnessed symptom onset time or in patients with symptom onset time exceeding the 4.5 hours window is ongoing. Dr. Tsivgoulis highlights two current randomized controlled clinical trials that are evaluating IVT for patients with AIS using tenecteplase instead of alteplase. “One is evaluating the utility of tenecteplase treatment compared with placebo for patients with large vessel occlusion and AIS symptom onset within 4.5 to 24 hours and target mismatch profile on perfusion imaging,” explains Dr. Tsivgoulis. “The other is evaluating the safety and efficacy of tenecteplase treatment for AIS patients with minor deficits and evidence of intracranial vessel occlusion on neuroimaging presenting within 12 hours from stroke onset.”

In the meantime, Dr. Tsivgoulis suggests that “the data support a significant benefit in treating eligible patients presenting with AIS with unknown symptom onset time, fluid-attenuated inversion recovery with diffusion-weighted imaging, or patients with symptom onset outside the conventional time window of 4.5 hours and evidence of viable tissue on penumbral imaging. In the absence of a large vessel occlusion amendable to endovascular intervention, clinicians should weigh the patient’s disability resulting from presenting symptoms against the potential risk for intracranial bleeding risk and consider prompt intravenous thrombolysis administration in the absence of other contraindications.”

References

Thrombolysis for acute ischemic stroke in the unwitnessed or extended therapeutic time window
https://n.neurology.org/content/94/12/e1241