Critically Appraised Topic

CAT: Patient presents to ED with stroke symptoms, onset 7 hours prior. Family wants hospital to provide all possible treatments, including thrombolytics to save their family member but is told that thrombolytics are indicated for stroke symptom onset within 4.5 hours.

Should alteplase administration for ischemic stroke be extended beyond 4.5 hours following onset of symptoms?

 

Population: Ischemic stroke patients

Intervention: Alteplase administration after 4.5 hours of symptom onset

Comparative: Alteplase administration within 4.5 hours of symptom onset

Outcome: minimize residuals of stroke and adverse effects of thrombolysis

 

Databases Searched: 12
Medline, New England Journal of Medicine, Cochrane Library, Google Scholar, EBSCO

Search terms: alteplase, ischemic stroke, onset, time of administration, over 4.5 hours, onset over 4.5 hours, extended time window. Articles within last 3 years.

Cochrane: 44
Medline: 19
Google Scholar: 2630

 

“Intravenous Thrombolysis for Acute Ischemic Stroke Within 3 Hours Versus Between 3 and 4.5 Hours of Symptom Onset”

Article link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4530422/

Abstract: Data from randomized clinical trials have supported the safety and efficacy of intravenous tissue-type plasminogen activator (IV tPA) for acute ischemic stroke when administered within 3 hours of symptom onset, and regulatory approvals for this indication have been in place for almost 20 years. However, recent clinical trials have provided evidence that IV tPA may be safe and effective in selected patients up to 4.5 hours after symptom onset, thereby increasing the proportion of patients that may be eligible for treatment. Although professional organizations in the United States and many regulatory agencies internationally have supported this expanded time window for IV tPA, the US Food and Drug Administration has declined to approve this expanded indication and so this use of IV tPA has remained off-label in the United States. Here we review the current evidence for IV tPA in the standard and the expanded time windows and the data on current clinical practice in the United States as it relates to IV tPA treatment for acute stroke within 3 to 4.5 hours of symptom onset.

 

“Time Window and Tissue Window: Two Approaches to Assist Decision-Making in Strokes”

Article link: https://link-springer-com.york.ezproxy.cuny.edu/article/10.1007/s00415-018-8933-5

Abstract: Intravenous alteplase given in an appropriate time window has been recommended in guidelines and effects are on the decline over time. In general, the clinical decision is primarily based on whether ischemic stroke patients are sent to hospitals within the time window. However, some patients sent to the hospital over time limitations are eligible to receive intervention for recanalization due to good collateral circulation. In this dilemma, “tissue window” can be more reliable, which means using the penumbra as a major criterion for patient recruitment. Hence, we herein aim to address how could “tissue window” be a complementary approach when it does not conform to the time window’s indication and affirming value of the later one. Some efforts obeying the time window are discussed first. In the later sections, we give the details of the definition of “tissue window”, and then compare various neuroimaging techniques to determine the penumbra and summarize favorable patterns. Finally, we will focus on how the “tissue window” extends the therapeutic time window under specific circumstances.

 

“Thrombolysis Guided by Perfusion Imaging up to 9 Hours after Onset of Stroke”

Article link: https://www.nejm.org/doi/full/10.1056/NEJMoa1813046?url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub%3Dpubmed

Abstract: The time to initiate intravenous thrombolysis for acute ischemic stroke is generally limited to within 4.5 hours after the onset of symptoms. Some trials have suggested that the treatment window may be extended in patients who are shown to have ischemic but not yet infarcted brain tissue on imaging.

We conducted a multicenter, randomized, placebo-controlled trial involving patients with ischemic stroke who had hypoperfused but salvageable regions of brain detected on automated perfusion imaging. The patients were randomly assigned to receive intravenous alteplase or placebo between 4.5 and 9.0 hours after the onset of stroke or on awakening with stroke (if within 9 hours from the midpoint of sleep). The primary outcome was a score of 0 or 1 on the modified Rankin scale, on which scores range from 0 (no symptoms) to 6 (death), at 90 days. The risk ratio for the primary outcome was adjusted for age and clinical severity at baseline.

After 225 of the planned 310 patients had been enrolled, the trial was terminated because of a loss of equipoise after the publication of positive results from a previous trial. A total of 113 patients were randomly assigned to the alteplase group and 112 to the placebo group. The primary outcome occurred in 40 patients (35.4%) in the alteplase group and in 33 patients (29.5%) in the placebo group (adjusted risk ratio, 1.44; 95% confidence interval [CI], 1.01 to 2.06; P=0.04). Symptomatic intracerebral hemorrhage occurred in 7 patients (6.2%) in the alteplase group and in 1 patient (0.9%) in the placebo group (adjusted risk ratio, 7.22; 95% CI, 0.97 to 53.5; P=0.05). A secondary ordinal analysis of the distribution of scores on the modified Rankin scale did not show a significant between-group difference in functional improvement at 90 days.

Among the patients in this trial who had ischemic stroke and salvageable brain tissue, the use of alteplase between 4.5 and 9.0 hours after stroke onset or at the time the patient awoke with stroke symptoms resulted in a higher percentage of patients with no or minor neurologic deficits than the use of placebo. There were more cases of symptomatic cerebral hemorrhage in the alteplase group than in the placebo group.

 

“Extending the Time Window for Intravenous Thrombolysis in Acute Ischemic Stroke Using Magnetic Resonance Imaging-based Patient Selection”

Article link: https://journals-sagepub-com.york.ezproxy.cuny.edu/doi/abs/10.1177/1747493019840938

Abstract: Intravenous thrombolysis with alteplase within a time window up to 4.5 h is the only approved pharmacological treatment for acute ischemic stroke. We studied whether acute ischemic stroke patients with penumbral tissue identified on magnetic resonance imaging 4.5–9 h after symptom onset benefit from intravenous thrombolysis compared to placebo.

Acute ischemic stroke patients with salvageable brain tissue identified on a magnetic resonance imaging were randomly assigned to receive standard dose alteplase or placebo. The primary end point was disability at 90 days assessed by the modified Rankin scale, which has a range of 0–6 (with 0 indicating no symptoms at all and 6 indicating death). Safety end points included death, symptomatic intracranial hemorrhage, and other serious adverse events.

The trial was stopped early for slow recruitment after the enrollment of 119 (61 alteplase, 58 placebo) of 264 patients planned. Median time to intravenous thrombolysis was 7 h 42 min. The primary endpoint showed no significant difference in the modified Rankin scale distribution at day 90 (odds ratio alteplase versus placebo, 1.20; 95% CI, 0.63–2.27, P = 0.58). One symptomatic intracranial hemorrhage occurred in the alteplase group. Mortality at 90 days did not differ significantly between the two groups (11.5 and 6.8%, respectively; P = 0.53).

Intravenous alteplase administered between 4.5 and 9 h after the onset of symptoms in patients with salvageable tissue did not result in a significant benefit over placebo.

Author; reference	Level of Evidence	Patient Group/Data Collection	Primary and Secondary Outcomes	Key Findings	Limitations / Bias
Cheng, Natalie T., 2015 Intravenous Thrombolysis for Acute Ischemic Stroke Within 3 Hours Versus Between 3 and 4.5 Hours of Symptom Onset	Analysis of several Randomized Clinical Trials	Over 30 randomized, double-blind controlled trials evaluating administration of tPA to ischemic stroke patients within 3 hours of symptom onset compared to 3-4.5 hours of symptom onset, with a few extending the treatment window beyond 4.5 hours	Primary: Minimal to no deficit evaluated with GCS and NIH stroke scale within 90 days Neurologic recovery within 90 days Secondary: Functional recovery at 30 and 90 days	Some RCT’s found no significant improvement with treatment after 4.5 hours, while others found decreased mortality rates in patients treated up to 6 hours after onset. Faster treatment was associated with reduced rate of intracranial hemorrhage, higher rate of ambulation at discharge, and higher chance of discharge to home. At time of analysis, the FDA deemed there was not enough data to definitively extend the tPA treatment window, despite the AHA recommending tPA administration up to 4.5 hours post symptom onset.	This analysis was conducted in 2015 so the research analyzed is not up to date but does provide valuable information on sole treatment with Alteplase for several time windows. The results were not all standardized, as different RCT’s used varying definitions for outcomes and measured outcomes at different times.
Xiang et al., 2019 Time Window and Tissue Window: Two Approaches to Assist Decision-Making in Strokes	Retrospective Case Study	Patients with ischemic stroke treated with tPA within 4.5 hours and those excluded based on time window for tPA but having sufficient penumbra to consider treatment based on tissue viability	Improvement in neurological function Adverse effect of intracranial hemorrhage due to tPA administration outside of 4.5 hour window	Using “tissue window” as criteria for strokes where penumbra (ischemic but not infarcted tissue) surrounds the occlusion and can be salvaged with tPA even if outside of typical 4.5 hour window. Penumbra need proper evaluation for level of ischemia and differentiation from occlusion, done with CT, MRI, and/or Perfusion-Weighted Imaging. Decision to treat is based on size/pattern of penumbra compared to infarcted core. Tissue window allows for a larger treatment window of ischemic stroke.	There is discrepancy between studies as what size/pattern of penumbra compared to core infarct qualifies for reperfusion. One study found an extended tissue window of 24 hours to provide effective reperfusion, while other studies did not reproduce the same results.
Ma, et al., 2019 Thrombolysis Guided by Perfusion Imaging up to 9 Hours after Onset of Stroke	Randomized placebo-controlled trial	Patients with ischemic stroke, with hypo-perfused but salvageable regions of brain Patients randomly assigned to IV alteplase or placebo within 4.5 to 9 hours after stroke onset	Score of 0 or 1 on modified Rankin Scale (6 point disability scale for stroke or other neurological disability. 0 is no symptoms, 1 is no significant disability, 6 is death, scored at 90 days)	The study evaluated patients using automated perfusion imaging and administered alteplase or placebo to those showing salvageable brain areas. Primary outcome occurred in 35.4% of patients in alteplase group and 29.5% of patients in placebo group. 7.6% of alteplase patients experienced intracerebral hemorrhage.	Trial was terminated due to only 225 of the planned 310 patients enrolling.
Ringleb, et al., 2019 Extending the Time Window for Intravenous Thrombolysis in Acute Ischemic Stroke Using Magnetic Resonance Imaging-based Patient Selection	Randomized placebo-controlled trial	Acute ischemic stroke patients with salvageable brain tissue identified by MRI Patients randomly assigned to IV alteplase or placebo within 4.5 to 9 hours after stroke onset	Score of 0 or 1 on modified Rankin Scale (6 point disability scale for stroke or other neurological disability. 0 is no symptoms, 1 is no significant disability, 6 is death, scored at 90 days)	119 patients were studied, with 61 receiving alteplase and 58 receiving placebo. Median time to IV reperfusion therapy was 7 hours and 42 minutes. The study found no significant difference in the modified Rankin Score distribution at day 90. One intracranial hemorrhage occurred in Alteplase group. No difference in mortality was found between the two groups.	Trial stopped early due to slow recruitment

 

Conclusions:

While the FDA may not approve of extending the time window due to lack of sufficient research, there is a lot of promising research on utilizing the tissue window when assessing ischemia with perfusion scans such as MRI. This research opens up possibilities for looking at ischemic stroke treatment from a different perspective than that which has become the norm and standard. The serious adverse effect of intracranial hemorrhage that is of worry when administering alteplase outside of the time window was still experienced, however with different frequencies between the two studies. There is limited definitive information on whether the possible elimination of neurologic deficits outweighs the risk of intracranial hemorrhage, but research so far has shown promise in treating according to tissue window outside of the standard 4.5 hour time limit.

 

Bottom Line and Clinical Relevance

Use of Alteplase within 4.5 hours of ischemic stroke onset has been the gold standard for decades but new research is showing that time should not be the only deciding factor for thrombolytic treatment. Evaluating tissue viability with perfusion scans instead of just considering a time window can increase the number of patients treated with Alteplase. The long-standing adverse effect of intracranial hemorrhage with Alteplase given outside of standard 4.5 hour window needs to be looked at in terms of penumbra and salvageable tissue. One study found a low rate of intracranial hemorrhage in a group of patients with considerable salvageable tissue and Alteplase administration within 4.5 to 9 hours of stroke onset, and more studies need to be done to see if the risk of ICH with tPA administration after 4.5 hours is considerably lower in patients like this. The use of perfusion imaging (tissue window) in addition to time window to decide treatment showed beneficial results in another study and should be implemented cautiously at stroke centers to increase the number of patients with favorable outcomes after ischemic stroke. Patients that would not normally qualify for thrombolytic treatment and end up with neurological deficits could potentially experience more favorable outcomes. It would be in the best interest of patients experiencing ischemic stroke to receive alteplaste treatment outside of the standard time window if they qualify for treatment within the “tissue window”.

 

References

1. Cheng, Natalie T., Kim, Anthony S. “Intravenous Thrombolysis for Acute Ischemic Stroke Within 3 Hours Versus Between 3 and 4.5 Hours of Symptom Onset.” Neurohospitalist 5, 101-109 (2015). Web. May 03 2020.
2. Xiang, X., Cao, F. “Time Window and Tissue Window: Two Approaches to Assist Decision-Making in Strokes.” J Neurol 266, 283-288 (2019). Web. 03 May 2020.
3. Ma, Henry, et al. “Thrombolysis Guided by Perfusion Imaging up to 9 Hours after Onset of Stroke.” New England Journal of Medicine (2019). Web. 04 May 2020.
4. Ringleb, Peter, et al. “Extending the Time Window for Intravenous Thrombolysis in Acute Ischemic Stroke Using Magnetic Resonance Imaging-based Patient Selection.” International Journal of Stroke (2019). Sage Journals. May 04 2020.