Going beyond 4.5 hours might prove beneficial if ischemic penumbra can be saved.
Background: No matter which side of the debate you sit on in regards to systemic thrombolysis in acute ischemic stroke (AIS), there is one truth. Systems have been changed to ensure tPA is offered to patients in the ≤ 4.5-hour window. The debate surrounding tPA in AIS lies in the equipoise surrounding benefits while there are very real harms. Advocates of tPA in AIS hang on to two trials that have never been replicated (i.e. NINDS and ECASS-III), and both have major methodological issues. Opponents of tPA in AIS appropriately state that there are 11 other randomized clinical trials that have shown almost no benefit, yet at the cost of early increased mortality and symptomatic intracranial hemorrhage (sICH).
More recent endovascular studies have shown that perfusion-based imaging can show potential viable brain tissue beyond the 4.5-hour mark in patients with large vessel occlusions and result in good neurologic outcomes. This advance has prompted investigators to look at perfusion-based technology to identify a larger cohort of patients without large vessel occlusions that may be candidates for systemic thrombolysis.
Now we have two more industry sponsored trials (EXTEND and WAKE UP) that have been recently published, that are now pushing to extend the window of tPA out to nine hours in AIS with newer imaging modalities such as MRI diffusion-weighted imaging in patients with unknown onset of symptoms.
Findings
The WAKE UP trial (PMID: 29766770)[1] was a multicenter, randomized, double-blind, placebo-controlled clinical trial of 503 adult patients with unknown time of onset of stroke (with signs of stroke onset <4.5 hours based on advanced MR imaging) to receive either systemic tPA or placebo. The primary outcome was modified Rankin score of 0 to 1 at 90 days (good neurologic outcome). Primary outcome was achieved in 53.3% of the tPA arm vs. 41.8% in the placebo arm, which was statistically significant. However, the rate of intracranial hemorrhage (ICH) was 4.0% with tPA vs. 0.4% with placebo (statistically significant) and the rate of death was 4.1% with tPA vs. 1.2% with placebo (not statistically significant).
To further muddy the waters, the WAKE UP trial was stopped early owing to cessation of funding after the enrollment of 503 of the anticipated 800 patients. The trial required 370 pts per group to provide a power of 80% to show a 10% between-group difference, which was not met. The confidence interval (CI) in this study already approaches 1, so completion of enrollment may have resulted in the CI crossing 1. Smaller trials stopped early have been shown to grossly overestimate the benefit of a drug/intervention. The authors even admit, “The trial was stopped early because of a discontinuation of funding and enrolled fewer patients than planned. This factor limits the interpretation of the safety results because the observed trend toward a higher rate of death in the alteplase group may have become significant with a larger sample size.”
Another major issue with this trial is that in five years, 1,362 stroke patients had to be screened to find 500 patients that met indications for randomization. This equates to about nine patients per month. Sounds very similar to endovascular therapy for large vessel occlusion stroke, as in this is a very select group of patients and not all stroke comers.
The next study published on this topic was the EXTEND trial (PMID: 31067369) [2], which was a multicenter, randomized placebo-controlled trial of 225 patients with ischemic stroke with hypoperfused, but salvageable regions of the brain on perfusion imaging in the 4.5 – 9.0 hour window after onset of stroke or on awakening with stroke (if within nine hours from the midpoint of sleep).
Patients were randomized to systemic tPA vs. placebo. The primary outcome was a modified Rankin score of 0 to 1 at 90 days (again a good neurologic outcome). Primary outcome was achieved in 35.4% of patients in the tPA arm and 29.5% in the placebo arm, which was statistically significant. However, the rate of symptomatic intracranial hemorrhage was also statistically significant with a rate of 6.2% in the tPA arm vs. 0.9% in the placebo arm.
The EXTEND trial was terminated early because of a loss of equipoise after the publication of positive results from the WAKE UP trial published in May 2018. Again, this is a methodological issue, as stated before, most trials that go to completion have a regression to the mean, meaning trials stopped early, tend to be hyperinflated in their results.
Original pre-specified analysis of the primary outcome was supposed to be with a standard logistic-regression model, however with no explanation the authors used a covariate-adjusted modified Poisson regression instead, which has not traditionally been used in previous stroke trials. Regression modeling is used to adjust for confounding variables. What is interesting is the original logistic regression modeling can be found in the supplementary appendix, which found no difference between groups, however the covariate-adjusted modified Poisson regression model, which is what was published in the manuscript, did find a small difference.
Conclusion
In the WAKE UP trial the use of tPA resulted in a 11% improvement in neurologic outcomes at 90 days. However this resulted in more death, which was not statistically significant and more ICH, which was statistically significant. The EXTEND trial was a ridiculous display of statistical hocus pocus (i.e. multiple regressions ran, and the one that worked for the authors was the one selected for the manuscript).
One of the big fears in stroke management is the concept of indication creep: finding more uses for a medication or product without strong evidence to support its use. The bigger question is, does this increase in use help the company’s bottom line or the patient? It is no wonder physicians are skeptical of industry sponsored trials, as we sometimes question the motives behind the studies. Both these trials are examples of small studies, stopped early, to help promote one thing…more money in the pockets of the company making the medication.
