Since the earliest trials examining the efficacy of tPA for acute ischemic stroke, there has been a tendency to play it fast and loose with the scientific method. The results of the landmark NINDS-2 trial, a moderate-sized randomized, controlled trial with a tenuously positive primary outcome (fragility index of 3), were never validated. (N Engl J Med. 1995;333:1581; http://bit.ly/2VYV1o9.)
The results of ECASS-3, the second positive randomized, controlled trial examining tPA for ischemic stroke, led to the extension of the treatment window from three to 4.5 hours despite conflicting with a decade of prior literature. (N Engl J Med. 2008;359:1317; http://bit.ly/2JBeVPz.)
IST-3, a negative trial, was the largest trial to date, and was broadly cited as a success based on a secondary measure using an ordinal regression of dubious methodological rigor. (Lancet. 2012;379:2352; http://bit.ly/2JCuCpI.)
But with the recent publication of the EXTEND trial by Ma, et al., in the New England Journal of Medicine, we have moved from a casual handling of the scientific method to brazen disregard. (2019;380:1795; http://bit.ly/2VkCPBl.)
Ma, et al., enrolled adult patients presenting with symptoms concerning for a cerebrovascular accident within 4.5 to nine hours of symptom onset with an NIH stroke scale score between four and 26 who had salvageable brain tissue detected on perfusion imaging. Patients were randomized to IV tPA or placebo. Patients who experienced stroke-like symptoms upon awakening from sleep were also eligible for enrollment if they demonstrated appropriate perfusion imaging.
The trial, initially planned to enroll 400 patients, was stopped prematurely due to “loss of equipoise” after the WAKE-UP trial found a fairly fragile signal of benefit in favor of IV tPA. (N Engl J Med. 2018;379:611; http://bit.ly/2VlVH2z.)
Ma, et al., ended up enrolling 225 patients at 28 centers across Australia, Asia, and Europe from August 2010 through June 2018. The majority of these patients (65%) presented with symptoms after awakening from sleep, 25 percent presented between six and nine hours after symptom onset, and 10 percent presented within 4.5 to six hours. The trial found no difference in the rate of their primary outcome—the number of patients with a modified Rankin scale (mRS) score of 0 or 1 at 90 days—which occurred in 35.4 percent of patients in the tPA group and 29.5 percent in the placebo group (RR1.2, 95% CI 0.82-1.76, P=0.35).
Nor did they observe a difference in the ordinal analysis or 90-day mortality. Of note, the rate of symptomatic intracranial hemorrhage within 36 hours, while not statistically significant, was consistent with every other trial examining IV tPA for CVA, occurring in 6.2 percent of the tPA group and 0.9 percent of the control group.
An Impressively Negative Trial
By all accounts, this is an impressively negative trial and yet somehow the authors conclude: “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.”
To support this claim, the authors cited the adjusted analysis performed on their primary outcome, reporting an adjusted risk ratio of 1.44 (95% CI 1.01-2.06; p=0.04). With what statistical wizardry were they able to transform an entirely unimpressive p-value of 0.35 to 0.04?
The methodological sleight of hand in this case came in the form of a Poisson regression analysis. Like all regression analyses, Poisson regression analyses are a means of controlling for covariants that may influence the outcome. It is not clear why the authors chose to use this specific form of regression analysis over the more traditional logistic regression model.
It is interesting that the authors did not plan a Poisson analysis in their original statistical analysis proposal, and stated they would perform a binary logistic regression. It was not until just prior to the publication of their final manuscript that the Poisson analysis was proposed as the preferred method of analysis. Their original binary logistic regression analysis can be found tucked away in the supplementary appendix, which, like the unadjusted results, found no difference between the groups.
More important than quibbling over the preferred regression analysis is to ask whether a regression analysis should have been performed in the first place. Regression analyses are statistical methods that attempt to control for any confounding variables present. They are a useful tool in observational cohorts, which typically have a great deal of nonrandom error.
Any differences in baseline variables in a randomized, controlled trial can be attributed to random chance and ideally limited by increasing the sample size—or in this case, not stopping the study prior to obtaining the preplanned sample. No amount of regression analyses will change the fact that this was a small trial that was stopped prematurely, with a minimal difference observed between the tPA and control groups. At best, the results of their Poisson analysis should be viewed as hypothesis-generating.
The problem with this study is not the regression analysis used by the authors but their underlying intentions. Were they attempting to unearth an otherwise obscured truth or simply manufacture a positive trial? Ma, et al., set out to examine the utility of IV tPA in patients within 4.5 to nine hours of symptom onset who had salvageable brain tissue on perfusion imaging.
This concept has been given some clinical legitimacy with the publication of endovascular trials demonstrating that certain patients far outside the traditional time windows benefited from reperfusion therapy. (N Engl J Med. 2018;378:11, http://bit.ly/2Ji0cKg; N Engl J Med. 2018;378:708; http://bit.ly/2VC0sKD.)
This is a valid hypothesis, but it was made in bad faith in this case. Why only examine patients outside the 4.5-hour window if the authors believed that time is a poor surrogate for salvageable tissue? If it is a poor surrogate, then patients presenting in under 4.5 hours without salvageable tissue on perfusion imaging should not benefit from reperfusion therapy. Why maintain empiric time thresholds for the first 4.5 hours and then move only toward individualized selection of patients with appropriate perfusion studies?
The answer is simple. This study, like all the studies before it, is not about identifying the small select subset of patients who may benefit from IV tPA, but is designed to expand the number of patients who receive this medication. To do so, the authors have created a positive trial from the remains of a negative study, a statistical parlor trick intended to EXTEND the use of IV tPA beyond what is supported by science.
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Dr. Spiegelis a clinical instructor in emergency medicine and a critical care fellow in the division of pulmonary and critical care medicine at the University of Maryland Medical Center. Visit his blog athttp://emnerd.com, follow him on Twitter @emnerd_, and read his past articles athttp://bit.ly/EMN-MythsinEM.Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.