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 (1), a moderate sized RCT, with a tenuously positive primary outcome (Fragility Index of 3), were never validated. The results of ECASS-3 (2), the second positive RCT examining tPA for ischemic stroke, led to the extension of the treatment window from 3 to 4.5 hours despite being in conflict with a decade of prior literature. IST-3 (3), a negative trial, is the largest trial to date, and has been broadly cited as a success based on a secondary measure using an ordinal regression of dubious methodological rigor. But with the publication of the EXTEND trial (4) by Ma et al in the NEJM, we have moved from a casual handling of the scientific method to a brazen disregard.
Ma et al enrolled adult patients presenting with symptoms concerning for a CVA, within 4.5-9 hours of symptom onset, with NIHSS between 4-26, who had salvageable brain tissue detected on perfusion imaging. Patients were randomized to either 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 publication of the WAKE-UP trial (5) found a fairly fragile signal of benefit in favor of IV tPA.
From August 2010 through June 2018 Ma et al enrolled 225 patients at 28 centers across Australia, Asia, and Europe. The majority of these patients (65%) presented with symptoms upon awakening from sleep, 25% presenting between 6-9 hours after symptom onset and 10% presenting within 4.5-6 hours. The trial found no difference in the rate of their primary outcome, number of patients with a modified Rankin scale (mRS) score of 0 or 1 at 90-days, occurring in 35.4% of patients in the tPA group and 29.5% 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, is consistent with every other trial examining IV tPA for CVA, occurring in 6.2% of the tPA group and 0.9% of the control group.
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 to 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? In this case the methodological sleight of hand came in the form of a Poisson regression analysis. Poisson regression analyses like, all regression analyses are a means of controlling for covariants that may influence the outcome in question. 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 to note that in their original statistical analysis plan the authors did not plan to perform a Poisson analysis, stating 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. Tucked away in the supplementary appendix one can find their original binary logistic regression analysis, which like the unadjusted results found no difference between the groups.
More important than quibbling over the preferred regression analysis is to question whether a regression analysis should have been performed in the first place. Regression analyses are statistical methods which attempt to control for any confounding variables that might be present. They are a useful tool in observational cohorts which typically have a great deal of non-random error. In an RCT any differences in baseline variables 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, stopped prematurely, with a minimal difference observed between the tPA and control groups. At very 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 rather 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 4.5-9 hours of symptom onset who had salvageable brain tissue demonstrated on perfusion imaging. This concept has been given some clinical legitimacy with the publication of the endovascular trials demonstrating that certain patients far outside the traditional time windows benefited from reperfusion therapy (6,7). And while this is a valid hypothesis, in this case it was made in bad faith. If the authors believe that time is a poor surrogate for salvageable tissue, then why only examine patients outside the 4.5-hour window? If time is a poor surrogate, then patients presenting in under 4.5-hours without salvageable tissue demonstrated on perfusion imaging should not benefit from reperfusion therapy. Why, maintain empiric time thresholds for the first 4.5-hours and only then move towards individualized selection of patients with appropriate perfusion studies? The answer is simple, because 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 rather is designed to expand the number of patients who receive this medication. To do so the authors have created a positive trial from the statistical remains of a negative study, a statistical parlor trick, intended to EXTEND the use of IV tPA beyond what is supported by science.
- Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995;333(24):1581-7.
- Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008;359(13):1317-29.
- Sandercock P, Wardlaw JM, Lindley RI, et al. The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST-3]): a randomised controlled trial. Lancet. 2012;379(9834):2352-63.
- Ma H, Campbell BCV, Parsons MW, et al. Thrombolysis guided by perfusion imaging up to 9 hours after onset of stroke. N Engl J Med 2019;380:1795-1803.
- Thomalla G, Simonsen CZ, Boutitie F, et al. MRI-Guided Thrombolysis for Stroke with Unknown Time of Onset. N Engl J Med. 2018;379(7):611-622.
- Nogueira RG, Jadhav AP, Haussen DC, et al. Thrombectomy 6 to 24 Hours after Stroke with a Mismatch between Deficit and Infarct. N Engl J Med. 2018;378(1):11-21.
- Albers GW, Marks MP, Kemp S, et al. Thrombectomy for Stroke at 6 to 16 Hours with Selection by Perfusion Imaging. N Engl J Med. 2018;378(8):708-718.
University of Maryland
Resuscitation Fellowship Graduate