On Sept. 25, 2020, ACEP Now published Ken Milne’s article entitled “After Re-Analysis, No Trials Show Efficacy of tPA in Acute Ischemic Stroke,” which focuses on reanalysis of NINDS (0–3 hours post-stroke onset) and ECASS III (3–4.5 hours post-stroke onset) data.
Explore This IssueACEP Now: Vol 40 – No 04 – April 2021
A [graphical] reanalysis of the NINDS data published in 2009 revealed that a baseline imbalance in stroke severity at presentation likely led to the difference in outcomes.1 After controlling for these baseline differences, the claimed efficacy of tPA was no longer statistically significant.
Concern 1: Two responses to the reanalysis were published. Saver et al indicate this reanalysis of NINDS “depart[s] from best practices appropriate for the visual display of quantitative information.”2 They continue on to say, “Several methods exist that are appropriate to the graphical depiction of scales with ordinal functional values and skewed population distributions, including charting normalized gain and loss and charting clinically relevant ordinal categories. Graphical analysis of the NIHSS and delta NIHSS scores in the two NINDS-TPA trials, when conducted in this proper manner, delineate large magnitude treatment benefits of under 3 hour fibrinolytic therapy in acute stroke.”
In a second response to this reanalysis, Dewey et al point out “such a conclusion cannot be justified by the findings from this post-hoc analysis of a secondary outcome from a randomized controlled trial with a positive primary outcome.”3 They also “question the relevance of the NIHSS as a measure of outcome at 90 days. At this late time point functional capacity is of much more direct relevance to patients and is routinely assessed with the modified Rankin and Barthel Scales.”
As noted by these two different responses, the reanalysis was performed on a secondary outcome and did not account for the ordinal, noninterval nature of NIHSS’ functional significance and the skewed population distribution, leading to misrepresentation of the results from the NINDS trial. The author also failed to discuss the graphical reanalysis of the two NINDS-tPA trials completed by Saver et al.4
Reanalysis of the ECASS III trial data with multiple approaches adjusting for baseline imbalances does not support any significant benefits and continues to support harms for the use of alteplase 3–4.5 hours after stroke onset.
Concern 2: Although Alper et al concluded their reanalysis of ECASS III data did not demonstrate significant benefits, they do note that a “limitation of reanalysis, or any method for adjusting for non-randomised factors influencing the effect estimates from a randomised trial, is such analyses cannot confidently produce new conclusions (neither a claim of efficacy nor a claim of absence of efficacy). … In this case the reanalysis does not negate the original findings, but it greatly reduces the certainty for those findings.”5
Although not obligatory, the author does not call attention to the flaws of conducting this reanalysis. As Activase in the 3–4.5-hour time frame is not FDA-approved, Genentech does not endorse the use of Activase use in this time frame. However, a reanalysis that examines the benefit or risk of a society-recommended treatment should be presented objectively to allow informed decision making on whether or not to offer such treatment to patients.