Response to Letter Regarding Article, “Adherence to Third European Cooperative Acute Stroke Study 3- to 4.5-Hour Exclusions and Association With Outcome: Data From Get With the Guidelines-Stroke”
We thank Drs Sen and Powers1 for their interest in our article.2 Their objective in their letter is “to caution readers that these data should not be interpreted as indicating that patients who do not meet European Cooperative Acute Stroke Study (ECASS) III eligibility criteria benefit from intravenous tissue-type plasminogen activator (tPA) at 3 to 4.5 hours.” We agree that as our data are observational, they do not provide absolute proof of benefit. However, we do feel that these data viewed in combination with other observational studies, and the randomized controlled Third International Stroke Trial (IST-3) suggest that patients with these additional exclusion criteria may benefit from treatment with IV tPA at >3 to 4.5 hours.
They state that “ECASS III medical and surgical patients both did better than their counterparts in NINDS… the natural history of the control patients in the two time periods is different.” Because these studies had no surgical arm, we assume that they refer to alteplase and placebo groups. That being the case, we would point out that this difference in control patients likely reflects the different exclusion criteria used. This is the factor we were trying to analyze by comparing similar patients (ie, with the additional exclusion criteria) treated in practice in the 2-time windows. In addition, we used multivariable regression to control for imbalances in age, stroke severity and medical history between patients treated at 0 to 3 and >3 to 4.5 hours.
They further suggest “a better analysis of the data would be to compare the treated 3 to 4.5 with and without exclusions.” We considered this analysis, but concluded it was not the best way to proceed given our goal “to address the practical question of whether different exclusion criteria should be used for patients presenting in different time windows.” Because patient age and stroke severity have been found to be highly predictive of outcome, regardless of treatment, patients with the additional exclusions would be expected to have worse outcomes. The question to address is whether these factors have a greater negative influence on outcome in the later time window than they do early on because the factors might then be expected to counteract the beneficial effects of tPA treatment in this time window. Our analysis of the odds ratio for adverse outcome did not find a detrimental effect of the exclusion criteria in the >3- to 4.5-hour time window when compared with 0 to 3 hours.
This question was further addressed in a recent meta-analysis from the Stroke Thrombolysis Trialists’ Collaborative Group using data from 9 randomized trials.3 This analysis confirmed previous findings that patients aged >80 years and those with large strokes have a lower rate of good outcome overall, independent of treatment. However, “proportional treatment benefits were similar irrespective of age or stroke severity.”
Drs Sen and Powers1 contend that proof of tPA effectiveness in patients excluded from ECASS III can only come from new randomized controlled trials in this patient population. However, to our knowledge, such trials are not underway or being planned and are unlikely to be undertaken. Therefore, we stand by our conclusion that the available data suggest that treatment with IV tPA should be considered in the >3- to 4.5-hour window for patients with acute stroke with one of the additional exclusion criteria used in the ECASS III trial.
Carolyn A. Cronin, MD, PhD
Department of Neurology
University of Maryland School of Medicine
Eric E. Smith, MD, MPH
Department of Clinical Neurosciences
and Hotchkiss Brain Institute
University of Calgary
Calgary, Alberta, Canada
Sources of Funding
This study was supported by American Heart Association.
Dr Cronin Recipient of a Young Investigator Database Research Seed Grant from the American Heart Association/American Stroke Association Stroke Council to conduct this study. Dr Smith serves as a member of the GWTG Steering Committee.
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- © 2014 American Heart Association, Inc.
- Sen S,
- Powers WJ
- Cronin CA,
- Sheth KN,
- Zhao X,
- Messé SR,
- Olson DM,
- Hernandez AF,
- et al
- Emberson J,
- Lees KR,
- Lyden P,
- Blackwell L,
- Albers G,
- Bluhmki E,
- et al