Transition of European Cooperative Acute Stroke Study III Results to Clinical Practice
Ninety-Day Outcomes in a US Cohort
Background and Purpose—The European Cooperative Acute Stroke Study (ECASS) III showed benefit of intravenous tissue-type plasminogen activator for acute ischemic stroke 3 to 4.5 hours from onset in selected patients from Europe, with this extended treatment subsequently recommended by the American Stroke Association. We prospectively enrolled patients with acute ischemic stroke treated with intravenous tissue-type plasminogen activator, during the time this recommendation was being applied in clinical practice to determine safety and efficacy in a representative cohort from the United States.
Methods—Patients with acute ischemic stroke treated with intravenous tissue-type plasminogen activator were enrolled at 18 primary stroke centers throughout Maryland, including community hospitals and academic medical centers. Patients grouped by time to treatment (≤3 versus 3–4.5 hours) were compared for the presence of exclusion criteria from ECASS III that are not standard practice in the United States for ≤3 hours (age, >80 years; history of stroke and diabetes mellitus; oral anticoagulant treatment; and National Institutes of Health Stroke Scale, >25). Outcomes included good function at 90 days (modified Rankin Scale, 0–1 and 0–2), mortality, and symptomatic intracerebral hemorrhage.
Results—In the 3- to 4.5-hour treatment group, there were significantly fewer patients aged >80 years and no patients with the combination of stroke and diabetes mellitus. There were no statistically significant differences by time to treatment in symptomatic intracerebral hemorrhage, mortality, or functional outcome.
Conclusions—For patients treated with intravenous tissue-type plasminogen activator 3 to 4.5 hours from onset in everyday practice in the United States, there is no evidence for increased risk or worse outcomes compared with standard treatment ≤3 hours.
The only treatment for acute ischemic stroke approved by the United States Food and Drug Administration is thrombolysis with intravenous tissue-type plasminogen activator (tPA) ≤3 hours of stroke onset. The third European Cooperative Acute Stroke Study (ECASS III), published September 2008, showed benefit of intravenous tPA 3 to 4.5 hours from onset.1 ECASS III used additional exclusion criteria that are not part of standard approved treatment for ≤3 hours in the United States (age, >80 years; history of stroke and diabetes mellitus; oral anticoagulant treatment regardless of prothrombin time; and National Institutes of Health Stroke Scale [NIHSS], >25). Expansion of the treatment window to 4.5 hours was recommended for patients who would have met the ECASS III inclusion criteria by a Scientific Advisory from the American Stroke Association in May 2009.2 As this recommendation was being transitioned into clinical practice, we sought to determine whether exclusion criteria were being strictly followed, and whether the expanded time window was safe and effective in everyday clinical practice using a representative cohort in the United States.
The Maryland intravenous tPA Stroke Outcomes Study (MITSOS) included 18 primary stroke centers throughout Maryland, ranging from small community hospitals to academic medical centers (study approved by the Institutional Review Board for each site). Consecutive patients were approached during hospitalization, and informed consent was obtained from them or their legally authorized representative. Enrollment occurred between July 2009 and March 2012; however, because of institutional review board schedules, sites became active at different times. During the enrollment period, 544 patients were treated with intravenous tPA for acute ischemic stroke at participating sites. Consent was unable to be obtained from 248 patients, and 296 were enrolled. Of those enrolled, 5 underwent intra-arterial treatment, 13 lost to follow-up, and 1 did not have time of tPA treatment recorded, leaving 277 for analysis.
Patient demographic, treatment, and hospital outcome data were obtained from the Get With The Guidelines performance improvement database at each site (described previously)3 or from the medical record. Study personnel at University of Maryland blinded to details of hospitalization, including time to tPA treatment, determined 90-day modified Rankin Scale through structured phone interviews.4
Functional outcome was evaluated using the 2 definitions most commonly used in stroke clinical trials: modified Rankin Scale 0 to 1 or 0 to 2. Safety outcomes were mortality and symptomatic intracerebral hemorrhage, as entered into Get With The Guidelines by local personnel using National Institute of Neurological Disorders and Stroke (NINDS) criteria.5 Baseline characteristics and outcomes were compared between the ≤3- and 3- to 4.5-hour groups, using Fisher exact test for proportions, t test for mean, or 2-sample median test. Adjusted analysis with logistic regression was performed to evaluate for confounding by baseline characteristics (see online-only Data Supplement for additional details of analysis). Statistical calculations were performed with SAS (version 9.2).
Of the remaining 277 patients in the analysis, the majority (183; 66%) were enrolled at community hospitals. However, community hospitals treated a significantly lower proportion of their patients in the later time window compared with academic medical centers (15.8% versus 38.3%; P<0.0001).
Patients treated in the later time window had less severe strokes (median NIHSS, 5 versus 8; P=0.04) and a trend toward younger age (mean, 62.6 versus 66.6 years; P=0.06). There were no other significant differences in demographic characteristics between the groups (Table I in the online-only Data Supplement). Our patients had a higher rate of comorbid conditions compared with patients enrolled in prior randomized clinical trials (notably, diabetes mellitus in 29% versus NINDS 21% and ECASS III 16%; Table II in the online-only Data Supplement).
The additional ECASS III exclusions did seem to influence which patients were treated, as there were significantly fewer patients aged >80 years, and there were no patients with the combination of stroke and diabetes mellitus in the later time window. However, it did not seem that NIHSS >25 or use of anticoagulants were significant factors in treatment (Table 1).
There was no significant difference in the proportion of patients with good outcome at 90 days between treatment groups. Treatment ≤4.5 hours also seemed to be safe, as there was no increase in symptomatic intracerebral hemorrhage or mortality.
Logistic regression analysis showed that the odds ratio for good outcome was influenced by age, NIHSS, and the combination of prior stroke, and diabetes mellitus. When corrected for baseline differences, there was still no statistically significant difference in the odds of good outcome in patients treated ≤3 versus 3 to 4.5 hours (Table 2).
We analyzed the limited data available on intravenous tPA-treated patients not enrolled in the study to determine whether our cohort was representative. Non-enrolled patients had more severe strokes (median NIHSS, 12.0 versus 8.0; P<0.0001), and a higher proportion of patients was >80 years (30% versus 18.4%; P=0.002). Notably, there was no difference in the proportion of patients treated 3 to 4.5 hours in the non-enrolled versus enrolled groups (22.6% versus 23.5%; P=0.81) and also no difference in the proportion treated at community hospitals (65% versus 66%).
In our cohort, there was incomplete adherence to the published treatment guidelines, with 14% of patients treated 3 to 4.5 hours having ≥1 of the additional exclusion criteria. Despite this, we found that for patients treated with intravenous tPA for acute ischemic stroke 3 to 4.5 hours from onset in everyday practice in the United States, there was no evidence for increased risk or worse outcome compared with standard treatment ≤3 hours from onset. The study limitations include small sample size that may have masked some differences between groups. Because there were no patients with the combination of stroke and diabetes mellitus treated 3 to 4.5 hours, we cannot comment on safety or efficacy of that practice. There were some differences between enrolled and non-enrolled intravenous tPA-treated patients, which may limit the generalizability of findings. However, as there was no difference in the proportion of patients treated in the extended time window, this is unlikely to affect comparisons related to time to treatment.
The history of acute stroke care is marked by randomized clinical trial results that are only slowly adopted into clinical practice. Some of the concerns clinicians have are whether trial results are generalizable to their patients, and whether the risk-benefit profile from trials will hold true in a broader context. To our knowledge, this study is the first to evaluate long-term functional outcomes in patients treated in the extended time window in the United States. It supports the application of the ECASS III results to practice settings within the United States.
Sources of Funding
This study was supported by an award from the American Heart Association/American Stroke Association.
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.113.002478/-/DC1.
- Received June 12, 2013.
- Accepted August 28, 2013.
- © 2013 American Heart Association, Inc.
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