Introduction
Acute ischemic stroke remains one of the few neurological disorders in which expeditious diagnosis and treatment could potentially lead to complete recovery. In 1995, the National Institute of Neurological Disorders and Stroke (NINDS) study group published their landmark randomized controlled trial (RCT) of intravenous thrombolysis with alteplase compared to placebo in acute ischemic stroke (1). Patients treated with intravenous alteplase within 3 hours of symptom onset were more likely to have minimal or no disability at three months compared with placebo, despite a higher incidence of symptomatic intracerebral hemorrhage. Two further RCTs followed; the ECASS trial included patients within 6 hours of symptom onset. Functional outcomes were more favorable with alteplase in patients with moderate to severe neurological deficits without extended signs of infarct on initial CT imaging (2). The ECASS II trial, published 3 years later, stratified patients according to the time since onset of symptoms, between 0–3 hours or 3–6 hours. No significant difference was observed in favorable neurological outcomes between the two groups, regardless of the duration of symptoms; however, most patients received treatment between 3–6 hours (3).
Subsequently, a pooled analysis evaluated outcomes from 6 RCTs, including 2775 patients that used intravenous recombinant tissue plasminogen activator (rt-PA) in acute ischemic stroke (4). Compared with placebo, the authors reported favorable clinical outcomes when thrombolytic treatment was administered between 3–4.5 hours after symptom onset. Furthermore, the extended time window did not result in an increased incidence of intracranial hemorrhage or death.
The ECASS III trial was designed to evaluate the efficacy of intravenous thrombolysis with alteplase among patients who present between 3–4.5 hours after the onset of stroke symptoms (5).
Population and design
The ECASS III RCT was a double-blind, parallel-group trial conducted across multiple centers in Europe. The study was conducted from July 2003 to November 2007 across 130 sites in 19 countries. Patients between 18–80 years old with a clinical diagnosis of stroke were eligible if the study drug could be administered within 3–4 hours of symptom onset. The time interval was extended to 4.5 hours after the enrollment of 228 patients, considering newly available evidence and slower than expected recruitment rate. Stroke symptoms had to persist for ≥30 minutes with no sign of improvement in between for eligibility.
Exclusion
Patients with intracranial hemorrhage and those in whom the time of symptom onset was unknown, those with severe stroke, and intracranial hemorrhage were excluded. Those with seizures, previous stroke or severe traumatic brain injury in the preceding 3 months, thrombocytopenia (platelet count <100,000), hypertension (systolic BP >185 or diastolic BP >110 mm Hg), extremes of blood glucose levels (<50 or >400 mg/dl), major surgery or severe trauma within the previous 3 months, and major disorders with an increased risk of bleeding were also excluded. Randomization was carried out at study centers in a 1:1 ratio, in blocks of four, to allow a balanced distribution of assignment to groups.
Alteplase group
Patients received alteplase, 0.9 mg/kg, intravenously, to a maximum dose of 90 mg. Ten percent of the dose was administered as a bolus, followed by the remaining dose over 60 minutes.
Placebo group
A matching placebo consisting of an identical lyophilized powder reconstituted in water was administered over the same duration.
Common management
During the first 24 hours after the administration of the study drug, intravenous heparin, oral anticoagulants, aspirin, and volume expanders including hetastarch or dextrans were not allowed. Subcutaneous unfractionated or low molecular weight heparin was allowed as prophylaxis against deep vein thrombosis. CT or MRI scans were performed before the commencement of treatment and at 22–36 hours later. Patients were evaluated on days 30 and 90 using the modified Rankin scale (Table 1).
Sample size
The investigators calculated the sample size based on the primary efficacy endpoint – disability on day 90. Disability was assessed using the modified Rankin scale and categorized into favorable (0 or 1) or unfavorable (2–6) scores.
Table 1. The modified Rankin scale
|
Score on the modified Rankin scale |
Description |
|
0 |
No symptoms |
|
1 |
No significant disability. Able to carry out all usual activities, despite some symptoms |
|
2 |
Slight disability. Able to look after own affairs without assistance, but unable to carry out all previous activities |
|
3 |
Moderate disability. Requires some help, but able to walk unassisted |
|
4 |
Moderately severe disability. Unable to attend to own bodily needs without assistance, or unable to walk unassisted |
|
5 |
Severe disability. Requires constant nursing care and attention, bedridden, incontinent |
|
6 |
Dead |
They assumed an odds ratio of 1.4 favoring alteplase based on data from the previous pooled analysis (4) that compared patients who received thrombolysis with placebo at 3–4.5 hours after stroke onset. A sample size of 800 patients provided the study with 90% power to detect a favorable effect with thrombolysis.
Results
A total of 821 patients were randomized – 418 patients were assigned to the alteplase group and 403 to the placebo group. Alteplase was administered at a median duration of 3 hours 59 minutes after onset of symptoms. Most patients were randomized between 3.5–4 hours (46.8%), followed by between 4–4.5 hours (39.2%), and 3–3.5 hours (10%). Stroke severity was higher in the placebo group (mean NIHSS score: 11.6 ± 5.9 vs. 10.7 ± 5.6). The incidence of previous stroke was also higher in the placebo group (14.1% vs. 7.7%). Apart from these characteristics, patients were well-matched at baseline.
The primary endpoint: disability at day 90
A favorable outcome, defined as a score of 0–1 on the modified Rankin scale (no symptoms or mild symptoms, but able to carry out all usual activities) was significantly greater with alteplase compared to placebo [52.4% vs. 45.2%, odds ratio: 1.34 (1.02–1.76), p = 0.04]. On post-hoc intention-to-treat analysis, after adjustment for confounding baseline characteristics, the favorable outcomes persisted with alteplase compared with placebo [odds ratio: 1.42 (1.02–1.98) P = 0.04)
The secondary endpoint: global outcome
The secondary endpoint was a global outcome measure that used a combination of outcomes at 90 days. The individual components of the global outcome included a score of 0 or 1 on the modified Rankin scale, a score of ≥95 on the Barthel Index, a score of 0 or 1 on the NIHSS, and a score of 1 on the Glasgow Outcome Scale. The Global outcome measure was more favorable in the alteplase group [odds ratio: 1.28 (1.0–1.65), p = 0.05]. Thus, the likelihood of a favorable outcome, with an independent lifestyle, was 28% higher with alteplase compared with placebo.
The individual components of the global outcome measure were assessed at 30 and 90 days. A modified Rankin score of 0–2 and a Barthel Index score (ranging from a score of 0 for total dependence to 100 for independent living) of ≥95 were similar in both groups. An NIHSS score (0 to 42, with higher values reflecting more severe neurologic impairment) of 0 or 1, or >8-point improvement from baseline, was more favorable at 30 days in the alteplase group.
Safety outcomes
A total of 66 patients died; mortality was not significantly different between the alteplase and placebo groups (7.7% vs. 8.4%, p = 0.68). The overall incidence of intracranial hemorrhage was higher with alteplase compared to placebo (27.0% vs. 17.6%, p = 0.001). Symptomatic intracranial hemorrhage, although uncommon, was significantly higher with alteplase (2.4% vs. 0.3%, p = 0.008). All cases of symptomatic intracranial hemorrhage occurred within 22–36 hours of commencement of treatment. The incidence of symptomatic cerebral edema did not differ significantly between the two groups. Adverse events involving other organ systems were few and were similar in both groups. The main outcomes are summarized in Table 2.
Table 2. Summary of main outcomes
|
Outcome |
Alteplase (418 patients) |
Placebo (403 patients) |
Odds ratio |
p-value |
|
mRS score of 0 or 1 |
219 (52.4%) |
182 (45.2%) |
1.34 (1.02–1.76) |
0.04 |
|
Global outcome |
1.28 (1.00–1.65) |
0.05 |
||
|
90-d mortality |
32 (7.7%) |
34 (8.4%) |
0.90 (0.54–1.49) |
0.68 |
|
Symptomatic ICH |
10 (2.4%) |
1 (0.2%) |
9.85 (1.26–77.32) |
0.008 |
Abbreviations: mRS, modified Rankin Scale; ICH, intracranial hemorrhage
Strengths
The NINDS trial had previously reported significantly favorable outcomes among stroke patients who received thrombolytic treatment within 3 hours of symptom onset. The ECASS III trial evaluated the efficacy of thrombolysis beyond this time window for up to 4.5 hours. This landmark trial represented an important milestone in stroke therapy, establishing the efficacy of thrombolysis in patients who may present beyond the previously studied time window of 3 hours after the onset of symptoms. The study had a robust design and was well-conducted. The authors applied multiple, pre-specified analytical approaches to overcome potential confounders. The outcomes studied were pre-specified and clinically relevant. The study raised optimism of improved neurological outcomes among patients who may present beyond the conventionally accepted duration of 3 hours after the onset of symptoms following ischemic stroke.
Limitations
The investigators excluded patients with severe stroke. A subgroup analysis of the NINDS trial had in fact, revealed improved outcomes with thrombolytic treatment in severe stroke among older patients. There were imbalances between groups at baseline; patients in the placebo group had more severe stroke by the NIHSS criteria and a higher incidence of previous stroke. Besides, in the placebo group, the incidence of large vessel occlusion was higher, smokers were more common, and fewer patients were on aspirin. The fragility index of the study was just 1 – which meant that the difference between groups would have been statistically non-significant if one additional patient in the placebo group had a favorable primary outcome. The study protocol was revised midway through the trial with the time window for thrombolysis being extended from 4 to 4.5 hours. The number of patients with diabetes was relatively low compared to previous stroke trials. Would the results be generalizable to diabetic patients?
Re-analysis of ECASS III
In 2020, Alper et al. performed a re-analysis of the ECASS III data, adjusting for differences in baseline characteristics between the alteplase and placebo groups (6). They carried out multivariable and stratified analyses; sensitivity analysis was performed for missing data. Baseline imbalances were identified between groups regarding the NIHSS score and previous history of stroke. The ECASS III paper had reported that their methodology of assessment of stroke severity was based on a range of 0–42 based on 15 parameters. However, the analysis was actually carried out on a score ranging from 0–46 that included two additional components of distal motor function. On re-analysis based on the standard NIHSS scale of 0–42, a favorable primary outcome of 0 or 1 on the modified Rankin scale at 90 days was not significantly greater in the alteplase group.
Further re-analysis after adjusting for baseline imbalances revealed that none of the secondary outcomes were significantly more favorable in the alteplase group; however, the significantly higher incidence of intracerebral hemorrhage persisted. This re-analysis of the ECASS III trial raises concerns regarding bias arising from baseline imbalances that could have confounded the results. However, as the authors of the re-analysis themselves state, although their findings may alter the certainty behind the unadjusted analysis of the original study, their findings can only be considered hypothesis-generating.
Summary
Thrombolysis, administered in a timely manner, was established as the definitive therapy for acute ischemic stroke within the first 3 hours of onset of symptoms following the NINDS study. The benefit of later administration of thrombolysis remained contentious despite RCTs and pooled analyses that followed. The ECASS III investigators conducted a multicentric, adequately powered RCT to evaluate the efficacy of alteplase compared with placebo among stroke patients between 3–4.5 hours after symptom onset. Compared with placebo, intravenous thrombolysis with alteplase resulted in improved neurological outcomes, resulting in more patients with either no disability or minimal deficit that did not restrict their usual activities. The incidence of intracranial hemorrhage was higher with alteplase; mortality was similar in both groups. Although the study was limited by imbalances between groups at baseline, it remains a landmark in the history of thrombolytic therapy for acute ischemic stroke and led to an extension of the time window for treatment.
References
1. National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995 Dec 14;333(24):1581–7.
2. Hacke W, Kaste M, Fieschi C, Toni D, Lesaffre E, von Kummer R, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The European Cooperative Acute Stroke Study (ECASS). JAMA. 1995 Oct 4;274(13):1017–25.
3. Hacke W, Kaste M, Fieschi C, von Kummer R, Davalos A, Meier D, et al. Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Second European-Australasian Acute Stroke Study Investigators. Lancet Lond Engl. 1998 Oct 17;352(9136):1245–51.
4. Hacke W, Donnan G, Fieschi C, Kaste M, von Kummer R, Broderick JP, et al. Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet Lond Engl. 2004 Mar 6;363(9411):768–74.
5. Hacke W, Kaste M, Bluhmki E, Brozman M, Dávalos A, Guidetti D, et al. Thrombolysis with Alteplase 3 to 4.5 Hours after Acute Ischemic Stroke. N Engl J Med. 2008 Sep 25;359(13):1317–29.
6. Alper BS, Foster G, Thabane L, Rae-Grant A, Malone-Moses M, Manheimer E. Thrombolysis with alteplase 3–4.5 hours after acute ischaemic stroke: trial reanalysis adjusted for baseline imbalances. BMJ Evid-Based Med. 2020 Oct;25(5):168–71.
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