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Thrombolysis for Acute Ischemic Stroke
In 1996, the FDA approved the use of intravenous alteplase for the treatment of acute ischemic stroke after publication of the National Institute of Neurological Disorders and Stroke (NINDS) trial. There were five randomized controlled trials that laid the groundwork for this initial approval and paved the path for thrombolytic therapy for acute stroke . Over the next 20 years, significant advances have occurred in the treatment of acute stroke patients. The focus has shifted away from the efficacy and safety of the medication to the development of pathways to more rapidly identify patients who will benefit from early treatment. Additionally, there have been rapid advances in catheter-based approaches leading to six randomized controlled trials that have shown substantial benefit to patients suffering from strokes secondary to large vessel occlusions .
Intravenous Tissue Plasminogen Activator
Intravenous tissue plasminogen activator (t-PA) was tested in five randomized trials in the early 1990s ( Table 136.1 ) . The NINDS trial demonstrated that patients treated under 3 h from onset had a 30% higher probability of an excellent recovery compared to the placebo group . The other four trials (ATLANTIS A and B and ECASS I and II) failed to demonstrate this result and showed higher rates of intracranial hemorrhage . The conflicting results were felt to be secondary to the expanded time window in the four trials as well as the use of a higher dose of intravenous t-PA of 1.1 mg/kg in ECASS I. The adoption rate for delivery of the medication was not only slow due to patients not presenting in time but also due to reluctance of clinicians to administer the medication because of the concerns of hemorrhagic risks. It is estimated that less than 2% of patients were receiving the drug after the several years after approval of the drug . Moreover, community hospitals were not replicating results of the NINDS trial with higher complication rates due to protocol violations further compounding the concerns surrounding hemorrhagic risks .
Table 136.1
Summary of Randomized Clinical Trials Used to Determine Time Curve for t-PA Administration
| Study | Year Started | Time Window (h) | Number of Patients | Median NIHSS t-PA Group | Symptomatic ICH Rate (%) |
|---|---|---|---|---|---|
| NINDS Part 1 | 1991 | 0–3 | 291 | 14 | 5.6 |
| NINDS Part 2 | 1991 | 0–3 | 333 | 14 | 7.1 |
| ECASS I | 1992 | 0–6 | 620 | 12 | 20 |
| ECASS II | 1996 | 3–6 | 635 | 11 | 8.3 |
| ATLANTIS A | 1991 | 0–6 | 142 | 10 | 11.3 |
| ATLANTIS B | 1993 | 0–5 | 613 | 10 | 7.6 |
Extended Time Window to 4.5 h
A pooled analysis of patients from the five randomized trials demonstrated a benefit of intravenous t-PA to patients treated up to 4.5 h with an odds ratio of 1.4 . This finding laid the foundation for the ECASS III study to assess if the drug was efficacious in the 3–4.5 h time window . This study randomized 821 patients who were under the age of 80, presenting National Institutes of Health Stroke Scale (NIHSS) <25 and absence of prior stroke and diabetes mellitus, and presented between 3 and 4.5 h from last known normal. The study demonstrated a moderate benefit of administration of the drug in this population with 52.4% of patients receiving t-PA having a modified Rankin Scales (mRS) of 0–1% versus 45.2% in the placebo arm ( p < .04, OR 1.34 [1.02–1.76]) . The investigators found a 7.9% rate of symptomatic hemorrhage when using the NINDS definition in the treatment group. Despite the hemorrhages, patients benefited from the treatment thus prompting the 2013 American Heart Association guidelines to recommend treatment with intravenous t-PA up to 4.5 h if the patient meets the inclusion and exclusion criterion of ECASS III .
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