In 1933, two researchers at Johns Hopkins Medical School, observed that broth cultures of Streptococcus hemolyticus isolated from patients had the ability to dissolve clots. Two decades later, two neurologists reported the first use of thrombolysis in a woman who was paralyzed due to a blocked middle cerebral artery. Although she improved clinically, two other patients with blocked cerebral arteries causing acute stroke did not show clinical improvement following thrombolysis.
Because of limited diagnostic tools and the high rate of hemorrhagic complications, it took another four decades before publication of the first trials to evaluate the use of thrombolysis in patients presenting with acute stroke. Current guidelines recommend that patients presenting within 4.5 hours after onset of ischemic stroke are treated with thrombolysis. However, questions remain regarding the use of thrombolysis in patients who present past the 4.5-hour window.
In a randomized, multicenter trial published in the NEJM, Ma and colleagues investigated whether patients presenting within 9 hours after onset of ischemic stroke and a favorable perfusion imaging profile benefited from thrombolysis with intravenous alteplase. Although the trial ended early because of loss of equipoise (loss of uncertainty about the therapeutic benefit of thrombolysis with intravenous alteplase) due to publication of results of another trial, the percentage of patients with no or minor neurologic deficits in the alteplase group was significantly higher than in the placebo group (35.4% vs. 29.5%; adjusted risk ratio, 1.44; 95% CI, 1.01-2.06, P=0.04).
The following NEJM Journal Watch summary further explains the study.
Moving Intravenous Thrombolysis for Stroke Beyond 4.5 Hours
Seemant Chaturvedi, MD and Ali Raja, MD, MBA, MPH reviewing Ma H et al. N Engl J Med 2019 May 9 Marshall RS. N Engl J Med 2019 May 9
Patients presenting 4.5 to about 9 hours after stroke onset had better functional outcomes but more symptomatic intracranial hemorrhage with alteplase than placebo.
Current guidelines recommend that intravenous (IV) alteplase should only be administered for patients with acute stroke who meet criteria and can be treated within 4.5 hours. However, some patients with salvageable brain tissue beyond the current time window might benefit from IV alteplase. These authors investigated whether alteplase could improve outcome in patients presenting within the 4.5- to 9-hour time window (or within 9 hours of the midpoint of sleep with stroke upon waking) who had radiologic evidence of salvageable brain tissue. Of those who underwent advanced brain imaging, 225 had a proven disparity between the infarct core and volume of hypoperfused tissue (radiologic mismatch). The primary study outcome was functional status at 90 days; modified Rankin scale score of 0–1 was considered an excellent outcome.
Patients randomized to alteplase were slightly older and had more-severe strokes than placebo patients. Stroke with unknown onset time occurred in 65%. Large vessel occlusion was present in 69% of alteplase and 72% of placebo patients. After adjustment for baseline imbalances, an excellent outcome was observed in 35.4% of alteplase patients and 29.5% of placebo patients, a significant difference. Reperfusion of at least 50% of the hypoperfused territory occurred in 72% of alteplase and 52% of placebo recipients. Symptomatic intracranial hemorrhage was more common with alteplase than with placebo (6.2% vs. 0.9%). Mortality did not differ between the two groups.
Comment — Neurology
Seemant Chaturvedi, MD
This study showed an approximately 6% increase in favorable outcome with alteplase, along with a 5.3% increase in symptomatic brain hemorrhage. Given the increased rate of hemorrhage, many of the patients who met study criteria are likely to be better off with mechanical thrombectomy only. However, in areas or situations where thrombectomy is not available or in patients with absence of large-vessel occlusion, IV thrombolysis could be cautiously offered in these late-presenting patients on a case-by-case basis.
Comment — Emergency Medicine
Ali Raja, MD, MBA, MPH
The data from this small study are hypothesis-generating but should not yet change practice. It remains unclear whether there truly was a difference in the primary outcome (modified Rankin scale score of 0–1), which showed no statistically significant difference between alteplase and placebo after logistic regression (P=0.06) but did after Poisson regression (P=0.04). Fortunately, given that most of the patients in the study had large vessel occlusions, the point is moot — they would have been better off with a thrombectomy. However, additional research is still needed before we consider extending the thrombolysis window beyond 4.5 hours.
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Amanda Fernandes is a 2018-2019 NEJM editorial fellow.