BACKGROUND: A minority of patients with stroke qualify for intravenous thrombolysis (IVT) within 4.5-hour window. The safety and efficacy of IVT beyond this period have not been well studied.
METHODS: We systematically searched MEDLINE, Embase, Cochrane, and ClinicalTrials.gov for relevant randomized clinical trials. Randomized clinical trials comparing IVT versus standard medical care in patients with ischemic stroke beyond 4.5 hours of symptom onset or last known well without mechanical thrombectomy (MT) were included. Primary outcomes were excellent (modified Rankin Scale score of 0-1) and good (modified Rankin Scale score of 0-2) functional outcomes at 90 days, symptomatic intracerebral hemorrhage (sICH), and death at 90 days. Pooled odds ratios (ORs) with 95% CIs were calculated using a random-effects model. Heterogeneity was assessed by Q test and quantified by I² values.
RESULTS: Eight randomized clinical trials (1742 patients; mean age, 69.8±9 years, 63.5% men) were included. Compared with standard medical care, IVT achieved higher rates of excellent (OR, 1.43 [95% CI, 1.17-1.75]; Q=2.30; P=0.94; I2=0%) and good functional outcomes (OR, 1.36 [95% CI, 1.12-1.66]; Q=2.07; P=0.96; I2=0%) at 90 days but also increased sICH rates (OR, 4.25 [95% CI, 1.67-10.84], Q=0.48; P=0.99; I2=0%). Mortality at 90 days did not significantly differ between treatment groups (OR, 1.28 [95% CI, 0.87-1.89]; Q=4.63; P=0.59; I2=0%). Subanalyses yielded numerically higher odds of excellent functional outcomes when patients were selected with perfusion imaging (3 studies, OR, 1.45 [95% CI, 1.08-1.94]) compared with diffusion-weighted imaging-fluid-attenuated inversion recovery mismatch (3 studies, OR, 1.34 [95% CI, 0.94-1.91]) and when treated with tenecteplase (3 studies, OR, 1.47 [95% CI, 1.06-2.04]) compared with alteplase (5 studies, OR, 1.38 [95% CI, 1.08-1.78]).
CONCLUSIONS: IVT for ischemic stroke beyond 4.5 hours, without MT, led to increased odds of excellent and good functional outcomes compared with standard medical care, despite higher odds of sICH, and a nonsignificant numerical increase in mortality.
| Discipline Area | Score |
|---|---|
| Emergency Medicine |  |
| Internal Medicine | |
| Neurology | Coming Soon... |
This meta-analysis of 8 out of 1132 studies, including 1742 patients, explored what happened when thrombolytics (alteplase, tenecteplase ) is given >4.5h post stroke. The outcomes seem to favor active treatment with some downside (increased death and symptomatic intracranial hemorrhage). Tenecteplase might be better. Discussion: There is so much heterogeneity in the data that many conclusions could be drawn. Thrombolytics for non-LVO stroke is still controversial, including safety and efficacy. Conclusion: This meta-analysis provides a question for a prospective study - In patients with time of stroke symptom onset >4.5h, do lytics provide meaningful benefit without added harm? This study is hypothesis-generating and nothing more.
Since ECASS-3, the 4.5-hour window was the latest timeframe for IV thrombolytics in acute ischemic stroke (http://pmid.us/20576390). This meta-analysis of 8 RCTs could turn that paradigm around, although this seems to fall under the "too good to be true" category. The subset analyses suggest improved functional outcomes when therapy focuses on those with perfusion imaging indications and treated with tenecteplase, but I'm left wondering why this meta-analysis suddenly demonstrates a benefit when individual RCTs for decades have suggested that harms outweigh benefits.
Strokes are incredibly disabling. As a hospitalist, there is probably no greater time-sensitive decision than instituting thrombolysis. Initial trials that failed with thrombolysis believed that outside of a window, thrombolysis and the bleeds from it potentially caused harm. The fact that there may be a subset of people who are outside that window and still may benefit is intriguing. Unsurprisingly, you are more likely to bleed if you are outside of the window as the ischemic tissue is believed to be susceptible. There very well may be selection bias in the patients knowingly given thrombolysis outside the window. If it was my brain, I would take a bleed and death gamble to have a better functional outcome. All of this needs to be challenged in its own RCT.
Meta-analysis of randomized studies highlighting the benefit of IVT beyond 4.5 hours, with an increase in ICH but no impact on mortality. It reinforces the importance of advanced neuroradiology techniques in patient selection, which should therefore be more widely adopted.
Due to the relevance of this topic, it is essential to clear the time frame for initiating thrombolysis in ischaemic stroke. For the moment, this is the largest meta-analysis of high quality and with almost no heterogeneity between studies. It establishes that thrombolysis beyond 4.5 hours is still effective.