Tsivgoulis G, Katsanos AH, Malhotra K, et al. Thrombolysis for acute ischemic stroke in the unwitnessed or extended therapeutic time window. Neurology. 2019 Dec 31. pii: WNL.0000000000008904. doi: 10.1212/WNL.0000000000008904. (Systematic review)

OBJECTIVE: To assess the utility of IV thrombolysis (IVT) treatment in patients with acute ischemic stroke (AIS) with unclear symptom onset time or outside the 4.5-hour time window selected by advanced neuroimaging.

METHODS: We performed random-effects meta-analyses on the unadjusted and adjusted for potential confounders associations of IVT (alteplase 0.9 mg/kg) with the following outcomes: 3-month favorable functional outcome (FFO; modified Rankin Scale [mRS] scores 0-1), 3-month functional independence (FI; mRS scores 0-2), 3-month mortality, 3-month functional improvement (assessed with ordinal analysis on the mRS scores), symptomatic intracranial hemorrhage (sICH), and complete recanalization (CR).

RESULTS: We identified 4 eligible randomized clinical trials (859 total patients). In unadjusted analyses, IVT was associated with a higher likelihood of 3-month FFO (odds ratio [OR] 1.48, 95% confidence interval [CI] 1.12-1.96), FI (OR 1.42, 95% CI 1.07-1.90), sICH (OR 5.28, 95% CI 1.35-20.68), and CR (OR 3.29, 95% CI 1.90-5.69), with no significant difference in the odds of all-cause mortality risk at 3 months (OR 1.75, 95% CI 0.93-3.29). In the adjusted analyses, IVT was also associated with higher odds of 3-month FFO (adjusted OR [ORadj] 1.62, 95% CI 1.20-2.20), functional improvement (ORadj 1.42, 95% CI 1.11-1.81), and sICH (ORadj 6.22, 95% CI 1.37-28.26). There was no association between IVT and FI (ORadj 1.61, 95% CI 0.94-2.75) or all-cause mortality (ORadj 1.75, 95% CI 0.93-3.29) at 3 months. No evidence of heterogeneity was evident in any of the analyses (I2 = 0).

CONCLUSION: IVT in patients with AIS with unknown symptom onset time or elapsed time from symptom onset >4.5 hours selected with advanced neuroimaging results in a higher likelihood of CR and functional improvement at 3 months despite the increased risk of sICH.

Discipline Area Score
Internal Medicine 6 / 7
Neurology 6 / 7
Emergency Medicine 6 / 7
Comments from MORE raters

Internal Medicine rater

As an internist and hospitalist, I find these results are directly pertinent to our field of practice. We have seen countless times the devastating morbidity effects that ischemic strokes can have on patients. Although the current understanding is to withhold IV thrombolysis in patients beyond the 4.5-hour window, we have also seen that with the advancement of medicine and technology (specifically advanced neuroimaging), what was previously a barrier has led us to explore boundaries. This meta-analysis shows that we need to continue to push these boundaries and find patients who may benefit from thrombolysis despite being outside of a pre-defined window as we may be able to restore quality-of-life that would otherwise be lost forever if we did not try.

Neurology rater

This is a reasonable summary of current data suggesting a perfusion mismatch on advanced imaging predicts possibility of improvement following lysis with a small chance of symptomatic bleed and no impact on mortality. The overall benefit is small, but the risks are acceptable.

Neurology rater

The decision to use alteplase in acute ischemic stroke is shifting from time-based to tissue-based because preservation of viable brain tissue is the goal of therapy. This meta-analysis will influence the treatment of patients who present at an unknown time post-stroke or after 4.5 hours.

Neurology rater

This is important in that it is probably the way of the future, and we are doing this "off-label."
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