Time to Treatment With Intravenous Thrombolysis Before Thrombectomy and Functional Outcomes in Acute Ischemic Stroke: A Meta-Analysis

Abstract

Importance: The benefit of intravenous thrombolysis (IVT) for acute ischemic stroke declines with longer time from symptom onset, but it is not known whether a similar time dependency exists for IVT followed by thrombectomy.

Objective: To determine whether the benefit associated with IVT plus thrombectomy vs thrombectomy alone decreases with treatment time from symptom onset.

Design, setting, and participants: Individual participant data meta-analysis from 6 randomized clinical trials comparing IVT plus thrombectomy vs thrombectomy alone. Enrollment was between January 2017 and July 2021 at 190 sites in 15 countries. All participants were eligible for IVT and thrombectomy and presented directly at thrombectomy-capable stroke centers (n = 2334). For this meta-analysis, only patients with an anterior circulation large-vessel occlusion were included (n = 2313).

Exposure: Interval from stroke symptom onset to expected administration of IVT and treatment with IVT plus thrombectomy vs thrombectomy alone.

Main outcomes and measures: The primary outcome analysis tested whether the association between the allocated treatment (IVT plus thrombectomy vs thrombectomy alone) and disability at 90 days (7-level modified Rankin Scale [mRS] score range, 0 [no symptoms] to 6 [death]; minimal clinically important difference for the rates of mRS scores of 0-2: 1.3%) varied with times from symptom onset to expected administration of IVT.

Results: In 2313 participants (1160 in IVT plus thrombectomy group vs 1153 in thrombectomy alone group; median age, 71 [IQR, 62 to 78] years; 44.3% were female), the median time from symptom onset to expected administration of IVT was 2 hours 28 minutes (IQR, 1 hour 46 minutes to 3 hours 17 minutes). There was a statistically significant interaction between the time from symptom onset to expected administration of IVT and the association of allocated treatment with functional outcomes (ratio of adjusted common odds ratio [OR] per 1-hour delay, 0.84 [95% CI, 0.72 to 0.97], P = .02 for interaction). The benefit of IVT plus thrombectomy decreased with longer times from symptom onset to expected administration of IVT (adjusted common OR for a 1-step mRS score shift toward improvement, 1.49 [95% CI, 1.13 to 1.96] at 1 hour, 1.25 [95% CI, 1.04 to 1.49] at 2 hours, and 1.04 [95% CI, 0.88 to 1.23] at 3 hours). For a mRS score of 0, 1, or 2, the predicted absolute risk difference was 9% (95% CI, 3% to 16%) at 1 hour, 5% (95% CI, 1% to 9%) at 2 hours, and 1% (95% CI, -3% to 5%) at 3 hours. After 2 hours 20 minutes, the benefit associated with IVT plus thrombectomy was not statistically significant and the point estimate crossed the null association at 3 hours 14 minutes.

Conclusions and relevance: In patients presenting at thrombectomy-capable stroke centers, the benefit associated with IVT plus thrombectomy vs thrombectomy alone was time dependent and statistically significant only if the time from symptom onset to expected administration of IVT was short.

Figure 1.. Influence of the Time From Symptom Onset to Expected Administration of Intravenous Thrombolysis on the Benefit Associated With Intravenous Thrombolysis Plus Thrombectomy

In A, there were 14 patients omitted from the graph (had symptom onset to expected administration of intravenous thrombolysis times of <45 minutes or >320 minutes). In B, the solid dark blue line indicates the best model fit of the log odds ratio for a favorable shift in the modified Rankin Scale scores at 90 days associated with intravenous thrombolysis plus thrombectomy vs thrombectomy alone and treatment delay between symptom onset to expected administration of intravenous thrombolysis. The shaded area reflects the 95% CI for the adjusted common odds ratio. An adjusted common odds ratio greater than 1 indicates better outcomes (favorable shifts in the modified Rankin Scale scores) associated with treatment with intravenous thrombolysis plus thrombectomy. The dashed blue lines indicate the time points at which the lower bound of the 95% CI and the point estimate crossed 1.0.

Figure 2.. Distribution of the 90-Day Modified Rankin Scale Scores by Treatment Group and Dichotomized Intervals From Symptom Onset to Expected Administration of Intravenous Thrombolysis (IVT)

If IVT was administered within 2 hours 20 minutes after stroke onset, there was a favorable shift across the modified Rankin Scale scores at 90 days associated with IVT plus thrombectomy vs thrombectomy alone (median modified Rankin Scale score of 2 [IQR, 1-4] for the IVT plus thrombectomy group vs 2 [IQR, 1-4] for the thrombectomy alone group; adjusted common odds ratio, 1.31 [95% CI, 1.04-1.66]). No between-group differences were observed in participants treated after 2 hours 20 minutes (median modified Rankin Scale score of 3 [IQR, 1-5] for the IVT plus thrombectomy group vs 3 [IQR, 1-5] for the thrombectomy alone group; adjusted common odds ratio, 0.97 [95% CI, 0.79-1.19]). The modified Rankin Scale scores at 90 days were available for 2310 of 2313 participants (99.9%). The modified Rankin Scale scores were missing for 1 patient treated with thrombectomy alone before 2 hours 20 minutes and 1 patient in each group treated later than 2 hours 20 minutes.