Charlotte Zerna, MD, MSc

Young-Saver DF, Gornbein J, Starkman S, Savel JL. Magnitude of Benefit of Combined Endovascular Thrombectomy and Intravenous Fibrinolysis in Large Vessel Occlusion Ischemic Stroke. Stroke. 2019

Little is known about the effect size of the combination of intravenous alteplase therapy (IVT) and endovascular therapy (EVT) compared to supportive treatment alone for patients with anterior circulation large vessel occlusion (LVO). At the time EVT was proven effective with the randomized controlled trials, IVT had already been the standard of care for almost 20 years and thus chosen as a comparator group. Since no randomized controlled trial data are available to compare IVT+EVT to supportive therapy alone, Young-Saver et al. chose to undertake a post-hoc analysis matching patients from the Solitaire With the Intention for Thrombectomy as Primary Endovascular Treatment (SWIFT-PRIME) trial with patients from the 2 National Institute for Neurological Disorders and Stroke Recombinant Tissue Plasminogen Activator (NINDS rt-PA) trials.

In the main analysis, a total of 240 patients (80 from the SWIFT-PRIME IVT+EVT group, 80 from the NINDS rt-PA Study IVT alone group, and 80 from the NINDS rt-PA Study placebo group) were 1:1 inverse variance matched for presenting National Institutes of Health Stroke Scale (NIHSS) score to identify NINDS rt-PA Study patients likely harboring LVOs and age since it is a strong determinant of outcome. The 90-day modified Rankin Scale (mRS) score was used as the outcome, analyzed both as an ordinal scale (shift across all 7 mRS levels) with ordinal logistic regression analysis and as a dichotomized outcome ( 0-1 vs. 2-6 and 0-2 vs. 3-6) using Fisher exact test.

In both dichotomized and ordinal mRS analysis, IVT+EVT was superior to both IVT alone and supportive care alone (Figure 2). The common odds ratio for the shift to lower degree of disability was 2.71 (95% CI 1.55 – 4.76) compared to IVT alone and 3.34 (95% CI 1.89 – 5.90) compared to supportive care alone. Interestingly, the functional outcomes of IVT alone were not statistically different from supportive care alone illustrating the modest likelihood of IVT at best to dissolve the substantial clot burden that usually comes with the presence of an LVO. This further strengthens the call for EVT to be offered to the largest proportion of the population possible as IVT alone has limited efficacy.

Stacked bar charts showing mRS outcomes at 3 mo for combined intravenous thrombolysis (IVT)+endovascular thrombectomy (EVT), IVT alone, and supportive care.
Figure 2. Stacked bar charts showing mRS outcomes at 3 mo for combined intravenous thrombolysis (IVT)+endovascular thrombectomy (EVT), IVT alone, and supportive care. The combined therapy group reflects outcomes of early dramatic responders to IVT alone (10%) and early nonresponders to IVT who proceed to EVT care (90%). mRS indicates modified Rankin Scale.

But expertise for EVT is usually centralized to achieve higher case-volumes, and thus the need for readily available reperfusion strategies in rural areas still exists and future research should focus on testing alternative and potentially more effective thrombolytic strategies like Tenecteplase. Conducted in Australia and New Zealand, the EXTEND-IA TNK trial was able to show that Tenecteplase compared to intravenous alteplase before EVT was associated with a higher incidence of reperfusion and better functional outcomes in patients with ischemic stroke treated within 4.5 hours after symptom onset. A subsequent trial with a higher weight-adjusted Tenecteplase dose is currently underway.

For now, the study by Young-Saver et al. helps to quantify the efficacy of the commonly used treatment strategy of IVT+EVT and thus adds to the current body of evidence available for EVT.