Magnitude of Benefit of Combined Endovascular Thrombectomy and Intravenous Fibrinolysis in Large Vessel Occlusion Ischemic Stroke.

Background and Purpose- Quantifying the benefit magnitude of combined endovascular thrombectomy (EVT) and intravenous thrombolysis (IVT) versus nonreperfusion care in patients with acute ischemic stroke caused by large vessel occlusion would aid organization of regional stroke care systems. Methods- NINDS rt-PA Study (National Institute for Neurological Disorders and Stroke Recombinant Tissue Plasminogen Activator) and SWIFT PRIME trial (Solitaire With the Intention for Thrombectomy as Primary Endovascular Treatment) patients were matched for prognosis (based on age and National Institutes of Health Stroke Scale) and definite/likely anterior circulation large vessel occlusion (based on National Institutes of Health Stroke Scale total score and item pattern), using optimal inverse variance matching, to determine comparative outcomes with nonreperfusion care alone, IVT alone, and IVT+EVT. Results- Matching yielded 240 patients, including 80 each treated with nonreperfusion care, IVT alone, and IVT+EVT, with, respectively, mean age 67.1, 67.1, and 66.9 and presenting deficit severity (National Institutes of Health Stroke Scale) mean 15.8, 15.9, and 15.9. Outcomes at 3 months for IVT+EVT versus nonreperfusion care included freedom from disability (modified Rankin Scale score, 0-1) 48.1% versus 21.3%, P=0.0004; functional independence (modified Rankin Scale score, 0-2) 62.9% versus 32.6, P=0.0001; and reduced disability over all 7 modified Rankin Scale levels, common odds ratio 3.34, P<0.0001. Outcomes for IVT alone versus nonreperfusion care included: freedom from disability 30.0% versus 21.3%, P=0.28 and reduced disability over all 7 modified Rankin Scale levels, common odds ratio 1.14, P=0.65. Compared with nonreperfusion care, the number needed to treat with EVT+IVT for 1 more patient to have reduced disability was 1.8. Conclusions- Matched patient analysis across randomized trials provides evidence that the strategy of combined IVT and mechanical thrombectomy is a highly beneficial treatment strategy for acute ischemic stroke caused by large vessel occlusion patients. A reasonable effect magnitude estimate is that, among every 100 patients treated, combined IVT+EVT reperfusion therapy, compared with no reperfusion therapy, reduces long-term disability in 57, including conferring functional independence upon 30.

Handling of Missing Outcome Data in Acute Stroke Trials: Advantages of Multiple Imputation Using Baseline and Postbaseline Variables.

BACKGROUND: In acute stroke randomized trials, missingness of final functional outcome data reduces study power and potentially biases findings of treatment effect. Best methods for handling missing outcome data have not been well delineated for diseases with monophasic onset and subsequent improvement, like acute stroke. METHODS: We simulated data missingness in the public dataset of the landmark, second NINDS-tPA trial, by randomly removing 5%-25% of actual values for the 3-month modified Rankin Scale (mRS) of global disability. We evaluated 5 missing data-handling methods: complete case analysis (CCA), worst case imputation (WCI), last observation carried forward (LOCF), multiple imputation using baseline covariates only (MI-B), and multiple imputation using baseline and postbaseline observations (MI-BP). RESULTS: With the original trial's 333 patients, tissue plasminogen activator was associated with 3-month disability benefit, both for mRS dichotomized at 0-1 (P = .014) and shift analysis (P = .035). Distance (root mean square error) of imputed from actual mRS values was best for LOCF (1.17) and MI-BP (1.28), intermediate for MI-B (1.89) and worst for WCI (3.77). Directional bias (mean difference) was least for MI-BP (.01) and MI-B (-.16), intermediate for LOCF (-.37), and worst for WCI (-3.22). Preservation of formally positive results was greatest for MI-BP and LOCF (preserved at all missingness rates), intermediate for CCA and MI-B (preserved only with missingness <10%-20%), and least for WCI (preserved only with missingness <5%-20%). CONCLUSIONS: For acute stroke trials, multiple imputation using baseline and postbaseline observations is an advantageous approach to missing outcome data-handling, yielding high accuracy, reduced directional bias, and greater preservation of study power.