An Outcome Model for Intravenous rt-PA in Acute Ischemic Stroke.
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Most early phase trials in stroke and brain trauma have failed in phase 3, including efforts to improve acute ischemic stroke outcomes beyond that achieved by intravenous recombinant tissue plasminogen activator (t-PA) (IVT). With the exception of more recent stent retriever trials, most subsequent phase 3 trials failed. We previously showed that baseline imbalances, non-linear relationships of these factors to outcome, and unrepresentative control populations invalidate traditional statistical analysis in early trials of heterogeneous diseases such as stroke. We developed an alternative approach using a pooled outcome model derived from control arms of randomized clinical trial (RCTs). This model then permits comparing treatment trials to an expected outcome of a pooled population. Here, we hypothesized we could develop such a model for IVT and tested it against outcomes without IVT. We surveyed literature for all trials involving one arm with IVT reporting baseline National Institute Stroke Scale (NIHSS), age, and outcome. A non-linear fit was performed including multi-dimensional statistical intervals (95 %) permitting visual comparison of outcomes at their own baselines. We compared models derived from non-IVT control arms. Models from 24 IVT RCTs representing 3195 subjects were successfully generated for functional outcome, modified Rankin Scale (mRS) 0-2 (r(2)=0. 83, p<0.001), and mortality (r(2)=0.54; p=0.001). We confirmed better outcomes compared to no IVT and mixed use IVT models across the range of baseline factors. It was possible to generate an expected outcome model for IVT from existing literature. We confirmed benefit compared to placebo. This model should be useful to compare to new agents without the need for statistical manipulation.