When intravenous (IV) tissue-type plasminogen activator (t-PA) was originally approved by the Food and Drug Administration (FDA) for acute ischemic stroke (AIS) in 1996, there was a lengthy list of contraindications. In the 19 years since the approval of t-PA for AIS, it has been used off label and in patients with those contraindications. In February 2015, the list of contraindications for IV t-PA in AIS was revised and several of the previous contraindications were removed. As only 4 % of patients with ischemic stroke receive treatment with IV t-PA, these changes increase the number of patients eligible for treatment. Anytime there is a significant change in the indications and treatment paradigm with a medication, there can be some resistance to the adaptation of the change into physician\'s treating habits. We seek to review what the changes to t-PA contraindications are, how they came about, as well as the literature on the previously off-label and currently off-label use of IV t-PA for patients with AIS.

OBJECTIVE: Since Food and Drug Administration approval of intravenous tissue-type plasminogen activator (tPA) for treatment of acute ischemic stroke in 1996, it has become clear that several criteria used for exclusion from therapy were not based on actual data or operationally defined for use in clinical practice. All eligibility criteria from the National Institute of Neurological Disorders and Stroke (NINDS) recombinant tPA Stroke Study were adopted within the alteplase package insert as contraindications/warnings. Many clinicians have expressed the need for clarification and better definition of these treatment criteria.
METHODS: A group of investigators who also practice as stroke physicians convened a collaborative endeavor to work toward developing more clinically meaningful and consensus-driven exclusion criteria for intravenous tPA. The first of these exclusion criteria chosen was rapidly improving stroke symptoms (RISS). We reviewed and clarified the historical context and intention with the original investigators, held e-mail discussions, convened an in-person RISS Summit, and obtained the understanding of experienced stroke physicians broadly.
RESULTS: Historically, the intent of this exclusion criterion within the NINDS recombinant tPA Stroke Trial was to avoid treatment of transient ischemic attacks-who would have recovered completely without treatment. There was unanimous consensus that, in the absence of other contraindications, patients who experience improvement of any degree, but have a persisting neurological deficit that is potentially disabling, should be treated with intravenous tPA. This statement is supported from the methods established for the original NINDS trial, on the basis of detailed discussions and interviews with the former NINDS trialists. It was agreed that improvement should only be monitored for the extent of time needed to prepare and administer the intravenous tPA bolus/infusion. An explicit operational definition of RISS was developed by consensus to guide future decision making in acute stroke. There was unanimous agreement that all neurological deficits present at the time of the treatment decision should be considered in the context of individual risk and benefit, as well as the patient\'s baseline functional status.
CONCLUSIONS: A structured framework and quantitative approach toward defining RISS emerged through expert opinion and consensus. The term, RISS, should be reserved for those who improve to a mild deficit, specifically one which is perceived to be nondisabling. This is recommended to guide decision making on intravenous tPA eligibility going forward, including the design of future studies. An additional study of patients with rapid improvement to nonmild deficits is not justified because these patients should be treated.

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