Likewise, the authors comment on stroke severity in this guideline, noting the relative exclusion of both very mild and very severe strokes. Again, these authors recommend use of tPA for very severe strokes with Level A evidence while noting the National Institute of Neurological Disorders and Stroke (NINDS) enrolled “relatively few patients” and IST-3’s adjusted odds ratio for good outcome with increasing the National Institutes of Health Stroke Scale (NIHSS) did not reach statistical significance.

More concerning is the authors’ approach to mild stroke syndromes. The authors recommend tPA as “proven clinical benefit” for “mild but disabling” stroke symptoms with Level A evidence. They do so in the same breath as acknowledging, “Because nearly 3,000 such cases of ischemic stroke were excluded from the two NINDS trials for mild symptoms, any analysis of mild symptoms within the two NINDS trials is difficult to interpret.” Furthermore, in a reversal from other recommendations touting favorable findings from IST-3, the authors of this section ignore the neutral outcomes of 612 patients treated with NIHSS 0-5 in that trial. These authors assured endorsement of use of tPA in mild stroke syndromes would seem to suggest its use is a settled question, even though Genentech is funding the Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis, or PRISMS, trial designed to investigate essentially this exact cohort.³

Rapidly improving symptoms are frequently cited as treatment exclusions. Transient cerebral ischemia, after all, is not an indication for tPA. In the section addressing this clinical scenario, these authors cite the work of The Re-Examining Acute Eligibility for Thrombolysis (TREAT) Task Force.⁴ As if the acronym of this expert panel was not an apparent enough bias, support for this panel was received from Genentech. Participants in the meeting had all travel expenses paid by Genentech, and most of the panel representatives had some conflict of interest due to a relationship with Genentech. The foregone conclusion of this panel, reiterated in these guidelines, is that improving symptoms should not exclude patients from tPA.

Frankly, the general theme of this document is that tPA should be given or considered for most of the previous exclusion criteria. This includes such apparently concerning clinical scenarios such as recent major surgery, recent major trauma, a known left-sided heart thrombus, recent gastrointestinal or genitourinary bleeding, and known extra-axial neoplasms. These authors also recommend considering tPA for patients with dementia and end-stage malignancy and those already moderately disabled without substantially framing the question of appropriateness. Finally, these authors also implicitly endorse the slash-and-burn processes taking root in our emergency departments by stating the 2 percent incidence of intracranial hemorrhage in stroke mimics is safety margin enough to not delay tPA administration to make an accurate diagnosis.