The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute iscAhemic stroke. N Engl J Med. 1995 Dec 14;333(24):1581-7.PMID: 7477192
What we already knew about the topic:
According to the AHA, around 800,000 people a year in the United States experience
a stroke, whether first time or recurrent. This equates to 1 stroke approximately
every 40 seconds. Prior to the widespread use of Tissue Plasminogen Activator (t-
PA) and now increasingly thombectomy for large vessel occlusions(LVOs), stroke
care focused on rehabilitation and risk factor modification.
Why this study is important:
This study provoked a conversation about the role of t-PA in acute stroke care
between emergency physicians and our neurology colleagues. It has since lead to
many subsequent studies, not only regarding the use of t-PA, but other advanced
therapies that have revolutionized acute stroke care and lead to a reduction in both
morbidly and mortality.
Brief overview of the study:
This was a randomized, double blinded placebo control trial that enrolled 624 acute
ischemic stroke patients that (1) had a clearly defined time of onset less than 180
minutes, (2) a CT head that was negative for ICH, and (3)had a measurable NIHSS.
Patients were randomized to placebo versus Tissue Plasmingen Activator 0.9
mg/kg with 10% given as a immediate bolus and the remaining given as an infusion
over 60 minutes. Patients were excluded if they had a stroke in previous 3 months,
major surgery within the last 14 days, bp of >185 / 110, rapidly improving
symptoms, symptoms suggestive of SAH, GI or GU hemorrhage in previous 21 days,
seizure at onset, or arterial puncture in the last 7 days at a non-compressible site, PT> 15seconds, or Platlets <100,000 platelets.
There were two major outcomes in this study: (1) “early clinical improvement”
defined as improvement in NIHSS score by 4 or more in the first 24 hours after
onset of stroke and (2) outcome at 3 months measured by several tools, most
notably the modified rankin scale. The authors found that there was no statistically
significant difference in the improvement of NIHSS score at 24 hours. However, at 3
months there was improved morbidity across the spectrum of tools; for modified
rankin score this meant an absolute increase in the % of patients with a mRS of 0-1
(no or mild symptoms) of 13%. There was also a 7% risk of symptomatic ICH in the
tPA group compared to placebo.
Limitations: While this study opened the way for additional research in this area
and revolutionized the way we treat stroke patients, there were some limitations. A
major limitation was a difference in disease characteristics between the two groups.
The placebo group had a larger portion of patients with large vessel occlusions
compared to the t-PA group. We know now from the thombectomy trials that these
LVOs are more amendable to retrieval than t-PA. The patients who received placebo
also seemed to have a higher median NIHSS score (which may be a reflection of the
variation in LVO vs small vessel disease). Therefore the placebo group may already
been predisposed to poorer 3 month outcomes.
Take home points: This study showed that t-PA may improve morbidity at 3 months.
It also helped define many of the inclusion and exclusion criteria for t-PA use that
have since been refined from additional studies. And finally, t-PA is not benign; the
symptomatic rate of ICH for patients with ischemic stroke who receive t-PA is ~7%.