In 1995, the first successful randomized study using rt-PA in stroke was published. The NINDS study, like ECASS I/II and ATLANTIS, was a double-blind trial. Unlike prior studies, NINDS restricted the treatment time to less than 3 h from symptom onset and reduced the dose of rt-PA to 0.9 mg/kg. Moreover, one half of the patients were treated within 90 min of symptom onset to maximize the likelihood of finding a benefit. NINDS consisted of two parts, the first measuring clinical activity within 24 h of stroke onset and the second using a global test to assess clinical outcome at 3 months.
In Part 1, no statistically significant differences between groups were found using the primary outcome measure (improvement of ≥4 points in National Institutes of Health Stroke Scale [NIHSS] score or complete resolution of neurologic deficits). It is worth remembering that the number of points (4) chosen to determine effectiveness was essentially a guess based on limited preclinical information, and post hoc analysis revealed statistically significant improvement using almost any other NIHSS improvement criteria or time strata [14
]. All secondary outcome measures used in the first NINDS trial, including 3-month outcome on the modified Rankin scale and Barthel index, statistically significantly favored rt-PA treatment.
In contrast to the previous trials, NINDS Part 1 was the only study to use 24-hour improvement as a primary outcome measure. In retrospect, this could be a shortcoming of the study because it ultimately may not be a relevant assessment. Final neurologic recovery is most important, and this cannot be determined accurately at 24 h. Although 3 months may not encompass the full extent of recovery either, it is much more reflective of eventual outcomes than the period when acute injury processes are still active.
Regardless of the debate surrounding 24-hour improvement, Part 2 of the NINDS trial assessed clinical results at 3 months as a primary outcome and did reveal statistically significant differences. Four primary outcomes were measured (Barthel index, modified Rankin scale, Glasgow outcome scale, and NIHSS), and the number of patients with favorable outcomes for each method was greater in the rt-PA group than in the placebo group. Compared with placebo, there was a 12% absolute increase and 32% relative increase in the number of patients with minimal or no disability among those treated with rt-PA. Importantly, this benefit was not offset with any increase in mortality. There were more symptomatic hemorrhages in rt-PA–treated patients (6.4% vs 0.1%, P
0.001), but these patients had more severe baseline deficits and the proportion with hemorrhage was lower than in other RCTs with rt-PA [10
The NINDS study demonstrated a clear benefit of rt-PA when used in the first 3 h, and it was hoped that rt-PA would become widely used. Licensing bodies granted approval in the United States (1996), Canada (1999), and Europe (2002), but widespread adoption of thrombolytic therapy for acute stroke proceeded slowly as several challenges emerged.
Initially, neurologists and emergency medicine physicians not experienced in making rapid decisions in stroke patients were reluctant to administer rt-PA [15
]. Intravenous thrombolytic therapy represented a radical change from the previous standards of care for ischemic stroke that consisted largely of supportive therapy. rt-PA offered a high-risk/high-reward alternative, but therapy often was withheld because of the fear of causing intracranial hemorrhage. Further analysis of hemorrhage rates from the NINDS data subsequently addressed many of these concerns by showing that the clinically relevant number needed to harm is close to 1 in 100 [16
]. rt-PA now is fully accepted by almost all neurologists, but debate still exists among emergency medicine physicians, especially in areas where stroke specialists are not available to assist in the decision-making process [17
At the same time, many patients are excluded from treatment because they are deemed to have neurologic deficits too mild or too rapidly improving to warrant the risks of rt-PA. Two published reports addressed this issue, and both found an unacceptably high number of patients (between one in three and one in four) deemed “too good to treat” on admission who were dead or dependant at discharge [18
]. Decisions about thrombolytics in patients with mild symptoms are often difficult, but it should be remembered that patients with unstable disease processes can quickly improve before quickly declining. Such patients remain challenging, but current literature seems to support thrombolytic treatment [20