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Thrombolytic therapy for acute ischaemic stroke has been approached cautiously
because there were high rates of intracerebral haemorrhage in early clinical trials. The NINDS Investigators performed
a randomized, double-blind trial of intravenous recombinant tissue plasminogen activator (t-PA) for ischaemic stroke
after recent pilot studies suggested that t-PA was beneficial when treatment was begun within three hours of the
onset of stroke. The trial had two parts. Part 1 (in which 291 patients were enrolled) tested whether t-PA had
clinical activity, as indicated by an improvement of 4 points over base-line values in the score of the National
Institutes of Health stroke scale (NIHSS) or the resolution of the neurologic deficit within 24 hours of the
onset of stroke. Part 2 (in which 333 patients were enrolled) used a global test statistic to assess clinical
outcome at three months, according to scores on the Barthel index, modified Rankin scale, Glasgow outcome scale,
and NIHSS.
rt-PA - The Studies: NINDS Parts 1 and 2
Study design
- Two studies, total number of patients: 624
- Time window 180 min, stratified for < 90 min and 91-180 min, 50% of patients in each stratum
- Dosage: 0.9 mg/kg (max. dose 90 mg)
- Inclusion symptom-based, no bleeding on CT
- Endpoint Part 1: Improvement at 24 hours (National Institutes of Health stroke scale (NIHSS))
- Endpoint Part 2: composite endpoint (modified Rankin scale (mRS), BI (Barthel Index), NIHSS, Glasgow outcome score (GOS))
There are some misunderstandings about the interpretation of the NINDS study. NINDS was not one study but two, with
similar designs, but different endpoints. In part 1, thrombolysis did not significantly affect the primary endpoint,
which was a neurological improvement on the NIH stroke scale. Without unblinding, part II started with a composite
endpoint (global endpoint statistics).
Part II was positive, and when the method was also applied to part I, part I also turned out to be positive. The basis
for approval of rt-PA was the positive result in part II and the supported results from part I and the ECASS 1 0-3 hour
cohort. An important aspect of the trial design was that 50% of the patients had to be in the 90 minutes cohort. It has
been suggested that this may have biased the study result. It did, but in a very desirable way. Since the effect in
the first 90 minutes is much higher than that between 90 and 180 minutes, the strict procedure of getting patients
into the trial very early resulted in the first successful early therapy of ischaemic stroke.
Results
- Part 1 missed primary endpoint
- Part 2 positive in primary endpoint
- Combined analysis also positive
- Roughly 10-13 % more t-PA treated patients had a favourable outcome (e.g. mRS 0-1; BI > 90)
- Mortality lower (nonsignificant)
- Risk of symptomatic haemorrhage increased
The global endpoint statistics shows that part I missed the primary endpoint and that part II was positive in the
primary endpoint. An analysis of the combination of both parts was also positive. For every 100 patients treated
with rt-PA 11-13 % will have a favourable outcome as compared to 100 not treated with rt-PA. Although the
mortality rate was lower, the risk of symptomatic haemorrhage increased.
In part I no statistically significant differences were detected between groups in the primary outcome. However, post
hoc comparisons of median NIHSS scores showed improvement in the condition of patients treated with t-PA as compared
with those given placebo in most time strata in parts I and II, and in the combined analysis. In part II the number
of patients with favourable outcome for each of the four primary outcome measures three months after stroke was
higher in the t-PA group than in the placebo group.
PubMed Abstract
Reference:
NINDS Investigators. N Engl J Med 1995; 333 (24): 1581-1587. |
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© 2005 Boehringer Ingelheim GmbH, Germany. All rights reserved.
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