Lancet: Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials.
Background
Quick administration of intravenous recombinant tissue plasminogen activator (rt-PA) after stroke improved outcomes in previous trials. Combined data for individual patients to confirm the importance of rapid treatment were analyzed.
Methods
The common data elements from six randomized placebo-controlled trials of intravenous rt-PA were pooled. Using multivariable logistic regression the relation of the interval from stroke onset to start of treatment (OTT) on favourable 3-month outcome and on the occurrence of clinically relevant parenchymal haemorrhage was assessed.
Findings
Treatment was started within 360 min of onset of stroke in 2775 patients randomly allocated to rt-PA or placebo. Median age was 68 years, median baseline National Institute of Health Stroke Scale (NIHSS) 11, and median OTT 243 min. Odds of a favourable 3-month outcome increased as OTT decreased (p=0·005). Odds were 2·8 (95% CI 1·8-4·5) for 0-90 min, 1·6 (1·1-2·2) for 91-180 min, 1·4 (1·1-1·9) for 181-270 min, and 1·2 (0·9-1·5) for 271-360 min in favour of the rt-PA group.
The hazard ratio for death adjusted for baseline NIHSS was not different from 1·0 for the 0-90, 91-180, and 181-270 min intervals; for 271-360 min it was 1·45 (1·02-2·07). Haemorrhage was seen in 82 (5·9%) rt-PA patients and 15 (1·1%) controls (p<0·0001). Haemorrhage was not associated with OTT but was with rt-PA treatment (p=0·0001) and age (p=0·0002).
Model estimating odds ratio for favourable outcome at 3 months in rt-PA-treated patients compared with controls by OTT
The figure shows OTT by treatment interaction through estimation of global odds ratio at different times from stroke onset. Assuming a fixed value for the other variables, we plotted the global odds ratio and 95% CIs predicted by the final model for different OTT.
Modified Rankin Scale measurement at day 90
0-90 min, n=311;
91-180 min, n=618;
181-270 min, n=801;
270-360 min, n=1046.
Values do not equal 100% because of rounding.
The figure shows measurements on the modified Rankin Scale at four OTT periods for placebo and rt-PA groups. After 3 months in the ITT analysis, 390 (14·0%) of 2775 patients were dead or had the worst score assigned, and 707 (25·5%) were severely disabled (modified Rankin 4-5). Fewer rt-PA patients treated within 90 min died compared with controls, but assuming all patients with missing data were alive at last follow-up the 95% CIs for the hazard ratio, adjusted for baseline NIHSS, included 1·0 (0·88, 0·54-1·46). Adjusted hazard ratios for the OTT strata 91-180 and 181-270 exceeded 1·0, but 95% CIs were not significant (1·15 [0·77-1·70]; 1·24, [0·84-1·84]). For the OTT interval 271-360, the adjusted hazard ratio exceeded 1·0 (1·45 [1·02-2·07]).
Interpretation
The sooner that rt-PA is given to stroke patients, the greater the benefit, especially if started within 90 min. The results suggest a potential benefit beyond 3 h, but this potential might come with some risks.
PubMed Abstract
References:
The ATLANTIS, ECASS, and NINDS rt-PA Study Group Investigators. Lancet 2004; 363 (9411): 768-774. |
