Neurology India, Vol. 58, No. 3, May-June, 2010, pp. 403-406
Predictors of major neurological improvement after intravenous thrombolysis in acute ischemic stroke: A hospital-based study from south India
Demudu Babu Boddu, V.C.S Srinivasarao Bandaru, Prasad G Reddy, M Madhusudan, MK Rukmini, T Suryaprabha, SA Jabeen, A Suvarna, Sita S Jayalakshmi, AK Meena, Rupam Borgohain, Subhash Kaul
Department of Neurology, Nizam's Institute of Medical Sciences, Hyderabad - 500 082, India
Date of Acceptance: 04-Feb-2010
Code Number: ni10104
Background : Despite the increasing use of recombinant tissue plasminogen activator (rt-PA) in acute ischemic stroke, uncertainty persists about the short- and long-term outcome of the thrombolysed patients.
Keywords: Acute ischemic stroke, intravenous rt-PA, major neurological outcome, mRS
The National Institute of Neurological Disorders and Stroke (NINDS) recombinant tissue plasminogen activator (rt-PA) Stroke Study demonstrated that intravenous rt-PA improves outcomes in acute ischemic stroke, when administered within 3 h of symptom onset.  The absolute benefit in the likelihood of a normal or near-normal outcome ranged from 11-15%, depending on the functional outcome scale. , A major neurological improvement was defined as a National Institute of Health Stroke Scale (NIHSS) score equal to 0 or 1 at 24 h or an improvement of ≥8 points compared to baseline.  The higher rate of major neurological improvement observed in the rt-PA group compared to the placebo was interpreted as a marker of treatment efficacy, ,,,,, and major neurological improvement in turn independently predicted good clinical outcome at three months. ,, In rt-PA-treated patients, age and time from stroke onset to treatment predicted both major neurological improvement at 24 h and three-month favorable outcome.  A recent meta-analysis showed that women have a better outcome at three months after rt-PA administration compared to men.  Female gender, glucose levels < 8 mmol/L, and absence of cortical involvement at 24 h in CT scan were reported to be associated with major neurological improvement at three months.  However, sparse data is available on early predictors for favorable outcome at 12 months. The identification of predictors of early major neurological improvement and good outcome at 12 months may help to improve patient selection, and to allow more accurate estimation of the prognosis.
Materials and Methods
This was a prospective study performed between January 2000 and June 2009 at Nizam's Institute of Medical Sciences, a tertiary care health center and a university hospital located in Hyderabad, the capital city of Andhra Pradesh, a province in south India. The study protocol was approved by the Ethics Committee of the university and informed written consent was obtained from all the participants. Data from consecutive patients with acute ischemic stroke treated with intravenous rt-PA were collected prospectively. Demographic variables, evaluation and treatment time, admission and 24-h NIHSS scores were recorded. For all patients, time of symptom onset was defined by the time they were "last seen to be well." The onset-to-door, onset-to-CT scan of the brain, and onset-to-needle time were obtained from the nursing records. Patients received rt-PA at the dose of 0.9 mg/kg; 10% as a bolus, and the rest as an infusion over 1 h.  A comprehensive work-up of all the patients was done to determine the stroke mechanism and subtype. Neuroimaging in addition to computed tomography (CT) brain scan also included magnetic resonance imaging (MRI) and MR angiography. Major neurological improvement was defined as NIHSS score equal to 0 or 1 at 24 h or an improvement ≥8 points compared to baseline.  Minor and major complications of rt-PA treatment after infusion and during hospital stay were assessed. Mortality during hospital stay and during follow-up was recorded and the possible cause of death was identified. All the patients who survived were followed on a regular basis for assessment of outcome. The predictive value of major neurological improvement for 12-month outcome was analyzed using the modified Rankin Scale (mRS) and Barthel Index (BI) score. Good outcome was defined as a mRS of ≤1 and BI score of ≥95.
Statistical analysis was done using SPSS 14.0 window software (statistical package for the Social sciences, SPSS Inc). Continuous variables were presented in titer of mean and +SD. The association between demographic characteristics, clinical and hemodynamic variables, and major neurological improvement was examined using logistic regression analysis. Major neurological improvement at 24 h was evaluated as an independent predictor of good outcome (mRS 0 to 1, BI ≥95) at 12 months in a multivariate analysis. All tests were two-sided and P value <0.05 was considered statistically significant.
A total of 72 patients with acute stroke were treated with intravenous rt-PA during the study period. The mean age was 53 ± 12.3 years and 48 (66%) patients were men [Table - 1]. The risk factors included: hypertension in 56 (77.7%), diabetes mellitus in 35 (48.6%), smoking in 38 (52.7%), and coronary artery disease (CAD) in 16 (22%) patients. The mechanism of stroke was: large vessel disease in 30 (41.6%), small artery disease in 17 (23.6%), cardioembolism in nine (12.5%), and stroke of other determined etiology in eight (11%) (hyperhomocysteinemia 5, Takayasu disease 1, systemic lupus erythematosus 1 and protein C and S deficiency 1) [Table - 2]. Twenty-three patients (32%) had major neurological improvement at 24 h after rt-PA administration. There were no significant differences in the gender, vascular risk factors, CT scan abnormalities, and time to rt-PA between patients with major neurological improvement and those with no significant improvement. On univariate analysis, age <60 years (P=0.001), admission glucose level < 8.0 mmol/L (P=0.001) and median baseline NIHSS 10±6 (P=0.005) were associated with major neurological improvement [Table - 3]. On multivariate logistic regression analysis, age <60 years (OR 1.9, 95% CI 1.7 -3.2), admission glucose levels <8 mmol/L (OR 3.87, 95% CI 1.9 - 9.2) and mild to moderate stroke severity (median baseline NIHSS 10±6) (OR 2.79, 95% CI 1.69 - 6.37) were independently associated with major neurological improvement after adjusting for gender, diabetes, and normal CT brain. Asymptomatic intracerebral hemorrhage (ICH) was observed in 3/23 (13%) patients with major neurological improvement and in 15/49 (30.6%) patients without major neurological improvement (P=0.47). Symptomatic ICH was found in 3/49 (6.1%) patients without major neurological improvement, in none of the patients with neurological improvement and in 3/72 (4.1%) patients, if both groups were combined.
Major neurological improvement at 24 h as a predictor of good outcome at three months
Among the 23 patients with major neurological improvement at 24 h, one patient was lost to follow-up and two had nine months follow-up. Of the remaining 20 patients, 18 (90%) had good outcome (mRS 0 to 1) at 12 months. In 49 patients without major neurological improvement at 24 h, six patients were dead (myocardial infarction - 2, ICH - 2, malignant cerebral edema - 1 and sepsis -1) and five patients were lost to follow-up at 12 months. Out of the remaining 38 patients, good outcome was found in nine patients (23.6%). Major neurological improvement at 24 h predicted good outcome (mRS≤1, P<0.0001; BI score> 95, P=0.0001) at 12 months [Table - 4]. After a multivariate analysis, major neurological improvement at 24 h continued to be a strong and independent predictor of good outcome (mRS≤1) at 12 months (OR 13.9, 95% CI 6.84 to 40.2) after adjusting for gender, vascular risk factors and brain CT scan abnormality.
In this study major neurological improvement was observed in 32% patients, similar to the NINDS trial.  Age <60 years, glucose levels < 8 mmol/L and mild to moderate stroke severity (10±6) were independently associated with major neurological improvement. The presence of major neurological improvement at 24 h was predictive of good outcome at 12 months after adjusting for gender, stroke risk factors and brain CT scan abnormality. The association between time to treatment and major neurological improvement seems biologically plausible because earlier treatment should result in earlier recanalization and a greater salvage of tissue at risk of infarction. ,
A recent pooled analysis of randomized controlled rt-PA trials demonstrated that women benefit more from rt-PA administration than men. , However, in the present study female gender was not preferentially associated with major neurological improvement at 24 h after intravenous rt-PA. In this study, younger age (<60 years) was associated with major neurological improvement, similar to an earlier study.  This relationship is likely to be a biological effect. Baseline glucose <8 mmol/L and mild to moderately severe stroke (median NIHSS score 10± 6) were also associated with major neurological improvement. These observations are in conformity with NINDS sub-study.  In the final multivariate model of the NINDS trial, treatment with rt-PA, diabetes, age, baseline NIHSS score, admission mean arterial pressure, and thrombus or hypodensity/mass effect on baseline CT scan were independently associated with three-month favorable outcome in both rt-PA and placebo-treated patients.  One of the worst feared complications of rt-PA is symptomatic ICH. Interestingly, the rate of overall symptomatic ICH in our series was 4.1%, which was lower than reported in NINDS study (6.4%).  Being able to predict good outcome at 24 h after intravenous rt-PA, may have implications for clinical management and discharge planning, which could significantly reduce costs associated with longer length of hospital stay. ,
This study has a limitation of having small numbers of subjects in each of the predictive variable subgroups, thereby lowering the power to detect predictive relationships with major neurological improvement. Nevertheless, the findings do help in the identification of predictors to prognosticate the outcome at 12 months, to a reasonable degree. Also, the present results are based on the window period of 3 h for intravenous thrombolysis, and are not directly applicable to the window period upto 4.5 h (according to ECASS III study). 
To conclude, this outcome based study about the use of rt-PA in acute ischemic stroke clearly showed that, age <60 years, base line glucose levels < 8 mmol/L and mild to moderate stroke severity (median NIHSS 10±6) were associated with major neurologic improvement after intravenous rt-PA. Major neurologic improvement at 24hours after intravenous thrombolysis was independently predictive of good outcome in terms of personal independence at the end of 12 months.
Copyright 2010 - Neurology India
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