Lack of Improvement in Patients With Acute Stroke After Treatment With Thrombolytic Therapy: Title and subTitle BreakPredictors and Association With Outcome FREE

Recombinant tissue plasminogen activator (alteplase) is one of the most efficacious treatments for ischemic stroke patients. Nine years after its approval, intravenous alteplase continues to be the only approved thrombolytic therapy for patients within 3 hours of an acute ischemic stroke.¹ However, several issues remain regarding its use. For example, there was no significant difference in recovery (measured by >4 points improvement on the National Institutes of Health Stroke Scale [NIHSS]) at 24 hours between the alteplase and placebo groups in the National Institute of Neurological Disorders and Stroke (NINDS) alteplase study.

A greater outstanding issue was the identification of accurate predictors of outcome.² Age, sex, mean arterial blood pressure, NIHSS score, and computed tomographic (CT) findings have been identified as independent predictors of good clinical outcome at 3 months.^{3 - 6} Other recent studies analyzed predictors for dramatic recovery or major neurological improvement at 24 hours after receiving alteplase.^{7 - 10} Nevertheless, the lack of improvement at 24 hours after receiving alteplase has not been studied systematically.

Many predictors have a univariate re lationship with poor outcome,^{11 - 13} but in multivariate analysis the relationship is less clear. Identifying predictors of lack of improvement may improve understanding of the clinical factors that influence the acute recovery and clinical response to alteplase. This perspective can help predict poor outcome earlier (24 hours after receiving alteplase) than at 3 months. An early and reliable prediction of poor outcome has important implications for clinical management and for discharge planning.

We hypothesized that baseline clinical, imaging, or laboratory factors are associated with lack of improvement at 24 hours; that these factors are different from those previously described with poor outcome at 3 months or major neurological improvement (NIHSS score, ≥8 points) within 24 hours; and that lack of improvement at 24 hours is an independent predictor of poor outcome at 3 months.

We analyzed consecutive patients with acute stroke who received alteplase. All patients were admitted to the university campus of the London Health Sciences Center (London, Ontario) from January 1999 to March 2003.

London is the largest city in southwestern Ontario with a population of 336 540 (432 450 in the metropolitan area).¹⁴ It has 2 academic medical centers with 24-hour access to CT and magnetic resonance imaging. These academic hospitals are a referral center for a large part of Ontario. In addition to serving the local population, the Health Sciences Centre receives acute stroke referrals from 33 rural hospitals from 7 counties. This catchment area covers 7800 square miles and serves a population of 1.5 million.¹⁴ Details concerning hospital characteristics and clinical assessment were outlined in 2 previous articles.^{15 - 16}

Patients with suspected ischemic stroke were seen within 3 hours of symptom onset at the Health Sciences Centre. Demographic variables, evaluation and treatment times, admission, and 24-hour NIHSS scores and outcomes were entered into a database by stroke fellows. The fellows were trained and certified in administering the NIHSS. For all patients, time of symptom onset was defined by the time when they were “last seen to be well.” Time of treatment with alteplase was obtained from the nursing records as onset to needle time for the alteplase infusion. Time to alteplase was calculated from these data.

The decision to treat with alteplase was made according to the NINDS protocol.¹ Informed consent was given by the patient or his/her relatives. The ethics review board at the University of Western Ontario in London determined that approval was not required because there was no intervention and the study only observed outcomes as part of standard care at this institution.

Inclusion and exclusion criteria were applied with one major difference from NINDS: patients with involvement of more than one third of the middle cerebral artery territory on the baseline CT scan were excluded. Management after alteplase infusion followed the published guidelines.¹ A control CT scan was performed at 24 hours to determine the presence of new infarction, cortical involvement, and extension of the ischemic lesion. The neuroradiologist who interpreted the CT scans was blinded to the neurological status of the patient.

A routine evaluation was performed to determine the stroke mechanism and stroke subtype in all patients, which included routine laboratory tests, electrocardiogram, transthoracic echocardiogram, and carotid ultrasound. Magnetic resonance imaging, magnetic resonance angiography, CT angiography, transesophageal echocardiogram, or conventional angiography were performed when appropriate.

Demographic, clinical, routine laboratory, and hemodynamic variables were recorded at admission. Data on history of risk factors were obtained from medical records, the patient, or his/her family. Stroke subtype (lacunar vs nonlacunar) was based on presenting symptoms, physical examination, and neuroimaging. The presence of cortical involvement, new infarction, or hemorrhagic transformation was established according to the neuroradiological report of the control CT scan.

We analyzed the distribution of all variables by both graphic and analytic methods (frequency distribution by quartiles or quintiles). If the relationship between a continuous variable and the primary outcome (lack of improvement, modified Rankin Scale score, or death) was linear, it was kept as continuous. If the relationship suggested a cutoff, the variable was categorized. When there was no clear relationship, we used clinical criteria to analyze the variable. According to the aforementioned analysis, glucose on admission was dichotomized as less than, greater than, or equal to 144 mg/dL (8 mmol/L). In our analysis, age, weight, baseline NIHSS, creatinine levels, hematocrit, white blood cell count, time from stroke onset to treatment (alteplase), and total alteplase dose were continuous variables.

Previous studies, including the NINDS alteplase stroke trial, used a difference of 4 points or more on the NIHSS to reflect a clinically significant improvement beyond interrater variability.^{3 ,17} Other studies showed a good interrater agreement when examiners did not differ in the total scores by 3 points or more.^{18 - 20} We defined lack of improvement as less than or equal to a 3-point difference between the baseline and 24-hour NIHSS score. Outcome measures were evaluated using the modified Rankin Scale score at 3 months, which is a commonly used period in studies of thrombolysis for acute stroke. Poor outcome was defined as a modified Rankin Scale score greater than or equal to 3 or death.

Two exploratory analyses were performed. First, predictors of lack of improvement at 24 hours were identified. The association between demographic characteristics, clinical and hemodynamic variables, and lack of improvement was examined using univariate logistic regression. We also retrospectively performed survival analyses to represent the number of patients at risk and the cumulative proportion of patients with lack of improvement by the time to treatment.

Second, lack of improvement at 24 hours was evaluated as an independent predictor of poor outcome (modified Rankin Scale score, 3-5 or death) at 3 months in a multivariate analysis. Step-wise multivariate logistic regression, allowing for entry at the.15 level of significance based on the score statistic, was used to determine a subset of these variables independently associated with lack of improvement. Covariates were checked for collinearity and interaction effects. Discrimination of the model was assessed by the area under the receiver operating characteristic curve and calibration was assessed using the goodness of fit test. No adjustment was made for multiple testing. Analysis was performed using STATA statistical software (version 7.0, STATA Corp, College Station, Tex). P<.05 was considered significant.

From January 1999 to March 2003, 1214 patients with acute stroke were admitted to the Health Sciences Center. During that period, 219 patients (18%) were treated with intravenous alteplase. Three patients were excluded because of missing 24-hour outcome data. Of the 216 remaining patients, 111 (51.4%) had lack of improvement at 24 hours after receiving alteplase (Table 1). Three patients (1.4%) were lost to follow-up.

There were no statistically significant differences in demographic variables, geographic location of symptom onset (London vs other), risk factors, previous medication, baseline NIHSS score, and alteplase dose between both groups (lack of improvement vs improvement; Table 1). There was no statistically significant difference between the baseline NIHSS score as a categorical variable (based on clinical categories 0-6, 7-15, ≥16) and lack of improvement.^{19 ,21} Median change in the NIHSS score was 7 in the group with improvement and 1 in the group with lack of improvement.

The mean time from symptom onset to arrival in the emergency department was 83 minutes (median, 70 minutes). The mean time from symptom onset to treatment was 157 minutes (median, 160 minutes). In the overall sample, only 4.1% of patients were treated within 90 minutes of stroke onset. The overall asymptomatic and symptomatic hemorrhage rates at 36 hours were 10.4% and 4.1%, respectively. Five patients (2.3%) with symptomatic intracranial hemorrhage died. Forty patients (18%) were treated outside the 3-hour time window. There was no statistically significant difference between the presence of intracranial hemorrhage and the time window (within or outside 180 minutes of symptom onset; P = .56).

The presence of hyperglycemia (glucose level >144 mg/dL [>8 mmol/L]), new infarction, cortical involvement, and time to treatment with alteplase were independent predictors of lack of improvement in the univariate analysis (Table 1). In logistic regression analysis, glucose level (odds ratio [OR], 2.89; 95% confidence interval [CI], 1.40-5.99), presence of cortical involvement (OR, 2.66; 95% CI, 1.36-5.20), and time to treatment with alteplase (OR, 1.01; 95% CI, 1.00-1.02 per 1-minute increase) were independent predictors after adjusting for age, sex, and stroke severity (Table 2). For each minute increase in time to treatment, the OR for lack of improvement is 1.01. The longer the time to treatment, the higher the probability of lack of improvement (Figure).

Lack of improvement was present in all 9 patients with symptomatic intracranial hemorrhage. In this small group, it is difficult to determine if lack of improvement was present before or after the development of the intracranial hemorrhage. Therefore, the clinical deterioration secondary to the intracranial hemorrhage and concomitant lack of improvement were probably nonindependent events. There was not a statistically significant difference in the presence of asymptomatic intracranial hemorrhage or hemorrhagic transformation between patients with and without lack of improvement (9% vs 12%; P = .50). Patients with lack of improvement had longer lengths of hospitalization (mean length, 14.5 vs 9.6 days; P = .02). For each 5-minute increase, the chance of lack of improvement increased by 5%.

The goodness of fit and Hosmer-Lemeshow tests used to evaluate the calibration of the model were not significant (goodness of fit P = .27; Hosmer-Lemeshow P = .13), indicating adequate fitness. There was no evidence of collinearity in inspection of tolerance warnings, SEs, and correlation matrix. Interaction was explored between age, sex, NIHSS score, and risk factors, but none achieved statistical significance. The model in its entirety was an adequate predictor of lack of improvement with an area under the receiver operating characteristic curve of 0.73.

Overall in-hospital mortality rate was 12.0% for all stroke admissions, including 28 deaths among those who received alteplase and 146 deaths among those not treated with alteplase. Among 213 patients evaluated at 90 days, 43 (20.2%) died. Among the same 43 who died, 5 patients (12%) died within 24 hours after receiving alteplase, while 23 died (53%) at 30 days.

Lack of improvement at 24 hours was significantly more likely in patients who died at 3 months (35/43 [81%] compared with 79/170 [46%]; P <.001). Lack of improvement at 24 hours was an independent predictor of death after adjusting for age, sex, and stroke severity (OR, 7.5; 95% CI, 2.9-19.6).

Of the 170 patients who survived to 90 days, 75 (44%) had poor outcome (modified Rankin Scale score, 3-5). Lack of improvement was also significantly more likely in patients who had poor outcome (49/75 [65%] compared with 30/95 [32%]; P<.001). Lack of improvement at 24 hours was an independent predictor of poor outcome after adjusting for age, sex, and stroke severity (OR, 12.9; 95% CI, 5.7-29.6).

The benefit of intravenous alteplase has been demonstrated in randomized clinical trials since 1995.¹ It is one of the most efficacious therapies to date for stroke with a number needed to treat of only 8.^{22 - 23} We examined the clinical relevance of lack of improvement in a prospective cohort of patients with acute stroke who received alteplase. We found that the presence of cortical involvement, hyperglycemia, and time to treatment with alteplase were associated independently with lack of improvement. Age, baseline NIHSS score, presence of carotid stenosis, prior medication use, presence of vascular risk factors, or stroke subtype were not associated with lack of improvement at 24 hours.

Alternately, lack of improvement at 24 hours was independently and strongly associated with an increased likelihood of poor outcome (modified Rankin Scale score, 3-5) and death at 3 months after stroke. Lack of improvement at 24 hours increased the risk of poor outcome or death at 3 months to more than 7-fold after adjusting for age, sex, and stroke severity. In addition, patients with lack of improvement had a longer period of hospitalization, which is a major factor in determining cost.²⁴

Several studies identified predictors of good or poor outcome at 3 months after thrombolytic therapy, but only a few analyzed outcome at 24 hours after treatment.^{22 - 23 ,25 - 26} These studies have shown that baseline NIHSS score, age, mean arterial blood pressure, no history of diabetes, hyperglycemia, and a normal CT are independent predictors of good outcome (modified Rankin Scale score, 0-1) at 3 months.⁴ To the best of our knowledge, lack of improvement at 24 hours, its predictors and prognostic value, has not been analyzed previously. This information may be useful for managing patient and family expectations as well as for organizing the health care system.

In the NINDS cohort, Brown et al¹⁰ reported major neurological improvement (NIHSS score >8) 24 hours after receiving alteplase. Age and time to treatment with alteplase were associated with major neurological improvement in a logistic regression model, which showed a moderate predictive value of 0.66 under the receiver operating curve area. Grotta et al²⁵ investigated the rate of clinical deterioration following improvement in the NINDS alteplase trial. The rate of clinical deterioration following improvement was defined by a 2-point increase in the NIHSS score. To address the relationship between recanalization/reocclusion and the clinical course, Grotta et al mainly used single positron emission tomographic scan of cerebral perfusion. Ten percent of patients in the alteplase group had a rate of clinical deterioration following improvement at 24 hours with no statistical difference compared with the placebo group—although neurological worsening did not suggest reocclusion.²⁵ However, the cutoff used in the NIHSS score cannot be specific enough for reflecting the parenchyma damage to the brain, which is probably related to additional conditions (such as fluctuations in blood pressure or concurrent medications).

More convincingly, an early clinical improvement correlated with recanalization assessed by transcranial Doppler.^{8 - 9} In these studies, dramatic recovery was defined as a total NIHSS score of 0 to 3 points and early recovery was defined as an improvement of 10 points or more at 2 hours after treatment with alteplase. Both clinical conditions were present in 22% of patients—75% of whom had good outcomes at 3 months. Therefore, detection of early collateral flow or restoration of flow in the penetrating artery territory assessed by transcranial Doppler seems to be a predictor of dramatic or early recovery after treatment with alteplase. Recently, the same group studied the clinical response after early recanalization, which was assessed by transcranial Doppler in 120 stroke patients following treatment with alteplase. They found that 37% of patients with early recanalization did not experience clinical changes or worsening 24 hours following treatment with alteplase and one third achieved a good outcome at 3 months. The authors theorized that a “stunned brain syndrome” explained the delayed recovery.²⁶ These studies differ from ours in that they analyzed neither clinical predictors of lack of improvement at 24 hours nor the prognostic value of lack of improvement at 3 months.

We observed that the presence of cortical involvement as detected by imaging of the brain obtained 24 hours after treatment with alteplase is a predictor of lack of improvement at 24 hours. Few studies identified the prognosis of cortical involvement in patients with acute stroke.^{27 - 28} The cerebral cortex is usually affected in patients with severe strokes; persistence of cortical signs is a marker of recanalization in the occluded vessels or absence of collateral flow.^{8 - 9} The presence of cortical signs, such as aphasia, neglect, and anosognosia, has been associated with poor long-term functional recovery and outcome.^{29 - 31} Although the present study did not provide direct evidence on vessel state, the observation that cortical involvement is an independent contributing factor of lack of improvement can be explained to some extent by the absence of recanalization or poor collateral flow.

In our study, the benefit of treatment with alteplase was demonstrated with similar results as the original NINDS trial.^{4 ,15 ,22} Acute stroke management requires a certain degree of expertise. Only a few institutions are sophisticated enough to provide highly specialized care for patients with acute stroke, such as 24-hour availability of transcranial doppler, diffusion-perfusion imaging, or endovascular therapy.^{32 - 33} Many of the current stroke units and hospitals, especially in developing countries, have only essential personnel and structure (CT scan of the head, carotid ultrasound, and basic routine laboratory) required to manage patients with acute stroke.^{34 - 36} These centers need to use a straightforward approach by extracting the most useful clinical information for acute management (eg, hyperglycemia, acute ischemic changes on CT scan, etc). Some early prediction rules of stroke recovery have been validated, but they require diffusion in weight imaging.^{37 - 38}

Our study adds a useful perspective concerning early prediction of outcome by introducing a clinical variable (lack of improvement) that can be easily measured. Its recognition can contribute to the management of patients with stroke after thrombolytic therapy with alteplase in terms of early prediction of outcome. Our report contains 2 exploratory analyses: predictors of lack of improvement at 24 hours and whether lack of improvement at 24 hours is a predictor of poor outcome at 3 months. Exploratory analyses are useful for generating hypotheses. However, an external validation in a large cohort of patients may be necessary to create a predictive score. It is possible that the small number and spurious associations of the sample may limit the generalizability of our findings.

On the other hand, the present study corroborates previous findings on the deleterious effect of hyperglycemia in acute stroke patients,^{3 - 4} and reinforces the concept that the timely administration of alteplase is a conditional factor for successful treatment of acute stroke. These data are not useful for making decisions about treatment with alteplase or withholding care for those with lack of improvement at 24 hours. Guidelines from the American Heart Association for the management of patients with acute ischemic stroke should be followed.³⁹

In summary, the results of our study suggest that lack of improvement at 24 hours is an independent predictor of poor outcome and death at 3 months. Time to treatment with alteplase, glucose level on admission, and cortical involvement were independent predictors of lack of improvement. The identification of these clinical variables at 24 hours after treatment with alteplase may improve early prediction of outcome at 3 months.