Predictors Of Clinical Outcome In Patients With Acute Ischemic Stroke Who Received Tissue Plasminogen Activator Therapy

Background and purposeStroke has ranked the first cause of death in China. The annual incidence of stroke exceeds2million and1.5million dead,4to5times higher than that of western countries, approximately75%are ischemic. The mortality of ischemic stroke in Chinese population is about38.7%in urban areas, most people died28days later after the ischemic attack, but the risk factors predicting death have not been fully elucidated. Although recombinant tissue plasminogen activator has been proved safe and effective in acute ischemic stroke therapy by large clinical trials, it is poorly used in China; only1.9%patients with acute ischemic stroke, who reached hospitals with symptoms onset within3hours, received thrombolysis. In western countries, pooled analysis have shown stroke mortality increased slightly with delay of thrombolysis of which onset-to-treatment time exceeded4.5hours and did not correlate with parenchymal hemorrhagic transformations, implying that there are still important factors such as age, gender, race, stroke severity, comobidities and clinical parameters that might affect death rate. Because of the lack of controlled clinical trials concerning thrombolysis in China, the truth is unclear. We aim to analyze predicting factors of mortality and hypothesize that some baseline clinical variables might also affect clinical outcome within90days after stroke in Chinese patients who have received tissue plasminogen activator therapy.Subjects and methodsPatients’selection and measurements:we searched patients diagnosed with International Classification of Diseases10th edition163-167at discharge who were prospectively and consecutively registered in our database from January,2005to April,2011. Because of the lack of uniform international classification of acute ischemic stroke, we defined it as rapidly developing loss of brain functions due to cerebral ischemia in study cohort, which was definitely demonstrated later by neuro imaging such as diffusion weighted image, computed tomography; or computed tomography angiography, magnetic resonance angiography and digital subtraction angiography. Patients with documented "definite" stroke with symptoms onset within72hours, who received tissue plasminogen activator (Actilyse(?), Boehringer Ingelheim GmbH), were included in this analysis. Inclusion criteria were:(1) National Institutes of Health Stroke Scale4to26before treatment;(2) tissue plasminogen activator used either intravenously or intra-arterially;(3) routine brain CT or magnetic resonance image at baseline negative or hypo dense size less than1/3blood supply area; Exclusion criteria were similar to those of NINDS trial, except prior ischemic stroke, and occasional use of insulin to control glucose level under22.2mmol per liter, or urapidil to lower high blood pressure preceding thrombolysis, which exceeded185/110millimeters of mercury. Patients with abnormal prothrombin time, or activated partial thromboplastin time and abnormal platelet counts were not excluded. Patient’s clinical variables, which nearest to the time point before thrombolysis, were collected using Microsoft Office Excel2003and were double entry and validated:age and gender, identified by resident card; body weight, obtained by self report or relatives or friends. Laboratory data:troponin, creatine kinase, blood urea nitrogen, creatinine, total cholesterol, high and low density lipoprotein, alanine aminotransferase, total protein, total bilirubin, blood glucose and bicarbonate were tested by Automatic Test System-LX20; prothrombin time, activated partial thromboplastin time, international normalized ratio and fibrinogen were tested by Coagulation Analyzer-Sta-R; white blood cell counts, neutrophil and lymphocyte counts, red blood cell counts, hematocrit and platelet counts were tested by Automatic Blood Cell Analyzer-LH755. Radiographic manifestations of brain CT, which was accomplished before treatment, were retrospectively assessed by radiologist who was unaware of the therapeutic regime, including hyper dense middle cerebral artery sign on CT in part1, hemorrhagic transformation and TIMI scale of re-canalization in part2. Cardiac abnormalities were defined as atrial fibrillation, atrial fluttering, arrhythmia and ST segment abnormalities verified by electrocardiograms or moderate to severe heart valve regurgitation, thrombus or septal defect by ultrasonography. Vital signs such as axilla body temperature, pulsation, and pulse oxygen saturation, systolic and diastolic blood pressure were collected through IntelliVue Information Center System. Onset to treatment time means the time loss after the symptoms onset until alteplase infusion, calculated automatically via Excel2003as onset and treatment time variables entered. Procedural delay indicates the preparation time loss before thrombolysis. Dosage of alteplase of each individual patient was obtained from the record of doctor’s advice. Route of thrombolysis was the route of alteplase administration, which either intravenously as per NINDS protocol or intra-arterially after responsible brain vessel was affirmed by digital subtraction angiography. The stroke severity at admission had been evaluated by neurologists and physicians who were medical practitioners in our teaching hospital. Values of NIHSS were achieved in documentations and were reviewed by one of our staff members who had ever passed the NIHSS training course in2009at Hong Kong Prince Wales Hospital. Past history of patients’high blood pressure, diabetes mellitus, stroke, atrial fibrillation, cardiac insufficiency and family history of ischemic stroke were ascertained by corresponding medications or medical records in outpatient or previously hospitalized individuals. The prognostic outcome was defined as favorable (modified Rankin scale0-2) and unfavorable (modified Rankin scale3-6). All cause mortality within90days after thrombolysis were also recorded. Follow-ups were carried out through January to July,2011by structured telephone interviews or letters or home visit. Statistical analysis:for baseline independent variables, quantitative missing values were replaced by linear regression estimates and pairwise process undertaken for categorical variables in multivariate analysis. Binary correlations were used to test the collinearities of independent variables; if correlation coefficient r>=0.8and P<=0.05, variables were checked and combinations or reductions were made under professional considerations, until no obvious correlations between candidate variables were observed. Candidate continuous variables were presented with median plus interquartile range and qualitative data with proportion. Differences between groups were tested by Mann-Whitney U test for continuous variables because of skewed distribution, and Chi-square or Fisher’s exact test was used for categorical variables. In multiple logistic regression process, important demographics and clinical variables such as onset to treatment and route of rtPA use were selected forcibly as candidates although some of them did not show differences in univariate analysis. Chi-square test was used for omnibus model coefficients; goodness of fit was assessed by Hosmer-Lemeshow test. The inclusion and exclusion criterion of stepping probability was0.05and0.10respectively. The cut point value was0.5and maximum iteration time was20, a=0.05(two sided) was considered significant. In Post hoc analysis, the cut value of predictor was determined by Receiver’s Operating Curve, and possible factors associated with each predictor were regressed using logistic procedure mentioned above. Data were calculated by IBM(?) SPSS(?) Statistics version19.ResultsIn part one, a total of90patients met the inclusion criteria; one patient lost follow up at90days after discharge,89(98.9%) cases were included in univariate analysis except7(7.8%) patients lack the data of hyper-dense middle cerebral artery sign and4(4.5%) lack cardiac abnormality, finally,82(91.1%) cases were enrolled in multivariate analysis. All of them were ethnic Han Chinese,40(44.9%) males and49(55.1%) females,8(8.9%) with prior stroke but modified Rankin scale less than3. Independent variables including low density lipoprotein, neutrophil and prothrombin time were removed because of their high collinearities with others. The median of age was72years, body weight59kilograms, NIHSS13, onset to treatment time4.42hours and dose of alteplase50milligrams respectively. Sixty patients (67.4%) received intravenous thrombolytic therapy and29(32.6%) intra-arterially. Sixteen people had died when follow-up accomplished, all them died within30days after stroke, the mortality rate was17.98%(16/73, n=89). The deceased patients had relatively severe NIHSS, elevated international normalized ratio and white blood cell count than the survived. The proportion of hyper-dense middle cerebral artery sign in deceased group was significantly higher than that of survived, and that of family history of stroke was marginal. In multiple logistic regression,13independent variables were thought to be candidate factors:age; gender; dose of rtPA use; hyper-dense middle cerebral artery sign; family history of stroke; white blood cell count; NIHSS; body temperature; international normalized ratio; pulse oxygen saturation; onset to treatment time; blood glucose level; systolic blood pressure; two variables were independently associated with mortality at the last step of backward stepwise logistic regression:NIHSS (P=0.001, OR1.48,95%C.I.1.18-1.86); body temperature (P=0.028, OR4.60,95%C.I.1.18-17.94). Pulse oxygen saturation showed a tendency of significance (P=0.054, OR0.71,95%C.I.0.49-1.01); other variables did not reach the significant level. The model chi-square was41.493and P=0.000; Nagelkerke R square was0.633. Hosmer-Lemeshow chi-square was0.927and P=0.999.The proportion of correctly predicted mortality by this model was89.0%. The likelihood of death for individual was y(?)=-31.280-0.349SPO2+1.526BT+0.395NIHSS+1.688HMCAS. C statistic showed the area under the curve was0.939, P=0.000,95%C.I.0.889-0.990; Influence on mortality by diurnal variation of body temperature was explored, time point as per the time of thrombolysis; no differences were found in mortality. Acute ischemic stroke patients under thrombolysis, higher NIHSS scale and higher body temperature at baseline were significantly and independently correlated with90days mortality; Every1point increase in NIHSS scale will multiply the likelihood of death by1.48, every1℃increase of body temperature will increase death by4.6times. Drop of pulse oxygen saturation might also leads to increased mortality. In Post hoc analysis, the area under the curve was0.620for body temperature and0.608for pulse oxygen saturation respectively, and the cut value was36.9℃and96%. Multiple analysis included8candidate variables (total cholesterol, blood glucose, history of diabetes mellitus, cardiac insufficiency, family history of ischemic stroke, age, body weight and onset to treatment time) with body temperature, and9variables (dose, onset to treatment time, age, total protein, white blood cell counts, platelet counts, systolic blood pressure, history of diabetes mellitus, history of cardiac insufficiency) with pulse oxygen saturation. High glucose level (P=0.008, OR,1.286,95%C.I.1.066-1.551) and family history of stroke (P=0.007, OR,9.191,95%C.I.1.827-46.241) were significant for body temperature; whilst higher platelet count (P=0.031, OR,0.990,95%C.I.0.981-0.999) and history of diabetes mellitus (P=0.008, OR,0.182,95%C.I.0.052-0.634) for pulse oxygen saturation. Patients with diabetes mellitus, who undergo acute ischemic stroke, may have a greater opportunity to present higher body temperature and lower pulse oxygen saturation at admission, similarly, patients with family history of stroke are apt to have fever. In part two, additional6patients were enrolled in the dataset to compare the efficacy and safety of intravenous and intra-arterially thrombolysis in Chinese populations. The inclusion and exclusion criteria were the same as part one. Additional stroke OCSP subtypes, TOAST classification and outcome variables such as hemorrhagic transformation and re-canalization of responsible vessels were re-evaluated. Forty three were males and53females. Sixty four patients received intravenous and32with intra-arterial thrombolysis. Favorable outcome achieved43.8%at90days. Univariate analysis showed a higher cost in intra-arterial thrombolysis (47623.6VS.25699.8RMB), longer procedure delay (3:10VS.1:44hours) and time window (5.54VS.3.58hours); the dose of intra-arterial thrombolysis was lower (20VS.50mg). No differences were found in re-canalization of responsible vessels (64.9%VS.53.8%), hemorrhagic transformation (25%VS.31.3%), favorable outcome (45.3%VS.40.6%) and mortality (22.2%VS.9.4%). Route of thrombolysis did not predict unfavorable outcome (P=0.263, OR2.24,95%CI0.55-9.15). Re-canalization independently predicts functional outcome (P=0.036, OR0.25,95%CI0.07-0.91).ConclusionsPretreatment high NIHSS scale, early increase in body temperature and low pulse oxygen saturation might be associated with90-day mortality in Chinese stroke patients with thrombolysis of alteplase. The efficacy and safety were similar whether thrombolysis was manipulated intravenously or intra-arterially.